A simple method for oral mucosal irritation test by intraoral instillation in rats.

Evaluation of oral mucosal irritation is required by regulatory agencies when the intended clinical route of the drug candidate is intraoral administration. In this study, we investigated whether it was possible to evaluate oral mucosal irritation in rats by an intraoral instillation which was thought to mimic the clinical route of gargle products. Although no oral mucosal irritation was observed in the animals instilled with 0.

Nonclinical safety profile of tolvaptan.

Purpose: In the present study, the nonclinical safety profile of tolvaptan was evaluated.

Methods: A series of safety pharmacology and toxicology studies were performed in vitro and in mice, rats, dogs, rabbits and guinea pigs.

Results: In safety pharmacological studies, tolvaptan had no adverse effects on the central nervous, somatic nervous, autonomic nervous, smooth muscle, respiratory and cardiovascular, or digestive systems.

Vital role of the calpain-calpastatin system for placental-integrity-dependent embryonic survival.

Although the calpain-calpastatin system has been implicated in a number of pathological conditions, its normal physiological role remains largely unknown. To investigate the functions of this system, we generated conventional and conditional calpain-2 knockout mice. The conventional calpain-2 knockout embryos died around embryonic day 15, preceded by cell death associated with caspase activation and DNA fragmentation in placental trophoblasts.

Effects of elevated cytoplasmic calcium and protein kinase C on endoplasmic reticulum structure and function in HEK293 cells.

In human embryonic kidney (HEK) cells stably transfected with green fluorescent protein targeted to the endoplasmic reticulum (ER), elevation of intracellular Ca2+ ([Ca2+]i) altered ER morphology, making it appear punctate. Electron microscopy revealed that these punctate structures represented circular and branched rearrangements of the endoplasmic reticulum, but did not involve obvious swelling or pathological fragmentation. Activation of protein kinase C with phorbol 12-myristate 13-acetate (PMA), prevented the effects of ionomycin on ER structure without affecting the elevation of [Ca2+]i.

Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition.

Alzheimer amyloid beta-peptide (Abeta) is a physiological peptide constantly anabolized and catabolized under normal conditions. We investigated the mechanism of catabolism by tracing multiple-radiolabeled synthetic peptide injected into rat hippocampus. The Abeta1-42 peptide underwent full degradation through limited proteolysis conducted by neutral endopeptidase (NEP) similar or identical to neprilysin as biochemically analyzed.

Modulation of cytosolic Ca2+ concentration by thapsigargin and cyclopiazonic acid in human aortic endothelial cells.

To clarify the agonist-induced Ca2+ entry mechanism, effects of thapsigargin and cyclopiazonic acid, selective inhibitors of endoplasmic reticulum Ca(2+)-ATPase, on intracellular free Ca2+ concentration ([Ca2+]i) were studied in cultured human aortic endothelial cells loaded with the fluorescent Ca2+ indicator fura-2. Thapsigargin (1-1000 nM) and cyclopiazonic acid (0.1-100 microM) produced a biphasic change in [Ca2+]i, which consisted of a transient peak elevation followed by a long-lasting decline of [Ca2+]i in a concentration-dependent manner.

Chloride-sensitive Ca2+ entry by histamine and ATP in human aortic endothelial cells.

The regulation of intracellular free Ca2+ concentration ([Ca2+]i) was studied in cultured human aortic endothelial cells loaded with the fluorescent Ca2+ indicator fura-2. Histamine and ATP at concentrations of 10 microM and higher produced a biphasic change in [Ca2+]i, which consisted of an initial transient elevation followed by a sustained elevation. Reduction of the extracellular Cl- concentration to 40 mM, or exposure to the Cl- channel antagonist N-phenylanthranilic acid selectively prevented the sustained response to histamine or ATP, but they did not affect the sustained response to the Ca2+ ionophore ionomycin.

General pharmacological properties of the new vasodilator flosequinan.

Pharmacological effects of a new vasodilator, flosequinan (7-fluoro-1-methyl-3-(methylsulfinyl)-4(1H)-quinolone, BTS 49 465, CAS 76568-02-0) on the central nervous system, somatic nervous system, autonomic nervous system and smooth muscle, digestive system and miscellaneous organs were investigated. 1. The central nervous system: Flosequinan inhibited acetic acid-induced writhing at doses of more than 30 mg/kg p.

General pharmacological properties of the main metabolite of flosequinan.

The general pharmacological profile of 7-fluoro-1-methyl-3-(methylsulfonyl)- 4(1H)-quinolone BTS 53 554, CAS 76568-68-8), the main metabolite of a new vasodilator, flosequinan (BTS 49 465), was investigated. 1. The central nervous system: BTS 53 554 at the dose of 30 mg/kg i.

Age-related decrease in endothelium-dependent dilator response to histamine in rat mesenteric artery.

The effect of aging on the vasodilator responses to histamine, 2-pyridylethylamine and 4-methylhistamine of ring segments of rat mesenteric arteries were investigated. The maximal extent of histamine-induced dilatation of the arteries previously contracted with norepinephrine was greatest for arteries from rats aged 2 and 8 weeks. The maximal response decreased progressively with an increase in age to 13 and 56 weeks.

Opioid receptor types on adrenergic nerve terminals of rabbit ear artery.

Methionine enkephalin, leucine enkephalin, [D-Ala2, D-Leu5] enkephalin, alpha-neoendorphin, beta-endorphin, dynorphin (1-13) and ethylketocyclazocine inhibited the contractions of rabbit ear artery ring segments elicited by transmural nerve stimulation at 8 Hz. Ethylketocyclazocine, dynorphin (1-13) and leucine enkephalin produced partial inhibition, their apparent intrinsic activities (alpha) being 0.57, 0.