Halofantrine is a new blood schizontocidal drug used for the treatment of multidrug-resistant falciparum malaria. The pharmacokinetics of halofantrine (HAL) and its principal metabolite, N-desbutylhalofantrine (BHAL), was investigated in 6 adult male patients of Melanesian origin with uncomplicated falciparum malaria. The patients received 500 mg of halofantrine hydrochloride at times 0, 6 and 12 h (total 1.5 g). All patients responded to treatment with a mean parasite clearance time of 52.7 h and a mean fever clearance time of 33.8 h. The following kinetic parameters (mean values) were determined for HAL and BHAL, respectively: maximum plasma concentration (Cmax) = 896 and 491 ng.ml-1; time to reach the Cmax (tmax) = 15 and 56 h; elimination half-life (t1/2) = 91 and 79 h and the mean residence time (MRT) = 71 and 102 h. Based on the clinical response the plasma concentrations of HAL and BHAL were adequate for the treatment of uncomplicated falciparum malaria in the 6 patients.
1 The multiple-dose kinetics of dapsone (DDS), its major metabolite monoacetyldapsone (MADDS) and pyrimethamine (PYR) were studied in six healthy adult male volunteers following weekly administration of Maloprim® (100 mg DDS plus 12.5 mg PYR). 2 After the last maintenance dose of Maloprim, the following kinetic parameters (mean values) were determined for DDS and PYR, respectively: maximum plasma concentration (Cmax) = 1,134 and 116 ng ml-1; elimination half-life (t½/2) = 23 and 105 h; plasma clearance (CL) = 37.6 and 15.9 ml h-1 kg-1 and apparent volume of distribution (V55) = 1.20 and 2.291 kg-'. The mean t/2 of MADDS was 22 h.3 The mean whole blood to plasma (B/P) and erythrocyte to plasma (E/P) concentration ratios for DDS were 1.04 and 1.09, respectively. MADDS had a B/P ratio of 0.69 and an E/P ratio of 0.33. The B/P and E/P ratios for PYR were 0.98 and 0.54, respectively. 4 The drug combination was assessed in vitro by measuring inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. The chloroquine (CQ)-and PYR-sensitive FC-27 isolate was completely inhibited by the sera but the drug combination was ineffective against the CQ-and PYR-resistant Kl strain. The in vitro findings suggest that Maloprim may not be effective against strains of P. falciparum with a high level of resistance to pyrimethamine.
The multiple-dose kinetics of a daily dose of proguanil (200 mg) coadministered with dapsone (10 mg) was investigated in 6 healthy adult male volunteers. The kinetics of dapsone (DDS), monoacetyldapsone (MADDS), proguanil (PROG) and its active metabolite cycloguanil (CYCLO) were derived from plasma drug concentrations after the last maintenance dose. The following kinetic parameters (mean values) were estimated for DDS and PROG, respectively: maximum concentration (Cmax) = 285 and 151 ng/ml, minimum concentration (Cmin) = 125 and 31 ng/ml, elimination half-life (t.½) = 23.3 and 18.3 h, plasma clearance (CI) = 0.032 and 1.27 1/h/kg and apparent volume of distribution (Vss) = 1.05 and 33.32 1/kg. The Cmax, Cmin and t½ of CYCLO were 56 ng/ml, 17 ng/ml and 15.0 h, respectively. The antimalarial activity of the proguanil/ dapsone combination was assessed in vitro by measuring the inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers’sera. Both FC-27 [chloroquine (CQ) and pyrimethamine (PYR)-sensitive] and Kl (CQ- and PYR-resistant) isolates were completely inhibited by the drug combination at steady-state concentrations. These findings suggest that the drug regimen may be effective against drug-resistant falciparum malaria.
Clofibric acid disposition was studied in four healthy men after 1 wk of clofibrate ingestion (500 mg orally every 12 hr) with and without probenecid (500 mg orally every 6 hr). Mean (+/- SD) free clofibric acid plasma concentration in the four subjects over a dosage interval at steady state was 2.5 +/- 0.03 mg/1 before and 9.05 +/- 1.09 mg/1 after the probenecid. Probenecid reached an average plasma concentration of 71.3 mg/1. No clofibric acid glucuronide was detected in plasma during either treatment. The fractions of the dose recovered in urine as clofibric acid, clofibric acid glucuronide, and clofibric acid liberated after acid hydrolysis were not altered by probenecid. These data suggest that probenecid causes a reduction in renal and metabolic clearance of clofibric acid, probably as a result of inhibition of the conjugation of clofibric acid with glucuronide.
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