Safety considerations for the management of cholestatic itch

Introduction: Pruritus is adisabling symptom common to cholestatic liver disorders. Its pathophysiology has not been completely elucidated and although multiple mediators have been identified, only lysophosphatidic acid (LPA) and its synthetizing enzyme autotaxin (ATX) appear to consistently correlate with symptom intensity. This review aims to summarize the most relevant safety and efficacy data regarding both standard and new medications utilized to treat pruritus in cholestatic liver disease. Areas covered: International societies like the AASLD and EASL recommend astepwise approach for the management of cholestatic itch. However, therapeutic response is variable. Cholestyramine is considered first-line, followed by rifampicin, naltrexone and sertraline. When used appropriately, these medications have afavorable adverse events profile with most side effects related to drug class and not to the underlying etiology of liver disease. Expert opinion: Although conventional therapies seem to be effective in aproportion of patients, asizable number of cases remain refractory and require the utilization of experimental treatments. Multiple potential targets, especially in the ATX-LPA axis have yet to be pharmacologically explored, with ongoing translational and clinical research. Novel drugs are currently being developed for the management of cholestatic itching with promising results and afavorable safety profile

Primary biliary cholangitis: Epidemiology, prognosis, and treatment

Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC vary widely in different regions and time periods, and although disproportionally more common among White non-Hispanic females, contemporary data show a higher prevalence in males and racial minorities than previously described. Outcomes largely depend on early recognition of the disease and prompt institution of treatment, which, in turn, are directly influenced by provider bias and socioeconomic factors. Ursodeoxycholic acid remains the initial treatment of choice for PBC, with obeticholic acid and fibrates (off-label therapy) reserved as add-on therapy for the management of inadequate responders or those with ursodeoxycholic acid intolerance. Novel and repurposed drugs are currently at different stages of clinical development not only for the treatment of PBC but also for its symptomatic management. Here, we summarize the most up-to-date data regarding the epidemiology, prognosis, and treatment of PBC, providing clinically useful information for its holistic management

Enabling Active/Passive Electricity Trading in Dual-Price Balancing Markets

In electricity markets with a dual-pricing scheme for balancing energy, controllable production units typically participate in the balancing market as "active" actors by offering regulating energy to the system, while renewable stochastic units are treated as "passive" participants that create imbalances and are subject to less competitive prices. Against this background, we propose an innovative market framework whereby the participant in the balancing market is allowed to act as an active agent (i.e., a provider of regulating energy) in some trading intervals and as a passive agent (i.e., a user of regulating energy) in some others. To illustrate and evaluate the proposed market framework, we consider the case of a virtual power plant (VPP) that trades in a two-settlement electricity market composed of a day-ahead and a dual-price balancing market. We formulate the optimal market offering problem of the VPP as a three-stage stochastic program, where uncertainty is in the day-ahead electricity prices, balancing prices and the power output from the renewable units. Computational experiments show that the VPP expected revenues can increase substantially compared to an active-only or passive-only participation, and in the paper we discuss how the variability of the stochastic sources affects the balancing market participation choice

Dasabuvir: a new direct antiviral agent for the treatment of hepatitis C

Introduction: Treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) has revolutionized the care of infected patients. Among these novel compounds are non-nucleoside analogs, which bind viral RNA-dependent RNA polymerase resulting in a conformational change inhibiting RNA synthesis. Areas covered: Efficacy and tolerability of treatment regimens containing the non-nucleoside analog polymerase inhibitor dasabuvir (ABT-333). Expert opinion: Dasabuvir-containing regimens achieve high rates of sustained virologic response in HCV genotype 1a and 1b-infected patients when combined with other DAAs, namely paritaprevir (ABT-450), ritonavir and ombitasvir (ABT-267). In the populations studied, dasabuvir seems to be well tolerated and safe. The major limitations of this novel drug are its genotype-restricted activity, the necessity to include ribavirin for HCV genotype 1a and the emergence of resistance if not combined with other DDAs

Novel targeted therapies for the management of liver fibrosis

Introduction: Prolonged liver injury results in tissue damage and replacement by extracellular matrix and fibrosis. Cirrhosis represents a leading cause of mortality worldwide and imposes a major financial burden on health-care systems. Fortunately, fibrogenesis has proven to be reversible if halted early, encouraging the development of novel anti-fibrotic agents that may accelerate histological restoration. Preclinical data have elucidated numerous potential therapeutic targets and many anti-fibrotic agents are currently at various stages of clinical research. Areas covered: The present review summarizes recent clinical data regarding anti-fibrotic drugs including monoclonal antibodies, targeted conjugates, and small molecule agents. Expert opinion: Although undeniable progress has been made in the development of anti-fibrotic agents in recent years, most data currently available are derived from preclinical and early clinical studies. The efficacy and safety of these agents will need to be corroborated by larger clinical trials, some of which are ongoing with results expected in the upcoming years. Combination therapy with agents targeting different pathways of fibrogenesis will also be of great interest for the future and will need to be explored in clinical trials