External malformations in chick embryos following concomitant administration of methylxanthines and β‐adrenomimetic agents: 1. Gross pathologic features

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Abstract
The objectives of this report are to document external malformations observed in chick embryos following concomitant administration of methylxanthines (caffeine, theophylline) and β‐adrenomimetic agents (isoproterenol, epinephrine) and to suggest reasonable explanations for the anomalies. Administration of caffeine or theophylline alone (2.5–5.0 mg/egg) retarded growth in a dose‐dependent fashion. Doses of 5.0 mg caffeine and theophylline produced beak malformations in 4.9% and 57.1% of embryos, respectively. Limb malformations, seen in low frequency (3.6% in 56 embryos) after administration of 1 μg isoproterenol, were not seen in 224 methylxanthine‐treated embryos. Structural defects following coadministration of methylxanthines and β‐adrenomimetics were frequently observed in limbs (primarily lower limbs with predilection for left‐sided oligodactyly) and beak. Other findings included limb hematomas, hygromas in the nuchal region, and prominent generalized edema. The most dramatic effects observed in this study were those induced by concomitant administration of 2.5 mg caffeine and 1 μg isoproterenol. This combination produced at least one of the embryopathies listed above in 87.9% of treated embryos and frequently induced beak (24.2%) and lower limb defects (75.8%) in addition to nuchal hygromas (9.1%). Similar severe malformations were observed following administration of 3.8 mg theophylline with 1 μg epinephrine. Embryos that died within 12–48 hours following drug insult demonstrated marked cardiac dilation, apparently due to congestive heart failure. The results of this study suggest that methylxanthines and β‐adrenomimetic agents are synertistic in their action in the developing chick. Doses of β‐adrenomimetic agents that were used in this study were not synergistic with methylxanthines. Increased intracellular cyclic adenosine monophosphate (AMP) is offered as an explanation for digital anomalies due to inhibition of proximodistal development of limbs. Increased intracellular cyclic AMP may also explain limb hypoplasia and loss of intermediate limb structures as a result of inhibited mitosis and/or necrosis of embryonic tissue.