Emricasan (IDN-6556) Lowers Portal Pressure in Patients with Compensated Cirrhosis and Severe Portal Hypertension

Caspases play a central role in apoptosis, inflammation and fibrosis. They produce hemodynamically-active, pro-inflammatory microparticles that cause intrahepatic inflammation, vasoconstriction and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (HVPG >5 mmHg). Emricasan 25 mg BID was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings.Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were NASH and HCV. Subjects were Child class A (87%) with median MELD score of 8 (range 6-15). Twelve had severe PH (HVPG?12mmHg). Overall, there was no significant change in HVPG after emricasan (mean [SD] -1.1[4.57] mmHg). HVPG decreased significantly (mean [SD] -3.7[4.05] mmHg; p=0.003) in those with severe PH. 4/12 had a ?20% decrease; 8/12 had a ?10% decrease; and 2/12 HVPG decreased below 12mmHg. There were no significant changes in blood pressure or heart rate. AST/ALT decreased significantly in the entire group and in severe PH. Serum cCK18 and caspase-3/7 decreased significantly. Emricasan was well-tolerated. One subject discontinued for non-serious adverse events.Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH. An effect upon portal venous inflow is likely and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Study of hemodynamic changes in models of fulminant hepatic failure: ischemic and anhepatic (experimental study)

Acute liver failure or fulminant hepatic failure (FHF) is a rare disorder that often leads to devastating consequences. Before transplantation was possible, the case mortality rate was 80%. Currently, liver transplantation is the only treatment universally accepted. The removal of the non functioning liver in case of terminal stage of fulminant hepatic failure or primary non function of the liver graft, and the patient’s support by various systems until a proper graft is found was thought to be a salvage procedure. The aim of our study was to compare the hemodynamic alterations in the anhepatic (total hepatectomy) and the ischemic experimental models FHF.Methods: Twenty young landrace pigs, weighting 20-25 kgr were studied. Ligation of the hepatic artery and portocaval anstomosis was performed (model of ischemic hepatic injury) and the animals were observed for a period of 18 hours. The induction of FHF was confirmed by biochemical indices and the animals were randomly assigned either to Group A (ischemic model) in which the liver was left in place and monitoring was performed , or Group B (anhepatic model) for which total hepatectomy was. No inotropic agents were administered during the period of observation. Statistical evaluation was performed using one way ANOVA analysis and t-testResults: Hemodynamic deterioration was observed in Group B (anhepatic model) (Cardiac index in Group A 7.59± 1.25 L min'1 m 2 vs. 2.92± 0.68 L min'1 m0 in Group B, P < 0.05.). Conclusions: The results of this study demonstrated a greater hemodynamic deterioration after total hepatectomy compared to the ischemic liver model. It is possible that the maintenance of a malfunctioning liver may be preferable in cases of FHF in terms of hemodynamic stability.Η οξεία ήπατική ή κεραυνοβόλος ηπατική ανεπάρκεια (ΚΗΑ) αν και όχι ιδιαίτερα συχνή, έχει χαρακτηρισθεί σαν μια από τις πιο επικίνδυνες νοσογόνες οντότητες με θνητότητα που κυμαίνεται μεταξύ 80 - 97 % προτού η μεταμόσχευση ήπατος ήταν δυνατή. Η μεταμόσχευση ήπατος είναι η μόνη αποδεκτή παγκοσμίως θεραπεία για ασθενείς με ΚΗΑ . Η αφαίρεση του μη λειτουργούντος ήπατος σε περίπτωση τελικού σταδίου ΚΗΑ ή μη λειτουργίας του μεταμοσχευμένου ήπατος αμέσως μετά τη μεταμόσχευση, και η υποστήριξη του ασθενή με διάφορα συστήματα υποστήριξης έως ότου βρεθεί ένα κατάλληλο μόσχευμα είναι, πιθανά, μια επέμβαση διάσωσης. Ο στόχος της μελέτης μας ήταν να συγκριθούν οι αιμοδυναμικές μεταβολές στο ανηπατικό (ολική ηπατεκτομή) και ισχαιμικό πειραματικό πρότυπο ΚΗΑ. Μέθοδοι: Είκοσι νέοι χοίροι γένους landrace, βάρους 20-25 kg μελετήθηκαν. Απολίνωση της ηπατικής αρτηρίας και πυλαιοκοιλική αναστόμωση εκτελέσθηκε (ισχαιμικό πρότυπο) και τα ζώα παρατηρήθηκαν για μια περίοδο 18ωρών. Η επαγωγή της ΚΗΑ επιβεβαιώθηκε χρησιμοποιώντας βιοχημικούς δείκτες. Στη συνέχεια τα ζώα χωρίσθηκαν τυχαία στη μία από τις δύο ομάδες : A (ισχαιμικό πρότυπο), 10 χοίροι, όπου καμία περαιτέρω χειρουργική επέμβαση δεν ακολουθούσε τη διάνοιξη και σύγκλειση του κοιλιακού τοιχώματος , ή ομάδα Β (ανηπατικό πρότυπο), 10 χοίροι που υποβλήθηκαν σε ολική ηπατεκτομή. Ινότροποι παράγοντες δεν χορηγήθηκαν καθ' όλη τη διάρκεια της περιόδου παρατήρησης. Η στατιστική αξιολόγηση εκτελέσθηκε χρησιμοποιώντας ανάλυση ANOVA και t-test.Αποτελέσματα: Αιμοδυναμική επιδείνωση παρατηρήθηκε στην ομάδα Β(ανηπατικόπρότυπο) (καρδιακός δείκτης στην ομάδα A 7.59± 1.25 Lmin 1 m'2 ενώ 2.92± 0.68 L min 1 m2 για την ομάδα Β, Ρ < 0.05.).Συμπεράσματα: Τα αποτελέσματα αυτής της μελέτης κατέδειξαν μεγαλύτερη αιμοδυναμική επιδείνωση μετά από ολική ηπατεκτομή. Είναι δυνατό η συντήρηση ενός δυσλειτουργώντος ήπατος να είναι προτιμητέα σε περιπτώσεις ΚΗΑ από την άποψη της αιμοδυναμικής σταθερότητας

Comparative Readability Analysis of Online Patient Education Resources on Inflammatory Bowel Diseases

Background. The National Institutes of Health recommend a readability grade level of less than 7th grade for patient directed information. In this study, we use validated readability metrics to analyze patient information from prominent websites pertaining to ulcerative colitis and Crohn’s disease. Methods. The terms “Crohn’s Disease,” “Ulcerative Colitis,” and “Inflammatory Bowel Disease” were queried on Google and Bing. Websites containing patient education material were saved as a text file and then modified through expungement of medical terminology that was described within the text. Modified text was then divided into subsections that were analyzed using six validated readability scales. Results. None of the websites analyzed in this study achieved an estimated reading grade level below the recommended 7th grade. The median readability grade level (after modification) was 11.5 grade levels for both Crohn’s disease and ulcerative colitis. The treatment subsection required the highest level of education with a median readability grade of 12th grade (range of 6.9 to 17). Conclusion. Readability of online patient education material from the analyzed popular websites far exceeds the recommended level of being less than 7th grade. Patient education resources should be revised to achieve wider health literacy