phenanthrenes and Malaria--Falciparum

Drug resistance is one of the major factors contributing to the resurgence of malaria, especially resistance to the most affordable drugs such as chloroquine and Fansidar, a combination drug of pyrimethamine and sulfadoxine. Understanding the mechanisms of such resistance and developing new treatments, including new drugs, are urgently needed. Great progress has been made recently in studying the mechanisms of drug action and drug resistance in malaria parasites, particularly in Plasmodium falciparum. These efforts are highlighted by the demonstration of mutations in the parasite dihydrofolate reductase and dihydropteroate synthase genes conferring resistance to pyrimethamine and sulfadoxine, respectively, and by the recent discovery of mutations in the gene coding for a putative transporter, PfCRT, conferring resistance to chloroquine. Mutations in a homologue of a human multiple-drug-resistant gene, pfmdr1, have also been shown to be associated with responses to multiple drugs. However, except in the case of resistance to antifolate drugs, the mechanisms of action and resistance to most drugs currently in use are essentially unknown or are being debated. Additionally, novel mechanisms of resistance exist in different malaria parasites, complicating the process of developing new drugs and treatment strategies. Here we summarise the progress made in drug resistance research in malaria parasites over the past 20 years, emphasising the most recent developments in the genetics of drug resistance.

Topics: Animals; Antimalarials; Chloroquine; Dihydropteroate Synthase; Drug Resistance; Drug Resistance, Multiple; Humans; Linkage Disequilibrium; Malaria; Malaria, Falciparum; Malaria, Vivax; Mefloquine; Membrane Proteins; Membrane Transport Proteins; Mutation; Phenanthrenes; Plasmodium falciparum; Plasmodium vivax; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase

The increasing prevalence of multi-resistant Plasmodium falciparum malaria worldwide is a serious public health threat to the global control of malaria, especially in poor countries like Pakistan. In many countries choloroquine-resistance is a huge problem, accounting for more than 90% of malaria cases. In Pakistan, resistance to choloroquin is on the rise and reported in up to 16- 62% of Plasmodium falciparum. four to 25% of Plasmodium falciparum also reported to be resistant to sulfadoxine-pyrimethamine and several cases of delayed parasite clearance have been observed in patients with Plasmodium falciparum malaria treated with quinine. In this article we have introduced the concept of artemisinin- based combination therapy (ACT) and emphasize the use of empiric combination therapy for all patients with Plasmodium falciparum malaria to prevent development of drug resistance and to obtain additive and synergistic killing of parasite.

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Drug Combinations; Drug Resistance, Multiple; Drug Therapy, Combination; Follow-Up Studies; Humans; Malaria, Falciparum; Pakistan; Phenanthrenes; Plasmodium falciparum; Quinidine; Quinine; Sesquiterpenes; Time Factors

A major challenge for successful treatment of Plasmodium vivax malaria is prevention of recurrence due to activation of dormant intrahepatic parasitic forms called hypnozoits. As a result of strain variability, recurrences are unpredictable and can occur months or even years after initial infection. Prevention requires elimination of both erythrocytic and hepatic parasite forms by combined use of chloroquine and primaquine. Primaquine is the only commercially available drug against hypnozoits. Several factors must be taken into account in planning treatment regimens. One factor is drug resistance of vivax strains, which as observed for Plasmodium falciparum strains is variable between geographical areas. Another factor is potential co-infection by Plasmodium vivax and falciparum, which is increasingly common. For optimal efficacy, treatment regimens must be adjusted with regard to dosage of primaquine and association with halofantrine, mefloquine or other new antimalarial agents. No regimen completely rules out the risk of recurrence.

Topics: Antimalarials; Chloroquine; Clinical Protocols; Drug Resistance; Drug Therapy, Combination; Humans; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes; Primaquine; Recurrence; Risk Factors; Treatment Outcome

The diagnosis of malaria should include the species involved and in case of P. falciparum infection the parasitaemia index: the percentage of the infected red cells. P. vivax, ovale and malariae infection are treated with chloroquine, in case of P. vivax and ovale malaria followed by primaquine. Mefloquine and halofantrine are indicated for chloroquine-resistant vivax infections. Advice on management and treatment is different for mild and severe (> or = 5% infected erythrocytes or presence of complications) P. falciparum infections. Mild infections may be treated on an outpatient basis. In severe infections quinine has to be started immediately, while frequent checks of vital functions and blood parameters are indicated. New treatment options are the use of artemisinine (preparations) or atovaquone, both efficacious and low in adverse effects and toxicity.

Topics: Adult; Antimalarials; Chloroquine; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Malaria; Malaria, Falciparum; Malaria, Vivax; Mefloquine; Phenanthrenes; Pregnancy; Primaquine

Halofantrine is an antimalarial drug which is widely prescribed for the treatment of infections with chloroquine-resistant strains of Plasmodium falciparum. Chemically, it is a phenanthrene methanol, belonging to the aryl-amino-alcohol family. It has recently been recognized that this drug may induce rare but serious, cardiotoxic effects, including lengthening of the QTc interval, 'torsade de pointes' and induction of late ventricular potentials. These events are thought to be related to a quinidine-like action of the drug. In addition, severe haemolytic accidents have been reported, mimicking blackwater fever and indicating an immunological process. As a result of these side-effects, new guidelines for prescription and more cautious use of halofantrine, particularly as a stand-by treatment for febrile access among travellers, are required.

Topics: Antimalarials; Electrocardiography; Heart Diseases; Hemolysis; Humans; Malaria, Falciparum; Phenanthrenes; Prospective Studies

Although more than 40% of the world's population live in malaria endemic areas, there are only 6 available antimalarial drugs for the treatment of Plasmodium falciparum infections. Three of these have been developed in the last 20 years and are discussed in this review. Mefloquine is relatively well tolerated and has the advantage of a single day regimen. It has ideal properties for prophylactic use. However, although rare, serious adverse reactions do occur and the drug cannot be used in severe malaria. Resistance has already emerged in some parts of the world. Halofantrine is also well tolerated and has a rapid antimalarial activity. It is more expensive than other antimalarials and the existence of cross-resistance links its usefulness to the demise of mefloquine. The discovery of a potentially lethal cardiotoxicity associated with halofantrine casts a further shadow over its use. The artemisinin derivatives represent an exciting breakthrough in the treatment of malaria. They are cheap and have a very rapid action. They seem remarkably free from toxic adverse effects, although the neurotoxicity seen in animal studies with the liposoluble derivatives gives rise for concern. However, the lack of pharmacokinetic and toxicity data as yet preclude their approval by Western drug regulation authorities. All antimalarials are threatened by the emergence of parasite resistance. Combination therapy using mefloquine and an artemisinin derivative may provide a way in which resistance can be combated.

Topics: Animals; Antimalarials; Artemisinins; Dose-Response Relationship, Drug; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Pregnancy; Risk Assessment; Sesquiterpenes

Chloroquine-resistant Plasmodium falciparum is now widespread in Africa, requiring new drugs for the control of both non-severe and severe forms of the disease. For non-severe malaria, pyrimethamine-sulphadoxine, an antifolate combination antimalarial, is at present efficacious, single-dose and cheap; important characteristics for treatments in Africa. However, alternative combinations are being investigated which are intrinsically more active, less toxic and with shorter elimination half-lives. In theory, short half-life compounds reduce the selective pressure for resistance, which may be a major determinant of the useful therapeutic life of an antimalarial drug. The potential advantages/disadvantages of alternative antifolates is discussed. While the use of mefloquine and halofantrine in Africa is at present limited by cost, these drugs are likely replacements for the antifolates when parasite resistance arises. For severe, life-threatening falciparum malaria, quinine remains the treatment of choice. In contrast to quinine, artemether rapidly reduces the viability of circulating, ring-stage parasites, produces more rapid parasite clearance and may reduce the length of coma, but does not significantly reduce the mortality of severe malaria which remains at about 15% even with optimal management. It seems unlikely that chemotherapy, even with "new" antimalarials, will reduce this high figure. Other strategies are required.

Topics: Africa; Antimalarials; Artemether; Artemisinins; Drug Costs; Drug Resistance; Humans; Malaria, Falciparum; Mefloquine; Phenanthrenes; Sesquiterpenes; Trimethoprim, Sulfamethoxazole Drug Combination

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, particu

Topics: Animals; Antimalarials; Dogs; Drug Interactions; Humans; Malaria, Falciparum; Mice; Phenanthrenes; Rats

Topics: Acute Disease; Adult; Animals; Antimalarials; Child, Preschool; Drug Evaluation; Humans; Incidence; Infant; Malaria; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes; Plasmodium falciparum; Prospective Studies; Travel

To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in healthy volunteers and patients with symptomatic falciparum malaria.. Healthy volunteer data were obtained from six volunteers who received three different doses of HF (250, 500 and 1000 mg) after an overnight fast with a washout period of at least 6 weeks between doses. Patient data (n = 188) were obtained from randomised controlled trials conducted on the Thai-Burmese border in the early 1990s. They were either assigned to receive a total HF dose of 24 mg/kg (8 mg/kg every 6 h for 24 h) or 72 mg/kg (8 mg/kg every 6 to 10 h for 3 days). The population pharmacokinetics of HF were evaluated using non-linear mixed effects modelling with a two-compartment model with first-order absorption.. The population estimates of apparent clearance (CL), volume of compartment one (V1), distributional clearance (CLD) and volume of compartment two (V2) of HF in healthy volunteers were 2453 l/day (102 l/h), 2386 l, 716 l/day (29.8 l/h) and 2641 l, respectively. The population estimates of the PK parameters in patients were 429 l/day (17.9 l/h), 729 l, 178 l/day (7.42 l/h) and 1351 l, respectively. All PK parameters were significantly related to body weight and some were related to sex, sampling method, pre-treatment parasite density and whether patients vomited or not. When the two datasets were analysed jointly using a maximum likelihood method, the population estimates in patients were 196 l/day (8.17 l/h), 161 l, 65 l/day (2.71 l/h) and 89 l, respectively, and the parameters were significantly related to body weight and sex. Bayesian analysis of the patient data, with a diffuse prior based on the healthy volunteer data analysis results, yielded the population estimates 354 l/day (14.8 l/h), 728 l, 162 l/day (6.75 l/h) and 1939 l, respectively.. The pharmacokinetic properties of HF in patients with malaria are affected by several demographic variables as well as other relevant covariates. Apparent differences between the healthy volunteer and the patient data analysis results are not entirely due to differences in bioavailability. For the patient data analysis, the Bayesian method was preferred, as the fitting procedure was more stable, allowing random effects to be estimated for all four dispositional parameters.

Topics: Adolescent; Adult; Antimalarials; Bayes Theorem; Biological Availability; Body Weight; Case-Control Studies; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Likelihood Functions; Malaria, Falciparum; Male; Middle Aged; Models, Biological; Myanmar; Nonlinear Dynamics; Phenanthrenes; Thailand; Tissue Distribution; Young Adult

One hundred two patients aged 2-43 years diagnosed with acute malaria due to P. falciparum or P. vivax were treated with 3 doses of halofantrine (500 mg for > or = 18 year old patients and 8 mg/kg of patient body weight for 2-17 year olds), with each dose administered once in 6 hours and followed up for 28 days. Out of 102 patients 63 had P. falciparum, 36 had P. vivax and 3 had unidentified species. Following three dose therapy, 96.1% (98/102) of patients were cured, 0.98% (1/102) showed improvement from baseline, 1.96% (2/102) did not respond and were considered as treatment failures and one patient had indeterminate data. The lone patient, who relapsed after 120 hours post dose 1, was cured following re-treatment on day 7. The median parasite clearance and fever clearance times, from the first dose, were 26 hours and 30 hours, respectively. Eleven point eight percent (12/102) of patients reported adverse events, of which abdominal pain, reported by one subject, was considered to be probably related to the drug and required corrective therapy. There were no serious adverse events or fatalities and none of the patients had a change in QTc interval greater than 10%. Thirteen point seven percent (14/102) of patients had abnormal clinical laboratory parameters that normalized later.

Topics: Adolescent; Adult; Blood Cell Count; Blood Chemical Analysis; Child; Child, Preschool; Electrocardiography; Female; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Pakistan; Parasitemia; Phenanthrenes; Treatment Outcome

To evaluate mefloquine versus halofantrine in children suffering from acute uncomplicated falciparum malaria.. Prospective non randomized study in hospitalized children during one year. Acute falciparum malaria was defined by fever and a positive thin and/or thick smear. Malaria was presumed to have been contracted in Comoros archipelago and/or Madagascar 6 months previously. Patients were excluded, when quinine had to be used, according to World Health Organization's severity criteria.. Forty-nine children were included: 29 were treated with halofantrine and 20 with mefloquine. Patients features in the two groups of treatment were identical, with exception for the mean time between first clinical signs and diagnosis (shorter in mefloquine group). Fever's and hospitalization's duration under treatment were similar. An increase in QTc interval was frequently observed in patients treated with halofantrine (56 versus 0%), although patients with mefloquine experienced vomiting (45 versus 0%). Relapses seemed to be more frequent with halofantrine (14 versus 0%).. Halofantrine and mefloquine are efficient for falciparum malaria treatment in our pediatric series, despite a high rate of adverse events. Mefloquine's tolerance may probably be improved with changes in regimen and dose. Relapses are more frequent with a single first treatment of halofantrine, than with mefloquine. Unfortunately, features of a second halofantrine treatment are not defined.

Topics: Adolescent; Antimalarials; Child; Child, Preschool; Female; Humans; Infant; Long QT Syndrome; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Treatment Outcome

Cardiotoxicity has become a major concern during treatment with antimalarial drugs. Lengthening of the QTc and severe cardiac arrhythmia have been observed, particularly after treatment with halofantrine for chloroquine-resistant Plasmodium falciparum malaria. The purpose of this prospective study was to evaluate whether antimalarial agents alter dispersion of the QTc and ventricular repolarization dynamicity. Sixty patients with uncomplicated falciparum malaria were randomly allocated in four groups of 15 patients and treated with quinine, mefloquine, artemether, or halofantrine at recommended doses. Patients in treatment groups were compared with a group including 15 healthy controls with no history of malaria and/or febrile illness within the last month. QTc dispersion was measured on surface electrocardiograms. Repolarization dynamicity was analyzed from Holter recordings, which allow automatic beat-to-beat measurement of QT and RR intervals. Plasma drug concentration was determined by reversed-phase high-performance liquid chromatography. No change in QTc dispersion was observed after treatment with quinine, mefloquine, or artemether. Treatment with halofantrine was followed by a significant increase in QTc dispersion at 9 hours (P < 0.0001) and 24 hours (P < 0.01). Assessment of QT heart rate variability by QT/RR nychtohemeral regression slope demonstrated no significant difference between the artemether (mean +/- SEM = 0.170 +/- 0.048), mefloquine (0.145 +/- 0.044), and the control groups (0.172 +/- 0.039). A significant decrease in the Q-eT/RR slope was observed in the quinine group compared with the control and artemether groups (0.135 +/- 0.057; P < 0.04). With halofantrine, a significant increase in the QT/RR regression slope (0.289 +/- 0.118) was observed (P < 0.0002). QTc interval, QT dispersion, and QT regression slope were significantly correlated with halofantrine and quinine plasma concentration. Mefloquine and artemether did not alter ventricular repolarization. Quinine induced a significant decrease in QT/RR slope of the same order of magnitude as those previously observed with quinidine. Both QTc dispersion and QT/RR slope were significantly modified by halofantrine. These repolarization changes were related to a class-III antiarrhythmic drug effect and may explain the occurrence of ventricular arrhythmia and/or sudden deaths reported after halofantrine intake.

Topics: Adult; Antimalarials; Electrocardiography; Female; Heart Rate; Heart Ventricles; Humans; Malaria, Falciparum; Male; Phenanthrenes; Prospective Studies

The spread of falciparum malaria resistant to chloroquine all over Southeast Asian continent has led to increasing use of alternative antimalarial drugs. Halofantrine has been shown to be effective against multidrug resistant Plasmodium falciparum. One hundred and twenty falciparum malaria cases were randomly assigned to one of three different halofantrine regimes. Group I (HA1) received 500 mg three times daily for 3 days (total dose: 4,500 mg), group II (HA2) received 500 mg three times daily for the first and the third day (total dose: 3,000 mg) and group III (HA3) received 500 mg three times for one day followed by 500 mg once daily for 7 days (total dose: 4,500 mg). No significant difference in the cure rate was observed among the three regimes (cure rate: 89%, 73%, 97% respectively). However, the cure rate was significantly higher in the HA3 group when compared to the HA2 group. There were no overt cardiac problems seen in this study. Thus, halofantrine has high efficacy in the recommended treatment dose of 500 mg three times after meals on the first day followed by 500 mg once a day after a meal for 7 days (total dose: 4,500 mg).

Topics: Adolescent; Adult; Antimalarials; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Thailand

Tafenoquine is an analogue of primaquine with an improved therapeutic and safety profile. It has a long half-life and activity against liver-stage malaria parasites, so may be useful for chemoprophylaxis. In this randomised, double-blind study we assessed the efficacy and safety of tafenoquine in different doses.. 2144 individuals aged 12-20 years living in Lambaréné, Gabon, an endemic area for Plasmodium falciparum malaria, were invited to take part. 535 attended, and 426 eligible participants were randomly assigned tafenoquine (250 mg, 125 mg, 62.5 mg, or 31.25 mg) or placebo daily for 3 days. 417 received initial curative treatment with halofantrine, and 410 completed the assigned prophylaxis regimen. During follow-up of 70 days, adverse events were recorded and thick blood smears were examined weekly. The primary and secondary endpoints were the number of individuals with positive blood smears by day 56 and day 77, respectively. Analyses were per-protocol.. Eight positive blood smears were recorded by day 56 (four/82 participants in the placebo group; four/79 tafenoquine 31.25 mg group). By day 77, 34 positive blood smears had been recorded (14/82 placebo; 16/79 tafenoquine 31.25 mg; three/86 tafenoquine 62.5 mg; one/79 tafenoquine 125 mg; none/84 tafenoquine 250 mg). Numbers of adverse events did not differ significantly between the treatment groups.. Tafenoquine is effective and well tolerated. It has the potential to replace currently used drugs for malaria chemoprophylaxis.

Topics: Adolescent; Adult; Aminoquinolines; Antimalarials; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Gabon; Humans; Malaria, Falciparum; Male; Phenanthrenes

Malaria is a major cause of pediatric mortality in sub-Saharan Africa. Worldwide estimates of mortality among children with Plasmodium falciparum malaria range from 1 to 2 million deaths per year. Management of malaria is increasingly difficult because of the global spread of drug-resistant strains of P. falciparum. There is an urgent need for safe and effective new therapies to treat multidrug-resistant malaria.. This open label, randomized trial compared atovaquone and proguanil hydrochloride with halofantrine for treatment of acute, uncomplicated P. falciparum malaria in children age 3 to 12 years (84 patients per group). Study drug dosages were adjusted by weight (approximately 20 and 8 mg/kg daily for three doses for atovaquone and proguanil hydrochloride and 8 mg/kg every 6 h for three doses for halofantrine). Patients were monitored by serial clinical and laboratory assessments for 28 days after starting treatment.. Both regimens were effective (cure rate, 93.8% for atovaquone and proguanil hydrochloride and 90.4% for halofantrine) and produced prompt defervescence. Mean parasite clearance times were 50.2 h for halofantrine and 64.9 h for atovaquone and proguanil hydrochloride. More adverse experiences were reported in children treated with halofantrine (119) than with atovaquone and proguanil hydrochloride (73).. In Kenyan children the combination of atovaquone and proguanil hydrochloride has efficacy comparable with that of halofantrine for treatment of acute uncomplicated multidrug-resistant falciparum malaria and is associated with a lower rate of adverse events.

Topics: Acute Disease; Animals; Antimalarials; Atovaquone; Child; Child, Preschool; Drug Therapy, Combination; Feces; Female; Humans; Malaria, Falciparum; Male; Naphthoquinones; Phenanthrenes; Plasmodium falciparum; Proguanil; Treatment Outcome

CGP 56697 (Riamet) is a new oral anti-malarial drug composed of artemether and lumefantrine (benflumetol) which combines the fast, short-acting artemether for rapid parasite clearance with the prolonged action of lumefantrine for intended radical cure. In this double-blind, comparative trial, the efficacy and tolerability of CGP 56697, given as a course of 4 x 4 tablets over 48 h, was compared to halofantrine, given as 3 x 2 tablets over 12 h with a second course 1 week later. Patients (mostly non-immune) with acute, uncomplicated Plasmodium falciparum infection were randomly assigned to either CGP 56697 (n = 51) or halofantrine (n = 52). CGP 56697 proved superior with respect to parasite clearance time (median 32 vs. 48 h, P < 0.001) and parasite reduction at 24 h (median 99.7 vs. 89.6%, P < 0.001) with a non-significant difference in resolution of fever (median 24 vs. 32 h, P = 0.835). However, a 28-day cure rate of 82% was observed for CGP 56697 and 100% for halofantrine. Significant QTc prolongations (> 30 ms) were seen 6-12 h after halofantrine intake but not after CGP 56697 intake. CGP 56697 is an effective, well-tolerated treatment for uncomplicated falciparum malaria but for this dosing regimen the recrudescence rate is unacceptablyhigh (18%). For travellers contracting malaria abroad, we propose a six-dose regimen of CGP 56697 over 3 days.

Topics: Adolescent; Adult; Africa; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fluorenes; France; Humans; Malaria, Falciparum; Male; Middle Aged; Netherlands; Parasite Egg Count; Phenanthrenes; Plasmodium falciparum; Sesquiterpenes; Time Factors; Travel; Tropical Climate

A novel Plasmodium falciparum gene, denoted cg2 gene, has been recently discovered, and a distinct genotype, characterized by 12 point mutations and 3 size polymorphisms, has been shown to be associated with chloroquine resistance in laboratory-adapted parasite strains. One of the polymorphic regions, denoted the omega region, consists of 16 tandem repeat units in chloroquine-resistant strains, while the chloroquine-sensitive strains have either < or = 15 or > or = 17 repeat units. In this study, the in vivo and in vitro responses were compared with the number of repeat units in the omega region of the cg2 gene for 75 Cameroonian isolates determined either by DNA sequencing or agarose gel electrophoresis. The 16-repeat units that characterize the resistant strains were found in 10 chloroquine-sensitive isolates (50% inhibitory concentration [IC50] < 100 nM) and 30 chloroquine-resistant isolates (IC50 > or = 100 nM). Thirty-five isolates (28 chloroquine-sensitive isolates and 7 chloroquine-resistant isolates) displayed < or = 15 or > or = 17 repeat units. Of the 18 patients responding with treatment failure, 15 were infected with parasites carrying 16 repeat units. Twenty-eight patients (11 with isolates carrying 16 repeat units and 17 with isolates carrying < or = 15 or > or = 17 repeat units) showed an adequate clinical response. The sensitivity, specificity, and predictive value were 81% (83%), 74% (61%), and 75% (58%), respectively compared with in vitro (or in vivo) responses. Neither the level of IC50 nor the key P. falciparum multidrug resistance gene 1 (pfmdr 1) allele at position 86 was associated with the number of omega repeat units. Although in vitro and in vivo resistance to chloroquine was statistically associated with the presence of 16 repeat units in the omega region (P < 0.05), the number of omega repeat units did not adequately discriminate patients infected with chloroquine-resistant parasites from those infected with chloroquine-sensitive parasites. Further studies on the cg2 gene are needed to determine whether cg2 gene is a reliable genetic marker for chloroquine resistance.

Topics: Adolescent; Adult; Animals; Antimalarials; Cameroon; Child; Chloroquine; DNA Primers; DNA, Protozoan; Drug Resistance; Electrophoresis, Agar Gel; Humans; Inhibitory Concentration 50; Malaria, Falciparum; Naphthyridines; Parasitemia; Phenanthrenes; Plasmodium falciparum; Polymerase Chain Reaction; Regression Analysis; Repetitive Sequences, Nucleic Acid; Scintillation Counting; Sequence Analysis, DNA

We evaluated the efficacy and safety of halofantrine in 19 patients with acute uncomplicated falciparum malaria. Each patient received oral halofantrine hydrochloride 500 mg every 6 hours for 3 doses (total 1.5 g). In almost all the patients clinical symptoms of malaria and parasitaemia disappeared within 2 and 3 days, respectively, of starting treatment. We observed no recurrence of parasitaemia during 14 days of follow-up. Tolerance to halofantrine was good except for minor and self-limiting gastrointestinal side-effects. Haematological and biochemical indices were not seriously affected. Halofantrine-induced prolongation of Q-T/Q-Tc intervals was the consistent cardiac manifestation in 84% of patients. The Q-T/Q-Tc interval prolongation increased with each dose; it reached a maximum between 18 and 24 hours and thereafter returned to baseline. These preliminary data indicate that, apart from the cardiac side-effects, halofantrine is an effective and safe drug, well tolerated by most of the patients in the study.. The authors evaluated the efficacy and safety of halofantrine in 19 patients with acute uncomplicated falciparum malaria. Each patient received oral halofantrine hydrochloride 500 mg every 6 hours, for a total of 3 doses (total 1.5 g). In almost all the patients clinical symptoms of malaria and parasitemia disappeared within 2 and 3 days, respectively, of starting treatment. They observed no recurrence of parasitemia during 14 days of follow-up. Tolerance to halofantrine was good except for minor and self-limiting gastrointestinal side effects. Hematological and biochemical indices were not seriously affected. Halofantrine-induced prolongation of Q-T/Q-Tc intervals was the consistent cardiac manifestation in 84% of patients. The Q-T/Q-Tc interval prolongation increased with each dose; it reached a maximum between 18 and 24 hours and thereafter returned to baseline. These preliminary data indicate that, apart from the cardiac side effects, halofantrine is an effective and safe drug, well tolerated by most of the patients in the study.

Topics: Adolescent; Adult; Antimalarials; Electrocardiography; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes

Topics: Adult; Animals; Antimalarials; Drug Administration Schedule; France; Gabon; Humans; Malaria, Falciparum; Male; Military Personnel; Phenanthrenes; Plasmodium falciparum

The combination of halofantrine and primaquine therapies was calculated as a regimen for achieving radical curve of falciparum or vivax malaria in Irian Jaya, Indonesia, and compared with combined chloroquine and primaquine therapies. The patients who volunteered for the study [adult, male, Indonesian immigrants with no previous exposure to endemic malaria, normal glucose-6-phosphate dehydrogenase (G6PD) activity, uncomplicated malaria illness, no prior use of antimalarials, and parasitaemias of 0.001%-1.1%] were randomized to receive either halofantrine (24 mg base/kg bodyweight, in three equal doses over 12 h) or chloroquine (25 mg base/kg bodyweight over 48 h, in doses of 10, 10 and 5 mg base/kg at 24-h intervals). Each patient also received concurrent daily primaquine (0.5 mg base/kg bodyweight) for 14 days followed by the same dose on alternate days to day 28. A recurrent parasitaemia during the 28 days of follow-up constituted drug failure. Of the 40 cases of falciparum malaria and 26 cases of vivax malaria treated with halofantrine-primaquine, none had a recurrent parasitaemia (100% efficacy). In contrast, 20 of 30 patients with falciparum malaria and three of 27 with vivax malaria had recurrent parasitaemias after chloroquine-primaquine, giving efficacies of 33% and 89%, respectively. Halofantrine-primaquine was significantly more effective than chloroquine-primaquine against falciparum malaria (P < 0.001) but was similarly efficacious against vivax malaria (P = 0.23). On average, fever associated with falciparum or vivax malaria cleared 17 h faster with halofantrine-primaquine (P < 0.01) although there were no significant differences (P > 0.4) in parasite-clearance times between the two regimens. The halofantrine-primaquine regimen was also associated with a more rapid and significant decline in malaria-related physical complaints.

Topics: Adult; Antimalarials; Chloroquine; Drug Therapy, Combination; Follow-Up Studies; Humans; Indonesia; Malaria, Falciparum; Malaria, Vivax; Male; Parasitemia; Phenanthrenes; Primaquine; Recurrence; Treatment Outcome

Pentoxifylline (POF) may suppress overproduction of tumor necrosis factor alpha (TNF alpha), which is thought to contribute to complications of human falciparum malaria. However, POF is believed to improve impaired capillary blood flow, which can be impaired in falciparum malaria. To test whether POF affects TNF alpha serum levels or other variables in this disease, we administered POF (20 mg/kg/day intravenously in 150 ml of saline for five days) randomized versus placebo (150 ml of saline without POF) in addition to standard antimalarial therapy. After recruitment of 51 patients with Plasmodium falciparum malaria, those receiving POF had more nausea and abdominal discomfort than the placebo group, as expected. Eleven of 27 patients receiving POF and three of 24 patients receiving placebo requested termination of the study medication (P < 0.05). Pentoxifylline did not change the decrease of TNF alpha levels or affect the clinical course in a significant way. Since POF failed to improve the clinical situation or to impact numerous laboratory parameters (including TNF alpha, thrombin-antithrombin III, thrombomodulin, and human neutrophil elastase), the study was terminated earlier than planned. While this study does not specifically address cerebral complications of malaria, the results suggest that POF is not useful as a routine adjunct to the standard therapy of falciparum malaria.

Topics: Acetaminophen; Adult; Aged; Analgesics, Non-Narcotic; Antimalarials; Biopterins; Drug Therapy, Combination; Female; Humans; L-Lactate Dehydrogenase; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Neopterin; Parasitemia; Pentoxifylline; Phenanthrenes; Phosphodiesterase Inhibitors; Severity of Illness Index; Single-Blind Method; Treatment Outcome; Tumor Necrosis Factor-alpha

A randomised controlled trial was carried out to determine the relative efficacy of four commonly used antimalarial drugs in children aged three to twelve years presenting with uncomplicated malaria at the Eldoret District Hospital, Kenya. One hundred and eighty eight children were studied between July 1993 and July 1994. There were no significant baseline differences between treatment groups with respect to age, sex, weight, ethnicity, haemoglobin, white blood cell (WBC) counts, parasite counts, previous exposure to malaria and prior treatment. Of the 188 patients, eleven were lost to follow-up while twelve were discontinued from the study due to poor clinical response. Most of the latter (eight out of twelve) were in the chloroquine group. By day seven, there were significant differences (p = 0.004) in parasite clearance between groups. There were no significant statistical differences between the groups (p = 0.12) with regard to the fever clearance time. However, there was a significant statistical difference (p = 0.00003) between the treatment groups in the cure rates. Halofantrine was the most efficacious drug with 82% of the cases cured followed by fansidar(R)(62%), amodiaquine (55%) and chloroquine (29%). RI and RII resistance were observed in all the treatment groups, i.e. halofantrine (18%), fansidar (38%), amodiaquine (45%) and chloroquine (67%) while RIII resistance was only observed in the chloroquine group(3%).

Topics: Amodiaquine; Antimalarials; Child; Child, Preschool; Chloroquine; Drug Combinations; Drug Resistance; Female; Follow-Up Studies; Humans; Malaria, Falciparum; Male; Phenanthrenes; Pyrimethamine; Sulfadoxine; Treatment Outcome

We used the WHO in vivo seven day test, extended to 14 day follow up to evaluate the efficacy of the alternative antimalarial drugs in Nigeria (1992), where chloroquine resistant P. falciparum (CRPD) has been confirmed. One thousand and four patients were screened. Those fulfilling recruitment criteria were randomly treated with chloroquine (CQ), n = 50, halofantrine (H), n = 53, pyrimethamine-sulfadoxine (P-S), n = 52 and qinghaosu (Q), n = 53. Parasitological treatment failures were found with all drugs i.e. CQ-53.6pc, H-9.5pc, P-S-28.5pc and Q-2.0pc. H and Q were significantly more efficacious than CQ and P-S, p < 0.003 and p < 0.006, respectively. similarly symptom clearance after 48 hours by H and Q, was 76.3pc and 94pc respectively, better than CQ. P-S was not significantly better than CQ, 64.4pc and 63.3pc, respectively, p > 0.05. The symptom clearance rate of CQ has markedly reduced from 97.7pc to 67.7pc, and in increased proportion of RIII, from 5.9pc to 14.3pc, are signs of increase in chloroquine resistant Plasmodium falciparum. Drug resistant P. falciparum in Nigeria constitutes a serious problem to malaria chemotherapy.

Topics: Adolescent; Antimalarials; Artemisinins; Artesunate; Child; Chloroquine; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Nigeria; Phenanthrenes; Pyrimethamine; Sesquiterpenes; Sulfadoxine; Time Factors; Urban Health

A total of 120 semi-immune adult male malaria patients from an area of multidrug-resistant Plasmodium falciparum malaria were hospitalized for 42 days in Medellin, Colombia (an area of no malaria transmission), and treated with halofantrine in a double-blind, randomized, prospective clinical trial according to five different treatment schedules. Each patient was assigned to one of the following halofantrine schedules: I, one dose of 1000 mg; II, three doses of 500 mg; III, two doses of 500 mg; IV, three doses of 250 mg; and V, one dose of 750 mg. Best results (75% cure rate) were obtained with schedule II, although there was no statistically significant difference compared with the other schedules. A total of 46 patients experienced recrudescent malaria. Drug levels in plasma 72 hours after beginning treatment showed no statistically significant difference between relapsing and cured patients. Side-effects (mainly gastrointestinal) were uncommon and mild. Cardiotoxicity was studied by electrocardiogram. A mean prolongation of 28.5 ms (6.6 +/- 6.3% increase from baseline) was observed in the Q-Tc interval on day 1 of the trial.

Topics: Adolescent; Adult; Aged; Antimalarials; Child; Colombia; Double-Blind Method; Drug Administration Schedule; Heart; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Recurrence

1. Kenyan children with uncomplicated malaria given oral halofantrine (HF; non-micronised suspension; 8 mg base kg-1 body weight 6 hourly for three doses) showed wide variation in the disposition of HF and desbutylhalofantrine (HFm). 2. Eight Kenyan children with severe (prostrate) falciparum malaria who were receiving intravenous quinine, were given the same HF regimen by nasogastric tube. One patient had undetectable HF and two had undetectable HFm at all times after drug administration. 3. The mean AUC(0,24 h) of HF in prostrate children was half (7.54 compared with 13.10 micrograms ml-1 h) (P = 0.06), and that for HFm one-third (0.84 compared with 2.51 micrograms ml-1 h) (P < 0.05) of the value in children with uncomplicated malaria. 4. Oral HF may be appropriate for some cases of uncomplicated falciparum malaria in Africa, but in patients with severe malaria, the bioavailability of HF and HFm may be inadequate.

Topics: Administration, Oral; Antimalarials; Biological Availability; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Infant; Kenya; Malaria, Falciparum; Male; Phenanthrenes; Tissue Distribution

The pharmacokinetics and tolerance of a 4.5 gm 7-day halofantrine loading dose regimen were evaluated in 10 Thai patients with malaria and in 10 noninfected volunteers. Halofantrine peak plasma concentrations and bioavailability on the first day of treatment were significantly lower in patients with malaria than in healthy volunteers. Halofantrine elimination half-life was significantly shorter in patients with malaria than healthy control subjects (9.5 versus 15.8 days). These data show a distinct effect of acute malaria on the absorption and elimination of the drug. In addition, marked intersubject and intrasubject variability in peak and trough halofantrine levels was observed, indicating variable drug absorption. This dosing regimen was effective and well tolerated, with mild transient diarrhea during the first few days of treatment in both groups. To produce consistently effective drug levels, the currently recommended dosing regimens may be suboptimal. Slow halofantrine elimination raises concern for induction of parasite resistance when the drug is used in endemic areas of the world.

Topics: Administration, Oral; Adult; Antimalarials; Biological Availability; Chromatography, High Pressure Liquid; Drug Administration Schedule; Half-Life; Humans; Malaria, Falciparum; Male; Phenanthrenes

In the last decade, Plasmodium falciparum resistance to a number of commonly used anti-malarials especially chloroquine, has increased considerably. Newer anti-malarial drugs are therefore being aggressively evaluated as alternatives. A randomized double-blind controlled trial was therefore undertaken, to compare the efficacy of halofantrine to that of metakelfin, in the treatment of moderately severe infections of Plasmodium falciparum in an endemic malaria area in Kenya. Three hundred and thirty five subjects with laboratory confirmed malaria were recruited and randomized to receive treatment with either halofantrine (171 subjects) or metakelfin (164 subjects). Two thirds (66%) of the study subjects were under the age of five years, and were therefore considered to have minimal immunity. All study subjects were initially admitted to hospital for three days and then followed up as out-patients on days 7, 14, 21, and 28. The level of parasitaemia, the presence of fever and the occurrence of adverse effects were evaluated. Halofantrine was found to be comparable to metakelfin in terms of resolution of fever (mean time 45 and 51 hours respectively). No major adverse side effects were observed. Halofantrine is a viable drug in the treatment of uncomplicated P. falciparum malaria.

Topics: Adolescent; Adult; Antimalarials; Child; Child, Preschool; Double-Blind Method; Drug Combinations; Drug Resistance; Female; Humans; Infant; Malaria, Falciparum; Male; Phenanthrenes; Pyrimethamine; Sulfalene; Survival Analysis; Time Factors; Treatment Outcome

Whole blood mefloquine, halofantrine, and desbutyl-halofantrine concentrations were measured by high-performance liquid chromatography in capillary blood, venous blood, and venous plasma samples from patients along the Thai/Burmese border with falciparum malaria who were treated with either mefloquine (25 mg/kg) or halofantrine (24 mg/kg or 72 mg/kg). The limits of detection for mefloquine, halofantrine, and desbutyl-halofantrine were 50, 15, and 10 ng/ml, respectively, with 200 microliters whole blood samples. There was a good linear correlation (r > 0.9) between capillary and venous blood and between whole blood and plasma for all three compounds. Mefloquine concentrations in venous and capillary blood were very similar (mean ratio 1.02, 95% confidence intervals [CI] 0.95-1.09, n = 60), but were 1.15 times higher (95% CI 1.03-1.29) in whole blood than in plasma (n = 22). The halofantrine and desbutyl-halofantrine concentrations were 1.27 (1.12-1.45, n = 23) and 1.34 (1.16-1.55, n = 24) times higher in venous compared to capillary blood, while halofantrine but not desbutyl-halofantrine concentrations were lower in whole blood than in plasma (mean ratios: halofantrine: 0.83 [0.72, 0.94], n = 39 and desbutyl-halofantrine: 1.05 [0.96-1.15], n = 41). Measurement of mefloquine, halofantrine, or desbutyl-halofantrine in capillary blood is an accurate and practical alternative to venous blood sampling, and is particularly useful for sampling with children, and under field conditions when technical facilities are limited.

Topics: Adolescent; Adult; Antimalarials; Child; Child, Preschool; Chromatography, High Pressure Liquid; Humans; Linear Models; Malaria, Falciparum; Mefloquine; Middle Aged; Phenanthrenes; Reproducibility of Results

Multidrug resistance of Plasmodium falciparum is spreading throughout Africa. In Lambarene, Gabon where chloroquine-resistant malaria is prevalent, a randomized comparative trial with three regimens for treating P. falciparum malaria in adults was performed. One hundred two patients evaluated received either a new micronized formulation of halofantrine (8 mg/kg every 6 hr in three doses) (group H) or chloroquine (25 mg/kg for a 48-hr period) plus clindamycin (5 mg/kg every 12 hr in six doses) (group CC1), or chloroquine (as above) plus doxycycline (2 mg/kg every 12 hr in six doses) (group CD). All treatment regimens were well-tolerated. In group H, 100% of the patients were cured, and in group CC1, 97% of the patients were cured by day 28 of follow-up. In group CD, a significantly lower cure rate of 75% (P < 0.01) and a slower parasite clearance was observed, but only low grade (RI) resistance occurred.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antimalarials; Chloroquine; Clindamycin; Doxycycline; Drug Therapy, Combination; Female; Follow-Up Studies; Gabon; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes

Topics: Adolescent; Antimalarials; Child; Child, Preschool; Chloroquine; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Phenanthrenes

New treatments for malaria are urgently needed in areas such as Thailand where highly drug-resistant strains of Plasmodium falciparum are prevalent. Mefloquine is rapidly losing efficacy and conventional doses of halofantrine are infective. We therefore used pharmacokinetic stimulation to design an extended-dose halofantrine regimen and tested it in 26 soldiers stationed along the Thai-Cambodian border. Halofantrine was given after meals as three doses of 500 mg each at 4-hr intervals on the first day, followed by 500 mg a day for six days (total dose 4.5 g). Twenty-six soldiers treated with quinine-tetracycline for seven days (Q7T7) served as controls. There were no significant differences in efficacy between halofantrine and Q7T7 (P > 0.1) as assessed by cure rate (92% versus 85%), mean parasite clearance time (82 hr versus 81 hr), or mean fever clearance time (93 hr versus 99 hr). Halofantrine was better tolerated than Q7T7. The side effects score was lower (2 versus 11; P < 0.001), there were less days on which side effects occurred (2.0 days versus 5.5 days; P < 0.001), and fewer patients had adverse effects on every treatment day (4% versus 42%; P < 0.01). High-dose halofantrine is as effective and better tolerated than quinine-tetracycline for multidrug-resistant falciparum malaria.

Topics: Adult; Animals; Chi-Square Distribution; Diarrhea; Dizziness; Drug Resistance; Drug Therapy, Combination; Humans; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Tetracycline; Thailand; Vomiting

Plasmodium falciparum susceptibility to halofantrine hydrochloride was investigated in a small village near Ouagadougou, Burkina Faso, where the parasite was known to be chloroquine resistant. An in vivo test was carried out in July 1992 at the beginning of the rainy season in children ranging in age from two to eight years with P. falciparum monospecific infections, asexual parasitemia greater than 800/microliters of blood, and a negative result on a Bergqvist urine test for 4-aminoquinolines. Among 206 children screened, 74 were selected for study. Blood samples were collected on days 0, 2, 4, 7 and 14, and 100 microscopic fields of thick and thin blood smears were examined for parasite density and species identification. Halofantrine hydrochloride was administered under supervision at the standard dose of 24 mg/kg as 8 mg/kg given three times at 6-hr intervals with an observation period of 1 hr after each 8-mg/kg dose. Parasitemias cleared in all 74 cases by day 7, but there was a recurrence of parasitemia in six subjects (8.1%) on day 14. A second course of therapy with halofantrine resulted in prompt clearance of parasitemias in all of these children. The drug was well-tolerated and the hematologic and biochemical indices were not adversely affected by treatment.

Topics: Alanine Transaminase; Animals; Antimalarials; Aspartate Aminotransferases; Bilirubin; Burkina Faso; Child; Child, Preschool; Chloroquine; Creatinine; Drug Resistance; Female; Follow-Up Studies; Hematocrit; Hemoglobins; Humans; Leukocyte Count; Malaria, Falciparum; Male; Phenanthrenes; Plasmodium falciparum

The continuing spread of multidrug resistance in Plasmodium falciparum malaria makes the search for alternative treatments ever more urgent. We have investigated the relative efficacy of halofantrine and mefloquine in two paired randomised trials on the Thai-Burmese border, a multidrug-resistant area. In the first trial, 198 patients with acute uncomplicated falciparum malaria were randomly assigned either the standard halofantrine regimen (24 mg/kg) or mefloquine (25 mg/kg). The cumulative failure rates by day 28 were 35% with halofantrine and 10% with mefloquine (p = 0.0002). In the second study of 437 patients, a higher dose of halofantrine (8 mg/kg every 8 h for 3 days = 72 mg/kg) was both more effective and better tolerated than mefloquine 25 mg/kg; the failure rates were 3% and 8% (p = 0.03), respectively, or 1% vs 6% after adjustment for possible reinfections (p = 0.009). The rate of failure was higher after retreatment than after primary treatment in all study groups. Halofantrine 72 mg/kg was especially effective in the retreatment of these recrudescent infections; the failure rate was 44% with mefloquine and 15% with high-dose halofantrine (relative risk 3.0 [95% CI 1.2-7.3], p = 0.008). Thus, high-dose halofantrine is better tolerated and more effective than mefloquine for the treatment of uncomplicated falciparum malaria in this area. However, evidence of possible cardiotoxicity will need to be investigated fully before a role can be established for halofantrine in the treatment of multidrug-resistant malaria.

Topics: Acute Disease; Adolescent; Adult; Animals; Antimalarials; Child; Child, Preschool; Drug Resistance; Female; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Myanmar; Phenanthrenes; Plasmodium falciparum; Prospective Studies; Recurrence; Refugees; Thailand; Treatment Failure

In a prospective electrocardiographic study of Karen patients with acute uncomplicated falciparum malaria, mefloquine (25 mg/kg) had no cardiac effects (n = 53), but halofantrine (72 mg/kg) induced consistent dose-related lengthening of the PR and QT intervals in all 61 patients treated. The likelihood of significant QTc prolongation (by more than 25% or a QTc of 0.55 s1/2 or more) was greater after halofantrine as retreatment following mefloquine failure than as primary treatment (7/10 vs 18/51; relative risk 2.0 [95% Cl 1.1-3.4], p = 0.04). More than 60% of the effect occurred with three doses of halofantrine (24 mg/kg). The arrhythmogenic potential of halofantrine should now be investigated.

Topics: Adolescent; Adult; Antimalarials; Electrocardiography; Female; Heart; Humans; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Prospective Studies

Topics: Animals; Antimalarials; Child; Drug Resistance; Gabon; Humans; Malaria, Falciparum; Phenanthrenes; Plasmodium falciparum

The clinical efficacy and tolerability of halofantrine, a new antimalarial schizontocide, was studied in a multi-centre trial involving 268 patients ranging in age from 6 months to 58 years. The patients were suffering from acute uncomplicated malaria due to either P. vivax or P. falciparum. Patients were treated orally with 3 doses of halofantrine hydrochloride, 500 mg/6-hourly in adults or 8 mg/kg body weight 6-hourly in children. The overall cure rate was 96.9%. The mean fever clearance time for different species was as follows: P. vivax--39.1 hours, P. falciparum--43.2 hours, mixed infection--60.0 hours, and the mean parasitaemia clearance times were 47.7, 55.1 and 72.0 hours, respectively. Recrudescence was reported in 11 (4.1%) patients, although all of them were parasite-free on Day 7 post-treatment. No haematological or biochemical abnormalities were noted. The drug was very well tolerated and no significant side-effects were reported. Halofantrine was found to be highly effective in acute malaria and offers an important alternative to existing medications.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Antimalarials; Body Weight; Child; Child, Preschool; Female; Fever; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Phenanthrenes; Recurrence; Time Factors; Treatment Outcome

Halofantrine was administered as prophylaxis for malaria to mine workers returning from endemic areas of Papua New Guinea. The men were randomly assigned to receive 500 mg of halofantrine daily for 3 days (n = 195) or 6 days (n = 150) or a total dose of 1,500 mg of chloroquine over 3 days (n = 55). None of the men receiving halofantrine developed falciparum malaria during the subsequent 28 days, whereas three men receiving chloroquine did develop this disease (P < .02). The administration of halofantrine after departure from an endemic area is one strategy for the prevention of falciparum malaria after short-term exposure.

Topics: Administration, Oral; Adult; Antimalarials; Chloroquine; Drug Administration Schedule; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Papua New Guinea; Phenanthrenes; Travel

The antimalarial efficacy of halofantrine was compared with mefloquine in an open-label, randomized comparative trial in adult male patients with acute uncomplicated falciparum malaria. Twenty-eight patients received halofantrine and 27 received mefloquine. Halofantrine was administered in 3 doses of 500 mg at 6 hour intervals and mefloquine was administered in divided doses of 1,250 mg or 1,500 mg depending on whether the patients weighed less than or more than 60 kg. The patients were followed for 42 days and observed for drug tolerance and evidence of recrudescence. Response to treatment was favorable with both drugs, but three patients (two treated with halofantrine and one with mefloquine) did not completely eliminate malaria parasites from peripheral blood films in seven days. The parasite and fever clearance times were 75.6 and 55.7 hours, and 80.1 and 61.3 hours, respectively for halofantrine and mefloquine. However, 12 patients recrudesced during the 42 day follow-up period. Nine of these had been treated with halofantrine and three with mefloquine. The 42-day cure rate for the two drugs was 56% and 84%, respectively. The side-effects of halofantrine and mefloquine were comparable and transient. These are diarrhea, dizziness, orthostatic hypotension and black out. However, vomiting was found to be more common in mefloquine group (41% vs 22%).

Topics: Adolescent; Adult; Antimalarials; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Phenanthrenes; Thailand

The efficacy (criteria: cure rate, time to resolution of fever or absence of parasites) and safety (criteria: clinical side effects, altered laboratory parameters) of halofantrin were investigated in a multi-centre study of 96 non-immune patients (71 men, 25 women, mean age 34.3 [21-62] years) with malaria imported from regions of high resistance into Germany or Switzerland. The initial 63 patients received one-day treatment (three doses of 500 mg halofantrin), while the last 33 patients received an additional course of treatment one week later. Treatment was curative in all patients in the second group, but relapses occurred in five of the 41 patients (12.2%) with falciparum malaria who received one-day therapy. Fever resolved after a mean of 45 hours and parasites were absent after a mean of 66 hours. There were small increases in transaminase values (most probably because of the infection) in five patients, but all became normal again within a few days. Halofantrin is a safe drug and is suitable for both therapy and stand-by therapy of resistant Plasmodium infections. Treatment should be repeated after 7 days.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Drug Therapy, Combination; Drug Tolerance; Female; Germany; Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Phenanthrenes; Plasmodium malariae; Primaquine; Prospective Studies; Recurrence; Switzerland; Time Factors; Travel

Topics: Acute Disease; Adult; Animals; Antimalarials; Child, Preschool; Drug Evaluation; Humans; Incidence; Infant; Malaria; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes; Plasmodium falciparum; Prospective Studies; Travel

We carried out in 1989 a non randomized comparative study in French army units which had been in Central Africa (Central African Republic and Gabon) for 4 months, in order to compare in 758 men on return from malaria areas the usual strategy of chemoprophylaxis with chloroquine and a radical cure by halofantrine (Halfan). Chloroquine was taken by 278 men (100 mg daily for 6 weeks after their return to France); the other 480 men were given two doses of 1,500 mg halofantrine on the third and on the tenth day after their return to France. In Africa both of the units were on chloroquine prophylaxis (100 mg daily for 4 months). The Plasmodium falciparum attack rates were, during a period of 5 months after the return to France, 0.2% in the halofantrine group (1/480) and 4.7% (13/228) in the chloroquine group (P < 10(-4)). The radical cure by halofantrine was more effective than chloroquine prophylaxis in preventing falciparum malaria on return from malaria areas.

Topics: Adult; Antimalarials; Chloroquine; Humans; Malaria, Falciparum; Male; Military Personnel; Phenanthrenes

With the appearance of strains of Plasmodium falciparum in the Trat Province, eastern Thailand, reported to have developed resistance to mefloquine there is a need for an alternative drug. This comparative trial with mefloquine and halofantrine has demonstrated extremely low cure rates with both drugs (33.3% and 28.13% respectively), cross-resistance is suggested.

Topics: Administration, Oral; Adult; Antimalarials; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Thailand; Treatment Outcome

Halofantrine chlorhydrate 2 per cent suspension was given to 50 children (mean age 6.2 years in a dose of 8 mg/kg three times a day as a single day treatment. The children were born and lived in Gabon, where malaria transmission is continuous. They all had acute Plasmodium falciparum malaria. The children were kept in hospital for 5 days, and regularly followed over a 15-day period. The 50 children were cured and efficacy was evaluated as good in 44 cases, and excellent in six cases, as judged by improvement in their clinical signs and parasitaemia. Two criterias were considered in the evaluation of efficacy: clearance of parasitaemia (mean day 4), fever clearance (mean hour 24). There were two cases of persistences of parasites at day 15 with a very low parasitaemia rate. Tolerance to halofantrine was good from a clinical and biological point of view. Acceptability was excellent in all cases. Halofantrine 2 per cent suspension is a good alternative in the treatment of acute Plasmodium falciparum malaria in children, especially with the present situation of multidrug-resistant strains in Central Africa.

Topics: Acute Disease; Adolescent; Antimalarials; Child; Child, Preschool; Drug Administration Schedule; Female; Gabon; Humans; Infant; Malaria, Falciparum; Male; Phenanthrenes

A multicenter prospective trial was performed to investigate the efficacy and the tolerability of halofantrine in nonimmune patients with malaria imported from areas with drug-resistant falciparum parasites (mainly Africa). Forty-five of the 74 subjects were treated with a one-day regimen (3 x 500 mg) of halofantrine, and the other 29 received the same regimen with an additional treatment on day 7. In the second group, a 100% efficacy rate was demonstrated, but in the group receiving the one-day regimen, four recrudescences were observed in patients with falciparum malaria. Only five mild adverse reactions were seen, which disappeared spontaneously after the end of the treatment. We conclude that halofantrine is highly effective in curing malaria in nonimmune subjects. The treatment scheme for such persons should include an additional treatment on day 7 for nonimmune individuals. This drug was well tolerated in our patients, indicating that halofantrine will be useful in the treatment of multidrug-resistant malaria in nonimmune persons.

Topics: Acute Disease; Adult; Antimalarials; Drug Resistance; Drug Tolerance; Female; Follow-Up Studies; Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Phenanthrenes; Travel

Halofantrine has been given to 14 children and 15 adults suffering from an acute attack of P. falciparum malaria and living in Dakar (Senegal) to a total dose of 24 mg/kg/body weight for the first group and 1,500 mg for the second in 3 times at 6-hourly intervals. This treatment has allowed the fever to clear in all cases within 36.3 +/- 19.9 hours and headache to disappear at D3 in 93.1% of cases. A reduction by 93.6% of the average parasite density which amounted before treatment to 27,710 trophozoites/mm3 of blood has been recorded from the day following the beginning of treatment and the parasite clearance obtained in all the patients of whom had chloroquine-resistant P. falciparum strains in mean time of 58.0 +/- 14.7 hours. In 3 cases (10.7%) a recrudescence of parasitemia has been noticed in D14. Only 1 of them was treated again with halofantrine which proved efficient from D2. The only adverse reactions have been nausea, vomiting, a slight diarrhoea and dizziness which affected only 13.8% of the patients. No abnormality has been noticed at a biological level. These results confirm the efficacy and good tolerance of halofantrine and allow to list it among the resource drugs used for the treatment of chloroquine-resistant P. falciparum malaria in our area.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Child; Child, Preschool; Drug Tolerance; Humans; Malaria, Falciparum; Middle Aged; Phenanthrenes; Senegal

In an open clinical trial, thirty patients 14 to 44 years old and with acute uncomplicated falciparum malaria were given halofantrine hydrochloride 500 mg (2 tablets) 6-hourly for 3 doses, a total dose of 1500 mg. All 30 patients were cured, with a mean asexual parasite clearance time of 47.6 hours and mean fever clearance time of 36.6 hours. Post-dosing side-effects occurred in 6 patients consisting of mild to moderate headache, dizziness and abdominal muscle spasm. Drug-induced hemolysis did not occur in two G6PD deficient patients. Twenty-three out of 28 isolates tested (82%) were resistant to amodiaquine, 3 (11%) were resistant to the sulfadoxine-pyrimethamine combination, and all were sensitive to chloroquine, quinine and mefloquine by in vitro microtests. The study confirms the efficacy of halofantrine hydrochloride as a blood schizonticide in falciparum malaria.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Blood Cell Count; Blood Chemical Analysis; Drug Resistance; Hematocrit; Hemoglobins; Humans; Malaria, Falciparum; Parasite Egg Count; Phenanthrenes

The drug combination atovaquone-proguanil, is recommended for treatment of uncomplicated falciparum malaria in France. Despite high efficacy, atovaquone-proguanil treatment failures have been reported. Resistance to cycloguanil, the active metabolite of proguanil, is conferred by multiple mutations in the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and resistance to atovaquone by single mutation on codon 268 of the cytochrome b gene (pfcytb).. A 47-year-old female, native from Congo and resident in France, was admitted in hospital for uncomplicated falciparum malaria with parasitaemia of 0.5%, after travelling in Congo (Brazzaville and Pointe Noire). She was treated with atovaquone-proguanil (250 mg/100 mg) 4 tablets daily for 3 consecutive days. On day 5 after admission she was released home. However, many weeks after this episode, without having left France, she again experienced fever and intense weakness. On day 39 after the beginning of treatment, she consulted for fever, arthralgia, myalgia, photophobia, and blurred vision. She was hospitalized for uncomplicated falciparum malaria with a parasitaemia of 0.375% and treated effectively by piperaquine-artenimol (320 mg/40 mg) 3 tablets daily for 3 consecutive days. Resistance to atovaquone-proguanil was suspected. The Y268C mutation was detected in all of the isolates tested (D39, D42, D47). The genotyping of the pfdhfr gene showed a triple mutation (N51I, C59R, S108N) involved in cycloguanil resistance.. This is the first observation of a late clinical failure of atovaquone-proguanil treatment of P. falciparum uncomplicated malaria associated with pfcytb 268 mutation in a traveller returning from Congo. These data confirm that the Y268C mutation is associated with delayed recrudescence 4 weeks or more after initial treatment. Although atovaquone-proguanil treatment failures remain rare, an increased surveillance is required. It is essential to declare and publish all well-documented cases of treatment failures because it is the only way to evaluate the level of resistance to atovaquone.

Topics: Antimalarials; Artemisinins; Atovaquone; Codon; Congo; Cytochromes b; Drug Combinations; Drug Resistance; Female; France; Humans; Malaria, Falciparum; Middle Aged; Mutation; Phenanthrenes; Plasmodium falciparum; Proguanil; Quinolines; Tetrahydrofolate Dehydrogenase; Travel

Malaria's ability to rapidly adapt to new drugs has allowed it to remain one of the most devastating infectious diseases of humans. Understanding and tracking the genetic basis of these adaptations are critical to the success of treatment and intervention strategies. The novel antimalarial resistance locus PF10_0355 (Pfmspdbl2) was previously associated with the parasite response to halofantrine, and functional validation confirmed that overexpression of this gene lowered parasite sensitivity to both halofantrine and the structurally related antimalarials mefloquine and lumefantrine, predominantly through copy number variation. Here we further characterize the role of Pfmspdbl2 in mediating the antimalarial drug response of Plasmodium falciparum. Knockout of Pfmspdbl2 increased parasite sensitivity to halofantrine, mefloquine, and lumefantrine but not to unrelated antimalarials, further suggesting that this gene mediates the parasite response to a specific class of antimalarial drugs. A single nucleotide polymorphism encoding a C591S mutation within Pfmspdbl2 had the strongest association with halofantrine sensitivity and showed a high derived allele frequency among Senegalese parasites. Transgenic parasites expressing the ancestral Pfmspdbl2 allele were more sensitive to halofantrine and structurally related antimalarials than were parasites expressing the derived allele, revealing an allele-specific effect on drug sensitivity in the absence of copy number effects. Finally, growth competition experiments showed that under drug pressure, parasites expressing the derived allele of Pfmspdbl2 outcompeted parasites expressing the ancestral allele within a few generations. Together, these experiments demonstrate that modulation of Pfmspdbl2 affects malaria parasite responses to antimalarial drugs.

Topics: Antimalarials; Base Sequence; DNA Copy Number Variations; Drug Resistance; Ethanolamines; Fluorenes; Gene Dosage; Gene Frequency; Genes, Protozoan; Lumefantrine; Malaria, Falciparum; Mefloquine; Mutation; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins; Sequence Analysis, DNA

Analysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring of Plasmodium falciparum drug resistance in the field. Here we genotype Pfcrt and Pfdmr1 of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively introduced and mefloquine was abandoned. Gene sequencing showed fixation of the 7G8-type Pfcrt SMVNT resistance haplotype and near fixation of the NYCDY Pfdmr1 haplotype. Pfdmr1 gene copy number correlated with 50% inhibitory concentrations of mefloquine and halofantrine (r = 0.64 and 0.47, respectively, n = 547); its temporal changes paralleled changes in in vitro mefloquine susceptibility. However, the molecular parameters studied did not account for the regained in vitro susceptibility to chloroquine and showed a poor correlation with susceptibility to artemether, lumefantrine, or quinine. Identification of novel markers of resistance to these antimalarials is needed in this South American area.

Topics: Aminoquinolines; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chloroquine; Drug Combinations; Drug Resistance; Ethanolamines; Evolution, Molecular; Fluorenes; French Guiana; Gene Dosage; Haplotypes; Humans; Inhibitory Concentration 50; Longitudinal Studies; Malaria, Falciparum; Mefloquine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Practice Guidelines as Topic; Protozoan Proteins; Quinine

In order to assess cardiac tolerance of halofantrine in children, we studied, retrospectively, 15 non complicated falciparum malaria cases treated with halofantrine, and focused on the effect on ventricular repolarisation. Our data showed that halofantrine can produce a moderate QTc prolongation without any life-threatening arrhythmia. As long as contraindications of the drug are respected, this treatment should be considered as a therapeutical option in young children presenting with non complicated falciparum malaria.

Topics: Adolescent; Antimalarials; Cardiac Electrophysiology; Child; Child, Preschool; Electrophysiological Phenomena; Female; Humans; Infant; Long QT Syndrome; Malaria, Falciparum; Male; Phenanthrenes

The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼ 1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.

Topics: Antimalarials; Drug Resistance; Ethanolamines; Fluorenes; Gene Dosage; Gene Expression; Genetic Association Studies; Genetic Loci; Genetic Variation; Genotype; Haplotypes; Linkage Disequilibrium; Lumefantrine; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Polymorphism, Single Nucleotide; Selection, Genetic

Malaria is the primary cause of hospitalization in Côte d'Ivoire. Early treatment is one of the strategies to control this illness. However, the spread of resistance of Plasmodium falciparum to antimalarial drugs can seriously compromise this strategy.. The aim of this study was to assess the in vitro susceptibility of P. falciparum to monodesethylamodiaquine and aminoalcohols in Abidjan (Côte d'Ivoire).. We assessed the in vitro susceptibility of isolates collected from patients with uncomplicated malaria by using the WHO optical microtest technique.. The proportions of resistance to monodesethylamodiaquine, méfloquine and halofantrine were 12.5%, 15.6% and 25.9%, respectively. For quinine, none of isolates showed evidence of in vitro resistance. However, two isolates (6.1%) had IC(50) values above 300 nM. The IC(50) of each drug was positively and significantly correlated to that of the other three drugs, and the correlation was higher between halofantrine and mefloquine.. Our results showed that the in vitro chloroquine resistance reported in previous studies has been extended to other antimalarial drugs investigated in this study except for quinine. Therefore, it is necessary to implement a long-term monitoring system of antimalarial drug resistance.

Topics: Adolescent; Adult; Amodiaquine; Antimalarials; Child; Child, Preschool; Cote d'Ivoire; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Microbial Sensitivity Tests; Middle Aged; Phenanthrenes; Plasmodium falciparum; Quinine; Young Adult

The known phenanthrenone trigonostemone (1), along with a new phenanthrenone, 9-O-demethyltrigonostemone (2), and two new phenanthropolones, 3,6,9-trimethoxyphenanthropolone (3) and 4,6,9-trimethoxyphenanthropolone (4), were isolated from the roots of Strophioblachia fimbricalyx. Compound 2 showed cytotoxicity against NCI-H187, KB, and MCF7 cancer cells with IC50 values of 0.8, 0.8, and 2.9 microg/mL, respectively, while 3 and 4 showed reduced cytotoxicity. Compounds 2 and 3 displayed antiplasmodial activity in vitro (IC50 values of 2.7 and 3.2 microg/mL, respectively) against Plasmodium falciparum (K1, resistant strain). In addition, the antioxidant activity of 1-4 toward DPPH radicals was determined, but only compound 2 showed any discernible activity.

Topics: Animals; Antimalarials; Antineoplastic Agents, Phytogenic; Chlorocebus aethiops; Drug Screening Assays, Antitumor; Euphorbiaceae; Female; Free Radical Scavengers; Humans; Malaria, Falciparum; Molecular Structure; Phenanthrenes; Plant Roots; Plants, Medicinal; Plasmodium falciparum; Thailand

In Ghana in 2004 (when choroquine was still the nationally recommended drug for the first-line treatment of malaria), the sensitivities, to chloroquine, amodiaquine, quinine, mefloquine, artesunate and halofantrine, of 60 Plasmodium falciparum isolates from two ecologically distinct areas of the country were assessed in vitro. The aim was to make available, to policy-makers, the field-based evidence needed to review the national strategy for malaria treatment. Drug susceptibilities were explored using the standardized protocol of the Antimalarial Drug Resistance Network. Although 32 of the P. falciparum isolates evaluated (56.1% of the 57 isolates successfully investigated for their susceptibility to choroquine) showed resistance to chloroquine and two showed slightly reduced sensitivity to amodiaquine, all the isolates were sensitive to mefloquine, artesunate, quinine and halofantrine. The median inhibitory concentrations (IC(50)) of chloroquine were positively correlated with those of quinine (r=0.4528; P=0.0008) but not those of any of the other drugs investigated. The IC(50) of amodiaquine and artesunate were also positively correlated (r=0.3703; P=0.0067). These results provide evidence of the presence, in Ghana, of P. falciparum isolates that are highly resistant to chloroquine but generally sensitive to most of the other antimalarial drugs commonly used in the country. Partly in consequence of these observations, the recommended first-line treatment for malaria in Ghana was changed to an amodiaquine-artesunate combination in January 2005.

Topics: Amodiaquine; Animals; Antimalarials; Artemisinins; Artesunate; Child, Preschool; Chloroquine; Drug Resistance; Ghana; Humans; Infant; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Sesquiterpenes

The global dissemination of drug-resistant Plasmodium falciparum is spurring intense efforts to implement artemisinin (ART)-based combination therapies for malaria, including mefloquine (MFQ)-artesunate and lumefantrine (LUM)-artemether. Clinical studies have identified an association between an increased risk of MFQ, MFQ-artesunate, and LUM-artemether treatment failures and pfmdr1 gene amplification. To directly address the contribution that pfmdr1 copy number makes to drug resistance, we genetically disrupted 1 of the 2 pfmdr1 copies in the drug-resistant FCB line, which resulted in reduced pfmdr1 mRNA and protein expression. These knockdown clones manifested a 3-fold decrease in MFQ IC(50) values, compared with that for the FCB line, verifying the role played by pfmdr1 expression levels in mediating resistance to MFQ. These clones also showed increased susceptibility to LUM, halofantrine, quinine, and ART. No change was observed for chloroquine. These results highlight the importance of pfmdr1 copy number in determining P. falciparum susceptibility to multiple agents currently being used to combat malaria caused by multidrug-resistant parasites.

Topics: Animals; Antimalarials; Artemisinins; ATP-Binding Cassette Transporters; DNA, Protozoan; Drug Resistance, Multiple; Ethanolamines; Fluorenes; Genes, MDR; Inhibitory Concentration 50; Lumefantrine; Malaria, Falciparum; Mefloquine; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Polymerase Chain Reaction; Protozoan Proteins; Quinine; Sesquiterpenes

A rising incidence of imported acute malaria has been observed in non-immune traveller children returning from the tropics to France. Halofantrine efficacy has been poorly assessed in non-immune children. In order to assess halofantrine efficacy in non-immune children with acute uncomplicated Plasmodium falciparum malaria, we collected data of children with positive blood smears in an open prospective study. Children with neurological manifestations, vomiting and congenital long QT were excluded. All children were hospitalised and received halofantrine (24 mg/kg divided into three doses per day) on an empty stomach. Persistent fever after day 3 defined failure. Relapse was defined by a positive blood smear with or without systemic symptoms within a 1 month follow-up period. In total, 52 children were enrolled. No failure was observed, but relapses occurred in 14/52. On univariate analysis, the mean age of children with relapse was significantly lower (P<0.05). Moreover, diarrhoea was more frequently associated with relapses (P<0.04). Age and diarrhoea were significant independent factors contributing to relapses.. This study shows that with a relapse rate of 27%, this regimen with a 1-day course of halofantrine is not to be recommended.

Topics: Adolescent; Antimalarials; Child; Child, Preschool; Female; France; Humans; Immunity; Infant; Malaria, Falciparum; Male; Phenanthrenes; Prospective Studies; Recurrence; Travel; Treatment Outcome

The development and spread of highly drug-resistant parasites pose a central problem in the control of malaria. Understanding mechanisms that regulate genomic stability, such as DNA repair, in drug-resistant parasites and during drug treatment may help determine whether this rapid onset of resistance is due to an increase in the rate at which resistance-causing mutations are generated. This is the first report to demonstrate DNA repair activities from the malaria-causing parasite Plasmodium falciparum that are specific for ultraviolet light-induced DNA damage. The efficiency of DNA repair differs dramatically among P. falciparum strains with varying drug sensitivities. Most notable is the markedly reduced level of repair in the highly drug-resistant W2 isolate, which has been shown to develop resistance to novel drugs at an increased rate when compared to drug-sensitive strains. Additionally, the antimalarial drug chloroquine and other quinoline-like compounds interfered with the DNA synthesis step of the repair process, most likely a result of direct binding to repair substrates. We propose that altered DNA repair, either through defective repair mechanisms or drug-mediated inhibition, may contribute to the accelerated development of drug resistance in the parasite.

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; DNA Damage; DNA Repair; Drug Resistance; Drug Resistance, Multiple; Humans; Malaria, Falciparum; Mefloquine; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Pyrimethamine; Quinine; Sesquiterpenes; Sulfanilamide; Sulfanilamides; Ultraviolet Rays

Little is known about severe imported malaria in nonendemic industrialized countries. The purpose of this retrospective study was to describe the clinical spectrum of severe imported malaria in adults and to determine factors that were present at admission and were associated with in-intensive care unit mortality. This retrospective study evaluated the 188 patients who were admitted to our intensive care unit in 1988-1999 with severe and/or complicated imported malaria. Among them, 93 had strictly defined severe malaria, and 95 had less severe malaria. The mean age was 38 years, 51% of patients were nonimmune whites, 94% acquired Plasmodium falciparum in sub-Saharan Africa, and 96% had taken inadequate antimalarial chemoprophylaxis. Mortality was 11% (10 patients) in the severe malaria group, whereas no patients died in the less severe malaria group (p = 0.002). In the bivariable analysis, the main factors associated with death in the severe malaria group were the Simplified Acute Physiology Score, shock, acidosis, coma, pulmonary edema (p < 0.001 for each), and coagulation disorders (p = 0.002). Bacterial coinfection is not infrequent and may contribute to death. Severe imported malaria remains a major threat to travelers. In our population, the most relevant World Health Organization major defining criteria were coma, shock, pulmonary edema, and acidosis.

Topics: Adolescent; Adult; Aged; Antimalarials; Community-Acquired Infections; Comorbidity; Cross Infection; Data Interpretation, Statistical; Exchange Transfusion, Whole Blood; Female; France; Glasgow Coma Scale; Humans; Injections, Intravenous; Intensive Care Units; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Phenanthrenes; Quinine; Retrospective Studies; Travel; World Health Organization

To determine the in vitro activity of antimalarial drugs against isolates of Plasmodium falciparum in Gabon.. Plasmodium falciparum isolates were collected from symptomatic infections in the hospitals of Bakoumba and Franceville, south-east Gabon and in 2000. In vitro activity of chloroquine, quinine, mefloquine, halofantrine was measured by the isotopic microtest.. A total of 60 and 62 isolates gave interpretable data in Franceville and Bakoumba, respectively. In Franceville, 50.0% (mean IC50 = 111.7 nm), 0% (mean IC50 = 156.7 nm), and 21.2% (mean IC50 = 12.4 nm) of isolates, respectively, showed in vitro resistance to chloroquine, quinine and mefloquine. In Bakoumba, we saw resistance to chloroquine, quinine, mefloquine and halofantrine in 95.0% (mean IC50 = 325.8 nm), 10.2% (mean IC50 = 385.5 nm), 47.5% (mean IC50 = 24.5 nm) and 18.2% (mean IC50 = 1.9 nm) of isolates, respectively. Activities of chloroquine and mefloquine, chloroquine and quinine, and mefloquine and quinine were positively correlated.. Antimalarial drug resistance is high in this area of Gabon. The extent of resistance is disparate, as all tested drugs were less efficacious in Bakoumba than in Franceville.

Topics: Animals; Antimalarials; Chloroquine; Drug Resistance; Gabon; Humans; Inhibitory Concentration 50; Malaria, Falciparum; Mefloquine; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Quinine

Drug-resistant Plasmodium falciparum is present in Vietnam. We assessed the in vivo sensitivity of P. falciparum to halofantrine in two villages in the southern part of central Vietnam. Halofantrine (8 mg/kg x 3 doses) was administered to 37 patients with either P. falciparum (n = 32) or mixed P. falciparum/P. vivax malaria (n = 5). End points were parasite sensitivity or resistance (RI/RII/RIII) determined by parasite clearance, persistence, or recurrence during 28 days of follow-up. By day 28, 31 (93.9%) of 33 (95% confidence interval = 79.8-99.2%) patients were sensitive. Two patients had recurrent P. falciparum parasitemia on days 14 and 21. Halofantrine effectively treated uncomplicated P. falciparum malaria in these Vietnamese patients.

Topics: Adolescent; Adult; Animals; Antimalarials; Child; Child, Preschool; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Recurrence; Vietnam

Halofantrine is the first regimen used for the treatment of uncomplicated Plasmodium falciparum malaria in children in France according to the recommendations of the French Consensus Conference held in 1999 and pending additional data in this population. In 1999, a high rate of clinical relapse after a single cure of halofantrine led us to switch to mefloquine for first line treatment of uncomplicated malaria. The aims of this study were to evaluate this change of attitude and to compare the efficacy of halofantrine and mefloquine in the treatment of uncomplicated P. falciparum malaria in children.. We retrospectively analysed 118 pediatric cases of malaria treated at Armand-Trousseau Children hospital in Paris between January 1st, 1999 and December 31st, 2000.. 93 patients were treated for an uncomplicated case of P. falciparum malaria: 48 received a unique cure of halofantrine and 21 were treated with mefloquine. Nine patients relapsed, all having previously received halofantrine. No patient treated with mefloquine relapsed.. These results and other recent published data suggest to recommend mefloquine instead of halofantrine as first line treatment of uncomplicated P. falciparum malaria in children with respect to specific contra-indications. A larger evaluation of mefloquine is however necessary. The association atovaquone-proguanil (Malarone) is promising but needs to be evaluated in large pediatric studies in comparison with other treatments. Its indication as a curative treatment of uncomplicated malaria is, to date, restricted to adults and children over 12 years in France.

Topics: Antimalarials; Child; Humans; Malaria, Falciparum; Mefloquine; Phenanthrenes; Retrospective Studies; Treatment Failure

Four truck drivers involved in a humanitarian mission across the Sahara towards Mali fell ill 15 days after their return. Plasmodium falciparum malaria (thankfully, non pernicious) was diagnosed with 3 to 4 days delay. The four drivers had been treated with chloroquine and proguanil but the dosage may have been insufficient with regard to their body weight (average weight = 110 kg). These 4 travelers had all slept outside (in Tintane, near Kiffa in Mauritania), without any anti-vectorial protection, whereas their other 8 companions (none of whom caught malaria) had slept in their vehicles. The evolution of the 4 cases was favourable despite the difficulties involved in urgently obtaining sufficient amounts of quinine for treatment. How can these cases be explained in relation to prophylactic treatment of associated chloroquine and proguanil? One explanation might be resistance of the P. falciparum strain. We were unable to study this possibility. The high incidence and similitude of cases points towards a hypothesis of resistance both to proguanil and chloroquine. Resistance to chloroquine, as has been formally ascertained in Mauritania, reinforces such a conviction. And yet prophylaxis does not prevent pernicious malaria. This clinical form of the disease, with P. falciparum primo-invasion occurring under rigorous chemoprophylaxis is characteristic of a partially resistant strain. The most reasonable explanation besides "chance" is that we are dealing here with a partially resistant strain of Plasmodium falciparum which is thus also partially sensitive to--in this case highly effective--therapeutic treatment. Indeed, chloroquino-resistant strains are more sensitive to mefloquine and halofantrine. Another explanation might be under-dosage of Savarine with relation to the body weight of these 4 patients. We should be aware of adapting more rigorously the posology of prescribed prophylaxis. But above all, this outbreak should remind us that we should recommend to travelers and drivers planning a trip to Sub-Saharan Africa to take with them anti-vectorial protective gear. Finally, the observation of these cases indicates once more the difficulty in France of establishing a proper diagnosis in face of malaria. Health personnel must systematically call to mind malaria in face of thrombopenia or fever following a sojourn in an endemic area even when chemoprophylaxis has been correctly followed.

Topics: Adult; Altruism; Animals; Antimalarials; Body Weight; Chemoprevention; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Male; Mali; Mauritania; Middle Aged; Morocco; Phenanthrenes; Plasmodium falciparum; Proguanil; Quinine; Travel

(1) Quinine, halofantrine and mefloquine are effective treatments for most cases of uncomplicated Plasmodium falciparum malaria. (2) The choice of drug for prevention of P. falciparum malaria in highly endemic regions depends on the risk of chloroquine resistance, and possibly mefloquine resistance. The reference treatments are the chloroquine + proguanil combination, and mefloquine. (3) Marketing authorisation has been granted in France for the atovaquone + proguanil combination, in curative and preventive treatment of P. falciparum malaria. (4) The efficacy of the atovaquone + proguanil combination in uncomplicated malaria is similar to that of other treatments. Some strains of malaria seem to have reduced sensitivity. (5) The atovaquone + proguanil combination is also effective as prophylaxis, but there are no clinical trials showing whether it is equivalent to or better than other preventive treatments in non immune travellers. (6) According to the French licensing terms, atovaquone + proguanil prophylaxis can be stopped 7 days after leaving an endemic area, rather than 3-4 weeks with other drugs. This recommendation is based on weak evidence: mainly on theoretical arguments and on the absence of clinical malaria in some patients with evidence of P. falciparum infection. (7) The atovaquone + proguanil combination is less effective against other Plasmodium species (P. malariae, P. ovale and P. vivax). Chloroquine remains the reference treatment for these forms of malaria, which do not carry a risk of serious complications. (8) There were few adverse events in people taking the atovaquone + proguanil combination during clinical trials. During curative treatment, this combination caused more nausea and vomiting than reference treatments, while, in the prophylactic setting, it had slightly fewer adverse effects than the chloroquine + proguanil combination or mefloquine alone. But the drop out rate was not significantly different between treatment groups. (9) Atovaquone should be taken with food, to improve absorption. (10) The atovaquone + proguanil combination is expensive and is not refunded in France. In contrast, curative treatment with quinine is cheap, and is fully refunded. (11) Mefloquine and quinine remain the treatments of choice for uncomplicated malaria where there is chloroquine resistance. The atovaquone + proguanil combination is useful if mefloquine and quinine are contraindicated; unlike halofantrine, this combination does not carry the r

Topics: Antimalarials; Clinical Trials as Topic; Developing Countries; Drug Approval; Drug Combinations; Drug Costs; Drug Interactions; Drug Resistance; Ethics, Medical; France; Humans; Malaria, Falciparum; Mefloquine; Naphthoquinones; Phenanthrenes; Proguanil; Quinine; Randomized Controlled Trials as Topic; Travel

To determine how sensitive Plasmodium falciparum is to the major antimalarial drugs in Madagascar.. Assessment of Plasmodium falciparum isolates sensitivity to antimalarials, by use of the in-vitro radioisotope method.. Ankazobe and Saharevo in the foothill areas; and Toamasina and Tolagnaro in the coastal areas (between January 1998 and November 1999).. Primary Plasmodium falciparum isolates from patients with uncomplicated malaria attack.. Between January 1998 and November 1999, of the 293 in-vitro tests done with at least one antimalarial, 70% (205/293) were interpretable. As there was no significant difference between results from the four study sites, the data have been expressed as a whole. All of the successfully tested isolates were sensitive to halofantrine (n = 56) and to quinine (n = 199), 5.8% (12/205) of the isolates were resistant to chloroquine and 2% (4/199) to mefloquine. The geometric mean IC50 was 0.3 microg/L for halofantrine (95% CI = 0.1-0.4 microg/L); 9.4 microg/L for chloroquine (95% CI = 7.3-10.8 microg/L); 3.8 microg/L for mefloquine (95% CI = 3.3-4.3 microg/L); and 26.8 microg/L for quinine (95% CI = 24.3-29.4 microg/L). The low positive correlation found between halofantrine and chloroquine IC50s (n = 56; r = 0.41, P = 0.002) suggests a risk of cross-resistance between these two drugs.. The degree and frequency of chloroquine resistance in-vitro is stationary in Madagascar compared to previous results during the last decade. The in-vitro sensitivity of P. falciparum to quinine, mefloquine and halofantrine encourages the use of these drugs as alternative in case of chloroquine treatment failure. Nevertheless, it is important to maintain and to extend malaria and drug sensitivity surveillance in Madagascar.

Topics: Animals; Antimalarials; Chloroquine; Drug Evaluation, Preclinical; Drug Resistance; Hospitals, Public; Hospitals, Urban; Humans; Madagascar; Malaria, Falciparum; Mefloquine; Microbial Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Quinine; Rural Health

Four cases of Plasmodium falciparum malaria who presented in Sierra Leone in November-December 2000 apparently failed to respond to treatment with artesunate. Three (75%) of the cases fulfilled the World Health Organization's criteria for late treatment failure. Although artesunate ranks only sixth as the first-line drug used by clinicians for the treatment of uncomplicated malaria in Sierra Leone, it is widely sold over the counter in pharmacies in the country. The indiscriminate and injudicious use of artesunate among the Sierra Leonean population is likely to increase the level and frequency of resistance among the local strains of P. falciparum. It is recommended that artesunate be reserved for patients who fail to respond to treatment with another of the antimalarial drugs available. Even then, the artesunate should preferably be used in combination with other, longer-acting antimalarial drugs, to slow the development of further resistance.

Topics: Adult; Antimalarials; Artemisinins; Artesunate; Child; Drug Administration Schedule; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Phenanthrenes; Quinine; Sesquiterpenes; Sierra Leone; Treatment Failure

Using an in vitro model of human lung endothelial cells, we studied different characteristics of Plasmodium falciparum isolates as potential factors for malaria severity in 2 Thai patient groups: 27 with complicated malaria and 42 with uncomplicated malaria. In regard to binding properties, no association existed between cytoadherence and rosette phenotypes (P = 0.1) and hypothrombocytemia increased the cytoadherence level (P = 0.007). Cytoadherence was significantly associated with malaria severity (P = 0.05) in contrast to rosette formation (P = 0.9). Intercellular adhesion molecule-1 and chondroitin-4-sulfate were major receptors of cytoadherence in those with complicated malaria compared with those with uncomplicated malaria (P < 10(-4)). Chondroitin-4-sulfate could act as a putative receptor for malaria complications in non-pregnant women. CD36 was the main receptor in patients with uncomplicated malaria (P < 10(-3)). Vascular cell adhesion molecule-1 and E-selectin played a minor role in 2 groups (P = 0.6). Qinghaosu derivatives were more efficient than other antimalarial drugs, but a positive correlation was observed between the 50% inhibitory concentrations of halofantrine and quinine and the number of adhesive parasitized red blood cells, suggesting their influence on cytoadherence.

Topics: Adolescent; Adult; Animals; Antibodies, Monoclonal; Antimalarials; Binding, Competitive; Cell Adhesion; Cells, Cultured; Chondroitin Sulfates; Endothelium; Female; Humans; Intercellular Adhesion Molecule-1; Lung; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Phenanthrenes; Plasmodium falciparum; Quinine; Rosette Formation; Thailand

The in vitro activity of pyronaridine was evaluated against 62 isolates of Plasmodium falciparum from Libreville, Gabon using an isotopic, drug susceptibility microtest and was compared with amodiaquine, chloroquine, quinine, and halofantrine activities. The mean 50% inhibitory concentration (IC50) values of the 62 isolates from Gabon to pyronaridine was 3.0 nM (95% confidence interval [CI] = 2.1-3.9). Pyronaridine was less potent against chloroquine-resistant isolates than chloroquine-susceptible isolates but more potent than chloroquine against chloroquine-resistant parasites. The cut-off value for in vitro reduced susceptibility to pyronaridine was an IC50 > 15 nM. Two isolates (3%) showed an IC50 > 15 nM. A significant positive correlation was found between the activities of pyronaridine and chloroquine (r2 = 0.26, P < 0.001), pyronaridine and quinine (r2 = 0.36, P < 0.001), pyronaridine and amodiaquine (r2 = 0.55, P < 0.001), and pyronaridine and halofantrine (r2 = 0.50, P < 0.001). This correlation suggests in vitro cross-resistance or at least in vitro cross-susceptibility, which is not necessarily predictive of cross-resistance in vivo. The present in vitro findings require comparison with those of clinical studies.

Topics: Adolescent; Amodiaquine; Animals; Antimalarials; Child; Child, Preschool; Chloroquine; Gabon; Humans; Infant; Malaria, Falciparum; Naphthyridines; Phenanthrenes; Plasmodium falciparum; Quinine

The factors affecting the development of patent Plasmodium falciparum gametocytemia were assessed in 5,682 patients entered prospectively into a series of antimalarial drug trials conducted in an area of low and seasonal transmission on the western border of Thailand. Of the 4,565 patients with admission thick smear assessments, 110 (2.4%) had gametocytemia. During the follow-up period 170 (3%) of all patients developed patent gametocytemia, which in 89% had developed by day 14 following treatment. In a multiple logistic regression model five factors were found to be independent risk factors at presentation for the development or persistence of gametocytemia during follow up; patent gametocytemia on admission (adjusted odds ratio [AOR] = 7.8, 95% confidence interval [CI] = 3.7-16, P < 0.001), anemia (hematocrit <30%) (AOR = 3.9, 95% CI = 2.3-6.5, P < 0.001), no coincident P. vivax malaria (AOR = 3.5, 95% CI = 1.04-11.5, P < 0.04), presentation with a recrudescent infection (AOR = 2.3, 95% CI = 1.3-4.1, P < 0.004), and a history of illness longer than two days (AOR = 3.3, 95% CI = 1.7-6.6, P < 0.001). Patients whose infections responded slowly to treatment or recrudesced subsequently were also more likely to carry gametocytes than those who responded rapidly or were cured (relative risks = 1.9, 95% CI = 1.3-2.7 and 2.8, 95% CI = 2.0-4.0, respectively; P < 0.001). These data provide further evidence of important epidemiologic interactions between P. falciparum and P. vivax, and drug resistance and transmission potential.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemisinins; Carrier State; Child; Child, Preschool; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Multivariate Analysis; Parasitemia; Phenanthrenes; Plasmodium falciparum; Prospective Studies; Quinine; Regression Analysis; Risk Factors; Seroepidemiologic Studies; Sesquiterpenes; Thailand

The drug sensitivity characteristics and Plasmodium falciparum pfmdr1 status of five isolates of P. falciparum recently isolated from patients presenting for treatment from the Thailand/Myanmar border have been investigated. The aim of the study was to avoid the criticisms of some earlier studies by focusing on newly collected isolates from a specific geographic location. Three of the isolates studied exhibited clear resistance to chloroquine similar to that observed in the K1 Thai standard isolate obtained in the 1970s, and the other two isolates were of intermediate sensitivity to chloroquine with concentrations of drug that inhibit parasite growth by 50% of 50 and 43 nmol. The sensitivity of all isolates was enhanced by verapamil but we found no clear association between chloroquine sensitivity and gene copy number or intra-allelic variation of pfmdr1. In contrast, clear cross-resistance was seen between mefloquine and halofantrine, with the most sensitive isolates carrying the K1 mutation in pfmdr1.

Topics: Animals; Antimalarials; Blotting, Western; Chloroquine; DNA Fingerprinting; DNA, Protozoan; Drug Resistance; Electrophoresis, Agar Gel; Gene Dosage; Genotype; Humans; Malaria, Falciparum; Mefloquine; Penfluridol; Phenanthrenes; Phenotype; Plasmodium falciparum; Polymerase Chain Reaction; Quinine; Thailand; Verapamil

Over a 5 month period (October 1996 to February 1997), a rotating company of 146 servicemen belonging to the Navy Airborne 6th Regiment were assigned along the Maroni River in French Guyana. During this mission, the medical personnel treated 387 local residents. Etiologies comprised 51 malaria attacks including 46 involving Plasmodium falciparum and 4 rattlesnake envenomations. The most common cause of consultation by military personnel was mycotic and staphylococcal skin infections, but 5 cases involving poor acclimatization were treated during the hot and dry season. Seven malaria attacks involving Plasmodium falciparum including 2 that were severe occurred despite prophylaxis using chloroquine-proguanil. Treatment with halofantrine was successful in all but one case which required combined chemotherapy using quinine and doxycycline. Five cases of cutaneous leishmaniasis were observed in subjects involved in jungle training. No case of HIV infection was detected upon returning home since most personnel either followed the recommendation to abstain from sex (51 p. 100) or used a condom (90 p. 100 of personnel who had sexual relations). These data illustrate the health risks for mainland French nationals in the region of the Maroni River and underline the need for preventive measures and education.

Topics: Acclimatization; Animals; Anti-Bacterial Agents; Antimalarials; Chloroquine; Condoms; Crotalid Venoms; Crotalus; Dermatomycoses; Doxycycline; France; French Guiana; Health Education; HIV Infections; Humans; Leishmaniasis, Cutaneous; Malaria, Falciparum; Military Personnel; Phenanthrenes; Quinine; Risk Factors; Sexual Abstinence; Snake Bites; Staphylococcal Skin Infections; Tropical Medicine

Imported malaria is frequently observed in pediatric practices within geographical areas which have a migrant population.. All the pediatric malaria cases of a university children's hospital (Marseilles, southern France) had been studied retrospectively. The period of the study was from January 1987 to December 1997. Inclusion criteria were based on clinical diagnosis criteria established by WHO.. Three hundred and fifteen clinical cases were observed. Ninety-nine percent were confirmed by blood smears. Eighty-six percent of the patients came from the archipelago of the Comoro Islands in the Indian Ocean. Twenty percent were not given chemoprophylaxis, and 77% of the patients with chemoprophylaxis were not compliant. Fever (92%), splenomegaly (61%), vomiting and/or diarrhea (50%) were frequently observed. Neurological signs (23%), especially headaches (15%), were noted. The causative species was Plasmodium falciparum in 76%; coinfections with two species were observed in 9%. Halofantrine was commonly used for therapy (64%), but relapses were noted with this drug. No death was observed during the study.. Imported pediatric malaria is rare in France. Clinical signs may lead to misdiagnosis when splenomegaly is not obvious, or when vomiting and/or diarrhea, cough or otitis occur. Diagnosis relies on blood smears. Curative medications are chloroquine or halofantrine, with special attention to heart troubles. Mefloquine is rarely used in children. Quinine is reserved for serious attacks. Concerning chimioprophylaxy, medical prescriptions should be adapted to the stay abroad, and patient compliance to medications could be improved.

Topics: Adolescent; Antimalarials; Child; Child, Preschool; Comorbidity; Emigration and Immigration; Female; France; Humans; Infant; Malaria; Malaria, Falciparum; Male; Phenanthrenes; Recurrence; Travel

Halofantrine has been shown to be very effective against multiple drug resistant falciparum malaria. It is usually administered in children at 24 mg/kg at six-hour intervals for three doses, and a second therapeutic course one week following the initial treatment is recommended. It is usually well tolerated. However, prolongation of the QT interval has been reported in adults receiving this drug for malaria.. Two children experienced a prolongation of the QTc interval while receiving halofantrine. The first child, aged two years, had a prolonged QTc interval (490 ms) six hours after the third administration, at the usual therapeutic dose. The second child, aged six years, had a normal QT interval (360 ms) after the first 24 mg/kg dose and had a prolonged QTc (450 ms) during the second course seven days later, 15 h after the last dose. In both cases, the QTc interval returned to normal values (below 440 ms) rapidly after the end of treatment.. Cardiotoxic effects are felt to be dose-dependant and young children may be particularly at risk due to pharmacological and cardiac immaturity. Therefore, guidelines for drug administration should be followed (administration in a child with an empty stomach, drug not recommended in combination with drugs known to prolong the QTc interval) and monitoring ECG in pediatric patients may be justified. The modalities of the second course in children, which is recommended by the manufacturer to travellers from non-endemic areas, should also be discussed.

Topics: Adult; Antimalarials; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Humans; Infant; Long QT Syndrome; Malaria, Falciparum; Male; Phenanthrenes

Artemisinin (QHS) and its derivatives are new antimalarials which are effective against Plasmodium falciparum parasites resistant to chloroquine (CQ). As these drugs are introduced it is imperative that resistance is monitored. In this paper we demonstrate that the inoculum size used in in vitro testing influences the measured in vitro susceptibility to QHS and its derivative dihydroartemisinin (DHA) and to mefloquine (MEF) and CQ over the range of parasitaemias routinely used in testing with the WHO in vitro microtest. An increase in parasitaemia and/or haematocrit was accompanied by a decrease in the measured sensitivity of 2 laboratory lines. In the context of a field study testing in vitro susceptibility of parasite isolates from patients with uncomplicated malaria in Fajara, The Gambia we demonstrate that failure to control for inoculum size significantly overestimates the level of resistance to QHS and DHA as well as MEF, halofantrine (HAL) and quinine (QUIN). When controlling for the inoculum effect, cross-resistance was observed between QHS, MEF and HAL suggesting the presence of a multidrug resistance-like mechanism. These studies underline the importance of inoculum size in in vitro susceptibility testing.

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Drug Resistance; Gambia; Hematocrit; Humans; Malaria, Falciparum; Mefloquine; Parasitemia; Phenanthrenes; Plasmodium falciparum; Quinine; Scintillation Counting; Sensitivity and Specificity; Sesquiterpenes

The in vitro activity of artemether against 56 African isolates of Plasmodium falciparum from Senegal was evaluated using an isotope-based drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in a narrow range from 0.8 to 15.2 nM (mean IC50 = 3.43 nM) and the 95% confidence interval (CI) was 2.50-4.36 nM. Artemether was equally effective on chloroquine-sensitive and chloroquine-resistant isolates (mean IC50 = 346 nM, 95% CI = 2.08-4.84 nM versus mean IC50 = 2.80 nM, 95% CI = 2.00-3.60 nM). There was a significant positive correlation between responses to artemether and mefloquine (r2 = 0.36, P < 0.001), artemether and quinine (r2 = 0.085, P < 0.05), artemether and halofantrine (r2 = 0.075, P < 0.05), quinine and mefloquine (r2 = 0.205, P < 0.01), quinine and halofantrine (r2 = 0.124, P < 0.05), and mefloquine and halofantrine (r2 = 0.801, P < 0.001). A positive correlation between these drugs suggests in vitro cross-resistance or at least in vitro cross-susceptibility.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Chloroquine; Drug Combinations; Drug Resistance; Erythrocytes; Humans; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Senegal; Sesquiterpenes

The sensitivity of Plasmodium falciparum to chloroquine, mefloquine, quinine, quinidine, halofantrine, artemisinin, and sulfadoxine/pyrimethamine was investigated in Lambarene, Gabon in 1994. The development of in vitro susceptibility has been traced from 1983 or 1992 to 1994 for chloroquine, mefloquine, halofantrine, and quinine. Standard in vitro microtests according to World Health Organization methodology were performed. Of 33 isolates tested for susceptibility to chloroquine, 31 were resistant, one was borderline, and one isolate was sensitive (mean 50% effective concentration [EC50] = 1.38 micromol/L of blood). With mefloquine, all isolates were fully inhibited below the threshold of resistance (mean EC50 = 0.51 micrmol/L of blood). Of 32 isolates tested with quinine, six had borderline resistance (mean EC50 = 0.54 micromol/L of blood medium mixture). Susceptibility to quinidine was higher with a mean EC50 of 0.15 micromol/L of blood medium mixture. With halofantrine, 26 of 32 isolates matured at 3 nmol/L of blood medium mixture (mean EC50 = 1.64 nmol/L of blood medium mixture), indicating a steep decrease in susceptibility in comparison with 1992. For artemisinin, the mean EC50 was 97.92 nmol/L of blood medium mixture. Sulfadoxine/pyrimethamine showed five of 16 resistant isolates with a mean EC50 of 2.46 nmol/L of blood medium mixture. Whereas chloroquine resistance remained stable with a tendency to decrease, susceptibility to mefloquine and quinine was slightly decreased. A significant increase in the mean EC50 and EC90 in comparison with our previous data from Gabon was found for halofantrine.

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Dose-Response Relationship, Drug; Drug Resistance; Follow-Up Studies; Gabon; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Sesquiterpenes; Sulfadoxine

The in vitro sensitivity of P. falciparum drug-resistant isolates was evaluated in the region of Bobo-Dioulasso during the 1995 and 1996 rainy seasons. Two routinely used antimalarials (chloroquine and quinine) and two new antimalarials (mefloquine and halofantrine) were assessed using 24-hour in vitro cultures with tritiated hypoxanthine and a parasite density > or = 4,000/microl of blood. The proportion of chloroquine-resistant isolates was 20% in 1995 and 19% in 1996, whilst in 1996, the proportion of isolates resistant to halofantrine was greater than in 1995 (9.6% versus 1%). No significant differences were seen in the mean IC50 values in relation to the susceptibility of chloroquine-resistant or chloroquine-sensitive isolates to mefloquine and halofantrine. In the case of quinine, the mean IC50 values were significantly higher in chloroquine-resistant isolates than in chloroquine-sensitive ones. A significant positive correlation was found between the following IC50 values: chloroquine versus quinine, quinine versus mefloquine and mefloquine versus halofantrine.

Topics: Animals; Antimalarials; Burkina Faso; Chloroquine; Drug Resistance; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine

Topics: Antimalarials; Humans; Malaria, Falciparum; Phenanthrenes; Quinine; Severity of Illness Index

Topics: Adolescent; Adult; Aged; Antimalarials; Child; Child, Preschool; Drug Administration Schedule; Follow-Up Studies; Humans; Malaria, Falciparum; Middle Aged; Pakistan; Parasitemia; Phenanthrenes

Topics: Animals; Antimalarials; Cote d'Ivoire; Drug Resistance; Female; Humans; Malaria, Falciparum; Middle Aged; Phenanthrenes; Plasmodium falciparum; Recurrence; Travel

The in vitro activity of artemether against 63 African isolates of Plasmodium falciparum from Libreville, Gabon was evaluated using an isotopic drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in a narrow range from 0.8 to 34.8 nM (mean IC50 5.0 nM) and the 95% confidence interval (CI95%) was 3.6-6.3 nM. In vitro decreased susceptibility or resistance were observed with artemether (14%), to chloroquine (90%), to quinine (32%). Isolate susceptibility to amodiaquine and halofantrine was high i.e. 100% and 98%, respectively. There was a significant positive correlation between responses to artemether and amodiaquine (r2 = 0.45, P < 0.001), artemether and chloroquine (r2 = 0.36, P < 0.001), artemether and quinine (r2 = 0.31, P < 0.001), and artemether and halofantrine (r2 = 0.19, P < 0.01). Positive correlation between these drugs suggests in vitro cross-resistance or at least common features in drug uptake and/or mode of action or resistance.

Topics: Adolescent; Amodiaquine; Animals; Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Chloroquine; Drug Resistance, Microbial; Gabon; Humans; Infant; Malaria, Falciparum; Phenanthrenes; Plasmodium falciparum; Quinine; Sesquiterpenes

French medical practitioners have at their disposal several antimalarial drugs for giving chemoprophylaxis to people travelling to a malaria endemic country or treating an imported malaria case in a patient. The choice depends on the contre-indications and indications of each drug, essentially subordinated to the presence and level of Plasmodium falciparum chemosensitivity in the visited area. For prevention, chloroquine alone can be taken in the areas where P. falciparum is absent or not chloroquine resistant; elsewhere, the choice between chloroquine/proguanil or mefloquine depends on knowing the prevalence and level of falciparum chloroquine resistance in these areas. For treatment, the only indications of chloroquine are imported malaria cases either due to P. vivax, P. ovale or P. malariae, or caused by P. falciparum contracted in one of the rare countries where the species is still sensitive to chloroquine. For uncomplicated falciparum malaria cases acquired in a chemoresistance area, mefloquine, halofantrine, sulfadoxine-pyrimethamine or oral quinine is selected, depending on the observed chemoprophylaxis, the contra-indications and the suspicion of chemoresistance type. Whatever the provenance area, P. falciparum in a patient with one or several serious symptoms or possibly profuse vomiting is treated by intravenous quinine, associated with tetracycline if the patient comes from an area known for a low quinine sensitivity of this species. The spectrum of falciparum malaria treatment has recently broadened to include new drugs such as artemisinin, artemether or atovaquone/proguanil, the latter being as yet unauthorized in France.

Topics: Animals; Antimalarials; Chemoprevention; Chloroquine; Contraindications; Drug Combinations; Drug Resistance; Endemic Diseases; Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Mefloquine; Phenanthrenes; Plasmodium; Plasmodium falciparum; Plasmodium malariae; Plasmodium vivax; Proguanil; Pyrimethamine; Quinine; Sulfadoxine; Travel

Pulmonary manifestations are frequently observed in children, pregnant women and travellers with malaria. The pathophysiology of these pulmonary manifestations is poorly understood but would appear to be secondary to an interaction between the parasitized red cells and the pulmonary capillary endothelium. Bronchitis and pneumonia do not directly compromise outcome but, left unrecognized, the delay in diagnosis and treatment may be fatal. Acute respiratory distress in children is the first cause of overmortality, coming before neurological involvement. The acute respiratory distress caused by severe malaria has no specific characteristics. Iatrogenic complications and pulmonary superinfections must be differentiated. The prevention of pulmonary manifestations associated with malaria can easily be accomplished by limiting water intake and carefully monitoring urinary output and weight. Treatment is the same as for acute flare-ups in combination with symptomatic respiratory treatment when required.

Topics: Adult; Anti-Bacterial Agents; Antimalarials; Bronchitis; Child; Chloroquine; Female; Humans; Infant, Newborn; Lung Diseases; Malaria, Falciparum; Male; Mefloquine; Oxygen Inhalation Therapy; Phenanthrenes; Pleurisy; Pregnancy; Pregnancy Complications, Parasitic; Pulmonary Edema; Quinidine; Quinine; Respiratory Distress Syndrome, Newborn; Travel

In vitro susceptibility to dihydroartemisinin (DHART) and to artemether of 476 Plasmodium falciparum fresh clinical isolates obtained from non immune travellers returning from Africa to France in 1993-1996 were analysed to search for natural resistance and cross resistance of these compounds with available antimalarials. The mean median inhibitory concentration (IC50) values for artemether and DHART were 2.69 nM and 1.17 nM, respectively. Nineteen isolates presented with a decreased IC50 to artemether or DHART. Chloroquine-resistant isolates were more susceptible to artemether (2.15 versus 3.26 nM) and DHART (0.876 versus 1.51 nM) than chloroquine-susceptible ones. Artemether and DHART responses were correlated (r2 = 0.599). The isolates identified as resistant to DHART or artemether in this study had IC50's close to the cut-off and limited cross-resistant profiles.

Topics: Africa; Animals; Antimalarials; Artemisinins; Chloroquine; Cross Reactions; Drug Evaluation, Preclinical; Drug Resistance; France; Humans; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Sesquiterpenes; Travel

Halofantrine is a newer antimalarial drug which has not been approved for clinical use in Papua New Guinea. We assessed 21 Central Province isolates of Plasmodium falciparum for their in vitro susceptibility to halofantrine. The concentration required to inhibit 50% of parasite growth (IC50) ranged from 0.05 to 7.0 nM with a mean of 1.90 nM and a median of 1.50 nM. The minimum inhibitory concentration (MIC) values ranged from 2.5 to 50 nM with a median of 5.0 nM. All but one isolate had an MIC of 10 nM or less. These results indicate that halofantrine would be a suitable alternative for the treatment of P. falciparum malaria in the region in the future, if and when the need arises, provided that its use was carefully monitored.. Halofantrine is a newer antimalarial drug which has not been approved for clinical use in Papua New Guinea. The authors assessed 21 Central Province isolates of Plasmodium falciparum for their in vitro susceptibility to halofantrine. The concentration required to inhibit 50% of parasite growth (IC50) ranged from 0.05 to 7.0 nmol with a mean of 1.90 nmol and a median of 1.50 nmol. The minimum inhibitory concentration (MIC) values ranged from 2.5 to 50 nmol with a median of 5.0 nmol. All but one isolate had an MIC of 10 nmol or less. These results indicate that halofantrine would be a suitable alternative for the treatment of P. falciparum malaria in the region in the future, if and when the need arises, provided that its use was carefully monitored.

Topics: Animals; Antimalarials; In Vitro Techniques; Inhibitory Concentration 50; Malaria, Falciparum; Microbial Sensitivity Tests; Papua New Guinea; Phenanthrenes; Plasmodium falciparum

Malaria is a major health priority. The aim of this study was to describe clinical expression, laboratory findings and therapeutic aspects of Plasmodium falciparum malaria observed in a French military population stationed in Gabon.. One hundred fifty-four cases of P. falciparum malaria were observed between July 1, 1994 and February 29, 1996. In 145 cases malarial fever predominated and in 9 others further complications occurred. Mean age of the patients was 23.7 years and mean delay to consultation was 30 hours. Seventy-two percent of the patients stated they took prophylaxis (chloroquine-proguanil) regularly.. Pain generally accompanied the episodes of fever. There were 21 atypical cases. Parasitemia was < 25000 HPM in 70% of the cases. Blood counts showed leukopenia, lymphopenia, and thombopenia. Plasma cholesterol was low and lactic acid dehydrogenase levels were elevated. Halofantrine was used for curative treatment (2 doses with a 7 day interval) in 145 cases. Intravenous quinine was used in 9 cases.. This series demonstrates the importance of malarial morbidity in French military men stationed in Africa and confirmed the performance of the acridine orange test. It also emphasized the importance of indirect laboratory findings for early diagnosis of malaria in foreigners living in Africa. A new dosage of halofantrine is proposed for the second injection due to cardiac toxicity.

Topics: Adult; Antimalarials; Female; France; Gabon; Humans; Malaria, Falciparum; Male; Military Personnel; Phenanthrenes; Quinine; Transients and Migrants

A patient is reported who contracted Plasmodium falciparum malaria in Lombok, Indonesia. The infection recrudesced after quinine/doxycycline and mefloquine. Treatment with halofantrine was successful after he developed cerebral malaria with recovery.

Topics: Adult; Animals; Anti-Bacterial Agents; Antimalarials; Doxycycline; Drug Combinations; Drug Resistance, Multiple; Humans; Indonesia; Malaria, Cerebral; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Recurrence

The correlation of P. falciparum lactate dehydrogenase (pLDH) activities and patent infections was evaluated for monitoring therapeutic responses and drug resistance in 70 patients with microscopically confirmed P. falciparum malaria in Nigeria. Each patient was treated with standard dosages of artemether (53 patients), chloroquine (7 patients), sulfadoxine-pyrimethamine (6 patients), or halofantrine (4 patients). Response of infection to treatment was monitored by microscopic examination of thick and thin blood smears, clinical symptoms, and levels of pLDH activities in blood products. pLDH activity was determined using an antibody capture technique and 3-acetyl pyridine adenine dinucleotide developed to enhance sensitivity of the enzyme detection. All patients treated with artemether were cured while 5 patients treated with chloroquine, 1 treated with sulfadoxine-pyrimethamine, and 2 treated with halofantrine suffered recrudescent infections after treatment. pLDH activity was detected in blood products obtained from patients with patent or recrudescent infections determined by microscopy and clinical symptoms. Levels of pLDH activities in whole blood and packed cells from the patients correlated with qualitative detection of parasites in blood smears and in patients with high gametocyte counts. Gametocyte counts in the patients after treatment ranged from 40 gametocytes/microliter of blood to 4923 gametocytes/microliter of blood. There is a consistent relationship between patent infection and pLDH activities that could easily be determined in whole blood and packed cells from the patients. Further development of the procedure will enhance its valuable application in clinical management of drug-resistant malaria in the endemic areas.

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Chloroquine; Drug Combinations; Drug Resistance; Female; Humans; Infant; L-Lactate Dehydrogenase; Malaria, Falciparum; Male; Monitoring, Physiologic; Nigeria; Phenanthrenes; Pyrimethamine; Sesquiterpenes; Sulfadoxine; Treatment Outcome

Topics: Aged; Antimalarials; Chloroquine; Glycogen Storage Disease Type I; Hemolysis; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Phenanthrenes

The antimalarial drug halofantrine hydrochloride has been associated with cardiac arrhythmias. This is a report of a study on the cardiac effects of standard-dose halofantrine (24 mg/kg) on a sample of 48 patients selected from a group of 402 Dega (Montagnard) refugees treated for Plasmodium falciparum infection. Prolongation of the rate-corrected QT interval (QTc) on the electrocardiogram (ECG) was used as an indicator of risk for halofantrine-associated cardiac arrhythmias. We found that standard-dose halofantrine was associated with a lengthening of the mean QTc from 0.04 sec(1/2) to 0.44 sec(1/2). Two patients had a QTc increase of greater than 25%, but none had a follow-up QTc of more than 0.55 sec(1/2), an interval length generally considered to be a risk factor for ventricular arrhythmias. Regression analysis indicated that pretreatment ECGs were poorly predictive of QTc lengthening during therapy, although pretreatment ECGs may be useful to evaluate patients with pre-existing cardiac conditions. The manufacturer has recommended that the halofantrine dose not exceed 24 mg/kg and revised the list of medication contraindications to include some cardiac conditions. Clinicians should weigh a patient's risk, including history of cardiac disease and availability of alternative therapy before use of halofantrine.

Topics: Adolescent; Adult; Aged; Antimalarials; Arrhythmias, Cardiac; Electrocardiography; Female; Heart; Heart Rate; Humans; Least-Squares Analysis; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Refugees; Vietnam

The aim of this study was 1) to assess the incidence of electrocardiographic changes after treatment with halofantrine and 2) to study the relationship between these changes and plasma levels of halofantrine and its main metabolite, N-desbutyl-halofantrine. Thirty-four male patients with uncomplicated falciparum malaria were enrolled in this study. Halofantrine was administered on two separate days at a total oral dosage of 24 mg/kg/day in three doses over a 12-hr period. The interval between the two treatments was seven days. Twelve-lead electrocardiography (ECG) was performed to measure the QT interval (QTc), ambulatory ECG monitoring was done to detect ventricular arrhythmia, signal-averaged ECG was performed to detect late ventricular potentials, and blood tests were performed to determine plasma concentrations of halofantrine and N-desbutyl-halofantrine. Maximum QTc was observed at 12 hr after both the first (P < 0.0002) and second treatments (P < 0.03). Signal-averaged ECG revealed late potentials in four cases (72 hr after the first treatment in one case and 24 hr after the second treatment in three cases). Ventricular arrhythmia was not observed. Significantly higher plasma concentrations of halofantrine were observed 2 hr after the second treatment. At this time, both the time effect and time interaction were significant (P < 0.008 and P < 0.02, respectively). The QTc interval was significantly correlated with the plasma halofantrine level (r = 0.41, P < 0.01) but not with the plasma N-desbutyl-halofantrine level (r = 0.30, not significant). In three cases, late ventricular potentials were associated with a maximum concentration of halofantrine. Our findings indicate that electrocardiographic changes are dose-dependent and that a second treatment at the same dosage may be hazardous.

Topics: Acute Disease; Adult; Antimalarials; Electrocardiography; Heart; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes

The in vivo and in vitro effects of antimalarials on cytoadherence and rosette formation were studied in 17 patients with severe and 46 with uncomplicated falciparum malaria. Cytoadherence was increased in severe malaria (P<.001). Artesunate and artemether were more potent than quinine in inhibiting both adherence properties. Artesunate was the most rapidly acting drug tested, producing >50% inhibition of both cytoadherence and rosetting in vivo and in vitro within 2 hr of drug exposure. Exposure to quinine for > or = to 4 h in vivo reduced rosetting by >50%, but not cytoadherence. Quinine did not reduce cytoadherence or rosetting significantly in vitro with exposure times of < or = to 8 h. These results suggest that artemisinin derivatives are more effective than quinine in preventing pathologic processes in parasitized erythrocytes that contribute to microvascular obstruction in severe malaria.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemether; Artemisinins; Artesunate; Cell Adhesion; Erythrocytes; Humans; In Vitro Techniques; Malaria, Falciparum; Middle Aged; Phenanthrenes; Plasmodium falciparum; Quinine; Rosette Formation; Sesquiterpenes

Electrocardiographic changes and their relationship with profiles of halofantrine (H) and desbutylhalofantrine (DBH) were assessed in a prospective study of 34 male patients with an uncomplicated falciparum malaria. H. was delivered in a one day in three intakes, 24 mg/kg/day. Seven days later the same regimen was administered. This study included a twelve-lead-electrocardiogram (to measure QTc interval), an ambulatory ECG monitoring a signal-averaged-electrocardiogram (to detect late ventricular potentials), and a kinetic-time profile of H. and DBH with high performance liquid chromatography. Data were obtained as follows: day 1 just prior to drug intake, 6 hours (H6), 12 hours (H12) after to drug delivery on day 1 and 8. There after on days 2, 3, 4, 9, 10, 11. Ambulatory ECG monitoring was recorded on day 1 and 8. QTc lengthening was noted in 10 patients with a mean QTc interval of 451 msec (range: 440-469 msec). Maximum QTc interval was obtained at H12 on day 1 (p < 0.0002) and 8 (p < 0.03). Signal-averaged electrocardiogram performed in 8 cases disclosed late potential in 4 cases (day 4: one case, day 9: 3 cases). No ventricular arrhythmia was observed on day 1 and 8. Plasma concentration time profile of H. showed a significant increase at day 8 H12 with a time effect (p < 0.0008) and a significant time-intake interaction (p < 0.02). QTc interval was significantly correlated with H. plasma level (p < 0.01) but not with D.B.H.. Late potentials were associated in 3 cases with a maximum plasma concentration level of H. These data showed that H. is potentially deleterious with a cardiac toxicity which appears dose-related, particularly during the second cure. Following this study, new prescription rules has been proposed before H. therapy.

Topics: Adult; Antimalarials; Data Interpretation, Statistical; Electrocardiography; Heart; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Prospective Studies; Time Factors

During the summer 1994, six cases of airport malaria occurred in France, near the Roissy-Charles-de-Gaulle airport. Due to Plasmodium falciparum, all cases underwent rapid and severe deterioration, and in one case, the patient died. The role of laboratory tests is essential to establish the diagnosis of persons who have never resided in the endemic malaria areas and follow up with the patients already under treatment to detect possible complications.

Topics: Adult; Aerospace Medicine; Antimalarials; Chloroquine; Female; France; Humans; Malaria, Falciparum; Male; Microbiological Techniques; Middle Aged; Phenanthrenes; Platelet Count; Prognosis; Quinine

The objective of this study was to evaluate the efficacy of halofantrine in the treatment of malaria caused by Plasmodium falciparum since the resistance of these plasmodium to chloroquine is increasing in countries of Western Africa.. Between January 1991 and June 1994 we studied 50 children from Equatorial Guinea. All of them were black and between the ages of 8 months and 13 years. They were treated with 3 doses of halofantrine (8 mg/kg every 6 hours). The definitive diagnosis was made by the demonstration of the parasites on thick and thin blood smears, stained by standard methods, repeated every 24-72 yours after therapy. We considered the disappearance of fever and the clearance of plasmodium from the red blood cells as signs of response to the treatment. We also monitored the tolerance and the adverse side effects of the drug.. All of the patients responded favorably with the disappearance of the fever after 24 hours and after 72 hours no parasites were seen in red blood cells. Only one patient had a recurrence, which occurred on the 10th day. All patient satisfactorily tolerated the drug and only 3 children showed an increase of aminotransferases that was spontaneously cured.. We conclude that halofantrine is a safe and efficient drug for the treatment of children diagnosed with malaria caused by Plasmodium falciparum.

Topics: Adolescent; Antimalarials; Child; Child, Preschool; Drug Evaluation; Equatorial Guinea; Female; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Phenanthrenes; Remission Induction; Spain

The efficacy of the standard formulation of halofantrine hydrochloride has been compromised by the formulation's irregular bio-availability. A micronized preparation of the drug has now been evaluated in the treatment of malaria in northern Tanzania. Overall, 100 patients with mild to moderate Plasmodium falciparum malaria were recruited and treated with the preparation over 18 h. Those weighing > 40 kg were each given three, 500-mg doses and those weighing less were given roughly equivalent doses/kg. The 95 evaluable patients were all successfully treated, with a mean fever-clearance time of 22.5 h (range 4-76 h) and a mean parasite-clearance time of 35.6 h (range 15-66 h). There were no relapses. Abdominal pain was the commonest adverse event reported (22 cases). A single patient died suddenly in the recovery phase; the cause of this event was not determined. Further studies are required to evaluate the pharmacokinetics of the halofantrine formulation under field conditions.

Topics: Adolescent; Adult; Antimalarials; Biological Availability; Child; Drug Compounding; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Treatment Outcome

A 43 year old man with falciparum malaria acquired in East Africa was treated with quinine intravenously at a loading dose of 500 mg and subsequently 500 mg tid. Within 42 hours after initiation of treatment the parasitaemia increased from 2% to 16%. A RIII-resistance against quinine was suspected and therapy was switched to oral administration of halofantrine (500 mg at 6 hourly intervals) which led to complete recovery. Blood samples were cultured for malaria parasites 42 hours after start of therapy with quinine but before initiation of therapy with halofantrine. In vitro resistance testing was performed with samples directly derived from the patient and after 24 and 48 hours of culturing. In repeated tests an in vitro resistance to quinine could be confirmed (IC50: 25.6 x 10(-6) mol/l, IC99: > 51.2 x 10(-6) mol/l) while the strain was fully susceptible to chloroquine (IC50: < 0.4 x 10(-6) mol/l, IC99: 1.6 x 10(-6) mol/l), mefloquine (IC50: < 0.4 x 10(-6) mol/l, IC99: 3.2 x 10(-6) mol/l), tetracycline (IC50: 0.16 x 10(-6) mol/l, IC99: 0.32 x 10(-6) mol/l) and halofantrine (IC50: 0.02 x 10(-6) mol/l, IC99: 0.04 x 10(-6) mol/l). Increased susceptibility to quinine after addition of verapamil was noted. The presence of a specific mutation, on the pfmdr1-gene on chromosome 5, previously associated with chloroquine drug resistance, could be confirmed by polymerase chain reaction. To our knowledge a R III-in vivo and in vitro resistance of Plasmodium falciparum to quinine has not been described yet in East Africa.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Africa, Eastern; Animals; Antimalarials; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Tetracycline

Topics: Adult; Antimalarials; Dose-Response Relationship, Drug; Humans; Malaria, Falciparum; Phenanthrenes

We compared the efficacy of azithromycin to the clinical antimalarial doxycycline in Plasmodium berghei-infected mice and in P. falciparum-infected Aotus monkeys. When mice were administered drug orally twice a day for three days, the minimum total dose of azithromycin that cured all mice was 768 mg/kg. Doxycycline at a dose of 1,536 mg/kg cured no mice. The efficacy of fast-acting blood schizonticides (quinine, halofantrine, artemisinin) against P. berghei was augmented by azithromycin. In monkey experiments in which there were two animals per experimental group, azithromycin (100 mg/kg/day for seven days) eliminated parasitemia; azithromycin (30 mg/kg/day) initially cleared 99.8-100% of the parasites with recrudescence in the one completely cleared case. Doxycycline (30 mg/kg/day) cleared 100% of the parasites with recrudescence in both cleared cases. Since azithromycin can be clinically administered at a somewhat higher daily dosage than doxycycline, the data suggest that it may be possible to replace drugs of the tetracycline class with azithromycin in combination with fast-acting blood schizonticides for the treatment of P. falciparum infection.

Topics: Administration, Oral; Animals; Antimalarials; Aotus trivirgatus; Artemisinins; Azithromycin; Disease Models, Animal; Doxycycline; Drug Therapy, Combination; Humans; Injections, Subcutaneous; Malaria; Malaria, Falciparum; Mice; Parasitemia; Phenanthrenes; Plasmodium berghei; Quinine; Sesquiterpenes

Lactate dehydrogenase, the terminal enzyme of anerobic Embden-Meyerhoff glycolysis, plays an important role in the carbohydrate metabolism of human malaria parasites. Based on the ability of malarial lactate dehydrogenase to use 3-acetylpyridine NAD as a coenzyme in a reaction leading to the formation of pyruvate from L-lactate, the enzymatic activity of fresh clinical isolates of Plasmodium falciparum and Plasmodium vivax was determined in relation to incubation time, asexual stages, and parasitemia and applied to a drug susceptibility assay. Lactate dehydrogenase activity was detectable at a parasitemia > 0.4%, at a hematocrit of 1.5%, and increased with parasitemia. Maximal lactate dehydrogenase activity was generally observed between 36 and 48 hr, when the trophozoites and schizonts predominated. The results of the in vitro drug susceptibility assays based on the inhibition of lactate dehydrogenase activity and on the incorporation of tritium-labeled hypoxanthine were correlated. For an optimal performance against fresh clinical malaria isolates, however, the enzymatic assay requires an initial parasitemia between 1 and 2% at a hematocrit of 1.5%.

Topics: Animals; Antimalarials; Chloroquine; Colorimetry; Erythrocytes; Humans; L-Lactate Dehydrogenase; Malaria, Falciparum; Malaria, Vivax; Mefloquine; Parasitemia; Phenanthrenes; Plasmodium falciparum; Plasmodium vivax; Quinine

50 patients (45 males + 5 females) suffering from acute uncomplicated attack of Plasmodium falciparum (Pf) malaria were treated with 1500 mg of halofantrine divided in three doses of 500 mg each given at an interval of 6 h. Results showed there were no primary treatment failures. Average Parasite Clearance Time (av. PCT) was 51.12 h and average Fever Clearance Time (av. FCT) was 31.25 h. Adverse Drug Reactions (ADR) were mild and self limiting. We conclude that halofantrine is a quite safe and effective new antimalarial agent in the treatment of Pf malaria cases.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes

A case of malaria treatment failure with chloroquine and halofantrine is reported. The likely determinants and policy considerations are addressed.

Topics: Adult; Antimalarials; Chloroquine; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Male; Phenanthrenes; Pyrimethamine; Sulfadoxine; Zimbabwe

Topics: Antimalarials; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes

Topics: Acute Disease; Antimalarials; Drug Resistance, Multiple; Humans; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes; Primaquine; Recurrence

Topics: Antimalarials; Drug Resistance; Heart Diseases; Humans; Malaria, Falciparum; Phenanthrenes; Travel

Topics: Antimalarials; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Recurrence

Topics: Adult; Antimalarials; Drug Resistance, Microbial; Humans; Madagascar; Malaria, Falciparum; Male; Phenanthrenes

Twenty-eight nonimmune patients with acute uncomplicated falciparum malaria returning from subSaharan Africa were treated with a micronized formulation of halofantrine hydrochloride (three doses of 250 mg at 6-hr intervals) to investigate the drug's efficacy, tolerance, and pharmacokinetics. In vitro drug susceptibility patterns were determined by the isotopic semimicrotest. Twenty-four of 28 patients were cured. Two of the four patients experiencing recrudescence were associated with low absorption of the drug and parasites susceptible in vitro to halofantrine. The other two patients had adequate plasma concentrations of halofantrine and its main human metabolite, N-desbutylhalofantrine, but the isolates were also resistant in vitro to the drugs, suggesting drug resistance as the cause of treatment failure. Only mild, transitory side effects were noted. A wide interindividual variation in plasma concentrations of halofantrine and its metabolite was observed. Pharmacokinetic studies suggested that the micronized formulation of halofantrine hydrochloride may not increase drug absorption considerably. Further studies using higher doses or longer treatment periods are needed to ensure that adequate plasma concentrations of the drug are used.

Topics: Acute Disease; Administration, Oral; Adult; Animals; Antimalarials; Chemistry, Pharmaceutical; Half-Life; Humans; Malaria, Falciparum; Middle Aged; Phenanthrenes; Plasmodium falciparum; Tablets; Treatment Outcome

Topics: Antimalarials; Contraindications; Humans; Malaria, Falciparum; Mosquito Control; Phenanthrenes

A 44-year-old male, who had been to Lagos, Nigeria, was admitted to our hospital because of a high grade fever on July 20, 1993. On admission, Plasmodium falciparum was detected in his blood smears and the antibody titers against P. falciparum and Plasmodium vivax antigens were 1:256 and < 1:4 respectively by the indirect fluorescent antibody test. Therefore, he was diagnosed as having P. falciparum malaria. He was treated with halofantrine (Halfan: Smith Kline Beecham Pharmaceuticals, England), two tablets at six-hourly intervals, a total of six tablets (1500 mg). Parasites were cleared rapidly and remission was achieved without any adverse reactions. Halofantrine can therefore be recommended for the treatment of imported P. falciparum malaria.

Topics: Adult; Animals; Antimalarials; Humans; Malaria, Falciparum; Male; Phenanthrenes; Plasmodium falciparum; Travel

Topics: Adult; Aged; Antimalarials; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes

Two chloroquine-resistant cloned isolates of Plasmodium falciparum were subjected to mefloquine selection to test if this resulted in alterations in chloroquine sensitivity and amplification of the pfmdr1 gene. The mefloquine-resistant lines derived by this selection were shown to have amplified and overexpressed the pfmdr1 gene and its protein product (Pgh1). Macrorestriction maps of chromosome 5, where pfmdr1 is encoded, showed that this chromosome has increased in size in response to mefloquine selection, indicating the presence of a gene(s) in this area of the genome that confers a selective advantage in the presence of mefloquine. Concomitant with the increase in mefloquine resistance was a corresponding increase in the level of resistance to halofantrine and quinine, suggesting a true multidrug-resistance phenotype. The mefloquine-selected parasite lines also showed an inverse relationship between the level of chloroquine resistance and increased pfmdr1 gene copy number. These results have important implications for the derivation of amplified copies of the pfmdr1 gene in field isolates, as they suggest that quinine pressure may be involved.

Topics: Animals; Chromosome Mapping; Drug Resistance; Gene Amplification; Gene Expression; Genes, Protozoan; Humans; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine

1 The pharmacokinetics, efficacy and toxicity of a new parenteral formulation of halofantrine hydrochloride were evaluated in 12 adults with acute uncomplicated falciparum malaria and nine adults who attended in convalescence. 2 Intravenous halofantrine (1 mg kg(-1) infused in 1 h) was given every 8 h for a total of three doses in the acute study. Halofantrine cleared parasitaemia rapidly in all but one patient, with a mean (s.d.) parasite clearance time of 71 (29) h. Convalescent patients received a single infusion (1 mg kg(-1) in 1 h). 3 An open two-compartment model with the following parameters described the pharmacokinetics of halofantrine in acute malaria (mean (s.d)): V1 = 0.36 (0.18) l kg(-1); CL = 0.355 (0.18) l h(-1) kg(-1); t1/2alpha = 0.19 (0.12) h; t1/2beta = 14.4 (7.5) h. 4 Intravenous halofantrine in acute malaria produced significant prolongations of the QT and QTc intervals (mean (s.d.)) of 20 (15%) and 8.2 (5.6)%, respectively (P < 0.001) after the third dose, but no clinically significant cardiotoxcity. Eight patients experienced mild to moderate thrombophlebitis at the halofantrine infusion site which had resolved in six by the time of follow-up. In the single treatment failure who received oral quinine, there was a large rise in plasma halofantrine concentration but this did not result in detectable toxicity. 5 These data provide the basis for the design of improved dosing regimens for the use of parenteral halofantrine in malaria.

Topics: Adolescent; Adult; Antimalarials; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Infusions, Parenteral; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Treatment Outcome

Topics: Adolescent; Adult; Animals; Antimalarials; Cameroon; Child; Child, Preschool; Congo; Drug Resistance; Humans; Infant; Malaria, Falciparum; Middle Aged; Phenanthrenes; Plasmodium falciparum

Topics: Adult; Antimalarials; Artemisinins; Artesunate; Cambodia; Drug Approval; Drug Resistance; Humans; Malaria, Falciparum; Male; Military Personnel; Netherlands; Phenanthrenes; Sesquiterpenes

Topics: Africa; Animals; Antimalarials; Congo; Drug Resistance; Humans; Malaria, Falciparum; Phenanthrenes; Plasmodium falciparum

Topics: Adult; Animals; Antimalarials; Child; Drug Resistance; Humans; Malaria, Falciparum; Phenanthrenes; Plasmodium falciparum; Treatment Failure

Topics: Adolescent; Adult; Antimalarials; Arrhythmias, Cardiac; Bradycardia; Electrocardiography; Heart; Heart Block; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes

Malaria attacks by Plasmodium falciparum have been observed in the European population living in Burkina Faso despite the use of bednets and regular chemoprophylaxis. In some cases, the diagnosis has been difficult because of an absence of severe symptoms. In other cases, malaria attacks have been severe after a dangerous delay in diagnosis and start of treatment. Moreover, treatment using halofantrine has, on occasion, been followed by relapses a few weeks later. These facts put into question the advisability of the routine use of chemoprophylaxis in an area of endemic infection and increasing drugs resistance.

Topics: Adult; Burkina Faso; Child, Preschool; Chloroquine; Drug Resistance; Europe; Humans; Infant; Malaria, Falciparum; Phenanthrenes; Recurrence

Incidence and malignant forms of imported Plasmodium falciparum malaria are increasing, and chemoprevention is more and more replaced by stand-by treatment and radical cure in preventing access on return from malaria areas. Halofantrine is recommended for this radical cure: it's an habitually well-tolerated amino-alcohol with very few side-effects. We report three cases of long QT-interval due to halofantine: three different young women coming back from Africa took halofantrine (500 mg (2 tablets) six hourly for three doses on the first and the seventh day) and all presented with syncopal episodes. Serum electrolyte concentrations and echocardiograms were normal. In one case only, a diagnosis of Plasmodium falciparum malaria was made, without severe manifestations, and in the two other cases, treatment was a radical cure. In two cases, several bursts of torsades de pointes ventricular tachycardia due to halofantrine were proven and electrophysiological cardiac tests concluded that they had a congenital long QT-interval/Romano-Ward syndrome). So far halofantrine cardiac toxicity was unknown with single dose of 24 mg/kg/d. This phenomenon can be very severe in case of preexisting cardiopathy. In spite of the rarity on the congenital Romano-Ward syndrome, systematic electrocardiogram is necessary before giving halofantrine.

Topics: Adult; Africa; Arrhythmias, Cardiac; Female; France; Heart Ventricles; Humans; Malaria, Falciparum; Phenanthrenes

Topics: Antimalarials; Electrocardiography; Humans; Long QT Syndrome; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes

Fifty subjects with acute uncomplicated falciparum malaria were treated orally with a new micronized formulation of halofantrine. The dose given corresponded to one-half the normal dose for the standard formulation. Parasitemia cleared in all subjects within 78 h. There was recrudescence of falciparum malaria in seven subjects after day 14. The mean +/- standard deviation clearance times of parasitemia and fever were 49.0 +/- 14.2 and 24.3 +/- 13.2 h, respectively. Other clinical symptoms related to malaria cleared within the first 3 days. Pruritus occurred in two subjects, back pain occurred in one subject, and diarrhea occurred in one subject; all of these symptoms were mild. Hematological and biochemical indices were not adversely affected by treatment except in five subjects in whom minor and transitory increases in aspartate aminotransferase and alanine aminotransferase were observed. Micronized halofantrine appears to be a safe, well-tolerated, and effective treatment for acute falciparum malaria in semiimmune patients.

Topics: Adolescent; Adult; Alanine Transaminase; Antimalarials; Aspartate Aminotransferases; Cameroon; Child; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Microbial Sensitivity Tests; Middle Aged; Phenanthrenes; Recurrence

Clinical trial of halofantrine was conducted in 32 cases of acute malaria. Twenty four patients with P. vivax and eight patients with P. falciparum infection were treated with 3 doses of halofantrine (500 mg each) orally, after food, at intervals of 6 hours. Mean parasite clearance time of P. vivax was 57.75 h and for P falciparum 75 h and mean defervescence time was 31.08 h and 34 h respectively. Post treatment followup was for 28 days. Clinical symptoms related to malaria cleared within the first 48 h. Mild adverse reactions of abdominal pain in one patient and vomiting in one patient were encountered which did not require any treatment. Halofantrine was found to be very effective and free from significant adverse events when used for the treatment of acute malaria.

Topics: Adolescent; Adult; Aged; Antimalarials; Female; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Phenanthrenes

A method of monitoring Plasmodium falciparum viability ex vivo was used to compare the ability of different antimalarial drugs to arrest the progression of young parasites to mature, potentially damaging stages. Neither pyrimethamine-sulfadoxine nor quinine, the treatment of choice for severe, life-threatening malaria, had a demonstrable effect on circulating parasites during the first 24 hr of therapy. In contrast, in vivo exposure to halofantrine for as little as six hours was sufficient to arrest parasite development. The method of assessing ex vivo parasite viability permits a comparison of antimalarial drug action at a time that may be critical for the therapy of life-threatening disease. If parenteral formulations of halofantrine prove to be safe and effective, they may have a role in the therapy of severe malaria.

Topics: Animals; Antimalarials; Drug Combinations; Drug Therapy, Combination; Humans; Malaria, Falciparum; Phenanthrenes; Plasmodium falciparum; Pyrimethamine; Quinine; Sulfadoxine; Time Factors

The modalities of prevention and treatment of malaria in expatriates residing in Brazzaville, capital of the Congo, have been studied in March 1989, April 1990 and April 1992. These surveys of the type Behavior, Attitude, Practice have been carried out in the Ecole Française where the same questionnaire has been distributed among the primary school children to complete by their parents. Only the data pertaining to Europeans, Lebanese, and North-Americans are presented. The proportion of French expatriates is 80%. A progressive decrease is noticed in the regular taking of chemoprophylaxis: the percentage varies between 86 and 43% according ot the duration of residence in 1989, to between 57 and 16% in 1992. Chloroquine alone remains the most widely used product, especially in long term expatriates. The association chloroquine-proguanil is mentioned only by a quarter or respondents. Apparently efficient, it is especially taken by people exposed for less than 4 years. Amodiaquine, although contra-indicated for prevention purposes, is cited in 1992 by 9% of subjects taking regular chemoprophylaxis; other products are only exceptionally used. In curative treatment, which generally is presumptive, halofantrine is since 1990 the most widely used drug, especially in children. In contrast, a relative disclaimer is noted for the amino-4-quinolines, due to resistance, but also and with no justification, for the association sulfadoxine-pyrimethamine and, to a lesser degree, for quinine. The occurrence of attacks considered to be malarial and their frequency, remained stable during the period of study.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aminoquinolines; Antimalarials; Child; Child, Preschool; Congo; Ethnicity; Female; Health Knowledge, Attitudes, Practice; Humans; Malaria, Falciparum; Male; Patient Compliance; Phenanthrenes; Surveys and Questionnaires

Topics: Antimalarials; Child; Heart; Humans; Malaria, Falciparum; Phenanthrenes

Drug resistance in Plasmodium falciparum is an expanding problem in most endemic areas. Recent studies have suggested the potential involvement of genes in the MDR gene family in resistance to quinoline-containing compounds in P. falciparum. In this study a molecular analysis of pfmdr 1 in recent isolates from Thailand was done (1) to further examine the role of pfmdr 1 in drug-resistant isolates and (2) to examine the reported association of pfmdr 1 intragenic alleles and chloroquine resistance. Most of the isolates (10 of 11) were resistant to all compounds tested. Analysis of pfmdr 1 revealed an apparent association between increased gene copy number and increased level of expression of pfmdr 1 and decreased susceptibility to mefloquine and halofantrine. Sequence analysis of pfmdr 1 in these isolates revealed no association of intragenic alleles with chloroquine resistance.

Topics: Animals; Antimalarials; Base Sequence; DNA, Protozoan; Drug Resistance; Gene Amplification; Genes, Protozoan; Humans; Malaria, Falciparum; Mefloquine; Molecular Sequence Data; Phenanthrenes; Plasmodium falciparum; RNA, Messenger; RNA, Protozoan; Thailand

Currently, most of the subjects presenting with Plasmodium falciparum malaria in France come from areas where chloroquine resistance has already been reported. Treatment of uncomplicated malaria should consist of oral administration of either quinine or mefloquine or halofantrine. In children, halofantrine seems to be the treatment of choice at any age. The prognosis of cerebral malaria depends on how fast the diagnosis is made and the treatment is undertaken. The detection of clinical and biological risk factors is crucial. The treatment of cerebral malaria is based on quinine perfusion administered according to pharmacokinetic data.

Topics: Antimalarials; Child; Chloroquine; France; Humans; Malaria, Cerebral; Malaria, Falciparum; Mefloquine; Phenanthrenes; Quinine

Malaria treatment of children is particularly difficult because of the absence of palatable suspensions for young children. Halofantrine hydrochloride is available as a suspension which is both palatable and simple to administer, and has been studied in a number of trials in the past 5 years. Children (331) ranging from 4 months to 17 years of age (mean 4.7 years) were treated with the 5% suspension using various dose regimens and 364 children ranging from 4 months to 14 years of age (mean 5.7 years) were treated with the 2% suspension 6 hourly for 3 doses. Using the 3-dose regimen there were only 2/462 (0.4%) who failed to clear the initial parasitaemia. Recrudescence occurred in 28/367 (7.6%) children with evaluable follow up data. The mean parasite clearance time in this group was 57.1 h (n = 417) and the mean fever clearance time was 50.9 h (n = 325). Symptoms related to malaria cleared rapidly following treatment generally by 24-48 h post treatment. Side effects possibly related to treatment were uncommon but were similar to those reported in adults. The frequency of diarrhoea and abdominal pain was lower than that seen in adults and was also less frequent following multiple doses and the use of the more dilute suspension. Since there was evidence that the majority of recrudescences were seen in younger children or those living in areas with low or seasonal transmission it is recommended that a further course of treatment 7 days later is given to these patients to prevent recrudescence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Antimalarials; Child; Child, Preschool; Drug Evaluation; Female; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Patient Acceptance of Health Care; Phenanthrenes; Recurrence; Safety; Suspensions; Treatment Outcome

Topics: Acute Disease; Adolescent; Animals; Antimalarials; Blackwater Fever; Blood; Central African Republic; Hemolysis; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Plasmodium falciparum; Renal Dialysis

The in vitro activity of halofantrine was studied in chloroquine-susceptible and chloroquine-resistant African clones of Plasmodium falciparum over a period of six months. The susceptibility level remained stable in both clones. The chloroquine-susceptible clone (50% inhibitory concentration [IC50] 6.88 nM) was less susceptible to halofantrine than the chloroquine-resistant clone (IC50 2.98 nM). Using an isotopic semimicro drug susceptibility test, the in vitro activity of halofantrine was compared with the activities of chloroquine, quinine, and mefloquine to study the cross-resistance patterns against 76 African isolates of P. falciparum isolated from cases of malaria imported into France. Chloroquine-resistant isolates (n = 47) were significantly less susceptible to quinine (IC50 234 nM), but were more susceptible to both mefloquine (IC50 3.20 nM) and halofantrine (IC50 1.14 nM) compared with the chloroquine-susceptible isolates (n = 29; IC50 147 nM for quinine, 7.16 nM for mefloquine, and 2.62 nM for halofantrine). A significant positive correlation was found between the activities of chloroquine and quinine and between those of mefloquine and halofantrine, indicating cross-resistance between these drugs, while a negative correlation was observed between chloroquine and mefloquine or halofantrine. The responses to quinine and mefloquine or halofantrine showed no correlation with each other. These results reinforce the importance of a cautious use of antimalarial drugs in Africa.

Topics: Africa; Animals; Antimalarials; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Phenanthrenes; Plasmodium falciparum

In order to evaluate the predictive value of parasitaemia, this parameter was measured on admission in 69 Gabonese children aged from 3 to 13 years hospitalized for Plasmodium falciparum malarial attacks. Fourteen of these children had cerebral malaria, 5 had isolated convulsions and 50 had uncomplicated attacks. The parasitaemia values measured were compared with those found in asymptomatic children of the same age range carrying trophozoites. There were no significant differences in mean parasitaemia count between the 3 types of malarial attack, and only the asymptomatic carriers had significantly lower counts. However, the wide scattering of individual values within each group indicated that simple measurement of parasitaemia is not discriminative enough to predict the course of malarial attacks in children living in endemic regions. In particular, malarial attacks with very low or very high parasitaemia value are possible, but similar values are found in asymptomatic carriers.

Topics: Adolescent; Antimalarials; Carrier State; Child; Child, Preschool; Gabon; Humans; Malaria, Falciparum; Phenanthrenes; Quinine; Seizures, Febrile

From simplified in vivo tests, authors set up a cartography of the sensitivity of Plasmodium falciparum to amino-4-quinolines in Cameroon; they also evaluated the clinical and parasitological efficacy of different therapeutic protocols which make use of amino-4-quinolines, quinine, mefloquine and halofantrine. All these drugs are administered orally. They recommend maintaining home medication with chloroquine at the dose of 25 mg/kg over 3 days, conserving quinine for use in the case of a possible failure. The use of most recent antimalarials can be proposed only as a last resort.

Topics: Administration, Oral; Aminoquinolines; Amodiaquine; Animals; Antimalarials; Cameroon; Child; Child, Preschool; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine

Mefloquine was introduced into Thailand in 1985 for the treatment of Plasmodium falciparum infection. Recently, clinical failure of mefloquine was observed in southeastern Thailand, where an epidemic of falciparum malaria occurred. Beginning in 1984 and continuing until 1989, in vitro monitoring of P. falciparum isolates from Borai, a border district in the southeastern part of the country, showed a progressive decrease in mefloquine sensitivity until 1989; in 1990, the degree and prevalence of resistance accelerated. A similar pattern of resistance was observed for halofantrine, an antimalarial drug not yet commercially available in Thailand. In vitro sensitivity patterns of mefloquine and halofantrine elsewhere in the country remained relatively unchanged. These observations suggest a serious deterioration in available drugs for the treatment of falciparum malaria in southeastern Thailand that is predicted to spread throughout the country and Southeast Asia.

Topics: Animals; Antimalarials; Drug Resistance; Humans; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum; Regression Analysis; Thailand

A total of 47 nonimmune febrile patients from Pikine, Senegal, with greater than 1,000 Plasmodium falciparum asexual forms per microliter whole blood were given 12.5 mg per kg body weight of mefloquine in a single oral dose and were followed up daily until day 7 and also on day 14 of the study. Seven of the patients who vomited, four who had 4-aminoquinolines in their blood, and five dropouts were excluded. Fever and parasitaemia were suppressed within four days until day fourteen in 29 of the 31 remaining patients, including 10 with P. falciparum strains that had a low sensitivity to mefloquine. Two failures were due to poor absorption of mefloquine. The presence of P. falciparum strains with low in vitro susceptibility to mefloquine did not affect, within 14 days, the clinical and parasitological efficacy of a single oral dose mefloquine regimen in patients who had received no previous antimalarial treatment and who did not have partial immune protection.

Topics: Adolescent; Adult; Aminoquinolines; Animals; Antimalarials; Child; Child, Preschool; Chloroquine; Humans; In Vitro Techniques; Infant; Malaria, Falciparum; Mefloquine; Phenanthrenes; Plasmodium falciparum

A case of recrudescent falciparum malaria after halofantrine treatment is described. The patient contracted Plasmodium falciparum in Ivory Coast and was treated with halofantrine. Plasma levels of halofantrine and its metabolite were adequate. Thirty-one days after treatment, the patient was rehospitalized with symptoms of malaria. Recrudescence was confirmed by microscopic examination, indicating a type RI resistance to halofantrine. Mefloquine was given to treat recrudescent malaria. The parasite was susceptible to chloroquine and quinine in vitro but displayed elevated values of 50% inhibitory concentration for mefloquine and halofantrine. The case reminds us that chloroquine still has an important therapeutic role against African strains of P. falciparum and that mefloquine and halofantrine should be reserved for multi drug-resistant P. falciparum.

Topics: Animals; Antimalarials; Biological Availability; Chloroquine; Cote d'Ivoire; Drug Resistance; Follow-Up Studies; France; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Phenanthrenes; Plasmodium falciparum; Quinine; Recurrence; Travel

Halofantrine is a new blood schizontocidal drug used for the treatment of multidrug-resistant falciparum malaria. The pharmacokinetics of halofantrine (HAL) and its principal metabolite, N-desbutylhalofantrine (BHAL), was investigated in 6 adult male patients of Melanesian origin with uncomplicated falciparum malaria. The patients received 500 mg of halofantrine hydrochloride at times 0, 6 and 12 h (total 1.5 g). All patients responded to treatment with a mean parasite clearance time of 52.7 h and a mean fever clearance time of 33.8 h. The following kinetic parameters (mean values) were determined for HAL and BHAL, respectively: maximum plasma concentration (Cmax) = 896 and 491 ng.ml-1; time to reach the Cmax (tmax) = 15 and 56 h; elimination half-life (t1/2) = 91 and 79 h and the mean residence time (MRT) = 71 and 102 h. Based on the clinical response the plasma concentrations of HAL and BHAL were adequate for the treatment of uncomplicated falciparum malaria in the 6 patients.

Topics: Antimalarials; Chromatography, High Pressure Liquid; Drug Administration Schedule; Humans; Malaria, Falciparum; Melanesia; Phenanthrenes

The authors report the results of a valuation of paludometric indices during mai 1990 in Democratic São Tomé e Príncipe Republic (RDSTP). These investigations (parasitic index and spleen index) suggest that malaria is mesoendemic in these area. Plasmodium susceptibility to chloroquine at posology of 25 mg/kg per os was evaluated (WHO standard 7 days field test). Among 58 children, ranging from 5 to 11 years old, resistance at level R I was observed in 9% of cases, at level R II in 14%. Among 10 strains of P. falciparum, 9 were chloroquine resistant in vitro. 2 strains were also less sensible to quinine.

Topics: Age Factors; Animals; Antimalarials; Atlantic Islands; Child; Child, Preschool; Chloroquine; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Seasons; Sex Factors; Splenomegaly

Thai soldiers who became slide-positive for malaria while receiving mefloquine chemoprophylaxis were treated with halofantrine to study its efficacy against mefloquine-resistant falciparum malaria. Thirty-two patients received three doses of 500 mg (1,500 mg total) of halofantrine at six-hr intervals, and were then observed for four weeks. Parasite recrudescence following treatment (median 21 days) occurred in seven of 23 patients (30%) who had mefloquine serum concentrations indicative of regular prophylaxis (greater than 500 ng/ml). Serum concentrations of mefloquine in all 32 patients averaged 950 ng/ml (range 26-2,515) prior to halofantrine treatment. The halofantrine serum concentrations were higher in patients cured by halofantrine than in patients with drug failure, but this was not statistically significant. Patients who were cured by halofantrine had parasites that were more sensitive in in vitro testing to mefloquine (mean [inhibitory concentration] IC50 = 12.5 ng/ml) than in patients whose parasitemias recrudesced (mean IC50 = 23.8 ng/ml) (P less than 0.01, by Wilcoxon rank sum test). These observations suggest that the current formulation and regimen of halofantrine are not optimal for the treatment of multiple drug-resistant falciparum malaria from Thailand.

Topics: Animals; Antimalarials; Drug Resistance; Humans; Malaria, Falciparum; Mefloquine; Military Personnel; Phenanthrenes; Plasmodium falciparum; Recurrence; Thailand