Characterization of antisecretory and antiulcer activity of CR 2945, a new potent and selective gastrin/CCK(B) receptor antagonist.
ABSTRACT The antigastrinic, antisecretory and antiulcer activities of CR 2945, (R)-1-naphthalenepropanoic acid,beta-[2-[[2-(8-azaspiro[4.5]dec-8-yl-carbonyl)-4,6-dimethylph enyl] amino]-2-oxoethyl], were investigated in vitro and in vivo in rats and cats. Its activities were compared with those of two gastrin/CCK(B) receptor antagonists, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin -3-yl)-N'-(3-methylphenyl)urea and CAM-1028 (4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[1,7,7-trimethylbicyclo [2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino -4-oxo-[1S-1alpha,2beta[S'(S')4alpha]]-butanoate -N-methyl-D-glucamine), of the histamine H2 receptor antagonist, ranitidine, and the proton pump inhibitor, omeprazole. Cytosolic Ca2+ elevation in rabbit parietal cells induced by gastrin (50 nM) was blocked by CR 2945 with an IC50 value of 5.9 nM. CAM-1028 and L-365,260 showed similar activity. CR 2945 antagonized pentagastrin-stimulated gastric acid secretion in rats (ED50 = 1.3 mg kg(-1) i.v. and 2.7 mg kg(-1) i.d.) and cats (1.6 mg kg(-1) i.v.). CR 2945 was slightly less potent than the reference compounds after i.v. administration, whereas after intraduodenal (i.d.) administration, it was more potent than both ranitidine and omeprazole. In the rat, the gastrin antagonism exhibited by CR 2945 was reversible and competitive, with a pA2 value of 7.33. CR 2945 had specific antigastrin activity, as it was unable to antagonize the gastric acid secretion stimulated by histamine or carbachol in rats up to the dose of 30 mg kg(-1). CR 2945 was about as efficacious as ranitidine against the indomethacin- and ethanol-induced gastric ulcers and the cysteamine-induced duodenal ulcer in rats. On the contrary, L-365,260 was only slightly effective. These results suggest that CR 2945 might be a promising compound for the therapy of acid-related disorders, and that its clinical use could help clarify the therapeutic potential of gastrin/CCK(B) receptor antagonists in the gut.
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ABSTRACT: Benzaldehyde semicarbazone (BS) has presented positive results in several pharmacological models, including anticonvulsivant and anti-inflammatory models. The present study evaluated the preclinical toxicity (acute and subchronic), as well as the toxicokinetic and gastroprotective effects of BS against ethanol lesions. Oral doses of 300 and 2000 mg/kg were used in the preclinical acute toxicity study; 100, 200, and 300 mg/kg were used in both the subchronic toxicity evaluation and the gastric study; and 300 mg/kg was used in the toxicokinetic study. No impact from the dose of 300 mg/kg could be identified; while, one animal died at 2000 mg/kg in the acute toxicity test. In the subchronic toxicity test, changes in the biochemical parameters of the liver, as well as in the histopatological evaluation, demonstrated that BS is a hepatotoxic drug. BS proved to be effective for moderate and severe gastric lesions. In the toxicokinetics study, BS presented a low concentration and rapid plasma disappearance. Several results also indicate that BS is likely to be mostly eliminated from the liver and may well undergo a first-pass effect after oral absorption. It was impossible to estimate the noobserved-adverse-effect-levels (NOAEL) and lowest-observed-adverse-effect-levels (LOAEL) due to the presence of hepatotoxicity in all tested doses.Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 02/2013; · 2.99 Impact Factor
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ABSTRACT: Gastroesophageal reflux disease (GERD) is a common acid-related disorder presenting with a broad spectrum of symptoms with or without esophageal mucosal damage and/or complications. In general, the frequency and severity of symptoms and esophagitis correlate with the severity and duration of acid exposure, particularly during the nighttime. Acid suppression, with proton pump inhibitors (PPIs), is the mainstay of acute and maintenance treatment of GERD. Optimizing the choice of PPI and dose is essential for controlling GERD symptoms, accelerating healing of esophagitis, and preventing the long-term complications. Postprandial acid control is needed during the day particularly to control the symptoms. Additionally, nocturnal acid control especially in those with nighttime symptoms or severe mucosal injury is important for preventing complicated GERD. However, there is a substantial proportion of patients who do not respond to routine PPI therapy probably because of inadequate acid suppression or nonacid-related problems. Failure to respond to twice daily PPIs can be partly explained by the short half-lives of currently available PPIs that may fail to adequately control acid secretion after midnight, even if given before the evening meal. There has been considerable discussion in recent years over nocturnal acid breakthrough, which is really a misnomer, as this represents the pattern of nocturnal acid secretion when there is no drug available to inhibit secretion. Several approaches to properly controlling nocturnal acid secretion have included b.i.d. dosing of PPIs, adding an H2-receptor antagonist at night and the development of an instant release PPI. The former approaches have not been universally effective and clinical studies not yet performed with the latter. There are several new acid suppressing drugs in development and these include PPIs with longer half-lives, which give more prolonged nocturnal acid suppression. In addition, there are drugs which block the potassium channel (potassium competitive acid blockers) of the proton pump and which have a rapid onset of action. These drugs are under investigation and some may require more than 1 dose daily to adequately control acid secretion. In this review, we further explore different aspects of the need for new PPIs for the optimal management of GERD.Journal of Clinical Gastroenterology 06/2007; 41:S72-S80. · 3.20 Impact Factor