Document Detail

Fifteen years of clinical studies and clinical practice in renal transplantation: reviewing outcomes with de novo use of sirolimus in combination with cyclosporine.
MedLine Citation:
PMID:  19100899     Owner:  NLM     Status:  MEDLINE    
Over the course of 15 years the use of sirolimus, a macrocyclic lactone, has evolved from an adjunct to calcineurin inhibitors (CNI) to the foundation of therapy due to the drug's unique properties: First, it displays synergistic pharmacodynamic interactions with CNI. Even among high immunologic risk patients, this regimen attenuates the risk of acute allograft rejection episodes when used in combination with cyclosporine or tacrolimus. Indeed >80% reduction in CNI exposure de novo yields better long-term renal function than full cyclosporine (CsA) doses, a useful tradeoff, despite the augmented occurrence of lymphoceles and impaired wound healing. Second, by inhibiting mammalian target of rapamycin (mTOR), it exerts profound anti-neoplastic effects reducing the incidence and mediating the regression of tumors displaying PTEN-deletions and/or Akt-activations in transplant and non-transplant patients. Third, it is relatively non-nephrotoxic although it may exacerbate that property of CNI agents. Fourth, it allows prompt withdrawal of steroid therapy. Fifth, it displays reduced rates of cytomegalovirus, and BK virus infections. The major adverse reactions can generally be controlled with countermeasure therapy. Myelosuppressive effects, which tend to be transient (unless sirolimus is combined with mycophenolic acid), are readily amenable to treatment with granulocyte colony stimulating factor for leukopenia, interleukin 11 for thrombocytopenia and erythropoietin for anemia. Combinations of statins and fibrates represent effective countermeasure therapy for hypercholesterolemia and hypertriglyceridemia, respectively. Idiosyncratic reactions include hypoxemic pulmonary toxicity, refractory edema and diarrhea. Thus, sirolimus represents the vanguard of a new class of maintenance agents for immunosuppression.
B D Kahan
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Transplantation proceedings     Volume:  40     ISSN:  0041-1345     ISO Abbreviation:  Transplant. Proc.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-12-22     Completed Date:  2009-07-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0243532     Medline TA:  Transplant Proc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  S17-20     Citation Subset:  IM    
University of Texas Medical School at Houston, Houston, Texas 77030, USA.
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MeSH Terms
Azathioprine / therapeutic use
Calcineurin / antagonists & inhibitors
Clinical Trials as Topic
Cyclosporine / therapeutic use*
Drug Therapy, Combination
Graft Survival / immunology
Immunosuppressive Agents / adverse effects,  therapeutic use*
Kidney Transplantation / immunology*
Sirolimus / therapeutic use*
Treatment Outcome
Reg. No./Substance:
0/Immunosuppressive Agents; 446-86-6/Azathioprine; 53123-88-9/Sirolimus; 59865-13-3/Cyclosporine; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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