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At least 505 records · Page 28Linked to original sources
PubMed2003

The effect of providing fansidar (sulfadoxine-pyrimethamine) in schools on mortality in school-age children in Malawi.

Malaria is a major cause of death in school-age (5-18 years) children in Malawi. Save the Children Federation helped schools in Mangochi District, Malawi, to obtain pupil-treatment kits, which enabled teachers to dispense sulfadoxine-pyrimethamine tablets according to national guidelines. The overall and malaria-specific mortality rates were calculated for the 3 years before and 2 years after the intervention was introduced; rates dropped from 2.2 to 1.44 deaths/1000 student-years and from 1.28 to 0.44 deaths/1000 student-years, respectively. School-based interventions could play a part in mitigating malaria.

Adolescent↗
PubMed2006

Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial.

BACKGROUND: In the Sahel and sub-Sahelian regions of Africa, malaria transmission is highly seasonal. During a short period of high malaria transmission, mortality and morbidity are high in children under age 5 years. We assessed the efficacy of seasonal intermittent preventive treatment-a full dose of antimalarial treatment given at defined times without previous testing for malaria infection. METHODS: We did a randomised, placebo-controlled, double-blind trial of the effect of intermittent preventive treatment on morbidity from malaria in three health-care centres in Niakhar, a rural area of Senegal. 1136 children aged 2-59 months received either one dose of artesunate plus one dose of sulfadoxine-pyrimethamine or two placebos on three occasions during the malaria transmission season. The primary outcome was a first or single episode of clinical malaria detected through active or passive case detection. Primary analysis was by intention-to-treat. This study is registered with , number NCT00132561. FINDINGS: During 13 weeks of follow-up, the intervention led to an 86% (95% CI 80-90) reduction in the occurrence of clinical episodes of malaria. With passive case detection, protective efficacy against malaria was 86% (77-92), and when detected actively was 86% (78-91). The incidence of malaria in children on active drugs was 308 episodes per 1000 person-years at risk, whereas in those on placebo it was 2250 episodes per 1000 person-years at risk. 13 children were not included in the intention-to-treat analysis, which was restricted to children who received a first dose of antimalarial or placebo. There was an increase in vomiting in children who received the active drugs, but generally the intervention was well tolerated. INTERPRETATION: Intermittent preventive treatment could be highly effective for prevention of malaria in children under 5 years of age living in areas of seasonal malaria infection.

Antimalarials↗
PubMed1981

Drug therapy for Plasmodium falciparum malaria resistant to pyrimethamine-sulfadoxine (Fansidar). A study of alternate regimens in Eastern Thailand, 1980.

A trial of drug regimens for treating Plasmodium falciparum malaria was conducted in a refugee camp in eastern Thailand where extensive 'Fansidar' (pyrimethamine-sulfadoxine) resistance had been demonstrated. The efficacy of quinine alone was compared to that of quinine combined with either fansidar or tetracycline. Quinine alone cleared the parasitaemia in 57 of 59 patients but failed to cure approximately one-third of these patients after 7 or 10 days of therapy. The addition of fansidar to quinine therapy did not significantly improve the overall cure rate. Tetracycline given for 10 days in combination with quinine cured all patients, suggesting that tetracycline should be considered in treating patients with falciparum malaria contracted in the area of the Thai-Kampuchean border.

Child↗
PubMed1981

Resistance of Plasmodium falciparum malaria to sulfadoxine-pyrimethamine ('Fansidar') in a refugee camp in Thailand.

Since it was first introduced 'Fansidar' (pyrimethamine 25 mg, sulfadoxine 500 mg) has been the preferred treatment for uncomplicated chloroquine-resistant Plasmodium falciparum malaria in Thailand. Because many patients at a refugee camp in Thailand did not seem to be responding to therapy 9 patients who received fansidar for P. falciparum infection were followed up with serial parasite counts. In all of them the infection was resistant to fansidar. The results of this study suggest that fansidar resistance is prevalent at this camp and should prompt more exhaustive studies of the epidemiology of fansidar resistance in the area.

Adolescent↗
PubMed1984

Randomised comparative study of mefloquine, qinghaosu, and pyrimethamine-sulfadoxine in patients with falciparum malaria.

A prospective trial in 80 patients randomly allocated to four antimalarial treatment regimens--mefloquine plus pyrimethamine-sulfadoxine ('Fansidar'); mefloquine plus qinghaosu; mefloquine, fansidar, and qinghaosu; and qinghaosu alone--was carried out on Hainan Island, China, in patients with chloroquine-resistant falciparum malaria. A radical cure with slight side-effects was obtained with mefloquine plus fansidar; the addition of qinghaosu greatly increased the rate of parasite clearance with no additional side-effects. Qinghaosu alone had a rapid rate of parasite clearance, no side-effects, but a high recrudescence rate. These antimalarial drugs seem to act at different stages of the asexual parasite cycle and their most efficient use may depend on when in the course of the disease they are given. Because of the continuing appearance of drug-resistant strains of Plasmodium falciparum combination drug therapy is now indicated, but which drugs and how best they should be used remains to be decided.

Adolescent↗
PubMed2001

Mutagenesis of dihydrofolate reductase from Plasmodium falciparum: analysis in Saccharomyces cerevisiae of triple mutant alleles resistant to pyrimethamine or WR99210.

Inhibitors of dihydrofolate reductase (DHFR) have been a mainstay of chemotherapy of falciparum malaria for >50 years. Unfortunately, point mutations in DHFR are the major cause of resistance to drugs of this class and mutations have rapidly diminished the clinical effectiveness of these drugs. We designed a simple yeast-based system to produce and analyze point mutations in the Plasmodium falciparum DHFR domain of the DHFR-thymidylate synthase gene that confers resistance to pyrimethamine (PM), the major antifolate currently used in malaria treatment, or to WR99210, an experimental antifolate. We used PCR mutagenesis, screened >1000 DHFR alleles that encoded functional enzymes and studied approximately 100 that were more resistant than a naturally occurring resistant allele (N51I and S108N). The IC(50) values for both drugs were determined for a subset of 44 alleles that carried only a single new mutation. Mutations that increased resistance to PM 10-100 fold (to >10(-4) M) were identified in three regions of the DHFR domain - around amino acids 50, 188 and 213. In contrast, mutations that caused WR-resistance were far less common and only conferred approximately 10-fold resistance (to approximately 10(-7) M). Even more interesting, only the mutations at 188 increased resistance to WR and mutations in the 213 and other regions either had no effect or actually increased sensitivity to WR. This collateral hypersensitivity raises the possibility that opposing selection for resistance/sensitivity to PM and WR might be used to slow selection of populations of P. falciparum resistant to antifolate treatment.

Alleles↗
PubMed1993

[Primary prevention of cerebral toxoplasmosis in patients with HIV infection: results of a double-blind randomized trial, pyrimethamine versus placebo].

To assess the efficacy of pyrimethamine (Pyr) for primary prophylaxis of cerebral toxoplasmosis (CT) in HIV patients (pts), 554 pts were randomized in a double-blind, placebo-controlled trial (mean follow-up: 14 months). The intent-to-treat analysis found no significant difference in the incidence of ct at 1 year: 12% (Pyr) versus 13% (Pcb) nor in survival. Side-effects leading to stop the study drug were more frequent in Pyr group, especially cutaneous rashes: 8% (Pyr) versus 2% (Pcb).

Double-Blind Method↗
PubMed1997

Alternative method for determination of pyrimethamine in plasma by high-performance liquid chromatography.

A rapid, selective, sensitive and reproducible reversed-phase high-performance liquid chromatography (HPLC) procedure for the quantitative determination of pyrimethamine (PYR) in plasma is described. The procedure involved the two-step extraction of PYR and the internal standard, quinine (QN) with acetonitrile and dichloromethane at basic pH. Chromatographic separation consisted of the mobile phase (methanol-water containing 0.005 M octanesulfonic acid, 50:50, v/v) running through the column (Techopak-10 C18) at a flow-rate of 1.6 ml/min. Detection was at UV wavelength of 240 nm. The mean recoveries of PYR and QN at a concentration range of 50 and 500 ng/ml were 98.9 and 89%, and 94.7 and 96% for PYR and QN. The within-day coefficients of variation were 2.1-5.1% for PYR and 5.9% for QN. The day-to-day coefficients of variation were 2.1-4.1% for PYR and 5% for QN. The minimum detectable concentrations for PYR and QN in plasma were 3 and 10 ng/ml. The method was found to be suitable for use in clinical pharmacokinetic study.

Calibration↗
PubMed1996

Persistent diarrhea caused by Isospora belli: therapeutic response to pyrimethamine and sulfadiazine.

A 54-year-old human immunodeficiency virus (HIV)-positive homosexual man developed overwhelming watery diarrhea and marked weight loss over a 3-week period. Although Entamoeba histolytica and other nonpathogenic enteric protozoa were observed along with Isospora belli in this patient's stool specimens, they were promptly eradicated after metronidazole (flagyl) treatment. The presence of I. belli oocysts in various stages of development in the stool and clinical symptoms related to Isospora infection persisted for 10 more months despite treatment with combined chemotherapeutic agents. Clinical and parasitiological resolution was ultimately achieved through an 8-week course of pyrimethamine and sulfadiazine.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: structural basis of antifolate resistance.

The nature of the interactions between Plasmodium falciparum dihydrofolate reductase (pfDHFR) and antimalarial antifolates, i.e., pyrimethamine (Pyr), cycloguanil (Cyc) and WR99210 including some of their analogues, was investigated by molecular modeling in conjunction with the determination of the inhibition constants (Ki). A three-dimensional structural model of pfDHFR was constructed using multiple sequence alignment and homology modeling procedures, followed by extensive molecular dynamics calculations. Mutations at amino acid residues 16 and 108 known to be associated with antifolate resistance were introduced into the structure, and the interactions of the inhibitors with the enzymes were assessed by docking and molecular dynamics for both wild-type and mutant DHFRs. The Ki values of a number of analogues tested support the validity of the model. A 'steric constraint' hypothesis is proposed to explain the structural basis of the antifolate resistance.

Amino Acid Sequence↗
PubMed1998

Detection of pyrimethamine-induced DNA damage in mouse embryo and maternal organs by the modified alkaline single cell gel electrophoresis assay.

We studied the embryonic and maternal genotoxicity of pyrimethamine (PYR), a potent teratogen and folate antagonist, using alkaline single cell gel electrophoresis (SCG, or Comet) assay as modified by us (we used isolated nuclei instead of isolated cells). ICR mice were treated on the 13th day of pregnancy with a single oral dose of 50 mg PYR/kg. Six maternal organs (liver, kidney, lung, brain, spleen, bone marrow), maternal and fetal placentas, and two embryos were taken 6 and 16 h after treatment; the embryos were divided into head and body portions. Each sample was minced, homogenized gently, and centrifuged. The nuclei from the precipitates were used. PYR induced DNA damage in all maternal organs except spleen and bone marrow 6 h after administration. The DNA damage in all the affected organs was less at 16 h than at 6 h, and that of the kidney and brain returned to control level at 16 h. PYR also induced DNA damage in maternal and fetal placentas and embryos that was detected at 6 and 16 h, with greater damage at 6 h. Co-treatment of folinic acid calcium salt (FNA, 10 mg/kg ip), a reduced active folate form, prevented the PYR-induced DNA damage in all target tissues examined 6 h after treatment. These data indicate that the observed embryonic and maternal DNA damage caused by PYR may be related to folate deficiency, and that the modified alkaline SCG assay can be used to predict fetal/embryonic genotoxicity in vivo, in addition to the organ-specific maternal genotoxicity.

Animals↗
PubMed2001

Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next?

Chemotherapy remains the only practicable tool to control falciparum malaria in sub-Saharan Africa, where >90% of the world's burden of malaria mortality and morbidity occurs. Resistance is rapidly eroding the efficacy of chloroquine, and the combination pyrimethamine-sulfadoxine is the most commonly chosen alternative. Resistant populations of Plasmodium falciparum were selected extremely rapidly in Southeast Asia and South America. If this happens in sub-Saharan Africa, it will be a public health disaster because no inexpensive alternative is currently available. This article reviews the molecular mechanisms of this resistance and discusses how to extend the therapeutic life of antifolate drugs.

Africa South of the Sahara↗
PubMed2001

Structural studies on bioactive compounds. 34. Design, synthesis, and biological evaluation of triazenyl-substituted pyrimethamine inhibitors of Pneumocystis carinii dihydrofolate reductase.

The triazenyl-pyrimethamine derivative 3a (TAB), a potent and selective inhibitor of Pneumocystis carinii DHFR, was selected as the starting point for a lead optimization study. Molecular modeling studies, corroborated by a recent crystal structure determination of the ternary complex of P. carinii DHFR--NADPH bound to TAB, predicted that modifications to the acetoxy residue of the lead inhibitor could exploit binding opportunities in the vicinity of an active site pocket bounded by residues Ile33, Lys37, and Leu72. Substitutions in the benzyl moiety with electron-donating and electron-withdrawing groups were predicted to probe face-edge interactions with amino acid Phe69 unique to the P. carinii enzyme. New triazenes 10a--v and 12a--f were prepared by coupling the diazonium tetrafluoroborate salt 6b of aminopyrimethamine with substituted benzylamines or phenethylamines. The most potent of the new inhibitors against P. carinii DHFR was the naphthylmethyl-substituted triazene 10t (IC(50): 0.053 microM), but a more substantial increase in potency against the rat liver DHFR led to a reduction in selectivity (ratio rat liver DHFR IC(50)/P. carinii DHFR IC(50): 5.36) compared to the original lead structure 3a (ratio rat liver DHFR IC(50)/P. carinii DHFR IC(50): 114).

Animals↗
PubMed2003

The efficacy of antimalarial monotherapies, sulphadoxine-pyrimethamine and amodiaquine in East Africa: implications for sub-regional policy.

Between 1998 and 2001, Kenya, Uganda, Tanzania, Zanzibar, Rwanda and Burundi changed antimalarial drug policy, in the face of widespread chloroquine resistance. The new first-line treatment is either sulphadoxine-pyrimethamine (SP) monotherapy, or a combination of SP with either chloroquine or amodiaquine. Two national malaria control programmes, Burundi and Zanzibar, have decided upon amodiaquine-artesunate as their first-line treatment, although SP will continue to fill this role until the new policy can be implemented. Given the broad uniformity of parasite chemoresistance in the six countries, The East African Network for Monitoring Antimalarial Treatment (EANMAT) has focused attention on, and worked towards, a sub-regional antimalarial drug policy, where the evidence base would be the entire portfolio of network in vivo test results. Currently, there are several different antimalarial drug policies within the EANMAT area: the intention is to eventually replace this plethora of policies with a single, sub-regional policy based upon combination therapy. Currently, successful malaria treatment depends primarily upon the efficacy of SP, and of amodiaquine, which is either a component of first-line treatment, or the second line drug. This report addresses the results of WHO in vivo tests on these two monotherapies within the network. Results are analysed to assess the evidence for change in parasite susceptibility over time; the range of susceptibility to each drug within countries, and the implications of test results on policy.

Africa, Eastern↗
PubMed1996

A randomized trial of chloroquine, amodiaquine and pyrimethamine-sulphadoxine in Gambian children with uncomplicated malaria.

The increasing occurrence of chloroquine-resistant Plasmodium falciparum in sub-Saharan Africa makes it essential to reconsider current recommendations for the treatment of uncomplicated P.falciparum malaria. In an open, randomized trial, we have compared chloroquine (CQ), amodiaquine (AQ), and pyrimethamine-sulphadoxine (PS) in rural Gambian children with uncomplicated P.falciparum malaria. Three hundred children were randomly assigned at the time of consultation (Do) to oral treatment with 25 mg/kg CQ, 25 mg/kg AQ (both given over 3 days), or 1.25/25 mg/kg PS. They were reviewed on day 7 (D7) and day 28 (D28) for symptoms, malaria parasitaemia, and packed cell volume (PCV). Significantly more children treated with PS compared to CQ (17 vs 7%, P = 0.03) or AQ (17 vs 3%, P = 0.001) returned with clinical complaints during the first 3 days after treatment. Five of these patients had a generalized convulsion (1 from the AQ group, 4 from the PS group), of whom 4 developed cerebral malaria. At D7, significantly more patients treated with CQ compared to AQ (25 vs 7%, P = 0.0009) or PS (25 vs 4%, P = 0.0001) were parasitaemic. By D28, the cumulative number of parasitological failures was significantly higher in the CQ group compared to the AQ group (65 vs 35%, P = 0.0001), and significantly higher in the AQ group compared to the PS group (35 vs 14%, P = 0.001). Overall, 91% of parasitological failures observed during the study period were symptomatic and were consequently treated with an alternative antimalarial drug. Over the 28-day study period the mean PCV increased significantly less in the CQ group than in the PS group (1.2 vs 3.8%, P = 0.016) and was lower in the CQ group than in the AQ group (1.2 vs 2.7%, P = 0.12, not significant). These results suggest that PS acts more slowly than 4-aminoquinolines in controlling the clinical features of malaria, and that AQ can be considered as an interim alternative to CQ in the first-line therapy of uncomplicated malaria in African areas of high CQ resistance.

Amodiaquine↗
PubMed2000

Efficacy of sulphadoxine-pyrimethamine for acute uncomplicated malaria due to Plasmodium falciparum in Malawian children under five years old.

In 1993, Malawi replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP) as its first-line treatment for uncomplicated malaria in children < 5 years of age. To assess the efficacy of SP after 5 years of widespread use, we undertook this study at 7 sites in 6 districts of Malawi. Febrile children < 5 years attending the outpatient clinics of selected hospitals whose parents consented were enrolled in the study if they had an axillary temperature of > or = 37.5 degrees C and pure Plasmodium falciparum parasitaemia of >or =2000 asexual parasites/mm3. They were then followed for 14 days or until clinical failure. Parasitological resistance rates (RII and RIII) ranged from 7% to 19%. Resistance was higher in the north than in the central and southern regions, although this difference was not statistically significant. Resistance rates were a mean 19% during the rainy season vs. 12% in the dry season (P > 0.05). 80% of parasitological resistance was at the RII level. Of all children who failed parasitologically (90/641), 84 (93%) had no fever on day 7 and their mothers did not report them as being ill; only 6 of 641 (0.9%) patients met the WHO criteria for clinical treatment failure. Regardless of study site, 75% of mothers reported their children as having improved by day 3; 90% reported improvement by day 7, and all reported improvement by day 14. None of the children experienced any serious adverse reactions and none died. We found that after more than 5 years of widespread use of SP in Malawi, its efficacy remains acceptable for treatment of uncomplicated malaria, and it should therefore be retained as first-line treatment.

Acute Disease↗
PubMed2000

Chloroquine- and sulfadoxine-pyrimethamine-resistant Falciparum malaria in vivo - a pilot study in rural Zambia.

BACKGROUND: Chloroquine (CQ) and Sulfadoxine-Pyrimethamine (SP) are the predominantly used antimalarials in Zambia and other parts of East Africa, but increasing resistance of P. falciparum is a major concern. METHODS: Seventy consecutive patients with uncomplicated falciparum malaria were enrolled. In 43 patients, no prior CQ use could be demonstrated by history and urianalysis (qualitative test, Dill & Glazko) and these patients were given CQ; the other 27 had taken CQ before and received SP. RESULTS: Combined R-II and R-III CQ-resistance was 58% (60% in under-fives), which is the range previously reported from Zambia. By contrast, SP-resistance (R-II and R-III) was much higher (26%) than previously reported (3% - 17%). The history of prior CQ intake correlated well with the results of the Dill-Glazko test; there was no evidence for prior SP intake to explain these results. CONCLUSION: If our findings of SP resistance are confirmed, other drugs such as quinine, atovaquone/proguanil and artemisinin are required to treat malaria in Zambia.

Animals↗
PubMed2001

Plasmodium falciparum pfcrt and pfmdr1 polymorphisms are associated with the pfdhfr N108 pyrimethamine-resistance mutation in isolates from Ghana.

The Plasmodium falciparum chloroquine resistance transporter gene (pfcrt) T76 and multidrug resistance gene analogue (pfmdr1) Y86 mutations are associated with chloroquine(CQ)-resistance. In isolates from 172 pregnant women living in the area of Agogo, Ghana, pfcrt T76 was detected in 69% and pfmdr1 Y86 in 66%. Pfcrt T76 but not pfmdr1 Y86 was more prevalent in samples from women with residual CQ in urine or serum. Parasite densities and multiplicity of infection of pfmdr wild type but not of resistant isolates were reduced by CQ. Adjusted for CQ and pyrimethamine (PYR) in urine, the P. falciparum dihydrofolate reductase (pfdhfr) N108 mutation which confers PYR-resistance was 3.1 and 3 times, respectively, more likely to be detected in isolates containing pfcrt and pfmdr1 mutations than in those comprising wild type alleles. Pfcrt, pfmdr, and pfdhfr mutations are frequent in P. falciparum from this part of Ghana which may limit the choice of drugs for the prevention of malaria in pregnancy. The association of CQ- and PYR-resistance mutations independent of recent drug use could indicate accelerated development of resistance to structurally unrelated drugs. Alternatively, it may reflect selection of resistance in persisting infections due to no longer detectable drug pressure.

ATP-Binding Cassette Transporters↗