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)

From 1979-1988, 427 patients with falciparum malaria were prospectively investigated for chloroquine resistance. About 90% were infected in sub-Saharan Africa. Of the 361 non-immune patients 235 were evaluable; in 158 (67%) chloroquine resistance of Plasmodium falciparum could be confirmed. Chloroquine sensitivity was found in 77 (32%) patients. Sulfadoxine-pyrimethamine resistance was found in 33 patients. The history of use of chemoprophylaxis was recorded in 357 patients: 168 (49%) took adequate, 103 inadequate and 86 no chemoprophylaxis. In 65 of the 168 patients with a history of good compliance, prophylactic serum concentrations could be measured; in 56 (86%) patients the history was confirmed by the chloroquine level. All but one of them were infected with a resistant P. falciparum strain. Of the 66 semi-immune patients, 60 were infected in their homeland; in 5 (8%) chloroquine resistance was found. Only 1 of the 60 patients had used adequate chemoprophylaxis and proved to be infected with a resistant P. falciparum strain. During the study the spread of drug resistance from East Africa to other parts of Africa could be observed. Monitoring for drug-resistant falciparum malaria in travellers returning from malaria-endemic areas is a helpful tool in predicting the evolution of drug resistance in that area. In the non-endemic area such monitoring is essential for optimal advice on treatment of patients and of chemoprophylaxis in travellers.
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PMID:Falciparum malaria, imported into The Netherlands, 1979-1988. I. Epidemiological aspects. 859 63

Drug resistance is a major problem in malaria. The resistance mechanism remains unresolved but contributing factors are probably heavy drug use, parasite selection, cross resistance and genetic influences of drugs. Plasmodium ovale en P. malariae are sensitive to the current antimalarial drugs. P. vivax has some chloroquine resistant strains, notably on Papua New Guinea, Irian Jaya and other islands in the Pacific. The geographical distribution of P. falciparum strains resistant to proguanil and pyrimethamine is not well known. Chloroquine-resistant strains are found in South East Asia, the Amazon region (almost 100% resistance in both regions) and in Africa south of the Sahara (resistance not everywhere 100%). Sulfadoxine-pyrimethamine is not an effective treatment in South East Asia and the Amazon region; it is useful in tropical Africa. Mefloquine resistance is a problem mainly confined to Thailand. There is cross resistance between halofantrine and mefloquine. Decreased sensitivity to quinine was reported from Thailand, but it remains an effective drug, notably when given in combination with tetracycline or doxycycline. In cases of severe or complicated malaria intravenous quinine is still the preferred therapy. Resistance to artemisinine has not yet been reported. Pharmaceutical companies show little interest in antimalarial drug development, which in view of the increasing drug resistance is a matter of great concern.
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PMID:[Malaria and drug resistance]. 861 36

Sulfadoxine/pyrimethamine (Fansidar) is widely used in Africa for treating chloroquine-resistant falciparum malaria. To clarify how parasite resistance to this combination arises, various lines of Plasmodium falciparum were used to investigate the role of naturally occurring mutations in the target enzyme, dihydropteroate synthetase (DHPS), in the parasite response to sulfadoxine inhibition. An improved drug assay was employed to identify a clear correlation between sulfadoxine-resistance levels and the number of DHPS mutations. Moreover, tight linkage was observed between DHPS mutations and high-level resistance in the 16 progeny of a genetic cross between sulfadoxine-sensitive (HB3) and sulfadoxine-resistant (Dd2) parents. However, we also demonstrate a profound influence of exogenous folate on IC50 values, which, under physiological conditions, may have a major role in determining resistance levels. Importantly, this phenotype does not segregate with dhps genotypes in the cross, but shows complete linkage to the two alleles of the dihydrofolate reductase (dhfr) gene inherited from the parental lines. However, in unrelated lines, this folate effect correlates less well with DHFR sequence, indicating that the gene responsible may be closely linked to dhfr, rather than dhfr itself. These results have major implications for the acquisition of Fansidar resistance by malaria parasites.
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PMID:Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization. 907 34

The 4-aminoquinolines, chloroquine or amodiaquine, have long been the drugs of choice for treating uncomplicated, falciparum malaria in Africa, although resistance to them is now common. Sulfadoxine-pyrimethamine (SP) is the usual alternative when 4-aminoquinoline treatment fails. A combination-treatment regimen could combine the rapid symptom relief offered by the 4-aminoquinolines with the prolonged parasiticidal activity of SP, and also slow down development of resistance to the individual drugs. A systematic review of randomized trials was conducted so that the evidence of effectiveness and safety of such combination treatment could be summarized and compared with the results of treatment with either drug given alone. The results of trials were sought by searching through electronic databases and by contact with researchers in the field. Five studies were identified. Although there are few data, there is evidence that control of clinical symptoms is better when a 4-aminoquinoline is used with SP than when SP is used alone, and the cure rate also tends to be higher with the combination regimen. No evidence of serious side-effects was found. Larger scale trials are needed if this combination is to be adopted more widely.
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PMID:Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine as a treatment for uncomplicated malaria--a systematic review. 971 41

Sulfadoxine/pyrimethamine (SP) is considered an alternative treatment for acute uncomplicated malaria caused by Plasmodium falciparum resistant to chloroquine. However, the appearance of resistance to this drug has been reported since its initial use in Colombia. Molecular analysis of the dihydrofolate reductase gene indicates a correlation between in vitro resistance to SP and the Asn-108 point mutation. Little is known about the association of this point mutation and in vivo resistance to SP. We used a mutation-specific polymerase chain reaction strategy to analyze the presence of the Asn-108 point mutation in 48 clinical samples with adequate clinical response (ACR), 2 early treatment failures (ETF), and 1 late treatment failure (LTF). The Asn-108 mutation was detected in 36 of the ACR samples and in all of the ETF and LTF samples. Eleven ACR samples amplified with the wild-type-specific primer and one amplified with the primer for the Thr-108 mutation described for resistance to cycloguanil. These results suggest that the Asn-108 marker may not be useful in predicting SP treatment failure.
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PMID:Lack of an association between the ASN-108 mutation in the dihydrofolate reductase gene and in vivo resistance to sulfadoxine/pyrimethamine in Plasmodium falciparum. 1046 74

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.
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PMID:[Antimalarial drugs and their ways to use in the African milieu]. 1122 40

Chloroquine (CQ) remains the first-line treatment for uncomplicated malaria in much of Africa despite the growing problem of resistance to this drug. Sulfadoxine-pyrimethamine (SP) is often used after CQ treatment failure and has replaced CQ as the first-line treatment in parts of Africa. To compare the efficacy of these 2 regimens, we evaluated, in March-August 1999, clinical and parasitological responses over 28 days in 214 children and adults from Kampala, Uganda, with uncomplicated falciparum malaria. Compared to SP, significantly more patients treated with CQ developed early or late clinical failure (54% vs 11%, P < 0.001) and parasitological failure (72% vs 30%, P < 0.001) during 14 days of follow-up. The risk of treatment failure occurring after day 14 was similar between the 2 treatment groups. Among those treated with CQ, children aged < 5 years were at higher risk of clinical failure than older individuals (76% vs 28%, P < 0.001), an association not seen with SP (11% vs 10%, P = 0.91). Although early parasite clearance was significantly better in the SP group (P = 0.001), fever clearance at day 3 was the same (CQ 85%, SP 86%). These and other recent findings suggest that consideration be given to replacing CQ as the first-line therapy for uncomplicated malaria in Uganda, particularly in young children.
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PMID:The comparative efficacy of chloroquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in Kampala, Uganda. 1128 66

The sulfonamide and sulfone (sulfa) group of antimalarials has been used extensively throughout malaria endemic regions of the world to control this important infectious disease of humans. Sulfadoxine is the most extensively used drug of this group of drugs and is usually combined with pyrimethamine (Fansidar), particularly for the control of Plasmodium falciparum, the causative agent of the most lethal form of malaria. Resistance to the sulfadoxine/pyrimethamine combination is widespread. Analysis using molecular, genetic and biochemical approaches has shown that the mechanism of resistance to sulfadoxine involves mutation of dihydropteroate synthase, the enzyme target of this group of drugs. Understanding the mechanism of resistance of P. falciparum to sulfa drugs has allowed detailed analysis of the epidemiology of the spread of drug resistance alleles in the field(1)and, in the future, opens the way to the development of novel antimalarials to this target enzyme. Copyright 1999 Harcourt Publishers Ltd.
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PMID:The mechanism of resistance to sulfa drugs in Plasmodium falciparum. 1150 65

Sulfadoxine-pyrimethamine (SP) and co-trimoxazole were both effective in reducing fever, clearing parasitaemia and improving anaemia in children aged < 5 years with uncomplicated malaria in 2 Kenyan endemic sites, Oyugis in the west and Tiwi on the coast. We compared the efficacy of these 2 regimens (in May-July 1998) by evaluating clinical and parasitological responses over 14 days. The combined incidence of parasitological failure for the combined sites for co-trimoxazole was 14/123 (11%) and for SP 23/145 (16%) (RR 0.72, 95% confidence interval [CI] 0.31-1.46, P = 0.289). The 14-day clinical failure rate for the combined sites for co-trimoxazole was 4/123 (3.3%), and for SP 8/145 (5.5%), (RR 1.69, 95% CI 0.91-3.15, P = 0.129). The results indicate that the risk of treatment failure for the 2 regimens was similar. The antimalarial use of co-trimoxazole in uncomplicated malaria needs further investigation, since the 10-12-h elimination half-life of both components should reduce selective pressure for resistance. In addition, use of a 2-day high-dose course, tested previously, requires further study to demonstrate its efficacy.
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PMID:Co-trimoxazole compared with sulfadoxine-pyrimethamine in the treatment of uncomplicated malaria in Kenyan children. 1181 40

With the increasing resistance to commonly used antimalarial drugs, different untested 'local' treatment regimens for malaria will arise. We compared commonly used treatment regimens for children in Guinea-Bissau. Symptomatic children with Plasmodium falciparum mono-infection were allocated at random to one of 4 treatments: 15 mg/kg quinine twice a day for 3 d (group 1); 10 mg/kg quinine twice a day for 3 d followed by a total dose of 25 mg chloroquine base given over 3 d (group 2); a total dose of 50 mg/kg chloroquine base given in 2 daily doses for 3 d (group 3), or sulfadoxine-pyrimethamine (group 4). On day 28 more children from group 1 (33%; relative risk [RR] = 2.9, 95% confidence interval [CI] 1.5-5.7) and group 2 (26%; RR = 2.1, CI 1.0-4.3) had had parasitaemia than in group 4 (12%), whereas no significant difference was found between group 3 (17%; RR = 1.3, CI 0.6-2.2) and group 4. No severe adverse reaction was observed in any of the groups. Chloroquine is still effective in Guinea-Bissau at an increased dose of 50 mg/kg, which appears safe when given orally in 2 daily doses for 3 d. Sulfadoxine-pyrimethamine could serve as an efficient, cheap and easy to administer second-line drug, leaving quinine to be used for third-line treatment. Quinine should not be used in short courses, nor does the combination of quinine and chloroquine have any advantage.
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PMID:Treatment of uncomplicated malaria in children in Guinea-Bissau with chloroquine, quinine, and sulfadoxine-pyrimethamine. 1217 85


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