Comparative in vitro and in vivo study of a sugar-coated chloroquine preparation marketed in Tanzania versus an ordinary brand.

OBJECTIVE: To investigate the absorption and the quality of a sugar-coated chloroquine (CQ) marketed in Tanzania. METHOD: Twenty healthy volunteers were randomised to take either the test brand (group A) or a control chloroquine phosphate (group B). Each subject received 300 mg chloroquine base. Whole blood dried on filter papers were collected at time 0 and at 15 and 30 min and at 1, 2, 3, 4, 6, 8, 24, 36, 48, 72 and 168 h after drug intake. Urine samples were collected at time 0, 0-4 h, 4-8 h, 8-24 h, 24-48 h and 48-72 h after drug administration. In an in vitro study, six tablets from each of the two CQ preparations were checked for the amount of active drug contained in each tablet and their dissolution rates. RESULTS: The blood concentration Area Under the Curve (AUC) of group B was about 10% larger than that of group A. The total amounts of CQ plus deethylchloroquine excreted with the urine during the 72-h study period were 5% for group A and 6% for group B. None of the pharmacokinetic parameters were significantly different between the two groups. All the tablets contained the labelled amount of chloroquine; however, one tablet from the test drug failed to fulfil the required dissolution rate. CONCLUSION: We found no major difference between the AUCs of the two CQ preparations, but the sugar-coated brand has shown to have variable dissolution rate.

Decreased capacity for debrisoquine metabolism among black Tanzanians: analyses of the CYP2D6 genotype and phenotype.

The cytochrome P450 2D6 (CYP2D6) genotypes and phenotypes of 106 unrelated, healthy black Tanzanians of Bantu origin were investigated. The results revealed a population with a generally decreased capacity to metabolize the CYP2D6 substrate debrisoquine with 59% of the Tanzanian extensive metabolisers having debrisoquine metabolic ratios (MRs) > 1 versus 20% in Caucasians. This decrease in metabolic capacity was not fully explained by the partially or fully detrimental CYP2D6 gene mutations analysed for in this study. As many as 7% poor metabolizers of debrisoquine were identified but none was homozygous for defective CYP2D6 alleles. The majority among the group of poor metabolizers had relatively low metabolic ratios. The mutational profile indicated a closer association of the Tanzanian CYP2D locus to that of Zimbabweans rather than to that of Ethiopians. The defective alleles CYP2D6*3, *4, *5 and *6 were found at low frequencies (0%, 1%, 6%, 0%, respectively), whereas the CYP2D6*17 allele causing an enzyme with altered specificity was common (allele frequency = 17%). It is concluded that the CYP2D6 genotype in the Tanzanian Bantu population is different from that of other African populations examined to date and that further studies are required to explain the generally lower capacity to metabolize CYP2D6 substrates.

Chloroquine blood concentrations and malaria prophylaxis in Tanzanian women during the second and third trimesters of pregnancy.

OBJECTIVE: Routine malaria prophylaxis with chloroquine (CQ) is recommended to pregnant semi-immune women in several countries in Africa. The dosage is empirically based. We investigated whether blood CQ concentrations and apparent oral blood clearance (CL/F) change during the course of pregnancy. We also studied whether malaria parasites could be detected together with low CQ blood levels. METHODS: Forty nine semi-immune Tanzanian women were recruited in the 16th week of pregnancy. They were given 310 mg oral CQ base once per week as prophylaxis during the whole pregnancy. Capillary blood samples were taken for analysis of CQ before treatment and at weeks 26 and 36. Blood samples were dried on filter paper and analysed by HPLC. Blood was also drawn to detect occurrence of malaria parasites. RESULTS: A total of 25 women fulfilled the sampling schedule. CL/F increased significantly from 160 ml.min-1 at week 26 to 180 ml.min-1 at week 36. In 7 of 25 women, CL/F increased > 20%. Trough blood CQ concentrations, determined on four occasions at week 26 and at week 36 varied between 200 and 900 nmol.l-1. No statistically significant differences between occasions were seen. Malaria parasites were seen in two individuals early in pregnancy. CONCLUSION: Blood CQ CL/F showed a small increase during the course of pregnancy. The estimated mean blood CL/F values of 160 and 180 ml.min-1 (week 26 and 36, respectively) were higher than the mean CL/F of 125 ml.min-1 in non-pregnant individuals, published previously. Efficacy of higher dosages of CQ in malaria prophylaxis in pregnant women could, therefore, be evaluated in controlled trials in high-risk malaria areas.

Metrifonate in healthy volunteers: interrelationship between pharmacokinetic properties, cholinesterase inhibition and side-effects.

Metrifonate concentrations in plasma, its inhibition of blood cholinesterase, and side-effects were studied in 16 healthy volunteers who received a single oral dose of 2.5, 5, 7.5 or 15 mg/kg in a randomized double-blind study (4 subjects for each dose). Metrifonate was determined by a gas chromatographic method. Peak plasma levels were reached within 2 hours; the half-life in plasma, oral clearance, and normalized Cmax and AUCs did not differ significantly between the four groups. Plasma cholinesterase (BuchE) was inhibited to low levels in all subjects, while erythrocyte cholinesterase (AchE) was affected in a dose-dependent fashion. The occurrence of side-effects correlated strongly with peak plasma levels but not with maximum AchE inhibition or with increase in salivation. This study shows that the absorption of metrifonate was not significantly different for doses between 2.5 and 15 mg/kg. The plasma levels of this drug correlated with the occurrence of side-effects.

Field trial of the efficacy of a simplified and standard metrifonate treatments of Schistosoma haematobium.

In a randomized double-blind study, the percentage egg reduction and cure rate after the standard schedule of metrifonate treatment of Schistosoma haematobium (3 doses of 7.5 mg.kg-1 at two-weekly intervals; A) and an abbreviated regimen (3 doses of 5 mg.kg-1 in one day; B) were compared in five villages in Somalia. 300 patients who were excreting 20 or more eggs of S. haematobium in 10 ml urine were recruited. The patients were classified according to their home villages and were then, randomly allocated to treatment A or B. They had similar ages, weights and egg output. Each patient received 3 doses of metrifonate and 2 doses of identical appearing placebo. Group A received metrifonate on the 1st, 4th and 5th dosing occasions and placebo on the 2nd and 3rd times. Group B received metrifonate on the 1st, 2nd and 3rd dosing times and placebo on the 4th and 5th times. Two hundred and one patients were followed up from 1 to 6 months. The remaining 99 (33%) patients either did not complete treatment or were lost during follow up. Egg reduction in the groups 1, 2, 3 and 6 months after treatment were 97, 97, 95 and 93% in Group A and 96, 96, 94 and 92% in Group B (NS). Corresponding cure rates for Group A were 52, 50, 48 and 44%, and in Group B they were 47, 48, 43 and 40% (NS). Seven patients from Group A and 9 from Group B complained of minor side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Poor patient compliance reduces the efficacy of metrifonate treatment of Schistosoma haematobium in Somalia.

The degree of compliance during metrifonate therapy of Schistosoma haematobium infection has been evaluated together with its impact on drug efficacy in two rural villages in Somalia. Drug treatment was offered to all subjects with S. haematobium infection. 243 subjects were screened for the presence of eggs in the urine using a sensitive Nucleopore filtration method and 211 were positive. All infected patients were put on a treatment schedule of 3 doses of metrifonate 7.5 mg/kg at fortnightly intervals. Drug efficacy was evaluated 6, 12 and 32 weeks after treatment. Only 48% of the patients took all 3 doses, 15% took 2 doses and 37% only took 1 dose. The cure rate was maximal in Week 6 at 60, 44 and 30% in those who took 3, 2 and 1 dose, respectively. Corresponding egg reduction rates were 98, 90 and 84%, respectively. Drug efficacy throughout the follow up period was much greater in patients who complied with all 3 doses. It is unlikely that the goal of mass treatment programmes for endemic S. haematobium in villages in Africa will be realized due to poor compliance with the current dosage schedule for metrifonate of 3 doses of 7.5 mg/kg at fortnightly intervals.

A simplified dosage schedule of metrifonate in the treatment of Schistosoma haematobium infection in Somalia.

We have carried out an open clinical study in Somalia to evaluate the efficacy and safety of a simplified dosage schedule of metrifonate in the treatment of Schistosoma haematobium infection. The doses used were: I. 10 mg X kg-1 once daily for 3 days II. 5 mg X kg-1 thrice daily for one day III. 7.5 mg X kg-1 thrice daily for one day. We screened a total of 550 subjects in four villages for egg excretion in urine, and selected patients with more than 200 eggs per 10 ml of urine. In the initial phase of the study eight patients were assigned to each of the three dose schedules. In an extended study 38 additional patients were treated with regimen II which gave the best outcome in the initial study. Dosage Schedules I and III turned out to be toxic, and none of the patients was treated with all three doses. Adverse effects, such as abdominal colic, nausea, salivation, dizziness, and headache, were seen in almost all the patients in those two groups. Two patients from Group I reported that they fainted within 2 h after the second dose. None of the patients in Group II reported adverse effects. After 4-6 weeks follow-up, egg reduction was 96-100% for Groups I and II and the cure rate was around 60%. This study has shown that a shorter course of treatment with metrifonate might be equally effective and safer than the recommended dosage schedule with three doses of 7.5-10 mg X kg-1 fortnightly.