Biomedical subjects

Barry D Kahan

Publications and source records attributed to Barry D Kahan.

41 records · Page 3Linked to original sources

PubMed2002

Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients.

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.

Adult↗

PubMed2001

Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations.

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.

Animals↗

PubMed2000

Low intraindividual variability of cyclosporin A exposure reduces chronic rejection incidence and health care costs.

The present study applied a receiver operating characteristic (ROC) analysis to assess the role of intraindividual variability of cyclosporin A (CsA) drug exposure in predisposing renal transplant recipients to the occurrence of chronic rejection, as well as to increased health care costs using a resource-based economic analysis. Two hundred and four adult renal transplant recipients were treated with tapering doses of prednisone (Pred) and with a concentration-controlled strategy that selected doses of the olive oil-based formulations of CsA (Sandimmune(R)) that achieved target concentrations based on serial pharmacokinetic profiles. The ROC analysis revealed an inflection point of plots of the coefficient of variation (%CV) of CsA exposure versus the risk of chronic rejection at >/=28.4% for the average concentration (C(av)), i.e., the dosing interval-corrected area under the concentration-time curves, and >/=36% for the trough concentration (C(0)). The incidence of chronic rejection over a period of 5 yr was 24% among the less variable (LV) versus 40% among the variable (V) cohort. The economic analysis revealed that the total mean facility and physician costs per patient were $48,789 versus $60,998, respectively (P < 0.01). The degree of variability displayed by any individual could only be predicted by serial measurements of CsA concentrations, and not by demographic features, laboratory determinations, clinical characteristics, individual or mean values of any observed CsA concentration, or other pharmacokinetic parameters calculated following a single drug exposure. Thus, strategies that reduce intrapatient variability of CsA exposure over time may lead to reductions in chronic allograft loss and in treatment costs.

Adult↗

PubMedDate not supplied

Long-term outcomes of single paediatric vs. ideal adult renal allograft transplants in adult recipients.

AIM: To compare the outcomes of single paediatric vs. adult kidneys transplanted into adult recipients. METHODS: A retrospective single-centre review of 38 single cadaver kidney transplants from donors less than five yr of age to wait-listed patients of low body mass index (BMI). Survival of grafts and quality of renal function were compared with 121 similarly low BMI recipients of grafts from donors 18-45 yr of age that were transplanted during the same period. Immunosuppression consisted of sirolimus, minimal-dose cyclosporine and prednisone. The mean age of the paediatric vs. adult donors was 2.8+/-1.0 and 31.1+/-9.2 yr, respectively (p<0.01) and of the recipients, 42.0+/-12.4 and 45.7+/-14.8 yr, respectively (p=NS). The mean BMI of paediatric vs. adult donor kidney recipients was 21.8+/-2.9 and 22.4+/-2.0 kg/m2 (p=NS). Sixty-six per cent of paediatric donor recipients were women compared with 44% of adult donor recipients (p=0.03). RESULTS: Death censored actuarial graft survivals at one and five yr for recipients of paediatric vs. adult donor grafts were 93 and 84% compared with 93 and 85% (p=NS). There were no graft losses because of technical complications in the paediatric kidney donor group. At one and five yr post-transplantation, the mean estimated creatinine clearances of the paediatric donor graft recipients were 52.9+/-19.6 and 54.0+/-17.8 mL/min, respectively, compared with 56.4+/-19.8 and 49.1+/-21.7 mL/min for recipients of adult donor grafts at the same times (p=NS). CONCLUSION: Transplantation of single paediatric donor kidneys into low BMI adult recipients provided equivalent outcomes to those of grafts from adult donors between the ages of 18 and 45 yr.

Adolescent↗

PubMedDate not supplied

Sirolimus-based immunosuppression: present state of the art.

Sirolimus, a macrocyclic lactone with a novel mechanism of action, augments acute rejection prophylaxis when administered in combination with cyclosporine (CsA) and steroids and seems to reduce the occurrence and progression of chronic vascular obliterative processes. Although clinical studies in psoriasis patients suggest that sirolimus is not nephrotoxic, the drug does show a range of toxic side effects, including altered lipid metabolism, myelosuppression, arthropathy, and impaired wound healing. Our experience with 1008 renal transplant patients who were administered sirolimus demonstrates that through careful therapeutic drug monitoring, it is possible to maximize the benefits and minimize the hazards of chronic immunosuppression with a sirolimus-based regimen. While sirolimus was initially introduced as an adjunctive agent to calcineurin inhibitors, it now serves as the base for therapies that spare the exposure to these nephrotoxic drugs. However, to optimize the use of sirolimus as base therapy, further work is necessary to determine appropriate target concentrations over time, the requirement for concomitant steroids and/or nucleoside synthesis blockers, and the best countermeasure strategies to overcome the drug's adverse effects.

Drug Interactions↗