Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various drugs are widely used in the prophylaxis and treatment of malaria. In the prevention of malaria in travellers, a careful risk-benefit analysis is required to balance the risk of acquiring potentially serious malaria against the risk of harm from the prophylactic agent. Unfortunately, the information needed to perform accurate analyses of this type is not available for most antimalarials. In the prophylaxis of malaria, chloroquine and proguanil have an excellent safety record, being very rarely associated with severe adverse reactions in the recommended dosages. However, in many parts of the world they are no longer effective prophylactic agents. Pyrimethamine-dapsone (Maloprim) is associated with agranulocytosis, especially if the recommended dose is exceeded, and should be reserved as a second-line agent for travellers to high risk areas. Pyrimethamine-sulfadoxine (Fansidar) and amodiaquine are associated with a relatively high incidence of potentially fatal reactions, and are no longer recommended for prophylaxis. Mefloquine, a relative newcomer, may provoke severe neuropsychiatric reactions with a frequency of 1 in 15,000 to 20,000 users at the prophylactic dosage. In the treatment of Plasmodium falciparum malaria, which has a high mortality if untreated, a greater risk of adverse reactions to antimalarial drugs is acceptable. As chloroquine resistance has become widespread, alternative agents including quinine, mefloquine, pyrimethamine-sulfadoxine, tetracyclines, halofantrine and artemisinin (qinghaosu) and its derivatives may be used in treatment regimens. The therapeutic ratios for chloroquine, quinine and mefloquine are narrow and toxicity is frequent when recommended treatment dosages are exceeded; parenteral administration above the recommended dose range is especially associated with the hazards of cardiac and neurological toxicity.
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PMID:Adverse effects of antimalarials. An update. 848 Dec 16

A sensitive, selective and rapid reversed-phase high-performance liquid chromatographic method was developed for the simultaneous analysis of dapsone, monoacetyldapsone and pyrimethamine in human whole blood and plasma. The procedure involved extraction of the compounds and the internal standard, monopropionyldapsone, with tert.-butylmethyl ether under alkaline conditions. A newly marketed column, Supelcosil LC-ABZ (Supelco, 15 cm x 4.6 mm I.D.), was employed. The mobile phase, consisting of acetonitrile-methanol-phosphate buffer (2:1:7, v/v/v), was delivered at a flow-rate of 1.2 ml/min, and ultraviolet absorbance was monitored at 286 nm. The limit of determination using a 150-microliters sample was 10 ng/ml (40 nM) for dapsone and pyrimethamine and 8 ng/ml (28 nM) for monoacetyldapsone. Given that only a small amount of blood is required in this method, it could now be applied in studies involving blood level monitoring and pharmacokinetics in children on Maloprim (dapsone-pyrimethamine) prophylaxis in malaria endemic areas.
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PMID:Simultaneous determination of dapsone, monoacetyldapsone and pyrimethamine in whole blood and plasma by high-performance liquid chromatography. 849 23

There are more than 1 million malaria deaths annually in Africa, approximately 90% of such deaths globally. Parasite resistance is such that chloroquine can no longer be relied upon to cure deadly Plasmodium falciparum infections. Pyrimethamine-sulfadoxine is almost as cheap as chloroquine and easier to use, but resistance to this drug is also likely to become widespread across Africa within the next five years. Practical alternatives to Fansidar must be identified now. The author describes pyronaridine, a drug which in Cameroon achieved 100% cure of uncomplicated falciparum malaria. It is a synthetic Chinese drug currently being assessed by the WHO Committee on Drugs for Malaria. Although pyronaridine's mode of action and disposition are poorly understood, it is nonetheless known to be effective against multidrug-resistant P. falciparum; that it does not seem to exhibit much cross-resistance with chloroquine, quinine, or mefloquine; that it has proved clinically effective in trials in China; and that it seems to be well-tolerated. Much remains to be seen, however, before pyronaridine can be recommended for routine use in Africa. Dose schedules are empirical and pharmacokinetic data are urgently needed; current formulations have low oral bioavailability; the geographic variation in parasite chemosensitivity, expected potential for resistance, and toxicity must be investigated; pyronaridine's toxicological profile has not been established to standards acceptable in the US or the European Union; and its clinical risk-benefit profile is poorly understood. Little clinical work has been conducted outside of China. Furthermore, Plasmodium species can develop resistance to the drug in the laboratory, which necessitates careful attention when used in areas of high transmission, and it remains unclear whether pyronaridine will be well tolerated in humans. Assembling the necessary data for regulatory approval will be costly. If pyronaridine is to be developed, attention must be given to further costs; treating an adult currently costs about $3, too expensive for Africa.
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PMID:Pyronaridine: a promising drug for Africa? 859 61

The basis of recrudescence, the reappearance of malaria parasites after chemotherapy or after failure of immune suppressions of the parasites, was studied in cultures of Plasmodium falciparum. When the cultured parasites were exposed eight times over a 4-day period to 5% D-sorbitol, which destroyed infected RBCs containing trophozoites or schizonts, they showed recrudescence several days after cessation of treatment. Pyrimethamine-sensitive parasites were cleared by 10(-6) M pyrimethamine; pyrimethamine-resistant parasites also were cleared by 10(-4) M pyrimethamine. Both groups of parasites underwent recrudescence in the same manner as those exposed to 5% D-sorbitol. These recrudescent parasites were found to be as susceptible to these treatments as were the parasites before treatment. Therefore, our results strongly suggest that a subpopulation of the parasites escapes the effect of drugs by a mechanism other than drug resistance.
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PMID:Plasmodium falciparum: recrudescence of parasites in culture. 854 97

Gambian children who had received malaria chemoprophylaxis for a variable period of time during their first 5 years of life were followed to determine whether they experienced a rebound in mortality or in morbidity from malaria during the period after chemoprophylaxis was stopped. The risk of dying between the ages of 5 years, when chemoprophylaxis was stopped, and 10 years was no higher among children who had received chemoprophylaxis with Maloprim (pyrimethamine plus dapsone) for some period during their first 5 years of life than among children who had received placebo (21 vs. 24 deaths) and the beneficial effect of chemoprophylaxis on mortality observed during the first 5 years of life was sustained. The incidence of clinical attacks of malaria during the year after medication was stopped was significantly higher among children who had previously received Maloprim for several years than among children who had previously received placebo. However, at the end of this year, there was no significant difference in spleen rate, parasite rate or packed cell volume between the 2 groups of children. Thus, stopping chemoprophylaxis after a period of several years increased the risk of clinical malaria but did not result in a rebound in mortality in Gambian children. However, the number of deaths recorded was small, so a modest effect on mortality cannot be excluded.
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PMID:Mortality and morbidity from malaria after stopping malaria chemoprophylaxis. 859 77

After her holiday in South Africa, a 50-year-old woman was admitted because of fever and pain in the upper abdomen. The laboratory tests showed moderately increased serum liver enzyme activities. The liver biopsy showed a granulomatous hepatitis. Further investigations revealed no evidence for sarcoidosis, tuberculosis or infectious hepatitis, nor for other granulomatous diseases or infectious diseases relevant to South Africa. Upon discontinuation of the malaria prophylaxis with Daraclor (pyrimethamine and chloroquine (sulphate)) the symptoms disappeared and the liver function tests returned to normal. It was concluded that Daraclor was the probable cause of granulomatous hepatitis in this patient. This adverse effect was not published before.
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PMID:[Granulomatous hepatitis attributed to the combination pyrimethamine-chloroquine]. 872 Jul 7

Pyrimethamine and cycloguanil resistance of Plasmodium falciparum has been linked to mutations in the dihydrofolate reductase (dhfr) portion of the dhfr-ts gene. In this paper, the DNA sequence of the dhfr-ts gene of 50 isolates from Vietnam and 2 clones (T9/94 and T9/96) isolated from a malaria patient from Thailand have been analyzed. A comparison between these isolates and clones showed differential mutation patterns. Forty-eight isolates were found to consist of mutations associated with Pyr. A novel leucine mutation at position 140 was found in the isolate VP8 and in clone T9/94. The isolate VP8 and the clone T9/94 were found to also have the characteristic changes at positions 16 (Val) and 108 (Thr) that have been found in cycloguanil-resistant isolates. The isolate VP35 was shown to be resistant to both antifolates, while the clone T9/96 was found to be sensitive to both antifolates and to have a sequence identical to that of wild-type dhfr-ts. The two clones from a single patient showed the coexistence of resistant and sensitive clones in the absence of treatment by antifolates. Since cycloguanil resistance seems to be rare in Vietnam, cycloguanil alone or in combination with other antimalarial agents might be an alternative for treatment and prophylaxis, even in areas with high resistance to pyrimethamine.
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PMID:Plasmodium falciparum: mutation pattern in the dihydrofolate reductase-thymidylate synthase genes of Vietnamese isolates, a novel mutation, and coexistence of two clones in a Thai patient. 888 32

Pyrimethamine-sulfadoxine (PS, Fansidar; Hoffman-LaRoche, Basel, Switzerland) is now the first-line antimalarial therapy in parts of Africa with high rates of chloroquine-resistant Plasmodium falciparum. With PS resistance increasing and no suitably inexpensive and effective third antimalarial drug available, strategies for delaying the spread of PS resistance in Africa are needed. Community PS usage was measured in two Malian villages, one rural and one periurban, and prevalence of pyrimethamine-resistant P. falciparum genotypes was determined at these sites and two urban sites. The prevalence of resistant genotypes was 22.6% (n = 84) in the periurban village where PS was available from multiple sources and large stocks of PS were observed, and 13.5% (n = 89) and 23.4% (n = 77) in a large town and a city, respectively, where PS is widely available. No pyrimethamine-resistant genotypes (n = 58) were detected in Kolle, a rural village with a community-supported dispensary and clinic where PS is used sparingly and no PS was available in pharmacies or markets. The high rates of pyrimethamine resistant genotypes concurrent with higher PS usage argue for a policy of judicious PS use in Mali and in similar settings. A possible model for slowing the spread of drug-resistant malaria is illustrated by the example of the Kolle clinic.
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PMID:Community pyrimethamine-sulfadoxine use and prevalence of resistant Plasmodium falciparum genotypes in Mali: a model for deterring resistance. 894 Sep 73

A randomized study on the in vivo efficacies of chloroquine and a pyrimethamine-dapsone combination (Maloprim) in clearing P. falciparum parasitaemia was carried out in 77 asymptomatic semi-immune schoolchildren in the Kilombero District of Tanzania. Children were randomized to receive either chloroquine at a dose of 25 mg/kg over three days, or Maloprim (6.25 mg pyrimethamine + 50 mg dapsone for children under 10 years, and 12.5 mg pyrimethamine + 100 mg dapsone for children 10 or more years old) as a single dose. Children were followed-up for malaria parasitaemia at days 2, 7 and 14 after screening, randomization and treatment. The slide positivity rate was lower in the Maloprim group at all cross-sectional surveys (23 vs 37% at day 2; 9 vs 20% at day 7; 21 vs 32% at day 14) but none of these differences reached statistical significance. No cases in the Maloprim group showed RII resistance, whereas in the chloroquine group, 2 cases showed RII resistance and a further 2 cases RIII resistance (6%). No major side-effects were reported. The combination of pyrimethamine-dapsone appears to be a better choice than chloroquine as a chemoprophylactic regimen for malaria in this area. Although they need to be confirmed in a larger study, these results may be of interest to the policy-makers as well as researchers.
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PMID:A comparative study of the efficacies of chloroquine and a pyrimethamine-dapsone combination in clearing Plasmodium falciparum parasitaemia in school children in Tanzania. 898 May 92

A randomized, double-'blind', placebo-controlled trial of weekly Maloprim (dapsone-pyrimethamine, D-P) for malaria prophylaxis was conducted at Magoda village in north-eastern Tanzania. The effect of D-P on the incidence of clinical malaria, Plasmodium falciparum prevalence and density, splenomegaly, and packed cell volume (PCV) was investigated in a cohort of 249 children (126 receiving D-P and 123 receiving placebo) aged 1-9 years. The case definition of clinical malaria (malaria fever) was measured axillary temperature > or = 37.5 degrees C and/or reported fever, and P. falciparum asexual parasitaemia > or = 5000/microL. Children aged 1-4 years given D-P experienced 1.56 episodes of clinical malaria per year, whereas children on placebo experienced 2.55 episodes (relative rate [RR] = 0.61, 95% confidence interval [CI] 0.47, 0.80). Thus, D-P protective efficacy against clinical malaria, in this age group, was 39% (95% CI 20%, 53%; P = 0.0002). The annual incidence of clinical malaria among children aged 5-9 years was 0.16 episodes in the D-P group and 0.26 episodes in those receiving placebo (RR = 0.58, 95% CI 0.26, 1.28; P = 0.17). Increased malaria transmission and drug resistance, during the course of the trial, resulted in a reduction in the protective efficacy of D-P. Overall, D-P was able to reduce parasite densities and splenomegaly. D-P prophylaxis also resulted in an increase in PCV but this effect diminished towards the end of the trial. D-P exerted a suppressive effect on asexual parasitaemia throughout the trial.
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PMID:Maloprim malaria prophylaxis in children living in a holoendemic village in north-eastern Tanzania. 909 33


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