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PubMed1986

The disposition of pyrimethamine in the rat isolated perfused liver: the effect of suramin.

The pharmacokinetics of pyrimethamine (0.5 mg) were determined in the rat isolated perfused liver in the presence of suramin (17.75 mg). The clearance, half life, area under the curve, and volume of distribution of pyrimethamine were unaffected by the concurrent administration of suramin, as was the hepatic sub-cellular disposition of the drug. This report is of relevance to the future concurrent administration of suramin and pyrimethamine in West Africa.

Animals↗
PubMed2007

Independent evolution of pyrimethamine resistance in Plasmodium falciparum isolates in Melanesia.

Pyrimethamine resistance in Plasmodium falciparum has previously been shown to have emerged once in Southeast Asia, from where it spread to Africa. Pyrimethamine resistance in this parasite is known to be conferred by mutations in the gene encoding dihydrofolate reductase (dhfr). We have analyzed polymorphisms in dhfr as well as microsatellite haplotypes flanking this gene in a total of 285 isolates from different regions of Melanesia (Papua New Guinea, Vanuatu, and the Solomon Islands) and Southeast Asia (Thailand and Cambodia). Nearly all isolates (92%) in Melanesia were shown to carry a dhfr double mutation (CNRNI [underlining indicates the mutation]) at positions 50, 51, 59, 108, and 164, whereas 98% of Southeast Asian isolates were either triple (CIRNI) or quadruple (CIRNL) mutants. Microsatellite analysis revealed two distinct lineages of dhfr double mutants in Melanesia. One lineage had the same microsatellite haplotype as that previously reported for Southeast Asia and Africa, suggesting the spread of this allele to Melanesia from Southeast Asia. The other lineage had a unique, previously undescribed microsatellite haplotype, indicative of the de novo emergence of pyrimethamine resistance in Melanesia.

Animals↗
PubMed1973

Chemotherapeutic activity of combination doses of chloroquine, pyrimethamine, and sulfamethoxy-diazine, a long-acting sulfanilamide, against Plasmodium berghei infections in mice.

During the course of antimalarial screening, it was discovered that sulfamethoxydiazine, a long-acting sulfanilamide extensively used in genitourinary tract infections, not only was effective against Plasmodium berghei infections in mice when administered alone but also was active when used in combination with chloroquine, in effect making it possible to use half as much of the latter drug as normally required to achieve the same results. The triple combination of chloroquine, sulfamethoxydiazine, and pyrimethamine, when administered in a ratio of 30:10:1, was found to be potentiating against both blood-induced and sporozoite-induced P. berghei NK(65) infections. Mean effective dose values were calculated for chloroquine, sulfamethoxydiazine, and pyrimethamine against blood-induced P. berghei infection, and when a combination of the three drugs was administered therapeutically in the ratio given above, only one-tenth as much chloroquine, one-thirtieth as much sulfamethoxydiazine, and one-sixtieth as much pyrimethamine were needed to cure 50% of murine infections as was needed for each drug alone. The triple combination also showed enhanced activity against lethal sporozoite-induced P. berghei NK(65) infection in A/J strain mice.

Animals↗
PubMed1991

Anti-Toxoplasma effects of dapsone alone and combined with pyrimethamine.

The efficacy of dapsone alone or combined with pyrimethamine against Toxoplasma gondii was investigated experimentally. For in vitro studies, a sensitive immunoassay was used for assessment of Toxoplasma growth in tissue cultures; dapsone was found to have a significant inhibitory effect at a concentration of 0.5 micrograms/ml in the cultures, and the 50% inhibitory concentration was estimated to be 0.55 micrograms/ml. When pyrimethamine and dapsone were combined, an important synergistic effect which was associated with morphological alterations of the parasites was observed. In vivo studies were performed in a murine model of acute toxoplasmosis in which a tissue culture method was used to estimate the parasite burden in the blood, lungs, and brains of infected mice. Dapsone alone, which was administered at 100 mg/kg/day for 10 days from day 1 after infection, was unable to prevent parasite dissemination and only delayed the time to death of treated mice compared with the time of death of untreated controls. When dapsone and pyrimethamine (18.5 mg/kg/day) were administered in combination from day 4 after infection, parasites were cleared from blood and organs within 6 days, but relapses were observed 15 days after the cessation of therapy. When treatment was started at day 1 after infection, 100% of mice survived and relapses were not observed, suggesting a good efficacy of this combination for preventive therapy.

Animals↗
PubMed1996

Enhanced in vitro activity of pyrimethamine in combination with dapsone against Mycobacterium avium complex.

The in vitro activities of pyrimethamine and dapsone alone and in combination were evaluated against 23 clinical isolates of Mycobacterium avium complex. The broth dilution MICs of dapsone and pyrimethamine alone ranged from 16 to > 64 micrograms/ml. Pyrimethamine in combination with a fixed concentration of dapsone at 0.5 microgram/ml showed enhanced activity, with an MIC range of 0.5 to 16 micrograms/ml.

Anti-Bacterial Agents↗
PubMed2003

Growth-inhibitory effects of artesunate, pyrimethamine, and pamaquine against Babesia equi and Babesia caballi in in vitro cultures.

Three antimalarial drugs, artesunate, pyrimethamine, and pamaquine, were evaluated for their growth-inhibitory effects against Babesia equi and Babesia caballi in in vitro culture. B. equi was more resistant to pyrimethamine than B. caballi. B. equi was also found to be more sensitive to artesunate and pamaquine than B. caballi. Of the three compounds, pyrimethamine gave the most promise for in vivo effectiveness.

Aminoquinolines↗
PubMed2004

Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum.

The development of resistance to sulfadoxine-pyrimethamine by Plasmodium parasites is a major problem for the effective treatment of malaria, especially P. falciparum malaria. Although the molecular basis for parasite resistance is known, the factors promoting the development and transmission of these resistant parasites are less clear. This paper reports the results of a quantitative comparison of factors previously hypothesized as important for the development of drug resistance, drug dosage, time of treatment, and drug elimination half-life, with an in-host dynamics model of P. falciparum malaria in a malaria-naïve host. The results indicate that the development of drug resistance can be categorized into three stages. The first is the selection of existing parasites with genetic mutations in the dihydrofolate reductase or dihydropteroate synthetase gene. This selection is driven by the long half-life of the sulfadoxine-pyrimethamine combination. The second stage involves the selection of parasites with allelic types of higher resistance within the host during an infection. The timing of treatment relative to initiation of a specific anti-P. falciparum EMP1 immune response is an important factor during this stage, as is the treatment dosage. During the third stage, clinical treatment failure becomes prevalent as the parasites develop sufficient resistance mutations to survive therapeutic doses of the drug combination. Therefore, the model output reaffirms the importance of correct treatment of confirmed malaria cases in slowing the development of parasite resistance to sulfadoxine-pyrimethamine.

Animals↗
PubMed1988

Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine.

As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared with the efficacy of chloroquine 500 mg weekly with sulfadoxine 500 mg-pyrimethamine 25 mg weekly in a randomised study of Scandinavian travellers to Kenya and Tanzania during 1984-5. A total of 767 subjects (416 male and 351 female; 384 taking chloroquine phosphate with proguanil hydrochloride and 383 taking chloroquine with sulfadoxine-pyrimethamine) completed a diary on the breakthrough of malaria and the side effects of treatment while taking the drugs. They were also asked to make thick blood films when symptoms like those of malaria occurred, which were sent to and analysed in Denmark. Four subjects taking chloroquine with proguanil hydrochloride and three taking chloroquine with sulfadoxine-pyrimethamine developed falciparum malaria, which was verified microscopically. Side effects were reported by 36 subjects taking chloroquine phosphate with proguanil hydrochloride and 55 taking the other regimen (p = 0.043). The side effects of both regimens were generally mild, but the combination of chloroquine phosphate with proguanil hydrochloride is recommended because it results in fewer side effects. As breakthroughs of malaria occurred at the earliest after seven weeks self treatment should not be recommended for travellers staying only a short time. Thick blood films are useful for diagnosis of suspected cases of malaria, can be prepared by non-specialists in Africa, and can be analysed successfully after long delays.

Adult↗
PubMed1987

Multiple-dose pharmacokinetics of the antimalarial drug Fansimef (pyrimethamine + sulfadoxine + mefloquine) in healthy subjects.

Fansimef is a new antimalarial combination containing pyrimethamine, sulfadoxine and mefloquine in the weight proportions 1 + 20 + 10. It has been designed to fight plasmodia resistant to the presently used antimalarial drugs and to counter the development of new resistant forms of the parasites. In the present study tablets containing 25 mg pyrimethamine, 500 mg sulfadoxine and 250 mg mefloquine were used. Six Brazilian volunteers received a loading dose of 2 tablets followed by 20 maintenance doses of 1 tablet at a dosage interval of 7 days. The pharmacokinetic evaluation of each of the three components was based on the assumption of an open linear two-compartment model. After the last maintenance dose the following kinetic parameters were determined for pyrimethamine, sulfadoxine and mefloquine, respectively: elimination half-life = 123, 179 and 550 h; volume of distribution in the postdistributive phase = 2.5, 0.15 and 18.6 1 X kg-1, and total systemic clearance = 14.0, 0.64 and 24.0 ml X h-1 X kg-1. All these values agree fairly well with those measured in previous single-dose kinetic studies. At steady state, Cmin values of each of the three components generally showed small variations. No unexpected accumulation of any of the three components was observed, indicating that induction or inhibition of metabolic enzymes did not occur during the trial.

Adult↗
PubMedDate not supplied

[Evaluation of the efficacy of azithromycin and pyrimethamine, for treatment of experimental infection of mice with Toxoplasma gondii cystogenic strain].

The efficacy of prolonged administration of azithromycin and pyrimethamine was evaluated in mice experimentally infected with cystogenic strain of Toxoplasma gondii. The animals were intraperitoneally inoculated with one cyst of T. gondii and after 20 days were allocated into four groups: GI, infected without treatment; GII, infected and treated with the association of pyrimethamine (12.5 mg/kg/day) and azithromycin (100 mg/kg/day); GIII, infected and treated with the same dose of pyrimethamine; and GIV, infected and treated in the same way with azithromycin. The oral treatment lasted 120 days, after this period all the animals were sacrificed and the count of cysts in the brain was done. The association of both drugs provided the best results, by diminishing the cyst count in the brain of the animals treated in this way.

Animals↗
PubMed1989

Pneumocystis carinii pneumonia in Stockholm, Sweden: treatment, outcome, one-year-follow-up and pyrimethamine prophylaxis.

In 33 consecutive AIDS patients with a first episode of Pneumocystis carinii pneumonia (PCP) we evaluated treatment, outcome, recurrence rate and pyrimethamine as chemoprophylaxis in a 1-year follow-up. Only 2 patients had a CD4 lymphocyte cell count greater than 0.2 X 10(9)/l. Trimethoprim-sulfamethoxazole (TMP-SMX) was initially given to 32 patients but in 20 of these patients severe adverse reactions caused us to discontinue treatment. Of these 20 patients 11 were started on i.v./i.m. pentamidine but in 6 adverse reactions forced us to withdraw pentamidine. Patients were retrospectively divided with regard to duration of therapy into 2 groups. We could not find any difference between patients in Group 1 treated for less than or equal to 14 days and patients in Group 2 treated for greater than 14 days when comparing outcome, number of recurrences and mean time until recurrence. In 16/21 patients given only TMP-SMX initially in a high dose (means = 16 mg trimethoprim/kg/day), dose reduction was performed to means = 10.5 mg trimethoprim/kg/day after a mean time of 6.9 days. The case-fatality rate for these patients was 10% (2/21) and the overall case-fatality rate was 15% (5/33). We chose pyrimethamine (50-175 mg/week) as secondary prophylaxis for PCP. At 1-year follow-up another 16 patients had died (21/32) and 9/27 (33%) discharged patients had had one recurrence each of PCP. All recurrences occurred among patients treated with only TMP-SMX for the acute episode of PCP. Of these 27 discharged patients 23 had been given pyrimethamine and 8 (36%) of these had experienced a recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed2002

A safety and efficacy trial of artesunate, sulphadoxine-pyrimethamine and primaquine in P falciparum malaria.

OBJECTIVE: To determine effectiveness and safety of the combination of artesunate, sulphadoxine + pyrimethamine and primaquine in the treatment of P falciparum malaria. DESIGN: A hospital based prospective study. SETTING: Base Hospital, Moneragala. METHODS: In 30 P falciparum infected patients admitted to the hospital, blood was taken for estimation of haemoglobin, white cell counts, and serum levels of aspartate aminotransferase, alanine aminotransferase, bilirubin and creatinine. They were administered artesunate, sulphadoxine + pyrimethamine (S + P) and primaquine on day 0 (artesunate 4 mg/kg, sulphadoxine 25 mg/kg, pyrimethamine 1.25 mg/kg and primaquine 0.75 mg/kg), and only artesunate on days 1 and 2 (artesunate 4 mg/kg each day). Blood was examined for malarial parasites, and patients were assessed on days 1, 2, 7, 14, 21 and 28. Patients assessed the severity of selected symptoms. Biochemical analyses were done on day 0 and repeated on days 7 and 28. RESULTS: Eight patients presented with fever which resolved in 7 patients in 48 hours. Asexual parasites were cleared in 80% of the 30 patients within 24 hours of treatment and in all 30 by day 7. Gametocytaemia cleared in all patients by day 14. There were no adverse effects experienced by the patients. The white cell and differential counts, liver enzymes and creatinine levels were within normal limits on all follow up days. CONCLUSIONS: The combination of artesunate, S + P and primaquine was found to be effective and safe in the treatment of uncomplicated P falciparum malaria.

Artemisinins↗
PubMed1976

Effects of pyrimethamine and sulfadiazine on the intestinal development of Toxoplasma gondii in cats.

Treatment with combined pyrimethamine and sulfadiazine prolonged the pre-patent period and shortened the patent period of cyst-induced toxoplasmosis in cats. Oocyst excretion was inhibited in 3 of 4 cats treated intramuscularly with 2 mg/kg body weight pyrimethamine and 100 mg/kg body weight sulfadiazine but not in 4 cats treated with one-half that dosage. Treatment with 2.2 mg/kg body weight pyrimethamine and 132 mg/kg body weight sulfadiazine mixed in cat food did not inhibit oocyst production but prevented antibody formation. No parasites were found upon histological examination of intramuscularly treated cats on days 3, 5, and 7 after infection. Infection with Toxoplasma gondii induced immunity to an oocyst-producing reinfection in both control and treated cats.

Animals↗
PubMed1986

The susceptibility of Plasmodium falciparum to sulfadoxine and pyrimethamine: correlation of in vivo and in vitro results.

In 1982, 2 of 14 Plasmodium falciparum infections acquired in East Africa and diagnosed in Copenhagen were resistant to treatment with sulfadoxine plus pyrimethamine (Fansidar), while in 1983, 6 of 18 were so. The in vivo tests were supplemented by determinations of drug concentrations in serum, and 4 isolates from in vivo-sensitive cases and 6 from in vivo-resistant cases were selected for in vivo tests. These were performed in ordinary RPMI 1640 medium and in a medium with physiological p-aminobenzoic acid and folic acid concentrations. Pharmacokinetic aberrations were found to be of possible importance in only 2 of the in vivo-resistant cases. In vitro susceptibility to sulfadoxine was found to be uniformly low in all isolates. Testing with a combination of sulfadoxine and pyrimethamine in the medium with physiological concentrations of cofactors probably reflects the in vivo situation most accurately, but in all but 1 of the isolates studied in vitro the in vivo susceptibility to Fansidar would be predicted by in vitro susceptibility to pyrimethamine in either medium. The concentration of p-aminobenzoic acid in serum, quantitated by high performance liquid chromatography, was found to be subject to wide variation, and this may have implications for in vitro testing.

Adult↗
PubMed2002

Development of a method for the determination of pyrimethamine concentrations in feeds by ion-pairing high-performance liquid chromatography.

An ion-pairing reversed-phase high-performance liquid chromatography (HPLC) method with diode array detection at 280 nm was developed to determine pyrimethamine concentrations in feed for laying hens. Pyrimethamine was extracted with a mixture of 5% isobutanol and 95% benzene, and the extract was cleaned up on an alumina column. The drug was eluted from an Intersil ODS-3V column (250 by 4.6 mm) with a mixture of 25% acetonitrile and 75% water (vol/vol) containing 0.01 M tetramethylammonium chloride as an ion-pairing agent and adjusted with acetic acid to pH 3.5. The flow rate was 1.0 ml/min. Mean recovery of pyrimethamine from supplemented feeds at concentrations of 2, 4, and 5 microg/g of feed were 100.5, 103.5, and 100.8%, respectively. Precision within a day ranged from 4.3 to 7.0% for the three concentrations, and day-to-day precision was 5.3% for feed supplemented at a concentration of 4 microg/g. No chromatographic interference was detected from other 2,4-diaminopyrimidine compounds or other major drugs used in poultry.

Animal Feed↗
PubMed1987

Use of pyrimethamine-sulfadoxine (Fansidar) in prophylaxis against chloroquine-resistant Plasmodium falciparum and Pneumocystis carinii.

The widespread emergence of chloroquine-resistant Plasmodium falciparum led to the formulation of an effective, fixed combination of two antimalarial agents, pyrimethamine and the long-acting sulfonamide sulfadoxine, for prophylaxis and treatment. These drugs act at sequential steps to inhibit the formation of tetrahydrofolate in the parasite. Recently, their use for malaria prophylaxis has been associated with severe, at times fatal, cutaneous reactions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. These reactions have necessitated a major reassessment of the indications for pyrimethamine-sulfadoxine use and increased the search for pharmacologic, immunologic and behavioral approaches to the prophylaxis and treatment of infection with P. falciparum. Pyrimethamine-sulfadoxine may be effective in preventing recurrent pneumonia caused by Pneumocystis carinii in patients with the acquired immunodeficiency syndrome, but life-threatening cutaneous reactions have also been reported in this setting.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Isospora belli infection: treatment with pyrimethamine.

Isosporiasis is an uncommon but important diarrheal disease of humans that, like cryptosporidiosis, is life-threatening in patients with the acquired immunodeficiency syndrome (AIDS). Isospora belli infection responds rapidly to therapy with trimethoprim-sulfamethoxazole, but patients with AIDS have a high rate of adverse reactions to this therapy. The cases of two patients with AIDS, sulfonamide allergy, and I. belli infection are reported. They were treated successfully with pyrimethamine alone, 75 mg/d, and recurrence was prevented with daily pyrimethamine therapy, 25 mg/d. In patients with AIDS with sulfonamide allergy or intolerance, pyrimethamine alone seems to be a reasonable alternative therapy for I. belli infection.

Adult↗