Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporine is a potent tool in the immunosuppressive armamentarium. It provides relatively selective inhibition of T-cell responses without dampening nonspecific resistance. However, its use is confounded by a pleiotropic array of side effects, the most important of which is renal dysfunction with the not uncommon sequelae of hypertension, hyperuricemia, and hyperkalemia. The hepatic injury associated with CyA administration, which is characterized by a chronic elevation of serum transaminase values, is potentiated by azathioprine or recrudescent or de novo viral infections. Finally, the proclivity of the drug to produce hyperlipidemia may jeopardize long-term survival; patients not infrequently require gemfibrizol and/or pravastatin therapy to control triglyceride and/or cholesterol levels, respectively. Two strategies appear to be useful. Our concentration-control strategy assesses CyA exposure by analyzing serial pharmacokinetic profiles, titering drug doses to achieve initial steady state concentrations of 400 ng/mL during continuous i.v. infusion, and to achieve average concentrations, namely AUC divided by dosing interval (in hours), of 550 ng/mL initially with trough levels of 200 ng/mL or above. Pretransplant pharmacokinetic profiling permits prediction of the appropriate initial i.v. dose in 73% of patients, and in combination with a posttransplant profile of the oral dose in about 60% of patients. The target oral concentrations are progressively reduced, thereby permitting prospective CyA control and minimizing adverse effects. The second synergistic drug strategy uses the median effect mathematical model to identify new drug combinations. The combination of CyA with RAPA, a macrolide which inhibits lymphokine signal transduction, and with BQR, a difluoro quinoline carboxylic acid analog that inhibits pyrimidine biosynthesis, permits at least a 20-fold reduction of the CyA dose in rat allograft models as well as prevents the activation of some CyA-resistant rejection pathways. Future investigations of pharmacologic strategies are undoubtedly likely to re-enforce the efficacy and safety of CyA administration for a range of immunologic disorders.
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PMID:Optimization of cyclosporine therapy. 835 18

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

Sirolimus (Rapammune, rapamycin, RAPA) is a potent immunosuppressive drug that reduces renal transplant rejection. Hyperlipidemia is a significant side effect of sirolimus treatment, and frequently leads to cardiovascular disease. This study was undertaken to determine the repeatability, reversibility, and dose dependence of the plasma lipid and apolipoprotein altering effects of sirolimus, and to elucidate the mechanism by which sirolimus induces hypertriglyceridemia in some renal transplant patients. Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short term (14 days) sirolimus administration. For longer-term treatment, each patient was started on 10 mg/day sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia. Timed blood samples were analyzed for lipid, apolipoprotein, and sirolimus levels. During sirolimus administration, mean total plasma cholesterol increased from 214 mg/dl to 322 mg/dl (+50%; range 25-92%); LDL-cholesterol levels followed a similar pattern. Mean triglyceride level rose from 227 to 432 mg/dl (+95%; range 9-254%). ApoB-100 concentration rose from 124 to 160 mg/dl (+28%; P < 0.05). ApoC-III level increased from 28.9 to 55.5 mg/dl, +92%; (P < 0.013). These lipid and apolipoprotein changes were found to be repeatable, reversible, and dose dependent. [(13)C(4)]palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 42.3%). Incorporation of [(13)C(4)]palmitate into triglycerides of VLDL, IDL, and LDL was decreased 38.3%, 42,1%, and 38.4%, respectively, by sirolimus treatment of these patients. These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity and/or decrease lipoprotein lipase activity, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia.
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PMID:Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. 1217 61