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PubMed1992

Antimalarial agents and the eye.

Antimalarial compounds have been demonstrated to be both safe and efficacious in the treatment of lupus erythematosus as well as several other dermatologic conditions. It is imperative, however, that physicians familiarize themselves with the potential complications associated with the use of these agents. Furthermore, it is essential that a successful collaborative relationship be developed between the dermatologist and the ophthalmologist who are to treat and monitor the patient to avoid any untoward complications that might afflict the patient. It is important to stress that patients on antimalarial drug therapy be evaluated by an ophthalmologist prior to starting treatment and every 4 to 6 months thereafter. The use of Amsler's grids in compliant patients is recommended. If the patient develops retinal changes consistent with the diagnosis of premaculopathy, then careful consideration should be given to the availability and use of alternative agents.

Antimalarials↗
PubMed2006

[The microfluorimetric assay (MFA) in in vitro testing the sensitivity of Plasmodium falciparum to antimalarial drugs].

OBJECTIVE: To determine the feasibility of the microfluorimetric assay (MFA) in screening antimalarial drugs. METHODS: The dose-response curves and effective concentration that resulted in a 50% inhibitory of parasitemia (IC50) of chloroquine, artemisinin, artemether and pyronaridine phosphate against Plasmodium falciparum strain FCC1/HN cultured in vitro were tested by microfluorimetric assay (MFA) and compared with those determined by microscopy-based assay. RESULTS: The IC50 of chloroquine, artemisinin, artemether and pyronaridine phosphate were 18.79, 6.32, 3.67 and 2.00 nmol/L by MFA and the IC50 of which were 19.65, 5.82, 4.38 and 2.83 nmol/L by microscopy-based technique respectively. The results from both techniques were similar or identical (P > 0.05). CONCLUSION: The microfluorimetric assay (MFA) is sensitive, rapid, easily interpreted and would be useful for testing the sensitivity of Plasmodium falciparum to antimalarials and for screening

Animals↗
PubMed2006

[Effects of antimalarial drugs and cardiomyocytes. Pathogenic approach and new therapeutic recommendations].

The cardiotoxicity of halofantrine was a major concern during the past decade. Other old antimalarials (quinine, mefloquine, etc.) and more recent drugs may carry a similar risk. Studies of ventricular repolarization and myocardial cells can throw light on these adverse effects. Studies of QT dispersion measured on the surface electrocardiogram and of QT dynamicity and variability (QT/RR slope) during long-term Holter recording help to identify patients at risk of drug-induced ventricular arrhythmia. Such electrocardiographic investigations have shown that quinine, mefloquine and artemisinin derivatives do not alter ventricular repolarization. In contrast, halofantrine significantly increases QT dispersion and the QT regression slope. At the cellular level, most major antimalarial drugs inhibit potassium channels, which are regulated by the LQT1 and HERG genes responsible for the congenital long-QT syndrome. We propose new recommendations for the use of these drugs in the treatment and prevention of malaria.

Antimalarials↗
PubMed1991

Antimalarial activity of crude extracts from Brazilian plants studied in vivo in Plasmodium berghei-infected mice and in vitro against Plasmodium falciparum in culture.

1. Ninety-five crude extracts obtained with either organic solvents or water from 48 Brazilian plants or parts of plants were evaluated experimentally as blood schizontocides. Seventy-three extracts were obtained from 33 plants randomly collected using an empirical approach, and 22 from 15 "medicinal" plants. 2. The crude extracts were screened in vivo at up to 1.0 g/kg, po, for 4 days in mice infected with blood forms of Plasmodium berghei and parasitemia was determined on the fifth day. 3. Six plants, 2 randomly collected, Vernonia brasiliana and Eupatorium squalidum, and 4 "medicinal" plants, Acanthospermum australe, Esenbeckia febrifuga, Lisianthus speciosus, and Tachia guianensis, were partly active against the rodent malaria, i.e., they showed 40-50% inhibition of P. berghei multiplication. Forty-two plants whose extracts presented no antimalarial activity are reported. 4. Four extracts with antimalarial activity were also tested in vitro using P. falciparum cultures and two of them, V. brasiliana and A. australe, were active. Extracts of V. brasiliana caused about 50% inhibition of parasite multiplication at relatively low doses (40 ng/ml) as compared to chloroquine (30 ng/ml) and quinine (50 ng/ml). 5. The relatively high percentage of positive results obtained here for "medicinal" plants vs randomly chosen plants demonstrates the effectiveness of the ethnopharmacological approach to drug testing.

Animals↗
PubMed1991

Antimalarial medications in dermatology. A review.

Antimalarial medications are effective for the treatment of a variety of dermatologic conditions. Their use is often curtailed by concern for adverse reactions, including ophthalmologic side effects; however, recent evidence points to a greater margin of safety with these medications than was previously appreciated. This article reviews the pharmacology of antimalarial medications as well as indications and safe guidelines for their use in the treatment of dermatologic conditions.

Antimalarials↗
PubMed1990

[Synthesis of 2-methyl-5-substituted phenoxy-primaquine and antimalarials activity].

In searching for efficient, safe and radically curative agent and causal prophylactics for malaria, seven 2-methyl-5-substituted phenoxy-6-methoxy-8-(1-methyl-4-aminobutylamino)-quinolines (II1-7) were synthesized and their antimalarial activities were compared with the corresponding 4-methyl substituted derivatives of primaquine. The starting material, 2-nitro-4-methoxy-5-bromo-acetanilide (III), was prepared from p-methoxy aniline through acetylation, bromination and nitration. III was then condensed with substituted phenols in the presence of potassium carbonate. The condensed products were subsequently hydrolyzed with dilute alcoholic hydrochloric acid to yield 2-nitro-4-methoxy-5-substituted phenoxy-aniline (V) which underwent Skraup's reaction with 2-butenal to provide the key intermediates 2-methyl-5-substituted phenoxy-6-methoxy-8-nitroquinolines (VI). These 8-nitroquinoline derivatives were reduced to 8-aminoquinoline derivatives (VII). The latter were condensed with 4-bromo-1-phthalimido-pentane and then hydrolyzed with hydrazine hydrate, the final products were obtained as oxalate or succinate. The structure of the target compounds and unknown intermediates were confirmed by elementary and spectral analysis. Primary biological evaluation showed that all compounds II1-7 were much less active than the 4-methyl substituted derivatives and slightly less active than primaquine in both causal prophylactic test against Plasmodium yoelii and suppressive antimalarial test against P. berhei.

Animals↗
PubMed1989

Peroxides as oxidant antimalarials.

To further explore the antimalarial activity of peroxides (e.g. artemisinin 1), twenty-three peroxides (all the compounds shown in Figures 3 and 4) of diverse chemical structure and acceptable stability were selected and tested for antimalarial activity in vitro against Plasmodium falciparum, and in mice against P. berghei. Included were hydroperoxides, dialkyl peroxides, acyl and diacylperoxides, peroxyketals, peroxycarbonates, and endoperoxides. None was active in vivo, although several were reasonably potent in vitro.

Animals↗
PubMed1988

Inhibition of tolbutamide metabolism by antimalarial drugs.

The effects of mefloquine (MQ), the combination of MQ with sulfadoxine-pyrimethamine (MSP), sulfadoxine (S), pyrimethamine (P) quinine (Q) and quinidine (Qd) on in vitro hepatic metabolism has been studied using tolbutamide as a substrate. The hydroxylation of tolbutamide was determined in the presence of variable concentrations of each compound. Tolbutamide hydroxylase activity in control microsomes was 0.20 +/- 0.13 nmole/min/mg microsomal protein at a substrate concentration of 150 microM. All compounds studied inhibited tolbutamide metabolism as shown by a decrease in 4-hydroxytolbutamide formation. The order of potency of the inhibitors was MSP greater than S greater than MQ greater than Q greater than Qd greater than P. MQ, MSP, S, Q, and Qd were examined in detail for the type of inhibition. MQ and Qd were non-competitive inhibitors, whereas MSP and S were competitive inhibitors and Q was an uncompetitive inhibitor of tolbutamide 4-hydroxylation. These data provide more information on the inhibitory potential of some antimalarial drugs on microsomal enzymes in human liver. S has been shown to be a potent inhibitor in vitro and this finding possibly explains the longer T 1/2 and MRT of MQ when co-administered with S in healthy volunteers. Further studies in man should be attempted in order to understand the clinical relevance of the inhibitory potential of the antimalarial drugs.

Adult↗
PubMed1988

[Synthesis of acridine derivatives of amino acid hydrazines and their antimalarial activity].

2-Methoxy-6-chloroacridine-9-yl- and 2-ethoxy-6-nitroacridine-9-yl-hydrazides of glycine, alpha- and beta-alanines, gamma-aminobutiric acid, epsilon-aminocaproic acid have been synthesized and their antimalarial activity has been investigated. The compounds were found to inhibit the growth of malaria parasite P. falciparum in in vitro cultures. Fifty per cent inhibitory concentrations ranged from 2 x 10(-7) to 6 x 10(-7) M and corresponded to therapeutic concentrations of known quinoline and acridine antimalarial drugs. The beta-alanine and gamma-aminobutiric acid derivatives were the most active and showed high activity against a chloroquine resistant strain of P. falciparum.

Acridines↗
PubMed1988

Effects of antimalarial agents on plasma levels of chlorpromazine and its metabolites in schizophrenic patients.

The plasma content of chlorpromazine (CPZ) and its two metabolites 7-OH-chlorpromazine (CPZ-OH) and chlorpromazine sulphoxide (CPZ-SO) were measured in the blood of schizophrenic patients established on chlorpromazine therapy. Administration of the commonly used antimalarial agents chloroquine sulphate, amodiaquine hydrochloride and Fansidar one hour before the first dose of chlorpromazine for the day led to marked increases in CPZ and CPZ-OH over control levels. There were no consistent changes in CPZ-SO levels. The implications of these findings are discussed, first with regard to possible therapeutic relevance for the management of schizophrenia and more particularly, with regard to the possible toxic effects of concurrent administration of antimalarial agents and chlorpromazine.

Adolescent↗
PubMed1974

Clinical testing of new antimalarial compounds.

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.

Amino Acids↗
PubMed1984

Toxicity and side-effects of antimalarials in Africa: a critical review.

Notwithstanding the presence of resistance to chloroquine in some parts of Africa, this drug is still the most widely used antimalarial in the continent. One adverse reaction of chloroquine that has an important bearing on its use is pruritus. The risk of increasing the incidence of ocular toxicity through prolonged use of chloroquine for prophylaxis must be borne in mind by physicians. Another antimalarial that is likely to be used in increasing amounts in Africa is pyrimethamine-sulfadoxine. With prolonged use of this combination for prophylaxis, the adverse reactions usually associated with the long-acting sulfonamides are possible.Genetic abnormalities may also play a part in the incidence and severity of adverse reactions to certain drugs, e.g., primaquine and quinine. Most of the common adverse reactions are mild and have little or no influence on the acceptability and utilization of the drugs, with the exception of chloroquine-induced pruritus. Studies to define the precise epidemiology and pathophysiology of this reaction are urgently needed.

Africa↗
PubMed1983

Mode of action of antimalarial drugs.

Chloroquine, quinine, quinacrine and related drugs are effective antimalarial agents only against parasites that degrade haemoglobin. This fact prompted an examination of the role of ferriprotoporphyrin IX (FP), a product of haemoglobin degradation, in the mode of action of chloroquine. FP was identified as a high affinity drug receptor of malaria parasites by showing that it has the appropriate affinity for chloroquine, with a dissociation constant on the order of 10(-8) M, and specificity for amodiaquine, quinacrine, quinine and mefloquine. Moreover, FP and its complex with chloroquine impair the ability of cell membranes to maintain cation gradients, and they lyse normal erythrocytes, Plasmodium berghei and P. falciparum. The amount of FP required for lysis is less than 0.1% of the haem in erythrocytic haemoglobin. Recently, evidence has been obtained that FP in the parasite forms transient, non-toxic complexes with cytoplasmic haem binders and that FP in this form can interact with chloroquine. Thus, chloroquine and related drugs may act as antimalarial agents by shunting FP away from natural haem binders and into toxic drug-FP complexes. In addition FP released from haemoglobin, either spontaneously or by oxidant drugs, may contribute to haemolysis and protection against malaria in patients with Heinz body haemolytic anaemias.

Anemia, Hemolytic↗
PubMed1983

Effects of antimalarial drugs on human natural killer cell activity.

Separation of null cell fraction from the other cellular components of human peripheral blood obtained from normal healthy individuals was effected through the Ficoll-Hypaque density gradient centrifugation, carbonyl iron phagocytosis-magnet application, E-rosette forming and binding to 19S-EAC respectively. The null cells were used as effector cells in the cytotoxic assay. The spontaneous cell-mediated cytotoxicity assay was employed and the highly NK-sensitive K562 labelled with Na251 CrO4 were used as targets. The null cell fraction was divided into several portions to allow for normal control, diluent control and tests. The test portions were those exposed to the various antimalarial drugs employed. It was observed that the T cell, B cells and null cell fractions accounted for 72%, 18% and 10% of the total lymphocyte population respectively. The mean cytotoxicity generated by the natural killer subset was 63%. The antimalarial drugs/drug combination used were chloroquine, quinine, pyrimethamine and sulfadoxine/pyrimethamine combination. Concentrations used were their respective minimal inhibitory concentration (MIC) and corresponding 5 X MIC. The inhibitory effects on natural killer cell activity of these drugs were observed. The possible reasons for these observations are discussed.

Antimalarials↗
PubMed1982

[Antimalarial 6-aminoquinolines XV. 6- and 4-aminoquinolines with a tertiary basic alkylated amino group].

Antimalarial 6-aminoquinolines (1a-c) were acylated (3a-c, 5a) and alkylated (4a-c, 6a) at the secondary aromatic 6-amino group with the aim of studying the influence of a tertiary aromatic 6-amino group on antimalarial activity and toxicity. 4 derivatives (9e-g) of 4-amino-7-chloroquinoline with a tertiary aromatic 4-amino group were synthesized to study the influence of such a variation on the biological activity of the 4-aminoquinolines. The N-alkylated derivatives 4a-c, 6a, 9f-g were active against malaria (P. vinckei/mice).

Aminoquinolines↗
PubMedDate not supplied

[Antimalarial chemotherapy one hundred years after Laveran (problems and prospects) (author's transl)].

Problems of experimental chemotherapy of human malaria are complex because of specificity of plasmodia of birds, rodents and monkeys to several animal hosts. Moreover antimalarial compounds now available or developed in the course of laboratory assessment of their potential value have also specific chemotherapeutic action on various plasmodia and on a particular phase of their cycle of development. Research aiming at the discovery of new antimalarials may follow two paths. One is a screening on an animal model of a very large number of compounds hoping that one of them will show a promising antiplasmodial effect. The other method is based on fundamental study of biochemical pathways of various species of malaria parasites, to find compounds that will interfere with the multiplication or survival of human plasmodia. The use of laboratory animals and particularly monkeys has been a paramount factor during the past twenty years. The recent possibility of assessing the value of new compounds on an in vitro culture of plasmodia is of considerable promise, although it could not replace the use of experimental animals. The final testing of compounds that have successfully passed the toxicity test, on cases of human malaria raises many important ethical and other issues.

Antimalarials↗