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PubMedDate not supplied

Simultaneous determination of dapsone and pyrimethamine by derivative spectrophotometry in pharmaceutical formulations.

A simple and fast method was developed for the simultaneous determination of dapsone and pyrimethamine by first-order digital derivative spectrophotometry. Acetonitrile was used as a solvent to extract the drugs from the pharmaceutical formulations, and the samples were subsequently evaluated directly by digital derivative spectrophotometry. The simultaneous determination of both drugs was performed by the zero-crossing method at 249.4 and 231.4 nm for dapsone and pyrimethamine, respectively. The best signal-to-noise ratio was obtained when the first derivative of the spectrum was used. The linear range of determination for the drugs was from 6.6 x 10(-7) to 2.0 x 10(-4) and from 2.5 x 10(-6) to 2.0 x 10(-4) mol/L for dapsone and pyrimethamine, respectively. The excipients of commercial pharmaceutical formulations did not interfere in the analysis. Chemical and spectral variables were optimized for determination of both analytes. A good level of repeatability, 0.6 and 1.7% for dapsone and pyrimethamine, respectively, was observed. The proposed method was applied for the simultaneous determination of both drugs in pharmaceutical formulations.

Antimalarials↗

PubMed1959

Effect of pyrimethamine upon sporogony and pre-erythrocytic schizogony of Laverania falciparum.

Studies have been conducted in Liberia on the effect of pyrimethamine on the sporogony and, for the first time, on the pre-erythrocytic schizogony of Laverania falciparum. From the results reported here it is concluded that it may reasonably be assumed that a mass monthly regimen of pyrimethamine in Liberia could afford protection to the individual and to the mosquito and thus to the population at large, provided that resistance to pyrimethamine does not intervene.Pyrimethamine in single doses of 25 mg or 50 mg administered to gametocyte carriers was able to render gametocytes of L. falciparum uninfective to A. gambiae for periods up to 28 days after administration.Mosquitos feeding upon a malaria-free pyrimethamine-treated subject before or after feeding upon a non-treated gametocyte carrier became infected and sporozoites appeared in the salivary glands.Pyrimethamine administered in 12.5-mg doses 13 days before, 6 days before and 2 days after sporozoite infection or administered in 25-mg doses 35 days and 7 days before sporozoite infection disallowed the development of the pre-erythrocytic schizonts of L. falciparum in the livers of two chimpanzees.

Antimalarials↗

PubMed1992

Efficacy of dapsone with pyrimethamine (Maloprim) for malaria prophylaxis in Maputo, Mozambique.

In a randomized controlled study of malaria prophylaxis, dapsone-pyrimethamine at a weekly dosage of dapsone 50-100 mg with pyrimethamine 6.25-12.5 mg or placebo was administered to 166 school children for 17 weeks. Fortnightly parasitological controls revealed 28 infections in the placebo group and none in the dapsone-pyrimethamine group. It is concluded that weekly dapsone-pyrimethamine is effective for the prophylaxis of falciparum malaria in Mozambique.

Child↗

PubMed2006

Molecular epidemiology of malaria in Cameroon. XXI. Baseline therapeutic efficacy of chloroquine, amodiaquine, and sulfadoxine-pyrimethamine monotherapies in children before national drug policy change.

The availability of epidemiologic data on drug-resistant malaria based on a standardized clinical and parasitological protocol is a prerequisite for a rational therapeutic strategy to control malaria. As part of the surveillance program on the therapeutic efficacy of the first-line (chloroquine and amodiaquine) and second-line (sulfadoxine-pyrimethamine) drugs for the management of uncomplicated Plasmodium falciparum infections, non-randomized studies were conducted in symptomatic children aged less than 10 years according to the World Health Organization protocol (14-day follow-up period) at 12 sentinel sites in Cameroon between 1999 and 2004. Of 1,407 children enrolled in the studies, 460, 444, and 503 were treated with chloroquine, amodiaquine, or sulfadoxine-pyrimethamine, respectively. Chloroquine treatment resulted in high failure rates (proportion of early and late failures, 48.6%). Amodiaquine was effective at all study sites (proportion of failures, 7.3%). Sulfadoxine-pyrimethamine therapy was less effective than amodiaquine (P < 0.05), with failures observed in 9.9% of patients. Chloroquine is no longer a viable option and has been withdrawn from the official drug outlets in Cameroon. Amodiaquine and, to a lesser extent, sulfadoxine-pyrimethamine monotherapies are still effective in Cameroon, but further development of resistance to these drugs should be delayed by the novel strategy using artemisinin-based combination therapy. Our findings indicate that amodiaquine is the most rational partner for artesunate. Studies on the efficacy of artesunate-amodiaquine combination are currently being undertaken at several sites in the country.

Amodiaquine↗

PubMed2006

A randomized trial of artesunate-sulfamethoxypyrazine-pyrimethamine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali.

The choice of artemisinin-based combination that is being adopted for malaria treatment in sub-Saharan Africa may depend on several factors, including cost, efficacy, side effects, and simplicity of administration. We tested the hypothesis that artesunate-sulfamethoxypyrazine-pyrimethamine is as efficacious as the four-dose regimen of artemether-lumefantrine for treatment of Plasmodium falciparum malaria. The study was carried out during two transmission seasons (2003 and 2004) in Sotuba, Mali. Participants at least 6 months of age with uncomplicated P. falciparum malaria were randomly assigned to receive artesunate-sulfamethoxypyrazine-pyrimethamine or artemether-lumefantrine. Treatment efficacy was assessed using the World Health Organization 28-day protocol. A total of 606 (303 in each arm) patients were enrolled. The cure rate was higher for artesunate-sulfamethoxypyrazine-pyrimethamine than for artemether-lumefantrine (98.7% versus 89.6%; P < 0.0001). After correction for cases of re-infection, the cure rates were 100% and 99.0%, respectively (P = 0.08). No serious adverse events occurred. Artesunate-sulfamethoxypyrazine-pyrimethamine is well-tolerated and effective against P. falciparum malaria. It showed an additional benefit of preventing new infections.

Adolescent↗

PubMed1991

Isocratic reversed-phase HPLC method to measure pyrimethamine extracted from plasma of infants treated for toxoplasmosis.

An isocratic HPLC method for measuring pyrimethamine extracted from infant plasma is reported. The method is an improvement over previously published methods by requiring lower volumes of plasma (100 microL) and having increased sensitivity to pyrimethamine at 210 nm. The procedure, which entails a basic organic extraction and subsequent HPLC chromatography of the reconstituted extract, can detect 1.4 ng and quantify 4.0 ng of pyrimethamine per 40-microL injection, with two analyses per 100-microL sample. Analytical recovery of pyrimethamine added to plasma at 10, 50, and 125 ng/100 microL averaged 80%, 92%, and 101%, respectively (n = 20). Within- and between-day CVs were less than 7%. Studies of various plasma samples from adults and infants (n = 15) revealed no interference from other plasma peaks with the analyte of interest.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

[Fetal toxoplasmosis. In utero treatment with pyrimethamine sulfamides].

The mothers of 52 cases of toxoplasmic fetopathy diagnosed in utero by fetal blood and/or amniotic fluid sampling were treated with the combination pyrimethamine-sulfadiazine (or sulfisoxazole) and by spiramycine. The infants were compared with 51 other infants with congenital toxoplasmosis whose mothers had received spiramycine alone. Patients of both groups received the same pyrimethamine-sulfadiazine and spiramycine treatment after birth. Parasitologic examination of the placenta was positive in 42 and 76.6% of patients, in group I and group II respectively. The newborns had specific IgM in 17.4 and 69.2% of cases respectively in both groups. These differences were significant. The mean specific IgG titer was significantly reduced at birth and 4 to 6 months of age in the first group. Patients in group I had more often subclinical infection than patients of the comparison group: 57% vs 33.3%. They had less often a high cerebro-spinal protein content during the first week. Prenatal treatment with pyrimethamine-sulfadrugs resulted in a less progressing infection at birth. However in cases with clinically patent toxoplasmosis, the frequency of overt localizations and their sequellae was not significantly altered. This might be related to a relatively late onset of the treatment. The pyrimethamine-sulfadrug combination given to mothers of proved infected fetuses can be rewarding. The indication might be extended to well-documented seroconverted mothers if, in the future, the acquired experience and necessary pharmacological studies bring the proof of its innocuousness.

Drug Therapy, Combination↗

PubMed1990

Efficacies of chloroquine and pyrimethamine-sulphadoxine in a Nigerian population with chloroquine resistant P. falciparum malaria.

A modification of the standard World Health Organisation 7--day in vivo test was used to assess the parasitologic and, to limited extent, the clinical response of children less than 5 years of age to defined oral dosages of chloroquine and pyrimethamine-sulphadoxine during the 14 days following the initiation of treatment. The study took place in Jato-Aka, a rural community in Benue State of Nigeria. 471 children were screened and 271 (59%) of these had plasmodium parasites thus showing a high transmission rate at a time of the year with scarce rainfall. Of the 42 children on chloroquine and who were followed up to day 2, 4 or 9.5% of them were parasitologic failures while none of the 45 children on pyrimethamine-sulphadoxine (P-S) failed parasitologically. By day 7, 21 (50%) of the children on chloroquine and 4 or 8.9% of those on P-S. had become parasitologic failures. The total number of parasitologic failures on day 14 were 21 (50%) and 4(8.9%) for chloroquine and P-S groups respectively. Chloroquine improved the clinical state of the patients better than P-S. However, P-S appears superior in clearing the parasites. These results confirm the existence of both chloroquine and pyrimethamine-sulphadoxine resistant strains of P. falciparum in some regions of Nigeria. The routine chloroquine chemoprophylaxis of children under 5 years of age should be discontinued so as not to hasten the intensification of chloroquine resistance and because of its probable marginal efficacy at chemoprophylaxis dosages. There is also need for a national policy on pyrimethamine-sulphadoxine usage in order not to hasten its resistance to P. falciparum.

Animals↗

PubMed1987

Evaluation of an in vitro test method for the assessment of sensitivity of Plasmodium falciparum to pyrimethamine and sulfadoxine.

Twenty three Plasmodium falciparum isolates collected from two highly pyrimethamine/sulfadoxine-resistant areas of Thailand were evaluated for their in vitro responses to pyrimethamine, sulfadoxine and combinations of these two drugs in various conditions. The test procedure was based on inhibition of parasite multiplication and of schizont formation, using the recommended modified RPMI medium 1640 with PABA 0.5 mug per litre and folic acid 10 mug per litre (LPLF). The optimum blood/medium ratios and inoculum sizes for parasite multiplication and for schizont formation were 1:19, 100 mul/well and 1:9, 50 mul/well, respectively. The appropriate incubation period was 48 hours. It was found that inhibition of either parasite multiplication or schizont formation could be used as the endpoint for evaluating the antiplasmodial action of pyrimethamine and combined pyrimethamine/sulfadoxine in vitro for field investigations; however, inhibition of only parasite multiplication should be used for determination of sulfadoxine activity. The actions of pyrimethamine in the combination pyrimethamine/sulfadoxine in ratios of 1:80 and 1:200 were similar. In vitro testing using combined pyrimethamine/sulfadoxine should be more precise than pyrimethamine alone for monitoring parasite susceptibility to the combined drug (Fansidar).

Animals↗

PubMed1985

In vitro sensitivity of Plasmodium falciparum to sulfadoxine and pyrimethamine.

An in vitro microtechnique of Rieckmann et al., (1978) modified by Yisunsri and Rieckmann (1980) using 3 media; Waymouth, Waymouth plus 10% human serum, and RPMI was assessed to determine the sensitivity of P. falciparum to sulfadoxine, pyrimethamine and its combination. The study confirmed the synergism between sulfadoxine and pyrimethamine. There was no interaction between media and drug tested. MIC1 and MIC2 of sulfadoxine in different media showed significant difference (p less than 0.001). No significant difference was observed in MIC1 and MIC2 of pyrimethamine in the three media used (p greater than 0.05). For sulfadoxine-pyrimethamine combination, MIC1 and MIC2 in Waymouth alone and plus 10% human serum showed no significance (p greater than 0.05) while in RPMI showed positive correlation (p less than 0.001). MIC1 might be more applicable for clinical evaluation than MIC2. At present Waymouth medium with 5% patient serum, is considered to be the most suitable for testing sensitivity of malarial parasites.

Culture Media↗

PubMed1984

[Congenital toxoplasmosis. Tolerability of the sulfadoxine-pyrimethamine combination. 24 cases].

The pyrimethamine-sulfadoxine combination, active against acute toxoplasmosis in the mouse, was administered to 24 children with congenital toxoplasmosis in doses of 500 mg sulfadoxine and 25 mg pyrimethamine per 20 kg bodyweight once every fortnight. The drug appeared to be as effective as other sulfonamide-pyrimethamine combinations. It was generally well tolerated and was withdrawn in only 3 patients on account of minor side-effects. Giving pyrimethamine-sulfadoxine together with folinic acid is a much simpler treatment of congenital toxoplasmosis than the usual ones.

Child, Preschool↗

PubMed1981

Effects of low concentrations of pyrimethamine on human bone marrow cells in vitro: possible implications for malaria prophylaxis.

The effects of low concentrations of pyrimethamine on the enzyme dihydrofolate reductase in human bone marrow cells were investigated in vitro using the deoxyuridine suppression test. The results indicated that drug concentrations which are achieved in the plasma of adults receiving 25 mg pyrimethamine per week inhibited the activity of this enzyme in a proportion of the marrow samples studied. Experiments using vitamin B12- or folate-deficient marrow cells showed that these concentrations of pyrimethamine may aggravate a pre-existing impairment of the methylation of deoxyuridylate. These in-vitro findings emphasize the importance of further studies into the toxicity of pyrimethamine when this drug is used for malaria prophylaxis in malnourished individuals.

Bone Marrow↗

PubMed1995

Treatment of acute Toxoplasma gondii infections in mice with diclazuril or a combination of diclazuril and pyrimethamine.

Diclazuril is a benzeneacetonitrile anticoccidial that is also effective in the prevention of toxoplasmosis. The present study was conducted to examine the efficacy of diclazuril alone or in combination with pyrimethamine for the treatment of acute toxoplasmosis in mice. Diclazuril administered at 10 mg/kg beginning 6 days after inoculation and given for 10 days protected 90% of mice over a 56-day observation period. Treatment with diclazuril at 1.0 or 0.5 mg/kg protected 20 and 0% of mice, respectively. Treatment with pyrimethamine at 12.5 or 6.0 mg/kg protected 60 and 0% of mice, respectively. When diclazuril (1.0 or 0.5 mg/kg) was combined with pyrimethamine (12.5 mg/kg) all mice survived the 56-day observation period. When diclazuril (1.0 or 0.5 mg/kg) was combined with pyrimethamine (6.0 mg/kg) 30 and 10% of mice, respectively, survived the 56-day observation period.

Acute Disease↗

PubMed1996

The cytogenetic effects of pyrimethamine on male mouse germ cells.

Pyrimethamine is an inhibitor of dihydrofolate reductase and is used in the treatment of malaria and toxoplasmosis. We examined the cytogenetic effects of this drug. Adult male mice were given doses of 20, 40, 80, and 120 mg/kg pyrimethamine intraperitoneally. Animals were killed by cervical dislocation on the 3rd, 6th, 9th, and 12th day after treatment, and the primary spermatocytes were harvested from their testes. These cells were analyzed for gaps, breaks, acentric fragments, and exchanges, as well as for numerical aberrations such as univalency. A dose-related increase in chromosomal aberrations was found in the pyrimethamine group compared with the control group. We suspect that pyrimethamine is a possible clastogen that may affect human germ cells.

Animals↗

PubMed1997

Treatment of chloroquine-resistant malaria using pyrimethamine in combination with berberine, tetracycline or cotrimoxazole.

Two hundred and fifteen patients with chloroquine-resistant malaria were randomised into three groups. The first group of 82 patients were given pyrimethamine and berberine (berberine group), the second group of 64 patients, pyrimethamine and tetracycline (tetracycline group) and the third group of 69 patients were given pyrimethamine and cotrimoxazole (cotrimoxazole group). In the berberine group, the clearance, rate of asexual parasitaemia was 74.4% after treatment, while in the tetracycline group it was 67.2% and in the cotrimoxazole group 47.8%. These results indicate that berberine is more effective in clearing the parasite than both tetracycline and cotrimoxazole, and that the combination of pyrimethamine and berberine gives the best results for chloroquine resistant malaria.

Adolescent↗

PubMed1970

Malaria suppression with fortnightly doses of pyrimethamine with sulfadoxine in the Gambia.

As it had been shown in previous trials that very small doses of pyrimethamine and sulfadoxine or dapsone were effective in eliminating Plasmodium falciparum in 2 or 3 days, small-scale field trials were carried out on children to investigate the efficacy of this combination of drugs in suppressing malaria.Doses of pyrimethamine 2 mg with sulfadoxine 40 mg, fortnightly, appeared to be completely successful in suppressing seasonal hyperendemic malaria in a group of 38 Gambian children over a 6-month period. On the other hand, pyrimethamine alone at the recommended dose failed to suppress falciparum malaria in some children of another group. Parasite resistance to the sulfonamide-pyrimethamine combination was not encountered nor was there any suggestion of toxicity. It is concluded that these drugs in combination could have a place in malaria chemoprophylaxis.

Child↗

PubMed1990

Activity of gamma interferon in combination with pyrimethamine or clindamycin in treatment of murine toxoplasmosis.

The activity of recombinant gamma interferon (rIFN-gamma) in combination with either pyrimethamine or clindamycin was examined in a murine model of acute toxoplasmosis. Mice received either pyrimethamine or clindamycin alone or in combination with rIFN-gamma. Significantly increased survival and/or time to death was observed in animals treated with pyrimethamine or clindamycin in combination with rIFN-gamma compared to those that received treatment with any of the agents alone.

Animals↗

PubMed1993

Pyrimethamine plus azithromycin for treatment of acute toxoplasmic encephalitis in patients with AIDS.

A prospective study was conducted to evaluate azithromycin in combination with pyrimethamine for treatment of acute Toxoplasma encephalitis in patients with AIDS. Of the 14 patients given 75 mg pyrimethamine and 500 mg azithromycin daily for four weeks, eight were evaluable for clinical response. Five responded favorably, one had an intermediate response and two an unfavorable response. Of the nine patients evaluable for radiological response, six responded favorably, and three had an intermediate response. Eleven adverse events occurred in nine patients: rash (n = 5), abnormal liver function (n = 2), vomiting (n = 3) and hypoacousia (n = 1). This pilot study suggests that the combination of pyrimethamine and azithromycin may be further investigated and that the optimal dosage of azithromycin has yet to be determined.

AIDS-Related Opportunistic Infections↗