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PubMedDate not supplied

Parenteral therapy of moderately severe malaria: comparison of intramuscular artemether and intramuscular sulfadoxine-pyrimethamine.

We have compared the efficacy of intramuscular artemether against intramuscular sulfadoxine-pyrimethamine in an open randomized study in children with severe but uncomplicated malaria. Parasite clearance time and fever clearance time were faster with artemether. The parasitological clearance on day 14 was 100% for artemether and 98% for sulfadoxine-pyrimethamine, but 8 patients in the artemether group and 1 in the other group had a recrudescence of parasitaemia. There was no toxic reaction of note in either group. We therefore suggest that artemether is a good alternative to the currently used drugs in the parenteral treatment of severe but uncomplicated malaria and may be useful in preventing the possible development of cerebral malaria.

Antimalarials↗
PubMed1985

Antagonism of sulfadoxine and pyrimethamine antimalarial activity in vitro by p-aminobenzoic acid, p-aminobenzoylglutamic acid and folic acid.

The activity of pyrimethamine and sulfadoxine against two strains of Plasmodium falciparum has been studied in vitro by a radioisotopic technique. Low level antagonism of pyrimethamine resulted from the inclusion of p-aminobenzoic acid, p-aminobenzoylglutamic acid or folic acid in the test medium. Sulfadoxine activity was antagonised slightly by p-aminobenzoic but not by p-aminobenzoylglutamic acid, and antagonised markedly by folic acid at concentrations above 4 X 10(-8) M. At 10(-7) M folic acid, a concentration lower than that of normal RPMI medium 1640, sulfadoxine activity was reduced 7000 to 9000-fold in comparison with controls. These results are of importance in terms of the utilisation of folates by P. falciparum, the susceptibility of the parasite to antifolate drugs and the in vitro determination of parasite susceptibility.

4-Aminobenzoic Acid↗
PubMed1989

Serine hydroxymethyltransferase from pyrimethamine-sensitive and -resistant strains of Plasmodium chabaudi.

Serine hydroxymethyltransferase (EC 2.1.2.1) was partially purified from a pyrimethamine sensitive strain of Plasmodium chabaudi. Km values of 2.91 and 1.08 mM were determined for tetrahydrofolate and serine, respectively. The effects of pH, of temperature and of some potential inhibitors were determined. The enzyme was also partially purified from a pyrimethamine-resistant strain of P. chabaudi and subjected to the same regime. No differences between the enzymes from the two sources could be detected. It would appear that the changes in properties in the enzymes dihydrofolate reductase and thymidylate synthetase associated with the development of drug resistance in P. chabaudi were not reflected in any obvious alterations in serine hydroxymethyltransferase.

Animals↗
PubMed1989

Structural studies on bio-active compounds. Part XV. Structure-activity relationships for pyrimethamine and a series of diaminopyrimidine analogues versus bacterial dihydrofolate reductase.

The phenylpyrimidine derivative pyrimethamine and its congeners inhibit the enzyme dihydrofolate reductase (5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) and are of interest as antiproliferative agents. In this study the equilibrium conformations of some pyrimethamine derivatives, and their interactions with Escherichia coli dihydrofolate reductase, were investigated using molecular modelling techniques. In each case the phenyl ring avoided coplanarity with the pyrimidine ring and attained a position approximately perpendicular to it, in agreement with crystal structures. A meta substituent could be placed either side of the pyrimidine plane, forming two non-equivalent, slowly interconverting solution conformations. Except for meta-azidopyrimethamine, both conformations of all the inhibitors were able to bind to the active site cleft of the enzyme with the diaminopyrimidine moiety, making the normal pattern of enzyme/inhibitor hydrogen bonds. One such conformation of the meta-azido compound failed to bind because of unacceptable steric clashes, whilst the other showed enhanced binding energy attributable to the occupation of a hydrophobic pocket by the azido group. The enhanced binding of 2,4-diamino-6-ethyl-5-phenylpyrimidine over its 6-methyl analogue was also related to attractive hydrophobic interactions.

Animals↗
PubMed1993

Effect of immunomodulators pyrimethamine and cimetidine on immunosuppression induced by sulfur mustard in mice.

Despite extensive world-wide research no effective therapy has been devised for the treatment and cure of patients exposed to sulfur mustard (S-M). A severe suppression of the immune system still remains the major cause of opportunist infections, septicemia and death in patients injured by S-M. In this report we present a model of S-M contamination in mice which is suitable for immunomodulation studies. Results show that differing doses of S-M caused an overall suppression of the immune response to SRBC as indicated by agglutination titers, (DTH) tests, spleen histology and spleen weight indices. In the second stage two immunomodulating agents; pyrimethamine and cimetidine were employed and their effectiveness in augmenting immune responses after S-M induced immunosuppression was evaluated. Pyrimethamine, at all doses employed, enhanced antibody titers to SRBC, augmented DTH responses, and restored splenic follicles as compared with controls only exposed to S-M. Cimetidine augmented antibody titers and enhanced DTH responses at doses of 10 and 15 mg/kg as compared with controls. At a dose of 5 mg/kg cimetidine did not exhibit any effect on titers or DTH responses. Histological studies revealed that cimetidine restored splenic follicles and increased macrophage numbers and phagocytic activity at all three doses. Spleen weight indices were not augmented by either drug. These data provide evidence that immunomodulating drugs may prove effective in countering the immunosuppressive effects of S-M.

Animals↗
PubMed1991

Reversed-phase liquid chromatographic method for the simultaneous determination of the antimalarial drugs sulfadoxine, pyrimethamine, mefloquine and its major carboxylic metabolite in plasma.

A high-performance liquid chromatographic (HPLC) method for the simultaneous determination of sulfadoxine, pyrimethamine, mefloquine and the carboxylic metabolite of mefloquine in plasma is described. After the proteins have been precipitated with a combination of zinc sulphate and acetonitrile containing two internal standards, pyrimethamine and mefloquine are extracted as bases and sulfadoxine and the carboxylic metabolite of mefloquine as ion-pairs with tetrabutylammonium. The drugs are separated by HPLC on a 3 micron octadecylsilica column with ultraviolet detection at 229 nm. The method is simple and reliable and enables the simultaneous determination of the drugs in 600-microliter plasma samples with a sensitivity suitable for standard drug monitoring purposes.

Antimalarials↗
PubMed2005

Simple and cost-effective liquid chromatographic method for determination of pyrimethamine in whole blood samples dried on filter paper.

A cost-effective HPLC method for determination of pyrimethamine (PYR) in human whole blood samples dried on filter paper (Whatman) is reported. Trimethoprim (TMP) was used as an internal standard. Whole blood spiked with PYR was transferred (100 microl) onto filter paper and dried at room temperature. Capillary blood samples (100 microl) after ingestion of three tablets of sulfadoxine-pyrimethamine (SP) by one subject were also tested. PYR and an internal standard (IS) TMP were extracted into di-isopropyl ether as bases and then re-extracted with 150 microl mobile phase. A C-18 column was used and the mobile phase consisted of phosphate buffer (0.05 M, pH 5):acetonitrile:concentrated perchloric acid (750:300:2.5, v/v/v). The absorbances of PYR and IS were monitored at 270 nm. The limit of quantification was 40 ng/ml. The within- and between-assay coefficient of variations were <10% at the limit of quantification.

Antimalarials↗
PubMed2005

Simultaneous determination of pyrimethamine, sulfadiazine and N-acetyl-sulfadiazine in plasma for monitoring infants in treatment of congenital toxoplasmosis.

A method for the simultaneous determination of pyrimethamine, sulfadiazine and its metabolite N-acetyl-sulfadiazine in small plasma samples from neonates in treatment for congenital toxoplasmosis has been developed. In this method only 25 microl of plasma is used and a simple sample preparation based on protein precipitation and centrifugation provides highly reliable data as the recovery is about 100% and the precision is good. The analysis is performed using high performance liquid chromatography with UV and mass spectrometric (MS) detection. Pyrimethamine was found to give a linear response using MS detection in the range 0.02-5 microg/ml. Sulfadiazine and its metabolite N-acetyl-sulfadiazine were preferably analysed by UV at 269 nm in the concentration ranges 0.2-200 microg/ml for sulfadiazine and 0.2-50 microg/ml for N-acetyl-sulfadiazine.

Chromatography, High Pressure Liquid↗
PubMed2005

Prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis.

OBJECTIVE: To compare the efficacy of the classic treatment of ocular toxoplasmosis (pyrimethamine, sulfadiazine, and prednisolone) with a regimen consisting of trimethoprim/sulfamethoxazole (co-trimoxazole) plus prednisolone. DESIGN: Prospective randomized single-blind clinical trial. PARTICIPANTS: Fifty-nine patients with active ocular toxoplasmosis were randomly assigned to 2 treatment groups: 29 were treated with pyrimethamine/sulfadiazine, and 30 patients received trimethoprim/sulfamethoxazole. INTERVENTION: Treatment consisted of 6 weeks' treatment with antibiotics plus steroids. Antitoxoplasmosis antibodies (immunoglobulin M [IgM] and IgG) were measured using an enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Changes in retinochoroidal lesion size after 6 weeks' treatment, visual acuity (VA) before and after intervention, adverse drug reactions during follow-up, and rate of recurrence. RESULTS: Active toxoplasmosis retinochoroiditis resolved in all patients over 6 weeks' treatment, with no significant difference in mean reduction of retinochoroidal lesion size between the 2 treatment groups (61% reduction in the classic treatment group and 59% in the trimethoprim/sulfamethoxazole group, P = 0.75). Similarly, no significant difference was found in VA after treatment between the 2 groups (mean VAs after treatment were 0.12 logarithm of the minimum angle of resolution [logMAR] [20/25] in the classic treatment group and 0.09 logMAR [20/25] in the trimethoprim/sulfamethoxazole group, P = 0.56). Adverse effects were similar in both groups, with one patient in each suffering from any significant drug side effects. The overall recurrence rate after 24 months' follow-up was 10.16%, with no significant difference between the treatment groups (P = 0.64). CONCLUSIONS: Drug efficacies in terms of reduction in retinal lesion size and improvement in VA were similar in a regimen of trimethoprim/sulfamethoxazole and the classic treatment of ocular toxoplasmosis with pyrimethamine and sulfadiazine. Therapy with trimethoprim/sulfamethoxazole seems to be an acceptable alternative for the treatment of ocular toxoplasmosis.

Adolescent↗
PubMed2005

Malaria in the Nuba Mountains of Sudan: baseline genotypic resistance and efficacy of the artesunate plus sulfadoxine-pyrimethamine and artesunate plus amodiaquine combinations.

Both northern and southern Sudan are deploying artemisinin-based combinations against uncomplicated Plasmodium falciparum malaria (artesunate+sulfadoxine-pyrimethamine [AS+SP] in the north, artesunate+amodiaquine [AS+AQ] in the south). In 2003, we tested the efficacy of 3 day AS+SP and AS+AQ regimens in vivo in the isolated, seasonally endemic Nuba Mountains region (the first study of AS combinations in southern Sudan). We also analysed pre-treatment blood samples for mutations at the P. falciparum chloroquine transporter (Pfcrt) gene (associated with CQ resistance), and at the dihydrofolate reductase (Dhfr) gene (associated with pyrimethamine resistance). Among 161 randomized children under 5 years, PCR-corrected cure rates after 28 days were 91.2% (52/57, 95% CI 80.7-97.1) for AS+SP and 92.7% (51/55, 95% CI 82.4-98.0) for AS+AQ, with equally rapid parasite and fever clearance. The Pfcrt K76T mutation occurred in 90.0% (144/160) of infections, suggesting CQ would work poorly in this region. Overall, 82.5% (132/160) carried mutations at Dhfr (N51I, C59R or S108N, but not I164L), but triple mutants (more predictive of in vivo SP failure) were rare (3.1%). CQ use should be rapidly discontinued in this region. SP resistance may propagate rapidly, and AS+AQ is likely to be a better long-term option, provided AQ use is limited to the combination.

Amodiaquine↗
PubMed2003

Intensity of transmission and spread of gene mutations linked to chloroquine and sulphadoxine-pyrimethamine resistance in falciparum malaria.

The number of malaria parasite clones per infection-multiplicity of parasite clones-is affected by the transmission intensity, multiplicity increases with increasing transmission. This affects the frequency of parasites' sexual recombination and, if several mutations in different genes are involved, can break down drug resistant genotypes. Therefore, the effects of malaria transmission intensity on the spread of drug resistance could vary depending on the number of genes involved. Here we show that, compared to low transmission, intermediate-high transmission is associated with a 20-100-fold lower risk for the mutations linked to chloroquine resistance and a 6-17 times higher risk for those linked to sulphadoxine-pyrimethamine resistance. This is consistent with the hypothesis of a multigenic basis for chloroquine resistance and a monogenic basis for that of sulphadoxine-pyrimethamine. Reducing transmission intensity could slow the spread of resistance. However, a reduction below a critical threshold (e.g. when parasite prevalence in children 2-9 years old is around 60-80%) could, paradoxically, accelerate the spread of resistance to chloroquine and possibly to other drug combinations whose basis is multigenic. Our findings have important implications for malaria control because increasing drug resistance has a substantial impact on mortality.

Animals↗
PubMedDate not supplied

Assessment of susceptibility of Plasmodium falciparum to chloroquine, quinine, mefloquine, sulfadoxine-pyrimethamine and artemisinin in southern Viet Nam.

Resistance to antimalarial chemotherapy is a major concern for malaria control in Viet Nam. In this study undertaken in 1998, 65 patients with uncomplicated Plasmodium falciparum malaria were monitored for 28 days after completion of a 5-day treatment course with artemisinin. Overall 36.9% (24/65) of patients had recurrent parasitaemia during the surveillance period. P. falciparum isolates were tested for sensitivity in vitro to chloroquine, mefloquine, quinine, sulfadoxine-pyrimethamine and results were compared to those from a similar study in 1995. Increased parasite sensitivity to sulfadoxine-pyrimethamine, chloroquine and quinine was demonstrated, with significantly lower mean EC50 and EC99 values in 1998 compared to 1995. Parasite sensitivity to mefloquine did not differ significantly in the 2 surveys. Isolates were also tested for sensitivity in vitro to artemisinin in the 1998 survey. The mean EC50 was 0.03 mumol/L and the EC99 was 0.94 mumol/L. Parasite sensitivity to artemisinin will need to be monitored in view of its increasing use in Viet Nam.

Animals↗
PubMedDate not supplied

A trial of proguanil-dapsone in comparison with sulfadoxine-pyrimethamine for the clearance of Plasmodium falciparum infections in Tanzania.

Considerable levels of resistance to sulfadoxine-pyrimethamine (SP) have been reported in Plasmodium falciparum in north-eastern Tanzania, and the identification of a suitable antimalarial to replace SP is now a high priority. We conducted a trial in July 2000 to determine the efficacy of proguanil (PG) plus dapsone (DS), compared with that of SP, for the treatment of asymptomatic falciparum infection. A total of 220 children with parasitaemia > or = 2000 per microL completed the study; 112 had received a single dose of SP (dosage calculated for pyrimethamine 1.25 mg/kg and sulfadoxine 25 mg/kg) and 108 had taken PG 10 mg/kg with DS 2.5 mg/kg each day for 3 days. Clearance of asexual parasites at day 7 was 14.3% with SP, but 93.5% with PG-DS. The remarkably high failure rate with SP was not associated with occurrence of leucine substitution at position 164 of the dhfr gene. Both treatment regimens were well tolerated. Compared with available data on another antifolate combination, chlorproguanil-dapsone ('Lapdap'), PG-DS was slightly but significantly inferior in achieving parasite clearance (99.5% versus 93.5%). The estimated cost of a 3-day course of PG-DS treatment for a child weighing 18 kg is US $0.15. With the rising incidence of SP-resistant P. falciparum infection, PG-DS could provide an effective, affordable and already available therapeutic alternative for malaria in East Africa at least until chlorproguanil-dapsone is registered.

Antimalarials↗
PubMedDate not supplied

Can pretreatment screening for dhps and dhfr point mutations in Plasmodium falciparum infections be used to predict sulfadoxine-pyrimethamine treatment failure?

This study examines the relationship between malaria treatment failure after sulfadoxine-pyrimethamine (S-P) chemotherapy and presence of mutations in the Plasmodium falciparum dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) genes (associated with resistance in vitro to S and P) before treatment. In Kenya, 38 malaria patients in a holoendemic area, and 21 in an epidemic area, participated in the trial in 1997-98. In the 2 areas, drug failure occurred in 76% and 75% of cases where any mutation in dhfr was seen (positive predictive values 76% and 75%: P = 0.003 and 0.008) and an identical association was seen with dhfr Asn-108. In the holoendemic area all occurrences of > or = 2 mutations in dhfr predicted drug failure. Only 3 instances were seen in the epidemic focus, but treatment failed in all. Only in the epidemic focus, 7 (88%) of 8 occurrences of > or = 1 mutations in dhps, and all occurrences of the Gly-437 allele of dhps, predicted failure. Association between mutations in dhps and mutations in dhfr was noted in the combined sites, irrespective of outcome. Although this makes the relationship of combined dhfr and dhps mutations to failure more difficult to interpret, it nevertheless supports S-P selection acting on both genes. In the holoendemic site, treatment success increased with age. In this location, acquired immunity may mask the impact of mutations in dhps, since sulfadoxine is a less effective treatment than pyrimethamine.

Adolescent↗
PubMedDate not supplied

Treatment of uncomplicated malaria in children in Guinea-Bissau with chloroquine, quinine, and sulfadoxine-pyrimethamine.

With the increasing resistance to commonly used antimalarial drugs, different untested 'local' treatment regimens for malaria will arise. We compared commonly used treatment regimens for children in Guinea-Bissau. Symptomatic children with Plasmodium falciparum mono-infection were allocated at random to one of 4 treatments: 15 mg/kg quinine twice a day for 3 d (group 1); 10 mg/kg quinine twice a day for 3 d followed by a total dose of 25 mg chloroquine base given over 3 d (group 2); a total dose of 50 mg/kg chloroquine base given in 2 daily doses for 3 d (group 3), or sulfadoxine-pyrimethamine (group 4). On day 28 more children from group 1 (33%; relative risk [RR] = 2.9, 95% confidence interval [CI] 1.5-5.7) and group 2 (26%; RR = 2.1, CI 1.0-4.3) had had parasitaemia than in group 4 (12%), whereas no significant difference was found between group 3 (17%; RR = 1.3, CI 0.6-2.2) and group 4. No severe adverse reaction was observed in any of the groups. Chloroquine is still effective in Guinea-Bissau at an increased dose of 50 mg/kg, which appears safe when given orally in 2 daily doses for 3 d. Sulfadoxine-pyrimethamine could serve as an efficient, cheap and easy to administer second-line drug, leaving quinine to be used for third-line treatment. Quinine should not be used in short courses, nor does the combination of quinine and chloroquine have any advantage.

Adolescent↗
PubMedDate not supplied

Do mutations in Plasmodium falciparum dihydropteroate synthase and dihydrofolate reductase confer resistance to sulfadoxine-pyrimethamine in Iran?

The key codons of dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) genes implicated in sulfadoxine-pyrimethamine (SP) resistance were determined by allele-specific polymerase chain reaction in Plasmodium falciparum isolates collected in 1999 from 35 Iranian patients treated with SP. Seven isolates had Glu-540 dhps allele but 5 of these isolates were characterized to possess wild-type dhfr alleles. Seven additional isolates were polyclonal with mixed Lys- and Glu-540. The key dhfr mutation associated with pyrimethamine resistance, Asn-108, was found in 4 isolates. In one patient the presence of Lys- and Glu-540 in dhps and Asn-108 and Arg-59 in dhfr was associated with treatment failure. However, more studies are needed to determine whether clinical response to SP and mutations in these genes are correlated in Iran.

Adolescent↗
PubMedDate not supplied

Artesunate plus sulfadoxine-pyrimethamine for uncomplicated malaria in Kenyan children: a randomized, double-blind, placebo-controlled trial.

Plasmodium falciparum has developed resistance to almost all routinely used antimalarial drugs. Sulfadoxine-pyrimethamine (SP) has replaced chloroquine as first-line treatment of uncomplicated malaria infection in Kenya but resistance to SP is already reported. The addition of artemisinin derivatives to SP may delay the development of drug resistance, improve cure rates, and reduce transmission. The efficacy and safety of artesunate plus SP in the treatment of uncomplicated P. falciparum malaria was evaluated in a randomized trial of 600 children at Siaya District Hospital, western Kenya between October 1999 and March 2000. Children aged < 5 years were randomly assigned to receive SP alone (1.25 mg/kg based on pyrimethamine), or in combination with artesunate (4 mg/kg/d) for either 1 or 3 d. Parasitological failure by days 14 and 28 (polymerase chain reaction [PCR]-corrected for new infections) were the primary endpoints. Treatment failure rates by day 14 were 25.5% in the SP alone group, 16.2% (risk difference [delta]-9.3%, 95% CI -17.3 to -1.2%, P= 0.027) in the 1-dose artesunate group, and 9.4% (delta-16.2%, 95% CI -23.6 to -8.7%, P< 0.001) in the 3-dose artesunate group. Corresponding rates by day 28 were 46.0% in the SP alone group, 38.2% (delta-7.8%, 95% CI -17.7 to 2.1%, P= 0.16) in the 1-dose artesunate group, and 26.0% (delta-20.0%, 95% CI -29.4 to -10.6%, P < 0.001) in the 3-dose artesunate group. The artesunate and SP combination was well tolerated. There were no serious drug-related adverse events. Parasite clearance and gametocyte carriage were reduced significantly in both combination groups compared with SP alone. Three days of artesunate were required to reduce significantly the risk of treatment failure by day 28. However, the high background rate of parasitological failure with SP may make this combination unsuitable for widespread use in Kenya.

Antimalarials↗