The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery

Abstract

Patients with decompensated cirrhosis are currently managed through targeted strategies aimed at preventing or treating specific complications. In contrast, a disease-modifying agent should, by definition, be aimed at globally addressing 'decompensated cirrhosis'. To be defined as a disease-modifying agent in decompensated cirrhosis, interventions need to demonstrate an unequivocal benefit on the course of disease in well-designed and adequately powered randomised clinical trials with hard endpoints (i.e. patient survival). These trials also need to define the target population, dosage and timing of administration, factors guiding treatment, temporary or permanent stopping rules, transferability to daily clinical practice, cost-effectiveness, and global treatment access. By eliminating the underlying cause of cirrhosis, aetiologic treatments can still influence the course of decompensated disease by halting or slowing down disease progression or even inducing reversion to the compensated state. In contrast, there remains an unmet clinical need for disease-modifying agents which can antagonise key pathophysiological mechanisms of decompensated cirrhosis, such as portal hypertension, gut translocation, circulatory dysfunction, systemic inflammation, and immunological dysfunction. However, in the last few years, the repurposing of "old drugs" that have already been prescribed for more limited indications in hepatology or for other diseases has provided a few candidates, including human albumin, statins, and poorly absorbable oral antibiotics, which are under further evaluation in large-scale randomised clinical trials. New disease-modifying agents are also expected to be identified in the next decade through the systematic repurposing of existing drugs and the development of novel molecules which are currently undergoing pre-clinical or early clinical testing.

Management of Ascites in Patients with Cirrhosis: An Update

“…Future research should focus on pathophysiological treatments, able to treat or prevent ascites in a wider context, ideally modifying the long-term clinical course of the disease, thus improving survival and quality of life for patients [75]. Such measures could derive from a better knowledge-and extended use-of currently available treatment (e.g., TIPS and albumin administration), from the repurposing or repositioning of existing drugs [76], or even from the development of innovative approaches or molecules.…”

A new model for identification of HBV-related pre-ACLF

“…Inflammatory markers, characterisation of immune cell function, cell-death markers, measurement of matrix proteins and use of agnostic approaches such as metabolomics and whole blood transcriptomics are starting to produce interesting data that may allow refinement of clinical prognostic models, whilst providing novel therapeutic targets [10]. Nevertheless, the data presented here provide the first clear indication of the importance of the type of precipitating event in defining progression of HBV cirrhosis patients with acute decompensation from no ACLF to ACLF.…”

Early Diagnosis and Prevention of Infections in Cirrhosis

“…Norfloxacin has favorable pharmacodynamics and pharmacokinetics [103]. The slow solubility, low permeability, and low systemic bioavailability of norfloxacin make it an ideal choice for SID [11].…”

“…[99][100][101][102] Norfloxacin has favorable pharmacodynamics and pharmacokinetics. 103 The slow solubility, low permeability, and low systemic bioavailability of norfloxacin make it an ideal choice for SID. 11 Furthermore, norfloxacin can reduce the LPS translocation-induced rise in iNOS, aortic Akt activity, and proinflammatory cytokine release and control systemic vasodilation.…”