Chiral chromatographic method to determine the enantiomers of halofantrine and its main chiral desbutyl metabolite in erythrocytes.

We describe a direct liquid chromatographic method with spectrofluorimetric detection to quantify the two enantiomers of halofantrine and the two enantiomers of its main chiral N-monodesbutylated metabolite in erythrocyte pellets. The method involves a Chiralpak AD column and a rapid one-step extraction procedure with acetonitrile. The method was validated for the four enantiomers within the range 0-1000 ng/ml. The absence of stereoconversion was studied in samples stored frozen for up to eight months. The optical rotation of the halofantrine and metabolite enantiomers was determined after separation on a semi-preparative Chiralcel OD column with polarimetric detection.

Quinine toxicity when given with doxycycline and mefloquine.

The pharmacokinetic and dynamic interactions among 3 antimalarials, ie quinine, doxycycline and mefloquine was observed in a 26-year-old Thai male patient with falciparum malaria. During the acute episode of the infection, the patient was treated with an intravenous dose of quinine hydrochloride at 600 mg qid, together with an oral dose of doxycycline 100 mg bid. Due to nausea, tinnitus and the persistence of parasitemia in peripheral blood smears, the dose of quinine was reduced 2 days after the first treatment to 300 mg; concurrently oral mefloquine 750 mg was given as 2 divided doses at 24 hours apart. During the course of treatment, the patient developed hearing loss; deafness of the right ear lasted for one week after stopping quinine administration. Higher plasma quinine and lower whole blood mefloquine concentrations than would be expected from the simulation profiles were detected 4 days after the first treatment. However, the concentration of mefloquine was increased upon the cessation of quinine treatment.

High dose of primaquine in primaquine resistant vivax malaria.

The efficacy of low dose chloroquine, characteristic pattern of relapse and the relapse rate in vivax malaria after high dose primaquine were investigated in 167 Thai patients. 87 patients were allocated at random to receive 300 mg, and 80 received 450 mg of chloroquine on the first day of admission. All patients in both groups showed a rapid response with comparable fever clearance times (27.3 vs. 26.1 h) and parasite clearance times (67.1 vs. 58.1 h). After recovery and clearance of parasitaemia, the patients were allocated at random (double blind) to receive 2 dosage regimens of primaquine, a daily dose of 15 mg or 22.5 mg for 14 d. Relapses in both groups occurred within 6 months; no patient relapsed beyond that period. The relapse rate in the primaquine 15 mg group was significantly higher than that in the 22.5 mg group (17.5% vs. 2.4%).

Pharmacokinetics of primaquine in G6PD deficient and G6PD normal patients with vivax malaria.

The pharmacokinetics of primaquine have been studied in 13 G6PD normal and 13 G6PD deficient Thai male patients with Plasmodium vivax malaria who were given daily doses of 15 mg of primaquine over 14 d, following a full course of chloroquine. After the first dose (15 mg), primaquine underwent rapid absorption. Mean values (SD in parentheses) of maximum plasma concentration of 57.7 (7.7) vs. 55.7 (7.4) ng/mL were reached at 2.2 (0.6) vs. 2.2 (0.6) h, for the G6PD deficient and G6PD normal groups, respectively. Thereafter, drug levels declined rapidly and monoexponentially with a t1/2 lambda of 6.4 (1.9) vs. 6.3 (2.7) h. The respective mean values (SD in parentheses) for MRT, AUC0-varies; is directly proportional to Cl/f, and Vz/f were 6.8 (0.4) vs. 6.8 (0.5) h, 0.547 (0.070) vs. 0.521 (0.090) micrograms/h/mL, 8.54 (0.37) vs. 8.97 (1.46) mL/min/kg and 4.8 (1.7) vs. 5.1 (1.2) L/kg. There was no difference in the plasma concentrations or pharmacokinetics of primaquine between patients with normal G6PD and G6PD deficiency. In the G6PD deficient group, no relationship between the severity of haemolysis (< 20% or > 20% haemolysis) and the concentrations/pharmacokinetics of primaquine was observed.

Whole blood concentrations of mefloquine enantiomers in healthy Thai volunteers.

We studied the pharmacokinetics of the enantiomers of mefloquine in whole blood in healthy Thai volunteers after administration of a single oral dose of 750 mg of the racemic mixture. Mefloquine pharmacokinetics were stereoselective. The peak concentrations and areas under the curve of the (-) enantiomer were significantly higher than those of its antipode (0.79 versus 0.46 microgram.ml-1 and 402 versus 94 micrograms.h.ml-1). The half-lives of (-)MQ were significantly longer than those of (+)MQ (531 versus 206 h). No stereoselectivity was observed for tmax values.

Mefloquine level monitoring in patients with multidrug resistant Plasmodium falciparum on the Thai Myanmar border.

A total of 42 patients with uncomplicated falciparum malaria who attended the malaria clinic in Mae Sot, Tak Province were treated with single oral dose of MSP 3 tablets (Fansimef, equivalent to 750 mg of mefloquine) concurrently with primaquine (30 mg). They all contracted the infection from Cambodia. The aim of the study was to monitor the efficacy of MSP 3 tablets for the treatment of this highly multiple drug resistant strains of Plasmodium falciparum in this area. Of the 39 patients included for efficacy assessment, 13 (33.3%) patients had sensitive responses, whereas 15 (38.5%) and 8 (20.5%) had RI and RII types of response, respectively. Melfoquine concentrations on Day-3 after treatment in patients with sensitive and treatment failure groups were comparable; the respective mean (SD) values were 665 (279) and 772 (264) ng/ml.

Comparison of oral artemether and mefloquine in acute uncomplicated falciparum malaria.

Plasmodium falciparum malaria in Thailand is highly resistant to available antimalarials, and alternative drugs are needed urgently. Artemether is effective against falciparum malaria but associated with a high recrudescence rate. The proper dosage regimen remains to be defined. We have done a clinical trial comparing mefloquine 1250 mg in divided doses with oral artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 patients, admitted to the Bangkok Hospital for Tropical Diseases, were randomised to receive either mefloquine (12) or artemether (34). Hospital follow-up was 28 days for the artemether group and 42 days for the mefloquine group. Oral artemether gave a significantly faster parasite clearance time than mefloquine (30 vs 64 h), and a significantly better cure rate (97 vs 64%) with fewer episodes of dizziness and vomiting. Oral artemether at 700 mg given over 5 days is effective and well tolerated. The cure rate with this regimen is higher than that reported by previous studies with 600 mg intramuscular artemether given over 5 days. Oral artemether can be considered as an alternative drug for multiple-drug-resistant falciparum malaria.

PIP: Plasmodium falciparum malaria in Thailand is resistant to available antimalarial drugs, which necessitates the search for alternative drugs. In a clinical trial mefloquine 1250 mg in divided doses was compared with oral artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 adult men, aged 15-50 years and weighing 45-65 kg, with acute uncomplicated falciparum malaria, no history of liver or kidney diseases, and not history of tasking antimalarials for this episode of illness were recruited at the Bangkok Hospitak for Tropical Diseases. 12 were treated with mefloquine and 34 with oral artemether. Hospital follow-up was 28 days for the artemether group and 42 days for the mefloquine group. Parasites did not clear from the blood of 2 patients in the mefloquine group, although there was a decrease in parasitemia. The other 10 patients in the mefloquine group has a good initial response with mean parasite clearance times and fever clearance times of 64 and 27 hours respectively. Oral artemether gave a significantly faster parasite clearance time than mefloquine (30 vs. 64 hours), and a significantly better cure rate (97 vs. 64%) with fewer episodes of dizziness and vomiting. Oral artemether at 700 mg given over 5 days is effective and well tolerated. The cure rate with this regimen is higher than that reported with 600 mg intramuscular artemether given over 5 days. Mefloquine 1250 mg has a cure rate of 80-84% but it produces side effects such as vomiting. The treatment with artemether should last at least 5 days with a dose above 600 mg for a cure rate approaching 100%. This treatment is still likely to be more acceptable to patients than the combination regimen of quinine plus tetracycline for 7 days. These findings suggest that neither artemether nor mefloquine is effective against the intrahepatic stage of Plasmodium vivax. Primaquine is the choice of drug for radical cure.

Primaquine metabolism by human liver microsomes: effect of other antimalarial drugs.

A number of drugs have been studied for their effect on the metabolism of the antimalarial drug primaquine by human liver microsomes (N = 4) in vitro. The only metabolite generated was identified as carboxyprimaquine by co-chromatography with the authentic standard. Ketoconazole, a known inhibitor of cytochrome P450 isozymes, caused marked inhibition of carboxyprimaquine formation with IC50 and K(i) values of 15 and 6.7 microM, respectively. This finding and the dependency of metabolite formation on NADPH indicates that cytochrome P450 isozyme(s) catalysed metabolite production. Of compounds actually or likely to be coadministered with primaquine to malaria patients, only mefloquine produced any inhibition (K(i) = 52.5 microM). Quinine, artemether, artesunate, halofantrine and chloroquine did not significantly inhibit metabolite formation. It seems unlikely that the concurrent administration of mefloquine, or other antimalarials, with primaquine will lead to appreciably altered disposition.

Mefloquine metabolism by human liver microsomes. Effect of other antimalarial drugs.

A number of drugs have been studied for their effect on the metabolism of the antimalarial drug mefloquine by human liver microsomes (N = 6) in vitro. The only metabolite generated was identified as carboxymefloquine by co-chromatography with the authentic standard. Ketoconazole caused marked inhibition of carboxymefloquine formation with IC50 and Ki values of 7.5 and 11.2 microM, respectively. The inhibition of ketoconazole, a known inhibitor of cytochrome P450 isozymes, and the dependency of metabolite formation on the presence of NADPH indicated that cytochrome P450 isozyme(s) catalysed metabolite production. Of compounds actually or likely to be coadministered with mefloquine to malaria patients only primaquine and quinine produced marked inhibition (IC50, 17.5 and 122 microM; Ki, 8.6 and 28.5 microM, respectively). However, despite these in vitro data with primaquine, clinical studies have failed to show any significant effect of single dose primaquine on the pharmacokinetics of mefloquine. With quinine, because peak plasma concentrations are very close to the Ki value, there is likely to be inhibition of mefloquine metabolism in patients receiving both drugs. Sulfadoxine, artemether, artesunate and tetracycline did not significantly inhibit carboxymefloquine formation.

Pharmacokinetics of prophylactic mefloquine in Thai healthy volunteers.

Malaria constitutes one of the most serious public health problems in Thailand. The disease undermines the health of the people and threatens the economy and security of the country as it is most prevalent in the rural region in forested mountain areas along the border where government officials (border police) have to perform their duties. A safe and effective prophylactic drug for use by these government officials is needed. Nine healthy border police volunteers who were working on the Thai-Cambodia border, aged between 22 to 50 years, and whose weight ranged between 48 and 61 kg, with no history of liver or kidney disease were recruited into the study. 375 mg of mefloquine (as Fansimef tablets) was given as a loading dose, followed by 250 mg every 4 weeks for 4 doses. Whole blood concentrations of mefloquine were measured by high performance liquid chromatography at intervals for 19 weeks. None of the volunteers developed malaria during study period. Seven volunteers had mild adverse effects which required no specific treatment. No changes in liver or renal function or in blood profiles occurred during 19 weeks of observation. Pharmacokinetic analysis revealed a mean maximum concentration of 420 +/- 141 ng/ml a time to peak concentration of 12 +/- 8 hours, terminal half-life was 14.93 +/- 4.43 days, apparent volume of distribution (Vd/f) was 16.5 +/- 5.6 l/kg and total clearance was 0.99 +/- 0.62 ml/min/kg. The mean minimum whole blood mefloquine concentration derived from this study was approximately 100 ng/ml which is considered to be low for treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of mefloquine in Thai patients with acute falciparum malaria.

A double-blind randomized comparative study of the pharmacokinetics and pharmacodynamics of a single oral dose of 750 mg or 1250 mg of mefloquine was carried out on 20 Thai male patients with acute uncomplicated falciparum malaria. In the 750-mg group, one patient exhibited an RII response, while the others responded to the treatment with a mean fever clearance time of 50.2 +/- 28.2 hours and a mean parasite clearance time of 70.2 +/- 17.3 hours. The main adverse effects were dizziness, nausea, vomiting, abdominal pain, and diarrhoea. Electrocardiogram monitoring detected sinus bradycardia in three patients and sinus arrhythmia in three others. In the 1250-mg group, one patient exhibited an RII response, while the others responded to the treatment with a mean fever clearance time of 43.4 +/- 36.6 hours and a mean parasite clearance time of 73.4 +/- 25.2 hours. However, during the follow-up period, two patients recrudesced on day 23 and on day 31 (RI response). Dizziness, nausea, vomiting, abdominal pain, and diarrhoea were the major adverse effects, with dizziness being more frequent compared with the 750-mg group. Sinus bradycardia occurred in four patients and sinus arrhythmia in four others. The pharmacokinetics of the two regimens were similar, with the absorption of mefloquine increasing linearly with the dose; however, vomiting within an hour of taking the drug reduced the whole blood mefloquine concentrations. The results do not indicate that there is any advantage in using a single dose of 1250 mg of mefloquine rather than 750 mg.