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Cureus May 2024The use of the antimalarial drug hydroxychloroquine is a standard treatment in patients with systemic lupus erythematosus. It helps reduce disease-associated damage,...
The use of the antimalarial drug hydroxychloroquine is a standard treatment in patients with systemic lupus erythematosus. It helps reduce disease-associated damage, prevents disease flare, and improves overall survival. The mechanism of action of hydroxychloroquine includes interference with lysosomal degradation of cells leading to the accumulation of vacuoles. Retinopathy is a well-described adverse effect of hydroxychloroquine, thus requiring screening with an ophthalmologist after prolonged use. Although rarely reported, cardiac adverse effects of hydroxychloroquine can also occur. In this report, we present a case of a 23-year-old woman with systemic lupus erythematosus on hydroxychloroquine who presented with stroke possibly due to Libman-Sacks endocarditis and was found to have severe hypertrophic cardiomyopathy on transthoracic echocardiogram.
PubMed: 38947707
DOI: 10.7759/cureus.61452 -
Research Square Jun 2024. The invasion of into Africa poses a potential threat to malaria control and elimination on the continent. However, it is not clear if the recent malaria resurgence...
. The invasion of into Africa poses a potential threat to malaria control and elimination on the continent. However, it is not clear if the recent malaria resurgence in Ethiopia has linked to the expansion of . We aimed to summarize the major achievements and lesson learnt in malaria control in Ethiopia from 2001 to 2022, to assess the new challenges and prospects for the control of . . We obtained the clinical malaria case reports, antimalarial drug treatment records, insecticide-treated and long-lasting insecticidal net (ITN/LLIN) distribution and utilization records, and indoor residual spraying (IRS) coverage data from the Ethiopian Ministry of Health (MoH) for the period 2001-2022. We analyzed clinical malaria hotspots using spatially optimized hotspot analysis. We investigated malaria outbreaks in 2022 and examined the potential role of in the outbreaks. Clinical malaria cases in Ethiopia decreased by 80%, from 5.2 million cases (11% confirmed) in 2004 to 1.0 million cases (92% confirmed) in 2018; however, cases increased steadily to 2.6 million confirmed cases (98% confirmed) in 2022. cases and proportion have increased significantly in the past 5 years. Clinical malaria hotspots are concentrated along the western Ethiopian border areas and have grown significantly from 2017 to 2022. Major malaria outbreaks in 2022/23 were detected in multiple sites across Ethiopia, and was the predominant vector in some of these sites, however, it was absence from many of the outbreak sites. The malaria burden has been significantly reduced in Ethiopia in the past two decades, but in recent years it has increased substantially, and the cause of such increase is a subject of further investigation. Major gaps exist in research, including vector ecology, surveillance, and control tools, especially for adult mosquito control.
PubMed: 38947038
DOI: 10.21203/rs.3.rs-4468361/v1 -
Chemistry & Biodiversity Jun 2024Flavonoids epitomize structural scaffolds in many biologically active synthetic and natural compounds. They showcase a diverse spectrum of biological activities...
Flavonoids epitomize structural scaffolds in many biologically active synthetic and natural compounds. They showcase a diverse spectrum of biological activities including anticancer, antidiabetic, antituberculosis, antimalarial, and antibiofilm activities. The antibiofilm activity of a series of new chalcones and flavonols against clinically significant Pseudomonas aeruginosa PAO1 strain was studied. Antivirulence activities were screened by analysing the effect of compounds on the production of virulence factors like pyocyanin, LasA protease, cell surface hydrophobicity, and rhamnolipid. The best ligands towards the quorum sensing proteins LasR, RhlR, and PqsR were recognised using a molecular docking study. The gene expression in P. aeruginosa after treatment with test compounds was evaluated on quorum sensing genes including rhlA, lasB, and pqsE. The antibiofilm potential of chalcones and flavonols was confirmed by the efficient reduction in the production of virulence factors and downregulation of gene expression.
PubMed: 38946224
DOI: 10.1002/cbdv.202400393 -
European Journal of Medicinal Chemistry Jun 2024An optimization of the pyridylpiperazine series against Plasmodium falciparum has been performed, exploring a structure-activity relationship carried out on the toluyl...
An optimization of the pyridylpiperazine series against Plasmodium falciparum has been performed, exploring a structure-activity relationship carried out on the toluyl fragment of hit 1, a compound with low micromolar activity against Plasmodium falciparum discovered by high-throughput screening. After confirming the crucial role played by this aryl fragment in the antiplasmodial activity, the replacement of the ortho-methyl substituent of 1 by halogenated ones led to an improvement for four analogs, either in terms of potency, expected pharmacokinetics profile, or both. Further introduction of endocyclic nitrogens in this fragment identified two more optimized compounds, 20 and 23, which are expected to be much more metabolically stable than 1. Additional assessment of the cytotoxicity, Ligand Lipophilic Efficiency, potency against the chloroquine-resistant Dd2 strain and in silico ADMET predictions revealed a satisfactory profile for most compounds, ultimately identifying the four optimized compounds 7, 9, 20 and 23 as promising compounds for further lead optimization of this series against Plasmodium falciparum.
PubMed: 38944935
DOI: 10.1016/j.ejmech.2024.116621 -
Nature Communications Jun 2024One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and... (Randomized Controlled Trial)
Randomized Controlled Trial
One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and mortality in participants with advanced HIV randomised to cotrimoxazole or enhanced antimicrobial prophylaxis in the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial (ISRCTN43622374). Biomarkers were assayed using ELISA and Luminex. Associations between baseline values and all-cause 24-week mortality were analysed using Cox models, and for cause-specific mortality used Fine & Gray models, including prophylaxis randomisation, viral load, CD4, WHO stage, age, BMI, and site as covariates; and weighted according to inverse probability of selection into the substudy. Higher baseline CRP, IFN-γ, IL-6 and IP-10 were associated with higher all-cause mortality; and higher IL-23, IL-2 and RANTES with lower all-cause mortality. Associations varied by cause of death: tuberculosis-associated mortality was most strongly associated with higher CRP and sST2, and cryptococcosis-associated mortality with higher IL-4 and lower IL-8. Changes in I-FABP (p = 0.002), faecal alpha-1 antitrypsin (p = 0.01) and faecal myeloperoxidase (p = 0.005) between baseline and 4 weeks post-ART were greater in those receiving enhanced versus cotrimoxazole prophylaxis. Our findings highlight how the immune milieu shapes outcomes following ART initiation, and how adjunctive antimicrobials can modulate the gut environment in advanced HIV.
Topics: Humans; HIV Infections; Biomarkers; Africa South of the Sahara; Male; Female; Adult; Adolescent; Trimethoprim, Sulfamethoxazole Drug Combination; Viral Load; Young Adult; Anti-HIV Agents; Child
PubMed: 38944653
DOI: 10.1038/s41467-024-49317-7 -
Parasites & Vectors Jun 2024Reliance on praziquantel for the treatment and control of schistosomiasis is likely to facilitate the emergence of drug resistance. Combination therapy targeting adult... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of single-dose artesunate plus sulfalene/pyrimethamine combined with praziquantel for the treatment of children with Schistosoma mansoni or Schistosoma haematobium in western Kenya: a randomised, open-label controlled trial.
BACKGROUND
Reliance on praziquantel for the treatment and control of schistosomiasis is likely to facilitate the emergence of drug resistance. Combination therapy targeting adult and juvenile schistosome worms is urgently needed to improve praziquantel efficacy and delay the potential development of drug resistance. We assessed the efficacy and safety of single-dose praziquantel combined with single-dose artesunate plus sulfalene-pyrimethamine in the treatment of Kenyan children with schistosomiasis.
METHODS
This was an open-label, randomised clinical trial involving 426 school-aged children (7-15 years old) diagnosed with Schistosoma mansoni (by Kato-Katz) or S. haematobium (by urine filtration). They were randomly assigned (1:1:1) to receive a single dose of praziquantel (40 mg/kg), a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate) or combination therapy using a single dose of praziquantel (40 mg/kg) combined with a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate). The primary outcome was cure and egg reduction rates at 6 weeks post-treatment in the available case population. Adverse events were assessed within 3 h after treatment.
RESULTS
Of the 426 children enrolled, 135 received praziquantel, 150 received artesunate plus sulfalene-pyrimethamine, and 141 received combination therapy. Outcome data were available for 348 (81.7%) children. For S. mansoni-infected children (n = 335), the cure rates were 75.6%, 60.7%, and 77.8%, and the egg reduction rates were 80.1%, 85.0%, and 88.4% for praziquantel, artesunate plus sulfalene-pyrimethamine, and combination therapy, respectively. For S. haematobium-infected children (n = 145), the corresponding cure rates were 81.4%, 71.1%, and 82.2%, and the egg reduction rates were 95.6%, 97.1%, and 97.7%, respectively. Seventy-one (16.7%) children reported mild-intensity adverse events. The drugs were well tolerated and no serious adverse events were reported.
CONCLUSIONS
A single oral dose of praziquantel combined with artesunate plus sulfalene-pyrimethamine cured a high proportion of children with S. haematobium but did not significantly improve the treatment efficacy for either urinary or intestinal schistosomiasis. Sequential administration of praziquantel and artesunate plus sulfalene-pyrimethamine may enhance the efficacy and safety outcomes.
Topics: Humans; Child; Praziquantel; Pyrimethamine; Animals; Adolescent; Artesunate; Female; Male; Schistosomiasis mansoni; Schistosoma haematobium; Schistosomiasis haematobia; Schistosoma mansoni; Drug Therapy, Combination; Kenya; Artemisinins; Treatment Outcome; Anthelmintics; Sulfalene; Drug Combinations; Parasite Egg Count
PubMed: 38943214
DOI: 10.1186/s13071-024-06359-6 -
BMC Microbiology Jun 2024Lactobacillus plantarum has been found to play a significant role in maintaining the balance of intestinal flora in the human gut. However, it is sensitive to commonly...
BACKGROUND
Lactobacillus plantarum has been found to play a significant role in maintaining the balance of intestinal flora in the human gut. However, it is sensitive to commonly used antibiotics and is often incidentally killed during treatment. We attempted to identify a means to protect L. plantarum ATCC14917 from the metabolic changes caused by two commonly used antibiotics, ampicillin, and doxycycline. We examined the metabolic changes under ampicillin and doxycycline treatment and assessed the protective effects of adding key exogenous metabolites.
RESULTS
Using metabolomics, we found that under the stress of ampicillin or doxycycline, L. plantarum ATCC14917 exhibited reduced metabolic activity, with purine metabolism a key metabolic pathway involved in this change. We then screened the key biomarkers in this metabolic pathway, guanine and adenosine diphosphate (ADP). The exogenous addition of each of these two metabolites significantly reduced the lethality of ampicillin and doxycycline on L. plantarum ATCC14917. Because purine metabolism is closely related to the production of reactive oxygen species (ROS), the results showed that the addition of guanine or ADP reduced intracellular ROS levels in L. plantarum ATCC14917. Moreover, the killing effects of ampicillin and doxycycline on L. plantarum ATCC14917 were restored by the addition of a ROS accelerator in the presence of guanine or ADP.
CONCLUSIONS
The metabolic changes of L. plantarum ATCC14917 under antibiotic treatments were determined. Moreover, the metabolome information that was elucidated can be used to help L. plantarum cope with adverse stress, which will help probiotics become less vulnerable to antibiotics during clinical treatment.
Topics: Lactobacillus plantarum; Metabolomics; Anti-Bacterial Agents; Ampicillin; Doxycycline; Reactive Oxygen Species; Purines; Stress, Physiological; Metabolic Networks and Pathways; Adenosine Diphosphate; Humans
PubMed: 38943061
DOI: 10.1186/s12866-024-03385-3 -
Nature Communications Jun 2024Transition metal-catalyzed asymmetric hydrogenation is one of the most efficient methods for the preparation of chiral α-substituted propionic acids. However, research...
Transition metal-catalyzed asymmetric hydrogenation is one of the most efficient methods for the preparation of chiral α-substituted propionic acids. However, research on this method, employing cleaner earth-abundant metal catalysts, is still insufficient in both academic and industrial contexts. Herein, we report an efficient nickel-catalyzed asymmetric hydrogenation of α-substituted acrylic acids affording the corresponding chiral α-substituted propionic acids with up to 99.4% ee (enantiomeric excess) and 10,000 S/C (substrate/catalyst). In particular, this method can be used to obtain (R)-dihydroartemisinic acid with 99.8:0.2 dr (diastereomeric ratio) and 5000 S/C, which is an essential intermediate for the preparation of the antimalarial drug Artemisinin. The reaction mechanism has been investigated via experiments and DFT (Density Functional Theory) calculations, which indicate that the protonolysis of the C-Ni bond of the key intermediate via an intramolecular proton transfer from the carboxylic acid group of the substrate, is the rate-determining step.
PubMed: 38942809
DOI: 10.1038/s41467-024-49801-0 -
Natural Product Research Jun 2024The study explored DC. for mosquito larvicidal potential by performing bioactivity-guided chemical investigation of its root extract resulting in isolation of the known...
The study explored DC. for mosquito larvicidal potential by performing bioactivity-guided chemical investigation of its root extract resulting in isolation of the known bioactive metabolite glaucarubinone (). Mosquito larvicidal activity of glaucarubinone () against the three vector species viz. and was determined using a modified WHO 2005 protocol. It was observed that larvae were the most susceptible species with LC 13.88 ppm and LC 70.01 ppm followed by and at 24 h of exposure. The mode of action as observed microscopically is the lysis of midgut and thorax cells of the third instar larvae. The crystal structure of the glaucarubinone () is reported for the first time using X-ray crystallography. This phytochemical product has the potential to act as a green alternative to existing chemical-based insecticides for integrated vector management.
PubMed: 38940013
DOI: 10.1080/14786419.2024.2371569 -
Journal of Global Health Jun 2024Malaria infection during pregnancy is associated with an increased risk of maternal death, as well as adverse birth outcomes. Intermittent preventive treatment in...
BACKGROUND
Malaria infection during pregnancy is associated with an increased risk of maternal death, as well as adverse birth outcomes. Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is known to improve pregnancy outcomes. However, the coverage of IPTp-SP in antenatal care (ANC) in sub-Saharan Africa remains well below the target. This study aims to estimate to what extent malaria service readiness affects the uptake of IPTp-SP during ANC visits in sub-Saharan African countries.
METHODS
This study included 3267 pregnant women attending ANC for the first time and 2797 pregnant women who had attended ANC more than a month ago in six sub-Saharan African countries. The readiness of malaria services at each institution includes four indicators: the presence of IPTp-SP guidelines, SP availability, integration of IPTp-SP service into ANC, and provider training on IPTp-SP. The outcome variable indicates whether a pregnant woman received IPTp-SP at her current ANC visit. A modified Poisson regression model estimated the associations between malaria service readiness and IPTp-SP uptake for women eligible for the first and subsequent doses.
RESULTS
For women eligible for their first dose, visiting an institution with available SP was associated with an increased probability of receiving IPTp-SP (risk ratio (RR) = 1.43; 95% confidence interval (CI) = 1.22 to 1.67, P < 0.001). For women who were eligible for their next dose, the availability of SP (RR = 1.17; 95% CI = 1.04 to 1.32, P = 0.008) and integration of IPTp-SP service into ANC (RR = 1.82; 95% CI = 1.21 to 2.74, P = 0.004) in the institution were associated with increased likelihood of IPTp-SP uptake. Counterfactual predictions indicated that enhanced provider training could boost IPTp-SP uptake in high-uptake countries, while better SP availability and IPTp-SP integration into ANC would significantly impact low-uptake countries.
CONCLUSIONS
For better IPTp-SP coverage, strategies should be customised. High uptake countries should focus on provider training, while low uptake ones should ensure IPTp-SP availability and service integration.
Topics: Humans; Female; Pregnancy; Antimalarials; Africa South of the Sahara; Pyrimethamine; Sulfadoxine; Malaria; Pregnancy Complications, Parasitic; Adult; Drug Combinations; Prenatal Care; Young Adult; Adolescent; Patient Acceptance of Health Care
PubMed: 38939971
DOI: 10.7189/jogh.14.04112