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The molecule of RC 12 which was found previously to exhibit antimalarial activity has been modified, by replacing groups in positions 1 and 2 by NHAr, S-Ar, NO2, sulfonamido and other substituents. The new derivatives (Table 1) were tested for toxicity and antimalarial activity agains Plasmodium berghei in mice (Table 2).
The electrophretic pattern of the red cell membrane protein, after the in vitro action on them of antimalarial agents, primaquine, quinine and chloroquine, is described. This electrophoretic study has proved that all studied antimalarial agents after the membrane proteins, causing a total loss of certain bands. This method has proved to be a new way of appreciation of the action of different agents on the red cell membrane.
We have used the whole-cell patch-clamp technique to study the effect of mefloquine (Lariam), a commonly used antimalarial drug, on the volume-regulated anion channel (VRAC) in cultured bovine pulmonary artery endothelial cells. We also examined its effects on other Cl(-) channels, i.e., the Ca(2+)-activated Cl(-) channel and the cystic fibrosis transmembrane conductance regulator, to assess the specificity of this compound for VRAC. At pH 7.4 mefloquine induced a fast and reversible block of the volume-sensitive chloride current (I(Cl,swell)), with an IC(50) value of 1.19 +/- 0.07 microM. The blocking efficiency increased with increasing extracellular pH (IC(50) value for pH 8.8 was 0.15 +/- 0.01 microM), indicating that this effect is mediated by the uncharged form of mefloquine. Ca(2+)-activated Cl(-) currents, I(Cl,Ca), activated by loading T84 cells via the patch pipette with 1 microM free Ca(2+) also were inhibited by mefloquine (IC(50) value 3.01 +/- 0.17 microM at pH 7.4). The cystic fibrosis transmembrane conductance regulator channel, transiently transfected in cultured bovine pulmonary artery endothelial cells, was not affected by 10 microM of the drug. This study describes for the first time effects of mefloquine on anion channels. Our data reveal a potent block of VRAC and Ca(2+)-activated Cl(-) channel at therapeutic concentrations. These results may contribute to a better understanding of the actions and side effects of this widely used antimalarial drug.
Hansch analysis of some antimalarial cyclic peroxy ketals (IV) having structural variations at the para substituted phenyl ring and an alicyclic ring of different size reveals that electronic and steric parameters of the phenyl ring substituents are important for explaining the variation in the activity while hydrophobicity parameter is of little significance. Electron withdrawing substituents with higher MR (molar refractivity) or V(W) (van der Waals volume) are preferred for the activity. Use of structural descriptors suggests that presence of a seven membered alicyclic ring attached to the peroxy bridge containing ring is conducive to the activity. Application of electrotopological state atom index (ETSAI) suggests a pharmacophore containing the peroxy bridge. This is corroborated by earlier observation on importance of oxygen atoms of the peroxy linkage of artemisinin for antimalarial activity. Although incorporation of ETSAI into Hansch model does not improve the relations, the electronic parameter sigma is found to be significantly correlated with it.
In the tropical African environment, malaria is both a major public health problem and a problem of socioeconomic development. It is caused by various agents, the most virulent and only lethal one of which is Plasmodium falciparum. This parasite is controlled by the appropriate use of antimalarial drugs and methods of individual and collective protection. The principal drugs used to treat bouts of malaria without vomiting caused by P. falciparum are amino-4-quinoleines, essentially chloroquine. This is based on the level of resistance of P. falciparum to drugs in most African countries, particularly those of Central and West Africa. Malawi is the only country of southern Africa to have replaced chloroquine by sulfadoxine-pyrimethamine for this indication, in 1993. In cases of bouts of benign malaria with vomiting, but that are not serious, and severe malaria caused by P. falciparum (suspected or confirmed) with or without drug resistance, quinine should be given intravenously for at least three days. Once the patient regains consciouness or the digestive problems cease, quinine treatment should be given orally for 5 to 7 days. Sulfadoxine-pyrimethamine can be given as an alternative to quinine. The other antimalarial drugs currently on the African market (halofantrine, mefloquine, artemisinine and its derivatives) are often used inappropriately and should be used only in exceptional cases of severe bouts of complicated P. falciparum malaria, with suspected or confirmed resistance to amino-4-quinoleines. Individual protection against the Anopheles mosquito, the principal vector of malaria in Africa, is based largely on the use of mosquito nets impregnated with pyrethroid insecticide and the use of aerosols. Collective protection involves essentially environment-based measures.
Eupatorium inulaefolium is used as an antimalarial agent by traditional healers of the Tumaco region (Nariño-Colombia). Several extracts of this plant have been tested by our laboratory and in vitro antimalarial activity against the FCB-2 strain of Plasmodium falciparum has been confirmed. For this reason, the mutagenic effect of the methanol, dichloromethane, and hexane extracts of Eupatorium inulaefolium (number 83377 university of Antioquia herbarium) were evaluated using the Ames test. None of the extracts evaluated had mutagenic effects on TA-98 or TA-100 strains of Salmonella typhimurium.
OBJECTIVE: To examine the extent to which district health teams could reduce the burden of malaria, a continuing major cause of mortality and morbidity, in a situation where severe resource constraints existed and integrated care was provided. METHODS: Antimalarial drugs were prepackaged into unit doses in an attempt to improve compliance with full courses of chemotherapy. FINDINGS: Compliance improved by approximately 20% in both adults and children. There were 50% reductions in cost to patients, waiting time at dispensaries and drug wastage at facilities. The intervention, which tended to improve both case and drug management at facilities, was well accepted by health staff and did not involve them in additional working time. CONCLUSION: The prepackaging of antimalarials at the district level offers the prospect of improved compliance and a reduction in the spread of resistance.
The three-dimensional crystal and molecular structure of benflumetol(I), alpha-(dibutylaminomethyl)-2, 7-dichloro-9-(p-chlorobenzylidene)-4-fluorenemethanol, was determined by X-ray crystallography and compared with the crystal structures of the cinchona alkaloids. The aromatic rings of fluorene-phenyl system of benflumetol are twisted from each other by 52.8 degrees. The torsion angle of N-C-C-O of benflumetol is 47.6 degrees. The intramolecular aliphatic N-O distance in benflumetol is 2.709A, which is close to the N-O distance found in antimalarial cinchona alkaloids. Benflumetol contains an intramolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms, no intermolecular hydrogen bond was found, which is different from the known amino alcohol antimalarials.
For the purpose of improving the oral antimalarial activities of the fluorenemethanols (reported by us in previous articles) which were less effective by oral than by subcutaneous administration, 24 alpha-(alkylaminomethyl)-2, 7-dichloro-9-substituted benzylidene-4-fluorenemethanols (III) were synthesized. The results of preliminary screenings demonstrated that five compounds (No. 1-4, 8) exhibited significant antimalarial activities against Plasmodium berghei NK65 strain in mice by oral administration, at dose of 6.25 mg.kg-1.d-1 x 3 with suppressive rate of 100%. Further evaluation of these 5 compounds showed that 4 of them (No. 1-4) were superior to chloroquine in parallel tests, their ED50 and ED90 were 1.0, 1.6; 0.6, 0.9; 0.7, 1.5 and 0.8, 1.6 mg.kg-1.d-1 x 3 respectively, while the ED50 and ED90 of chloroquine were 1.9 and 2.9 mg.kg-1. d-1 x 3 respectively; one compound (No 8) was equal to chloroquine, its ED50 and ED90 were 1.5 and 3.2 mg.kg-1.d-1 x 3 respectively. Further assessment of these 4 compounds are in progress.
We relate the evolution of a patient with Systemic Lupus Erythematosus with mucocutaneous, hematological, joint and renal expression. The skin lesions were treated with Chloroquine and Hydroxychloroquine and severe ocular toxicity related with antimalarials agent was developed. We revised the antimalarials use in Rheumatology, their utility, doses, adverse events and risk factors as cumulate doses, ideal daily doses, renal function and ophthalmological reviews recommendations.
A longitudinal pharmacoepidemiological study on prescribing patterns of antimalarials was conducted in Gezira State, Sudan. Different core drug prescribing indicators were identified, measured and correlated. Chloroquine and quinine were the most frequently prescribed antimalaria drugs but in 44.7% of cases, the dosage was inappropriate and did not conform to standard regimens. Due to variable and unmonitored patterns of drug resistance, most medical practitioners in Sudan tend to follow their own protocols to treat severe cases of malaria rather than conforming to standard regimens. We attribute the emergence of a high rate of resistance to malaria chemotherapy to such practices. We recommend interventions to ensure rational prescribing, and call for the formulation of a national antimalarial drugs policy.
Heptyl prodigiosin was purified from a culture of alpha-proteobacteria isolated from a marine tunicate collected in Zamboanga, Philippines, as part of a program to screen natural products for antiparasitic activity. An in vitro antimalarial activity similar to that of quinine was found against the chloroquine-sensitive strain Plasmodium falciparum 3D7. The in vitro antimalarial activity was about 20 times the in vitro cytotoxic activity against L5178Y mouse lymphocytes. A single subcutaneous administration of 5 and 20 mg/kg significantly extended survival of P. berghei ANKA strain-infected mice but also caused sclerotic lesions at the site of injection. A single administration by gavage of 50 mg/kg did not increase survival time. The compound was not found to be mutagenic using in vitro micromethods for the Ames Salmonella typhimurium assay and the micronucleus assay using L5178Y mouse lymphoma cells.
OBJECTIVE: To investigate the in vitro antimalarial effect of daphentin relating to its iron-chelating activity. METHODS: Schizontocidal activity of daphnetin and desferrioxamine B was tested through an in vitro assay based on the routine in vitro cultivation of Plasmodium faciparum FCC1 strain. The iron-chelating ability of each was measured by the fluorescent probe calcein. RESULTS: Daphnetin exhibited a modest iron-chelating ability compared with the powerful iron-chelator desferrioxamine B. In vitro test at the range of 0-12 mumol/L daphnetin showed a dose-dependent schizontocidal activity which could be inhibited if mixed with Fe2+ in a ratio of 2:1. CONCLUSION: The dose-dependent antimalarial activity of daphnetin is related to its iron-chelating activity.
The therapeutic efficacy of the synthetic antimalarial agents in lupus erythematosus and the polymorphous light eruptions is well established. Severe toxic reactions are rare but mild disturbances are relatively common. Although gold therapy probably is as effective in discoid lupus erythematosus, the antimalarials are easier to administer and cause fewer serious side effects. The mechanism of action of these drugs is poorly understood although definite anti-inflammatory properties have been noted. Perhaps further investigations of known biological processes such as free radical formation and neutralization, redox potential alterations or enzymatic changes may shed more light on this problem.
BACKGROUND: Malaria is a major public health problem representing 2.3% of the overall global disease burden. The cost of treatment of malaria continues to rise as older drugs and insecticides become less effective and are replaced by more effective, but also more expensive products. METHODS: A post-hoc pharmacoeconomic analysis (direct and indirect costs only) of three antimalarials, chloroquine, mefloquine and co-artemether, was carried out to address the problem of switch to a more expensive first-line antimalarial in the face of growing chloroquine resistance. RESULTS: From the perspective of a large public hospital, it was seen that in an area of high grade chloroquine resistance, the total expenditure on patients who fail chloroquine would exceed the excess expenditure on mefloquine when the RII + RIII resistance exceeded 9%. CONCLUSIONS: Switch to a more expensive drug like mefloquine as a first-line option would be cost-effective when the moderate-severe chloroquine resistance exceeded 9%.
Treatment failures to the first- and second-lines antimalarial drugs chloroquine and sulfadoxine-pyrimethamine have increased in the Purworejo district on the island of Java, Indonesia. A molecular epidemiologic study was conducted to determine the frequency distribution of mutant alleles of the genes associated with the resistance among the isolates of Plasmodium falciparum from the area. Analyses using a polymerase chain reaction and restriction fragment length polymorphism showed that nearly all of the 111 samples carried mutant alleles in genes associated with chloroquine resistance: P. falciparum multi-drug resistance 1 (pfmdrl) 86Y (92%), 1042D (4.5%), and P. falciparum chloroquine resistance transporter (pfcrt) 76T (99.1%). Mutant alleles of the in the dihydrofolate reductase (dhfr) gene were also high (84.7%), either as 108N and 108T or paired with 59R, and 16V, respectively. Mutant alleles in the dihydropteroate synthase gene were the least common, either as a single 437G mutation (35.3%) or paired with 540E (26.5%). These results are consistent with the antimalarial drug resistance situation in the area and emphasize the need for a proper treatment strategy.
This review describes the present status of purely synthetic peroxides and 1,2,4-trioxanes and how they perform in various preclinical tests as potential antimalarial drug candidates. The literature is reviewed from 1986 onwards, comprising mostly articles published in the last ten years. As several papers on antimalarial peroxides have already been published, this review focuses on more recent studies detailing the novelty and potential of synthetic peroxides.
Resistance of Plasmodium falciparum to antimalarials is considered one of the factors responsible for the impairment of the malaria treatment and control worldwide. Resistance emerges as a result of selection and then disemination of spontaneous mutant parasites with reduced drug susceptibility. Combination therapy is considered as the main strategy to control antimalarial drug resistance. Currently, combination therapies that include artemisinin derivatives are highly recommended. Combination therapy has been used in Colombia for more than 20 years; however, its impact on preventing the dissemination of drug resistance is unknown. This paper reviews the theoretical bases and clinical studies that support the use of combination therapy.