Teratogenic Effect of Tedral (Theophylline, Ephedrine, and Phenobarbital) on Cardiac Development in Chick Embryos

Abstract

Abstract We employed the chick embryo in a comparative study of the effect of Tedral and theophylline on anatomical development. Tedral, which contains theophylline in combination with ephedrine and phenobarbital in the relative dose ratio of theophylline 33: ephedrine 6: phenobarbital 2, or saline for control was dropped onto the surface of the chorioallantoic membrane of 2, 3, 4 and 5-day-old chick embryos. In groups A (theophylline 0.015 M, ephedrine 0.0027 M, phenobarbital 0.0009 M) and B (theophylline 0.011 M, ephedrine 0.0020 M, phenobarbital 0.0007 M), 100% of embryos treated on the 5th day of incubation developed aortic aneurysms with associated cardiovascular malformations. In group C (theophylline 0.005 M, ephedrine 0.0009 M, phenobarbital 0.0003 M), 36.8% of embryos treated on the 5th day of incubation developed aortic aneurysms, and 73.7% of embryos had cardiovascular malformations. These data were compared with those obtained by using theophylline, ephedrine or phenobarbital alone. The commonest cardiovascular anomalies induced by Tedral were double-outlet right ventricle with ventricular septal defect. Aneurysms were larger in size and cardiovascular malformations were more complex in embryos exposed to Tedral than in those treated with theophylline alone. Complex cardiac defects produced by Tedral included transposition of the great arteries, double-outlet right ventricle with double-inlet left ventricle, and truncus arteriosus communis. A slit-like small ventricular septal defect was found in 9.5% of the ephedrine-treated (0.51 mg) chick embryo group and 9.1% in the control embryos. These data show: (1) theophylline, a major component of Tedral, produces cardiovascular anomalies in embryonic chick hearts; (2) there is synergy of all three drugs in Tedral; (3) the specific type of conotruncal defect depends on the timing of administration, e.g., truncus arteriosus communis was produced on day 4 of Tedral administration in chick embryos.