AbstractThe transport mechanisms of thyrotropin-releasing hormone (TRH) and its pharmacologically active analogues ((3-methyl-His2)TRH (MeTRH), taltirelin, montirelin, azetirelin) across Caco-2 cell monolayers were characterized. The results of kinetic analysis showed a linear relationship between the concentration (over the range 0.5–10 mm) and apical-to-basolateral transport rate of these agents. The permeability coefficients (Papp) of these agents were not substantially different from each other, and their (Papp) ratios of the basolateral-to-apical over the apical-to-basolateral transport were close to one (0.73–1.23). The cellular transport of [3H]MeTRH at low concentrations (3–15 nm) showed a linear relationship between the concentration and transport rate. The transport of [3H]MeTRH in Caco-2 cell monolayers was neither affected by TRH nor TRH analogues, and there was little difference in (Papp) values between [3H]MeTRH and [14C]mannitol. The cell-per-medium ratio of [3H]MeTRH in the cellular uptake experiment was similar to the value of [14C]mannitol. A large excess of TRH and MeTRH did not significantly influence cell-per-medium ratios of [3H]MeTRH in Caco-2 cell monolayers. The k'IAM value, which represents lipophilicity, was decreased in the following order: montirelin > taltirelin > TRH > azetirelin, and the values varied from 0.234 to 1.028. These results indicate that a paracellular passive diffusion may be the major route for the transport of TRH and its analogues in Caco-2 cell monolayers.

01 Jan 2000·Journal of Physiology-Paris

Gastric acid secretion in streptozotocin-diabetic rats – Different responses to various secretagogues

Article

Author: Akinobu Fujita ; Koji Takeuchi ; Kimihito Tashima ; Masato Nishijima ; Shoji Kawauchi

We compared gastric acid secretion in response to various stimuli in normal and streptozotocin (STZ)-induced diabetic rats, in an attempt to characterize the alteration of acid secretory response in diabetic conditions. Animals were injected STZ (70 mg x kg(-1), i.p.) and used after 5 weeks of diabetes with blood glucose > 350 mg x dL(-1). Under urethane anesthesia, a rat stomach was mounted on an ex vivo chamber, perfused with saline and acid secretion was measured at pH 7.0 using a pH-stat method and by adding 100 mM NaOH. The acid secretion was stimulated by i.v. infusion of either histamine (4 mg x kg(-1) x h(-1)), pentagastrin (60 microg x kg(-1) x h(-1)) or carbachol (20 microg x kg(-1) x h(-1)) or i.v. injection of YM-14673 (0.3 mg x kg(-1)), an analog of thyrotropin-releasing hormone, or vagal electrical stimulation (2 ms, 3 Hz, 0.5 mA). In normal rats, gastric acid secretion was increased in response to either histamine, pentagastrin, carbachol, YM-14673 or electrical vagal stimulation. In STZ diabetic rats, however, changes in acid secretion varied depending on the stimuli; the acid secretory responses to histamine remained unchanged, those to YM-14673 and vagal electrical stimulation significantly decreased, but the responses to both pentagastrin and carbachol were significantly enhanced as compared to normal rats. Luminal release of histamine in response to both pentagastrin and carbachol was increased in STZ-diabetic rats as compared to normal animals. The altered acid secretory responses in STZ diabetic rats were partially reversed by daily injection of insulin with amelioration of high blood glucose levels. These results suggest that STZ-diabetic rats showed different changes in gastric acid secretory responses to various stimuli; no change in response to histamine, a decrease to both YM-14673 and vagal electrical stimulation and an increase to both pentagastrin and carbachol. The increased acid secretory response may be associated with an enhanced release of mucosal histamine, while the decreased response may be due to vagal neuropathy.

01 Oct 1999·American Journal of Physiology-Regulatory, Integrative and Comparative Physiology

Novel TRH analog improves motor and cognitive recovery after traumatic brain injury in rodents

Article

Author: Fox, Gerard B. ; Wang, Shaomeng ; Fan, Lei ; Kozikowski, Alan P. ; Araldi, Gian Luca ; Qiao, Lixin ; Faden, Alan I.

Thyrotropin-releasing hormone (TRH) and certain TRH analogs show substantial neuroprotective effects in experimental brain or spinal cord trauma but also have other physiological actions (autonomic, analeptic, and endocrine) that may be undesirable for the treatment of neurotrauma in humans. We developed a novel TRH analog (2-ARA-53a), with substitutions at the NH2-terminus and imidazole ring, that preserves the neuroprotective action of TRH-like compounds while decreasing or eliminating their autonomic, analeptic, and endocrine effects. Rats administered 2-ARA-53a (1.0 mg/kg, n = 17) intravenously 30 min after lateral fluid percussion brain injury showed marked improvement in motor recovery compared with vehicle-treated controls ( n = 14). Treatment of mice subjected to moderate controlled cortical impact brain injury, at the same dose and time after trauma ( n = 8), improved both motor recovery and cognitive performance in a water maze place learning task compared with vehicle-treated controls ( n = 8). In injured rats, no autonomic or analeptic effects were observed with this compound, and endocrine effects were significantly reduced with 2-ARA-53a, in contrast to those found with a typical NH2-terminal-substituted TRH analog (YM-14673). These findings demonstrate that the neuroprotective effects of TRH-related compounds can be dissociated from their other major physiological actions and suggest a potential role for dual-substituted TRH analogs in the treatment of clinical neurotrauma.

100 Deals associated with Azetirelin dihydrate

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Indication	Highest Phase	Country/Location	Organization	Date
Nervous System Diseases	Preclinical	JP	Yamanouchi Pharmaceutical Co., Ltd.	01 Nov 1987
Alzheimer Disease	Discovery	-	Astellas Pharma, Inc.	-
Alzheimer Disease	Discovery	JP	Yamanouchi Pharmaceutical Co. Ltd. /Over-the-Counter Phar Bus	-

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