New Uses for Old Drugs

Julie S. Green, MD, PhD, University of Colorado Denver
Lowell A. Goldsmith, MD, MPH, University of North Carolina

 

Modern drug design and development is often mechanistically and rationally based.  One such example is the TNF-α inhibitor class of agents, which were developed based on evidence that levels of TNF-α and IL-1 are increased in autoimmune inflammatory diseases of the joint and the gastrointestinal tract (Brynskov et al., 1992; Saxne et al., 1988; Tetta et al., 1990).  Improvement of cutaneous psoriatic lesions during treatment of psoriatic arthritis led to approval of several TNF-α inhibitors to treat psoriasis (Mease et al., 2000), therapies that have revolutionized the approach to treating this physically and emotionally debilitating disease.

Another method by which treatments for diseases are developed involves the expansion over time of indications for which a particular drug is used after its initial FDA approval for a  limited set of indications.   After FDA approval and release of a drug onto the market, clinical experience is gathered from an often much larger patient population than was employed during clinical trials; experience accumulated over years of usage often informs clinicians about various side effects of the medication, both adverse and serendipitous.  Such accumulated experiences, if significant, may grant more expeditious approval of a new indication for a drug.  There are a number of examples of agents currently used for dermatologic indications that were initially developed for other purposes.

One noteworthy such example is thalidomide, developed in the 1950s as a hyponotic and an anticonvulsant.  This drug was licensed in 1956 as an over-the-counter sleeping aid in Europe and in other parts of the world.  By 1959, an increased incidence of phocomelia, an otherwise rare condition characterized by shortening of the limbs, was being reported, but its association with maternal thalidomide use was not suggested until 1961 (Mellin and Katzenstein, 1962).  By the time thalidomide was removed from the market, over 10,000 children had been born with thalidomide embryopathy.  Though the drug could have been permanently removed from the market, it was found to be an effective treatment for erythema nodosum leprosum (Sheskin, 1965), which remains the only FDA-approved indication for thalidomide.  A rigorous screening and monitoring program (System for Thalidomide Education and Prescribing Safety [S.T.E.P.S.])  administered by the manufacturer of thalidomide ensures that patients and physicians understand the potential risks of the medication and that no patient who might become pregnant gains access to the drug.

Now, Kim et al (2013) describe in the Journal of Investigative Dermatology the use of ketotifen, an agent currently FDA-approved for the prevention of asthma exacerbations and for treating allergic eye disease, as a potential treatment to reduce the effects of UV damage on chronically sun-exposed skin.   The authors report that ketotifen attenuates mast cell recruitment and matrix metalloproteinase (MMP) activation and reduces UV-induced wrinkling in hairless mice.  These findings apply established knowledge of both ketotifen’s mechanism of action and the  processes that underlie UV-induced photoaging to investigate a potential novel treatment strategy for this phenomenon.  As understanding of the pathophysiological basis of disease increases, novel uses for existing medications with well-elucidated physiologic effects and development of new therapeutics targeted to specific pathologic processes are both likely to remain important strategies for developing new treatments for various dermatologic diseases.

 

REFERENCES

Brynskov J, Tvede N, Andersen C, Vilien M (1992) Increased production of interleukin-1alpha, interleukin-2 and soluble interleukin-2 receptor in endoscopic mucosal biopsy specimens with active inflammatory bowel disease. Gut 33:55-8.

Kim M-S, Lee DH, Lee C-W, et al.  Mast Cell Stabilizer, Ketotifen, Prevents UV_Induced Wrinkle Formation.  J Invest Dermatol doi:  10.1038/jid.2012.424

Mease P, Goffe B, Metz J, VanderStoep A, Finck B, Burge D (2000) Etanercept in the treatment of psoriatic arthritis and psoriasis. Lancet 356:385-90.

Mellin GW, Katzenstein M (1962) The Saga of Thalidomide — Neuropathy to Embryopathy, with Case Reports of Congenital Anomalies. New Engl J Med 267:1238-44.

Saxne T, Palladino M, Heinegård D, Talal N, Wollheim F (1988) Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 31:1041-5.

Sheskin J (1965) Thalidomide in the treatment of lepra reactions. N Engl J Med 6:303-6.

Tetta C, Camussi G, Modena V, Di Vittorio C, Baglioni C (1990) Tumour necrosis factor in serum and synovial fluid of patients with active and severe rheumatoid arthritis. Ann Rheum Dis 49:665-7.

 

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