Spontaneous contractions suppressed in late-term rat pregnancy

A long-time aim of obstetrical research has been to find agents that could delay or diminish pre-term labor because even today pre-term birth is a leading cause of infant mortality and morbidity.

In the U.S. in 2000, disorders associated with short gestation and low birth weight accounted for 4,400 or 15.7% of infant deaths, second only to congenital disorders with 5,750; third was Sudden Infant Death Syndrome with 2,520.  

There is considerable evidence indicating that oxytocin (OT) plays an important role in pre-term labor, especially causing contractions of the myometrial muscles. OT receptor antagonists inhibit spontaneous myometrial contractions in vitro and suppress myometrial activity in live animal models. In a clinical trial, the mixed OT-vasopressin receptor antagonist atosiban (Ferring Pharmaceuticals Ltd.) showed similar efficacy as betablockers in treating pre-term labor, but with markedly lower maternal cardiovascular side effects.

“Delaying labor with an oxytocin receptor antagonist may significantly reduce infant morbidity, including lung disease, intraventricular hemorrhage, and possibly even death,” according to David P. Brooks, of GlaxoSmithKline Pharmaceuticals (GSK). He said GSK researchers have developed a series of non-peptide selective oxytocin receptor antagonists that have a high affinity for the human and rat OT receptors with a greater than 1,000-fold selectivity over the human vasopressin receptors.

Brooks adds that the GSK compounds “result in a concentration-dependent, competitive inhibition of OT-induced contractions of isolated rat myometrial strips and dose-dependent inhibition of OT-induced contractions of the uterus in anesthetized rats. Furthermore, these compounds suppress spontaneous contractions in late-term (19-21 days) pregnant rats.”

Brooks is speaking at the American Physiological Society’s 2005 Conference, “Neurohypophyseal Hormones: From Genomics and Physiology to Disease,” and the latest developments toward clinical applications, July 16-20 in Steamboat Springs, Colorado.

David P. Brooks, Vice President Biology U.S., Cardiovascular and Urogenital Drug Discovery Centre, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

“Development of non-peptide oxytocin receptor antagonists for the treatment of preterm labor.”

Brooks is participating in a symposium, “Clinical utility of NH receptor analogs,” chaired by Joseph Verbalis of Georgetown University and Maurice Manning of the Medical College of Ohio. The other participants in the symposium are:

Robert H. Ring, head of molecular neurobiology, depression & anxiety disorders, discovery Neuroscience, Wyeth Research, Princeton, New Jersey.

“The central vasopressinergic and oxytocinergic systems as targets for psychiatric  drug development.”

Patrice Collins, Medical Affairs, Astellas Pharmaceuticals Inc.

“Effects of a novel vasopressin V1a/V2 antagonist conivaptin on serum sodium concentration and effective water clearance in hyponatremia clinical trials.”