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.

Investigation of HPLF-111624 in Modified Experimental Models of Ulcerative Proctitis and Anal Fissure in Rats.

Background: Although ulcerative proctitis (UP) and anal fissure (AF) are common anorectal diseases, there are no appropriate experimental models to screen the drugs intended for these conditions. In this context, existing experimental models mimicking these diseases were modified and the polyherbal formulation, HPLF-111624 was evaluated in these models. Objective: To establish animal model for UP and AF and to evaluate polyherbal formulation, HPLF-111624 in these disease models. Methods: An experimental model of UP was selected based on the modification of the ulcerative colitis model using different concentrations of acetic acid. The concentration used for induction were 2.5%, 5% and 10% v/v and different weights used to induce AF were 25 g, 50 g and 100 g, which were selected based on the severity of inflammation, fecal score, gross pathology, and histopathological evaluation. Furthermore, these animal models were used to evaluate the efficacy of HPLF-111624, a polyherbal formulation known to be beneficial in anal diseases. Results: Acetic acid at 5% produced typical pathological changes that resembled UP, with a significant increase in the fecal score, gross lesion, and histopathological changes. Similarly, among the three weights, physical injury with a 100 g weight produced significant changes in the histopathological score in the model of AF. Intervention with HPLF-111624 at doses of 250 and 500 mg/kg b.wt., showed a reduction in the inflammatory cytokines and a significant improvement in the histopathological findings in both the conditions. Conclusion: The results showed that the modified experimental models for UP and AF resemble the human pathological conditions and are simple, versatile and may be used for screening drugs intended for these conditions. Intervention with HPLF-111624 was found to be effective in improving the pathological state of UP and AF.

Effect of "DXB-2030," a Polyherbal Formulation, on Experimental Polycystic Ovary Syndrome Associated with Hyperandrogenism.

The objective of the present study was to evaluate "DXB-2030," a polyherbal combination of Trigonella foenum-graecum, Aloe vera, Sphaeranthus indicus, Nardostachys jatamansi, and Symplocos racemosa extracts in an experimental model of testosterone propionate (TP), induced polycystic ovary syndrome (PCOS) in female rats. Thirty animals were divided into 3 groups of 10 each; group 1 served as normal control; group 2 was administered with TP and served as positive control; along with TP, group 3 was treated with "DXB-2030" at a dose of 100 mg/kg p.o., for 60 days. At the end of the study period, the animals were subjected for the estimation of serum testosterone levels, oral glucose tolerance test (OGTT), weight of the ovaries, estrous cycle, and histopathological evaluation. An in vitro assay on GLUT4 expression was carried out to understand the effect of "DXB-2030" on insulin resistance. Results showed that treatment with "DXB-2030" reversed the TP-induced changes by increasing the GLUT4 expression and decreasing the body weight, testosterone levels, AUC of glucose in OGTT, and the cystic follicles of the ovaries, thus indicating its beneficial effect in PCOS by ameliorating the metabolic dysfunction and reproductive impairment, which are the pathophysiological conditions associated with PCOS. From the results obtained, it can be concluded that "DXB-2030" was effective in the management of experimental PCOS and hence may be recommended in the treatment of PCOS.