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Biomedical subjects

J R Veenendaal

Publications and source records attributed to J R Veenendaal.

18 recordsLinked to original sources
PubMed1991

Pharmacokinetics of halofantrine and n-desbutylhalofantrine in patients with falciparum malaria following a multiple dose regimen of halofantrine.

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.

Antimalarials↗
PubMed1990

Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man.

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 (t1/2) = 23 and 105 h; plasma clearance (CL) = 37.6 and 15.9 ml h-1 kg-1 and apparent volume of distribution (Vss) = 1.20 and 2.29 l kg-1. The mean t1/2 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 K1 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.

Acetylation↗
PubMed1990

Multiple-dose kinetics in healthy volunteers and in vitro antimalarial activity of proguanil plus dapsone.

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 (t1/2) = 23.3 and 18.3 h, plasma clearance (Cl) = 0.032 and 1.27 l/h/kg and apparent volume of distribution (Vss) = 1.05 and 33.32 l/kg. The Cmax, Cmin and t1/2 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 K1 (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.

Adult↗
PubMed1988

Excretion of mefloquine in human breast milk.

Concentrations of mefloquine in plasma and breast milk were measured in 2 women following the administration of one Lariam tablet (250 mg mefloquine). The milk-to-plasma ratio of mefloquine based on the area under the plasma and milk concentration curves was 0.13 and 0.16. After a maternal mefloquine dose of 3.73 mg/kg and assuming a daily milk ingestion of 1 litre over a week, the maximum amount of drug ingested by an infant would be 0.14 mg/kg. During lactation the plasma clearance and apparent volume of distribution of mefloquine were about 50% less than the same parameters calculated after lactation had ceased.

Adult↗
PubMed1988

Steady-state kinetics of proguanil and its active metabolite, cycloguanil, in man.

The pharmacokinetics of proguanil and its active metabolite, cycloguanil, were determined at steady-state in 6 healthy male volunteers after daily administration of 2 Paludrine tablets (200 mg proguanil hydrochloride). A maximum plasma proguanil concentration of 130.3 +/- 16.0 ng/ml (mean +/- SD) was reached at 3.8 +/- 1.3 h while a maximum cycloguanil concentration of 52.0 +/- 15.2 ng/ml was obtained at 5.3 +/- 1.0 h after dosing. The elimination half-lives of proguanil and cycloguanil were 14.5 +/- 3.0 h and 11.7 +/- 3.1 h, respectively. The plasma clearance of proguanil was 1.43 +/- 0.33 l/h/kg and the apparent volume of distribution was 30.7 +/- 12.3 l/kg. Renal clearance of proguanil (0.33 +/- 0.19 l/h/kg) was about 23% of the plasma clearance and 35.6 +/- 9.6% of the oral dose was recovered as proguanil and cycloguanil.

Administration, Oral↗
PubMed1988

Pharmacokinetics of chlorproguanil in man after a single oral dose of Lapudrine.

The pharmacokinetic parameters of chlorproguanil (Lapudrine) and its active metabolite, chlorcycloguanil, were determined in 6 healthy male volunteers after a single oral dose of 4 Lapudrine tables (80 mg). The mean maximum plasma chlorproguanil concentration was 36.7 +/- (SD) 7.9 ng/ml and was reached at 3.8 +/- 1.3 h. The chlorproguanil elimination half-life was 17.5 +/- 6.7 h and its plasma clearance was 1.28 +/- 0.12 l/h/kg. The mean whole blood to plasma ratio was 3.1 at 4 h after dosing. Chlorcycloguanil could not be quantified in plasma and whole blood at the detection limit of 10 ng/ml using a high-performance liquid chromatographic method. An excretion rate-time plot from urine data shows a rapid (t1/2 = 20 h) and a slow phase (t1/2 = 51 h) in the elimination of chlorcycloguanil. Our findings suggest that the current prophylactic regimen of chlorproguanil hydrochloride (20 mg weekly) may not be optimal in preventing infections with chloroquine-resistant falciparum malaria.

Administration, Oral↗
PubMed1987

Decreased hepatic elimination of pyrimethamine during malaria infection. Studies in the isolated perfused rat liver.

The elimination of the antimalarial drug pyrimethamine was studied in isolated liver preparations from young rats (80-100 g) infected with merozoites of Plasmodium berghei two weeks earlier. Perfusate half-life of pyrimethamine was increased in livers from M.I. rats (t1/2 beta control group = 56 +/- 11 min vs M.I. group = 101 +/- 12, P less than 0.01), reflecting a decrease in hepatic clearance (3.6 +/- 1.1 ml/min vs 1.9 +/- 0.5 ml/min, P less than 0.01). There was no significant difference in volume of distribution between livers from M.I. and control groups. Intrahepatic concentration of unchanged drug at 3 hr was 4-5-fold greater in livers from infected rats (control group = 4725 +/- 2287 ng/ml vs M.I. group = 22,324 +/- 6824 ng/ml), while liver: perfusate concentration ratios were not significantly different (control group = 30.8 +/- 24.1 vs M.I. group = 35.6 +/- 20.3). We conclude that the hepatic elimination of pyrimethamine is substantially impaired in the malaria-infected rat.

Animals↗
PubMed1987

Chlorproguanil and chlorcycloguanil concentrations in human plasma and urine after Lapudrine administration.

Chlorproguanil and chlorcycloguanil concentrations in human plasma and urine were measured using a high performance liquid chromatographic method. The detection limit in plasma and urine was 5 ng/ml for chlorproguanil and 10 ng/ml for chlorcycloguanil. The elimination half-life of chlorproguanil (Lapudrine) in 2 healthy volunteers, after a single oral dose of the drug, was 14.7 and 16.1 h. No chlorcycloguanil could be detected in plasma over 32 h after dosing.

Adult↗
PubMed1986

Excretion of chloroquine, dapsone and pyrimethamine in human milk.

The concentration of chloroquine (CQ), dapsone (DDS) and pyrimethamine (PYR) in plasma and milk were measured following the coadministration of a single dose of chloroquine and Maloprim to lactating women. The milk to plasma area under the concentration-time curve (AUC) ratio ranged from 1.96 to 4.26 for CQ, 0.22 to 0.45 for DDS and 0.46 to 0.66 for PYR. Assuming a daily milk ingestion of 1 l by the infant, the maximum percentage of the maternal dose for CQ, DDS and PYR in milk was 4.2%, 14.3% and 45.6%, respectively, over a 9 day period.

Adult↗
PubMed1983

Diflunisal disposition and hypouricemic response in osteoarthritis.

The disposition of diflunisal was studied at daily doses of 250, 500, 750, 1000 mg/day in 24 male patients (mean age 65 yr and mean creatinine clearance 72 ml/min). Each dose was given for 14 days and diflunisal apparent oral clearance and serum urate was measured on the last day of each dosing regimen. There was a dose-dependent decrease in mean diflunisal apparent oral clearance with dose from 628 ml/hr at 250 mg/day to 426 ml/hr at 1000 mg/day, with most of the decrease occurring at the lower doses and becoming less pronounced at doses of 750 and 1000 mg/day. There was a strong positive correlation between diflunisal apparent oral clearance and creatinine clearance. Diflunisal induced a hypouricemic effect at all doses, but the responses at doses of 750 and 1000 mg/day did not differ.

Aged↗
PubMed1983

Reduced clofibric acid clearance in renal dysfunction is due to a futile cycle.

Although clofibric acid is cleared predominantly by formation of an ester glucuronide, its plasma clearance is reduced in renal dysfunction. The mechanism of this phenomenon has been investigated in rabbits in which uranyl nitrate administration (0.0625-0.5 mg/kg) produced a dose-dependent decrease in creatinine clearance and clofibric acid plasma clearance. Uranyl nitrate doses of 0.3 mg/kg reduced creatinine clearance by approximately 90%, clofibric acid plasma clearance by approximately 60%, clofibric acid glucuronide renal clearance by approximately 85% and increased the time averaged plasma concentration of clofibric acid glucuronide approximately by 6-fold, compared to control values. Fifty percent of administered clofibric acid glucuronide is hydrolyzed to clofibric acid in rabbits with normal renal function. These studies support a mechanism for the renal function dependent plasma clearance of clofibric acid involving a futile cycle in which the net plasma clearance of clofibric acid is determined by the conjugation of clofibric acid and competition between renal clearance and hydrolysis of the ester glucuronide.

Acute Kidney Injury↗
PubMed1983

A renal mechanism for the clofibric acid-probenecid interaction.

A rabbit model has been used to investigate two hypotheses for the decrease in clofibric acid plasma clearance on probenecid coadministration in man. Rabbits administered probenecid (10 mg/kg followed by 10 mg/kg/hr) showed a mean reduction from control values of 68% for clofibric acid plasma clearance, 80% for clofibric acid glucuronide renal clearance and an elevation in the area under the plasma clofibric acid glucuronide concentration-time curve of 5.2-fold. These findings support the hypotheses that the decrease in clofibric acid plasma clearance involves the inhibition of the renal secretion of clofibric acid glucuronide by probenecid and the subsequent hydrolysis of the glucuronide as the major mechanism, rather than direct inhibition of clofibric acid glucuronide synthesis by probenecid, but do not exclude a mechanism in which both processes operate.

Animals↗
PubMed1981

The simultaneous analysis of clofibric acid and probenecid and the direct analysis of clofibric acid glucuronide by high-performance liquid chromatography.

A rapid and selective high-performance liquid chromatographic method for the simultaneous quantitative analysis of clofibric acid and probenecid in plasma and urine and for the direct analysis of clofibric acid glucuronide in plasma is described. Both methods involve direct injection of deproteinised body fluids. Concentrations of as low as 10 mg/l of clofibric acid and probenecid and 1.5 mg/l of clofibric acid glucuronide can be measured by the analysis. The coefficient of variance for these methods ranges from 1--7%.

Chromatography, High Pressure Liquid↗
PubMed1981

Probenecid-clofibrate interaction.

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.

Adolescent↗