Effect of 7 years' daily oral administration of omeprazole to beagle dogs.

Ten beagle dogs were given omeprazole orally at a dose of 0.17 mg/kg (0.5 mumol/kg) daily for 7 years. Six dogs served as controls. Regularly evaluated criteria were clinical signs, body weight, food consumption, rectal temperature, electrocardiography, hematology, blood chemistry, urinalysis, ophthalmoscopy, gastroscopic examination including gastric mucosal biopsy sampling for histological evaluation, pharmacokinetics of omeprazole, and plasma gastrin levels. After approximately 5 years, a quantitative gastric acid secretion test was performed. No treatment-related adverse clinical signs or effects were observed in the dogs, and all animals survived to term. The annual gastroscopy with histological examinations of gastric mucosa did not show any treatment-related changes. At all investigations and in all dogs, the parietal cells were morphologically normal, and there were no changes of pattern or any increase in the number of argyrophil enterochromaffin-like cells compared to the control animals. In the plasma samples collected 24 h after dosing, there were no significant differences in either basal or meal-stimulated gastrin levels between the controls and the omeprazole-treated animals. Peak plasma concentration of omeprazole occurred within 2 h of dosing. The area under the concentration curve (AUC) was not affected by dosing over 7 years and was in good agreement with the AUC in humans given a dose of 20 mg omeprazole daily. Acid secretion tests after 5 years of treatment showed that the mean inhibition of acid secretion by omeprazole 4-7 h after dosing was as expected--about 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

General toxicity of the new calcium antagonist felodipine in dogs.

Felodipine 4-(2,3-dichlorophenyl)-1,4-dihydropyridine-2,6-dimethyl-3,5- dicarboxylic 3-ethyl ester and 5-methyl ester, CAS 72509-76-3) is a new selective calcium antagonist for use in the management of hypertension or other cardiovascular disease, which requires reduction of peripheral vascular resistance. A combined 6- and 12-month study in dogs has been performed as a part of the preclinical safety program. 30 dogs, 5 males and 5 females per group, were treated with felodipine for 12 months. Additional 18 dogs, 3 males and 3 females per group, were interim-sacrificed after 6-month treatment. The dose levels were 2 x 0.38, 2 x 1.2 and 2 x 2.3 mg/kg daily. Initially, 2 x 3.8 mg/kg/d was used as a high dose. At this dose level 2 animals died preterminally after 4 days of dosing. They were replaced and the high dose level was reduced. Two similar control groups were given a placebo formulation for 12 and 6 months, respectively. All animals were treated b.i.d. using a 4-h time interval. Mucosal hyperemia and tachycardia, as an expression of the vasodilating properties of felodipine, were observed in a somewhat variable but dose-related manner. Noninflammatory gingival hyperplasia, similar to that after treatment with phenytoin and the calcium antagonist nifedipine, occurred with a propensity for the males after 12 months of treatment. Slight-degree gingival hyperplasia was also noted after 6 months of treatment. This change occurred dose- and time related in the medium and high dose groups but was absent in the low dose group.(ABSTRACT TRUNCATED AT 250 WORDS)