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)
Säfholm
C
C
Safety Assessment, AB Astra, Södertälje, Sweden.
Havu
N
N
D000311:Adrenal Glands / Q000473:pathology; D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D001774:Blood Chemical Analysis; D002121:Calcium Channel Blockers / Q000633:toxicity*; D004285:Dogs; D015736:Felodipine / Q000633:toxicity*; D005260:Female; D005885:Gingival Hyperplasia / Q000139:chemically induced / Q000473:pathology; D006940:Hyperemia / Q000139:chemically induced; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D016482:Urinalysis
D002121:Calcium Channel Blockers; D015736:Felodipine