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    Isotretinoin’s discovery and development

    Expert discusses pearls gleaned from initial clinical observations

     

    Isotretinoin’s early days

    Dr. Siegfried: I want to help listeners and readers get some of the wisdom that I was able to get from those experiences. First, isotretinoin has been around for a really long time. It was FDA-approved in September 1982, which was right before I started my residency. People have learned just from clinical observation, but in many places, they didn’t have the opportunity to have that memory of all the clinical observation. Give me some insider history about the early days of isotretinoin use and development.

    READ: Isotretinoin risks in acne treatment

    Jim Leyden, M.D.Dr. Leyden: Well, the story began with a basic researcher at the National Institutes of Health (NIH), Michael Sporn. He had developed an organ culture system. At that point, there was a great deal of interest in cell biology in general, about the potential antitumor effects of retinoids, tretinoin being the one that had been most studied. There was a great deal of interest in looking at other molecules that were either vitamin A derivatives or manufactured versions of the vitamin A molecule. And then subsequently when receptors were discovered, looking at various molecules that could interact with retinoid receptors because of the potential effect on cell differentiation that could potentially be beneficial in interrupting the process of carcinogenesis.

    Sporn found that the 13-cis-isomer of all trans-retinoic acid (tretinoin), which is isotretinoin, was very biologically active. Hoffmann-La Roche then made up some crude formulations and gelatin capsules of this isomer and shipped it down to the NIH to be given to people with severe disorders of keratinization. These were the worst cases of ichthyosis and Darier’s disease.

    Dr. Siegfried: There was some basic science that was done on these molecules and then the drug just sort of became available for investigator-initiated clinical use?

    Dr. Leyden: Yes. This wouldn’t happen today. We have so many regulations, etc. But the same thing actually happened with griseofulvin. It’s a great story, too. Harvey Blank read an article by Jimmy Gentles who described the activity of griseofulvin in eradicating experimentally induced fungal infections in guinea pigs.[1] At that point, there was no real treatment other than X-ray treatment and epilation for the epidemics of tinea capitis. He wrote to Gentles asking for some, and Gentles sent it in the mail. Blank gave it to a  patient with widespread T. rubrum granulomas and they cleared. A year later, there was an international meeting with hundreds of tinea capitis cases successfully treated, and that was the birth of griseofulvin, one of the landmark therapeutic developments in our specialty.

    READ: Isotretinoin misconceptions, misinformation still thrive

    Almost the same speed of development occurred with isotretinoin. Gary Peck, who was the dermatologist performing most of the clinical work at the NIH, gave the molecule to patients with severe  ichthyosis and Darier’s disease. It didn’t eradicate these problems, but it was a huge step forward. Subsequently, he came to give a seminar at our weekly Kligman corned beef lunch and talk. When he finished, Albert jumped up and said, “What did you find in acne?” It never occurred to anybody at the NIH that maybe acne was a disease in which there were epithelial abnormalities and isotretinoin might be useful.

    Gary went back and, in collaboration with John, they treated a very small group of patients — I think it was 10 or so. Miraculously they cleared up and the study was published in the New England Journal of Medicine.[2] Subsequently, there was a dose-ranging study in which John, Alan, and Peter Pochi looked at 0.1, 0.5, and 1 mg/kg/day.[3] I got involved in a very complicated pharmacokinetic study. We had a group of about 20 who spent a month in our clinical research unit. These patients, were 12s on a scale of 1 to 10, as far as severity. Many came from various parts of the country. They were the worst of the worst, and they all cleared up in a miraculous-like fashion.

    NEXT: Dose ranging studies

    Elaine Siegfried, M.D.
    Elaine Siegfried, M.D., is professor of pediatrics and dermatology, Saint Louis University Health Sciences Center, St. Louis, Mo. She ...

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