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Exploration of solubilisation effects facilitated by the combination of Soluplus® with ionic surfactants.
Eur J Pharm Sci
November 2024
Roche Pharmaceutical Research & Early Development, preclinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, Basel, CH-4070, Basel City, Switzerland.
Preclinical testing of new drug candidates frequently necessitates high-dose solution formulations to support robust testing in rodent models. This study aimed to expand the range of high solubilisation capacity formulations by exploring the solubilisation effects of the polymeric surfactant Soluplus® in combination with ionic surfactants. The interactions between Soluplus® and three ionic surfactants, sodium dodecyl sulphate, dioctyl sodium succinate, and sodium oleate, with a primary focus on solubility enhancement were investigated over a range of ionic surfactant concentrations.
View Article and Find Full Text PDFLeveraging large-scale Mycobacterium tuberculosis whole genome sequence data to characterise drug-resistant mutations using machine learning and statistical approaches.
Sci Rep
November 2024
Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
Tuberculosis disease (TB), caused by Mycobacterium tuberculosis (Mtb), is a major global public health problem, resulting in > 1 million deaths each year. Drug resistance (DR), including the multi-drug form (MDR-TB), is challenging control of the disease. Whilst many DR mutations in the Mtb genome are known, analysis of large datasets generated using whole genome sequencing (WGS) platforms can reveal new variants through the assessment of genotype-phenotype associations.
View Article and Find Full Text PDFSelective HLA Class II Allele-Restricted Activation of Atabecestat Metabolite-Specific Human T-Cells.
Chem Res Toxicol
October 2024
Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K.
Elevations in hepatic enzymes were detected in several trial patients exposed to the Alzheimer's drug atabecestat, which resulted in termination of the drug development program. Characterization of hepatic T-lymphocyte infiltrates and diaminothiazine (DIAT) metabolite-responsive, human leukocyte antigen (HLA)-DR-restricted, CD4+ T-lymphocytes in the blood of patients confirmed an immune pathogenesis. Patients with immune-mediated liver injury expressed a restricted panel of HLA-DRB1 alleles including HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01.
View Article and Find Full Text PDFPhysiologically-Based Pharmacokinetic Modeling of Total and Unbound Valproic Acid to Evaluate Dosing in Children With and Without Hypoalbuminemia.
Clin Pharmacokinet
October 2024
Division of Clinical Pharmacology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Background And Objective: Valproic acid (VPA) demonstrates nonlinear pharmacokinetics (PK) due to a capacity-limited protein binding, which has potential implications on its total and unbound plasma concentrations, especially during hypoalbuminemia. A physiologically based pharmacokinetic (PBPK) model was developed to assess the nonlinear dose-exposure relationship of VPA with special emphasis on pediatric patients with hypoalbuminemia.
Methods: A PBPK model was first developed and evaluated in adults using PK-Sim and MoBi (v.
Unlabelled: Successful tuberculosis therapy requires treatment with an unwieldy multidrug combination for several months. Thus, there is a growing need to identify novel genetic vulnerabilities that can be leveraged to develop new, more effective antitubercular drugs. Consequently, recent efforts to optimize TB therapy have exploited Mtb chemical genetics to identify pathways influencing antibiotic efficacy, novel mechanisms of antibiotic action, and new targets for TB drug discovery.
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