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PubMed1977

The effect of chemo-immunotherapy with SDDS, pyrimethamine and anti-toxoplasma serum on toxoplasma gondii cysts in latent infected NMRI mice.

A substantial reduction of brain cyst numbers could be obtained through a six week therapy with SDDS-pyrimethamine combination or a high titer anti-Toxoplasma serum. NMRI mice experimentally infected three months earlier with cyst-forming Toxoplasma strains Witting, Alt or Gail were used. The effectiveness of the treatments could be increased considerably by simultaneous administration of anti-Toxoplasma serum and SDDS-pyrimethamine. A highly significant reduction of brain cyst numbers, upto 65%, could be obtained by using this mode of chemoimmunotherapy. The effectiveness of the treatments used varied amongst the three Toxoplasma strains.

Animals↗
PubMed1984

Cross resistance of pyrimethamine and sulfadoxine to their related compounds in Plasmodium falciparum.

Cross resistance of pyrimethamine and amethopterin, sulfadoxine and the other sulfonamides in Plasmodium falciparum culture lines was studied. Our results indicate some evidence of a cross resistance between pyrimethamine to amethopterin a drug sharing the same mode of action but never been used as an antimalarial before. Studies on sulfonamides revealed that the minimal inhibitory concentration for sulfadoxine was lower than for sulfadiazine and sulfisoxasole, and that a cross resistance between sulfadoxine and the other sulfonamides may not occur.

Animals↗
PubMed1980

Pyrimethamine sensitivity in Plasmodium falciparum: determination in vitro by a modified 48-hour test.

Four strains of Plasmodium falciparum recently isolated in culture were assessed in vitro for their response to pyrimethamine. A simple modified 48-hour test was used, which showed two strains to be sensitive to the drug in vitro, while the other two were resistant at a very high level. In the two strains for which relevant clinical information was available the in vivo response to pyrimethamine was corroborated by the in vitro findings. This modified 48-hour test is thus useful for determining patterns of drug sensitivity in laboratory-adapted strains, and would be a valuable asset if found to be equally applicable under field conditions.

Adult↗
PubMed1980

Immunopotentiation by pyrimethamine in the mouse.

Pyrimethamine, a 2,4-diaminopyrimidine useful in the treatment of malaria and toxoplasmosis, was found to enhance antibody and delayed-type hypersensitivity responses to sheep red cells in mice. The immunodepression of tumour-bearing mice was also reversed by pyrimethamine. This drug may prove useful as a general immunostimulant in clinical situations where the immune system has been compromised by cancer or other debilitating illnesses.

Adjuvants, Immunologic↗
PubMed1995

Stage sensitivity of Plasmodium vinckei petteri to quinine, mefloquine, and pyrimethamine.

The stage-dependent sensitivity of Plasmodium vinckei petteri to the antimalarial drugs quinine, mefloquine, and pyrimethamine was investigated using single subcurative doses and 2 different tests: a prepatency test evidencing the extension of the prepatent period according to the stage at which the drug was administered, and a patency test showing the morphological alterations of the parasites and the modifications of the parasitic pattern following drug treatment. Quinine activity was maximal when it hit the midterm trophozoite. No pigment clumping was seen and parasites developed normally until they reached the schizogonic stage when they became morphologically altered and unproductive. Mefloquine also acted on the midterm trophozoites. Parasites at this stage were killed immediately by the drug as evidenced by their degenerative appearance, and dead parasites lingered in the blood smears for at least 6 hr. However, although mefloquine was active during at least 48 hr (2 cycles), some trophozoites escaped destruction. The schizont stage was found to be the most sensitive to pyrimethamine, as previously reported for other parasite species. These results add to our previous reports showing that each drug acts preferentially on a specific stage of parasite development.

Animals↗
PubMed1994

A study of the comparative bioavailability of pyrimethamine-sulfadoxine obtained from two oral preparations.

The bioavailability of two oral preparations of pyrimethamine-sulfadoxine are compared in a randomised cross-over study. Pyrimethamine(PM)-sulfadoxine(SD) was given orally in a single dose to healthy male adults (SD 12 mgkg-1; PM 0.64 mgkg-1). For Fansidar(Hoffman-LaRoche) the mean AUC for PM and SD were; 0.47 mghl-1 and 45.4 mghl-1, and for Falcidin(Cosmos), the mean AUC for PM and SD were; 0.49 mg hl-1 and 42.9 mghl-1 respectively. There was no significant difference in bioavailability of PM or SD between the two preparations.

Administration, Oral↗
PubMed1996

Efficacy of sulfadoxine-pyrimethamine in chloroquine resistant falciparum malaria in Bombay.

Several reports have confirmed the existence of chloroquine resistant Plasmodium falciparum malaria in Bombay. In the management of these cases, of the therapeutic options available, sulfadoxine-pyrimethamine (SP) (administered as a single dose) is preferred, since quinine has to be administered over a period of 7 days while mefloquine is yet to be marketed in India. With increasing reports of falciparum malaria resistant to SP from Thailand and Africa, the present study was conducted to determine the efficacy of SP in the treatment of chloroquine resistant falciparum malaria cases in Bombay. 17 uncomplicated falciparum malaria patients documented to be resistant to chloroquine (10 RI, 5 RII and 2 RIII) by the WHO (1973) in-vivo extended field test criteria and by estimation of plasma chloroquine levels by High Performance Liquid Chromatography were included in the study. These adult patients were then treated with a supervised single dose of 3 tablets of SP and peripheral blood smears were then repeated on days 3, 4, 5, 7, 14, 21, 28, 35 and 42 after treatment. 14 patients responded and were sensitive while 3 patients showed RII grade resistance to SP. These 3 patients then responded to a 7 day course of quinine (30 mg/kg/day)+doxycycline (100 mg/day). These results thus document that SP can be used as an effective second-line antimalarial drug. However one should monitor the patient for plasmodial resistance to sulfadoxine-pyrimethamine.

Adult↗
PubMed1997

Detection of fragile sites induced by pyrimethamine.

In this study, the effect of pyrimethamine in inducing expression of fragile sites in human peripheral blood lymphocyte cultures is investigated. In vitro lymphocyte cultures of 15 healthy individuals were treated with 0.02 mg/ml of pyrimethamine for 48 and 72 hr. One culture was used as control. The number of cells showing chromosomal aberration increases significantly in the cultures after 48 and 72 hr in comparison to the control group (P < 0.001). Localization of fragile sites was determined by the G-banding method and light microscopy. As a result, five folic acid-sensitive fragile sites (1p32, 1q32, 3p14, 6p22, 14q24) were detected.

Adult↗
PubMed1997

In vitro sensitivity of Plasmodium falciparum to anti-folinic agents (trimethoprim, pyrimethamine, cycloguanil): a study of 29 African strains.

The in vitro drug sensitivity of three dihydrofolate reductase inhibitors (pyrimethamine, cycloguanil, trimethoprim) was determined against 29 strains and isolates of Plasmodium falciparum by an isotopic semi-microtest. Trimethoprim is less active than pyrimethamine or cycloguanil and its activity is correlated with that of two other inhibitors, suggesting cross-resistance in vitro among the dihydrofolate reductase inhibitors.

Animals↗
PubMed1997

Status of ammonia, glutamate, lactate and pyruvate during Plasmodium yoelii infection and pyrimethamine treatment in mice.

Ammonia, lactate, glutamate and pyruvate levels in blood, liver, brain, spleen and kidney were determined during Plasmodium yoelii infection and pyrimethamine treatment in mice. Ammonia and lactate levels showed significant increase with rise in parasitaemia except in spleen where decrease in the lactate levels was observed. The glutamate level displayed a marked decrease in blood, liver and splenic tissues, whereas, significant increase in glutamate level in kidney was observed, although its level in cerebral tissue remained unaltered. The pyruvate level in blood and liver showed a noticeable decrease but brain, spleen and kidney registered an elevation of the same due to the parasitic infection. Pyrimethamine (oral) treatment (10 mg/kg body weight) to infected mice (5-10%) for four days brought back the altered levels of the above cellular constituents in different tissues to normal, a week after cessation of drug treatment.

Ammonia↗
PubMed1984

Mefloquine-pyrimethamine-sulfadoxine combination delays emergence of mefloquine resistant Plasmodium falciparum in continuous culture.

The efficacy of mefloquine against Plasmodium falciparum in continuous culture was studied. The development of mefloquine resistance in P. falciparum was significantly inhibited by a combination of mefloquine, pyrimethamine and sulfadoxine. By contrast, more resistant variants were selected in continuous culture without drug pressure or with pyrimethamine-sulfadoxine pressure. The most mefloquine resistant variants were selected by step-wise increases in mefloquine pressure.

Animals↗
PubMed1964

POTENTIATION OF ACTIVITY OF DIAPHENYLSULFONE AND PYRIMETHAMINE AGAINST PLASMODIUM GALLINACEUM AND PLASMODIUM CYNOMOLGI BASTIANELLII.

In view of the fact that diaphenylsulfone has been shown to have low schizontocidal activity against Plasmodium gallinaceum and to lead to resistance in strains of P. cynomolgi, investigations were undertaken into the joint action of diaphenylsulfone and pyrimethamine against P. gallinaceum in chicks and P. cynomolgi bastianellii in monkeys. These drugs were assayed separately and in various combinations. It was found that at certain dose levels combination of the two drugs led to potentiation of their plasmocidal activity. On the other hand, this synergistic effect was not noted with combinations containing lower dosages of either drug; with these, a simple additive effect occurred. The authors suggest that the two drugs probably act on the same metabolic pathway but that their points of attack may be different. They note also that there was a difference in the response of P. gallinaceum in chicks and of P. cynomolgi bastianellii in monkeys to the combined use of the two drugs.

Animals↗
PubMed2005

Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine for treating uncomplicated malaria.

BACKGROUND: Chloroquine (CQ), amodiaquine (AQ), and sulfadoxine-pyrimethamine (SP) are inexpensive drugs, but treatment failure is a problem. Combination therapy may reduce treatment failure. CQ or AQ plus SP are affordable options of combination treatment, but there is debate about their effectiveness. OBJECTIVES: To assess the combination of CQ or AQ plus SP compared with SP alone for first-line treatment of uncomplicated falciparum malaria. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register (April 2005), CENTRAL (The Cochrane Library Issue 2, 2005), MEDLINE (1966 to April 2005), EMBASE (1974 to April 2005), LILACS (1982 to April 2005), Science Citation Index (1981 to April 2005), African Index Medicus (1993 to 1998), and reference lists. We also contacted researchers at relevant organizations and a pharmaceutical company. SELECTION CRITERIA: Randomized controlled trials in adults or children with uncomplicated Plasmodium falciparum malaria were eligible for inclusion. The main outcomes of interest were total and clinical failure at day 28 follow up and serious adverse events. DATA COLLECTION AND ANALYSIS: Two people independently applied the inclusion criteria. One author extracted data and another checked them independently. We used relative risk (RR) and 95% confidence intervals (CI). MAIN RESULTS: Twelve trials (2107 participants) met the inclusion criteria. A meta-analysis of five AQ trials (461 participants) showed a statistically significant reduction in total failure at day 28 with the combination therapy (RR 0.64, 95% CI 0.46 to 0.91), and meta-analysis of three trials (384 participants) showed a significant reduction in clinical failure at day 28 (RR 0.23, 95% CI 0.11 to 0.49). The statistical significance in the total failure analysis was sensitive to losses to follow up. Data from two CQ trials showed no advantage for total failure with combination therapy at day 28. There was no evidence from the included trials of serious adverse events. AUTHORS' CONCLUSIONS: The evidence base is not strong enough to support firm conclusions. The available evidence suggests that AQ plus SP can achieve less treatment failure than SP, but this might depend on existing levels of parasite resistance to the individual drugs.

Adult↗
PubMed2002

Investigation of the genotoxic effect in bone marrow of Swiss albino mice exposed long-term to pyrimethamine.

In the present study, we investigated the genotoxic effect of pyrimethamine, which is a drug used in the therapy of toxoplasmosis and malaria, in bone marrow cells of Swiss albino mice exposed to three doses (1, 4, 8 mg/kg) of this agent for eight months orally in vivo. We used a chromosome analysis and micronucleus test for evaluation of genotoxic effect. While a statistically significant change was not determined in numerical chromosome abnormalities, structural chromosome aberrations and micronuclei were increased in a dose-dependent manner by cytogenetic and statistical evaluations.

Animals↗
PubMed2000

Studies on hepatic mitochondrial cytochrome P-450 during Plasmodium yoelii infection and pyrimethamine treatment in mice.

Hepatic mitochondrial cytochrome P-450 and b(5) activities were significantly depressed, whereas heme and hemozoin were increased during Plasmodium yoelii infection. Type II, aniline-HCl binding efficacy and polyacrylamide gel electrophoretic profile also depicted impairment of cytochrome P-450 during infection. However, the above alterations were more pronounced in the infected hepatic mitochondria, compared to microsomes. Oral treatment of pyrimethamine (10 mg/kg body weightx4 days) to P. yoelii-infected mice brought the altered levels of mitochondrial and microsomal cytochrome P-450 and b(5) to almost normal, whereas heme and hemozoin levels remained unchanged.

Animals↗
PubMed2002

Synergistic bone marrow toxicity of pyrimethamine and zidovudine in murine in vivo and in vitro models: mechanism of toxicity.

Pyrimethamine (Pyr) is commonly used for treatment of toxoplasmic encephalitis in AIDS patients; however, in two clinical studies, an increased number of deaths were observed when Pyr was coadministered with zidovudine (ZDV). The BALB/c mouse was chosen as a model to study the mechanism underlying the unexpected toxicity from coadministration of these drugs. Daily administration by oral gavage of 60 mg/kg Pyr and 240 mg/kg ZDV resulted in 100% lethality after 30 days. These dose levels produced no effect when the drugs were given individually for the same period. Administration of combinations of Pyr and ZDV resulted in macrocytic anemia and leukopenia with synergistic decreases in lymphocyte and neutrophil numbers. To examine the mechanism of this hematotoxicity at the cellular level, mouse bone marrow colony-forming unit (mCFU) assays were employed. A combination of ZDV with various concentrations of Pyr resulted in synergistic decreases in numbers of erythroid and granulocyte-macrophage precursors (mCFU-E and mCFU-GM). mCFU-GM precursors appeared more sensitive than erythroid precursors to combinations of Pyr and ZDV. Incorporation of (14)C-ZDV into cellular DNA was increased in a dose-dependent manner in the presence of increasing concentrations of Pyr in the mCFU-GM assay. This suggested that inhibition of dihydrofolate reductase by Pyr and accompanying inhibition of dTTP synthesis allows preferential incorporation of ZDV into DNA, with resulting strand breakage and cell death. (14)C-ZDV incorporation was also observed when human GM cultures were analyzed, however, incorporation was less and required higher concentrations of Pyr.

Administration, Oral↗
PubMed1998

Pyrimethamine impairs host resistance to infection with Listeria monocytogenes in BALB/c mice.

Increased mortality has been observed when HIV-infected patients were treated with pyrimethamine (Pyr) as prophylaxis for toxoplasmic encephalitis, suggesting that Pyr might possess immunosuppressive activity. To analyze this in an animal model, immune function was assessed in BALB/c mice using a battery of in vivo and ex vivo assays and an in vivo model of host resistance to Listeria monocytogenes infection. Treatment for 30 days with 60 mg/kg Pyr decreased circulating white blood cell and lymphocyte counts but not neutrophil, red blood cell, or platelet counts or hemoglobin levels. Splenic B cell percentages and lipopolysaccharide-induced B cell proliferation decreased significantly after treatment with 60 mg/kg Pyr, as did levels of anti-keyhole limpet hemocyanin (KLH) IgM in serum 7 days after immunization with KLH. Anti-KLH IgG levels 14 days after immunization were not affected. Percentages of splenic T cells and macrophages and T cell proliferation in the presence of concanavalin A or allogeneic cells were not decreased by Pyr treatment. An ex vivo assay of T-cell-mediated cytotoxicity was also unaffected. When host resistance to L. monocytogenes infection was assessed, dramatic increases in mortality were observed in Pyr-treated compared to control mice. Increased numbers of L. monocytogenes organisms were observed in liver and spleen of Pyr-treated mice, compared to controls. The reduction in Listeria resistance, which is T cell mediated, contrasts with the fact that no significant changes in T-cell-mediated immunity were observed. It is possible that Pyr affects parameters of innate immunity, which were not monitored in this study.

Animals↗
PubMed1987

The pharmacokinetics of mefloquine when given alone or in combination with sulphadoxine and pyrimethamine in Thai male and female subjects.

The kinetics of mefloquine were studied in 12 healthy Thai male and 12 healthy Thai female volunteers. Mefloquine (MQ) was administered either alone (750 mg orally) or in combination (MSP) with sulphadoxine (1.5 g) and pyrimethamine (75 mg) to each of 6 male and 6 female subjects. Plasma concentrations of MQ were measured by HPLC at intervals for 42 days. There was considerable interindividual variability in the pharmacokinetic parameters; for example in the male subjects receiving MQ alone peak concentrations ranged between 638 and 2494 ng X ml-1 with a mean concentration of 1442 ng X ml-1. Compared to previously published data on MQ concentrations in Caucasian male subjects, the present study indicates that higher concentrations are achieved in Thai subjects. The only significant difference in kinetic parameters between male and female subjects receiving MQ alone was in the mean residence time (MRT) which was greater in females. However, an analysis of pharmacokinetic parameters following administration of the combination preparation showed that the time to peak (tmax) was significantly reduced in females receiving MSP compared to the corresponding females given MQ alone and males given MSP. When data obtained from all subjects (male and female) receiving either MQ alone or MSP were combined, both MRT and half-life were significantly greater in subjects given MSP. There is therefore some evidence that therapeutic concentrations of MQ are maintained for a longer period of time following MSP administration.

Adult↗