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V o l u m e
9
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N u m b e r
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J u n e - J u l y
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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
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4. Wahlberg JE, Liden C. Is the skin affected by work at visual display
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6. Faergemann J. Seborrhoeic dermatitis and Pityrosporum orbiculare:
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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
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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).
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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.
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Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 6 • June-July 2004