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We compared the individual effects of mitiglinide and glibenclamide administered in combination with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin on plasma DPP-IV activity and blood glucose levels in rats with streptozotocin-nicotinamide-induced type 2 diabetes (STZ-NA rats). We examined the inhibitory activity of mitiglinide and glibenclamide as well as their combination with sitagliptin on plasma DPP-IV activity in STZ-NA rats. The oral glucose tolerance test (OGTT) was used to compare effects of mitiglinide, glibenclamide, and their combination with sitagliptin on blood glucose levels in STZ-NA rats. Mitiglinide and glibenclamide did not inhibit rat DPP-IV and did not influence the inhibitory effect of sitagliptin on rat plasma DPP-IV activity. In STZ-NA rats, plasma glucose levels were stronger suppressed by a combination of mitiglinide and sitagliptin than by either drug used alone. However, no clear effect of the combination of glibenclamide and sitagliptin was observed. These results indicate that the combination of mitiglinide and sitagliptin has a lower risk of hypoglycemia in the rats with induced type 2 diabetes compared with the combination of glibenclamide and sitagliptin. The combination of mitiglinide and sitagliptin can be a promising combination for the treatment of diabetic patients.

Rovatirelin is a newly synthetized thyrotropin-releasing hormone (TRH) analog. This study aimed to investigate the effect of rovatirelin on motor function using rolling mouse Nagoya (RMN), a mouse model of hereditary ataxia, and compare it with that of taltirelin, which is clinically used to treat spinocerebellar degeneration in Japan. We also examined the effect of rovatirelin on glucose metabolism in various brain regions of RMN using autoradiography (ARG). Rovatirelin (1, 3, 10, and 30 mg/kg) dose-dependently reduced the fall index in RMN, and its effect was more potent than that of taltirelin (3, 10, 30, and 100 mg/kg). No attenuation of the effect was observed by repeated daily administration for 2 weeks. Furthermore, the reduction in the fall index by rovatirelin persisted for 2 weeks after completing treatment. In the ARG study, rovatirelin induced a significantly elevated uptake of glucose in the prefrontal cortex, nucleus accumbens shell, nucleus accumbens core, striatum, anterior cingulate cortex, secondary motor area, pretectal area, ventral tegmental area, black pars compacta, locus coeruleus, nucleus cerebellaris middle nucleus, medial nucleus of the vestibular nerve, fourth/fifth lobule, and third lobule. Furthermore, rovatirelin increased cerebellar mRNA level of brain derived neurotrophic factor. These results suggest that rovatirelin activates the cerebellum and other parts of the central nervous system to improve motor function in spinocerebellar ataxia (SCA) model animals, and its action is more potent than that of taltirelin. Therefore, rovatirelin can be a potential alternative to the traditionally used therapeutics for SCA.

This study was performed to investigate the effects of silodosin (selective α1A-adrenoceptor antagonist) on bladder blood flow (BBF) and bladder function in a rat model of bladder outlet obstruction (BOO) and to determine the expression of α1-adrenoceptor subtype mRNA in human and rat bladder microvessels. BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. The BOO rats received either silodosin at a rate of 0.3mg/kg/day or vehicle subcutaneously via an osmotic pump for 2 weeks after BOO surgery. A metabolic cage study was performed in conscious animals. BBF was measured using a Laser Speckle Blood Flow Imager. Urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nerve growth factor (NGF) were measured. Immunohistological examinations of nerve distribution and NGF expression in the rat bladder were conducted. The expression of each α1-adrenoceptor subtype mRNA in human and rat bladder microvessels was determined by in situ hybridization. Silodosin ameliorated the increase in voiding frequency and decrease in mean voided volume in BOO rats in the metabolic cage study. Silodosin also abrogated the decrease in BBF in BOO rats. The levels of 8-OHdG and NGF in BOO rats were significantly decreased by administration of silodosin. Silodosin prevented the decrease in nerve distribution and increase in NGF expression. Human and rat bladder microvessels showed expression of all α1-adrenoceptor subtype mRNAs. The results presented here suggest that silodosin improves voiding behavior in rat models with BOO by inducing recovery of BBF.

We examined the effects of combining the rapid insulin secretagogue, mitiglinide, with various oral hypoglycemic drugs including biguanides, pioglitazone, α-glucosidase inhibitors, and sodium-glucose co-transporter 2 inhibitors in a rat model of type 2 diabetes. The oral glucose tolerance test (OGTT) using glucose, sucrose, or a liquid meal was used to compare the effects of mitiglinide with those of the four oral hypoglycemic drugs and examine their combined effects on blood glucose levels and insulin secretion in the rat model. The combination of mitiglinide with other oral hypoglycemic drugs suppressed the plasma glucose levels more than either agent did alone. Furthermore, the combination of these agents decreased insulin secretion more than mitiglinide did alone. These results indicate that mitiglinide is suitable for use in combination with other hypoglycemic drugs because it inhibits postprandial hyperglycemia by rapidly stimulating insulin secretion. This article is protected by copyright. All rights reserved.

The efficacy of the combination of the rapid-acting insulin secretagogue mitiglinide and the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin was explored in streptozotocin-nicotinamide-induced type 2 diabetic (STZ-NA) rats and in Zucker fatty (ZF) rats. The STZ-NA rats were prepared at 8 weeks of age. At 9 weeks of age, the combination study was conducted by oral glucose tolerance test (OGTT). At 13 weeks of age, ZF rats were dosed orally with dapagliflozin once daily up to the 22(nd) day. At days 15 and 22, the combination study was conducted by OGTT. In 2 different animal models, plasma glucose levels were strongly suppressed by the combination of mitiglinide and dapagliflozin as compared with either drug alone. The urinary glucose excretion was drastically elevated in the dapagliflozin group, but the combination with mitiglinide suppressed it about 50%. In STZ-NA rats, the plasma insulin secretion by the combination of both drugs was about at the same level as in the mitiglinide group. In ZF rats, the plasma insulin secretion by the combination of both drugs was less than mitiglinide group. Thus, in 2 different animal models, the combination of mitiglinide and dapagliflozin showed stronger antihyperglycemic action accompanied by less insulin secretion than mitiglinide alone, and reduced the urinary glucose excretion as compared with dapagliflozin used alone. These results indicate that the combination of mitiglinide and dapagliflozin can be a promising combination for the treatment of diabetic patients.