General toxicity of the new calcium antagonist felodipine in dogs
Säfholm, C.; Havu, N.
Arzneimittel-Forschung 43(7): 729-733
1993
ISSN/ISBN: 0004-4172 PMID: 8369003 Document Number: 413297
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 times 0.38, 2 times 1.2 and 2 times 2.3 mg/kg daily. Initially, 2 times 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. Hyperplasia of the adrenal zona glomerulosa was observed in the high dose group animals after 6 months and in medium and high dose group animals after 12 months of treatment. This change is a well-known adaptive pharmacological effect with some antihypertensive and natriuretic drugs. Minor alterations in erythrocyte number, packed cell volume, hemoglobin concentration, serum concentration of glucose and urine osmolality occurred during the studies. These latter findings were judged to be of minor toxicological importance.