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The Debate on Isotretinoin Carol Chyau What is Isotetrinoin? Also known as Accutane, licensed by FDA in 1982 Oral drug used to treat acne Taken 1x/2x a day, 16-20 weeks Synthetic molecule from vitamin A Vitamin A involved in growth and maintenance of skin Expensive but top selling drug worldwide, prescribed to 12 million people Manufactured by Hoffman-La Roche Why is Isotetrinoin Important? Topic of persisting debate between dermatologists and FDA The only effective treatment for severe acne Very effective but may have severe side effects Facts about Acne Most common skin disease - effects nearly 17 million people in US Common in adolescents with rising hormone levels of androgens (male sex hormones) during puberty Often hereditary Not caused by dirty skin What is Acne? Disorder of sebaceous (oil) glands that plugs pores and causes outbreaks of lesions (pimples) Disease of pilosebaceous units Sebaceous gland connected to a follicle (hair-containing canal) Units most common on face, upper back, and chest Normal pilosebaceous unit What Causes Acne? Change in inner lining of follicle Cells shed too fast, clump together, plug opening of follicle Sebum cannot reach surface of skin Mixture of oils and cells fosters Propionibacterium acnes (P. acnes) to grow in plugged follicles P. acnes produces chemicals and enzymes that cause inflammation Types of Acne Comedo – enlarged follicle plugged with oil and bacteria Whitehead – comedo beneath skin Blackhead – comedo that opens up on surface of skin Papules – inflamed lesions that are small pink bumps, could be tender Pustules – inflamed pus-filled lesions, red at base Nodules – large, painful, solid lesions deep within skin Cysts – deep, inflamed, pus-filled lesions, can cause pain and scarring Commons Drugs for Acne Topical medication Benzoyl peroxide cream/gel/lotion, salicylic acid, sulfur, resorcinol Oral medication Antibiotics such as tetracycline, minocycline, doxycycline, erythromycin Isotretinoin Isotretinoin and Vitamin A Vitamin A is also known as retinoic acid The most active metabolite of retinol is the main factor in skin regeneration Isotretinoin is 13-cisretinoic acid, the less toxic of the retinoids Discovery revolutionized acne treatment Isotretinoin Treatment Treats severe nodular or cystic acne Reduces size of oil glands, decreases sebum production, reduces cells shedding and sticking in follicles -> less P. acnes. After treatment, acne almost, if not completely goes away, though may come back for some people Decreases scarring Molecular Action Human organism not capable of synthesizing retinol Must in take with food Through digestion retinal absorbed in the liver in an inactive esterized form On demand, retinol attaches to a specific transport protein transported to the target cells Links to receptor at keratinocyte cell membrane to penetrates the cell, where it is bound to CRBP Stored inactive as retinylester or enzymatically oxidized to retinaldehyde Made active as retinol acid (RA)through additional enzymatic oxidation Transported to nucleus via CRABP to attaches itself to the specific retinoic acid receptor RAR. RARs belong to a "superfamily" of receptors considered to be a skin hormone RA/RAR complex is attached to DNA via RARE (retinoic acid response element) to regulate epidermal cell functions through induction of protein synthesis 99.9% bound to plasma proteins, particularly albumin Single polypeptide chain wit multiple binding sites for many lipophilic metabolites Side Effects? Mild: Dry mouth, nose, or skin; itching; nosebleeds; muscle aches; rarely, decreased night vision and headaches; tendonitis Serious: Fatigue, increased blood cholesterol, lipid, and triglyceride levels and abnormal liver enzymes, teratogenic (serious birth defects), *depression, *suicide What’s the Debate? 1. Seriousness of birth defects 2. Whether or not isotretinoin can really cause depression and suicide - Democrat Bart Stupak, blamed his 17year-old son’s suicide on Accutane 3. Regulation of the “dangerous drug” Birth Defects 25-30% of female users during pregnancy report birth defects Large doses of vitamin known to cause birth abnormalities Preventive measures Must have bright yellow label for female prescriptions Must use two birth control methods starting from one month before therapy until one month after therapy Can Isotretinoin Cause Psychological Problems? Evidence 19% of adverse events reported to Roche were psychiatric Numerous “personal” stories Last month, MedWatch reported 140 users worldwide that committed suicide during prescription period or soon after Current study at Emory University Depression may be caused by affecting the brain’s frontal cortex Use PET scans of 40 users to observe signs of decreased functioning in frontal cortex How Valid is the Evidence? Hoffmann – La Roche sponsored extensive study Accutane users no more likely than others to be depressed or suicidal Self-image actually increased without acne First population based study Suicide and depression have many environmental causes that often go unnoticed Suicide common to teenagers, largest risk group to acne to begin with May be false correlation Current Regulation Patients must acknowledge in writing the awareness of psychiatric side effects – implemented last year. Pharmacists must give out medication guide in lay terms Other Regulation Issues Should be weary of prescribing the “miracle” but “dangerous” drug While issue of birth defects always provided, few doctors inform about relations with depression and suicide. In many cases, was prescribed to less severe acne problems FDA tightly regulates it in the US – what about 3rd world countries? Bibliography "Accutane Is this Acne Drug Treatment Linked to Depression and Suicide?” Congressional Hearing on Accutane. December 5, 2000 http://www.accutane-suicide-help.com/pages/burton.html Duenwalk, Mary. “After 20 Years, Debate Over Drug Persists.” New York Times. January 22, 2002 Jick SS. Kremers HM. Vasilakis-Scaramozza C. “Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide.” Archives of Dermatology. 136(10):1231-6, Oct. 2000. O'Donoghue MN. “Update on acne therapy.” Dermatology Nursing. 11(3):205-8, June 1999. “Product Information.” Roche USA http://www.rocheusa.com/products/accutane/pi.pdf “Questions and Answers About Acne.” National Institute of Health.” http://www.niams.nih.gov/hi/topics/acne/acne.htm