Prenatal toxicity studies in rats and rabbits with the calcium channel blocker diproteverine.
In prenatal toxicity studies, diproteverine, a calcium channel blocker with demonstrated antianginal properties, produced an unusual pattern of digital, heart, tail, and vertebral defects in rat fetuses from mothers treated during the major period of organogenesis, but only a very low incidence of heart abnormalities was seen in the rabbit. Heart changes were rarely seen in association with digital defects. The findings were consistent with those seen with other calcium channel blockers and add weight to the suggestion of Danielsson and colleagues (5) that digital malformations are a class effect for this type of compound, the effects being related to reduced uteroplacental blood flow. In addition, it is proposed that cardiovascular malformations are also a class response with calcium channel blockers. The distribution of fetal death and hemorrhages and the varying association between cardiovascular, digital, and tail abnormalities seen in the rat with increasing doses of diproteverine fits the pattern of changes reported following hypoxia in the chick embryo. Reduced uteroplacental blood flow with resultant embryonic hypoxia secondary to pharmacologic action is considered a probable mechanism of action for the induction of abnormalities produced by calcium channel blockers.
Ridings
J E
JE
Smithkline Beecham Pharmaceuticals, Toxicology Department UK, Welwyn, Hertfordshire, UK.
Palmer
A K
AK
Davidson
E J
EJ
Baldwin
J A
JA
D000015:Abnormalities, Multiple / Q000139:chemically induced; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity*; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005121:Extremities / Q000196:embryology; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D006330:Heart Defects, Congenital / Q000139:chemically induced; D000860:Hypoxia / Q000139:chemically induced; D007546:Isoquinolines / Q000008:administration & dosage / Q000633:toxicity*; D017880:Limb Deformities, Congenital; D021041:Placental Circulation / Q000187:drug effects; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011297:Prenatal Exposure Delayed Effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013131:Spine / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology
D002121:Calcium Channel Blockers; D007546:Isoquinolines; C049847:diproteverine