{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T07:37:03Z","timestamp":1773733023307,"version":"3.50.1"},"reference-count":58,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2005,5,19]],"date-time":"2005-05-19T00:00:00Z","timestamp":1116460800000},"content-version":"vor","delay-in-days":7901,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratology"],"published-print":{"date-parts":[[1983,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The objectives of this report are to document external malformations observed in chick embryos following concomitant administration of methylxanthines (caffeine, theophylline) and \u03b2\u2010adrenomimetic agents (isoproterenol, epinephrine) and to suggest reasonable explanations for the anomalies. Administration of caffeine or theophylline alone (2.5\u20135.0 mg\/egg) retarded growth in a dose\u2010dependent 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 \u03bcg isoproterenol, were not seen in 224 methylxanthine\u2010treated embryos. Structural defects following coadministration of methylxanthines and \u03b2\u2010adrenomimetics were frequently observed in limbs (primarily lower limbs with predilection for left\u2010sided 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 \u03bcg 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 \u03bcg epinephrine. Embryos that died within 12\u201348 hours following drug insult demonstrated marked cardiac dilation, apparently due to congestive heart failure. The results of this study suggest that methylxanthines and \u03b2\u2010adrenomimetic agents are synertistic in their action in the developing chick. Doses of \u03b2\u2010adrenomimetic 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.<\/jats:p>","DOI":"10.1002\/tera.1420280216","type":"journal-article","created":{"date-parts":[[2005,6,11]],"date-time":"2005-06-11T14:45:23Z","timestamp":1118501123000},"page":"257-269","source":"Crossref","is-referenced-by-count":6,"title":["External malformations in chick embryos following concomitant administration of methylxanthines and \u03b2\u2010adrenomimetic agents: 1. Gross pathologic features"],"prefix":"10.1002","volume":"28","author":[{"suffix":"Jr.","given":"Harold J.","family":"Bruyere","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John F.","family":"Fallon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enid F.","family":"Gilbert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,5,19]]},"reference":[{"key":"e_1_2_1_2_1","first-page":"2199","article-title":"Sur un effet t\u00e9ratog\u00e9ne syst\u00e9matique et sp\u00e9cifique de la caf\u00e9ine chez les Rongeurs","volume":"159","author":"Bertrand M.","year":"1965","journal-title":"C. R. Soc. Biol. (Paris)"},{"key":"e_1_2_1_3_1","first-page":"31A","article-title":"The teratogenic effect of prenalterol on the embryonic chick heart","volume":"21","author":"Bruyere H. 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