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PubMed1975

Host failure in treatment of malaria with sulfalene and pyrimethamine.

An individual infected with a multidrug-resistant strain of Plasmodium falciparum failed to respond to treatment with sulfalene and pyrimethamine. Subinoculation studies showed that parasite resistance to the drug combination was not present. Plasma levels of sulfalene and pyrimethamine in this individual were similar to those of three individuals, subinoculated from him, who were cured by the drug combination. Erythrocyte levels of sulfalene in this individual were similar to those in an individual, subinoculated from him, who was cured by the drug combination. After treatment with the drug combination, in vitro tests showed similar antimalarial activity in the serum of this individual in comparison with the serum of this individual in comparison with the serum of an individual subinoculated from him. The failure of this individual to respond to treatment with sulfalene and pyrimethamine is attributed to an undefined host factor (or factors) that appear(s) to be present in his erythrocytes.

Adult↗
PubMedDate not supplied

[Pyrimethamine and sulfadoxine as a preventive treatment for Pneumocystis carinii and Toxoplasma encephalitis].

BACKGROUND: Few studies have been reported on the potential usefulness of Fansidar combination at a fixed doses of pyrimethamine and sulfadoxine as prophylaxis for pneumonia by Pneumocystis carinii and toxoplasmic encephalitis. METHODS: The clinical histories of the patients seen in our department from January, 1992 to December, 1994 who were prescribed pyrimethamine and sulfadoxine for the above prophylactic treatment were reviewed. RESULTS: One hundred fifty clinical histories fulfilled the requisites for evaluation. Thirty-seven patients (24%) had a previous diagnosis of AIDS, with the median CD4 count being of 134/mm3. The median follow up of treatment with Fansidar was of 31 months. Twenty-eight cases of pneumonia by Pneumocystis carinii (6.9 cases for 100 patients-years) and 10 cases of toxoplasmic encephalitis (2.5 cases for 100 patients-years) were diagnosed. CONCLUSIONS: These values are similar to those presented with respect to other pharmacologic interventions commonly used for the prevention of pneumonia by Pneumocystis carinii and toxoplasmic encephalitis and suggest that pyrimethamine and sulfadoxine is a useful alternative and requires consideration in individualized cases for the prophylaxis of these diseases.

AIDS-Related Opportunistic Infections↗
PubMed1999

Measurements of reproductive function in stallions treated with trimethoprim-sulfamethoxazole and pyrimethamine.

OBJECTIVE: To evaluate the effects of trimethoprim-sulfamethoxazole and pyrimethamine treatment on various measures of reproductive function in healthy pony stallions. DESIGN: Randomized complete block study. ANIMALS: 12 healthy, mature pony stallions. PROCEDURE: Stallions were assigned to treatment and control groups balanced for age and various characteristics of reproductive function. The treated group received trimethoprim-sulfamethoxazole and pyrimethamine for 90 days during summer and fall; the control group was not treated. Semen characteristics, sexual behavior, testicular volume, and sperm production efficiency were evaluated before treatment started and at 30-day intervals until 60 days after treatment ended. RESULTS: Effects of treatment were not detected for semen characteristics, testicular volume, sperm production efficiency, libido, erection, and quantitative measures of ejaculatory efficiency. At 30, 60, and 90 days, 4 of 6 treated stallions had unsteadiness upon mounting, clumsy or weak thrusting, failure to flex the back, and thready or inapparent ejaculatory pulses that resulted in dribbling of semen rather than forceful expulsion. CONCLUSIONS AND CLINICAL RELEVANCE: Although treatment with trimethoprim-sulfamethoxazole and pyrimethamine may not affect semen quality, testicular volume, sperm production efficiency, erection, or libido of healthy stallions, treatment may induce changes in copulatory form and agility and alter the pattern and strength of ejaculation. Stallions that develop neurologic signs during treatment should be used with caution for breeding.

Animals↗
PubMed1975

Comparative efficiency of pyrimethamine-sulphormethoxine in malaria suppression given as single weekly, fortnightly and monthly doses.

2. One hundred and seventy inhabitants of the Ilorin area, Nigeria, were observed over a period of five months during the season of maximum malaria transmission while taking pyrimethamine-sulphormethoxine weekly, fortnightly and every four weeks. 2. There was no episode of malaria parasitaemia in the group receiving weekly doses of 25 mg. pyrimethamine and 0-5 mg. sulphormethoxine throughout the course of the trials. 3. There was one episode of asexual parasitaemia at the second month in the group receiving double fortnightly doses, but none by the third or fourth months. 4. The group receiving 75 mg. pyrimethamine and 1-5 mg. of sulphormethoxine had seven episodes of asexual parasitaemia throughout the course of the trial. 5. In all three groups there was no evidence of clinical acute malaria. 6. There were no appriciable side-effects in all groups within a follow-up period of four months. 7. The present trials confirm the advantage of the drug combination which proved to be more effective when given as weekly or fortnightly doses.

Administration, Oral↗
PubMedDate not supplied

Determination of pyrimethamine in animal tissue and egg by liquid chromatography with fluorescence detection.

A sensitive and selective liquid chromatographic (LC) assay was developed to determine the concentration of pyrimethamine in animal tissue and egg by fluorescent derivative. Animal samples were extracted with acetonitrile, centrifuged, and purified by hexane. Fluorescent derivatization was performed by reacting pyrimethamine with chloroacetaldehyde and subjected to LC with fluorescence detection (excitation wavelength 300 nm, emission wavelength 420 nm). The limit of detection was 10 ng/g (10 ppb) and the standard calibration curve was linear in the range of 1-100 ppb (0.01-1 ng/10 microL). Recoveries from samples fortified at levels of 0.1 and 1 ppm (microg/g) were 61.0-77.4 and 65.5-81.2%, respectively. The method was applied to the monitoring of marketed samples. Pyrimethamine was not determined in any of the 70 samples: 20 swine muscle; 20 chicken muscle; 10 chicken liver; and 20 egg.

Animals↗
PubMed1999

Effect of deferoxamine alone and combined with pyrimethamine on acute toxoplasmosis in mice.

The standard regimen of treatment for toxoplasmosis is pyrimethamine with sulfadiazine. However, it is not suitable in some conditions, and nontolerable in AIDS patients. Deferoxamine (DFO), an iron chelator, is well tolerated clinically in transfusion induced - iron overload. The present study had shown that DFO is a promising drug against acute toxoplasmosis in mice. Three doses of 200, 300 and 400 mg/kg DFO were used either alone or in combination with pyrimethamine. Alone, it was effective in a dose- related response with the resultant of 70% protection of infected mice. When DFO was combined with a low minimally effective dose of pyrimethamine, a 100% protection was recorded with the prolongation in duration of survival of mice. Different possible mechanisms of action of DFO against Toxoplasma gondii were discussed.

Acute Disease↗
PubMedDate not supplied

[Monitoring the chemoresistance of Plasmodium falciparum malaria in Yopougon (Abidjan): in vivo study of chloroquine sensitivity and evaluation of pyrimethamine resistance following the analysis of point mutation in the dihydrofolate reductase gene].

A major endemic in Côte d'Ivoire, malaria is the first cause of hospital admissions and mortality in tropical Africa. The decrease of morbidity and mortality depends on early diagnosis and relevant treatment. This situation is hampered by an emerging resistance of P. falciparum to usual drugs such as chloroquine and sulfadoxine-pyrimethamine. In recognition of this problem, we established a monitoring system in the north of Abidjan (Yopougon) in order to better analyse P. falciparum resistance. The molecular basis of P. falciparum resistance to pyrimethamine is associated with point mutations in the dihydrofolate reductase (dhfr) gene. The presence of a wild-type codon 108-ser is defined by the presence of an Alu1 restriction site. A single base change resulting in the change of amino acid from 108-Ser to 108-Asn or 108-Thr results in the appearance of a Bsr1 or a Scrf1 restriction site respectively. In response to these needs, 42 children aged 6 to 59 months were enrolled in the study by using tests of therapeutic efficacy of chloroquine (14-day in vivo test of WHO). Before treatment, infected blood samples were stored at 20 C until P. falciparum DNA extraction. The results of the in vivo sensitivity of chloroquine showed 84.3% of plasmodic rate, 97.7 % of P. falciparum against 2.3% of P. malariae. However, 78.6% of adequate clinical response (ACR) was obtained and 21.4% of early therapeutic failure (ETF). At the end of the study, clearance of parasitemia and fever was obtained but the gametocytic rate was 4.8%. More, RFLP studies of amplified DNA fragment revealed that P. falciparum from 12 children (44.5%) had point mutation in the codon 108 of the dhfr gene. The mutation of these isolates was based on the change of amino-acid from 108-Ser to 108-Asn. Moreover, 51.8% of isolates were of the wild type. In conclusion, our results showed that chloroquine resistance is a reality in Abidjan just like anywhere else in West Africa. However, the number of isolates which had point mutation in the dhfr gene suggested that the future approach must be the study of possible correlation between the in vivo sulfadoxine-pyrimethamine test and point mutations in the dihydrofolate reductase and in the dihydropteroate synthase gene of P. falciparum from Côte d'Ivoire.

Animals↗
PubMed1962

The appearance of pyrimethamine resistance in Plasmodium falciparum following self-medication by a rural community in Ghana.

During the preparatory phase of the Malaria Eradication Pilot Project in Ghana, a weekly pyrimethamine regimen was instituted at two hyperendemic villages, primarily to assess the reliability of self-administration techniques under local conditions.After initial supervised individual administrations, weekly distribution of family drug requirements was made to a responsible member of each household by volunteer community leaders.Although parasite rates fell from 71% to 6.5% after four weeks, recurrence of Plasmodium falciparum parasitaemia was observed by the 37th week. Resistance in that species was confirmed, associated with successful sporogony in Anopheles gambiae, after supervised pyrimethamine treatment equivalent to twice the routine dosage.Emergence of this high-grade drug resistance was attributable to irregular self-administration by the local population of the tablets collected for each household. It was therefore concluded that under the conditions obtaining, self-medication was not a reliable method for mass distribution of pyrimethamine.

Antimalarials↗
PubMed1992

[The risks of pyrimethamine-sulfadoxine combination in the prenatal treatment of toxoplasmosis].

Some of the alternative treatments to avoid termination of pregnancy in cases where the fetus is affected by toxoplasmosis is to treat it as soon as the diagnosis has been made. The authors who already have experience of using pyrimethamine with sulfadoxoine (Fansidar) in the post-natal treatment of congenital infection, thought after reviewing the literature that this association of drugs would be harmless if applied during pregnancy. The principal risk that arises in the fetus is the teratogenicity of each of the components of pyrimethamine and sulfadoxine and also their associations. In animals pyrimethamine can increase the frequency of cleft palates probably because of its antifolinic action but there is no formal proof that it is teratogenic in human beings. Furthermore, the theoretical risk of karnicerus in the new born using the Sulfonamide has not been demonstrated. In the mother the main but rare risk (1 in 75,000) seems to be for the production of severe skin lesions such as Lyell and Stevens-Johnson which could be brought about by sulfonamides, but not particularly sulfadoxine.

Antimalarials↗
PubMed2003

Molecular epidemiology of malaria in Cameroon. XVI. Longitudinal surveillance of in vitro pyrimethamine resistance in Plasmodium falciparum.

Clinical observations have shown that pyrimethamine resistance develops rapidly in endemic countries where antifolate drugs are used massively for the treatment of Plasmodium falciparum infections. To analyze this phenomenon, the in vitro response of clinical isolates to pyrimethamine and the dihydrofolate reductase (dhfr) gene sequence were analyzed in 2000-2001 and compared with the results obtained since 1994 in Yaounde, Cameroon. Of 139 samples obtained in 2000-2001, 10 (7.2%) isolates were of the wild-type, 116 had pure mutant alleles (2 [1.4%] with a single mutation, 11 [7.9%] with double mutations, and 103 [74.1%] with triple mutations), and 13 (9.4%) had mixed alleles. With the exception of a single isolate with triple mutations (50% inhibitory concentration [IC50] = 84.3 nM), all isolates with pure wild-type dhfr alleles (IC50 < 100 nM) and those with pure mutant dhfr alleles (between 1 and 3 point mutations; IC50 > or = 100 nM) were clearly distinguished by in vitro drug sensitivity assays. The results of the two methods are highly correlated, and both methodologic approaches indicate an increasing proportion of pyrimethamine-resistant isolates in Yaounde over the past eight years (42-45% in 1994-1995, 63-67% in 1997-1998, and 88-92% in 2000-2001). At present, clinical isolates carrying triple dhfr mutations predominate in Yaounde. This situation calls for a regular surveillance of the efficacy of antifolate drugs by all available means, including clinical evaluation, in vitro drug sensitivity assays, molecular markers, and pharmacologic studies.

Adolescent↗
PubMed1992

Pharmacokinetics of intravenously and orally administered pyrimethamine in horses.

Single-dose pharmacokinetic variables of pyrimethamine were studied in horses. Pyrimethamine (1 mg/kg of body weight) was administered IV and orally to 6 adult horses, and plasma samples were obtained at frequent intervals thereafter. Plasma pyrimethamine concentration was assayed by gas chromatography, and concentration-time data were analyzed, using a pharmacokinetic computer program. The IV and oral administration data were best described by 3-compartment and 1-compartment models, respectively. The median volume of distribution at steady state after IV administration was 1,521 ml/kg and the median elimination half-time was 12.06 hours. Mean plasma concentration after oral administration fluctuated between a maximal concentration of 0.18 microgram/ml and 0.09 microgram/ml (24 hours after dosing). Bioavailability after oral administration was 56%.

Administration, Oral↗
PubMed2005

Effect of pyrimethamine in experimental rheumatoid arthritis.

BACKGROUND: Recent evidence has shown that the antimalarials are useful drugs in the treatment of various rheumatic diseases. The present study was designed to test the therapeutic effect of pyrimethamine (PYR) in collagen-induced arthritis (CIA). MATERIAL/METHODS: CIA was induced in Lewis rats. The intraperitoneal administration of PYR and methotrexate (MTX) were started on day 25 post-immunization and continued until final assessment on day 35. During this period, clinical examination was performed intermittently. Anti-C II Ab and nitric oxide (NO) synthesis were measured. The paws and knees were then removed for histopathology and radiography assay. The biocompatibility of PYR and MTX were assessed using a fibrosarcoma cell line. RESULTS: Data showed that i.p. injection of pyrimethamine to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed reduced inflammatory cell infiltrate in the joints of treated rats, and tissue edema and bone erosion in the paws were markedly reduced following PYR therapy. Moreover, our radiography results paralleled our histological findings. Cytotoxicity analysis of PYR showed greater tolerability compared with MTX. Treatment with PYR significantly diminished nitric oxide formation in treated rats compared with untreated controls. CONCLUSIONS: Our findings shed light on the therapeutic efficacy of pyrimethamine in experimental rheumatoid arthritis compared with a choice drug (methotrexate), which may recommended it as a second-line drug in the treatment of rheumatoid arthritis.

Animals↗
PubMed2006

Short report: molecular markers associated with Plasmodium falciparum resistance to sulfadoxine-pyrimethamine in the Democratic Republic of Congo.

Sulfadoxine-pyrimethamine (SP) is the first line antimalarial treatment in the Democratic Republic of Congo. Using polymerase chain reaction, we assessed the prevalence of mutations in the dihydrofolate reductase (dhfr) (codons 108, 51, 59) and dihydropteroate synthase (dhps) (codons 437, 540) genes of Plasmodium falciparum, which have been associated with resistance to pyrimethamine and sulfadoxine, respectively. Four hundred seventy-four patients were sampled in Kilwa (N = 138), Kisangani (N = 112), Boende (N = 106), and Basankusu (N = 118). The proportion of triple mutations dhfr varied between sites but was always > 50%. The proportion of dhps double mutations was < 20%, with some sites as low as 0.9%. A quintuple mutation was present in 12.8% (16/125) samples in Kilwa; 11.9% (13/109) in Kisangani, 2.9% (3/102) in Boende, and 0.9% (1/112) in Basankusu. These results suggest high resistance to pyrimethamine alone or combined with sulfadoxine. Adding artesunate to SP does not seem a valid alternative to the current monotherapy.

Animals↗
PubMed1991

In vitro sensitivity of southern African reference isolates of Plasmodium falciparum to chloroquine and pyrimethamine.

The in vitro sensitivity to chloroquine and pyrimethamine of 19 culture-adapted southern African reference isolates of Plasmodium falciparum was determined using a 48-hour assay. Four isolates collected in KwaZulu, Natal, were sensitive to chloroquine, and one of these was sensitive to the drug in vivo. Eight isolates from KwaZulu or Mozambique were resistant to chloroquine in vitro. Six of these isolates were chloroquine-resistant in varying degrees in vivo. Four of five isolates from north-eastern Transvaal and two clinically chloroquine-resistant Malawian isolates were resistant to chloroquine in vitro. A wide range of pyrimethamine susceptibilities was detected (0.01 mumol/l to greater than 3.0 mumol/l), although most isolates were inhibited at 0.1 mumol/l, indicating a low level of resistance. These results confirm the presence of both chloroquine and pyrimethamine resistance in the endemic areas of South Africa. This has serious implications for the prophylaxis and treatment of P. falciparum malaria in South Africa.

Africa, Southern↗
PubMedDate not supplied

Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man.

With the aim of developing anticancer compounds which overcome some of the clinical limitations of the polar dihydrofolate reductase inhibitor, methotrexate, the physicochemical properties, kinetics, and metabolism of a series of lipid-soluble 2,4-diamino-5-phenylpyrimidine folate antagonists have been studied. Metoprine and etoprine, potent inhibitors of mammalian dihydrofolate reductase, were compared with pyrimethamine, a widely used antimalarial drug. The development of assay procedures in our laboratory and the synthesis of radiolabeled compounds have enabled a comparison of the kinetic characteristics and tissue distribution of these compounds in several species. The relative lipophilicities as indicated by the octanol/water partition coefficient are: etoprine (log P = 3.19) greater than metoprine (log P = 2.82) greater than pyrimethamine (log P = 2.69). Etoprine has the greatest affinity for plasma proteins, but all three compounds are bound to human plasma protein by 87% or more at therapeutic concentrations. Pharmacokinetic studies in the mouse, rat, dog, and man indicate that metoprine has the longest plasma half-life in all four species. The mean plasma half-lives in man are: pyrimethamine, 85 hr; metoprine, 216 hr; etoprine, 176 hr.

Adult↗
PubMed1989

Mefloquine sulfadoxine pyrimethamine (MSP) combination delays in vitro emergence of mefloquine resistance in multiple drug resistant Plasmodium falciparum.

Sulfadoxine-pyrimethamine-resistant and chloroquine resistant, but mefloquine sensitive (MIC 5 x 10(-9] isolates of Plasmodium falciparum were used to study the emergence of mefloquine resistance. The continuously cultured isolates which were exposed intermittantly to varying concentrations of mefloquine alone became insensitive to the drug at 1 x 10(-7) M after 12 months, whereas the culture line exposed to the combination of mefloquine, sulfadoxine and pyrimethamine became only slightly insensitive to mefloquine (MIC 2 x 10(-8]. Thus, the efficacy of mefloquine may be prolonged through use in combination with sulfadoxine-pyrimethamine.

Animals↗
PubMed1988

Effectiveness of amodiaquine, sulfadoxine-pyrimethamine, and combinations of these drugs for treating chloroquine-resistant falciparum malaria in Hainan Island, China.

The study was carried out in 1985-86 in Hainan Island where Plasmodium falciparum is resistant to chloroquine. Fifty cases of falciparum malaria were treated with 1800 mg amodiaquine for 3 days: the cure rate was 65.3%, and the mean time to clear fever and asexual parasitaemia was 30.7 and 60.3 hours, respectively; 34.7% of cases showed RI or RII recrudescence, and one patient's temperature did not come down to normal within 7 days.Twenty-one cases were treated with sulfadoxine-pyrimethamine (1500 mg and 75 mg, respectively): 19 were cured, I showed RI and another had an S or RI response; the mean time for fever control was 56.1 hours.Fifty cases were treated with amodiaquine plus sulfadoxine and 49 received amodiaquine plus sulfadoxine-pyrimethamine: the cure rate was 97.9% and 100%, respectively; the mean time for fever clearance was 25.0 and 25.7 hours and for parasite clearance 57.1 and 52.8 hours, respectively. These drug combinations gave much better results for cure and for symptom control than amodiaquine or sulfadoxine-pyrimethamine alone, and may be considered for treatment of chloroquine-resistant falciparum malaria.

Adolescent↗
PubMed1988

Fatal toxic epidermal necrolysis during prophylaxis with pyrimethamine and sulfadoxine in a human immunodeficiency virus-infected person.

The combination of pyrimethamine and sulfadoxine (Fansidar) has been reported to cause severe skin reactions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Recently, this drug combination has been used for prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. After two months of weekly prophylaxis with pyrimethamine and sulfadoxine, a 48-year-old homosexual man who was antibody positive for human immunodeficiency virus developed severe widespread erythema, blisters, and loss of skin in sheets, and subsequently died. To our knowledge, this is the first reported case of fatal toxic epidermal necrolysis occurring in a patient with acquired immunodeficiency syndrome-related complex. The lack of absolute safety of prophylaxis with pyrimethamine and sulfadoxine is emphasized in our case, and mandates cautious use and the consideration of less toxic prophylactic measures such as therapy with the recently introduced aerosolized pentamidine.

Acquired Immunodeficiency Syndrome↗