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Compliance With Guidelines on Seasonal Malaria Chemoprevention in Kwara State, Northcentral Nigeria.West African Journal of Medicine Jan 2024Seasonal malaria chemoprevention (SMC) is an effective strategy for reducing malaria morbidity and mortality in children aged 3-59 months in areas with seasonal malaria...
BACKGROUND
Seasonal malaria chemoprevention (SMC) is an effective strategy for reducing malaria morbidity and mortality in children aged 3-59 months in areas with seasonal malaria transmission. Sulphadoxine-pyrimethamine plus amodiaquine is given to an eligible child at monthly intervals during the peak malaria transmission season. The aim of this study was to determine the level of compliance with SMC guidelines by community drug distributors during SMC implementation in Kwara State.
METHOD
Caregivers of eligible children from six Local Government Areas were interviewed using a structured questionnaire on the KoboCollect app downloaded on hand-held android devices. The questionnaire was composed of questions on caregiver's demographics, SMC drug administration, and adherence to SMC protocol.
RESULTS
A total of 1,314 caregivers were interviewed, most of them were female 1076 (81.9%), married 1200 (91.3%) and literate 795 (60.5%). The mean SMC coverage for the 4 cycles was 1183(88.5%). SMC information was received by 1166 (88.7%) of caregivers. Most of the caregivers 1166 (88.7%) heard about SMC. Overall, SPAQ administration was directly observed in most cases 1169 (91.5%), second dose was given 1226 (96.0%) and drugs were fully ingested 1140(89.3%). Poor compliance was observed in home visits by lead mothers 988 (77.4%). The report of adverse drug reactions was low 132 (10.3% [95% CI: 8.8-12.3%]), the commonest being severe vomiting 50 (37.9%). There were significant (P<0.05) variations in SMC implementation across the 6 LGAs in virtually all the performance indicators. SPAQ administration to over-age children was low 128 (10.0%).
CONCLUSION
Overall, the compliance with SMC implementation guidelines in Kwara state was good though significant differences in performance were observed across the six LGAs. Home visits by lead mothers were generally poor. The self-reported coverage of SMC by caregivers was commendable.
Topics: Child; Female; Humans; Infant; Male; Antimalarials; Seasons; Nigeria; Malaria; Chemoprevention
PubMed: 38412205
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Apr 2024Malaria remains a leading cause of morbidity and mortality in Burkina Faso, which utilizes artemether-lumefantrine as the principal therapy to treat uncomplicated...
Malaria remains a leading cause of morbidity and mortality in Burkina Faso, which utilizes artemether-lumefantrine as the principal therapy to treat uncomplicated malaria and seasonal malaria chemoprevention with monthly sulfadoxine-pyrimethamine plus amodiaquine in children during the transmission season. Monitoring the activities of available antimalarial drugs is a high priority. We assessed the susceptibility of to 11 drugs in isolates from patients presenting with uncomplicated malaria in Bobo-Dioulasso in 2021 and 2022. IC values were derived using a standard 72 h growth inhibition assay. Parasite DNA was sequenced to characterize known drug resistance-mediating polymorphisms. Isolates were generally susceptible, with IC values in the low-nM range, to chloroquine (median IC10 nM, IQR 7.9-24), monodesethylamodiaquine (22, 14-46) piperaquine (6.1, 3.6-9.2), pyronaridine (3.0, 1.3-5.5), quinine (50, 30-75), mefloquine (7.1, 3.7-10), lumefantrine (7.1, 4.5-12), dihydroartemisinin (3.7, 2.2-5.5), and atovaquone (0.2, 0.1-0.3) and mostly resistant to cycloguanil (850, 543-1,290) and pyrimethamine (33,200, 18,400-54,200), although a small number of outliers were seen. Considering genetic markers of resistance to aminoquinolines, most samples had wild-type PfCRT K76T (87%) and PfMDR1 N86Y (95%) sequences. For markers of resistance to antifolates, established PfDHFR and PfDHPS mutations were highly prevalent, the PfDHPS A613S mutation was seen in 19% of samples, and key markers of high-level resistance (PfDHFR I164L; PfDHPS K540E) were absent or rare (A581G). Mutations in the PfK13 propeller domain known to mediate artemisinin partial resistance were not detected. Overall, our results suggest excellent susceptibilities to drugs now used to treat malaria and moderate, but stable, resistance to antifolates used to prevent malaria.
Topics: Child; Humans; Antimalarials; Plasmodium falciparum; Malaria, Falciparum; Artemether, Lumefantrine Drug Combination; Folic Acid Antagonists; Burkina Faso; Artemether; Pyrimethamine; Malaria; Lumefantrine; Drug Combinations; Polymorphism, Genetic; Drug Resistance; Protozoan Proteins
PubMed: 38411062
DOI: 10.1128/aac.01534-23 -
Cureus Jan 2024Introduction Congenital toxoplasmosis (CT), despite being mostly subclinical at birth, can cause disabling disease in the fetus and lead to long-term sequelae. It is an...
Introduction Congenital toxoplasmosis (CT), despite being mostly subclinical at birth, can cause disabling disease in the fetus and lead to long-term sequelae. It is an important cause of chorioretinitis in infants and adolescents. Data on postnatal treatment are controversial, and there is a lack of universal guidelines. Methods A cross-sectional study of newborns with suspected CT was conducted between January 2007 and December 2021. Results Seventy-one patients with suspected CT were included. During pregnancy, 64 (90.1%) of the mothers underwent therapy, of which 59 (83.1%) with spiramycin. Amniocentesis identified one positive polymerase chain reaction assay. Most newborns were asymptomatic with normal laboratory, ophthalmological, and hearing screening. There was one case of hyperproteinorrachia. Fifty-seven patients (80.3%) started treatment: 42 (73.7%) with spiramycin, seven (12.3%) with pyrimethamine, sulfadiazine, and folinic acid (P+S+FA), and eight (14%) with P+S+FA intercalated with spiramycin. Adverse effects were found in 11 (19.3%) cases, mainly neutropenia. After investigation, we found three confirmed CT cases corresponding to 4.2% of suspected cases and an incidence of 0.4 per 10,000 births. All had normal clinical and laboratory exams in the neonatal period and started P+S+FA, fulfilling 12 months of therapy. During the follow-up, all presented normal psychomotor development without any long-term sequelae. Conclusion The lower incidence in our study, compared to the incidence in Europe, may be related to the decline in the prevalence of toxoplasmosis as well as the effectiveness of measures to prevent primary infection and a well-established program of antenatal screening, followed by the early initiation of treatment during pregnancy to prevent vertical transmission.
PubMed: 38406029
DOI: 10.7759/cureus.52971 -
RSC Advances Feb 2024The current work is about the modification of primary amine functionalized drugs, pyrimethamine and 4-amino--(2,3-dihydrothiazol-2-yl)benzenesulfonamide, condensation...
A synthetic approach towards drug modification: 2-hydroxy-1-naphthaldehyde based imine-zwitterion preparation, single-crystal study, Hirshfeld surface analysis, and computational investigation.
The current work is about the modification of primary amine functionalized drugs, pyrimethamine and 4-amino--(2,3-dihydrothiazol-2-yl)benzenesulfonamide, condensation reaction with 2-hydroxy-1-naphthaldehyde to produce new organic zwitterionic compounds ()-1-(((4-(-(2,3-dihydrothiazol-2-yl)sulfamoyl)phenyl)iminio)methyl)naphthalen-2-olate (DSPIN) and ()-1-(((4-amino-5-(4-chlorophenyl)-6-ethylpyrimidin-2-yl)iminio)methyl)naphthalen-2-olate (ACPIN) in methanol as a solvent. The crystal structures of both compounds were confirmed to be imine-based zwitterionic products single-crystal X-ray diffraction (SC-XRD) analysis which indicated that the stabilization of both crystalline compounds is achieved various noncovalent interactions. The supramolecular assembly in terms of noncovalent interactions was explored by the Hirshfeld surface analysis. Void analysis was carried out to predict the crystal mechanical response. Compound geometries calculated in the DFT (Density Functional Theory) study showed reasonably good agreement with the experimentally determined structural parameters. Frontier molecular orbital (FMO) analysis showed that the DSPIN HOMO/LUMO gap is by 0.15 eV smaller than the ACPIN HOMO/LUMO gap due to some destabilization of the DSPIN HOMO and some stabilization of its LUMO. The results of the charge analysis implied formation of intramolecular hydrogen bonds and suggested formation of intermolecular hydrogen bonding and dipole-dipole and dispersion interactions.
PubMed: 38390507
DOI: 10.1039/d3ra08727a -
RSC Medicinal Chemistry Feb 2024The emergence of drug resistance against the frontline antimalarials is a major challenge in the treatment of malaria. In view of emerging reports on drug-resistant...
The emergence of drug resistance against the frontline antimalarials is a major challenge in the treatment of malaria. In view of emerging reports on drug-resistant strains of against artemisinin combination therapy, a dire need is felt for the discovery of novel compounds acting against novel targets in the parasite. In this study, we identified a novel series of quinolinepiperazinyl-aryltetrazoles (QPTs) targeting the blood stage of . anti-plasmodial activity screening revealed that most of the compounds showed IC < 10 μM against chloroquine-resistant INDO strain, with the most promising lead compounds 66 and 75 showing IC values of 2.25 and 1.79 μM, respectively. Further, compounds 64-66, 68, 75-77 and 84 were found to be selective (selectivity index >50) in their action against over a mammalian cell line, with compounds 66 and 75 offering the highest selectivity indexes of 178 and 223, respectively. Explorations into the action of lead compounds 66 and 75 revealed their selective cidal activity towards trophozoites and schizonts. In a ring-stage survival assay, 75 showed cidal activity against the early rings of artemisinin-resistant Cam3.1. Further, 66 and 75 in combination with artemisinin and pyrimethamine showed additive to weak synergistic interactions. Of these two lead molecules, only 66 restricted rise in the percentage of parasitemia to about 10% in -infected mice with a median survival time of 28 days as compared to the untreated control, which showed the percentage of parasitemia >30%, and a median survival of 20 days. Promising antimalarial activity, high selectivity, and additive interaction with artemisinin and pyrimethamine indicate the potential of these compounds to be further optimized chemically as future drug candidates against malaria.
PubMed: 38389888
DOI: 10.1039/d3md00417a -
MedRxiv : the Preprint Server For... Feb 2024Genomic surveillance plays a critical role in monitoring malaria transmission and understanding how the parasite adapts in response to interventions. We conducted...
Genomic surveillance plays a critical role in monitoring malaria transmission and understanding how the parasite adapts in response to interventions. We conducted genomic surveillance of malaria by sequencing 241 genomes from regions with varying levels of malaria transmission across Zambia. We found genomic evidence of high levels of within-host polygenomic infections, regardless of epidemiological characteristics, underscoring the extensive and ongoing endemic malaria transmission in the country. We identified country-level clustering of parasites from Zambia and neighboring countries, and distinct clustering of parasites from West Africa. Within Zambia, our identity by descent (IBD) relatedness analysis uncovered spatial clustering of closely related parasite pairs at the local level and rare cases of long-distance sharing. Genomic regions with large shared IBD segments and strong positive selection signatures identified genes involved in sulfadoxine-pyrimethamine and artemisinin combination therapies drug resistance, but no signature related to chloroquine resistance. Together, our findings enhance our understanding of transmission nationwide in Zambia and highlight the urgency of strengthening malaria control programs and surveillance of antimalarial drug resistance.
PubMed: 38370674
DOI: 10.1101/2024.02.09.24302570 -
Scientific Reports Feb 2024We explored whether isotope ratio mass spectrometry (IRMS) is useful to investigate the origin of falsified antimalarials. Forty-four falsified and genuine antimalarial...
We explored whether isotope ratio mass spectrometry (IRMS) is useful to investigate the origin of falsified antimalarials. Forty-four falsified and genuine antimalarial samples (artesunate, artemether-lumefantrine, dihydroartemisinin-piperaquine and sulphamethopyrazine-pyrimethamine) were analyzed in bulk for carbon (C), nitrogen (N), and oxygen (O) element concentrations and stable isotope ratios. The insoluble fraction ("starch") was extracted from 26 samples and analyzed. Samples of known geographical origin maize, a common source of excipient starch, were used to produce a comparison dataset to predict starch source. In both an initial (n = 18) and a follow-on set of samples that contained/claimed to contain artesunate/artemether (n = 26), falsified antimalarials had a range of C concentrations less than genuine comparator antimalarials and δC values higher than genuine comparators. The δC values of falsified antimalarials suggested that C plant-based organic material (e.g., starch derived from maize) had been included. Using the known-origin maize samples, predictions for growth water δO values for the extracted "starch" ranged from - 6.10 to - 1.62‰. These findings suggest that IRMS may be a useful tool for profiling falsified antimalarials. We found that C ingredients were exclusively used in falsified antimalarials versus genuine antimalarials, and that it may be possible to predict potential growth water δO values for the starch present in falsified antimalarials.
Topics: Antimalarials; Artesunate; Pilot Projects; Artemether; Artemether, Lumefantrine Drug Combination; Mass Spectrometry; Isotopes; Starch; Water
PubMed: 38369604
DOI: 10.1038/s41598-024-54168-9 -
The Lancet. Global Health Mar 2024Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on...
BACKGROUND
Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on the administration of sulfadoxine-pyrimethamine plus amodiaquine. However, poor regimen adherence and the increased frequency of parasite mutations conferring sulfadoxine-pyrimethamine resistance might threaten the effectiveness of SMC. Guidance is needed to de-risk the development of drug compounds for malaria prevention. We aimed to provide guidance for the early prioritisation of new and alternative SMC drugs and their target product profiles.
METHODS
In this modelling study, we combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic and pharmacodynamic models. We modelled SMC drug attributes for several possible modes of action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum parasite killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions.
FINDINGS
Model predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When children younger than 5 years receive four SMC cycles with high levels of coverage (ie, 69% of children receiving all cycles), drug candidates require a duration of protection half-life higher than 23 days (elimination half-life >10 days) to achieve reductions higher than 75% in clinical incidence and severe disease (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is crucial to achieve these targets, requiring more than 60% of children to receive all SMC cycles and more than 90% of children to receive at least one cycle regardless of the protection duration of the drug.
INTERPRETATION
Although efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determining cycle timing. Explicitly designing or selecting drug properties to increase community uptake is paramount.
FUNDING
Bill & Melinda Gates Foundation and the Swiss National Science Foundation.
Topics: Child; Humans; Infant; Antimalarials; Pharmaceutical Preparations; Public Health; Seasons; Malaria; Drug Combinations; Chemoprevention
PubMed: 38365418
DOI: 10.1016/S2214-109X(23)00550-8 -
Journal of Cellular Biochemistry Mar 2024Dihydrofolate reductase (DHFR) is a ubiquitous enzyme that regulates the biosynthesis of tetrahydrofolate among various species of Plasmodium parasite. It is a validated...
Dihydrofolate reductase (DHFR) is a ubiquitous enzyme that regulates the biosynthesis of tetrahydrofolate among various species of Plasmodium parasite. It is a validated target of the antifolate drug pyrimethamine (Pyr) in Plasmodium falciparum (Pf), but its clinical efficacy has been hampered due to the emergence of drug resistance. This has made the attempt to screen Food & Drug Administration-approved drugs against wild- and mutant PfDHFR by employing an in-silico pipeline to identify potent candidates. The current study has followed a virtual screening approach for identifying potential DHFR inhibitors from DrugBank database, based on a structure similarity search of candidates, followed by absorption, distribution, metabolism, and excretion estimation. The screened drugs were subjected to various parameters like docking, molecular mechanics with generalized born and surface area solvation calculations, and molecular simulations. We have thus identified two potential drug candidates, duloxetine and guanethidine, which can be repurposed to be tested for their efficacy against wild type and drug resistant falciparum malaria.
Topics: Humans; Antimalarials; Tetrahydrofolate Dehydrogenase; Pharmaceutical Preparations; Drug Repositioning; Malaria; Folic Acid Antagonists; Drug Resistance; Folic Acid
PubMed: 38345373
DOI: 10.1002/jcb.30533 -
Molecular Ecology Mar 2024Malaria cases are frequently recorded in the Ethiopian highlands even at altitudes above 2000 m. The epidemiology of malaria in the Ethiopian highlands, and, in...
Malaria cases are frequently recorded in the Ethiopian highlands even at altitudes above 2000 m. The epidemiology of malaria in the Ethiopian highlands, and, in particular, the role of importation by human migration from the highly endemic lowlands is not well understood. We sequenced 187 Plasmodium falciparum samples from two sites in the Ethiopian highlands, Gondar (n = 159) and Ziway (n = 28), using a multiplexed droplet digital PCR (ddPCR)-based amplicon sequencing method targeting 35 microhaplotypes and drug resistance loci. Here, we characterize the parasite population structure and genetic relatedness. We identify moderate parasite diversity (mean H : 0.54) and low infection complexity (74.9% monoclonal). A significant percentage of infections share microhaplotypes, even across transmission seasons and sites, indicating persistent local transmission. We identify multiple clusters of clonal or near-clonal infections, highlighting high genetic relatedness. Only 6.3% of individuals diagnosed with P. falciparum reported recent travel. Yet, in clonal or near-clonal clusters, infections of travellers were frequently observed first in time, suggesting that parasites may have been imported and then transmitted locally. 31.1% of infections are pfhrp2-deleted and 84.4% pfhrp3-deleted, and 28.7% have pfhrp2/3 double deletions. Parasites with pfhrp2/3 deletions and wild-type parasites are genetically distinct. Mutations associated with resistance to sulphadoxine-pyrimethamine or suggested to reduce sensitivity to lumefantrine are observed at near-fixation. In conclusion, genomic data corroborate local transmission and the importance of intensified control in the Ethiopian highlands.
Topics: Animals; Humans; Plasmodium falciparum; Parasites; Protozoan Proteins; Antigens, Protozoan; Ethiopia; Gene Deletion; Malaria, Falciparum; Malaria
PubMed: 38339833
DOI: 10.1111/mec.17292