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PubMed1975

Chemotherapy in experimental toxoplasmosis: comparison of the efficacy of trimethoprim-sulfur and pyrimethamine-sulfur combinations.

Mice infected by intraperitoneal inoculation of the RH strain of Toxoplasma gondii were treated with various drugs. Trimethoprim was found to have no effect. Sulphamethoxazole, sulphadiazine and pyrimethamine had significant therapeutic effects on the course of murine toxoplasmosis. The therapeutic efficacy of sulphamethoxazole was enhanced by the addition of trimethoprim. A pyrimethamine-sulphadiazine combination was found to be superior to a trimethoprim-sulphamethoxazole combination in the treatment of experimental murine toxoplasmosis.

Animals↗
PubMed1958

Chloroquine or pyrimethamine in salt as a supressive against sporozoite-induced vivax malaria (Chesson strain).

The authors present the results of a study carried out to determine the efficacy of chloroquine- and pyrimethamine-salt mixtures as a suppressive against sporozoite-induced vivax malaria (Chesson strain). The test subjects used in this study were volunteers of military age in the US Penitentiary at Atlanta, Ga. The subjects chosen were all in good physical condition and had no previous history of malaria.Both drug-salt mixtures were entirely acceptable to the volunteers, were indistinguishable in taste and appearance from ordinary salt, and remained stable under the conditions of food preparation. The weekly dosage of the drugs (300 mg of chloroquine base or 25 mg of pyrimethamine per 50 g of salt) had in each case been adjusted to the average salt consumption. Suppression of malaria was found to be complete throughout the salt-drug regimen and for 28-43 days thereafter, even though the subjects were exposed to repeated heavy doses of sporozoites. In contrast, the control subjects, exposed to the same infective doses, all exhibited parasitaemia 13-15 days after exposure.The procedures for preparing the drug-salt mixtures are described in detail and a simple method for determining the salt consumption by measurement of the urinary chloride excretion is outlined.

Animals↗
PubMed1959

Pyrimethamine resistance in Plasmodium vivax malaria.

P. vivax infection (Korean, St Elizabeth or Chesson strain) was induced in 17 neurosyphilitic patients. Pyrimethamine in single doses of either 25, 50, 100 or 200 mg was given to test the schizontocidal and sporontocidal effects.The first single-dose treatment of 25 mg or 100 mg was given between the 8th and 61st days of parasite patency and gave moderately rapid schizontocidal and very rapid sporontocidal effects. All observed cases relapsed.The second treatment, usually three weeks or longer after the first and with the same or higher doses, had either a diminished effect or none on the schizogonous and sporogonous cycles. Subsequent treatment, even at weekly intervals, had no effect.The resistant quality was undiminished in subsequent infections transmitted by mosquito bites, by the injection of preserved sporozoites, or by transfusion of infected blood. Preserving sporozoites or erythrocytic parasites at very low temperatures did not materially affect the resistant quality.In view of the evidence presented, it appears that resistance could also occur in the field when large single doses of pyrimethamine alone are given at less than monthly intervals to febrile persons having active P. vivax infections.

Antimalarials↗
PubMed1959

The development of pyrimethamine resistance by Plasmodium falciparum.

Sixteen patent P. falciparum infections (McLendon and Panama strains) in non-immunes were treated with single doses of pyrimethamine. The schizontocidal and sporontocidal response to the initial dose was rapid.Seven blood-induced infections, of which three were treated with 100 mg and four with 50 mg, did not relapse. Of seven cases observed after 25-mg treatment, five relapsed.Delayed treatment of the relapsing infections (Panama strain) with single doses of 25 mg or 50 mg, and subsequently 100 mg, had virtually no schizontocidal or sporontocidal effect. In one case the resistant infection was transmitted by mosquitos to another patient; the subsequent infection was also highly resistant to the drug.It is concluded that under the experimental conditions of this study resistance to pyrimethamine by P. falciparum may occur rapidly after a single dose of 25 mg, being manifested during relapses on the second challenge with the drug. Increasing the drug dosage does not overcome the resistance. The resistant character is readily transmitted by mosquitos.

Antimalarials↗
PubMed1992

Parasitological, clinical and haematological response of children with Plasmodium falciparum to 4-aminoquinolines and to pyrimethamine-sulfadoxine with quinine in western Kenya.

Children with Plasmodium falciparum infections in Western Province, Kenya, were studied in 1987 for their parasitological, clinical and haematological response to chloroquine, to amodiaquine and to pyrimethamine-sulfadoxine plus quinine. Ninety-eight children under 5 years of age were treated in 1 of 2 hospitals. Of the 56 patients treated with chloroquine base 25 mg/kg, 91% had resistant infections, with 36% having no significant decrease in parasitaemia (RIII resistance); however, 69% responded clinically within a week. Of the 27 patients treated with amodiaquine base 25 mg/kg, 67% had resistant infections, with 7% RIII resistant; 81% responded clinically. The parasites cleared in all 15 children given pyrimethamine-sulfadoxine plus 3 days of quinine. Only when parasites cleared did patients have improved haemoglobins and haematocrits. This study shows that parasitaemia in children hospitalized in western Kenya responds poorly to 4-aminoquinolines, although the patients improve clinically, at least during the first 7 days. Young children may need to clear parasites to avoid the risk of severe anemia and the need for blood transfusions.

Amodiaquine↗
PubMed2005

Blood folate concentrations and in vivo sulfadoxine-pyrimethamine failure in Malawian children with uncomplicated Plasmodium falciparum malaria.

Folate antagonizes the antimalarial action of sulfadoxine-pyrimethamine (SP) in vitro, but its role in vivo is not well understood. We measured blood folate concentrations and SP therapeutic outcomes in Malawian children. Children with late treatment failure and those with adequate clinical and parasitologic responses had similar demographic characteristics, prevalence of parasite mutations conferring resistance to SP, and blood concentrations of anti-malarial drugs following treatment. However, a higher folate concentration was associated with late treatment failure. Patients from a low malaria transmission site had higher blood folate concentrations than those in a higher transmission site (mean +/- SEM = 39 +/- 9.3 ng/mL versus 29 +/- 10 ng/mL; P < 0.0001), and there was a higher rate of late treatment failure in the low transmission area (54.4% versus 40.2%; P = 0.010). This study also provides the first evidence of the independent role of physiologic folate concentrations in in vivo SP therapeutic efficacy, and the critical role of pyrimethamine concentrations in the therapeutic efficacy of SP when one controls physiologic folate levels and the frequency of critical dihydrofolate reductase/dihydropteroate synthase mutations.

Analysis of Variance↗
PubMed2005

A molecular epidemiologic study of point mutations for pyrimethamine-sulfadoxine resistance of Plasmodium falciparum isolates from Lao PDR.

To understand the current condition of pyrimethamine-sulfadoxine (PS) resistant falciparum malaria in Lao PDR, the frequency of point mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes of Plasmodium falciparum were examined in 50 blood samples collected from the patients with P. falciparum infection in Southern Lao PDR. Point mutations in 5 codons of the DHFR gene, which is known to be related to pyrimethamine resistance, were detected in 15 out of the 50 samples (30%). Among the 15 samples, 10 samples showed a double mutation of codons 59 and 108 (Cys59Arg with Ser108Asn). In the remaining 5 samples, an additional mutation was observed in codon 51 (Asn51 lle), providing a triple mutation of codons 51, 59 and 108. On the other hand, point mutations in the 4 codons of DHPS gene related to sulfadoxine resistance were observed only in 2 samples (4.0%), namely in codon 437 (Ala437Gly). Only one sample showed mutations in both DHFR and DHPS genes. From the results, it should be considered that the frequency of PS resistant malaria is still low in Lao PDR. Continuous monitoring for the PS resistant malaria, however, is necessary because of the increasing use of PS in this country.

Animals↗
PubMed2006

Point mutations in the dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum and resistance to sulfadoxine-pyrimethamine in Sri Lanka.

Sulfadoxine-pyrimethamine (SP) is the second-line treatment for Plasmodium falciparum malaria in Sri Lanka. Resistance to SP is caused by point mutations in the dihydrofolate reductase (Pf-dhfr) and dihydropteroate synthase (Pf-dhps) genes of P. falciparum. We determined the genotype of Pf-dhfr and Pf-dhps and the clinical response to SP in 30 field isolates of P. falciparum from Sri Lanka. All patients treated with SP had an adequate clinical response. Eighty-five percent (23 of 27) of pure field isolates carried parasites with double mutant alleles of Pf-dhfr (C59R + S108N) and showed about 200-fold higher levels of resistance to pyrimethamine than the wild type in a yeast system. None of the isolates had either known or novel mutations at other positions in the dhfr domain. In contrast, 67% (20 of 30) of the isolates carried parasites that were wild type for Pf-dhps. In Sri Lanka, detection of the triple mutant allele of Pf-dhfr will require tracking mutations at codon 51.

Animals↗
PubMed2006

Interaction studies of omeprazole with mefloquine, pyrimethamine and sulfadoxine.

Mefloquine hydrochloride, pyrimethamine and sulfadoxine as readily tolerated antimalarial drugs that are highly active against both usual and multidrug resistant strains of Plasmodium falciparum. Omeprazole reduce gastric acid secretion, irreversibly by inhibition of H+-K+ ATPase of the apical membrane of the parietal cell. In order to study the drug interactions of the later with antimalarials, in vitro availability of omeprazole has been studied in presence of mefloquine hydrochloride, pyrimethamine and sulfadoxine. The availability of antimalarial drugs was found to be influenced considerably in presence of omeprazole. The effect of dissolution mediums, simulating various body environments with respect to pH and the influence of temperature on these interactions has been examined in order to elucidate the mechanism of these interactions.

Antimalarials↗
PubMed1991

Pharmacokinetics of pyrimethamine in healthy young volunteers using a new solid phase extraction/HPLC method.

The single dose pharmacokinetics of pyrimethamine were determined in 12 healthy young volunteers using a newly developed fully automated analytical system which combines liquid solid extraction on disposable extraction columns and high performance liquid chromatography. This technique is highly sensitive (detection 1 ng/ml) and reproducible. Following a 50mg dose of the drug, the plasma concentration peaked at 0.48 0.13 g/ml (msd) and was attained 2.5 hours (median value) post dosing. Thereafter, the plasma level of pyrimethamine decreased slowly, the level at 336 hours after administration being still about 40 ng/ml. The area under the plasma concentration-time curve (AUC0-inf) was 56.8 18.4 h.mg/ml. The volume of distribution Vd was: 2.42 1.25 l/kg and the total clearance: 15.55 4.48 ml/h/kg. Urinary excretion represented about 20% to 40% of the dose after seven days of the administered dose.

Adult↗
PubMedDate not supplied

Inhibition of Pneumocystis dihydrofolate reductase by analogs of pyrimethamine, methotrexate and trimetrexate.

Dihydrofolate reductase was obtained from Pneumocystis carinii isolated from heavily infected lungs of female Sprague-Dawley rats infected by transtracheal inoculation. The enzyme differed significantly from other forms of dihydrofolate reductase in response to KCl and to antifolate drugs. Dihydrofolate reductase from P. carinii was used to assess activity of analogs of pyrimethamine, methotrexate, and trimetrexate. One pyrimethamine analog was selective for P. carinii dihydrofolate reductase; potency was in the micromolar range. In contrast, 21 methotrexate analogs and 2 trimetrexate analogs were selective for P. carinii dihydrofolate reductase; potencies for these were in the nanomolar range.

Animals↗
PubMed1991

Comparison of mefloquine, chloroquine plus pyrimethamine-sulfadoxine (Fansidar), and chloroquine as malarial prophylaxis in eastern Thailand.

From July 1983 to March 1984 a randomized double blind prophylactic trial in Thai gem miners working across the border in Cambodia was conducted to determine the prophylactic efficacy of 3 drug regimens against P. falciparum and P. vivax malaria along the Thai-Cambodian border. Gem miners have a high incidence of malaria. Maximum duration of individual participation was 14 weeks. Of 334 participants in this study who were seen every 2 weeks, 145 received mefloquine 500 mg fortnightly, 112 received chloroquine 300 mg base weekly plus Fansidar (1000 mg sulfadoxine and 50 mg pyrimethamine) fortnightly and 77 received chloroquine as 300 mg base weekly. The significant reduction of vivax malaria in study subjects (compared to background incidence) implied good compliance with self administration of chloroquine in the intervening weeks between scheduled appointments. The attack rate in each prophylactic regimen was 2188 cases/1000/year with mefloquine, 8338 cases/1000/year with chloroquine-Fansidar and 10,207 cases/1000/year receiving chloroquine alone. There was a 79% prophylactic efficacy for mefloquine and 18% efficacy for the chloroquine plus Fansidar regimen compared to chloroquine. Using life table analysis, 56% of the mefloquine group, 6% of the chloroquine-Fansidar group and 4% of the chloroquine group were malaria free at the end of the 14 weeks study. The chloroquine plus sulfadoxine-pyrimethamine regimen prescribed for prophylaxis is no longer effective for multidrug resistant strains of P. falciparum in the study area. This study also seriously questions the efficacy of mefloquine prophylaxis.

Adolescent↗
PubMed1990

Efficacy of sulfalene and pyrimethamine combination drugs alone and with quinine in treatment of P. falciparum cases in chloroquine resistant areas of north east India.

Studies were carried out in some areas of Assam, Nagaland, West Bengal and Mizoram where chloroquine resistant strains of Plasmodium falciparum were present during 1983 and 1984, to see the efficacy of treatment of P. falciparum cases with SLP alone or with quinine sulphate. The findings have indicated that SLP in the dosage of sulfalene (1000 mg) + Pyrimethamine (50 mg) is suitable for treatment of P. falciparum cases not responding to chloroquine therapy in N.E. India. Treatment with sulfalene (1500 mg) + Pyrimethamine (75 mg) has no advantage over the SLP (1000 + 50) mg. Combination of quinine (1000 mg x 3 days) + SLP (1000 + 50) mg is better with 100 per cent cure rate. In Karhi Anglong district (Manja PHC) of Assam response to these drug combination is however less.

Adolescent↗
PubMed1989

Antimalarial and toxic effect of triple combination of pyronaridine, sulfadoxine and pyrimethamine.

The triple combination of pyronaridine, sulfadoxine and pyrimethamine which has been proven to be efficient in delaying emergence of drug resistance of rodent malarial parasites was further studied for potential application to malaria control. The antimalarial effect of the triple combination on Plasmodium berghei ANKA-infected mice and the toxic effects in mice and rats were additive. A single dose of pyronaridine 500 mg in combination with sulfadoxine, 1000 or 1500 mg, and pyrimethamine, 50 or 75 mg, given to 72 acute falciparum malaria patients resulted in a 100% cure rate with nil or mild side effects, and no recrudescence of asexual parasite over 4-week follow-up. Preliminary experiments on the drug effect on sporogony showed that the drug combination at the dose used could not completely interrupt the sporozoite formation although many retarded oocysts were found.

Animals↗
PubMed1977

Drug reaction simulating malignant lymphoma: a case due to pyrimethamine.

A 9 1/2-year-old boy who had been treated with pyrimethamine and sulphadimidine presented with generalised lymphadenopathy, fever, and an unusual sun-tanning. He was found to have mild anaemia, severe leucopenia and thrombocytopenia. The bone marrow was megaloblastic. Lymph node biopsy was initially interpreted as showing malignant lymphoma. No treatment for neoplasia was given and he was well 4 1/2 years later. We consider that the seemingly malignant changes were due to pyrimethamine.

Child↗
PubMed1988

[Teratogenic effect of pyrimethamine in the rat. In vivo prevention by calcium folinate].

In vivo prevention of malformations induced by pyrimethamine was studied in the rat. The administration of calcium folinate had an almost complete antiteratogenic effect on external, visceral and skeletal malformations, provided that the vitamin was administered together with the pyrimethamine and that the treatment was continued for the following two days.

Abnormalities, Drug-Induced↗
PubMed1986

A combination of sulfamonomethoxine and pyrimethamine versus other drugs for the treatment of malaria.

Sixty-eight cases of vivax and 30 cases of falciparum malaria patients were treated with a combination of sulfamonomethoxine-pyrimethamine (MP tablet with 500 mg of sulfamonomethoxine and 25 mg of pyrimethamine) and the results were compared with those with chloroquine, Fansidar and quinine. Vivax malaria: Fever and parasites were cleared by the 4th day of treatment in 94 and 92% of the patients, respectively. Chloroquine was the most effective drug and Fansidar and MP tablets shared the next position. Falciparum malaria: Fever and asexual parasites were cleared by the 4th day of treatment in 67 and 78% of the patients, respectively. MP tablets were effective in chloroquine-resistant falciparum malaria contracted in Kalimantan (Indonesia) and Oceanian countries (Vanuatu etc.). Fever and parasite clearance times were shorter with chloroquine or with Fansidar than with MP tablets. Defective preschizonts used to appear following administration of MP tablets both in vivax and falciparum malarias. They were the premonitory laboratory indications that the asexual parasites will be soon eradicated.

Adolescent↗
PubMed1985

[Eosinophilic lung infiltration during malaria prophylaxis with pyrimethamine-sulfadoxine (Fansidar)].

The case is reported of a 40-year-old woman who developed an eosinophilic lung infiltration during malaria prophylaxis with pyrimethamine-sulfadoxine (Fansidar). The patient had a severe condition with cough, fever, chills, dyspnea, weight loss and an unusual but characteristic radiologic picture. Corticosteroid medication was followed by a dramatic improvement in symptoms and complete resolution of the radiographic opacities within a few days. There was no recurrence after cessation of steroids. The authors believe that the cause of this lung disease was an allergic reaction to pyrimethamine-sulfadoxine (Fansidar). Some aspects of drug-induced eosinophilic pulmonary infiltrations are discussed.

Adult↗