Salve Hailed as Anti-Wrinkle Breakthrough

Times Staff Writer

A medical milestone almost as eagerly sought as the fountain of youth appears to have been reached with a Michigan research report today on the promising results from a prescription drug treatment for wrinkles.

The report that the anti-wrinkle salve called tretinoin, which is sold under the brand name Retin-A, is effective in causing sun-induced wrinkles to disappear appears in the Journal of the American Medical Assn.

The apparent major advance, in a study conducted by a prominent University of Michigan dermatologist whose work was financed by the drug company that makes the compound, comes after years of promises by cosmetic makers promoting wrinkle-elimination products that turn out to have no quantifiable medical effect.

A researcher not involved in the new study said in an editorial published in the journal and in a telephone interview with The Times that tretinoin can appropriately be called the first effective medical treatment for skin aging.

"Up until the advent of (this use of) tretinoin, there wasn't anything out there. Nothing," said Dr. Barbara Gilchrest of Boston and Tufts universities. "To me, this is clearly a major, major breakthrough clinically and research-wise. This is truly a very dramatic event."

Used in Acne Treatment

The development is probably not yet enough to bring Ponce de Leon back from the grave because the drug involved--a long-established acne treatment--does not appear potent enough to produce truly dramatic changes in facial lines and other lines caused by chronic exposure to the sun.

The new research found that quantifiable improvement in facial wrinkles was observed in 14 of 15 patients who used tretinoin on their faces and in all 30 patients who used it on their forearms. The researchers speculated that tretinoin will eventually prove effective on age wrinkles, as well as those induced by sun-exposure, which the study proposes should be reclassified because cigarette smoke, heat, wind and chemical exposure may also play a role in creating them.

The wrinkle improvement was far from dramatic, however. The majority of changes in sun-caused wrinkles were classified by researchers as only "slight" and the therapy produced less-pronounced improvement on facial wrinkles than on those on the forearms of the patients, who ranged in age from 35 to 70. Moreover, 92% of the patients who used tretinoin experienced some sort of side effects from it--usually skin irritation or reddening--that caused them to temporarily discontinue use of the drug.

The drug would probably have to be used between three times a week and daily, which would mean an annual cost of about $175 based on the price of $19 a tube widely charged at Los Angeles- area drugstores.

Researchers who have tested tretinoin say they expect that tinkering with its chemistry could, within the next few years, produce more specific molecules that would allow the erasure or near-erasure of not only sun-caused wrinkles but also skin lines that result from the natural aging process. The new study concludes the tretinoin treatment does not now affect deeper, age-induced, wrinkles. The Michigan researchers did not include data on long-term maintenance therapy with tretinoin, but the head of the research said ongoing, long-term use would be necessary to maintain the improvement.

Dr. John Voorhees, who headed the study, said most cosmetics touted as wrinkle treatments have temporarily increased the water content of the outer layer of the skin and caused it to reflect light differently so there was an illusion of improvement in the wrinkles. But to truly repair wrinkle damage, Voorhees said, a product must penetrate to the deeper levels of the skin--called the stratum corneum.

Looking 20, 30 at 50 or 60

"I think it's a shame that we all feel that we have to look 20 or 30 when we're 50 or 60, but the fact of the matter is that whether I like it or not, that is the way it is," Voorhees said of the intense public interest in the new findings. "I guess I don't see any harm in this as long as it makes people happier, as long as they have the money to pay for a tube of it (tretinoin)."

Microscopic evaluation of changes induced by tretinoin, Voorhees said, made it clear skin cells themselves are changed and improved by the drug. Official approval of the use of Retin-A to combat wrinkles won't be sought from the U.S. Food and Drug Administration for at least a year, according to Ortho Pharmaceutical Corp., the drug's maker, to allow further work on at least 16 other research studies currently under way. But Ortho, a subsidiary of Johnson & Johnson, and government officials noted that there is no legal bar to doctors prescribing Retin-A for the new use now.

The long-term safety of the chemistry involved may also require additional verification, researchers say, because tretinoin is a derivative of Vitamin A--itself a known cause of birth defects when used in extremely high dosages.

Retin-A, sold in salve form, has shown no birth defect complications in the 17 years it has been on the market, but researchers agreed any new Vitamin A chemical derivative would have to be carefully evaluated.

Ortho's experimentation with tretinoin as a wrinkle treatment has been widely known within the pharmaceutical industry for at least a year, and the drug's original developer, Dr. Albert Kligman, of the University of Pennsylvania, suggested in a journal article published in 1986 that it might be an effective anti-wrinkle agent. Kligman owns the Retin-A patent and the drug is produced by Ortho under license.

Anticipation Builds

Rumors of the impending Ortho study created something of a sensation as word spread about the impending AMA journal publication this past week. New Jersey-based Ortho took the unusual step of hiring a New York public relations agency to arrange interviews and a press conference for Voorhees.

In the study, patients used the drug or a placebo salve containing no active ingredient daily for 16 weeks each. Neither the patients nor the researchers evaluating them knew who was using the salve and who was using the placebo. Forty patients began the study and three withdrew because of severe skin irritation side effects. The size of the total group eventually dropped to 30.

By the end of the study, tretinoin used on the forearms produced "much" improvement in fine wrinkles and skin color between 10% and 20% of the time. "Slight" improvement was noted between 43% and 57% of the time. On the face, there was "slight" improvement 20% to 87% of the time and "much" response in no more than 7%.

Voorhees said that, because tretinoin is a derivative of Vitamin A, it is possible that a vitamin salve rubbed on the skin might have at least some of the same results, but he said the greatest benefit of the new study may be to point the way toward more sophisticated tretinoin-like chemicals that will be better equipped to bring about wrinkle improvement.

No foreseeable version of the drug will ever be able to make all wrinkles completely disappear, he added. "One thing it does not do is change gravity," he said. "It removes fine wrinkles."

Dr. Frank Yoder, a former National Cancer Institute researcher and chief of dermatology at Children's Hospital in Columbus, Ohio, noted that Accutane--whose generic name is isotretinoin--is a compound similar to Retin-A that has shown an ability to precipitate birth defects so significant that Accutane can only be prescribed to women of childbearing age if they use contraceptives and are verified not to be pregnant before therapy begins.

Significant Differences

But Yoder said the chemical differences between isotretinoin and tretinoin are significant enough and tretinoin's long-term safety is so well established that fears about birth defect side effects appear, at the moment, to be unfounded.

"Everything else about wrinkles and anti-aging creams has been just really nonscientific products, essentially to make money, and none have been approved or even looked at to see if they are effective," Yoder said. "These are good researchers and I would tend to believe their results." Gilchrest urged creation of a separate class of chemical agents--between drugs and cosmetics--to make it more readily possible for legitimate products to come on the market.

"There has been interest in doing something about skin aging for millennia, along with an industry addressing itself to satisfying public demand," Gilchrest said. "There has been some good-faith effort, but there have also been, unfortunately, a great deal of products put out on the market that were really embarrassing to anyone interested in this area. They have been an insult to the scientific community, an insult to the public and an insult all the way around."

Sometimes using prominent physicians as spokesmen, cosmetic companies in the last few years have tried to market a wide variety of products said to induce the smoothing of wrinkles. In one of the most recent episodes, heart transplant pioneer Christiaan Barnard participated in promotion of a line of skin care products called Glycel in 1986. The products were promoted as being able to rejuvenate or renew cells and make tired, wrinkled skin feel young again.

But after a major commercial push when the line was launched, the products failed in the midst of publicity over questionable claims made on their behalf. The FDA asked the makers of Glycel and several other firms to submit data to justify claims about anti-wrinkling properties, taking the position that anything that could actually smooth wrinkled skin would be considered a drug and be subject to strict safety and effectiveness rules.

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