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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.
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PMID:Comparison of oral artemether and mefloquine in acute uncomplicated falciparum malaria. 135 18

A 27-year-old man was admitted to the hospital with a seven-day history of fever, nausea, vomiting, diarrhea, and pruritic rash. He was not diagnosed as having malaria until a history was obtained of Plasmodium falciparum malaria two years previous to this admission, and a review of the peripheral blood smear confirmed the diagnosis. The patient was admitted for inpatient therapy. He responded well and was discharged on the fourth hospital day to complete the remainder of the therapy as an outpatient. This case is a somewhat atypical presentation and reemphasizes several key points in the prophylaxis, diagnosis, and treatment of malaria.
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PMID:It's not a viral syndrome, it's malaria. 264 81

A randomized double blind study in long term malaria chemoprophylaxis was performed to compare the tolerability of Fansimef (1 tablet containing 250 mg mefloquine + 500 mg sulfadoxine + 25 mg pyrimethamine per week) with chloroquine (300 mg per week). 211 Austrian industrial workers and their families in Warri, Nigeria, participated in this study; 101 received Fansimef and 110 chloroquine for 3-18 months (mean 41 weeks). Prophylaxis was discontinued because of adverse effects in 7 volunteers in the Fansimef group (mainly insomnia, palpitations, dizziness, nausea and headache) and in 2 volunteers of the chloroquine group (headache and loss of hair in one volunteer, nausea, dizziness and vomiting in the other). Most of the adverse effects could be due to the mefloquine component. A few minor complaints of burning eyes, nausea and gastric pain were reported in both groups. Laboratory checks performed at 3-monthly intervals showed a slight, transient and clinically irrelevant (but statistically significant) increase of serum glutamic-oxalacetic transaminase and gamma-glutamyl transpeptidase at month 3 in the Fansimef group. An attack of acute Plasmodium falciparum malaria occurred in one volunteer 6 weeks after discontinuation of prophylaxis with Fansimef. Antibodies against blood stage parasites could be demonstrated by the indirect immunofluorescence test at different stages of the study, indicating that these two antimalarials are not causal prophylactic agents.
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PMID:Tolerability of long-term malaria prophylaxis with the combination mefloquine + sulfadoxine + pyrimethamine (Fansimef): results of a double blind field trial versus chloroquine in Nigeria. 290 58

Halofantrine (WR 171,669) hydrochloride was administered orally to 82 patients infected with Plasmodium falciparum malaria on the Thai-Kampuchean border between June 1982 and December 1983 in a randomized double-blind treatment trial which compared the efficacy of halofantrine with that of mefloquine. Halofantrine was curative with oral treatment on a single day in 65% of patients (13/20) who received 1000 mg followed 6 hours later by an additional 500 mg, and in 88% of patients (53/60) who received 500 mg every 6 hours for 3 doses. Mefloquine was curative in 88% of patients (22/25) given a single oral dose of 1000 mg and in 97% of patients (38/39) given a single oral dose of 1500 mg. The difference in cure rates between the 3-dose halofantrine regimen and either of the mefloquine regimens was not significant. The mean parasite clearance time for all regimens ranged from 75 to 84 hours. The mean fever clearance time for all four treatment groups was in the range 50-60 hours, with no significant differences between groups. Post-dosing side-effects in patients treated with halofantrine consisted of nausea, vomiting, abdominal pain and diarrhoea and were not significantly different from those treated with mefloquine. Halofantrine therefore appeared to be of comparable efficacy to mefloquine in the treatment of multidrug-resistant P. falciparum malaria.
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PMID:Malaria: treatment efficacy of halofantrine (WR 171,669) in initial field trials in Thailand. 329 28

Chloroquine-resistant Plasmodium falciparum malaria is increasing in prevelance in Papua New Guinea and alternative therapies for acute malaria are being sought. A trial of sulfadoxine-pyrimethamine for the treatment of acute falciparum malaria in children has been carried out in Madang, Papau New Guinea. Eighty-five children were treated with sulfadoxine-pyrimethamine, either alone or in combination with a single 10 mg/kg dose of chloroquine. Of 78 children completing 28-days follow-up, treatment failures occurred in 15 (19.2%) and of these, 8 (10.3%), are believed to be sulfadoxine-pyrimethamine resistant; the others remain equivocal. There was no advantage in this study in combining a single dose of chloroquine with sulfadoxine-pyrimethamine; indeed, this combination was associated with an increased incidence of vomiting. It is argued that sulfadoxine-pyrimethamine should not become the standard presumptive treatment for acute malaria in Papua New Guinea.
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PMID:Sulfadoxine-pyrimethamine for the treatment of acute malaria in children in Papua New Guinea. I. Plasmodium falciparum. 703 64

Forty cases of cerebral Plasmodium falciparum malaria seen at San Lazaro Hospital, Manila, Philippines from 1979-1981 were reviewed. These cases represented 7% of all Plasmodium falciparum cases seen during this period. All of the patients had fever and headache, 73% confusion, 70% chills, 68% jaundice or abdominal pain, 60% sweats. Findings more frequent in the fatal compared to the non-fatal cases were: the presence of schizonts in the peripheral smear, oliguria, coma, convulsions, urinary incontinence, jaundice, pulmonary symptoms and vomiting. Fatal cases were less likely to be clinically diagnosed as malaria and more likely to be diagnosed as hepatitis than malaria. The treatment and management of these cases is discussed.
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PMID:Cerebral malaria at San Lazaro Hospital, Manila, Philippines. 717 Jun 37

Studies of 652 adults and children with acute uncomplicated falciparum malaria were done to determine the optimum treatment of multidrug-resistant Plasmodium falciparum malaria on the Thai-Burmese border. Single-dose artesunate (4 mg/kg) plus mefloquine (25 mg of base/kg) gave more rapid symptomatic and parasitologic responses than high-dose mefloquine alone but did not improve cure rates. Three days of artesunate (total dose, 10 mg/kg) plus mefloquine was 98% effective compared with a 28-day failure rate of 31% with high-dose mefloquine alone (relative risk [RR], 0.06; 95% confidence interval [CI], 0.02-0.2; P < .0001). By day 63, the reinfection adjusted failure rates were 2% and 44%, respectively (P < .0001). Artesunate also prevented high-grade failures. Both drugs were well tolerated. No adverse effects were attributable to artesunate. Vomiting was reduced significantly by giving mefloquine on day 2 of treatment (RR, 0.40; 95% CI, 0.20-0.79; P = .009. Artesunate (10 mg/kg over 3 days) plus mefloquine (25 mg/kg) is currently the most effective treatment for falciparum malaria in this area of increasing mefloquine resistance.
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PMID:Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. 793 Jul 43

Halofantrine is a phenanthrenemethanol antimalarial that is effective against asexual forms of multidrug-resistant Plasmodium falciparum malaria. It has no action on gametocytes or hypnozoites in the liver. The drug is administered as a racemic mixture but the (+)- and (-)-enantiomers show no difference in activity in vitro. Three formulations for oral administration are available for human use, i.e. tablets, capsules and suspension. Toxicity studies in animals suggest that halofantrine has very low toxicity both in short term and long term animal studies, and there has been no evidence of mutagenicity in these studies. Phase I, II and III clinical trials of halofantrine conducted in several tropical countries found the drug to be well tolerated and effective against multidrug-resistant P. falciparum malaria when 500mg was administered every 6 hours for 3 doses. The majority of clinical adverse effects reported, including nausea, vomiting, abdominal pain, diarrhoea, orthostatic hypotension, prolongation of QTc interval, pruritus and rash, have been mild and transient. There is wide interindividual variation in halofantrine absorption. The maximal plasma concentration (Cmax) is achieved approximately 6 hours after oral administration. Bioavailability is not dose-proportional for doses over 500mg, but there is a dose-proportional increase in Cmax and area under the plasma concentration-time curve (AUC) for doses between 250 and 500mg. In patients with malaria the bioavailability of halofantrine is decreased. The mean half-life of absorption is 4 hours and Cmax is significantly lower than that obtained in healthy individuals. Furthermore, halofantrine absorption is enhanced when the drug is taken with fatty food. Therefore, halofantrine should be taken with food to ensure optimal absorption in patients with malaria. The terminal elimination half-life is 5 days in patients with malaria. Halofantrine is biotransformed in the liver to its major metabolite N-debutyl-halofantrine. Plasma concentrations of this metabolite are observed soon after administration of halofantrine, but in much lower concentrations. The elimination half-life is similar to that of halofantrine. There have been increasing reports of halofantrine treatment failure, particularly in the eastern part of Thailand. The majority of treatment failures have been associated with incomplete drug absorption. The dose-dependent cardiotoxic effects (e.g. cardiac arrhythmia) are a major concern, particularly when the bioavailability of the drug cannot be predicted. Ongoing and future studies should aim at developing more appropriate drug formulation(s) and/or optimising dosage regimens. This will allow therapeutic concentrations to be achieved with minimum adverse effects, particularly cardiotoxicity.
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PMID:Clinical pharmacokinetics of halofantrine. 795 74

We have carried out a retrospective study on 100 children in hospital in Marseilles, France with a diagnosis of Plasmodium falciparum malaria. On admission, the main clinical features were anaemia (90 cases), fever (83 cases, > 40 degrees C in 22 cases), hepatomegaly (44 cases), vomiting (29 cases), neurological signs (22 cases), thrombocytopenia (13 cases), hyperparasitaemia (6 cases), jaundice (4 cases), shock (1 case) and hypoglycaemia (1 case). Severe malaria, as defined by the World Health Organization Malaria Action Programme, was rare in our study (only 2 cases) and the prognosis was good (no death, no sequela). The search for neurological signs such as impaired consciousness, prostration or convulsions is an effective and simple way to diagnose potentially severe cases. In the presence of these signs, intravenous quinine treatment resulted in a shortened duration of fever (30 h instead of 63 h) and thereby avoided patients becoming worse. In children without neurological signs or persistent vomiting, oral therapy may be used even if there is high fever or hyperparasitaemia, but close surveillance is required. Patients treated with halofantrine or mefloquine had a shorter stay in hospital than those treated with chloroquine (mean = 4 d instead of 5.7 d). The resistance of some strains to chloroquine may explain this difference.
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PMID:Choice of therapy for imported cases of falciparum malaria in children: a retrospective study of 100 cases seen in Marseilles, France. 846 3

Artesunate is an antimalarial agent, available in oral, rectal and parenteral formulations, that provides a rapid clinical effect in patients with Plasmodium falciparum malaria. The rapidity of effect, availability of an intravenous and intramuscular formulation and convenient dosage regimen make artesunate an ideal candidate for the treatment of severe malaria, including cerebral disease. While some results have been promising, there is no clear evidence to date that artesunate reduces mortality in patients with cerebral malaria to any greater extent than standard quinine therapy. When given as monotherapy, treatment should be continued for at least 5 to 7 days to prevent recrudescence. Combination therapy with mefloquine allows artesunate to be administered over 3 days or less, with a satisfactory clinical outcome maintained. Although optimal dosages remain to be determined, this combination continues to provide the rapid onset of clinical effect observed with artesunate monotherapy, but decreases the rate of recrudescence to 2% (i.e. radical cure rate of 98%) when used as treatment in patients with uncomplicated malaria from areas with a high risk of multidrug-resistance falciparum malaria. Although assessment of tolerability is complicated by the difficulty of distinguishing between disease- and treatment-related events, artesunate and artesunate-mefloquine combinations appear to be well tolerated in adults and children. Indeed, it is possible that prior administration of artesunate may reduce the incidence of mefloquine-induced vomiting. Clinical findings to date have not revealed any pattern of resistance to artesunate after use of the drug. However, given the history of the development of resistance to other antimalarial drugs, the use of artesunate should be restricted to areas of multidrug resistance, the drug should be used in combination with a longer acting agent such as mefloquine, and it should be used in regimens that provide radical cure rates of 90 to 100%. If used according to these treatment principles, artesunate will provide a well tolerated and valuable addition to the current extremely limited treatment options for multidrug-resistant falciparum malaria, a widespread parasitic disease associated with considerable mortality.
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PMID:Artesunate. A review of its pharmacology and therapeutic efficacy in the treatment of malaria. 853 55


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