Subject(s)
Deamino Arginine Vasopressin/administration & dosage , Diabetes Insipidus, Neurogenic/drug therapy , Abnormalities, Multiple/drug therapy , Administration, Intravenous , Administration, Oral , Cleft Lip/complications , Cleft Lip/drug therapy , Cleft Palate/complications , Cleft Palate/drug therapy , Drug Administration Routes , Drug Compounding , Female , Gastrostomy , Holoprosencephaly/complications , Holoprosencephaly/drug therapy , Humans , Infant , Infusions, ParenteralABSTRACT
Covering: 1950s to 2015During the 1950s, sheep ranchers in the western United States experienced episodic outbreaks of cyclopic lambs. In this highlight I describe how these mysterious incidents were traced to the grazing of Veratrum californicum wildflowers by pregnant ewes, leading to the discovery of cyclopamine () as a plant-derived teratogen. The precise mechanism of cyclopamine action remained enigmatic for 30 years, until this steroid alkaloid was found to be the first specific inhibitor of Hedgehog (Hh) signalling and a direct antagonist of the transmembrane receptor Smoothened (SMO). In addition to being a valuable probe of Hh pathway function, cyclopamine has been used to demonstrate the therapeutic potential of Hh pathway inhibitors. I discuss the development of SMO antagonists as anticancer therapies and emerging challenges.
