The effect of d-penicillamine of the skeletal development of rat foetuses

Abstract

Rats received 20, 50 or 100 mg/animal D-penicillamine i.p. twice daily on days 15, 16, 17, 18, and 19 of gestation, i.e. a total dose of 200, 500 resp. 1000 mg/animal. At all dosages the number of fetal resorptions did not increase significantly. Weight of the 20 day old embryos as well as length of the long bones in the extremities in the 100 mg-group showed a significant decrease. Numerous skeletal alterations could be observed in the 1000 mg-group such as absence, deformations or incomplete mineralisation of bones. Light microscopic examinations revealed an inhibition of the ossification as well as a decrease of number and size of the trabecula and of the thickness of the perichondrial bone sheath. A swelling of the collagenous fibrils can be demonstrated with the electron microscope. The first apatite crystals aggregate in collagen-free areas. The fusion of these aggregates to homogenously mineralized trabecula is inhibitied. In contrast to bones from untreated embryos, mineralized areas show varying content of collagen and apatide crystals. A regular spatial relationship between apatite crystals and collagenous fibrils does not develop. These findings show that even after the so-called "critical period" malformations can be pproduced by substances which disturb synthesis and maturation of the mesenchymal intercellular substance.

Teratogenic exposures

“…Penicillamine given in high doses to pregnant rats and mice has been associated with increases in connective tissue, skeletal, palate, and lung abnormalities in the offspring [Steffek et al, 1972; Merker et al, 1975; Irino et al, 1982; Keen et al, 1982, 1983; Kilbourn and Hess, 1982; Mark‐Savage et al, 1983; Myint, 1984; Dubick et al, 1985]. In some of these studies, copper supplementation reduced the teratogenic effects of penicillamine.…”

Adverse Effects of Drugs on Bone and Calcium Metabolism/Physiology

“…In patients with systemic sclerosis, use of penicillamine did not seem to alter the changes in forearm bone mineral compared to other treatments (glutamine, hydralazine, phenytoin, chlorpromazine) [151]. In animal experiments, large probably non-pharmacological doses of penicillamine induced a number of skeletal changes [152][153][154]. Use of chloroquine treatment in patients with rheumatoid arthritis seems associated with a prednisolone sparing effect and possibly a positive effect on BMD [155,156].…”