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Journal of Toxicology 2022The sulfadoxine-pyrimethamine combination is a product used in the intermittent preventive treatment (IPT) of malaria in pregnant women in our country. To date, there is...
BACKGROUND
The sulfadoxine-pyrimethamine combination is a product used in the intermittent preventive treatment (IPT) of malaria in pregnant women in our country. To date, there is very little data on the teratogenic effect of this product. This study proposed to evaluate the teratogenic effect of sulfadoxine-pyrimethamine on chicken embryos.
METHODS
The teratogenic effect of the product was evaluated on chicken embryos at a dose of 1.3 mg/g sulfadoxine and 0.06 mg/g pyrimethamine. The product was injected before the start of incubation and on days 12, 14, 16, and 18 of incubation. One batch received a double injection of the product on days 16 and 18 of incubation. The quality of the hatched chicks was evaluated by the Tona Score followed by the determination of hematological and biochemical parameters.
RESULTS
From the aforementioned, it appears that the eggs treated with sulfadoxine-pyrimethamine significantly decreased the hatchability rate of the eggs. The chicks obtained were all of very good quality. Apart from a significant decrease in the weight of the chicks of the batch that received the injection twice and a significant increase in the weight of the yolk sac of the chicks of the batch that received the injection on day 16 compared to the control, no variation was obtained. A significant increase in the white blood cell count of the chicks compared to the control was reported in the chicks of the batch injected before incubation and on day 12, as well as a significant increase in the platelet count of the chicks of the batch injected twice. For biochemical parameters, no significant difference was reported in ALT and AST.
CONCLUSION
Sulfadoxine-pyrimethamine decreased egg hatch and caused an increase in embryo and chick mortality as well as a loss in relative chick weight and an increase in relative yolk sac weight. More in-depth studies would be needed on sulfadoxine-pyrimethamine teratogenicity and the benefit/risk ratio of this drug during pregnancy.
PubMed: 35340707
DOI: 10.1155/2022/2995492 -
The New England Journal of Medicine Mar 2016
Topics: Antimalarials; Artemisinins; Female; Humans; Malaria; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Quinolines; Sulfadoxine
PubMed: 26962733
DOI: 10.1056/NEJMe1601193 -
Molecules (Basel, Switzerland) Nov 2019Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine,... (Review)
Review
Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine, amodiaquine, mefloquine and sulfadoxine, were used as inspiration. We demonstrated the importance of quinoline and non-quinoline derivatives in vitro with activity against the W2 chloroquine-resistant (CQR) clone strain and in vivo against -infected mouse model. Among the quinoline derivatives, new hybrids between chloroquine and sulfadoxine were designed, which gave rise to an important prototype that was more active than both chloroquine and sulfadoxine. Hybrids between chloroquine-atorvastatin and primaquine-atorvastatin were also synthesized and shown to be more potent than the parent drugs alone. Additionally, among the quinoline derivatives, new mefloquine derivatives were synthesized. Among the non-quinoline derivatives, we obtained excellent results with the triazolopyrimidine nucleus, which gave us prototype that inspired the synthesis of new heterocycles. The pyrazolopyrimidine derivatives stood out as non-quinoline derivatives that are potent inhibitors of the dihydroorotate dehydrogenase (DHODH) enzyme. We also examined the pyrazolopyridine and pyrazolopyrimidine nuclei.
Topics: Animals; Antimalarials; Chemistry Techniques, Synthetic; Dose-Response Relationship, Drug; Drug Development; Humans; Malaria; Molecular Structure; Plasmodium; Pyrazoles; Pyridines; Quinolines
PubMed: 31766184
DOI: 10.3390/molecules24224095 -
The Korean Journal of Parasitology Apr 2022Drug resistance is an important problem hindering malaria elimination in tropical areas. Point mutations in Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and...
Drug resistance is an important problem hindering malaria elimination in tropical areas. Point mutations in Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes confer resistance to antifolate drug, sulfadoxine-pyrimethamine (SP) while P. falciparum chloroquine-resistant transporter (Pfcrt) genes caused resistance to chloroquine (CQ). Decline in Pfdhfr/Pfdhps and Pfcrt mutations after withdrawal of SP and CQ has been reported. The aim of present study was to investigate the prevalence of Pfdhfr, Pfdhps, and Pfcrt mutation from 2 endemic areas of Thailand. All of 200 blood samples collected from western area (Thai-Myanmar) and southern area (Thai-Malaysian) contained multiple mutations in Pfdhfr and Pfdhps genes. The most prevalent haplotypes for Pfdhfr and Pfdhps were quadruple and double mutations, respectively. The quadruple and triple mutations of Pfdhfr and Pfdhps were common in western samples, whereas low frequency of triple and double mutations was found in southern samples, respectively. The Pfcrt 76T mutation was present in all samples examined. Malaria isolated from 2 different endemic regions of Thailand had high mutation rates in the Pfdhfr, Pfdhps, and Pfcrt genes. These findings highlighted the fixation of mutant alleles causing resistance of SP and CQ in this area. It is necessary to monitor the re-emergence of SP and CQ sensitive parasites in this area.
Topics: Antimalarials; Chloroquine; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Thailand
PubMed: 35500892
DOI: 10.3347/kjp.2022.60.2.109 -
Malaria Journal Jan 2021Malaria caused by Plasmodium falciparum in pregnancy can result in adverse maternal and fetal sequelae. This review evaluated the adherence of the national guidelines... (Review)
Review
BACKGROUND
Malaria caused by Plasmodium falciparum in pregnancy can result in adverse maternal and fetal sequelae. This review evaluated the adherence of the national guidelines drawn from World Health Organization (WHO) regions, Africa, Eastern Mediterranean, Southeast Asia, and Western Pacific, to the WHO recommendations on drug treatment and prevention of chloroquine-resistant falciparum malaria in pregnant women.
METHODS
Thirty-five updated national guidelines and the President's Malaria Initiative (PMI), available in English language, were reviewed. The primary outcome measures were the first-line anti-malarial treatment protocols adopted by national guidelines for uncomplicated and complicated falciparum malaria infections in early (first) and late (second and third) trimesters of pregnancy. The strategy of intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) was also addressed.
RESULTS
This review evaluated the treatment and prevention of falciparum malaria in pregnancy in 35 national guidelines/PMI-Malaria Operational Plans (MOP) reports out of 95 malaria-endemic countries. Of the 35 national guidelines, 10 (28.6%) recommend oral quinine plus clindamycin as first-line treatment for uncomplicated malaria in the first trimester. As the first-line option, artemether-lumefantrine, an artemisinin-based combination therapy, is adopted by 26 (74.3%) of the guidelines for treating uncomplicated or complicated malaria in the second and third trimesters. Intravenous artesunate is approved by 18 (51.4%) and 31 (88.6%) guidelines for treating complicated malaria during early and late pregnancy, respectively. Of the 23 national guidelines that recommend IPTp-SP strategy, 8 (34.8%) are not explicit about directly observed therapy requirements, and three-quarters, 17 (73.9%), do not specify contra-indication of SP in human immunodeficiency virus (HIV)-infected pregnant women receiving cotrimoxazole prophylaxis. Most of the guidelines (18/23; 78.3%) state the recommended folic acid dose.
CONCLUSION
Several national guidelines and PMI reports require update revisions to harmonize with international guidelines and emergent trends in managing falciparum malaria in pregnancy. National guidelines and those of donor agencies should comply with those of WHO guideline recommendations although local conditions and delayed guideline updates may call for deviations from WHO evidence-based guidelines.
Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artesunate; Chloroquine; Drug Combinations; Female; Humans; Malaria; Parasitemia; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Quinine; Sulfadoxine
PubMed: 33485330
DOI: 10.1186/s12936-020-03565-2 -
CPT: Pharmacometrics & Systems... Jul 2017Sulfadoxine/pyrimethamine is recommended for intermittent preventative treatment of malaria during pregnancy. Data from 98 women during pregnancy and 77 after delivery... (Clinical Trial)
Clinical Trial
Sulfadoxine/pyrimethamine is recommended for intermittent preventative treatment of malaria during pregnancy. Data from 98 women during pregnancy and 77 after delivery in four African countries were analyzed using nonlinear mixed-effects modeling to characterize the effects of pregnancy, postpartum duration, and other covariates such as body weight and hematocrit on sulfadoxine/pyrimethamine pharmacokinetic properties. During pregnancy, clearance increased 3-fold for sulfadoxine but decreased by 18% for pyrimethamine. Postpartum sulfadoxine clearance decreased gradually over 13 weeks. This finding, together with hematocrit-based scaling of plasma to whole-blood concentrations and allometric scaling of pharmacokinetics parameters with body weight, enabled site-specific differences in the pharmacokinetic profiles to be reduced significantly but not eliminated. Further research is necessary to explain residual site-specific differences and elucidate whether dose-optimization, to address the 3-fold increase in clearance of sulfadoxine in pregnant women, is necessary, viable, and safe with the current fixed dose combination of sulfadoxine/pyrimethamine.
Topics: Adult; Africa; Antimalarials; Drug Combinations; Female; Humans; Malaria; Models, Biological; Postpartum Period; Pregnancy; Pyrimethamine; Sulfadoxine; Young Adult
PubMed: 28597978
DOI: 10.1002/psp4.12181 -
Malaria Journal Oct 2022Resistance to anti-malarial drugs is associated with polymorphisms in target genes and surveillance for these molecular markers is important to detect the emergence of...
Molecular surveillance for anti-malarial drug resistance and genetic diversity of Plasmodium falciparum after chloroquine and sulfadoxine-pyrimethamine withdrawal in Quibdo, Colombia, 2018.
BACKGROUND
Resistance to anti-malarial drugs is associated with polymorphisms in target genes and surveillance for these molecular markers is important to detect the emergence of mutations associated with drug resistance and signal recovering sensitivity to anti-malarials previously used.
METHODS
The presence of polymorphisms in genes associated with Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine was evaluated by Sanger sequencing, in 85 P. falciparum day of enrollment samples from a therapeutic efficacy study of artemether-lumefantrine conducted in 2018-2019 in Quibdo, Colombia. Samples were genotyped to assess mutations in pfcrt (codons 72-76), pfdhfr (codons 51, 59, 108, and 164), and pfdhps genes (codons 436, 437, 540, and 581). Further, the genetic diversity of infections using seven neutral microsatellites (NMSs) (C2M34, C3M69, Poly α, TA1, TA109, 2490, and PfPK2) was assessed.
RESULTS
All isolates carried mutant alleles for pfcrt (K76T and N75E), and for pfdhfr (N51I and S108N), while for pfdhps, mutations were observed only for codon A437G (32/73, 43.8%). Fifty samples (58.8%) showed a complete neutral microsatellites (NMS) profile. The low mean number of alleles (2 ± 0.57) per locus and mean expected heterozygosity (0.17 ± 0.03) showed a reduced genetic diversity. NMS multilocus genotypes (MMG) were built and nine MMG were identified.
CONCLUSIONS
Overall, these findings confirm the fixation of chloroquine and pyrimethamine-resistant alleles already described in the literature, implying that these drugs are not currently appropriate for use in Colombia. In contrast, mutations in the pfdhps gene were only observed at codon 437, an indication that full resistance to sulfadoxine has not been achieved in Choco. MMGs found matched the clonal lineage E variant 1 previously reported in northwestern Colombia.
Topics: Humans; Sulfadoxine; Pyrimethamine; Antimalarials; Plasmodium falciparum; Chloroquine; Colombia; Malaria, Falciparum; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Drug Resistance; Polymorphism, Genetic; Codon
PubMed: 36307852
DOI: 10.1186/s12936-022-04328-x -
SAGE Open Medicine 2022The study examined the differentials in prevalence and correlates on the uptake of tetanus toxoid and intermittent preventive treatment of malaria among pregnant women...
Differentials in prevalence and correlates on uptake of tetanus toxoid and intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy: A community-based cross-sectional study in The Gambia.
OBJECTIVES
The study examined the differentials in prevalence and correlates on the uptake of tetanus toxoid and intermittent preventive treatment of malaria among pregnant women in The Gambia.
METHODS
The 2018 data from The Gambia Multiple Indicators Cluster Survey were analyzed. Data from 6143 women of reproductive age who have given birth were extracted for the analysis. Percentages and Chi-square tests were used. In addition, a multivariable logistic regression model was used to calculate the adjusted odds ratios (with a corresponding 95% confidence interval). The level of significance was set at < 0.05.
RESULTS
The prevalence of tetanus toxoid uptake among women in The Gambia was 88.2%, while that of the adequate tetanus toxoid doses was 34.8%. The prevalence of intermittent preventive treatment with sulfadoxine-pyrimethamine uptake among maternal women in The Gambia was 98.6%, while that of the adequate intermittent preventive treatment with sulfadoxine-pyrimethamine doses taken was 34.3%. The identified statistically significant covariates of tetanus toxoid immunization and intermittent preventive treatment with sulfadoxine-pyrimethamine uptake includes women's age, local government areas, parity, use of radio, use of newspaper, and antenatal care visits.
CONCLUSION
The current utilization rate for adequate intermittent preventive treatment with sulfadoxine-pyrimethamine and tetanus toxoid immunization during pregnancy in The Gambia is very low and even below universal levels. The country needs to strengthen more and effective mass media advocacy programs that would target both rural and urban populace, and motivate maternal women to ensure adequate vaccination against malaria and tetanus.
PubMed: 35024140
DOI: 10.1177/20503121211065908 -
The Lancet. Global Health Nov 2023The effectiveness of community delivery of intermittent preventive treatment (C-IPT) of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine has been evaluated in...
Prevalence of molecular markers of resistance to sulfadoxine-pyrimethamine before and after community delivery of intermittent preventive treatment of malaria in pregnancy in sub-Saharan Africa: a multi-country evaluation.
BACKGROUND
The effectiveness of community delivery of intermittent preventive treatment (C-IPT) of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine has been evaluated in selected areas of the Democratic Republic of the Congo, Madagascar, Mozambique, and Nigeria. We aimed to assess the effect of C-IPTp on the potential development of Plasmodium falciparum resistance to sulfadoxine-pyrimethamine, since it could threaten the effectiveness of this strategy.
METHODS
Health facility-based cross-sectional surveys were conducted at baseline and 3 years after C-IPTp implementation in two neighbouring areas per country, one with C-IPTp intervention, and one without, in the four project countries. Dried blood spots from children under five years of age with clinical malaria were collected. Sulfadoxine-pyrimethamine resistance-associated mutations of the P falciparum dhfr (Asn51Ile/Cys59Arg/Ser108Asn/Ile164Leu) and dhps (Ile431Val/Ser436Ala/Ala437Gly/Lys540Glu/Ala581Gly/Ala613Ser) genes were analysed.
FINDINGS
2536 children were recruited between June 19 and Oct 10, 2018, during baseline surveys. Endline surveys were conducted among 2447 children between July 26 and Nov 30, 2021. In the Democratic Republic of the Congo, the dhfr/dhps IRNI/ISGEAA inferred haplotype remained lower than 10%, from 2% (5 of 296) at baseline to 8% (24 of 292) at endline, and from 3% (9 of 300) at baseline to 6% (18 of 309) at endline surveys in intervention and non-intervention areas respectively with no significant difference in the change between the areas. In Mozambique, the prevalence of this haplotype remained stable at over 60% (194 [64%] of 302 at baseline to 194 [64%] of 303 at endline, and 187 [61%] of 306 at baseline to 183 [61%] of 301 in endline surveys, in non-intervention and intervention areas respectively). No isolates harbouring the dhps ISGEAA genotype were found in Nigeria. In Madagascar, only five isolates with this haplotype were found in the non-intervention area (2 [>1%] of 300 at baseline and 3 [1%] of 300 at endline surveys). No isolates were found carrying the dhps ISGEGA genotype.
INTERPRETATION
C-IPTp did not increase the prevalence of molecular markers associated with sulfadoxine-pyrimethamine resistance after three years of programme implementation. These findings reinforce C-IPTp as a strategy to optimise the control of malaria during pregnancy, and support the WHO guidelines for prevention of malaria in pregnancy.
FUNDING
UNITAID [2017-13-TIPTOP].
Topics: Pregnancy; Child; Female; Humans; Child, Preschool; Antimalarials; Prevalence; Cross-Sectional Studies; Drug Resistance; Pyrimethamine; Sulfadoxine; Malaria; Malaria, Falciparum; Drug Combinations; Plasmodium falciparum; Mozambique; Biomarkers
PubMed: 37858587
DOI: 10.1016/S2214-109X(23)00414-X -
The Lancet. Infectious Diseases Mar 2023Seasonal malaria chemoprevention is used in 13 countries in the Sahel region of Africa to prevent malaria in children younger than 5 years. Resistance of Plasmodium...
Prevalence of Plasmodium falciparum haplotypes associated with resistance to sulfadoxine-pyrimethamine and amodiaquine before and after upscaling of seasonal malaria chemoprevention in seven African countries: a genomic surveillance study.
BACKGROUND
Seasonal malaria chemoprevention is used in 13 countries in the Sahel region of Africa to prevent malaria in children younger than 5 years. Resistance of Plasmodium falciparum to seasonal malaria chemoprevention drugs across the region is a potential threat to this intervention.
METHODS
Between December, 2015, and March, 2016, and between December, 2017, and March, 2018, immediately following the 2015 and 2017 malaria transmission seasons, community surveys were done among children younger than 5 years and individuals aged 10-30 years in districts implementing seasonal malaria chemoprevention with sulfadoxine-pyrimethamine and amodiaquine in Burkina Faso, Chad, Guinea, Mali, Nigeria, Niger and The Gambia. Dried blood samples were collected and tested for P falciparum DNA by PCR. Resistance-associated haplotypes of the P falciparum genes crt, mdr1, dhfr, and dhps were identified by quantitative PCR and sequencing of isolates from the collected samples, and survey-weighted prevalence and prevalence ratio between the first and second surveys were estimated for each variant.
FINDINGS
5130 (17·5%) of 29 274 samples from 2016 and 2176 (7·6%) of 28 546 samples from 2018 were positive for P falciparum on quantitative PCR. Among children younger than 5 years, parasite carriage decreased from 2844 of 14 345 samples (19·8% [95% CI 19·2-20·5]) in 2016 to 801 of 14 019 samples (5·7% [5·3-6·1]) in 2018 (prevalence ratio 0·27 [95% CI 0·24-0·31], p<0·0001). Genotyping found no consistent evidence of increasing prevalence of amodiaquine resistance-associated variants of crt and mdr1 between 2016 and 2018. The dhfr haplotype IRN (consisting of 51Ile-59Arg-108Asn) was common at both survey timepoints, but the dhps haplotype ISGEAA (431Ile-436Ser-437Gly-540Glu-581Ala-613Ala), crucial for resistance to sulfadoxine-pyrimethamine, was always rare. Parasites carrying amodiaquine resistance-associated variants of both crt and mdr1 together with dhfr IRN and dhps ISGEAA occurred in 0·05% of isolates. The emerging dhps haplotype VAGKGS (431Val-436Ala-437Gly-540Lys-581Gly-613Ser) was present in four countries.
INTERPRETATION
In seven African countries, evidence of a significant reduction in parasite carriage among children receiving seasonal malaria chemoprevention was found 2 years after intervention scale-up. Combined resistance-associated haplotypes remained rare, and seasonal malaria chemoprevention with sulfadoxine-pyrimethamine and amodiaquine is expected to retain effectiveness. The threat of future erosion of effectiveness due to dhps variant haplotypes requires further monitoring.
FUNDING
Unitaid.
Topics: Child; Humans; Plasmodium falciparum; Amodiaquine; Haplotypes; Antimalarials; Seasons; Prevalence; Pyrimethamine; Sulfadoxine; Malaria; Malaria, Falciparum; Drug Combinations; Chemoprevention; Nigeria; Tetrahydrofolate Dehydrogenase; Genomics; Drug Resistance
PubMed: 36328000
DOI: 10.1016/S1473-3099(22)00593-X