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Scientific Reports May 2023Little is known about the existence of drug-resistant Toxoplasma gondii strains and their possible impact on clinic outcomes. To expand our knowledge about the existence...
Little is known about the existence of drug-resistant Toxoplasma gondii strains and their possible impact on clinic outcomes. To expand our knowledge about the existence of natural variations on drug susceptibility of T. gondii strains in Brazil, we evaluated the in vitro and in vivo susceptibility to sulfadiazine (SDZ) and pyrimethamine (PYR) of three atypical strains (Wild2, Wild3, and Wild4) isolated from free-living wild birds. In vitro susceptibility assay showed that the three strains were equally susceptible to SDZ and PYR but variations in the susceptibility were observed to SDZ plus PYR treatment. Variations in the proliferation rates in vitro and spontaneous conversion to bradyzoites were also accessed for all strains. Wild2 showed a lower cystogenesis capacity compared to Wild3 and Wild4. The in vivo analysis showed that while Wild3 was highly susceptible to all SDZ and PYR doses, and their combination, Wild2 and Wild4 showed low susceptibility to the lower doses of SDZ or PYR. Interestingly, Wild2 presented low susceptibility to the higher doses of SDZ, PYR and their combination. Our results suggest that the variability in treatment response by T. gondii isolates could possibly be related not only to drug resistance but also to the strain cystogenesis capacity.
Topics: Sulfadiazine; Pyrimethamine; Toxoplasma; Antiprotozoal Agents; Brazil
PubMed: 37147353
DOI: 10.1038/s41598-023-34502-3 -
The New England Journal of Medicine Sep 2021Malaria control remains a challenge in many parts of the Sahel and sub-Sahel regions of Africa. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Malaria control remains a challenge in many parts of the Sahel and sub-Sahel regions of Africa.
METHODS
We conducted an individually randomized, controlled trial to assess whether seasonal vaccination with RTS,S/AS01 was noninferior to chemoprevention in preventing uncomplicated malaria and whether the two interventions combined were superior to either one alone in preventing uncomplicated malaria and severe malaria-related outcomes.
RESULTS
We randomly assigned 6861 children 5 to 17 months of age to receive sulfadoxine-pyrimethamine and amodiaquine (2287 children [chemoprevention-alone group]), RTS,S/AS01 (2288 children [vaccine-alone group]), or chemoprevention and RTS,S/AS01 (2286 children [combination group]). Of these, 1965, 1988, and 1967 children in the three groups, respectively, received the first dose of the assigned intervention and were followed for 3 years. Febrile seizure developed in 5 children the day after receipt of the vaccine, but the children recovered and had no sequelae. There were 305 events of uncomplicated clinical malaria per 1000 person-years at risk in the chemoprevention-alone group, 278 events per 1000 person-years in the vaccine-alone group, and 113 events per 1000 person-years in the combination group. The hazard ratio for the protective efficacy of RTS,S/AS01 as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20. The protective efficacy of the combination as compared with chemoprevention alone was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against hospital admission with severe malaria according to the World Health Organization definition, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria. The protective efficacy of the combination as compared with the vaccine alone against these outcomes was 59.6% (95% CI, 54.7 to 64.0), 70.6% (95% CI, 42.3 to 85.0), and 75.3% (95% CI, 12.5 to 93.0), respectively.
CONCLUSIONS
Administration of RTS,S/AS01 was noninferior to chemoprevention in preventing uncomplicated malaria. The combination of these interventions resulted in a substantially lower incidence of uncomplicated malaria, severe malaria, and death from malaria than either intervention alone. (Funded by the Joint Global Health Trials and PATH; ClinicalTrials.gov number, NCT03143218.).
Topics: Amodiaquine; Antimalarials; Burkina Faso; Chemoprevention; Combined Modality Therapy; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Hospitalization; Humans; Infant; Malaria Vaccines; Malaria, Falciparum; Male; Mali; Pyrimethamine; Seasons; Seizures, Febrile; Sulfadoxine
PubMed: 34432975
DOI: 10.1056/NEJMoa2026330 -
Frontiers in Endocrinology 2019Mitochondrion is a multi-functional organelle, which is associated with various signaling pathway networks, including energy metabolism, oxidative stress, cell... (Review)
Review
Mitochondrion is a multi-functional organelle, which is associated with various signaling pathway networks, including energy metabolism, oxidative stress, cell apoptosis, cell cycles, autophagy, and immunity process. Mitochondrial proteins have been discovered to modulate these signaling pathway networks, and multiple biological behaviors to adapt to various internal environments or signaling events of human pathogenesis. Accordingly, mitochondrial dysfunction that alters the bioenergetic and biosynthetic state might contribute to multiple diseases, including cell transformation and tumor. Multiomics studies have revealed that mitochondrial dysfunction, oxidative stress, and cell cycle dysregulation signaling pathways operate in human pituitary adenomas, which suggest mitochondria play critical roles in pituitary adenomas. Some drugs targeting mitochondria are found as a therapeutic strategy for pituitary adenomas, including melatonin, melatonin inhibitors, temozolomide, pyrimethamine, 18 beta-glycyrrhetinic acid, gossypol acetate, Yougui pill, T-2 toxin, grifolic acid, cyclosporine A, dopamine agonists, and paeoniflorin. This article reviews the latest experimental evidence and potential biological roles of mitochondrial dysfunction and mitochondrial dynamics in pituitary adenoma progression, potential molecular mechanisms between mitochondria and pituitary adenoma progression, and current status and perspectives of mitochondria-based biomarkers and targeted drugs for effective management of pituitary adenomas.
PubMed: 31649621
DOI: 10.3389/fendo.2019.00690 -
West African Journal of Medicine Dec 2021Chemoprophylaxis against Plasmodium falciparum (Pf) is advocated in children with sickle cell anaemia (SCA). Among them, antifolates: proguanil and pyrimethamine had...
Prevalence of Molecular Markers of Plasmodium Falciparum Resistance to Proguanil and Pyrimethamine in Children with Haemoglobin Phenotypes SS and AA in Benin City, Nigeria.
BACKGROUND
Chemoprophylaxis against Plasmodium falciparum (Pf) is advocated in children with sickle cell anaemia (SCA). Among them, antifolates: proguanil and pyrimethamine had replaced initial chemoprophylactic drugs because of widespread resistance. In recent past, efficacy of these antifolates has also come under scrutiny due to increasing level of drug resistance. Specific point mutations on Plasmodium falciparum dihydrofolate reductase gene (pfdhfr) have been linked with resistance to proguanil and pyrimethamine and they can be used as markers in monitoring prevalence and level of resistance to the drugs.
OBJECTIVES
To determine the prevalence of molecular markers of Plasmodium falciparum resistance to proguanil and pyrimethamine in children with SCA.
METHODS
A total of 146 Plasmodium falciparum isolates (71 from children with SCA and 75 from those with Haemoglobin AA: HbAA) were evaluated for point mutations and mutant haplotypes on the pfdhfr gene using nested polymerase chain reaction amplification followed by direct sequencing.
RESULTS
The triple (S108N+N51I+C59N) mutant haplotype was present in 100.0% and 96.0% of samples from children with SCA and HbAA respectively. S108T, A16V and 1164L mutationswere not present in both groups.
CONCLUSION
High prevalence of triple mutant haplotype mediates significant resistance to pyrimethamine and implies that pyrimethamine resistance is fixed in the study locale. However, the absence of pfdhfr S108T and A16V mutations, which indicate specific resistance to proguanil but not to pyrimethamine, suggests that proguanil is still useful even in the face of pyrimethamine resistance. The threat of proguanil resistance is however real due to high prevalence of the triple mutant pfdhfr haplotype.
Topics: Anemia, Sickle Cell; Antimalarials; Drug Combinations; Hemoglobin, Sickle; Humans; Malaria, Falciparum; Mutation; Nigeria; Phenotype; Plasmodium falciparum; Prevalence; Proguanil; Pyrimethamine; Sulfadoxine
PubMed: 35037448
DOI: No ID Found -
The Journal of General Virology Aug 2021Human respiratory syncytial virus (hRSV) is a major cause of respiratory illness in young children and can cause severe infections in the elderly or in immunocompromised...
Human respiratory syncytial virus (hRSV) is a major cause of respiratory illness in young children and can cause severe infections in the elderly or in immunocompromised adults. To date, there is no vaccine to prevent hRSV infections, and disease management is limited to preventive care by palivizumab in infants and supportive care for adults. Intervention with small-molecule antivirals specific for hRSV represents a good alternative, but no such compounds are currently approved. The investigation of existing drugs for new therapeutic purposes (drug repositioning) can be a faster approach to address this issue. In this study, we show that chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A (long strain) and synergistically increase the anti-replicative effect of ribavirin . Moreover, chloroquine, but not pyrimethamine, inhibits hRSV replication in the mouse model. Our results show that chloroquine can potentially be an interesting compound for treatment of hRSV infection in monotherapy or in combination with other antivirals.
Topics: Animals; Antiviral Agents; Cell Line; Cell Survival; Chloroquine; Disease Models, Animal; Female; Humans; Immunocompromised Host; Mice; Mice, Inbred BALB C; Pyrimethamine; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Ribavirin; Virus Replication
PubMed: 34342560
DOI: 10.1099/jgv.0.001627 -
PloS One 2022This study aimed to ascertain the prevalence and risk factors of malaria and anaemia as well as the impact of preventive methods among pregnant women at the Akatsi South...
AIM
This study aimed to ascertain the prevalence and risk factors of malaria and anaemia as well as the impact of preventive methods among pregnant women at the Akatsi South District Hospital of Ghana.
SUBJECTS AND METHODS
A hospital based cross-sectional study using simple random sampling technique was conducted among 200 pregnant women receiving antenatal care and laboratory services at the Akatsi District Hospital from May 2016 to July 2016. A semi-structured questionnaire was administered to obtain participants' malaria preventive methods in addition to demographic and gestational details. Participants' hemoglobin and malaria status were assessed using one milliliter (1 ml) whole blood collected from each participant following standard procedures. Factors that produced a p-value of ≤0.2 from the univariate model were included in the final model. Association between potential covariates and the outcomes was assessed using multivariate logistic regression. The Clopper-Pearson test statistic was used to determine the 95% confidence intervals of the outcome variables of interest. We also estimated the population attributable fraction (PAF) of anaemia due to malaria by substituting the adjusted relative risk estimates (RRi) (using the adjrr command in STATA) of anaemia due to malaria into the category-specific attributable formula. P-values of <0.05 were considered statistically significant.
RESULTS
Prevalence of anaemia in pregnancy (AiP), malaria in pregnancy (MiP) and AiP/MiP comorbidity was 63.5% (95% CI:56.4-70.2), 11.0% (96% CI:7.0-16.2) and 10.5% (95% CI:6.6-15.6) respectively. Prevalence rates of AiP (66.7%) and MiP (18.5%) predominated among pregnant women aged < 20 years. PAF of AiP due to MiP was 34.5% (95% CI:23.8-43.6). High use of IPTp-SP, 64.0% (95% CI:56.9-70.6) and LLIN, 90.0% (95% CI:85.0-93.8) was observed in this study. Only 42.0% (95% CI:35.1-49.2) used repellent. Not being on the IPTp-SP program posed a 11.70 times risk of MiP (95% CI:2.32-58.96; p = 0.003) compared to pregnant women on the IPTp-SP program. Similarly, not sleeping under LLIN posed an 8.07 times risk of MiP (95% CI:1.98-32.2; p = 0.004) compared to pregnant women who slept under LLIN. Meanwhile, being positive for MiP posed a 12.10 times risk (95% CI:1.35-85.06; p = 0.025) of AiP compared to those negative for malaria whereas failure to attend ANC as scheduled posed 6.34 times risk (95% CI:1.81-22.19; p = 0.004) of AiP among the pregnant women studied.
CONCLUSION
The prevalence of MiP and AiP among pregnant women in the Akatsi South District remains a great concern. High utilization of IPTp-SP and LLIN was observed with a resultant positive effect on malaria prevalence among pregnant women. Improved access to IPTp-SP and LLIN is hence encouraged to help further diminish the risk of malaria infection amongst pregnant women in the District.
Topics: Anemia; Antimalarials; Cross-Sectional Studies; Drug Combinations; Female; Ghana; Humans; Malaria; Pregnancy; Pregnancy Complications, Parasitic; Pregnant Women; Prevalence; Pyrimethamine; Risk Factors; Sulfadoxine
PubMed: 35877761
DOI: 10.1371/journal.pone.0271211 -
Malaria Journal Mar 2022Chemoprevention strategies reduce malaria disease and death, but the efficacy of anti-malarial drugs used for chemoprevention is perennially threatened by drug... (Review)
Review
Chemoprevention strategies reduce malaria disease and death, but the efficacy of anti-malarial drugs used for chemoprevention is perennially threatened by drug resistance. This review examines the current impact of chemoprevention on the emergence and spread of drug resistant malaria, and the impact of drug resistance on the efficacy of each of the chemoprevention strategies currently recommended by the World Health Organization, namely, intermittent preventive treatment in pregnancy (IPTp); intermittent preventive treatment in infants (IPTi); seasonal malaria chemoprevention (SMC); and mass drug administration (MDA) for the reduction of disease burden in emergency situations. While the use of drugs to prevent malaria often results in increased prevalence of genetic mutations associated with resistance, malaria chemoprevention interventions do not inevitably lead to meaningful increases in resistance, and even high rates of resistance do not necessarily impair chemoprevention efficacy. At the same time, it can reasonably be anticipated that, over time, as drugs are widely used, resistance will generally increase and efficacy will eventually be lost. Decisions about whether, where and when chemoprevention strategies should be deployed or changed will continue to need to be made on the basis of imperfect evidence, but practical considerations such as prevalence patterns of resistance markers can help guide policy recommendations.
Topics: Chemoprevention; Drug Combinations; Drug Resistance; Female; Humans; Infant; Malaria; Policy; Pregnancy; Pyrimethamine; Sulfadoxine
PubMed: 35331231
DOI: 10.1186/s12936-022-04115-8 -
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 -
MalariaWorld Journal 2022Malaria in pregnancy is a significant public health concern in Nigeria. It threatens pregnant women and their unborn babies and undermines the achievement of Sustainable...
BACKGROUND
Malaria in pregnancy is a significant public health concern in Nigeria. It threatens pregnant women and their unborn babies and undermines the achievement of Sustainable Development Goal 3. The World Health Organization has recommended intermittent preventive treatment with sulfadoxine-pyrimethamine [IPTp-SP] for its control, but there are challenges to its access and uptake.
METHODS
Using the Arksey and O'Malley framework and the cascade of care model, we conducted a scoping review to investigate barriers and facilitators of IPTp-SP access and uptake, including their influence on pregnant women's health-seeking behaviour for the control of malaria in pregnancy in Nigeria. We searched seven scientific databases for papers published from 2005 to date.
RESULTS
We included a total of 31 out of 2149 articles in the review. Poor provider knowledge of the IPTp-SP protocol and lack of essential commodities for sulphadoxine-pyrimethamine administration in clinics are significant barriers to IPTp-SP use. Staff shortages and poor remuneration of health care professionals are obstacles to IPTp-SP utilisation.
CONCLUSIONS
To improve IPTp-SP access and uptake, the government should ensure a continuous supply to clinics and support the employment of additional health care professionals who should be well paid and trained on using the IPTp-SP protocol.
PubMed: 35813271
DOI: No ID Found -
Malaria Journal Nov 2022Evaluating malaria control strategies for pregnant women is essential. The objective of this study was to determine the factors influencing antenatal care (ANC) visit...
Intermittent preventive treatment and malaria amongst pregnant women who give birth at the Centre Hospitalier Régional Paul Moukambi de Koula-Moutou in southeastern Gabon.
BACKGROUND
Evaluating malaria control strategies for pregnant women is essential. The objective of this study was to determine the factors influencing antenatal care (ANC) visit attendance, complete intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) and its impact on the health of pregnant women and their newborn babies living in semi-urban and rural areas of southeastern Gabon.
METHODS
This transversal study was performed at the Centre Hospitalier Régional Paul Moukambi de Koula-Moutou (CHRPMK). Information regarding age, frequency of prenatal consultations, obstetric history, use of malaria control measures, use of IPTp-SP, malaria diagnostic of women and their newborns, were collected: (i): from birth registers from 1 January, 2018 to 31 December, 2019 and, (ii): a questionnaire from January to April 2020.
RESULTS
In total, 1,851 and 323 pregnant women were included during the first and the second sub-set of study, respectively. In the first sub-set of data, the mean age was 26.18 ± 7.02 years and 96.54% (1,787/1,851) of pregnant women had attended ANC service but 54.45% had complete ANC visit attendance (at least 4 ANC). The complete ANC visit was linked with age (p < 0.001) and profession (p < 0.001). The complete IPTp-SP (at least 3 doses) was 58.87%. Complete IPTp-SP was linked to profession (aOR = 1.49, 95% CI [1.04-2.18], p < 0.001), ANC visit (aOR = 0.176, 95% CI [0.14-0.22], p < 0.034) and age (p = 0.03). Birth weight was higher for babies whose mothers had received complete IPTp-SP (p < 0,001) but the Apgar score was not influenced by the use of IPTp-SP (p = 0.71). In the second sub-set of data, the prevalence of plasmodial infection was 3.10% (95% IC [1.21-5]) and Plasmodium falciparum was responsible for 100% of infections. The prevalence of plasmodial infection was the same for all age groups (p = 0.69), gravidity (p = 0.13) and domestic control measures (p > 0.05). A low birth weight was statistically linked to the mother's plasmodial infection (p < 0.01). Furthermore, plasmodial infection was statistically linked to premature birth (p < 0.001).
CONCLUSIONS
It was observed that attendance of women to ANC service and a complete IPTp-SP course is insufficient.
Topics: Female; Infant, Newborn; Pregnancy; Humans; Young Adult; Adult; Pregnant Women; Pregnancy Complications, Parasitic; Antimalarials; Gabon; Sulfadoxine; Pyrimethamine; Malaria; Drug Combinations
PubMed: 36333739
DOI: 10.1186/s12936-022-04305-4