Journal ArticleDOI
The temporal profile of calcineurin inhibition by cyclosporine in vivo.
TLDR
CsA induces partial CN inhibition that varies directly with the blood and tissue levels, and may be greater in some tissues due to higher drug accumulation, relevant to nephrotoxicity.Abstract:
Background Cyclosporine (CsA) acts by inhibiting the phosphatase calcineurin (CN), but the time course and extent of inhibition in vivo are unknown. We examined the effect of single oral CsA doses on CN activity in humans and mice in vivo. Methods In humans, blood CsA levels were determined and CN activity was measured in whole blood and in blood leukocytes of patients up to 12 hr after CsA dosing (just before the second dose). Samples were collected from patients receiving a first single dose (2.5 mg/kg), and up to 14 days later after repeated dosing. In mice, after CsA dosing (12.5-200 mg/kg) by oral gavage, CsA levels in blood and tissue (spleen, kidney) were determined and CN activity was measured in spleen and kidney. Results In humans, peak CsA levels of 800-2285 microg/L at 1-2 hr produced 70-96% CN inhibition. Inhibition correlated closely with the rise and fall of CsA levels with no observable lag at the times sampled. Repeated doses showed similar CN inhibition to first dose, with no significant adaptation. In mice, CsA peaked at 1 hr in blood, spleen, and kidney, with higher concentrations in spleen and kidney than in blood. CN inhibition closely followed CsA concentrations/doses, and was greater in kidney than spleen. Conclusion Thus CsA induces partial CN inhibition that varies directly with the blood and tissue levels, and may be greater in some tissues due to higher drug accumulation. The high CsA concentrations and CN inhibition in kidney may be relevant to nephrotoxicity.read more
Citations
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Journal ArticleDOI
Calcineurin Inhibitor Nephrotoxicity
TL;DR: The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cycloporine or tacolimus could be more important than systemic exposure.
Journal ArticleDOI
Recommendations for the Outpatient Surveillance of Renal Transplant Recipients
Bertram L. Kasiske,Bertram L. Kasiske,Miguel A. Vazquez,William E. Harmon,Robert S. Brown,Gabriel M. Danovitch,Robert S. Gaston,David M. Roth,John D. Scandling,Gary G. Singer +9 more
TL;DR: These guidelines are applicable to all adult and pediatric renal transplant recipients, and they cover the outpatient screening for and prevention of diseases and complications that commonly occur after renal transplantation.
Journal ArticleDOI
Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy : Second Consensus Report
Mercè Brunet,Teun van Gelder,Anders Åsberg,Vincent Haufroid,Vincent Haufroid,Dennis A. Hesselink,Loralie J. Langman,Florian Lemaitre,Pierre Marquet,Christoph Seger,Maria Shipkova,Alexander A. Vinks,Alexander A. Vinks,Pierre Wallemacq,Eberhard Wieland,Jean-Baptiste Woillard,Markus J. Barten,Klemens Budde,Helena Colom,Maja Theresa Dieterlen,Laure Elens,Kamisha L. Johnson-Davis,Paweł K. Kunicki,Iain MacPhee,Satohiro Masuda,Binu S. Mathew,Olga Millán,Tomoyuki Mizuno,Tomoyuki Mizuno,Dirk Jan A.R. Moes,Caroline Monchaud,Ofelia Noceti,Tomasz Pawinski,Nicolas Picard,Ron H.N. van Schaik,Claudia Sommerer,Nils Tore Vethe,Brenda C. M. de Winter,Uwe Christians,Stein Bergan +39 more
TL;DR: It is concluded that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade, and the Expert Committee concludes that Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacolimus therapy and to improve long-term outcomes for treated patients.
Journal ArticleDOI
Therapeutic drug monitoring of immunosuppressant drugs in clinical practice
TL;DR: Current data on TDM of the following immunosuppressant drugs used in organ transplantation are summarized, and recent findings indicate that monitoring of drug levels 2 hours after dosing is a more sensitive predictor of outcome than trough (C0) monitoring.
Journal ArticleDOI
Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies.
Stefan Vitko,H. Tedesco,Josette Eris,Julio Pascual,J. Whelchel,John C. Magee,Scott B. Campbell,Giovanni Civati,Bernard Bourbigot,Gentil Alves Filho,John Leone,Valter Duro Garcia,Paolo Rigotti,Ronaldo de Matos Esmeraldo,Vincenzo Cambi,Tomas Haas,Annette Jappe,Peter Bernhardt,Johanna Geissler,Nathalie Cretin +19 more
TL;DR: Concentration‐controlled everolimus with low‐exposure CsA provided effective protection against rejection with good renal function in de novo renal transplant patients.
References
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Journal ArticleDOI
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes
Jun Liu,Jesse D. Farmer,Willam S. Lane,Jeffrey S. Friedman,Irving L. Weissman,Stuart L. Schreiber +5 more
TL;DR: The results suggest that calcineurin is involved in a common step associated with T cell receptor and IgE receptor signaling pathways and that cyclophilin and FKBP mediate the actions of CsA and Fk506 by forming drug-dependent complexes with and altering the activity of calcineURin-calmodulin.
Journal ArticleDOI
The mechanism of action of cyclosporin A and FK506
TL;DR: Recent findings that indicate CsA and FK506 operate as prodrugs are reviewed: they bind endogenous intracellular receptors, the immunophilins, and the resulting complex targets the protein phosphatase, calcineurin, to exert the immunosuppressive effect.
Journal ArticleDOI
Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation
TL;DR: It is reported here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription.
Journal ArticleDOI
Biological effects of cyclosporin A: A new antilymphocytic agent
TL;DR: Experimental evidence suggests that cyclosporin A affects an early stage of mitogenic triggering of the immunocompetent lymphoid cell, which contrasts with other immunosuppressives and cytostatic drugs in its weak myelotoxicity.
Journal ArticleDOI
JNK is involved in signal integration during costimulation of T lymphocytes
TL;DR: In this article, the authors investigated the effect of phorbol ester and Ca2+ ionophore stimuli on mitogen activated protein (MAP) kinases and found that activation of the MAP kinases that phosphorylate the Jun activation domain, JNK1 and JNK2, required costimulation of T cells with either TPA and Ca 2+ ionsophore or antibodies to TCR and CD28.
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