E3710, a new proton pump inhibitor, with a long-lasting inhibitory effect on gastric acid secretion.

We have investigated the pharmacology of sodium (R)-2-[4-(2,2-dimethyl-1,3-dioxan-5-yl) methoxy-3,5-dimethylpyridin-2-yl]methylsulfinyl-1H-benzimidazol (E3710), a new proton pump inhibitor (PPI), and its effect on gastric acid secretion. E3710 irreversibly inhibited H(+),K(+)-ATPase activity in pig gastric vesicles with an acidic internal environment with an IC(50) of 0.28 microM. Administration of E3710 (0.1, 0.2, 0.4, and 0.8 mg/kg; n = 6) intraduodenally in a gastric fistula model in dogs inhibited histamine-stimulated gastric acid secretion at 0 to 2 and 24 to 26 h after administration with ED(50) values of 0.18 and 0.22 mg/kg, respectively. The inhibition by E3710 was 2.3 times more potent than that of another representative PPI, esomeprazole (0.2, 0.4, 0.8, and 1.6 mg/kg; n = 6) at 0 to 2 h after administration (ED(50) = 0.40 mg/kg) and 2.8 times more potent at 24 to 26 h (ED(50) = 0.71 mg/kg). In the gastric fistula dogs, the intragastric pH was >or=4 for 17% (n = 27) of a 24-h period with vehicle alone, but when E3710 was administered, at 0.2 (n = 4), 0.4 (n = 8), and 0.8 mg/kg (n = 5), the pH was >or=4 for 40, 79, and 88% of a day, respectively. The corresponding values for esomeprazole at 0.8 (n = 4) and 1.6 mg/kg (n = 8) were 55 and 59%, respectively. In a crossover study with vehicle, E3710 at 0.4 mg/kg and esomeprazole at 1.6 mg/kg (n = 6), E3710 increased the intragastric pH to >4 for 82% of a day compared with 61% of a day with esomeprazole. These results show that E3710 is a long-acting inhibitor of gastric acid secretion and a promising novel therapy for acid-related diseases, such as gastroesophageal reflux disease.

Protective effect of donepezil in a primary culture of rat cortical neurons exposed to oxygen-glucose deprivation.

Donepezil hydrochloride (donepezil: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride) is a potent acetylcholinesterase inhibitor used for treatment of Alzheimer's disease. Although acetylcholinesterase inhibitors are used as a symptomatic treatment for Alzheimer's disease, it is not clear whether or not they are effective against progressive degeneration of neuronal cells. In this study, we investigated the neuroprotective effects of donepezil and other acetylcholinesterase inhibitors used for treatment of Alzheimer's disease, i.e., galantamine, rivastigmine, and tacrine. As a neurodegenerative model, we used rat cortical neurons exposed to oxygen-glucose deprivation. Lactate dehydrogenase (LDH) released into the culture medium was measured as a marker of neuronal cell damage. First, the effects of donepezil (10 microM) on three different treatment schedules (from 12 h before to 24 h after oxygen-glucose deprivation (pre-12 h), from 1 h before to 24 h after oxygen-glucose deprivation (pre-1 h) and from 1 h after to 24 h after oxygen-glucose deprivation (post-1 h)) were compared. The pre-12-h treatment most effectively inhibited LDH release. The protective effect of donepezil was confirmed morphologically. Next, the effects of donepezil and the other three acetylcholinesterase inhibitors were compared under the pre-12-h treatment condition. Donepezil (0.1, 1, and 10 microM) significantly decreased LDH release in a concentration-dependent manner. However, galantamine (1, 10, and 100 microM), tacrine (0.1, 1, and 10 microM), and rivastigmine (0.1, 1, and 10 microM) did not significantly decrease LDH release. The neuroprotective effect of donepezil was not antagonized by scopolamine or mecamylamine. These results demonstrate that donepezil has a protective effect against oxygen-glucose deprivation-induced injury to rat primary cultured cerebral cortical neurons. Besides, it is suggested that this effect of donepezil is independent of muscarinic cholinergic system and nicotinic cholinergic system. Thus, donepezil is expected to have a protective effect against progressive degeneration of brain neuronal cells in ischemic cerebrovascular disease and Alzheimer's disease.