Clin Pharmacol Ther. 2022 Sep 10. doi: 10.1002/cpt.2745. Online ahead of print.
ABSTRACT
High saturated fat diets have been shown to raise blood levels of cholecystokinin (CCK) and induce nonalcoholic steatohepatitis (NASH). CCK receptors are expressed on stellate cells and responsible for hepatic fibrosis when activated. The purpose of this study was to test the safety and dose of a CCK receptor antagonist, proglumide, in human subjects with NASH. An open-labeled single ascending dose study was conducted in 18 subjects with clinical NASH based upon steatosis by liver ultrasound, elevated hepatic transaminases, and a component of the metabolic syndrome. Three separate cohorts (N=6 each) were treated with oral proglumide for 12 weeks in a sequential ascending fashion with 800 (cohort-1), 1200 (cohort-2), and 1600 (cohort-3) mg/day, respectively. Blood hematology, chemistries, proglumide levels, a biomarker panel for fibrosis, and symptom surveys were determined at baseline and every four weeks. Abdominal ultrasounds and transient elastography utilizing FibroScan® were obtained at baseline and at week-12. Proglumide was well tolerated at all doses without any serious adverse events. There was no change in body weight from baseline to week-12. For Cohorts-1, -2, and -3, the median percent change in alanine aminotransferase was 8.42, -5.05, and -22.23 and median percent change in fibrosis score by FibroScan® was 8.13, -5.44, and -28.87 (kPa), respectively. Hepatic steatosis as measured by CAP score significantly decreased with proglumide, (P<0.05). Blood microRNA biomarkers and serum 4-hydroxyproline were consistent with decreased fibrosis at week-12 compared to baseline. These findings suggest proglumide exhibits anti-inflammatory and anti-fibrotic properties and this compound is well tolerated in subjects with NASH.
PMID:36087237 | DOI:10.1002/cpt.2745
