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Treatment of pyrimethamine with blood plasma in vitro yields a metabolite which is also produced when the drug is administered through intravenous injection in the rat. A thin layer liquid chromatographic method for quantitative and qualitative determination of pyrimethamine and its metabolite in plasma and biological tissues is described.
The various causative and mechanistic phenomena associated with aneuploidy induction require considerable investigation to better understand the etiology of chromosome missegregation. We investigated the potential of vinblastine sulfate, pyrimethamine, diethylstilbestrol diphosphate, and chloral hydrate to induce numerical and structural chromosome changes in female mouse germ cells. Superovulated ICR mice were administered the compounds either by intraperitoneal injection or oral gavage, and oocytes were collected and processed for cytogenetic analysis 17 hr later. Vinblastine sulfate, administered i.p., induced a significant increase in the frequency of ovulated MI oocytes and of hyperploid MII oocytes compared to controls, but did not increase the frequency of structural aberrations. Pyrimethamine, diethylstilbestrol diphosphate, and chloral hydrate did not increase the frequency of numerical or structural chromosome changes in female mouse germ cells.
Pyrimethamine injected into the rat on days 12, 13, and 14 of gestation induces several types of malformations, including limb and facial deformities. These malformations appear in the same location as the hemorrhages and hematomas induced by this substance. In order to visualize the extent of the vascular disorders in the affected areas, a polymerizable substance was injected intravenously into the fetus. After pyrimethamine treatment, the fetal vascular network was simplified and reorganized in a different way according to the severity of the malformations. The appearance of vascular pathology, followed by malformations in the same regions, raises the hypothesis of a vascular cause of fetal defects.
Methotrexate resistance induced in cultured Plasmodium falciparum depends on an altered dihydrofolate reductase with decreased affinity for methotrexate as well as for pyrimethamine. In contrast, pyrimethamine-resistant field isolates of P. falciparum lack cross-resistance to methotrexate and 2,4-diamino-5-(substituted benzyl) pyrimidines. The structure of the latter class was optimized by the use of trimethoprim as a lead and the substitution of methoxy groups at the benzyl ring by 3-(4'-aminophenyl-4-sulfonylphenylamino)propoxy or by (4'-aminophenyl-4-sulfonylphenyl)methoxy, which resulted in antimalarials of high potency. The efficiency of these newly designed 2,4-diamino-5-(substituted benzyl) pyrimidines was confirmed by their strong inhibitory effect on plasmodial dihydrofolate reductase as well as by in vitro screening against drug-sensitive and -resistant strains of P. falciparum.
The effectiveness of combinations of rifabutin with atovaquone, clindamycin, pyrimethamine, or sulfadiazine in the treatment of toxoplasmic encephalitis in a murine model was investigated. Doses of each drug that were not effective in reducing inflammation in the brain of mice with toxoplasmic encephalitis when used alone were used in combination with a dose of rifabutin which was minimally effective. At the end of each period of therapy (15 or 30 days), brains of mice were examined histopathologically and the severity of the inflammatory lesions scored. Treatment with rifabutin in combination with pyrimethamine or sulfadiazine did not reduce brain inflammation significantly when compared to treatment with each drug alone. In contrast, treatment with rifabutin plus atovaquone for 15 or 30 days or with rifabutin plus clindamycin for 15 days resulted in statistically significant reduction in the inflammation. These results suggest that combining rifabutin with certain drugs that are active against Toxoplasma gondii may be useful for the treatment of toxoplasmic encephalitis in humans and may allow for a reduction in dosage of either or both drugs with a resulting reduction in untoward side effects.
Prophylaxis for toxoplasma encephalitis was performed with pyrimethamine alone (50 mg daily) in 56 patients with advanced HIV infection. Thirty-eight patients were at high risk for toxoplasma encephalitis (CD4+ counts < or = 200/microliter, and presence of serum IgG antibodies to Toxoplasma gondii). The overall treatment period was 697 months (mean 12.5 +/- 12.1). During prophylaxis, only one patient developed toxoplasma encephalitis, four patients discontinued treatment due to adverse reactions. Steady state pyrimethamine plasma concentrations were measured by gas chromatography. Mean plasma level was 1,887 +/- 1,161 ng/ml, during liver enzyme-inducing comedication plasma levels were significantly (p = 0.0001) reduced (1,488 +/- 884 ng/ml versus 1,978 +/- 1,196 ng/ml without comedication). All patients received a folinic acid supplement of 7.5 mg daily. Serum folate levels ranged from 5.7-105 (43.7 +/- 29.2) nmol/l; severe hematological side effects did not occur.
Through the European Network in the Treatment of AIDS, a multicenter trial is being conducted to compare the efficacy and safety of pyrimethamine (50 mg/day) plus clindamycin (2.4 g/day) with the regimen of pyrimethamine (50 mg/day) and sulfadiazine (4.0 g/day) for induction and maintenance treatment of toxoplasmic encephalitis. By 1 September 1990, 281 patients had been randomized to enter the study. Preliminary data show that 77% of the 148 patients evaluated showed a complete response or improvement with minor sequelae during therapy. Twenty percent of the patients deteriorated. This was due to toxoplasmosis in only 10% of the patients. Side-effects were common in all patients regardless of treatment regimen and consisted mainly of rash (52 cases), fever (31 cases), diarrhea (17 cases) and nausea (12 cases). The final analysis should be available by the middle of 1991.
13C nuclear magnetic resonance (NMR) of methotrexate, trimethoprim, and pyrimethamine enriched 90% with 13C at C2 has provided a sensitive means of detecting the state of protonation of the heterocyclic rings of these inhibitors. In each case, protonation of N1 causes an upfield movement of the chemical shift of C2 by more than 6 ppm. By this method it has been shown that, at pH values up to 9.2, methotrexate is bound to bovine liver dihydrofolate reductase with N1 of the inhibitor protonated, just as in the case of the complex with reductase from Streptococcus faecium and Lactobacillus casei. Furthermore, trimethoprim bound to reductase from any of the three sources, and pyrimethamine bound to either of the bacterial reductases also have N1 protonated even at pH values up to 10. This implies that in all cases there is a strong interaction between protonated N1 of the inhibitor and the carboxylate group of the active site aspartate or glutamate. In every case pKa of the bound inhibitor is increased by several units, a finding in accord with crystallographic evidence that inhibitor bound to L. casei reductase is in a hydrophobic environment and that N1 is not hydrogen-bonded to water. It was confirmed by titration of protein fluorescence that trimethoprim has greater affinity for bacterial reductase than for vertebrate (bovine) reductase, and that this selectivity is more marked in ternary complexes in which NADPH is also bound to the active site. However, the data cited above indicate that this difference in affinities is not due to a weaker ionic interaction between protonated N1 of trimethoprim and the bovine enzyme. Instead, binding of the trimethoprim side chain to hydrophobic sites on the enzyme must provide less binding energy in the case of the mammalian enzyme.
The inhibitory effect of pyrimethamine on the growth of TMP-permeable strains of Saccharomyces cerevisiae in a fermentable medium supplemented with adenine, glycine, methionine and pantothenate was substantially reduced by exogenous TMP. This compound also suppressed the drug's killing effect, and to some extent its ability to induce the mitochondrial petite mutation. In a non-fermentable medium, TMP failed to reduce growth inhibition, in line with our earlier finding that as well as blocking synthesis pyrimethamine prevents mitochondrial protein synthesis.
The authors describe the characters in two pyrimethamine-resistant lines of Plasmodium berghei berghei SP 11-RR after long storage at very low temperatures. In one case the line had maintained its original virulence but lost its resistance to pyrimethamine. Gametocytogenesis increased and cyclical transmission was successful. Furthermore, parasites crossed the blood-brain barrier and provoked cerebral malaria. In the other case no physiological changes could be detected. The authors conclude that, after cryopreservation, biological behaviour should always be carefully observed.
The in vitro response of wild Gambian Plasmodium falciparum to pyrimethamine is described. Parasites were grown in 100 microliter cultures through schizogony. The number of rings present after 48 hours in drug-treated cultures was expressed as a percentage of the controls. Neither a medium and drug change after 24 hours nor different starting parasitaemias were found to affect the outcome of the assay, although a medium and drug change did increase the multiplication rate. 60 randomly taken pure P. falciparum infections were studied. 57 were sensitive. The ID50 and ID90 of drug-sensitive infections were 1.7 X 10(-9) M and 4.5 X 10(-9) M pyrimethamine respectively. Three infections were resistant (5%) with individual ID50 values of greater than 10(-6) M, 3 and 4 X 10(-9) M and ID90 values of greater than 10(-6) M, 8 and 9 X 10(-7) M.
Immunoglobulins IgG, IgM, IgA were estimated on 3 occasions in 59 male volunteers who were taking dapsone-pyrimethamine once weekly (dapsone: 100 mg + pyrimethamine: 12.5 mg) for malaria chemoprophylaxis. Immunoglobulins IgG and IgM measured at the 7th week of chemoprophylaxis were significantly lower than baseline values (using Students' t-test for paired data), but none of the values were below 700 mg% for IgG or 30 mg% for IgM. Immunoglobulin concentrations estimated in 45 of the 59 men 6 weeks after discontinuation of chemoprophylaxis showed a return to baseline for IgM but not IgG, which remained low. On all 3 occasions there was no significant change in the IgA concentrations. The clinical implication of these findings is not known. Further studies are required to define the effects of antimalarial drugs on the antibody response to infection and immunization.
The sensitivity of Plasmodium falciparum infections to pyrimethamine-sulfadoxine was studied in 18 Indonesian patients in Jayapura, Irian Jaya. In 16 of the 18 patients parasitaemia was cleared by day 6 and the patients remained without parasitaemia through day 28. Two of the 18 patients had late recrudescences consistent with RI-type resistance; one each on days 14 and 21. Pyrimethamine-sulfadoxine is still an effective antimalarial for most patients with falciparum malaria in Jayapura.
In a field study conducted in Burma, 60 semi-immune adults were randomly assigned to 2 treatment groups. The first (mean parasite count, 12717/mm3) received a single dose of a fixed combination of 500 mg mefloquine base, 1000 mg sulfadoxine and 50 mg pyrimethamine (2 tablets of 'Fansimef') plus 1 tablet placebo. The second group (mean parasite count, 11 863/mm3) were given 3 tablets of the same medication. The study was double-blind. Parasite count was checked daily for the first week and weekly for a further 3 weeks. Average times for parasite clearance were 1.47 d in patients receiving 2 tablets, and 1.87 d in those given 3 tablets. Asexual parasites reappeared on day 28 in one patient in each group, although they had been free of parasites during the previous 4 weeks; this could be due to reinfection. The drugs were generally well tolerated, though mild and transient giddiness was seen in 80% of patients in the first group and 96% in the second. Nausea was reported by 33% and 43% of patients respectively. No vomiting occurred in the first group but 8 patients vomited in the second (P less than 0.01). In conclusion it seems possible to treat falciparum malaria in semi-immune adults, weighing less than 60 kg, with a single dose of 500 mg mefloquine base, 1000 mg sulfadoxine and 50 mg pyrimethamine (2 tablets), instead of the higher dose (3 tablets) currently recommended. This reduces treatment cost and improves tolerance of the drugs.
A randomized double blind study was performed to evaluate the tolerance and the acceptance of mefloquine alone (Lariam) compared to a combined drug regimen consisting of mefloquine, sulfadoxine and pyrimethamine (MSP; Fansimef) in the prophylaxis of malaria. 175 Europeans travelling to different malaria endemic areas received either mefloquine alone (250 mg/week) or its combination with sulfadoxine (500 mg/week) plus pyrimethamine (25 mg/week). One person taking mefloquine and two taking MSP discontinued the drug intake because of moderate clinical side effects. Mild and moderate adverse clinical reactions predominantly concerning the gastro-intestinal tract and the autonomous nervous system were reported with a significantly higher occurrence in the MSP group. With both prophylactic regimens, reversibly elevated liver enzyme activities (glutamate oxalate transaminase and glutamate pyruvate transaminase [GPT]) were observed after prophylaxis. The increase of GPT serum activity correlated significantly with relatively high GPT levels before prophylaxis in both groups. This finding suggests a limited use of both regimens in cases of liver dysfunction. One case of mefloquine-resistant Plasmodium falciparum malaria was observed from West Africa; this patient was cured by a standard regimen of chloroquine.
A comparison has been made of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine +dapsone) as malaria chemoprophylactics when given every two weeks for 3 years to Gambian children under the age of 5 years. Both drugs produced falls in spleen and malaria parasite rates and an increase in packed cell volume. Maloprim, but not chlorproguanil, significantly reduced the incidence of episodes of fever accompanied by malaria parasitaemia. Children who received Maloprim, but not those who received chlorproguanil, grew better than children in the placebo group. This finding suggests that brief clinical episodes of malaria are more important in impairing growth than more prolonged periods of asymptomatic parasitaemia. No serious side-effect attributable to either drug was observed. After chemoprophylaxis had been given for 3 malaria transmission seasons the level of resistance of Plasmodium falciparum to pyrimethamine and to chlorproguanil was about 10%.
The World Health Organization (WHO) extended field test was employed to assess the in vivo sensitivity of Plasmodium falciparum to sulfadoxine-pyrimethamine combination in 44 children in Zaria urban area. 36 children (82%) were fully sensitive to the drug and 8 (18%) were resistant at the RI level. 8 parasite isolates were obtained from the children and successfully cultured in vitro using the WHO microtest (mark II) system. The 8 isolates underwent schizogony at concentrations of 10,000 pmol sulfadoxine/125 pmol pyrimethamine per well, indicating in vitro resistance.
It has been suggested that sulfadoxine-pyrimethamine (SD/PM) may be useful in the treatment of severe malaria since it could enhance the killing of parasites by quinine (QN) and it can be given as a single intramuscular injection. Eighty Kenyan children with severe malaria were allocated at random to receive either intramuscular QN alone (quinine dihydrochloride 20 mg salt/kg as a loading dose, followed by 10 mg salt/kg 12 hourly for a total of 6 doses) or the same QN regimen plus one intramuscular injection of SD/PM (sulfadoxine 25 mg/kg, pyrimethamine 1.25 mg/kg). There was no difference in time to defervescence, aparasitaemia, or 50% reduction in parasitaemia, parasite elimination half-life, or mortality between the 2 groups. In addition, the concentrations of SD and PM were measured in 14 children and of QN in 8 of these children. Concentrations needed to achieve synergy against PM-resistant strains of Plasmodium falciparum were achieved in all of the children with severe malaria within the first hour and maintained for more than 72 h. SD/PM did not perturb the pharmacokinetics of QN.