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At least 19 recordsLinked to original sources
PubMed1986

Potentiating effect of pyrimethamine and sulfadoxine against dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium chabaudi.

Dihydrofolate reductase was partially purified from a pyrimethamine-sensitive Plasmodium chabaudi clone and a pyrimethamine-resistant clone derived from it and used in a study of the inhibitory effect of pyrimethamine and sulfadoxine, both alone and in combination. Kinetic analysis of the inhibitory effect of sulfadoxine against the enzyme from pyrimethamine-sensitive and -resistant parasites revealed that the drug inhibited the former enzyme competitively, with an inhibition constant (Kis) of 0.7 +/- 0.4 mM, but inhibited the latter enzyme noncompetitively, with Kis and Kii of 8.9 +/- 1.2 and 4.1 +/- 1.2 mM, respectively. Previous studies also showed competitive inhibition by pyrimethamine on the former enzyme and noncompetitive inhibition on the latter enzyme, with some 200-fold-lower affinity. Sulfadoxine and pyrimethamine exhibited a mutually potentiating effect on the enzyme activity, as revealed by the concave isoboles and the fractional inhibitions of less than unity. A potentiating effect was observed for the enzymes from both sources and was not dependent on the degree of the purification of the enzyme. Our results can be explained by assuming simultaneous binding of two inhibitors on the enzyme.

Animals↗
PubMedDate not supplied

The disposition of pyrimethamine base and pyrimethamine pamoate in the mouse: effect of route of administration.

We have investigated the plasma pharmacokinetics and mass fate in mice, of pyrimethamine administered as either the base or as the poorly soluble pamoate salt, in each case by the intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Following the administration of pyrimethamine base (i.p. and s.c.) and pyrimethamine pamoate (i.p.), maximum measured plasma levels of pyrimethamine were attained within 1 h, before declining monoexponentially. There was no significant difference between these three groups in the clearance (0.29 +/- 0.05, 0.30 +/- 0.03, 0.26 +/- 0.05 ml min-1), elimination half-life (4.5 +/- 0.5, 4.8 +/- 0.8, 4.9 +/- 0.5 h) and AUC (19.4 +/- 4.4, 17.3 +/- 2.2, 21.1 +/- 4.4 micrograms.h ml-1). By contrast, after s.c. dosage of pyrimethamine pamoate, drug absorption was significantly delayed, maximum plasma levels being reached after 4 h, these levels being approximately one-third of those in the other three groups. Absorption was however complete, as the values for AUC and clearance were not significantly different from the other groups. The pattern of faecal and urinary elimination of 14C radioactivity was unaffected by either dose site or formulation of pyrimethamine. The majority of the dose (44.5-64.2 per cent) was eliminated in the faeces suggesting extensive biliary excretion. Localization of 14C radioactivity in the major organs was negligible in all groups. Following each dose, between 85 and 98 per cent of the dose was accounted for. These studies indicate that of the four treatment groups only pyrimethamine pamoate on s.c. administration demonstrates a sustained release action from the dose site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Kinetic and molecular properties of the dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant clones of the human malaria parasite Plasmodium falciparum.

Dihydrofolate reductase (DHFR) (5,6,7,8-tetrahydrofolate: NADPH+-oxidoreductase; EC 1.5.1.3) was partially purified by affinity chromatography from three clones of the human malaria parasite Plasmodium falciparum. The three clones were representative of pyrimethamine-sensitive (clone 3D7) and pyrimethamine-resistant (clone HB3 and clone 7G8) parasites with ID50 values of 0.53 nM (3D7), 210 nM (HB3), and 540 nM (7G8), when tested in vitro against the drug. The specific activities of the partially purified DHFR differed by less than a factor of 2 between the sensitive clone 3D7 (442 +/- 39 nmol min-1 mg-1 protein) and the resistant clones HB3 (634 +/- 25 nmol min-1 mg-1 protein) and 7G8 (565 +/- 85 nmol min-1 mg-1 protein). The number of catalytic sites in partially purified DHFR from the three clones was similar and ranged from 151 to 194 pmol mg-1 protein. The Km value for NADPH was similar in all three clones (4.5-11.6 microM). The Km value for dihydrofolate was altered 13-fold comparing the sensitive clone 3D7 (3.2 +/- 0.6 microM) with the resistant clone HB3 (42.6 +/- 1.6 microM), with the Km for the resistant clone 7G8 falling in between (11.9 +/- 1.2 microM). The inhibition constants for pyrimethamine increased from 0.19 +/- 0.08 nM (3D7) to 2.0 +/- 0.3 nM (HB3) to 8.9 +/- 0.8 nM (7G8). The inhibition by pyrimethamine of the sensitive clone 3D7 was noncompetitive and competitive for the two other clones. The titration of partially purified DHFR with pyrimethamine revealed a 500-fold increase in the concentration of the drug needed to inhibit the DHFR activity by 50%, when the sensitive clone 3D7 (0.18 +/- 0.02 nM) was compared to the resistant clone 7G8 (95 +/- 16 nM). From the comparison of the specific activities and the catalytic center activities with the Km values for the substrate and the inhibition constants for pyrimethamine, both of which are altered in the resistant clones, we conclude that the molecular mechanism for pyrimethamine resistance in the three clones studied is not based on an overproduction of the DHFR but is due to a decreased affinity to antifolates by a structurally altered enzyme.

Chromatography, Affinity↗
PubMed1990

Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in Britain.

All reports of adverse reactions with pyrimethamine-sulphadoxine (Fansidar), pyrimethamine-dapsone (Maloprim), and amodiaquine spontaneously reported through the UK national post-marketing system were reviewed. Retrospective reporting rates of serious reactions associated with these drugs were analysed using prescription data from the Department of Health, derived from the Prescription Pricing Authority, and relevant pharmaceutical companies. Whilst interpretation of these data requires caution, they allowed comparison with reporting rates from other studies. The reported rate for all serious reactions to pyrimethamine-sulphadoxine was 1:2100 prescriptions, and for cutaneous reactions was 1:4900 prescriptions, with a fatality rate of 1:11,100. The reported rate for serious reactions to pyrimethamine-dapsone was 1:9100 prescriptions, and for blood dyscrasias was 1:20,000 prescriptions, with a fatality rate of 1:75,000. The reported rate of blood dyscrasias associated with amodiaquine was 1:2100 users with a fatality rate of 1:31,000. Serious hepatic disorders occurred in 1:11 1000 pyrimethamine-sulphadoxine prescriptions, 1:75,200 pyrimethamine-dapsone prescriptions, and in 1:15,650 amodiaquine users. 35% of cases received these drugs needlessly as they were not exposed to drug resistant strains of Plasmodium falciparum. Since few serious reactions have been reported to chloroquine plus proguanil, these data support guidelines which restrict the use of reviewed drugs for those at greatest risk of infection. Dosage data indicated that fatalities had taken higher doses and continued prophylaxis after onset of symptoms. Two thirds of serious reactions to the compound antimalarials were reported in females.

Adolescent↗
PubMed1979

Treatment of vivax malaria with sulfadoxine-pyrimethamine and with pyrimethamine alone.

The effect of pyrimethamine and the combination of pyrimethamine-sulfadoxine (Fansidar) upon the termination of the acute attack of vivax malaria was studied in Thailand. Pyrimethamine was found to be ineffective, providing clearance of parasitaemia in only two of six patients by the end of seven days following treatment. The combination, administered in a two-tablet single dose (sulfadoxine 1 gm, pyrimethamine 50 mg) eliminated parasitaemia in only six of ten patients within seven days. Three tablets (sulfadoxine 1 . 5 gm, pyrimethamine 75 mg) given to 11 patients, provided clearance of parasitaemia in all within seven days; however, mean parasite and fever clearance times in this group were prolonged at 90 and 50 hours respectively. Chloroquine remains the drug of choice for the termination of the acute attack of vivax malaria. Subsequent primaquine is necessary for the prevention of relapse.

Acute Disease↗
PubMed1985

The sustained release of pyrimethamine base or pyrimethamine pamoate from a biodegradable injectable depot preparation in mice.

The pharmacokinetics and mass fate in mice, of pyrimethamine (425 mg kg-1 s.o.) administered subcutaneously either as the base (BASE) or the pamoate salt (PAM) in an injectable oil mixture (benzyl benzoate-peanut oil 50:50 v/v) have been evaluated. Maximum measured plasma pyrimethamine levels after BASE were attained within 24 h, and were twice as high as after PAM. 25% of animals dosed with BASE died; among the survivors plasma drug levels fell rapidly below the minimum inhibitory concentration (MIC) for Plasmodium berghei (100-200 ng ml-1) by 5 weeks. In contrast, no mice dosed with PAM died and plasma levels were sustained above the MIC for 13 weeks, drugs still being detectable in plasma after four months. Overall, there was no significant difference between areas under the curve from zero time to the time of the final sampling of pyrimethamine following PAM or BASE. The rapid initial elimination of 14C-radioactivity (2.64 +/- 0.47% dose day-1 over 4 weeks) seen after dosage with [14C]BASE reflected the plasma disposition of pyrimethamine in the mice dosed with BASE. 90% of the excreted 14C was eliminated by one month by which time less than 1% (0.03 +/- 0.02%) of the [14C]BASE was recovered from the injection site. Both BASE and [14C]BASE studies suggest that exhaustion of this preparation occurred by 7 weeks. Excretion of 14C-radioactivity after [14C]PAM was gradual and sustained with a low mean daily rate, that was maintained throughout the study i.e. 1.21 +/- 0.17% day-1 (4 weeks), 0.88 +/- 0.28% day-1 (8 weeks), 0.5 +/- 0.31% day-1 (12 weeks), 0.42 +/- 0.27% day-1 (16 weeks).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Prospective double-blind trial of two different doses of mefloquine plus pyrimethamine-sulfadoxine compared with pyrimethamine-sulfadoxine alone in the treatment of falciparum malaria.

This double-blind study is based on the treatment of 75 adult male patients suffering from Plasmodium falciparum malaria in Medellín, Colombia, a city in which there is no malaria transmission. The patients, who came from regions with high resistance to antimalarials, were divided into three groups receiving single-dose treatment as follows: a combination of 280 mg mefloquine, 800 mg sulfadoxine and 40 mg pyrimethamine; a combination of 420 mg mefloquine, 1200 mg sulfadoxine and 60 mg pyrimethamine; and a combination of 1500 mg sulfadoxine and 75 mg pyrimethamine. After treatment, follow-up examination was performed daily for I week and then weekly for another 3 weeks. The cure rate in the mefloquine groups (within the study period of 28 days) was 100%, and in the third group 75%. Normal blood levels of the administered drugs were found in 6 patients of the third group who were not cured; they were subsequently cured with a single dose of 1000 mg of mefloquine. Drug tolerance was good and no toxic effects were demonstrated in blood and urine examinations. While the doses in the drug combinations (containing mefloquine) gave very good results, we would recommend a slightly higher dose combination of mefloquine with sulfadoxine-pyrimethamine for the treatment of falciparum malaria in areas with a high prevalence of chloroquine resistance.

Adolescent↗
PubMed1992

Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group.

OBJECTIVE: To compare pyrimethamine plus clindamycin (PC) to pyrimethamine plus sulfadiazine (PS) as a treatment for toxoplasmic encephalitis (TE) in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Randomized, unblinded phase II, multicenter trial with provision for crossover for failure or intolerance of the assigned regimen. SETTING: University hospitals. PATIENTS: Eighty-four patients with presumptive TE were entered. Thirteen were excluded when they were found to have another diagnosis, and 12 were excluded because they did not meet entry criteria. The baseline characteristics in the remaining 26 patients randomized to PC and 33 randomized to PS were comparable. INTERVENTIONS: Patients were treated for 6 weeks with pyrimethamine and folinic acid plus either sulfadiazine or clindamycin. Clindamycin was given intravenously during the first 3 weeks. MEASUREMENTS AND MAIN RESULTS: There was a trend toward greater survival in patients randomized to PS (hazard ratio, 3.25; 95% CI, 0.63 to 16.8; P = 0.13), but most study deaths were not directly related to TE. In contrast, patients randomized to PC appeared more likely to achieve complete clinical (odds ratio, 0.67; CI, 0.2 to 1.97; P greater than 0.2) and radiologic responses (odds ratio, 0.28; CI, 0.08 to 0.96; P = 0.02). Multivariate analysis revealed drug effects to be largely independent of other variables. Similar efficacy of the treatments was also suggested by a hazard analysis of resolution of abnormal mental status, fever, and headache. Skin rash was the most common adverse event in both treatment arms. Because of toxicity, six patients randomized to PC and 11 patients randomized to PS had to switch to the alternate treatment, but only three were unable to complete therapy after crossover. CONCLUSIONS: The results of several end points of efficacy, taken together, suggest that the relative efficacy of PC approximately equals that of PS. PC appears to be an acceptable alternative in patients unable to tolerate PS.

Acquired Immunodeficiency Syndrome↗
PubMed1990

[Comparative study of sulfadoxine-pyrimethamine and amodiaquine + sulfadoxine-pyrimethamine for the treatment of malaria caused by chloroquine-resistant Plasmodium falciparum in Maputo, Mozambique].

To compare the efficacy and side-effects of two therapeutic regimens for chloroquine-resistant falciparum malaria, a randomized study was carried out in 69 patients in Maputo Central Hospital in 1986-1987. The two treatments were sulfadoxine 25 mg/kg + pyrimethamine 1.25 mg/kg as a single dose (S + P) and amodiaquine 10 + 10 + 5 mg/kg over three days with sulfadoxine + pyrimethamine on the third day (A + S + P). The cure rate was 25/29 (86%) with S + P and 27/30 (90%) with A + S + P. No serious side-effects were observed. The probably slightly higher cure rate with the triple combination is hardly of clinical importance in semi-immune patients, but may theoretically help retard the development of resistance to sulfadoxine-pyrimethamine. This point and the question of the incidence of side-effects with the two regimens should be made the object of an epidemiological study.

Adult↗
PubMed1973

Sulfalene with pyrimethamine and chloroquine with pyrimethamine in single-dose treatment of Plasmodium falciparum infections. A trial in a rural population in northern Nigeria.

A comparative trial was carried out in northern Nigeria of the ability of the drug combinations chloroquine-pyrimethamine and sulfalene-pyrimethamine to clear the peripheral blood stream of asexual forms of P. falciparum within 7 days. The reappearance of asexual P. falciparum forms within the 70-day follow-up period and the occurrence of vomiting during the 2-3 hours following administration of the drugs were also recorded. The purpose of the trial was to choose the more suitable of the two drug combinations for repeated mass administration in the intervention phase of a collaborative field research project in the epidemiology and control of malaria in the African savannah. No differences were observed between the two drug combinations from a parasitological point of view. However, the sulfalene-pyrimethamine combination was found easier to administer and occasioned fewer records of vomiting. It was therefore recommended for use in the project.

Adult↗
PubMed1991

Falciparum malaria fully cleared by amodiaquine, pyrimethamine-sulfadoxine and pyrimethamine-sulfalene in areas of chloroquine resistance in Dodoma, Tanzania.

The in vivo response of Plasmodium falciparum to chloroquine, amodiaquine, pyrimethamine-sulfalene (MetakelfinR) and pyrimethamine-sulfadoxine (FansidarR) was assessed in Dodoma in 1988. Asymptomatic schoolchildren with pure P. falciparum infection were given full curative doses of one of the above antimalarials. Daily parasitological follow-ups were made for seven days. Overall successful follow-up cases were 101, 108, 95 and 97 on chloroquine, amodiaquine, MetakelfinR and FansidarR respectively. The overall resistance rate in the area was 28%. Most of the resistant cases were RII type. There was only one case of MetakelfinR resistance. Amodiaquine and FansidarR were fully effective in eliminating asexual parasitaemia from the blood in all the cases during the seven days of follow-up. The results indicate that chloroquine, a commonly used antimalarial in Tanzania, is not as effective as amodiaquine, a less used drug. Although the 'antifols' are still highly effective in Tanzania, their potency could change with continued use. These drugs should, therefore, be protected and used judiciously.

Amodiaquine↗
PubMed1987

A double-blind trial of a fixed combination of mefloquine plus sulfadoxine-pyrimethamine compared with sulfadoxine-pyrimethamine alone in symptomatic falciparum malaria.

A total of 100 male Zambian patients with symptomatic falciparum malaria were treated with either two tablets of mefloquine plus sulfadoxine-pyrimethamine (Fansimef) or three tablets of sulfadoxine-pyrimethamine (Fansidar) as a single dose. The patients were kept under observation from day 0 (day of treatment) to day 28 and all were cured. An S-type of response was seen in all patients; one patient in the Fansimef group inexplicably remained positive for Plasmodium falciparum trophozoites until day 6. There were no cases of recrudescence.The rate of clearance of parasitaemia was similar in both groups. The rate of clearance of fever was marginally faster in the Fansimef group. Side-effects such as pruritus, diarrhoea and abdominal pain occurred after both drugs but were mild and transient; tolerance was slightly better with Fansimef. Severe orthostatic hypotension occurred in 20% of the Fansidar patients and in only 2% of the Fansimef patients; this was reversed by bed rest. Haematological and biochemical parameters were generally not modified in an undesirable manner by the administration of these drugs.

Administration, Oral↗
PubMed1985

The disposition of pyrimethamine in the isolated perfused rat liver.

We have investigated the disposition of pyrimethamine base in the isolated perfused rat liver (IPRL) preparation after the administration of pyrimethamine (0.5 mg, 5 microCi). In the first half hour of the study, pyrimethamine underwent marked hepatic uptake, thereafter perfusate plasma drug levels declined monoexponentially with a half life (t 1/2) of 3.0 +/- 1.0 hr. Area under the perfusate plasma concentration/time curve (AUC)0----infinity was 6.9 +/- 1.9 microgram/hr/ml. Pyrimethamine was found to be a low clearance compound (78.4 +/- 25.3 ml/hr identical to 8.6% of liver perfusate flow) with a large volume of distribution (267.5 +/- 55.3 ml) in the IPRL. The combined AUCS(0----5hr) for pyrimethamine (AUC 4.8 +/- 0.5 microgram/hr/ml) and pyrimethamine 3-N-oxide (AUC0----5hr 0.9 +/- 0.6 microgram/hr/ml) accounted for 57% of the total AUC0----5hr of [14C] radioactivity (10.0 +/- 2.6 micrograms/hr/ml). This indicates the presence of metabolites of pyrimethamine as yet unidentified in the perfusate. Biliary excretion of [14C] during the course of the IPRL preparations was extensive (29.0 +/- 10.3%) though only a small proportion was due to pyrimethamine and the 3-N-oxide metabolite. The majority of radioactivity in the bile was attributable to highly polar, but unidentified metabolites of pyrimethamine. At the conclusion of each experiment (5 hr), a significant proportion of [14C] radioactivity was recovered from the livers (22.9 +/- 5.3%). Subsequent HPLC analysis of the liver tissue indicated this to be unchanged pyrimethamine, with trace levels of the 3-N-oxide metabolite. Sub-cellular fractionation of the homogenized livers revealed the most pronounced localisation of pyrimethamine to be in the lipid rich 10,000 g pellet (13.0 +/- 2.6%), the remainder being distributed equally between the 105,000 g pellet and supernatant. Neither pyrimethamine, [14C] radioactivity, nor pyrimethamine 3-N-oxide were extensively taken up by red cells throughout the study. Therefore, the large volume of distribution (267.5 +/- 55.3 ml) underlines the extent of pyrimethamine localisation in the liver.

Animals↗
PubMed1992

Levels of pyrimethamine in sera and cerebrospinal and ventricular fluids from infants treated for congenital toxoplasmosis. Toxoplasmosis Study Group.

Pyrimethamine levels in sera, cerebrospinal fluid (CSF), and ventricular fluid were measured by using reversed-phase high-pressure liquid chromatography. The specimens were from 37 infants receiving pyrimethamine for treatment of suspect or proven congenital toxoplasmosis. Pyrimethamine half-life in serum was 64 +/- 12 h when determined by study of terminal-phase kinetics of samples obtained from nine babies. This half-life was significantly different (P = 0.008) from the pyrimethamine half-life (33 +/- 12 h) determined by terminal-phase kinetics for two babies of the same age taking phenobarbital. Serum pyrimethamine levels at various intervals after dosages of pyrimethamine were also lower for infants receiving phenobarbital. Levels measured in sera from babies taking the same dose of pyrimethamine throughout their first year of life did not appear to vary significantly over time or at different ages (P greater than 0.05). Mean +/- standard deviation serum levels 4 h after a pyrimethamine dose were 1.297 +/- 0.54 micrograms/ml for babies taking 1 mg of pyrimethamine per kg of body weight daily and 0.7 +/- 0.26 microgram/ml for babies taking 1 mg/kg each Monday, Wednesday, and Friday. Levels in CSF were approximately 10 to 25% of concomitant levels in serum. Serum folate levels for infants who took 0.64 to 1.7 mg leukovorin per kg ranged from 33 to 663 ng/ml. To determine whether the levels of pyrimethamine in serum and CSF of treated infants were in a range that affected the most virulent, rapidly replicating, and standard laboratory strain of Toxoplasma gondii, effects of various concentrations of pyrimethamine and sulfadiazine on replication of T. gondii in vitro were assessed. The levels of the antimicrobial agents effective in vitro were in the range of levels of pyrimethamine achieved in sera and CSF. Although folinic acid could inhibit the therapeutic effect of pyrimethamine and sulfadiazine in vitro, inhibition was noted only at levels (> or = 4,800 ng/ml) that were considerably higher than the folate levels found in the treated infants' sera.

Chromatography, High Pressure Liquid↗
PubMed1988

Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum.

We describe the isolation and the sequence of the gene for the bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS; EC 1.5.1.3 and EC 2.1.1.45, respectively) from two pyrimethamine-resistant clones of Plasmodium falciparum, HB3 and 7G8. We have also derived the sequence of the DHFR portion of the gene, by amplification using polymerase chain reaction, for the pyrimethamine-sensitive clone 3D7 and the pyrimethamine-resistant strains V-1, K-1, Csl-2, and Palo-alto. The deduced protein sequence of the resistant DHFR portion of the enzyme from HB3 contained a single amino acid difference from the pyrimethamine-sensitive clone 3D7. It is highly likely that this difference is involved in the mechanism of drug resistance in HB3. The sequence of the DHFR gene from other pyrimethamine-resistant strains contains the same amino acid difference from the sensitive clone 3D7. However, they all differ at one other site that may influence pyrimethamine resistance. The DHFR-TS gene is present as a single copy on chromosome 4 in all pyrimethamine-sensitive and pyrimethamine-resistant isolates tested. Therefore, the molecular basis of pyrimethamine resistance in the parasites tested is not amplification of the DHFR-TS gene.

Amino Acid Sequence↗