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PubMed1997

Increased risk of toxoplasmic encephalitis in human immunodeficiency virus-infected patients with pyrimethamine-related rash. ANRS 005-ACTG 154 Trial Group. Agence Nationale de Recherche sur le SIDA (ANRS-INSERM) and the NIAID-AIDS Clinical Trials Group.

Although drug-induced rash is frequent in human immunodeficiency virus (HIV)-infected patients, rash due to pyrimethamine has not been described previously. In a randomized, double-blind, placebo-controlled study of pyrimethamine as primary prophylaxis for toxoplasmic encephalitis, the incidence of rash (per hundred patient-years) was 8.1 in the pyrimethamine group versus 1.5 in the placebo group (P < .0002). The 1-year incidence of toxoplasmic encephalitis after occurrence of rash was 37%, as compared with 9.6% in the pyrimethamine group without rash, with a 3.7 times higher risk for patients with pyrimethamine-induced rash (P = .001); the incidence was 13% in the placebo group. At the time of toxoplasmic encephalitis, pyrimethamine was successfully readministered to 80% of patients who discontinued it because of rash. Thus, pyrimethamine, when used for prophylaxis, does induce rash in HIV-infected patients. These patients are at higher risk for toxoplasmic encephalitis and should be carefully monitored for it.

AIDS-Related Opportunistic Infections↗
PubMed1993

Pyrimethamine inhibits renal secretion of creatinine.

The mechanism of increased serum creatinine after administration of pyrimethamine and dapsone was evaluated for six healthy volunteers. Serum parameters, urine sediment, and clearances of creatinine, inulin, and para-aminohippurate were assessed prior to and 28 h after the ingestion of a single, combined dose of 100 mg of pyrimethamine and 200 mg of dapsone. In a second series, the same renal function tests were performed for nine human immunodeficiency virus-infected men before and after 1 month of prophylactic treatment with a weekly dose of 75 mg of pyrimethamine and 200 mg of dapsone to evaluate sustained effects on renal function. Serum creatinine increased within 28 h from 81 +/- 14 to 102 +/- 16 mumol/liter (P = 0.002) in the healthy volunteers. Blood urea nitrogen, beta 2-microglobulin, and urine remained normal. Creatinine clearance decreased from 125 +/- 27 to 91 +/- 26 ml/min (P < 0.02) without changes in inulin clearance. The effect was reversible within 21 days and attributable to pyrimethamine, as determined by administration of each drug alone. The sustained effect of four doses of pyrimethamine and dapsone in human immunodeficiency virus-infected patients consisted of an analogous rise in serum creatinine from 69 +/- 17 to 87 +/- 32 mumol/liter (P < 0.05). Both creatinine and inulin clearances, however, were unchanged, representing a new equilibrium between creatinine production and elimination at a higher level in serum. Pyrimethamine, thus, may reversibly inhibit renal tubular secretion of creatinine without affecting the glomerular filtration rate. This physiologic effect in pyrimethamine-treated patients must be differentiated from possible organ-related nephropathies.

Adult↗
PubMed1976

Single-dose therapy of Falciparum malaria using pyrimethamine in combination with diformyldapsone or sulfadoxine.

Patients with naturally acquired chloroquine-resistant falciparum malaria were studied in Thailand. The fixed combination of pyrimethamine 75 mg and sulfadoxine 1,500 mg (adult dose) cured 85% of patients with an average pretreatment parasite count of 60,000 per mm(3). The fixed combination of pyrimethamine 50 mg and 800 mg diformyldapsone (DFD) cured 43% of patients with an average pretreatment parasite count of only 17,000 per mm(3). The difference in cure rates was statistically significant (p less than 0.01). Pyrimethamine alone was ineffective. Pyrimethamine-DFD, in the dose tested, was not sufficiently active for the treatment of established infections. Pyrimethamine-sulfadoxine did produce an acceptable cure rate but clinical improvement was often slow. We do not recommend that pyrimethamine-sulfadoxine be administered alone. Optimal results are obtained when a short course of quinine (2 to 6 days) is given until parasitemia has been eliminated, then a dose of pyrimethamine-sulfadoxine to assist in the radical cure of the falciparum infection. A modification to the W.H.O. classification is suggested. An RIII response (early treatment failure) is diagnosed if the patient's clinical condition and/or parsite density worsens within a few hours after administration of the test regimen; distinct improvement occurring within a few hours of the subsequent initiation of an intravenous infusion of quinine confirms the diagnosis of an RIII response. The RII response has been defined as marked reduction, but not clearance of asexual parasitemia. It is suggested that an RII response may be diagnosed before 7 days have elapsed.

Adolescent↗
PubMed1991

Prevalence of the dihydrofolate reductase Asn-108 mutation as the basis for pyrimethamine-resistant falciparum malaria in the Brazilian Amazon.

Pyrimethamine resistance in cultivated laboratory isolates of Plasmodium falciparum is linked to the dihydrofolate reductase mutation Asn-108, a mutation that acts by interrupting drug binding within the active site of the enzyme. To determine the prevalence of this mutation in endemic regions harboring pyrimethamine-resistant malaria, we used a mutation-specific polymerase chain reaction assay to survey P. falciparum strains from a wide section of the Brazilian Amazon. Mutations were identified directly from blood samples without intervening steps of in vitro cultivation. Of 42 samples collected from four states in Brazil, 38 (90%) contained the Asn-108 codon AAC that confers pyrimethamine resistance, four samples contained only the wild-type Ser-108 codon AGC, and none contained the Thr-108 codon ACC found in cycloguanil-resistant pyrimethamine-sensitive strains. These findings indicate that a very high incidence of the Asn-108 DHFR mutation is responsible for pyrimethamine resistance in the Amazon, and they are consistent with recent failure rates reported for Fansidar (pyrimethamine-sulfadoxine). We suggest that limited use of proguanil be evaluated as an alternative to pyrimethamine.

Animals↗
PubMed1996

Rapid detection of pyrimethamine susceptibility of Plasmodium falciparum by restriction endonuclease digestion of the dihydrofolate reductase gene.

A rapid and simple method to detect pyrimethamine susceptibility of Plasmodium falciparum by analyzing DNA from whole blood is presented. Samples from cultured isolates and from patients infected with P. falciparum were spotted onto filter paper disks, dried, and stored for subsequent analyses. After extracting the P. falciparum DNA using Chelex-100 ion-chelating resin (Bio-Rad, Richmond, CA), the polymerase chain reaction (PCR) was used to amplify the dihydrofolate reductase (dhfr) gene. The PCR product of 727 basepairs was digested with the Alu I restriction endonuclease to detect whether the isolates were sensitive or resistant to the antimalarial drugs pyrimethamine and cycloguanil. This reaction endonuclease digests only DNA from pyrimethamine-sensitive parasites because the recognition locus of Alu I is changed by mutations giving rise to pyrimethamine and cycloguanil resistance. This method is simple and sensitive and could therefore bu used to study the epidemiology of pyrimethamine resistant in P. falciparum. The DHFR gene of pyrimethamine-resistance clones from Vietnamese patients showed three amino acid changes that were previously found in pyrimethamine-resistant isolates. Two other clones, T9/94 and T9/96, originally isolated from a single malaria patient from Thailand, had different DHFR gene sequences. The nucleotide sequence of the DHFR gene from T9/96 was identical to the wild-type DHFR sequence, whereas T9/94 possessed amino acid substitutions at positions 16 and 108 that have been described in cycloguanil-resistant parasites.

Animals↗
PubMed1997

Pyrimethamine-resistant Plasmodium falciparum parasites among Tanzanian children: a facility-based study using the polymerase chain reaction.

A mutation-specific polymerase chain reaction method was used to estimate the proportion of pyrimethamine-resistant parasites in 101 children reporting with malaria at the hospital in Ifakara, a town in southern Tanzania. The method is based on the observation that a point mutation (Asn-108) in the dihydroifolate reductase gene confers resistance to pyrimethamine. Twenty-eight percent of the examined 101 children had pyrimethamine-resistant parasites, 65% had pyrimethamine-sensitive parasites with the wild-type Ser-108 codon, and 9% had both alleles, suggesting a mixed infection. None of the 21 children with clinical malaria had pyrimethamine-resistant parasites. Currently, sulfadoxine-pyrimethamine is considered a potential first-line drug for malaria treatment in most African countries. We suggest that although sulfadoxine-pyrimethamine could still be effective against chloroquine-resistant malaria in this area, its judicious use is important so as to minimize the spread of resistance.

Animals↗
PubMed2000

Molecular epidemiology of malaria in Yaounde, Cameroon. VI. Sequence variations in the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene and in vitro resistance to pyrimethamine and cycloguanil.

Pyrimethamine and cycloguanil, the major human metabolite of proguanil, are inhibitors of dihydrofolate reductase that play a key role in the treatment and prevention of chloroquine-resistant Plasmodium falciparum infections in sub-Saharan Africa. Resistance to these antifolate drugs has emerged in some areas of Africa. Earlier molecular studies have demonstrated that point mutations at key positions of the dihydrofolate reductase-thymidylate synthase gene are strongly associated with antifolate resistance. However, whether the same or distinct mutations are involved in the development of resistance to both pyrimethamine and cycloguanil has not been well established in naturally occurring P. falciparum isolates. In this study, the in vitro responses to both antifolate drugs were measured in 42 Cameroonian isolates and compared with the complete sequence of the dihydrofolate reductase domain of the gene (from 34 of 42 isolates) to analyze the genotype that may distinguish between pyrimethamine and cycloguanil resistance. The wild-type profile (n = 11 isolates) was associated with low 50% inhibitory concentrations (IC50s) ranging from 0.32 to 21.4 nanamole for pyrimethamine and 0.60-6.40 nM for cycloguanil. Mutant isolates had at least one amino acid substitution, Asn-108. Only three mutant codons were observed among the antifolate-resistant isolates: Ile-51, Arg-59, and Asn-108. The increasing number of point mutations was associated with an increasing level of pyrimethamine IC50 and, to a much lesser extent, cycloguanil IC50. These results support a partial cross-resistance between pyrimethamine and cycloguanil that is based on similar amino acid substitutions in dihydrofolate reductase and suggest that two or three mutations, including at least Asn-108, may be necessary for cycloguanil resistance, whereas a single Asn-108 mutation is sufficient for pyrimethamine resistance.

Animals↗
PubMed2001

Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women.

Drug resistance in Plasmodium falciparum affects prevention of malaria in pregnancy. In a cross-sectional study of 530 pregnant Ghanaian women, P. falciparum dihydrofolate reductase (DHFR) gene mutations linked with pyrimethamine resistance were assessed and associations with pyrimethamine intake were analyzed. P. falciparum infected 69% of women without pyrimethamine use, 59% of those who had a history of pyrimethamine consumption but a negative urine test, and 53% of individuals with a positive urine test. Eighty-one percent, 43%, and 74% of the isolates contained the mutations Asn-108, Ile-51, and Arg-59, respectively. Thr-108 occurred in 8%. Pyrimethamine use was associated with increased frequencies of Asn-108 and Arg-59 but not of Ile-51 or Thr-108. In women with prophylaxis, wild-type parasites were absent and anemia tended to be more common with an increasing number of DHFR gene mutations. Pyrimethamine appears to be not adequately effective in this part of Ghana, most likely due to the predominance of resistant parasites. Selection for resistance following insufficient prophylaxis could possibly affect the efficacy of future intermittent sulfadoxine-pyrimethamine treatment.

Alleles↗
PubMed1995

Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV.

OBJECTIVE: To evaluate the efficacy and safety of two oral, intermittent drug regimens for the simultaneous primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmosis in patients with HIV infection. DESIGN: Nonblinded randomized study: Patients received either 1) trimethoprim-sulfamethoxazole (160 mg-800 mg orally twice a day on a thrice weekly regimen) or 2) 100 mg of dapsone plus 50 mg of pyrimethamine orally twice weekly. SETTING: University teaching hospital in Barcelona. PATIENTS: 230 patients infected with HIV who had CD4 cell counts of less than 200 x 10(6)/L and who had not previously had P. carinii pneumonia or toxoplasmosis. MEASUREMENTS: Clinical and biological evaluations; adverse reactions; and end points of P. carinii pneumonia, toxoplasmosis, and death. RESULTS: After a median follow-up of 430 days, 6 (6.3%) of 96 evaluable patients receiving dapsone-pyrimethamine and 0 of 104 evaluable patients receiving trimethoprim-sulfamethoxazole developed P. carinii pneumonia (P < 0.0001). The cumulative rates of P. carinii pneumonia at 12 and 24 months were 0% and 0% for patients receiving trimethoprim-sulfamethoxazole and 4% and 11% for patients receiving dapsone-pyrimethamine (Mantel-Cox, P = 0.014). However, only one episode of P. carinii pneumonia developed while patients were taking these drugs. No differences were observed for toxoplasmosis (one episode in the trimethoprim-sulfamethoxazole arm and two in the dapsone-pyrimethamine arm), with cumulative rates at 12 and 24 months of 0% and 4% for the trimethoprim-sulfamethoxazole arm and 2% and 7% for the dapsone-pyrimethamine arm (P = 0.65). Similar mortality rates were observed during follow-up (P = 0.85). Nineteen patients (9.5%) discontinued therapy with the drugs because of adverse effects: Ten were in the trimethoprim-sulfamethoxazole arm and 9 were in the dapsone-pyrimethamine arm (P = 0.95). CONCLUSIONS: Thrice-weekly trimethoprim-sulfamethoxazole is an effective and well-tolerated regimen for the simultaneous primary prophylaxis of P. carinii pneumonia and toxoplasmosis in patients infected with HIV. Twice-weekly dapsone-pyrimethamine appears to be a safe and effective alternative.

AIDS-Related Opportunistic Infections↗
PubMed1993

Primary prophylaxis for Pneumocystis carinii pneumonia: a randomized trial comparing cotrimoxazole, aerosolized pentamidine and dapsone plus pyrimethamine.

OBJECTIVE: To compare the efficacy and tolerance of monthly aerosolized pentamidine versus cotrimoxazole versus dapsone plus pyrimethamine to prevent the initial episodes of Pneumocystis carinii pneumonia (PCP) in HIV-infected patients. DESIGN: An open randomized clinical trial. PATIENTS AND METHODS: HIV-infected patients (n = 331) with CD4 cell counts < 200 x 10(6)/l or with AIDS but without a history of PCP or cerebral toxoplasmosis (CT) were randomized to receive pentamidine (300 mg every 4 weeks), cotrimoxazole (160/800 mg 3 days a week) or dapsone plus pyrimethamine (100 and 25 mg weekly). If immunoglobulin G (IgG) antibodies to Toxoplasma were present, patients in the first two groups were randomized further to 25 mg pyrimethamine per week or to no treatment. RESULTS: The mean follow-up was 313 days (range, 30-670 days). The three groups were homogeneous for age, sex, risk group for HIV infection, initial CD4 cell count and mean follow-up. PCP developed in 16 patients, with an estimated cumulative probability of 5.3% at 1 year of follow-up. The PCP rate per year of observation, using an intention-to-treat analysis, was 5.6% [95% confidence interval (CI), 0.9-10.3], 3% (95% CI, 0-6.3) and 8.3% (95% CI, 2.8-13.8) in the groups treated with pentamidine, cotrimoxazole and dapsone plus pyrimethamine, respectively (P > 0.05). Moderate or severe side-effects were observed in one patient on pentamidine, 10 on cotrimoxazole and nine on dapsone plus pyrimethamine (P < 0.05); the study drug had to be discontinued in no, 10 and six patients, respectively (P < 0.05). Neither cotrimoxazole alone nor pyrimethamine combined with dapsone or cotrimoxazole prevented initial episodes of toxoplasmosis among patients with IgG antibodies to Toxoplasma gondii. CONCLUSIONS: Low-dose thrice-weekly cotrimoxazole or weekly dapsone plus pyrimethamine was not significantly worse (differences > 15% would have been detected with 90% certainty) than monthly aerosolized pentamidine in preventing a first episode of PCP in patients at high risk, but aerosolized pentamidine was better tolerated.

AIDS-Related Opportunistic Infections↗
PubMed1978

Bioassay of pyrimethamine for possible carcinogenicity.

A bioassay of pyrimethamine, a prophylactic antimalarial, for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered pyrimethamine 5 days per week at one of two doses, either 200 or 400 ppm for the rats and either 500 or 1,000 ppm for the mice. The animals were administered the chemical for 78 weeks, then observed for 26 or 27 additional weeks. Matched controls consisted of 15 untreated rats and 15 untreated mice of each sex; pooled controls consisted of the matched controls combined with 30 untreated rats and 30 untreated mice from similar bioassays of two other test compounds. All surviving rats and mice were killed at 102-105 weeks. Mean body weights of the rats and mice fed diets containing pyrimethamine were slightly lower than those of the matched controls. Survival of the rats was not affected adversely by the chemical. In mice, survival rates of both dosed and matched-control males were low, with nearly two-thirds of the dosed and one-half of the control mice dying by week 52. Some of the deaths were associated with respiratory infections and may not have been related to administration of the chemical. Numbers of animals at risk in the dosed and control groups of female mice were adequate, however, for the development of late-appearing tumors. In rats of each sex, no neoplastic lesions were found at a statistically significant incidence in the groups fed the pyrimethamine as compared with control groups. An increased frequency of bone-marrow atrophy occurred in both male and female dosed groups. In male mice, the markedly decreased life spans may have prevented the observation of late-appearing tumors, since only two tumors were observed, one in a high-dose mouse and one in a low-dose mouse. In female mice, no neoplastic lesions were found at a statistically significant incidence in the groups fed the pyrimethamine as compared with control groups. It is concluded that under the conditions of this bioassay, pyrimethamine was not carcinogenic for male or female Fischer 344 rats or for female B6C3F1 mice. The carcinogenic potential of pyrimethamine for male B6C3F1 mice cannot be assessed by this bioassay, because of the markedly reduced life span.

Journal Article↗
PubMed1998

Viability of Plasmodium falciparum ex vivo: comparison of the effects of artemether and sulfadoxine-pyrimethamine.

OBJECTIVE: Severe malaria is increasingly treated with artemether and sulfadoxine-pyrimethamine, but their effects on the viability of Plasmodium falciparum ex vivo following therapeutic doses, and the relationship between conventional indices of therapeutic response and parasite viability, have not been evaluated. We assessed these parameters in children with severe non-cerebral falciparum malaria. METHODS: Between May and August 1995, 17 children with severe non-cerebral malaria were randomized to receive therapeutic doses of artemether or sulfadoxine-pyrimethamine. Parasitemia quantification and withdrawal of blood culture of P. falciparum in vitro were done before and at specific intervals after drug administration. Therapeutic indices of response were determined by the conventional method. The corresponding viability estimates ex vivo were derived for each drug and compared with conventional therapeutic indices. RESULTS: Artemether produced a significantly more rapid reduction of parasitemia and fever than sulfadoxine-pyrimethamine. Resistance to sulfadoxine-pyrimethamine was present in three out of seven patients (RI, RII and RIII) and was readily detectable by the functional viability estimate ex vivo. Ex vivo, functional reduction of parasite viability was significant 8 or 12 h after administration of artemether, with no functionally viable parasites 30 h after administration. In contrast, functional viability in isolates sensitive to sulfadoxine-pyrimethamine became significant by 16-20 h after drug administration and viable parasites were still evident after 36 h in some isolates. Indices of therapeutic response estimated by the conventional methods, i.e., time to 50% or 90% reduction of parasitemia and parasite clearance time, were significantly higher than those derived from the corresponding functional viability estimates ex vivo for each drug. There was correlation between some of the two sets of parameters. CONCLUSIONS: These data suggest the rapid and relatively broad stage effects of artemether when compared with sulfadoxine-pyrimethamine on P. falciparum asexual forms. Estimation of parasite viability indices ex vivo permits comparison of the relative speed of antimalarial drug action.

Adolescent↗
PubMed1985

A comparison of chloroquine and pyrimethamine as malaria chemoprophylactics in young Nigerian children.

The efficacy of chloroquine and pyrimethamine as malaria chemoprophylactics was investigated in young Nigerian children. Chloroquine resistance had not been documented in the study area; pyrimethamine resistance was probably present but uncommon. Children who received weekly chemoprophylaxis with pyrimethamine had a lower prevalence of malaria parasitaemia and malaria antibodies than children who received weekly chemoprophylaxis with chloroquine. Pyrimethamine given monthly gave a comparable degree of protection to chloroquine given weekly. Chloroquine frequently induced vomiting in young children and this may have impaired its efficacy as a prophylactic. We conclude that, in an area where neither chloroquine nor pyrimethamine resistance is prevalent, pyrimethamine is a better chemoprophylactic for young children than chloroquine.

Antibodies↗
PubMedDate not supplied

Comparison of intramuscular sulfadoxine-pyrimethamine and intramuscular quinine for the treatment of falciparum malaria in children.

The efficacy of intramuscular (i.m.) sulfadoxine-pyrimethamine (sulfadoxine 25 mg/kg plus pyrimethamine 1.25 mg/kg in a single dose; n = 48) was compared with that of i.m. quinine (10 mg/kg 8-hourly for at least 3 d followed by oral quinine to complete 7 d; n = 54) in children with severe malaria without life-threatening complications in Maputo Central Hospital, Mozambique, in 1989. Mean parasite clearance time and mean fever clearance time were 55.4 h and 48.1 h, respectively, in the sulfadozine-pyrimethamine group, and 60.7 h and 54 h in the quinine group. Seven cases in the sulfadoxine-pyrimethamine group were RII/RIII resistant compared with none in the quinine group, but parasite reduction during the first 48 h was no slower in the resistant cases than in the 7 poorest responders to quinine. Blood sugar levels were slightly, but not significantly, lower in the quinine group. On day 7, leucocyte counts were significantly lower in the sulfadoxine-pyrimethamine group, but within the normal range. It is concluded that a single dose of sulfadoxine-pyrimethamine may be useful for the treatment of complicated malaria at health care units without facilities for admission, or if transferral is necessary after start of treatment.

Animals↗
PubMed1987

Pyrimethamine resistant Plasmodium falciparum: overproduction of dihydrofolate reductase by a gene duplication.

The accumulation of [3H]pyrimethamine by pyrimethamine-resistant (Pyrr) mutants of the Plasmodium falciparum strain FCR3 was examined by measuring the accumulation of drug in infected red blood cells. [3H]Pyrimethamine was stage specifically accumulated in trophozoites and schizont infected red blood cells. The mutant parasites accumulated drug as efficiently as FCR3. Pyrimethamine was associated with a high molecular weight protein that eluted from a Sephadex G200 column exactly as [3H]fluorodeoxyuridinemonophosphate (FdUMP) labeled parasite dihydrofolate reductase-thymidylate synthetase (DHFR-TS) enzyme. These results suggested that the pyrimethamine resistance was not associated with decreased drug permeability of the membrane. DHFR-TS-[3H]FdUMP enzyme complex of all the Pyrr mutants and FCR3 had a monomer of 70 kDa as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. One highly resistant mutant, FCR3-D7, exhibited a 5-10 fold higher uptake of pyrimethamine and a proportionately higher amount of DHFR-TS protein than FCR3 but only a normal level of DHFR activity. The genomic DNA of FCR3-D7 was shown to contain at least twice as much DHFR-TS specific DNA than either FCR3-D8, another Pyrr mutant, or FCR3. Preliminary results suggested some of the DHFR-TS genetic material in FCR3-D7 is associated with a gene duplication.

Animals↗
PubMed1992

Pyrimethamine resistant mutations in Plasmodium falciparum.

Three mutations in Plasmodium falciparum yielding increased resistance to pyrimethamine were obtained following treatment with chemical mutagens and selection in presence of pyrimethamine. From parasite clone TM4/8.2 a mutant, TM4/8.2/4.1, was produced which raised pyrimethamine resistance about 500 times and was found to involve an amino acid change in the DHFR-TS enzyme molecule from Ser108 to Asn108. A clone of another isolate, T9/94, yielded a mutant, T9/94/300.300, raising pyrimethamine resistance about 10 times and involving an amino acid change from Ile164 to Met164. However, another mutant from T9/94, T9/94/M1-1(b3), although it raised the pyrimethamine resistance 100 times, did not involve any changes in the coding sequence of the DHFR-TS gene, but resulted in the production of about twice as much DHFR-TS enzyme as the original clone T9/94. No amplification of the DHFR-TS gene was detected. It is concluded that changes in pyrimethamine resistance of malaria parasites may arise in at least 2 ways: (1) by structural changes in the DHFR domain of the DHFR-TS gene (as previously found by other workers); (2) by other changes, possibly affecting the expression of the DHFR-TS gene. The relative importance of these 2 mechanisms in causing resistance in wild populations of P. falciparum is discussed.

Animals↗
PubMed2003

High prevalence of quintuple mutant dhps/dhfr genes in Plasmodium falciparum infections seven years after introduction of sulfadoxine and pyrimethamine as first line treatment in Malawi.

Malawi changed its national policy for malaria treatment in 1993, becoming the first country in Africa to replace chloroquine by sulfadoxine and pyrimethamine combination (SP) as the first-line drug for uncomplicated malaria. Seven years after this change, we investigated the prevalence of dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) mutations, known to be associated with decreased sensitivity to SP, in 173 asymptomatic Plasmodium falciparum infections from Salima, Malawi. A high prevalence rate (78%) of parasites with triple Asn-108/Ile-51/Arg-59 dhfr and double Gly-437/Glu-540 dhps mutations was found. This 'quintuple mutant' is considered as a molecular marker for clinical failure of SP treatment of P. falciparum malaria. A total of 11 different dhfr and dhps combinations were detected, 3 of which were not previously reported. Nineteen isolates contained the single Glu-540 mutant dhps, while no isolate contained the single Gly-437 mutant dhps, an unexpected finding since Gly-437 are mostly assumed to be one of the first mutations commonly selected under sulfadoxine pressure. Two isolates contained the dhps single or double mutant coupled with dhfr wild-type. The high prevalence rates of the three dhfr mutations in our study were consistent with a previous survey in 1995 in Karonga, Malawi, whereas the prevalences of dhps mutations had increased, most probably as a result of the wide use of SP. A total of 52 P. falciparum isolates were also investigated for pyrimethamine and sulfadoxine/pyrimethamine activity against parasite growth according to WHO in vitro standard protocol. A pyrimethamine resistant profile was found. When pyrimethamine was combined with sulfadoxine, the mean EC(50) value decreased to less than one tenth of the pyrimethamine alone level. This synergistic activity may be explained by sulfadoxine inhibition of dhps despite the double mutations in the dhps genes, which would interact with pyrimethamine acting to block the remaining folate despite dhfr mutations in the low p-aminobenzoic acid and low folic acid medium mixed with blood.

Adolescent↗
PubMed2002

Intermittent administration of iron and sulfadoxine-pyrimethamine to control anaemia in Kenyan children: a randomised controlled trial.

BACKGROUND: Iron supplementation is recommended for children at high risk of anaemia, but its benefits may not outweigh the associated risk of malaria in areas of seasonal transmission. We investigated the effect on haemoglobin concentrations of intermittent administration of iron supplements and sulfadoxine-pyrimethamine in symptom-free children under intense health surveillance. METHODS: In a trial of two by two factorial design, 328 anaemic Kenyan children were randomly assigned either iron or placebo and sulfadoxine-pyrimethamine or placebo (82 to each group). Primary outcomes were haemological indicators of iron status and inflammation at the end of the follow-up, and occurrence of malaria attacks. Morbidity surveillance consisted of medical examinations every 4 weeks, continuous passive case detection, and visits twice a week to community health-workers. Analyses were by intention to treat. FINDINGS: After 12 weeks, the groups assigned iron plus sulfadoxine-pyrimethamine, iron alone, or sulfadoxine-pyrimethamine alone had higher haemoglobin concentrations than the group assigned placebo (treatment effect adjusted for prognostic factors at baseline: 11.1 g/L [95% CI 7.5 to 14.7]; 10.7 g/L [7.1 to 14.3]; and 3.1 g/L [-0.5 to 6.7]). Administration of iron plus sulfadoxine-pyrimethamine also lowered the proportion with anaemia from 100% at baseline to 36% at 12 weeks, and of iron deficiency from 66% at baseline to 8% at 12 weeks. Survival analysis showed no evidence of substantially increased risk of malaria after iron supplementation. INTERPRETATION: Iron supplementation gives substantial health benefits, which may outweigh possible inherent risks caused by malaria. A larger study than ours is needed to assess benefits and risks of intermittent administration of sulfadoxine-pyrimethamine in reducing the incidence of malaria attacks in areas of seasonal malaria transmission.

Anemia↗