A phase-III clinical trial of mefloquine in children with chloroquine-resistant falciparum malaria in Thailand

Mefloquine is a highly effective drug for the treatment of falciparum malaria among adults, but studies of its effects on children are lacking. An open, noncomparative trial of mefloquine was therefore carried out among 84 children aged 5-12 years who were patients at the Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand. The drug was administered as a single dose of 18-29 mg base per kg body weight. Eighty-two of the 84 children completed a 42-day period of post-treatment observation. The drug was well tolerated also by 11 children with glucose-6-phosphate dehydrogenase deficiency, and all the children in the study cleared their parasitaemia initially (average clearance time, 65 hours). Furthermore, the clinical-chemical parameters measured exhibited no drug-related changes during the study. The radical cure rate of nearly 98% and high tolerance indicate that mefloquine can be used effectively and safely for the treatment of children aged 5-12 years who are suffering from uncomplicated falciparum malaria.     

In vitro response of chloroquine-resistant Plasmodium falciparum to mefloquine.

The present study was conducted to evaluate the application of the in vitro microtechnique system in determining the response of chloroquine-resistant Plasmodium falciparum to mefloquine.     

A phase II clinical trial of mefloquine in patients with chloroquine-resistant falciparum malaria in Thailand

A double-blind, randomized, dose-finding, phase II mefloquine trial was carried out in 147 adult male patients suffering from acute, uncomplicated, falciparum malaria and admitted to the Hospital for Tropical Diseases, Bangkok, between January 1980 and April 1981. Mefloquine was administered as a single oral dose of 500, 750, or 1000 mg (base) in the form of the hydrochloride. The clinical and parasitological responses were satisfactory with all three dosage regimens. The cure rates for the 1000-, 750-, and 500-mg doses were 100%, 92.5%, and 95% respectively, over an observation period of 63 days.     

Absence of malaria mortality in villagers with chloroquine-resistant Plasmodium falciparum treated with chloroquine

We carried out a series of malaria studies in Robek , Flores, Indonesia, a coastal village of 900 farmers and fishermen where malaria is hyperendemic by parasite rate and holoendemic by spleen rate. The studies showed that: (i) 28 of 31 isolates (90%) of Plasmodium falciparum were resistant to chloroquine in vitro, (ii) 3 of 12 isolates (25%) were resistant at the R-11 level in vivo, (iii) 376 P. falciparum infections occurred in 301 individuals during one year, (iv) no villagers who were treated with chloroquine for P. falciparum infections during the year died, and (v) increasing the dosage of chloroquine base from 15 to 25 to 37.5 mg/kg led to improved clearing of parasitaemia. We conclude that chloroquine can still be used as the primary antimalarial in Robek , but the dosage may have to be increased to clear parasitaemia.     

Isoenzyme characterization of chloroquine-resistant isolates of Plasmodium falciparum from Burma

Sixty isolates of Plasmodium falciparum collected from hospital in-patients in Rangoon and out-patients from villages near Rangoon were tested in vitro for chloroquine sensitivity and then cultured to carry out starch gel electrophoresis of the following parasite enzyme: glucose phosphate isomerase (GPI) (EC.5.3.1.9.), NADP-dependent glutamate dehydrogenase (GDH) EC.1.4.1.4), lactate dehydrogenase (LDH) (EC.1.1.1.27) and 6-phosphogluconate dehydrogenase (6PGD) (E.C.I.1.1.44). Variations were observed in three (GPI, GDH and LDH) of the four enzymes examined. Three forms of parasite GPI, two forms of parasite GDH, two forms of parasite LDH and only one form of parasite 6PGD were identified. Enzyme polymorphism was more common in isolates with higher resistance to chloroquine. One isolate with parasite GDH-2 and six isolates with parasite LDH-2 were recorded from chloroquine-resistant cases.     

Studies on a strain of chloroquine-resistant Plasmodium falciparum from Thailand

Infections with a strain of Plasmodium falciparum from Thailand, termed the Thailand (JHK) strain, were established in 25 non-immune volunteers in a non-endemic area under conditions precluding reinfection. Eleven volunteers received chloroquine in usually curative doses on a three-day schedule during acute clinical malaria attacks. Volunteers also received (again during acute clinical attacks) hydroxychloroquine, amodiaquine, mepacrine, pyrimethamine, proguanil or 377-C-54, alone or in combination. These regimens failed, both before and after passage of the strain through mosquitos, to effect radical cure of the infection. Radical cure was achieved by administration of 1350 mg or 1620 mg of quinine base daily for seven days.     

Studies on a strain of chloroquine-resistant Plasmodium falciparum from Viet-Nam

This report presents the results of chemotherapeutic studies carried out with non-immune volunteers infected with a strain of Plasmodium falciparum from Viet-Nam, termed the Viet-Nam (Sn.) strain, under conditions of study precluding reinfection. Nine volunteers received, during acute clinical attacks, three-day courses of chloroquine, seven receiving 1500 mg of chloroquine base orally, one 3000 mg of chloroquine base orally, and one 2160 mg of chloroquine base intramuscularly. Volunteers also received, again during acute clinical attacks, various regimens of hydroxychloroquine (1500 mg base), amodiaquine (1400 mg base), mepacrine (2198 mg base), proguanil (2610 mg base), or 377-C-54 (1500 or 2500 mg base). These drugs failed to effect radical cure of the infections, both before and after passage of the strain through mosquitos.     

The relationship between the response of Plasmodium falciparum malaria to mefloquine in African children and its sensitivity in vitro.

The clinical efficacy of two doses of mefloquine (15 and 25 mg/kg body weight) was evaluated in 85 children suffering from acute symptomatic falciparum malaria. The cure rate on day 28 was 100% in both groups. There was no significant difference (P > 0.05) in the mean parasite and fever clearance times in both groups (48.5 +/- 14.6 and 32.0 +/- 12.7 h respectively for the 25 mg/kg group and 49.0 +/- 15.1 and 30.0 +/- 13.3 h respectively for the 15 mg/kg group). There was also no significant difference (P > 0.05) in these values between children with hyperparasitaemia (53.6 +/- 11.1 and 36.0 +/- 17.0 h respectively) and those without hyperparasitaemia (49.1 +/- 13.6 and 31.8 +/- 14.6 h respectively). Recurrence of parasitaemia was observed after day 30 in 2 patients in the 15 mg/kg group and in 1 patient in the 25 mg/kg group. In vitro, 3 of 21 isolates showed reduced susceptibility to mefloquine, with minimum inhibitory concentrations (MIC) > 67 nM/litre. The MIC and 50%, 90% and 99% inhibitory concentrations were 200.8, 6.27, 31.7 and 119.6 nM/litre respectively. Four of 22 isolates were resistant to chloroquine (MIC > 108 nM/litre). Isolates that showed low sensitivity to mefloquine in vitro were sensitive to chloroquine in vitro, and the 4 that were resistant to chloroquine were sensitive to mefloquine. Irrespective of MIC and dose of mefloquine, parasitaemia cleared in all subjects in 96 h or less.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasmodium falciparum: mefloquine resistance produced in vitro

Camp and Smith strains of the human malaria parasite Plasmodium falciparum became resistant to mefloquine after continuous cultivation in the presence of the drug. The 50% inhibitory dose (ID₅₀) values for mefloquine, as assessed by [³H]hypoxanthine incorporation, were found to have increased 4-fold, from 3 μg/l to 12 μg/l. The ID₅₀ values obtained by morphological examination of the cultures increased 10-fold. Resistance was stable in both strains either when grown in a drug-free medium or when kept frozen in liquid nitrogen. The mefloquine-resistant Camp strain remained sensitive to chloroquine and amodiaquine, and became slightly more resistant to quinine; there was increased sensitivity to pyrimethamine. The mefloquine-resistant Smith strain remained sensitive to amodiaquine and resistant to pyrimethamine; there was increased resistance to quinine, and an increase in sensitivity to chloroquine.     

Sulfadoxine-pyrimethamine for the treatment of Plasmodium falciparum malaria in Gabonese children

Chloroquine can no longer be recommended as the first-line treatment for falciparum malaria in several parts of Africa, given the increasing resistance of Plasmodium falciparum to this drug. The sulfadoxine-pyrimethamine combination (SP) is obviously an alternative candidate, that has already been selected as first-line antimalarial treatment by a few African countries. However, the extent of resistance to SP appears to be highly variable within Africa. Therefore, we investigated the efficacy of SP to treat uncomplicated malaria attacks in children from south-east Gabon. Sixty-six children presenting with a P. falciparum malaria attack were given a standard regimen of SP, and were followed at Days 3, 7, 14, and 21. No RIII response was observed, but relatively high prevalences of RII (18.2%) and RI (12.1%) were present. Moreover, analysis of the clinical outcome according to CDC criteria showed that initial clinical response was lacking in 8.5% of children, and that clinical failure occurred in 9.1%.     

Chloroquine blood concentrations and molecular markers of chloroquine-resistant Plasmodium falciparum in febrile children in northern Ghana

Plasmodium falciparum malaria is a predominant reason for health care utilization among children in sub-Saharan Africa. Despite the spread of resistance, chloroquine (CQ) is the most commonly used antimalarial. Little is known about the pattern of CQ use and resistance to the drug prior to attendance at a health care facility, and its impact on clinical presentation in children attending health care facilities in endemic regions. In a cross-sectional study among 840 febrile children presenting at a primary health care facility in northern Ghana from September to December 2000, CQ blood levels were measured by enzyme-linked immunosorbent assay and parasite isolates were genotyped for the CQ resistance markers pfcrt T76 and pfmdr1 Y86. Plasmodium falciparum was present in 95% by polymerase chain reaction and CQ was detected in 64% of the children. Concentrations of CQ in blood ranged from 31 to 3897 nmol/L (median 198 nmol/L). The pfcrt T76 and pfmdr1 Y86 resistance markers were detected in 84% and 57% of the isolates, respectively, and were selected by CQ. A significant trend for higher frequencies of the resistance markers with increasing CQ concentrations was observed. In this typical primary health care setting in sub-Saharan Africa, CQ use prior to attendance at a health care facility and CQ-resistant P. falciparum are frequent. As CQ selects resistant P. falciparum genotypes, CQ should be omitted as a first-line drug even in primary health care facilities when self-treatment with CQ is common.     

Clinical efficacy of chloroquine or sulfadoxine-pyrimethamine in children under five from south-western Uganda with uncomplicated falciparum malaria

We conducted a 14-day study (during March-May 1998) to assess the efficacy of chloroquine and sulfadoxine-pyrimethamine (SP) for treating uncomplicated Plasmodium falciparum malaria in Uganda. Overall treatment failure rates were 43 (81.1%) of 53 chloroquine recipients and 16 (25.0%) of 64 SP patients. Strategies to improve the life-span of standard and affordable anti-malarial drugs are needed.