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 are 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 participants with NASH. An open-label single ascending dose study was conducted in 18 participants 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), 1,200 (Cohort 2), and 1,600 (Cohort 3) mg/day, respectively. Blood hematology, chemistries, proglumide levels, a biomarker panel for fibrosis, and symptom surveys were determined at baseline and every 4 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 controlled attenuation parameter score significantly decreased with proglumide, (P < 0.05). Blood microRNA biomarkers and serum 4-hydroxyproline were consistent with decreased fibrosis at Week 12 compared with baseline. These findings suggest proglumide exhibits anti-inflammatory and anti-fibrotic properties and this compound is well tolerated in participants with NASH.

中文翻译：

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胆囊收缩素受体拮抗剂治疗非酒精性脂肪性肝炎的安全性和剂量研究


高饱和脂肪饮食已被证明会提高血液中胆囊收缩素（CCK）的水平并诱发非酒精性脂肪性肝炎（NASH）。 CCK 受体在星状细胞上表达，激活后会导致肝纤维化。本研究的目的是测试 CCK 受体拮抗剂丙谷胺对 NASH 人类参与者的安全性和剂量。对 18 名患有临床 NASH 的受试者进行了一项开放标签单剂量递增研究，该研究基于肝脏超声显示的脂肪变性、肝转氨酶升高以及代谢综合征的一个组成部分。三个独立队列（每组N = 6）以连续递增的方式口服丙谷胺治疗 12 周，剂量分别为 800（队列 1）、1,200（队列 2）和 1,600（队列 3）mg/天。在基线和每 4 周测定一次血液学、化学、丙谷胺水平、纤维化生物标志物组和症状调查。在基线和第 12 周时使用 FibroScan 进行腹部超声检查和瞬时弹性成像。丙谷胺在所有剂量下均具有良好的耐受性，没有任何严重的不良事件。从基线到第 12 周，体重没有变化。对于队列 1、2 和 3，丙氨酸氨基转移酶的中位百分比变化为 8.42、-5.05 和 -22.23，FibroScan 的纤维化评分中位百分比变化为 8.13，分别为-5.44和-28.87 (kPa)。通过受控衰减参数评分测量的肝脂肪变性在丙谷胺使用后显着降低（ P < 0.05）。与基线相比，第 12 周时血液 microRNA 生物标志物和血清 4-羟脯氨酸与纤维化减少一致。 这些发现表明丙谷胺具有抗炎和抗纤维化特性，并且该化合物在 NASH 患者中具有良好的耐受性。