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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
1
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pubmed:dateCreated |
1997-5-13
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pubmed:abstractText |
The studies presented herein examined the mechanism(s) whereby sirolimus (SRL) and cyclosporin (CsA) act synergistically to block allograft rejection. Combination index (CI = 1 reflects additive, CI > 1 antagonistic, and CI < 1 synergistic, effects) analysis documented potent synergism between SRL and CsA to block allograft rejection. Combinations of the two drugs produced synergistic prolongation of heart (CI = 0.001-0.2) or kidney (CI = 0.03-0.5) allograft survival at SRL/CsA ratios ranging from 1:12.5 to 1:200. Pharmacokinetic analysis of the individual drugs showed that CsA does not affect the blood levels of SRL, and SRL mildly increases the levels of CsA in SRL/CsA-treated rats. Quantitative polymerase chain reaction analysis was used to document that both subtherapeutic (1.0 mg/kg) and therapeutic (2.0 or 4.0 mg/kg) CsA doses inhibited the expression of interferon-gamma (IFN-gamma) (P < 0.03) and IL-2 (P < 0.003) mRNA produced by T helper (Th) 1 cells, as well as IL-10 (P < 0.001), but not IL-4 (NS) mRNA produced by Th2 cells. Contrariwise, all tested SRL doses (0.02, 0.04 or 0.08 mg/kg) did not affect cytokine mRNA expression. However, heart allografts from rat recipients treated with synergistic SRL/CsA doses displayed reduced levels of IFN-gamma (P < 0.01), IL-2 (P < 0.001) and IL-10 (P < 0.001) mRNA. Thus, because subtherapeutic doses of CsA reduce Th1/Th2 activity, thereby facilitating the inhibition of signal transduction by low does of SRL, the two agents act synergistically to inhibit allograft rejection.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cyclosporine,
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/Immunosuppressive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Polyenes,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Sirolimus
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0009-9104
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
108
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
63-8
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pubmed:dateRevised |
2008-11-20
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pubmed:meshHeading |
pubmed-meshheading:9097913-Animals,
pubmed-meshheading:9097913-Cyclosporine,
pubmed-meshheading:9097913-Cytokines,
pubmed-meshheading:9097913-Drug Synergism,
pubmed-meshheading:9097913-Graft Rejection,
pubmed-meshheading:9097913-Heart Transplantation,
pubmed-meshheading:9097913-Immunosuppressive Agents,
pubmed-meshheading:9097913-Kidney Transplantation,
pubmed-meshheading:9097913-Male,
pubmed-meshheading:9097913-Polyenes,
pubmed-meshheading:9097913-RNA, Messenger,
pubmed-meshheading:9097913-Rats,
pubmed-meshheading:9097913-Rats, Inbred BN,
pubmed-meshheading:9097913-Rats, Inbred BUF,
pubmed-meshheading:9097913-Rats, Inbred WF,
pubmed-meshheading:9097913-Sirolimus,
pubmed-meshheading:9097913-Transplantation, Homologous
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pubmed:year |
1997
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pubmed:articleTitle |
Synergistic mechanisms by which sirolimus and cyclosporin inhibit rat heart and kidney allograft rejection.
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pubmed:affiliation |
Department of Surgery, University of Texas Medical School at Houston, 77030, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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