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)

A randomized, blinded comparison of malaria prophylaxis with dapsone-pyrimethamine vs. placebo was conducted in 166 schoolchildren from Maputo, Mozambique, from February to June 1989. The children, aged 7-12, received 1 tablet of Maloprim (Wellcome, 100 mg dapsone and 12.5 mg pyrimethamine), or half a tablet if they weighed 30 kg. After being tested for malaria parasites, children were started on Maloprim the next day, or if infected, after treatment with sulfadoxine-primethamine for 2 weeks. Drugs were administered weekly, and capillary blood was checked by-weekly. There were 28 Plasmodium falciparum infections among children taking placebos, and none in those given prophylaxis. Hematocrits were unchanged. This is the 1st study of dapsone-pyrimethamine for prophylaxis in a chloroquine-resistant malaria area. Since use of this agent on a massive scale could result in resistance, it is recommended that its use be restricted to target groups such as primigravidas or to narrow time periods such as early stage of epidemics.
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PMID:Efficacy of dapsone with pyrimethamine (Maloprim) for malaria prophylaxis in Maputo, Mozambique. 150 11

1. H.p.l.c. methods are described for the measurement of pyrimethamine and sulphadoxine in small volumes of plasma dried on filter paper strips. 2. Pyrimethamine/sulphadoxine (Fansidar, Hoffman LaRoche) was given by mouth and by intramuscular injection to children with uncomplicated falciparum malaria but with high parasitaemia (n = 8 for both routes; pyrimethamine 1.25 mg kg-1, sulphadoxine 25 mg kg-1). 3. Plasma concentrations of pyrimethamine and sulphadoxine associated with synergistic effects against pyrimethamine-resistant strains of Plasmodium falciparum in vitro were achieved within 1 h of administration and were maintained beyond the end of sampling. 4. After both oral and parenteral administration the plasma concentrations of both compounds were lower than those predicted by data from healthy subjects. 5. Areas under the plasma concentration-time curves of sulphadoxine after oral and i.m. administration did not differ significantly, although maximum plasma drug concentrations were higher after the i.m. route (P = 0.03). 6. The AUC values of pyrimethamine did not differ significantly between the two routes of administration. However, after i.m. administration AUC(0,24 h) values were smaller (P = 0.03), and the time to maximum plasma drug concentration (tmax) was longer (P = 0.004) than when the drug was given orally.
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PMID:The disposition of oral and intramuscular pyrimethamine/sulphadoxine in Kenyan children with high parasitaemia but clinically non-severe falciparum malaria. 155 Jun 95

In this study the clastogenic effect of pyrimethamine (Daraprim), a folic acid antagonist used for the treatment of toxoplasmosis and malaria on human chromosomes, was investigated. Pyrimethamine was added to in vitro lymphocyte cultures at six different concentrations: 0.05 (normal therapeutic dose), 0.1, 0.2, 0.4, 0.8, and 1.6 mg/ml. No proliferation was observed in any of the cultures containing 1.6 mg/ml pyrimethamine. The results of the cytogenetic evaluations show that the frequency of breaks and gaps increase significantly in dose-dependent manner. Thus, pyrimethamine has a clastogenic effect on human chromosomes.
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PMID:The clastogenic effect of pyrimethamine (Daraprim) on human chromosomes in lymphocyte cultures. 179 9

383 Thai soldiers on the Thai-Cambodian border were entered into a randomized malaria chemoprophylactic trial. Proguanil (200 mg/day) combined with sulfamethoxazole (1000 or 1500 mg/day) were compared to a standard combination of weekly pyrimethamine/dapsone (Maloprim). Men receiving proguanil/sulfamethoxazole had a significantly lower malaria attack rate than those taking pyrimethamine/dapsone. This was true of both the first five-week phase in which 1000 mg of sulfamethoxazole was used (0.11 vs 0.26; p less than 0.001) and in the second ten weeks in which 1500 mg of sulfamethoxazole was used (0.13 vs 0.30; p less than 0.001). Combined relative efficacy indicated that proguanil/sulfamethoxazole was better than pyrimethamine/dapsone by 64% for Plasmodium vivax and by 38% for P. falciparum. Unenforced compliance as measured by returned pills was greater than 86% in both groups. No serious drug side-effects were observed. Proguanil/sulfamethoxazole may represent a useful chemoprophylactic option in areas of multiple drug-resistant malaria.
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PMID:Proguanil/sulfamethoxazole malaria chemoprophy-laxis on the Thai-Cambodian border. 194 64

Pyrimethamine resistance in cultivated laboratory isolates of Plasmodium falciparum is linked to the dihydrofolate reductase mutation Asn-108, a mutation that acts by interrupting drug binding within the active site of the enzyme. To determine the prevalence of this mutation in endemic regions harboring pyrimethamine-resistant malaria, we used a mutation-specific polymerase chain reaction assay to survey P. falciparum strains from a wide section of the Brazilian Amazon. Mutations were identified directly from blood samples without intervening steps of in vitro cultivation. Of 42 samples collected from four states in Brazil, 38 (90%) contained the Asn-108 codon AAC that confers pyrimethamine resistance, four samples contained only the wild-type Ser-108 codon AGC, and none contained the Thr-108 codon ACC found in cycloguanil-resistant pyrimethamine-sensitive strains. These findings indicate that a very high incidence of the Asn-108 DHFR mutation is responsible for pyrimethamine resistance in the Amazon, and they are consistent with recent failure rates reported for Fansidar (pyrimethamine-sulfadoxine). We suggest that limited use of proguanil be evaluated as an alternative to pyrimethamine.
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PMID:Prevalence of the dihydrofolate reductase Asn-108 mutation as the basis for pyrimethamine-resistant falciparum malaria in the Brazilian Amazon. 195 58

Compliance with malaria prophylaxis or reserve drugs was investigated in 477 individuals travelling to regions with endemic malaria. Correct intake of prophylactic medication was confirmed in 225 out of 285 (= 78%). Compliance was independent of type of drug (Mefloquine, Sulfadoxine-Pyrimethamine, Chloroquine). Two tourists missed to start prophylaxis one week before the onset of their travel. 14 travellers stopped prophylactic medication too early after their return, 31 tourists took too high doses of mefloquine. None of the tourists travelling to countries with a therapeutic reserve only became sick, whereas two travelling to Africa contracted malaria.
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PMID:[Malaria study]. 199 82

Chemotherapy keeps an important place in malaria control programme. The development of schizonticidal formulations, which may maintain their efficacy for at least one month after single administration, becomes needful. These formulations should allow to assure a suitable patient compliance and to avoid the disadvantages of high plasmatic peaks. The aim of this study is to evaluate the therapeutic efficacy of implantable bioresorbable reservoir-forms. The use of these polymers allow to avoid the surgical extraction of implanted preparations. Two drug delivery systems were prepared: microspheres and rods. Pyrimethamine, as a drug model was incorporated. Therapeutic activity of these preparations was evaluated on a TB mice-Plasmodium berghei model. Polycaprolactone and polylactide 100 microspheres are not suitable for long-term treatment. In contrast, implantable subdermic rods allowed to fulfil the long-term coverage requirements. Their activity depend on the administered dose and the drug content in implants. Polycaprolactone, polylactide 100 and polylactide 50 implants containing respectively 21.5%, 19-40% of pyrimethamine have protected animals for at least three months.
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PMID:[New antimalarial sustained-release formulations based on bioresorbable polymers: therapeutic evaluation using the Plasmodium berghei model]. 218 57

Serious adverse reactions during malaria chemoprophylaxis are reviewed. Three drugs considered to have caused serious reactions in recent years are pyrimethamine/sulfadoxine (Fansidar), pyrimethamine/dapsone (Maloprim) and amodiaquine. These reactions are principally independent of dose and cannot be determined during screening for optimal doses. However, host factors may precipitate dose-dependent reactions, some of which could be avoided with improvements in drug licensing. Since serious and life-threatening reactions are relatively rare (between 1:1000 and 1:20,000), Phase I to III trials cannot identify them. Reliance must therefore be placed on Phase IV post-marketing studies, including ongoing reviews of national registers, and specially tailored studies to identify the risk using prescription-event monitoring in high-risk populations. Occasionally, medical-record linkage, case-control and cohort studies may provide supportive data. Although large numbers of travellers must, of necessity, be exposed to a drug before relatively rare reactions are identified, the ascertainment of risk using post-marketing surveillance was prevented by the following five deficiencies: lack of awareness of early alerts, inadequate use of national registers, poor attention to epidemiological and statistical rigour, inadequate verification of denominators, and inadequacy of data records. Recommendations are given for minimizing such errors in the future.
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PMID:Ascertainment of risk of serious adverse reactions associated with chemoprophylactic antimalarial drugs. 220 62

We have reviewed a malaria chemoprophylaxis programme in which Maloprim (pyrimethamine and dapsone) has been administered fortnightly by village health workers (VHWs) to approximately 1500 children each year aged 6-59 months resident in 15 primary health care villages in a rural area of The Gambia over 5 years. Reasonable levels of compliance with chemoprophylaxis have been maintained by many children over this period. this has occurred despite minimal outside supervision and support of the programme. Factors which may have affected the level of compliance in individual villages are identified. Large villages and those where social or political factionalism were evident tended to have low levels of compliance. The attitudes of VHWs and mothers to the programme were determined. Most VHWs cooperated enthusiastically and kept accurate records of compliance, despite receiving no compensation from the villagers for administering chemoprophylaxis. The administration of a drug to prevent illness in children was complementary to the curative service provided by VHWs. The chemoprophylactic was widely acceptable and nearly all mothers stated that the tablets were good for their children's health. However, knowledge of the specific purpose of chemoprophylaxis in the prevention of malaria was limited. Improvements in the programme which may result in higher levels of compliance are discussed.
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PMID:Compliance with malaria chemoprophylaxis over a five-year period among children in a rural area of The Gambia. 223 39

A high-performance liquid chromatographic (HPLC) assay was developed for pyrimethamine in plasma, red blood cells (RBCs), and buffer for the purpose of studying its plasma protein binding and RBC partitioning. Pyrimethamine (1000 ng/ml) was 94% bound to plasma proteins on average, depending on the pH of plasma. A comparison of the lower and upper range of plasma concentrations that would be achieved after a malaria prophylaxis dosing regimen (25 mg/week) showed that the fraction unbound was significantly lower at 120 ng/ml than at the upper plasma concentration of 360 ng/ml, 3.5 vs 4.9%, respectively. Nonlinear regression of the effect of albumin concentration (g/L) on plasma binding yielded the equation: fraction unbound = 1/[(0.421 * albumin concentration) + 1] (R2 = 0.99). There was no binding to normal levels of alpha 1-acid glycoprotein (AAG). The mean ratio of the concentration of pyrimethamine in RBCs to that in plasma (RBC:plasma ratio) was 0.42, while the mean RBC:buffer ratio was 5.2. Binding to hemolysate did not account for all of the RBC uptake, suggesting that binding to or partitioning into RBC membranes may be important. Because pyrimethamine binding depends on both albumin concentration and pyrimethamine concentration in the plasma, these studies predict greater free fractions of pyrimethamine associated with the higher doses given for toxoplasmosis (75 mg/day) and with the hypoalbuminemia associated with AIDS and malaria.
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PMID:Binding of pyrimethamine to human plasma proteins and erythrocytes. 228 Oct 36


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