Taltirelin Hydrate

Teratogenicity study of taltirelin hydrate, a thyrotropin releasing hormone analogue, was carried out in Wistar rats. Female rats were orally given taltirelin hydrate at a dose of 0 (control), 0.15, 1.5, or 15 mg/kg from day 7 to day 17 of gestation. Twenty-seven female rats in each group were sacrificed on day 21 of gestation and their fetuses were examined. The remaining 13 female rats in each group were allowed to deliver spontaneously and their newborns were examined. In the 15 mg/kg group, the dams (P) showed wet dog shaking behavior and hyperlocomotion. No adverse effect of taltirelin hydrate on the body weight gain, food consumption, water intake, and reproductive performance was observed in this group. In the 0.15 and 1.5 mg/kg groups, taltirelin hydrate did not show any adverse effects. In F1 generation groups, taltirelin hydrate had no teratogenic, lethal, or growth retardation effects in any groups. There were also no adverse effects of taltirelin hydrate on postnatal development, emotionality, coordinated activity, sensitivity, learning ability, and reproductive performance of F1 offspring, and development of F2 fetuses. These results show that the no-toxic dose levels of taltirelin hydrate are 1.5 mg/kg for general toxicity in dams, and 15 mg/kg for reproductive function of dams (P) and for development of F1 generation.

We investigated the effect of taltirelin hydrate ((-)-N-[(S)-hexahydro-1-methyl- 2,6-dioxo-4-pyrimidinyl-carbonyl]-L-histidyl-L-prolinamide tetrahydrate; taltirelin), a metabolically stable thyrotropin-releasing hormone (TRH) analog, on circulatory function, respiratory function, and viable time after bleeding in urethane-anesthetized rats. Massive volume-controlled bleeding caused marked reductions in mean arterial pressure (MAP) and respiratory rate (RR). The vital signs of control rats were lost within an average of 23 min after bleeding. Intravenous administration of taltirelin (0.03-0.3 mg/kg) and TRH (1 and 3 mg/kg) immediately after bleeding accelerated recovery of MAP and RR, and prolonged viable time in a dose-dependent manner. The potency of taltirelin in accelerating MAP and RR recovery and prolonging viable time was higher when compared with that of TRH. In addition, recovery of MAP and RR and the extension of viable time by taltirelin were inhibited by preintraperitoneal administration of atropine sulfate, which is a centrally acting muscarinic antagonist, but not by that of atropine methylbromide, which is a peripherally acting muscarinic antagonist. Taltirelin also recovered decreased arterial pH, bicarbonate ions, and base excess, and prevented a decrease in arterial oxygen saturation. In conclusion, the anti-shock effect of taltirelin was more potent than that of TRH. Taltirelin activity was mediated by the central muscarinic cholinergic system. In addition, taltirelin also corrected metabolic acidosis. These results suggest that taltirelin could be useful in the treatment of hypovolemic shock.

Taltirelin hydrate[1-methyl-(S)-4,5-dihydroorotyl-L-histidyl-L-prolineamide tetrahydrate] is a new orally active thyrotropin releasing hormone (TRH) peptide analog synthetized from aspartic acid. From preclinical studies with mice and rats, Taltirelin hydrate was found to be highly stable in the blood and brain as compared with TRH. Furthermore, the CNS stimulating actions of Taltirelin hydrate such as antagonistic actions against pentobarbital-induced anesthesia and reserpine- induced hypothermia were found to be about 100 times stronger and about 8 times longer-lasting as compared with those of TRH. Meanwhile, the affinity of Taltirelin hydrate for TRH-receptors was about 10 times lower, and the endocrine action was about 5 times less potent than those of TRH. Therefore, high CNS-selectivity and long-lasting action of Taltirelin hydrate would be attributed to its high stability in the body and low affinity for TRH-receptors. Oral administrations of Taltirelin hydrate ameliorated consiousness impairment, memory impairment and motor dysfunction in several models. The clinical studies for patients with spinocerebellar degeneration are in progress.