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The effect of sulfomethoxypyrazine-pyrimethamine therapy on the fine structure of Toxoplasma gondii-cysts in the brain of Mastomys natalensis. Scanning and transmission electron microscopical investigations.

Two month old chronically infected Mastomys natalensis, which had been treated for ten days with sulfomethoxypyrazine-pyrimethamine, were utilized for testing the effect of chemotherapy on the fine structure of Toxoplasma cysts (strain ALT). After completion of the therapy, cysts were examined from the brains of killed animals in scanning and transmission electron microscopes. The scanning electron microscopic experiments revealed no or only slight morphological differences between the cysts of the untreated controls (Fig. 1) and the treated animals (Fig 2). In transmission electron microscopic studies the cyst membrane appeared less rugged (see Fig. 3,7 and the untreated control Fig. 6). The cyst basic substance often produces an optically empty space (Fig. 3,4). The pellicle of individual parasites display an unusual affinity for the pellicle of neighboring parasites (Fig. 3,5,7). In direct contrast to the untreated cysts no endodyogeny could be observed on the treated cysts examined to this point.

Animals↗

[A case of acute pyrimethamine poisoning].

Intoxication by pyrimethamine is rare compare to these of patients who ingest a massive dose of amino-4-quinoleine. Clinic manifestations can be delayed and they are specially based on haematologic disorder as shown by literature data. Others organs can be concerned. The authors would like to present the case of a patient with a severe pancytopenia accompanied with: ocular blow like hyperhaemia of conjunctiva then iris siderosis. skin attack as Gũnther's disease. Etiologic treatment by folinic acid is the only deduction. Recovery is complete.

Acute Disease↗

Status of urea and related enzymes during Plasmodium yoelii infection and pyrimethamine treatment in mice.

Plasmodium yoelii infection alters the hepatic levels of key enzymes of urea cycle, viz.carbamoyl phosphates synthetase (EC 6.3.4.16) and ornithine transcarbamoylase (EC 2.1.3.3) and urea levels in mice. The urea level was found elevated in liver, brain and plasma during P. yoelii infection. However, carbamoyl phosphate synthetase and ornithine transcarbamoylase were noticeably decreased during P. yoelii infection. Pyrimethamine treatment (10 mg/kg body weight for 4 days) brought back the altered parameters to normal a week after cessation of drug treatment.

Animals↗

Induction of sister chromatid exchanges by pyrimethamine in human lymphocyte cultures.

This study examined the effect of pyrimethamine (PYR) on sister chromatid exchanges (SCEs) in human lymphocytes. PYR is a folic acid antagonist used for the treatment of malaria and toxoplasmosis. PYR was added to peripheral blood lymphocyte cultures at three different doses: 0.05, 0.1, and 0.2 mg/ml. The results of the cytogenetic and statistical evaluations showed that the frequency of SCEs increased significantly in a dose-dependent manner. Thus, it is shown that PYR has a genotoxic effect on human chromosomes.

Adult↗

[Ocular manifestations and sequelae of Lyell syndrome caused by sulfadoxine-pyrimethamine in Cameroon].

We report a Lyell syndrome secondary to anti-malarial treatment with sulfadoxine-pyrimethamine. Eye lesions predominated: symblepharon and corneal opacification. Desinsertion of conjunctival synechias was performed by ophthalmologists. There were corneal opacities and fibro-vascular veil on the two eyes. A keratoprosthesis was done on one eye. It is very likely that the incidence of this syndrome will increase mainly because of two factors. The continuous increase of plasmodii resistance to chloroquine hence the more frequent use of sulfonamides for the treatment of malaria; secondly, sulfonamides are used in the treatment and prevention of opportunistic infections in AIDS patients. It is important for ophthalmologists in tropical areas to be aware of Lyell's syndrome so that proper and early management may be undertaken.

Adult↗

Structural studies on bioactive compounds. 28. Selective activity of triazenyl-substituted pyrimethamine derivatives against Pneumocystis carinii dihydrofolate reductase.

Triazenyl-substituted pyrimethamine derivatives 10a-s have been prepared by coupling diazotized 2,4-diamino-5-(3-amino-4-chlorophenyl)-6-ethyl pyrimidine (1c) with a series of secondary amines in aqueous sodium carbonate solution. The triazenes which are stable and poorly soluble as free bases form more soluble, but unstable, salts with alkanesulfonic acids. The lead dimethyltriazene 2,4-diamino-5[4-chloro-3-(3,3-dimethyltriazen-1-yl)phenyl]-6-et hylpyrimidine (4a) forms a crystalline ethanesulfonic acid salt (solvated with 2-propanol), which is protonated at the pyrimidine N-1 position, as determined by X-ray crystallography. The ability of these new triazenes to inhibit Pneumocystis carinii dihydrofolate reductase in vitro has been compared to that of triazene 4a. The most potent and selective compound, 2,4-diamino-5-[3-[3-[2-(acetyloxy)ethyl]-3-benzyltriazen-1-y l]-4- chlorophenyl]-6-ethylpyrimidine (14a), has an IC50 value of 0.17 microM against the microbial enzyme and potentially useful selectivity (rat liver IC50/P. carinii IC50 = 114).

Animals↗

A randomized controlled trial of folate supplementation when treating malaria in pregnancy with sulfadoxine-pyrimethamine.

OBJECTIVES: Sulfadoxine-pyrimethamine (SP) is an antimalarial drug that acts on the folate metabolism of the malaria parasite. We investigated whether folate (FA) supplementation in a high or a low dose affects the efficacy of SP for the treatment of uncomplicated malaria in pregnant women. DESIGN: This was a randomized, placebo-controlled, double-blind trial. SETTING: The trial was carried out at three hospitals in western Kenya. PARTICIPANTS: The participants were 488 pregnant women presenting at their first antenatal visit with uncomplicated malaria parasitaemia (density of >or= 500 parasites/microl), a haemoglobin level higher than 7 g/dl, a gestational age between 17 and 34 weeks, and no history of antimalarial or FA use, or sulfa allergy. A total of 415 women completed the study. INTERVENTIONS: All participants received SP and iron supplementation. They were randomized to the following arms: FA 5 mg, FA 0.4 mg, or FA placebo. After 14 days, all participants continued with FA 5 mg daily as per national guidelines. Participants were followed at days 2, 3, 7, 14, 21, and 28 or until treatment failure. OUTCOME MEASURES: The outcomes were SP failure rate and change in haemoglobin at day 14. RESULTS: The proportion of treatment failure at day 14 was 13.9% (19/137) in the placebo group, 14.5% (20/138) in the FA 0.4 mg arm (adjusted hazard ratio [AHR], 1.07; 98.7% confidence interval [CI], 0.48 to 2.37; p = 0.8), and 27.1% (38/140) in the FA 5 mg arm (AHR, 2.19; 98.7% CI, 1.09 to 4.40; p = 0.005). The haemoglobin levels at day 14 were not different relative to placebo (mean difference for FA 5 mg, 0.17 g/dl; 98.7% CI, -0.19 to 0.52; and for FA 0.4 mg, 0.14 g/dl; 98.7% CI, -0.21 to 0.49). CONCLUSIONS: Concomitant use of 5 mg FA supplementation compromises the efficacy of SP for the treatment of uncomplicated malaria in pregnant women. Countries that use SP for treatment or prevention of malaria in pregnancy need to evaluate their antenatal policy on timing or dose of FA supplementation.

Journal Article↗

Rifampicin/Cotrimoxazole/Isoniazid versus mefloquine or quinine + sulfadoxine- pyrimethamine for malaria: a randomized trial.

OBJECTIVES: Previous studies of a fixed combination including cotrimoxazole, rifampicin, and isoniazid (Cotrifazid) showed efficacy against resistant strains of Plasmodium falciparum in animal models and in small-scale human studies. We conducted a multicentric noninferiority trial to assess the safety and efficacy of Cotrifazid against drug-resistant malaria in Papua New Guinea. DESIGN: The trial design was open-label, block-randomised, comparative, and multicentric. SETTING: The trial was conducted in four primary care health facilities, two in urban and two in rural areas of Madang and East Sepik Province, Papua New Guinea. PARTICIPANTS: Patients of all ages with recurrent uncomplicated malaria were included. INTERVENTIONS: Patients were randomly assigned to receive Cotrifazid, mefloquine, or the standard treatment of quinine with sulfadoxine-pyrimethamine (SP). OUTCOME MEASURES: Incidence of clinical and laboratory adverse events and rate of clinical and/or parasitological failure at day 14 were recorded. RESULTS: The safety analysis population included 123 patients assigned to Cotrifazid, 123 to mefloquine, and 123 to quinine + SP. The Cotrifazid group experienced lower overall incidence of adverse events than the other groups. Among the efficacy analysis population (72 Cotrifazid, 71 mefloquine, and 75 quinine + SP), clinical failure rate (symptoms and parasite load) on day 14 was equivalent for the three groups (0% for Cotrifazid and mefloquine; 1% for quinine + SP), but parasitological failure rate (P. falciparum asexual blood-stage) was higher for Cotrifazid than for mefloquine or quinine + SP (9% [PCR corrected 8%] versus 0% and 3%, respectively [p = 0.02]). CONCLUSION: Despite what appears to be short-term clinical equivalence, the notable parasitological failure at day 14 in both P. falciparum and P. vivax makes Cotrifazid in its current formulation and regimen a poor alternative combination therapy for malaria.

Journal Article↗