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V o l u m e 9 • N u m b e r 6 • J u n e - J u l y 2 0 0 4 Indexed by the US National Library of Medicine and PubMed EDITOR-IN-CHIEF Stuart Maddin, MD University of British Columbia, Vancouver, Canada ASSOCIATE EDITORS Hugo Degreef, MD, PhD - Medical Dermatology Catholic University, Leuven, Belgium Jason Rivers, MD - Medical Dermatology University of British Columbia, Vancouver, Canada Jeffrey S. Dover, MD - Surgical Dermatology Topical Agents Used in the Management of Hyperpigmentation R. M. Halder, MD and G. M. Richards, MD Department of Dermatology, Howard University, Washington DC, USA Yale University School of Medicine, New Haven, USA Dartmouth Medical School, Hanover, USA ABSTRACT ASSISTANT ASSOCIATE EDITOR Murad Alam, MD - Surgical Dermatology Northwestern University Medical School, Chicago, USA EDITORIAL ADVISORY BOARD Kenneth A. Arndt, MD Beth Israel Hospital Harvard Medical School, Boston, USA Wilma Fowler Bergfeld, MD Cleveland Clinic, Cleveland, USA Jan D. Bos, MD University of Amsterdam, Amsterdam, Holland Enno Christophers, MD Universitäts-Hautklinik, Kiel, Germany Richard L. Dobson, MD Medical University of South Carolina, Charleston, USA Disorders of hyperpigmentation are difficult to treat, particularly in dark-skinned individuals. The goal is to reduce the hyperpigmentation without causing undesirable hypopigmentation or irritation in the surrounding normally pigmented skin. The psychosocial impact caused by these disorders must be considered. Although there are many effective therapeutic modalities available, there are potentially significant side-effects associated with treatment. The most commonly used treatment is topical hydroquinone. There are other phenolic agents, such as Nacetyl-4-cystaminylphenol (NCAP), that are currently being studied and developed. The nonphenolic agents, which include tretinoin, adapalene, topical corticosteroids, azelaic acid, arbutin, kojic acid, and licorice extract, are also used for hyperpigmentation disorders. Key Words: hyperpigmentation, management Boni E. Elewski, MD University of Alabama, Birmingham, USA Barbara A. Gilchrest, MD Boston University School of Medicine, Boston, USA W. Andrew Griffiths, MD St. John’s Institute of Dermatology, London, UK Aditya K. Gupta, MD, PhD University of Toronto, Toronto, Canada Vincent C. Y. Ho, MD University of British Columbia, Vancouver, Canada Mark Lebwohl, MD Mt. Sinai Medical Center, New York, USA James J. Leydon, MD University of Pennsylvania, Philadelphia, USA Harvey Lui, MD University of British Columbia, Vancouver, Canada Howard I. Maibach, MD University of California Hospital, San Francisco, USA Larry E. Millikan, MD Tulane University Medical Center, New Orleans, USA Takeji Nishikawa, MD Keio University School of Medicine, Tokyo, Japan Constantin E. Orfanos, MD Freie Universitäts Berlin Universitätsklinikum Benjamin Franklin, Berlin, Germany Alan R. Shalita, MD SUNY Health Sciences Center, Brooklyn, USA Richard Thomas, MD Hyperpigmentation is a common and distressing problem caused by various inflammatory skin disorders, such as eczema, allergic contact dermatitis, and irritant contact dermatitis Acne is also a frequent cause. Papulosquamous disorders in general commonly predispose a patient to postinflammatory hyperpigmentation. Melasma is a common form of noninflammatory hyperpigmentation. Sun exposure often reverses the results of therapy, compromising the lengthy treatment process. Consequently, the first line of therapy for hyperpigmentation is a broad-spectrum sunscreen used in conjunction with a phenolic agent such as a hydroquinone, or with a nonphenolic agent such as tretinoin, azelaic acid, or kojic acid. There are hundreds of sunscreen formulations with different UV absorbing chemicals in various concentrations.1 The UVB and UVA absorbing chemicals used in the formulation of topical sunscreens include paraaminobenzoic acid-related products, salicylates, cinnamates, benzophenones, zinc oxide, and titanium oxide. Almost all sunscreen products contain a mixture of one or more UVB absorbing chemicals.1 Hydroquinone and related compounds reduce the production of melanin by their inhibition of the enzyme tyrosinase. Topical corticosteroids also inhibit tyrosinase activity and affect endoplasmic reticulum secretory function of melanocytes. Agents such as salicylic acid and glycolic acid act to remove melanin in the epidermis by their peeling action. Tretinoin, which has a mild peeling effect, acts in a similar manner. It may also inhibit tyrosinase. University of British Columbia, Vancouver, Canada Stephen K. Tyring, MD, PhD University of Texas Medical Branch, Galveston, USA John Voorhees, MD University of Michigan, Ann Arbor, USA Klaus Wolff, MD University of Vienna, Vienna, Austria MANAGING EDITOR Penelope Gray-Allan Hydroquinone Hydroquinone, which is a hydroxyphenolic chemical, has been the gold standard for treatment of hyperpigmentation for over 50 years. It acts by inhibiting the enzyme tyrosinase, thereby reducing the conversion of DOPA to melanin. Some of the other possible mechanisms of action are the destruction of melanocytes, degradation of melanosomes, and the inhibition of the synthesis of DNA and RNA.2 Hydroquinone can be compounded into 5%-10% concentrations, but at these strengths, may be irritating and unstable. The 2% concentrations of hydroquinone available over the counter in the US and Canada are not as efficacious as the 3% and 4% prescription formulations, as their onset of action is later than with the higher concentrations. Antioxidants, such as vitamin C and retinoids, as well as alpha-hydroxy acids may be used as additives to increase penetration and enhance efficacy. Exogenous ochronosis with the use of hydroquinone has been reported in dark-skinned patients, in particular South African women who frequently use very high concentrations of hydroquinone over large surface areas.3 Although hydroquinone is used extensively in North America, there have only been about 30 reported cases of exogenous ochronosis from hydroquinone use in North America. Adverse reactions from hydroquinone use include irritant and allergic contact dermatitis, and nail discoloration. Postinflammatory hyperpigmentation may occur from the contact dermatitis. Hypopigmentation of the normal skin surrounding the treated areas may also occur. These usually resolve with the discontinuation of the hydroquinone treatment.2 Other Phenolic Agents Monobenzone, the monobenzyl ether of hydroquinone, is a special topical phenolic agent, which is indicated only for the final depigmentation of disfiguring vitiligo. It is applied topically to permanently depigment normal skin surrounding vitiliginous areas in patients with disseminated vitiligo (greater than 50% body surface area). The cream is applied in a thin layer, rubbed into the normally pigmented areas two or three times daily. Depigmentation is usually achieved after 6-12 months with 20% monobenzone treatment. It should then be applied only as often as required to maintain depigmentation. Monobenzone cream can produce satellite depigmentation at sites distant from the site of initial application. N-acetyl-4-cysteaminylphenol (NCAP) is another phenolic agent that is currently being developed and is not yet available in North America. NCAP acts to decrease intracellular glutathione by stimulating pheomelanin rather than eumelanin.4 It also inhibits tyrosinase activity, has been found to be more stable, and causes less irritation than hydroquinone. In a retrospective study of 12 patients with melasma using 4% NCAP, 66% showed marked improvement, and 8% showed complete loss of melasma lesions. Changes of melanoderma were evident after 2-4 weeks of daily topical application of NCAP.5 Azelaic Acid Azelaic acid is a naturally occurring non-phenolic, saturated, nine-carbon dicarboxylic acid. Its use originated from the finding that Pityrosporum species can oxidize unsaturated fatty acids to dicarboxylic acids, which competitively inhibit tyrosinase. Azelaic acid was initially developed as a topical drug with therapeutic effects for the treatment of acne. However, because of its effect on tyrosinase, it has also been used to treat melasma, lentigo maligna and other disorders of hyperpigmention.2,6 Azelaic acid has been reported to be 2 effective for hypermelanosis caused by physical or photochemical agents, and lentigo maligna melanoma as well as other disorders characterized by abnormal proliferation of melanocytes. Its mechanism of action is to inhibit DNA synthesis and mitochondrial enzymes, thereby inducing direct cytotoxic effects toward the melanocyte.6 Topical azelaic acid has no depigmentation effect on normally pigmented skin, freckles, senile lentigines, and nevi. This specificity may be attributed to its selective effects on abnormal melanocytes. Azelaic acid can be used for postinflammatory hyperpigmentation in acne.7 Free radicals are believed to contribute to hyperpigmentation, and azelaic acid acts by reducing free radical production.8 Azelaic acid 20% is currently available in the US and is only indicated for the treatment of acne, although it has off-label use for hyperpigmentation. In the treatment of melasma, a 24-week study in South America found that a 20% concentration of azelaic acid was equivalent to 2% hydroquinone.9 In the Philippines, a study found that 20% azelaic acid was better than 2% hydroquinone.10 Kojic Acid Kojic acid (5-hydroxy-2-(hydroxy methyl)-4-pyrone), a naturally occurring hydrophilic fungal derivative evolved from certain species of Acetobacter, Aspergillus and Penicillium, is used in the treatment of hyperpigmentation disorders.11 It acts by inhibiting the production of free tyrosinase with efficacy similar to hydroquinone. In Japan, kojic acid has been increasingly used in skin care products. This is because, until recently, topically applied kojic acid at 1% concentration had not exhibited any sensitizing activity.12 However, more recent long-term Japanese studies have shown that kojic acid has the potential for causing contact dermatitis and erythema.12 Arbutin Arbutin, which is the b-D-glucopyranoside derivative of hydroquinone, is a naturally occurring plant derived compound that has been used for postinflammatory hyperpigmentation.13 It is effective in the treatment of disorders of hyperpigmentation characterized by hyperactive melanocytes.13 The action of arbutin is dependent on its concentration. Higher concentrations are more efficacious than lower concentrations, but they may also result in a paradoxical hyperpigmentation.13 In comparative in vitro studies of various compounds used to improve the appearance of disorders of hyperpigmentation, arbutin was found to be less toxic than hydroquinone. A dose-dependent reduction in tyrosinase activity, as well as melanin content in melanocytes, was also demonstrated.14 Licorice Extract Licorice extract is not yet available in North America, but has been used in other parts of the world, particularly in Egypt. Its mechanism of action is similar to that of kojic acid. The main component of the hydrophobic fraction of licorice extract is glabridin, which has an effect on the skin. Studies investigating the inhibitory effects of glabridin on melanogenesis and Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June - July 2004 inflammation have shown that it inhibits tyrosinase activity of melanocytes. No effect on DNA synthesis was detectable.15 2. Grimes PE. Melasma Etiologic and Therapeutic Considerations. Arch Dermatol 131(12):1453-7 (1995 Dec). Topical Retinoids 3. Levin CY, Maibach H. Exogenous ochronosis. An update on clinical features, causative agents and treatment options. Am J Clin Dermatol 2(4):213-7 (2001). The efficacy of topical tretinoin 0.05-0.1% as monotherapy for postinflammatory hyperpigmentation has been reported.16 Tretinoin was also used as monotherapy in a study on 38 AfricanAmerican patients with melasma and 68%-73% of patients improved. In 88% of the patients, moderate side-effects of desquamation and erythema were observed.17,18 Darker skinned patients who develop a dermatitis from tretinoin may develop postinflammatory hyperpigmentation secondary to the dermatitis. The mechanism of action of tretinoin in the treatment of melasma is poorly understood. Clinical improvement has been found to be associated with a reduction in epidermal melanin, possibly as a result of the inhibition of tyrosinase by the action of tretinoin.19 Although tretinoin can be effective as monotherapy for hyperpigmentation and melasma, it requires 20 to 40-week treatment periods. Tretinoin can also be used in conjunction with hydroquinone or other depigmenting agents to improve efficacy. The first published study of combination therapy used tretinoin 0.1%, hydroquinone 5%, and dexamethasone 0.1% for postinflammatory hyperpigmentation.20 Tretinoin was shown to reduce the atrophy of the corticosteroid and facilitated the epidermal penetration of the hydroquinone. The tretinoininduced irritation was reduced by the corticosteroid. The first triple combination topical therapy approved by the US FDA for melasma is a modified formulation comprising fluocinolone acetonide, hydroquinone 4% and tretinoin 0.05%. In studies of patients with melasma, 78% had complete or near clearing after 8 weeks of therapy. Similar results and favorable safety profile were seen in a 12-month study.21 In a randomized clinical trial, the efficacy of adapalene 0.1% was found to be comparable to that of tretrinoin 0.05% cream in the treatment of melasma (mainly epidermal type). The results showed fewer side-effects and greater acceptability among patients using adapalene.19 Conclusion The treatment of hyperpigmentation disorders can be a long process. The psychosocial impact of these disorders should be taken into consideration. There are several topical treatment options available, the most common of which is hydroquinone. The use of combination therapy and monotherapy with nonphenolic agents is increasingly common. These treatment options are primarily for epidermal disorders of hyperpigmentation. Dermal disorders of hyperpigmentation are difficult to treat, and have not been effectively managed using currently available therapy. 4. Alena F, Dixon W, Thomas P, Jimbow K. Glutathione plays a key role in the depigmenting and melanocytotoxic action of N-acetyl-4-Scysteaminylphenol in black and yellow hair follicles. J Invest Dermatol 104(5):792-7 (1995 May). 5. Jimbow K. N-Acetyl-4-S-Cysteaminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma. Arch Dermatol 127(10):1528-34 (1991 Oct). 6. Nguyen QH, Bui TP. Azelaic acid: pharmacokinetic and pharmacodynamic properties and its therapeutic role in hyperpigmentary disorders and acne. Int J Dermatol 34(2)75-84 (1995 Feb). 7. Breathnach AS. Melanin hyperpigmentation of skin: melasma, topical treatment with azelaic acid, and other therapies. Cutis 57(1 Suppl.):36-45 (1996 Jan). 8. Lowe NJ, Rizk D, Grimes P, Billips M, Pincus S. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin Ther 20(5):945-59 (1998 Sep-Oct). 9. Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol 30(12):893-5 (1991 Dec). 10. Verallo-Rowell VM, Verallo V, Graupe K, Lopez-Villafuerte L, Garcia-Lopez M. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol Suppl (Stockh) 143:58-61 (1989). 11. Serra-Baldrich E, Tribo MJ, Camarasa JG. Allergic contact dermatitis from kojic acid. Contact Dermatitis 39(2):86-7 (1998 Aug). 12. Nakagawa M, Kawai K, Kawai K. Contact allergy to kojic acid in skin care products. Contact Dermatitis 32(1):9-13 (1995 Jan). 13. Maeda K, Fukuda M. Arbutin: mechanism of its depigmenting action in human melanocyte culture. J Pharmacol Exp Ther 276(2):765-9 (1996 Feb). 14. Lei TC, Virador VM, Vieira WD, Hearing VJ. A melanocytekeratinocyte coculture model to assess regulators of pigmentation in vitro. Anal Biochem 305(2):260-8 (2002 Jun). 15. Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res 11(6):355-61 (1998 Dec). 16. Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med 328(20):1438-43 (1993 May). 17. Kimbrough-Green CK, Griffiths CE, Finkel LJ, et al. Topical retinoic acid (tretinoin) for melasma in black patients. A vehicle-controlled clinical trial. Arch Dermatol 130(6):727-33 (1994 Jun). 18. Griffiths CE, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees JJ. Topical tretinoin (retinoic acid) improves melasma. A vehiclecontrolled, clinical trial. Br J Dermatol 129(4):415-21 (1993 Oct). 19. Dogra S, Kanwar AJ, Parsad D. Adapalene in the treatment of melasma: a preliminary report. J Dermatol 29(8):539-40 (2002 Aug). References 1. Pathak MA, Fitzpatrick TB, Nghiem P, Aghassi DS. Sun-protective agents: formulations, effects, and side effects. In: Fitzpatrick TB, Editor. Dermatology in General Medicine, 4th ed, New York: McGraw-Hill, pp 2742-60 (1993). 20. Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol 111(1):40-48 (1975 Jan). 21. Galderma laboratories. Data on file. Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June-July 2004 3 Ciclopirox Shampoo for Treating Seborrheic Dermatitis A. K. Gupta MD, PhD, FRCPC1,2 and R. Bluhm BSc (Hons), BA, MA2,3 Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Centre (Sunnybrook site) and the University of Toronto, Toronto, Canada 2 Mediprobe Research, London, Ontario, Canada 3 University of Western Ontario, London, Ontario, Canada 1 ABSTRACT Seborrheic dermatitis is a common inflammatory skin disease, affecting between 1% and 3% of immunocompetent adults. While its cause is unknown, a number of predisposing factors have been reported, including the implications of Malassezia yeasts. Various treatment options are available, such as ciclopirox shampoo, which combines anti-Malassezia activity with an anti-inflammatory action. This agent has been shown to be an effective and safe treatment for seborrheic dermatitis of the scalp. Key Words: ciclopirox, seborrheic dermatitis Clinically, seborrheic dermatitis presents as red, flaking, slightly greasy-looking patches, which are located primarily on the scalp, nasolabial folds, ears, eyebrows and chest. The degree of flaking and erythema can vary markedly between patients.1 The exact cause of seborrheic dermatitis is not known, however, a number of predisposing factors have been reported. Such endogenous host factors include nutritional,2 environmental,3,4 and immunological5 factors, as well as the presence of Malassezia yeast.6 While there is some controversy with regard to the relationship between seborrheic dermatitis of the scalp and dandruff, it has been argued that dandruff is a mild form of seborrheic dermatitis.7,8 Furthermore, the relationship between Malassezia yeasts and the effective treatment of seborrheic dermatitis with antifungal agents helps to support the claim that these yeasts are the primary cause of seborrheic dermatitis.9 Due to the fact that there is an increased prevalence of seborrheic dermatitis in HIV-positive and AIDS patients,10,11 it is thought that the disease may be caused by an abnormal immune response to Malassezia. However, it is unclear exactly what this immune response might be. Many individuals without seborrheic dermatitis have antibodies to Malassezia yeasts and while some authors have found that the level of IgG antibodies to the yeasts is increased in patients with seborrheic dermatitis,5,12 others1 have found no difference in the number of antibodies produced by patients with seborrheic dermatitis and controls. It has recently been suggested that the reaction by seborrheic dermatitis patients to Malassezia is best characterized as an irritant response 13 involving an inflammatory reaction and that reduction of Malassezia yeast on the skin reduces the clinical signs of seborrheic dermatitis. Treating Seborrheic Dermatitis The two main classes of treatment for seborrheic dermatitis are topical corticosteroids and antifungal agents. Corticosteroids 4 reduce inflammation, thus resulting in clinical improvement of seborrheic dermatitis. However, prolonged treatment with topical steroids may result in adverse effects on the skin, such as atrophy, telangiectasia, or perioral dermatitis14 and, especially in the case of higher potency, fluorinated topical steroids, to dysfunction of the adrenal cortex.15 Because of the adverse effects associated with topical steroids, there has been a shift in treatment strategies for seborrheic dermatitis with an increased interest in antifungal agents. Several antifungal agents have been found to be effective in the treatment of seborrheic dermatitis. These include non-specific agents (e.g., zinc pyrithione, selenium sulfide, propylene glycol, lithium succinate), hydroxypyridones (e.g., ciclopirox), azoles (e.g., bifonazole, fluconazole, itraconazole, ketoconazole, miconazole, metronidazole), and the allylamines (e.g., terbinafine). Ciclopirox Ciclopirox is the ethanolamine salt of 6-cyclohexyl-I-hydroxy-4methyl-2(IH)-pyridone.16 The empirical formula of ciclopirox is C12H17NO2, with a molecular weight of 207.27.17 Ciclopirox shampoo 1% is a colorless, translucent solution,17 which has been used in the treatment of seborrheic dermatitis. In addition to its effect on Malassezia yeasts, ciclopirox has been shown to decrease inflammation. Rosen et al.18 found that the anti-inflammatory activity of ciclopirox was greater than that of several azole agents or hydrocortisone. Ciclopirox appears to exert its anti-inflammatory effect via several pathways, including the inhibition of 5-lipoxygenase and cyclo-oxygenase.19,20 Clinical Trials of Ciclopirox Vardy et al.21 conducted a double-blind, randomized, placebocontrolled clinical study of ciclopirox olamine 1% shampoo to determine its effectiveness in the treatment of scalp seborrheic dermatitis. One hundred and two patients were randomly selected to apply either ciclopirox olamine 1% shampoo or the vehicle shampoo to the scalp for 5 minutes, Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June-July 2004 twice per week for 4 weeks. Signs and symptoms of erythema, scaling, and pruritus were assessed at the end of the study, which revealed that 93% of the ciclopirox shampoo-treated patients had significantly improved or cleared compared to 41% in the placebo group (P<0.00001). Another double-blind, randomized, vehicle-controlled study was conducted to assess the efficacy of 1% ciclopirox shampoo in the treatment of seborrheic dermatitis of the scalp.22 Subjects were randomly selected to 5ml (10ml for shoulder-length hair or longer) of either 1% ciclopirox or vehicle shampoo twice per week for 4 weeks. Grading of erythema, scaling, and the overall status of seborrheic dermatitis was performed at week 4, using a 6-point rating scale (0=none, 1=slight, 2=mild, 3=moderate, 4=pronounced, and 5=severe). Effective treatment was defined as a score of 0 (or 1 if baseline score was ≥3) for the combined rating of global status, erythema, and scaling. It was reported that 26% of the ciclopirox-treated patients were effectively treated compared to 13% of the vehicle group (P=0.0001).22 Adverse Effects Ciclopirox shampoo 1% was used twice a week in 626 patients.17 Increased itching was the most frequent adverse event found in 1% of the subject population. Furthermore, application reactions, such as burning, erythema, and itching also occurred in 1% of the subjects.17 Dosage and Administration After wetting hair, apply approximately 1 teaspoon (5ml) of ciclopirox shampoo 1% to the scalp.17 If the patient has long hair, it is recommended to use up to 2 teaspoons (10ml). Lather and leave on for 3 minutes before rinsing. Treatment should be repeated twice per week for 4 weeks, with a minimum of 3 days between each application.17 Conclusion Evidence suggests that an abnormal or inflammatory immune system reaction to Malassezia yeasts may be the cause of seborrheic dermatitis. An available treatment for this disease is ciclopirox shampoo, which is an antifungal agent that also has antibacterial and anti-inflammatory properties. The proven efficacy and safety of ciclopirox shampoo in the treatment of seborrheic dermatitis of the scalp makes it an important addition to the treatment options available. References Health 11(6):489-93 (1985 Dec). 4. Wahlberg JE, Liden C. Is the skin affected by work at visual display terminals? Dermatol Clin 6(1):81-5 (1988 Jan). 5. Bergbrant IM, Johansson S, Robbins D, Scheynius A, Faergemann J, Soderstrom T. An immunological study in patients with seborrhoeic dermatitis. Clin Exp Dermatol 16(5):331-8 (1991 Sep). 6. Faergemann J. Seborrhoeic dermatitis and Pityrosporum orbiculare: treatment of seborrhoeic dermatitis of the scalp with miconazolehydrocortisone (Daktacort), miconazole and hydrocortisone. Br J Dermatol 114(6):695-700 (1986 Jun). 7. Bulmer AC, Bulmer GS. The antifungal action of dandruff shampoos. Mycopathologia 147(2):63-5 (1999). 8. McGrath J, Murphy GM. The control of seborrhoeic dermatitis and dandruff by antipityrosporal drugs. Drugs 41(2):178-84 (1991 Feb). 9. Shuster S. The aetiology of dandruff and the mode of action of therapeutic agents. Br J Dermatol 111(2):235-42 (1984 Aug). 10. Berger RS, Stoner MF, Hobbs ER, Hayes TJ, Boswell RN. Cutaneous manifestations of early human immunodeficiency virus exposure. J Am Acad Dermatol 19(2 Pt 1):298-303 (1988 Aug). 11. Marino CT, McDonald E, Romano JF. Seborrheic dermatitis in acquired immunodeficiency syndrome. Cutis 48(3):217-8 (1991 Sep). 12. Midgley G, Hay RJ. Serological responses to Pityrosporum (Malassezia) in seborrhoeic dermatitis demonstrated by ELISA and western blotting. Bull Soc Fr Mycol Med 17:267-76 (1988). 13. Faergemann J, Bergbrant IM, Dohse M, Scott A, Westgate G. Seborrhoeic dermatitis and Pityrosporum (Malassezia) folliculitis: characterization of inflammatory cells and mediators in the skin by immunohistochemistry. Br J Dermatol 144(3):549-56 (2001 Mar). 14. Guin JD. Complications of topical hydrocortisone. J Am Acad Dermatol 4(4):417-22 (1981 Apr). 15. Morman MR. Possible side effects of topical steroids. Am Fam Physician 23(2):171-4 (1981 Feb). 16. Sakurai K, Sakaguchi T, Yamaguchi H, Iwata K. Mode of action of 6cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone ethanolamine salt (Hoe 296). Chemotherapy 24(2):68-76 (1978). 17. Loprox® Shampoo (ciclopirox) 1% Package Insert. MEDICIS Pharmaceutical Corp., Scottsdale, AZ (2003 Feb). 18. Rosen T, Schell BJ, Orengo I. Anti-inflammatory activity of antifungal preparation. Int J Dermatol 36(10):788-92 (1997 Oct). 19. Hanel H, Smith-Kurtz E, Pastowsky S. [Therapy of seborrheic eczema with an antifungal agent with an antiphlogistic effect]. Mycoses 34(Suppl 1):91-3 (1991). 20. Lassus A, Nolting KS, Savopoulos C. Comparison of ciclopirox olamine 1% cream with ciclopirox 1%-hydrocortisone acetate 1% cream in the treatment of inflamed superficial mycoses. Clin Ther 10(5):594-9 (1988). 1. Parry ME, Sharpe GR. Seborrhoeic dermatitis is not caused by an altered immune response to Malassezia yeast. Br J Dermatol 139(2):254-63 (1998 Aug). 21. Vardy DA, Zvulunov A, Tchetov T, Biton A, Rosenman D. A doubleblind, placebo-controlled trial of a ciclopirox olamine 1% shampoo for the treatment of scalp seborrheic dermatitis. J Dermatol Treat 11:73-7 (2000). 2. Brenner S, Horwitz C. Possible nutrient mediators in psoriasis and seborrheic dermatitis. I. Prevalence, etiology, symptomatology, histological and biochemical features. World Rev Nutr Diet 55:15364 (1988). 22 Lebwohl M. A multicenter, randomized, double-blind, vehiclecontrolled study of the efficacy and safety of 1% ciclopirox shampoo in the treatment of seborrheic dermatitis of the scalp. Int J Dermatol. In Press (2004). 3. Liden C, Wahlberg JE. Work with video display terminals among office employees. V. Dermatologic factors. Scand J Work Environ Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June-July 2004 5 ADVANCES IN DERMATOLOGIC SURGERY Editors: Jeffrey S. Dover, MD and Murad Alam, MD Face-Lifting: An Overview B.R. Moody1, MD and R. Sengelmann2, MD Vanderbilt University, Nashville, TN, USA Washington University, St. Louis, MO, USA 1 2 ABSTRACT Numerous adaptations of face-lift techniques have been devised, and each surgical approach has its own risks and benefits, as well as proponents and detractors. All of the conventionally accepted techniques achieve removal of redundant skin. However, it’s the variations in approach to the deeper soft tissue structures that separate the many face-lifting procedures. A skin only face-lift was the earliest form of surgical rhytidectomy, but failed to achieve significant long-term benefit. Cosmetic surgeons of various backgrounds thus sought to achieve a more durable benefit from the surgery. While certain techniques have been classically ascribed to a particular surgeon, innovation does not occur in a vacuum and many surgeons are responsible for our current state of knowledge with regards to facial rhytidectomy surgery. Key Words: face-lift, rhytidectomy An appreciation of the concept of the superficial musculoaponeurotic system (SMAS) occurred in the 1970s.1 SMAS manipulation is a common approach to face-lifting, and appropriate modification of the SMAS can produce long lasting esthetically pleasing results. SMAS rhytidectomy begins with the creation of a cheek skin flap. The SMAS is handled in a number of ways. The simplest approach is to plicate the SMAS. The plication approach relies upon folding the SMAS onto itself without SMAS undermining. This technique tends to be a very safe approach to face-lifting as the SMAS and sub-SMAS structures are left intact.2,3 Baker popularized the lateral SMASectomy approach. His method, similar to plication, does not undermine the SMAS; rather, a strip of the SMAS overlying the parotid gland is resected. Using large absorbable sutures, the resected edges of the SMAS are joined, thereby elevating the lower portions of the SMAS. Baker’s technique is also very safe as the facial nerve is protected by the parotid gland in the area of SMAS resection.4 More extensive SMAS management is obtained by creating a limited SMAS flap (conventional SMAS face-lift) or an extended SMAS flap. The SMAS flap is created in addition to the skin flap, and is separately repositioned. While SMAS modification remedies many of the problems with the skin-only rhytidectomy, some surgeons felt that key elements of the aging face were inadequately corrected. Concern with the ability to adequately reposition the nasolabial fold and elevate the midface led to further surgical modifications. Techniques to reposition deeper tissues were developed, and this process culminated in the composite rhytidectomy. In the late 1960s, Skoog described a sub-platysmal plane of dissection that left the skin and platysma together as a single unit. Skoog’s initial work Figure 1. Illustration of dissection planes of traditional face-lift approaches. Used with permission from Lippincott, Williams & Wilkins.5 6 Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June-July 2004 ADVANCES IN DERMATOLOGIC SURGERY Editors: Jeffrey S. Dover, MD and Murad Alam, MD Face-Lift Technique Essential Features Comments Skin Only Skin flap created. No manipulation of deeper tissues. Limited benefit. SMAS Plication Skin flap created. SMAS is folded on itself. No SMAS undermining. Straightforward, limited anesthetic requirements. S-Lift and Variants Skin flap created. SMAS is plicated with purse string type sutures. No SMAS undermining. Similar to SMAS plication with sutures elevating the SMAS and platysma. Limited anesthetic requirements. Lateral SMASectomy Skin flap created. SMAS overlying parotid is resected and tightened. No SMAS undermining. Little risk of nerve injury. Limited recovery time. SMAS Lift (conventional) Skin flap created. Separate SMAS flap created. Flaps advanced independently. Increased risk of nerve injury. Benefit over plication alone is uncertain. SMAS Lift (extended) Skin flap created. Separate SMAS flap created. Flaps advanced independently. Similar to conventional SMAS lift with greater degree of SMAS flap undermining. Composite Rhytidectomy Single flap of skin, orbicularis oculi, cheek fat, and platysma is created. Flap advanced as a single unit. Successor to “Deep Plane” face-lift. Relatively long recovery period. Addresses midface descent. Increased risk of nerve injury. Table 1: Summary of rhytidectomy approaches. prompted surgeons to create deeper planes of dissection. The deeper tissues were left attached to the overlying skin and repositioned as a single unit. In the early 1990s, Hamra described the composite rhytidectomy. This technique involves creating a deep plane of dissection for tissue suspension. A unified flap that consists of skin, platysma, midface cheek fat and orbicularis is created, elevated, and repostioned. This approach seeks to add, among other things, cheek fat and nasolabial fold correction into the facelift procedure.5 Concern has been expressed with regard to the relatively long recovery period from these deep plane dissections.3 Figure 1 illustrates the planes of dissection in the traditional face-lift techniques discussed, while Table 1 summarizes various rhytidectomy approaches. As face-lift approaches multiplied and became more complex, patient desires changed. Younger patients began to seek cosmetic surgery and trends toward less invasive approaches to facial rejuvenation developed. Patients wanted less downtime from their procedure. Additionally, despite increased tissue rearrangement with more complex surgery, a clear and compelling benefit of one type of face-lift over another failed to materialize. While controversial, the few studies that directly compared the various techniques failed to show a significant difference in outcome.3,6 The desire for a less invasive face-lift prompted techniques such as Saylan’s “S-lift” and Tonnard’s “Minimal Access Cranial Suspension” face-lift. These approaches rely upon a limited face-lift incision, conservative skin flap creation, and the use of sutures in a loop configuration to plicate the deeper tissues. No SMAS flap is created. Local anesthesia (with or without oral or IV sedation) is all that is required for these ambulatory, and in many cases office-based, procedures.7,8 In many cases, these limited approaches are augmented by the use of adjuvant procedures such as botulinum toxin injections, laser skin resurfacing or chemical peeling, fat transplantation, and soft tissue fillers to achieve the desired result through multiple small interventions rather than one more involved Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June-July 2004 7 ADVANCES IN DERMATOLOGIC SURGERY Editors: Jeffrey S. Dover, MD and Murad Alam, MD Technique Essential Features Comments Radiofrequency energy (Thermage) Contact cooling with no epidermal disruption. Seeks to achieve skin tightening. New technology. Limited data to date. Simple to operate. Topical anesthetic only. No downtime. Percutaneous Suspension Sutures (including APTOS) Uses suture material to suspend ptotic soft tissues. Does not address skin redundancy. Uncertain long-term correction. Local anesthetic only. Table 2: Summary of the most promising minimally invasive facial rejuvenation techniques. procedure. Figure 2 shows a patient before a Minimal Access Cranial Suspension face-lift and at 1-year follow up. These less invasive approaches have been favored by dermatologic surgeons. The popularity of these procedures stems from several factors. The procedure is performed on an outpatient basis, utilizing tumescent anesthesia and occasionally with moderate oral, IM, or IV sedation. Recovery from these procedures is relatively rapid and can be seen in a matter of a few days to weeks. Complications are few and minor. In Saylan’s original series, he noted that the most frequent complaint was short-term pain and tightness in the pre-tragal region. Temporary facial nerve palsy was observed in three secondary face-lift patients. The platysmal plicating suture caused temporary dimpling beneath the earlobe in most patients.7 In their series, Tonnard and colleagues also Figure 2a. Preoperative appearance prior to suture plication rhytidectomy modeled after Tonnard’s “Minimal Access Cranial Suspension.” 8 found this approach very safe. They noted that most patients returned to normal activity within one week.8 Both Saylan and Tonnard feel that their patients are achieving lasting benefit from this approach.9,10 A number of face-lift alternatives and adjuvant procedures have been recently popularized. For the patient with primarily soft tissue ptosis and little skin redundancy, the use of percutaneously placed suspension sutures is an option. This approach has been proposed for elevation of the brow, midface, and jowl regions.11,12 The advantages of these procedures are the use of local anesthesia and minimal scarring, downtime and expense when compared with traditional surgical rhytidectomy. As no skin excision occurs, these techniques will not remove redundant skin and may be best suited for younger patients. Most surgeons using suspension techniques utilize a variety of nonabsorbable sutures. Recently, a Figure 2b. Intraoperative view. Subcutaneous plane of dissection illustrated along with placement of a permanent suspension suture. Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June-July 2004 Figure 2c. One-year postoperative view. Noticeable sustained improvement in jawline. ADVANCES IN DERMATOLOGIC SURGERY Editors: Jeffrey S. Dover, MD and Murad Alam, MD specially modified polypropylene suture with sharp, barb-like projections has been described. These percutaneously placed sutures, dubbed APTOS threads, serve to securely grasp and elevate soft tissues.13 Table 2 summarizes the most promising minimally invasive techniques. Conclusion While the myriad of options for face-lifting may seem confusing to physicians and patients at first glance, there are advantages and disadvantages to each. With more options available, we can cater our treatments for each patient. With proper education and a firm preoperative assessment of goals, the surgeon and patient can select the approach that optimizes their probability of a successful outcome. Clearly there is no one solution to all forms of facial aging. References 1. Jost G, Lamouche GL. SMAS in rhytidectomy. Aesthetic Plast Surg 6(2):69-74 (1982). 2. Webster RC, Smith RC, Smith KF. Face Lift, Part 3: Plication of the superficial musculoaponeurotic system. Head Neck Surg 6(2):696701 (1983 Nov-Dec). 4. Baker D. Rhytidectomy with lateral SMASectomy. Facial Plast Surg 16(3):209-13 (2000). 5. Hamra ST. Composite rhytidectomy. Plast Reconstr Surg 90(1):1-13 (1992 Jul). 6. Webster RC, Smith RC, Papsidero MJ, Karolow WW, Smith KF. Comparison of SMAS plication with SMAS imbrication in face lifting. Laryngoscope 92(8 Pt 1):901-12 (1982 Aug). 7. Saylan Z. Purse String-Formed Plication of the SMAS with fixation to the zygomatic bone. Plast Reconstr Surg 110(2):667-71 (2002 Aug). 8. Tonnard P, Verpaele A, Monstrey S, et al. Minimal access cranial suspension lift: a modified S-lift. Plast Reconstr Surg 109(6):207486 (2002 May). 9. Saylan Z. Personal communication (2003 Aug). 10. Tonnard P. Personal communication (2003 Aug). 11. Sasaki GH, Cohen AT. Meloplication of the malar fat pads by percutaneous cable-suture technique for midface rejuvenation: outcome study (392 Cases, 6 Years’ Experience). Plast Reconstr Surg 110(2):635-54 (2002 Aug). 12. Erol OO, Sozer SO, Velidedeoglu HV. Brow suspension, a minimally invasive technique in facial rejuvenation. Plast Reconstr Surg 109(7):2521-32 (2002 Jun). 13. Sulamanidze MA, Fournier PF, Paikidze TG, Sulamanidze GM. Removal of facial soft tissue ptosis with special threads. Dermatol Surg 28(5):367-71 (2002 May). 3. Ivy EJ, Lorenc ZP, Aston SJ. Is there a difference? A prospective study comparing lateral and standard SMAS face lifts with extended SMAS and composite rhytidectomies. Plast Reconstr Surg 98(7):1135-47 (1996 Dec). SkinCareGuide Presents SkinCancerGuide: www.SkinCancerGuide.ca • SkinCancerGuide is a comprehensive website offering information about skin cancer for physicians and their patients • Physicians register for free. Just click on “Physician View” SkinCareGuide welcomes a new sponsor 3M PHARMACEUTICALS, A DIVISION OF 3M CANADA COMPANY Introducing A-DetailingTM An online academic drug presentation written for doctors by doctors. The content is third party, academic-based information and includes clinical evidence and practical experience. For the complete A-Detail™ visit www.SkinCareGuide.ca and click on “Physician View”. Registration is free. Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June-July 2004 9 Update on Drugs Class Name/Company Approval Dates and Comments Dermal Filler Hylan-B gel Hylaform® Inamed/Genzyme The US FDA approved this hyaluronic acid-based dermal filler in April 2004, for injection into the mid-deep dermis for correction of moderate-to-severe facial wrinkles and folds. Monoclonal Antibody SGN-30 The US FDA granted Orphan Drug Designation to this monoclonal antibody in February 2004, for treatment of T-cell lymphomas. This product is currently in phase II clinical trials for the treatment of anaplastic large cell lymphoma and Hodgkin’s disease. The US FDA previously granted orphan drug designation for Hodgkin’s disease in July 2003. Seattle Genetics Antibacterial Agent Staphylococcus aureus The US FDA granted Fast-Track Designation in March 2004, for Immune Globulin (Human) immediate protection against S. aureus infections in low birth-weight infants. Altastaph™ Nabi Biopharmaceuticals Antipruritic Agent Cetirizine HCl Zyrtec® Pfizer/UCB Pharma HIV/AIDS Injectable poly-L-lactic acid A US FDA advisory committee unanimously recommended approval with conditions for this polymer in March 2004, for the correction of SCULPTRA™ shape and contour deficiencies resulting from facial fat loss (lipoatrophy) Dermik in people with HIV. Conditions include a post-approval study, a physician training program, product use that is limited to people with HIV who have lipoatrophy, provision of product specification information and wording changes to the proposed label. HIV/AIDS Fosamprenavir Telzir® GlaxoSmithKline/Vertex Pharmaceuticals The US FDA approved this new chewable formulation in March 2004, for the treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria in children >2 years of age. The European Committee for Proprietary Medicinal Products (CPMP) gave a positive opinion in March 2004, for this product for the treatment of HIV infection in adults in combination with other antiretroviral medications. Drug News Antipsoriatic Agent Genentech and XOMA announced preliminary results in March 2004, of a randomized placebo-controlled Phase II study with RAPTIVA® (efalizumab) in 107 patients with psoriatic arthritis. The study did not reach statistical significance at 12 weeks for the primary endpoint, ACR response, indicating that while psoriatic arthritis is associated with psoriasis, they are distinct diseases. This T-cell modulator was approved by the US FDA in October 2003, for the treatment of chronic moderate-to-severe plaque psoriasis in adults > 18 years of age who are candidates for systemic therapy or phototherapy. Antiviral Agent A European Phase III trial of Polyphenon E Ointment achieved excellent results for the treatment of genital warts. The statistically significant trial with more than 500 patients showed a high and lasting efficacy of the drug with extremely low systemic adverse effects. US Phase III trials are ongoing with results expected by the end of 2004. Erratum: There was an error in the Update on Drugs published in Volume 9, Issue 4 of the Skin Therapy Letter. Under Etanercept/Enbrel®, the company is listed as Wyeth Pharmaceuticals. It should be AMGEN Canada/Wyeth Pharmaceuticals (Canada) and Wyeth Pharmaceuticals (Europe). Skin Therapy Letter®(ISSN 1201–5989) Copyright 2004 by SkinCareGuide.com. The Skin Therapy Letter© is published 10 times annually by SkinCareGuide.com Ltd, 1107 – 750 West Pender, Vancouver, British Columbia, Canada, V6C 2T8. Managing Editor: Penelope Gray-Allan, Tel: 604-926-4320, Fax: 604-926-5455, email: [email protected]. All rights reserved. Reproduction in whole or in part by any process is strictly forbidden without prior consent of the publisher in writing. While every effort is made to see that no inaccurate or misleading data, opinion or statement appears in the Skin Therapy Letter©, the Publishers and Editorial Board wish to make it clear that the data and opinions appearing in the articles herein are the responsibility of the contributor. Accordingly, the Publishers, the Editorial Committee and their respective employees, officers and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described herein should only be followed in conjunction with the drug manufacturer’s own published literature. Printed on acid free paper effective with Volume 1, Issue 1, 1995. Subscription Information. Annual subscription: Canadian $94 individual; $171 institutional (plus GST); US $66 individual; $121 institutional. Outside North America: US$88 individual; $143 institutional. We sell reprints in bulk (100 copies of the same article or more). For individual reprints, we sell photocopies of the articles. The cost is $20 to fax and $15 to mail. Prepayment is required. Student rates available upon request. Sales inquiries: [email protected] 10 Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June-July 2004