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Journal of Vector Borne Diseases 2023The utilization of Intermittent Preventive Treatment (sulphadoxine-pyrimethamine) in pregnancy (IPTp-SP) for combating malaria has indicated control over adverse birth...
BACKGROUND & OBJECTIVES
The utilization of Intermittent Preventive Treatment (sulphadoxine-pyrimethamine) in pregnancy (IPTp-SP) for combating malaria has indicated control over adverse birth outcomes and has been recommended for use by pregnant women. The aim of this study was to determine the effectiveness of IPTp-SP on maternal, neonatal and placental malaria in Port Harcourt, Nigeria.
METHODS
316 samples of maternal peripheral blood (MPB), placental blood (PLB), neonatal cord blood (NCB) and placental tissue (PT) were collected each from consenting mothers. Blood samples were processed and stained by the Giemsa method. Placental tissues were processed and stained in haematoxylin. Examination of samples for malaria parasitaemia was carried out using standard parasitological methods. Demography of participants was collected through questionnaires and from ante natal care (ANC) records.
RESULTS
Overall prevalence of 74 (23.42%) was recorded. Age-related prevalence indicated that ≤ 20 years, 9 (56.25%) had the highest prevalence followed by 21-30 years (23.48%), and ≥41 years (16.67%) (p <0.05). Malaria in MPB showed that SP-users had 26 (13.20%) while non-users had 48 (40.33%) (p <0.05). In NCB, SP-users recorded 20 (10.15%) while non-users had 13 (10.92) (p>0.05). The prevalence in PLB and PT revealed that SP-users had a lower prevalence in PLB, 31 (15.73%) and PT, 12 (6.09%) while non-users recorded a higher prevalence 48 (40.33%) in PLB and 21 (17.65%) in PT (P<0.05).
INTERPRETATION & CONCLUSION
The utilization of IPTp-SP is seen to significantly reduce the occurrence of malaria in pregnancy, placental tissue and in neonates thereby helping in improving birth outcomes.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Young Adult; Adult; Antimalarials; Nigeria; Placenta; Pregnancy Complications, Parasitic; Pyrimethamine; Sulfadoxine; Malaria; Drug Combinations
PubMed: 37843239
DOI: 10.4103/0972-9062.374243 -
Microbiology Spectrum Oct 2022Sulfadoxine-pyrimethamine (SP) resistance impairs the efficacy of antimalarial drugs. Monitoring molecular markers in exported malaria infections provides an efficient...
Molecular Determinants of Sulfadoxine-Pyrimethamine Resistance in Plasmodium falciparum Isolates from Central Africa between 2016 and 2021: Wide Geographic Spread of Highly Mutated and Alleles.
Sulfadoxine-pyrimethamine (SP) resistance impairs the efficacy of antimalarial drugs. Monitoring molecular markers in exported malaria infections provides an efficient way to trace the emergence of drug resistance in countries where malaria is endemic. Molecular markers in and of 237 Plasmodium falciparum infections imported from central Africa between 2016 and 2021 were detected. The spatial and temporal distributions of and mutations were analyzed. A high prevalence of single-nucleotide polymorphisms (SNPs) (~92.34% to 99.10%) and a high frequency of the triple mutation haplotype were observed. Cameroon, Equatorial Guinea, and Gabon showed a higher frequency (~96.61% to 100.00%) of than other countries (~71.11% to 88.10%). The prevalence of C59R and increased while that of other SNPs or haplotypes did not fluctuate greatly from 2016 to 2021. Large proportions of SNPs (A437G and K540E) were demonstrated. The SNP distribution of differed between countries, with S436A dominating in northern countries and A437G dominating in others. The proportions of I431V, A437G, and the triple mutant haplotype declined between 2016 and 2021, whereas the prevalence of the single mutant haplotype rose from 61.60% to 73.68%. Combinations of - alleles conferring partial resistance, full resistance, and superresistance to SP, as defined in the text, were detected in 63.64%, 8.64%, and 0.91% of the samples, respectively. The octuple - allele (-K) was seen in 5.00% of the samples. We demonstrated the wide geographic spread and increasing trends in highly SP-resistant genes and varying spatial patterns of mutants across countries in central Africa. The high prevalences of partially resistant, fully resistant, and superresistant combinations observed here indicated impaired SP efficacy. Increased molecular surveillance is required to monitor the changing status of the and genes. Monitoring drug resistance is important for malaria control because its early detection enables timely action to prevent its spread and mitigate its impact. The wide geographic spread and the increasing trend of highly resistant genes between 2016 and 2021 found in our study are worrisome and emphasize the urgency to monitor their updated status in central Africa. This study also illustrated the wide spread of the novel mutant I431V as well as the high prevalence of "partially resistant," "fully resistant," and "superresistant" - combinations, indicating the urgent concern for SP efficacy in central Africa. These findings are alarming in central African countries where malaria is endemic, where SP was is widely used for the intermittent preventive treatment of malaria in pregnancy (IPTp) and the intermittent preventive treatment of malaria in infants below 5 years of age (IPTi), and urge enhanced molecular surveillance and responses to the threat of drug resistance.
Topics: Humans; Africa, Central; Alleles; Antimalarials; Drug Resistance; Malaria, Falciparum; Mutation; Plasmodium falciparum; Protozoan Proteins
PubMed: 36121226
DOI: 10.1128/spectrum.02005-22 -
The Journal of Infectious Diseases Feb 2022The Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria...
BACKGROUND
The Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria chemoprevention, but drug resistance challenges their efficacies. A new compound, P218, was designed to overcome resistance, but drug-susceptibility data for P falciparum field isolates are limited.
METHODS
We studied ex vivo PfDHFR inhibitor susceptibilities of 559 isolates from Tororo and Busia districts, Uganda, from 2016 to 2020, sequenced 383 isolates, and assessed associations between genotypes and drug-susceptibility phenotypes.
RESULTS
Median half-maximal inhibitory concentrations (IC50s) were 42 100 nM for pyrimethamine, 1200 nM for cycloguanil, 13000 nM for proguanil, and 0.6 nM for P218. Among sequenced isolates, 3 PfDHFR mutations, 51I (100%), 59R (93.7%), and 108N (100%), were very common, as previously seen in Uganda, and another mutation, 164L (12.8%), had moderate prevalence. Increasing numbers of mutations were associated with decreasing susceptibility to pyrimethamine, cycloguanil, and P218, but not proguanil, which does not act directly against PfDHFR. Differences in P218 susceptibilities were modest, with median IC50s of 1.4 nM for parasites with mixed genotype at position 164 and 5.7 nM for pure quadruple mutant (51I/59R/108N/164L) parasites.
CONCLUSIONS
Resistance-mediating PfDHFR mutations were common in Ugandan isolates, but P218 retained excellent activity against mutant parasites.
Topics: Antimalarials; Drug Resistance; Folic Acid Antagonists; Humans; Malaria, Falciparum; Plasmodium falciparum; Polymorphism, Genetic; Proguanil; Pyrimethamine; Tetrahydrofolate Dehydrogenase; Uganda
PubMed: 34460932
DOI: 10.1093/infdis/jiab435 -
Pharmacological Research Aug 2019Malaria affects 200 million people worldwide. Today, the most successful treatments are artemisinin-based combination therapies (ACT). Resistance has already been...
Malaria affects 200 million people worldwide. Today, the most successful treatments are artemisinin-based combination therapies (ACT). Resistance has already been described for the elder anti-malarials chloroquine, sulfadoxine-pyrimethamine and mefloquine. Unfortunately, over the last few years there has also been an emerging resistance to the successfully used drug artemisinin, especially in African and Asian countries. A systematic PubMed literature research was conducted for studies published between January 2002 and December 2018. Despite ACTs continue to be first line treatment, the number of studies is rising reporting on artemisinin resistance mutations. Most publications reported on kelch13 mutations (45 studies), the second most frequent mutations were found in pfmdr1 (32 studies). PfATPase6 mutations have been mainly studied in Asian countries (4 of 6 studies). Bearing this in mind, there is a pressing need to further examine the role and spread of mutations conferring artemisinin resistance. A further decline of treatment efficacy could result in increased rates of malaria-related deaths.
Topics: Animals; Antimalarials; Artemisinins; Drug Resistance; Humans; Malaria; Mutation; Polymorphism, Genetic
PubMed: 31100335
DOI: 10.1016/j.phrs.2019.104275 -
Malaria Journal Aug 2020Artesunate plus sulfadoxine-pyrimethamine (ASP) is first-line treatment for uncomplicated Plasmodium falciparum malaria in most of India, except for six North-eastern...
Stable high frequencies of sulfadoxine-pyrimethamine resistance associated mutations and absence of K13 mutations in Plasmodium falciparum 3 and 4 years after the introduction of artesunate plus sulfadoxine-pyrimethamine in Ujjain, Madhya Pradesh, India.
BACKGROUND
Artesunate plus sulfadoxine-pyrimethamine (ASP) is first-line treatment for uncomplicated Plasmodium falciparum malaria in most of India, except for six North-eastern provinces where treatment failure rates were high. In Ujjain, central India, the frequency of mutations associated with increased drug tolerance, but not overt resistance to sulfadoxine and pyrimethamine were 9% and > 80%, respectively, in 2009 and 2010, just prior to the introduction of ASP. The frequency of drug resistance associated mutations in Ujjain in 2015-2016 after 3-4 years of ASP use, are reported.
METHODS
Blood samples from patients with P. falciparum mono-infection verified by microscopy were collected on filter-paper at all nine major pathology laboratories in Ujjain city. Codons pfdhfr 16-185, pfdhps 436-632 and K13 407-689 were identified by sequencing. Pfcrt K76T and pfmdr1 N86Y were identified by restriction fragment length polymorphism.
RESULTS
Sulfadoxine-pyrimethamine resistance-associated pfdhfr 108 N and 59R alleles were found in 100/104 (96%) and 87/91 (96%) samples, respectively. Pfdhps 437G was found in 10/105 (10%) samples. Double mutant pfdhfr 59R + 108 N were found in 75/81 (93%) samples. Triple mutant pfdhfr 59R + 108 N and pfdhps 437G were found in 6/78 (8%) samples. Chloroquine-resistance-associated pfcrt 76T was found in 102/102 (100%). Pfmdr1 N86 and 86Y were identified in 83/115 (72%) and 32/115 (28%) samples, respectively.
CONCLUSION
The frequency of P. falciparum with reduced susceptibility to sulfadoxine-pyrimethamine remained high, but did not appear to have increased significantly since the introduction of ASP. No polymorphisms in K13 associated with decreased artemisinin susceptibility were found. ASP probably remained effective, supporting continued ASP use.
Topics: Adolescent; Adult; Aged; Antimalarials; Artesunate; Child; Child, Preschool; Drug Combinations; Drug Resistance; Humans; India; Infant; Malaria, Falciparum; Middle Aged; Mutation; Plasmodium falciparum; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Young Adult
PubMed: 32795288
DOI: 10.1186/s12936-020-03274-w -
Clinical Pharmacology and Therapeutics Sep 2022Endogenous biomarkers for transporter-mediated drug-drug interaction (DDI) predictions represent a promising approach to facilitate and improve conventional DDI...
Endogenous biomarkers for transporter-mediated drug-drug interaction (DDI) predictions represent a promising approach to facilitate and improve conventional DDI investigations in clinical studies. This approach requires high sensitivity and specificity of biomarkers for the targets of interest (e.g., transport proteins), as well as rigorous characterization of their kinetics, which can be accomplished utilizing physiologically-based pharmacokinetic (PBPK) modeling. Therefore, the objective of this study was to develop PBPK models of the endogenous organic cation transporter (OCT)2 and multidrug and toxin extrusion protein (MATE)1 substrates creatinine and N -methylnicotinamide (NMN). Additionally, this study aimed to predict kinetic changes of the biomarkers during administration of the OCT2 and MATE1 perpetrator drugs trimethoprim, pyrimethamine, and cimetidine. Whole-body PBPK models of creatinine and NMN were developed utilizing studies investigating creatinine or NMN exogenous administration and endogenous synthesis. The newly developed models accurately describe and predict observed plasma concentration-time profiles and urinary excretion of both biomarkers. Subsequently, models were coupled to the previously built and evaluated perpetrator models of trimethoprim, pyrimethamine, and cimetidine for interaction predictions. Increased creatinine plasma concentrations and decreased urinary excretion during the drug-biomarker interactions with trimethoprim, pyrimethamine, and cimetidine were well-described. An additional inhibition of NMN synthesis by trimethoprim and pyrimethamine was hypothesized, improving NMN plasma and urine interaction predictions. To summarize, whole-body PBPK models of creatinine and NMN were built and evaluated to better assess creatinine and NMN kinetics while uncovering knowledge gaps for future research. The models can support investigations of renal transporter-mediated DDIs during drug development.
Topics: Biomarkers; Cimetidine; Creatinine; Drug Interactions; Humans; Organic Cation Transport Proteins; Pharmaceutical Preparations; Pyrimethamine; Trimethoprim
PubMed: 35527512
DOI: 10.1002/cpt.2636 -
Journal of Analytical Methods in... 2022Falsified drugs are of serious concern to public health worldwide, particularly for developing countries where quality control of drugs is inefficient. In law...
Falsified drugs are of serious concern to public health worldwide, particularly for developing countries where quality control of drugs is inefficient. In law enforcement against such fake medicines, there is a need to develop reliable, fast, and inexpensive screening methods. In this work, the ability of an innovative low-cost handheld near-infrared spectrometer to identify falsifications among two antimalarial fixed dose combination tablets, dihydroartemisinin/piperaquine and sulfadoxine/pyrimethamine, has been investigated. Analyzed samples were collected in Burkina Faso mainly in rural transborder areas that could be infiltrated by illicit drugs. A principal component analysis was applied on the acquired near-infrared spectra to identify trends, similarities, and differences between collected samples. This allowed to detect some samples of dihydroartemisinin/piperaquine and sulfadoxine/pyrimethamine which seemed to be falsified. These suspicious samples were semiquantitatively analyzed by thin-layer chromatography using Minalab® kits. Obtained results allowed to confirm the falsifications since the suspected samples did not contain any of the expected active pharmaceutical ingredients. The capacity of the low-cost near-infrared device to identify specifically a brand name of dihydroartemisinin/piperaquine or sulfadoxine/pyrimethamine has been also studied using soft independent modelling of class analogy (SIMCA) in the classical and data driven versions. The built models allowed a clear brand identification with 100% of both sensitivity and specificity in the studied cases. All these results demonstrate the potential of these low-cost near-infrared spectrometers to be used as first line screening tools, particularly in resource limited laboratories, for the detection of falsified antimalarial drugs.
PubMed: 35558651
DOI: 10.1155/2022/5335936 -
Iranian Journal of Parasitology 2021One of the main obstacles to malaria control in the world has been the emergence of resistance in to chloroquine and other anti-malarial drugs. This study aimed to... (Review)
Review
BACKGROUND
One of the main obstacles to malaria control in the world has been the emergence of resistance in to chloroquine and other anti-malarial drugs. This study aimed to review studies in Iran on resistance in and to drugs, and to reveal the mechanisms and molecular markers of resistance of these two species.
METHODS
The databases of PubMed, Scopus, Google Scholar, Magiran, and reputable Iranian journals were searched to find published studies on the resistance in and to antimalarial drugs in Iran.
RESULTS
There is a significant relationship between resistance to chloroquine in and the emergence of K76T mutation in the chloroquine-resistance transporter gene in Iran. Resistance to sulfadoxine-pyrimethamine (SP) in is also significantly associated with the development of mutations in the dihydrofolate reductase and dihydropteroate synthase genes. Resistance to chloroquine in has not been reported in Iran and it is used as a first-line treatment for malaria.
CONCLUSION
has become resistant to chloroquine in different regions of Iran and is not currently used to treat malaria Besides, cases have emerged of resistance to SP in different parts of southern Iran, and SP is not administered alone for treating .
PubMed: 34557232
DOI: 10.18502/ijpa.v16i2.6265 -
BMJ Global Health Apr 2023Coverage of antenatal iron and folic acid (IFA) supplementation and malaria chemoprophylaxis remains low in many low-income and middle-income settings. We assessed the... (Randomized Controlled Trial)
Randomized Controlled Trial
Improving coverage of antenatal iron and folic acid supplementation and malaria prophylaxis through targeted information and home deliveries in Côte d'Ivoire: a cluster randomised controlled trial.
INTRODUCTION
Coverage of antenatal iron and folic acid (IFA) supplementation and malaria chemoprophylaxis remains low in many low-income and middle-income settings. We assessed the effectiveness of personal information (INFO) sessions and personal information session plus home deliveries (INFO+DELIV) to increase coverage of IFA supplementation and intermittent preventive treatment in pregnancy (IPTp), and their effectiveness on postpartum anaemia and malaria infection.
METHODS
We included 118 clusters randomised to a control (39), INFO (39) and INFO+DELIV (40) arm, in a trial conducted between 2020 and 2021 with pregnant women (age ≥15 years) in their first or second trimester of pregnancy in Taabo, Côte d'Ivoire. We used generalised linear regression models to assess intervention impact in postpartum anaemia and malaria parasitaemia, and displayed resulting estimates as prevalence ratios.
RESULTS
Overall, 767 pregnant women were enrolled and 716 (93.3%) were followed up after delivery. Neither intervention had an impact on postpartum anaemia, with estimated adjusted prevalence ratios (aPRs) of 0.97 (95% CI 0.79 to 1.19, p=0.770) for INFO and 0.87 (95% CI 0.70 to 1.09, p=0.235) for INFO+DELIV. While INFO had no effect on malaria parasitaemia (aPR=0.95, 95% CI 0.39 to 2.31, p=0.915), INFO+DELIV reduced malaria parasitaemia by 83% (aPR=0.17, 95% CI 0.04 to 0.75, p=0.019). No improvements in antenatal care (ANC) coverage (aPR=1.05, 95% CI 0.81 to 1.36, p=0.692), IFA (aPR=2.00, 95% CI 0.89 to 4.46, p=0.093) and IPTp (aPR=1.03, 95% CI 0.87 to 1.21, p=0.728) compliance were found for INFO. INFO+DELIV increased ANC attendance (aPR=1.35, 95% CI 1.02 to 1.78, p=0.037) and compliance with IPTp (aPR=1.60, 95% CI 1.41 to 1.80, p<0.001) and IFA recommendations (aPR=7.06, 95% CI 3.68 to 13.51, p<0.001).
CONCLUSIONS
INFO+DELIV can substantially increase compliance with IFA supplementation and improve malaria prevention. However, the increases in IFA supplementation are likely insufficient to address the prevalence of often severe anaemia in this population.
TRIAL REGISTRATION NUMBER
NCT04250428.
Topics: Pregnancy; Female; Humans; Adolescent; Sulfadoxine; Pyrimethamine; Iron; Cote d'Ivoire; Drug Combinations; Malaria; Folic Acid; Anemia; Dietary Supplements
PubMed: 37076197
DOI: 10.1136/bmjgh-2022-010934 -
Current Medicinal Chemistry 2023Microwave radiation is used as a heating source during the synthesis of heterocyclic compounds. The heating mechanisms involved in microwave-induced synthesis include... (Review)
Review
Microwave radiation is used as a heating source during the synthesis of heterocyclic compounds. The heating mechanisms involved in microwave-induced synthesis include dipolar polarization and ionic conduction. This heating technology follows the green protocol as it involves the use of recyclable organic solvents during synthesis. The microwave heating approach offers a faster rate of reaction, easier work-up procedure, and higher product yield with purity and also reduces environmental pollution. So, microwave heating is applied as a sustainable technology for the efficient production of pyrimidine compounds as one of the heterocyclic moieties. Pyrimidine is a six-membered nitrogenous heterocyclic compound that plays a significant role due to several therapeutic applications. This moiety acts as an essential building block for generating drug candidates with diverse biological activities, including anti-cancer (capecitabine), anti-thyroid (propylthiouracil), antihistaminic (pemirolast), antimalarial (pyrimethamine), antidiabetic (alloxan), antihypertensive (minoxidil), anti-inflammatory (octotiamine), antifungal (cyprodinil), antibacterial (sulfamethazine), etc. This review is focused on the synthesis of pyrimidine analogs under microwave irradiation technique and the study of their therapeutic potentials.
Topics: Humans; Microwaves; Pyrimidines; Heterocyclic Compounds; Technology
PubMed: 35733315
DOI: 10.2174/0929867329666220622150013