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Malaria Journal Jul 2023Artemisinin-based combinations therapy (ACT) is the current frontline curative therapy for uncomplicated malaria in Burkina Faso. Sulfadoxine-pyrimethamine (SP) is used...
BACKGROUND
Artemisinin-based combinations therapy (ACT) is the current frontline curative therapy for uncomplicated malaria in Burkina Faso. Sulfadoxine-pyrimethamine (SP) is used for the preventive treatment of pregnant women (IPTp), while SP plus amodiaquine (SP-AQ) is recommended for children under five in seasonal malaria chemoprevention (SMC). This study aimed to assess the proportions of mutations in the P. falciparum multidrug-resistance 1 (Pfmdr1), P. falciparum chloroquine resistance transporter (Pfcrt), P. falciparum dihydrofolate reductase (pfdhfr), and P. falciparum dihydropteroate synthase (pfdhps), genes from isolates collected during household surveys in Burkina Faso.
METHODS
Dried blood spots from Plasmodium falciparum-positive cases at three sites (Orodara, Gaoua, and Banfora) collected during the peak of transmission were analysed for mutations in Pfcrt (codons 72-76, 93, 97, 145, 218, 343, 350 and 353), Pfmdr-1 (codons 86, 184, 1034, 1042 and 1246) dhfr (codons 51, 59, 108, 164) and dhps (at codons 431, 436, 437, 540, 581, 613) genes using deep sequencing of multiplexed Polymerase chaine reaction (PCR) amplicons.
RESULTS
Of the 377 samples analysed, 346 (91.7%), 369 (97.9%), 368 (97.6%), and 374 (99.2%) were successfully sequenced for Pfcrt, Pfmdr-1, dhfr, and dhps, respectively. Most of the samples had a Pfcrt wild-type allele (89.3%). The 76T mutation was below 10%. The most frequent Pfmdr-1 mutation was detected at codon 184 (Y > F, 30.9%). The single mutant genotype (NFSND) predominated (66.7%), followed by the wild-type genotype (NYSND, 30.4%). The highest dhfr mutations were observed at codon 59R (69.8%), followed by codons 51I (66.6%) and 108 N (14.7%). The double mutant genotype (ACIRSI) predominated (52.4%). For mutation in the dhps gene, the highest frequency was observed at codon 437 K (89.3%), followed by codons 436 A (61.2%), and 613 S (14.4%). The double mutant genotype (IAKKAA) and the single mutant genotype (ISKKAA) were predominant (37.7% and 37.2%, respectively). The most frequent dhfr/dhps haplotypes were the triple mutant ACIRSI/IAKKAA (23%), the wild-type ACNCSI/ISKKAA (19%) and the double mutant ACIRSI/ISKKAA (14%). A septuple mutant ACIRNI/VAKKGA was observed in 2 isolates from Gaoua (0.5%).
CONCLUSION
The efficacy of ACT partner drugs and drugs used in IPTp and SMC does not appear to be affected by the low proportion of highly resistant mutants observed in this study. Continued monitoring, including molecular surveillance, is critical for decision-making on effective treatment policy in Burkina Faso.
Topics: Humans; Child; Female; Pregnancy; Plasmodium falciparum; Antimalarials; Burkina Faso; Pyrimethamine; Sulfadoxine; Malaria, Falciparum; Malaria; Mutation; Tetrahydrofolate Dehydrogenase; Drug Combinations; Drug Resistance; Codon
PubMed: 37474966
DOI: 10.1186/s12936-023-04645-9 -
Malaria Journal Jun 2005Malaria has always been a major public health problem in Yemen. Several studies in developing countries have demonstrated ineffective and poor quality drugs including...
BACKGROUND
Malaria has always been a major public health problem in Yemen. Several studies in developing countries have demonstrated ineffective and poor quality drugs including antimalarials. Therefore, quality assessment of antimalarial drugs is of crucial importance. This study aimed to assess the quality of antimalarials (chloroquine and sulfadoxine/pyrimethamine) available in Yemen and to determine whether the quality of these products was related to the level of the distribution chain at which the samples were collected or related to the manufacturers.
METHODS
Four samples from each antimalarial product were collected from each of the various levels of the distribution chain. One sample was kept with the research team. Two were tested at Sana'a and Aden Drug Quality Control Laboratories. The fourth was sent to the Centre for Quality Assurance of Medicines in Potchefstroom, South Africa, for analysis. Quality indicators measured were the content of the active ingredient and dissolution rate (for tablets only) in comparison to standard specifications for these products in the relevant pharmacopoeia.
RESULTS
The results identified several problems of sub-standard products within the drug distribution chain. They included high and low failures in ingredient content for chloroquine tablets and chloroquine syrup. There was some dissolution failure for chloroquine tablets, and high sulfadoxine/pyrimethamine tablets dissolution failures. Failures with the dissolution of the pyrimethamine were found at most of the collection points. No clear relationship neither between the quality products and the level of the distribution chain, nor between locally manufactured and imported products was observed.
CONCLUSION
There are sub-standard antimalarial products circulating within the drug distribution chains in the country, which will have serious implications on the reduced therapeutic effectiveness and on the development of drug resistance. This appears to be due to non-compliance with Good Manufacturing Practice guidelines by manufacturers in the production of the antimalarials.
Topics: Antimalarials; Chloroquine; Dosage Forms; Drug Combinations; Product Surveillance, Postmarketing; Pyrimethamine; Quality Control; Sulfadoxine; Yemen
PubMed: 15987508
DOI: 10.1186/1475-2875-4-28 -
British Journal of Clinical Pharmacology Jun 2004To develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis.
AIMS
To develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis.
METHODS
Children were treated with PYR (1.25 mg kg(-1)) and SDX (25 mg kg(-1)) (Fansidar) plus folinic acid (Lederfoline) 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model.
RESULTS
Eighty-nine children, aged 1 week to 14 years and weighing 2.9-59 kg, were available for evaluation. Both PYR and SDX concentration-time profiles were best described by a one-compartment open model. Volume of plasma distribution (V) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day(-1) and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day(-1) and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half-lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX.
CONCLUSION
This study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low-wight children are probably appropriate.
Topics: Adolescent; Child; Child, Preschool; Chromatography, High Pressure Liquid; Drug Combinations; Female; Humans; Infant; Infant, Newborn; Male; Pyrimethamine; Sulfadoxine; Toxoplasmosis, Congenital
PubMed: 15151519
DOI: 10.1111/j.1365-2125.2004.02077.x -
The American Journal of Tropical... Jul 2002The safety and efficacy of amodiaquine (AQ), sulfadoxine-pyrimethamine (SP), and coadministered AQ+SP was assessed in 351 Tanzanian children (age range, 6-59 months)... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The safety and efficacy of amodiaquine (AQ), sulfadoxine-pyrimethamine (SP), and coadministered AQ+SP was assessed in 351 Tanzanian children (age range, 6-59 months) with uncomplicated Plasmodium falciparum malaria. This open, randomized study followed the 28-day World Health Organization (WHO) protocol and evaluated safety using clinical and laboratory parameters. Children receiving SP were more likely to vomit during follow-up (32% vs. 17%: P = 0.03), and SP alone resulted in prolonged fever clearance times. Although Day 7 and Day 14 clinical and parasitological cure rates were similar, by Day 28 45% of children treated with AQ demonstrated R1 resistance and 27.5% were clinical failures compared with 25% and 6.3%, respectively, for SP alone. Coadministered AQ+SP was safe, combined the greater clinical (96.2%) and parasitological (64.2%) efficacy of SP with the more rapid symptom resolution of AQ, and reduced the incidence of gametocytemia during follow-up (AQ+SP 12.6% vs. SP 29.9%; P = 0.001). The level of R1 resistance to SP may herald a rapid decline in its efficacy as SP drug pressure increases. Coadministration of AQ+SP may delay this.
Topics: Amodiaquine; Animals; Antimalarials; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Treatment Outcome
PubMed: 12363058
DOI: 10.4269/ajtmh.2002.67.17 -
Antimicrobial Agents and Chemotherapy May 2020The continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance...
The continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple I- K / haplotypes, including the A581G and A613S/T mutations, was high at delivery among post-SP treatment isolates (18.2%) compared to those of first antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine [IPTp-SP]; 6.1%; 0.03). Regarding the marker gene, two nonsynonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast Asia. These mutations were predicted to alter the stability of the propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance of additional mutations associated with increased SP resistance as well as emergence of resistance against artemisinin derivatives.
Topics: Animals; Antimalarials; Drug Combinations; Drug Resistance; Female; Ghana; Humans; Malaria, Falciparum; Parasites; Pharmaceutical Preparations; Plasmodium falciparum; Pregnancy; Pregnant Women; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase
PubMed: 32179528
DOI: 10.1128/AAC.02029-19 -
Malaria Journal Nov 2016Intermittent preventive treatment of malaria in pregnancy with 3+ doses of sulfadoxine-pyrimethamine (IPTp-SP) reduces maternal mortality and stillbirths in malaria...
Scaling-up the use of sulfadoxine-pyrimethamine for the preventive treatment of malaria in pregnancy: results and lessons on scalability, costs and programme impact from three local government areas in Sokoto State, Nigeria.
BACKGROUND
Intermittent preventive treatment of malaria in pregnancy with 3+ doses of sulfadoxine-pyrimethamine (IPTp-SP) reduces maternal mortality and stillbirths in malaria endemic areas. Between December 2014 and December 2015, a project to scale up IPTp-SP to all pregnant women was implemented in three local government areas (LGA) of Sokoto State, Nigeria. The intervention included community education and mobilization, household distribution of SP, and community health information systems that reminded mothers of upcoming SP doses. Health facility IPTp-SP distribution continued in three intervention (population 661,606) and one counterfactual (population 167,971) LGAs. During the project lifespan, 31,493 pregnant women were eligible for at least one dose of IPTp-SP.
METHODS
Community and facility data on IPTp-SP distribution were collected in all four LGAs. Data from a subset of 9427 pregnant women, who were followed through 42 days postpartum, were analysed to assess associations between SP dosages and newborn status. Nominal cost and expense data in 2015 Nigerian Naira were obtained from expenditure records on the distribution of SP.
RESULTS
Eighty-two percent (n = 25,841) of eligible women received one or more doses of IPTp-SP. The SP1 coverage was 95% in the intervention LGAs; 26% in the counterfactual. Measurable SP3+ coverage was 45% in the intervention and 0% in the counterfactual LGAs. The mean number of SP doses in the intervention LGAs was 2.1; 0.4 in the counterfactual. Increased doses of IPTp-SP were associated with linear increases in newborn head circumference and lower odds of stillbirth. Any antenatal care utilization predicted larger newborn head circumference and lower odds of stillbirth. The cost of delivering three doses of SP, inclusive of the cost of medicines, was US$0.93-$1.20.
CONCLUSIONS
It is feasible, safe, and affordable to scale up the delivery of high impact IPTp-SP interventions in low resource malaria endemic settings, where few women access facility-based maternal health services. ClinicalTrials.gov Identifier NCT02758353. Registered 29 April 2016, retrospectively registered.
Topics: Adolescent; Adult; Antimalarials; Drug Combinations; Female; Health Care Costs; Humans; Infant, Newborn; Local Government; Malaria; Male; Middle Aged; Nigeria; Pregnancy; Pregnancy Complications, Infectious; Pyrimethamine; Sulfadoxine; Young Adult
PubMed: 27814763
DOI: 10.1186/s12936-016-1578-x -
Antimicrobial Agents and Chemotherapy Dec 2002Artemisinin-derivative combination therapies (ACT) are highly efficacious against multidrug-resistant Plasmodium falciparum malaria. Few efficacy data, however, are... (Clinical Trial)
Clinical Trial
Therapeutic efficacies of artesunate-sulfadoxine-pyrimethamine and chloroquine-sulfadoxine-pyrimethamine in vivax malaria pilot studies: relationship to Plasmodium vivax dhfr mutations.
Artemisinin-derivative combination therapies (ACT) are highly efficacious against multidrug-resistant Plasmodium falciparum malaria. Few efficacy data, however, are available for vivax malaria. With high rates of chloroquine (CQ) resistance in both vivax and falciparum malaria in Papua Province, Indonesia, new combination therapies are required for both species. We recently found artesunate plus sulfadoxine-pyrimethamine (ART-SP) to be highly effective (96%) in the treatment of falciparum malaria in Papua Province. Following a preliminary study of CQ plus sulfadoxine-pyrimethamine (CQ-SP) for the treatment of Plasmodium vivax infection, we used modified World Health Organization criteria to evaluate the efficacy of ART-SP for the treatment of vivax malaria in Papua. Nineteen of 22 patients treated with ART-SP could be evaluated on day 28, with no early treatment failures. Adequate clinical and parasitological responses were found by day 14 in all 20 (100%) of the patients able to be evaluated and by day 28 in 17 patients (89.5%). Fever and parasite clearance times were short, with hematological improvement observed in 70.6% of the patients. Double (at positions 58 and 117) and quadruple (at positions 57, 58, 61, and 117) mutations in the P. vivax dihydrofolate reductase (PvDHFR) were common in Papuan P. vivax isolates (46 and 18%, respectively). Treatment failure with SP-containing regimens was significantly higher with isolates with this PvDHFR quadruple mutation, which included a novel T-->M mutation at residue 61 linked to an S-->T (but not an S-->N) mutation at residue 117. ART-SP ACT resulted in a high cure rate for both major Plasmodium species in Papua, though progression of DHFR mutations in both species due to the continued use of SP monotherapy for clinically diagnosed malaria threatens the future utility of this combination.
Topics: Adolescent; Adult; Animals; Artemisinins; Artesunate; Child; Child, Preschool; Chloroquine; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infant; Malaria, Vivax; Male; Plasmodium vivax; Pyrimethamine; Sesquiterpenes; Sulfadoxine; Tetrahydrofolate Dehydrogenase; Treatment Outcome
PubMed: 12435700
DOI: 10.1128/AAC.46.12.3947-3953.2002 -
Bulletin of the World Health... 1988The study was carried out in 1985-86 in Hainan Island where Plasmodium falciparum is resistant to chloroquine. Fifty cases of falciparum malaria were treated with 1800... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The study was carried out in 1985-86 in Hainan Island where Plasmodium falciparum is resistant to chloroquine. Fifty cases of falciparum malaria were treated with 1800 mg amodiaquine for 3 days: the cure rate was 65.3%, and the mean time to clear fever and asexual parasitaemia was 30.7 and 60.3 hours, respectively; 34.7% of cases showed RI or RII recrudescence, and one patient's temperature did not come down to normal within 7 days.Twenty-one cases were treated with sulfadoxine-pyrimethamine (1500 mg and 75 mg, respectively): 19 were cured, I showed RI and another had an S or RI response; the mean time for fever control was 56.1 hours.Fifty cases were treated with amodiaquine plus sulfadoxine and 49 received amodiaquine plus sulfadoxine-pyrimethamine: the cure rate was 97.9% and 100%, respectively; the mean time for fever clearance was 25.0 and 25.7 hours and for parasite clearance 57.1 and 52.8 hours, respectively. These drug combinations gave much better results for cure and for symptom control than amodiaquine or sulfadoxine-pyrimethamine alone, and may be considered for treatment of chloroquine-resistant falciparum malaria.
Topics: Adolescent; Adult; Amodiaquine; Animals; Antimalarials; Chloroquine; Drug Resistance; Drug Therapy, Combination; Female; Humans; Malaria; Male; Plasmodium falciparum; Pyrimethamine; Sulfadoxine
PubMed: 3048759
DOI: No ID Found -
Bulletin of the World Health... 1988A randomized study on the effect of the following four treatment regimens on Plasmodium falciparum parasitaemia was carried out on 200 asymptomatic schoolchildren in... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A randomized study on the effect of the following four treatment regimens on Plasmodium falciparum parasitaemia was carried out on 200 asymptomatic schoolchildren in Maputo, Mozambique: chloroquine (25 mg/kg body weight), amodiaquine (25 mg/kg), sulfadoxine-pyrimethamine (25 mg/kg and 1.25 mg/kg), or amodiaquine (25 mg/kg) + sulfadoxine-pyrimethamine (25 mg/kg and 1.25 mg/kg) administered on the third day of the study. The results of in vivo tests indicated that 94% of the infections were resistant to chloroquine, 76% to amodiaquine, and 16% to sulfadoxine-pyrimethamine. The cure rate with amodiaquine + sulfadoxine-pyrimethamine was 100%, which was not significantly different from that with sulfadoxine-pyrimethamine alone; the latter regimen was the most rapidly acting of the treatments studied. It is concluded that amodiaquine is not an appropriate substitute for chloroquine, but that the effect of the combination amodiaquine + sulfadoxine-pyrimethamine may be superior to that of sulfadoxine-pyrimethamine alone, although this requires further study.
Topics: Amodiaquine; Animals; Antimalarials; Child; Chloroquine; Drug Resistance; Drug Therapy, Combination; Humans; Malaria; Mozambique; Plasmodium falciparum; Pyrimethamine; Sulfadoxine
PubMed: 3293827
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Sep 2005Sulfadoxine-pyrimethamine (SP) has been widely used in recent years to treat acute uncomplicated Plasmodium falciparum malaria. Risk factors for SP therapeutic failure...
Sulfadoxine-pyrimethamine (SP) has been widely used in recent years to treat acute uncomplicated Plasmodium falciparum malaria. Risk factors for SP therapeutic failure include young age, subtherapeutic SP concentrations, and resistance-conferring genetic mutations in parasite target enzymes. A substantial proportion of patients are able to clear genetically highly resistant P. falciparum genotypes. To determine whether blood SP concentrations independently affect the patient's ability to clear resistant genotypes, we compared SP pharmacokinetics of cases of adequate clinical and parasitological response (ACPR) with cases of treatment failure (TF). When patients with ACPR and TF were compared, mean values were similar for the day 3 blood pyrimethamine (205 ng/ml versus 172 ng/ml; P = 0.25) and estimated maximum sulfadoxine (79 +/- 6.52 versus 69 +/- 6.27 mug/ml; P = 0.60) concentrations, for sulfadoxine terminal-phase elimination half-lives (7.15 versus 6.41 days; P = 0.42), and for the extents of sulfadoxine absorption (areas under the concentration-time curve of 932 +/- 100 versus 888 +/- 78.9 mug day ml(-1); P = 0.72). Among patients infected with the quintuple resistant parasites, day 3 blood pyrimethamine concentrations were higher in those who cleared the infection than in those who did not (305 +/- 35.4 versus 228 +/- 21.7 ng/ml; P = 0.037). Within this subgroup, this finding remained significant after adjusting for endogenous folate levels, age, site, and resistance-conferring mutations (odds ratio: 1.011 [1.003 to 1.024]; P = 0.018). However, as a subgroup analysis, our biologically plausible observation that higher blood pyrimethamine concentrations enhance the ability of patients to clear resistant P. falciparum should be interpreted with caution and needs further validation.
Topics: Animals; Antimalarials; Child; Child, Preschool; Drug Combinations; Drug Resistance; Female; Genotype; Humans; Infant; Malaria, Falciparum; Malawi; Male; Multivariate Analysis; Mutation; Plasmodium falciparum; Pyrimethamine; Reverse Transcriptase Polymerase Chain Reaction; Sulfadoxine; Treatment Failure; Treatment Outcome
PubMed: 16127028
DOI: 10.1128/AAC.49.9.3601-3606.2005