All feature a chromanol ring, with a group that can donate an atom to reduce free radicals LDK378 manufacturer and a side chain that allows for penetration into biological membranes. There are substantial differences in the biological properties of these compounds. The natural form of vitamin E (rrr α-tocopherol) has been shown to improve the histological features of NASH in a large, prospective, controlled

trial.30 These data are corroborated by several smaller studies. It is, however, important to note that vitamin E is not a panacea and only improves histological features in 43% of subjects.30 There is considerable controversy over whether vitamin E produces a small but significant increase in all-cause mortality when taken as a health supplement.33-36 Therefore, there is room for additional therapies for NASH. In this issue of HEPATOLOGY, Zein et al.37 provide evidence of improvement of NASH following pentoxifylline administration. The rationale for the use of pentoxifylline is based on its reported ability to inhibit the synthesis/release of tumor necrosis factor-α (TNF-α) and its ability to inhibit TNF- and eicosanoid-induced

inflammatory responses.38 TNF-α is a proinflammatory, proapoptotic cytokine that is activated as part of the innate immune system and has been implicated as a key player in the development of hepatic steatosis and steatohepatitis. The development of hepatic steatosis has also been shown to increase the susceptibility of hepatocytes to TNF-mediated apoptosis.39 Prior small trials have also shown the promise of efficacy of pentoxifylline NVP-AUY922 clinical trial for treatment of NASH.40, 41 The data from Zein et al.37 further corroborate these early data. The ideal treatment for NASH should be one that decreases overall mortality, including liver-related and cardiovascular Alectinib deaths, while

remaining safe, widely available, and relatively inexpensive. Demonstration of an improvement of all-cause mortality would require a very large study followed over an extended period of time. These considerations make it impractical to use this as a primary endpoint in clinical trials, and instead has led to the use of surrogate endpoints to determine the efficacy of a drug for NASH. Because liver-related mortality is associated mainly with cirrhosis, prevention of cirrhosis or reversal of the disease associated with cirrhosis, i.e., steatohepatitis, is often considered acceptable as an endpoint for NASH. Because steatohepatitis may disappear with disease progression, it is further imperative to combine this endpoint with “at least no worsening of fibrosis” to make it clinically relevant.42 In the study by Zein et al., the primary endpoint was a decrease in the NAFLD activity score (NAS) of 2 or greater. This score was developed as a relatively quantifiable way to evaluate the impact of drug treatment on the severity of key histological features of NASH.