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PubMed1989

Characterisation of the dihydrofolate reductase-thymidylate synthetase gene from human malaria parasites highly resistant to pyrimethamine.

To investigate the genetic basis of drug resistance in human malaria parasites, we have sequenced the entire dihydrofolate reductase thymidylate synthetase DHFR-TS bifunctional gene from the highly pyrimethamine-resistant K1 isolate of Plasmodium falciparum. The protein is predicted to consist of 607 amino acids (aa), (71,685 Da), with an N-terminal methionine encoded by the second start codon of the open reading frame. Compared to the sequence from drug-sensitive parasites, there are two nucleotide changes in the coding region which bring about a substitution of Arg for Cys at aa position 59 and Asn for Thr at aa position 108. Both changes occur in regions of the DHFR domain involved in inhibitor and cofactor binding and are hence strongly implicated in drug resistance. The gene is present as a single copy in both K1 and drug-sensitive FCR3 isolates, and is assigned to chromosome 4. Codon usage follows the pattern observed in that of malarial surface antigen genes, with the exception fo codons corresponding to Val and Pro. The Asn and Lys contents of the predicted protein are exceptionally high, these residues being particularly concentrated in the DHFR and junction domains.

Amino Acid Sequence↗
PubMed1982

Teratogenic activity of pyrimethamine in Göttingen minipig.

Pyrimethamine (PY) was mixed with mashed feed and given to the Göttingen miniature pig (G-mini) during gestional days 11-35. Major malformations such as cleft palate, club-foot and micrognathia were observed in 11 out of 16 newborns from 3 pregnant sows which received 3.6 mg/kg/day. Two sows of a high-dose group (7.2 mg/kg) showed severe anemia and low appetite during the experiment and did not give birth. No malformation was found in 22 newborns of low-dose groups (0.9 and 1.8 mg/kg). Among 130 offspring which died before weaning out of 505 from 47 farrows in a breeding farm, major teratoses such as cleft palate were found in 8 newborns.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Synergistic embryotoxicity of combination pyrimethamine and folic acid in rats.

The increased embryotoxicity of pyrimethamine (PYM) with concomitant oral dosing of folic acid (FA) was examined in rats. The preventive effects of folinic acid (FNA) on PYM embryotoxicity were also examined. Six groups were constructed: PYM I (PYM 1.2 mg/kg/day), FA (FA 50 mg/kg/day), PYM I+FA (1.2 and 50 mg/kg/day, respectively), PYM II (2.7 mg/kg/day), PYM II+FNA (2.7 and 12 mg/kg/day, respectively), and a vehicle control group. The agents were administered for 11 days from day 7 throughout 17 of gestation. PYM and FA were administered by gavage and FNA was administered intraperitoneally. Visceral and skeletal malformations were observed in the fetuses of both PYM I+FA and PYM II groups; these included dilatation of the lateral ventricle and fused ribs. No malformed fetuses were observed in the fetuses of the other four groups. External malformations were observed only in the fetuses of PYM II groups; these included cleft palate, cleft lips, and brachygnathia, among others. These results show that the concomitant gavage dosing of FA augments PYM embryotoxicity. The preventive effects of FNA were also confirmed.

Abnormalities, Drug-Induced↗
PubMed2005

Polymorphisms in Plasmodium falciparum dhfr and dhps genes and age related in vivo sulfadoxine-pyrimethamine resistance in malaria-infected patients from Nigeria.

Mutations in Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes have been used as means to predict treatment failure to sulfadoxine-pyrimethamine (SP) and for monitoring/surveillance of resistance to the drug in many areas where malaria is endemic. However, patients responses to treatment are significantly dependent on factors like host immunity profile of treated patients. In order to investigate the relationship between molecular markers of SP resistance, host immunity and clinical outcome, the association between pre-treatment dhfr and dhps genotypes, age and treatment outcomes was evaluated in 109 children treated with SP for acute uncomplicated malaria in Ibadan, Nigeria. Seventy-three percent of the children were cured with the drug, while 27% failed treatment after 28 days of follow-up. All children infected with parasites harboring less than two dhfr/dhps mutations were cured with SP. The dhfr triple (Asn-108/Ile-51/Arg-59) mutants or the dhps double mutants (Gly-437/Glu-540) were independently associated with SP treatment failure in children aged less than 5 years, but not in older children. The dhfr and dhps quintuple mutant (dhfr triple mutant+dhps double mutant) was the genotype most strongly associated with SP treatment failure (OR=24.72, 95%CI=8.24-74.15) in both younger and older children.

Animals↗
PubMed2006

Predictors of the failure of treatment with pyrimethamine-sulfadoxine in children with uncomplicated falciparum malaria.

The prevalence of pyrimethamine-sulfadoxine (PS)-resistant Plasmodium falciparum malaria has been increasing in sub-Saharan Africa or other parts of the world in the last one or two decades. The factors that identify children at risk of treatment failure after being given PS were evaluated in 291 children with acute, symptomatic, uncomplicated, P. falciparum malaria. The children took part in four antimalarial drug trials between July 1996 and July 2004 in a hyperendemic area of southwestern Nigeria. Following treatment, 64 (22%) of 291 children failed treatment by day 7 or 14. In a multivariate analysis, an age < or = 1.5 years (AOR=2.9, 95% CI 1.3-6.4, P = 0.009) and presence of fever (AOR = 3.3, 95% CI 1.28-7.14, P = 0.01) were independent predictors of the failure of treatment with PS at presentation. Following treatment, delay in parasite clearance >3 days (AOR = 2.56, CI 1.19-5.56, P = 0.016) was an independent predictor of the failure of treatment with PS. In addition, compared with the children who had no fever then, children with fever three or more days after starting treatment were more likely to be treatment failures. These findings may have implications for malaria control efforts in some sub-Saharan African countries where treatment of malaria disease depends almost entirely on PS monotherapy, and for programmes employing PS or PS-based combination therapy.

Aging↗
PubMed2006

Continued efficacy of sulfadoxine-pyrimethamine as second line treatment for malaria in children in Guinea-Bissau.

BACKGROUND: Sulfadoxine-pyrimethamine (S/P) is widely used for treatment of failures following the first line treatment for malaria in Africa. In Guinea-Bissau, it has been recommended as second line therapy by the National Malaria Programme since 1996. In order to monitor any change of the in vivo sensitivity, the efficacy of S/P was studied immediately before the introduction of the drug and 6-9 years later. METHODS: Children participating in clinical in vivo studies were given S/P if having late clinical treatment failure following the treatment with quinine, chloroquine, or amodiaquine. Parasitological and clinical failures were evaluated during a 35-day follow-up. During the first study period whole blood sulfadoxine concentrations were measured on day 7. RESULTS: Altogether, 56 children failed the initial treatment and were included in 1995/1996 as well as 55 children in 2002/2004. The PCR-uncorrected adequate clinical and parasitological response rates on day 28 were 94% and 91%, and on day 35 they were 89% and 91%, respectively, in the two periods. No difference between median blood drug concentration in children with and without treatment failure was observed. INTERPRETATION: The efficacy of S/P as second line treatment for uncomplicated malaria has remained unchanged in spite of a relatively high level of genetic markers associated with Plasmodium falciparum resistance to S/P previously found in the area.

Adolescent↗
PubMed2005

Liquid chromatographic-mass spectrometric assay for simultaneous pyrimethamine and sulfadoxine determination in human plasma samples.

We present a liquid chromatographic-mass spectrometric assay for the simultaneous determination of sulfadoxine and pyrimethamine in human plasma samples. Sample clean-up was achieved by adding acetonitrile for protein precipitation. Gradient elution in only 10 min resulted in high throughput capability. Tandem mass spectrometric detection in multiple reaction monitoring was used for quantification. The developed analytical approach was successfully validated and was applied in the pharmacokinetic evaluation of the bioavailability between two sulfadoxine/pyrimethamine formulations available on the Eastern African market, using a cross-over design.

Antimalarials↗
PubMed2006

Validation of a liquid chromatography-mass spectrometry multi-residue method for the simultaneous determination of sulfonamides, tetracyclines, and pyrimethamine in milk.

A multiresidue method suitable for confirmation and determination of six sulfonamides (SAs), three tetracyclines (TCs), and pyrimethamine (PYR) in cow milk was validated. Milk samples were extracted using copolymer Oasis HLB solid-phase extraction (SPE) and analyzed by liquid chromatography-electrospray mass spectrometry with positive ion mode. Estimated method detection limits (MDL) and method quantitation limits (MQL) ranged from 0.48 to 2.64 and 0.61 to 8.64ng/mL, respectively. These values are far lower than the maximum residue limits (MRLs) established by several control authorities. Excellent linear dynamic range was observed from the method quantitation limits to 300ng/mL with correlation coefficients better than 0.9900 for all compounds. The method was accurate with recoveries ranging from 72.01 to 97.39%. Good intra-precision and intermediate precision were obtained with RSD better than 11.08%. The method is fairly robust with sample pH being the only critical control point.

Animals↗
PubMed2005

Plasmodium falciparum: evaluation of a quantitative nucleic acid sequence-based amplification assay to predict the outcome of sulfadoxine-pyrimethamine treatment of uncomplicated malaria.

A quantitative nucleic acid sequence-based amplification (QT-NASBA) assay was employed to predict retrospectively the outcome of sulfadoxine-pyrimethamine (SP) treatment of uncomplicated malaria in children aged <6 years in an endemic region. Blood samples were collected at initial diagnosis and during follow-up. Mutation-specific nested PCR methods to analyse DHFR (Arg-59) and DHPS (Glu-540) mutations that are associated with SP drug resistance were applied. Parasite genotyping was performed to distinguish between re-infection and recrudescence. Eighty-six patients were recruited of which 66 were available for follow-up. Nine children were classified as early treatment failure, 13 cases were classified as late clinical failure, 32 as late parasitological failure, and only 12 children had an adequate clinical and parasitological response. DHFR and DHPS mutations conferring SP resistance were abundant in the Plasmodium population. Blood samples obtained 7 days after treatment were used to predict retrospectively the outcome of SP treatment. QT-NASBA was able to give a correct prediction of treatment outcome in 85.7% of the cases. Positive predictive value (PPV) of QT-NASBA case was 95% (95% confidence interval = 88.3-100) and negative predictive value (NPV) was 63% (95% CI = 39.5-86.5). In contrast, microscopy correctly predicted outcome in only 37.5% of the cases. PPV of microscopy was 100% (95% CI = 73.9-100) and the NPV was 25.5% (95% CI = 13.0-38.0). The analysis of a day 7 blood sample with QT-NASBA allows for the prediction of late clinical or parasitological treatment failure in the majority of the cases analysed in the present study.

Animals↗
PubMed2005

Perceptions on use of sulfadoxine-pyrimethamine in pregnancy and the policy implications for malaria control in Uganda.

In malaria endemic areas intermittent treatment with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in pregnancy. Yet, data on perceptions regarding use of this drug are scarce. An exploratory study was conducted to assess perceptions on SP in Mukono district, Uganda. This is an initial step towards a review of the policy aimed at improving access and use of SP in pregnancy, which is currently low. Results show that SP is perceived to be an effective drug that cures malaria quickly. However there are negative perceptions related to its use in pregnancy. SP is believed to be strong and weakens pregnant women, causes abortions and foetal abnormalities. There is also a perception that resorting first to SP for malaria treatment may lead to the development of drug resistance. This perception may limit access to effective treatment of malaria in this community since the policy in Uganda recommends SP in combination with chloroquine as the first-line treatment. The policy implications of these findings include developing a health promotion package to demystify the misconceptions on the strength of SP, to explain its benefits and side-effects. This package will involve giving health workers refresher training on communication and counselling on use of SP in pregnancy targeting special groups like pregnant adolescents. These results provide important lessons to policy makers and programme managers who aim at scaling up access of SP for malaria prevention in pregnancy.

Adolescent↗
PubMed2006

(Sub)microscopic Plasmodium falciparum gametocytaemia in Kenyan children after treatment with sulphadoxine-pyrimethamine monotherapy or in combination with artesunate.

The effects of drugs on Plasmodium falciparum transmission stages may reduce the spread of parasites in the population and contribute to malaria control. Detailed quantitative studies on (sub)microscopic gametocytaemia have become feasible with the availability of real-time Pfs25 quantitative Nucleic Acid Sequence-based Amplification (QT-NASBA), which can be used to detect gametocyte densities above 20 gametocytes per millilitre from in vitro cultures. Gametocyte dynamics were investigated in children with uncomplicated P. falciparum malaria after treatment with sulphadoxine-pyrimethamine (SP) or a combination of SP and artesunate (SP+AS), in a 28-days drug efficacy study. This study demonstrated that gametocyte prevalence in 873 samples from symptomatic Kenyan children was 2.8 times higher by QT-NASBA compared with microscopy. Microscopy-positive cases showed a significant correlation with QT-NASBA for gametocyte density. At enrolment, gametocyte prevalence was 86% by QT-NASBA compared with 22% by microscopy. Gametocytes were detected in 97% of children in at least one blood sample and in 38% of children in all samples obtained during the 28-days follow-up. Both the risk of gametocyte carriage and gametocyte density were considerably higher after treatment with SP compared with SP+AS. Gametocyte prevalence and density decreased with time in the SP+AS group, but not in the SP-treated children. Our data suggest that the potential of malaria transmission remains high even after treatment with artemisinin combination therapy, although prevalence and density of gametocytes is lower after SP+AS.

Animals↗
PubMed2006

Simultaneous quantification of alpha-/beta-diastereomers of arteether, sulphadoxine and pyrimethamine: a promising anti-relapse antimalarial therapeutic combination, by liquid chromatography tandem mass spectrometry.

A rapid, sensitive, selective and specific HPLC/ESI-MS/MS assay method was developed and validated for the simultaneous quantitation of alpha-/beta-diastereomers of arteether (AE), sulphadoxine (SDX) and pyrimethamine (PYR) in rat blood plasma using propyl ether analogue of beta-arteether as internal standard. The method involved a single-step, liquid-liquid extraction with ethyl acetate and the analytes were chromatographed on a C18 chromatographic column by isocratic elution with methanol:ammonium acetate buffer (10 mM, pH 4) (90:10%, v/v) and analyzed by tandem mass spectrometry. The run time was 4.5 min and the weighted (1/x2) calibration curves were linear over a range of 0.78-400 ng ml-1. The method was validated fully and the lower limit of quantification (LLOQ) in plasma was 0.78 ng ml-1 for all the analytes. The intra- and inter-day precision and accuracy were found to be well within the acceptable limits (<15%) and the analytes were stable after three freeze-thaw (f-t) cycles. The absolute recoveries were consistent and reproducible. The assay method was applied to pre-clinical pharmacokinetic interaction studies of alpha-/beta-AE, SDX and PYR in rats.

Animals↗
PubMed2004

Two mutations in dihydrofolate reductase combined with one in the dihydropteroate synthase gene predict sulphadoxine-pyrimethamine parasitological failure in Ugandan children with uncomplicated falciparum malaria.

The point mutations in the Plasmodium falciparum dihydrofolate reductase (dhfr) and the dihydropteroate synthase (dhps) genes that are linked to sulphadoxine-pyrimethamine (SP) resistance in vitro have been well characterised. To determine whether a few of these mutations could predict SP treatment failure in vivo, two mutations (Asn-108 and Arg-59) in the dhfr gene and one (Glu-540) in the dhps gene were analysed according to the risk of SP parasitological failure (RI-RIII) at day 28 in pre-treatment isolates in 79 Ugandan children aged 6-59 (mean = 18.4, S.D. = 8.8) months with uncomplicated falciparum malaria. Neither the dhfr-108 (P = 0.3) nor the dhps-540 (P = 0.6) or dhfr-108 + dhps-540 (P = 0.04) mutations were significantly associated with SP parasitological failure. However, the dhfr-108 + dhfr-59 (P = 0.04), the dhfr-59 + dhps-540 (P = 0.04) and the dhfr-108 + dhfr-59 + dhps-540 (P = 0.02) mutations significantly increased the risk for SP parasitological failure. Our findings confirm an earlier report that the dhfr-59 and the dhps-540 mutations could be useful genetic markers for rapid screening of populations at high risk of SP resistance.

Animals↗
PubMed2005

Spectrophotometric study of the reaction mechanism between DDQ Pi- and iodine sigma-acceptors and chloroquine and pyrimethamine drugs and their determination in pure and in dosage forms.

Two simple and accurate spectrophotometric methods are presented for the determination of anti-malarial drugs, chloroquine phosphate (CQP) and pyrimethamine (PYM), in pure and in different pharmaceutical preparations. The charge transphere (CT) reactions between CQP and PYM as electron donors and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) pi-acceptor and iodine sigma-acceptor reagents to give highly coloured complex species have been spectrophotometrically studied. The optimum experimental conditions have been studied carefully. Beer' law is obeyed over the concentration range of 1.0-15 microg ml(-1) for CQP and 1.0-40 microg ml(-1) for PYM using I(2) and at 5.0-53 microg ml(-1) for CQP and 1.0-46 microg ml(-1) for PYM using DDQ reagents, respectively. For more accurate results, Ringbom optimum concentration range is calculated and found to be 10-53 and 8-46 microg ml(-1) for CQP and PYM using DDQ, respectively and 5-15 and 8-40 microg ml(-1) for CQP and PYM using iodine, respectively. The Sandell sensitivity is found to be 0.038 and 0.046 g cm(-2) for DDQ method and 0.0078 and 0.056 g cm(-2) for I(2) method for CQP and PYM, respectively which indicates the high sensitivity of both methods. Standard deviation (S.D.=0.012-0.014 and 0.013-0.015) and relative standard deviation (R.S.D.=0.09-1.4 and 1.3-1.5%) (n=5) for DDQ and I(2) methods respectively, refer to the high accuracy and precision of the proposed methods. These results are also confirmed by between day precision of percent recovery of 99-100.6%, and 98-101% for CQP and PYM by DDQ method and 99-102% and 99.2-101.4% for CQP and PYM by I(2) method respectively. These data are comparable to those obtained by British and American pharmacopoeias assay for the determination of CQP and PYM in raw materials and in pharmaceutical preparations.

Antimalarials↗
PubMed2004

Efficacy of combined chloroquine and sulfadoxine-pyrimethamine in uncomplicated Plasmodium falciparum malaria in Bangladesh.

A study of the therapeutic efficacy of combined chloroquine and sulfadoxine-pyrimethamine (SP) for the treatment of uncomplicated Plasmodium falciparum malaria was carried out from June to November 2002, using the standard protocol recommended by the WHO for a low-to-moderate transmission area, in two sentinel sites in Bangladesh: Alikadam Upazilla in Bandarban district and Matiranga Upazilla in Khagrachari district. A total of 133 patients was followed-up to 28 d. Total failure rates were 25.9 and 30.7% in Alikadam and Matiranga, respectively. No severe side effects due to the drugs were encountered during the study period. Chloroquine and SP is not a suitable combination for the first-line treatment of P. falciparum in Bangladesh.

Administration, Oral↗
PubMed2005

Efficacy of chloroquine + sulfadoxine--pyrimethamine, mefloquine + artesunate and artemether + lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh.

Bangladesh faces growing levels of Plasmodium falciparum resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP). Alternative antimalarial therapies, particularly combination regimens, need to be considered. Therefore, the efficacy of three antimalarial combination therapies was assessed in Chittagong Hill Tracts. A total of 364 P. falciparum patients were recruited and randomly assigned to either CQ + SP, mefloquine + artesunate (MQ + AS) or lumefantrine + artemether (Coartem). Results showed that CQ + SP therapy was less effective than the two artemisinin-based combination therapies. The day 42 PCR-corrected efficacy rate was 62.4% for CQ + SP, 100% for MQ + AS and 97.1% for Coartem. Failures occurred at a shorter interval after CQ + SP treatment than after Coartem. The artemisinin-based therapies effectively prevented development of gametocytes, whereas CQ + SP did not. All three therapies were well tolerated, although reports of mild complaints during treatment appeared higher with MQ + AS. We conclude that CQ + SP is not a viable option for replacing CQ monotherapy as first-line P. falciparum treatment in this area of Bangladesh. A change to artemisinin-based combination therapy is recommended. Both Coartem and MQ + AS appear to be good options, effective in curing P. falciparum malaria and in preventing recrudescences following treatment.

Adolescent↗
PubMed2005

Efficacy of chloroquine, sulfadoxine-pyrimethamine and amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria among children under five in Bongor and Koumra, Chad.

We report two 28-day in-vivo antimalarial efficacy studies carried out in the urban centres of Bongor and Koumra, southern Chad. We assess chloroquine (CQ), sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) to treat Plasmodium falciparum uncomplicated malaria. Methods and outcome classification complied with latest WHO guidelines. Out of the 301 and 318 children aged 6-59 months included in Bongor and Koumra, respectively, 246 (81.7%) and 257 (80.8%) were eligible for analysis. In Bongor and Koumra, the 28-day PCR-adjusted failure rates for CQ were 23.7% (95% CI 14.7-34.8%) and 32.9% (95% CI 22.1-45.1%), respectively, and those for SP were 16.3% (95% CI 9.4-25.5%) and 4.3% (95% CI 1.2-10.5%). AQ failure rates were 6.4% (95% CI 2.1-14.3%) and 2.2% (95% CI 0.3-7.6%). The current use of CQ in Bongor and Koumra is questionable, and a more efficacious treatment is needed. Considering the reduced efficacy of SP in Bongor, AQ seems to be the best option for the time being. Following WHO recommendations that prioritize the use of artemisinin-based combinations, artesunate plus amodiaquine could be a potential first-line treatment. Nevertheless, the efficacy of this combination should be evaluated and the change carefully prepared, implemented and monitored.

Amodiaquine↗
PubMed2006

Artesunate plus sulfadoxine-pyrimethamine in the treatment of uncomplicated Plasmodium falciparum malaria during pregnancy in eastern Sudan.

Malaria during pregnancy is associated with serious adverse effects; these could be avoided with effective treatment. Artesunate plus sulfadoxine-pyrimethamine (AS+SP) is a promising antimalarial combination; however, few data are available on its safety during pregnancy. The present study was carried out in New Halfa Hospital, eastern Sudan, between September 2004 and March 2005. Thirty-two pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria were treated with AS+SP at a mean of 29.7 weeks of gestation. The patients were followed-up until delivery and the babies were followed-up until the age of 1 month. The drug was well tolerated, the parasitaemia was cleared and the patients were symptom-free within 2 days. All the patients delivered full-term live babies. One of the babies died on the fourth day; none of the women died and there was no miscarriage, stillbirth, or congenital abnormalities in the newborn babies. Thus, this small descriptive study failed to detect unintended effects of AS+SP during pregnancy.

Adolescent↗