A new wrinkle in drug therapy already being used to treat motion sickness, high blood pressure and angina pectoris pain has been tested at UCLA with apparent success in treating the effects of menopause.
The method uses stick-on patches to introduce into the body a drug that was being administered in pills or some other form. Called a "transdermal" application, the patch procedure may help the patient avoid some of the side effects brought on by conventional therapy.
In the case of motion sickness, a drug called scopolaomine is now available in stick-on form to prevent seasickness; the drug clonidine is being used for blood pressure therapy, and a staple of pharmacology, nitroglycerin, is used in its familiar role as the drug of choice for angina.
Now, however, the stick-on patch--whose development was greeted initially in some consumer circles more as a novelty than anything else--is being advocated by UCLA scientists as a way to infuse doses of replacement estrogen into postmenopausal women. A report of the new research findings--focusing on 23 women on whom the estrogen patches were tested--is being published today in the New England Journal of Medicine.
And though the stick-on patch is not yet ready to be sold to the public, independent experts not involved in its development say the research has "the potential of being a real breakthrough." That was the careful assessment of Dr. Jacob Brody, dean of the University of Illinois School of Public Health and a former associate director of the National Institute of Aging.
Alternative to Daily Pills
In the new method, instead of pills taken daily--with the risk of possible uterine cancer, liver damage, high blood pressure and other complications, including nausea and vomiting--women might stick patches of a hormone called estradiol on their bellies twice a week, allowing the drug to be absorbed through the skin directly into their bloodstreams.
So far, the stick-on method seems to have few, if any, of the disadvantages of estrogen replacement pills and the same therapeutic benefits--which come in the form of avoidance of the bone deterioration of osteoporosis, vaginal atrophy and hot flashes.
If the estrogen patch proves in larger tests to work as it has up until now, the new method may avoid most, if not all, of the serious side effects that have kept estrogen replacement therapy highly controversial since it was first used more than 20 years ago.
And for Alza Corp. and Ciba-Geigy Corp., the two drug companies with a cooperative stake in the new product, the so far-favorable test results keep alive the dream of vast commercial success in a market whose size will burgeon between now and the year 2010 as the Baby Boom generation cycles through the population and women probably retain their 7.5-year longevity advantage over men.
In Final Testing Phase
The Alza-Ciba product, which has been given the brand name Estraderm, is in the final phases of pre-market testing, and its makers believe that it could be approved for sale by the U.S. Food and Drug Administration as early as within a year from now.
The UCLA research report follows publication in another journal last August of a preliminary study of Estraderm conducted by the two drug companies themselves.
A side effect-free estrogen replacement therapy could have broad appeal in a market which FDA and U.S. Census Bureau figures indicate may grow exponentially from only about 4 million to 5 million of 40 million postmenopausal women using estrogen now.
Census projections indicate that, by the year 2000, there will be nearly 55 million women over 44--the age range in which menopause becomes commonplace, and, by 2010, there will be more than 65 million in the age bracket.
Until now, the market has been dominated by Premarin, a so-called conjugated estrogen product that has done better than any other pill in treating menopause but about which enough questions about short-term and long-term side effects have been raised to keep it from becoming anything approaching universally used.
The newly published UCLA research was done by a team in Westwood and at Veterans Administration hospitals in Los Angeles and in St. Louis. The project was headed by Dr. Howard Judd of UCLA, one of the nation's half dozen most prominent experts on the phenomenon of menopause.
It has been recognized for a decade that the hormone called estradiol could reverse much of the deterioration of the body characteristic of menopause, reducing the nagging, painful annoyance of hot flashes and also inhibiting osteoporosis. It is the bone loss effect that is most important, Brody and Judd agreed, since an estimated 200,000 to 250,000 elderly American women annually sustain disabling and often fatal hip fractures directly as a result of breakdown of their skeletons caused by the cessation of normal hormone production when they underwent menopause years earlier. The problem with estradiol, however, has been that, like any drug given in pill form, it breaks down in the intestines and enters the bloodstream through the intestinal walls, passing to arteries that carry it directly to the liver, Judd said. In the case of estradiol, inordinate concentrations build up in the liver, causing in many users a situation in which the adverse effects of estrogen replacement significantly outweigh the benefits.
A Different Route
But administering drugs through the skin, Judd said, enables the estrogen to find a different route--entering the bloodstream through tiny capillaries near the skin and going into solution throughout the body in essentially uniform concentrations. The liver doesn't act as a trap for high levels, and the estrogen enters the bloodstream at a constant rate, without the highs and lows characteristic of the pill form.
In addition, the skin patch may also be a more convenient way to get estrogen, Judd said, since there is no pill-taking schedule to remember. He said the adhesive used in the new product permits the patch to be left on during bathing and exercise; but, he said, the patch can be removed and put back on if a woman does not want it to be seen on her abdomen--if, for instance, she was wearing a two-piece bathing suit.
"What we have (now) is a series of advantages of estrogens and a series of side effects and risks," Judd said. "What we think we have done with this (the patch) is answer the element of the side effects and risks."
In the study being published today, Judd and the research team used the stick-on patch on 23 women, all of whom had had their last menstrual period at least a year before the tests began. The stick-on form of estrogen produced similar benefits to the pill form, but none of the side effects characteristic of oral estrogen was recorded in any of the 23 subjects.
Left unresolved, however, Judd emphasized, was the effect of the stick-on patch estrogen on blood fat levels linked to the possible development of heart disease. Estrogen appears to sometimes have a protective effect in terms of preventing heart attack, and Judd said it is not clear now whether the stick-on patch form of the drug duplicates the effect. He said additional tests will be necessary to resolve this remaining uncertainty.
In an editorial accompanying publication of the research report, two pharmacologists at Tufts University School of Medicine in Boston noted that, though the new estrogen replacement method will require additional and larger studies to verify that it offers the benefit it seems to promise, "attempts to develop ingenious and superior new delivery systems for old drugs must be applauded."
One of the Tufts experts, Dr. David Greenblatt, emphasized in a telephone interview that, while use of the stick-on patch in such drugs as nitroglycerin has already established itself as a major advance, it remains too early to tell for sure if the same can be said of using a similar patch for estrogen.
The editorial, written by Greenblatt and Dr. Louis Lasagna--one of the nation's foremost drug authorities--also noted that there has already been at least one report of an unintended problem with stick-on patches. That report, published two months ago in the New England Journal of Medicine, recounted an incident in which a doctor taking clonidine for high blood pressure treatment via the stick-on patch awoke one morning and found his patch had fallen off during the night. However, the patch could not be found.
Hours later, the doctor and his wife discovered the patch had stuck to the skin of their 9-month-old son who had been taken to bed with his parents because he was crying. The infant was unusually irritable, indifferent to food and underactive before his parents discovered what had happened. The little boy quickly recovered.
'A Major Advance'
In all, said Greenblatt: "In principle, this could be a major advance. In practice, we don't know."
Brody was similarly cautious but, he said in a telephone interview from Chicago, the new stick-on patch estrogen is enormously promising because there seems to be reason to believe it will work to cut the toll of osteoporosis.
"If (the patch) can deliver estrogen so that the proper level is maintained, the potential of it being a real breakthrough exists," Brody said. "Any mechanism that we can introduce that does that just has gigantic benefits."
In 1979, Brody was one of the organizers of a major National Institutes of Health conference on the state of estrogen replacement therapy and the controversy that surrounded it at the time.
Brody said the highest risk for serious hip fractures seems to be among white women--for reasons doctors do not yet understand. Brody said that the average age for major hip fractures now is 79 1/2 and that, if the age of highest risk could be postponed for just an average of five years, the toll in suffering and pain from the injuries would be significantly reduced since death from some other cause would probably intervene.
"Right now," he said, "there is tremendous interest in alternate forms of delivery, and I think the whole idea of transdermal medications is a breakthrough and this is one of the really promising areas."