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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 -
Case Reports in Ophthalmological... 2024To the best of our knowledge, we present the first case of type II acute macular neuroretinopathy (AMN) exhibiting in a patient suffering from malarial retinopathy...
To the best of our knowledge, we present the first case of type II acute macular neuroretinopathy (AMN) exhibiting in a patient suffering from malarial retinopathy concomitant with cerebral malaria acquired after travelling to West Africa without taking the necessary antimalarial prophylaxis. The patient complained of bilateral blurring of vision after being removed off sedation whilst at the intensive care unit. Subsequent examination revealed bilateral retinal haemorrhages, cotton-wool spots, and foveal pigmentary changes in keeping malarial retinopathy. Macular optical coherence tomography (OCT) revealed patchy hyperreflective changes at the level of the outer plexiform and outer nuclear layers (ONL) in keeping with the areas of deep capillary plexus flow void noted on OCT-angiography (OCT-A). This case report sheds more light on the extent of neurosensory retinal ischaemia in malarial retinopathy and showcases a new imaging biomarker which may be utilized in assessing and quantifying the functional deficit created by this disease.
PubMed: 38938742
DOI: 10.1155/2024/1577127 -
The Senior Care Pharmacist Jul 2024The objective of this analysis is to investigate the risk of hyperkalemia in hospitalized patients using sulfamethoxazole-trimethoprim (Co-trimoxazole) and a... (Observational Study)
Observational Study
The objective of this analysis is to investigate the risk of hyperkalemia in hospitalized patients using sulfamethoxazole-trimethoprim (Co-trimoxazole) and a potassium-sparing drug (potassium-sparing diuretic or renin-angiotensin system [RAS]-inhibitor). Researchers conducted a nested case control study within a cohort of hospitalized patients using a potassium-sparing diuretic and/or a RAS-inhibitor from the PHARMO Database Network. Researchers estimated the odds ratios (ORs) and 95% confidence intervals (CI) for the risk of hyperkalemia in patients receiving both Co-trimoxazole and a potassium-sparing drug compared with patients only receiving a potassium-sparing drug. Among a cohort of 25,849 patients, researchers identified 2054 cases of hyperkalemia during hospitalization in patients also using a potassium-sparing drug. Using Co-trimoxazole in addition to a potassium-sparing drug was associated with an increased risk of hyperkalemia in hospitalized patients (OR = 1.65, 95% CI 1.26-2.16) compared with using only a potassium-sparing drug. There was a trend of a more pronounced association between hyperkalemia and the co-use of Co-trimoxazole and potassium-sparing drugs in patients with an estimated GFR of 15-29 mL/min (OR = 3.15, 95% CI 1.29-7.70). The number needed to harm for hyperkalemia induced by adding Co-trimoxazole to patients receiving a potassium-sparing drug is 19.5. Using the combination of Co-trimoxazole with a potassium-sparing drug in hospitalized patients increases the risk of hyperkalemia compared with using only a potassium-sparing drug. Physicians and other prescribers should be aware of hyperkalemia and routinely monitor serum potassium levels in hospitalized patients using this combination of drugs.
Topics: Hyperkalemia; Humans; Trimethoprim, Sulfamethoxazole Drug Combination; Male; Female; Aged; Hospitalization; Middle Aged; Case-Control Studies; Diuretics, Potassium Sparing; Cohort Studies; Aged, 80 and over; Potassium; Adult
PubMed: 38937893
DOI: 10.4140/TCP.n.2024.259 -
Current Molecular Pharmacology Jun 2024Artemisinin and its derivatives, the well-known anti-malarial drugs extracted from traditional Chinese medicine, have been implicated in treating fibrotic diseases....
BACKGROUND AND OBJECTIVES
Artemisinin and its derivatives, the well-known anti-malarial drugs extracted from traditional Chinese medicine, have been implicated in treating fibrotic diseases. However, whether artemisinin affects cardiac fibrosis in the pathogenesis of heart failure is still unknown. This study aimed to evaluate the possible effects of artemisinin on cardiac function and myocardial fibrosis in the heart failure model and to explore the underlying mechanisms.
METHODS
Isoproterenol was injected subcutaneously for induction of the cardiac fibrosis model. Proteomic analysis was performed after 4 four weeks of artemisinin treatment. Echocardiography was used to evaluate cardiac function and structure. Hematoxylin and eosin (H&E) staining, as well as Masson staining, were performed for histopathology. The α-SMA, collagen I, and III expression in the myocardium was detected by Immunohistochemical staining. The ratio of heart weight (HW) to body weight (HW/BW, mg/kg) and the ratio of heart weight to tibia length (HW/TL, mg/mm) were calculated as indicators for cardiac remodeling. Brain natriuretic peptide (BNP) levels were quantified in rat plasma using enzyme-linked immunosorbent assay (ELISA). In contrast, the protein levels of TGF-β1, p-Smad2/3, and Smad2/3 were assessed in myocardium and fibroblasts via western blot analysis. RT-qPCR analysis of Col-I, Col-III, α-SMA, NLRP3, Caspase-1, IL-1β, and IL-18 was performed in the heart.
RESULTS
Proteomic analysis identified 227 differentially expressed proteins (DEPs), including 119 upregulated and 108 downregulated proteins. These proteins were identified as the core proteins targeted by artemisinin for improving myocardial remodeling. GO annotation of the DEPs indicated that the DEPs were mainly associated with biological processes such as TGF-β and NLRP3 inflammasome regulation. In the in vivo study of an isoproterenol-induced SD rat cardiac remodeling model, we found that artemisinin administration significantly ameliorated cardiac dysfunction and reduced collagen production by suppressing TGFβ-1/Smads signaling and inhibiting NLRP3 inflammasome activation. As manifested by downregulating the expression of α-SMA, Col-I, and Col-III, NLRP3, IL-1β, IL-18, Caspase-1 mRNA, and TGF-β1, p-SMAD 2/3 protein in the myocardium. Similar beneficial effects of artemisinin were consistently observed in TGF-β1 treated primary cardiac fibroblasts.
CONCLUSIONS
Artemisinin relieves myocardial remodeling through TGF-β1/Smad2/3 pathway and NLRP3 inflammasome.
.PubMed: 38934281
DOI: 10.2174/0118761429304142240528093541