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Objectives:To explore the general physiological and molecular changes occurring as a result of acute hypothyroidism.Materials and Methods:Hypothyroidism was developed by thyroidectomy in wistar rats. After surgery, animals were observed for 14 days in order to determine changes in body weight, feed consumption, rectal temperature, heart rate, and blood pressure, clinical pathological and hormonal alteration. In addition, relative changes in weight, histopathology and MHC – α and β gene expression of heart was also evaluated.Results:Thyroidectomised rats showed lethargy, piloerection and decreased locomotors activity. Day dependent significantly decreased body weight and feed consumption were seen in hypothyroid rats. Rectal temperature was significantly reduced at day 7 and 14 after surgery. Heart rate and blood pressure were significantly decreased at day 14 in thyroidectomized rats in comparison with euthyroid rats. Haematological parameters shown high WBC count. Serum LDL and phosphorous levels were high where as triglycerides; total protein, creatinine kinase and globulin were low. Heart weight was significantly high. Histopathology of heart tissue showed myocardial segmental degeneration. Downregulation of MHC – α and upregulation of MHC – β were seen in hypothyroid rats in comparison with euthyroid rats.Conclusion:This finding suggests that deficiency of thyroid hormone (TH) in hypothyroidism is associated to a cardiac dysfunction and acute changes in body homoeostasis as result of sudden arrest of thyroid hormone.

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GPR40 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. Agonists of GPR40 are known to stimulate insulin secretion and reduces circulating glucose levels in a glucose-dependent manner. TAK-875, a GPR40 small molecule agonist developed by Takeda Pharmaceuticals showed antidiabetic efficacy in animals and humans, but its development was terminated in phase 3 due to adverse liver effects. ZYDG2 is a safer GPR40 agonist that has shown desirable profile in preclinical studies. ZYDG2 was identified as a potent and selective agonist for GPR40, exhibiting EC50 of 13 nM and 41 nM for hGPR40, in HEK-293 cell-based Ca2+ mobilization assay and IP1 ELISA assays respectively. It increased insulin secretion and showed dose-dependent improvement in glucose tolerance test in n-STZ Wistar rats, DIO mice and db/db mice. It also showed anti-hyperglycemic effects in rats unresponsive to sulfonylureas. No tachyphylaxis was observed after repeated administration for 15 weeks in n-STZ rats. ZYDG2 showed glucose-stimulated insulin secretion as revealed by significant increase in glucose infusion rate in hyperglycemic clamp study using SD rats. ZYDG2 treatment was associated with significant rise in plasma total GLP1 levels in nondiabetic and diabetic animal models which was not observed in case of TAK-875. Since TAK-875 was terminated due to hepatotoxicity associated with bile acid transporter inhibition, this aspect was studied in details. TAK-875 inhibited the hBSEP and hMRP2 at efficacy concentrations whereas ZYDG2 does not show any inhibition (up to 300 µM) for hBSEP and hMRP2. TAK-875 also showed significantly increased cholic acid levels in Sprague Dawley rat which was not shown by ZYDG2. The maximum tolerated dose for ZYDG2 was 2000 mg/kg and 28 days NOAEL was 300 mg/kg. This clearly demonstrates that ZYDG2 has a great potential to become a safe and effective candidate for treatment of type 2 diabetes. Disclosure M.R. Jain: None. S.R. Giri: None. C.J. Trivedi: None. B.B. Bhoi: None. A.C. Rath: None. R.M. Rathod: None. R. Sundar: None. D. Bandyopadhyay: None. R. Ramdhave: None. G.D. Patel: None. B.K. Srivastava: None. R.C. Desai: None.

Objective:Combination therapy of lisinopril and rosuvastatin may be an important concept in developing more effective strategies to treat and prevent atherosclerosis, coronary heart disease, and co-morbid metabolic disorders. The present study was designed to evaluate toxic effects of lisinopril and rosuvastatin alone or its combination therapy on hematological and biochemical analytes in Wistar rats.Materials and Methods:Forty-two rats were divided into seven groups, with each group comprising six rats. Rats were administered with lisinopril, rosuvastatin alone, or in-combination at two different doses. The blood samples were collected from rats after 21 days of oral administration of the drug/s and analyzed for various hematological and biochemical analytes.Results:Lisinopril alone and its combination treatment with rosuvastatin at high doses decreased hemoglobin and hematocrit. Rosuvastatin alone at high dose and its concomitant administration with lisinopril at two different doses showed increase in total white blood cells and absolute lymphocyte count and neutrophil count. Serum levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin were significantly increased in rosuvastatin alone and its combination with lisinopril at both the doses. Besides this, lisinopril treatment decreased serum levels of sodium and increased the levels of potassium. Serum creatine kinase (CK) levels were increased in the animals treated with rosuvastatin at both the doses. However, increased serum CK level because of rosuvastatin became normal with co-administration of lisinopril at low doses.Conclusion:Our results indicate that administration of lisinopril with rosuvastatin does not ameliorate hepatotoxicity caused by rosuvastatin. However, combination treatment reduces serum CK levels elevated due to rosuvastatin, implicating protective effect of combination treatment on myopathy at low doses.