Herbal combination 'HAGE-101912' Ameliorates gastroesophageal reflux disease in rats

Background: Gastroesophageal reflux disease (GERD) is a chronic, relapsing disorder. In this era of modern and fast-track lifestyle and food habits, the incidence of GERD is rapidly increasing. Currently, proton pump inhibitors (PPIs) are the primary choice of treatment. However, the associated side effects and a high relapse rate give rise to the need to explore alternative therapies. Objective: The study aimed to evaluate HAGE-101912, an herbal combination, in different experimental models of GERD. Methods: Antacid activity was assessed based on H+/K+ATPase inhibitory activity of parietal cells using artificial gastric juice. Tonic contraction of the lower esophageal sphincter (LES) was evaluated using an AD Instrument. A GERD model of the pylorus and fundus ligation (preventive and curative models) in rats was selected to assess the efficacy of HAGE-101912 at a dose of 250 mg/kg body weight, and various parameters such as the gastric pH, gastric volume, total acidity, gross esophageal ulcer index, and histopathological changes were evaluated. The prokinetic activity was assessed using the phenol red method. Results: HAGE-101912 increased the acid-neutralizing capacity (P < 0.001), decreased H+/K+ATPase activity (P < 0.01), and increased the contraction of the LES. In the preventive model, HAGE-101912 significantly reduced the gastric acid volume (P < 0.01), total acidity (P < 0.001), and gross esophageal ulcer index (P < 0.01); increased the gastric acid pH (P < 0.01); and protected the esophageal epithelium. In addition, HAGE-101912 increased gastric emptying and gastrointestinal transit through its prokinetic activity (P < 0.05). Conclusion: HAGE-101912 has a beneficial effect in GERD as it effectively inhibits the H+/K+ATPase, increases the gastric pH, restores the LES function, protects the esophageal epithelium, and increases gastric emptying and transit

CNX-012-570, a direct AMPK activator provides strong glycemic and lipid control along with significant reduction in body weight; studies from both diet-induced obese mice and db/db mice models

OBJECTIVES: AMP activated protein kinase (AMPK) regulates the coordination of anabolic and catabolic processes and is an attractive therapeutic target for T2DM, obesity and metabolic syndrome. We report the anti-hyperglycemic and anti-hyperlipidemic effects of CNX-012-570 is an orally bioavailable small molecule (molecular weight of 530 Daltons) that directly activates AMPK in DIO and db/db animal models of diabetes. METHODS: Activity and efficacy of the compound was tested in cell based as well as cell free systems in vitro. Male C57BL/6 mice fed with high fat diet (HFD) were assigned to either vehicle or CNX-012-570 (3 mg/kg, orally once a day) for 8 weeks (n = 8). Genetically diabetic db/db mice on chow diet were dosed with vehicle control or CNX-012-570 (2.5 mg/kg, orally once a day) for 6 weeks (n = 8). RESULTS: CNX-012-570 is a highly potent and orally bioavailable compound activating AMPK in both cell and cell free systems. It inhibits lipolysis (33%) and gluconeogenesis (28%) in 3T3L1 cells and rat primary hepatocytes respectively. The efficacy of the molecule was translated to both DIO and db/db animal models of diabetes. CNX-012-570 has reduced fasting blood glucose levels by 14%, body weight by 24% and fasting serum triglycerides (TG) by 24%. CNX-012-570 showed a 22% reduction in fed serum cholesterol levels and 19% increase in HDL levels. In db/db mice model, CNX-012-570 has shown 18% decrease in fed glucose and 32% decrease in fasting glucose with a 2.57% reduction in absolute HbA1c. Decrease in serum insulin and glucose AUC indicates the increased insulin sensitivity. Body weight was reduced by 13% with increased browning of adipose tissue and decreased inguinal and mesenteric fat mass. There was significant reduction in liver TG and liver total cholesterol. CONCLUSIONS: CNX-012-570 has the potential to control hyperglycemia and hyperlipidemia. It also reduces body weight gain with an additional benefit of minimizing cardiovascular risks in diabetics