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PubMed1986

ELISA tests for dapsone and pyrimethamine and their application in a malaria chemoprophylaxis programme.

Enzyme-linked immunosorbent asays (ELISAs) are described for determining levels of dapsone and pyrimethamine in urine. Both assays have a sensitivity of about 20 mug/l and are reproducible, but each produces some false positives. The problem of false positive reactions was partially obviated by requiring positive results in both assays. In a pilot study involving 50 children aged 3 months to 4 years who were given a single dose of Maloprim (pyrimethamine + dapsone), 75% were positive for dapsone 7 days after administration of the drug, while 25% were still positive 15 days after its administration. The corresponding proportions for pyrimethamine were 73% and 30%, respectively. Comparison of the results obtained in a larger chemoprophylaxis trial with those from the pilot study indicated that the assays described could be used to investigate whether antimalarials had been taken.

Child, Preschool↗
PubMed1985

In vitro susceptibility of Plasmodium falciparum collected from pyrimethamine-sulfadoxine sensitive and resistant areas in Thailand.

Seventy Plasmodium falciparum isolates, collected from two geographically separate areas of Thailand, were tested for their in vitro responses to pyrimethamine, sulfadoxine, and a combination of these two drugs. The effects of pyrimethamine and pyrimethamine-sulfadoxine combinations against P. falciparum isolates were found to be significantly greater in a northern area where the combined drug was an effective therapeutic agent than in a south-eastern area, near the Thai-Kampuchean border, where the combined drug was no longer effective. However, the actions of sulfadoxine against parasites obtained from the two areas were not significantly different. There was no significant difference between the mean values of plasma 4-aminobenzoic acid (PABA) in falciparum malaria patients and in healthy controls. The test for PABA determinations used in this study gave positive readings with both PABA and sulfadoxine.

4-Aminobenzoic Acid↗
PubMed1968

Gametocytocidal and sporontocidal effects of primaquine and of sulfadiazine with pyrimethamine in a chloroquine-resistant strain of Plasmodium falciparum.

Studies with 3 volunteers were conducted to determine the effects of a combination of sulfadiazine and pyrimethamine and the effects of primaquine upon mature gametocytes of a strain of chloroquine-resistant Plasmodium falciparum-the Malayan (Camp.) strain. One volunteer was treated with sulfadiazine and pyrimethamine; two other volunteers each received a single dose of 45 mg of primaquine base. The combination of sulfadiazine and pyrimethamine, although active against blood schizonts, did not exert a marked sporontocidal effect against the Malayan (Camp.) strain. In sharp contrast, primaquine, although not effective as a blood schizontocide, exerted a marked gametocytocidal and sporontocidal effect against this strain.The findings emphasize the need for further studies of the sporontocidal and gametocytocidal effects of drugs, particularly primaquine, against chloroquine-resistant strains of P. falciparum and suggest that primaquine may come to play an important role in preventing the transmission of such strains.

Adult↗
PubMed1984

Long-acting, repository antimalarial agents. Duration of protection in mice and monkeys following administration of pyrimethamine pamoate.

The duration of protection from blood-stage malarial challenge following single injections of pyrimethamine pamoate was assessed in mice and monkeys. This duration was dose-related and ranged from several weeks in mice to over 4 months in the monkeys. Comparisons with the previously reported repository drugs, cycloguanil pamoate and acedapsone (diacetyldiaminodiphenyl sulfone), in mice demonstrated that pyrimethamine pamoate provides an equal or greater duration of protection. Studies with mixtures containing acedapsone gave good protection against a pyrimethamine-resistant strain of Plasmodium berghei.

Acedapsone↗
PubMed1982

Plasma concentrations in pyrimethamine and sulfadoxine and evaluation of pharmacokinetic data by computerized curve fitting.

For the determination of the plasma concentration profiles of pyrimethamine and sulfadoxine after the administration of 1 tablet of Fansidar, highly specific analytical methods are needed as the pyrimethamine concentration is low (0.2 - 0.02 mg/litre) and the concentration ratio of the two components in the plasma is high (> 1: 500). The microbiological method described in this paper fulfils these requirements for high specificity and sensitivity (the sensitivity limit for sulfadoxine is 1 mg/litre and for pyrimethamine is 0.013 mg/litre).Pharmacokinetic data were evaluated for 14 volunteers after administration of 1 tablet of Fansidar, and a computer simulation of multiple dosing (1 tablet per week) was performed.

Adult↗
PubMed1981

Sulfadoxine-pyrimethamine resistant falciparum malaria in Thai children.

Sixty-eight children with uncomplicated falciparum malaria admitted to the Hospital for Tropical Diseases in Bangkok during April-December 1980 were randomly divided into 3 groups and given 3 regimens. Group 1 of 27 cases were treated with a single dose of sulfadoxine 20 mg per kg body wt and pyrimethamine 1.0 mg per kg body wt. Two cases (7.4%) were cured (S) while 4 cases (14.8%) showed RI failure, 17 cases (63.0%) RII failure and 4 cases (14.8) RIII failure. In Group 2, 18 cases were treated with a single dose of sulfadoxine 30 mg per kg body wt and pyrimethamine 1.5 mg per kg body wt. Two cases (11.1%) were cured (S), while 7 cases (38.9%) showed RI failure, 7 cases (38.9%) RII failure and 2 cases (11.1%) RIII failure. In Group 3, 23 cases were treated with quinine 10 mg base per kg body wt 8 hourly for 5 days plus sulfadoxine 20 mg per kg body wt and pyrimethamine 1.0 mg per kg body wt, single dose given with the last dose of quinine. Thirteen cases (56.5%) were cured (S), while 10 cases (43.5%) showed RI failure.

Child↗
PubMed1982

In vitro experiments on chloroquine and pyrimethamine absorption in the presence of antacid constituents or kaolin.

A study was made in vitro of the effect of five gastrointestinal medications on the absorption of chloroquine and pyrimethamine, the two most commonly used antimalarial agents in the Sudan. Activated dimethicone did not appreciably affect the absorption of either antimalarial drug. All other agents tested significantly decreased the absorption of both chloroquine and pyrimethamine. The decreases observed were as follows: calcium carbonate (-52.8 and -31.5%), a local remedy, gerdiga (-36.1 and -38.0%), kaolin (-46.5 and -49.9%) and magnesium trisilicate (-31.3 and -37.5%) for chloroquine and pyrimethamine respectively. The results indicate that concomitant therapy of these antimalarials with the implicated antacid and antidiarrhoeal agents will result in poor bioavailability of the antimalarials.

Animals↗
PubMed1993

Severe morbidity among children in a trial malaria chemoprophylaxis with pyrimethamine or chloroquine in Ibarapa, Nigeria.

In a controlled trial of weekly malaria chemoprophylaxis with chloroquine and pyrimethamine there were no significant differences in type and frequency of severe morbidity during chemoprophylaxis. Administration of chemoprophylaxis during the current and immediately preceding month was associated with significantly fewer episodes of severe morbidity in the chloroquine and pyrimethamine groups when each was compared with the control multivite group. After chemoprophylaxis had been stopped, significantly more episodes of severe morbidity occurred in the chloroquine group than the control group, but a similar trend in the pyrimethamine group was not statistically significant. In the control group most of the episodes of severe morbidity, including those episodes which were associated with heavy parasitaemia, occurred below the age of 4 years. In contrast, the children who received chemoprophylaxis continued to experience such illness at older ages. The difference between the chloroquine group and the control group in respect of age at time of severe morbidity was statistically significant.

Age Factors↗
PubMed1994

[Primary prophylaxis against cerebral toxoplasmosis. Efficacy of folinic acid in the prevention of hematologic toxicity of pyrimethamine].

OBJECTIVES: Cerebral toxoplasmosis is the most frequent opportunistic infection in patients with acquired immune deficiency syndrome in France. We evaluated the effect of adding folic acid to the standard treatment (including pyrimethamine) on preventing induced cytopenia in order to determine the optimal dose. METHODS: From January to September 1990, pyrimethamine (50 mg 3 times per week) was given as primary prophylaxis against toxoplasmosis to 30 patients who were positive for human immunodeficiency virus (CDC classes II or II, CD4 counts < 200/mm3). The patients were randomly divided into three groups given 5, 25 and 0 mg folic acid 3 times per week. Associated treatments were the same in all patients (zidovudine 600 mg/d, pentamidine isethionate aerosol, 300 mg, once a month). Blood cell counts and lymphocyte subset counts were made on days 0, 30, 90 and 180. RESULTS: Two patients were lost to follow-up and between day 90 and 180, 3 were excluded due to other opportunist infection and 1 due to zidovudine induced anaemia. Between the groups, there was no difference in haemoglobin level or cell counts on day 0. No haematologic toxicity was observed at day 90. Haemoglobin was significantly reduced in the control group (0 mg folic acid) on day 180 (mean haemoglobin on day 180, 13.8, 13.1 and 12.1 g/dl in groups 1, 2 and 3 respectively). No variation in polynuclear neutrophil counts was observed. CONCLUSION: These findings suggest that folic acid has a moderate beneficial effect on preventing haematologic disease in patients treated with pyrimethamine. There was no observed dose effect.

AIDS-Related Opportunistic Infections↗
PubMed1993

Assessment of the response in vivo and in vitro of Plasmodium falciparum to sulphadoxine-pyrimethamine in the malarious areas of Iran.

Studies of drug resistance of Plasmodium falciparum cases from SE Iran were carried out in vivo and in vitro during 1990-91. In a study of 26 chloroquine-resistant infections, using amodiaquine (25 mg kg-1 over 3 days), followed by two-thirds of the standard dose of sulphadoxine-pyrimethamine, six cases were resistant at the RI(3) and RII(3) levels. An additional study testing the standard dose of sulphadoxine-pyrimethamine in 43 chloroquine-resistant cases revealed five (11.6%) resistant at the RI(2) and RII(3) levels. Six of the above resistant infections were contracted in Hormozgan, three in Sistan-Baluchestan, one in Kerman provinces of Iran and one in Pakistan. In five of 22 successful in-vitro tests, carried out on different isolates, the parasites grew to schizonts (> or = 8 nuclei) in the wells containing 1000 pmol sulphadoxine and 12.5 pmol pyrimethamine, indicative of resistance.

Adolescent↗
PubMed1977

Treatment of servere psoriasis with pyrimethamine.

Pyrimethamine, a folate antagonist similar to methrotrexate without known hepatotoxcity in man, was administer orally, once a week, to seven patients with severe, long-standing psoriasis. Four patients obtained a good to excellent response; a fifth withdrew from the study early after a partial response; a sixth had minimal response to high doses, and the seventh was withdrawn due to a probable drug-induced hepatotoxic reaction. Hepatotoxic reaction was suspected in another patient with abnormal liver biopsy and experienced severe gastrointestinal toxic reactions and two developed significant thrombocytopenia, which resolved after oral treatment with folic acid or discontinuation of the drug. These did not recur at lower doses. Pyrimethamine appears to be effective in severe psoriasis, but offers no advantage, and several disadvantages over methotrexate. Pyrimethamine is probably hepatotoxic. It should be used with caution in patients with liver disease or impaired renal function; pretreatment liver biopsy is recommended.

Adult↗
PubMed1996

Susceptibility studies of Plasmodium falciparum isolates and clones against cycloguanil and pyrimethamine using the modified in vitro microtechnique.

Six clones were derived from each Malaysian Plasmodium falciparum isolate and characterized for their susceptibilities against type II antifolate drugs, cycloguanil and pyrimethamine. Results showed that these isolates were of a heterogeneous population, with average IC50 values of Gombak C clones at 0.012-0.084 microM and 0.027-0.066 microM, ST 9 clones at 0.019-0.258 microM and 0.027-0.241 microM, ST 12 clones at 0.015-0.342 microM and 0.012-0.107 microM, ST 85 clones at 0.022-0.087 microM and 0.024-0.426 microM, and ST 148 clones at 0.027-0312 microM and 0.029-0.690 microM against cycloguanil and pyrimethamine, respectively. Generally, most of these clones displayed susceptibility patterns similar to their parent isolates except ST 9/A4, ST 9/A7, ST 9/B5, ST 9/D9, ST 9/D10, ST 148/A4, ST 148/A5, ST 148/A7, ST 148/F7, ST 148/F8 clones, which were sensitive at 0.027 microM, 0.019 microM, 0.022 microM, 0.063 microM, 0.037 microM, 0.031 microM, 0.042, microM, 0.042 microM, 0.062 microM, and 0.027 microM, whereas, ST 12/D7 clone was resistant at 0.342 microM, against cycloguanil respectively. However, ST 9/A4, ST 9/D8, ST 12/D5, ST 85/A5, ST 85/B3, ST 85/B4, ST 85/D3, ST 85/D7, ST 148/A6, and ST 148/A7 clones were resistant to pyrimethamine at 0.158 microM, 0.241 microM, 0.107 microM, 0.223 microM, 0.393 microM, 0.402 microM, 0.426 microM, 0.115 microM, 0.690 microM, and 0.520 microM, respectively.

Animals↗
PubMed1997

Malaria in Mvumi, central Tanzania and the in vivo response of Plasmodium falciparum to chloroquine and sulphadoxine pyrimethamine.

A study on the prevalence of malaria and the response of Plasmodium falciparum to chloroquine and sulphadoxine-pyrimethamine was conducted in Mvumi area of central Tanzania. Splenomegaly was observed at a rate of 62% and 36% in children and adults respectively. Crude malaria parasite rate was 55.4% in children and 32% in adults. Plasmodium falciparum accounted for the highest proportion (62.7%) of the malaria parasites in the area. This malaria parasite was sensitive to standard dosage of either chloroquine or sulphadoxine-pyrimethamine. Sulphadoxine-pyrimethamine cleared the parasites to undetectable levels by day seven of administration whereas chloroquine cleared parasitaemia in 91% of the subjects by the seventh day. Despite the virtual absence of adult Anopheles mosquitoes during the study period, a larval survey indicated that breeding of Anopheles gambiae s.l. was taking place in nearby irrigation streams. Culex quinquefasciatus was the dominant man-biting mosquito in the area.

Adolescent↗
PubMed1998

Sulfadoxine-pyrimethamine embryopathy in Wistar rats.

Pregnant Wistar rats received a therapeutic dose (0.72 mg/kg body weight) of intramuscular sulfadoxine-pyrimethamine on days 5, 12, and 19 of gestation. The treated animals showed elevated neutrophilic lobe average and increased urinary excretion of formiminoglutamic acid (FIGLU) as compared with controls (p < 0.001), confirming folic acid deficiency due to sulfadoxine-pyrimethamine treatment. Complete embryo resorption occurred in the treatment group, while the control animals littered normally. These findings imply that sulfadoxine-pyrimethamine should be used with utmost caution in early pregnancy as this regimen can lead to folic acid deficiency and consequent pregnancy wastage.

Animals↗
PubMed1998

Plasma containing artemether-pyrimethamine has ex vivo blood schizonticidal activity against Plasmodium falciparum.

Plasma samples collected at intervals from healthy volunteers, after administration of 3 drug regimens [artemether (ART) 300 mg, pyrimethamine (PYR) 100 mg, and ART 300 mg plus PYR 100 mg] were examined for blood schizonticidal activity against K1 strain and T(9/94) clone of Plasmodium falciparum ex vivo. A synergistic effect against T(9/94), a pyrimethamine sensitive clone, was observed in plasma collected after ART+PYR administration, when the test was carried out in low p-aminobenzoic acid, low folic acid medium. The maximum activity (Amax), expressed as equivalent dihydroartemisinin concentration, for plasma samples collected after the combined ART+PYR regimen [6,935 (1,330-13,400) nmol/l] was significantly higher than those for the single ART or PYR regimens [935 (397-2,000) and 9.9 (5.6-15.6) nmol/l, respectively]. In addition, the area under the activity curve (AUA) for the combined regimen [12,8397 (39,274-19,7901) nmol.h/l] was significantly higher than those for the single ART or PYR regimens [(3618 (1406-5597) or 334 (82.3-733.3) nmol.h/l, respectively]. Microscopic observation revealed that ART in the combined regimen exerted its inhibitory effect against all erythrocytic stages and that this occurred before effects of PYR activity. Prolongation of inhibitory effects for the combined ART+PYR regimen was shown to be due to PYR activity by comparison to the activity from the single ART regimen. Results clearly demonstrated no PYR activity against K1, a pyrimethamine resistant strain, in plasma samples collected after the single PYR regimen and the ART+PYR regimen. Microscopic examination confirmed that growth inhibition of K1 was caused by ART activity only.

Animals↗
PubMed1989

Point mutations and pyrimethamine resistance in Plasmodium falciparum.

Pyrimethamine was first introduced as a prophylactic antimalarial in 1952, with the advantages of low toxicity and freedom from side-effects. As early as the mid-1950s, parasite resistance to this compound had been reported from several areas, and it has since become widespread on all continents where malaria is found. Although it is still used for the suppression of infection, predominantly in conjunction with sulphone or sulphonamide drugs, even these combinations are now useless in many areas. Pyrimethamine resistance is less important globally than resistance to the major curative drug chloroquine, but it has long tantalized molecular parasitologists because pyrimethamine belongs to the only class of antimalarials for which the target molecule is unambiguously known.

Journal Article↗
PubMed2000

Evaluation of the genotoxic effects of pyrimethamine, an antimalarial drug, in the in vivo mouse.

Pyrimethamine is an antimalarial drug and a known teratogenic agent. With this drug, positive and negative results have been reported by various investigators in in vivo and in vitro genotoxicity/mutagenicity assays. In this investigation the genotoxic effects of pyrimethamine (PY) were tested in mice in vivo systems, using the bone marrow micronucleus test (MNT) and the transplacental MN test (TMNT). PY at the highest dose (40 mg/kg) induced statistically significant MN in bone marrow cells at 24 and 48 h. In the transplacental MN test, PY did not induce significant MN in fetal liver or in maternal bone marrow. Teratogenesis Carcinog. Mutagen. 20:65-71, 2000.

Animals↗
PubMed1978

Pyrimethamine in prevention of relapses of meningeal leukemia: report of two cases.

Relapses of meningeal leukemia occurred in two children during hematologic remission of acute lymphoblastic leukemia. Treatment of CNS leukemia consisted of radiotherapy and repeated intrathecal injections of methotrexate and cytosine arabinoside. Intrathecal installations of the drugs were accompanied with increasing neurological side effects which seemed to be lifethreatening. To avoid them, repeated courses of pyrimethamine were introduced. No further relapse of meningeal leukemia occurred after pyrimethamine. Hematologic remissions in both children have lasted for over 7 years. All therapy was stopped 16 months ago.

Central Nervous System↗