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PubMed1979

Abnormal haemoglobins in the Sudan savanna of Nigeria. IV. Malaria, immunoglobulins and antimalarial antibodies in haemoglobin AC individuals.

Haemoglobin (Hb) AC electrophoretic pattern was found in 0.7% of the population at Garki, Kano State, northern Nigeria, an area where malaria is hyperendemic. Twenty-one Hb.AC subjects at all ages did not differ from the rest of the population in their frequency or density of Plasmodium falciparum, P. malaria or P. ovale infections, nor in their IgM concentrations and titres of specific antimalarial antibodies. However, IgG levels in Hb.AC subjects were frequently above the average of the reference population (P less than 0.05), especially during a period of protection against malaria (P less than 0.01). These observations suggest that the Hb.C gene may be maintained in certain environments by an enhanced ability to produce IgG antibodies against an antigen or antigens other than malaria, and that its geographical relationship to malaria may be a coincidence. This hypothesis needs to be tested where Hb.C is seen at high frequency, in northern Ghana and Upper Volta or Gwoza (Nigeria).

Adolescent↗
PubMed1984

In vitro assessment of the antimalarial activity of chloroquine and its major metabolites.

A quantitative assessment of the antimalarial activity of chloroquine and its two major metabolites, desethylchloroquine (DEC) and bis-desethylchloroquine (bis-DEC), was made using a semi-automated microdilution technique. Two isolates of Plasmodium falciparum were used: the multi-drug resistant Vietnam Smith LA 137 strain and the chloroquine-sensitive Camp LA 137 strain. Mefloquine served as the standard for the Vietnam Smith strain and chloroquine for the Camp strain. Chloroquine and DEC demonstrated nearly equivalent activities in their inhibition of the growth of the chloroquine-sensitive Camp strain. Bis-DEC was less active since its ID50 was more than twice that of chloroquine. Against the chloroquine-resistant Vietnam Smith strain, DEC showed a three-fold loss of activity and bis-DEC showed no activity at concentrations as high as 340 ng ml-1. A combination of chloroquine and DEC showed an additive effect against both the Vietnam Smith and Camp strains.

Chloroquine↗
PubMed1987

Community-based malaria control in Saradidi, Kenya: description of the programme and impact on parasitaemia rates and antimalarial antibodies.

A community-based malaria control programme initiated in Saradidi, Kenya in 1982 is described. Antimalarial treatment provided by volunteer community health workers was made available in each village. Malaria was holoendemic. Parasitaemia rates by age were high and did not change after the control programme began. Plasmodium falciparum was the most common species and was present alone or mixed in 98.2% of 8105 infections. Virtually all (98.5%) of 2040 blood samples collected in May 1981 were positive (reciprocal titre greater than or equal to 80) to P. falciparum by the indirect fluorescent antibody (IFA) test. Seropositivity rates to P. falciparum in the IFA test or the enzyme-linked immunosorbent assay (ELISA) were high in all age groups and did not change significantly in longitudinal surveys or in a cohort of children zero to nine years old followed at intervals. While the malaria control programme was successful in bringing treatment to each village, malaria prevalence was not reduced. Parasitologic and serologic studies alone were not adequate to describe the impact of the community-based malaria control programme in Saradidi. Morbidity and mortality rates caused by malaria can decline, significantly improving the health of the population, in the absence of any decrease in parasitaemia rates.

Animals↗
PubMed2004

Stability indicating method for SPf66 antimalarial peptide in solution.

Stability studies on the SPf66 antimalarial peptide with different pH and temperature conditions were carried out. The degradation mechanism was elucidated by the size-exclusion chromatography (SEC) technique and the experimental data obtained at 37 degrees C and different pH were fitted to a kinetic degradation model that could explain the loss of its immunogenic capacity. At 5, 25, 37, and 70 degrees C and pH 2, changes were detected in the areas of the different species, although the values obtained could not be fitted to any known degradation kinetics.

Chromatography, Gel↗
PubMed1994

Saccharomyces cerevisiae mutants sensitive to the antimalarial and antiarrhythmic drug, quinidine.

Mutations at three loci in Saccharomyces cerevisiae have been shown to confer increased sensitivity to the antimalarial and antiarrhythmic alkaloid, quinidine. Two of these groups are composed of strains carrying recessive mutations, the other group contains two dominant alleles. The largest complementation group has been designated QDS1, for increased quinidine-sensitivity. Exposure of qds1 cells to lethal concentrations of quinidine results in a novel small-budded terminal morphology in about 70% of the cells in the culture. Strains which carry qds1 alleles share other pleiotropic phenotypes. qds1 mutants are incapable of mating as alpha but not a cells, due to a defect in alpha-factor production. Homozygous diploid qds1 strains cannot sporulate. Genetic evidence indicates that QDS1 is allelic to KEX2, a precursor processing protease. Loss of QDS1/KEX2 function results in quinidine sensitivity.

Alleles↗
PubMed1978

Antimalarial activities of various 4-pyridinemethanols with special attention to WR-172,435 and WR-180,409.

Pilot appraisals of the activities of 10 specially selected 2,6-substituted-4-pyridinemethanols against acute Plasmodium falciparum infections in owl monkeys identified three derivatives that were two to three times as active as chloroquine against infections with a 4-aminoquinoline-susceptible strain and, at the same doses, were equally effective against infections with a strain fully resistant to treatment with maximally tolerated doses of chloroquine, quinine, and pyrimethamine. Two of these derivatives, WR-172,435 and WR-180,409, deemed worthy of evaluation in human volunteers, were studied in greater depth in owl monkeys infected with either the multidrug-resistant Smith strain of P. falciparum or the pyrimethamine-resistant Palo Alto strain of P. vivax. These studies showed (i) that at the same total oral dose, 3-day and 7-day treatment schedules were equally effective and slightly superior to a single-dose schedule; (ii) that WR-172,435 was slightly more active than WR-180,409 in each treatment regimen; (iii) that intravenous delivery of WR-180,409 phosphate was feasible and effective; (iv) that both compounds effected control of parasitemia more rapidly than any standard or newly discovered antimalarial drug; and (v) that WR-172,435 and WR-180,409 had therapeutic indexes at least four to eight times those exhibited by chloroquine in infections with 4-aminoquinoline-susceptible strains, indexes retained by these pyridinemethanols against infections with various drug-resistant strains.

Animals↗
PubMed1992

Use of radioactive ethanolamine incorporation into phospholipids to assess in vitro antimalarial activity by the semiautomated microdilution technique.

Phospholipid biosynthetic activity is intense in the erythrocytic stage of Plasmodium falciparum because of the parasite's own enzymatic machinery. The incorporation of various labeled phospholipid precursors in comparison with the incorporation of nucleic acid and protein precursors was tested to evaluate P. falciparum growth in vitro. These precursors, namely, [3H]ethanolamine, [3H]hypoxanthine, [3H]palmitate, [14C]serine, [3H]choline, [3H]inositol, and [3H]isoleucine, were all accurate indicators of parasite growth. However, because of its high level of incorporation, [3H]ethanolamine proved to be the best tool for assessing parasite viability. When culture parameters were carefully controlled, [3H]ethanolamine incorporation into phospholipids was proportional to pulse time, precursor concentration, and initial parasitemia and was sensitive to the number of uninfected erythrocytes (hematocrit). It can be used for a wide range of infected erythrocytes, from 2 x 10(4) to 5 x 10(5). The use of [3H]ethanolamine for in vitro antimalarial drug screening is a good alternative to the method of Desjardins et al. (R. E. Desjardins, C. J. Canfield, J. D. Haynes, and J. D. Chulay, Antimicrob. Agents. Chemother. 16:710-718, 1979). The major advantage is that the culture medium can be supplemented with hypoxanthine, which results in better parasite growth. [3H]ethanolamine is also an ideal tool when compounds that interfere with DNA and/or RNA metabolism are to be investigated for their effect on Plasmodium growth.

Animals↗
PubMed1990

Multiple-dose kinetics in healthy volunteers and in vitro antimalarial activity of proguanil plus dapsone.

The multiple-dose kinetics of a daily dose of proguanil (200 mg) coadministered with dapsone (10 mg) was investigated in 6 healthy adult male volunteers. The kinetics of dapsone (DDS), monoacetyldapsone (MADDS), proguanil (PROG) and its active metabolite cycloguanil (CYCLO) were derived from plasma drug concentrations after the last maintenance dose. The following kinetic parameters (mean values) were estimated for DDS and PROG, respectively: maximum concentration (Cmax) = 285 and 151 ng/ml, minimum concentration (Cmin) = 125 and 31 ng/ml, elimination half-life (t1/2) = 23.3 and 18.3 h, plasma clearance (Cl) = 0.032 and 1.27 l/h/kg and apparent volume of distribution (Vss) = 1.05 and 33.32 l/kg. The Cmax, Cmin and t1/2 of CYCLO were 56 ng/ml, 17 ng/ml and 15.0 h, respectively. The antimalarial activity of the proguanil/dapsone combination was assessed in vitro by measuring the inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. Both FC-27 [chloroquine (CQ)- and pyrimethamine (PYR)-sensitive] and K1 (CQ- and PYR-resistant) isolates were completely inhibited by the drug combination at steady-state concentrations. These findings suggest that the drug regimen may be effective against drug-resistant falciparum malaria.

Adult↗
PubMed1982

Antimalarial properties of bredinin. Prediction based on identification of differences in human host-parasite purine metabolism.

Human malaria parasites (Plasmodium falciparum) grown in continuous erythrocyte culture utilize hypoxanthine for synthesis of both guanosine and adenosine nucleotides. Unlike the mature human erythrocyte, the malaria parasite depends on a constant supply of guanylates, primarily for synthesis of nucleic acids. This parasite specific requirement for guanylates led us to predict that a block in the hypoxanthine to guanosine monophosphate pathway would be selectively lethal to the parasite. Bredinin (4-carbamoyl-1-beta-D-ribofuranyosyl-imidazolium-5-olate) inhibited the synthesis of guanosine monophosphate from inosine monophosphate by parasitized erythrocytes. This block in guanylate synthesis was fatal to both a drug-sensitive (FCR-3) and a drug-resistant (VNS) strain of the malaria parasite at a bredinin concentration of 50 microM, arresting growth of the parasite at the trophozoite stage of development. These studies emphasize the essential role of guanylates and their synthesis from hypoxanthine in the metabolism of malaria parasite. They further suggest that bredinin or similar agents that selectively interfere with parasite guanylate metabolism may have potential for antimalarial chemotherapy.

Cells, Cultured↗
PubMed2001

Emerging targets for antimalarial drugs.

The absence of an effective vaccine against malaria and the ability of the parasite to develop resistance to known antimalarial drugs makes it mandatory to unravel newer drug targets with a view to developing newer pharmacophores. While conventional targets such as the purine, pyrimidine and folate pathways are still being investigated in the light of newer knowledge, a new opportunity has emerged from an understanding of certain unique features of the parasite biology. These include the food vacuole, haemoglobin catabolism, haeme biosynthesis, apicoplasts and their metabolism as well as macromolecular transactions, import of host proteins, parasite induced alterations in the red cell surface and transport phenomena. This review seeks to emphasise the new and emerging targets, while giving a brief account of the targets that have already been exploited.

Journal Article↗
PubMed1983

The Rockefeller Foundation's antimalarial program in Latin America: donating or dominating?

This paper analyzes the origins, methods, and hidden objectives of the antimalarial campaigns carried out by the Rockefeller Foundation in Latin America. These campaigns are examined in the context of the imperialist domination of Latin America over the course of this century. The close relationship between prevailing economic, political, and military priorities and the thrust of the Foundation's work in the field of malaria is detailed. In spite of its relatively small financial investment in malaria research and eradication, the Rockefeller Foundation was able to reap enormous benefits from its work in this area. Not only was the Foundation able to increase the profit margins of the Rockefeller empire by ameliorating some of the dire economic consequences of malaria, but also it was able to use its participation to penetrate the public health field and consolidate the hegemony of scientific medicine. It is concluded that the Rockefeller Foundation's attention to the malaria problem reflected more than mere philanthropic concern.

Foundations↗
PubMed1979

Quinacrine hydrochloride. Review and mode of action of an antimalarial, used as an occlusive agent for transvaginal human sterilization.

Quinacrine hydrochloride, mainly used as an antimalarial, has been used as a nontoxic chemosterilant in a transvaginal procedure in the human female. Clinical experiments indicate that Quinacrine acts as a powerful obstructive agent exclusively on the epithelium of the intramural portion of the tube without alterating the histology of the endometrium. The precise mechanism of Quinacrine's obstructive action on the mucosa of the uterotubal junction is unknown. Its possible mode of action is binding to epithelial DNA thus forming a clot of granulomatous tissue, as Quinacrine is known to form adhesions when used in the control of neoplastic effusions. Zinc is known to inhibit Quinacrine-DNA binding. The human endometrium, rich in Zinc is unaffected by Quinacrine, whereas the tubal cornua, with little Zinc promote the obstruction by Quinacrine DNA bondage. The procedure is effective in 90 per cent of the cases with two instillations of Quinacrine. Further studies are essential to find agents that would potentiate the action of Quinacrine on the human Fallopian tube epithelium.

DNA↗
PubMed1984

In vitro antimalarial activity of tetrahydrofolate dehydrogenase inhibitors.

Three tetrahydrofolate dehydrogenase (dihydrofolate reductase = EC 1.5.1.3) inhibitors were tested for antimalarial activity against Plasmodium falciparum, using an in vitro radioisotopic technique. Activity of each drug was tested in both normal RPMI medium 1640 and in modified medium (containing no p-aminobenzoic acid and 2.27 X 10(-8) M folic acid) after a 24- or 48-hour exposure. Activity was increased 20- to 85-fold using the modified medium and the longer exposure time. Under all conditions, pyrimethamine and cycloguanil were of equal or greater potency than an experimental pyrimethamine analogue, M&B 35769, against pyrimethamine-sensitive strains, but M&B 35769 was more active than either pyrimethamine or cycloguanil against pyrimethamine-resistant strains.

Animals↗
PubMed1993

Antimalarial activity of azithromycin and erythromycin against Plasmodium berghei.

Several antibiotics that inhibit protein synthesis on 70S ribosomes, including the macrolide erythromycin, and the azalides azithromycin (ZITHROMAX) and CP-63,956, demonstrated antimalarial activity against two strains of Plasmodium berghei. In a four-day in vivo test, the azalides were 25-fold more potent than erythromycin against the chloroquine-sensitive P. berghei N strain, and displayed additive effects with chloroquine. This effect was not observed with the erythromycin-chloroquine combination. Against the chloroquine-resistant P. berghei MSU/RC strain, the azalides were 60-fold more potent than erythromycin. Additive effects were observed with azalide-chloroquine combinations against this strain, but these results were not significantly different from the erythromycin-chloroquine combination.

Animals↗
PubMed2001

In-vivo antimalarial activity of Cassia occidentalis, Morinda morindoides and Phyllanthus niruri.

The ethanolic, dichloromethane and lyophilized aqueous extracts of Cassia occidentalis root bark, Morinda morindoides leaves and whole plants of Phyllanthus niruri were evaluated for their antimalarial actvity in vivo, in 4-day, suppressive assays against Plasmodium berghei ANKA in mice. No toxic effect or mortality was observed in mice treated, orally, with any of the extracts as a single dose, of 500 mg/kg body weight, or as the same dose given twice weekly for 4 weeks (to give a total dose of 4 g/kg). No significant lesions were observed, by eye or during histopathological examinations, in the hearts, lungs, spleens, kidneys, livers, large intestines or brains of any mouse. At doses of 200 mg/kg, all the ethanolic and dichloromethane extracts produced significant chemosuppressions of parasitaemia (of > 60% for C. occidentalis root bark and Ph. niruri whole plant, and of 30% for M. morindoides leaves) when administered orally. The most active ethanolic extract, that of Ph. niruri, reduced parasitaemia by 73%. The dichloromethane extracts of M. morindoides and Ph. niruri produced similar reductions (74% and 72% chemosuppression, respectively), whereas that of C. occidentalis was slightly less active (60% chemosuppression). Each lyophilized aqueous extract was less active than the corresponding ethanolic extract.

Administration, Oral↗
PubMed1990

An in-vitro profile of the action of four antimalarials on indigenous cases of Plasmodium falciparum malaria in Karnataka.

In view of the emergence of chloroquine resistant Plasmodium falciparum from more and more geographical areas profiling of the responses to other available antimalarials by in vitro methods have become essential. A preliminary study undertaken in two Primary Health Centres of Karnataka State, India show the presence of strains of P. falciparum resistant to chloroquine and amodiaquine. The response for amodiaquine was poor as compared to chloroquine. The isolates were, however, sensitive to mefloquine and quinine.

Amodiaquine↗
PubMed1990

Is corneal deposition of antimalarial any indication of retinal toxicity?

Ninety-five percent of patients on chloroquine demonstrate corneal deposition of the drug with the pupil dilated; less than 10% of patients on hydroxychloroquine show any corneal changes when so examined. I describe one patient on chloroquine and two on hydroxychloroquine who demonstrated large amounts of corneal antimalarial drug, leading to the early diagnosis of definite retinopathy. Examination of the cornea with the pupil dilated may reveal the presence of retinal toxicity in some patients.

Adult↗
PubMed1989

Gametocytocidal and sporontocidal activity of some standard antimalarials on P. berghei (NK 65) infection M. natalensis.

Three standard antimalarials pyrimethamine, primaquine and quinine were tested against P. berghei (NK 65) for gametocytocidal and sporontocidal action. Pyrimethamine at 7.5, 3.25, 2.5 and 1.25 mg/kg., primaquine at 15, 10 and 7.5 mg/kg, quinine at 225, 168.5, 140.62 and 112.5 mg/kg were given orally to infected M. natalensis for 3 consecutive days i.e., day 6, 7 and 8 post inoculation of sporozoites. To assess sporontocidal action batches of mosquitoes (A. stephensi) were fed on infected-treated and control animals on day 8. Mosquitoes were dissected on day 10 post infective feed to compare the number of oocysts from control groups. Pyrimethamine at 2.5, primaquine at 10 and quinine at 140.62 mg/kg had total sporontocidal action. When mosquitoes were fed on animals treated with 2.5 mg/kg of pyrimethamine and 10 mg/kg of primaquine, very few oocysts were developed and sporozoites from these mosquitoes were not infective to Mastomys. When mosquitoes were fed on Mastomys treated with 140.62 mg/kg of quinine, no oocyst was observed.

Animals↗