PMID- 11825325
OWN - NLM
STAT- MEDLINE
DCOM- 20020926
LR  - 20190916
IS  - 1465-6566 (Print)
IS  - 1465-6566 (Linking)
VI  - 2
IP  - 11
DP  - 2001 Nov
TI  - Sirolimus: a comprehensive review.
PG  - 1903-17
AB  - Sirolimus (Rapamune), Wyeth-Ayerst, Madison, NJ) is a new, potent, 
      immunosuppressant that is emerging as a foundation for long-term 
      immunosuppressive therapy in renal transplantation. The drug acts during both 
      co-stimulatory activation and cytokine-driven pathways via a unique mechanism: 
      inhibition of a multifunctional serine-threonine kinase, mammalian target of 
      rapamycin (mTOR). Although there is no a priori reason to assume it, sirolimus 
      displays a synergistic interaction to enhance the efficacy of cyclosporin A 
      (CsA). In trials wherein the concentrations of CsA and sirolimus were tightly 
      controlled, rates of acute rejection episodes were < 10%, despite markedly 
      reduced exposures to each agent. In pivotal multi-centre blinded dose-controlled 
      trials, the rates of acute rejection episodes within 12 months following 
      administration of 2 or 5 mg/day sirolimus in combination with CsA and steroids 
      were reduced to 19 and 14%, respectively. Since the inhibitory effect of 
      sirolimus disables virtually all responses to cytokine mediators due to the 
      widespread involvement of mTOR in multiple signalling pathways, the agent is 
      likely also to retard proliferation of endothelial and vascular smooth muscle 
      cells, an important component of the immuno-obliterative processes associated 
      with chronic rejection. The advantages of this unique therapeutic action combined 
      with an intrinsic lack of nephrotoxicity are counterbalanced by myelosuppressive 
      and hyperlipidaemic side effects. Ongoing studies are assessing whether the 
      long-term benefits of sirolimus to permit reduction in exposure to or elimination 
      of calcineurin inhibitors ameliorate the progression of chronic nephropathy, the 
      condition that erodes long-term renal transplant survival.
FAU - Kahan, B D
AU  - Kahan BD
AD  - Division of Immunology and Organ Transplantation, University of Texas-Houston, 
      6431 Fannin, Suite 6.240, Houston, TX 77030, USA. barry.d.kahan@uth.tmc.edu
LA  - eng
GR  - DK 38016-1/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - England
TA  - Expert Opin Pharmacother
JT  - Expert opinion on pharmacotherapy
JID - 100897346
RN  - 0 (Immunosuppressive Agents)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Clinical Trials, Phase I as Topic
MH  - Clinical Trials, Phase II as Topic
MH  - Clinical Trials, Phase III as Topic
MH  - Graft Rejection/*prevention & control
MH  - Humans
MH  - Immunosuppressive Agents/adverse effects/metabolism/pharmacokinetics/*therapeutic 
      use
MH  - Kidney Transplantation/*immunology
MH  - Sirolimus/adverse effects/metabolism/pharmacokinetics/*therapeutic use
RF  - 108
EDAT- 2002/02/05 10:00
MHDA- 2002/09/27 06:00
CRDT- 2002/02/05 10:00
PHST- 2002/02/05 10:00 [pubmed]
PHST- 2002/09/27 06:00 [medline]
PHST- 2002/02/05 10:00 [entrez]
AID - 10.1517/14656566.2.11.1903 [doi]
PST - ppublish
SO  - Expert Opin Pharmacother. 2001 Nov;2(11):1903-17. doi: 
      10.1517/14656566.2.11.1903.