#10#
Revisiones-Ciencias
Básicas-Molecular, Bioquímica, Metabolismo & Genética *** Reviews-Basic
Sciences-Molecular, Biochemistry, Metabolism & Genetics
AGENTES
INMUNOSUPRESORES *** IMMUNOSUPPRESSIVE COMPOUNDS
(Conceptos
/ Keywords: Immunosuppressive comp; Muromonab-cd3; Sirolimus; Tacrolimus;
Cyclosporine; Mycophenolic acid; Antilymphocyte serum; Immunosuppressive comp.
used in oncology, etc).
Enero /
January 2001 --- Marzo / March 2004
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Only articles written in Spanish and/or English are included.
[1]
TÍTULO / TITLE: - Integration of growth
factor and nutrient signaling: implications for cancer biology.
REVISTA
/ JOURNAL: - Mol Cell 2003 Aug;12(2):271-80.
AUTORES
/ AUTHORS: - Shamji AF; Nghiem P; Schreiber SL
INSTITUCIÓN
/ INSTITUTION: - Harvard Biophysics Program, Harvard
University, 12 Oxford Street, Cambridge, MA 02138, USA.
RESUMEN
/ SUMMARY: - Signaling networks that promote cell
growth are frequently dysregulated in cancer. One regulatory network, which
converges on effectors such as 4EBP1 and S6K1, leads to growth by promoting
protein synthesis. Here, we discuss how this network is regulated by both
extracellular signals, such as growth factors, and intracellular signals, such
as nutrients. We discuss how mutations amplifying either type of signal can
lead to tumor formation. In particular, we focus on the recent discovery that a
tumor suppressor complex whose function is lost in tuberous sclerosis patients
regulates the nutrient signal carried by the critical signaling protein TOR to
the effectors 4EBP1 and S6K1. Finally, we describe how the small molecule
rapamycin, which inhibits TOR and thereby the activation of these effectors,
could be useful to treat tumors that have become dependent upon this pathway
for growth. N. Ref:: 80
----------------------------------------------------
[2]
- Castellano -
TÍTULO / TITLE:La ruta de senalizacion
CA++/calcineurina/NFAT en activacion endotelial y angiogenesis: efectos de la
ciclosporina A. CA++/ calcineurin/NFAT signaling in endothelial activation and
angiogenesis: effects od cyclosporin A .
REVISTA
/ JOURNAL: - Nefrologia. Acceso gratuito al texto
completo.
●●
Enlace a la Editora de la Revista http://www.aulamedica.es/nefrologia/
●●
Cita: Nefrologia: <> 2003;23 Suppl 3:44-8.
AUTORES
/ AUTHORS: - Quesada AJ; Redondo JM
INSTITUCIÓN
/ INSTITUTION: - Centro de Biologia Molecular Severo Ochoa,
Consejo Superior de Investigaciones Cientificas, Universidad Autonoma de Madrid
y Centro Nacional de Investigaciones Cardiovasculares (CNIC), Sinesio Delgado,
4 28049 Cantoblanco, Madrid. jmredondo@cbm.uam.es N. Ref:: 31
----------------------------------------------------
[3]
TÍTULO / TITLE: - Identification of TOR
signaling complexes: more TORC for the cell growth engine.
REVISTA
/ JOURNAL: - Cell 2002 Oct 4;111(1):9-12.
AUTORES
/ AUTHORS: - Abraham RT
INSTITUCIÓN
/ INSTITUTION: - Program in Signal Transduction Research,
Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road,
La Jolla, CA 92037, USA. abraham@burnham.org
RESUMEN
/ SUMMARY: - The Target of Rapamycin (TOR) proteins
function in signaling pathways that promote protein synthesis and cell growth.
In yeast, TOR signaling is regulated by nutrient availability, whereas in
metazoan cells TOR activities may be controlled by both nutrients and growth
factors. The recent identification of novel TOR-interacting proteins has
provided crucial insights into TOR regulation and function. N. Ref:: 20
----------------------------------------------------
[4]
TÍTULO / TITLE: - Interleukin-2 receptor
monoclonal antibodies in renal transplantation: meta-analysis of randomised
trials.
REVISTA
/ JOURNAL: - British Medical J (BMJ). Acceso gratuito
al texto completo.
●●
Enlace a la Editora de la Revista http://bmj.com/search.dtl
●●
Cita: British Medical J. (BMJ): <> 2003 Apr 12;326(7393):789.
●●
Enlace al texto completo (gratuito o de pago) 1136/bmj.326.7393.789
AUTORES
/ AUTHORS: - Adu D; Cockwell P; Ives NJ; Shaw J;
Wheatley K
INSTITUCIÓN
/ INSTITUTION: - Department of Nephrology, Queen Elizabeth
Hospital, Birmingham, B15 2TH. dwomoa.adu@uhb.nhs.uk
RESUMEN
/ SUMMARY: - OBJECTIVE: To study the effect of
interleukin-2 receptor monoclonal antibodies on acute rejection episodes, graft
loss, deaths, and rate of infection and malignancy in patients with renal
transplants. DESIGN: Meta-analysis of published data. DATA SOURCES: Medline,
Embase, and Cochrane library for years 1996-2003 plus search of medical
editors’ trial amnesty and contact with manufacturers of the antibodies.
SELECTION OF STUDIES: Randomised controlled trials comparing interleukin-2
receptor antibodies with placebo or no additional treatment in patients with
renal transplants receiving ciclosporin based immunosuppression. RESULTS: Eight
randomised controlled trials involving 1871 patients met the selection criteria
(although only 1858 patients were analysed). Interleukin-2 receptor antibodies
significantly reduced the risk of acute rejection (odds ratio 0.51, 95%
confidence interval 0.42 to 0.63). There were no significant differences in the
rate of graft loss (0.78, 0.58 to 1.04), mortality (0.75, 0.46 to 1.23),
overall incidence of infections (0.97, 0.77 to 1.24), incidence of
cytomegalovirus infections (0.81, 0.62 to 1.04), or risk of malignancies at one
year (0.82, 0.39 to 1.70). The different antibodies had a similar sized effect
on acute rejection (test for heterogeneity P=0.7): anti-Tac (0.37, 0.16 to
0.89), BT563 (0.37, 0.1 to 1.38), basiliximab (0.56, 0.44 to 0.72), and
daclizumab (0.46, 0.32 to 0.67). The reduction in acute rejections was similar
for all ciclosporin based immunosuppression regimens (test for heterogeneity
P=1.0). CONCLUSIONS: Adding interleukin-2 receptor antibodies to ciclosporin
based immunosuppression reduces episodes of acute rejection at six months by
49%. There is no evidence of an increased risk of infective complications.
Longer follow up studies are needed to confirm whether interleukin-2 receptor
antibodies improve long term graft and patient survival.
----------------------------------------------------
[5]
TÍTULO / TITLE: - Novel therapeutic
molecular targets for prostate cancer: the mTOR signaling pathway and epidermal
growth factor receptor.
REVISTA
/ JOURNAL: - J Urol 2004 Feb;171(2 Pt 2):S41-3;
discussion S44.
●●
Enlace al texto completo (gratuito o de pago) 1097/01.ju.0000108100.53239.b7
AUTORES
/ AUTHORS: - Tolcher AW
INSTITUCIÓN
/ INSTITUTION: - Director Clinical Research, Institute for
Drug Development Cancer Therapy and Research Center, San Antonio, Texas, USA.
RESUMEN
/ SUMMARY: - PURPOSE: The scientific rationale and
existing evidence for the use of novel molecular targets in the chemoprevention
of cancer are reviewed, with special attention to prostate cancer. MATERIALS
AND METHODS: A search for relevant literature on basic science and clinical
trials was conducted using PubMed/MEDLINE. RESULTS: The emergence of
molecularly targeted therapies for advanced malignancies creates an important
opportunity to examine these agents for the chemoprevention of prostate cancer.
Two critical targets in the proliferation and malignant transformation of
normal cells, the PI3/Akt signal transduction pathway and the epidermal growth
factor receptor, are currently the focus of several novel investigational
therapies that are in late stage phase II and phase III studies. CONCLUSIONS:
Research to date supports consideration of these novel molecular targets as
future agents in the chemoprevention of prostate cancer. N. Ref:: 28
----------------------------------------------------
[6]
TÍTULO / TITLE: - The target of rapamycin
(TOR) proteins.
REVISTA
/ JOURNAL: - Proc Natl Acad Sci U S A. Acceso gratuito
al texto completo a partir de los 6 meses de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.pnas.org/
●●
Cita: Proc Natl Acad Sci USA (PNAS): <> 2001 Jun 19;98(13):7037-44.
●●
Enlace al texto completo (gratuito o de pago) 1073/pnas.121145898
AUTORES
/ AUTHORS: - Raught B; Gingras AC; Sonenberg N
INSTITUCIÓN
/ INSTITUTION: - Department of Biochemistry and McGill
Cancer Centre, McGill University, 3655 Promenade Sir-William-Osler, Montreal,
QC H3G 1Y6 Canada.
RESUMEN
/ SUMMARY: - Rapamycin potently inhibits downstream
signaling from the target of rapamycin (TOR) proteins. These evolutionarily
conserved protein kinases coordinate the balance between protein synthesis and
protein degradation in response to nutrient quality and quantity. The TOR
proteins regulate (i) the initiation and elongation phases of translation, (ii)
ribosome biosynthesis, (iii) amino acid import, (iv) the transcription of
numerous enzymes involved in multiple metabolic pathways, and (v) autophagy.
Intriguingly, recent studies have also suggested that TOR signaling plays a
critical role in brain development, learning, and memory formation. N. Ref:: 132
----------------------------------------------------
[7]
TÍTULO / TITLE: - Regulation of
translation initiation by FRAP/mTOR.
REVISTA
/ JOURNAL: - Genes Dev. Acceso gratuito al texto
completo a partir de 1 año de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.genesdev.org/
●●
Cita: Genes & Development: <> 2001 Apr 1;15(7):807-26.
●●
Enlace al texto completo (gratuito o de pago) 1101/gad.887201
AUTORES
/ AUTHORS: - Gingras AC; Raught B; Sonenberg N
INSTITUCIÓN
/ INSTITUTION: - Department of Biochemistry, McGill
University, Montreal, Quebec H3G 1Y6, Canada.
N. Ref:: 236
----------------------------------------------------
[8]
TÍTULO / TITLE: - Rapamycin plays a new
role as differentiator of vascular smooth muscle phenotype. focus on “The
mTOR/p70 S6K1 pathway regulates vascular smooth muscle differentiation”.
REVISTA
/ JOURNAL: - Am J Physiol Cell Physiol. Acceso gratuito
al texto completo.
●●
Enlace a la Editora de la Revista http://ajpcell.physiology.org/contents-by-date.0.shtml
●●
Cita: Am J Physiol Cell Physiol: <> 2004 Mar;286(3):C480-1.
●●
Enlace al texto completo (gratuito o de pago) 1152/ajpcell.00526.2003
AUTORES
/ AUTHORS: - Lucchesi PA N. Ref:: 12
----------------------------------------------------
[9]
TÍTULO / TITLE: - CD3-specific antibody-induced
active tolerance: from bench to bedside.
REVISTA
/ JOURNAL: - Nat Rev Immunol 2003 Feb;3(2):123-32.
●●
Enlace al texto completo (gratuito o de pago) 1038/nri1000
AUTORES
/ AUTHORS: - Chatenoud L
INSTITUCIÓN
/ INSTITUTION: - Centre de l’Association Claude Bernard sur
les Maladies Autoimmunes and Hopital Necker Enfants Malades IRNEM, 161 Rue de
Sevres, 75015 Paris, France. chatenoud@necker.fr
RESUMEN
/ SUMMARY: - Although they were used initially as
non-specific immunosuppressants in transplantation, CD3-specific monoclonal
antibodies have elicited renewed interest owing to their capacity to induce
immune tolerance. In mouse models of autoimmune diabetes, CD3-specific
antibodies induce stable disease remission by restoring tolerance to pancreatic
beta-cells. This phenomenon was extended recently to the clinic—preservation of
beta-cell function in recently diagnosed patients with diabetes was achieved by
short-term administration of a CD3-specific antibody. CD3-specific antibodies
arrest ongoing disease by rapidly clearing pathogenic T cells from the target.
Subsequently, they promote long-term T-cell-mediated active tolerance. Recent
data indicate that transforming growth factor-beta-dependent CD4+CD25+
regulatory T cells might have a central role in this effect. N. Ref:: 117
----------------------------------------------------
[10]
TÍTULO / TITLE: - Neuroimmunophilins:
novel neuroprotective and neuroregenerative targets.
REVISTA
/ JOURNAL: - Ann Neurol 2001 Jul;50(1):6-16.
AUTORES
/ AUTHORS: - Guo X; Dillman JF 3rd; Dawson
VL; Dawson TM
INSTITUCIÓN
/ INSTITUTION: - Department of Neurology, The Johns Hopkins
University School of Medicine, Baltimore, MD 21287, USA.
RESUMEN
/ SUMMARY: - Cyclosporin A (CsA) and FK506 (tacrolimus)
are immunosuppresants that are widely used in organ transplantation. CsA is an
11-member cyclic peptide, whereas FK506 is a macrolide antibiotic. Recently,
these powerful and useful compounds have become of great interest to
neuroscientists for their unique neuroprotective and neuroregenerative effects.
These drugs and nonimmunosuppressive analogs protect neurons from the effects
of glutamate excitotoxicity, focal ischemia, and
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell
death. They also stimulate functional recovery of neurons in a variety of
neurologic injury paradigms. These drugs exert their effects via immunophilins,
the protein receptors for these agents. The immunophilin ligands show
particular promise as a novel class of neuroprotective and neuroregenerative
agents that have the potential to treat a variety of neurologic disorders. N. Ref:: 102
----------------------------------------------------
[11]
TÍTULO / TITLE: - New agents in acute
myeloid leukemia and other myeloid disorders.
REVISTA
/ JOURNAL: - Cancer 2004 Feb 1;100(3):441-54.
●●
Enlace al texto completo (gratuito o de pago) 1002/cncr.11935
AUTORES
/ AUTHORS: - Ravandi F; Kantarjian H; Giles F; Cortes J
INSTITUCIÓN
/ INSTITUTION: - Department of Leukemia, The University of
Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. fravandi@mdanderson.org
RESUMEN
/ SUMMARY: - Over the past several decades,
improvements in chemotherapeutic agents and supportive care have resulted in
significant progress in treating patients with acute myeloid leukemia (AML).
More recently, advances in understanding the biology of AML have resulted in
the identification of new therapeutic targets. The success of
all-trans-retinoic acid in acute promyelocytic leukemia and of imatinib
mesylate in chronic myeloid leukemia have demonstrated that targeted therapy
may be more effective and less toxic when well defined targets are available.
At the same time, understanding mechanisms of drug resistance and means to
overcome them has led to modification of some of the existing cytotoxic agents.
Rational design and conduct of clinical trials is necessary to ensure that the
full potential of these new agents is realized. N. Ref:: 140
----------------------------------------------------
[12]
TÍTULO / TITLE: - The transplantation of
hematopoietic stem cells after non-myeloablative conditioning: a cellular
therapeutic approach to hematologic and genetic diseases.
REVISTA
/ JOURNAL: - Immunol Res 2003;28(1):13-24.
AUTORES
/ AUTHORS: - Maris M; Storb R
INSTITUCIÓN
/ INSTITUTION: - Fred Hutchinson Cancer Research Center,
and University of Washington, Seattle, WA, USA. mmaris@fhcrc.org
RESUMEN
/ SUMMARY: - Originally, allogeneic hematopoietic stem
cell transplantation (HSCT) was viewed as a form of rescue from the marrow
lethal effects of high doses of chemo-radiotherapy used to both eradicate
malignancy and to provide sufficient immunosuppression to ensure allogeneic
engraftment. Clear evidence of a therapeutic graft-versus-tumor (GVT) effect
mediated by allogeneic effector cells (T cells) has prompted the exploration of
HSCT regimens that rely solely upon host immunosuppression (non-myeloablative)
to facilitate allogeneic donor engraftment. The engrafted donor effector cells
are then used to accomplish the task of eradicating host malignant cells. The
non-myeloblative regimen developed in Seattle uses 2 Gy total body irradiation
(TBI) before transplant followed by postgrafting cyclosporine (CSP) and
mycophenolate mofetil (MMF). This regimen resulted in initial mixed donor-host
chimerism in all patients with hematologic malignancies and genetic disorders
who received HLA-matched sibling allografts. The 17% incidence of graft
rejection was reduced to 3% with the addition of fludarabine, 30 mg/m2/day on d
-4, -3, and -2. The non-myeloablative combination of fludarabine/TBI has also
been successful at achieving high engraftment rates in recipients of 10 of 10
HLA antigen matched unrelated donor HSCTs in patients with hematologic
malignancies. By reducing acute toxicities relative to conventional HSCT, most
patients have received their pre- and post-HSCT therapy almost exclusively as
outpatients. Acute and chronic GVHD occur after non-myeloablative HSCT, but the
incidence and severity appear less compared to conventional HSCT. As in
conventional transplants, immune dysregulation from GVHD and its treatment and
delayed reconstitution of immune function continue to present risks to patients
who have otherwise undergone successful non-myeloablative HSCT. Cellular
therapeutic effects have been observed after non-myeloablative HSCT such as
correction of inherited genetic disorders, and eradication of hematologic
malignant diseases and renal cell carcinoma via GVT responses. N. Ref:: 52
----------------------------------------------------
[13]
TÍTULO / TITLE: - Treatment of idiopathic
nephrosis by immunophillin modulation.
REVISTA
/ JOURNAL: - Nephrol Dial Transplant. Acceso gratuito
al texto completo a partir de los 2 años de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://ndt.oupjournals.org/
●●
Cita: Nephrology Dialysis Transplantation: <> 2003 Aug;18 Suppl
6:vi79-86.
AUTORES
/ AUTHORS: - Meyrier A
INSTITUCIÓN
/ INSTITUTION: - Service de Nephrologie, Hopital Europeen
Georges Pompidou, 20 rue Leblanc, F-75015 Paris, France. alain.meyrier@brs.ap-hop-paris.fr
RESUMEN
/ SUMMARY: - Until 1985, glucocorticoids and cytotoxic
drugs were the only treatments available for idiopathic nephrotic syndrome
(nephrosis), that is, minimal change disease (MCD) and focal segmental
glomerulosclerosis (FSGS). Trials of cyclosporine (CsA) treatment of nephrosis,
the rationale of which was based on pathophysiologic considerations, have shown
that this immunophillin modulator is effective in inducing and maintaining
remission in patients suffering from idiopathic nephrotic syndrome. It appears
that the best results, in the order of 80% remission rate, are obtained in
steroid-sensitive cases, essentially MCD, and that in steroid-resistant FSGS
the drug obtains remission in no more than 20% of the cases. Addition of
glucocorticoids increases the success rate to approximately 30% of cases. Renal
toxicity is proportional to previous impairment of renal function, primary
renal disease (FSGS vs MCD) dosage >5.5 mg/kg/day and duration of treatment.
The better bioavailability of the new formulation of CsA (Neoral), implies that
the former dosage recommendations be reconsidered for distinctly lower figures.
Repeat renal biopsy after 1 year of continuous CsA treatment is advisable, as
stable serum creatinine levels may be falsely reassuring. CsA dependency is the
rule during the first year of treatment. However, in some 25% of cases stable
remission may be maintained after slow tapering off following 3-4 years of
treatment. Other immunophillin modulators have been tried in the treatment of
idiopathic nephrotic syndrome. Despite few preliminary reports indicating some
success of tacrolimus the effects of this drug do not seem convincingly
superior to CsA in terms of remission rate, toxicity and dependency. Rapamycin
has not been tried in the treatment of nephrosis. Anecdotal cases of de novo
FSGS induced by rapamycin in transplanted patients might indicate that this
drug is in fact contraindicated in the treatment of nephrosis. N. Ref:: 36
----------------------------------------------------
[14]
TÍTULO / TITLE: - In vitro generation of
IL-10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs
and inhibited by Th1- and Th2-inducing cytokines.
REVISTA
/ JOURNAL: - Immunol Lett 2003 Jan 22;85(2):135-9.
AUTORES
/ AUTHORS: - O’Garra A; Barrat FJ
INSTITUCIÓN
/ INSTITUTION: - Division of Immunoregulation, The National
Institute for Medical Research (NIMR), The Ridgeway, Mill Hill, NW7 1AA,
London, UK. N. Ref:: 40
----------------------------------------------------
[15]
TÍTULO / TITLE: - Renal transplantation:
can we reduce calcineurin inhibitor/stop steroids? Evidence based on protocol
biopsy findings.
REVISTA
/ JOURNAL: - J Am Soc Nephrol. Acceso gratuito al texto
completo a partir de 1 año de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.jasn.org/
●●
Cita: Journal of the American Society of Nephrology: <> 2003
Mar;14(3):755-66.
AUTORES
/ AUTHORS: - Gotti E; Perico N; Perna A; Gaspari F;
Cattaneo D; Caruso R; Ferrari S; Stucchi N; Marchetti G; Abbate M; Remuzzi G
INSTITUCIÓN
/ INSTITUTION: - Department of Medicine and
Transplantation, Ospedali Riuniti di Bergamo, Mario Negri Institute for
Pharmacological Research, Italy.
RESUMEN
/ SUMMARY: - How to combine antirejection drugs and
which is the optimal dose of steroids and calcineurin inhibitors beyond the
first year after kidney transplantation to maintain adequate immunosuppression
without major side effects are far from clear. Kidney transplant patients on
steroid, cyclosporine (CsA), and azathioprine were randomized to per-protocol
biopsy (n = 30) or no-biopsy (n = 29) 1 to 2 yr posttransplant. Steroid or CsA
were discontinued or reduced on the basis of biopsy to establish effects on
drug-related complications, acute rejection, and graft function over 3 yr of
follow-up. Serum creatinine, GFR (plasma clearance of iohexol), RPF (renal
clearance of p-aminohippurate), CsA pharmacokinetics, and adverse events were
monitored yearly. At the end, patients underwent a second biopsy. Per-protocol
biopsy histology revealed no lesions (n = 5, steroid withdrawal), CsA
nephropathy (n = 13, CsA discontinuation/reduction), or chronic rejection (n =
12, standard therapy). Reducing the drug regimen led to overall fewer side
effects related to immunosuppression as compared with standard therapy or
no-biopsy. Steroids were safely stopped with no acute rejection or graft loss.
Complete CsA discontinuation was associated with acute rejection in the first
four patients. Lowering CsA to low target CsA trough (30 to 70 ng/ml) never led
to acute rejection or major renal function deterioration. Biopsy patients on
conventional regimen had no acute rejection, one graft loss, no significant
change in GFR, and significant RPF decline. No-biopsy controls: no acute
rejection, one graft loss, significant decline of GFR and RPF. By serial biopsy
analysis, severe lesions did not develop in patients with steroid
discontinuation in contrast to patients on standard therapy over follow-up. CsA
reduction did not adversely affect histology. Per-protocol biopsy more than 1
yr after kidney transplantation is a safe procedure to guide change of drug
regimen and to lower the risk of major side effects.
----------------------------------------------------
[16]
TÍTULO / TITLE: - Mammalian target of
rapamycin inhibition as therapy for hematologic malignancies.
REVISTA
/ JOURNAL: - Cancer 2004 Feb 15;100(4):657-66.
●●
Enlace al texto completo (gratuito o de pago) 1002/cncr.20026
AUTORES
/ AUTHORS: - Panwalkar A; Verstovsek S; Giles FJ
INSTITUCIÓN
/ INSTITUTION: - Section of Developmental Therapeutics,
Department of Leukemia, University of Texas M. D. Anderson Cancer Center,
Houston, Texas, USA.
RESUMEN
/ SUMMARY: - The mammalian target of rapamycin (mTOR)
is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt
(protein kinase B) signaling pathway, which mediates cell survival and
proliferation. mTOR regulates essential signal-transduction pathways, is
involved in the coupling of growth stimuli with cell cycle progression, and
initiates mRNA translation in response to favorable nutrient environments. mTOR
is involved in regulating many aspects of cell growth, including membrane
traffic, protein degradation, protein kinase C signaling, ribosome biogenesis,
and transcription. Because mTOR activates both the 40S ribosomal protein S6
kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein 1, its
inhibitors cause G1-phase cell cycle arrest. Inhibitors of mTOR also prevent
cyclin dependent kinase (CDK) activation, inhibit retinoblastoma protein
phosphorylation, and accelerate the turnover of cyclin D1, leading to a
deficiency of active CDK4/cyclin D1 complexes, all of which may help cause
G1-phase arrest. It is known that the phosphatase and tensin homologue tumor
suppressor gene (PTEN) plays a major role in embryonic development, cell migration,
and apoptosis. Malignancies with PTEN mutations, which are associated with
constitutive activation of the PI3K/Akt pathway, are relatively resistant to
apoptosis and may be particularly sensitive to mTOR inhibitors. Rapamycin
analogs with relatively favorable pharmaceutical properties, including CCI-779,
RAD001, and AP23573, are under investigation in patients with hematologic
malignancies. N.
Ref:: 116
----------------------------------------------------
[17]
TÍTULO / TITLE: - Cholesteryl ester transfer
protein facilitates the movement of water-insoluble drugs between lipoproteins:
a novel biological function for a well-characterized lipid transfer protein.
REVISTA
/ JOURNAL: - Biochem Pharmacol 2002 Dec
15;64(12):1669-75.
AUTORES
/ AUTHORS: - Kwong M; Wasan KM
INSTITUCIÓN
/ INSTITUTION: - Division of Pharmaceutics and
Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British
Columbia, 2146 East Mall Avenue, Vancouver, BC, Canada V6T 1Z3.
RESUMEN
/ SUMMARY: - This review article addresses the recently
discovered finding that cholesteryl ester transfer protein (CETP) can
facilitate the transfer of water-insoluble drugs between different lipoprotein
subclasses. This protein, which is often referred to as lipid transfer protein
I (LTP I), is involved in the lipid regulation of lipoproteins. It is
responsible for the facilitated transfer of core lipoprotein lipids,
cholesteryl ester and triglycerides, and approximately one-third of the coat
lipoprotein lipid, phosphatidylcholine, between different plasma lipoproteins.
The human body appears to recognize exogenous water-insoluble drugs as
lipid-like particles, which suggests that these compounds may interact with
lipoproteins just like endogenous plasma lipids, and thus their transfer
between lipoproteins may be facilitated by plasma CETP. Patients with a variety
of diseases (i.e. diabetes, cancer, AIDS) often exhibit hypo- and/or
hypercholesterolemia and triglyceridemia, commonly referred to as
dyslipidemias, which result in changes in their plasma lipoprotein-lipid
composition and concentration. The interaction of water-insoluble drugs with
these dyslipidemic lipoproteins may be responsible for the differences seen in
the pharmacokinetics and pharmacodynamics of the drug within different diseased
patient populations. It is possible that these differences may be linked to the
ability of CETP to transfer these compounds from one lipoprotein to another.
This review examines the current understanding of the relationship between CETP
activity and the lipoprotein distribution of a number of compounds (e.g.
amphotericin B and cyclosporine A). It further suggests that additional
research will expand our understanding of the role of CETP to explain other
functions in lipophilic drug distribution and metabolism. N. Ref:: 45
----------------------------------------------------
[18]
TÍTULO / TITLE: - Clinical development of
mammalian target of rapamycin inhibitors.
REVISTA
/ JOURNAL: - Hematol Oncol Clin North Am 2002
Oct;16(5):1101-14.
AUTORES
/ AUTHORS: - Dancey JE
INSTITUCIÓN
/ INSTITUTION: - Cancer Treatment Evaluation Program,
Division of Cancer Treatment and Diagnosis, Investigational Drug
Branch/CTEP/DCTD/NCI, 6130 Executive Boulevard, EPN 7131, Rockville, MD 20854,
USA. danceyj@ctep.nci.nih.gov
RESUMEN
/ SUMMARY: - Rapamycin and CCI-779 have significant in
vitro and in vivo anti-proliferative activity against a broad range of human
tumor cell lines, justifying the clinical evaluation of this class of agent in
cancer patients. Preliminary results from phase I studies of CCI-779 suggest
that the agent is well tolerated and has anti-tumor activity. The challenge to
investigators is to efficiently determine what role this class of agent will
play in the treatment of cancer patients.
N. Ref:: 69
----------------------------------------------------
[19]
TÍTULO / TITLE: - Treatment of nephrotic
syndrome in children and controlled trials.
REVISTA
/ JOURNAL: - Nephrol Dial Transplant. Acceso gratuito
al texto completo a partir de los 2 años de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://ndt.oupjournals.org/
●●
Cita: Nephrology Dialysis Transplantation: <> 2003 Aug;18 Suppl 6:vi75-8.
AUTORES
/ AUTHORS: - Filler G
INSTITUCIÓN
/ INSTITUTION: - Department of Paediatrics, Division of
Nephrology, Children’s Hospital of Eastern Ontario, University of Ottawa,
Canada. filler@cheo.on.ca
RESUMEN
/ SUMMARY: - AIM: To determine the sequential therapy
of childhood nephrotic syndrome (NS) with presumed minimal change nephropathy
using the evidence from clinical trials. METHODS: Meta-analysis of 22
randomized controlled trials was performed, using frequency of relapse and side
effects of therapeutic regimes. RESULTS: A meta-analysis of seven trials
comparing duration of therapy for initial onset showed that duration of at
least 3 months significantly reduced the risk of relapse at 12-24 months
(relative risk 0.73; 95% confidence interval 0.60-0.89) without an increase in adverse
events. Five trials were performed for steroid treatment of relapse.
Deflazacort reduced relapses during therapy, but is not generally available. No
difference was observed when comparing single and divided dosing of prednisone.
Frequency of relapses could not be influenced by duration of relapse therapy.
Alternate day therapy was more effective than intermittent use of prednisone.
Two studies out of five on cyclophosphamide or chlorambucil showed consistently
that alkylating agents should be used before cyclosporine as alternative
therapy to steroids. CONCLUSIONS: Children with initial onset of NS should be
treated with prednisone at a dose of 60 mg/m(2)/day for 6 weeks, followed by a
dose of 40 mg/m(2)/48 h for at least another 6 weeks. If steroid toxicity for
treatment of relapsing NS requires alternative treatment, cyclophosphamide (2
mg/kg/day for at least 8 weeks) remains the drug of choice with a curative
potential. If children still relapse after alkylating agents, levamisole may
serve as an alternative only for frequent relapsing NS, whereas
steroid-dependent NS should be treated with cyclosporine.
----------------------------------------------------
[20]
TÍTULO / TITLE: - Donor-specific
tolerance in fully major histocompatibility major histocompatibility
complex-mismatched limb allograft transplants under an anti-alphabeta T-cell
receptor monoclonal antibody and cyclosporine A protocol.
REVISTA
/ JOURNAL: - Transplantation 2003 Dec 27;76(12):1662-8.
●●
Enlace al texto completo (gratuito o de pago) 1097/01.TP.0000105343.49626.6F
AUTORES
/ AUTHORS: - Siemionow MZ; Izycki DM; Zielinski M
INSTITUCIÓN
/ INSTITUTION: - Department of Plastic Surgery, Cleveland
Clinic Foundation, A60, 9500 Euclid Avenue, Cleveland, OH 44195, USA. siemiom@ccf.org
RESUMEN
/ SUMMARY: - BACKGROUND: Recent studies have
demonstrated that treatment with alphabeta-T-cell receptor (TCR) monoclonal
antibody and cyclosporine A (CsA) can extend survival in composite tissue
allografts (CTA). The purpose of this study was to induce tolerance in fully
major histocompatibility complex (MHC)-mismatched rat limb allografts under 7
days of a combined alphabeta-TCR-CsA protocol. METHODS: The authors performed
30 hind-limb allotransplantations across the MHC barrier between Brown Norway
donors (BN; RT1n) and Lewis recipients (LEW; RT1l). Isograft and allograft
controls received no treatment. The experimental groups received monotherapy of
alphabeta-TCR and CsA or a combination of alphabeta-TCR and CsA for 7 days
only. Donor-specific tolerance and immunocompetence were determined by standard
skin grafting in vivo and mixed lymphocyte reaction (MLR) in vitro. The
efficacy of immunosuppressive therapy and the level of donor-specific chimerism
were determined by flow cytometry. RESULTS: Long-term survival (>350 days)
was achieved in allograft recipients (n=6) under the 7-day protocol of combined
alphabeta-TCR-CsA. Donor-specific tolerance and immunocompetence of long-term
chimeras were confirmed by acceptance of skin grafts from the donors and
rejection of the third-party alloantigens (AxC Irish). At day 120, MLR
demonstrated unresponsiveness to the host and donor antigens but strong reactivity
against third-party alloantigens. Flow cytometry confirmed the high efficacy of
immunosuppressive treatment and the development of donor-specific chimerism
(7.6% of CD4+-RT1n+ cells, 1.3% of CD8+-RT1n+ cells, and 16.5% of CD45RA+-RT1n+
cells) in the periphery of tolerated recipients. CONCLUSIONS: Combined therapy
of alphabeta-TCR-CsA for 7 days resulted in tolerance induction in fully
MHC-mismatched rat hind-limb allografts. Tolerance was directly associated with
stable, donor-specific chimerism.
----------------------------------------------------
[21]
TÍTULO / TITLE: - Dimerizer-regulated
gene expression.
REVISTA
/ JOURNAL: - Curr Opin Biotechnol 2002
Oct;13(5):459-67.
AUTORES
/ AUTHORS: - Pollock R; Clackson T
INSTITUCIÓN
/ INSTITUTION: - ARIAD Gene Therapeutics, 26 Landsdowne
Street, Cambridge, MA 02139, USA. roy.pollock@ariad.com
RESUMEN
/ SUMMARY: - Control of gene expression using small
molecules is a powerful research tool and has clinical utility in the context
of regulated gene therapy. Use of chemical inducers of dimerization, or
dimerizers, for this purpose has several advantages, including tight
regulation, modularity to facilitate iterative improvements, and assembly from
human proteins to minimize immune responses in clinical applications. Recent
developments include the use of the rapamycin-based dimerizer system to
regulate the expression of endogenous genes, the generation of new chemical
dimerizers based on FK506, dexamethasone and methotrexate, and progress towards
the clinical use of adeno-associated virus and adenovirus vectors regulated by
rapamycin analogs. N.
Ref:: 40
----------------------------------------------------
[22]
TÍTULO / TITLE: - The fission yeast TOR
proteins and the rapamycin response: an unexpected tale.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol 2004;279:85-95.
AUTORES
/ AUTHORS: - Weisman R
INSTITUCIÓN
/ INSTITUTION: - Department of Molecular Microbiology and
Biotechnology, Faculty of Life Sciences, Tel-Aviv University, 69978 Tel-Aviv,
Israel. ronitt@post.tau.ac.il
RESUMEN
/ SUMMARY: - The TOR proteins are known as key
regulators of cell growth in response to nutritional and mitogenic signals and
as targets for the immunosuppressive and anti-cancerous drug rapamycin. The
fission yeast Schizosaccharomyces pombe has two TOR homologues, tor1+ and
tor2+. Despite their structural similarity, these genes have distinct
functions: tor1+ is required under starvation, extreme temperatures, and
osmotic or oxidative stress conditions, whereas tor2+ is required under normal
growth conditions. Surprisingly, rapamycin does not seem to inhibit the S.
pombe TOR-related functions. Rapamycin specifically inhibits sexual development
in S. pombe, and this seems to stem from direct inhibition of the S. pombe
FKBP12 homologue. Why S. pombe cells are resistant to rapamycin during the
growth phase is as yet unclear and awaits further analysis of the TOR-dependent
signaling pathways. N.
Ref:: 27
----------------------------------------------------
[23]
TÍTULO / TITLE: - Composite tissue
allotransplantation in chimeric hosts part II. A clinically relevant protocol
to induce tolerance in a rat model.
REVISTA
/ JOURNAL: - Transplantation 2003 Dec
15;76(11):1548-55.
●●
Enlace al texto completo (gratuito o de pago) 1097/01.TP.0000085288.12571.65
AUTORES
/ AUTHORS: - Prabhune KA; Gorantla VS; Perez-Abadia G;
Francois CG; Vossen M; Laurentin-Perez LA; Breidenbach WC; Wang GG; Anderson
GL; Pidwell DJ; Barker JH; Maldonado C
INSTITUCIÓN
/ INSTITUTION: - Division of Plastic and Reconstructive
Surgery, University of Louisville, Louisville, Kentucky, USA.
RESUMEN
/ SUMMARY: - BACKGROUND: We and others have shown that
mixed allogeneic chimerism induces donor-specific tolerance to composite tissue
allografts across major histocompatibility complex barriers without the need
for immunosuppression. However, a delay period between bone marrow
transplantation and limb allotransplantation is required, making such protocols
impractical for clinical application. This study eliminates this delay period
in a rat hind limb allotransplantation model by performing mixed allogeneic
chimerism induction and transplantation “simultaneously.” METHODS: Group 1
included controls in which naive Wistar Furth (WF) hosts received ACI hind
limbs. Group 2 included (ACI-->WF) chimeras that received limbs from
third-party donors (Fisher), and group 3 included chimeras that received
irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy
received irradiated (1,050 cGy) ACI limbs followed by infusion of 100 x 10(6)
ACI T-cell-depleted bone marrow cells and immunotherapy (tacrolimus and
mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment
as group 4 animals without immunotherapy. RESULTS: The rats in groups 1 and 2
rejected their limbs within 10 days. Only one rat in group 4 survived to the
end of the study. Groups 3 and 5 demonstrated long-term limb survival without
rejection or graft-versus-host disease. High levels of donor chimerism
(>80%) were achieved and maintained throughout the study. Mixed lymphocyte
reaction assays in both groups revealed donor-specific hyporesponsiveness with
vigorous third-party reactivity. CONCLUSIONS: This study demonstrated that
infusion of donor bone marrow cells into conditioned hosts immediately after
limb transplantation results in stable mixed chimerism, robust tolerance, and
reliable limb allograft survival.
----------------------------------------------------
[24]
TÍTULO / TITLE: - mTOR as a positive
regulator of tumor cell responses to hypoxia.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol
2004;279:299-319.
AUTORES
/ AUTHORS: - Abraham RT
INSTITUCIÓN
/ INSTITUTION: - Program in Signal Transduction Research,
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. abraham@burnham.org
RESUMEN
/ SUMMARY: - Rapamycin is a clinically approved
immunosuppressive agent that has recently shown promising antitumor activities
in human patients. In contrast to many conventional chemotherapeutic agents,
rapamycin displays a remarkably high level of selectivity for certain types of
tumors. The pharmacological activities of rapamycin are attributable to the
functional inhibition of a single target protein, termed the mammalian target
of rapamycin (mTOR). Because mTOR is widely expressed in both normal and
transformed cells, variations in mTOR expression levels are likely not a
primary determinant of tumor sensitivity to rapamycin. However, recent studies
highlighted an intriguing link between cancer cell sensitivity to rapamycin and
deregulated signaling through the phosphoinositide (PI) 3-kinase pathway. These
findings have prompted a search for cancer-related responses that are jointly
regulated by the PI 3-kinase signaling cascade and mTOR. The oxygen-regulated
transcription factor, hypoxia-induced factor (HIF)-1, has emerged as a
candidate target for both of these two highly interactive signaling proteins.
Here we review evidence that mTOR functions as a positive regulator of
HIF-1-dependent responses to hypoxic stress in human cancer cells. N. Ref:: 71
----------------------------------------------------
[25]
TÍTULO / TITLE: - TGF-beta expression in
protocol transplant liver biopsies: a comparative study between cyclosporine-A
(CyA) and tacrolimus (FK 506) immunosuppression.
REVISTA
/ JOURNAL: - Transplant Proc 2001
Feb-Mar;33(1-2):1378-80.
AUTORES
/ AUTHORS: - Mohamed MA; Burt AD; Robertson H; Kirby
JA; Talbot D
INSTITUCIÓN
/ INSTITUTION: - Transplant Immunobiology Group, Department
of Surgery, University of Newcastle, NE2 4HH, Newcastle Upon Tyne, UK.
----------------------------------------------------
[26]
TÍTULO / TITLE: - CD30+ T-cell lymphoma
in a patient with psoriasis treated with ciclosporin and infliximab.
REVISTA
/ JOURNAL: - Br J Dermatol 2003 Jul;149(1):170-3.
AUTORES
/ AUTHORS: - Mahe E; Descamps V; Grossin M; Fraitag S;
Crickx B
INSTITUCIÓN
/ INSTITUTION: - Department of Dermatology, Bichat-Claude
Bernard Hospital, 46 Rue Henri-Huchard, Paris Cedex 18, France. emmanuel.mahe@bch.ap-hop-paris.fr
RESUMEN
/ SUMMARY: - There is a known relationship between the
use of immunosuppressive therapies and the development of lymphoproliferative
malignancies. These lymphomas are mainly B-cell nonHodgkin’s lymphomas
associated with Epstein-Barr virus. Most cases concern classical
immunosuppressive treatments including ciclosporin and methotrexate. A
relationship between the new antitumour necrosis factor (TNF)-alpha agents and
lymphoproliferative malignancies is debated. Patients with psoriasis on immunosuppressive
therapies, mainly ciclosporin, are considered to have a low risk of developing
lymphoid proliferation. We report a patient with erythrodermic psoriasis
treated with ciclosporin and infliximab who developed a CD30+ T-cell lymphoma.
This lymphoma regressed after stopping these treatments. In this case, the
anti-TNF-alpha agent may have played a role in association with ciclosporin in
the development of the lymphoproliferative disorder. Whereas the combination of
anti-TNF-alpha therapies with methotrexate has been well studied, their
combination with ciclosporin has been evaluated only in a few patients.
Psoriatic patients who may require anti-TNF-alpha treatment have often been or
will be treated with ciclosporin. The combination of ciclosporin and
anti-TNF-alpha warrants further investigation.
N. Ref:: 17
----------------------------------------------------
[27]
TÍTULO / TITLE: - Elucidating TOR
signaling and rapamycin action: lessons from Saccharomyces cerevisiae.
REVISTA
/ JOURNAL: - Microbiol Mol Biol Rev. - Acceso gratuito
al texto completo a partir de 1 año de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://mmbr.asm.org/
●●
Cita: Microbiology & Molecular Biology Reviews: <> 2002
Dec;66(4):579-91, table of contents.
AUTORES
/ AUTHORS: - Crespo JL; Hall MN
INSTITUCIÓN
/ INSTITUTION: - Division of Biochemistry, Biozentrum,
University of Basel, CH-4056 Basel, Switzerland.
RESUMEN
/ SUMMARY: - TOR (target of rapamycin) is a
phosphatidylinositol kinase-related protein kinase that controls cell growth in
response to nutrients. Rapamycin is an immunosuppressive and anticancer drug
that acts by inhibiting TOR. The modes of action of TOR and rapamycin are
remarkably conserved from S. cerevisiae to humans. The current understanding of
TOR and rapamycin is derived largely from studies with S. cerevisiae. In this
review, we discuss the contributions made by S. cerevisiae to understanding
rapamycin action and TOR function. N.
Ref:: 171
----------------------------------------------------
[28]
TÍTULO / TITLE: - Structures of
calcineurin and its complexes with immunophilins-immunosuppressants.
REVISTA
/ JOURNAL: - Biochem Biophys Res Commun 2003 Nov
28;311(4):1095-102.
AUTORES
/ AUTHORS: - Ke H; Huai Q
INSTITUCIÓN
/ INSTITUTION: - Department of Biochemistry and Biophysics
and Lineberger Comprehensive Cancer Center, The University of North Carolina,
Chapel Hill, NC 27599-7260, USA. hke@med.unc.edu
RESUMEN
/ SUMMARY: - Calcineurin (CN) is a
Ca(2+)/calmodulin-dependent serine/threonine protein phosphatase and is
involved in many physiological processes such as T-cell activation and cardiac
hypertrophy. The crystal structures of CN and its complexes with FKBP12-FK506
and cyclophilin-cyclosporin showed that the two structurally unrelated
immunophilins-immunosuppressants bind to a common composite surface made up of
the residues from both catalytic subunit and regulatory subunit of CN. The
recognition of the immunophilins and immunosuppressive drugs is achieved by
common but few distinct CN residues. However, the binding pattern of
FKBP12-FK506 such as hydrogen bonding is significantly different from that of
CyPA-CsA. This common but distinct recognition may indicate capacity of the
composition surface for binding of other inhibitory proteins. The recognition
site and the active site are adjacent and form an “L” shaped cleft. This
implies that the immunophilin recognition site may also serve as a recognition
site to define the narrow substrate specificity of calcineurin. N. Ref:: 61
----------------------------------------------------
[29]
TÍTULO / TITLE: - Multidrug resistance
reversal agents.
REVISTA
/ JOURNAL: - J Med Chem 2003 Nov 6;46(23):4805-17.
●●
Enlace al texto completo (gratuito o de pago) 1021/jm030183a
AUTORES
/ AUTHORS: - Robert J; Jarry C
INSTITUCIÓN
/ INSTITUTION: - Institut Bergonie, 229, Cours de
l’Argonne, 33076 Bordeaux Cedex, France. robert@bergonie.org N. Ref:: 151
----------------------------------------------------
[30]
TÍTULO / TITLE: - Prevention by dietary
(n-6) polyunsaturated phosphatidylcholines of intrahepatic cholestasis induced
by cyclosporine A in animals.
REVISTA
/ JOURNAL: - Life Sci 2003 Jun 13;73(4):381-92.
AUTORES
/ AUTHORS: - Chanussot F; Benkoel L
INSTITUCIÓN
/ INSTITUTION: - INSERM U. 476, Faculte de Medecine, 27 bd
Jean Moulin, 13385 Marseille cedex 05, France. Francoise.Chanussot@medecine.univ-mrs.fr
RESUMEN
/ SUMMARY: - Previous findings showed that dietary
(n-6) polyunsaturated phosphatidylcholines (vegetable lecithin) could
efficiently prevent intrahepatic cholestasis induced by cyclosporine A in rats.
Mechanistic studies showed that expressions in rat liver of Na(+), K(+)-ATPase,
Ca(2+), Mg(2+)-ATPase and F-actin were both decreased by drug administration
and both enhanced by (n-6) lecithin enriched diet. There is a possible direct
effect of phosphatidylcholines, vectors of polyunsaturated fatty acids provided
by the metabolism of the dietary lecithin, on the aforesaid hepatic parameters.
Such modulations by drug and diet result in reversed modifications of membrane
composition and fluidity. Final outcome is decreased and enhanced bile lipid
secretion by cyclosporine and vegetable lecithin enriched diet respectively.
Moreover, we advance the hypothesis of a bypass process including a separate and
functional actin-independent way for the non micellar and
phospholipid-dependent secretion of bile lipids. The relationships between the
ATPases, the microfilament components such as F-actin and the different
transporters still remain to be clarified. Furthermore, one can speculate on
beneficial effects in humans of diets enriched in vegetable lecithins that
might prevent cholestasis induced by cyclosporine A. N. Ref:: 75
----------------------------------------------------
[31]
TÍTULO / TITLE: - Calcineurin
inhibitor-free CD28 blockade-based protocol protects allogeneic islets in
nonhuman primates.
REVISTA
/ JOURNAL: - Diabetes. Acceso gratuito al texto
completo a partir de 1 año de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://diabetes.diabetesjournals.org/
●●
Cita: Diabetes: <> 2002 Feb;51(2):265-70.
AUTORES
/ AUTHORS: - Adams AB; Shirasugi N; Durham MM; Strobert
E; Anderson D; Rees P; Cowan S; Xu H; Blinder Y; Cheung M; Hollenbaugh D;
Kenyon NS; Pearson TC; Larsen CP
INSTITUCIÓN
/ INSTITUTION: - Emory Transplant Center, Department of
Surgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
RESUMEN
/ SUMMARY: - Recent success using a steroid-free immunosuppressive
regimen has renewed enthusiasm for the use of islet transplantation to treat
diabetes. Toxicities associated with the continued use of a calcineurin
inhibitor may limit the wide-spread application of this therapy. Biological
agents that block key T-cell costimulatory signals, in particular the CD28
pathway, have demonstrated extraordinary promise in animal models. LEA29Y
(BMS-224818), a mutant CTLA4-Ig molecule with increased binding activity, was
evaluated for its potential to replace tacrolimus and protect allogeneic islets
in a preclinical primate model. Animals received either the base
immunosuppression regimen (rapamycin and anti-IL-2R monoclonal antibody [mAb])
or the base immunosuppression and LEA29Y. Animals receiving the LEA29Y/rapamycin/anti-IL-2R
regimen (n = 5) had significantly prolonged islet allograft survival (204, 190,
216, 56, and >220 days). In contrast, those animals receiving the base
regimen alone (n = 2) quickly rejected the transplanted islets at 1 week (both
at 7 days). The LEA29Y-based regimen prevented the priming of anti-donor T- and
B-cell responses, as detected by interferon-gamma enzyme-linked immunospot and
allo-antibody production, respectively. The results of this study suggest that
LEA29Y is a potent immunosuppressant that can effectively prevent rejection in
a steroid-free immunosuppressive protocol and produce marked prolongation of
islet allograft survival in a preclinical model.
----------------------------------------------------
[32]
TÍTULO / TITLE: - Nutrient signaling
through TOR kinases controls gene expression and cellular differentiation in
fungi.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol 2004;279:53-72.
AUTORES
/ AUTHORS: - Rohde JR; Cardenas ME
INSTITUCIÓN
/ INSTITUTION: - Department of Molecular Genetics and
Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
RESUMEN
/ SUMMARY: - The TOR kinases were first identified in
Saccharomyces cerevisiae as the targets of the immunosuppressive drug
rapamycin. Subsequent studies employing rapamycin as a tool in yeast have given
us insight into the structure and function of the TOR kinases, as well as the
biological role of the TOR signaling program in transmitting nutrient signals
to promote cell growth. One of the major advances from this area has been in
defining an unexpected role for TOR signaling in the regulation of
transcription. The identification of target genes subject to regulation by TOR
has provided a platform for the dissection of the signaling events downstream
of the TOR kinases. Studies aimed at understanding TOR-regulated transcription
have begun to shed light on how TOR signaling cooperates with other signaling
programs. In addition, the TOR pathway regulates the developmental program of
pseudohyphal differentiation in concert with highly conserved MAP kinase and
PKA signaling programs. Remarkably, rapamycin also blocks filamentation in a
number of important human and plant pathogens and the mechanism of rapamycin
action is conserved in Candida albicans and Cryptococcus neoformans. The
antimicrobial properties of less immunosuppressive analogs of rapamycin hold
promise for the development of an effective antifungal therapy. N. Ref:: 65
----------------------------------------------------
[33]
TÍTULO / TITLE: - Signaling pathways
involved in translational control of protein synthesis in skeletal muscle by
leucine.
REVISTA
/ JOURNAL: - J Nutr. Acceso gratuito al texto completo
a partir de 1 año de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.nutrition.org/
●●
Cita: Journal of Nutrition: <> 2001 Mar;131(3):856S-860S.
AUTORES
/ AUTHORS: - Anthony JC; Anthony TG; Kimball SR;
Jefferson LS
INSTITUCIÓN
/ INSTITUTION: - Department of Cellular and Molecular
Physiology, P.O. Box 850, The Pennsylvania State University College of
Medicine, Hershey, PA 17033, USA.
RESUMEN
/ SUMMARY: - Numerous reports established that in
skeletal muscle the indispensable branched-chain amino acid leucine is unique
in its ability to initiate signal transduction pathways that modulate
translation initiation. Oral administration of leucine stimulates protein
synthesis in association with hyperphosphorylation of the translational
repressor, eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1),
resulting in enhanced availability of the mRNA cap-binding protein eIF4E, for
binding eIF4G and forming the active eIF4F complex. In addition, leucine
enhances phosphorylation of the 70-kDa ribosomal protein S6 kinase (S6K1).
These results suggest that leucine upregulates protein synthesis in skeletal
muscle by enhancing both the activity and synthesis of proteins involved in
mRNA translation. The stimulatory effects of leucine on translation initiation
are mediated in part through the protein kinase mammalian target of rapamycin
(mTOR), where both insulin signaling and leucine signaling converge to promote
a maximal response. N.
Ref:: 34
----------------------------------------------------
[34]
TÍTULO / TITLE: - A benefit-risk
assessment of basiliximab in renal transplantation.
REVISTA
/ JOURNAL: - Drug Saf. Acceso gratuito al texto
completo.
●●
Enlace a la Editora de la Revista http://www.csmwm.org/
●●
Cita: Drug Safety: <> 2004;27(2):91-106.
AUTORES
/ AUTHORS: - Boggi U; Danesi R; Vistoli F; Del Chiaro
M; Signori S; Marchetti P; Del Tacca M; Mosca F
INSTITUCIÓN
/ INSTITUTION: - Division of General Surgery and
Transplants, Department of Oncology, Transplants and Advanced Technologies in
Medicine, University of Pisa, Pisa, Italy. uboggi@med.unipi.it
RESUMEN
/ SUMMARY: - Interleukin-2 (IL-2) and its receptor
(IL-2R) play a central role in T lymphocyte activation and immune response
after transplantation. Research on the biology of IL-2R allowed the
identification of key signal transduction pathways involved in the generation
of proliferative and antiapoptotic signals in T cells. The alpha-chain of the
IL-2R is a specific peptide against which monoclonal antibodies have been
raised, with the aim of blunting the immune response by means of inhibiting
proliferation and inducing apoptosis in primed lymphocytes. Indeed,
basiliximab, one of such antibodies, has proved to be effective in reducing the
episodes of acute rejection after kidney and pancreas transplantation. The use
of basiliximab was associated with a significant reduction in the incidence of
any treated rejection episodes after kidney transplantation in the two major
randomised studies (placebo 52.2% vs basiliximab 34.2% at 6 months, European
study; placebo 54.9% vs basiliximab 37.6% at 1 year, US trial). Basiliximab and
equine antithymocyte globulin (ATG) administration resulted in a similar rate
of biopsy-proven acute rejection at 6 months (19% for both) and at 12 months
(19% and 20%, respectively). The use of basiliximab appears not to be
associated with an increased incidence of adverse events as compared with
placebo in immunosuppressive regimens, including calcineurin inhibitors,
mycophenolate mofetil or azathioprine and corticosteroids, and its safety
profile is superior to ATG. Moreover, a similar occurrence of infections is
noted in selected studies (65.5% after basiliximab vs 65.7% of controls),
including cytomegalovirus infection (17.3% vs 14.5%), and cytokine-release
syndrome is not observed. Finally, economic analysis demonstrated lower costs of
overall treatment in patients treated with basiliximab. Therefore, the use of
basiliximab entails a very low risk, allows safe reduction of corticosteroid
dosage and reduces the short- and mid-term rejection rates. However, the
improvement in the long-term survival of kidney grafts in patients treated
according to modern immunosuppressive protocols is still to be demonstrated.
These conclusions are based on a systematic review of the scientific
literature, indexed on Medline database, concerning the mechanism of action,
therapeutic activity, safety and pharmacoeconomic evaluation of basiliximab in
renal transplantation. N.
Ref:: 62
----------------------------------------------------
[35]
TÍTULO / TITLE: - Role of leucine in the
regulation of mTOR by amino acids: revelations from structure-activity studies.
REVISTA
/ JOURNAL: - J Nutr. Acceso gratuito al texto completo
a partir de 1 año de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.nutrition.org/
●●
Cita: Journal of Nutrition: <> 2001 Mar;131(3):861S-865S.
AUTORES
/ AUTHORS: - Lynch CJ
INSTITUCIÓN
/ INSTITUTION: - Department of Cellular and Molecular
Physiology, The Pennsylvania State University College of Medicine, 500
University Drive, Hershey, PA 17033, USA. clynch@psu.edu
RESUMEN
/ SUMMARY: - In this study an overview is presented of
the mTOR signaling pathway and its regulation by amino acids, particularly
L-leucine. Our laboratory is studying amino acid regulation of mTOR in
adipocytes. Potential roles for mTOR in adipocytes that were previously posited
include hypertrophic growth, leptin secretion, protein synthesis and adipose
tissue morphogenesis. A current area of interest in the field is how amino
acids regulate mTOR and which amino acids are regulatory. Revelations
concerning mechanism and recognition are emerging from different laboratories
that examined the structural requirements for stimulation and inhibition of the
mTOR signaling pathway by leucine and amino acid analogs. In adipocytes and
some other cell types, leucine appears to be the main regulatory amino acid.
However, this is not uniformly the case. In those cells where mTOR is regulated
by several amino acids, there is evidence that the mechanism of mTOR activation
may be different from cells where mainly leucine is regulatory. Furthermore, in
tissues where leucine regulates mTOR, the possible existence of different
tissue-specific leucine recognition sites may be indicated. N. Ref:: 47
----------------------------------------------------
[36]
TÍTULO / TITLE: - Drug-eluting stents and
glycoprotein IIb/IIIa inhibitors: combination therapy for the future.
REVISTA
/ JOURNAL: - Am Heart J 2003 Oct;146(4 Suppl):S13-7.
●●
Enlace al texto completo (gratuito o de pago) 1016/j.ahj.2003.09.004
AUTORES
/ AUTHORS: - Leon MB; Bakhai A
RESUMEN
/ SUMMARY: - BACKGROUND: Although coronary stenting has
improved the results of coronary interventions compared to coronary angioplasty
alone, in-stent restenosis remains a significant limitation of this procedure.
Drug-eluting stents with or without glycoprotein IIb/IIIa inhibitor therapy
represent an additional advance in the evolution of this strategy. METHODS: We
review the currently available trials comparing studies of non-drug-eluting and
drug-eluting stents using sirolimus and paclitaxel agents and their
derivatives. RESULTS: Ten studies are available that compare drug-eluting to
traditional non-drug-eluting stents. A variety of antiplatelet regimes have
been used. The majority of these studies are in the process of being published.
No head-to-head studies comparing different drug-eluting stents are available.
CONCLUSIONS: Drug-eluting stents using sirolimus and paclitaxel in combination
with enhanced antiplatelet strategies represent an important advantage over
non-drug-eluting stents for the reduction of in-stent restenosis. The rate at
which drug-eluting stents are adapted into widespread practice depends heavily
on whether they are safe, efficacious, and cost-effective in various clinical
settings. N. Ref:: 28
----------------------------------------------------
[37]
TÍTULO / TITLE: - Tissue factor and
coronary artery disease.
REVISTA
/ JOURNAL: - Cardiovasc Res 2002 Feb 1;53(2):313-25.
AUTORES
/ AUTHORS: - Moons AH; Levi M; Peters RJ
INSTITUCIÓN
/ INSTITUTION: - Department of Cardiology, Academic Medical
Center, Room F3-236, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
RESUMEN
/ SUMMARY: - Plaque disruption with superimposed
thrombosis is the main cause of acute coronary events such as acute myocardial
infarction and unstable angina. Among other factors, tissue factor seems to
play an important role determining plaque thrombogenicity. Tissue factor is a
potent initiator of the coagulation cascade situated within the vessel wall and
is highly exposed to the blood after plaque rupture. Several mediators involved
in the process of atherosclerotic plaque formation are capable of inducing
tissue factor expression in cells such as monocytes, macrophages and
endothelial cells, which under normal conditions do not express tissue factor
or to a limited extent only. The increased expression of tissue factor is not
limited to the plaque but is also found in circulating monocytes in patients
with acute coronary syndromes. In addition, studies have shown an important
contribution of tissue factor in the pathogenesis of thrombosis and restenosis
after balloon angioplasty. Recent basic studies focus on the therapeutic
inhibition of tissue factor. Specific and non-specific inhibitors of tissue
factor or the tissue factor/factor VIIa complex have been developed or
identified, and have been tested in experimental studies. Clinical studies are
currently being initiated. In this review, we present the current knowledge on
the role of tissue factor in atherosclerosis, arterial intervention and potential
pharmacological approaches, with focus on acute coronary syndromes. N. Ref:: 162
----------------------------------------------------
[38]
- Castellano -
TÍTULO / TITLE:Las inmunofilinas: agentes
neuroprotectores y promotores de la regeneracion neural. Immunophilins:
neuroprotective agents and promoters of neural regeneration.
REVISTA
/ JOURNAL: - Neurologia. Acceso gratuito al texto
completo.
●●
Enlace a la Editora de la Revista http://www.stmeditores.com/Revistas/ffasciculo.php?Mw==&MTk=&MjUy
●●
Cita: Neurologia: <> 2002 Apr;17(4):200-13.
AUTORES
/ AUTHORS: - Udina E; Navarro X
INSTITUCIÓN
/ INSTITUTION: - Grupo de Neuroplasticidad y Regeneracion,
Departamento de Biologia Celular, Fisiologia e Inmunologia, Universitat
Autonoma de Barcelona, Bellaterra, España.
RESUMEN
/ SUMMARY: - Immunophilins are a family of proteins
mainly known because they act as receptors of the immunosuppressant drugs
cyclosporin A (CsA) and FK506. Immunophilins serve several general functions,
including regulation of mitochondrial permeability, modulation of ion channels
stability and acting as chaperones for a variety of proteins. However,
immunophilins are also present at high density in the nervous system. CsA,
FK506 and other derivatives inhibit the function of immunophilins and, through
bloking or activating several intracellular pathways, it has been shown that
they exert neuroprotective effects in different experimental models of
ischemia, Parkinson’s disease and excitotoxic insults. Moreover, FK506 also has
neuroregenerative effects, by enhancing the axonal regeneration rate after
lesions of the peripheral nervous system. The development of new agents that
selectively bind to immunophilins opens new interesting perspectives for the
therapy of degenerative diseases and injuries of the nervous system. N. Ref:: 100
----------------------------------------------------
[39]
TÍTULO / TITLE: - Protein phosphatase 2A
on track for nutrient-induced signalling in yeast.
REVISTA
/ JOURNAL: - Mol Microbiol. Acceso gratuito al texto
completo a partir de los 2 años de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.blackwell-synergy.com/
●●
Cita: Molecular Microbiology: <> 2002 Feb;43(4):835-42.
AUTORES
/ AUTHORS: - Zabrocki P; Van Hoof C; Goris J; Thevelein
JM; Winderickx J; Wera S
INSTITUCIÓN
/ INSTITUTION: - Laboratorium voor Moleculaire Celbiologie,
K.U.Leuven, Kasteelpark Arenberg 31, B-3001 Leuven-Heverlee, Flanders, Belgium.
RESUMEN
/ SUMMARY: - Early studies identified two bona fide
protein phosphatase 2A (PP2A)-encoding genes in Saccharomyces cerevisiae,
designated PPH21 and PPH22. In addition, three PP2A-related phosphatases,
encoded by PPH3, SIT4 and PPG1, have been identified. All share as much as 86%
sequence similarity at the amino acid level. This review will focus primarily
on Pph21 and Pph22, but some aspects of Sit4 regulation will also be discussed.
Whereas a role for PP2A in yeast morphology and cell cycle has been readily
recognized, uncovering its function in yeast signal transduction is a more
recent breakthrough. Via their interaction with phosphorylated Tap42, PP2A and
Sit4 play a pivotal role in target of rapamycin (TOR) signalling. PPH22
overexpression mimics overactive cAMP-PKA (protein kinase A) signalling and
PP2A and Sit4 might represent ceramide signalling targets. The methylation of
its catalytic subunit stabilizes the heterotrimeric form of PP2A and might
counteract TOR signalling. We will show how these new elements could lead us to
understand the role and regulation of PP2A in nutrient-induced signalling in
baker’s yeast. N.
Ref:: 41
----------------------------------------------------
[40]
TÍTULO / TITLE: - mTOR as a target for
cancer therapy.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol
2004;279:339-59.
AUTORES
/ AUTHORS: - Houghton PJ; Huang S
INSTITUCIÓN
/ INSTITUTION: - Department of Molecular Pharmacology, St.
Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794,
USA. peter.houghton@stjude.org
RESUMEN
/ SUMMARY: - The target of rapamycin, mTOR, acts as a
sensor for mitogenic stimuli, such as insulin-like growth factors and cellular
nutritional status, regulating cellular growth and division. As many tumors are
driven by autocrine or paracrine growth through the type-I insulin-like growth
factor receptor, mTOR is potentially an attractive target for
molecular-targeted treatment. Further, a rationale for anticipating
tumor-selective activity based on transforming events frequently identified in
malignant disease is becoming established.
N. Ref:: 73
----------------------------------------------------
[41]
TÍTULO / TITLE: - Serine-threonine
protein phosphatase inhibitors: development of potential therapeutic
strategies.
REVISTA
/ JOURNAL: - J Med Chem 2002 Mar 14;45(6):1151-75.
AUTORES
/ AUTHORS: - McCluskey A; Sim AT; Sakoff JA
INSTITUCIÓN
/ INSTITUTION: - School of Biological & Chemical
Science, Medicinal Chemistry Group, The University of Newcastle, Callaghan, NSW
2308, Australia. amcclusk@mail.newcastle.edu.au N. Ref:: 329
----------------------------------------------------
[42]
TÍTULO / TITLE: - Inflammatory
myopathies: clinical, diagnostic and therapeutic aspects.
REVISTA
/ JOURNAL: - Muscle Nerve 2003 Apr;27(4):407-25.
●●
Enlace al texto completo (gratuito o de pago) 1002/mus.10313
AUTORES
/ AUTHORS: - Mastaglia FL; Garlepp MJ; Phillips BA;
Zilko PJ
INSTITUCIÓN
/ INSTITUTION: - Centre for Neuromuscular and Neurological
Disorders, University of Western Australia, Queen Elizabeth II Medical Centre,
Nedlands, Australia. flmast@cyllene.uwa.edu.au
RESUMEN
/ SUMMARY: - The three major forms of immune-mediated
inflammatory myopathy are dermatomyositis (DM), polymyositis (PM), and
inclusion-body myositis (IBM). They each have distinctive clinical and
histopathologic features that allow the clinician to reach a specific diagnosis
in most cases. Magnetic resonance imaging is sometimes helpful, particularly if
the diagnosis of IBM is suspected but has not been formally evaluated.
Myositis-specific antibodies are not helpful diagnostically but may be of
prognostic value; most antibodies have low sensitivity. Muscle biopsy is
mandatory to confirm the diagnosis of an inflammatory myopathy and to allow
unusual varieties such as eosinophilic, granulomatous, and parasitic myositis,
and macrophagic myofasciitis, to be recognized. The treatment of the
inflammatory myopathies remains largely empirical and relies upon the use of
corticosteroids, immunosuppressive agents, and intravenous immunoglobulin, all
of which have nonselective effects on the immune system. Further controlled
clinical trials are required to evaluate the relative efficacy of the available
therapeutic modalities particularly in combinations, and of newer
immunosuppressive agents (mycophenolate mofetil and tacrolimus) and
cytokine-based therapies for the treatment of resistant cases of DM, PM, and
IBM. Improved understanding of the molecular mechanisms of muscle injury in the
inflammatory myopathies should lead to the development of more specific forms
of immunotherapy for these conditions. N.
Ref:: 256
----------------------------------------------------
[43]
TÍTULO / TITLE: - Mitochondrial
permeability transition in acute neurodegeneration.
REVISTA
/ JOURNAL: - Biochimie 2002 Feb-Mar;84(2-3):241-50.
AUTORES
/ AUTHORS: - Friberg H; Wieloch T
INSTITUCIÓN
/ INSTITUTION: - Laboratory for Experimental Brain
Research, Wallenberg Neuroscience Center, BMC A13, 221 84 Lund, Sweden.
RESUMEN
/ SUMMARY: - Acute neurodegeneration in man is
encountered during and following stroke, transient cardiac arrest, brain
trauma, insulin-induced hypoglycemia and status epilepticus. All these severe
clinical conditions are characterized by neuronal calcium overload, aberrant
cell signaling, generation of free radicals and elevation of cellular free
fatty acids, conditions that favor activation of the mitochondrial permeability
transition pore (mtPTP). Cyclosporin A (CsA) and its analog
N-methyl-valine-4-cyclosporin A (MeValCsA) are potent blockers of the mtPTP and
protect against neuronal death following excitotoxicity and oxygen glucose
deprivation. Also, CsA and MeValCsA diminish cell death following cerebral
ischemia, trauma, and hypoglycemia. Here we present data that strongly imply
the mtPT in acute neurodegeneration in vivo. Compounds that readily pass the
blood-brain-barrier (BBB) and block the mtPT may be neuroprotective in
stroke. N. Ref:: 100
----------------------------------------------------
[44]
TÍTULO / TITLE: - Calcineurin-free
protocols with basiliximab induction allow patients included in “old to old”
programs achieve standard kidney transplant function.
REVISTA
/ JOURNAL: - Transplant Proc 2003 Jun;35(4):1326-7.
AUTORES
/ AUTHORS: - Emparan C; Laukotter M; Wolters H; Dame C;
Heidenreich S; Senninger N
INSTITUCIÓN
/ INSTITUTION: - Department of Surgery, Division of
Transplantation, Uniklinikum Munster, Munster, Germany. cemparan@teleline.es
RESUMEN
/ SUMMARY: - INTRODUCTION: The EuroTransplant “old to
old” program establishes that patients older than 60 years can receive offers
of organs from donors older than 60 years. The compromised function of these
organs makes it a priority to preserve their initial kidney function.
HYPOTHESIS: Calcineurin-sparing protocols using anti-IL-2 receptor (IL-2R)
antibody induction (Simulect) may benefit initial kidney function in these
patients, as assessed by the rates of delayed graft function and of rejection
during the first month after transplant. PATIENTS AND METHODS: A cohort of 15
consecutive elderly patients were prospectively compared with 30 cadaveric
kidney transplants in younger recipients. Study patients were induced with
Simulect (20 mg, 30 minutes before reperfusion and 4 days after
transplantation) and steroids, delaying the introduction of CsA until the serum
creatinine was below 3 mg/dL. The other cohort of patients were
immunosuppressed with tacrolimus (trough 8 to 12), mycophenolats mofetil (MMF,
1 g/d), and an identical taper of steroids. The analysis compared donor and
recipient ages, mean cold ischemic time, incidence of initial kidney function
(diuresis in the first 24 h) serum creatinine levels, glomerular filtration
rate (GFR), number of dialysis sessions, and rejection rate in the two groups.
RESULTS: Except for the donor and recipient ages (72 vs 54 in donors, and 67
versus 52 years in recipients), no significant differences were observed
between the groups among the rates of acute rejection (6.6% vs 13.2%), delayed
graft function (13.2% required dialysis), or infection (6.6%). Within 1 month
all 45 grafts showed primary function with equal creatinine levels (mean 1.65).
CONCLUSIONS: Calcineurin-free protocols using IL-2 therapy as the initial
suppression allow patients in the “old to old” ET program to display equal
results to cadaveric kidney transplants with initial treatment with calcineurin
antagonists.
----------------------------------------------------
[45]
TÍTULO / TITLE: - Measle virus-infected
dendritic cells develop immunosuppressive and cytotoxic activities.
REVISTA
/ JOURNAL: - Immunobiology 2001 Dec;204(5):629-38.
AUTORES
/ AUTHORS: - Vidalain PO; Azocar O; Rabourdin-Combe C;
Servet-Delprat C
INSTITUCIÓN
/ INSTITUTION: - Immunobiologie Fondamentale et Clinique,
CERVI-INSERM, Lyon, France. servet@cervi-lyon.inserm.fr
RESUMEN
/ SUMMARY: - Measle virus (MV) infection induces a
transient but profound immunosuppression characterized by a panlymphopenia
which occasionally results in opportunistic infections responsible for a high
rate of mortality in malnourished children. MV can encounter human dendritic
cells (DC) in the respiratory mucosa or in the secondary lymphoid organs. After
a brief presentation of DCs, we review progress in understanding the
immunobiology of MV-infected DCs that could account for MV-induced immunosuppression.
In addition, we develop the newly described TRAIL-mediated cytotoxic function
of DCs that is turned on by MV infection, but also by interferons or
double-stranded RNA (poly (I:C)). Finally, we propose a model where the
measles-associated lymphopenia could be mediated by TRAIL and the
measles-induced immunosuppression could be transiently prolonged by
Fas-mediated destruction of DCs. N.
Ref:: 38
----------------------------------------------------
[46]
TÍTULO / TITLE: - Antiproliferative prostaglandins
and the MRP/GS-X pump role in cancer immunosuppression and insight into new
strategies in cancer gene therapy.
REVISTA
/ JOURNAL: - Biochem Pharmacol 2001 Oct 1;62(7):811-9.
AUTORES
/ AUTHORS: - Homem de Bittencourt PI Jr; Curi R
INSTITUCIÓN
/ INSTITUTION: - Department of Physiology, Institute of
Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento
Leite 500, 90050-170, Porto Alegre, RS, Brazil. pauloivo@vortex.ufrgs.br
RESUMEN
/ SUMMARY: - A dramatic complication in late-stage
cancer patients is host immunosuppression. Cyclopentenone prostaglandins
(CP-PGs) overproduced in cancer may impair the function of the immune system.
These agents, if produced at high concentrations, are powerful cytostatic and
cytotoxic compounds that may arrest cell proliferation and immune response in
cancer. Lymphoid tissues of tumor-bearing animals accumulate large amounts of
CP-PGs, whereas the tumor tissue does not. This may be because cancer cells are
able to overexpress multidrug resistance-associated protein (Mg(2+)-dependent
vanadate-sensitive GS-conjugate export ATPase, MRP/GS-X pump), which extrudes
CP-PGs to the extracellular space as glutathione S-conjugates. In contrast,
MRP/GS-X pump activity is disproportionately low in lymphocytes. This led us to
propose the transfection of lymphocytes with multidrug resistance-associated
protein genes (MRP) for further autologous transfusion or direct in vivo
delivery to lymphocytes by using adenovirus-retrovirus chimeras in order to
restore immune system function in cancer, at least partially. We are currently
evaluating MRP-transfected lymphocyte (MTL) therapy, using Walker 256
tumor-bearing rats as a model. N.
Ref:: 49
----------------------------------------------------
[47]
TÍTULO / TITLE: - Cytokine and
anti-cytokine therapies for inflammatory bowel disease.
REVISTA
/ JOURNAL: - Curr Pharm Des 2003;9(14):1107-13.
AUTORES
/ AUTHORS: - Ogata H; Hibi T
INSTITUCIÓN
/ INSTITUTION: - Department of Internal Medicine, Keio
University School of Medicine, Tokyo, Japan.
RESUMEN
/ SUMMARY: - Although the pathogenesis of inflammatory
bowel disease (IBD) remains elusive, it appears that there is chronic
activation of the immune and inflammatory cascade in genetically susceptible
individuals. Current disease management guidelines have therefore focused on
the use of anti-inflammatory agents, aminosalicylates and corticosteroids.
These conventional therapies continue to be a first choice in the management of
IBD. Immunomodulators, such as azathioprine, 6-mercaptopurine, methotrexate or
cyclosporin, are demonstrating increasing importance against steroid-resistant
and steroid-dependent patients. However, some patients are still refractory to
these therapies. Recent advances in the understanding of the pathophysiological
conditions of IBD have provided new immune system modulators as therapeutic
tools. Other immunosuppressive agents including FK506 and thalidomide have
expanded the choice of medical therapies available for certain subgroups of
patients. Furthermore, biological therapies have begun to assume a prominent
role. Studies with chimeric monoclonal anti-TNF-alpha antibody treatment have
been reported with dramatic successes. However, observations in larger numbers
of treated patients are needed to explicate fully the safety of or risks posed
by this agent such as developing lymphoma, or other malignancies. Another
anti-inflammatory cytokine-therapy includes anti anti-IL-6R, anti-IL-12 or
toxin-conjugated anti IL-7R, recombinant cytokines (IL-10 or IL-11). Given the
diversity of proinflammatory products under its control, NF-kappaB may be
viewed as a master switch in lymphocytes and macrophages, regulating
inflammation and immunity. Although some of them still need more confirmatory
studies, those immune therapies will provide new insights into cell-based and
gene-based treatment against IBD in near future. N. Ref:: 46
----------------------------------------------------
[48]
TÍTULO / TITLE: - Amino acid transport
regulates blastocyst implantation.
REVISTA
/ JOURNAL: - Biol Reprod. Acceso gratuito al texto
completo a partir de los 2 años de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.biolreprod.org/
●●
Cita: Biol Reprod: <> 2003 Oct;69(4):1101-8. Epub 2003 Jun 11.
●●
Enlace al texto completo (gratuito o de pago) 1095/biolreprod.103.018010
AUTORES
/ AUTHORS: - Martin PM; Sutherland AE; Van Winkle LJ
INSTITUCIÓN
/ INSTITUTION: - Department of Cell Biology, University of
Virginia, Charlottesville, Virginia, USA.
RESUMEN
/ SUMMARY: - Mouse blastocyst outgrowth in vitro and
probably implantation in vivo require amino acid signaling via the target of
rapamycin (TOR) pathway. This signaling does not simply support protein
synthesis and trophoblast differentiation. Rather, it regulates development of
trophoblast protrusive activity and may act as a developmental checkpoint for
implantation. Moreover, intracellular amino acids per se are insufficient to
elicit TOR signaling. Instead, de novo transport of amino acids, and
particularly of leucine, stimulate mTOR activity at the blastocyst stage. The
activity of the broad-scope and yet leucine-selective amino acid transport
system B0,+ could produce such increases in intracellular amino acid
concentrations. For example, system B0,+ uses a Na+ gradient to drive amino
acid uptake, and the Na+ concentration in uterine secretions increases by
nearly two-fold about 18 h before implantation. The resultant mTOR signaling
could trigger polyamine, insulin-like growth factor II, and nitric oxide
production in blastocysts and the increased cell motility sometimes associated
with synthesis of these bioactive molecules.
N. Ref:: 106
----------------------------------------------------
[49]
TÍTULO / TITLE: - Potassium channels in T
lymphocytes: toxins to therapeutic immunosuppressants.
REVISTA
/ JOURNAL: - Toxicon 2001 Sep;39(9):1269-76.
AUTORES
/ AUTHORS: - George Chandy K; Cahalan M; Pennington M;
Norton RS; Wulff H; Gutman GA
INSTITUCIÓN
/ INSTITUTION: - Department of Physiology and Biophysics,
University of California Irvine, Room 291, John Irvine Smith Hall, Medical
School, Irvine, CA92697, USA. gchandy@uci.edu N. Ref:: 60
----------------------------------------------------
[50]
TÍTULO / TITLE: - Targeted cancer therapy
and immunosuppression using radiolabeled monoclonal antibodies.
REVISTA
/ JOURNAL: - Semin Oncol 2004 Feb;31(1):68-82.
AUTORES
/ AUTHORS: - Bethge WA; Sandmaier BM
INSTITUCIÓN
/ INSTITUTION: - Clinical Research Division, Fred
Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
RESUMEN
/ SUMMARY: - Radioimmunotherapy (RIT) as a means to
target radiation therapy to tumor cells or to specifically suppress host
immunity specifically in the setting of allogeneic transplantation is a
promising new strategy in the armory of today’s oncologist. Different
approaches of RIT such as injection of a stable radioimmunoconjugate or the use
of pretargeting are available. The choice of the radionuclide used for RIT
depends on its radiation characteristics with respect to the malignancy or
cells targeted. beta-Emitters with their lower energy and longer path length
are more suitable for targeting bulky, solid tumors, whereas alpha-emitters
with their high linear energy transfer and short path length are better suited
to target cells or tumors of the hematologic system. Encouraging results have
been obtained using these approaches treating patients with hematologic
malignancies. While the results in solid tumors are somewhat less favorable,
new strategies for patients with minimal residual disease (MRD), using adjuvant
and locoregional treatment, are currently being investigated. In this report,
we outline basic principles of RIT, give an overview of available
radioimmunoconjugates and their clinical applications with special emphasis on
their use in hematologic malignancies, including use in conditioning regimens
for stem cell transplantation (SCT). N.
Ref:: 99
----------------------------------------------------
[51]
TÍTULO / TITLE: - TOR inhibitors and
cardiac allograft vasculopathy: is inhibition of intimal thickening an adequate
surrogate of benefit?
REVISTA
/ JOURNAL: - J Heart Lung Transplant 2003
May;22(5):501-4.
AUTORES
/ AUTHORS: - Mehra MR; Uber PA
INSTITUCIÓN
/ INSTITUTION: - Cardiomyopathy and Heart Transplantation
Center, Ochsner Clinic Foundation, New Orleans, Louisiana 70121, USA. mmehra@ochsner.org N. Ref:: 30
----------------------------------------------------
[52]
TÍTULO / TITLE: - The TOR kinases link
nutrient sensing to cell growth.
REVISTA
/ JOURNAL: - J Biol Chem. Acceso gratuito al texto
completo a partir de 1 año de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.jbc.org/
●●
Cita: J. of Biological Chemistry: <> 2001 Mar 30;276(13):9583-6. Epub
2001 Feb 2.
●●
Enlace al texto completo (gratuito o de pago) 1074/jbc.R000034200
AUTORES
/ AUTHORS: - Rohde J; Heitman J; Cardenas ME
INSTITUCIÓN
/ INSTITUTION: - Departments of Genetics, Howard Hughes
Medical Institute, Duke University Medical Center, Durham, North Carolina 27710,
USA.
RESUMEN
/ SUMMARY: - Rapamycin is an immunosuppressive natural
product that inhibits the proliferation of T-cells in response to nutrients and
growth factors. Rapamycin binds to the peptidyl-prolyl isomerase FKBP12 and
forms protein-drug complexes that inhibit signal transduction by the TOR
kinases. The FKBP12 and TOR proteins are conserved from fungi to humans, and in
both organisms the TOR signaling pathway plays a role in nutrient sensing. In
response to nitrogen sources or amino acids, TOR regulates both transcription
and translation, enabling cells to appropriately respond to growth-promoting
signals. Rapamycin is having a profound impact on clinical medicine and was
approved as an immunosuppressant for transplant recipients in 1999. Ongoing clinical
studies address new clinical applications for rapamycin as an antiproliferative
drug for chemotherapy and invasive cardiology.
N. Ref:: 74
----------------------------------------------------
[53]
TÍTULO / TITLE: - Transmitting the signal
of excess nitrogen in Saccharomyces cerevisiae from the Tor proteins to the
GATA factors: connecting the dots.
REVISTA
/ JOURNAL: - FEMS Microbiol Rev 2002 Aug;26(3):223-38.
AUTORES
/ AUTHORS: - Cooper TG
INSTITUCIÓN
/ INSTITUTION: - Department of Molecular Sciences,
University of Tennessee, 858 Madison Ave., Memphis, TN 38163, USA. tcooper@utmem.edu
RESUMEN
/ SUMMARY: - Major advances have recently occurred in
our understanding of GATA factor-mediated, nitrogen catabolite repression
(NCR)-sensitive gene expression in Saccharomyces cerevisiae. Under
nitrogen-rich conditions, the GATA family transcriptional activators, Gln3 and
Gat1, form complexes with Ure2, and are localized to the cytoplasm, which
decreases NCR-sensitive expression. Under nitrogen-limiting conditions, Gln3
and Gat1 are dephosphorylated, move from the cytoplasm to the nucleus, in
wild-type but not rna1 and srp1 mutants, and increase expression of
NCR-sensitive genes. ‘Induction’ of NCR-sensitive gene expression and
dephosphorylation of Gln3 (and Ure2 in some laboratories) when cells are
treated with rapamycin implicates the Tor1/2 signal transduction pathway in
this regulation. Mks1 is posited to be a negative regulator of Ure2, positive
regulator of retrograde gene expression and to be itself negatively regulated
by Tap42. In addition to Tap42, phosphatases Sit4 and Pph3 are also argued by
some to participate in the regulatory pathway. Although a treasure trove of
information has recently become available, much remains unknown (and sometimes
controversial) with respect to the precise biochemical functions and regulatory
pathway connections of Tap42, Sit4, Pph3, Mks1 and Ure2, and how precisely Gln3
and Gat1 are prevented from entering the nucleus. The purpose of this review is
to provide background information needed by students and investigators outside
of the field to follow and evaluate the rapidly evolving literature in this
exciting field. N.
Ref:: 61
----------------------------------------------------
[54]
TÍTULO / TITLE: - Interactions between
cyclosporin and lipid-lowering drugs: implications for organ transplant
recipients.
REVISTA
/ JOURNAL: - Drugs 2003;63(4):367-78.
AUTORES
/ AUTHORS: - Asberg A
INSTITUCIÓN
/ INSTITUTION: - Laboratory for Renal Physiology, Section
of Nephrology, Medical Department, The National Hospital, Oslo, Norway. anderas@klinmed.uio.no
RESUMEN
/ SUMMARY: - Dyslipidaemia is more frequent in solid
organ transplant recipients than in the general population, primarily as a
result of immunosuppressive drug treatment. Both cyclosporin and
corticosteroids are associated with dyslipidaemic adverse effects. In order to
reduce the overall cardiovascular risk in these patients, lipid-lowering drugs
have become widely used, especially HMG-CoA reductase inhibitors (statins).
Cyclosporin, as well as most statins (lovastatin, simvastatin, atorvastatin and
pravastatin) are metabolised by cytochrome P450 (CYP)3A4, so a bilateral
pharmacokinetic interaction between these drugs is theoretically possible.
However, results from several studies show that statins do not induce increased
systemic exposure of cyclosporin. A small (but not clinically relevant)
reduction in systemic exposure of cyclosporin has actually been shown in many
studies. Cyclosporin-treated patients on the other hand show several-fold
higher systemic exposure of all statins, both those that are metabolised by
CYP3A4 and fluvastatin (metabolised by CYP2C9). Therefore, the mechanism for
this interaction does not seem to be solely caused by inhibition of CYP3A4
metabolism, but it is probably also a result of inhibition of statin-transport
in the liver, at least in part. Other lipid-lowering drugs, such as fibric acid
derivatives, bile acid sequestrants, probucol, fish oils and orlistat are also
used in solid organ transplant recipients. Most of them do not interact with
cyclosporin, but there are reports indicating that both probucol and orlistat
may reduce cyclosporin bioavailablility to a clinically relevant degree. There
is no information on possible interaction effects of cyclosporin on the
pharmacokinetics of lipid-lowering drugs other than statins, but it is not
likely that any clinical relevant interference exists with fish oil, orlistat,
probucol or bile acid sequestrants. N.
Ref:: 71
----------------------------------------------------
[55]
TÍTULO / TITLE: - European best practice
guidelines for renal transplantation. Section IV: Long-term management of the
transplant recipient. IV.3.1 Long-term immunosuppression. Late steroid or
cyclosporine withdrawal.
REVISTA
/ JOURNAL: - Nephrol Dial Transplant. Acceso gratuito
al texto completo a partir de los 2 años de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://ndt.oupjournals.org/
●●
Cita: Nephrology Dialysis Transplantation: <> 2002;17 Suppl 4:19-20.
RESUMEN
/ SUMMARY: - GUIDELINES: A. In order to reduce or avoid
long-term serious adverse effects of corticosteroids, such as bone fractures,
diabetes mellitus, arterial hypertension, osteoporosis and eye complications,
steroid withdrawal should be considered. B. Steroid withdrawal is safe only in
a proportion of graft recipients and is recommended only in low-risk patients.
The efficacy of the remaining immunosuppression should be considered. C. After
steroid withdrawal, graft function has to be monitored very carefully because
of the risk of a delayed but continuous loss of function due to chronic graft
dysfunction. In the case of functional deterioration or dysfunction, steroids
should be re-administered. D. Cyclosporine withdrawal might be considered in
order to ameliorate nephrotoxicity, arterial hypertension, lipid disorders and
hypertrichosis. This can be carried out with no significant long-term risk of
progressive graft loss. The efficacy of the remaining immunosuppression should
be considered. After cyclosporine withdrawal, careful monitoring for acute
rejection is recommended.
----------------------------------------------------
[56]
TÍTULO / TITLE: - Fluorescence
polarization detection for affinity capillary electrophoresis.
REVISTA
/ JOURNAL: - Electrophoresis 2002 Mar;23(6):903-8.
●●
Enlace al texto completo (gratuito o de pago) 1002/1522-2683(200203)23:6<903::AID-ELPS903>3.0.CO;2-2
[pii]
AUTORES
/ AUTHORS: - Le XC; Wan QH; Lam MT
INSTITUCIÓN
/ INSTITUTION: - Environmental Health Sciences Program,
Department of Public Health Sciences, Faculty of Medicine, University of
Alberta, Edmonton, Alberta T6G 2G3, Canada. xc.le@ualberta.ca
RESUMEN
/ SUMMARY: - Affinity capillary electrophoresis (ACE)
with laser-induced fluorescence polarization (LIFP) detection is described,
with examples of affinity interaction studies. Because fluorescence
polarization is sensitive to changes in the rotational motion arising from
molecular association or dissociation, ACE-LIFP is capable of providing
information on the formation of affinity complexes prior to or during CE
separation. Unbound, small fluorescent probes generally have little
fluorescence polarization because of rapid rotation of the molecule in
solution. When the small fluorescent probe is bound to a larger affinity agent,
such as an antibody, the fluorescence polarization (and anisotropy) increases
due to slower motion of the much larger complex molecule in the solution.
Fluorescence polarization results are obtained by simultaneously measuring
fluorescence intensities of vertical and horizontal polarization planes.
Applications of CE-LIFP to both strong and weak binding systems are discussed
with antibody-antigen and DNA-protein binding as examples. For strong affinity
binding, such as between cyclosporine and its antibody, complexes are formed
prior to CE-LIFP analysis. For weaker binding, such as between single-stranded
DNA and its binding protein, the single-stranded DNA binding protein is added
to the CE separation buffer to enhance dynamic formation of affinity complexes.
Both fluorescence polarization (and anisotropy) and mobility shift results are
complementary and are useful for immunoassays and binding studies. N. Ref:: 25
----------------------------------------------------
[57]
TÍTULO / TITLE: - A novel pathway
regulating the mammalian target of rapamycin (mTOR) signaling.
REVISTA
/ JOURNAL: - Biochem Pharmacol 2002 Oct 1;64(7):1071-7.
AUTORES
/ AUTHORS: - Chen J; Fang Y
INSTITUCIÓN
/ INSTITUTION: - Department of Cell and Structural Biology,
University of Illinois at Urbana-Champaign, 601 South Goodwin Avenue, B107,
Urbana, IL 61801, USA. jiechen@uiuc.edu
RESUMEN
/ SUMMARY: - Originally discovered as an anti-fungal
agent, the bacterial macrolide rapamycin is a potent immunosuppressant and a
promising anti-cancer drug. In complex with its cellular receptor, the
FK506-binding protein (FKBP12), rapamycin binds and inhibits the function of the
mammalian target of rapamycin (mTOR). By mediating amino acid sufficiency, mTOR
governs signaling to translational regulation and other cellular functions by
converging with the phosphatidylinositol 3-kinase (PI3K) pathway on downstream
effectors. Whether mTOR receives mitogenic signals in addition to
nutrient-sensing has been an unresolved issue, and the mechanism of action of
rapamycin remained unknown. Our recent findings have revealed a novel link
between mitogenic signals and mTOR via the lipid second messenger phosphatidic
acid (PA), and suggested a role for mTOR in the integration of nutrient and
mitogen signals. A molecular mechanism for rapamycin inhibition of mTOR
signaling is proposed, in which a putative interaction between PA and mTOR is abolished
by rapamycin binding. Collective evidence further implicates the regulation of
the rapamycin-sensitive signaling circuitry by phospholipase D, and potentially
by other upstream regulators such as the conventional protein kinase C, the Rho
and ARF families of small G proteins, and calcium ions. As the mTOR pathway has
been demonstrated to be an important anti-cancer target, the identification of
new components and novel regulatory modes in mTOR signaling will facilitate the
future development of diagnostic and therapeutic strategies. N. Ref:: 67
----------------------------------------------------
[58]
TÍTULO / TITLE: - ATP-binding cassette
transporters and calcineurin inhibitors: potential clinical implications.
REVISTA
/ JOURNAL: - Transplant Proc 2001 May;33(3):2420-1.
AUTORES
/ AUTHORS: - van Gelder T; Klupp J; Sawamoto T;
Christians U; Morris RE
INSTITUCIÓN
/ INSTITUTION: - Department of Internal Medicine (T.vG.),
University Hospital Rotterdam, Rotterdam, The Netherlands. vangelder@INW1.AZR.NL N. Ref:: 17
----------------------------------------------------
[59]
TÍTULO / TITLE: - Recent developments in
inflammatory bowel disease.
REVISTA
/ JOURNAL: - Med Clin North Am 2002 Nov;86(6):1497-523.
AUTORES
/ AUTHORS: - Su C; Lichtenstein GR
INSTITUCIÓN
/ INSTITUTION: - Division of Gastroenterology, Department
of Medicine, Hospital of the University of Pennsylvania, University of
Pennsylvania School of Medicine, Third Floor Ravdin Building, 3400 Spruce
Street, Philadelphia, PA 19104-4283, USA.
RESUMEN
/ SUMMARY: - The evolving medical armamentarium holds
promise for more precise and effective therapies for IBD. The experience with
anti-TNF therapy, particularly infliximab, illustrates the potential efficacy
of therapies targeted at specific mediators or pathways involved in the
pathogenesis. Advances in molecular technology have enabled the development of
novel and potentially effective targeted therapies. Equally important is the
increasing scientific understanding of the pathogenesis of IBD, which will
likely improve the ability to stratify disease and to select therapies based on
genotypic, immunologic, and phenotypic profiles in the future. N. Ref:: 191
----------------------------------------------------
[60]
TÍTULO / TITLE: - Neonatal toxic shock
syndrome-like exanthematous disease (NTED).
REVISTA
/ JOURNAL: - Pediatr Int 2003 Apr;45(2):233-7.
AUTORES
/ AUTHORS: - Takahashi N
INSTITUCIÓN
/ INSTITUTION: - Department of Pediatrics, Jichi Medical
School, Tochigi-ken, Tokyo Women’s Medical University, Tokyo, Japan. naoto-t@jichi.ac.jp
RESUMEN
/ SUMMARY: - The author and colleagues recently
discovered an emerging neonatal infectious disease: neonatal toxic shock
syndrome-like exanthematous disease (NTED), which is induced by the
superantigen toxic shock syndrome toxin-1 (TSST-1), produced by
methicillin-resistant Staphylococcus aureus (MRSA). The massively expanded
Vbeta2+ T cells were rapidly deleted in the peripheral blood of patients with
NTED. A marked depletion of Vbeta2+ T cells was also observed in the peripheral
blood before the expansion of these T cells. Anergy is specifically induced in
the TSST-1 reactive T cells of patients with NTED. Rapid recovery from NTED
without complications is expected to be related to the induction of immunologic
tolerance in neonatal patients. Anti-TSST-1 IgG antibody of maternal origin was
found to play a protective role in preventing the development of NTED. The number
of hospitals that have experience caring for patients with NTED has increased
threefold in the past 5 years. Most MRSA isolates from neonatal intensive care
units in Japan were found to be a single clone of coagulase type II and to
possess TSST-1 and staphylococcal enterotoxin C genes. The timing and increased
incidence of NTED suggest the emergence of a new MRSA clone. By recognizing
that TSST-1 can induce NTED, healthcare providers may give increased attention
to this disease in neonatal wards. N.
Ref:: 43
----------------------------------------------------
[61]
TÍTULO / TITLE: - Basiliximab: a review
of its use as induction therapy in renal transplantation.
REVISTA
/ JOURNAL: - Drugs 2003;63(24):2803-35.
AUTORES
/ AUTHORS: - Chapman TM; Keating GM
INSTITUCIÓN
/ INSTITUTION: - Adis International Limited, Auckland, New
Zealand. demail@adis.co.nz
RESUMEN
/ SUMMARY: - Basiliximab (Simulect), a chimeric
(human/murine) monoclonal antibody, is indicated for the prevention of acute
organ rejection in adult and paediatric renal transplant recipients in
combination with other immunosuppressive agents.Basiliximab significantly
reduced acute rejection compared with placebo in renal transplant recipients
receiving dual- (cyclosporin microemulsion and corticosteroids) or
triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and
patient survival rates at 12 months were similar. Significantly more
basiliximab than placebo recipients were free from the combined endpoint of
death, graft loss or acute rejection 3 years, but not 5 years, after
transplantation.The incidence of adverse events was similar in basiliximab and
placebo recipients, with no increase in the incidence of infection, including
cytomegalovirus (CMV) infection. Malignancies or post-transplant
lymphoproliferative disorders after treatment with basiliximab were rare, with
a similar incidence to that seen with placebo at 12 months or 5 years
post-transplantation. Rare cases of hypersensitivity reactions to basiliximab
have been reported.The efficacy of basiliximab was similar to that of equine
antithymocyte globulin (ATG) and daclizumab, and similar to or greater than
that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte
globulin (RATG) in patients at relatively low risk of acute rejection, but less
effective in high-risk patients. Numerically or significantly fewer patients
receiving basiliximab experienced adverse events considered to be related to
the study drug than ATG or RATG recipients. The incidence of infection,
including CMV infection, was similar with basiliximab and ATG or
RATG.Basiliximab plus baseline immunosuppression resulted in no significant
differences in acute rejection rates compared with baseline immunosuppression
with or without ATG or antilymphocyte globulin in retrospective analyses
conducted for small numbers of paediatric patients. Limited data from
paediatric renal transplant recipients suggest a similar tolerability profile
to that in adults. Basiliximab appears to allow the withdrawal of
corticosteroids or the use of corticosteroid-free or calcineurin
inhibitor-sparing regimens in renal transplant recipients.Basiliximab did not
increase the overall costs of therapy in pharmacoeconomic studies.CONCLUSION:
Basiliximab reduces acute rejection without increasing the incidence of adverse
events, including infection and malignancy, in renal transplant recipients when
combined with standard dual- or triple-immunotherapy. The overall incidence of
death, graft loss or acute rejection was significantly reduced at 3 years;
there was no significant difference for this endpoint 5 years after
transplantation. Malignancy was not increased at 5 years. The overall efficacy,
tolerability, ease of administration and cost effectiveness of basiliximab make
it an attractive option for the prophylaxis of acute renal transplant
rejection. N. Ref:: 85
----------------------------------------------------
[62]
TÍTULO / TITLE: - Pharmacokinetics of
tacrolimus-based combination therapies.
REVISTA
/ JOURNAL: - Nephrol Dial Transplant. Acceso gratuito
al texto completo a partir de los 2 años de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://ndt.oupjournals.org/
●●
Cita: Nephrology Dialysis Transplantation: <> 2003 May;18 Suppl 1:i12-5.
AUTORES
/ AUTHORS: - Undre NA
INSTITUCIÓN
/ INSTITUTION: - Fujisawa GmbH, Neumarkter Str. 61, D-81673
Munich, Germany. nas.undre@fujisawa.de
RESUMEN
/ SUMMARY: - This paper reviews the pharmacokinetics of
tacrolimus, with special reference to its combination with adjunctive
immunosuppressants. Oral bioavailability of tacrolimus, which is variable
between patients, averages approximately 25%. This is largely due to
extrahepatic metabolism of tacrolimus in the gastrointestinal epithelium.
Nevertheless, intra-patient variability is low, as evidenced by the small
number of dose changes required to maintain patients within the recommended
tacrolimus target levels. Tacrolimus is distributed extensively in the body
with most partitioned outside the blood compartment. Concentrations of
tacrolimus in blood are used as a surrogate marker of clinically relevant
concentration of the drug at the site(s) of action. Convenient whole-blood
sampling within a +/-2-h window around 12 h post-dose (C(min)) is highly
predictive of systemic exposure to tacrolimus and is thus used to optimise
therapy. Sampling at other time-points offers no advantage over C(min)
monitoring. The interactions of tacrolimus with other immunosuppressive agents
are well characterized. After cessation of concomitant corticosteroid
treatment, exposure to tacrolimus increases by approximately 25%. In contrast,
there is no pharmacokinetic interaction between mycophenolate mofetil (MMF) and
tacrolimus. Therefore, systemic exposure to the active metabolite of MMF,
mycophenolic acid, is higher with MMF-tacrolimus combination than with
MMF-cyclosporin combination. Therefore, 1 g/day MMF may be an adequate
maintenance dose in tacrolimus-based regimens. Co-administration of tacrolimus
and sirolimus, while having no effect on exposure to sirolimus, results in
reduced exposure to tacrolimus at sirolimus doses of 2 mg/day and above. In conclusion,
tacrolimus levels should be monitored when sirolimus is co-administered at
doses >2 mg/day and after cessation of corticosteroid treatment. N. Ref:: 13
----------------------------------------------------
[63]
- Castellano -
TÍTULO / TITLE:La enfermedad linfoproliferativa
difusa postrasplante renal y su relacion con el virus Epstein-Barr. Experiencia
de un centro. Diffuse lymphoproliferative disease after renal transplantation
and its relation with Epstein-Barr virus. Experience at one center.
REVISTA
/ JOURNAL: - Nefrologia. Acceso gratuito al texto
completo.
●●
Enlace a la Editora de la Revista http://www.aulamedica.es/nefrologia/
●●
Cita: Nefrologia: <> 2002;22(5):463-9.
AUTORES
/ AUTHORS: - Franco A; Jimenez L; Aranda I; Alvarez L;
Gonzalez M; Rocamora N; Olivares J
INSTITUCIÓN
/ INSTITUTION: - Servicio de Nefrologia Hospital General
Alicante Maestro Alonso, 109 03010 Alicante. franco_ant@gva.es
RESUMEN
/ SUMMARY: - Post-transplant lymphoproliferative disorders
(PTLD) are a group of heterogeneous lymphoid proliferations in chronic
immunosuppressed recipients which appear to be related to Epstein Barr Virus
(EBV). Receptor EBV seronegativity, use of antilymphocyte antibodies and CMV
disease have been identified as risk factors that may tigger development of
PTLD. We have studied the incidence of PTLD and its relationship with EBV in
588 adult renal transplant recipients who were transplanted in our hospital
from 1988 to 2001. We have also evaluated the diagnostic and therapeutic
methods used, the risk factors and outcome of the patients who developed PTLD.
We identified 8 recipients (4 males and 4 females), range from 18 to 67 years
(mean age 45.6 years) with a median time between grafting and PTLD of 4.1 years
(0.1-7 years), who developed PTLD (1.3%). Only 1 patient received OKT3 and had
CMV disease, two of them (25%) had been treated with hight doses of
prednisolone, another was EBV seronegative, but the rest of them (50%) had no
risk factors. Two patients were diagnosed at autopsy, the diagnosis of 5 was
based on the histology of biopsy and the last one by CT scans of chest-abdomen
and cytology. The presence of EBV in the lymphoproliferative cells was assessed
in 5 out of the 7 studied patients (71.4%). The outcome of our recipients was
poor. Five out of 8 patients died shortly after diagnosis as a direct
consecuence of PTLD and another of an infectious complication of the treatment
(75%). The 2 patients alive started dialysis and 1 of them died 2 years later of
a non-related cause. In conclusion, PTLD is a relatively frequent disease with
a poor prognosis in renal transplant patients. It seems to have a close
relationship with EBV and can develop in the absence of the classical risk
factors. N. Ref:: 18
----------------------------------------------------
[64]
TÍTULO / TITLE: - TOR action in mammalian
cells and in Caenorhabditis elegans.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol
2004;279:115-38.
AUTORES
/ AUTHORS: - Long X; Muller F; Avruch J
INSTITUCIÓN
/ INSTITUTION: - Diabetes Research Laboratory, Department
of Molecular Biology, Land Medicine Massachusetts General Hospital, Boston, MA
02114, USA.
RESUMEN
/ SUMMARY: - The p70 S6 kinase (p70 S6K) was the first
signaling element in mammalian cells shown to be inhibited by rapamycin. The
activity of the p70 S6K in mammalian cell is upregulated by extracellular amino
acids (especially leucine) and by signals from receptor tyrosine kinases
(RTKs), primarily through activation of the type 1A PI-3 kinase. The amino
acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but
largely independent, in that deletion of the amino-terminal and
carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain
renders the kinase insensitive to inhibition by both rapamycin and by
withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to
activation by RTKs and to inhibition by wortmannin. At a molecular level, this
dual control of p70 S6K activity is attributable to phosphorylation of the two
p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70
S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located
in a hydrophobic motif carboxyterminal to the catalytic domain. Together these
two phosphorylations engender a strong, positively cooperative activation of
p70 S6K, so that each is indispensable for physiologic regulation. Like RTKs,
the p70 S6K appears early in metazoan evolution and comes to represent an
important site at which the more ancient, nutrient-responsive TOR pathway
converges with the RTK/PI-3 kinase pathway in the control of cell growth. Dual
regulation of p70 S6K is seen in Drosophila; however, this convergence is not
yet evident in Caenorhabditis elegans, wherein nutrient activation of the
insulin receptor (InsR) pathway negatively regulates dauer development and
longevity, whereas the TOR pathway regulates overall mRNA translation through
effectors distinct from p70 S6K, as in yeast. The C. elegans TOR and InsR pathways
show none of the cross- or convergent regulation seen in mammalian cells. The
nature of the elements that couple nutrient sufficiency to TOR activity remain
to be discovered, and the mechanisms by which RTKs influence TOR activity in
mammalian cells require further study. One pathway for RTK control involves the
tuberous sclerosis complex, which is absent in C. elegans, but of major
importance in Drosophila and higher metazoans.
N. Ref:: 98
----------------------------------------------------
[65]
- Castellano -
TÍTULO / TITLE:Alteraciones del metabolismo oseo
tras el trasplante renal. Bone metabolism alterations after kidney
transplantation.
REVISTA
/ JOURNAL: - Nefrologia. Acceso gratuito al texto
completo.
●●
Enlace a la Editora de la Revista http://www.aulamedica.es/nefrologia/
●●
Cita: Nefrologia: <> 2003;23 Suppl 2:122-6.
AUTORES
/ AUTHORS: - Torres A; Garcia S; Barrios Y; Hernandez
D; Lorenzo V
INSTITUCIÓN
/ INSTITUTION: - Servicio de Nefrologia, Unidad de
Investigacion, Hospital Universitario de Canarias, Instituto Reina Sofia de
Investigacion. atorres@ull.es
RESUMEN
/ SUMMARY: - Early after renal transplantation (RT) a
rapid decrease in bone mineral density at the lumbar spine, femoral neck, and
femoral shaft has been documented. In addition, an appreciable proportion of
patients still remain losing bone late after RT. As a consequence, RT patients
are at a high risk of bone fractures as compared to general population. Most
fractures involve appendicular skeleton, particularly the feet and ankles, and
the diabetic patient is at increased risk of fractures. Thus, early institution
of preventive measures and treatment of established osteoporosis are central.
The major cause of post-transplantation bone loss is corticosteroid treatment,
and this should be used at the lower dose compatible with graft survival.
Preexisting hyperparathyroidism also affects the early cancellous bone loss at
the spine, and post-transplantation bone loss reflects variable individual
susceptibility, resembling the polygenic determination of bone mineral density
in general. Clinical trials have demonstrated that bisphosphonates or vitamin D
plus calcium supplementation, prevent post-transplantation bone loss during the
first 6-12 months. However, their role in preventing bone fractures has not
been proven. Finally, recommendations for management, prevention and treatment,
are summarized. N.
Ref:: 24
----------------------------------------------------
[66]
TÍTULO / TITLE: - Efficacy and toxicity
of a protocol using sirolimus, tacrolimus and daclizumab in a nonhuman primate
renal allotransplant model.
REVISTA
/ JOURNAL: - Am J Transplant 2002 Apr;2(4):381-5.
AUTORES
/ AUTHORS: - Montgomery SP; Mog SR; Xu H; Tadaki DK;
Hirshberg B; Berning JD; Leconte J; Harlan DM; Hale D; Kirk AD
INSTITUCIÓN
/ INSTITUTION: - NIDDK/Navy Transplantation and
Autoimmunity Branch, Naval Medical Research Center, Bethesda, Maryland 20892,
USA.
RESUMEN
/ SUMMARY: - A regimen combining sirolimus, tacrolimus,
and daclizumab has recently been shown to provide adequate immunosuppression
for allogeneic islet transplantation in humans, but remains unproven for primarily
vascularized allografts. We evaluated this regimen for renal allograft
transplantation in mismatched nonhuman primates. Dosages of sirolimus and
tacrolimus were adjusted for trough levels of 10-15 ng/mL and 4-6 ng/mL,
respectively. Treated monkeys (n = 5) had significantly prolonged allograft
survival, with a mean survival of 36 days vs. 7 days in untreated controls (n =
6, p = 0.008). Four of five treated animals, but none of the controls,
developed fibrinoid vascular necrosis of the small intestine. A review of gut
histology from animals on other immunosuppressive protocols performed by our
laboratory suggested that these lesions were a result of sirolimus exposure. In
summary, this regimen prolongs the survival of vascularized renal allografts,
but is limited by profound GI toxicity in rhesus macaques.
----------------------------------------------------
[67]
TÍTULO / TITLE: - Treatment responses of
childhood aplastic anaemia with chromosomal aberrations at diagnosis.
REVISTA
/ JOURNAL: - Br J Haematol 2002 Jul;118(1):313-9.
AUTORES
/ AUTHORS: - Ohga S; Ohara A; Hibi S; Kojima S; Bessho
F; Tsuchiya S; Ohshima Y; Yoshida N; Kashii Y; Nishimura S; Kawakami K;
Nishikawa K; Tsukimoto I
INSTITUCIÓN
/ INSTITUTION: - Aplastic Anaemia Committee of the Japanese
Society of Paediatric Haematology, Tokyo, Japan. ohgas@pediatr.med.kyushu-u.ac.jp
RESUMEN
/ SUMMARY: - The clinical outcome of childhood aplastic
anaemia (AA) with aberrant cytogenetic clones at diagnosis was surveyed. Among
198 children with newly diagnosed AA registered with the AA Committee of the
Japanese Society of Paediatric Hematology between 1994 and 1998, cytogenetic
studies of bone marrow (BM) cells were completed in 159 patients. Apart from
one Robertsonian translocation, seven patients (4.4%) showed clonal chromosomal
abnormalities in hypoplastic BM without myelodysplastic features. The patients
included six girls and one boy with a median age of 11 years (range 5-14
years). Six patients had del(6), del(5), del(13), del(20), or -7, and one
showed add(9). Four patients responded to the first immunosuppressive therapy
(IST: cyclosporin A plus anti-thymocyte globulin) and one obtained a
spontaneous remission. Cytogenetic abnormalities remained in two patients with
an IST response. On the other hand, two patients showed no IST response. One
did not respond to repeat IST and died of acute graft-versus-host disease after
an unrelated-BM transplant. Another obtained a complete response after a
successful BM transplant. No haematological findings at diagnosis predicted the
treatment response. No significant morphological changes developed during the
course of the illness. A literature review revealed that half of 24 AA patients
with chromosomal abnormalities responded to the first IST, and that +6 was the
sole predictable marker for IST unresponsiveness. These results suggest that
IST can be applied as the initial therapy for AA with cytogenetic abnormalities
in the absence of completely matched donors.
N. Ref:: 32
----------------------------------------------------
[68]
TÍTULO / TITLE: - Treatment of membranous
nephropathy.
REVISTA
/ JOURNAL: - Nephrol Dial Transplant. Acceso gratuito
al texto completo a partir de los 2 años de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://ndt.oupjournals.org/
●●
Cita: Nephrology Dialysis Transplantation: <> 2001;16 Suppl 5:8-10.
AUTORES
/ AUTHORS: - Ponticelli C; Passerini P
INSTITUCIÓN
/ INSTITUTION: - Division of Nephrology, Ospedale Maggiore
di Milano, Italy.
RESUMEN
/ SUMMARY: - Several therapeutic approaches have been
tried in patients with membranous nephropathy. Corticosteroids have been
largely used, but a meta-analysis of the available controlled trials did not
show any benefit of corticosteroids either in favouring remission of the
nephrotic syndrome or in preventing renal dysfunction. Controversial results
have been obtained with cytotoxic agents. Unfortunately, most of the available
trials were small in size and had short-term follow-ups. Three controlled
trials evaluated the role of a 6-month treatment with methylprednisolone and
chlorambucil. The first trial showed that the 10-year renal survival rate was
92% in treated patients compared with 60% in untreated controls. A second trial
compared the effects of methylprednisolone/chlorambucil with those of
methylprednisolone alone. The combined treatment achieved remission of
nephrotic syndrome in 64% of cases vs 38% in patients given steroids alone. A
third trial showed equivalent results in patients randomized to be given
methylprednisolone/chlorambucil or methylprednisolone/cyclophosphamide. A
number of non-controlled studies and a randomized trial also showed the
efficacy of cyclosporine in reducing proteinuria. In many but not all cases,
proteinuria reappeared when cyclosporine was stopped. In conclusion, although
the treatment of membranous nephropathy remains difficult, some therapeutical
approaches have proved to favour remission and protect renal function N. Ref:: 53
----------------------------------------------------
[69]
TÍTULO / TITLE: - Inhibitors of mammalian
target of rapamycin as novel antitumor agents: from bench to clinic.
REVISTA
/ JOURNAL: - Curr Opin Investig Drugs 2002
Feb;3(2):295-304.
AUTORES
/ AUTHORS: - Huang S; Houghton PJ
INSTITUCIÓN
/ INSTITUTION: - Department of Molecular Pharmacology, St
Jude Children’s Research Hospital, Memphis, TN 38105-2794, USA.
RESUMEN
/ SUMMARY: - Rapamycin and its derivatives, CCI-779 and
RAD-001, inhibit the mammalian target of rapamycin (mTOR), downregulating
translation of specific mRNAs required for cell cycle progression from G1 to S
phase. Preclinically, mTOR inhibitors potently suppress growth and proliferation
of numerous tumor cell lines in culture or when grown in mice as xenografts.
CCI-779 and RAD-001 are being developed as antitumor drugs and are undergoing
clinical trials. Clinically, CCI-779 has shown evidence of antitumor activity
but induced relatively mild side effects in patients. Here we discuss potential
antitumor mechanisms and resistance mechanisms of mTOR inhibitors, and
summarize the current status of these compounds as novel antitumor agents. N. Ref:: 90
----------------------------------------------------
[70]
TÍTULO / TITLE: - Regulation of
translation via TOR signaling: insights from Drosophila melanogaster.
REVISTA
/ JOURNAL: - J Nutr. Acceso gratuito al texto completo
a partir de 1 año de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.nutrition.org/
●●
Cita: Journal of Nutrition: <> 2001 Nov;131(11):2988S-93S.
AUTORES
/ AUTHORS: - Miron M; Sonenberg N
INSTITUCIÓN
/ INSTITUTION: - Department of Biochemistry and McGill
Cancer Center, McGill University, Montreal, Quebec, Canada.
RESUMEN
/ SUMMARY: - The target of rapamycin (TOR) proteins are
large protein kinases evolutionarily conserved from yeast to human. A large
body of evidence demonstrates that TOR proteins function in a nutrient-sensing
checkpoint whose role is to restrict growth under conditions of low nutrient
availability. Under such conditions, TOR blocks the transmission of
growth-promoting signals from extracellular stimuli. Recent data obtained by
genetic studies in the fruit fly Drosophila melanogaster demonstrate the
importance of both insulin-like signaling and TOR signaling in promoting
growth. Importantly, these studies identified a major downstream target of TOR
and insulin-like signaling as the translational machinery. N. Ref:: 63
----------------------------------------------------
[71]
TÍTULO / TITLE: - Mitochondrial
involvement in the point of no return in neuronal apoptosis.
REVISTA
/ JOURNAL: - Biochimie 2002 Feb-Mar;84(2-3):223-31.
AUTORES
/ AUTHORS: - Chang LK; Putcha GV; Deshmukh M; Johnson
EM Jr
INSTITUCIÓN
/ INSTITUTION: - Department of Neurology, Washington
University School of Medicine, 660 South Euclid Avenue, Campus Box 8103, St.
Louis, MO 63110-1031, USA.
RESUMEN
/ SUMMARY: - Programmed cell death (PCD) contributes to
development, maintenance, and pathology in various tissues, including the
nervous system. Many molecular, biochemical, and genetic events occur within
cells undergoing PCD. Some of these events are incompatible with long-term cell
survival because they have irreversible, catastrophic consequences. The onset
of such changes marks the point of no return, a decisive regulatory event
termed ‘the commitment-to-die.’ In this review, we discuss events that underlie
the commitment-to-die in nerve growth factor-deprivation-induced death of
sympathetic neurons. Findings in this model system implicate the mitochondrion
as an important site of regulation for the commitment-to-die in the presence or
absence of caspase inhibition. N.
Ref:: 57
----------------------------------------------------
[72]
TÍTULO / TITLE: - T-cell receptor-derived
peptides in immunoregulation and therapy of retrovirally induced
immunosuppression.
REVISTA
/ JOURNAL: - Crit Rev Immunol 2001;21(1-3):57-74.
AUTORES
/ AUTHORS: - Marchalonis JJ; Robey IF; Edmundson AB;
Sepulveda RT; Watson RR
INSTITUCIÓN
/ INSTITUTION: - Microbiology and Immunology, College of
Medicine, University of Arizona, Tucson 85724, USA. dianah@u.arizona.edu
RESUMEN
/ SUMMARY: - Retrovirally infected humans and mice
showed progressive acquired immunodeficiency accompanied by the production of
elevated levels of autoantibodies directed against T-cell receptor variable-domain
epitopes. Epitope mapping analyses indicated that a major determinant
recognized was defined by a 16-mer peptide containing the entire CDR1 segment
and part of the FR2 region of human Vbeta8, and that both species showed
reactivity to the same sequence. Either prophylactic or therapeutic
administration of this peptide to retrovirus-infected C57/BL/6 mice normalized
the balance of T(H)1- and T(H)2-type helper activity and restored the
resistance to infection by the opportunistic parasite Cryptosporidium.
Administration of the peptide did not generate significantly increased levels
of autoantibody, but had a profound effect on T-cell activity as well as other
aspects of inflammation, including NK-cell activity. A 16-mer derived from the
Jbeta sequence showed similar functional effects on T cells from
retrovirus-infected mice. Direct binding of the VbetaCDR1 peptide to
recombinant TCR Valpha/Vbeta constructs, as well as to IgM natural
autoantibodies, suggests that the cell surface receptor for the peptide is the
alpha/beta TCR on T cells and surface IgM in B cells. The Vbeta CDR1 peptide
stimulated division of murine splenocytes in vitro, stimulated the production
of the T(H)1 cytokine IL-2, and synergized with the T-cell mitogen concanavalin
A in proliferation and IL-2 production. These studies indicate that
administration of peptides derived from T-cell receptor variable domains to
animals immunosuppressed as a result of retroviral infection has a profound
immunomodulatory effect enhancing overall T-cell functional capacity,
particularly with respect to the cytokine production characteristic of
T(H)1-type cells. Our studies are interpreted in the context of other recent
investigations of immunomodulatory peptides.
N. Ref:: 69
----------------------------------------------------
[73]
TÍTULO / TITLE: - P-glycoprotein in acute
myeloid leukaemia: therapeutic implications of its association with both a
multidrug-resistant and an apoptosis-resistant phenotype.
REVISTA
/ JOURNAL: - Leuk Lymphoma 2002 Jun;43(6):1221-8.
AUTORES
/ AUTHORS: - Pallis M; Turzanski J; Higashi Y; Russell
N
INSTITUCIÓN
/ INSTITUTION: - Academic Haematology, Nottingham City
Hospital, Nottingham, UK. monica.pallis@nottingham.ac.uk
RESUMEN
/ SUMMARY: - P-glycoprotein (Pgp) expression is an
independent prognostic factor for response to remission-induction chemotherapy
in acute myeloblastic leukaemia, particularly in the elderly. There are several
potential agents for modulating Pgp-mediated multi-drug resistance, such as
cyclosporin A and PSC833, which are currently being evaluated in clinical
trials. An alternative therapeutic strategy is to increase the use of drugs
which are unaffected by Pgp. However, in this review, we explain why this may
be more difficult than it appears. Evidence from in vitro studies of primary
AML blasts supports the commonly held supposition that chemoresistance may be
linked to apoptosis-resistance. We have found that Pgp has a drug-independent
role in the inhibition of in vitro apoptosis in AML blasts. Modulation of
cytokine efflux, signalling lipids and intracellular pH have all been suggested
as ways by which Pgp may affect cellular resistance to apoptosis; these are
discussed in this review. For a chemosensitising agent to be successful, it may
be more important for it to enhance apoptosis than to increase drug
uptake. N. Ref:: 95
----------------------------------------------------
[74]
TÍTULO / TITLE: - The potential of
antibody-based immunosuppressive agents for corneal transplantation.
REVISTA
/ JOURNAL: - Immunol Cell Biol 2003 Apr;81(2):93-105.
AUTORES
/ AUTHORS: - Thiel MA; Coster DJ; Williams KA
INSTITUCIÓN
/ INSTITUTION: - Department of Ophthalmology, Flinders
University of South Australia, Adelaide, Australia.
RESUMEN
/ SUMMARY: - Corneal transplantation is a
sight-restorative procedure but its success is limited by irreversible graft
rejection, which accounts for up to 50 per cent of failures. The normal eye is
an immune-privileged site. Multiple mechanisms maintain ocular privilege,
including the blood-eye barrier, the lack of blood vessels and lymphatics in
the normal cornea, the relative paucity of mature antigen-presenting cells in
the central cornea, the presence of immunomodulatory factors in ocular fluids,
and the constitutive expressive of CD95L (Fas ligand) within the eye. However,
privilege can be eroded by the sequelae of inflammation and neovascularization.
Corneal graft rejection in humans is currently suppressed with topical glucocorticosteroids,
which are moderately effective. Systemically administered immunosuppressive
therapy is of limited efficacy and may be accompanied by unacceptable
morbidity. Alternative therapies are needed to improve outcomes. Corneal graft
rejection is primarily a cell-mediated response controlled by the CD4+ T cell,
and thus CD4 and costimulatory molecule blockade are appealing targets for new
therapeutic interventions. A number of monoclonal antibodies have shown promise
as immunosuppressants to prolong corneal graft survival in experimental animal
models, and may eventually prove to be useful adjuncts to corticosteroids. N. Ref:: 205
----------------------------------------------------
[75]
TÍTULO / TITLE: - Old and new tools to
dissect calcineurin’s role in pressure-overload cardiac hypertrophy.
REVISTA
/ JOURNAL: - Cardiovasc Res 2002 Feb 1;53(2):294-303.
AUTORES
/ AUTHORS: - Zhang W
INSTITUCIÓN
/ INSTITUTION: - Department of Internal
Medicine/Hypertension Division, The University of Texas Southwestern Medical
Center at Dallas, Dallas, TX 75390-8586, USA. wzhang@mednet.swmed.edu
RESUMEN
/ SUMMARY: - In the last several years, a number of
experiments have implicated a pivotal role of the calcium/calmodulin-calcineurin
dependent pathway as a final common signaling mechanism by which diverse
hypertrophic stimuli converge to mediate hypertrophic responses in
cardiomyocytes. Calcineurin inhibitors, i.e. cyclosporine A (CsA) and FK506,
can interrupt the pathway, thereby preventing cardiac hypertrophy. The data
that convincingly support this novel hypothesis were derived either from in
vitro studies in cultured cardiomyocytes or from in vivo studies in transgenic
mice. However, when the hypothesis was tested in clinically relevant animal
models of cardiac hypertrophy, controversial results and conclusions emerged.
In conventional models of cardiac hypertrophy, two questions remain to be
answered: (1) whether calcineurin is activated in hypertrophied cardiac muscle,
and (2) whether calcineurin inhibitors prevent cardiac hypertrophy. In
addition, clinical observations have revealed that calcineurin inhibitors
appear to exert pro-hypertrophic effects in organ transplant recipients. The
controversies suggest that current calcineurin inhibitors are blunt tools for
testing the hypothesis in pressure-overload hypertrophy in vivo, because there
are so many confounding effects that are associated with systemic
administration of the drugs. As such, new genetic approaches may overcome some
of the problems associated with pharmacological inhibitors. This invited review
will focus on the controversies surrounding the ability of calcineurin
inhibition to prevent conventional (pressure-overload) cardiac hypertrophy and
the new genetic approaches to address the question. N. Ref:: 93
----------------------------------------------------
[76]
TÍTULO / TITLE: - Regulation of glycogen
synthesis in human muscle cells.
REVISTA
/ JOURNAL: - Biochem Soc Trans. Acceso gratuito al texto
completo a partir de 1 año de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://bst.portlandpress.com/bst//default.htm
●●
Cita: Biochemical Society Transactions: <> 2001 Aug;29(Pt 4):537-41.
AUTORES
/ AUTHORS: - Yeaman SJ; Armstrong JL; Bonavaud SM;
Poinasamy D; Pickersgill L; Halse R
INSTITUCIÓN
/ INSTITUTION: - School of Biochemistry and Genetics,
Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK. s.j.yeaman@ncl.ac.uk
RESUMEN
/ SUMMARY: - Glucose uptake into muscle and its
subsequent storage as glycogen is a crucial factor in energy homeostasis in
skeletal muscle. This process is stimulated acutely by insulin and is impaired
in both insulin-resistant states and in type 2 diabetes mellitus. A signalling
pathway involving protein kinase B and glycogen synthase kinase 3 seems certain
to have a key role in stimulating glycogen synthesis but other signalling
pathways also contribute, including a rapamycin-sensitive pathway stimulated by
amino acids. Although glycogen synthesis is one of the classical
insulin-regulated pathways, it is also regulated in an insulin-independent
manner; for example glycogen synthesis in muscle is stimulated significantly
after strenuous exercise, with much of this stimulation being independent of
the involvement of insulin. Evidence suggests that glucose and the glycogen
content of the muscle have a key role in this stimulation but the molecular
mechanism has yet to be fully explained.
N. Ref:: 24
----------------------------------------------------
[77]
TÍTULO / TITLE: - Immunophilins in
nervous system degeneration and regeneration.
REVISTA
/ JOURNAL: - Curr Top Med Chem 2003;3(12):1376-82.
AUTORES
/ AUTHORS: - Avramut M; Achim CL
INSTITUCIÓN
/ INSTITUTION: - Department of Pathology, School of
Medicine, University of Pittsburgh, S-433 Biomedical Science Tower, 200 Lothrop
Street, Pittsburgh, PA 15213, USA. avramut@pitt.edu
RESUMEN
/ SUMMARY: - Immunophilins are receptors for
immunosuppressive drugs like cyclosporin A, FK506, rapamycin and their non-
immunosuppressive analogs, which are collectively referred to as “immunophilin
ligands” (IPL). Cyclosporin A binds to a class of IP called cyclophilins,
whereas the receptors for FK506 and rapamycin belong to the family of FK506-
binding proteins (FKBP). The latter are designated according to their molecular
weight: FKBP12, 25, 52 etc. FKBP levels in the rat brain are up to 50 times
higher than in the immune system. FKBP12 is associated with IP3 and ryanodine
receptors present on the endoplasmic reticulum and plays a role in stabilizing
calcium release. It has also been proposed to be a modulator of the TGFbeta
receptor activity. Crush injury of facial or sciatic nerves in rat leads to
markedly increased FKBP12 levels in the respective nerve nuclei and this
increase is related to nerve regeneration. Cyclophilin A protects cells from
death following expression of mutant Cu/ Zn superoxide dismutase, which is
associated with familial amyotrophic lateral sclerosis. Our recent studies show
that FKBP12 and FKBP52 are expressed in the human nervous system, especially in
the substantia nigra- deep gray matter axis. In neurodegenerative diseases,
FKBP12 levels increase in neurons situated in areas of pathology. This IP
colocalizes with synaptophysin and alpha- synuclein, suggesting that it may
become a novel marker of pathology. Immunophilins participate in axonal
transport, synaptic vesicle assembly and may play a role in neuroprotection
against abnormal protein aggregation, suggesting a potential avenue of
therapeutic interventions. N.
Ref:: 62
----------------------------------------------------
[78]
TÍTULO / TITLE: - Treatment of atopic
dermatitis and impact on quality of life: a review with emphasis on topical
non-corticosteroids.
REVISTA
/ JOURNAL: - Pharmacoeconomics 2003;21(3):159-79.
AUTORES
/ AUTHORS: - Schiffner R; Schiffner-Rohe J; Landthaler
M; Stolz W
INSTITUCIÓN
/ INSTITUTION: - Department of Dermatology, University of
Regensburg, Regensburg, Germany. jr.schiffner@t-online.de
RESUMEN
/ SUMMARY: - Atopic dermatitis (AD) is a chronic skin
disease with increasing prevalence and rising costs. Stigmatisation and
pruritus are only some aspects of potential quality-of-life (QOL) impairments.
AD is not curable and repeated treatments are often necessary. At present,
treatment with topically-applied corticosteroids is state-of-the-art for mild
to moderate flare-ups. However, many patients are worried about the use of
corticosteroids due to the widespread fear of adverse effects. In this review
the present literature is analysed concerning impact on quality of life for
topically-applicable alternatives to the state-of-the-art treatment. For
comparison reasons, data from other treatment modalities are additionally
given. Characteristics of studies were analysed using ‘general’ (year and mode
of publication, type and aim of study, number of patients, and clinical
measurement) and ‘QOL specific’ criteria (type and number of QOL measurements
including relevance for study aim and age group, validation in used language,
sensitivity to change, and improvement at end of study). QOL data are published
only in the minority of studies evaluating treatment efficacy and do not cover
the variety of possible therapies. Data are available for tacrolimus,
pimecrolimus, UVA/UVB combination and UVB narrowband (topical
non-corticosteroidal treatments), as well as for topical corticosteroids,
cyclosporin, and inpatient treatment. All studies provided a marked improvement
in quality of life after therapy. One study assessed quality of life after a
treatment-free follow-up period obtaining a clear increase in impact on quality
of life. Since studies used different QOL measurements and vary in inclusion
criteria, treatment schedules and presentation of results, a comparison of QOL
improvement is not recommended. A single randomised study compared topically
applied non-corticosteroidal treatment (UVA/UVB combination) with another
treatment modality (cyclosporin) and found no difference in QOL improvement. At
present, there is a clear lack of controlled randomised studies evaluating
different active treatment modalities and their impact on quality of life.
Consensus meetings are desirable to formulate guidelines for the selection and
correct use of QOL measurements. Patients’ fear of side effects (e.g.
concerning corticosteroids) should be integrated in QOL questionnaires for
evaluation of possible compliance problems and real costs. Since relapse after
treatment is frequent in AD, QOL measurements should also be performed after a
treatment-free follow-up period. At present, we can not answer the question
‘which treatment best improves quality of life in AD?’. N. Ref:: 128
----------------------------------------------------
[79]
TÍTULO / TITLE: - St John’s Wort
supplements endanger the success of organ transplantation.
REVISTA
/ JOURNAL: - Arch Surg 2002 Mar;137(3):316-9.
AUTORES
/ AUTHORS: - Ernst E
INSTITUCIÓN
/ INSTITUTION: - Department of Complementary Medicine,
School of Sport and Health Sciences, University of Exeter, 25 Victoria Park Rd,
Exeter EX2 4NT, England. E.Ernst@ex.ac.uk
RESUMEN
/ SUMMARY: - HYPOTHESIS: St John’s wort is one of the
most popular herbal medicines, and health care professionals often are unaware
that their patients take such supplements. St John’s wort causes a decrease in
cyclosporine levels, thus endangering the success of organ transplantations.
DESIGN: Systematic review. METHODS: Five independent computerized literature
searches were conducted to identify all reports of such interactions. Data were
extracted and are summarized in narrative form. RESULTS: Eleven case reports
and 2 case series were located. In most instances, causality between St John’s
wort and the clinical or biochemical result is well established. The mechanism
of interaction between St John’s wort and cyclosporine has been recently
elucidated and involves both P-glycoprotein and cytochrome P 450 3A4
expression. Collectively these data leave little doubt that St John’s wort
interacts with cyclosporine, causing a decrease of cyclosporine blood levels
and leading in several cases to transplant rejection. CONCLUSIONS: St John’s
wort can endanger the success of organ transplantations. Adequate information
may be the best way to avoid future incidences. N. Ref:: 33
----------------------------------------------------
[80]
TÍTULO / TITLE: - Engineered CD3
antibodies for immunosuppression.
REVISTA
/ JOURNAL: - Clin Exp Immunol 2003 Sep;133(3):307-9.
AUTORES
/ AUTHORS: - Renders L; Valerius T N. Ref:: 30
----------------------------------------------------
[81]
TÍTULO / TITLE: - St John’s wort (Hypericum
perforatum): drug interactions and clinical outcomes.
REVISTA
/ JOURNAL: - Br J Clin Pharmacol 2002 Oct;54(4):349-56.
AUTORES
/ AUTHORS: - Henderson L; Yue QY; Bergquist C; Gerden
B; Arlett P
INSTITUCIÓN
/ INSTITUTION: - Pharmacovigilance Group, Medicines Control
Agency, UK. leigh.henderson@mca.gsi.gov.uk
RESUMEN
/ SUMMARY: - AIMS: The aim of this work is to identify
the medicines which interact with the herbal remedy St John’s wort (SJW), and
the mechanisms responsible. METHODS: A systematic review of all the available
evidence, including worldwide published literature and spontaneous case reports
provided by healthcare professionals and regulatory authorities within Europe
has been undertaken. RESULTS: A number of clinically significant interactions
have been identified with prescribed medicines including warfarin,
phenprocoumon, cyclosporin, HIV protease inhibitors, theophylline, digoxin and
oral contraceptives resulting in a decrease in concentration or effect of the
medicines. These interactions are probably due to the induction of cytochrome
P450 isoenzymes CYP3A4, CYP2C9, CYP1A2 and the transport protein P-glycoprotein
by constituent(s) in SJW. The degree of induction is unpredictable due to
factors such as the variable quality and quantity of constituent(s) in SJW
preparations. In addition, possible pharmacodynamic interactions with selective
serotonin re-uptake inhibitors and serotonin (5-HT(1d)) receptor-agonists such
as triptans used to treat migraine were identified. These interactions are
associated with an increased risk of adverse reactions. CONCLUSIONS: In Sweden
and the UK the potential risks to patients were judged to be significant and
therefore information about the interactions was provided to health care
professionals and patients. The product information of the licensed medicines
involved has been amended to reflect these newly identified interactions and
SJW preparations have been voluntarily labelled with appropriate warnings. N. Ref:: 44
----------------------------------------------------
[82]
TÍTULO / TITLE: - Calcineurin phosphatase
in signal transduction: lessons from fission yeast.
REVISTA
/ JOURNAL: - Genes Cells 2002 Jul;7(7):619-27.
AUTORES
/ AUTHORS: - Sugiura R; Sio SO; Shuntoh H; Kuno T
INSTITUCIÓN
/ INSTITUTION: - Division of Molecular Pharmacology and
Pharmacogenomics, Department of Genome Sciences, Kobe University Graduate
School of Medicine, Kobe 650-0017, Japan.
RESUMEN
/ SUMMARY: - Calcineurin (protein phosphatase 2B), the
only serine/threonine phosphatase under the control of Ca2+/calmodulin, is an
important mediator in signal transmission, connecting the Ca2+-dependent
signalling to a wide variety of cellular responses. Furthermore, calcineurin is
specifically inhibited by the immunosuppressant drugs cyclosporin A and
tacrolimus (FK506), and these drugs have been a powerful tool for identifying
many of the roles of calcineurin. Calcineurin is enriched in the neural
tissues, and also distributes broadly in other tissues. The structure of the
protein is highly conserved from yeast to man. The combined use of powerful
genetics and of specific calcineurin inhibitors in fission yeast
Schizosaccharomyces pombe (S. pombe) identified new components of the calcineurin
pathway, and defined new roles of calcineurin in the regulation of the many
cellular processes. Recent data has revealed functional interactions in which
calcineurin phosphatase is involved, such as the cross-talk between the Pmk1
MAP kinase signalling, or the PI signalling. Calcineurin also participates in
membrane traffic and cytokinesis of fission yeast through its functional
connection with members of the small GTPase Rab/Ypt family, and Type II myosin,
respectively. These findings highlight the potential of fission yeast genetic
studies to elucidate conserved elements of signal transduction cascades. N. Ref:: 51
----------------------------------------------------
[83]
TÍTULO / TITLE: - FTY720: targeting
G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and
autoimmunity.
REVISTA
/ JOURNAL: - Curr Opin Immunol 2002 Oct;14(5):569-75.
AUTORES
/ AUTHORS: - Brinkmann V; Lynch KR
INSTITUCIÓN
/ INSTITUTION: - Novartis Pharma AG Transplantation
Research WSJ-386.101, CH-4002 Basel, Switzerland. volker.brinkmann@pharma.novartis.com
RESUMEN
/ SUMMARY: - The novel immunomodulator FTY720 is
remarkably effective in models of transplantation and autoimmunity. Recent data
show that phosphorylated FTY720 is an agonist at four sphingosine 1-phosphate
receptors. Stimulation of sphingosine 1-phosphate receptors leads to
sequestration of lymphocytes in secondary lymphatic tissues and thus away from
inflammatory lesions and graft sites. N.
Ref:: 44
----------------------------------------------------
[84]
TÍTULO / TITLE: - The mucosa of the small
intestine: how clinically relevant as an organ of drug metabolism?
REVISTA
/ JOURNAL: - Clin Pharmacokinet 2002;41(4):235-53.
AUTORES
/ AUTHORS: - Doherty MM; Charman WN
INSTITUCIÓN
/ INSTITUTION: - Department of Pharmaceutics, Victorian
College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria
3052, Australia. margaret.doherty@vcp.monash.edu.au
RESUMEN
/ SUMMARY: - The intestinal mucosa is capable of
metabolising drugs via phase I and II reactions. Increasingly, as a result of
in vitro and in vivo (animal and human) data, the intestinal mucosa is being implicated
as a major metabolic organ for some drugs. This has been supported by clinical
studies of orally administered drugs (well-known examples include cyclosporin,
midazolam, nifedipine and tacrolimus) where intestinal drug metabolism has
significantly reduced oral bioavailability. This review discusses the
intestinal properties and processes that contribute to drug metabolism. An
understanding of the interplay between the processes controlling absorption,
metabolism and P-glycoprotein-mediated efflux from the intestinal mucosa into
the intestinal lumen facilitates determination of the extent of the intestinal
contribution to first-pass metabolism. The clinical relevance of intestinal
metabolism, however, depends on the relative importance of the metabolic
pathway involved, the therapeutic index of the drug and the inherent inter- and
intra-individual variability. This variability can stem from genetic
(metabolising enzyme polymorphisms) and/or non-genetic (including concomitant
drug and food intake, route of administration) sources. An overwhelming
proportion of clinically relevant drug interactions where the intestine has
been implicated as a major contributor to first-pass metabolism involve drugs
that undergo cytochrome P450 (CYP) 3A4-mediated biotransformation and are
substrates for the efflux transporter P-glycoprotein. Much work is yet to be
done in characterising the clinical impact of other enzyme systems on drug
therapy. In order to achieve this, the first-pass contributions of the
intestine and liver must be successfully decoupled. N. Ref:: 130
----------------------------------------------------
[85]
TÍTULO / TITLE: - Transplantation:
toxicokinetics and mechanisms of toxicity of cyclosporine and macrolides.
REVISTA
/ JOURNAL: - Curr Opin Investig Drugs 2003
Nov;4(11):1287-96.
AUTORES
/ AUTHORS: - Serkova N; Christians U
INSTITUCIÓN
/ INSTITUTION: - Department of Anesthesiology, Clinical
Research & Development, University of Colorado Health Sciences Center, 4200
East Ninth Ave, Room UH-2122, Campus Box B113, Denver, CO 80262, USA.
RESUMEN
/ SUMMARY: - For over two decades, calcineurin
inhibitors (CIs) have been the mainstay of immunosuppressive therapy following
solid-organ transplantation. However, CI nephrotoxicity is one of the main
contributors to chronic kidney allograft dysfunction. A novel class of
immunosuppressants that inhibit the kinase mammalian target of rapamycin
(mTOR), although not nephrotoxic themselves, enhance CI nephrotoxicity. The
biochemical basis of CI toxicity and their toxicodynamic interaction with mTOR
inhibitors is still poorly understood. Studies using a magnetic resonance
spectroscopy-based metabonomic approach indicate that CI toxicity is caused by
drug-induced mitochondrial dysfunction and that mTOR inhibitors enhance the
negative effects of CIs on cell energy metabolism. N. Ref:: 77
----------------------------------------------------
[86]
TÍTULO / TITLE: - Risk factors for and
management of post-transplantation cardiovascular disease.
REVISTA
/ JOURNAL: - BioDrugs 2001;15(4):261-78.
AUTORES
/ AUTHORS: - Fellstrom B
INSTITUCIÓN
/ INSTITUTION: - Department of Medical Sciences, University
Hospital, SE-751 85 Uppsala, Sweden. bengt.fellstrom@medsci.uu.se
RESUMEN
/ SUMMARY: - The mortality rates due to cardiovascular
disease (CVD) in transplant recipients are greater than in the general
population. CVD is a major cause of both graft loss and patient death in renal
transplant recipients, and improving cardiovascular health in transplant
recipients will presumably help to extend both patient and graft survival.
Further studies are needed to better evaluate the effectiveness of risk
modification on subsequent CVD morbidity and mortality. There is no reason to consider
risk factors for CVD such as hyperlipidaemia, hypertension and diabetes
mellitus in transplant recipients differently from in the general population.
In addition, there are specific transplantation risk factors such as acute
rejection episodes and the use of immunosuppressive drugs. It is obvious that
several of the immunosuppressive agents used today have disadvantageous
influences on risk factors for CVD such as hyperlipidaemia, hypertension and
post-transplantation diabetes mellitus (PTDM), but the relative importance of
immunosuppressant-induced increases in these risk factors is basically unknown.
This may be a strong argument for the selective use and individual tailoring of
immunosuppressive agents based upon the risk factor profile of the patient,
without jeopardising the function of the graft. Hyperlipidaemia is common after
transplantation, and immunosuppression with corticosteroids, cyclosporin, or
sirolimus (rapamycin) causes different types of post-transplantation
hyperlipidaemia. However, to date, no studies have demonstrated that lipid
lowering strategies significantly reduce CVD morbidity or mortality and improve
allograft survival in transplant recipients. Several studies using preventive
or interventional approaches are ongoing and will be reported in the near
future. Post-transplantation hypertension appears to be a major risk factor
determining graft and patient survival, and immunosuppressive agents have
different effects on hypertension. Controlled studies support the opinion that post-transplantation
hypertension must be treated as strictly as in a population with essential
hypertension, diabetes mellitus, or chronic renal failure. As increasing
numbers of immunosuppressive agents become available for use, we may be in a
better position to tailor immunosuppressive therapy to the individual patient,
avoiding the use of diabetogenic drugs, drug combinations, or inappropriate
doses in patients susceptible to PTDM. Multiple acute rejection episodes have
also been demonstrated to be a risk factor for CVD - a strong argument for the
use of immunosuppressive drugs to reduce acute rejection. Until we have a
better understanding from ongoing landmark studies on the management of CVD,
presently available therapy to reduce risk factors needs to be used together
with individual tailoring of immunosuppressive therapy with the aim of reducing
CVD in these patients. N.
Ref:: 138
----------------------------------------------------
[87]
TÍTULO / TITLE: - The role of
phosphatases in TOR signaling in yeast.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol 2004;279:19-38.
AUTORES
/ AUTHORS: - Duvel K; Broach JR
INSTITUCIÓN
/ INSTITUTION: - Department of Molecular Biology, Princeton
University, Princeton, NJ 08544, USA.
RESUMEN
/ SUMMARY: - The TOR pathway controls cellular
functions necessary for cell growth and proliferation of yeast and larger
eukaryotes. The search for members of the TOR signaling cascade in yeast led to
the discovery of type 2A protein phosphatases (PP2A) as important players within
the pathway. We describe the roles in yeast of PP2A and the closely related
phosphatase, Sit4, and then focus on complexes formed between the catalytic
subunit of these phosphatases and Tap42, a direct target of the Tor protein
kinases in yeast. Recent results suggest that Tap42 mediates many of the Tor
functions in yeast, especially those involved in transcriptional modulation.
However, whether Tap42 executes its function by inhibiting phosphatase activity
or by activating phosphatases is still uncertain. In addition, Tor affects some
transcriptional and physiological processes through Tap42 independent pathways.
Thus, Tor proteins use multiple mechanisms to regulate transcriptional and
physiological processes in yeast. N.
Ref:: 46
----------------------------------------------------
[88]
TÍTULO / TITLE: - Raptor and mTOR:
subunits of a nutrient-sensitive complex.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol
2004;279:259-70.
AUTORES
/ AUTHORS: - Kim DH; Sabatini DM
INSTITUCIÓN
/ INSTITUTION: - Whitehead Institute for Biomedical
Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
RESUMEN
/ SUMMARY: - mTOR/RAFT1/FRAP is the target of the
FKBP12-rapamycin complex as well as a central component of a nutrient- and
hormone-sensitive pathway that controls cellular growth. Recent work reveals
that mTOR interacts with a novel evolutionarily conserved protein that we named
raptor, for “regulatory associated protein of mTOR.” Raptor has several roles
in the mTOR pathway. It is necessary for nutrient-mediated activation of the
downstream effector S6K1 and increases in cell size. In addition, under
conditions that repress the mTOR pathway, the association of raptor with mTOR
is strengthened, leading to a decrease in mTOR kinase activity. Raptor is a critical
component of the mTOR pathway that regulates cell growth in response to
nutrient levels by associating with mTOR.
N. Ref:: 40
----------------------------------------------------
[89]
TÍTULO / TITLE: - A prospective study of
rapid corticosteroid elimination in simultaneous pancreas-kidney
transplantation: comparison of two maintenance immunosuppression protocols:
tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus.
REVISTA
/ JOURNAL: - Transplantation 2002 Jan 27;73(2):169-77.
AUTORES
/ AUTHORS: - Kaufman DB; Leventhal JR; Koffron AJ;
Gallon LG; Parker MA; Fryer JP; Abecassis MM; Stuart FP
INSTITUCIÓN
/ INSTITUTION: - Department of Surgery, Division of
Transplantation, Northwestern University Medical School, 675 N. St. Clair
Street, Galter Pavilion, Suite 17-200, Chicago, IL 60611, USA.
RESUMEN
/ SUMMARY: - BACKGROUND: We examined the feasibility of
rapid corticosteroid elimination in simultaneous pancreas kidney
transplantation. METHODS: Forty consecutive simultaneous pancreas-kidney (SPK)
transplant recipients were enrolled in a prospective study in which
antithymocyte globulin induction and 6 days of corticosteroids were
administered along with tacrolimus and MMF (n=20) or tacrolimus and sirolimus
(n=20). Mean+/-SD follow-up for recipients receiving tacrolimus/MMF and
tacrolimus/sirolimus were 12.7+/-3.9 and 13.4+/-2.9 months, respectively.
Patient and graft survival, and rejection rates were compared to an historical
control group (n=86; mean follow-up 41.5+/-15.4 months) of SPK recipients that
received induction and tacrolimus, MMF, and corticosteroids. RESULTS:
Demographic characteristics of recipient and donor variables were similar among
all groups. The 1-year actuarial patient, kidney, and pancreas survival rates
in the 40 SPK transplant recipients with rapid corticosteroid elimination were
100, 100, and 100%, respectively. In the historical control group the 1-year
actual patient, kidney, and pancreas survival rates were 96.5, 93.0, and 91.9%,
respectively. The 1-year rejection-free survival rate recipients in the rapid
steroid elimination group collectively was 97.5 vs 80.2% in the historical
control group (P=0.034). At 6 and 12 months posttransplant the serum creatinine
values remained stable in all groups. CONCLUSIONS: We conclude that chronic
corticosteroid exposure is not required in SPK transplant recipients receiving
antithymocyte globulin induction and maintenance immuno-suppression consisting
of either tacrolimus and mycophenolate mofetil or tacrolimus and sirolimus.
----------------------------------------------------
[90]
TÍTULO / TITLE: - The potential of
chitosan in ocular drug delivery.
REVISTA
/ JOURNAL: - J Pharm Pharmacol 2003 Nov;55(11):1451-63.
●●
Enlace al texto completo (gratuito o de pago) 1211/0022357022476
AUTORES
/ AUTHORS: - Alonso MJ; Sanchez A
INSTITUCIÓN
/ INSTITUTION: - Department of Pharmacy and Pharmaceutical
Technology, Faculty of Pharmacy, University of Santiago de Compostela, 15782
Santiago de Compostela, España. ffmjalon@usc.es
RESUMEN
/ SUMMARY: - This paper presents an overview of the
potential of chitosan-based systems for improving the retention and
biodistribution of drugs applied topically onto the eye. Besides its low
toxicity and good ocular tolerance, chitosan exhibits favourable biological
behaviour, such as bioadhesion- and permeability-enhancing properties, and also
interesting physico-chemical characteristics, which make it a unique material
for the design of ocular drug delivery vehicles. The review summarizes the
techniques for the production of chitosan gels, chitosan-coated colloidal
systems and chitosan nanoparticles, and describes their mechanism of action
upon contact with the ocular mucosa. The results reported until now have
provided evidence of the potential of chitosan gels for enhancing and
prolonging the retention of drugs on the eye surface. On the other hand,
chitosan-based colloidal systems were found to work as transmucosal drug
carriers, either facilitating the transport of drugs to the inner eye
(chitosan-coated colloidal systems containing indometacin) or their
accumulation into the corneal/conjunctival epithelia (chitosan nanoparticles
containing ciclosporin). Finally, the tolerance, toxicity and biodegradation of
the carriers under evaluation were reviewed.
N. Ref:: 75
----------------------------------------------------
[91]
TÍTULO / TITLE: - Rejection rate in
living donor kidney transplantation with and without basiliximab in
tacrolimus/mycophenolate mofetil-based protocol.
REVISTA
/ JOURNAL: - Transplant Proc 2003 Mar;35(2):653-4.
AUTORES
/ AUTHORS: - Rahamimov R; Yussim A; After T; Lustig S;
Bar-Nathan N; Shaharabani E; Shapira Z; Shabthai E; Mor E
INSTITUCIÓN
/ INSTITUTION: - Department of Transplantation, Rabin
Medical Center, Beilinson Campus, Petah-Tiqwa, Israel. rutir@clalit.org.il
----------------------------------------------------
[92]
TÍTULO / TITLE: - B19 virus infection in
renal transplant recipients.
REVISTA
/ JOURNAL: - J Clin Virol. Acceso gratuito al texto
completo.
●●
Enlace a la Editora de la Revista http://www.elsevier.com/gej-ng/29/46/32/show/Products/VIRUSINT/index.htt
●●
Cita: J Clinical Virology: <> 2003 Apr;26(3):361-8.
AUTORES
/ AUTHORS: - Cavallo R; Merlino C; Re D; Bollero C;
Bergallo M; Lembo D; Musso T; Leonardi G; Segoloni GP; Ponzi AN
INSTITUCIÓN
/ INSTITUTION: - Virology Unit, Department of Public Health
and Microbiology, University of Turin, Via Santena 9, 10126, Turin, Italy. rossana.cavallo@unito.it
RESUMEN
/ SUMMARY: - BACKGROUND: B19 virus infection with
persistent anaemia has been reported in organ transplant recipients. Detection
of B19 virus DNA in serum is the best direct marker of active infection.
OBJECTIVE: The present study evaluated the incidence and clinical role of
active B19 virus infection in renal transplant recipients presenting with
anaemia. STUDY DESIGN: Forty-eight such recipients were investigated by nested
PCR on serum samples. The controls were 21 recipients without anaemia. Active
HCMV infection was also investigated as a marker of high immunosuppression.
RESULTS AND CONCLUSIONS: In 11/48 (23%) patients B19 virus DNA was demonstrated
in serum versus only 1/21 (5%) of the controls. Ten of these 11 patients had
already been seropositive at transplantation and active infection occurred in
eight of them during the first 3 months after transplantation. The remaining
patient experienced a primary infection 9 months after transplantation. Eight
(73%) of these 11 patients displayed a concomitant HCMV infection and four
(36%) showed increasing serum creatinine levels but none developed
glomerulopathy; 3/11 (27%) recovered spontaneously from anaemia whereas 8/11
(73%) needed therapy. In conclusion, the relatively high occurrence (23%) of
B19 virus infection in patients presenting with anaemia, suggests that it
should be considered in the differential diagnosis of persistent anaemia in
renal transplant recipients. Presence of the viral DNA should be assessed early
from transplantation and the viral load should be monitored to follow
persistent infection and better understand the relation between active
infection and occurrence of anaemia, and to assess the efficacy of IVIG therapy
and/or immunosuppression reduction in clearing the virus. N. Ref:: 56
----------------------------------------------------
[93]
TÍTULO / TITLE: - A mitochondrial
perspective on cell death.
REVISTA
/ JOURNAL: - Trends Biochem Sci 2001 Feb;26(2):112-7.
AUTORES
/ AUTHORS: - Bernardi P; Petronilli V; Di Lisa F; Forte
M
INSTITUCIÓN
/ INSTITUTION: - Dept. of Biomedical Sciences, Viale
Giuseppe Colombo 3, I-35121, Padova, Italy. bernardi@civ.bio.unipd.it
RESUMEN
/ SUMMARY: - The role of mitochondria as crucial
participants in cell death programs is well established, yet the mechanisms
responsible for the release of mitochondrial activators and the role of BCL2
family proteins in this process remain controversial. Here, we point out the
limitations of current approaches used to monitor the physiological responses
of mitochondria during cell death, the implications arising from modern views
of mitochondrial structure, and briefly assess two proposed mechanisms for the
release of mitochondrial proteins during apoptosis. N. Ref:: 50
----------------------------------------------------
[94]
TÍTULO / TITLE: - Molecular diagnosis of
an Enterocytozoon bieneusi human genotype C infection in a moderately
immunosuppressed human immunodeficiency virus seronegative liver-transplant
recipient with severe chronic diarrhea.
REVISTA
/ JOURNAL: - J Clin Microbiol. Acceso gratuito al texto
completo a partir de los 6 meses de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://jcm.asm.org/
●●
Cita: J. Clinical Microbiology: <> 2001 Jun;39(6):2371-2.
AUTORES
/ AUTHORS: - Sing A; Tybus K; Heesemann J; Mathis
A N. Ref:: 5
----------------------------------------------------
[95]
TÍTULO / TITLE: - Eradication of
parvovirus B19 infection after renal transplantation requires reduction of
immunosuppression and high-dose immunoglobulin therapy.
REVISTA
/ JOURNAL: - Nephrol Dial Transplant. Acceso gratuito
al texto completo a partir de los 2 años de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://ndt.oupjournals.org/
●●
Cita: Nephrology Dialysis Transplantation: <> 2002 Oct;17(10):1840-2.
AUTORES
/ AUTHORS: - Liefeldt L; Buhl M; Schweickert B;
Engelmann E; Sezer O; Laschinski P; Preuschof L; Neumayer HH
INSTITUCIÓN
/ INSTITUTION: - Department of Nephrology, Charite,
Humboldt-University Berlin, Germany. lutz.liefeldt@charite.de N. Ref:: 17
----------------------------------------------------
[96]
- Castellano -
TÍTULO / TITLE:Presentacion de canceres en
receptores trasplantados con organo solido. Presentation of cancers in
recipients of a solid-organ transplant.
REVISTA
/ JOURNAL: - Nefrologia. Acceso gratuito al texto
completo.
●●
Enlace a la Editora de la Revista http://www.aulamedica.es/nefrologia/
●●
Cita: Nefrologia: <> 2001;21(6):528-37.
AUTORES
/ AUTHORS: - Lampreabe I; Gomez-Ullate P; Amenabar JJ;
Zarraga S; Gainza FJ; Urbizu JM
INSTITUCIÓN
/ INSTITUTION: - Servicio de Nefrologia, Hospital de
Cruces, Facultad de Medicina, Universidad del Pais Vasco. ilampreave@hcru.osakidetza.net N. Ref:: 35
----------------------------------------------------
[97]
TÍTULO / TITLE: - Limited dose monoclonal
IL-2R antibody induction protocol after primary kidney transplantation.
REVISTA
/ JOURNAL: - Am J Transplant 2002 Jul;2(6):568-73.
AUTORES
/ AUTHORS: - Ahsan N; Holman MJ; Jarowenko MV; Razzaque
MS; Yang HC
INSTITUCIÓN
/ INSTITUTION: - Nephrology and Transplant Division,
University of Medicine and Dentistry of New Jersey, New Brunswick 08904, USA. ahsanna@umdnj.edu
RESUMEN
/ SUMMARY: - This study prospectively compared
immunoprophylaxis with a single intraoperative dose (2 mg/kg) of monoclonal
interleukin-2 receptor (IL-2R) antibody vs. noninduction in kidney transplant
recipients treated with tacrolimus (FK 506), mycophenolate mofetil (MMF) and a
prednisone-based immunosuppression regimen. One hundred recipients of
first-kidney transplant were enrolled into the study to receive either
anti-IL-2R monoclonal antibody, daclizumab (2 mg/kg intraoperatively, limited
anti-IL-2R) or no induction (control). Each patient also received oral
tacrolimus (dosed to target trough level 10-15 ng/mL), MMF (500 mg bid) and
prednisone. The primary efficacy end-point was the incidence of biopsy proven
acute rejection during the first 6 months post-transplant. The patients were
also followed for 12-month graft function, and graft and patient survival
rates. Other than the donor’s age being significantly lower in the control
group, both groups were comparable with respect to age, weight, gender, race,
human leukocyte antigen (HLA)-DR mismatch, panel reactive antibody (%PRA), cold
ischemic time, cytomegalovirus (CMV) status, causes of renal failure, and
duration and modes of renal replacement therapy (RRT). During the first 6 months,
episodes of first biopsy confirmed acute rejection was 3/50 (6%) in the limited
anti-IL-2R group and 8/50 (16%) in the controls (p < 0.05). Twelve-month
patient 100/98 (%) and graft survival 100/96 (%) were not statistically
different. The group receiving limited anti-IL-2R did not have any adverse
reactions. Our study demonstrates that a limited (single) 2 mg/kg
immunoprophylaxis dose with monoclonal IL-2R antibody (daclizumab) when
combined with tacrolimus/MMF/steroid allows significant reduction in early
renal allograft rejection to the single digit level. The therapy with
anti-IL-2R antibody is simple and is well tolerated.
----------------------------------------------------
[98]
TÍTULO / TITLE: - The utility of
monoclonal antibody therapy in renal transplantation.
REVISTA
/ JOURNAL: - Transplant Proc 2002 May;34(3):797-800.
AUTORES
/ AUTHORS: - Loertscher R
INSTITUCIÓN
/ INSTITUTION: - Division of Transplantation, McGill
University Health Centre, Montreal, Quebec, Canada. rolf.loertscher@mcgill.ca N. Ref:: 37
----------------------------------------------------
[99]
TÍTULO / TITLE: - Low-intensity
hematopoietic stem-cell transplantation across human leucocyte antigen barriers
in dyskeratosis congenita.
REVISTA
/ JOURNAL: - Bone Marrow Transplant 2003
May;31(10):847-50.
●●
Enlace al texto completo (gratuito o de pago) 1038/sj.bmt.1703931
AUTORES
/ AUTHORS: - Dror Y; Freedman MH; Leaker M; Verbeek J;
Armstrong CA; Saunders FE; Doyle JJ
INSTITUCIÓN
/ INSTITUTION: - Marrow Failure and Myelodysplasia
Programme, Division of Haematology and Oncology, Department of Paediatrics, The
Hospital for Sick Children and the University of Toronto, Toronto, Ontario,
Canada.
RESUMEN
/ SUMMARY: - Since the results of conventional hematopoietic
stem-cell transplantation (HSCT) for patients with dyskeratosis congenita (DC)
are poor owing to the high incidence of transplant-related complications, we
explored the use of a low-intensity HSCT regimen. We report two children with
DC with severe cytopenia, who underwent successful HSCT from a matched
unrelated donor after conditioning with fludarabine, cyclophosphamide, and
antithymocyte globulin. Graft-versus-host-disease (GVHD) prophylaxis consisted
of corticosteroids and cyclosporin A. The regimen was well tolerated, no
significant transplant-related complications were observed, and engraftment was
rapid and complete. At 15 and 16 months after HSCT, the children were fully
engrafted, in excellent clinical condition, full-donor chimerism, and no signs
of GVHD. We conclude that a low-intensity regimen is sufficient to induce
durable engraftment using matched unrelated donor HSCT in DC patients, with
minimal 1-year transplant-related toxicity. Longer follow-up will determine
whether this regimen also reduces long-term toxicity. N. Ref:: 35
----------------------------------------------------
[100]
TÍTULO / TITLE: - Role of prostanoids and
endothelins in the prevention of cyclosporine-induced nephrotoxicity.
REVISTA
/ JOURNAL: - Prostaglandins Leukot Essent Fatty Acids
2001 Apr-May;64(4-5):231-9.
●●
Enlace al texto completo (gratuito o de pago) 1054/plef.2001.0265
AUTORES
/ AUTHORS: - Darlametsos IE; Varonos DD
INSTITUCIÓN
/ INSTITUTION: - Centre Franco-Hellenique de Recherches
Biomedicales, Nikolaos Papanikolaou, Corporation of the Municipality Agrinion,
Agrinion, 30100, Greece. darlamet@otenet.gr
RESUMEN
/ SUMMARY: - Cyclosporine A nephrotoxicity includes
both functional toxicity and histological changes, whose seriousness is
dependent upon the dose and the duration of the drug administration. Several
vasoactive agents have been found to be implicated in cyclosporine induced
nephrotoxicity, among which prostanoids and endothelins are the most important.
In previous studies we were able to prevent the early stage (7 days) of
cyclosporine (37.4 micromol [45 mg]/kg/day) induced nephrotoxicity in rats
either by the administration, i) of OKY-046, a thromboxane A(2)synthase
inhibitor, ii) of ketanserine, an antagonist of S(2)serotonergic,
a(1)adrenergic, and H(1)histaminergic receptors and iii) of nifedipine, a
calcium channel blocker, or by diet supplementation either with evening
primrose oil or fish oil. All these protective agents elevated ratios of
excreted renal prostanoid vasodilators (prostaglandins E(2), 6ketoF(1 alpha))
to vasoconstrictor (thromboxane B(2)), a ratio which was decreased by the
administration of cyclosporine alone. Nifedipine averted the cyclosporine
induced increase of urinary endothelin-1 release. All protections were
associated with the reinstatement of glomerular filtration rate forwards normal
levels whereas renal damage defence, consisting of a decrease of the cyclosporine
induced vacuolizations, was variable. Ketanserine and evening primrose oil were
the only agents which prevented the animal body weight loss. These data suggest
that prostanoids and endothelin-1 may mediate functional toxicity while
thromboxane A(2)is involved the morphological changes too, provoked in the
early stage of cyclosporine treatment. However, other nephrotoxic factors and
additional mechanisms could also be implicated in the cyclosporine induced
nephrotoxicity. N.
Ref:: 91
----------------------------------------------------
[101]
TÍTULO / TITLE: - Role of chiral
chromatography in therapeutic drug monitoring and in clinical and forensic
toxicology.
REVISTA
/ JOURNAL: - Ther Drug Monit 2002 Apr;24(2):290-6.
AUTORES
/ AUTHORS: - Williams ML; Wainer IW
INSTITUCIÓN
/ INSTITUTION: - Department of Oncology, Leicester
University, Leicester, United Kingdom.
RESUMEN
/ SUMMARY: - Advances in chiral chromatographic
separations have given pharmacologists and toxicologists the tools to examine
unexpected clinical results involving chiral drugs. The ability to unravel
complex phenomena associated with drug transport and drug metabolism is
presented in this manuscript. The relation between the chirality of the drug
mefloquine and the intracellular concentrations of the drug cyclosporine is
illustrated by examining the effect of the enantiomers of mefloquine on the
transport activity of P-glycoprotein (Pgp). These studies were conducted using
a liquid chromatographic column containing immobilized Pgp. The results
demonstrated that (+)-mefloquine competitively displaced the Pgp substrate
cyclosporine whereas (-)-mefloquine had no effect on cyclosporine-Pgp binding.
The data suggest that cyclosporine cellular and CNS concentrations can be
increased through the concomitant administration of (+)-mefloquine. The use of
chirality in clinical and forensic situations is also illustrated by the
metabolism of the enantiomers of ketamine (KET). The plasma concentrations of
(+)-KET and (-)-KET and the norketamine metabolites (+)-NK and (-)-NK were
measured in rat plasma using enantioselective gas chromatography. The
separations were accomplished using a gas chromatography chiral stationary
phase based on beta-cyclodextrin. The pharmacokinetic profiles of (+)-, (-)-KET
and (+)-, (-)-NK were determined in control and protein-calorie malnourished
(PCM) rats to determine the effect of PCM on ketamine metabolism and clearance.
The results indicate that PCM produced a significant and stereoselective
decrease in KET and NK metabolism. The data suggest that the effects of
environmental factors (smoking, alcohol use, diet) and drug interactions
(coadministered agents) can be measured using the changes in stereochemical
metabolic and pharmacokinetic patterns of KET and similar drugs. N. Ref:: 33
----------------------------------------------------
[102]
TÍTULO / TITLE: - Molecular actions of
sirolimus: sirolimus and mTor.
REVISTA
/ JOURNAL: - Transplant Proc 2003 May;35(3
Suppl):227S-230S.
AUTORES
/ AUTHORS: - Kirken RA; Wang YL
INSTITUCIÓN
/ INSTITUTION: - Department of Integrative Biology and
Pharmacology, The University of Texas Health Science Center at Houston,
Houston, Texas 77030, USA. robert.a.kirken@uth.tmc.edu
RESUMEN
/ SUMMARY: - Recent therapeutic strategies to combat
organ allograft rejection have focused on T-cell signaling pathways and the
molecules that comprise them. The macrolide antibiotic produced by the
bacterium Streptomyces hygroscopicus, known as sirolimus or rapamycin, has
shown great therapeutic potential in the transplant setting. Sirolimus alone or
in combination with other immunosuppressive agents can block acute rejection,
chronic graft destruction, and promote permanent allograft acceptance. Sirolimus
targets a unique serine-threonine kinase, mammalian target of rapamycin (mTor),
which plays a key role in mitogenic and nutritional cells signals. Within T
cells, mTor regulates a number of proteins likely dependent on T cell growth
factors such as interleukin 2. This review is focused on the molecular
mechanisms by which mTor may regulate T-cell signaling cascades and affect
T-cell responsiveness, and how sirolimus likely uncouples this activity. N. Ref:: 32
----------------------------------------------------
[103]
TÍTULO / TITLE: - The treatment of atopic
dermatitis with systemic immunosuppressive agents.
REVISTA
/ JOURNAL: - Clin Dermatol 2003 May-Jun;21(3):225-40.
AUTORES
/ AUTHORS: - Akhavan A; Rudikoff D
INSTITUCIÓN
/ INSTITUTION: - Department of Dermatology, Mount Sinai
School of Medicine, New York, New York 10029, USA. N. Ref:: 165
----------------------------------------------------
[104]
TÍTULO / TITLE: - Retroviral oncogenes
and TOR.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol 2004;279:321-38.
AUTORES
/ AUTHORS: - Aoki M; Vogt PK
INSTITUCIÓN
/ INSTITUTION: - Department of Molecular and Experimental
Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road,
BCC-239, La Jolla, CA 92037, USA.
RESUMEN
/ SUMMARY: - Retroviruses have recruited the catalytic
subunit of PI 3-kinase and its downstream target, Akt, as oncogenes. These
viruses cause tumors in animals and induce oncogenic transformation in cell
culture. The oncogenicity of these viruses is specifically inhibited by
rapamycin; retroviruses carrying other oncogenes are insensitive to this
macrolide antibiotic. Rapamycin is an inhibitor of the TOR (target of
rapamycin) kinase whose downstream targets include p70 S6 kinase and the
negative regulator of translation initiation 4E-BP. Emerging evidence suggests
that the TOR signals transmitted to the translational machinery are essential
for oncogenic transformation by the PI 3-kinase pathway. N. Ref:: 93
----------------------------------------------------
[105]
TÍTULO / TITLE: - Regulation of MAPK
signaling pathways through immunophilin-ligand complex.
REVISTA
/ JOURNAL: - Curr Top Med Chem 2003;3(12):1358-67.
AUTORES
/ AUTHORS: - Matsuda S; Koyasu S
INSTITUCIÓN
/ INSTITUTION: - Department of Microbiology and Immunology,
Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo
160-8582, Japan.
RESUMEN
/ SUMMARY: - It is well established that the
immunosuppressive effects of cyclosporin A (CsA) and FK506 (also known as
tacrolimus) are mediated through binding to their cognate cellular proteins
cyclophilin and FKBP (collectively termed immunophilins), respectively.
Biochemical analysis had revealed that cyclophilin-CsA and FKBP-FK506 complexes
bind to and inactivate Ca(2+)-dependent serine/threonine phosphatase
calcineurin. Since calcineurin regulates nuclear translocation and subsequent
activation of nuclear factor of activated T cells (NFAT) transcription factors
that is one of essential steps for cytokine gene expression in activated T
cells, it is believed that inhibition of calcineurin is a molecular basis of
the immunosuppressive properties of CsA and FK506. However, recent studies
indicate that both CsA and FK506 can block activation of JNK and p38 signaling
pathways during T cell activation. CsA and FK506, thus, have two distinct
mechanisms of action; one is the inhibition of the protein phosphatase activity
of calcineurin, leading to the blockade of the nuclear translocation of NFAT
transcription factors, and the other is the suppression of JNK and p38
activation pathways. It is likely that the presence of two distinct targets in
T cell activation makes CsA and FK506 highly potent immunosuppressive drugs.
Here we discuss the action of immunophilin-ligand complexes on JNK and p38
activation pathways. We also argue the possibility of immunotherapeutic
application targeting at JNK and p38 signaling pathways. N. Ref:: 121
----------------------------------------------------
[106]
TÍTULO / TITLE: - Cytokine and
immunosuppressive therapies of type 1 diabetes mellitus.
REVISTA
/ JOURNAL: - Endocrinol Metab Clin North Am 2002
Jun;31(2):477-95.
AUTORES
/ AUTHORS: - Gottlieb PA; Hayward AR
INSTITUCIÓN
/ INSTITUTION: - Barbara Davis Center for Childhood
Diabetes, Department of Pediatrics, University of Colorado Health Sciences
Center, Box B140, 4200 East 9th Ave., Denver, CO 80262, USA.
RESUMEN
/ SUMMARY: - In this article, the authors covered a
number of issues that affect how researchers approach prevention of diabetes.
The focus has been the use of cytokines and immunosuppressive therapies. The
historical understanding of cytokine and immunosuppressive approaches, new
developments in using these agents in humans, and the issues involved in
designing diabetes prevention trials were reviewed. Although progress at times
appears slow, the current research activities predict new developments in the
next few years that may improve the understanding of the progression of
diabetes and possible ways to intervene.
N. Ref:: 79
----------------------------------------------------
[107]
TÍTULO / TITLE: - Regulation of
endothelial-type NO synthase expression in pathophysiology and in response to
drugs.
REVISTA
/ JOURNAL: - Nitric Oxide 2002 Nov;7(3):149-64.
AUTORES
/ AUTHORS: - Li H; Wallerath T; Munzel T; Forstermann U
INSTITUCIÓN
/ INSTITUTION: - Department of Pharmacology, Johannes
Gutenberg University, Obere Zahlbacher Strasse 67, D-55101, Mainz, Germany.
RESUMEN
/ SUMMARY: - In many types of cardiovascular
pathophysiology such as hypercholesterolemia and atherosclerosis, diabetes,
cigarette smoking, or hypertension (with its sequelae stroke and heart failure)
the expression of endothelial NO synthase (eNOS) is altered. Both up- and
downregulation of eNOS have been observed, depending on the underlying disease.
When eNOS is upregulated, the upregulation is often futile and goes along with
a reduction in bioactive NO. This is due to an increased production of
superoxide generated by NAD(P)H oxidase and by an uncoupled eNOS. A number of
drugs with favorable effects on cardiovascular disease upregulate eNOS
expression. The resulting increase in vascular NO production may contribute to
their beneficial effects. These compounds include statins,
angiotensin-converting enzyme inhibitors, AT1 receptor antagonists, calcium
channel blockers, and some antioxidants. Other drugs such as glucocorticoids,
whose administration is associated with cardiovascular side effects,
downregulate eNOS expression. Stills others such as the immunosuppressants
cyclosporine A and FK506/tacrolimus or erythropoietin have inconsistent effects
on eNOS. Thus regulation of eNOS expression and activity contributes to the
overall action of several classes of drugs, and the development of compounds
that specifically upregulate this protective enzyme appears as a desirable
target for drug development. N.
Ref:: 201
----------------------------------------------------
[108]
TÍTULO / TITLE: - What’s in the pipeline?
New immunosuppressive drugs in transplantation.
REVISTA
/ JOURNAL: - Am J Transplant 2002 Nov;2(10):898-903.
AUTORES
/ AUTHORS: - Vincenti F
INSTITUCIÓN
/ INSTITUTION: - University of California, San Francisco,
Kidney Transplant Service, 505 Parnassus Avenue, Room 884M, San Francisco, CA
94143-0116, USA. vincentif@surgery.ucsf.edu
RESUMEN
/ SUMMARY: - In the pipeline, there are a number of
novel immunosuppressive drugs in preclinical development or in early clinical
trials. The major target of new agents are cell-surface molecules important in
immune cell interactions (especially the costimulatory pathway), signaling
pathways that activate T cells, T-cell proliferation and trafficking and
recruitment of immune cells responsible for rejection. The most promising
biologic agents include a humanized anti-CD11a (anti-LFA1), humanized
anti-B7.1/B7.2, a second-generation CTLA4Ig (LEA29Y) and a humanized antibody
to anti-CD45 RB. Inhibitors of T-cell activation and signaling are still in
preclinical development. The most interesting inhibitors of T-cell
proliferation include inhibitors of the Janus protein tyrosine kinase, JAK3,
and FK778, a leflunomide analog. Chemokines play an important role in rejection
by virtue of their critical role as regulator of trafficking and activation of
lymphocytes. Early trials of FTY720, a synthetic small molecule with functional
homology to sphingosine-1 phosphate leading to lymphocyte sequestration, appear
very promising; however, enthusiasm for this drug is mitigated by its potential
cardiac side-effects. Antagonists to several chemokine receptors, including
CCR1, CXCR3 and CCR5, have been shown to be effective in experimental
transplantation and are likely to be considered for clinical development. N. Ref:: 46
----------------------------------------------------
[109]
TÍTULO / TITLE: - Current and potential
agents for the treatment of alopecia areata.
REVISTA
/ JOURNAL: - Curr Pharm Des 2001 Feb;7(3):213-30.
AUTORES
/ AUTHORS: - Freyschmidt-Paul P; Hoffmann R; Levine E;
Sundberg JP; Happle R; McElwee KJ
INSTITUCIÓN
/ INSTITUTION: - Department of Dermatology, Philipp
University, Marburg, Germany. freyschm@mailer.uni-marburg.de
RESUMEN
/ SUMMARY: - Alopecia areata is considered to be a
T-cell mediated autoimmune disease of the hair follicle. Current
immunosuppressive approaches and immunomodulatory treatment with contact
sensitizers such as diphenylcyclopropenone and squaric acid dibutylester are
dealt with in this review article. The efficacy of the various modes of
treatment is evaluated by a review of literature and their mode of action is
discussed. In accordance with the mechanism of autoimmune pathogenesis of AA,
improved future treatments may be immunosuppressive or immunomodulatory, or
they should otherwise protect the hair follicle from the injurious effects of
the inflammation. Such possible future therapeutic approaches include the use
of liposomes as an improved vehicle, application of immunosuppressive cytokines
like TGF-beta and IL-10, inhibition of apoptosis mediated by the Fas-FasL
system, inhibition of the lymphocyte homing receptor CD44v10, induction of
tolerance as well as principles of gene therapy. N. Ref:: 141
----------------------------------------------------
[110]
TÍTULO / TITLE: - Tolerance to islet
autoantigens in type 1 diabetes.
REVISTA
/ JOURNAL: - Annu Rev Immunol 2001;19:131-61.
●●
Enlace al texto completo (gratuito o de pago) 1146/annurev.immunol.19.1.131
AUTORES
/ AUTHORS: - Bach JF; Chatenoud L
INSTITUCIÓN
/ INSTITUTION: - INSERM U 25, Hopital Necker, 161 rue de
Sevres, Paris Cedex 15, 75743 France. bach@necker.fr
RESUMEN
/ SUMMARY: - Tolerance to beta cell autoantigens
represents a fragile equilibrium. Autoreactive T cells specific to these
autoantigens are present in most normal individuals but are kept under control
by a number of peripheral tolerance mechanisms, among which CD4(+) CD25(+)
CD62L(+) T cell-mediated regulation probably plays a central role. The
equilibrium may be disrupted by inappropriate activation of
autoantigen-specific T cells, notably following to local inflammation that
enhances the expression of the various molecules contributing to antigen
recognition by T cells. Even when T cell activation finally overrides
regulation, stimulation of regulatory cells by CD3 antibodies may reset the
control of autoimmunity. Other procedures may also lead to disease prevention.
These procedures are essentially focused on Th2 cytokines, whether used
systemically or produced by Th2 cells after specific stimulation by
autoantigens. Protection can also be obtained by NK T cell stimulation.
Administration of beta cell antigens or CD3 antibodies is now being tested in
clinical trials in prediabetics and/or recently diagnosed diabetes. N. Ref:: 153
----------------------------------------------------
[111]
TÍTULO / TITLE: - The role of newer
monoclonal antibodies in renal transplantation.
REVISTA
/ JOURNAL: - Transplant Proc 2001
Feb-Mar;33(1-2):1000-1.
AUTORES
/ AUTHORS: - Vincenti F
INSTITUCIÓN
/ INSTITUTION: - University of California, San Francisco,
California, USA. N.
Ref:: 5
----------------------------------------------------
[112]
TÍTULO / TITLE: - Advances in the
management of psoriasis: monoclonal antibody therapies.
REVISTA
/ JOURNAL: - Int J Dermatol 2002 Dec;41(12):827-35.
AUTORES
/ AUTHORS: - Mehrabi D; DiCarlo JB; Soon SL; McCall CO
INSTITUCIÓN
/ INSTITUTION: - Department of Dermatology, Emory
University School of Medicine, Atlanta, GA 30322, USA.
RESUMEN
/ SUMMARY: - Psoriasis is a common skin disorder
characterized by erythematous, scaling plaques. Until recently, therapies for
this disease have been aimed at reducing keratinocyte proliferation. We have
learned that psoriasis is not primarily a disorder of keratinocyte
hyperproliferation, but is an inflammatory disease. This knowledge, especially
our current understanding of the role of activated T cells in psoriasis, has
led to new therapeutic options and new areas of research. Immunosuppressive
agents such as cyclosporine have proven very useful in the treatment of
psoriasis, but their use is limited by toxicity. Monoclonal antibodies directed
against key components of the inflammatory process have been studied in an
attempt to produce safer, more selective immunosuppressive agents. This review
summarizes much of the available literature describing the use of monoclonal
antibodies in the treatment of psoriasis.
N. Ref:: 59
----------------------------------------------------
[113]
TÍTULO / TITLE: - Molecular mechanisms of
renal allograft fibrosis.
REVISTA
/ JOURNAL: - Br J Surg 2001 Nov;88(11):1429-41.
●●
Enlace al texto completo (gratuito o de pago) 1046/j.0007-1323.2001.01867.x
AUTORES
/ AUTHORS: - Waller JR; Nicholson ML
INSTITUCIÓN
/ INSTITUTION: - Division of Transplant Surgery, University
of Leicester, Leicester, UK. julian@waller79.fsnet.co.uk
RESUMEN
/ SUMMARY: - BACKGROUND: Chronic graft nephropathy
(CGN) remains the leading cause of renal allograft loss after the first year
following transplantation. Histologically it is characterized by
glomerulosclerosis, intimal hyperplasia and interstitial fibrosis. The
pathogenesis is unclear, but is likely to involve both immunological and
non-immunological factors. Despite improvements in short-term graft survival
rates, new immunosuppressive regimens have made no impact on CGN. METHODS: A
review of the current literature on renal transplantation, novel
immunosuppression regimens and advances in the molecular pathogenesis of renal
allograft fibrosis was performed. RESULTS AND CONCLUSION: Recent advances in
understanding of the underlying molecular mechanisms involved suggest autocrine
secretion of cytokines and growth factors, especially transforming growth
factor beta, are associated with a change in fibroblast phenotype leading to
the deposition of extracellular matrix. Repeated insults trigger upregulation
of the tissue inhibitors of matrix metalloproteinases, favouring accumulation
of extracellular matrix. To date, no drug has proved effective in inhibiting or
reducing allograft fibrosis. The deleterious consequences of chronic
immunosuppression on the development of such fibrosis are now recognized; newer
immunosuppressive drugs, including rapamycin and mycophenolate mofetil, reduce
profibrotic gene expression in both experimental and clinical settings, and
offer potential strategies for prolonging allograft survival. N. Ref:: 155
----------------------------------------------------
[114]
TÍTULO / TITLE: - Daclizumab: a review of
its use in the management of organ transplantation.
REVISTA
/ JOURNAL: - BioDrugs 2001;15(11):745-73.
AUTORES
/ AUTHORS: - Carswell CI; Plosker GL; Wagstaff AJ
INSTITUCIÓN
/ INSTITUTION: - Adis International Limited, Auckland, New
Zealand. demail@adis.co.nz
RESUMEN
/ SUMMARY: - The humanised monoclonal antibody
daclizumab is an immunosuppressive agent that reduces acute rejection in solid
organ transplantation. It is specific for the alpha subunit (Tac/CD25) of the
interleukin (IL)-2 receptor on activated T cells and achieves immunosuppression
by competitive antagonism of IL-2-induced T cell proliferation. When added to
standard triple immunosuppression regimens, daclizumab significantly reduces
the rate of acute rejection at 1 year in renal transplantation by 36% and there
are indications that it may be effective in other solid organ transplantations.
Three-year outcomes of two phase III clinical trials in renal transplantation
indicate similar values for graft and patient survival between daclizumab and
placebo when given in addition to triple immunosuppression; however, these
pivotal trials were not designed with sufficient power to demonstrate any
statistical significance. The addition of daclizumab induction shows potential
in allowing calcineurin inhibitor- and corticosteroid-sparing regimens without
increasing the rate of acute graft rejection or adverse effects in renal and
liver transplantation. Preliminary reports indicate that daclizumab may also be
a useful agent in delayed graft function and graft versus host disease (GVHD).
Further investigation of its efficacy in these groups and in children is
needed. Data from clinical trials show daclizumab to be well tolerated in solid
organ transplantation. It does not increase the incidence of infection,
including cytomegalovirus infection, when compared with placebo or no induction
groups. Preliminary comparative data with muromonab CD3 indicate that
daclizumab may be associated with a lower rate of infectious complications and
similar or better efficacy. CONCLUSIONS: In conclusion, daclizumab has been
proven to reduce acute rejection in renal transplant recipients when given in
addition to traditional baseline immunosuppression. It has shown potential to
reduce acute rejection in other solid organ transplants; however, well
designed, randomised studies are required to confirm this. Clinical experience
from trials to date indicate that daclizumab has a tolerability profile similar
to placebo with no significant effect on the incidence of infection. The
relative efficacy and tolerability of daclizumab compared with other induction
agents has yet to be defined. Available data suggest that daclizumab may allow
the use of calcineurin inhibitor-sparing and corticosteroid-sparing regimens
and may have potential in the treatment of GVHD. N. Ref:: 80
----------------------------------------------------
[115]
TÍTULO / TITLE: - Neuroimmunophilin
ligands: the development of novel neuroregenerative/ neuroprotective compounds.
REVISTA
/ JOURNAL: - Curr Top Med Chem 2003;3(12):1368-75.
AUTORES
/ AUTHORS: - Gold BG; Villafranca JE
INSTITUCIÓN
/ INSTITUTION: - Center for Research on Occupational and
Environmental Toxicology, Developmental Biology, Oregon Health & Science
University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201-3098, USA. gold@ohsu.edu
RESUMEN
/ SUMMARY: - FK506 (tacrolimus), initially developed as
an immunosuppressant drug, represents a class of compounds with potential high
impact for the treatment of human neurological disorders. While immunosuppression
is mediated by the 12-kD FK506-binding-protein (FKBP-12), the neurite
elongation activity of FK506 involves FKBP-52 (also known as FKBP-59 or
Hsp-56), a component of mature steroid receptor complexes: FKBP-52 binds to
Hsp-90, which bind to p23 and the steroid receptor protein to form the complex.
The brief review focuses on how three classes of compounds (FK506 derivatives,
steroid hormones, and ansamycin anti-cancer drugs, e.g., geldanamycin) increase
neurite elongation/nerve regeneration (axonal elongation). A model is presented
whereby neurite elongation is elicited by compounds that bind to steroid
receptor chaperone proteins (e.g., FKBP-52 and Hsp-90) and thereby disrupt
mature steroid receptor complexes (comprising FKBP-52, Hsp-90 and p23 in addition
to the steroid receptor binding protein). Disruption of the complex leads to a
“gain-of-function” whereby one or more of these steroid receptor chaperone
proteins (i.e, FKBP-52, Hsp-90 or p23) activates mitogen-associated protein
(MAP) kinase/extracellular signal-regulated kinase (ERK) pathway. Thus, the
neurotrophic actions of these distinct classes of compounds can be understood
from their ability to bind steroid receptor chaperones, thereby providing a
unique receptor-mediated means to activate the ERK pathway. These studies
thereby shed new light on the intrinsic mechanism regulating axonal elongation.
Furthermore, this mechanism may also underlie calcineurin-independent
neuroprotective actions of FK506. We suggest that components of steroid receptor
complexes are novel targets for the design of neuroregenerative/neuroprotective
drugs. N. Ref:: 98
----------------------------------------------------
[116]
TÍTULO / TITLE: - Sequential protocol
biopsies from renal transplant recipients show an increasing expression of
active TGF beta.
REVISTA
/ JOURNAL: - Transpl Int 2002 Dec;15(12):630-4. Epub
2002 Oct 19.
●●
Enlace al texto completo (gratuito o de pago) 1007/s00147-002-0472-3
AUTORES
/ AUTHORS: - Jain S; Mohamed MA; Sandford R; Furness
PN; Nicholson ML; Talbot D
INSTITUCIÓN
/ INSTITUTION: - University Department of Surgery,
Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK. sj34@le.ac.uk
RESUMEN
/ SUMMARY: - Chronic allograft nephropathy (CAN) is a
major cause of graft loss after renal transplantation. Implicated in the
pathogenesis of this complication is overproduction of the cytokine
transforming growth factor beta (TGF beta). In this study we measured changes
in CAN’s expression in stable patients early after transplantation, and studied
links with established risk factors for CAN, such as delayed graft function,
acute rejection, and cyclosporine exposure. We took biopsies from 40 renal
allografts at time of transplantation (pre-perfusion), and then, using
ultrasound guidance, at 1 week and 6 months after transplantation. An
immunofluorescence technique was used to stain sections for active TGF beta.
These were then assessed by semi-quantitative scanning laser confocal
microscopy. There was very little variation in active TGF-beta expression among
patients in their pre-perfusion biopsies. Expression had increased by 1 week
and then very significantly by 6 months ( P<0.0001). Patients who suffered
delayed graft function had increased TGF-beta expression at both time points.
There was no difference regarding donor type, acute rejection, and
immunosuppressive drug (cyclosporine or tacrolimus). There was no correlation
between the amount of TGF-beta expression at any time-point and isotope
glomerular filtration rate (GFR) at 12 months. This study demonstrated that in
a group of stable renal allograft recipients, TGF-beta expression in the kidney
increased after transplantation. As the study used protocol biopsies, this
increase is unlikely to be due to acute events, and probably represents a genuine
increase.
----------------------------------------------------
[117]
TÍTULO / TITLE: - The macrolide
immunosuppressants in dermatology: mechanisms of action.
REVISTA
/ JOURNAL: - Eur J Dermatol 2002 Nov-Dec;12(6):618-22.
AUTORES
/ AUTHORS: - Marsland AM; Griffiths CE
INSTITUCIÓN
/ INSTITUTION: - Dermatology Centre, University of
Manchester School of Medicine, Hope Hospital, United Kingdom. sacha.marsland@virgin.net
RESUMEN
/ SUMMARY: - Macrolides are xenobiotics, produced by
soil fungi, which have immunosuppressant properties. They will probably
revolutionise the treatment of inflammatory dermatoses. This article outlines
the context and putative mechanisms of action of this novel class of drugs. Cyclosporin,
and the structurally distinct macrolides tacrolimus and pimecrolimus (an
ascomycin derivative), modulate immune-cell function by inhibiting
calcineurin-dependent dephosphorylation-activation of specific nuclear factors,
thus preventing transcription of pro-inflammatory cytokines. The macrolide
rapamycin (sirolimus) acts by abrogating Target of Rapamycin, a key signalling
protein that controls activation of a number of proteins which direct
progression of the cell cycle in response to pro-inflammatory cytokines.
Tacrolimus and pimecrolimus are small enough molecules to penetrate skin and
are available in topical formulations. “Skin-specific” pimecrolimus seems not
to cause systemic immunosuppression when given orally. Neither topical
tacrolimus nor pimecrolimus are capable of producing skin atrophy. Sirolimus
has anti-angiogenic properties that may be beneficial to the treatment of
psoriasis and perhaps skin cancer. N.
Ref:: 27
----------------------------------------------------
[118]
TÍTULO / TITLE: - Pharmacokinetic aspects
of treating infections in the intensive care unit: focus on drug interactions.
REVISTA
/ JOURNAL: - Clin Pharmacokinet 2001;40(11):833-68.
AUTORES
/ AUTHORS: - Pea F; Furlanut M
INSTITUCIÓN
/ INSTITUTION: - Institute of Clinical Pharmacology and
Toxicology, Department of Experimental and Clinical Pathology and Medicine,
Medical School, University of Udine, Italy. federico.pea@med.uniud.it
RESUMEN
/ SUMMARY: - Pharmacokinetic interactions involving
anti-infective drugs may be important in the intensive care unit (ICU).
Although some interactions involve absorption or distribution, the most
clinically relevant interactions during anti-infective treatment involve the
elimination phase. Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the
major isoforms responsible for oxidative metabolism of drugs. Macrolides
(especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones
(especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole
antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole
and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism
and may therefore be responsible for toxicity of other coadministered drugs by
decreasing their clearance. On the other hand, rifampicin is a nonspecific
inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4)
and may therefore cause therapeutic failure of other coadministered drugs by
increasing their clearance. Drugs frequently used in the ICU that are at risk
of clinically relevant pharrmacokinetic interactions with anti-infective agents
include some benzodiazepines (especially midazolam and triazolam),
immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents
(theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin,
carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and
anticoagulants (warfarin). Some lipophilic anti-infective agents inhibit
(clarithromycin, itraconazole) or induce (rifampicin) the transmembrane
transporter P-glycoprotein, which promotes excretion from renal tubular and
intestinal cells. This results in a decrease or increase, respectively, in the
clearance of P-glycoprotein substrates at the renal level and an increase or
decrease, respectively, of their oral bioavailability at the intestinal level.
Hydrophilic anti-infective agents are often eliminated unchanged by renal
glomerular filtration and tubular secretion, and are therefore involved in
competition for excretion. Beta-lactams are known to compete with other drugs
for renal tubular secretion mediated by the organic anion transport system, but
this is frequently not of major concern, given their wide therapeutic index.
However, there is a risk of nephrotoxicity and neurotoxicity with some
cephalosporins and carbapenems. Therapeutic failure with these hydrophilic
compounds may be due to haemodynamically active coadministered drugs, such as
dopamine, dobutamine and furosemide, which increase their renal clearance by
means of enhanced cardiac output and/or renal blood flow. Therefore,
coadministration of some drugs should be avoided, or at least careful
therapeutic drug monitoring should be performed when available. Monitoring may
be especially helpful when there is some coexisting pathophysiological
condition affecting drug disposition, for example malabsorption or marked
instability of the systemic circulation or of renal or hepatic function. N. Ref:: 397
----------------------------------------------------
[119]
TÍTULO / TITLE: - Plant growth and the
TOR pathway.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol
2004;279:97-113.
AUTORES
/ AUTHORS: - Menand B; Meyer C; Robaglia C
INSTITUCIÓN
/ INSTITUTION: - CEA Cadarache DSV DEVM, Laboratoire du
Metabolisme Carbone, UMR 163 CNRS CEA, Univ-Mediterranee UMR 163,
Saint-Paul-lez-Durance, France.
RESUMEN
/ SUMMARY: - In mammalian, insect, and yeast cells, TOR
proteins are essential regulators of cell growth in response to environmental
signals including nutrients, mitogens, and stresses. Although many aspects of
the TOR-dependent signalling pathway are conserved between animals and fungi,
important differences have also been found and are likely to be related to the
ecophysiological adaptations of these organisms. The TOR protein also exists in
plants. This review will first discuss specific aspects of plants concerning
the contribution of cell growth to overall growth, as well as their responses
to nutrient starvation, with emphasis on recent results obtained through
genetic analysis in the model plant Arabidopsis thaliana. This is followed by
the current status of the genetic analysis of the TOR gene in this plant and
the search for potential members of a TOR pathway in the Arabidopsis
genome. N. Ref:: 51
----------------------------------------------------
[120]
TÍTULO / TITLE: - Cyclophilin D as a drug
target.
REVISTA
/ JOURNAL: - Curr Med Chem 2003 Aug;10(16):1485-506.
AUTORES
/ AUTHORS: - Waldmeier PC; Zimmermann K; Qian T;
Tintelnot-Blomley M; Lemasters JJ
INSTITUCIÓN
/ INSTITUTION: - Nervous System Research, Novartis Pharma
Ltd., CH-4002 Basel, Switzerland. peter.waldmeier@pharma.novartis.com
RESUMEN
/ SUMMARY: - The mitochondrial permeability transition
(MPT) plays an important role in damage-induced cell death, and agents
inhibiting the MPT may have a therapeutic potential for treating human
conditions such as ischemia/reperfusion injury, trauma, and neurodegenerative
diseases. The mitochondrial matrix protein, cyclophilin D (CYP D), a member of
a family of highly homologous peptidylprolyl cis-trans isomerases (PPIases),
plays a decisive role in MPT, being an integral constituent of the MPT pore.
Other putative MPT pore proteins include the adenine nucleotide translocator
(ANT) and the voltage-dependent anion channel (VDAC). In an alternative model,
the MPT pore is formed by clusters of misfolded membrane proteins outlining
aqueous channels that are regulated by CYP D and other chaperone-like proteins.
Like cyclophilin A (CYP A) and other cyclophilin family members, CYP D is
targeted by the immunosuppressant cyclosporin A (CsA). CsA is cytoprotective in
many cellular and animal models, but protection may result from either
inhibition of the MPT through an interaction with CYP D or inhibition of
calcineurin-mediated dephosphorylation of BAD through an interaction with CYP
A. The relevance of MPT inhibition by CsA for its cytoprotective effects is
well documented in many cellular models. Mechanisms of action in vivo are more
difficult to define, and accordingly the evidence is as yet less compelling in
in vivo animal models of ischemia/reperfusion injury, trauma and
neurodegenerative diseases. Notwithstanding, CYP D is a drug target of high
interest. Structural considerations suggest feasibility of designing CYP D
ligands without immunosuppressant properties. This is highly desirable, since
they have the potential of being useful therapeutic agents in a variety of
disease states. It might be a tougher challenge to obtain compounds specific
for CYP D vs. other cyclophilins, and/or of small molecular weight, allowing
brain penetration to make them suitable for treating neurodegenerative
diseases. N. Ref:: 204
----------------------------------------------------
[121]
TÍTULO / TITLE: - T-cell depleting
antibodies: new hope for induction of allograft tolerance in bone marrow
transplantation?
REVISTA
/ JOURNAL: - BioDrugs 2003;17(3):147-54.
AUTORES
/ AUTHORS: - Simpson D
INSTITUCIÓN
/ INSTITUTION: - North Shore Hospital, PB 93-503, Takapuna,
Auckland 1309, New Zealand. david.simpson@whl.co.nz
RESUMEN
/ SUMMARY: - Graft versus host disease (GVHD) remains
the main barrier to successful allogeneic bone marrow transplant outcomes.
Depletion of graft T cells is an effective way of reducing the incidence of
acute and chronic GVHD, and a variety of methods have been used to achieve this
depletion. Donor CD8+ T cells seem to be the critical effector cells; GVHD is
reduced when the depletion process eliminates these cells, but not when CD4
cells are targeted alone. However, despite the successful reduction in GVHD,
transplant outcomes are usually inferior with T-cell depleted transplants,
because of increased graft failure, infections and relapse. Alternative
approaches are needed. In vivo T-cell depletion, using antithymocyte globulin
(ATG) as part of the conditioning regimen, seems an attractive option.
Pre-transplant ATG lingers in the bone marrow to deplete engrafting donor T
cells, but also depletes host T cells to prevent graft rejection and allow
de-escalation of the conditioning regimen. It also avoids the need for graft
manipulation with its associated costs, need for expertise and CD34+ cell loss.
The efficacy of pre-transplant horse ATG remains anecdotal but it has been
reported to modestly lower GVHD in single arm studies. Rabbit ATG has been
studied in prospective randomised trials. There is evidence of a dose-response
effect in reducing GVHD; however, there was no improvement in outcome, because
of increased mortality associated with infection. In contrast, pre-transplant
alemtuzumab (campath-1H) or an earlier version of this molecule (campath-1G),
which target CD52+ cells, do appear to be effective in reducing both acute and
chronic GVHD. There is speculation that this is not solely due to the effect of
campath on T cells but that it may also be due to the elimination of host
antigen-presenting cells (APC), which seem to be important in GVHD
pathogenesis. Host APC are more efficient at expressing endogenous and
exogenous host antigens on class I MHC to donor CD8+ cells than donor APC,
which need to cross-prime exogenous antigen. Campath-1G eliminates host dendritic
cells by the time of graft infusion, supporting this as a possible mechanism of
action. Pre-transplant alemtuzumab has not yet been studied in a prospective
randomised study, and this is required to quantify any benefit on outcome;
despite this, published studies do show cause for optimism. N. Ref:: 42
----------------------------------------------------
[122]
TÍTULO / TITLE: - Subcutaneous infection
with Mycobacterium fortuitum after allogeneic bone marrow transplantation.
REVISTA
/ JOURNAL: - Bone Marrow Transplant 2001
Oct;28(7):709-11.
●●
Enlace al texto completo (gratuito o de pago) 1038/sj/bmt/1703211
AUTORES
/ AUTHORS: - Okano A; Shimazaki C; Ochiai N; Hatsuse M;
Takahashi R; Ashihara E; Inaba T; Fujita N; Noda Y; Nakagawa M
INSTITUCIÓN
/ INSTITUTION: - Second Department of Medicine, Kyoto
Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kami-gyoku,
Kyoto, 602-8566, Japan.
RESUMEN
/ SUMMARY: - Reports of cases of mycobacterial
infections after SCT are rare. We report a 30-year-old female with a cutaneous
infection of Mycobacterium fortuitum 30 months after allogeneic bone marrow
transplantation for acute lymphoblastic leukemia. The patient was successfully
treated with surgical debridement followed by oral minocycline and
clarithromycin. Mycobacterial infections should be considered in SCT patients
with undiagnosed refractory chronic cutaneous infection, and surgical
debridement is useful for the diagnosis and treatment of such infections. N. Ref:: 7
----------------------------------------------------
[123]
TÍTULO / TITLE: - mTOR signaling to
translation.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol
2004;279:169-97.
AUTORES
/ AUTHORS: - Gingras AC; Raught B; Sonenberg N
INSTITUCIÓN
/ INSTITUTION: - Department of Biochemistry, McGill Cancer
Centre, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec,
H3G 1Y6, Canada.
RESUMEN
/ SUMMARY: - Over the past few years, the target of
rapamycin (TOR) pathway has been implicated in the control of translation, both
in yeast and in higher eukaryotes. In this review, we provide an overview of
translation in eukaryotes, and discuss the mechanisms and advantages of the
regulation of translation. We then describe how the TOR pathway can modulate
translation in yeast and in mammals, through the modulation of the
phosphorylation of key translation components, and the regulation of the
abundance of ribosomes and translation factors. N. Ref:: 117
----------------------------------------------------
[124]
TÍTULO / TITLE: - The involvement of
mammalian and plant FK506-binding proteins (FKBPs) in development.
REVISTA
/ JOURNAL: - Transgenic Res 2002 Aug;11(4):321-35.
AUTORES
/ AUTHORS: - Breiman A; Camus I
INSTITUCIÓN
/ INSTITUTION: - Department of Plant Science, Tel Aviv
University, Israel. adina@post.tau.ac.il
RESUMEN
/ SUMMARY: - The FK506-binding proteins (FKBPs) are
peptidyl prolyl cis/trans isomerases and the information gathered in the last
10 years reveals their involvement in diverse biological systems affecting the
function and structure of target proteins. Members of the FKBP family were
shown to be growth-regulated and participate in signal transduction. In this
review we have chosen to focus on a few examples of the mammalian and plant
systems in which members of the FKBP family have been demonstrated to affect
the function of proteins or development. The technologies that enable
production of knockout mice, Arabidopsis mutants and overexpression in transgenic
organisms have revealed the contribution of FKBP to development in higher
eukaryotes. It appears that members of the FKBP family have conserved some of
their basic functions in the animal and plant kingdom, whereas other functions
became unique. Studies that will take advantage of the full genome sequence
available for Arabidopsis and the human genome, DNA chip technologies and the
use of transgenic complementation system will contribute to the elucidation of
the molecular mechanism and biological function of FKBPs. N. Ref:: 120
----------------------------------------------------
[125]
TÍTULO / TITLE: - Treatment with
immunotoxin.
REVISTA
/ JOURNAL: - Philos Trans R Soc Lond B Biol Sci. Acceso
gratuito al texto completo a partir de los 2 años de la fecha de publicación.
●●
Enlace a la Editora de la Revista http://www.pubs.royalsoc.ac.uk/
●●
Cita: Philos Trans R Soc Lond B Biol Sci: <> 2001 May 29;356(1409):681-9.
AUTORES
/ AUTHORS: - Knechtle SJ
INSTITUCIÓN
/ INSTITUTION: - Department of Surgery, Division of Organ
Transplantation, 600 Highland Avenue, University of Wisconsin Medical School,
Madison,WI 53792-7375, USA. stuart@tx.surgery.wisc.edu
RESUMEN
/ SUMMARY: - T-cell depletion prior to or beginning at
the time of transplantation has been shown to be a valuable adjunct to the
induction of immunological unresponsiveness. Both total lymphoid irradiation
and anti-lymphocyte globulin have been used for this purpose in experimental
models of transplantation as well as in human organ transplant recipients.
However, these methods of T-cell depletion are limited in their ability to
deplete T cells selectively due to non-specific targeting and limited efficacy.
A new anti-CD3 immunotoxin has been developed with a far more potent ability to
deplete T cells selectively as measured by flow cytometry analysis of
peripheral blood T lymphocytes as well as lymph node lymphocytes. This
immunotoxin is well tolerated by rhesus monkeys when administered in vivo. When
administered as a single immunosuppressive agent pretransplant, it
substantially promotes allograft survival, inducing tolerance in at least
one-third of recipients as measured by subsequent acceptance of donor skin
grafts and rejection of third-party skin grafts. When administered on the day
of transplant in combination with steroid pretreatment and a brief course of
deoxyspergualin or mycophenolate mofetil (4 to 14 days), long-term
unresponsiveness is also produced and in a more reliable manner than using
immunotoxin alone. A new immunotoxin directed at the human CD3epsilon has been
developed with excellent potency in T-cell killing and lacking the Fc portion
of the CD3 antibody. This construct may be useful for T-cell depletion in
humans and has a potential application in tolerance induction in human organ
transplantation. Lessons learned from anti-CD3 immunotoxin in the non-human
primate model to date include (i) profound (2-3 log) depletion of T-cells can
be accomplished safely without inducing lymphoma or infection, (ii) such
depletion is a useful adjunct for tolerance induction to allogeneic organ
transplants, and (iii) tolerance to both allogeneic renal transplants and
xenogeneic islet transplants has been accomplished using such strategies to
date in non-human primates and in pigs. Immunotoxin may be useful for the
induction of chimerism using strategies that include donor bone marrow
infusion. Successful strategies for tolerance induction have also been
developed using immunotoxin without the adjunct of donor bone marrow or stem
cell infusion. Clinical application of immunotoxin will use a newly engineered
construct with the potential for causing cytokine release, less susceptibility
to neutralization by anti-diphtheria antibody and not dependent on chemical
conjugation of an antibody and toxin. The usefulness of immunotoxin is directly
related to its tremendous potency for depleting T cells. Based on results in
nonhuman primates, it is anticipated that it will become a useful agent in
tolerance induction in humans. N.
Ref:: 63
----------------------------------------------------
[126]
TÍTULO / TITLE: - Insights into
pharmacogenomics and its impact upon immunosuppressive therapy.
REVISTA
/ JOURNAL: - Transpl Immunol 2002 May;9(2-4):203-9.
AUTORES
/ AUTHORS: - Yagil Y; Yagil C
INSTITUCIÓN
/ INSTITUTION: - Department of Nephrology and Hypertension,
Faculty of Health Sciences, Ben-Gurion University, Barzilai Medical Center,
Ashkelon, Israel. labmomed@bgumail.bgu.ac.il
RESUMEN
/ SUMMARY: - The advent of the genomic era has brought
about several new fields of study, one of them being pharmacogenomics, which
seeks to link drug treatment (pharmaco-) with the individual’s genetic make-up
(genomics). Pharmacogenomics holds many promises for improved treatment of a
large variety of medical conditions, including immunosuppression for organ
transplantation and autoimmune disease. Many of these promises have, however,
not yet been fulfilled. In this brief overview of the subject, we attempt to
provide insights into the evolving field of pharmacogenomics and discuss some
of its potential benefits and promises, technological tools used by
pharmacogenomics, the reasons for delays in breakthroughs in the field, and the
relevance of pharmacogenornics to immunosuppression. N. Ref:: 65
----------------------------------------------------
[127]
TÍTULO / TITLE: - Clinically significant
drug interactions with agents specific for migraine attacks.
REVISTA
/ JOURNAL: - CNS Drugs 2001;15(2):105-18.
AUTORES
/ AUTHORS: - Eadie MJ
INSTITUCIÓN
/ INSTITUTION: - Department of Medicine, University of
Queensland, Royal Brisbane Hospital, Australia. M.Eadie@mailbox.uq.edu.au
RESUMEN
/ SUMMARY: - The drugs which provide specific relief
from migraine attacks, the ergopeptides (ergotamine and dihydroergotamine) and
the various ‘triptans’ (notably sumatriptan), are often prescribed for persons
already taking various migraine preventative agents, and sometimes drugs for
other indications. As a result, migraine-specific drugs may become involved in
drug-drug interactions. The migraine-specific drugs all act as agonists at
certain subclasses of serotonin (5-hydroxytryptamine; 5-HT) receptor,
particularly those of the 5-HT1D subtype, and produce vasoconstriction through
these receptor-mediated mechanisms. The oral bioavailabilities of these drugs,
particularly those of the ergopeptides, are often incomplete, due to extensive
presystemic metabolism. As a result, if migraine-specific agents are
coadministered with drugs with vasoconstrictive properties, or with drugs which
inhibit the metabolism of the migraine-specific agents, there is a risk of
interactions occurring which produce manifestations of excessive
vasoconstriction. This can also occur through pharmacodynamic mechanisms, as
when ergopeptides or triptans are coadministered with methysergide or
propranolol (although a pharmacokinetic element may apply in relation to the
latter interaction), or if one migraine-specific agent is used shortly after
another. When ergopeptide metabolism is inhibited by the presence of macrolide
antibacterials, particularly troleandomycin and erythromycin, the resultant
interaction can produce ergotism, sometimes leading to gangrene. Similar
pharmacokinetic mechanisms, with their vasoconstrictive consequences, probably
apply to combination of the ergopeptides with HIV protease inhibitors
(indinavir and ritonavir), heparin, cyclosporin or tacrolimus. Inhibition of
triptan metabolism by monoamine oxidase A inhibitors, e.g. moclobemide, may
raise circulating triptan concentrations, although this does not yet seem to
have led to reported clinical problems. Caffeine may cause increased plasma
ergotamine concentrations through an as yet inadequately defined
pharmacokinetic interaction. However, a direct antimigraine effect of caffeine
may contribute to the claimed increased efficacy of ergotamine-caffeine combinations
in relieving migraine attacks. Serotonin syndromes have been reported as
probable pharmacodynamic consequences of the use of ergots or triptans in
persons taking serotonin reuptake inhibitors. There have been two reports of
involuntary movement disorders when sumatriptan has been used by patients
already taking loxapine. Nearly all the clinically important interactions
between the ergopeptide antimigraine agents and currently marketed drugs are
likely to have already come to notice. In contrast, new interactions involving
the triptans are likely to be recognised as additional members of this family
of drugs, with their different patterns of metabolism and pharmacokinetics, are
marketed. N. Ref:: 101
----------------------------------------------------
[128]
TÍTULO / TITLE: - Methods and assays to
investigate nuclear export.
REVISTA
/ JOURNAL: - Curr Top Microbiol Immunol
2001;259:119-28.
AUTORES
/ AUTHORS: - Stauber RH
INSTITUCIÓN
/ INSTITUTION: - Institute for Clinical and Molecular
Virology, University of Erlangen-Nurnberg, Schlossgarten 4, 91054 Erlangen,
Germany. N. Ref:: 34
----------------------------------------------------
[129]
TÍTULO / TITLE: - Structures of
immunophilins and their ligand complexes.
REVISTA
/ JOURNAL: - Curr Top Med Chem 2003;3(12):1392-409.
AUTORES
/ AUTHORS: - Dornan J; Taylor P; Walkinshaw MD
INSTITUCIÓN
/ INSTITUTION: - Structural Biochemistry, The University of
Edinburgh, Michael Swann Building, King’s Buildings, Edinburgh EH9 3JR,
Scotland, UK. M.WALKINSHAW@ed.ac.uk
RESUMEN
/ SUMMARY: - This review includes an analysis of
available X-ray and NMR structures of both members of the immunophilin family;
cyclophilins and the FK-506 binding proteins (FKBPs). Available structures are
compared and contrasted to highlight different structural features seen both
within and between species. Each immunophilin family has been structurally
characterised with a variety of small molecule ligands, principally
immunosuppressive drugs and their analogues and an overview of these complexes
is also presented. Currently the Protein Data Base contains over 60 entries for
cyclophilins and over 40 entries for FKBPs. A number of FKBP related structures
are also available including structures of MIP (Macrophage Infectivity
Potentiator protein) from Legionella pneumophila and Trypanosoma cruzi and
Trigger Factor from Mycoplasma genitalium. For all structures discussed in the
review a summary of the available biological data is also presented. N. Ref:: 106
----------------------------------------------------
[130]
TÍTULO / TITLE: - Novel therapies for
anti-neutrophil cytoplasmic antibody-associated vasculitis.
REVISTA
/ JOURNAL: - Curr Opin Nephrol Hypertens 2001
Mar;10(2):211-7.
AUTORES
/ AUTHORS: - Tervaert JW; Stegeman CA; Kallenberg CG
INSTITUCIÓN
/ INSTITUTION: - University Hospital Maastricht, Department
of Clinical and Experimental Immunology, Maastricht, the Netherlands. jw.cohentervaert@immuno.unimaas.nl
RESUMEN
/ SUMMARY: - High-dose corticosteroids in combination
with cytotoxic drugs are universally accepted as the initial approach in
vasculitides that are associated with anti-neutrophil cytoplasmic antibodies.
Cyclophosphamide is the most effective cytotoxic drug and is used in more
severe cases. Because cyclophosphamide has more severe short- and long-term
side-effects than methotrexate, methotrexate is used in less severe cases. New
prospects for the treatment of vasculitis include novel immunosuppressive
agents (e.g. mycophenolate, 15-deoxyspergualin, and leflunomide), sequential
chemotherapy (e.g. cyclophosphamide followed by azathioprine or
cyclophosphamide followed by methotrexate), intravenous immunoglobulin, tumour
necrosis factor-alpha directed therapy, anti-lymphocyte directed therapy (e.g.
antithymocyte globulin or anti CD52/anti CD4 antibodies), anti-adhesion
molecule directed therapy (e.g. anti-CD18 or intercellular adhesion molecule-1
antisense) or immunoablation using high-dose cytotoxic medication with or
without stem cell rescue. N.
Ref:: 60
----------------------------------------------------
[131]
TÍTULO / TITLE: - Role of
anti-interleukin-2 receptor antibodies in kidney transplantation.
REVISTA
/ JOURNAL: - BioDrugs 2001;15(10):655-66.
AUTORES
/ AUTHORS: - Cibrik DM; Kaplan B; Meier-Kriesche HU
INSTITUCIÓN
/ INSTITUTION: - University of Michigan, Ann Arbor,
Michigan 48109-0704, USA. dcibrik@umich.edu
RESUMEN
/ SUMMARY: - From the early 1960s, the mainstay of
immunosuppression for kidney transplantation has been corticosteroids. Since
then, many new drugs have been developed to maintain the renal allograft.
Current maintenance immunosuppression commonly consists of corticosteroids,
antiproliferative agents and calcineurin inhibitors (e.g. cyclosporin). More
recently, antihuman antibodies, either monoclonal or polyclonal, have been
developed to use for induction at the time of transplantation or to treat
rejection. With the advances in molecular technology, a new class of antihuman
antibodies [the anti-interleukin-2 receptor (IL-2R) antibodies] has emerged
that incorporate a murine antigen-binding site on to a human immunoglobulin
backbone. Such methodology creates antihuman antibodies with high affinity for
the epitope and with prolonged serum antibody half-lives. Interleukin-2 and its
receptor are central to lymphocyte activation and are the main targets of
calcineurin inhibitors. In addition, the anti-IL-2R antibodies inhibit a key
target in immune activation. Daclizumab and basiliximab have been shown to
significantly reduce the incidence of acute rejection in kidney
transplantation. Since these anti-IL-2R antibodies are well tolerated and since
calcineurin inhibitors are intrinsically nephrotoxic, anti-IL-2R antibodies
have been used in an attempt to avoid cyclosporin after transplantation. Data
from clinical trials seem to indicate that the addition of an anti-IL-2R
antibody is not sufficient to warrant complete withdrawal of calcineurin
inhibitors for more than a very short period after transplantation. A more
promising role for anti-IL-2R antibodies may be in renal transplant recipients
with delayed graft function (DGF). Recent data on the use of either low-dose
calcineurin inhibitors or sirolimus (rapamycin) in conjunction with the
anti-IL-2R antibodies for patients with DGF showed no increased risk of acute
rejection. Long-term graft survival with use of these low-dose calcineurin
inhibitor protocols has yet to be established.
N. Ref:: 41
----------------------------------------------------
[132]
TÍTULO / TITLE: - Chromomycosis due to
Exophiala jeanselmei in a renal transplant recipient.
REVISTA
/ JOURNAL: - Eur J Dermatol 2003 May-Jun;13(3):305-7.
AUTORES
/ AUTHORS: - Pena-Penabad C; Duran MT; Yebra MT;
Rodriguez-Lozano J; Vieira V; Fonseca E
INSTITUCIÓN
/ INSTITUTION: - Department of Dermatology, Complejo
Hospitalario Juan Canalejo, Servicio de Dermatologia, Xubias de Arriba, 84,
15006. a Coruna, España.
RESUMEN
/ SUMMARY: - Chromomycosis is a rare mycotic infection
that is more frequent in tropical and subtropical regions. Dematiaceous fungi
are the causal agents of this mycosis. Several cases of chromomycosis in organ
transplant recipients have been reported. We present a case of chromomycosis by
Exophiala jeanselmei in a Spanish male who had received a renal transplant
several months previously, and was receiving treatment with tacrolimus,
prednisone and mycophenolate mofetil. Very few cases of chromomycosis due to
Exophiala have been reported, and this is, to our knowledge, the first European
case. N. Ref:: 16
----------------------------------------------------
[133]
TÍTULO / TITLE: - Transcriptional
reprogramming during T helper cell differentiation.
REVISTA
/ JOURNAL: - Immunol Res 2001;23(2-3):193-204.
AUTORES
/ AUTHORS: - Aune TM
INSTITUCIÓN
/ INSTITUTION: - Department of Medicine, Vanderbilt
University School of Medicine, Nashville, TN 37232, USA. thomas.aune@mcmail.vanderbilt.edu
RESUMEN
/ SUMMARY: - Our laboratory employs reporter transgenic
mice as model systems to study the transcriptional reprogramming that
accompanies T helper cell differentiation. These studies demonstrate that
changes in the activity of simple transcriptional elements associated with the
IFN-gamma gene can recapitulate alterations in gene expression. In addition,
our studies have revealed a key role for the transcription factor, CAMP
response element binding protein (CREB), in the protection of differentiating T
cells from apoptosis. Together, these findings further our understanding of the
logic employed by T cells to alter gene expression profiles in response to
differentiation signals. N.
Ref:: 49
----------------------------------------------------
[134]
TÍTULO / TITLE: - Good fungi gone bad:
the corruption of calcineurin.
REVISTA
/ JOURNAL: - Bioessays 2002 Oct;24(10):894-903.
●●
Enlace al texto completo (gratuito o de pago) 1002/bies.10157
AUTORES
/ AUTHORS: - Fox DS; Heitman J
INSTITUCIÓN
/ INSTITUTION: - Department of Molecular Genetics and
Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
RESUMEN
/ SUMMARY: - Calcineurin is a
Ca(2+)/calmodulin-activated protein phosphatase that is conserved in
eukaryotes, from yeast to humans, and is the conserved target of the
immunosuppressive drugs cyclosporin A (CsA) and FK506. Genetic studies in yeast
and fungi established the molecular basis of calcineurin inhibition by the
cyclophilin A-CsA and FKBP12-FK506 complexes. Calcineurin also functions in
fungi to control a myriad of physiological processes including cell cycle
progression, cation homeostasis, and morphogenesis. Recent investigations into
the molecular mechanisms of pathogenesis in Candida albicans and Cryptococcus
neoformans, two fungi that cause life-threatening infections in humans, have
revealed an essential role for calcineurin in morphogenesis, virulence, and
antifungal drug action. Novel non-immunosuppressive analogs of the calcineurin
inhibitors CsA and FK506 that retain antifungal activity have been identified
and hold promise as candidate antifungal drugs. In addition, comparisons of
calcineurin function in both fungi and humans may identify fungal-specific
components of calcineurin-signaling pathways that could be targeted for
therapy, as well as conserved elements of calcium signaling events. N. Ref:: 88
----------------------------------------------------
[135]
TÍTULO / TITLE: - The limitations of
calcineurin and mTOR inhibitors: new directions for immunosuppressive
strategies.
REVISTA
/ JOURNAL: - Transplant Proc 2002 Feb;34(1):130-3.
AUTORES
/ AUTHORS: - Kahan BD
INSTITUCIÓN
/ INSTITUTION: - Division of Organ Transplantation,
Department of Surgery, The University of Texas Medical School, Houston, Texas
77030, USA. N. Ref:: 76
----------------------------------------------------
[136]
TÍTULO / TITLE: - Acquired anti-FVIII
inhibitors in children.
REVISTA
/ JOURNAL: - Haemophilia 2002 Jan;8(1):28-32.
AUTORES
/ AUTHORS: - Moraca RJ; Ragni MV
INSTITUCIÓN
/ INSTITUTION: - The Department of Medicine, Division of
Hematology/Oncology, University of Pittsburgh Medical Center, PA, USA.
RESUMEN
/ SUMMARY: - Acquired inhibitors to FVIII (anti-FVIII)
are uncommon in children. An acquired anti-FVIII developed in a previously
healthy 4-year-old boy treated with penicillin for streptococcal pharyngitis.
Aspirin prophylaxis begun for suspected rheumatic fever led to compartment
syndromes of all four extremities, which resolved with high-dose FVIII and
surgical decompression. Anti-FVIII in this patient, and the five additional
cases identified in a survey of 160 haemophilia treatment centres, occurred at
a median age of 8 years, with median initial and peak titres of 4.6 and 6.9
Bethesda Units (BU), respectively. All six presented with bleeding, including
haematomas (three intramuscular, one intracranial), and ecchymoses in three.
The median baseline FVIII was 0.05 U mL(-1), and the median baseline activated
partial thromboplastin time (APTT) was 79.8 s. The inhibitor resolved
completely in five patients (83%) within a median 5 months, after treatment with
FVIII concentrate, steroids, cytoxan, methotrexate, and no treatment. The
inhibitor persisted in the patient with Goodpasture’s disease, despite
steroids, cytoxan, cyclosporin, and intravenous gamma globulin. Aspirin
therapy, in two, worsened ongoing bleeding. The association of penicillin-like
drugs in this and three other cases in the literature suggest that to avoid
potential catastrophic bleeding, it is prudent to obtain an APTT prior to
initiating aspirin for suspected rheumatic fever. In conclusion, acquired
anti-FVIII inhibitors in children may cause severe bleeding, and remit in the
majority after FVIII and/or immunosuppressive therapy. N. Ref:: 21
----------------------------------------------------
[137]
TÍTULO / TITLE: - Safety of the new macrolide
immunomodulators.
REVISTA
/ JOURNAL: - Semin Cutan Med Surg 2001 Dec;20(4):242-9.
AUTORES
/ AUTHORS: - Robinson N; Singri P; Gordon KB
INSTITUCIÓN
/ INSTITUTION: - Department of Dermatology, Northwestern
University, Chicago, IL 60611, USA.
RESUMEN
/ SUMMARY: - With the wide acceptance of cyclosporine
in the treatment of skin disease, there has been an effort to find new
immunomodulating agents with superior safety profiles for use in dermatology.
Among the most promising of the classes are the new macrolide immunomodulators,
including tacrolimus and pimecrolimus. Of these, only tocrolimus has had
widespread use for nondermatologic indications, primarily solid organ
transplantation. Both of these agents have been studied for inflammatory diseases
of the skin. In this article, we review the systemic and topical toxicities of
these macrolide immunomodulators. N.
Ref:: 68
----------------------------------------------------
[138]
TÍTULO / TITLE: - Signalling pathways in
cardiac myocyte hypertrophy.
REVISTA
/ JOURNAL: - Ann Med 2001 Dec;33(9):611-22.
AUTORES
/ AUTHORS: - Sugden PH
INSTITUCIÓN
/ INSTITUTION: - National Heart and Lung Institute
Division, Faculty of Medicine, Imperial College of Science, Technology and
Medicine, London, UK. p.sugden@ic.ac.uk
RESUMEN
/ SUMMARY: - In response to a requirement for increased
contractile power in vivo, mammalian cardiac myocytes adapt through a
hypertrophic response (cell enlargement in the absence of cell division). This
response can be simulated by exposing isolated myocytes in primary culture to
alpha-adrenergic agonists or the vasoactive peptide, endothelin-1. The
signalling pathways responsible for hypertrophic growth have been actively
studied, and it is likely that reversible protein phosphorylation and
dephosphorylation are involved. Three signalling pathways show particular
potential as regulators of the response, ie protein kinase C (PKC),
mitogen-activated protein kinase (MAPK) cascades, and calcineurin. These
species are thought to regulate the rate and specificity of gene transcription
ultimately through modifying the transactivating activity of nuclear
transcription factors. There are three pertinent MAPK cascades, the
extracellular signal-regulated kinase (ERK) cascade, the c-Jun N-terminal
kinase (JNK or SAPK1) cascade, and the p38-MAPK (SAPK2-5) cascade. PKC
participates in the activation of the ERK cascade but does not contribute
significantly to the activation of the two remaining cascades. Calcineurin (or
protein phosphatase 2B) is activated by increases in [Ca2+i] through the
[Ca2+]-sensing protein, calmodulin. In this review, I discuss the evidence for
and against the involvement of these signalling proteins in the induction of
myocyte hypertrophy and emphasize that the ERK cascade should perhaps feature
more widely in the collective consciousness.
N. Ref:: 136
----------------------------------------------------
[139]
TÍTULO / TITLE: - Cyclosporin A as a
model antigen: immunochemical and structural studies.
REVISTA
/ JOURNAL: - J Mol Recognit 2002 Sep-Oct;15(5):277-85.
●●
Enlace al texto completo (gratuito o de pago) 1002/jmr.588
AUTORES
/ AUTHORS: - Altschuh D
INSTITUCIÓN
/ INSTITUTION: - UMR 7100 - CNRS/ULP ‘Biotechnologie des
Interactions Moleculaires’, Ecole Superieure de Biotechnologie de Strasbourg,
Pole API, Bld Sebastien Brandt, 67400 Illkirch, France. daniele.altschuh@esbs.u-strasbg.fr
RESUMEN
/ SUMMARY: - The immunosuppressant drug cyclosporin
(Cs) A is a cyclic undecapeptide which has been used as a model antigen because
structural information and a large number of analogs, modified at each of its
11 positions, were available. This review summarizes immunochemical and
crystallographic studies of the interaction between the Fab of monoclonal
antibody R45-45-11 and Cs. Three points are discussed: (1) the different
conformations of CsA and the question of its biologically active form; (2) the
Fab-CsA recognition mechanism; and (3) the relationship between structure and
binding properties of CsA analogs. N.
Ref:: 50
----------------------------------------------------
[140]
TÍTULO / TITLE: - Homocysteine levels
among transplant recipients: effect of immunosuppressive protocols.
REVISTA
/ JOURNAL: - Transplant Proc 2001 Sep;33(6):2945-6.
AUTORES
/ AUTHORS: - Mor E; Helfmann L; Lustig S; Bar-Nathan N;
Yussim A; Sela BA
INSTITUCIÓN
/ INSTITUTION: - Department of Transplantation, Rabin
Medical Center, Petach-Tikva, Israel.
----------------------------------------------------
[141]
TÍTULO / TITLE: - Advances in the
treatment of lupus nephritis.
REVISTA
/ JOURNAL: - Annu Rev Med 2001;52:63-78.
●●
Enlace al texto completo (gratuito o de pago) 1146/annurev.med.52.1.63
AUTORES
/ AUTHORS: - Zimmerman R; Radhakrishnan J; Valeri A;
Appel G
INSTITUCIÓN
/ INSTITUTION: - Columbia University College of Physicians
and Surgeons, New York, New York 10032, USA.
RESUMEN
/ SUMMARY: - Systemic lupus erythematosus (SLE) is an
autoimmune disease that leads to the formation and deposition of immune
complexes throughout the body, which are pathogenic for the disease. Different
forms of glomerulonephritis can occur in patients with SLE and can contribute
significantly to the associated morbidity and, ultimately, mortality from the
disease. Over the past two decades, there have been significant strides in our
understanding of the disease and in treatments that attempt to control the
formation and deposition of anti-DNA auto-antibodies and immune complexes, as
well as the subsequent inflammatory cascade mediated through various cellular
and humoral pathways leading to progressive renal damage and end-stage renal
disease. In this chapter, we review the current understanding of the
pathogenesis and treatment of lupus nephritis in its various stages and discuss
the experimental and human data regarding some of the potential newer forms of
therapy. We discuss data regarding the use of steroids, azathioprine,
cyclophosphamide, cyclosporine A, mycophenolate mofetil, gammaglobulin,
plasmapheresis, LJP 394, flaxseed oil, bindarit, anti-CD40 ligand, and CTLA4Ig. N. Ref:: 89
----------------------------------------------------
[142]
TÍTULO / TITLE: - Molecular and cellular
mechanisms of donor cell-induced tolerance.
REVISTA
/ JOURNAL: - Immunol Res 2002;26(1-3):119-29.
AUTORES
/ AUTHORS: - George JF; Ahumada L; Lu A
INSTITUCIÓN
/ INSTITUTION: - Department of Surgery, University of
Alabama at Birmingham, 35294-0007, USA. jgeorge@uab.edu
RESUMEN
/ SUMMARY: - The induction of immunologic tolerance to
solid organ allografts is a subject of intense investigation because of the
morbidity and mortality associated with standard immunosuppressive therapy. One
method that is currently in clinical and preclinical testing involves the
transient ablation of recipient T cells using polyclonal antithymocyte sera or
monoclonal anti-CD4/CD8 antibody treatment, followed by the posttransplant
administration of donor bone marrow cells or of donor peripheral lymphoid
populations. Recent studies in our laboratory have shown that the molecular and
cellular basis of the prolongation of graft survival by donor cell
administration depends on the cellular compartment from which the donor cells
were derived. We provide here a brief review of these data followed by new data
suggesting that the mode of peripheral and central selection is also dependent
on the source from which the donor cells were derived. N. Ref:: 38
----------------------------------------------------
[143]
TÍTULO / TITLE: - mTOR inhibitors: an
overview.
REVISTA
/ JOURNAL: - Liver Transpl 2001 Jun;7(6):473-84.
●●
Enlace al texto completo (gratuito o de pago) 1053/jlts.2001.24645
AUTORES
/ AUTHORS: - Neuhaus P; Klupp J; Langrehr JM
INSTITUCIÓN
/ INSTITUTION: - Department of Surgery, Charite Virchow, Berlin,
Germany. chirurgie@charite.de
RESUMEN
/ SUMMARY: - Inhibitors of the mammalian target of
rapamycin are a new class of immunosuppressants. In contrast to other
macrolides, such as tacrolimus and cyclosporine A, they do not inhibit
calcineurin and thus signal I of T-cell activation. By inhibiting signal III,
the mechanism of action and side effects of sirolimus (rapamycin) and its
derivative RAD are distinct from other immunosuppressants. Reports of synergism
with cyclosporine A and tacrolimus in preclinical and clinical studies,
avoidance of nephrotoxicity, and possible treatment or prevention of chronic
allograft rejection are leading to high expectations for this new class of
immunosuppressants. Furthermore, studies evaluating tolerance induction are
being conducted. This review summarizes preclinical and clinical results
published to date and exploits the future value of sirolimus and RAD for
clinical transplantation. N.
Ref:: 119
----------------------------------------------------
[144]
TÍTULO / TITLE: - IL-17 as a potential
target for modulating airway neutrophilia.
REVISTA
/ JOURNAL: - Curr Pharm Des 2002;8(20):1855-61.
AUTORES
/ AUTHORS: - Laan M; Linden
INSTITUCIÓN
/ INSTITUTION: - Lung Pharmacology Group, Department of
Respiratory Medicine Allergology, Guldhedsgatan 10A, Gothenburg, SE-413 46,
Sweden. martti.laan@hjl.gu.se
RESUMEN
/ SUMMARY: - Several chronic inflammatory airway
diseases are characterized by an increased number of neutrophils in the
airways. There is evidence that the recruitment of these neutrophils can be
controlled by certain T-lymphocytes. However, the mechanisms behind this T-cell
control of airway neutrophilia are poorly understood. In this review, we
summarize the evidence that interleukin (IL)-17 released from T-lymphocytes of
the CD45RO+ subset can link the activation of these T-cells to the recruitment
and activation of neutrophils. This evidence suggests that pharmacotherapeutical
modulation of neutrophilic airway inflammation can be achieved using several
different strategies, including inhibition of IL-17 production by cAMP
elevating agents or certain nuclear factor inhibitors, neutralization of
released IL-17 protein by specific anti-IL-17-antibodies, blockade of the IL-17
receptor as well as inhibition of certain MAP kinases mediating the post
receptor effects of IL-17 in airway cells. Additional studies on animals in
vivo and patients, respectively, are needed to further evaluate the
pharmacotherapeutical potential of these strategies. N. Ref:: 57
----------------------------------------------------
[145]
TÍTULO / TITLE: - n-3 Fatty acids and
their role in nephrologic practice.
REVISTA
/ JOURNAL: - Curr Opin Nephrol Hypertens 2001
Sep;10(5):639-42.
AUTORES
/ AUTHORS: - Donadio JV
INSTITUCIÓN
/ INSTITUTION: - Mayo Clinic and Foundation, Rochester,
Minnesota 55905, USA. donadio.james@mayo.edu
RESUMEN
/ SUMMARY: - During the past year, a newly reported
clinical trial has strengthened the argument for recommending daily treatment
with n-3 polyunsaturated fatty acids in patients with immunoglobulin A
nephropathy (the most common form of primary glomerulonephritis in the world)
who are at high risk for progression of renal disease. Studies are underway
that involve a combination of cyclosporine A, a commonly prescribed
immunosuppressive agent in solid-organ transplantation, with a high-potency n-3
polyunsaturated fatty acid to reduce cyclosporine toxicity. Two studies
reported during the past year show promise that dietary supplementation with
n-3 polyunsaturated fatty acids will substantially decrease vascular access
graft thrombosis in patients receiving maintenance hemodialysis, and may reduce
hypercalciuria in patients who suffer from kidney stones. N. Ref:: 26
----------------------------------------------------
[146]
TÍTULO / TITLE: - Solid-state
fermentation: a promising microbial technology for secondary metabolite production.
REVISTA
/ JOURNAL: - Appl Microbiol Biotechnol 2001
Apr;55(3):284-9.
AUTORES
/ AUTHORS: - Robinson T; Singh D; Nigam P
INSTITUCIÓN
/ INSTITUTION: - Biotechnology Research Group, University
of Ulster, Coleraine, UK.
RESUMEN
/ SUMMARY: - Solid state (substrate) fermentation (SSF)
has been used successfully for the production of enzymes and secondary
metabolites. These products are associated with the stationary phase of
microbial growth and are produced on an industrial scale for use in agriculture
and the treatment of disease. Many of these secondary metabolites are still
produced by submerged liquid fermentations (SmF) even though production by this
method has been shown to be less efficient than SSF. As large-scale production
increases further, so do the costs and energy demands. SSF has been shown to
produce a more stable product, requiring less energy, in smaller fermenters,
with easier downstream processing measures. In this article we review an
important area of biotechnology, since the recent evidence indicates that
bacteria and fungi, growing under SSF conditions, are more than capable of
supplying the growing global demand for secondary metabolites. N. Ref:: 53
----------------------------------------------------
[147]
TÍTULO / TITLE: - Multimodular
biocatalysts for natural product assembly.
REVISTA
/ JOURNAL: - Naturwissenschaften 2001 Mar;88(3):93-101.
AUTORES
/ AUTHORS: - Schwarzer D; Marahiel MA
INSTITUCIÓN
/ INSTITUTION: - Fachbereich Chemie/Biochemie,
Philipps-Universitat Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany.
RESUMEN
/ SUMMARY: - Nonribosomal peptides and polyketides
represent a large class of natural products that show an extreme structural
diversity and broad pharmacological relevance. They are synthesized from simple
building blocks such as amino or carboxy acids and malonate derivatives on
multimodular enzymes called nonribosomal peptide synthetases (NRPSs) and
polyketide synthases (PKSs), respectively. Although utilizing different
substrates, NRPSs and PKSs show striking similarities in the modular
architecture of their catalytic domains and product assembly-line mechanism.
Among these compounds are well known antibiotics (penicillin, vancomycin and
erythromycin) as well as potent immunosuppressive agents (cyclosporin,
rapamycin and FK 506). This review focuses on the modular organization of
NRPSs, PKSs and mixed NRPS/PKS systems and how modules and domains that build
up the biosynthetic templates can be exploited for the rational design of
recombinant enzymes capable of synthesizing novel compounds. N. Ref:: 50
----------------------------------------------------
[148]
TÍTULO / TITLE: - Management of fistulas
in patients with Crohn’s disease: antibiotic to antibody.
REVISTA
/ JOURNAL: - Can J Gastroenterol 2001 Nov;15(11):751-6.
AUTORES
/ AUTHORS: - Pare P
INSTITUCIÓN
/ INSTITUTION: - Universitaire de Quebec, Hopital
St-Sacrement, Laval University, Quebec, Canada. pierre.pare@cha.quebec.qc.ca
RESUMEN
/ SUMMARY: - Fistulas are common in patients with
Crohn’s disease and, when associated with inflammatory disease and established
for several weeks, tend to be chronic. Perianal fistulas are the most frequent
complication of, and are most often associated with, colonic disease. Perianal
fistulas commonly require surgical resection and permanent ileostomy.
Antibiotics, cyclosporine, methotrexate and thalidomide have been used in
uncontrolled trials; only azathioprine, 6-mercaptopurine and infliximab have been
assessed in double-blind, placebo controlled studies. Relapse of the fistula
occurs with all drugs, unless treatment is continued long term. Each drug
differs in its onset of action and long term tolerability. An approach to
fistulizing disease in Crohn’s disease is suggested. N. Ref:: 44
----------------------------------------------------
[149]
TÍTULO / TITLE: - New aspects of
cyclosporin a mode of action: from gene silencing to gene up-regulation.
REVISTA
/ JOURNAL: - Mini Rev Med Chem 2003 May;3(3):205-14.
AUTORES
/ AUTHORS: - Mascarell L; Truffa-Bachi P
INSTITUCIÓN
/ INSTITUTION: - Unite Biologie des Populations
Lymphocytaires, CNRS URA 1961, Institut Pasteur, Paris, France.
RESUMEN
/ SUMMARY: - Cyclosporin A (CSA) has transformed
clinical transplantation, both in term of success and of quality-of-life of the
patient. Studies aimed to unfold the site of CSA action have shown that this
molecule binds to cytosolic proteins of the cyclophilin family. CSA:cyclophilin
complexes have a high affinity for calcineurin, a key enzyme in T-cell
activation. By blocking the calcineurin activity, CSA prevents the induction of
genes encoding for cytokines and their receptors. Thus, humoral and cellular
immune responses are abolished, this resulting in the successful graft
acceptance. Disappointingly, CSA and the other molecules as FK506, sharing the
capacity to inhibit calcineurin, should be administered for all patient life,
as tolerance to alloantigens is not achieved by these molecules. The long term
utilization of this class of immunosuppressors increases the incidence of
different tumors. The finding that CSA does not interfere with various
biochemical pathways has prompted different groups to analyze a possible effect
of CSA on molecules that might be involved in different functions of the immune
response and/or in tumorogenesis. A new picture of CSA mode of action is
emerging in which the immunosuppressor prevents the transcription of a group of
genes, concomitantly inducing the transcription of another set. Here, we review
the data and discuss the consequences of these new findings in term of T-cell
activation mechanisms. N.
Ref:: 80
----------------------------------------------------
[150]
TÍTULO / TITLE: - Cap-dependent
translation and control of the cell cycle.
REVISTA
/ JOURNAL: - Prog Cell Cycle Res 2003;5:469-75.
AUTORES
/ AUTHORS: - Cormier P; Pyronnet S; Salaun P;
Mulner-Lorillon O; Sonenberg N
INSTITUCIÓN
/ INSTITUTION: - Station Biologique de Roscoff, Universite
Pierre et Marie Curie (EI 37), CNRS-UMR 7127, (INSU), BP 74, 29682 Roscoff,
France.
RESUMEN
/ SUMMARY: - The control of gene expression at the
translational level has emerged in the past decade as an important aspect of
cell growth, proliferation and malignant transformation. Translation is
primarily regulated at the initiation step, and mitogen-dependent signaling
pathways converge to modulate the activity of translation initiation factors.
In most tumors tested, at least one translation initiation factor is
overexpressed and overexpression of translation initiation factors often
provokes transformation. Malignant transformation could be caused by the
increased translation of a subset of mRNAs encoding important proteins which
are required for cell growth and proliferation. These mRNAs usually possess
regulatory sequences that render their translation more sensitive to changes in
the activity of translation initiation factors. In this chapter, we describe
recent advances illustrating the importance of translation in cell cycle
progression and cell transformation. Control of translation initiation may
represent an excellent target for antitumor drugs. N. Ref:: 96
----------------------------------------------------
[151]
TÍTULO / TITLE: - Lichen planus
esophagitis: report of three patients treated with oral tacrolimus or
intraesophageal corticosteroid injections or both.
REVISTA
/ JOURNAL: - Dis Esophagus 2003;16(1):47-53.
AUTORES
/ AUTHORS: - Keate RF; Williams JW; Connolly SM
INSTITUCIÓN
/ INSTITUTION: - Division of Gastroenterology and
Hepatology, Mayo Clinic, Scottsdale, AZ 85259, USA. keate.ray@mayo.edu
RESUMEN
/ SUMMARY: - Clinically significant involvement of the
esophagus is uncommon in patients who have lichen planus, a common disorder of
squamous epithelium. In three patients who had oral, cutaneous, and esophageal
lichen planus, endoscopic intralesional esophageal injection of corticosteroids
(in all three patients) and oral tacrolimus (FH506) (in two patients) resulted
in improvement in dysphagia, a less frequent need for dilation, and improvement
in esophageal inflammation. N.
Ref:: 36
----------------------------------------------------
[152]
TÍTULO / TITLE: - Therapeutic
implications for immunophilin ligands in the treatment of neurodegenerative
diseases.
REVISTA
/ JOURNAL: - Curr Drug Target CNS Neurol Disord 2003
Dec;2(6):349-56.
AUTORES
/ AUTHORS: - Pong K; Zaleska MM
INSTITUCIÓN
/ INSTITUTION: - Department of Neuroscience, Wyeth
Research, Princeton, NJ 08543, USA. pongk@wyeth.com
RESUMEN
/ SUMMARY: - There is a significant unmet need for
therapeutic agents in the treatment of neurodegenerative diseases. Given their
clinical importance, prototypical molecules that clearly exhibit both
neuroprotective and neuroregenerative activities have been highly sought after.
The journey led to the exploitation of neurotrophins, a family of proteins that
had extraordinary therapeutic properties in pre-clinical models of
neurodegeneration. Although experimentally promising, clinical development of
neurotrophins for various neurological indications, such as Alzheimer’s
Disease, Amyotrophic Lateral Sclerosis, and Parkinson’s Disease was met with
severe obstacles and setbacks, such as the inability to deliver these large
proteins to target population of neurons, instability of the proteins, and
non-specific activity. Immunophilins are proteins that act as receptors for
immunosuppresant drugs, i.e. FK506 (tacrolimus), cyclosporin A, and rapamycin
(sirolimus, Rapamune). Studies indicate immunophilins are expressed 10-100 fold
higher in CNS and PNS tissue than in immune tissue. Subsequent studies revealed
potent neuroprotective and neuroregenerative properties of immunophilin ligands
in both culture and animal models. In contrast to neurotrophins, most
immunophilin ligands are highly stable, small molecules that can readily cross
the blood-brain barrier and are orally bioavailable. Taken together, these data
prompted the development of nonimmunosuppressive immunophilin ligands with
potent therapeutic activities, although the potency of select compounds has
come into question in more recent studies. This review will examine the
experimental evidence supporting the use of immunophilin ligands for the
treatment of neurodegenerative diseases and the current progression of these
molecules in clinical trials. N.
Ref:: 91
----------------------------------------------------
[153]
TÍTULO / TITLE: - The state of the art in
the management of inflammatory bowel disease.
REVISTA
/ JOURNAL: - Rev Gastroenterol Disord 2003
Spring;3(2):81-92.
AUTORES
/ AUTHORS: - Hanauer SB; Present DH
INSTITUCIÓN
/ INSTITUTION: - Section of Gastroenterology and Nutrition,
University of Chicago, Pritzker School of Medicine, Chicago, IL, USA.
RESUMEN
/ SUMMARY: - Ulcerative colitis (UC) and Crohn’s
disease (CD), collectively known as inflammatory bowel disease (IBD), afflict
an estimated one million Americans and produce symptoms that impair quality of
life and ability to function. Progress in IBD management strategies has led to
optimized approaches for achieving the two primary clinical goals of therapy:
induction and maintenance of remission. Although surgery is indicated to treat
refractory disease or specific complications, pharmacotherapy is the
cornerstone of IBD management. The efficacy of aminosalicylates for induction
of remission in mild to moderate UC and CD is well established, as is their
role for maintenance of remission in UC. The sulfa-free mesalamine formulation
offers an adverse effect profile similar to that of placebo, enabling the
administration of higher, more effective doses. Although corticosteroids
provide potent anti-inflammatory effects, their benefits are countermanded by
the risk of intolerable and serious adverse effects, and they are ineffective
for maintenance therapy. Other agents effective in inducing or maintaining
remission are azathioprine, 6-mercaptopurine, infliximab, cyclosporine,
methotrexate, and antibiotics. Ongoing clinical trials of experimental
therapies will generate new tools for IBD treatment. Currently, a broad range
of options allows physicians to tailor treatment to each patient’s needs and
preferences. Such considerations are essential for maximizing adherence to
therapy. N. Ref:: 62
----------------------------------------------------
[154]
TÍTULO / TITLE: - The immunosuppressive
activity of proinflammatory cytokines in experimental models: potential for
therapeutic intervention in autoimmunity.
REVISTA
/ JOURNAL: - Curr Drug Targets Inflamm Allergy 2002
Mar;1(1):77-87.
AUTORES
/ AUTHORS: - Grohmann U; Puccetti P
INSTITUCIÓN
/ INSTITUTION: - Department of Experimental Medicine,
University of Perugia, Perugia, Italy. ugrohmann@tin.it
RESUMEN
/ SUMMARY: - The role of cytokines in the pathogenesis
of T cell-mediated diseases, and in particular autoimmune responses, has been
the subject of intense investigation in the past few years. Transgenic strains
of mice have been generated, each expressing individual cytokines in organs
targeted by autoimmunity. These animal models provide the most advanced tool
available for analyzing the relationship between cytokines and T-dependent
autoimmune responses. On the one hand, these experiments confirm that the local
expression of proinflammatory cytokines is pivotal in initiating and
maintaining pathogenic responses to self. On the other hand, and somewhat
unexpectedly, these models have also revealed that cytokine factors controlling
autoimmunity can act both as potentiating and inhibitory agents, depending upon
the site and timing of exposure. As a result, one major concept emerging from
different experimental models, including those originally established in our
laboratory, is that proinflammatory cytokines may ameliorate autoimmunity. In
this review, we analyze the mechanisms whereby cytokines that are considered as
proinflammatory may in contrast suppress immune responses to self antigens.
Besides emphasizing that the proinflammatory/immunogenic properties of a given
cytokine may not be an intrinsic property, we review evidence that the
regulation imposed by the cytokine network on autoimmunity is a finely tuned
balance between activation and downmodulation of an individual autoreactive T
cell repertoire. By emphasizing that factors such as the duration of cytokine
exposure and the type of cell population involved strongly influence that
balance, we underline the potential therapeutic implications of
cytokine-mediated modulation of autoimmunity.
N. Ref:: 92
----------------------------------------------------
[155]
TÍTULO / TITLE: - Pharmacotherapeutic
management of pulmonary sarcoidosis.
REVISTA
/ JOURNAL: - Am J Respir Med 2003;2(4):311-20.
AUTORES
/ AUTHORS: - Fazzi P
INSTITUCIÓN
/ INSTITUTION: - Cardiac and Thoracic Department,
Respiratory Pathophysiology Section, University of Pisa, Pisa, Italy. pfazzi@dcap.med.unipi.it
RESUMEN
/ SUMMARY: - Corticosteroids are the mainstay of
treatment for sarcoidosis. Although the indications for medical therapy of
sarcoidosis are controversial, standard therapy for symptomatic, progressive
disease consists of corticosteroids. The British Thoracic Society concluded,
with respect to systemic corticosteroids for the treatment of sarcoidosis, that
some patients required no treatment, some required prednisone for control of
symptoms, and others, with persistent disease, appeared to benefit from
long-term corticosteroid therapy. Inhaled budesonide can be an effective treatment
for lung sarcoidosis, with few adverse effects, when used in combination with
oral systemic corticosteroids such as deflazacort administered in a tapered
regimen for 6 months. A randomized controlled trial has also demonstrated the
efficacy of 3 months of treatment with oral prednisolone in a tapered regimen
followed by inhaled budesonide for 15 months in patients with early stage
pulmonary sarcoidosis.Alternative drugs are required in chronic resistant
sarcoidosis and/or in conditions where systemic corticosteroids are
contraindicated. Immunosuppressive agents (chlorambucil, cyclophosphamide,
methotrexate, cyclosporine, azathioprine), anticytokine agents (thalidomide,
pentoxifylline), antimalarials (chloroquine, hydroxychloroquine), melatonin and
monoclonal antibody (infliximab) have been used in such situations.Chlorambucil
and cyclophosphamide have been used in anecdotal cases of pulmonary sarcoidosis
as corticosteroid-sparing agents. However, their toxicity and neoplastic
potential recommend prudence in patient selection. A comparison between
combination therapy with cyclosporine and prednisone and prednisone alone has
shown an increased prevalence of serious adverse effects with combined therapy
with no between-group differences in treatment efficacy. The cost and toxicity
of cyclosporine limit its use to patients in whom its efficacy has been
proven.In patients with chronic or refractory disease, methotrexate, usually
administered once a week as a single oral dose for at least 2 years, has
resulted in a significant improvement in respiratory function, chest
radiographs and extrapulmonary manifestations. In most patients, this treatment
enabled discontinuation of corticosteroids.Azathioprine may be effective as a
corticosteroid-sparing agent in the long-term treatment of sarcoidosis. The
combination of prednisolone and azathioprine over a period of 2 years has
induced long-lasting remission in patients with resistant sarcoidosis.
Thalidomide at low doses is effective in selected cases of sarcoidosis with cutaneous
and mild pulmonary involvement. Pentoxifylline alone or combined with low doses
of corticosteroids has achieved significant improvement in respiratory function
in patients with pulmonary sarcoidosis. Chloroquine and hydroxychloroquine have
been shown to have a specific effect in cutaneous manifestations, neurological
involvement and hypercalcemia associated with sarcoidosis. Infliximab has
yielded good results in patients with chronic resistant pulmonary and
extrapulmonary sarcoidosis resistant to corticosteroid and cytotoxic therapy.
The effectiveness of melatonin in cutaneous and pulmonary sarcoidosis has also
been confirmed in a single center. N.
Ref:: 52
----------------------------------------------------
[156]
TÍTULO / TITLE: - Polymorphisms in
immunoregulatory genes: towards individualized immunosuppressive therapy?
REVISTA
/ JOURNAL: - Am J Pharmacogenomics 2002;2(1):13-23.
AUTORES
/ AUTHORS: - Daly AK; Day CP; Donaldson PT
INSTITUCIÓN
/ INSTITUTION: - Centre for Liver Research, University of
Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. A.K.Daly@ncl.ac.uk
RESUMEN
/ SUMMARY: - In organ transplantation, successful
immunosuppression requires that both rejection and infection episodes be
minimized. Unfortunately it is currently impossible to predict individual dose
requirement for immunosuppressive drugs, but a number of studies of various
immune response genes are now being performed with a view to identifying
genotypes associated with rejection and/or infection. The key role of cytokines
in the immune response and other processes, including fibrosis, has
concentrated most of this attention on polymorphisms in cytokine genes. Data on
polymorphisms in genes encoding tumor necrosis factor-alpha, transforming
growth factor-beta, interferon-gamma and interleukin (IL)-1, 4, 6 and 10
together with the IL-4 receptor have been analyzed but so far there is
currently no indication of any consistently positive associations between graft
rejection and any of these polymorphisms. Studies of other immunomodulatory
genes including the CTLA4 gene and the chemokine receptor CCR-5 have proved
more positive though the data, so far, are only preliminary. In conclusion,
additional large series studies of these and other cytokine genes, as well as
other immunoregulatory gene polymorphisms of proven functional significance are
needed to achieve major progress in this area.
N. Ref:: 112
----------------------------------------------------
[157]
TÍTULO / TITLE: - Small molecule
immunosuppressive agents in experimental and clinical transplantation.
REVISTA
/ JOURNAL: - Curr Drug Targets Cardiovasc Haematol
Disord 2002 Dec;2(2):57-71.
AUTORES
/ AUTHORS: - Ma A; Chen H
INSTITUCIÓN
/ INSTITUTION: - Laboratory of Experimental Surgery,
Research Center of CHUM, Notre-Dame Hospital, University of Montreal, 1560
Sherbrooke Street East, Montreal, Quebec, Canada.
RESUMEN
/ SUMMARY: - Immunosuppression is currently the major
approach used for the prevention and management of transplant rejection. In
this overview, preclinical and clinical studies of the small molecule
immunosuppressive agents are reviewed from the discovery of cyclosporine. More
recently it was demonstrated that certain agents, namely tacrolimus (FK506),
sirolimus (rapamycin), and mycophenolate mofetil (CellCept, MMF), act
selectively on adaptive host responses at different stages of T- and B-cell
cycles and spare nonspecific host resistance. Because each agent has its
specific and significant toxic effects, it has been difficult to optimize the
use of individual agents in monotherapy. Therefore, drug combination therapy
has been of great interest in addition to the introduction of new small
molecule agents, such as malononitrilamides [MNAs (leflunomide, FK778, FK779)],
15-deoxyspergualin (DSG) and its analogues, FTY720 and inhibitors of signal
transduction, which offer promising modes of immunosuppression. N. Ref:: 129
----------------------------------------------------
[158]
TÍTULO / TITLE: - The molecular target of
rapamycin (mTOR) as a therapeutic target against cancer.
REVISTA
/ JOURNAL: - Cancer Biol Ther 2003 Jul-Aug;2(4 Suppl
1):S169-77.
AUTORES
/ AUTHORS: - Mita MM; Mita A; Rowinsky EK
INSTITUCIÓN
/ INSTITUTION: - Institute for Drug Development; Cancer
Therapy and Research Center; San Antonio, Texas 78229, USA. mmita@saci.org
RESUMEN
/ SUMMARY: - The molecular target of rapamycin (mTOR),
which is a member of the phosphoinositide 3-kinase related kinase (PIKK) family
and a central modulator of cell growth, is a prime strategic target for
anti-cancer therapeutic development. mTOR plays a critical role in transducing
proliferative signals mediated through the phosphatidylinositol 3 kinase (PI3K)/protein
kinase B (Akt) signaling pathway, principally by activating downstream protein
kinases that are required for both ribosomal biosynthesis and translation of
key mRNAs of proteins required for G(1) to S phase traverse. By targeting mTOR,
the immunsuppressant and antiproliferative agent rapamycin (RAP) inhibits
signals required for cell cycle progression, cell growth, and proliferation.
RAP, a complex macrolide and highly potent fungicide, immunosuppressant, and
anti-cancer agent, is a highly specific inhibitor of mTOR. In essence, RAP
gains function by binding to the immunophilin FK506 binding protein 12 (FKBP12)
and the resultant complex inhibits the activity of mTOR. Since mTOR activates
both the 40S ribosomal protein S6 kinase ((p)70(s6k)) and the eukaryotic
initiation factor 4E-binding protein-1 (4E-BP1), RAP blocks activation of these
downstream signaling elements, which results in cell cycle arrest in the G1
arrest. RAP also prevents cyclin-dependent kinase (cdk) activation, inhibits
retinoblastoma protein ((p)Rb) phosphorylation, and accelerates the turnover of
cyclin D1 that leads to a deficienciy of active cdk4/cyclin D1 complexes, all
of which potentially contribute to the prominent inhibitory effects of RAP at
the G(1)/S phase transition. Both RAP and several RAP analogs with more
favorable pharmaceutical properties have demonstrated prominent growth
inhibitory effects against a broad range of human cancers in both preclinical
and early clinical evaluations. This review will summarize the principal
mechanisms of action of RAP and RAP derivatives and their potential utility of
these agents as anti-cancer therapeutics. The preliminary results of early
clinical evaluations with RAP analogs and the unique developmental challenges
that lie ahead will also be discussed. N.
Ref:: 112
----------------------------------------------------
[159]
TÍTULO / TITLE: - Combination treatment
in autoimmune diseases: systemic lupus erythematosus.
REVISTA
/ JOURNAL: - Springer Semin Immunopathol 2001;23(1-2):75-89.
AUTORES
/ AUTHORS: - Moroni G; Della Casa Alberighi O;
Ponticelli C
INSTITUCIÓN
/ INSTITUTION: - Divisione di Nefrologia e Dialisi,
Ospedale Maggiore IRCCS, Via della Commenda 15, 20122 Milan, Italy. N. Ref:: 84
----------------------------------------------------
[160]
TÍTULO / TITLE: - New developments in the
prophylaxis and treatment of graft versus host disease.
REVISTA
/ JOURNAL: - Expert Opin Pharmacother 2001
Jul;2(7):1109-17.
AUTORES
/ AUTHORS: - Simpson D
INSTITUCIÓN
/ INSTITUTION: - North Shore Hospital, Auckland, New
Zealand. david.simpson@whl.co.nz
RESUMEN
/ SUMMARY: - Graft versus host disease (GVHD) remains
the major obstacle to successful allogeneic bone marrow transplantation. Cyclosporin
with methotrexate is the most common prophylactic regimen. Tacrolimus is
associated with less GVHD and is gaining ground especially in unrelated donor
transplants where current regimens are unsatisfactory. Mycophenolate mofetil
(MMF) and rapamycin have not yet shown benefit in acute GVHD prophylaxis. In
vivo T-cell depletion with Campath 1H or thymoglobulin used during transplant
conditioning are increasingly used in place of ex vivo T-cell depletion, where
results remain disappointing. Steroids remain first choice for therapy of GVHD
but anti-CD25 antibodies, daclizumab or basiliximab are gaining popularity as
second-line therapy ahead of ATG. Chronic GVHD is increasing with greater use
of peripheral blood stem cell grafts and older patients. The combination of
tacrolimus and MMF is promising for patients with extensive disease. Tolerance
induction using CTLA-4-Ig, anti-CD40L, tresperimus and/or rapamycin may
revolutionise GVHD therapy. However, due to the desirability of tumour
intolerance, tolerance is likely to be developed in organ transplantation
before bone marrow transplantation for traditional indications. Bone marrow
transplants performed to induce organ tolerance may see increasing use of these
agents. TNF blockade using infliximab or etanercept (Enbrel) is promising but
the role of these agents is not yet defined.
N. Ref:: 68
----------------------------------------------------
[161]
TÍTULO / TITLE: - Influence of one human
leukocyte antigen mismatch on outcome of allogeneic bone marrow transplantation
from related donors.
REVISTA
/ JOURNAL: - Hematology 2003 Feb;8(1):27-33.
●●
Enlace al texto completo (gratuito o de pago) 1080/1024533031000072054
AUTORES
/ AUTHORS: - Hasegawa W; Lipton JH; Messner HA; Jamal
H; Yi QL; Daly AS; Kotchetkova N; Kiss TL
INSTITUCIÓN
/ INSTITUTION: - Bone Marrow Transplant Service, Princess
Margaret Hospital/University Health Network, Toronto, Ont, M5G 2M9, Canada.
RESUMEN
/ SUMMARY: - This study compares the clinical outcomes
of 60 consecutive patients who received an allogeneic blood or marrow stem cell
transplant (BMT) from one Human Leukocyte Antigen (HLA) mismatched related
donors with those of 120 matched patients who had HLA identical sibling donors.
The control patients were matched for diagnosis, disease status, conditioning
regimen, and age at BMT. All patients received standard CYA and MTX for GVHD
prophylaxis. The probability of overall survival (OS) at 5 years was 35% in the
study group compared to 56% in the control group. The relapse rates and acute
GVHD rates did not differ between the two groups. Graft failure was a
significant problem in the study group compared to the control group (13 vs.
0%, p < 0.0001). All cases of graft failure occurred in patients with a
mismatch in the host-versus-graft direction. BMT-related deaths were also
increased in the study group. Forty percent of deaths were caused by infection
in the study group vs. 19% in the control group (p < 0.01). In conclusion,
the OS of patients receiving marrow/stem cells from one antigen mismatched
related donors was inferior to that of controls with HLA-identical related
donors. There was an increase in mortality related to infections occurring in
the setting of an increased frequency of graft failure in these patients. N. Ref:: 21
----------------------------------------------------
[162]
TÍTULO / TITLE: - Heat shock proteins:
novel therapeutic tools for HIV-infection?
REVISTA
/ JOURNAL: - Expert Opin Biol Ther 2001 Jan;1(1):67-77.
AUTORES
/ AUTHORS: - Brenner BG; Wainberg Z
INSTITUCIÓN
/ INSTITUTION: - McGill University, Montreal, Quebec,
Canada. bbrenn1@po-box.mcgill.ca
RESUMEN
/ SUMMARY: - Heat shock proteins (Hsps), cyclophilins
(Cyps) and FK binding proteins (FKBPs) form a family of intracellular chaperone
molecules that facilitate protein folding and assembly. These stress proteins
are selectively expressed in cells in response to a range of stimuli, including
heat, lymphokine and microbial/viral infections. This review discusses the role
of stress proteins in the HIV-1 viral life cycle, with regard to the
development of specific Hsp-based therapeutic strategies against HIV-1
infection. Cumulative findings are cited implicating CypA, Hsp27, Hsp70 and
FKBPs in host cell and viral activation, viral entry, assembly or formation of
infectious virions. Biological response modifiers that show specific
high-affinity interactions with Cyp, FKBPs and Hsps, including cyclosporins,
FK-506 and cyclopentenone prostaglandins respectively, may block HIV-1
replication and infection, providing novel HIV-1 therapeutic strategies.
Moreover, Hsp binding to viral complexes can enhance antiviral immunity,
including natural killer (NK), antibody-dependent (ADCC), gamma delta T-cell
and cytotoxic T-lymphocyte (CTL) activities against HIV-1 infected cells. The
ability of Hsps to interact with HIV-1 viral proteins, combined with their
inherent adjuvant and immunogenic properties indicates that Hsps may also serve
as vehicles for antigen delivery and the design of AIDS vaccines. N. Ref:: 94
----------------------------------------------------
[163]
TÍTULO / TITLE: - Transporter-enzyme
interactions: implications for predicting drug-drug interactions from in vitro
data.
REVISTA
/ JOURNAL: - Curr Drug Metab 2003 Oct;4(5):393-8.
AUTORES
/ AUTHORS: - Benet LZ; Cummins CL; Wu CY
INSTITUCIÓN
/ INSTITUTION: - University of California, Department of
Biopharmaceutical Sciences Box 0446, San Francisco, CA 94143-0446, USA. benet@itsa.ucsf.edu
RESUMEN
/ SUMMARY: - As discussed in earlier articles,
predictions of in vivo drug-drug interactions from in vitro studies is a
subject of high interest with obvious therapeutic as well as economic benefits.
Up until now little attention has been given to the potential interplay between
metabolic enzymes and transporters that could confound the in vivo-in vitro
relationships. Drug efflux by intestinal P-glycoprotein (P-gp) is known to
decrease the bioavailability of many CYP3A4 substrates. We have demonstrated
that the interplay between P-gp and CYP3A4 at the apical intestinal membrane
can increase the opportunity for drug metabolism by determining bidirectional
extraction ratios across CYP3A4 transfected Caco-2 cells for two dual
P-gp/CYP3A4 substrates, K77 (an experimental cysteine protease inhibitor) and
sirolimus, as well as two negative control, CYP3A4 only substrates, midazolam
and felodipine. Studies were carried out under control conditions, with a P-gp
inhibitor (GG918) and with a dual inhibitor (cyclosporine). Measurement of
intracellular concentration changes is an important component in calculating
the extraction ratios. We hypothesize that the inverse orientation of P-gp and
CYP3A4 in the liver will result in an opposite interactive effect in that
organ. In vivo rat intestinal perfusion studies with K77 and rat liver
perfusion studies with tacrolimus under control conditions and with inhibitors
of CYP3A4 (troleandomycin), P-gp (GG918) and both CYP3A4/P-gp (cyclosporine)
lend support to our hypotheses. These results serve as a template for
predicting enzyme- transporter (both absorptive and efflux) interactions in the
intestine and the liver. N.
Ref:: 24
----------------------------------------------------
[164]
TÍTULO / TITLE: - Apoptosis, TGF beta and
transfusion-related immunosuppression: Biologic versus clinical effects.
REVISTA
/ JOURNAL: - Transfus Apheresis Sci 2003
Oct;29(2):127-9.
AUTORES
/ AUTHORS: - Dzik WH
INSTITUCIÓN
/ INSTITUTION: - Blood Transfusion Service, J-224,
Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. sdzik@partners.org
RESUMEN
/ SUMMARY: - Whether or not blood transfusion exerts an
immunosuppressive effect on the recipient remains an area of controversy. The
mechanism to clearly explain the effect has been elusive. We have previously
suggested that there may be two categories of immunosuppressive transfusion
effect: one which is HLA-dependent and directed against adaptive immunity and a
second category which is mild, non-specific, and directed against innate
immunity. This non-specific effect might result from the infusion of apoptotic
blood cells. There is solid evidence that blood cells undergo apoptotic changes
during refrigerated storage. The infusion of apoptotic cells has recently been
shown in animal models to be immunosuppressive. Immunosuppression resulting
from the infusion of apoptotic cells may be linked to transforming growth
factor beta (TGF-beta). N.
Ref:: 10
----------------------------------------------------
[165]
TÍTULO / TITLE: - Treatment of the
extraintestinal manifestations of inflammatory bowel disease.
REVISTA
/ JOURNAL: - Curr Gastroenterol Rep 2002
Dec;4(6):513-6.
AUTORES
/ AUTHORS: - Bernstein CN
INSTITUCIÓN
/ INSTITUTION: - Inflammatory Bowel Disease Clinical and
Research Centre, University of Manitoba, John Buhler Research Centre, 804F-715
McDermot Avenue, Winnipeg, Manitoba, Canada R3E 3P4. cbernst@cc.umanitoba.ca
RESUMEN
/ SUMMARY: - There is a paucity of randomized,
controlled therapy studies of the extraintestinal manifestations of
inflammatory bowel disease (IBD). Most current therapeutic approaches are
empiric or based on approaches to therapy in other settings. In the past year
anecdotal evidence has emerged for the use of therapies that neutralize tumor
necrosis factor-a in both ankylosing spondylitis and the dermatologic extraintestinal
manifestations. Topical tacrolimus has also emerged as a potentially useful
therapy for dermatologic manifestations. Finally, patients with IBD
occasionally become transplant recipients. One study reported worsening IBD
after orthotopic liver transplantation for primary sclerosing cholangitis, and
another reported the benefit of renal transplantation in amyloidosis-induced
renal failure. N.
Ref:: 28
----------------------------------------------------
[166]
TÍTULO / TITLE: - A new class of cyclosporin
analogues for the treatment of asthma.
REVISTA
/ JOURNAL: - Expert Opin Investig Drugs 2003
Apr;12(4):647-53.
AUTORES
/ AUTHORS: - Eckstein JW; Fung J
INSTITUCIÓN
/ INSTITUTION: - Enanta Pharmaceuticals,500 Arsenal Street,
Watertown, MA 02472, USA. eckstein@enanta.com
RESUMEN
/ SUMMARY: - The disease management of asthma - in
particular severe and steroid-resistant asthma - remains a real and daily
challenge in the clinic. Cyclosporin A has been a mainstay of immunosuppression
therapy in organ transplantation for many years. While its application clearly
is efficacious in the inhibition of T-cell proliferation and results in the
decrease of inflammatory processes, its side effects in long-term use manifested
most prominently through nephrotoxicity have been the main concern against
broader use of the drug in inflammatory and immune diseases other than organ
transplantation. Several new strategies are currently being pursued to address
cyclosporin A toxicity, as summarised in this review. The improved safety
profile of novel cyclosporin analogues appear to promise potential new
treatments of asthma. N.
Ref:: 48
----------------------------------------------------
[167]
TÍTULO / TITLE: - Use of basiliximab in
pediatric liver transplantation for Langerhans cell histiocytosis.
REVISTA
/ JOURNAL: - Pediatr Transplant 2003 Jun;7(3):247-51.
AUTORES
/ AUTHORS: - Rajwal SR; Stringer MD; Davison SM;
Gerrard M; Glaser A; Tanner MS; McClean P
INSTITUCIÓN
/ INSTITUTION: - Children’s Liver and G.I. Unit, St James’s
University Hospital, Leeds, UK.
RESUMEN
/ SUMMARY: - This report describes a 16-month-old girl
with multi-system Langerhans cell histiocytosis (LCH), who developed end-stage
liver disease despite intensive chemotherapy. She underwent a liver transplant
at 28 months of age while receiving maintenance chemotherapy for bony lesions.
In view of previous reports of a high incidence of acute cellular rejection and
post-transplant lymphoproliferative disease (PTLD) in children transplanted for
LCH, basiliximab was added to the post-transplant immunosuppression regime of
tacrolimus and prednisolone. Sixteen months post-transplant, she has had no
episodes of acute rejection or PTLD and her LCH has remained in remission.
Current literature regarding liver transplantation (LTx) for LCH and the use of
basiliximab in pediatric LTx is reviewed.
N. Ref:: 17
----------------------------------------------------
[168]
TÍTULO / TITLE: - Oral lichen planus:
clinical presentation and management.
REVISTA
/ JOURNAL: - J Can Dent Assoc 2002 Sep;68(8):494-9.
AUTORES
/ AUTHORS: - Edwards PC; Kelsch R
INSTITUCIÓN
/ INSTITUTION: - Department of Dental Medicine, Long Island
Jewish Medical Center, New Hyde Park, New York 11040, USA. dental919@hotmail.com
RESUMEN
/ SUMMARY: - Oral lichen planus (OLP) is a chronic
mucosal condition commonly encountered in clinical dental practice. Lichen
planus is believed to represent an abnormal immune response in which epithelial
cells are recognized as foreign, secondary to changes in the antigenicity of
the cell surface. It has various oral manifestations, the reticular form being
the most common. The erosive and atrophic forms of OLP are less common, yet are
most likely to cause symptoms. Topical corticosteroids constitute the mainstay
of treatment for symptomatic lesions of OLP. Recalcitrant lesions can be
treated with systemic steroids or other systemic medications. However, there is
only weak evidence that these treatments are superior to placebo. Given reports
of a slightly greater risk of squamous cell carcinoma developing in areas of
erosive OLP, it is important for clinicians to maintain a high index of
suspicion for all intraoral lichenoid lesions. Periodic follow-up of all
patients with OLP is recommended. N.
Ref:: 36
----------------------------------------------------
[169]
TÍTULO / TITLE: - Immunosuppression with
limited toxicity: the characteristics of nucleoside analogs and anti-lymphocyte
antibodies used in non-myeloablative hematopoietic cell transplantation.
REVISTA
/ JOURNAL: - Cancer Treat Res 2002;110:39-49.
AUTORES
/ AUTHORS: - Bashey A
INSTITUCIÓN
/ INSTITUTION: - Blood and Marrow Transplantation Division,
University of California San Diego, Department of Medicine, UCSD Cancer Center,
La Jolla, CA 92093-0960, USA.
RESUMEN
/ SUMMARY: - The availability of two groups of
pharmacologic agents, the nucleoside analogs and anti-lymphocyte antibody
preparations of various specificities has enabled the development of NST.
Although these agents are significantly less cytotoxic than high-dose
alkylating agents and total-body irradiation (TBI), they are profoundly
immunosuppressive. Opportunistic infections such as the reactivation of cytomegalovirus
remain clinical obstacles when NST are performed using these agents, especially
in elderly and previously immunosuppressed patients. For anti-lymphocyte
antibody preparations, the degree of immunosuppression produced and hence the
risk of opportunistic infection varies depending upon specificity of the
antibody (broad versus narrow). Allergic reactions and infusion related
toxicity can occur with any antibody preparation, but the infusion of
muromonab-CD3 is sometimes associated with a particularly potent
cytokine-release syndrome. Although fludarabine has been the mainstay of
nucleoside analog usage for NST, the other nucleoside analogs-cladribine and
pentostatin are beginning to be investigated in this context. N. Ref:: 12
----------------------------------------------------
[170]
TÍTULO / TITLE: - Pharmacogenomic
considerations for immunosuppressive therapy.
REVISTA
/ JOURNAL: - Pharmacogenomics 2003 May;4(3):309-19.
AUTORES
/ AUTHORS: - Yagil Y; Yagil C
INSTITUCIÓN
/ INSTITUTION: - Department of Nephrology and Hypertension,
Faculty of Health Sciences, Ben-Gurion University Barzilai Medical Center
Campus, Ashkelon 78306, Israel. labmomed@bgumail.bgu.ac.il
RESUMEN
/ SUMMARY: - Immunosuppression, the art of suppressing
the endogenous immune system to allow organ transplantation or treatment of
autoimmune disease, is a clinico-pharmacological field that has markedly
developed over the past three decades with the advent of highly potent and rationally
targeted immunosuppressive agents. Pharmacogenomics, the art of providing
tailored pharmacological therapy with the highest therapeutic index based on
the genomic composition of the individual, is a science that has rapidly
developed over the past decade, along with the advances in the human genome
project and in biotechnology. Pharmacogenomics of immunosuppression is the
combined art of tailoring specific immunosuppressive drug therapy to specific
immune-mediated clinical entities which require immunosuppression, with optimum
matching of the drug to the individual’s genomic makeup. Timely and judicious
application of pharmacogenomics to clinical immunosuppression should direct the
clinician to the best immunosuppressive drug for any given clinical condition,
and markedly increase its efficacy as well as decreasing the incidence of side
effects and toxicity, thereby decreasing morbidity and prolonging survival. Is
this a description of an ongoing clinical evolution in immunosuppression or a
prediction of future events? The promises of pharmacogenomics of
immunosuppression are high, yet the availability and/or application and/or
realization of the promises of this highly specialized clinical science are
very slow to come. N.
Ref:: 20
----------------------------------------------------
[171]
TÍTULO / TITLE: - Control of translation
by the target of rapamycin proteins.
REVISTA
/ JOURNAL: - Prog Mol Subcell Biol 2001;27:143-74.
AUTORES
/ AUTHORS: - Gingras AC; Raught B; Sonenberg N
INSTITUCIÓN
/ INSTITUTION: - Department of Biochemistry and McGill
Cancer Centre, McGill University, 3655 Dummond Street, Montreal, Quebec, H3G
1Y6, Canada. N.
Ref:: 181
----------------------------------------------------
[172]
TÍTULO / TITLE: - Interaction of
cyclosporine A and the renin-angiotensin system; new perspectives.
REVISTA
/ JOURNAL: - Curr Drug Metab 2002 Feb;3(1):61-71.
AUTORES
/ AUTHORS: - Lassila M
INSTITUCIÓN
/ INSTITUTION: - Institute of Biomedicine, Pharmacology,
Biomedicum Helsinki, University of Helsinki, Finland. markus.lassila@helsinki.fi
RESUMEN
/ SUMMARY: - Despite extensive research, the exact
mechanisms of cyclosporine A (CsA)-induced hypertension and nephrotoxicity
remain obscure. Several lines of evidence suggest an involvement of the
renin-angiotensin system (RAS) in CsA toxicity, but the issue is still
controversial in more ways than one. Some interesting data of the interaction
of CsA and RAS have been presented by us and others during the last years. In
rats, activation of RAS by CsA is a consistent finding while the results from
clinical studies show controversial results. The mechanisms of activation of
RAS may be multifactorial. CsA increases renin release directly from
juxtaglomerular cells. However, RAS activation may at least partly account for
glomerular ischemia by vasoconstriction. A totally different view about the
interaction of CsA and RAS has recently been presented. CsA antagonised the
harmful effects of RAS over-expression on renal damage in double transgenic
rats harbouring human renin and angiotensinogen genes. The protection was due
to anti-inflammatory properties of CsA by inhibition of interleukin-6 and
inducible nitric oxide synthase (iNOS) expression. Other studies have confirmed
the inhibitory effect of CsA on iNOS. Calcium antagonists have been proposed to
be the antihypertensive drugs of choice in treatment of CsA-induced
hypertension because of their favourable haemodynamic effects on the kidneys.
However, because angiotensin II plays a major role in the development of
CsA-induced structural renal damage, pharmacological inhibition of RAS in
CsA-treatment may have some beneficial effects beyond blood pressure
control. N. Ref:: 120
----------------------------------------------------
[173]
TÍTULO / TITLE: - The pharmacogenetics of
immunosuppression for organ transplantation: a route to individualization of
drug administration.
REVISTA
/ JOURNAL: - Am J Pharmacogenomics 2003;3(5):291-301.
AUTORES
/ AUTHORS: - Fredericks S; Holt DW; MacPhee IA
INSTITUCIÓN
/ INSTITUTION: - Department of Cardiovascular Medicine,
Analytical Unit, St George’s Hospital Medical School, Cranmer Terrace, London
SW17 0RE, UK.
RESUMEN
/ SUMMARY: - Transplantation has transformed the
treatment of patients with organ failure in a number of clinical settings, and
immunosuppressive drug therapy is fundamental to its success. However, all the
drugs in current use have a narrow therapeutic index. Under-dosing can lead to
rejection, while over-dosing increases the risks of infection, malignant
disease, and serious drug-specific adverse effects, including diabetes
mellitus, nephrotoxicity, hypertension, and hyperlipidemia.Heterogeneity in the
pharmacokinetics of these drugs makes initial dose determination difficult, as
there is a poor correlation between dose and blood concentration. This results
in difficulties in achieving target blood concentrations early after
transplantation, which are important for reducing the rate of immunological
rejection. This problem is compounded by the observation that neither drug dose
nor drug blood concentration accurately predict clinical efficacy or
toxicity.The main determinant of heterogeneity in dose requirements is
intestinal absorption of the active drug. The oxidative enzymes, cytochrome
P450 (CYP) 3A4 and CYP3A5, and the drug efflux pump P-glycoprotein (P-gp) in
enterocytes regulate this process. Most substrates for the P-gp pump are also
substrates for the CYP3A enzymes. An efficient barrier to xenobiotic absorption
is formed by the CYP enzymes and P-gp, and by the two systems working
synergistically. Genetic polymorphisms have been reported for the genes
associated with the expression of the CYP3A enzymes and P-gp. Genotyping
patients for CYP3A genes has the potential to aid the establishment of optimal
dosage regimens for transplant patients.Genetic polymorphism of the multiple
drug resistance gene-1 (MDR1, also known as ABCB1) [3435C/T] and the CYP3A5
genes (CYP3A5*1, CYP3AP1*1) have the greatest potential to influence the
pharmacokinetics of immunosuppressants. Homozygosity of the T allele of the
MDR1 3435C/T polymorphism has been associated with reduced enterocyte
expression of P-gp resulting in increased drug absorption. The presence of the
CYP3A5*1 allele is necessary for the production of a fully catalytic CYP3A5
protein, and also influences the ratio of CYP3A4 : CYP3A5 as well as the
overall CYP3A catalytic activity. The CYP3A4 : CYP3A5 ratio may, in turn,
influence the pattern of drug metabolites formed. Heterogeneity in the
production of active and inactive metabolites has implications for both the
pharmacokinetics and pharmacodynamics of these drugs.Gene frequencies and drug
dose requirements differ between ethnic groups. Ethnic differences in dose requirements
for immunosuppressants have been discussed widely. However, ethnicity is a
rather crude marker for genotype. Pharmacogenetic typing offers the possibility
of significant improvement in the individualization of immunosuppressive drug
prescribing with reduced rates of rejection and toxicity. N. Ref:: 145
----------------------------------------------------
[174]
TÍTULO / TITLE: - Mammalian target of
rapamycin: a new molecular target for breast cancer.
REVISTA
/ JOURNAL: - Clin Breast Cancer 2003 Jun;4(2):126-37.
AUTORES
/ AUTHORS: - Mita MM; Mita A; Rowinsky EK
INSTITUCIÓN
/ INSTITUTION: - Institute for Drug Development, Cancer
Therapy and Research Center, San Antonio, TX, USA. mmita@idd.org
RESUMEN
/ SUMMARY: - The mammalian target of rapamycin (mTOR),
a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein
kinase B) signaling pathway that mediates cell survival and proliferation, is a
prime strategic target for anticancer therapeutic development. By targeting
mTOR, the immunosuppressant and antiproliferative agent rapamycin inhibits
signals required for cell cycle progression, cell growth, and proliferation.
Both rapamycin and novel rapamycin analogues with more favorable pharmaceutical
properties, such as CCI-779, RAD 001, and AP23573, are highly specific
inhibitors of mTOR. In essence, these agents gain function by binding to the
immunophilin FK506 binding protein 12 and the resultant complex inhibits the
activity of mTOR. Because mTOR activates both the 40S ribosomal protein S6
kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1,
rapamycin-like compounds block the actions of these downstream signaling
elements, which results in cell cycle arrest in the G1 phase. Rapamycin and its
analogues also prevent cyclin-dependent kinase (CDK) activation, inhibit
retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin
D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which
potentially contribute to the prominent inhibitory effects of rapamycin at the
G1/S boundary of the cell cycle. Rapamycin and rapamycin analogues have
demonstrated impressive growth-inhibitory effects against a broad range of
human cancers, including breast cancer, in preclinical and early clinical
evaluations. In breast cancer cells, PI3K/Akt and mTOR pathways seem to be
critical for the proliferative responses mediated by the epidermal growth
factor receptor, the insulin growth factor receptor, and the estrogen receptor.
Furthermore, these pathways may be constitutively activated in cancers with
many types of aberrations, including those with loss of PTEN suppressor gene
function. Therefore, the development of inhibitors of mTOR and related pathways
is a rational therapeutic strategy for breast and other malignancies that
possess a wide range of aberrant molecular constituents. This review will
summarize the principal mechanisms of action of rapamycin and rapamycin
derivatives, as well as the potential utility of these agents as anticancer
therapeutic agents with an emphasis on breast cancer. The preliminary results
of early clinical evaluations with rapamycin analogues and the unique
developmental challenges that lie ahead will also be discussed. N. Ref:: 148
----------------------------------------------------
[175]
TÍTULO / TITLE: - NF-kappaB in
transplantation: friend or foe?
REVISTA
/ JOURNAL: - Transpl Infect Dis 2001 Dec;3(4):212-9.
AUTORES
/ AUTHORS: - Tsoulfas G; Geller DA
INSTITUCIÓN
/ INSTITUTION: - Department of Surgery, University of
Pittsburgh, Starzl Transplant Institute, Pittsburgh, Pennsylvania 15213, USA.
RESUMEN
/ SUMMARY: - NF-kappaB is an inducible nuclear
transcription factor regulating the expression of many genes. NF-kappaB
activation may function as a master switch in a variety of immune and
inflammatory processes, including sepsis and transplant tolerance. In this
review, we summarize features of NF-kappaB regulation, as well as describe its
role in intracellular signal transduction pathways. Subsequently, we
concentrate on the role of NF-kappaB in the field of organ transplantation and
the role of NF-kappaB in organ ischemia/reperfusion injury and graft rejection.
Finally, potential therapeutic strategies are discussed to modify NF-kappaB activity
with certain immunosuppression medications, including cyclosporine, tacrolimus,
and glucocorticoids. N.
Ref:: 54
----------------------------------------------------
[176]
TÍTULO / TITLE: - Non-ribosomal peptide
synthetases as technological platforms for the synthesis of highly modified
peptide bioeffectors—Cyclosporin synthetase as a complex example.
REVISTA
/ JOURNAL: - Biotechnol Annu Rev 2003;9:151-97.
AUTORES
/ AUTHORS: - Velkov T; Lawen A
INSTITUCIÓN
/ INSTITUTION: - Monash University, Department of
Biochemistry and Molecular Biology, School of Biomedical Sciences, P.O. Box
13D, Melbourne, Victoria 3800, Australia.
RESUMEN
/ SUMMARY: - Many microbial peptide secondary
metabolites possess important medicinal properties, of which the immunosuppressant
cyclosporin A is an example. The enormous structural and functional diversity
of these low-molecular weight peptides is attributable to their mode of
biosynthesis. Peptide secondary metabolites are assembled non-ribosomally by
multi-functional enzymes, termed non-ribosomal peptide synthetases. These
systems consist of a multi-modular arrangement of the functional domains
responsible for the catalysis of the partial reactions of peptide assembly. The
extensive homology shared among NRPS systems allows for the generalisation of
the knowledge garnered from studies of systems of diverse origins. In this
review we shall focus the contemporary knowledge of non-ribosomal peptide
biosynthesis on the structure and function of the cyclosporin biosynthetic
system, with some emphasis on the re-direction of the biosynthetic potential of
this system by combinatorial approaches.
N. Ref:: 205
----------------------------------------------------
[177]
TÍTULO / TITLE: - Role of plasma
lipoproteins in modifying the toxic effects of water-insoluble drugs: studies
with cyclosporine A.
REVISTA
/ JOURNAL: - AAPS PharmSci 2002;4(4):E30.
●●
Enlace al texto completo (gratuito o de pago) 1208/ps040430
AUTORES
/ AUTHORS: - Wasan KM; Ramaswamy M; Kwong M; Boulanger
KD
INSTITUCIÓN
/ INSTITUTION: - Division of Pharmaceutics and
Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British
Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Kwasan@interchange.ubc.ca
RESUMEN
/ SUMMARY: - Lipoproteins are a heterogeneous population
of macromolecular aggregates of lipids and proteins that are responsible for
the transport of lipids through the vascular and extravascular fluids from
their site of synthesis or absorption to peripheral tissues. Lipoproteins are
involved in other biological processes as well, including coagulation and
tissue repair, and serve as carriers of a number of hydrophobic compounds
within the systemic circulation. It has been well documented that disease
states (eg, AIDS, diabetes, cancer) significantly influence circulating
lipoprotein content and composition. Therefore, it appears possible that
changes in the lipoprotein profile would affect not only the ability of a
compound to associate with lipoproteins but also the distribution of the
compound within the lipoprotein subclasses. Such an effect could alter the
pharmacokinetics and pharmacological action of the drug. This paper reviews the
factors that influence the interaction of one model hydrophobic compound,
cyclosporine A, with lipoproteins and the implications of altered plasma
lipoprotein concentrations on the pharmacological behavior of this
compound. N. Ref:: 28
----------------------------------------------------
[178]
TÍTULO / TITLE: - Safety and tolerability
of caspofungin acetate in the treatment of fungal infections.
REVISTA
/ JOURNAL: - Transpl Infect Dis 2002 Mar;4(1):25-30.
AUTORES
/ AUTHORS: - Sable CA; Nguyen BY; Chodakewitz JA;
DiNubile MJ
INSTITUCIÓN
/ INSTITUTION: - Department of Infectious Diseases, Merck
Research Laboratories, West Point, Pennsylvania 19486, USA.
RESUMEN
/ SUMMARY: - Caspofungin acetate is the first member of
the novel echinocandin class of antifungal drugs to be marketed in the United
States. It has recently been approved for use in patients with invasive aspergillosis
who are refractory to or intolerant of conventional therapy. Accordingly, its
safety profile is particularly important to review. The safety and tolerability
of caspofungin have been examined in 623 persons, including 295 patients who
received >/= 50 mg/day for at least one week in clinical studies. In the 263
patients, given caspofungin in randomized double-blind active-control trials to
date, there have been no serious clinical or laboratory drug-related adverse
events; caspofungin was discontinued in only 2% of these patients because of
drug-related adverse experiences. Caspofungin may have potentially important
drug interactions with cyclosporine and tacrolimus. N. Ref:: 13
----------------------------------------------------
[179]
TÍTULO / TITLE: - Creating polyketide
diversity through genetic engineering.
REVISTA
/ JOURNAL: - Front Biosci 2003 Jan 1;8:c1-13.
AUTORES
/ AUTHORS: - Kealey JT
INSTITUCIÓN
/ INSTITUTION: - Kosan Biosciences, 3832 Bay Center Place,
Hayward, CA 94545, USA. kealey@kosan.com
RESUMEN
/ SUMMARY: - Modular polyketide synthases (PKS) are
large multifunctional enzymes that synthesize complex polyketides, a
therapeutically important class of natural products. The linear order and
composition of catalytic sites that comprise the PKS represent a “code” that
determines the identity of the polyketide product. By re-programming the PKS
through genetic engineering, it is possible to alter the code in a predictable
manner to create specific structural modifications of polyketides and to
produce new libraries of these natural products. N. Ref:: 43
----------------------------------------------------
[180]
TÍTULO / TITLE: - Molecular actions of
calcineurin inhibitors.
REVISTA
/ JOURNAL: - Drug News Perspect 2003 Jun;16(5):277-82.
AUTORES
/ AUTHORS: - Hamawy MM
INSTITUCIÓN
/ INSTITUTION: - Department of Surgery, Division of
Transplantation, University of Wisconsin, H4/749, CSC 600 Highland Avenue,
Madison, WI 53792, USA. hamawy@surgery.wisc.edu
RESUMEN
/ SUMMARY: - The immunosuppressive drugs cyclosporin A
and FK-506, also called calcineurin inhibitors, have been useful for treating
immune system-mediated diseases and have truly revolutionized allograft
transplantation. Both drugs block T-cell proliferation by mechanisms that
involve the inhibition of the key signaling phosphatase calcineurin, hence, the
name calcineurin inhibitors. The inhibition of calcineurin activation by
cyclosporin A and FK-506 blocks T-cell receptor-mediated production of
interleukin-2 (IL-2), a growth factor critical for T-cell proliferation. Recent
studies, however, suggest that the effects of the drugs are not limited to
blocking calcineurin activation and IL-2 production. This review discusses the
molecular actions of cyclosporin A and FK-506.
N. Ref:: 79
----------------------------------------------------
[181]
TÍTULO / TITLE: - Current thinking in
atopic eczema.
REVISTA
/ JOURNAL: - Practitioner 2003 Oct;247(1651):806-10.
AUTORES
/ AUTHORS: - Katugampola R; Finlay AY
INSTITUCIÓN
/ INSTITUTION: - Department of Dermatology, University
Hospital of Wales, Cardiff. N.
Ref:: 16
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[182]
TÍTULO / TITLE: - Daclizumab as induction
therapy in kidney and simultaneous pancreas-kidney transplantation.
REVISTA
/ JOURNAL: - Minerva Urol Nefrol 2003 Mar;55(1):43-56.
AUTORES
/ AUTHORS: - Ciancio G; Mattiazzi A; Miller J; Burke GW
INSTITUCIÓN
/ INSTITUTION: - Division of Transplantation, Department of
Surgery, University of Miami School of Medicine, Miami, FL 33101, USA. gciancio@med.miami.edu
RESUMEN
/ SUMMARY: - Acute rejection still remains a major
problem in organ transplantation and is a significant risk factor for chronic
rejection, and chronic rejection is one of the most important causes of late
graft loss. Current new immunosuppressive drugs such as tacrolimus, rapamycin
and mycophenolate mofetil have been developed to reduce acute rejection and to
improve renal allograft survival. More recently, antihuman antibodies, either
monoclonal or polyclonal, have been developed to use for induction therapy at
the time of transplantation or to treat rejection. Daclizumab, a new engineered
human immunoglobulin monoclonal antibody to the interleukin-2 receptor
a-subunit was approved to prevent acute rejection after solid organ
transplantation. Data from clinical trials show daclizumab to be well tolerated
in solid organ transplantation. It does not increase the incidence of
infection, including cytomegalovirus infection. N. Ref:: 72
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[183]
TÍTULO / TITLE: - Modulation of inducible
nitric oxide synthase activation by immunosuppressive drugs.
REVISTA
/ JOURNAL: - Curr Drug Metab 2001 Sep;2(3):315-29.
AUTORES
/ AUTHORS: - Trajkovic V
INSTITUCIÓN
/ INSTITUTION: - Institute of Microbiology and Immunology,
Medical School, University of Belgrade, Yugoslavia. vladtr@eunet.yu
RESUMEN
/ SUMMARY: - The activation of inducible form of nitric
oxide (NO) synthase (iNOS, type II, or macrophage NOS) and subsequent
production of free radical gas NO is an important anti-infectious and
anti-tumor mechanism of innate immunity. On the other hand, high amounts of
iNOS-derived NO have been implicated in self-tissue destruction during
autoimmune diseases, allograft rejection, sepsis, and other disorders
accompanied by excessive activation of the immune system. It is generally
accepted that beneficial effects of some recently designed immunosuppressive
agents primarily stem froin their ability to interfere with the function of T
and/or B cells, thus preventing deleterious consequences of specific
immunity-innate immunity positive feedback, with high NO production being one
of them. However, it has been recently observed that drugs like cyclosporin A,
FK506, leflunomide, mycophenolate mofetil, pentoxifylline, and linomide can
directly modulate cytokine and/or LPS-induced NO production in various cell
types in vitro, probably by interfering with iNOS gene transcription or
catalytic activity of iNOS enzyme. Interestingly, some of these drugs exhibited
cell-specific pattern of iNOS modulation, thus indirectly revealing distinct
requirements for iNOS induction in different cell types. Possible impact of
this direct and cell-selective interference with iNOS activation on the
therapeutic effectiveness of immunosuppressive drugs is discussed. N. Ref:: 128
----------------------------------------------------
[184]
TÍTULO / TITLE: - Review: metabolism of
immunosuppressant drugs.
REVISTA
/ JOURNAL: - Curr Drug Metab 2002 Jun;3(3):275-87.
AUTORES
/ AUTHORS: - Kelly P; Kahan BD
INSTITUCIÓN
/ INSTITUTION: - Novartis Pharmaceuticals Corp., Medical
Affairs/Transplantation, Summit, NJ 07901, USA.
RESUMEN
/ SUMMARY: - Pharmacokinetic concepts provide a basis
for individualization of drug therapy to optimize outcomes of the critical-dose
drugs cyclosporine (CsA), tacrolimus (TRL), sirolimus (SRL), and mycophenolate
mofetil (MMF). The therapeutic range of a drug-defined as the concentrations at
which the desired pharmacologic effect is produced without adverse effects in
most patients-is difficult to achieve given the significant inter-and
intrapatient variability of the effects of a given concentration of therapeutic
agents. Because of the highly variable rates of absorption of immunosuppressive
agents and clinical responses to given concentrations in transplant recipients,
individualization of drug regimens by using therapeutic drug monitoring (TDM)
is essential to optimize pharmacotherapy Assessing proclivity for acute
rejection episodes in transplant recipients currently is attempted by
estimating drug exposure using the area under the time-concentration curve
(AUC) for MMF and the average concentration (Cav, the quotient of the AUC and
the dosing interval) for CsA. These studies have revealed that low oral
bioavailability was a more important predictor of rejection than was a rapid
clearance rate. In addition, the degree of intra-individual variability of AUC
values correlated with the development of chronic rejection in renal transplant
recipients. Similarly, TDM of MMF requires AUC determinations. Low mycophenolic
acid (MPA) exposure, as estimated by the AUC, demonstrates a significant
association with an increased risk of an acute renal transplant rejection
episode. The AUC0-2 estimate of MPA shows good agreement with the 12-hr AUC
estimate from samples obtained during the entire dosing interval. In contrast,
trough levels are utilized during treatment with TRL or SRL, potent new
immunosuppressive agents that display a pleiotropic array of side effects.
Standard body measures, including weight and body mass index, poorly predict
the concentration of SRL in whole blood. Large inter- and intra-individual
differences displayed in patients also could not be predicted by demographic
features or by laboratory parameters. When SRL is given with other
immunosuppressive agents such as CsA, which shares with SRL mutual microsomal
metabolism by the cytochrome P450 3A system, pharmacokinetic interactions
occur, especially when the agents are administered concomitantly. Because of
the critical-dose nature of most of the recent generation of immunosuppressive
agents, therapeutic drug monitoring is becoming increasingly important in the
selection of doses and treatment regimens.
N. Ref:: 155
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[185]
TÍTULO / TITLE: - Initial experience with
paclitaxel-coated stents.
REVISTA
/ JOURNAL: - J Interv Cardiol 2002 Dec;15(6):471-5.
AUTORES
/ AUTHORS: - Grube E; Bullesfeld L
INSTITUCIÓN
/ INSTITUTION: - Heart-Center Siegburg, Ringstrasse 49,
53721 Siegburg, Germany. GrubeE@aol.com
RESUMEN
/ SUMMARY: - Local delivery of immunosuppressive or
antiproliferative agents using a drug-eluting stent is a new technology that is
supposed to inhibit in-stent restenosis, thus providing a biological and
mechanical solution. This technique is a very promising. To date, several
agents have been used, including paclitaxel, QP-2, rapamycin, actinomycin D,
dexamethason, tacrolimus, and everolimus. Several studies, published recently
or still ongoing, have evaluated these drugs as to their release kinetics,
effective dosage, safety in clinical practice, and benefit. These studies
include: SCORE (paclitaxel derivative), TAXUS I-VI, ELUTES, ASPECT, DELIVER
(paclitaxel), RAVEL, SIRIUS (sirolimus), ACTION (actinomycin), EVIDENT, PRESENT
(tacrolimus), EMPEROR (dexamethason), and FUTURE (everolimus). Paclitaxel was
one of the first stent-based antiproliferative agents under clinical
investigation that provided profound inhibition of neointimal thickening
depending on delivery duration and drug dosage. The randomized, multicenter
SCORE trail (Quanam stent, paclitaxel-coated) enrolled 266 patients at 17
sites. At 6-month’s follow-up, a drop of 83% in stent restenosis using the
drug-eluting stent could be achieved (6.4% drug-eluting stent vs 36.9% control
group), which was attributable to a remarkable decrease in intimal
proliferation. Unfortunately, due to frequent stent thrombosis and side-branch
occlusions, the reported 30-day MACE rate was 10.2%. The randomized TAXUS-I
safety trial (BSC, NIRx, paclitaxel-coated) also demonstrated beneficial
reduction of restenotic lesions at 6-month’s follow-up (0% vs 10%) but was
associated with the absence of thrombotic events presumably due to less drug
dosage. The ongoing TAXUS II-VI trials are addressing additional insight
regarding the efficacy of the TAXUS paclitaxel-eluting stent. ASPECT and ELUTES
evaluated paclitaxel-coated stents (i.e., Cook and Supra G), including
subgroups with different drug dosages. With respect to stent restenosis and
neointimal proliferation, both studies demonstrated a clear dose response. The
RAVEL and the SIRIUS trials evaluated sirolimus-coated stents (i.e., Cordis,
Johnson & Johnson, and Bx VELOCITY stents). Results confirmed the
beneficial findings regarding reduction of renarrowing using a drug-eluting
stent without any major adverse effects. Although parameters such as drug
toxicity, optimal drug dosage, or delayed endothelial healing still need to be
evaluated, today’s clinical experience indicates that drug-coated stents are
extremely beneficial in the interventional treatment of coronary lesions. N. Ref:: 20
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[186]
TÍTULO / TITLE: - Metabolic aspects of
tacrolimus in renal transplantation. Consequences for the choice of an
immunosuppressive regimen and for the management of post-transplant diabetes
mellitus.
REVISTA
/ JOURNAL: - Minerva Urol Nefrol 2003 Mar;55(1):33-42.
AUTORES
/ AUTHORS: - van Duijnhoven EM; Boots JM; Christiaans
MH; van Hooff JP
INSTITUCIÓN
/ INSTITUTION: - Department of Internal Medicine,University
Hospital Maastricht, Maastricht, The Netherlands. evd@sint.azm.nl
RESUMEN
/ SUMMARY: - The occurrence of post-transplant diabetes
mellitus (PTDM) is an important complication after renal transplantation
associated with an increased risk of chronic transplant dysfunction and of
cardiovascular morbidity and mortality. Both tacrolimus and cyclosporine have
been associated with PTDM. In the initial studies, PTDM seemed to occur more
often in tacrolimus treated patients than in cyclosporine treated patients. The
mechanism by which tacrolimus could cause PTDM was unknown and the relative
roles of tacrolimus and corticosteroids, which are often prescribed concomitantly
with tacrolimus, were unknown. In several studies we used fasting glucose and
insulin levels to assess (peripheral) insulin resistance, and intravenous
glucose tolerance tests to assess insulin secretion by the pancreatic b-cells
in response to a stimulus (glucose load). Thus, we evaluated the mechanism by
which tacrolimus causes glucose metabolic disorders, risk factors for glucose
metabolic disorders during tacrolimus treatment, the relative roles of
corticosteroids and tacrolimus trough levels in glucose metabolic disorders,
and also differences in glucose metabolism between patients using tacrolimus
versus patients using cyclosporine. Based on the results of these studies and
the available literature, the consequences for the choice of a primary immunosuppressive
agent and guidelines for the treatment of PTDM during tacrolimus-based
immunosuppression are discussed. N.
Ref:: 40
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[187]
TÍTULO / TITLE: - New monoclonal
antibodies in renal transplantation.
REVISTA
/ JOURNAL: - Minerva Urol Nefrol 2003 Mar;55(1):57-66.
AUTORES
/ AUTHORS: - Vincenti F
INSTITUCIÓN
/ INSTITUTION: - Kidney Transplant Service, University of
California, San Francisco, CA 94143-0780, USA. vincentif@surgery.ucsf.edu
RESUMEN
/ SUMMARY: - A decade of spectacular innovation in
maintenance immunosuppression drugs has resulted in dramatic reductions in
acute rejection and improvement in short and long term outcome after renal
transplantation. However the new drugs continue to lack specificity, many
require frequent therapeutic drug monitoring and all are associated with acute
and chronic toxicities. The new biologic agents, monoclonal antibodies
(chimeric, humanized, and fully human) and receptor-fusion proteins, lack
immunogenicity, have long half-life and prolonged biologic effects, require
intermittent administration and have minimal toxicity. The specificity and
selectively of the targets of the new biologic agents render them less toxic
than the oral maintenance drugs and thus could possibly replace the maintenance
drugs most associated with long-term toxicity such as the corticosteroids and
the calcineurin inhibitors. The recently introduced anti-interleukin 2 receptor
(IL-2R) monoclonal antibodies (mAbs) are the prototype of future biologic
agents; selective, safe, and inducing prolonged biologic effects. The IL-2R
mAbs have been used with a variety of maintenance immunosuppression regimens
double therapy with cyclosporine and prednisone, triple therapy with
cyclosporine, azathioprine and prednisone and with newer regimens such as
cyclosporine or tacrolimus, mycophenolate mofetil (MMF) and prednisone, and
most recently with sirolimus, MMF and prednisone. The major thrust of the new
biologics in clinical development is to block the co-stimulatory pathway. The
first attempt at blockade of the CD40-CD154 with anti-CD154 mAbs was
disappointing. Anti-CD 154 therapy was associated with thromboembolic events
and acute rejection. Attempts at blocking the CD28-B7s (CD80-CD86) pathway are
currently underway with the receptor fusion protein, LEA29Y a second generation
CTL4Aig, and humanized mAbs to CD 80 and CD86. LFA1, an adhesion molecule that
also participates in the co-stimulatory pathway, has also been targeted with a
mAb that binds to the CD11a chain of LFA1. Efalizumab, a humanized anti-CD11a
mAb, was shown in a phase I trial to be potentially effective in renal
transplantation. A humanized anti-CD45 RB mAb is currently in pre-clinical studies
and will likely be tested in a phase I trial of renal transplantation within 1
year. While excellent results with anti-CD45 RB mAbs have been published in
experimental transplantation, the mechanism of action of anti-CD45 RB mAbs
remains to be determined. Several antibodies that are currently approved for
non-transplant indications are currently used in single center clinical trials
in renal transplantation including Campath 1 H, a humanized anti-CD52 mAb,
Rituxamab, an anti-CD20 chimeric mAb, and Infliximab an anti-TNFa chimeric mAb.
In addition, several humanized mutagenized anti-CD3 mAbs, huOKT3g1, aglycosyl
CD3 and HuM291 have been used in limited trials in renal transplantation but
have yet to have a formal clinical development. Humanized mAbs and receptor
fusion proteins offer the potential of providing renal transplant recipients
with a novel algorithm for immunosuppression that relies on chronic
intermittent intravenous administration of safe, non-toxic agents replacing
oral drug therapy maintenance. N.
Ref:: 50
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[188]
TÍTULO / TITLE: - Molecular mechanisms of
the immunosuppressive effect of erythroid cells.
REVISTA
/ JOURNAL: - Russ J Immunol 2002 Oct;7(3):211-8.
AUTORES
/ AUTHORS: - Kozlov VA
INSTITUCIÓN
/ INSTITUTION: - Institute of Clinical Immunology, Siberian
Branch of RAMS, Yandritsovskaya str. 14, Novosibirsk-99 630099, Russia. v_kozlov@online.nsk.su
RESUMEN
/ SUMMARY: - This review presents data suggesting a new
immunoregulatory role of the erythroid nucleus-containing cells. The three main
mechanisms of the possible immunosuppressive effect of these cells are
described. It has been demonstrated that the erythroid nucleus-containing cells
produce a variety of both pro- and anti-inflammatory cytokines. The p15 protein
(a product of the env gene) is considered to provide a novel immunosuppressive
mechanism. Finally, the existing data suggest that the erythroid
nucleus-containing cells are able to produce an immunosuppressive factor, which
is different from the known cytokines. It has been proposed that the
immunosuppressive effect of the erythroid nucleus-containing cells greatly
contributes to the regulation of the immune homeostasis in normal and
immunopathological conditions. N.
Ref:: 33
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[189]
TÍTULO / TITLE: - Reversal of multidrug
resistance: lessons from clinical oncology.
REVISTA
/ JOURNAL: - Novartis Found Symp 2002;243:83-96;
discussion 96-102, 180-5.
AUTORES
/ AUTHORS: - Bates SF; Chen C; Robey R; Kang M; Figg
WD; Fojo T
INSTITUCIÓN
/ INSTITUTION: - Molecular Therapeutics Section, Medicine
Branch, National Cancer Institute, Bethesda, MD 20892, USA.
RESUMEN
/ SUMMARY: - Modulation of P glycoprotein (Pgp) in
clinical oncology has had limited success. Contributing factors have included
the limitation in our understanding of the tumours in which Pgp overexpression
is mechanistically important in clinical drug resistance; the failure to prove
that concentrations of modulators achieved in patients were sufficient to
inhibit Pgp; and the inability to conclusively prove that Pgp modulation was
occurring in tumours in patients. New approaches are needed to determine the
clinical settings in which Pgp overexpression plays a major role in resistance.
(Clinical trials with third generation modulators are ongoing, including trials
with the compounds LY335979, R101933 and XR9576. Using the Pgp substrate Tc-99m
Sestamibi as an imaging agent, increased uptake has been seen in normal liver
and kidney after administration of PSC 833, VX710 and XR9576. These studies
confirm that the concentrations of modulator achieved in patients are able to
increase uptake of a Pgp substrate. Furthermore, CD56+ cells obtained from
patients treated with PSC 833 demonstrate enhanced rhodamine retention in an ex
vivo assay after administration of the antagonist. Finally, a subset of
patients treated with Pgp antagonists show enhanced Sestamibi retention in imaged
tumours. These results suggest that Pgp modulators can increase drug
accumulation in Pgp-expressing tumours and normal tissues in patients. Using
third generation Pgp antagonists and properly designed clinical trials, it
should be possible to determine the contribution of modulators to the reversal
of clinical drug resistance. N.
Ref:: 40
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[190]
TÍTULO / TITLE: - Clinical development of
P glycoprotein modulators in oncology.
REVISTA
/ JOURNAL: - Novartis Found Symp 2002;243:103-15;
discussion 115-8, 180-5.
AUTORES
/ AUTHORS: - Oza AM
INSTITUCIÓN
/ INSTITUTION: - Princess Margaret Hospital, Toronto,
Ontario, Canada.
RESUMEN
/ SUMMARY: - The last two decades have witnessed
dramatic advances into the mechanisms of drug resistance in cancer. The
identification of P glycoprotein (Pgp) as a specific mechanism led to the
initial hope and expectation that it would be possible to modulate this and
increase sensitivity to drug therapy. Clinical trials using first- and
second-generation Pgp modulators did establish proof of principle that in some
settings, clinical drug resistance could be overcome with the addition of a Pgp
modulator-for example, clinical resistance to paclitaxel, a Pgp substrate, in
women with ovarian cancer was shown to be overcome in approximately 20% with
the addition of PSC 833, a highly effective Pgp modulator. However,
evolutionary and adaptive redundancy in resistance mechanisms have tempered
clinical results, even with very effective second- and third-generation
modulators. The lessons from oncology establish sound methodology for the
evaluation of Pgp modulators for safety, tolerability and efficacy in Phase I,
II and III clinical trials. This review will focus on some of the early-phase
clinical trials with earlier and newer Pgp modulators, either as single agents
or in combination with chemotherapy. N.
Ref:: 46
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