First-in-human study of alpibectir (BVL-GSK098), a novel potent anti-TB drug.

Background: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo.

Objectives: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143).

Methods: Eighty participants were randomized.

A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial.

New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis.

Investigating dihydroorotate dehydrogenase inhibitor mediated mitochondrial dysfunction in hepatic in vitro models.

Inhibition of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzymatic step in de novo pyrimidine synthesis, has broad immunosuppressive effects in vivo and shows promise as a therapeutic target for the treatment of malignancies, viral infections and auto-immune diseases. Whilst there are numerous DHODH inhibitors under development, leflunomide and teriflunomide are the only FDA approved compounds on the market, each of which have been issued with black-box warnings for hepatotoxicity. Mitochondrial dysfunction is a putative mechanism by which teriflunomide and leflunomide elicit their hepatotoxic effects, however it is as yet unclear whether this is shared by other nascent DHODH inhibitors.

Cell Membrane Transporters Facilitate the Accumulation of Hepatocellular Flucloxacillin Protein Adducts: Implication in Flucloxacillin-Induced Liver Injury.

Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver reactions. Although expression of HLA-B*57:01 increases susceptibility, little is known about the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the presentation of flucloxacillin-modified peptides by the risk allele.

The utility of a differentiated preclinical liver model, HepaRG cells, in investigating delayed toxicity via inhibition of mitochondrial-replication induced by fialuridine.

During its clinical development fialuridine caused liver toxicity and the death of five patients. This case remains relevant due to the continued development of mechanistically-related compounds against a back-drop of simple in vitro models which remain limited for the preclinical detection of such delayed toxicity. Here, proteomic investigation of a differentiated, HepaRG, and proliferating, HepG2 cell model was utilised to confirm the presence of the hENT1 transporter, thymidine kinase-1 and -2 (TK1, TK2) and thymidylate kinase, all essential in order to reproduce the cellular activation and disposition of fialuridine in the clinic.

Safety perspectives on presently considered drugs for the treatment of COVID-19.

Intense efforts are underway to evaluate potential therapeutic agents for the treatment of COVID-19. In order to respond quickly to the crisis, the repurposing of existing drugs is the primary pharmacological strategy. Despite the urgent clinical need for these therapies, it is imperative to consider potential safety issues.

The mitochondrial paradox.

A structural motif that is found in two cancer drugs may be responsible for their ability to tackle cancers and for the side-effects caused by the drugs.

Investigating the importance of individual mitochondrial genotype in susceptibility to drug-induced toxicity.

The mitochondrion is an essential organelle responsible for generating cellular energy. Additionally, mitochondria are a source of inter-individual variation as they contain their own genome. Evidence has revealed that mitochondrial DNA (mtDNA) variation can confer differences in mitochondrial function and importantly, these differences may be a factor underlying the idiosyncrasies associated with unpredictable drug-induced toxicities.

Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells.

Bile acids (BAs) are recognised as the causative agents of toxicity in drug-induced cholestasis (DIC). Research in isolated mitochondria and HepG2 cells have demonstrated BA-mediated mitochondrial dysfunction as a key mechanism of toxicity in DIC. However, HepG2 cells are of limited suitability for DIC studies as they do not express the necessary physiological characteristics.