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PubMed1984

High-performance liquid chromatographic assay of pyrimethamine, sulfadoxine and its N4-acetyl metabolite in serum and urine after ingestion of Suldox.

A sensitive and selective reversed-phase high-performance liquid chromatographic assay has been developed to determine the concentration of pyrimethamine, sulfadoxine and N4-acetylsulfadoxine in serum and urine after oral administration of the antimalarial remedy Suldox. Hitherto the literature describes no method being able to quantitate all three compounds in these fluids. The compounds are extracted successively from the same sample and subjected to liquid chromatography followed by ultraviolet detection (280 nm). Calibration curves were linear (r2 = 0.999; S.E.M. less than 3%; n = 10) in the range 0-300 micrograms/ml (sulfadoxine) and 0-1000 ng/ml (N4-acetylsulfadoxine and pyrimethamine). The limits of quantitation for the latter compounds were as low as about 5 ng/ml and 1 ng/ml, respectively. At therapeutic serum concentrations of 30 micrograms/ml (sulfadoxine), 350 ng/ml (N4-acetylsulfadoxine) and 120 ng/ml (pyrimethamine) an interassay reproducibility below 8% (relative standard deviation) was found for all three compounds. The assay was evaluated in a pilot study and proved convenient for pharmacokinetic studies in man following oral co-administration of pyrimethamine and sulfadoxine.

Acetylation↗

PubMedDate not supplied

Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial.

BACKGROUND: Many countries in Africa are considering a change to combination treatment for falciparum malaria because of the increase in drug resistance. However, there are few effectiveness data for these combinations. Our aim was to study the effectiveness of three drug combinations that have proven efficacious in east Africa compared with amodiaquine monotherapy. METHODS: We undertook a randomised trial of antimalarial drug combinations for children (aged 4-59 months) with uncomplicated malaria in Muheza, Tanzania, an area with a high prevalence of resistance to sulfadoxine-pyrimethamine and chloroquine. Children were randomly allocated 3 days of amodiaquine (n=270), amodiaquine +sulfadoxine-pyrimethamine (n=507), or amodiaquine+artesunate (n=515), or a 3-day six-dose regimen of artemether-lumefantrine (n=519). Drugs were taken orally, at home, unobserved by medical staff. The primary endpoint was parasitological failure by day 14 assessed blind to treatment allocation. Secondary endpoints included day 28 follow-up and gametocyte carriage. Analysis was by intention to treat. FINDINGS: Of 3158 children screened, 1811 were randomly assigned treatment and 1717 (95%) reached the 14-day follow-up. The amodiaquine group was stopped early by the data and safety monitoring board. By day 14, the parasitological failure rates were 103 of 248 (42%) for amodiaquine, 97 of 476 (20%) for amodiaquine+sulfadoxine-pyrimethamine, 54 of 491 (11%) for amodiaquine+artesunate, and seven of 502 (1%) for artemether-lumefantrine. By day 28, the parasitological failure rates were 182 of 239 (76%), 282 of 476 (61%), 193 of 472 (40%), and 103 of 485 (21%), respectively. The difference between individual treatment groups and the next best treatment combination was significant (p<0.001) in every case. Recrudescence rates by day 28, after correction by genotyping, were 48.4%, 34.5%, 11.2%, and 2.8%, respectively. INTERPRETATION: The study shows how few the options are for treating malaria where there is already a high level of resistance to sulfadoxine-pyrimethamine and amodiaquine. The WHO-packaged six-dose regimen of artemether-lumefantrine is effective taken unsupervised, although cost is a major limitation.

Amodiaquine↗

PubMed1997

Species-specificity of pyrimethamine in the rodent bone marrow micronucleus test.

An antiprotozoal agent pyrimethamine is a potent clastogen that induces structural chromosome aberrations and micronuclei in cultured Chinese hamster (CHL) cells in vitro. Our previous study on the compound, however, demonstrated no significant induction of micronuclei in the mouse bone marrow micronucleus test, even with dosings on 4 consecutive days. In the present study, we investigated the clastogenicity of pyrimethamine in the rat bone marrow micronucleus test. An obvious dose-dependent increase in the frequency of micronucleated polychromatic erythrocytes (MNPCEs) was observed when the compound was given 3 times by oral gavage at 20-120 mg/kg/day. The MNPCE frequency at the highest dose was 80 times that of the control group. Single dose of pyrimethamine at 80 and 160 mg/kg also significantly induced MNPCEs. Thus, pyrimethamine showed species-specific effects in rodent bone marrow micronucleus assays. Our finding implies that micronucleus tests using not only mouse, but also rat, may be necessary for the evaluation of clastogens detected in in vitro cytogenetic studies.

Administration, Oral↗

PubMed2004

Genetic markers of resistance to pyrimethamine and sulfonamides in Plasmodium falciparum parasites compared with the resistance patterns in isolates of Escherichia coli from the same children in Guinea-Bissau.

The antifolate drugs sulphadoxine and pyrimethamine are used for treatment of chloroquine-resistant Plasmodium falciparum in Africa. Resistance to pyrimethamine has been associated with point mutations in the dhfr-gene and resistance to sulphadoxine with mutations in the dhps-gene. There is concern that the use of the antifolates trimethoprim and sulphamethoxazole for treatment of other infectious diseases will result in the selection of malaria parasites with mutations in these genes. In Guinea-Bissau, where sulfonamide and trimethoprim-containing drugs have been used extensively, we decided to assess the prevalence of mutations in the dhfr-and dhps-gene in P. falciparum isolated from children suffering from acute malaria and to assess the resistance patterns to trimethoprim/sulphamethoxazole in Escherichia coli isolated from the same patients. A thick film and a blood sample for polymerase chain reaction (PCR) were obtained from 100 children attending the Bandim Health Centre in Bissau with symptoms compatible with malaria. Furthermore, a stool sample was collected from the same children and cultured for E. coli. Of the cultured E. coli, 67% were resistant both to sulfonamides and trimethoprim, 4% to sulfonamides alone, 3% to trimethoprim alone while 26% were fully sensitive to both drugs. PCR was successfully performed in 97 blood samples. Of these, 41% had triple mutations at the dhfr-gene (at codons 51, 59 and 108), and 15% had triple mutations plus mutation at codon 437 in the dhps-gene. Only 45% harboured the wild-type dhfr-gene. Thus both bacterial resistance and mutations in the parasitic genes were common, but not linked in the individual child. As sulphadoxine-pyrimethamine has only been used as a second line treatment for chloroquine resistant malaria in Guinea-Bissau for a few years, it is worrying to find a high prevalence of mutations in the parasitic genes coding for resistance to these drugs. Therefore, restricting the use of sulphadoxine-pyrimethamine for the treatment of chloroquine resistant malaria might not be sufficient to prevent the development of resistance in the parasites as long as antifolate drugs are used extensively.

Adolescent↗

PubMed1990

Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance.

Cycloguanil, the active metabolite of the antimalarial drug proguanil, is an inhibitor of dihydrofolate reductase as is another antimalarial, pyrimethamine. Its use has been limited by the rapid development of resistance by parasites around the world. We have determined the cycloguanil- and pyrimethamine-sensitivity status of 10 isolates of Plasmodium falciparum and have sequenced in all these isolates the dihydrofolate reductase (DHFR; 5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) portion of the DHFR-thymidylate synthase (TS; 5,10-methylenetetrahydrofolate: dUMP C-methyltransferase, EC 2.1.1.45) gene. Instead of the known serine-to-asparagine change at position 108 that is important in pyrimethamine resistance, a serine-to-threonine change at the same position is found in cycloguanil-resistant isolates along with an alanine-to-valine change at position 16. We conclude that pyrimethamine and cycloguanil resistance most commonly involve alternative mutations at the same site. However, we also have identified a parasite with a unique set of changes that results in resistance to both drugs.

Amino Acid Sequence↗

PubMed1992

Plasmodium falciparum: effect of chloroquine, halofantrine and pyrimethamine on the infectivity of gametocytes for Anopheles stephensi mosquitoes.

The activity of chloroquine, halofantrine and pyrimethamine against the gametocytes and sporogonic stages of Plasmodium falciparum (strain NF54) was tested. Five-day-old gametocytes (stages I and II) from in vitro cultures were exposed to the drugs for 48 hours. The effect of the drugs on gametocyte development was assessed by counting gametocytes on days nine and 15 of culture and determining the infectivity of the drug-treated gametocytes to mosquitoes. Gametocytogenesis was partially inhibited by all three drugs; there were 71% of the number of gametocytes in drug-free control cultures in cultures with 3 x 10(-8) M chloroquine, 51% with 5 x 10(-8) M chloroquine, 78% with 5-7 x 10(-9) M halofantrine, and 48% with 10(-7) M pyrimethamine. Halofantrine- and pyrimethamine-treated gametocytes were found to be more infective to Anopheles stephensi than untreated controls. The three drugs were also administered to the mosquitoes, either in the first bloodmeal, which contained gametocytes from in vitro cultures, or in the second, parasite-free bloodmeal, given four days after infection. The sporontocidal activity of the drugs was evaluated by counting the number of oocysts on the midgut seven or eight days after infection, or the number of sporozoites in the salivary glands 15 days after infection. A sporontocidal effect was observed only when pyrimethamine was administered with the infective bloodmeal. Neither chloroquine nor halofantrine had any marked effect on sporogony at the concentrations tested.

Animals↗

PubMed2000

Rapid selection of Plasmodium falciparum dihydrofolate reductase mutants by pyrimethamine prophylaxis.

A prospective study was conducted to measure the selective effect of pyrimethamine prophylaxis on point mutations in Plasmodium falciparum dihydrofolate reductase (DHFR). A total of 109 Malian children were given pyrimethamine weekly for 5 weeks. P. falciparum infections were analyzed by polymerase chain reaction for DHFR mutations, which were dramatically more frequent among prophylaxis-breakthrough infections than at baseline: the prevalence of Asn-108 rose from 13% to 100%, Ile-51 from 4% to 50%, and Arg-59 from 11% to 90%. Eight persistent infections lacking detectable DHFR mutations at baseline developed multiple mutations within 1 week of the patients' starting pyrimethamine prophylaxis. Microsatellite analysis found no evidence of clonal identity among baseline and breakthrough infections. Analysis of these data demonstrates that under prophylaxis conditions, pyrimethamine is strongly selective for DHFR mutations, which arise extremely rapidly under drug pressure, even when undetectable in the initial infection. These findings have implications for prophylaxis regimens with other antifolate drugs.

Animals↗

PubMed1995

Pyrimethamine analysis by enzyme inhibition and HPLC assays.

Pyrimethamine is an antiparasitic agent currently used for therapy of central nervous system toxoplasmosis, a disease seen with increasing frequency in association with the AIDS epidemic. Monitoring of pyrimethamine levels may be particularly important because patients may be treated with high doses of the drug for extended periods of time. The authors have developed and validated both a new enzyme inhibition assay that can be run on an automated analyzer and an improved high performance liquid chromatography (HPLC) method. The calibration range of both methods is 100 to 3,000 micrograms/L. Both demonstrate good linearity, specificity, and precision, and correlate well with one another (r = 0.99). The CVs of the enzyme inhibition assay were < or = 8.6% and those of the HPLC method were < or = 5.4%. No interference was noted for a variety of drugs likely to be used concomitantly with or in lieu of pyrimethamine with the exception of a minor interference from trimethoprim in the enzyme inhibition assay. The major advantage of the enzyme inhibition assay is its ease of automation. The major advantages of the HPLC assay are its precision and relative simplicity. These methods should facilitate therapeutic monitoring of pyrimethamine.

Calibration↗

PubMed1995

In-vitro and in-vivo activities of roxithromycin in combination with pyrimethamine or sulphadiazine against Toxoplasma gondii.

The efficacy of roxithromycin alone or in combination with pyrimethamine or sulphadiazine was examined in vitro and in a murine model of acute toxoplasmosis. In-vitro studies were performed with MRC5 fibroblast tissue cultures, with quantification of toxoplasma growth by an enzyme-linked immunosorbent assay. For in-vivo studies, mice were infected with 10(4) tachyzoites of the virulent RH strain and then treated perorally for 10 days from day 1 after infection. The efficacy of each drug regimen was assessed by determination of survival rates and sequential titration of parasites in blood, brain and lungs, using a tissue culture method. In vitro, roxithromycin inhibited toxoplasma growth at a concentration of > or = 0.02 mg/L; the 50% inhibitory concentration was estimated to be 1.34 mg/L. No synergistic effect was observed when it was combined with pyrimethamine or sulphadiazine. In vivo, roxithromycin alone at 50 or 200 mg/kg/day slightly prolonged survival compared with untreated mice, but a striking synergistic effect was observed when roxithromycin was administered in combination with pyrimethamine or sulphadiazine at subtherapeutic doses, i.e., 12.5 and 100 mg/kg/day, respectively. Combination regimens consistently resulted in a marked reduction fo the parasite burdens in blood and tissue, compared with those in mice treated with any of the agents alone. These results suggest that in-vivo activities of either pyrimethamine or sulphadiazine against T. gondii are reinforced by roxithromycin and such combinations should be considered in development of alternative treatments for human toxoplasmosis.

Animals↗

PubMed2001

Dose-escalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS.

OBJECTIVE: To assess the safety, tolerance and activity of increasing doses of azithromycin in combination with pyrimethamine for the treatment of toxoplasmic encephalitis (TE) in patients with AIDS. DESIGN: A phase I/II dose-escalation study of oral azithromycin in combination with pyrimethamine. SETTING: Eight clinical sites in the United States. PATIENTS: Forty-two adult HIV-infected patients with confirmed or presumed acute TE. METHODS: Patients were enrolled into three successive cohorts receiving azithromycin 900, 1200 and 1500 mg a day with pyrimethamine as induction therapy. The induction period was 6 weeks followed by 24 weeks of maintenance therapy. MAIN OUTCOME MEASURES: Patient response was evaluated clinically and radiologically. RESULTS: Of the 30 evaluable patients, 20 (67%) responded to therapy during the induction period. Ten experienced disease progression. Of the 15 patients who received maintenance therapy, seven (47%) relapsed. Six patients discontinued treatment during the induction period as a result of reversible toxicities. Treatment-terminating adverse events occurred most frequently among the patients receiving the 1500 mg dose. CONCLUSION: The combination of azithromycin (900-1200 mg a day) and pyrimethamine may be useful as an alternative therapy for TE among patients intolerant of sulfonamides and clindamycin, but maintenance therapy with this combination was associated with a high relapse rate. The combination was safe, but low-grade adverse events were common.

AIDS-Related Opportunistic Infections↗

PubMed1996

High-performance liquid chromatography determination of pyrimethamine, dapsone, monoacetyldapsone, sulfadoxine, and N-acetyl-sulfadoxine after rapid solid-phase extraction.

A solid-phase extraction procedure and a corresponding high-performance liquid chromatographic technique based on methods previously published by Edstein et al. (Edstein M. Quantification of antimalarial drugs. I. Simultaneous measurement of sulphadoxine, N4acetylsulphadoxine and pyrimethamine in human plasma. J Chromatogr 1984;305:502-7; Edstein M. Quantification of antimalarial drugs. II. Simultaneous measurement of dapsone, monoacetyldapsone and pyrimethamine in human plasma. J Chromatogr 1984;307:426-31) were developed for simultaneous determination of either dapsone (DDS), monoacetyldapsone (MADDS), and pyrimethamine (PYR) or sulfadoxine (SDX), N-acetyl-sulfadoxine (NAS) and pyrimethamine in plasma. Solid-phase extraction was achieved using C-18 extraction columns. An ionpair chromatography was performed on a C-18 analytical column (mu Bondapak C-18, 300 x 3.9 mm I.D.). Gradient elution with methanol, acetonitrile, PIC B6 reagent (1-hexanesulphonic acid), and water as mobile phase was applied. Ultraviolet detection was done at 210 nm for PYR, at 254 nm for SDX and NAS, and at 295 nm for DDS and MADDS. The extraction recoveries averaged 92.1% for PYR, 87.6% for DDS, 87.5% for MADDS, 91.2% for SDX, and 92.4% for NAS. The limit of quantification using 1.0-ml plasma samples was 15 ng/ml for PYR, DDS, MADDS, NAS, and 25 ng/ml for SDX (precision < 15%).

Anti-Infective Agents↗

PubMed1987

Pyrimethamine in the myeloproliferative disorders: a forgotten treatment?

Eight patients with myeloproliferative disorders, five with polycythaemia rubra vera (PRV) and three with essential thrombocythaemia (ET), have been treated with the anti-folate drug Pyrimethamine for periods ranging from 1 to 24 years. In PRV this treatment was comparable in efficacy to that achieved with Busulphan or radioactive phosphorus, but required more frequent supervision. One patient was controlled on Pyrimethamine, having failed on conventional treatment. The major side effect was thrombocytopenia which was rapidly reversible on stopping the drug. In ET, Pyrimethamine produced satisfactory control of the platelet count and thrombocytopenia did not arise. No neurological sequelae were encountered. One patient developed a non-Hodgkin's lymphoma of the gut, but there were no other cases of secondary malignancy. Pyrimethamine may still have a role in the treatment of selected cases of myeloproliferative disorders.

Adult↗

PubMed1996

A comparative study of the efficacies of chloroquine and a pyrimethamine-dapsone combination in clearing Plasmodium falciparum parasitaemia in school children in Tanzania.

A randomized study on the in vivo efficacies of chloroquine and a pyrimethamine-dapsone combination (Maloprim) in clearing P. falciparum parasitaemia was carried out in 77 asymptomatic semi-immune schoolchildren in the Kilombero District of Tanzania. Children were randomized to receive either chloroquine at a dose of 25 mg/kg over three days, or Maloprim (6.25 mg pyrimethamine + 50 mg dapsone for children under 10 years, and 12.5 mg pyrimethamine + 100 mg dapsone for children 10 or more years old) as a single dose. Children were followed-up for malaria parasitaemia at days 2, 7 and 14 after screening, randomization and treatment. The slide positivity rate was lower in the Maloprim group at all cross-sectional surveys (23 vs 37% at day 2; 9 vs 20% at day 7; 21 vs 32% at day 14) but none of these differences reached statistical significance. No cases in the Maloprim group showed RII resistance, whereas in the chloroquine group, 2 cases showed RII resistance and a further 2 cases RIII resistance (6%). No major side-effects were reported. The combination of pyrimethamine-dapsone appears to be a better choice than chloroquine as a chemoprophylactic regimen for malaria in this area. Although they need to be confirmed in a larger study, these results may be of interest to the policy-makers as well as researchers.

Antimalarials↗

PubMed1957

Sulphadimidine, pyrimethamine and dapsone in the treatment of toxoplasmosis in mice.

Sulphadimidine, dapsone, and pyrimethamine have been tested alone and in various combinations for their therapeutic effect against toxoplasma infection in mice. In the treatment of active infection, sulphadimidine by itself was effective, but relapses were common. Pyrimethamine gave complete cures and prevented the carrier state when used in doses near to the toxic level. Dapsone alone was not as good as either of the other two drugs tested. The best combination was found to be sulphadimidine and pyrimethamine, which were synergic. In doses well below the toxic level, this combination not only controlled the acute infection but also prevented relapses and the development of the carrier state. Dapsone and pyrimethamine were also synergic, but were not as effective as the previous combination. No synergy was found between dapsone and sulphadimidine. The mechanism of relapse and the development of the carrier state and the modes of action of the drugs alone and in combination are discussed.

Animals↗

PubMed1981

Augmentation of human lymphocyte proliferative responses in vitro by pyrimethamine.

Thymidine incorporation by human blood mononuclear cells, unstimulated and stimulated with phytohaemagglutinin (PHA), pokeweed mitogen (PWM) and purified protein derivative of tuberculin (PPD) was studied with and without addition of pyrimethamine. Responses were increased significantly by pyrimethamine in the PWM and PPD stimulated cultures, in the PPD cultures even by concentrations of pyrimethamine, which can be achieved with therapeutic doses of this drug. The closely related compound trimethoprim did not alter PHA-, PWM- and PPD-responses significantly. The possibility of using pyrimethamine--a widely used prophylactic antimalarial--as an immunopotentiator is mentioned.

Adult↗

PubMed1984

Mechanism of pyrimethamine resistance in recent isolates of Plasmodium falciparum.

Clones of Plasmodium falciparum prepared from recent isolates of infected blood were studied to determine the molecular mechanism of naturally occurring pyrimethamine resistance. Total DNA, as well as thymidylate synthetase and dihydrofolate reductase activities, were characterized from these lines. Restriction analysis of DNA from pyrimethamine-susceptible and -resistant lines of the parasite showed no obvious amplification of any DNA fragment. Further, analysis of DNA from resistant and susceptible lines by centrifugation in cesium chloride-ethidium bromide revealed no extrachromosomal amplification in the resistant line. Comparison of the dihydrofolate reductase enzyme activity in the two lines revealed similar KmS for substrate but a large difference in the inhibition constant for pyrimethamine. Additionally, the enzyme from the resistant line was considerably more stable in vitro than the corresponding enzyme from the susceptible line. The thymidylate synthetase activity in the two lines was similar and unaffected by pyrimethamine. The mechanism of drug resistance in this isolate involves altered properties of the dihydrofolate reductase conferring both a different affinity for the drug and increased stability.

Animals↗

PubMed1989

Zidovudine antagonizes the action of pyrimethamine in experimental infection with Toxoplasma gondii.

The effect of zidovudine (azidothymidine; AZT) on the action of pyrimethamine against Toxoplasma gondii was investigated. Zidovudine was found to antagonize the toxoplasmacidal effect of low concentrations of pyrimethamine in vitro, and in vitro synergism of pyrimethamine and sulfadiazine against T. gondii was reversed by zidovudine. Zidovudine also antagonized the therapeutic effect of pyrimethamine in mice acutely infected with T. gondii.

Animals↗

PubMed1991

Pyrimethamine-clarithromycin combination for therapy of acute Toxoplasma encephalitis in patients with AIDS.

Clarithromycin, a new macrolide, is effective in treating experimental Toxoplasma gondii infection. A pyrimethamine-clarithromycin combination was evaluated for the treatment of acute Toxoplasma encephalitis in 13 AIDS patients. The scheduled regimen was 2 g of clarithromycin per day and 75 mg of pyrimethamine per day for 6 weeks. The protocol was completed in eight patients and stopped in five patients (because of voluntary withdrawal by two patients, deterioration of neurological condition and thrombocytopenia in two patients, and suspicion of liver toxicity in one patient). The clinical and computed tomography scan responses at week 6 of treatment were 80 and 50%, respectively. Two patients died, one of toxoplasmic encephalitis and the other of cerebral bleeding due to pyrimethamine-induced thrombocytopenia. Adverse events related to therapy were nausea and/or vomiting (38%), skin rash (38%), significant increase of liver tests (24%), hearing loss (15%), and severe hematological abnormalities (31%). In this pilot study, a pyrimethamine-clarithromycin combination was shown to be comparable to the conventional regimen for the treatment of acute Toxoplasma encephalitis in AIDS patients.

Acquired Immunodeficiency Syndrome↗