An estrogen analog described by the government chemist whocreated it as "five times more potent than ethynyl estradiol" _ ahormone basic to oral contraceptives now on the market _ isseeking to join that market.
A notice submitted to the Federal Register last week invites"pharmaceutical or biotechnology companies" to join forces with theContraceptive Development Branch in the National Institute of ChildHealth and Human Development in commercializing "novel, orallyactive esters of estradiol."
Physiologist Nancy Alexander, who heads the branch, recently saidthat "in the last 20 years, we've had no fundamentally new type ofcontraceptive." (See BioWorld Today, Dec. 5, 1994, p. 2.) Now herchief chemist, H. K. Kim, has a synthetic estrogen derivative in theworks, which she believes has the potential to move thecontraceptive market off its dead center.
"The compound's five-fold greater potency," Alexander toldBioWorld Today, would make it "incredibly effective, so the doseswould be very low." This, she pointed out, could benefit smokers,for whom contraceptive hormones pose a special health hazard.
Today, more than half of all women who use a reversible method ofbirth control rely on the Pill, now into its third decade on the market.The Physician's Desk Reference, a leading guide to prescriptiondrugs, describes 47 brands of oral contraceptive, manufactured byeight pharmaceutical companies. Despite their 99-percent-plusreliability, these hormone cocktails pose certain health risks to somenon-smokers too.
"Some people have clotting disorders," Alexander observed, "andthere are some problems with liver function." She describes thathepatic function as the "first pass," which some clinicians holdresponsible for side-effects affecting some users of the Pill.
"When an orally ingested hormonal compound reaches the liver,"she explained, "that organ rapidly metabolizes it, so high doses arerequired to override this effect.
One end-run around that first pass through the liver, Alexandersuggests, is to administer the new analog transdermally, by a topicalcream or skin patch. "That way, you can use incredibly loweramounts, she said; "you don't have that first-pass breakdown."
Her branch is now testing percutaneous, topical and oral routes ofdelivery in primates.
Another potential market for the new estrogen analogs is as a"morning-after" pill. "They are very potent post-coital agents," thecooperative research and development agreement (CRADA) noticereports, as determined "following oral administration in rats on days0-4 of gestation."
Yet another profitable application would be for replacement estrogenmaintenance in menopausal women. "With the graying of America,"Alexander pointed out, "more and more women will require suchhormonal maintenance for more and more years after menopause.
"All these things have to be tested," she observed, "but if ourestrogen analog would actually give better liver-function parameters,and if it looked better for clotting disorders, it might reduce veryserious side effects." She concluded: "So far it's looking good _ butwho knows?"
Kim told BioWorld Today, German chemists tinkered with thehormone's molecular structure in 1938, "converting estradiol'ssecondary alcohol to a tertiary alcohol. That's how they got the oralactivity."
But they also got liver problems. "If the users use this kind of pillcontinuously," Kim continued, "It would burden the liver to unloadthat kind of compound."
So Kim in turn, over half a century later, tinkered further, andsynthesized several non-ethynylated estradiol nitrate esters that seemto circumvent the liver's first-pass metabolic burden. He is firstinventor on the pending patent (filed Aug. 17, 1993), which NICHDis now offering to industry for exclusive or non-exclusive researchand development licensure, and a CRADA.
"Our goal is not to try to develop products ourselves," Alexanderexplained. "We continue to do things to develop them to show thatthey are marketable, but we ourselves couldn't do it in the timeframe that a pharmaceutical or biotech company could."
Editor's note: For CRADA information, consult Gordon Guroff,deputy scientific director, NICHD. Telephone: (301) 496-4751; forpatent licensing call Carol Lavrich, NIH Office of TechnologyTransfer. Telephone (301) 496-7735, ext. 287; for technicalquestions concerning this invention call Nancy Alexander,Contraceptive Development Branch, NICHD, (301) 496-1661. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.