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Antimicrobial Agents and Chemotherapy May 1986Dihydrofolate reductase was partially purified from a pyrimethamine-sensitive Plasmodium chabaudi clone and a pyrimethamine-resistant clone derived from it and used in a...
Dihydrofolate reductase was partially purified from a pyrimethamine-sensitive Plasmodium chabaudi clone and a pyrimethamine-resistant clone derived from it and used in a study of the inhibitory effect of pyrimethamine and sulfadoxine, both alone and in combination. Kinetic analysis of the inhibitory effect of sulfadoxine against the enzyme from pyrimethamine-sensitive and -resistant parasites revealed that the drug inhibited the former enzyme competitively, with an inhibition constant (Kis) of 0.7 +/- 0.4 mM, but inhibited the latter enzyme noncompetitively, with Kis and Kii of 8.9 +/- 1.2 and 4.1 +/- 1.2 mM, respectively. Previous studies also showed competitive inhibition by pyrimethamine on the former enzyme and noncompetitive inhibition on the latter enzyme, with some 200-fold-lower affinity. Sulfadoxine and pyrimethamine exhibited a mutually potentiating effect on the enzyme activity, as revealed by the concave isoboles and the fractional inhibitions of less than unity. A potentiating effect was observed for the enzymes from both sources and was not dependent on the degree of the purification of the enzyme. Our results can be explained by assuming simultaneous binding of two inhibitors on the enzyme.
Topics: Animals; Drug Resistance, Microbial; Drug Synergism; Folic Acid Antagonists; Kinetics; Plasmodium; Pyrimethamine; Sulfadoxine; Sulfanilamides; Tetrahydrofolate Dehydrogenase
PubMed: 3729346
DOI: 10.1128/AAC.29.5.899 -
The American Journal of Tropical... May 2024Surveillance for genetic markers of resistance can provide valuable information on the likely efficacy of antimalarials but needs to be targeted to ensure optimal use of...
Surveillance for genetic markers of resistance can provide valuable information on the likely efficacy of antimalarials but needs to be targeted to ensure optimal use of resources. We conducted a systematic search and review of publications in seven databases to compile resistance marker data from studies in India. The sample collection from the studies identified from this search was conducted between 1994 and 2020, and these studies were published between 1994 and 2022. In all, Plasmodium falciparum Kelch13 (PfK13), P. falciparum dihydropteroate synthase, and P. falciparum dihydrofolate reductase (PfDHPS) genotype data from 2,953, 4,148, and 4,222 blood samples from patients with laboratory-confirmed malaria, respectively, were extracted from these publications and uploaded onto the WorldWide Antimalarial Resistance Network molecular surveyors. These data were fed into hierarchical geostatistical models to produce maps with a predicted prevalence of the PfK13 and PfDHPS markers, and of the associated uncertainty. Zones with a predicted PfDHPS 540E prevalence of >15% were identified in central, eastern, and northeastern India. The predicted prevalence of PfK13 mutants was nonzero at only a few locations, but were within or adjacent to the zones with >15% prevalence of PfDHPS 540E. There may be a greater probability of artesunate-sulfadoxine-pyrimethamine failures in these regions, but these predictions need confirmation. This work can be applied in India and elsewhere to help identify the treatments most likely to be effective for malaria elimination.
Topics: Plasmodium falciparum; Pyrimethamine; Sulfadoxine; India; Drug Resistance; Antimalarials; Drug Combinations; Humans; Malaria, Falciparum; Artemisinins; Tetrahydrofolate Dehydrogenase; Genetic Markers; Dihydropteroate Synthase; Protozoan Proteins
PubMed: 38574550
DOI: 10.4269/ajtmh.23-0631 -
Journal of Clinical Pharmacy and... Oct 2007There are several reports of sub-standard and counterfeit antimalarial drugs circulating in the markets of developing countries; we aimed to review the literature for... (Review)
Review
BACKGROUND AND OBJECTIVE
There are several reports of sub-standard and counterfeit antimalarial drugs circulating in the markets of developing countries; we aimed to review the literature for the African continent.
METHODS
A search was conducted in PubMed in English using the medical subject headings (MeSH) terms: 'Antimalarials/analysis'[MeSH] OR 'Antimalarials/standards'[MeSH] AND 'Africa'[MeSH]' to include articles published up to and including 26 February 2007. Data were augmented with reports on the quality of antimalarial drugs in Africa obtained from colleagues in the World Health Organization. We summarized the data under the following themes: content and dissolution; relative bioavailability of antimalarial products; antimalarial stability and shelf life; general tests on pharmaceutical dosage forms; and the presence of degradation or unidentifiable impurities in formulations.
RESULTS AND DISCUSSION
The search yielded 21 relevant peer-reviewed articles and three reports on the quality of antimalarial drugs in Africa. The literature was varied in the quality and breadth of data presented, with most bioavailability studies poorly designed and executed. The review highlights the common finding in drug quality studies that (i) most antimalarial products pass the basic tests for pharmaceutical dosage forms, such as the uniformity of weight for tablets, (ii) most antimalarial drugs pass the content test and (iii) in vitro product dissolution is the main problem area where most drugs fail to meet required pharmacopoeial specifications, especially with regard to sulfadoxine-pyrimethamine products. In addition, there are worryingly high quality failure rates for artemisinin monotherapies such as dihydroartemisinin (DHA); for instance all five DHA sampled products in one study in Nairobi, Kenya, were reported to have failed the requisite tests.
CONCLUSIONS
There is an urgent need to strengthen pharmaceutical management systems such as post-marketing surveillance and the broader health systems in Africa to ensure populations in the continent have access to antimalarial drugs that are safe, of the highest quality standards and that retain their integrity throughout the distribution chain through adequate enforcement of existing legislation and enactment of new ones if necessary, and provision of the necessary resources for drug quality assurance.
Topics: Africa; Antimalarials; Artemisinins; Biological Availability; Dosage Forms; Drug Combinations; Drug Stability; Drug Storage; Humans; Product Surveillance, Postmarketing; Pyrimethamine; Quality Control; Sesquiterpenes; Sulfadoxine
PubMed: 17875107
DOI: 10.1111/j.1365-2710.2007.00847.x -
Tropical Medicine & International... Jun 2003Plasmodium falciparum malaria in pregnancy poses substantial risk to a pregnant woman and her neonate through anaemia and low birth weight (LBW), respectively, and is... (Review)
Review
Safety, efficacy and determinants of effectiveness of antimalarial drugs during pregnancy: implications for prevention programmes in Plasmodium falciparum-endemic sub-Saharan Africa.
Plasmodium falciparum malaria in pregnancy poses substantial risk to a pregnant woman and her neonate through anaemia and low birth weight (LBW), respectively, and is responsible for up to 35% of preventable LBW in malaria-endemic areas. Chemoprophylaxis or intermittent preventive treatment (IPT) with an effective antimalarial can ameliorate the adverse effects of malaria during pregnancy. Current guidelines from the WHO recommend that women in highly malarious areas receive IPT with an effective antimalarial. Two central considerations in evaluating drugs for use during pregnancy are safety for the mother and her foetus and effectiveness, which is determined by efficacy, cost, availability, deliverability and acceptability of the drug. These factors may be scored and potential drugs or drug combinations ranked in order of potential effectiveness for use in prevention programmes. The seven most promising regimens are all IPT, primarily because they are more easily delivered and less expensive than chemoprophylaxis. Currently, IPT with sulphadoxine-pyrimethamine (SP) is more likely to have the best overall effectiveness in preventing adverse outcomes associated with malaria in pregnancy. Its low cost, wide availability, easy deliverability and acceptability make it the clear choice in countries where efficacy of the drug remains good. For countries where resistance to SP is rising or already high, amodiaquine (alone or in combination with SP or artesunate) artesunate + SP, chlorproguanil-dapsone (with and without artesunate) and artemether-lumefantrine require urgent evaluation for use in pregnancy.
Topics: Africa South of the Sahara; Antimalarials; Drug Combinations; Endemic Diseases; Female; Humans; Infectious Disease Transmission, Vertical; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Sulfadoxine
PubMed: 12791054
DOI: 10.1046/j.1365-3156.2003.01066.x -
Molecules (Basel, Switzerland) Dec 2022The continual rise in sulfadoxine (SDX) resistance affects the therapeutic efficacy of sulfadoxine-pyrimethamine; therefore, careful monitoring will help guide its...
Global Analysis of Dihydropteroate Synthase Variants Associated with Sulfadoxine Resistance Reveals Variant Distribution and Mechanisms of Resistance: A Computational-Based Study.
The continual rise in sulfadoxine (SDX) resistance affects the therapeutic efficacy of sulfadoxine-pyrimethamine; therefore, careful monitoring will help guide its prolonged usage. Mutations in dihydropteroate synthase (dhps) are being surveilled, based on their link with SDX resistance. However, there is a lack of continuous analyses and data on the potential effect of molecular markers on the dhps structure and function. This study explored single-nucleotide polymorphisms (SNPs) in dhps that were isolated in Africa and other countries, highlighting the regional distribution and its link with structure. In total, 6336 genomic sequences from 13 countries were subjected to SNPs, haplotypes, and structure-based analyses. The SNP analysis revealed that the key SDX resistance marker, A437G, was nearing fixation in all countries, peaking in Malawi. The mutation A613S was rare except in isolates from the Democratic Republic of Congo and Malawi. Molecular docking revealed a general loss of interactions when comparing mutant proteins to the wild-type protein. During MD simulations, SDX was released from the active site in mutants A581G and A613S before the end of run-time, whereas an unstable binding of SDX to mutant A613S and haplotype A437A/A581G/A613S was observed. Conformational changes in mutant A581G and the haplotypes A581G/A613S, A437G/A581G, and A437G/A581G/A613S were seen. The radius of gyration revealed an unfolding behavior for the A613S, K540E/A581G, and A437G/A581G systems. Overall, tracking such mutations by the continuous analysis of dhps SNPs is encouraged. SNPs on the dhps structure may cause protein-drug function loss, which could affect the applicability of SDX in preventing malaria in pregnant women and children.
Topics: Child; Female; Humans; Pregnancy; Antimalarials; Dihydropteroate Synthase; Drug Combinations; Drug Resistance; Malaria, Falciparum; Molecular Docking Simulation; Mutation; Plasmodium falciparum; Sulfadoxine; Tetrahydrofolate Dehydrogenase
PubMed: 36615340
DOI: 10.3390/molecules28010145 -
British Medical Journal Nov 1976
Topics: Adult; Antimalarials; Chloroquine; Humans; Malaria; Plasmodium falciparum; Proguanil; Pyrimethamine; Sulfadoxine; Travel
PubMed: 791446
DOI: No ID Found -
Journal of Global Antimicrobial... Jun 2021Pregnancy-associated malaria (PAM) is a complex form of malaria. To prevent PAM, several African countries have adopted intermittent preventive treatment with...
OBJECTIVES
Pregnancy-associated malaria (PAM) is a complex form of malaria. To prevent PAM, several African countries have adopted intermittent preventive treatment with sulfadoxine/pyrimethamine (IPT-SP). However, resistance to SP has been reported, associated with mutations in the genes Plasmodium falciparum dihydropteroate synthase (Pfdhps) and P. falciparum dihydrofolate reductase (Pfdhfr). The aim of this study was to investigate the prevalence of mutations in Pfdhfr and Pfdhps in P. falciparum isolates from rural areas of Gabon.
METHODS
A cross-sectional survey of febrile patients (n = 202) who consulted Fougamou Health Center between February-May 2016 was performed. DNA was extracted from patient samples and the Pfdhfr and Pfdhps genes were genotyped using PCR-RFLP. Statistical analyses were performed.
RESULTS
The malaria prevalence in febrile patients included in the study was 60.4% (122/202). The main parasite species was P. falciparum (96.7%; 118/122), followed by Plasmodium malariae (3.3%; 4/122). Genotypes on codons 16, 51, 59 and 108 of Pfdhfr were highly mutated (>96%). In Pfdhps, codons 436, 437, 540 and 613 also expressed high mutation rates. The prevalence of triple mutations of Pfdhfr VIRNI and AIRNI was 12.1% and 84.5%, respectively. The prevalence of mutant haplotypes of Pfdhps SGEA, SGKA and AGEA was 37.9%, 25.9% and 12.1%, respectively. The prevalence of quadruple mutants IRN-A and IRN-G was 20.0% and 93.1%, respectively, whereas quintuple mutants were found at 57.8% (IRN-GE) and 5.0% (IRN-AE).
CONCLUSION
Our data show a high prevalence of genotypes associated with SP resistance. Clinical trials to investigate the efficacy of IPT-SP are much needed.
Topics: Antimalarials; Cross-Sectional Studies; Drug Resistance; Female; Gabon; Genotype; Humans; Plasmodium falciparum; Pregnancy; Prevalence; Pyrimethamine; Sulfadoxine
PubMed: 33774217
DOI: 10.1016/j.jgar.2021.03.003 -
The Lancet. Infectious Diseases Oct 2018Sulfadoxine-pyrimethamine resistance threatens efficacy of intermittent preventive treatment of malaria during pregnancy, and alternative regimens need to be identified.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sulfadoxine-pyrimethamine resistance threatens efficacy of intermittent preventive treatment of malaria during pregnancy, and alternative regimens need to be identified. With the return of chloroquine efficacy in southern Africa, we postulated that chloroquine either as an intermittent therapy or as weekly chemoprophylaxis would be more efficacious than intermittent sulfadoxine-pyrimethamine for prevention of malaria in pregnancy and associated maternal and newborn adverse outcomes.
METHODS
We did an open-label, single-centre, randomised controlled trial at Ndirande Health Centre, Blantyre, in southern Malawi. We enrolled pregnant women (first or second pregnancy) at 20-28 weeks' gestation who were HIV negative. Participants were randomly assigned in a 1:1:1 ratio using a computer-generated list to either intermittent sulfadoxine-pyrimethamine (two doses of 1500 mg sulfadoxine and 75 mg pyrimethamine, 4 weeks apart), intermittent chloroquine (two doses of 600 mg on day 1, 600 mg on day 2, and 300 mg on day 3), or chloroquine prophylaxis (600 mg on day 1 then 300 mg every week). The primary endpoint was placental malaria in the modified intent-to-treat population, which consisted of participants who contributed placental histopathology data at birth. Secondary outcomes included clinical malaria, maternal anaemia, low birthweight, and safety. This trial is registered with ClinicalTrials.gov, number NCT01443130.
FINDINGS
Between February, 2012, and May, 2014, we enrolled and randomly allocated 900 women, of whom 765 contributed histopathological data and were included in the primary analysis. 108 (14%) women had placental malaria, which was lower than the anticipated prevalence of placental malaria infection. Protection from placental malaria was not improved by chloroquine as either prophylaxis (30 [12%] of 259 had positive histopathology; relative risk [RR] 0·75, 95% CI 0·48-1·17) or intermittent therapy (39 [15%] of 253; RR 1·00, 0·67-1·50) compared with intermittent sulfadoxine-pyrimethamine (39 [15%] of 253). In protocol-specified analyses adjusted for maternal age, gestational age at enrolment, bednet use the night before enrolment, anaemia at enrolment, and malaria infection at enrolment, women taking chloroquine as prophylaxis had 34% lower placental infections than did those allocated intermittent sulfadoxine-pyrimethamine (RR 0·66, 95% CI 0·46-0·95). Clinical malaria was reported in nine women assigned intermittent sulfadoxine-pyrimethamine, four allocated intermittent chloroquine (p=0·26), and two allocated chloroquine prophylaxis (p=0·063). Maternal anaemia was noted in five women assigned intermittent sulfadoxine-pyrimethamine, 15 allocated intermittent chloroquine (p=0·038), and six assigned chloroquine prophylaxis (p>0·99). Low birthweight was recorded for 31 babies born to women allocated intermittent sulfadoxine-pyrimethamine, 29 assigned intermittent chloroquine (p=0·78), and 41 allocated chloroquine prophylaxis (p=0·28). Four women assigned intermittent sulfadoxine-pyrimethamine had adverse events possibly related to study product compared with 94 women allocated intermittent chloroquine (p<0·0001) and 26 allocated chloroquine prophylaxis (p<0·0001). Three women had severe or life-threatening adverse events related to study product, of whom all were assigned intermittent chloroquine (p=0·25).
INTERPRETATION
Chloroquine administered as intermittent therapy did not provide better protection from malaria and related adverse effects compared with intermittent sulfadoxine-pyrimethamine in a setting of high resistance to sulfadoxine-pyrimethamine. Chloroquine chemoprophylaxis might provide benefit in protecting against malaria during pregnancy, but studies with larger sample sizes are needed to confirm these results.
FUNDING
US National Institutes of Health.
Topics: Adult; Antimalarials; Chloroquine; Drug Combinations; Female; Humans; Infant, Newborn; Malaria; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Sulfadoxine
PubMed: 30195996
DOI: 10.1016/S1473-3099(18)30415-8 -
Malaria Journal Feb 2012The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as... (Review)
Review
The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination.
Topics: Antimalarials; Chemoprevention; Drug Combinations; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Infectious; Probenecid; Pyrimethamine; Sulfadoxine; Treatment Outcome
PubMed: 22321288
DOI: 10.1186/1475-2875-11-39 -
BMJ Global Health Aug 2021Ghana adopted the revised WHO recommendation on intermittent preventive treatment in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) in 2012. This study has assessed...
INTRODUCTION
Ghana adopted the revised WHO recommendation on intermittent preventive treatment in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) in 2012. This study has assessed the effectiveness and safety of this policy in Ghana.
METHODS
A total of 1926 pregnant women enrolled at antenatal care (ANC) clinics were assessed for birth outcomes at delivery, and placental histology results for malaria infection were obtained from 1642 participants. Association of reduced placental or peripheral malaria, anaemia and low birth weight (LBW) in women who received ≥4 IPTp-SP doses compared with 3 or ≤2 doses was determined by logistic regression analysis.
RESULTS
Among the 1926 participants, 5.3% (103), 19.2% (369), 33.2% (640) and 42.3% (817) of women had received ≤1, 2, 3 or ≥4 doses, respectively. There was no difference in risk of active placental malaria (PM) infection in women who received 3 doses compared with ≥4 doses (adjusted OR (aOR) 1.00, 95% CI 0.47 to 2.14). The risk of overall PM infection was 1.63 (95% CI 1.07 to 2.48) in 2 dose group and 1.06 (95% CI 0.72 to 1.57) in 3 dose group compared with ≥4 dose group. The risk of LBW was 1.55 (95% CI 0.97 to 2.47) and 1.06 (95% CI 0.68 to 1.65) for 2 and 3 dose groups, respectively, compared with the ≥4 dose group. Jaundice in babies was present in 0.16%, and 0% for women who received ≥4 doses of SP.
CONCLUSION
There was no difference in the risk of PM, LBW or maternal anaemia among women receiving 3 doses compared with ≥4 doses. Receiving ≥3 IPTp-SP doses during pregnancy was associated with a lower risk of overall PM infection compared with 2 doses. As there are no safety concerns, monthly administration of IPTp-SP offers a more practical opportunity for pregnant women to receive ≥3 doses during pregnancy.
Topics: Antimalarials; Drug Combinations; Female; Ghana; Humans; Placenta; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Sulfadoxine
PubMed: 34417272
DOI: 10.1136/bmjgh-2021-005877