The disposition of amiodarone, an antiarrhythmic agent was evaluated after a single intravenous infusion (5 mg/kg over 15 minutes) in patients of various ages and with various degrees of renal function and left ventricular function. The plasma concentration-time data were obtained from three clinical studies with similar protocols. The data were analyzed by nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters of amiodarone and to determine the significant demographic covariates affecting these parameters.
View Article and Find Full Text PDFTo evaluate the potential need for modification of dose regimens of intravenous amiodarone in patients with left ventricular dysfunction, the pharmacokinetics of amiodarone and its active metabolite, desethylamiodarone (DEA), were examined after a single 15-minute intravenous infusion of amiodarone 5 mg/kg. Three parallel groups of otherwise healthy volunteers with normal (n = 12), moderately impaired (ejection fraction > 30 but < or = 45%; n = 6), or severely impaired (ejection fraction < or = 30%; n = 6) left ventricular function were enrolled in the study. Serial blood samples were obtained over a 76-day period for estimation of pharmacokinetic parameters.
View Article and Find Full Text PDFThe present study attempted to evaluate pentoxifylline's mechanism(s) of action in the prevention of acute renal failure by examining its vascular decongestant activity in a rat model for acute renal failure and inhibitory activity of nitric oxide release from activated macrophage-like (RAW 264.7 cells) and murine mammary adenocarcinoma (EMT-6 cells) cell lines. Radiolabeled chromium-erythrocytes were injected intravenously into all rats.
View Article and Find Full Text PDFJ Clin Pharmacol
February 1996
In a study designed to determine the influence of renal dysfunction on the disposition of amiodarone and its metabolite, desethylamiodarone (DEA), 30 subjects received a single 5 mg/kg intravenous dose of amiodarone over 15 minutes. Of the 30, 11 had normal renal function (group I; mean +/- SD glomerular filtration rate [GFR] = 118 +/- 20 mL/min/1.73 m2), 9 had renal impairment (group II; GFR = 23 +/- 10 mL/min/1.
View Article and Find Full Text PDFThe pharmacokinetics of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) and cisplatin (CDDP) were studied after i.v. and i.
View Article and Find Full Text PDFNephrol Dial Transplant
June 1992
The significance of vascular congestion in the pathogenesis of cisplatin acute renal failure (ARF) was studied in rats given pentoxifylline. Rats were administered single intraperitoneal doses of 1.0, 2.
View Article and Find Full Text PDFThe distribution and immunosuppressive activity of liposomal cyclosporine (L-CSA) when administered iv as single- and multiple-doses were compared with the commercially available cyclosporine (C-CSA) in rats. CSA concentrations in the spleen and liver were significantly greater 1 hr after dosing in rats given L-CSA compared with C-CSA. The apparent tissue to blood partition coefficient at 1 hr after dosing was significantly greater for the liver and spleen of rats treated with L-CSA compared with C-CSA.
View Article and Find Full Text PDFHWA-138, a pentoxifylline analog, has been shown to increase yeast urinary clearance and to reduce yeast counts in the kidneys of rats infected with Candida albicans. Furthermore, HWA-138 has also been shown to prevent amphotericin B-induced acute renal failure in rats. We report here on the effects of HWA-138 alone and in combination with amphotericin B in the treatment of systemic candidiasis in mice.
View Article and Find Full Text PDFDose-limiting nephrotoxicity has hampered the clinical usefulness of amphotericin-B (AmpB). Recently, vascular decongestants, such as pentoxifylline, have shown benefit in reducing drug-associated renal damage of AmpB in rats. The present study investigated a dose-dependent protection of a structurally similar methylxanthine, HWA-448, in the candidiasis rat model given a single dose of AmpB.
View Article and Find Full Text PDFThe influence of food and water intake on renal function was assessed by comparisons between the hyperphagic Zucker obese rat and its lean littermate, which demonstrates nocturnal dominance in activity. Serum creatinine and cortisol levels, creatine kinase activities, creatinine and urine clearances, and sodium and potassium excretion rates were measured over a 24-hour period in both lean and obese rats (n = 24 each). Six rats in each group were studied every 8 h to permit characterization over a 12-hour light/dark cycle at 2-hour intervals.
View Article and Find Full Text PDFThe pharmacokinetics and toxicity of the lipophilic antifungal agent, amphotericin-B (AmpB), were studied in the hyperlipidemic obese rat model and compared with lean litter-mates. Serial blood samples were obtained for 36 h following a single intravenous infusion of AmpB (1.2 mg/kg) with pre- and post-drug measurements of renal function.
View Article and Find Full Text PDFThe combined use of lovastatin, a hypolipidemic agent effective in the reduction of cholesterol levels, and the lipophilic immunosuppressant, cyclosporine, was studied in the obese rat model. Pharmacokinetics, immunosuppressive activity, lipid levels, and creatinine clearances were compared between groups administered drug-free vehicle, lovastatin or cyclosporine alone, or concomitant cyclosporine and lovastatin. All groups were pre-treated with either oral lovastatin 2.
View Article and Find Full Text PDFThe pharmacokinetics, tissue distribution, and toxicity of free amphotericin B (free AmB) or amphotericin B encapsulated in liposomes (L-AmB) were characterized in experimental diabetic rats and compared with data obtained from nondiabetic rats. After 7 days of insulin-controlled diabetes or saline, each rat was administered a single intravenous bolus dose of free AmB or L-AmB (0.8 mg/kg body weight).
View Article and Find Full Text PDFDrug Metab Dispos
July 1990
Systemic availability determines the net loss of drug through poor dosage form design, incomplete absorption, first-pass metabolism, and other reasons for drug destruction. The present study demonstrates the wide variability in assessment of single-dose bioavailability of cyclosporine A (CSA) based on the route of parenteral administration. Rats were administered CSA (10 or 25 mg/kg) orally or via the ip route, and the systemic availability was estimated from drug administered via the penile, femoral, or jugular route.
View Article and Find Full Text PDFThe mechanism of acute nephrotoxicity following the administration of amphotericin B (AmpB) remains unclear despite a number of studies describing hypermagnesuria, hyperkaluria, and hemodynamic changes. The present experiments attempted to elucidate the mechanism by using a novel hemorheologic probe, pentoxifylline (PTX). Acute studies were performed with rats given single intravenous doses of AmpB (1 mg/kg of body weight) with or without intraperitoneal PTX (45 mg/kg).
View Article and Find Full Text PDFThe metabolic effects of intravenous cyclosporine on lipids and lipoproteins were studied in 29 allogeneic bone marrow recipients compared with 13 autologous bone marrow patients not requiring cyclosporine therapy. Patients were monitored continuously from 5 days prior to 27 days following transplantation; cyclosporine treatment was initiated 4 days before transplantation. Fasting lipid and lipoprotein levels were measured in serial blood samples throughout the study period.
View Article and Find Full Text PDFProg Clin Biol Res
November 1990
The influences of time and hyperphagia on cholesterol, triglyceride, glucose and insulin levels were compared in the obese Zucker rat and compared to its lean litter-mates. Following a 28 day acclimation period in a 12 hr light/dark cycle (08-20-08) animal facility, blood samples were obtained every 2 hr in both obese and lean rats over a 24 hr period (N = 48; Dec 1988); serum was measured enzymatically for cholesterol, triglyceride and glucose and by radioimmunoassay for insulin and cortisol levels. Synchronization with other animal studies was established by endogenous serum cortisol measurements (acrophase 18-20 HALO in both groups).
View Article and Find Full Text PDFThe investigation of drug-induced nephrotoxicity depends on the adequate estimation of renal function at baseline and upon completion of the study. Typically, this procedure requires housing of the animal in an individual wire-bottom metabolic cage to facilitate complete urine collection. The present study compared the effects of 4 consecutive days of isolation on Sprague-Dawley rats from four breeders: Harlan Sprague-Dawley, Charles River Laboratories, BioLab and TIMCO Breeders.
View Article and Find Full Text PDFEur J Drug Metab Pharmacokinet
May 1990
Recent clinical studies have demonstrated the potential benefit of the T-cell-specific immunosuppressant, cyclosporine, in the treatment of Type I insulin-dependent diabetes. In the present study, steady-state cyclosporine pharmacokinetics, fasting glucose and insulin levels and renal function were examined in stable insulin-dependent diabetic rats and compared to non-diabetic rats. Mean creatinine clearance 30 days following diabetes induction was not significantly different from saline controls.
View Article and Find Full Text PDFThe beneficial effects of post-insult administration of pentoxifylline, a novel hemorheologic agent experimentally studied in various ischemic diseases, were evaluated in two models of acute renal failure (ARF): direct nephrotoxicity (mercuric chloride 4 mg/kg via femoral vein) and hemoglobinuria (glycerol 10 ml/kg i.m.).
View Article and Find Full Text PDFAlthough cyclosporine (CSA) is established in the prevention of allograft rejection, its use has been associated with dose-limiting toxicities, most notably to the kidney and liver. To date, the pathogenesis of the acute form of nephrotoxicity is unclear but may be related to inhibition of vasodilatory prostaglandins resulting in vasoconstriction and ischemia. The present study investigated the coadministration of CSA with a unique hemorheologic agent, pentoxifylline (PTX), in the murine model.
View Article and Find Full Text PDFRes Commun Chem Pathol Pharmacol
March 1988
Since cyclosporine is heavily bound to plasma lipoproteins, its pharmacokinetic profile was evaluated in the Zucker hyperlipidemic rat model (N = 4) and compared to Zucker lean (N = 4) and Sprague-Dawley (N = 4) rat models. Following a single i.v.
View Article and Find Full Text PDFAlthough the circadian pattern of cyclosporine (CSA) pharmacokinetics and toxicity has been described previously in both animal and clinical studies, the mechanism of this action is unknown. The present study compared the pharmacokinetics and experimental nephrotoxicity of chronic CSA in both the genetically-hyperlipidemic rat model and the lean litter-mate. Once daily dosing (25 mg/kg via gavage) was either at the start of the active (1900) or inactive (0700) cycle (Nov 1987 to Jan 1988).
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