Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RAPA represents a likely candidate for addition to the maintenance immunosuppressive regimen, for it seems to potentiate markedly the efficacy fo CyA-based therapy. RAPA reduces the incidence of acute rejection episodes; indeed, it may even be useful to disrupt ongoing steroid- and antibody-resistant cellular and humoral acute rejection reactions. Some data in model systems, both in vitro and in vivo, suggest that RAPA may afford prophylaxis against chronic rejection. The enhanced immunosuppression is likely to permit reduction in CyA doses/concentration, thereby mitigating its nephrotoxic effects, and to permit withdrawal of corticosteroids, providing relief from their osteopenic, myopathic, and metabolic effects. As with other potent immunosuppressives, RAPA causes a range of adverse side effects, most importantly myelosuppression and hyperlipidemia. Hypothesis-testing investigations are already underway to elucidate the mechanisms of the adverse effects so as to design strategies to minimize their impact on posttransplant morbidity.
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PMID:Rapamycin: personal algorithms for use based on 250 treated renal allograft recipients. 972 35

This study correlated the dynamic effects of sirolimus (rapamycin; RAPA) and cyclosporine (CsA) alone versus in combination to produce renal dysfunction, myelosuppression, or hyperlipidemia, with their corresponding blood and tissue concentrations. After salt-depleted rats were treated with RAPA (0.4 to 6.4 mg/kg per d) and/or CsA (2.5 to 20.0 mg/kg per d) for 14 d, the GFR, lipid levels, bone marrow cellularity, and CsA/RAPA concentrations in whole blood versus liver or renal tissues were measured, and the median effect model was used to discern the type of drug interactions. Compared with vehicle controls (1.98 +/- 0.34 ml/min), GFR values were reduced only by large doses of drug monotherapy, namely RAPA (3.2 mg/kg per d = 1.2 +/- 0.02 ml/min or 6.4 mg/kg per d = 1.3 +/- 0.2 ml/min; both P < 0.01) or CsA (10.0 mg/kg per d = 1.2 +/- 0.1 ml/min or 20.0 mg/kg per d = 0.8 +/- 0.4 ml/min; both P < 0.01). In contrast, hosts that were treated with smaller doses of CsA/RAPA combinations showed more pronounced effects in reduction of GFR values: 2.5/0.4 mg/kg per d, modestly (1.5 +/- 0.5 ml/min; P < 0.01); 5.0/0.8 mg/kg per d, moderately (0.23 +/- 0.01 ml/min; P < 0.001); and higher-dose groups, markedly. The exacerbation of renal dysfunction seemed to be due to a pharmacokinetic interaction of RAPA to greatly increase CsA concentrations in whole blood and, particularly, in kidney tissue. In contrast, the pharmacodynamic effects of CsA to potentiate two RAPA-mediated toxicities-myelosuppression and increased serum cholesterol/low-density lipoprotein cholesterol-occurred independently of pharmacokinetic interactions. RAPA aggravates CsA-induced renal dysfunction owing to a pharmacokinetic interaction, whereas CsA produces a pharmacodynamic effect that augments RAPA-induced myelosuppression and hyperlipidemia.
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PMID:Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. 1131 66