Utilizing graph machine learning within drug discovery and development.

Graph machine learning (GML) is receiving growing interest within the pharmaceutical and biotechnology industries for its ability to model biomolecular structures, the functional relationships between them, and integrate multi-omic datasets - amongst other data types. Herein, we present a multidisciplinary academic-industrial review of the topic within the context of drug discovery and development. After introducing key terms and modelling approaches, we move chronologically through the drug development pipeline to identify and summarize work incorporating: target identification, design of small molecules and biologics, and drug repurposing.

Combating resistance while maintaining innovation: the future of antimicrobial stewardship.

Antimicrobial resistance represents a significant global health threat. However, a commercial model that does not offer a return on investment resulting in a lack of investment in antibiotic R&D, means that the current pipeline of antibiotics lacks sufficient innovation to meet this challenge. Those responsible for defining, promoting and monitoring the rationale use of antibiotics (the antimicrobial stewardship programme) are key to addressing current shortcomings.

Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial.

Importance: There are no medical interventions for the orphan disease CYLD cutaneous syndrome (CCS). Transcriptomic profiling of CCS skin tumors previously highlighted tropomyosin receptor kinases (TRKs) as candidate therapeutic targets.

Objective: To investigate if topical targeting of TRK with an existing topical TRK inhibitor, pegcantratinib, 0.

Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study.

Background: Clostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection.

Methods: We did a phase 2, randomised, double-blind, active-controlled, non-inferiority study.

Tropomyosin Receptor Antagonism in Cylindromatosis (TRAC), an early phase trial of a topical tropomyosin kinase inhibitor as a treatment for inherited CYLD defective skin tumours: study protocol for a randomised controlled trial.

Background: Patients with germline mutations in a tumour suppressor gene called CYLD develop multiple, disfiguring, hair follicle tumours on the head and neck. The prognosis is poor, with up to one in four mutation carriers requiring complete surgical removal of the scalp. There are no effective medical alternatives to treat this condition.

Topical TrkA Kinase Inhibitor CT327 is an Effective, Novel Therapy for the Treatment of Pruritus due to Psoriasis: Results from Experimental Studies, and Efficacy and Safety of CT327 in a Phase 2b Clinical Trial in Patients with Psoriasis.

Pruritus is an important symptom in psoriasis with no targeted treatment. Tropomyosin-receptor kinase A (TrkA) is associated with pruritus and psoriatic plaque formation. We report the efficacy of a TrkA inhibitor, CT327, on pruritus in psoriasis.

Translational research in the pharmaceutical industry: from theory to reality.

Translational research is the collaboration between scientists and clinicians to identify novel targets and develop biomarkers that increase confidence in rationale and therefore help select the mechanisms that are most likely to lead to breakthrough therapies. Here, we describe examples of the utility of linked preclinical and clinical biomarkers to measure pharmacological effects, to estimate clinical dose range, to determine efficacy, and to determine differentiation compared with existing therapies. The use of pharmacogenomics to identify novel drug targets and define enriched patient subpopulations is also discussed.

Translational research in the pharmaceutical industry: from bench to bedside.

Current developments in basic discovery sciences have not been mirrored by the same level of progress in understanding the clinical basis of disease and ultimately the development of novel effective therapies. This can be improved by applying translational research throughout the late-stage discovery and exploratory development stages of drug development. A bi-directional dialogue between research scientists and clinicians concerning the biology of mechanism of action and clinical basis for disease will deliver biomarkers that enable drug development decisions to be made earlier and with increased confidence.

Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease.

Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction. The wide use of sildenafil by patients with erectile dysfunction and cardiovascular disease has resulted in a considerable number of independent studies investigating the cardiovascular safety and functional role of the phosphodiesterase type 5-cyclic guanosine monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide, is associated with many of the common risk factors for cardiovascular disease and erectile dysfunction.