The therapeutic responses to the eight most widely used antimalarial drugs were assessed in 207 adult patients with Plasmodium vivax malaria. This parasite does not cause marked sequestration, so parasite clearance can be used as a direct measure of antimalarial activity. The activities of these drugs in descending order were artesunate, artemether, chloroquine, mefloquine, quinine, halofantrine, primaquine, and pyrimethamine-sulfadoxine (PS). Therapeutic responses to PS were poor; parasitemias did not clear in 5 of the 12 PS-treated patients, whereas all the other patients made an initial recovery. Of 166 patients monitored for >28 days, 35% had reappearance of vivax malaria 11 to 65 days later and 7% developed falciparum malaria 5 to 21 days after the start of treatment. There were no significant differences in the times taken for vivax malaria reappearance among the different groups except for those given mefloquine and chloroquine, in which all vivax malaria reappearances developed >28 days after treatment, suggesting suppression of the first relapse by these slowly eliminated drugs. There was no evidence of chloroquine resistance. The antimalarial drugs vary considerably in their intrinsic activities and stage specificities of action.Plasmodium vivax affects millions of people living in tropical areas and is an important cause of morbidity in Central and South Americas and Asia. Until recently, P. vivax has remained uniformly sensitive to chloroquine, and this cheap and widely available antimalarial agent has been the treatment of choice for the past 50 years. Although P. vivax developed resistance to the dihydrofolate reductase inhibitors within a few years of their initial deployment as single drugs (7), chloroquine resistance has developed only in the last decade. High-level chloroquine resistance has been well documented on the northern part of the island of New Guinea and in Sumatra, Indonesia, and there have been sporadic reports from other geographic locations (1). The evaluation of alternative antimalarial drugs for the treatment of vivax malaria is therefore needed.Most research on the efficacies of antimalarial drug treatments concerns Plasmodium falciparum, the most dangerous and the most drug resistant of the four human malaria parasites. P. vivax is less virulent than P. falciparum because it does not reach high parasite densities and it does not sequester in the capillaries and venules. As all stages of asexual development are present in the peripheral blood, the initial decline in the level of parasitemia following drug treatment of P. vivax malaria reflects antimalarial activity and not a combination of accelerated parasite clearance and sequestration (13). This allows a direct comparison of the antimalarial activities of different antimalarial agents, including drugs which act predominantly in the second half of the asexual life cycle. In contrast, in falciparum malaria comparison of the pharmacodynamic properties of antimalarial agents in vivo is confounded by the sequestration of parasiti...
The blood stage antimalarial efficacy of primaquine (0.25 mg of base/kg of body weight/day over 14 days) and chloroquine (25 mg of base/kg over 3 days) were compared in 85 adult Thai men with acute Plasmodium vivax malaria. Most (75%) had at least one malaria episode previously. Parasite clearance times after primaquine alone (n = 30) were slower than after chloroquine (n = 30) or combined chloroquine-primaquine (n = 25), but all patients had a satisfactory initial therapeutic response. P. vivax malaria recurred in 10 (17%) of 60 patients followed for > or = 2 months and Plasmodium falciparum malaria developed in another 5 (8%) without reexposure to infection. Recurrences occurred < or = 5 weeks after primaquine treatment (n = 4), suggesting recrudescence, whereas recurrences after chloroquine treatment (n = 6) occurred > or = 5 weeks later, suggesting relapse. Vivax malaria responds well initially to either primaquine or chloroquine. The blood stage antimalarial activity of primaquine may mask chloroquine resistance in combined regimens.
Between 1981 and 1992, 196 Thai adults with severe falciparum malaria were treated with a quinine loading dose regimen. Nineteen patients died (10%) and 6 developed late hypoglycaemia. There was no serious cardiovascular or nervous system toxicity. Although there was no evidence of high grade resistance, and no change in the mortality rate, in recent years an increasing proportion of patients had a delayed clinical and parasitological response to treatment. Since 1988, 78% (29/37) of patients with cerebral malaria were unconscious for > 72 h compared with 41% (11/27) between 1981 and 1987 (P = 0.002). In the past 2 years parasite clearance times have exceeded 96 h in 33% (26/78) of patients compared with 14% (15/102) previously (P = 0.006). Quinine remains an effective treatment for severe multi-drug resistant falciparum malaria in this area, but there is now evidence of a decline in the immediate therapeutic response, and its efficacy will need close monitoring as resistance increases further.
Therapeutic responses to clindamycin in combination with quinine were assessed in adult Thai patients with uncomplicated multidrug-resistant Plasmodium falciparum malaria. In total 204 patients were randomized to receive a 7-day oral treatment regimen of quinine (Q 7 ) either alone (n ؍ 68), in combination with clindamycin (Q 7 C 7 ; n ؍ 68), or in combination with tetracycline (Q 7 T 7 ; n ؍ 68). All patients had uncomplicated recoveries with no serious adverse effects. Fever clearance times for both of the two combination regimens (median of 47 h and range of 8 to 120 h for Q 7 C 7 and median of 36 h and range of 8 to 117 h for Q 7 T 7 ) were significantly shorter than that for the Q 7 -only regimen (median, 56; range, 4 to 152 h) (P ؍ 0.002). Parasite clearance times (overall mean ؎ standard deviation, 78 ؎ 23 h) were not significantly different between the three treatment groups (P ؍ 0.98). The cure rates assessed at 28 days of follow-up were 100% for Q 7 C 7 and 98% for Q 7 T 7 , whereas the cure rate was 87% for the Q 7 -only regimen (P < 0.04). Clindamycin in combination with quinine is a safe and effective treatment for multidrug-resistant P. falciparum malaria. This combination may be of particular value in children and pregnant women, in whom tetracyclines are contraindicated.Multidrug-resistant Plasmodium falciparum malaria is of increasing public health concern in the tropics. For adult patients, combination treatments with quinine-tetracycline, artesunate-mefloquine, or artemether-lumefantrine are effective worldwide. These regimens yield high cure rates of 95 to 100% (3,7,14,15,17). When quinine is used for the treatment of children and pregnant women, it is often given alone, as the tetracyclines are contraindicated in these two important highrisk groups. Combinations with other antibiotics with antimalarial activity such as erythromycin or rifampin (9) have shown disappointing efficacies.Clindamycin, usually combined with quinine, had been used extensively in South America and has also proved effective in adults and children with acute malaria in Africa (4-6, 13). The efficacy of clindamycin plus quinine has not been evaluated in the Southeast Asian region (12), where the most drug-resistant P. falciparum strains are found. We have recently assessed the antimalarial activity of clindamycin in adult patients with Plasmodium vivax malaria and found that it has antimalarial activity similar to that of tetracycline or doxycycline (9). The present study assessed the efficacy of clindamycin in combination with quinine in comparison with those of quinine-tetracycline and quinine alone for the treatment of adult patients with falciparum malaria in Thailand, which harbors the world's most drug-resistant P. falciparum. MATERIALS AND METHODS Patients.The study was conducted with adult male patients with acute P. falciparum malaria admitted to the Bangkok Hospital for Tropical Diseases, Bangkok, Thailand, between 1995 and1997. Fully informed consent was obtained from each subject. Exclusion criter...
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