Thanavibul A

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 and bioavailability of oral and intramuscular artemether

AbstractObjective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; tmax: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).

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.

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.

Comparison of artemether and quinine in the treatment of severe falciparum malaria in south-east Thailand

One hundred and two Thai patients with severe falciparum malaria (92 males and 10 females) were allocated at random to receive either the standard regimen of quinine infusion (52 cases) or intramuscular artemether (50 cases). The patients in both groups had comparable admission clinical and laboratory data. Artemether gave a better survival rate (87.2% vs. 63.3%) and parasite clearance time (54 vs. 78 h) than quinine. Fever clearance times (79 h vs. 84 h) and time to recovery of consciousness (48 h in both groups) were comparable. Previous treatment with quinine or mefloquine had no influence on treatment outcome. The most common adverse effect in patients treated with quinine was tinnitus. Two patients had severe hearing impairment which resolved within 1 week after the end of treatment. Mild, transient pain was noted at the injection site of artemether but no abscess formed. QTc wave prolongation was seen in most patients receiving quinine; however, no arrhythmia was observed despite the high concentration of quinine in some patients who had received quinine before admission. Complications developed in 7 survivors in each treatment group. No patient in the artemether group had neurological sequelae after recovery of consciousness, but 2 in the quinine group had left facial palsy and one had a myasthenia gravis-like syndrome. No patient died with complications in he artemether group, but 7 died with pulmonary complications in the quinine group.

A comparative clinical trial of two different regimens of artemether plus mefloquine in multidrug resistant falciparum malaria

Plasmodium falciparum in Thailand is highly resistant to available antimalarial drugs. Artemether, a derivative of artemisinin, is a promising compound currently used to cope with this situation but the course of treatment has to be at least 5 d. An effective short treatment course of this drug is possible when used in combination with mefloquine. We now report a trial of different regimens of the combination artemether/mefloquine. Fifty-seven male Thai patients, admitted to the Bangkok Hospital for Tropical Diseases, were allocated at random to receive oral artemether 300 mg as an initial dose, followed by either the standard dose of mefloquine (750 mg) at 24 h or a higher dose of mefloquine (750 mg at 24 h, then 500 mg at 30 h). Patients were followed up in hospital for 42 d. Two patients, both in the high dose mefloquine group, were excluded as they failed to attend for follow-up. All patients had a rapid initial response to treatment with median parasite clearance times of 37 and 40 h, median fever clearance times of 33.5 and 30.5 h, and cure rates of 75 and 96% (P = 0.0248), for the standard and high doses of mefloquine respectively. No serious adverse effect was found; mild and transient dizziness, nausea, vomiting and diarrhoea were noted in half of the patients in each group. The results suggest that a 30 h short course of artemether plus mefloquine at high dose should be used in areas with documented mefloquine resistance.

PHARMACOKINETICS OF ORAL ARTESUNATE IN THAI PATIENTS WITH UNCOMPLICATED FALCIPARUM MALARIA

SummaryThe pharmacokinetics of artesunate and its major plasma metabolite, dihydroartemisinin, were investigated in 11 Thai male patients with acute uncomplicated falciparum malaria during the acute and recovery phases. Patients were given an oral dose of 200mg artesunate (Guilin Pharmaceutical) on the first day, followed by 100mg 12 hours later, then 100mg daily for another 4 days (total dose of 700mg). All the patients showed a rapid initial response with median (range) parasite and fever clearance times of 30 (18 to 60) and 24 (4 to 94) hours, respectively; no patients showed reappearance of parasites during the 28-day follow-up period. No significant clinical adverse effects were detected in any patient. Acute phase malaria infection significantly influenced the pharmacokinetics of artesunate and its active metabolite, dihydroartemisinin. Maximum plasma drug concentration (Cmax), absorption half-life (t1/2 a), area under the plasma concentration-time curve from zero to the last observed time (AUC) and terminal elimination half-life (t1/2 z) of artesunate were decreased, while apparent total body clearance (CL/f) was increased during the acute phase, compared with the recovery phase. In addition, a decrease in the Cmax and an increase in the AUCdha/ARS ratio were found. Optimisation of therapy with oral artesunate should therefore be based on the kinetics of the drug and dihydroartemisinin in malaria patients with acute phase infection.

Pharmacokinetics of mefloquine, when given alone and in combination with artemether, in patients with uncomplicated falciparum malaria

Summary— The pharmacokinetics of mefloquine at a single oral dose of 750 mg, when given alone or 24 hours after a single oral dose of artemether. (300 mg) was investigated in 27 Thai patients with acute uncomplicated falciparum malaria (17 with mefloquine alone, 10 with the combination). The oral bioavailability of mefloquine was significantly decreased when administered 24 hours after an oral dose of artemether. This was evident by the significantly lower values of Cmax, AUC[0–24 h], AUC[0–48 h], AUC[0–72 h], as well as total AUC[Cmax: 1,290 (827‐2,619) vs 1,820 (1,283‐2,531) ngṁml−1; AUC[0–24 h]: 0.99 (0.64‐1.41) vs 1.33 (1.07–1.95) μgṁdayṁml−1; AUC[0–48 h]: 1.78(1.23‐2.58) vs 2.67 (2.09‐3.84) μgṁdayṁml−1; AUC[0–72 h]: 2.74 (1.63‐3.6) vs 4.54 (2.88‐5.38) μgṁdayṁml−1; AUC: 11.11 (6–20.96) vs 15.29 (9.3–36.71) μgṁdayṁml−1]. Tmax was also delayed with the combination regimen [14 (5–24) vs 6 (4–16) h). Terminal elimination half‐lives were comparable [t1/2z: 11.1 (6.8–14.3) vs 13.4 (10.5–19.1) h].

Pharmacokinetics of oral artemether in Thai patients with uncomplicated falciparum malaria.

Artemether has been demonstrated to be highly effective against multidrug resistant Plasmodium fulcipurum malaria [4]. Pharmacokinetic data of artemether available to date however, have been limited, particularly in patients with malaria. The aim of the present study was to investigate the absorptioddisposition kinetics of artemether and its active plasma metabolite dihydroartemisinin during acute and recovery phases of uncomplicated falciparum malaria.

Pharmacokinetics of mefloquine in the presence of primaquine

In the c h e m o t h e r a p y of malar ia the ach ievement of radical t r ea tmen t requires antimalarial drugs that act on various stages of the parasi te cycle. As there is no single drug which can affect radical t reatment , a combina t ion o f a fast-acting b lood schizonticide and a gametocytoc ida l drug has been advoca ted [1, 2]. The role of p r imaqu ine as a gametocy toc ida l drug in P.falciparum infections is controversial . Mef loquine has been shown to be effective in the prophylaxis and treatmen t of infections with mul t i -drug resistant P.falciparum [3, 4] and its use in combina t ion with the gametocytoc ida l drug pr imaquine could be of great value in the control of malaria, p rov ided that there was no adverse effect due to a drug interaction. Pr imaquine does inhibit hepat ic microsomal enzymes, bo th in vitro and in vivo [5, 6], and since mef loquine is metabol ized in the liver to a carboxylic acid [7, 8], perhaps via isozyme(s) of cy toch rome P450 (Na Bangchang , unpubl i shed observat ions) , it was impor tan t to ascertain if the co-adminis t ra t ion of p r imaquine would alter the pharmacokine t ics of mefloquine. The present study was conduc ted to examine this pharmacok ine t i c possibility.