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)

Sulfadoxine/pyrimethamine (SP) is increasingly used against malaria in sub-Saharan Africa because of chloroquine resistance. However, chloroquine may have a beneficial antipyretic effect. We therefore compared the combination of SP plus chloroquine, chloroquine alone, SP alone, and SP plus paracetamol in the treatment of uncomplicated Plasmodium falciparum malaria in 175 Tanzanian children (1-4 years old) in a randomized trial. Outcome variables were axillary temperatures every six hours, daily parasitemias, and serum levels of IgG antibodies to P. falciparum. Lower mean temperatures (6-48 hours) were achieved with SP plus chloroquine or paracetamol than with SP alone (P < 0.001) or chloroquine alone (P < 0.05). All three SP-treated groups showed high and similar parasite reduction (0-48 hours), whereas treatment with chloroquine alone was much less effective. Levels of IgG antibodies to P. falciparum increased significantly (P < 0.001) and similarly in the four treatment groups between days 0, 2, and 3. Thus, the addition of chloroquine or paracetamol to SP improved the clinical outcome, but did not affect the parasitologic response or antibody production.
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PMID:Antipyretic, parasitologic, and immunologic effects of combining sulfadoxine/pyrimethamine with chloroquine or paracetamol for treating uncomplicated Plasmodium falciparum malaria. 1464 Apr 94

Malaria, caused mostly by Plasmodium falciparum and P. vivax, remains one of the most important infectious diseases in the world. Antimalarial drug toxicity is one side of the risk-benefit equation and is viewed differently depending upon whether the clinical indication for drug administration is malaria treatment or prophylaxis. Drug toxicity must be acceptable to patients and cause less harm than the disease itself. Research that leads to drug registration tends to omit two important groups who are particularly vulnerable to malaria--very young children and pregnant women. Prescribing in pregnancy is a particular problem for clinicians because the risk-benefit ratio is often very unclear. The number of antimalarial drugs in use is very small. Despite its decreasing efficacy against P. falciparum, chloroquine continues to be used widely because of its low cost and good tolerability. It remains the drug of first choice for treating P. vivax malaria. Pruritus is a common adverse effect in African patients. As prophylaxis, chloroquine is usually combined with proguanil. This combination has good overall tolerability but mouth ulcers and gastrointestinal upset are more common than with other prophylactic regimens. Sulfadoxine/pyrimethamine is well tolerated as treatment and when used as intermittent preventive treatment in pregnant African women. Sulfadoxine/pyrimethamine is no longer used as prophylaxis because it may cause toxic epidermal necrolysis and Stevens Johnson syndrome. Mefloquine remains a valuable drug for prophylaxis and treatment. Tolerability is acceptable to most patients and travellers despite the impression given by the lay press. Dose-related serious neuropsychiatric toxicity can occur; mefloquine is contraindicated in individuals with a history of epilepsy or psychiatric disease. Quinine is the mainstay for treating severe malaria in many countries. Cardiovascular or CNS toxicity is rare, but hypoglycaemia may be problematic and blood glucose levels should be monitored. Halofantrine is unsuitable for widespread use because of its potential for cardiotoxicity. There is renewed interest in two old drugs, primaquine and amodiaquine. Primaquine is being developed as prophylaxis, and amodiaquine, which was withdrawn from prophylactic use because of neutropenia and hepatitis, is a potentially good partner drug for artesunate against falciparum malaria. Atovaquone/proguanil is a new antimalarial combination with good efficacy and tolerability as prophylaxis and treatment. The most important class of drugs that could have a major impact on malaria control is the artemisinin derivatives. They have remarkable efficacy and an excellent safety record. They have no identifiable dose-related adverse effects in humans and only very rarely produce allergic reactions. Combining an artemisinin derivative with another efficacious antimalarial drug is increasingly being viewed as the optimal therapeutic strategy for malaria.
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PMID:Antimalarial drug toxicity: a review. 1472 85

A study was carried out to assess the patterns of resistance and occurrence of DHFR/DHPS genotypes of Plasmodium falciparum prior to the adoption of sulfadoxine-pyrimethamine (SP) as first-line treatment for uncomplicated malaria in Tanzania. Children under five years (n = 117) with clinical, uncomplicated malaria were randomly allocated to standard treatments of either chloroquine (CQ) (25 mg/kg) or SP (25 mg sulfadoxine and 1.25 mg pyrimethamine/kg). Patients were monitored for 28 days. Clinical recovery was achieved in 98% (n = 58) and 90% (n = 59) of the patients in the SP and CQ groups, respectively. Parasitologically, 14% of the patients in the SP group and 51% in the CQ group exhibited RII/RIII resistance. When relating pre-treatment blood drug levels to treatment outcome and the degree of parasite resistance to the number of mutations, no relationships could be detected. There was an overall significant increase in haemoglobin levels from day 0 to day 28 in both patient groups. Sulfadoxine-pyrimethamine produced an acceptable clinical response but the high degree of parasitological resistance (RII/RIII) observed two years prior to the introduction of the drug as first-line treatment is of concern, especially considering the long half-lives of sulfadoxine and pyrimethamine.
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PMID:Patterns of resistance and DHFR/DHPS genotypes of Plasmodium falciparum in rural Tanzania prior to the adoption of sulfadoxine-pyrimethamine as first-line treatment. 1509 90

Mutations in the dihydrofolate reductase gene (dhfr) of Plasmodium falciparum have been proposed as molecular markers for the surveillance of sulfadoxine-pyrimethamine (SP)-resistant malaria, but such proposals have not been validated. At 7 Ugandan sites in 1999, we determined the population-based prevalence of infections with mutations and the mutant allele frequency of dhfr codons 108, 51, and 59 using a random sample of infected individuals aged 1-45 years. Sulfadoxine-pyrimethamine treatment failure was independently estimated by in vivo tests in 327 children aged 6-59 months with clinical malaria. The prevalence of infections with the single point mutations and the dhfr codons 108 and 51 mutant allele frequency were not correlated to SP treatment failure. However, the dhfr codon 59 mutant allele frequency was positively correlated to SP treatment failure (r = 0.72, P = 0.06). The ratio of the infections with the mutant to wild genotype (M/W) and that of the mutant to wild allele (MA/WA) had the same values. Both dhfr codon 59 M/W and MA/WA ratio were significantly and positively correlated to SP treatment failure (r = 0.73, P = 0.05). Moreover, the prevalence of infections with only 2 mutations (Asn-108 plus Ile-51) was significantly and inversely correlated to the prevalence of infections with 3 mutations (Asn-108 plus Ile-51 plus Arg-59) (r = 0.92, P = 0.004), suggesting the stepwise accumulation of the dhfr mutations is Asn-108 Ile-51 Arg-59 and further supporting the idea of using the dhfr codon 59 M/W ratio as a molecular index for the prediction of SP treatment failure. Atthe population level, the dhfr codon 59 M/W ratio is a simple and stable index for the estimation of SP treatment failure.
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PMID:Population-based validation of dihydrofolate reductase gene mutations for the prediction of sulfadoxine-pyrimethamine resistance in Uganda. 1522 55

Plasmodium falciparum has developed resistance to almost all routinely used antimalarial drugs. Sulfadoxine-pyrimethamine (SP) has replaced chloroquine as first-line treatment of uncomplicated malaria infection in Kenya but resistance to SP is already reported. The addition of artemisinin derivatives to SP may delay the development of drug resistance, improve cure rates, and reduce transmission. The efficacy and safety of artesunate plus SP in the treatment of uncomplicated P. falciparum malaria was evaluated in a randomized trial of 600 children at Siaya District Hospital, western Kenya between October 1999 and March 2000. Children aged < 5 years were randomly assigned to receive SP alone (1.25 mg/kg based on pyrimethamine), or in combination with artesunate (4 mg/kg/d) for either 1 or 3 d. Parasitological failure by days 14 and 28 (polymerase chain reaction [PCR]-corrected for new infections) were the primary endpoints. Treatment failure rates by day 14 were 25.5% in the SP alone group, 16.2% (risk difference [delta]-9.3%, 95% CI -17.3 to -1.2%, P= 0.027) in the 1-dose artesunate group, and 9.4% (delta-16.2%, 95% CI -23.6 to -8.7%, P< 0.001) in the 3-dose artesunate group. Corresponding rates by day 28 were 46.0% in the SP alone group, 38.2% (delta-7.8%, 95% CI -17.7 to 2.1%, P= 0.16) in the 1-dose artesunate group, and 26.0% (delta-20.0%, 95% CI -29.4 to -10.6%, P < 0.001) in the 3-dose artesunate group. The artesunate and SP combination was well tolerated. There were no serious drug-related adverse events. Parasite clearance and gametocyte carriage were reduced significantly in both combination groups compared with SP alone. Three days of artesunate were required to reduce significantly the risk of treatment failure by day 28. However, the high background rate of parasitological failure with SP may make this combination unsuitable for widespread use in Kenya.
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PMID:Artesunate plus sulfadoxine-pyrimethamine for uncomplicated malaria in Kenyan children: a randomized, double-blind, placebo-controlled trial. 1530 33

The changing epidemiology of malaria since 1975 was studied in a tribal forested belt of central India, Chhattisgarh state, which is the second most highly malarious state in India. Chhattisgarh, which accounts for 2% of the total population of the country, contributed >16% of the total malaria cases, 23% of Plasmodium falciparum, and 7% of deaths due to malaria in the country. Retrospective analysis further revealed that, in 1975--76, P. vivax was the predominant species (58%); however, since 1979, P. falciparum showed a steady upward trend (50%), and in 2002. P. vivax reduced to 28%. Between 1986 and 2000, P. falciparum cases reported by the National Anti Malaria Programme have increased 500%, and the number of deaths also showed a similar alarming increase. From 2000 to 2002, though the number of malaria infections and number of deaths declined sharply as a result of intensive intervention measures (30% and 95%, respectively), which included new drugs like Sulfadoxine Pyrimethamine and Arteether under Enhanced Malaria Control Programme, the proportion of P. falciparum has held steady without any decline. Moreover, along with Anopheles fluviatilis, the traditional vector in the forest, An. culicifacies has also established itself in the forest. The comeback of malaria and establishment of new vectors was largely due to the deterioration of health services along with emergence of resistance in P. falciparum to Chloroquine and in An. culicifacies to DDT. Therefore, a more diversified malaria control program might be needed for sustainable malaria control.
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PMID:The changing dynamics of Plasmodium vivax and P. falciparum in central India: trends over a 27-year period (1975--2002). 1563 Oct 69

Approximately one million pregnancies are complicated by both malaria and HIV infection in sub-Saharan Africa annually. Both infections have been associated with maternal and infant morbidity and mortality. Intermittent preventive treatment, usually with sulfadoxine-pyrimethamine, has been shown to prevent pregnancy-related malaria and its complications. Several different regimens of antiretroviral therapy are now available to prevent mother-to-child transmission of HIV and/or progression of maternal HIV infection during pregnancy. However, no published studies have yet shown whether standard intermittent preventive treatment and antiretroviral regimens are medically and operationally compatible in pregnancy. We reviewed existing policies regarding prevention and treatment of HIV and malaria in pregnancy, as well as published literature on adverse effects of antiretrovirals and antimalarials commonly used in pregnancy in developing countries, and found that concurrent prescription of sulfadoxine-pyrimethamine, co-trimoxazole (trimethoprim-sulfamethoxazole), and antiretroviral agents including nevirapine and zidovudine per existing protocols for prevention of malaria and vertical HIV transmission may result in adverse drug interactions or overlapping, diagnostically challenging drug toxicities. Insecticide-treated bednets should be provided for HIV-infected pregnant women at risk for malaria. Sulfadoxine-pyrimethamine should be prescribed cautiously in women concurrently receiving daily nevirapine and/or zidovudine, and should be avoided in women on daily co-trimoxazole. Further research is urgently needed to define safe and effective protocols for concurrent management of HIV and malaria in pregnancy, and to define appropriate interventions for different populations subject to differing levels of malaria transmission and antimalarial drug resistance.
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PMID:Challenges in the concurrent management of malaria and HIV in pregnancy in sub-Saharan Africa. 1643 30

Resistance of the most virulent human malaria parasite, Plasmodium falciparum, to antifolates is spreading with increasing speed, especially in Africa. Antifolate resistance is mainly caused by point mutations in the P. falciparum dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) target proteins. Homology models of the bifunctional P. falciparum dihydropterin pyrophosphokinase-dihydropteroate synthase (PPPK-DHPS) enzyme as well as the separate domains complete with bound substrates were constructed using the crystal structures of Saccharomyces cerevisiae (PPPK-DHPS), Mycobacterium tuberculosis (DHPS), Bacillus anthracis (DHPS), and Escherichia coli (PPPK) as templates. The resulting structures were subsequently solvated and refined using molecular dynamics. The active site residues of DHPS are highly conserved in S. cerevisiae, M. tuberculosis, E. coli, S. aureus, and B. anthracis, an attribute also shared by P. falciparum DHPS. Sulfadoxine was superimposed into the equivalent position of the p-aminobenzoic acid substrate and its binding parameters were refined using minimization and molecular dynamics. Sulfadoxine appears to interact mainly with P. falciparum DHPS mainly through hydrophobic interactions. Rational explanations are provided by the model for the sulfadoxine resistance-causing effects of four of the five known mutations in P. falciparum DHPS. A possible structure for the bifunctional PPPK-DHPS was derived from the structure from the S. cerevisiae bifunctional enzyme. The active site residues of P. falciparum PPPK are also conserved when compared to S. cerevisiae, Haemophilus influenzae, and E. coli. The informative nature of these models opens up avenues for structure-based drug design approaches toward the development of alternative and more effective inhibitors of P. falciparum PPPK-DHPS.
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PMID:Elucidation of sulfadoxine resistance with structural models of the bifunctional Plasmodium falciparum dihydropterin pyrophosphokinase-dihydropteroate synthase. 1651 68

The availability of epidemiologic data on drug-resistant malaria based on a standardized clinical and parasitological protocol is a prerequisite for a rational therapeutic strategy to control malaria. As part of the surveillance program on the therapeutic efficacy of the first-line (chloroquine and amodiaquine) and second-line (sulfadoxine-pyrimethamine) drugs for the management of uncomplicated Plasmodium falciparum infections, non-randomized studies were conducted in symptomatic children aged less than 10 years according to the World Health Organization protocol (14-day follow-up period) at 12 sentinel sites in Cameroon between 1999 and 2004. Of 1,407 children enrolled in the studies, 460, 444, and 503 were treated with chloroquine, amodiaquine, or sulfadoxine-pyrimethamine, respectively. Chloroquine treatment resulted in high failure rates (proportion of early and late failures, 48.6%). Amodiaquine was effective at all study sites (proportion of failures, 7.3%). Sulfadoxine-pyrimethamine therapy was less effective than amodiaquine (P < 0.05), with failures observed in 9.9% of patients. Chloroquine is no longer a viable option and has been withdrawn from the official drug outlets in Cameroon. Amodiaquine and, to a lesser extent, sulfadoxine-pyrimethamine monotherapies are still effective in Cameroon, but further development of resistance to these drugs should be delayed by the novel strategy using artemisinin-based combination therapy. Our findings indicate that amodiaquine is the most rational partner for artesunate. Studies on the efficacy of artesunate-amodiaquine combination are currently being undertaken at several sites in the country.
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PMID:Molecular epidemiology of malaria in Cameroon. XXI. Baseline therapeutic efficacy of chloroquine, amodiaquine, and sulfadoxine-pyrimethamine monotherapies in children before national drug policy change. 1696 11

Sulfadoxine-pyrimethamine (SP) is still a useful drug to combat chloroquine-resistant Plasmodium falciparum malaria in Cameroon. Because of several disadvantages of the in vivo test and in vitro drug sensitivity assays, molecular assays are an alternative laboratory tool to monitor the evolution of antifolate resistance, especially over the entire country that is characterized by several epidemiologic strata and malaria transmission patterns. In this study, 1,430 blood samples from either symptomatic children or asymptomatic carriers were collected from 14 sites throughout the country between 1999 and 2003 for the analysis of dihydrofolate reductase (dhfr) sequence. Of 1,368 samples (95.7%) that were successfully amplified, 1,180 were analyzed by direct sequencing of the polymerase chain reaction product, and 188 were analyzed by restriction enzymes. The prevalences of the wild-type, single Asn-108 mutation, double Arg-59/Asn-108 mutations, double Ile-51/Asn-108 mutations, triple Ile-51/Arg-59/Asn-108 mutations, and mixed alleles were 20.8%, 2.8%, 5.7%, 0.8%, 62.2%, and 7.6%, respectively. The proportions of triple dhfr mutations were > 60% at all study sites, with the exception of the eastern province (42% triple mutants in Bertoua in 1999) and the northern provinces (11-35% triple mutants in Ngaoundere, Garoua, and Maroua). In these two provinces, the proportion of mutant parasites increased significantly (P < 0.05) over the period of 2-4 years. Furthermore, there was a higher proportion (P < 0.05) of wild-type parasites in the northern provinces, compared with the rest of the country. The geographic mapping of molecular markers offers a novel tool for monitoring the epidemiology of drug-resistant malaria.
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PMID:Molecular epidemiology of malaria in Cameroon. XXII. Geographic mapping and distribution of Plasmodium falciparum dihydrofolate reductase (dhfr) mutant alleles. 1696 12


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