phenanthrenes and Malaria

Topics: Antimalarials; Drug Industry; Financing, Government; Forecasting; Humans; Interprofessional Relations; Malaria; Mefloquine; Mental Disorders; Military Personnel; Phenanthrenes; Technology, Pharmaceutical; United States; United States Food and Drug Administration

Most available antimalarial drugs induce cardiac side effects. These side effects include various mild heart rate changes (amodiaquine) to excessive prolongation of the QT interval (halofantrine) which may lead to lethal arrhythmias such as Torsade de Pointes (TdP). The cellular mechanism of such events during antimalarial therapy is principally related to ion channel inhibition (e.g., human ether-a-go-go related gene channel) which may slow the repolarisation process and create a good substrate for arrhythmia (when dispersion of repolarisation is present). However, other antimalarial drugs do not show as potent cardiac side effects, like co-arthemeter and sulfadoxine-pyrimethamine. Considering that TdP are favoured by a complex combination of electrophysiological changes, a predictive cardiosafety strategy for new antimalarial drugs should comprise assays with an increasing level of information from ion channel level, cellular and organ level, to the whole organism. In this review, the actual knowledge on underlying mechanisms of QT prolongation and TdP is described, followed by the cardiac safety profiles of present antimalarial drugs.

Topics: Amodiaquine; Drug Approval; Electrophysiology; Humans; Long QT Syndrome; Malaria; Phenanthrenes; Risk Assessment; Risk Factors; Torsades de Pointes

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

To evaluate the safety and efficacy of the currently used antimalarial drugs in six African countries.. A meta-analysis.. The role of efficacy, safety and cost on the selection of antimalarial drugs.. The comparative efficacy study showed that amodiaquine (with > 90% cure rate) was superior to chloroquine and sulphadoxine-pyrimethamine at seven days schedule. The efficacy of amodiaquine was also observed to be comparable to that of mefloquine and halofantrine. The parasite clearance time (PCT) of these drugs ranged between two days and a week and the fever clearance time (FCT) was within 48 hours. The recrudescence rate at D14-D21 was found to be 12-17% in chloroquine and amodiaquine, while sulphadoxine-pyrimethamine showed a trend similar to halofantrine and mefloquine (0-12% recrudescence rate). Similarly, a big difference was also noted in the cost of the different antimalarial drugs. The pharmacokinetic data, however, showed that they are of similar profile, except in adverse features and contraindications, and values like their half-life (t1/2) where the long (t1/2) in drugs like sulphadoxine-pyrimethamine endows them with suppressive-cure feature, especially against recrudescent strains. Nevertheless, as these data are obtained from resident population in Africa, who however naive are exposed to few malaria challenges in their life, the results should not be directly extrapolated to total non immunes such as visitors from Europe.. The choice of alternative antimalarial drugs should be mainly based on their relative efficacy, safety and cost.. A meta-analysis study evaluating the efficacy and safety of chloroquine and alternative antimalarial drugs used in six African countries including Ethiopia, Kenya, Uganda, Cote D'Ivoire, Gambia and Nigeria is presented. Findings from the six countries showed a higher efficacy of amodiaquine and quinine (over 90%) in malaria treatment compared to chloroquine, which was found to be 70% or more effective. The efficacy of amodiaquine can also be compared to other antimalarial drugs such as mefloquine and halofantrine. Data showed that fever clearance time of these drugs was less than 2 days, but parasite clearance time ranged from 2.5 days to 1 week. Recrudescence rate also varied among the different drugs. This is a very important indicator in determining which drug can be used for prophylactic or suppressive treatment of malaria. Pharmacokinetic profile demonstrates that all these drugs have similar therapeutic effects, but differ in their adverse reactions, contraindications, and half-life. A significant difference was also noted in the cost of these antimalarial drugs; chloroquine was the cheapest, while halofantrine was the most expensive among the drugs. Based on these results, the study recommends that different aspects of antimalarial drugs have to be considered before deciding which drug is the best alternative treatment.

Topics: Africa, Eastern; Africa, Western; Amodiaquine; Antimalarials; Chloroquine; Drug Combinations; Drug Costs; Humans; Malaria; Mefloquine; Patient Selection; Phenanthrenes; Pyrimethamine; Quinine; Safety; Sulfadoxine; 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

Topics: Antimalarials; Clinical Protocols; Drug Administration Schedule; Drug Resistance; Humans; Malaria; Mefloquine; Phenanthrenes; Quinine

In recent years major advances have been made in the clinical pharmacology of many drugs used for the treatment of tropical diseases, particularly in the design and development of dosage regimens for the treatment of severe malaria. For example, by careful manipulation of its rate of administration, chloroquine has been shown to be well tolerated when used for treatment of severe disease caused by susceptible parasites. Similarly, important advances have been made in the rational design of quinine dosage regimens for patients in South East Asia and Africa. Investigation of the pharmacokinetics of mefloquine has drawn attention to the problems associated with its administration as combination therapy with pyrimethamine and sulfadoxine in Thailand. Similarly, evaluation of the pharmacokinetic properties of halofantrine has led to the demonstration that poor and erratic absorption could be just as likely to explain therapeutic failure as resistance of the parasite to effects of this drug. Disposition of the antimalarial biguanides has highlighted the role of host-related effects in the determination of drug response. For example, a small percentage of individuals are unable to convert proguanil (chloroguanide) to its active triazine metabolite, cycloguanil. Finally, agents that reverse chloroquine resistance are currently under development for the treatment of malaria. The importance of assessing the clinical pharmacokinetic properties of potential resistance reversers must be recognised. While limited success has been achieved in antifilarial chemotherapy, other parasitic diseases have been largely neglected with advances in the laboratory still awaiting full recognition of their clinical application. For example, clinical pharmacokinetic concepts may be used to improve the therapy of human hydatid disease. We believe that clinical management of tropical diseases can be improved by the application of clinical pharmacokinetic principles. However, this may not be universally advantageous. For example, the artemisinin (qinghaosu) derivatives are among the most recently developed antimalarials that have great therapeutic promise. Recent evidence suggests that pharmacokinetic data would be of limited value in the design and optimisation of dosage regimens because of its chemical reactivity and the unusual mechanism by which these drugs kill parasites. Similar limitations may apply to the microfilaricidal drug, ivermectin.

Topics: Chloroquine; Diethylcarbamazine; Drug Resistance; Echinococcosis; Filariasis; Humans; Malaria; Mefloquine; Pharmacokinetics; Phenanthrenes; Pyrimethamine; Quinine; Sulfadoxine; Tropical Medicine

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

Topics: Administration, Oral; Animals; Antimalarials; Drug Administration Schedule; Drug Evaluation; Half-Life; Humans; Malaria; Phenanthrenes; Plasmodium falciparum

Topics: Animals; Antimalarials; Drug Resistance, Microbial; Folic Acid Antagonists; Humans; Malaria; Phenanthrenes; Plasmodium; Plasmodium falciparum; Plasmodium malariae; Plasmodium vivax; Pyrimethamine; Quinine; Quinolines; Sulfadiazine; Sulfisoxazole; Sulfonamides; Sulfones; Tetracycline

Topics: Amodiaquine; Antimalarials; Chloroquine; Drug Resistance, Microbial; Folic Acid Antagonists; Humans; Malaria; Methanol; Phenanthrenes; Plasmodium falciparum; Primaquine; Proguanil; Pyrimethamine; Quinolines; Research; Sulfadiazine; Sulfonamides; Sulfones; United States

Topics: Antimalarials; Child; France; Humans; Malaria; Phenanthrenes

Topics: Adolescent; Adult; Antimalarials; Drug Monitoring; Electrocardiography; Humans; Long QT Syndrome; Malaria; Male; Phenanthrenes; Prospective Studies

Topics: Antimalarials; Child; Child, Preschool; Female; Humans; Infant; Malaria; Male; Phenanthrenes

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

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

The incidence and nature of pruritus induced by chloroquine and halofantrine were studied in 82 patients with acute malaria and in 40 healthy subjects, using a visual analogue scale for quantitating pruritus. Results showed that the proportion of patients with acute malaria manifesting itch to halofantrine was significantly lower than the proportion manifesting itch to chloroquine. Furthermore, the intensity and duration of halofantrine-induced pruritus were significantly lower than those of chloroquine-induced pruritus. The few patients who itched to halofantrine all had a history of itching to chloroquine. The incidence and intensity of chloroquine-induced pruritus were significantly higher in patients with malaria than in healthy subjects. By contrast, there was no significant difference between malaria patients and healthy subjects as regards halofantrine-induced pruritus. These results suggest that itchers to halofantrine may constitute a small group within the population of itchers to chloroquine. Malaria infection appears to enhance chloroquine-induced pruritus but not halofantrine-induced pruritus and this may be of therapeutic importance.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Chloroquine; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Kinetics; Malaria; Male; Middle Aged; Pain Measurement; Phenanthrenes; Pruritus

Halofantrine hydrochloride given to 46 Kenyan children with falciparum malaria at 10 mg/kg for two doses, and to 60 other children at 8 mg/kg for three doses, resulted in rapid parasite clearance, mean parasite clearance times being 45.4 h and 54.8 h, respectively. In-vitro chemosensitivity tests showed that most infections were due to chloroquine-resistant parasites, and that parasite maturation was inhibited by considerably lower concentrations of halofantrine than of chloroquine.

Topics: Administration, Oral; Adolescent; Animals; Antimalarials; Child; Child, Preschool; Chloroquine; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Drug Resistance; Female; Follow-Up Studies; Half-Life; Humans; Infant; Kenya; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Time Factors

Two clinical trials of the phenanthrene methanol compound halofantrine in the treatment of Plasmodium falciparum were conducted in Malawi, in areas where the parasite was known to be chloroquine resistant. In the first trial all 46 patients had symptoms of malaria and parasite densities ranging from 2500/microliter to 212,000/microliter. They were given a single dose of halofantrine hydrochloride, 16 mg/kg body weight. The recrudescence rate on day 14 of follow up was unacceptably high (38%). In the second trial the dose given was 8 mg/kg 6 hourly for three doses. Of the 49 children followed up for 14 days, 47 became aparasitaemic--ie, the cure rate was 96%. In both trials the drug was very well tolerated. Halofantrine hydrochloride seems to be effective against P falciparum chloroquine sensitive and resistant strains in Africa.

Topics: Administration, Oral; Adolescent; Animals; Antimalarials; Child; Child, Preschool; Chloroquine; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Female; Follow-Up Studies; Humans; Infant; Malaria; Malawi; Male; Phenanthrenes; Plasmodium falciparum; Recurrence; Time Factors

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

Topics: Adult; Antimalarials; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Humans; Malaria; Male; Mefloquine; Middle Aged; Phenanthrenes; Quinolines; Random Allocation

Topics: Adolescent; Adult; Antibodies; Antimalarials; Clinical Trials as Topic; Ethanolamines; Fever; Follow-Up Studies; Hematocrit; Humans; Kidney Function Tests; Leukocyte Count; Liver Function Tests; Malaria; Male; Middle Aged; Parasite Egg Count; Phenanthrenes; Plasmodium falciparum; Quinine; Thailand

More than 200 000 chemical compounds have been screened for antimalarial activity over the past 10 years by the US Army Antimalarial Drug Development Program. By means of extensive animal testing, 26 of these compounds were selected for clinical study in human subjects volunteering for such trials. Of these, 7 have received complete clinical trials and are in various stages of field evaluation, 4 are currently undergoing clinical trial, and 2 are still awaiting testing in volunteer subjects. Thus far, 2 compounds (WR 33 063 and WR 30 090) have demonstrated greater activity against drug-resistant Plasmodium falciparum than any other known drug. Several other compounds presently being tested in human subjects are even more potent.

Topics: Amino Acids; Antimalarials; Clinical Trials as Topic; Drug Evaluation; Drug Resistance; Guanidines; Humans; Malaria; Naphthoquinones; Phenanthrenes; Plasmodium falciparum; Pteridines; Pyridines; Pyrimidines; Quinazolines; Quinolines; Sulfones; Triazines; Xylenes

WR 33063, a phenanthrene methanol, was studied in human volunteers for tolerance and toxicity. In normal volunteers, it was possible to give 4.6 g in four divided doses without adverse effect for 10 days. At this dose level, there was neither evidence of photosensitivity nor adverse renal or cardiac effect. At a dose level of 1.6 g in four divided doses for 6 days, WR 33063 cured 18 of 23 nonimmune volunteers infected with the Smith strain of Plasmodium falciparum from Vietnam. In addition, infections due to the Marks and Braithwaite Vietnam strains were also treated because these strains represent a major therapeutic challenge to chloroquine; six of six and two of three volunteers, respectively, were cured. With the Malayan Camp strain, 1.6 g in four divided doses for 6 days cured all of five volunteers. The African Uganda I strain of chloroquine-responsive malaria was even more responsive to WR 33063; all of six men who received 1.6 g in four divided doses for 6 days were cured, and all of three men who received this same dosage for 3 days were cured. One subject infected with a Haitian strain of P. falciparum was treated and cured. Blood-induced infections with the Chesson strain of P. vivax also responded well to WR 33063 with four of five men cured. In all, 52 men received WR 33063 in tolerance trials, and 59 men with experimental malaria and one man with clinical malaria were treated with WR 33063.

Topics: Antimalarials; Clinical Trials as Topic; Haiti; Humans; Indonesia; Malaria; Methanol; Methylamines; Phenanthrenes; Plasmodium falciparum; Uganda; Vietnam

In the present study, we have investigated the role of antimalarial drug halofantrine (HF) in inducing the sterile protection against challenges with sporozoites of the live infectious Plasmodium yoelii (Killick-Kendrick, 1967) in Swiss mice malaria model. We observed that during the first to third sequential sporozoite inoculation cycles, blood-stage patency remains the same in the control and chemoprophylaxis under HF drug cover (CPS-HF) groups. However, a delayed blood-stage infection was observed during the fourth and fifth sporozoite challenges and complete sterile protection was produced following the sixth sporozoite challenge in CPS-HF mice. We also noticed a steady decline in liver stage parasite load after 3th to 6th sporozoite challenge cycle in CPS-HF mice. CPS-HF immunisation results in a significant up-regulation of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-12 and iNOS) and down-regulation of anti-inflammatory cytokines (IL-10 and TGF-β) mRNA expression in hepatic mononuclear cells (HMNC) and spleen cells in the immunised CPS-HF mice (after 6th sporozoite challenge) compared to control. Overall, our study suggests that the repetitive sporozoite inoculation under HF drug treatment develops a strong immune response that confers protection against subsequent challenges with sporozoites of P. yoelii.

Topics: Animals; Chemoprevention; Immunization; Malaria; Mice; Mice, Inbred BALB C; Pharmaceutical Preparations; Phenanthrenes; Plasmodium yoelii

Structural optimization of 3-hydroxy-N'-arylidenepropanehydrazonamides provided new analogs with nanomolar to subnanomolar antiplasmodial activity against asexual blood stages of Plasmodium falciparum, excellent parasite selectivity, and nanomolar activity against the earliest forms of gametocyte development. Particularly, derivatives with a 1,3-dihalo-6-trifluoromethylphenanthrene moiety showed outstanding in vivo properties and demonstrated in part curative activity in the Plasmodium berghei mouse model when administered perorally.

Topics: Amides; Animals; Antimalarials; Hep G2 Cells; Humans; Hydrazones; Malaria; Mice; Phenanthrenes; Plasmodium berghei; Stereoisomerism; Structure-Activity Relationship

3-Hydroxy-N'-arylidenepropanehydrazonamides represent a new class of antiplasmodial compounds. The two most active phenanthrene-based derivatives showed potent in vitro antiplasmodial activity against the 3D7 (sensitive) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum with nanomolar IC50 values in the range of 8-28 nM. Further studies revealed that the most promising derivative, bearing a 4-fluorobenzylidene moiety, demonstrated in vivo antiplasmodial activity after oral administration in a P. berghei malaria model, although no complete parasite elimination was achieved with a four-dose regimen. The in vivo efficacy correlated well with the plasma concentration levels, and no acute toxicity symptoms (e.g., death or changes in general behavior or physiological activities) were observed, which is in agreement with a >1000-fold lower activity against L6 cells, a primary cell line derived from mammalian (rat) skeletal myoblasts. This indicates that lead compound 29 displays selective activity against P. falciparum. Moreover, both phenanthrene-based derivatives were active against stage IV/V gametocytes of P. falciparum in vitro.

Topics: Animals; Antimalarials; Chloroquine; Malaria; Mice; Parasitemia; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium berghei; Plasmodium falciparum; Rats; Structure-Activity Relationship

A dichloromethane extract of the stem bark of Cryptocarya nigra showed strong in vitro inhibition of Plasmodium falciparum growth, with an IC50 value of 2.82 μg/mL. The phytochemical study of this extract has led to the isolation and characterization of four known alkaloids: (+)-N-methylisococlaurine (1), atherosperminine (2), 2-hydroxyathersperminine (3), and noratherosperminine (4). Structural elucidation of all alkaloids was accomplished by means of high field 1D- and 2D-NMR, IR, UV and LCMS spectral data. The isolated extract constituents (+)-N-methylisococlaurine (1), atherosperminine (2) and 2-hydroxy-atherosperminine (3) showed strong antiplasmodial activity, with IC50 values of 5.40, 5.80 and 0.75 μM, respectively. In addition, (+)-N-methylisocolaurine (1) and atherosperminine (2) showed high antioxidant activity in a DPPH assay with IC50 values of 29.56 ug/mL and 54.53 ug/mL respectively. Compounds 1 and 2 also both showed high antioxidant activity in the FRAP assay, with percentages of 78.54 and 70.66 respectively and in the metal chelating assay, with IC50 values of 50.08 ug/mL and 42.87 ug/mL, respectively.

Topics: Alkaloids; Antimalarials; Cryptocarya; Humans; Isoquinolines; Magnetic Resonance Spectroscopy; Malaria; Molecular Structure; Phenanthrenes; Plant Bark; Plant Extracts; Plasmodium falciparum

In malarial endemic countries especially in the tropics, conventional antimalarial drugs are used with herbal remedies either concurrently or successively. Khaya grandifoliola is one of such popular herbs used in the treatment of malaria.Various doses of ethanol extract of K. grandifoliola stem bark (50-400 mg/kg/day) were administered orally to Swiss albino mice infected with Plasmodium yoelii nigerense. A dose of 100 mg/kg/day of the extract was also combined with 2.5 mg/kg/day of chloroquine or 6.25 mg/kg/day of halofantrine in both early and established malaria infection test models. The results showed that in the early malaria infection test, K. grandifoliola in combination with chloroquine or halofantrine elicited enhanced antiplasmodial effect in the established infection, there was significantly greater parasite clearance following administration of the combination when compared to the effects of K. grandifoliola or the conventional drugs alone. The mean survival period of parasitized animals was also enhanced by the extract/halofantrine combination. Lower therapeutic doses of halofantrine may be required to potentiate parasite clearance when used in combination with K. grandifoliola. This may constitute great advantage to halofantrine which is associated with cardiotoxicity at high doses.

Topics: Administration, Oral; Animals; Antimalarials; Chloroquine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Malaria; Meliaceae; Mice; Nigeria; Phenanthrenes; Plant Bark; Plant Extracts; Plasmodium yoelii; Treatment Outcome

The main objective of the present study was to evaluate the reduction in halofantrine (Hf) toxicity, an antimalarial drug frequently associated with QT interval prolongation in electrocardiogram, by its entrapment in poly-epsilon-caprolactone nanocapsules (NC). The acute lethal dose (LD(100)) of Hf.HCl experimentally observed was 200 mg/kg whereas the calculated LD(50) was 154 mg/kg. In contrast, the LD(100) for Hf-NC was 300 mg/kg with a longer mean time to death than Hf.HCl. The calculated LD(50) was 249 mg/kg for Hf-NC. The Hf entrapped in PCL NC presented a greater efficacy than PLA-PEG NC and than Hf solution in P. berghei-infected mice at 1 mg/kg. The cardiovascular parameters, ECG and arterial blood pressure, were evaluated in anaesthetized Wistar rats after the IV administration of a single, especially high dose (100 and 150 mg/kg) of halofantrine base loaded-nanocapsules (Hf-NC) or halofantrine chlorhydrate (Hf.HCl) solution. It was observed that Hf solution caused prolongation of the QT and PR intervals of the ECG; however, this effect was significantly (P<0.001) reduced when Hf was administered entrapped in nanocapsules. The treatment with Hf.HCl induced a pronounced bradycardia and severe hypotension leading to death. The effect of Hf-NC upon heart rate was reduced from 58 to 75% for 100 and 150 mg/kg, respectively, when compared with Hf.HCl solution. These findings show that the encapsulation of halofantrine reduces the QT interval prolongation of ECG in rats and suggest that a modification of drug distribution was possible by using nanocapsules. Hf encapsulation was the main factor responsible for the significant reduction in cardiac toxicity observed.

Topics: Animals; Antimalarials; Bradycardia; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart; Hypotension; Lethal Dose 50; Long QT Syndrome; Malaria; Male; Mice; Nanocapsules; Phenanthrenes; Plasmodium berghei; Rats; Rats, Wistar

Topics: Antimalarials; Humans; Malaria; Mefloquine; Mental Disorders; Phenanthrenes; Randomized Controlled Trials as Topic; Time Factors

Topics: Antimalarials; Child; Child, Preschool; Hemolysis; Humans; Malaria; Male; Nigeria; Phenanthrenes; Risk Factors

The efficacy and pharmacokinetics of a new parenteral formulation of halofantrine were studied in mice infected with Plasmodium berghei. The formulation consisted of nanocapsules with an oily core, prepared from either poly(D,L-lactide) (PLA) homopolymer or PLA that was surface modified with grafted polyethylene glycol chains. They were compared with a previously described intravenous halofantrine preparation. No toxic effects were observed with halofantrine in form of nanocapsules after intravenous administration for doses of up to 100 mg/kg, whereas the solubilized form in polyethylene glycol-dimethylacetamide was toxic at this dose. The halofantrine-loaded nanocapsules showed activity that was similar to or better than that of the solution in the 4-day test and as a single dose in severely infected mice, with only minimal differences between the two nanocapsule formulations. Halofantrine pharmacokinetics were determined in parallel with parasite development in severely infected mice. Nanocapsules increased the area under the curve for halofantrine in plasma more than sixfold compared with the solution throughout the experimental period of 70 h. Furthermore, nanocapsules induced a significantly faster control of parasite development than the solution in the first 48 h posttreatment. While the parasitemia fell more rapidly with PLA nanocapsules, the effect was more sustained with the surface-modified ones. This is consistent with surface-modified nanocapsules remaining longer in the circulation. These results suggest that nanocapsule formulations could provide a more favorable halofantrine profile in the plasma and reduce the intravenous dose necessary and therefore the toxicity, thus suggesting the use of halofantrine by a parenteral route in severe malaria.

Topics: Animals; Antimalarials; Area Under Curve; Biotransformation; Capsules; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Injections, Intravenous; Malaria; Mice; Phenanthrenes; Plasmodium berghei

The aim of the work was to develop a new submicronic delivery system that can be used with poorly water soluble drugs for which sustained circulating concentrations are necessary. This system consists of oily core surrounded by a shell made of a copolymer of poly (D,L-lactid) and poly (ethylene glycol). Covalent coupling between the hydrophylic poly (ethylene glycol) and poly (D,L lactid) and high molecular weight of the poly (ethylene glycol) chains yield long circulating particles after intra-venous administration in mice. Halofantrine, a very effective drug administrated for the treatment of severe malaria caused by Plasmodium, for which no injectable preparation exists. Results showed that percentage of loading, yield of encapsulation and physical stability were more favourable with surface modified nanocapsules. Release of halofantrine was clearly related to partition between oil and external medium. Serum proteins in the medium, increased halofantrine release from nanocapsules and poly (ethylene glycol) grafted nanocapsules reduced this phenomenum. The pharmacokinetics of the free drug was modified to maintain it in blood circulation. It is important to note that high plasma concentrations of halofantrine were correlated with higher activity against parasites in mice infected with Plasmodium berghei.

Topics: Animals; Antimalarials; Capsules; Chemical Phenomena; Chemistry, Physical; Drug Delivery Systems; Malaria; Mice; Phenanthrenes; Plasmodium berghei; Solubility

Eighty children were treated at the hospital Armand-Trousseau (Paris, France) for a malaria attack from 1999-01-01 to 2000-02-01.. The parasites were: Plasmodium falciparum: 87.5%, Plasmodium malariae: 12.6%, Plasmodium ovale: 10%, Plasmodium vivax: 6.3%. Mean age was 8.1 years (range: three months to 15 y). The origin of patients was: West Africa for 60 children, Central Africa for ten children and Comores for seven. Sixty-six patients suffered from common malaria attack and seven children were admitted with a presentation of severe malaria. The severe attacks were cerebral malaria for six cases, associated with severe anemia in five cases; the 7th child had a respiratory distress (ARDS) and died. The other six cases were cured without sequelae. Relapses were observed for eight patients: one after a severe cerebral malaria, six after a common P. falciparum attack, one after a P. ovale attack. Parasitemia was higher than in preceding years (mean 2.9%) and more than 5% in 11 cases, but without clear link with severity. Treatment by halofantrine with a single cure was followed by five relapses. None of those children received an effective prophylaxis during and after travel (55/80 without any prophylaxis).. These data emphasize the importance of a good appraisal of criteria of severe malaria and lead to advice hospitalization of children with malaria in temperate zone.

Topics: Adolescent; Antimalarials; Child; Child, Preschool; Emigration and Immigration; Female; Hospitalization; Humans; Incidence; Infant; Malaria; Male; Paris; Phenanthrenes; Recurrence; Retrospective Studies; Travel

Topics: Adult; Antimalarials; Cardiomyopathy, Hypertrophic; Contraindications; Death, Sudden, Cardiac; Humans; Long QT Syndrome; Malaria; Male; Mefloquine; Phenanthrenes; Togo; Travel

To determine the importance of prolonged QT interval and electrocardiographic changes in children treated with halofantrin for an acute malaria attack.. Out of 25 children treated with halofantrin, nine had an increase of QTc interval < 440 ms and ten a QTc > 440 ms on control 24 h after the first dose. A 9-year-old girl, treated with halofantrin, had bradycardia and increase of QTc interval for six days, with a normal halofantrin blood level.. These data show that cardiac monitoring during halofantrin treatment is mandatory in children as in adults. Contraindications of halofantrin treatment must be respected, particularly a long congenital QT interval.

Topics: Adolescent; Antimalarials; Bradycardia; Child; Child, Preschool; Electrocardiography; Female; Humans; Infant; Long QT Syndrome; Malaria; Male; Phenanthrenes

Suspected tropical malaria is an acute emergency. Immediate effective pharmacological treatment is of the essence. As in the case of prevention, various antimalarials are now available for treatment. Complicated tropical malaria requires treatment in hospital and intensive monitoring. The risk of infection and serious illness leading to a fatal outcome can be considerably reduced by suitable chemoprophylaxis or the use of stand-by medication for self-treatment, which, however, must be matched to resistance zones and the incidence of the four species of Plasmodium, in particular Plasmodium falciparum.

Topics: Adolescent; Adult; Animals; Antimalarials; Child; Child, Preschool; Emergencies; Humans; Infant; Malaria; Phenanthrenes; Plasmodium falciparum; Quinine; Travel; Tropical Climate

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

We describe a direct liquid chromatographic method with spectrofluorimetric detection to quantify the two enantiomers of halofantrine and the two enantiomers of its main chiral N-monodesbutylated metabolite in erythrocyte pellets. The method involves a Chiralpak AD column and a rapid one-step extraction procedure with acetonitrile. The method was validated for the four enantiomers within the range 0-1000 ng/ml. The absence of stereoconversion was studied in samples stored frozen for up to eight months. The optical rotation of the halofantrine and metabolite enantiomers was determined after separation on a semi-preparative Chiralcel OD column with polarimetric detection.

Topics: Administration, Oral; Antimalarials; Chromatography, Liquid; Erythrocytes; Humans; Malaria; Phenanthrenes; Reproducibility of Results; Stereoisomerism

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

Fenozan B07, a 1,2,4-trioxane endoperoxide with potent blood schizontocidal activity against drug-sensitive and drug-resistant rodent malaria parasites, exerted a modest potentiating action when administered with chloroquine (CQ) to mice infected with parasites of the CQ-resistant P. yoelii ssp. NS, but not when given to mice infected with the CQ-sensitive P. berghei N strain. The reason why this potentiation may be of particular value in the treatment of severe falciparum malaria is discussed. Mefloquine and halofantrine displayed a similar level of potentiation with Fenozan B07 against the CQ-resistant parasites. However, antagonism was shown by combinations of Fenozan B07 with pyronaridine or the 8-aminoquinoline WR 238 605 when used against CQ-resistant parasites. Mefloquine with Fenozan B07 is also antagonistic against a highly mefloquine-resistant line of P. yoelii ssp. NS. The reasons behind such antagonism are not known. The importance is stressed of using carefully selected drug combinations of novel antimalarials, rather than single drugs, in order to impede the selection of drug-resistant parasites, but only after adequate, preclinical, toxicity testing.

Topics: Aminoquinolines; Animals; Antimalarials; Chloroquine; Drug Antagonism; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Malaria; Mefloquine; Mice; Naphthyridines; Parasitemia; Phenanthrenes; Phenylpropionates; Plasmodium berghei; Plasmodium yoelii

Topics: Adult; Antimalarials; Fatal Outcome; Humans; Malaria; Male; Middle Aged; Phenanthrenes

Biological variations of 5'nucleotidase (5'NU) and alkaline phosphatase (AP) in 102 Gabonese children with malaria features (MF) and malaria infection (MI) receiving treatment are reported. [formula: see text] During the therapeutic assay, 5'NU rate decreases faster than AP'S; Fourteen days after the beginning of treatment, difference between AP MF and AP M1 is still significant. Enzymes decrease is an indication of the malaria drugs tolerance (MSP (*)).

Topics: 5'-Nucleotidase; Alkaline Phosphatase; Antimalarials; Child; Child, Preschool; Drug Combinations; Gabon; Humans; Infant; Malaria; Mefloquine; Phenanthrenes; Pyrimethamine; Reference Values; Sulfadoxine

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

Topics: Administration, Oral; Antimalarials; Humans; Malaria; Phenanthrenes

Topics: Antimalarials; Blood Coagulation Disorders; Humans; Liver Diseases; Malaria; Phenanthrenes; Serum Albumin

The plasma concentrations of the enantiomers of halofantrine and its N-desbutyl metabolite in six patients with malaria were measured after oral administration of 3 x 750 mg doses of micronised, racemic halofantrine hydrochloride given at 6-hour intervals. Significant differences were observed between the plasma concentrations of the enantiomers both of halofantrine and its N-monodesbutyl metabolite. AUC(0)84h values were higher for (+)halofantrine (9917 micrograms.ml-1.h) than for (-)-halofantrine (6127 micrograms.ml-1.h). The clinical significance of these observations is not known. The isomers have equipotent activity in vitro but their relative toxicity has not yet been assessed.

Topics: Adult; Antimalarials; Humans; Malaria; Middle Aged; Phenanthrenes; Stereoisomerism

Topics: Antimalarials; Arrhythmias, Cardiac; Humans; Malaria; Phenanthrenes; Self Medication

Topics: Antimalarials; Appendicitis; Diagnostic Errors; Humans; Malaria; Male; Netherlands; Papua New Guinea; Phenanthrenes; Self Administration; Travel

Topics: Antimalarials; Humans; Malaria; Phenanthrenes

Topics: Antimalarials; Contraindications; Humans; Malaria; Phenanthrenes

Fifty patients suffering from acute malaria were treated with 'Halofantrine Hydrochloride'. They were observed for 4 weeks. Clinical, haematological and biochemical parameters were assessed for evaluation of halofantrine in acute malaria, with special reference to its effectiveness, tolerability and side effects.

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

Topics: Antimalarials; Female; Humans; Malaria; Male; Middle Aged; Phenanthrenes; Travel

Topics: Antimalarials; Appendicitis; Diagnosis, Differential; Fever; Humans; Malaria; Male; Middle Aged; Phenanthrenes

Topics: Animals; Antimalarials; Culicidae; Humans; Insect Bites and Stings; Malaria; Phenanthrenes

Topics: Animals; Antimalarials; Chloroquine; Drug Resistance; Forecasting; Humans; Malaria; Mosquito Control; Phenanthrenes; Plasmodium; Protozoan Vaccines

Topics: Aminoquinolines; Amodiaquine; Antimalarials; Artemisinins; Calcium Channel Blockers; Chloroquine; Humans; Malaria; Mefloquine; Naphthoquinones; Phenanthrenes; Primaquine; Quinine; Sesquiterpenes; Sulfadoxine

Thirty two children with symptomatic malaria due to P. vivax and P. Falciparum infections were treated with three doses of Halofantrine hydrochloride 8 mg/kg body weight every 6 hours. Mean fever clearance was 30 hours (range 24-48 hours). No significant clinical or biochemical side effects were observed. Symptoms cleared rapidly. Halofantrine hydrochloride was found to be highly effective and appeared to have no side effects in children with acute malaria infections.

Topics: Acute Disease; Animals; Antimalarials; Child; Child, Preschool; Female; Humans; Infant; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Plasmodium vivax; Safety

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

Twelve patients with acute uncomplicated falciparum malaria were admitted to the Hospital for Tropical Diseases for 42 days. The patients were treated with halofantrine 500 mg 6 hourly for three doses and halofantrine and its desbutyl metabolite were analysed in plasma by h.p.l.c. Cmax values of halofantrine and desbutylhalofantrine (n = 12) were 1192 +/- 410 (mean +/- s.d.) and 397 +/- 160 ng ml-1 with tmax values of 16 +/- 2 and 55 +/- 26 h, respectively. AUC was 60.6 +/- 23.9 and 48.5 +/- 22.2 mg l-1 h, respectively, for halofantrine and its metabolite. Halofantrine cured 83% of the patients but in two patients a reduction only in asexual parasitaemia was seen and no overall parasite clearance occurred. One of these, however had relatively low plasma concentrations of both halofantrine and its desbutyl metabolite and it appeared to be a case of inadequate treatment rather than true resistance. We suggest that the large intersubject variability in plasma drug concentrations may relate in part to its poor and inconsistent bioavailability and this rather than true resistance might be responsible for some of the treatment failures.

Topics: Acute Disease; Adolescent; Adult; Animals; Antimalarials; Humans; Malaria; Middle Aged; Phenanthrenes; Plasmodium falciparum

A rapid, accurate, and sensitive high-performance liquid chromatographic (HPLC) method, with ultraviolet detection, for simultaneous measurement of halofantrine (HAL) and desbutylhalofantrine (BHAL) in human serum is described. Sample preparation involved protein precipitation, followed by a solid-phase clean-up and a liquid-liquid extraction. Chromatographic separation was carried out on an Ultrasphere C8 column (25 cm x 4.6 mm I.D., 5 microns particle size) using a mobile phase of acetonitrile:water, 75:25, (vol/vol), with 0.2% (w/vol) sodium dodecyl sulfate and 0.2% (vol/vol) glacial acetic acid. The serum sample volume used was 0.5 ml, with concentrations normalized to 1 ml. Retention times for BHAL, HAL, and the internal standard were 5.5, 8.3, and 11.5 min, respectively, with a total run time of 13.5 min. The average extraction recovery for HAL was 85.6% and 100.5% for BHAL. Inter- and intra-assay precisions of HAL and BHAL were less than or equal to 7.5%, with an accuracy of less than or equal to 10.8% over three concentrations (0.02, 0.5, 2.0 micrograms/ml). Detection limits of HAL and BHAL were 5 and 3 ng/ml, respectively. The new HPLC method resulted in cleaner chromatograms and a 1.7-fold faster run time than previous HPLC methods. Application of the method with clinical specimens was demonstrated.

Topics: Antimalarials; Chromatography, High Pressure Liquid; Humans; Malaria; Phenanthrenes; Ultraviolet Rays

Topics: Adult; Africa, Western; Animals; Antimalarials; Drug Resistance; Humans; In Vitro Techniques; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Recurrence; Travel

Topics: Africa, Central; Animals; Antimalarials; Humans; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Travel

Topics: Adult; Animals; Antimalarials; Drug Resistance; Humans; Malaria; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum

In 1989 there were 71 cases of imported malaria admitted to the hospital in Bordeaux. This is 16.5% and 29% lower than in 1988 and 1987 respectively, thanks to the widespread use in Africa of mefloquine chemoprophylaxis. Sub-Saharan Africa is involved in 95% of cases, mainly West Africa (70% of cases), unlike the situation in 1987, and the first cases of paludism despite mefloquine chemoprophylaxis appeared during the second semester from the seasonal mid-summer recrudescence onwards, in travellers returning from this region. The most frequent species is still Plasmodium falciparum (80% of declared cases). This imported disease especially affects young adults despite regular prophylaxis in 59% of cases. It is therefore important to recommend rigorous protection against anopheles. Male predominance (sex ratio: 5.5) was greater in 1989 than in the previous two years, and French nationals represented 85% of the population. Falciparum malaria presents symptoms in 95% of cases before the end of the month following the patient's return to France, while for P. ovale the time for symptoms to appear is between 39 days and two years after return. Management of patients on their return poses a problem of information, since in 40% of cases diagnosis is made more than a week after the first symptoms. Attacks are mild in most cases (93%); among the serious cases death occurred in a 3-year-old child. Thrombopenia is the most frequent biological sign (22.5% of cases), followed to a lesser degree by anaemia and leukopenia. Mild attacks respond well to classical treatment (halofantrine, mefloquine, quinine, chloroquine), while two cases of more complicated symptoms required exchange transfusion.

Topics: Animals; Antimalarials; Chloroquine; Female; France; Humans; Malaria; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine; Travel

59 cases of Plasmodium falciparum malaria fever occurring in non-immune Caucasian subjects having got a correct chemoprophylaxis by chloroquine were treated by halofantrine (HALFAN). They were given 1500 mg divided in 3 doses of 500 mg every 6 hours from D1 to D8. All them were back from a malarial highly endemic zone with chloroquine resistance. Analysis of the main biological and clinical efficiency parameters displayed very satisfactory results: disappearances of fever (mean 22 H) and parasitemia (mean 36 H) are short. After two months of monitoring, no malaria recrudescence was noted. With an efficacy of 10 p.c. associated to a noticeable clinical and biological tolerance Halofantrine is a first-class treatment of chloroquine resistant malaria fever.

Topics: Adolescent; Adult; Animals; Antimalarials; Chloroquine; Drug Resistance; Female; Humans; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Travel

Halofantrine hydrochloride (HF) belongs to a new class of antimalarials, the phenanthrene methanols. Preliminary clinical studies suggested that an adult dose of 500 mg 6-hourly for three doses, with a weight-based regimen of 8 mg/kg 6-hourly for three doses in children, would be effective. In an ongoing clinical programme, 1973 patients with acute malaria were analysed, of whom 1474 (1315 with P. falciparum and 122 with P. vivax malaria) received the above regimen. In the studies 931 adults and older children were treated (61 with capsules and 870 with tablets) while 520 infants and young children used 5% or 2% suspension. The majority of studies were performed in areas of high chloroquine or multidrug resistance. Only eight (0.6%) of 1282 evaluable patients with falciparum malaria failed to clear their parasitaemias within 7 days. Recrudescence of parasitaemia occurred in 77 patients (6.0%). Reinfection cannot be excluded in several of the cases, where protection from malaria transmission was not maintained. The majority of recrudescent patients were either non-immune (normally residing in malaria-free areas) or were infants below 2 years of age. In vivax malaria cases, there were six recrudescences (5.4%). The mean parasite clearance time was 57.9 h and the fever clearance time 50.2 h in falciparum malaria cases, while the clearance times for vivax cases were 57.3 h and 49.6 h respectively. Clinical events were uncommon and consisted of mild transient diarrhoea or abdominal pain in less than 5% of cases. Laboratory findings were generally abnormalities related to the acute disease rather than drug treatment. Experience to date would indicate that HF is a safe and useful drug for the treatment of acute malaria, particularly in areas where there is extensive resistance to current antimalarials.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Child; Child, Preschool; Evaluation Studies as Topic; Follow-Up Studies; Hematologic Tests; Humans; Infant; Liver Function Tests; Malaria; Male; Middle Aged; Phenanthrenes; Plasmodium falciparum; Plasmodium vivax

Topics: Animals; Drug Resistance, Microbial; Humans; Malaria; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinine

Malaria caused by P. falciparum occurred during prophylaxis with mefloquine upon return from Sierra Leone (zone II). A typical and not recognized, with negative results of initial hematological examinations. Diagnosed on D.26 with parasitemia of 0.2%. Successful treatment of clinical symptoms with halofantrine but increased anemia and positive parasitemia at D.7. Successful treatment with chloroquine. Chemosensitivity tests confirmed sensitivity to chloroquine, threshold sensitivity to quinine (IC50 = 297), resistance to mefloquine (IC50 = 76) despite high levels in bloods, and to halofantrine (IC50 = 7-laboratory normal value = 1). This cross-resistance of P. falciparum originating from Sierra Leone to mefloquine-halofantrine seems to be the first observation of this danger in Africa. Prescription of chloroquine is still imperative in zone 11 countries.

Topics: Adult; Animals; Antimalarials; Chloroquine; Cross Reactions; Drug Resistance; Humans; Malaria; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum

54 children (mean age: 43 months), with initial parasitemia up to 1,000 Plasmodium falciparum isolates per mm3, were treated with halofantrine hydrochloride 8 mg/kg twice daily at 6 hours intervals. 35 of these 54 children had received unsuccessful chloroquine and/or quinine treatment during 15 days before admission to the trial. Fever, which was observed in 52 of the children, and parasitemia disappeared respectively 18 hours and 37 hours after initial administration of the drug (mean values). Clinical and biological tolerance was excellent for all patients. Halofantrine is a new precious alternative for the treatment of malaria in regions with extensive multi-drug resistant strains of Plasmodium.

Topics: Animals; Antimalarials; Child; Child, Preschool; Democratic Republic of the Congo; Drug Resistance; Female; Humans; Infant; Malaria; Male; Phenanthrenes; Plasmodium falciparum

Topics: Adult; Animals; Antimalarials; Chloroquine; Drug Resistance; Female; Humans; Malaria; Phenanthrenes; Plasmodium falciparum; Sierra Leone

Twelve children, 2 to 15 years of age, with falciparum malaria (parasitaemia 4,500 to 170,000/mm3) have taken 24 mg/kg body weight of halofantrine hydrochloride (Halfan) per os in three divided doses given within 12 hours. The symptomatology improved after 24 to 48 hours, with no more fever 5 to 90 hours after treatment and with a decrease of splenomegaly in 80% of the cases. The parasitic clearance was obtained after 24 to 60 hours. The haematocrit started raising again in 58% of the cases. Halofantrine hydrochloride is an efficient antimalarial drug in semi-immune patients. It is well tolerated and well accepted, thus representing an alternative for the cure of chloroquine-resistant falciparum malaria.

Topics: Adolescent; Animals; Antimalarials; Cameroon; Child; Child, Preschool; Female; Humans; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Rural Population

Halofantrine (WR 171.669) is a phenanthrene methanol derivative effective against the multidrug resistant strains of Plasmodium falciparum. One hundred and one patients, 48 men and 53 women, 53 adults and 48 children (less than or equal to 12 years old) aged from 1.5 to 57 years were treated. Fifty-one patients received a single 16 mg/kg dose and 50 patients received 24 mg/kg/day in 3 doses at 6-hour intervals. Parasite counts with examination of both thin and thick smears were performed twice daily for 5 to 6 days following treatment, or until smears were negative for parasites for 24 hours, and then weekly for 4 weeks. Thirteen patients reported clinical side effects. Six treated patients had no parasites. One patient had mixed parasitemia. Eighty three patients had P. falciparum malaria, with mean parasitemias between 26,850 +/- 36,679 and 35,412 +/- 50,527 per cubic millimeter. Halofantrine was very effective in the two doses tested from 87.5 to 100 p. 100. Eleven patients had in vivo resistant strains; ten in vitro tests were successful and nine were resistant to chloroquine. Thirteen patients with P. vivax and a mean parasitemia of 13,858 +/- 10,835 per cubic millimeter were cured but 3 had a relapse 3 to 4 weeks after treatment. At the 2 dosage levels tested halofantrine proved highly effective in the treatment of malaria caused by resistant and sensitive strains to P. falciparum.

Topics: Adolescent; Adult; Animals; Antimalarials; Child; Child, Preschool; Drug Resistance; Drug Tolerance; Female; French Guiana; Humans; Infant; Malaria; Male; Middle Aged; Phenanthrenes; Plasmodium falciparum; Plasmodium vivax

Prevention and treatment of malaria are endangered by the appearance of chemoresistance against the common anti-malarial drugs by Plasmodium falciparum. Today, only a quinoline derivative, mefloquine, is a safe and effective agent against P. falciparum. An in vitro antiplasmodial activity having been found for the quassinoid glaucarubinone we tested its in vivo therapeutic action on mice infected with a P. berghei strain. At low doses, glaucarubinone retarded mortality by exerting a partial, temporary, inhibition of parasitaemia; its toxicity, however, precludes, further applications at the present time.

Topics: Administration, Oral; Animals; Drug Evaluation, Preclinical; Female; Glaucarubin; Injections, Intraperitoneal; Malaria; Mice; Phenanthrenes; Plasmodium berghei

As a blood schizontocide, halofantrine is about three times as active against a drug-sensitive line of Plasmodium berghei (N strain) as chloroquine, but it lacks any causal prophylactic effect. This activity is retained against parasites highly resistant to primaquine, cycloguanil, pyrimethamine, sulphaphenazole and menoctone. A marked resistance to halofantrine is shown by parasites resistant to mefloquine, quinine, chloroquine and amodiaquine, although the moderately chloroquine-resistant 'NS line' is sensitive. The artemisinin-resistant line shows a moderately reduced response. A high level of resistance was rapidly developed in the 'NS line' to halofantrine (NS/HAL line) but not in the N strain (N/HAL). The NS/HAL line was cross-resistant to mefloquine, amodiaquine and, to a lesser degree, artemisinin, but remained sensitive to chloroquine and quinine. The implications to a lesser degree, artemisinin, but remained sensitive to chloroquine and quinine. The implications of these observations for the possible future clinical deployment of halofantrine are discussed, and emphasis is laid on the need to find means of impeding the resistance to it of Plasmodium falciparum.

Topics: Animals; Antimalarials; Drug Resistance; Malaria; Male; Mice; Phenanthrenes; Plasmodium berghei

Fourteen quassinoids, obtained from simaroubaceous plants, were tested for in vitro antimalarial activity. All of these inhibited the incorporation of [3H]hypoxanthine into Plasmodium falciparum in vitro at concentrations below 0.41 microgram ml-1. The two most potent quassinoids, bruceantin and simalikalactone D, showed 50% inhibitory concentration values of 0.0008 and 0.0009 microgram ml-1, respectively. The results are compared with the antiamoebic, antileukemic, and cytotoxic activities of these compounds reported in the literature.

Topics: Amebicides; Animals; Antimalarials; Cell Survival; Erythrocytes; Glaucarubin; Humans; In Vitro Techniques; Leukemia P388; Malaria; Phenanthrenes; Plant Extracts; Plants, Medicinal; Plasmodium falciparum

Halofantrine is a 9-phenanthrenemethanol which is effective against multi-drug resistant strains of Plasmodium falciparum. It has been shown to be highly effective and extremely well tolerated in the treatment of imported cases of falciparum malaria in France. A total of 1,500 mg administered in three 500 mg doses at six-hour intervals results in a 100% cure rate in semi-immune subjects. This dosage should be repeated after 14 days to obtain the same cure rate in non-immune patients. Minor clinical side effects included epigastric pains, nausea and, in one case, a skin rash.

Topics: Adult; Antimalarials; Female; France; Humans; Malaria; Male; Middle Aged; Phenanthrenes; Plasmodium falciparum

Antimalarial activity of chloroquine, quinine, mefloquine and halofantrine against 33 strains of P. falciparum isolated from naturally acquired malaria infections in Thailand was determined using a radioisotope microdilution method. A microtitration procedure was used to test isolates of P. falciparum against the 4 drugs simultaneously. The mean ID50 for chloroquine and quinine reflected known resistance to those drugs in Thailand. The mean ID50 for mefloquine and halofantrine showed susceptibility to these drugs. Four isolates of P. falciparum however had markedly decreased susceptibility to mefloquine (ID50 greater than 15 ng/ml); one case of which was confirmed as the first case of RII resistance for mefloquine in Thailand. Several parasite isolates were also observed to have decreased susceptibility to the new drug, halofantrine. These studies strongly recommend that in vitro testing be done in conjunction with field evaluation of new antimalarial drugs.

Topics: Adult; Animals; Antimalarials; Chloroquine; Drug Resistance, Microbial; Humans; Lethal Dose 50; Malaria; Male; Mefloquine; Microbial Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Quinine; Quinolines; Thailand

In a volunteer with infection induced by injection of the mefloquine-sensitive, multidrug-resistant Vietnam Smith isolate of P. falciparum, parasitemia recurred following treatment with the candidate antimalarial drug enpiroline. Parasitemia also recurred after subsequent treatment with mefloquine and again after retreatment with the same drug. All recurrences were at the RI level. Parasite drug sensitivities determined by a semi-automated isotope microdilution method after the second and third recurrences revealed a progressive decrease in sensitivity to all arylaminoalcohols tested (halofantrine, enpiroline, and mefloquine). Decreased sensitivity persisted after 30 days of isolate culture. The parallel changes in parasite sensitivity to the synthetic arylaminoalcohols argue for development of drugs which are chemically dissimilar.

Topics: Adult; Antimalarials; Chloroquine; Drug Resistance, Microbial; Humans; Malaria; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Pyridines; Quinine; Quinolines

The sensitivity level of Plasmodium falciparum isolates to chloroquine and the activity of six other antimalarials were studied in the different climatic zones of Madagascar in 1983. In vivo tests were done with 10 and 25 mg kg-1 of chloroquine and amodiaquine. Early recrudescence or RII resistance was observed after treatment with 10 mg kg-1 of these drugs in 34% of the cases for chloroquine and 6.5% for amodiaquine, and after the 25 mg kg-1 dose in 7% and 0% of the cases respectively. In vitro sensitivity of 84 P. falciparum isolates to seven drugs were studied with a semi-microtest. For chloroquine, 9% of the isolates had an IC50 above 250 nM, indicating resistance. In vitro activity of piperaquine was high for all isolates except two. In vitro activity of amodiaquine, dichlorquinazine, quinine, mefloquine and halofantrine was good against all isolates (maximum IC50 was 76, 92, 560, less than or equal to 20 and less than or equal to 12 nM, respectively). Correlation between the WHO standard field test and the in vitro semi-microtest was good. Resistance of P. falciparum to chloroquine was observed in the six survey areas, but the other tested drugs showed good activity. Since no cross-resistance to 4-aminoquinolines seems to exist in Madagascar, amodiaquine (the only one available at present) should be studied as an alternative to chloroquine in the prevention and treatment of falciparum malaria in this area.

Topics: Adolescent; Adult; Aged; Amodiaquine; Antimalarials; Child; Child, Preschool; Chloroquine; Humans; Infant; Madagascar; Malaria; Mefloquine; Microbial Sensitivity Tests; Middle Aged; Phenanthrenes; Piperazines; Plasmodium falciparum; Quinine; Quinolines

563 cases of Falciparum malaria were detected in 1984 and 1985 in 7 malarial zones covering 3 climatic regions in Madagascar. All subjects underwent a therapeutic test; 175 strains of Plasmodium falciparum were isolated for in vitro drug sensitivity studies. 28 strains which were moderately chloroquine resistant in vitro were identified in 1983 in these various zones. However, 16% strains studied in 1984 in Alatsinainy (plateaux area), were chloroquine-resistant in vitro. The in vitro sensitivity to the other amino-4-quinolines seemed to be retained. In vivo, 7% of resistance type RI or RII were noted with 25 mg/kg of chloroquine but none with 25 mg/kg of amodiaquine. The usual therapeutic schedule for partially immune subjects (10 mg/kg in one dose) was ineffective on day 7 in 34% of the cases with chloroquine and 5% of the cases with amodiaquine. In conclusion to this study, we recommend that chemoprophylaxis should be stopped in schools in Madagascar and that presumed malarial attacks should be treated with a minimum dose of 25 mg/kg of chloroquine in 3 days. We suggest that amodiaquine should be used in cases of therapeutic failure with chloroquine.

Topics: Aminoquinolines; Amodiaquine; Animals; Antimalarials; Chloroquine; Drug Resistance, Microbial; Humans; In Vitro Techniques; Madagascar; Malaria; Phenanthrenes; Piperazines; Plasmodium falciparum; Quinine; Quinolines

Resistance to mefloquine in Plasmodium falciparum has begun to occur along the border of Thailand and Kampuchea. As a means of assessing the natural occurrence of mefloquine resistance, the admission and post-treatment parasite isolates from a mefloquine treatment failure were cloned and characterized. Clones from the admission isolate were susceptible to mefloquine in vitro (ID50 of 3.4 [2-5], G [95% CI] ng/ml) and showed a mixture of isozyme types for glucose phosphate isomerase (GPI types I and II). The post-treatment clones were resistant to mefloquine in vitro (ID50 of 17.3 [13-23] ng/ml) with only one isozyme (GPI type I) detected. These observations suggest that under mefloquine pressure a resistant parasite population was selected in the patient, indicating that the potential for mefloquine resistance already exists in the indigenous P. falciparum gene pool. In addition, the mefloquine-resistant clones showed decreased susceptibility in vitro to halofantrine suggesting possible cross-resistance to this new antimalarial drug currently under development.

Topics: Adult; Animals; Antimalarials; Clone Cells; Drug Resistance; Glucose-6-Phosphate Isomerase; Humans; Isoenzymes; Malaria; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinolines; Thailand

Halofantrine is a 9-phenanthrene-methanol effective against multiresistant strains of Plasmodium falciparum. It is extremely effective and well-tolerated in treating cases of malaria imported into France. 1,500 mg in 3 doses at 8 hour intervals produced 100% cure rate in semi-immune patients. This dosage could be repeated after 14 days in order to obtain the same cure rate in non-immune patients. Side-effects are minor and include epigastric pain, nausea and one case of skin rash.

Topics: Adult; Africa, Western; Antimalarials; Female; France; Humans; Malaria; Male; Middle Aged; Phenanthrenes; Plasmodium falciparum; Travel

Analysis of the antimalarial activity of a selected series of 17 9-phenanthrenecarbinols against cultured strains of Plasmodium falciparum and against P. berghei in mice following oral administration indicated that the rankings of activities within the series were influenced by substituents on the 9-carbinol and the route of administration. Compounds with alkylamino-alkyl groups were ranked as most active by an in vitro screening system which assayed activity against chloroquine-sensitive and chloroquine-resistant strains of cultured P. falciparum by the inhibition of uptake of radiolabelled hypoxanthine. There were few differences in ranking of activities between the two strains. Although there was a significant difference between activities of an erythro- and a threo-racemate, activities of the four optical isomers of this compound were comparable. Among the series, compounds with a 2-piperidyl substituent on the 9-carbinol were ranked most active by the oral route of administration as assayed by the cure rates of mice infected with P. berghei. Correlation of these observations with previously published data on the activity of these compounds against P. falciparum in Owl monkeys and P. berghei in mice following subcutaneous administration suggested that neither species of host nor strains of parasite significantly influenced the ranking of activities of this class of compound.

Topics: Animals; Antimalarials; Female; Malaria; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Phenanthrenes; Plasmodium berghei; Plasmodium falciparum

Topics: Adult; Antimalarials; Drug Resistance, Microbial; Humans; Malaria; Male; Mefloquine; Phenanthrenes; Plasmodium falciparum; Quinolines; Thailand

Halofantrine (WR 171,669) was administered to 27 nonimmune subjects infected with the multi-drug resistant Vietnam Smith strain of Plasmodium falciparum. It was also administered to three other subjects, one infected with the Cambodian Buchanan strain of P. falciparum, and two with blood-induced infection with the Chesson strain of P. vivax. It cured infections with all three parasites. Against the highly chloroquine-resistant Smith strain, it was curative in single day treatment regimens. The drug was well tolerated and produced rapid clearance of parasitemia in every case.

Topics: Animals; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Humans; Malaria; Phenanthrenes; Plasmodium falciparum; Recurrence

A quantitative structure-activity relationship has been formulated for 646 antimalarials acting against P. berghei in mice. The equation developed has 14 terms, 9 of which are indicator variables. The correlation coefficient for the QSAR is 0.898 and the standard deviation is 0.309. The antimalarials are all arylcarbinols of the type X-ArCHOHCH2NR1R2. Sixty different aryl structures, including a variety of heterocyles, are contained in the study. The most important determinate of activity is found to be the electron-withdrawing ability of the substituents X; the hydrophobic character of X and R plays less important roles. Suggestions for more potent analogues are made and the lack of activity of about 100 additional analogues is also considered.

Topics: Animals; Antimalarials; Ethanolamines; Malaria; Mice; Models, Biological; Phenanthrenes; Plasmodium berghei; Pyridines; Quinolines; Structure-Activity Relationship

This report describes, illustrates, and validates the major features of a procedure designed to provide primary assessments of the activities of potential antimalarial drugs against infections with chloroquine-resistant or pyrimethamine-resistant strains of Plasmodium falciparum in owl monkeys of Colombian origin. Studies with 14 specially selected compounds have shown that the test method has the capacity to identify and quantify diverse levels of therapeutic efficacy among agents that differ widely in chemical structure. Extended studies with two of the above compounds indicate that such assessments have an acceptable level of reproducibility. Experiments with two other agents, structurally different from those in the selected group, have shown that the impacts of pyrimethamine resistance (or chloroquine resistance) on the activity of a compound can be readily identified during routine application of the test procedure, as can emergence of parasites resistant to the test agent. The above body of information can usually be acquired in infections with two strains of P. falciparum, one chloroquine-resistant, the other pyrimethamine-resistant, with commitments of no more than 1.5 g of test compound and 12 owl monkeys. These modest requirements have made it possible to utilize human plasmodial infections in the owl monkey in the search for new blood schizonticidal drugs more broadly effective than those currently available.

Topics: Animals; Antimalarials; Aotus trivirgatus; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance; Female; Guanidines; Haplorhini; Hydroxamic Acids; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Plasmodium vivax; Pyridines; Pyrimidines; Quinazolines; Quinolines; Sulfones; Triazines

Pilot appraisals of the activities of 16 specially selected 9-phenanthrenemethanols against acute infections with Plasmodium falciparum in owl monkeys showed that all were more active than the reference compound, WR-33,063. WR-122,455, the most active derivative, and WR-171,669, ranked sixth, were selected for study in human volunteers. To assist this undertaking, appraisals of both compounds in owl monkeys infected with various strains of P. falciparum were expanded. These assessments showed: (i) that WR-122,455 was four times as active as chloroquine against infections with chloroquine-sensitive strains and that WR-171,669 equalled chloroquine in activity; (ii) that these compounds were fully active against infections with strains resistant to chloroquine, pyrimethamine, or quinine, or to all three standard drugs; (iii) that the activity of WR-122,455 was a function of total dose, single doses being as effective as the same amounts delivered in three or seven daily fractions; and (iv) that a single dose of WR-122,455 conferred extended, although only partial, protection against challenges with trophozoites. Complementary experiments in rhesus monkeys inoculated with sporozoites of P. cynomolgi showed that the activity of WR-122,455 was limited to blood schizonts and did not extend to early or late tissue schizonts. These evaluations were compatible with the results of preliminary studies of the activities of WR-122,455 and WR-171,669 in human volunteers.

Topics: Animals; Antimalarials; Chloroquine; Haplorhini; Humans; Malaria; Phenanthrenes; Plasmodium falciparum; Pyrimethamine; Quinine

Topics: Animals; Antimalarials; Chloroquine; Cytoplasmic Granules; Erythrocytes; Female; Malaria; Mice; Phenanthrenes; Pigments, Biological; Piperidines; Plasmodium berghei; Quinine; Quinolines; Vacuoles

Nine di- and trisubstituted 9-phenanthrenemethanols bearing methylthio and methylfulfonyl substituents in the 2 and/or 6 positions of the phenanthrene nucleus were prepared and screened for antimalarial activity against Plasmodium berghei in mice. Six of the nine compounds were curative at or below 160 mg/kg. The most active structures contained a methylthio substituent in combination with two chlorine atoms.

Topics: Animals; Antimalarials; Malaria; Mice; Phenanthrenes; Plasmodium berghei; Sulfides; Sulfones

WR 122,455, 3,6-bis-(trifluoromethyl)-alpha-(2-piperidinyl)-9-phenanthrenemethanol HCl, suppresses infection with drug-sensitive Plasmodium berghei N strain in mice. It acts rapidly and affects all the stages of the asexual intraerythrocytic parasites, the effective dose levels being about three times those of chloroquine and one-twelfth to one-fifteenth those of quinine. Under the influence of WR 122,455 haemozoin seems to disappear from the affected parasites following an initial coarsening of the fine pigment granules. These changes are similar to those exerted by quinine. Large doses of WR 122,455 have a residual affect due in part, at least, to deposition of insoluble material in the tissues. The drug appears to exert an antagonistic action on chloroquine when both drugs are administered simultaneously. It has no causal prophylactic effect. In vitro WR 122,455 is a competitive antagonist of chloroquine in a similar manner to quinine, and appears to have a dissociation constant (Ki) of 2-26 x 10(-8) M, making it about 18 times as active as quinine. WR 122,455 interacts strongly with calf thymus DNA, but the mechanism of interaction has yet to be defined. Mice tolerate single doses of a saline/Tween 80 suspensions up to about 400 mg/kg but sc administration induces necrotic changes at the injection site. Up to 30 mg/kg daily po for seven consecutive days is well tolerated systemically but local tissue reaction may occur if the drug is given by the sc or ip routes. However, systemically up to 60 mg/kg is tolerated sc or ip. The relation of WR 122,455 to drug resistant malaria will be reported later.

Topics: Administration, Oral; Animals; Antimalarials; Chloroquine; Dose-Response Relationship, Drug; Drug Tolerance; Erythrocytes; Injections, Intraperitoneal; Injections, Subcutaneous; Malaria; Male; Mice; Phenanthrenes; Piperidines; Plasmodium berghei

The phenanthrenemethanol compound WR 122,455 is an effective blood schizontocide against lines of Plasmodium berghei that are highly resistant to primaquine, sulphonamides, pyrimethamine and cycloguanil. It is also active against the NS line that is moderately resistant to chloroquine. WR 122,455 is inactive against the RC line which is highly resistant to chloroquine. Resistance to WR 122,455 is fairly readily developed by the drug-sensitive N strain of P. berghei, using a relapse technique. Resistance develops very readily to the NS line of P. berghei. Both resistant lines exhibit cross-resistance to quinine, but a roughly normal response to chloroquine, primaquine, sulphonamides, dapsone, pyrimethamine and cycloguanil. Resistance to WR 122,455 is stable through cyclical transmission and through cryopreservation, as well as in the absence of drug selection pressure. The resistant parasites have an essentially normal morphology and virulence. A warning is given against the widescale use of WR 122,455 or similar new drugs for human malaria other than in a suitable combination, in order to minimize the danger of the development of resistance to them.

Topics: Animals; Antimalarials; Chloroquine; Drug Resistance; Erythrocytes; Malaria; Male; Mice; Phenanthrenes; Piperidines; Plasmodium berghei; Quinine; Virulence

An antimalarial drug testing system is described which utilizes trophozoite induced Plasmodium cynomolgi malaria in rhesus monkeys. The schizonticidal activity of standard antimalarial drugs in this system is reported. The system accurately predicted antimalarial activity in man of 8 of 9 compounds selected for clinical trials.

Topics: Amodiaquine; Animals; Antimalarials; Dapsone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Tolerance; Haplorhini; Macaca mulatta; Malaria; Phenanthrenes; Primaquine; Prodigiosin; Pyrimethamine; Quinine; Sulfadiazine; Sulfadimethoxine; Sulfalene; Trimethoprim

Topics: Amino Alcohols; Animals; Antimalarials; Malaria; Mice; Optical Rotation; Phenanthrenes; Plasmodium berghei

The effects of quinine and a 9-phenanthrenemethanol, WR 122,455 on the fine structure of Plasmodium berghei have been investigated. Changes consequent upon quinine treatment were noted in the outer membranes (including those that surround the "food vacuole") and the digestive vacuoles. These changes were followed by cytoplasmic degeneration and vacuolization. WR 122,455 caused morphological changes in at least three areas of the parasite, (1) the outer membranes, (2) the digestive vacuole and (3) the nucleus. The relationship of these changes to the mode of action of these compounds is discussed. It seems possible that they interfere primarily with limiting membrane-mitochondrial functions. The modifications of pigment formation are characteristic of these compounds and differ from those seen with chloroquine or primaquine.

Topics: Animals; Cell Membrane; Drug Resistance, Microbial; Erythrocytes; Humans; Malaria; Mice; Mitochondria; Phenanthrenes; Plasmodium berghei; Quinine; Vacuoles

A series of new 9-phenanthrene amino alcohols has been prepared in which each compound bears from one to five halogen or halogen-containing moieties. A number of these compounds are extremely active against Plasmodium berghei in the mouse. Some structural requirements for optimal efficacy are considered.

Topics: Amino Alcohols; Animals; Antimalarials; Chickens; Halogens; Malaria; Malaria, Avian; Mice; Phenanthrenes; Plasmodium berghei; Structure-Activity Relationship

Quinine was compared with a 9-phenanthrene methanol (WR33063) and a 4-quinoline methanol (WR30090) for the treatment of 207 patients with falciparum malaria in Southeast Thailand. Quinine eradicated parasitaemia (average 70 hours) more rapidly than either WR30090 (72 hours) or WR33063 (77 hours). But WR33063 had a higher cure rate (92%) than WR30090 (86%) or quinine (85%). The mean duration of fever and of parasitaemia were combined with the failure rate to form an arbitrary efficacy index. Using this concept WR33063 was the most effective drug. The recrudescence rate correlated with the degree and duration of parasitaemia and with the duration of fever. WR33063 was the least toxic drug. Side effects associated with WR30090 appeared to be headache, backache and urticaria. Quinine was the most toxic drug. All 3 drugs were inconvenient in having to be administered every 8 hours for 6 days. One patient did not respond to oral quinine but did respond to an intravenous quinine infusion (IVQ). A "Medication Ward Round" was perfected during the study and comprised sequential history, drug administration, physical examination, dose notation and patient observation. Falciparum nephrosis was diagnosed in one patient.

Topics: Adolescent; Drug Administration Schedule; Drug Evaluation; Drug Hypersensitivity; Drug Resistance, Microbial; Humans; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Proteinuria; Quinine; Quinolines; Thailand; Urticaria

Topics: Adult; Alanine Transaminase; Anopheles; Antimalarials; Aspartate Aminotransferases; Dapsone; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Malaria; Male; Methylamines; Military Medicine; Phenanthrenes; Plasmodium falciparum; Pyrazines; Pyrimethamine; Quinine; Sulfanilamides; Trimethoprim; Vietnam

Topics: Animals; Antimalarials; Malaria; Methanol; Mice; Phenanthrenes; Plasmodium berghei; Structure-Activity Relationship

Topics: Alcohols; Amines; Animals; Chickens; Malaria; Mice; Phenanthrenes; Plasmodium berghei; Structure-Activity Relationship

Topics: Antimalarials; Butylamines; Ethanolamines; Fever; Humans; Malaria; Male; Methanol; Military Medicine; Phenanthrenes; Plasmodium falciparum; Quinine; Quinolines; Thailand; Vietnam

Topics: Animals; Antimalarials; Drug Resistance, Microbial; Haplorhini; Humans; Malaria; Methanol; Phenanthrenes; Quinolines

Topics: Animals; Antimalarials; Aza Compounds; Chickens; Malaria; Methanol; Mice; Phenanthrenes; Photosensitivity Disorders; Piperidines; Plasmodium berghei; Pyridines

Topics: Amines; Animals; Antimalarials; Malaria; Methanol; Mice; Phenanthrenes; Plasmodium berghei; Solubility

Topics: Amino Alcohols; Animals; Antimalarials; Chickens; Malaria; Mice; Molecular Conformation; Phenanthrenes; Plasmodium berghei; Stereoisomerism; Structure-Activity Relationship

Topics: Binding Sites; Chloroquine; Drug Resistance, Microbial; Malaria; Phenanthrenes; Plasmodium berghei

WR 33063 (3-bromo-10-[alpha-hydroxy-beta-(n, n-diheptylamino)ethyl]-phenanthrene hydrochloride) and WR 30090 (6,8-dichloro-2,3,4-dichlorphenyl-di-n-butylaminoethyl-4- quinolinemethanol hydrochloride) were tested for suppressive prophylactic effect on induced malaria in nonimmune volunteers living in an area where malaria is not naturally transmitted. Doses of 800 mg of WR 33063 and 690 or 460 mg of WR 30090 were given at weekly intervals to men exposed on the day of the first dose to mosquitoes heavily infected with chloroquine- and pyrimethamine-resistant strains of Plasmodium falciparum. WR 33063 did not interfere with early development of infection, but WR 30090 given for 8 weeks provided suppressive cures in 20 of 26 men. P. vivax infections similarly induced broke through WR 30090 treatment in 4 of 15 men, and most of the remainder experienced malaria after completion of the prophylactic course. No side effects of treatment were observed.

Topics: Antimalarials; Butylamines; Humans; Indonesia; Malaria; Methanol; Methylamines; Phenanthrenes; Philippines; Plasmodium falciparum; Plasmodium vivax; Quinolines; Vietnam

Two new investigational antimalarial drugs developed by the U.S. Army Malaria Research Program were tested in patients with multi-drug-resistant falciparum malaria from Vietnam. WR 33063, a phenanthrene methanol, cured 13 patients treated in the United States. All of these patients had suffered multiple recrudescences after treatment with standard antimalarial drugs. In addition, 23 of 25 patients with acute attacks of falciparum malaria treated in Vietnam were cured. The rate of clinical response was prompt. WR 30090, a quinoline methanol, similarly cured eight patients with multiple recrudescences in the United States and 23 of 26 patients in Vietnam. Adverse effects associated with the drugs were not seen. These drugs signify a major advance in the chemotherapy of drug-resistant falciparum malaria.

Topics: Antimalarials; Butylamines; Humans; Malaria; Methanol; Methylamines; Phenanthrenes; Plasmodium falciparum; Quinolines; Vietnam

Previous studies of thyroid function during various infections have yielded conflicting results, but most have suggested an acceleration of peripheral thyroxine (T(4)) turnover during the acute infectious illness. In the present studies, thyroid function was examined by a method allowing simultaneous analysis of both endogenous thyroidal release and peripheral T(4) disposal in normal volunteers after induction of acute falciparum malaria. Subjects received iodide-(125)I, followed in 5-7 days by (131)I-T(4) intravenously. 4 days later, infection was induced by the injection of parasitized red blood cells. Bidaily measurements of serum protein-bound (125)I and protein-bound (131)I, and urinary (125)I and (131)I, together with frequent estimates of serum (127)I-T(4) (Murphy-Pattee) and free T(4) (FT(4)), were made during a control period, during acute illness, and during convalescence. Alterations in the peripheral metabolism of (131)I-T(4) during infection included significant decreases in the fractional disappearance rate for T(4) [(k)], and in the clearance and daily disposal of T(4), all of which returned to control values during convalescence. Total serum (127)I-T(4) increased late in the infected period to become greater during convalescence than either before or during infection, while FT(4) did not increase significantly until convalescence. An analysis of serum (131)I-T(4)/(127)I-T(4) and (131)I-T(4)/PB(125)I ratios confirmed these observations. The slope with time of ratios for urinary (125)I/(131)I, a reflection of thyroidal iodine release, was decreased during infection, but rebounded to control values during the convalescent period. The observed increments in serum (127)I-T(4) concentration in the convalescent phase may reflect in part the slowing of (k), but together with the rising ratios of urine (125)I/(131)I suggests enhanced thyroidal T(4) secretion immediately after the acute illness. Thus, with malarial infection, there appears to be an initial depression followed by a rebound in rates of thyroidal iodine release. In contradistinction to other infections, fractional turnover and daily disposal of hormone is decreased in malaria, perhaps due to hepatic dysfunction and the consequent impairment in cellular deiodinative processes.

Topics: Antimalarials; Blood Proteins; Humans; Iodine; Iodine Radioisotopes; Malaria; Male; Methimazole; Methods; Phenanthrenes; Plasmodium falciparum; Protein Binding; Quinolines; Thyroid Function Tests; Thyroid Gland; Thyroxine

Topics: Amino Alcohols; Animals; Antimalarials; Chickens; Infrared Rays; Malaria; Mice; Phenanthrenes; Spectrum Analysis; Structure-Activity Relationship; Ultraviolet Rays

Topics: Animals; Antimalarials; Chemical Phenomena; Chemistry; Chickens; Magnetic Resonance Spectroscopy; Malaria; Methanol; Mice; Phenanthrenes; Piperidines; Stereoisomerism

Topics: Amino Alcohols; Animals; Antimalarials; Fluorine; Malaria; Methanol; Mice; Phenanthrenes; Structure-Activity Relationship

Topics: Amino Alcohols; Animals; Antimalarials; Chemical Phenomena; Chemistry; Fluorine; Malaria; Methanol; Mice; Phenanthrenes

Topics: Acridines; Amines; Amino Alcohols; Anti-Bacterial Agents; Antimalarials; Benzene; Benzene Derivatives; Biphenyl Compounds; Coloring Agents; Cyclohexanes; Malaria; Methane; Naphthalenes; Phenanthrenes; Plasmodium gallinaceum; Quinolines; Sulfonamides

Topics: Antimalarials; Malaria; Phenanthrenes

Topics: Antimalarials; Biguanides; Guanidine; Guanidines; Malaria; Phenanthrenes

Topics: Antimalarials; Biguanides; Guanidines; Malaria; Phenanthrenes

Topics: Amino Alcohols; Humans; Malaria; Phenanthrenes

Topics: Amino Alcohols; Animals; Malaria; Malaria, Vivax; Phenanthrenes; Sporozoites

Topics: Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Amino Alcohols; Antimalarials; Ketones; Malaria; Phenanthrenes

Topics: Antimalarials; Malaria; Phenanthrenes

Topics: Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Amino Alcohols; Anthracenes; Antimalarials; Malaria; Phenanthrenes

Topics: Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Alcohols; Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Alcohols; Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Alcohols; Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Alcohols; Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Alcohols; Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Alcohols; Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Amino Alcohols; Antimalarials; Malaria; Phenanthrenes

Topics: Amino Alcohols; Antimalarials; Malaria; Phenanthrenes