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Journal of the Royal Society, Interface Jan 2024The emergence and spread of drug-resistant parasites have hindered efforts to eliminate malaria. Monitoring the spread of drug resistance is vital, as drug resistance...
The emergence and spread of drug-resistant parasites have hindered efforts to eliminate malaria. Monitoring the spread of drug resistance is vital, as drug resistance can lead to widespread treatment failure. We develop a Bayesian model to produce spatio-temporal maps that depict the spread of drug resistance, and apply our methods for the antimalarial sulfadoxine-pyrimethamine. We infer from genetic count data the prevalences over space and time of various malaria parasite haplotypes associated with drug resistance. Previous work has focused on inferring the prevalence of individual molecular markers. In reality, combinations of mutations at multiple markers confer varying degrees of drug resistance to the parasite, indicating that multiple markers should be modelled together. However, the reporting of genetic count data is often inconsistent as some studies report haplotype counts, whereas some studies report mutation counts of individual markers separately. In response, we introduce a latent multinomial Gaussian process model to handle partially reported spatio-temporal count data. As drug-resistant mutations are often used as a proxy for treatment efficacy, point estimates from our spatio-temporal maps can help inform antimalarial drug policies, whereas the uncertainties from our maps can help with optimizing sampling strategies for future monitoring of drug resistance.
Topics: Humans; Antimalarials; Bayes Theorem; Malaria, Falciparum; Malaria; Plasmodium falciparum; Mutation; Biomarkers; Protozoan Proteins
PubMed: 38228183
DOI: 10.1098/rsif.2023.0570 -
The Journal of Maternal-fetal &... Dec 2023Therapeutic regimens for the treatment of toxoplasmosis are not standardized. Treatment strategy mainly at the end of the second and the beginning of the third...
Comparison of adverse reactions of spiramycin versus pyrimethamine/sulfadiazine treatment of toxoplasmosis in pregnancy: is spiramycin really the drug of choice for unproven infection of the fetus?
BACKGROUND
Therapeutic regimens for the treatment of toxoplasmosis are not standardized. Treatment strategy mainly at the end of the second and the beginning of the third trimester, especially in cases of negative prenatal diagnosis, is the least uniform. In some situations, the choice of treatment may be ambiguous, and adverse drug reactions of the therapy should be taken into consideration.
METHODS
Adverse drug reactions of anti-toxoplasma therapy with spiramycin ( = 77) versus pyrimethamine/sulfadiazine ( = 35) were compared in 112 pregnant women.
RESULTS
Up to 36.6% of women reported adverse reactions to the treatment overall ( = 41). Out of those 38.9% ( = 30) were treated with spiramycin and 31.4% ( = 11) with pyrimethamine/sulfadiazine. Toxic allergic reactions were the only indication for discontinuation of treatment in 8.9% of patients ( = 10), where 9.1% ( = 7) were reported in spiramycin and 8.6% ( = 3) in pyrimethamine/sulfadiazine cohort. Neurotoxic complications (acral paraesthesia) were significantly more frequent during the therapy with spiramycine in 19.5% ( = 15) compared to no cases in pyrimethamine/sulfadiazine group ( = .003). Other adverse drug reactions, such as gastrointestinal discomfort, nephrotoxicity, vaginal discomfort were reported, but the differences between the cohorts were not significant.
CONCLUSIONS
The superiority of one of the therapeutic regimens was not statistically demonstrated, since the differences in overall toxicity or incidence of toxic allergic reactions between the cohorts were not confirmed ( = .53 and = 1.00, respectively). However, although the isolated neurotoxicity of spiramycin was the only significant adverse reaction demonstrated in this study, pyrimethamine/sulfadiazine therapy should be preferred, because it is known to be more effective and with limited adverse reactions.
Topics: Female; Humans; Pregnancy; Spiramycin; Pyrimethamine; Sulfadiazine; Toxoplasmosis; Drug Therapy, Combination; Fetus; Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Toxoplasmosis, Congenital
PubMed: 37217458
DOI: 10.1080/14767058.2023.2215377 -
Pharmaceuticals (Basel, Switzerland) Nov 2023Nowadays, interest in the use of nanotechnology for medical purposes is increasing. The current experimental investigation is planned for the green synthesis,...
BACKGROUND
Nowadays, interest in the use of nanotechnology for medical purposes is increasing. The current experimental investigation is planned for the green synthesis, characterization, and efficacy of copper nanoparticles (CLN) against chronic infection.
METHODS
Green synthesis of CNP was performed using the extract via the precipitation method. The effects of CNP on tachyzoites, infectivity rate, parasites inside THP-1 cells, nitric oxide (NO) triggering, iNOS, and IFN-γ expression genes were evaluated. Following toxoplasmosis in BALB/c mice via the ME49 strain, mice received CNP at 5 and 10 mg/kg/day alone and combined with pyrimethamine (PYM) at 5 mg/kg for two weeks. CNP's in vivo effects were evaluated by analyzing the load and size of cysts, oxidant/antioxidant enzymes, and bradyzoite surface antigen 1 (BAG1) expression gene levels.
RESULTS
CNP displayed a circular shape ranging from 10 to 85 nm. The IC50 value of CNP and PYM against tachyzoites was 37.2 and 25.7 µg/mL, respectively, whereas the CC50 value of CNP and pyrimethamine against THP-1 cells was 491.4 μg/mL and 269.5 μg/mL, respectively. The rate of infectivity and parasite load among THP-1 cells exposed to CNP was obviously reduced ( < 0.05). CNP at the doses of 5 and 10 mg/kg predominantly along with PYM evidently ( < 0.05) reduced the number and size of the cysts in the infected mice. The levels of NO, iNOS, and IFN-γ genes were remarkably ( < 0.001) boosted compared with the cells without treatment. CNP at the doses of 10 and 20 mg/kg drastically ( < 0.05) reduced the oxidative stress markers in the infected mice, whereas CNP significantly elevated the level of antioxidant factors. CNP also revealed no toxicity in the liver and kidney at the tested doses in healthy mice.
CONCLUSIONS
Our experimental study reported the beneficial effects of CNP principally along with existing chemical drugs against latent toxoplasmosis in mice, whereas the possible action mechanisms of CNP are controlling oxidative stress, refining antioxidant enzymes, and increasing the production of immunomodulatory cytokines with no toxicity to the function of vital organs. But, additional trials are required to confirm these results, as well as to clarify the accurate mechanisms and their toxicity.
PubMed: 38004439
DOI: 10.3390/ph16111574 -
Journal of Biomolecular Structure &... 2023dihydrofolate reductase-thymidylate synthase (DHFR-TS) is an important target enzyme in malarial chemotherapy. An understanding of how novel inhibitors interact with...
Key interactions of pyrimethamine derivatives specific to wild-type and mutant dihydrofolate reductase based on 3D-QSAR, MD simulations and quantum chemical calculations.
dihydrofolate reductase-thymidylate synthase (DHFR-TS) is an important target enzyme in malarial chemotherapy. An understanding of how novel inhibitors interact with wild-type (wtDHFR), quadruple-mutant (qmDHFR), and human (DHFR) enzymes is required for the development of these compounds as antimalarials. This study is focused on a series of -Cl and -Cl phenyl analogs of pyrimethamine with various flexible 6-substituents. The interactions of these compounds with DHFR enzymes were investigated by 3 D-QSAR, MD simulations, MM-PBSA, and DFT calculations. CoMFA and CoMSIA models were developed with good predictive abilities for wtDHFR and qmDHFR. For DHFR, CoMSIA models combined with clogP descriptor were successfully derived. Binding free energy using MM-PBSA and comparison of per residue decomposition energy analyses with the DFT method at M06-2X/6-31G ++(d,p) level of theory indicated that Asp54 and Phe58 play important roles in the binding of the most potent compound in the series (compound 27) with both wtDHFR and qmDHFR, whereas Arg59 and Arg122 were additionally found to interact with this inhibitor in qmDHFR. For DHFR, the residues Glu30 and Phe34 but not Arg70, equivalent to Asp54, Phe58, and Arg122 in DHFR, also play role in compound 27 binding through strong hydrophobic interactions (Phe34) and hydrogen bond network with Glu30, Ile7, and Val115. From the key interactions identified in the DHFR-inhibitor complexes, a general scheme is proposed for designing new inhibitors selective for DHFR that is important for the development of novel antifolate antimalarials.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Pyrimethamine; Antimalarials; Quantitative Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Plasmodium falciparum; Folic Acid Antagonists
PubMed: 35815526
DOI: 10.1080/07391102.2022.2096114 -
PLoS Neglected Tropical Diseases Sep 2023We evaluate the drug treatment for pregnant women with acute toxoplasmosis to reduce the risk of congenital infection, side effects (prenatal and postnatal treatment in...
BACKGROUND
We evaluate the drug treatment for pregnant women with acute toxoplasmosis to reduce the risk of congenital infection, side effects (prenatal and postnatal treatment in children) and the hazard of discontinuing the infant's medication.
METHODS
We conducted a prospective cohort study to assess the risks of congenital toxoplasmosis among children born to acutely infected women with and without treatment. We examined the relationship between "exposed" and "infected children", "number of infant neutrophils", "prenatal" and "postnatal treatment". Factor analysis of mixed data (FAMD) was used to analyze the data. All children started treatment at the hospital.
FINDINGS
Between 2017 and 2021, 233 pregnant women were evaluated at the University Hospital of Maringá; ninety-four met criteria for acute gestational toxoplasmosis. We followed up 61 children; eleven (18%) had the infection confirmed and 50 (82%) were free of toxoplasmosis (exposed). Children born to untreated mothers have 6.5-times higher risk of being infected; the transmission rate among untreated mothers was 50% versus 8.3% among treated ones. Three decreasing values of immunoglobulin G were a security parameter for stopping the child's medication in the exposed group (50/61). Neutropenia was the leading side effect among children and the infected had a 2.7 times higher risk. There was no correlation between maternal use of pyrimethamine and children's neutropenia.
INTERPRETATION
The follow-up of women with acute T. gondii infection and their children, through a multidisciplinary team, availability of anti-T. gondii serology and pre- and post-natal treatments reduced the risk of toxoplasmosis transmission.
Topics: Infant; Humans; Female; Pregnancy; Child; Cohort Studies; Pregnancy Complications, Infectious; Prospective Studies; Brazil; Toxoplasmosis; Toxoplasmosis, Congenital; Neutropenia; Toxoplasma; Pregnancy Complications, Parasitic
PubMed: 37773943
DOI: 10.1371/journal.pntd.0011544 -
Global Health Action Dec 2023Malaria during pregnancy is a major global health concern, with approximately 10,000 pregnant women dying from malaria-related anaemia each year. The World Health...
Malaria during pregnancy is a major global health concern, with approximately 10,000 pregnant women dying from malaria-related anaemia each year. The World Health Organization has suggested intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) to avert malaria infection in pregnant women in malaria-endemic areas, but this intermittent preventive (IP) treatment is at risk of becoming ineffective due to parasite resistance and the contraindication in HIV-infected women. This paper argues that alternative IP treatments such as dihydroartemisinin-piperaquine (DP) should be explored, alongside the urgent need to investigate antimalarial cycling strategies. Additionally, the cost-effectiveness of IPTp-DP should be evaluated, as well as potential barriers to IP treatment such as medication stockouts, late attendance at antenatal clinics, lack of autonomy and freedom among women, and lack of knowledge about malaria prevention. Health education focusing on malaria prevention should be incorporated into routine antenatal care programmes to improve patient compliance. A comprehensive approach that includes the administration of IPTp-DP alone along with other measures such as insecticide-treated nets and medical education is the key to addressing the devastating effects of malaria infection in pregnant women.
Topics: Female; Pregnancy; Humans; Pregnant Women; Cost-Benefit Analysis; Antimalarials; Malaria
PubMed: 37459385
DOI: 10.1080/16549716.2023.2231257 -
International Journal of Infectious... Oct 2023Malaria and sexually transmitted and reproductive tract infections (STIs/RTIs) are highly prevalent in sub-Saharan Africa and associated with poor pregnancy outcomes. We...
Fetal growth and birth weight are independently reduced by malaria infection and curable sexually transmitted and reproductive tract infections in Kenya, Tanzania, and Malawi: A pregnancy cohort study.
OBJECTIVES
Malaria and sexually transmitted and reproductive tract infections (STIs/RTIs) are highly prevalent in sub-Saharan Africa and associated with poor pregnancy outcomes. We investigated the individual and combined effects of malaria and curable STIs/RTIs on fetal growth in Kenya, Tanzania, and Malawi.
METHODS
This study was nested within a randomized trial comparing monthly intermittent preventive treatment for malaria in pregnancy with sulfadoxine-pyrimethamine vs dihydroartemisinin-piperaquine, alone or combined with azithromycin. Fetal weight gain was assessed by serial prenatal ultrasound. Malaria was assessed monthly, and Treponema pallidum, Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, and bacterial vaginosis at enrollment and in the third trimester. The effect of malaria and STIs/RTIs on fetal weight/birthweight Z-scores was evaluated using mixed-effects linear regression.
RESULTS
In total, 1435 pregnant women had fetal/birth weight assessed 3950 times. Compared to women without malaria or STIs/RTIs (n = 399), malaria-only (n = 267), STIs/RTIs only (n = 410) or both (n = 353) were associated with reduced fetal growth (adjusted mean difference in fetal/birth weight Z-score [95% confidence interval]: malaria = -0.18 [-0.31,-0.04], P = 0.01; STIs/RTIs = -0.14 [-0.26,-0.03], P = 0.01; both = -0.20 [-0.33,-0.07], P = 0.003). Paucigravidae experienced the greatest impact.
CONCLUSION
Malaria and STIs/RTIs are associated with poor fetal growth especially among paucigravidae women with dual infections. Integrated antenatal interventions are needed to reduce the burden of both malaria and STIs/RTIs.
Topics: Female; Pregnancy; Humans; Birth Weight; Reproductive Tract Infections; Cohort Studies; Kenya; Fetal Weight; Malawi; Tanzania; Sexually Transmitted Diseases; Malaria; Pregnancy Outcome; Fetal Development
PubMed: 37516425
DOI: 10.1016/j.ijid.2023.07.012 -
Malaria Journal Aug 2023Malaria in pregnancy remains a major public health problem in endemic areas of the sub-Saharan African (SSA) region. However, there is limited understanding of the...
Women's empowerment and uptake of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy: results from a cross-sectional baseline survey in the Lake endemic region, Kenya.
BACKGROUND
Malaria in pregnancy remains a major public health problem in endemic areas of the sub-Saharan African (SSA) region. However, there is limited understanding of the association between women's empowerment and the uptake of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy (IPTp-SP) in Kenya. This study examines the association between women's empowerment indicators (decision-making power, control of assets, education, and employment status) and the uptake of three or more doses of IPTp-SP in the Lake endemic region of Kenya.
METHODS
The analysis utilized a dataset from a cross-sectional baseline survey of 3129 women aged 15-49 years in Kisumu and Migori Counties who had a live birth within the last 2 years preceding the study. Data were collected between June to August 2021. A descriptive analysis was conducted to show the distribution of respondents by key background characteristics, and bivariate and multivariate logistic regression to examine statistically significant associations between women's empowerment measures and the uptake of 3+ doses of IPTp-SP.
RESULTS
Among the 3129 women surveyed, 1978 (65.7%) received 3+ doses of IPTp-SP during their most recent pregnancy. Controlling for individual characteristics and the number of ANC visits, the odds of taking 3+ doses of IPTp-SP increased among women who had high decision-making autonomy (AOR = 2.33; CI = 1.81-3.01; P < 0.001); and tertiary level of educational attainment (AOR = 1.51; CI = 1.10-2.06). However, the association between control of assets and uptake of IPTp-SP was positive but not statistically significant.
CONCLUSION
Women's decision-making autonomy and educational attainment were positively associated with the uptake of IPTp-SP. As a result, maternal health interventions should focus on less empowered women, specifically those with less decision-making autonomy and no/low formal education, as they are less likely to achieve optimal uptake of IPTp-SP during pregnancy.
Topics: Pregnancy; Female; Humans; Kenya; Cross-Sectional Studies; Lakes; Malaria
PubMed: 37612754
DOI: 10.1186/s12936-023-04679-z -
Malaria Journal Dec 2023Resistance against artemisinin-based combination therapy is one of the challenges to malaria control and elimination globally. Mutations in different genes (Pfdhfr,...
BACKGROUND
Resistance against artemisinin-based combination therapy is one of the challenges to malaria control and elimination globally. Mutations in different genes (Pfdhfr, Pfdhps, Pfk-13 and Pfmdr1) confer resistance to artesunate and sulfadoxine-pyrimethamine (AS + SP) were analysed from Mandla district, Madhya Pradesh, to assess the effectiveness of the current treatment regimen against uncomplicated Plasmodium falciparum.
METHODS
Dried blood spots were collected during the active fever survey and mass screening and treatment activities as part of the Malaria Elimination Demonstration Project (MEDP) from 2019 to 2020. Isolated DNA samples were used to amplify the Pfdhfr, Pfdhps, Pfk13 and Pfmdr1 genes using nested PCR and sequenced for mutation analysis using the Sanger sequencing method.
RESULTS
A total of 393 samples were subjected to PCR amplification, sequencing and sequence analysis; 199, 215, 235, and 141 samples were successfully sequenced for Pfdhfr, Pfdhps, Pfk13, Pfmdr1, respectively. Analysis revealed that the 53.3% double mutation (C59R, S108N) in Pfdhfr, 89.3% single mutation (G437A) in Pfdhps, 13.5% single mutants (N86Y), and 51.1% synonymous mutations in Pfmdr1 in the study area. Five different non-synonymous and two synonymous point mutations found in Pfk13, which were not associated to artemisinin resistance.
CONCLUSION
The study has found that mutations linked to SP resistance are increasing in frequency, which may reduce the effectiveness of this drug as a future partner in artemisinin-based combinations. No evidence of mutations linked to artemisinin resistance in Pfk13 was found, suggesting that parasites are sensitive to artemisinin derivatives in the study area. These findings are a baseline for routine molecular surveillance to proactively identify the emergence and spread of artemisinin-resistant parasites.
Topics: Humans; Plasmodium falciparum; Antimalarials; Pyrimethamine; Sulfadoxine; Artemisinins; Malaria; Biomarkers; Drug Resistance; India; Drug Combinations; Malaria, Falciparum; Protozoan Proteins
PubMed: 38072967
DOI: 10.1186/s12936-023-04817-7 -
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