Knockoff: The Deadly Trade in Counterfeit Goods By Tim Phillips London, England & Sterling, VA; Kogan Page Ltd., 2005, ISBN 0-7494-4389-0 (Price $29.95), pp. 231 Reviewed by Erika Jacobsen White Journal of High Technology Law Suffolk University Law School The global counterfeit market currently wields nearly $538 billion annually. The U.S. counterfeit market alone is estimated to rake in
Update on the Treatment of Acne Vulgaris
Kimberly W. Lai, BS, and Mary Gail Mercurio, MD
Four major factors associated with the pathogenesis of • Objective: To provide an evidence-based review of acne are increased sebum production, follicular hyperkera- tinization, Propionibacterium acnes proliferation, and inflam- • Methods: Review of the literature.
• Results: Acne vulgaris is a chronic inflammatory Androgenic stimulation causes sebum production from condition affecting 40 to 50 mil ion people in the the sebaceous glands. Excess sebum production can result United States. Current treatments target at least 1 of from pilosebaceous unit hyperresponsiveness, increased the known pathophysiologic mechanisms involved circulating androgens, or both . However, most patients in acne development. Combination therapy with a do not have significant endocrine abnormalities .
topical retinoid and antimicrobial agent is general y Keratinocyte proliferation and abnormal desquamation recommended as first-line treatment for most pa- cause follicular hyperkeratinization . Keratinocytes accu- tients. Oral antibiotics are often used for moderate to mulate and become densely packed with monofilaments and severe acne, and their combined use with benzoyl sebum, forming a microcomedo [5,6]. Further sebum produc- peroxide can prevent the development of bacterial tion converts a microcomedo to a closed comedo (whitehead) resistance. There is also good evidence to suggest when the follicular orifice is closed, or to an open comedo that oral contraceptives containing estrogen and (blackhead) when the follicular orifice is open . a progestin are effective in reducing acne lesions P. acnes is a gram-positive anaerobe that resides in the pi- in women. Oral isotretinoin has been shown to be losebaceous unit. These bacteria attract lymphocytes, which effective in clearing severe nodulocystic acne and invade and destroy the follicular wall . Rupture of the fol- inducing remission, although it is unclear whether licular epithelium causes lipids, keratinocytes, and P. acnes an association between oral isotretinoin use and to leak into the surrounding dermis . This leads to further suicidal behaviors exists. Lasers, light sources, and recruitment of inflammatory cytokines and neuropeptides, photodynamic therapy are effective in the treatment thus perpetuating the inflammatory process and resulting of acne; however, further studies are needed to de- in inflammatory papules or nodules .
termine the appropriate duration and light source. Several systems for grading acne exist with most involv- • Conclusion: Effective treatment for acne is avail- ing a global assessment of the severity (eg, mild, moderate, able. Patient responses vary, and often more than severe) that takes into account the number, type, and extent of acne lesions . Although there is no consensus on which classification system is the best, clinicians may find it useful cne vulgaris is a chronic inflammatory dermatosis to use a consistent system to select appropriate treatment of the pilosebaceous unit characterized by open or regimens and assess responses to treatment .
closed comedones and inflammatory papules, pus- Routine endocrinologic testing is not necessary in the tules, nodules, or cysts. It affects 40 to 50 million individuals majority of patients with acne . However, laboratory in the United States , including 70% to 87% of adolescents evaluation of free testosterone, dehydroepiandrosterone sul- . Acne is also a common skin problem in adults. Goulden fate, luteinizing hormone, and follicle-stimulating hormone et al  found that the prevalence of facial acne in men and is indicated in females presenting with signs of hyperan- women over age 25 determined by clinical examination was drogenism. Such signs can include menstrual dysfunction, 3% and 12%, with 82% of cases being persistent from ado- hirsutism, or polycystic ovaries in adult women [5,7].
lescence. More recently, Collier et al  assessed the preva- lence of acne reported by women and men by age-group. Prevalence for women and men, respectively, was 50.9% and 42.5% for ages 20 to 29 years, 35.2% and 20.1% for ages 30 to 39 years, 26.3% and 12.0% for ages 40 to 49 years, and 15.3% and 7.3% in ages 50 years and older.
From the University of Rochester, Rochester, NY. Vol. 16, No. 3 March 2009 JCOM 115
treatment for mild acne
First-line therapy for mild acne involves a topical retinoid [5,6]. Benzoyl peroxide is bactericidal and is effective in treating If an inflammatory component exists, a topical antibiotic such acne. Benzoyl peroxide plus a topical retinoid are often used as clindamycin or erythromycin may be added to enhance in conjunction with antibiotics to prevent or eliminate the the efficacy [5,6]. Antibiotics should not be used as mono- development of antibiotic-resistant P. acnes .
therapy and should be discontinued when the inflammatory In studies, patients using benzoyl peroxide 20% lotion component is adequately treated in order to minimize the , benzoyl peroxide 5% gel , and benzoyl peroxide 5% occurrence of antibiotic-resistant bacteria . Topical benzoyl gel or 10% cream  had a significantly greater reduction peroxide or azelaic acid may be added to antibiotic therapy to of acne lesions, including both inflammatory and nonin- reduce the potential for developing P. acnes resistance .
flammatory lesions, compared with controls. There appears to be no difference in efficacy among the benzoyl peroxide Topical Retinoids
Topical retinoids should be the foundation of treatment for Randomized trials by Belknap  and Montes  showed most patients with acne because they act to reduce obstruc- that both topical tretinoin and benzoyl peroxide effectively re- tion of the follicle and therefore treat both comedonal and duced inflammatory and noninflammatory lesions. Montes inflammatory acne . They are also recommended for  also concluded that benzoyl peroxide was clinically better maintenance therapy . Three topical retinoids are avail- than topical tretinoin for reducing the total number of lesions, able in the United States: tretinoin, adapalene, and tazaro- tene. The number of inflammatory and noninflammatory lesions is significantly reduced by topical tretinoin [8–11], Topical Antibiotics
adapalene [12–14], and tazarotene [15–17]. Topical antibiotics are indicated for mild inflammatory acne Tretinoin was the first topical retinoid used in the treat- . Both erythromycin and clindamycin are topical antibiot- ment of acne, and adapalene and tazarotene are synthetic ics that have been shown to be effective and well-tolerated. agents . Retinoids exert their effects by binding to nuclear Because P. acnes can develop resistance to either of these anti- retinoid acid receptors (RAR) and retinoid X receptors (RXR) biotics , their use as a single therapeutic agent is limited.
. Cellular binding proteins (CRBP I and II) and cellular Double-blind, randomized controlled studies have dem- retinoic acid binding proteins (CRABP I and II) are involved onstrated the efficacy of various topical erythromycin prep- in cellular transport and metabolism of retinoids . Studies arations, including erythromycin 1.5% solution and erythro- suggest that because adapalene activity is not dependent on mycin 2% gel and ointment, in reducing inflammatory acne CRABP II binding, it is associated with less irritation and less erythema . Tretinoin may cause more adverse effects be- Clindamycin has also been shown to be effective in the cause of its involvement in several pathways, including RAR treatment of acne. In several multicenter, investigator or and RXR activation and CRABP II binding . double-blind, randomized, placebo-controlled trials, pa- Tazarotene appears to be the most efficacious topical tients using clindamycin 1% hydrochloride solution, clinda- retinoid. In randomized, double-blind controlled trials and a mycin 1% phosphate solution, clindamycin 1% phosphate meta-analysis, tazarotene 0.1% gel or cream was shown to be lotion, or clindamycin 1% phosphate gel had a significantly more effective than tretinoin 0.025% gel , tretinoin 0.1% greater reduction in papule and pustule counts compared microsphere gel , adapalene 0.1% gel , or adapalene with patients receiving placebo [48–50]. Additionally, the 0.1% cream . However, some randomized, evaluator- study by Ellis et al  showed the clindamycin solution and blind, controlled trials showed that tazarotene 0.1% cream gel both were associated with significant reduction of open was equally efficacious to adapalene 0.1% gel and 0.3% gel in total acne lesion reduction [23–25].
Topical clindamycin and erythromycin appear to have Adverse effects of topical retinoids include erythema, comparative efficacy. In double-blind and investigator-blind dryness, itching, and stinging. Adapalene seems to be as- randomized comparisons of topical erythromycin versus sociated with fewer adverse effects. Adapalene 0.1% gel or topical clindamycin, both formulations showed comparative solution is equally effective or superior to tretinoin 0.025% efficacy in reducing acne lesions [51–53].
gel [26,27], tretinoin microsphere 0.1% gel , and tretinoin An analysis of clinical trials showed that the efficacy of 0.05% cream , but it is generally better tolerated and less 1.5% to 2% topical erythromycin formulations in the treat- likely to cause skin irritation [26,28–33]. Topical retinoids ment of inflammatory or noninflammatory acne decreased are available in a variety of strengths and formulations and over time, especially in studies of greater than 12 weeks’ generally should be started at a low strength to minimize duration . The efficacy of topical clindamycin remained stable throughout the study period .
116 JCOM March 2009 Vol. 16, No. 3
with baseline in patients treated with combination therapy, Although few well-designed trials evaluating the safety and whereas P. acnes counts increased by greater than 1600% in efficacy of topical salicylic acid exist, a review of 3 placebo- those receiving clindamycin monotherapy.
controlled trials and 1 comedoytic assay concluded that salicylic acids pads reduce the number of primary lesions treatment for moderate acne
The use of systemic antibiotics is indicated for moderate or Azelaic acid has comedolytic and antibacterial properties severe acne . The most commonly used systemic antibiot- and is effective in treating acne. Several studies have shown ics are tetracycline and its derivatives . Other less com- that 20% azelaic acid is superior to placebo in reducing inflam- monly used antibiotics include macrolides, trimethoprim- matory and noninflammatory acne lesions or total number of sulfamethoxazole (TMP-SMX), and trimethoprim . Like acne lesions [56–58]. One study showed that 20% azelaic acid topical antibiotics, systemic antibiotics should be combined had similar efficacy compared with 0.05% tretinoin cream and with a topical retinoid to enhance efficacy . The addition of another showed that although benzoyl peroxide has a more topical benzoyl peroxide reduces the development of P. acnes rapid effect, azelaic acid is better tolerated [57,59]. resistance . In women, oral contraceptives containing an Randomized, double-blind, vehicle-controlled trials have estrogen and progestin are indicated for moderate acne and shown that topical dapsone 5% gel is effective in reducing can be used as a component of combination therapy [5,6]. inflammatory and noninflammatory acne lesions and that For moderate nodular acne that is resistant to primary treat- adverse effects were comparable with those in the control ments, oral isotretinoin may be used [5,7].
group [60–62]. Use of oral dapsone may be associated with hematologic adverse effects; however, in patients with glucose- Systemic Antibiotics
6-phosphate dehydrogenase (G6PD) deficiency treated with Systemic antibiotics are the standard of care for moderate dapsone 5% gel, there was no clinical or laboratory evidence and severe acne and treatment-resistant forms of acne . They are generally not used as monotherapy and are ideally discontinued within 8 to 12 weeks because of the concern Combinations
for increased bacterial resistance [5,7]. There is evidence to Combination therapy is likely to have a more significant ef- support the use of tetracycline, doxycycline, minocycline, fect because it targets 3 major areas of acne pathophysiology: erythromycin, TMP-SMX, trimethoprim, and azithromycin.
P. acnes proliferation, inflammation, and hyperkeratiniza- Oral antibiotics are also associated with a variety of side tion . Topical retinoids in combination with topical or oral effects . All antibiotics can result in vaginal candidiasis. antimicrobials have been shown to reduce inflammatory Tetracyclines should not be used in pregnant women and and noninflammatory acne lesions faster and to a greater children under age 8 due to deposition in bones and tooth degree than antimicrobial agents alone . Additionally, discoloration . Doxycycline is associated with photosensi- combination therapy is one strategy to limit the increase in tivity and esophageal irritation . Minocycline may cause resistance of P. acnes in patients [5,64].
vestibular disturbances, pigment deposition, and rarely au- In an 8-week study by Mills and Kligman , groups of toimmune hepatitis or a systemic lupus erythematosus–like patients with moderate acne who received topical erythro- mycin plus topical tretinoin experienced better results than In double-blind randomized controlled studies, treat- those receiving monotherapy or placebo. In double-blind ment with oral tetracycline was associated with significantly randomized trials, the combination topical clindamycin 1% greater improvement in acne compared with placebo [78– phosphate and a topical retinoid was found to be more effica- 84]. There are conflicting data on whether oral tetracycline is cious in reducing inflammatory acne and noninflammatory superior to topical tetracycline or whether there is no signifi- acne lesions than either agent alone [66–69]. Topical retinoids cant difference in efficacy [79–81], and it is unclear whether plus benzoyl peroxide have also been effective in the treat- topical clindamycin is equally efficacious or superior to oral ment of acne in randomized, controlled investigator- and There is insufficient evidence to support the use of 1 tet- Several double- or single-blind randomized controlled racycline over another [85,86]. A Cochrane review of mino- studies have demonstrated the efficacy of topical antibiotics cycline in the treatment of acne concluded that there was no combined with benzoyl peroxide in treating inflamma- reliable randomized controlled trial evidence to justify the tory acne [64,72–75]. Additionally, 1 double-blind random- use of minocycline as first-line treatment for acne, especially ized study by Cunliffe et al  demonstrated a reduc- considering the higher cost and concerns about more severe tion in clindamycin-resistant P. acnes counts as compared Vol. 16, No. 3 March 2009 JCOM 117
A double-blind randomized controlled study by Gam- Spironolactone
mon et al  showed that oral erythromycin and oral tetra- Spironolactone inhibits the biosynthesis of testosterone cycline were equal in efficacy in the treatment of moderate and also blocks androgen receptors . This results in to moderately severe acne. Bacterial resistance is most com- decreased androgen-stimulated sebocyte proliferation and mon with erythromycin , and its use should be limited to those who cannot use tetracyclines . In randomized, placebo-controlled, double-blind studies, Although oral TMP-SMX and oral trimethoprim are not Muhlemann et al  showed that spironolactone is signifi- recommended as first-line therapy, they have been shown to cantly more effective than placebo in reducing the number significantly reduce acne severity and can be used for acne of inflamed acne lesions, and Goodfellow et al  found treatment when other oral antibiotics cannot be used or pa- that patients tended to have greater improvement when tients are refractory to other oral antibiotic regimens [89–92].
taking higher doses (150–200 mg) of spironolactone. Hatwal An open-label, noncomparative study by Bardazzi et al et al  found that acne severity improved significantly  demonstrated a significant reduction in inflammatory le- more in participants using spironolactone compared with sions in patients receiving azithromycin relative to baseline.
those using cimetidine, which has antiandrogenic effects. However, these studies had relatively small sample popula- Oral Contraceptives
Estrogen-containing oral contraceptives can be useful in Side effects of spironolactone therapy may include hy- the treatment of acne for women. In 5 randomized placebo- perkalemia, menstrual irregularities, breast tenderness, or controlled trials, oral contraceptives reduced inflamma- hypotension . A retrospective analysis by Shaw  tory and noninflammatory acne lesion counts and severity showed that a lower frequency of adverse effects may be as- grades and improved global and patient self-assessment sociated with lower doses of spironolactone (50–100 mg).
compared with placebo [94–98]. These trials included com- binations of ethinyl estradiol plus levonorgestrel, norethin- treatment of Severe acne
Oral isotretinoin is indicated for severe nodulocystic acne or The comparative effectiveness of combination oral con- treatment-resistant moderate acne . Education of patient traceptives with varying progestin components is unclear. regarding the side effects, teratogenicity, potential psychiatric Randomized controlled trials suggest that chlormadinone effects, and monitoring is critical in patients who are interested acetate–containing or cyproterone acetate–containing oral in initiating oral isotretinoin . Alternatives to oral isotreti- contraceptives improved acne better than those containing noin treatment include the combination of a systemic antibiot- levonorgestrel, but the superiority is based on little evidence ic, topical retinoid, and topical benzoyl peroxide . In women, [99,100]. Comparisons between other oral contraceptives con- an oral contraceptive can be added to the combination .
taining diphasic desogestrel [101–105], cyproterone acetate [101–103], levonorgestrel [104–107], drospirenone [108–112], Isotretinoin
norgestimate , gestodene [110–112], and norethindrone Although oral isotretinoin is approved for the treatment of acetate  were either conflicting or found no differences severe nodulocystic treatment-resistant acne, it is also indi- between the combinations in the ability to reduce acne.
cated for all cases of treatment-resistant acne or acne that In a multicenter, controlled trial by Monk et al , no produces physical or psychological scarring . Isotretinoin significant difference was found between low-dose cypro- has been shown to be effective in clearing acne lesions terone acetate and oral minocycline in the reduction of acne and inducing remission. The prolonged remission may be lesions or in the patients’ self-assessments.
related to continued sebaceous gland inhibition in some Overall, good evidence suggests that combination oral contraceptives containing an estrogen and a progestin are In a randomized, double-blind study by Peck et al , effective for reducing acne lesions in women, even those patients receiving isotretinoin had 95% improvement, which without increased serum androgens . To date, ethi- was significantly greater than those receiving placebo, who nyl estradiol-drospirenone, ethinyl estradiol-norethindrone had an overall 57% increase in the number of lesions. Sixteen acetate, and ethinyl estradiol-norgestimate are the oral of the 17 patients who initially received placebo were then contraceptives that are specifically approved by the U.S. given isotretinoin with a 98% improvement. Twenty-seven Food and Drug Administration for the treatment of acne of 32 patients cleared completely, with 18 receiving only one , although few differences are found between various 4-month course of treatment. All patients were in remission combination oral contraceptives. There are limited data to at the time of the report, averaging 38 months of remission.
determine the comparative effectiveness between oral con- A double-blind study concluded that there were no sig- traceptives and antibiotics in reducing acne lesions.
nificant differences in efficacy between doses of 0.1 mg/kg, 118 JCOM March 2009 Vol. 16, No. 3
0.5 mg/kg, and 1 mg/kg, but they recommended 0.5 mg/kg evidence to rule out a weak association . Therefore, pa- as the initial dose for the initial course of isotretinoin treat- tients must be aware of the potential effects, and physicians ment because those treated with 1 mg/kg had more severe should monitor for these adverse effects .
side effects and those treated with 0.1 mg/kg had a higher incidence of relapse . Similarly, another double-blind maintenance therapy
study concluded that the optimal dose-range for the treat- Topical retinoids are the preferred agent for maintenance ment of patients with nodulocystic acne is 0.5 to 1.0 mg/kg therapy . Antibiotics should be discontinued once inflam- because a lower dose was associated with much lower main- matory lesions are well-controlled . If an antimicrobial tenance of clinical improvement . In general, treatment agent is need, benzoyl peroxide should be used in conjunc- continues until a cumulative dose of 120 to 150 mg/kg is Layton et al  concluded that isotretinoin is safe and alternative acne treatments
effective and is capable of producing long-term remission in A variety of alternative acne treatments exist. While there are the majority of patients in a 10-year follow-up study. Factors limited data to indicate their use as first-line therapy, these al- associated with the need for further courses of treatment in- ternatives may be used in conjunction with other treatments.
cluded lower dosage regimens (0.1 mg/kg and 0.5 mg/kg), the presence of severe acne, females older than age 25 years, Oral corticosteroids
and a prolonged history of acne .
There are limited data to support the effectiveness of oral All patients are required to register and comply with the corticosteroids in the treatment of acne. One study by Nader iPLEDGE program . Isotretinoin has potential teratogenic et al  showed that oral prednisone lowered elevated effects, and therefore adequate contraception is necessary androgen levels in hyperandrogenic women with acne and before, during, and 6 weeks after treatment . Laboratory was associated with clearing or significant improvement. monitoring during therapy should include measurement A consensus of expert opinion supports the idea that short of triglycerides, cholesterol, transaminases, and complete courses of high-dose oral corticosteroids may be of tempo- blood counts . Common adverse effects of isotretinoin rary benefit in patients with severe inflammatory acne .
therapy include dry skin and eyes, secondary skin infection, myalgias, epistaxis, and decreased night vision .
In a multicenter, double-blind controlled study, patients Corticosteroids can be injected intralesional y in order to obtain with severe recalcitrant nodular acne were randomized a high concentration of steroid at the lesion site with minimal to either micronized isotretinoin or standard isotretinoin systemic absorption. In smal studies, improvement has been [127,128]. Both formulations had similar clinical efficacy noted in the treatment of individual acne cysts and nodules , but the micronized isotretinoin appeared to lower the within 24 to 72 hours [133–135]. Injection of lesions may be as- risk of mucocutaneous adverse events and hypertriglyceri- sociated with local atrophy , and systemic absorption may occur leading to suppression of the hypothalamic-pituitary- Depression and suicidal behaviors have been reported in adrenal axis . Decreasing the concentration or volume may patients taking isotretinoin . However, a causal relation- ship has not been established. A systematic review found that rates of depression in the included studies showed simi- Chemical Peels
lar rates of depression in antibiotic control groups, and there Glycolic acid is an alpha-hydroxy acid that can be used as was no significant increase in depression after isotretinoin a chemical peeling agent by inducing removal and then treatment compared with before treatment . A recent regeneration of the epidermis and/or dermis . Salicylic case-crossover study is the first controlled study to find acid is a keratolytic agent that has a strong comedolytic ef- a statistically significant association between isotretinoin fect because of its lipophilic nature and ability to penetrate and depression . Treatment of severe acne is often as- deep into pores . However, there is little evidence in the sociated with mood improvement [7,129]; however, given the peer-reviewed literature supporting the efficacy of glycolic profound consequences of depression in young patients, it is acid–based or salicylic acid–based peeling preparations. prudent to advise patients on isotretinoin that the possibility One randomized controlled trial compared glycolic acid of an association with depression has been raised and close and Jessner’s solution (resorcinol, salicylic acid, lactic acid, and ethanol) and demonstrated improvement in facial acne Although these studies do not support a causal rela- in both treatments compared with baseline . There tionship between isotretinoin use and increased rate of was no statistically significant difference between the treat- depression or suicidal behavior, there may not be sufficient ments. Several controlled trials and case series have also Vol. 16, No. 3 March 2009 JCOM 119
reported improvement in inflammatory and noninflamma- cacy of infrared lasers for the treatment of acne. A 1320-nm Nd: tory acne in patients using chemical peels compared with YAG laser produced a significantly greater reduction of open comedones but had no difference in the reduction of papules, Although chemical peels do not replace topical or sys- pustules, or closed comedones compared with no treatment temic medications for the treatment of acne, they can be . A 1450-nm wavelength laser produced a significantly greater reduction in the total acne lesion count compared to the control . Clinical efficacy has not been demonstrated Comedo Removal
to be enhanced with the addition of microdermabrasion to There is little evidence in the peer-reviewed literature re- 1450-nm laser treatment  nor has a significant difference garding the efficacy of comedo removal. The extraction of been shown between 2 fluencies (14 and 16 J/cm2) .
comedones maybe more beneficial in superficial acne but not in cystic acne . Comedo removal does not affect the Light Sources
course of the disease but may provide immediate improve- As part of its normal metabolism, P. acnes produces porphy- ment of the patient’s appearance , increase patient satis- rins, which can absorb light at the near ultraviolet and blue faction , and positively impact compliance .
light spectrum [156,157]. Irradiation of P. acnes with blue light can induce photoexcitation, leading to singlet oxygen Complementary and Alternative Medicines
production, and eventually bacterial destruction. Several Complementary and alternative medicines are used to treat trials have studied the efficacy of various light sources and a variety of health conditions including acne. However, there are very limited data addressing the safety and ef- In a randomized, evaluator-blinded study by Sigurdsson et al , green light and violet light significantly improved Two clinical trials have shown that tea tree oil is an effec- face, back, and/or chest acne, with a tendency toward violet tive treatment for acne [144,145]. In double-blind, randomized, placebo-controlled clinical evaluations, certain herbal tablets Other randomized controlled trials evaluating blue light have been associated with a significant reduction in the num- have shown its safety and efficacy in the reduction of ber of inflammatory and noninflammatory lesions [146,147].
inflammatory lesions [157,159,160] but worsening of nodulo- In addition to causing stress and having a significant psychological impact on patients, acne may be exacerbated The randomized controlled trial by Na and Suh  by stress because of an associated increased sebum excre- concluded that red light alone is effective in the treatment of tion rate, free fatty acid production, and endocrine activity. inflammatory and noninflammatory acne lesions, although The results of an intervention by Hughes et al  provided it does not eradicate the lesions completely and effects are support for the efficacy of biofeedback relaxation-imagery therapy in the treatment of acne. However, the literature sup- A randomized controlled study by Papageorgious et al porting the possible benefit of biofeedback-assisted relaxation  demonstrated that phototherapy with mixed blue and and cognitive therapy in the treatment of acne is weak.
red light was significantly better that blue light alone, white light, and benzoyl peroxide 5% cream in improving inflam- matory acne, and nonsignificantly better in improving Some data indicate that the use of pulsed dye lasers, potas- sium titanyl phosphate lasers, and infrared lasers may be of benefit in reducing acne lesions. However, data are very Photodynamic Therapy
Photodynamic therapy is a therapeutic modality that uti- Two randomized controlled studies evaluated the efficacy lizes a photosensitizing agent and its activating wavelength of pulsed dye lasers versus sham treatments. Seaton et al of light to selectively destroy target tissue . The few ran-  showed significant reduction of inflammatory acne le- domized controlled studies that have evaluated the efficacy sions and total acne lesions, but Orringer et al  failed to of photodynamic therapy have shown positive results. show a significant difference between the laser-treated skin Topically applied 5-aminolevulinic acid (ALA) is me- tabolized to protoporphyrin IX, a potent photosensitizer, that In a randomized controlled trial, Baugh and Kucaba  accumulates in epidermal cells and pilosebaceous units . showed that after 4 treatments with the potassium titanyl When the ALA-treated skin is irradiated with light, protopor- phosphate laser, patients had significant improvement in their phyrin IX is excited and reacts with oxygen to form singlet, acne at 1 week and nonsignificant improvement at 4 weeks. causing membrane damage and cell destruction . Four randomized control ed studies have evaluated the effi- In a randomized controlled trials comparing photodynamic 120 JCOM March 2009 Vol. 16, No. 3
therapy with either treatment alone or no treatment, ALA Table. Treatment Recommendations for Acne Vulgaris
plus red light produced significantly greater reduction of inflammatory acne lesions [163,164], and ALA plus blue Addition of a topical antibiotic/benzoyl peroxide light produced a greater reduction in papules, pustules, and combination if papules/pustules present. Ben- comedones . Significant improvement in acne lesions zoyl peroxide without antibiotic also an option was demonstrated using intense pulsed light (IPL) plus ALA basing strength of formulation on skin dryness and using IPL plus short-contact ALA [162,166]. Complete (oily skin higher concentration) or azelaic acid with topical antibiotic clearance of acne in all patients using long-pulsed dye laser Topical retinoid plus systemic antibiotic (LPDL) plus ALA was shown by Alexiades-Armenakas in a Addition of a topical antibiotic/benzoyl peroxide Methyl aminolevulinate (MAL) is another agent that has If treatment-resistant, may consider isotretinoin been studied in the photodynamic therapy of acne. It is de- esterified to ALA by intracellular enzymes . Because of If isotretinoin contraindicated or not tolerated, its lipophilicity, MAL is expected to penetrate more easily alternatives include a systemic antibiotic in com- and deeper into the targeted tissue .
Randomized controlled trials have shown a significantly greater reduction in inflammatory acne lesions in patients treated with MAL plus red light compared with patients receiving placebo or no treatment [168,170]. In a randomized, half-face treatment study by Yeung et al , patients who received MAL plus IPL had a nonsignificantly greater reduc- tion in inflammatory acne lesions compared with controls who received IPL alone or topical adapalene. The patients Author contributions: conception and design, KWL, MGM; drafting of article, KWL; critical revision of the article, MGM; col ection and assem- receiving MAL plus IPL and IPL alone had a significantly greater reduction of noninflammatory acne lesions com- pared with the adapalene group . Haedersdal et al  found that the half of the face treated with MAL plus LPDL- references
treated had a significantly greater reduction of acne lesions 1. White GM. Recent findings in the epidemiological evidence, compared with the side treated with LPDL-treated alone. classification, and subtypes of acne vulgaris. J Am Acad Der- ALA plus red light and MAL plus red light appear to be effective in the treatment of acne with no significant differ- 2. Dreno B, Poli F. Epidemiology of acne. Dermatol 2003;206: Although several studies demonstrate the effectiveness 3. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999;41:577–80.
of photodynamic therapy in the treatment of acne, further 4. Col ier CN, Harper JC, Cantrel WC, et al. The prevalence studies are needed to determine the proper incubation time of acne in adults 20 years and older. J Am Acad Dermatol of the photosensitizer and the appropriate light source.
5. Gol nick H, Cunliffe WJ, Berson D, et al. Management of acne: conclusion
a report from a global al iance to improve outcomes in acne. Acne is a common condition that is often accompanied by physical and psychological morbidity. Current acne treat- 6. Zaenglein AL, Thiboutot DM. Expert committee recommen- ments target at least 1 of the known pathophysiologic mecha- dations for acne management. Pediatr 2006;118:1188–99.
nisms involved in acne development. The Table summa-
7. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care rizes treatment recommendations for acne. Combining these for acne vulgaris management. J Am Acad Dermatol 2007;6: therapies can often lead to significantly better improvement 8. Berger R, Barba A, Fleischer A, et al. A double-blinded, and/or inhibit the development of antibiotic-resistant bac- randomized, vehicle-control ed, multicenter, paral el-group teria. With proper treatment of this condition, the negative study to assess the safety and efficacy of tretinoin gel micro- sphere 0.04% in the treatment of acne vulgaris in adults. Cutis 2007;80:152–7.
Corresponding author: Mary Gail Mercurio, MD, University of Rochester, 9. Lucky AW, Cul en SI, Funicel a T, et al. Double-blind, vehicle- 601 Elmwood Ave., Box 697, Rochester, NY 14642, marygail_mercurio@ control ed, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris. J Am Acad Dermatol 1998;38:S24–30.
10. Lucky AW, Cul en SI, Jarratt MT, Quigley JW. Comparative Vol. 16, No. 3 March 2009 JCOM 121
efficacy and safety of two 0.025% tretinoin gels: results from a 25. Thiboutot D, Arsonnaud S, Soto P. Efficacy and tolerability of multicenter, double-blind, paral el study. J Am Acad Dermatol adapalene 0.3% gel compared to tazarotene 0.1% gel in the treatment of acne vulgaris. J Drugs Dermatol 2008;7:S3–10.
11. Berger R, Rizer R, Barba A, et al. Tretinoin gel microspheres 26. Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A com- 0.04% versus 0.1% in adolescents and adults with mild to mod- parison of the efficacy and tolerability of adapalene 0.1% gel erate acne vulgaris: a 12-week, multicenter, randomized, double- versus tretinoin 0.025% gel in patients with acne vulgaris: a blind, paral el-group, phase IV trial. Clin Ther 2007;29:1086–97.
meta-analysis of five randomized trials. Br J Dermatol 1998; 12. Lucky A, Jorizzo JL, Rodriguez D, et al. Efficacy and tolerance of adapalene cream 0.1% compared with its cream vehicle for 27. El is CN, Mil ikan LE, Smith EB, et al. Comparison of ada- the treatment of acne vulgaris. Cutis 2001;68(Suppl 4):34–40.
palene 0.1% solution and tretinoin 0.025% gel in the topical 13. Pariser DM, Thiboutot DM, Clark SD, et al. The efficacy and treatment of acne vulgaris. Br J Dermatol 1998;139(Suppl 52): safety of adapalene gel 0.3% in the treatment of acne vulgaris: a randomized, multicenter, investigator-blinded, control ed com- 28. Thiboutot D, Gold MH, Jarratt MT, et al. Randomized con- parison study versus adapalene gel 0.1% and vehicle. Cutis trol ed trial of the tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment 14. Thiboutot D, Pariser DM, Egan N, et al. Adapalene gel 0.3% of acne vulgaris. Cutis 2001;68(Suppl 4):10–9.
for the treatment of acne vulgaris: a multicenter, randomized, 29. Cunliffe WJ, Danby FW, Dunlap F, et al. Randomized, con- double-blind, control ed phase III trial. J Am Acad Dermatol trol ed trial of the efficacy and safety of adapalene gel 0.1% and tretinoin cream 0.05% in patients with acne vulgaris. Eur J 15. Shalita AR, Chalker DK, Griffith RF, et al. Tazarotene gel is safe and effective in the treatment of acne vulgaris: a multicenter, 30. Galvin SA, Gilbert R, Baker M, et al. Comparative tolerance of double-blind, vehicle-control ed study. Cutis 1999;63:349–54.
adapalene 0.1% gel and six different tretinoin formulations. Br 16. Bershad S, Singer GK, Parent JE, et al. Successful treatment of J Dermatol 1998;139(Suppl 52):34–40.
acne vulgaris using a new method: results of a randomized 31. Egan N, Loesche MC, Baker MM. Randomized, control ed, vehicle-control ed trial of shirt-contact therapy with 0.1% taz- bilateral (split-face) comparison trial of the tolerability and arotene gel. Arch Dermatol 2002;138:481–9.
patient preference of adapalene gel 0.1% and tretinoin micro- 17. Shalita AR, Berson DS, Thiboutot DM, et al. Effects of tazarotene sphere gel 0.1% for the treatment of acne vulgaris. Cutis 2001; 0.1% cream in the treatment of facial acne vulgaris: pooled re- sults from two multicenter, double-blind, randomized, vehicle- 32. Dosik JS, Homer K, Arsonnaud S. Cumulative irritation poten- control ed, paral el-group trials. Clin Ther 2004;26:1865–73.
tial of adapalene 0.1% cream and gel compared with tretinoin 18. Bikowski JB. Mechanisms of the comedolytic and anti- microsphere 0.04% and 0.1%. Cutis 2005;75:238–43.
inflammatory properties of topical retinoids. J Drugs Dermatol 33. Dosik JS, Homer K, Arsonnaud S. Cumulative irritation potential of adapalene 0.1% cream and gel compared with 19. Webster GF, Berson D, Stein LF, et al. Efficacy and tolerability tazarotene cream 0.5% and 0.1%. Cutis 2005;75:289–93.
of once-daily tazarotene 0.1% gel versus once-daily tretinoin 34. Smith EB, Padil a RS, McCabe JM, Becker LE. Benzoyl perox- 0.025% gel in the treatment of facial acne vulgaris: a random- ide lotion (20 percent) in acne. Cutis 1980;25:90–2.
ized trial. Cutis 2001;67(6 Suppl):4–9.
35. Hughes BR, Norris JFB, Cunliffe WJ. A double-blind evaluation 20. Leyden JJ, Tanghetti EA, Mil er B, et al. Once-daily tazarotene of topical isotretinoin 0.05%, benzoyl peroxide gel 5%, and pla- 0.1 % gel versus once-daily tretinoin 0.1 % microsponge gel for cebo in patients with acne. Clin Exp Dermatol 1992;17:165–8.
the treatment of facial acne vulgaris: a double-blind random- 36. Cunliffe WJ, Dodman B, Ead R. Benzoyl peroxide in acne. ized trial. Cutis 2002;69(2 Suppl):12–9.
21. Webster GF, Guenther L, Poulin YP, et al. A multicenter, 37. Mil s OH, Kligman AM, Pochi P, Comite H. Comparing 2.5%, double-blind, randomized comparison study of the efficacy 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. and tolerability of once-daily tazarotene 0.1% gel and ada- palene 0.1% gel for the treatment of facial acne vulgaris. Cutis 38. Yong CC. Benzoyl peroxide gel therapy in acne in Singapore. 22. Shalita A, Mil er B, Menter A, et al. Tazarotene cream versus 39. Belknap BS. Treatment of acne with 5 percent benzoyl peroxide adapalene cream in the treatment of facial acne vulgaris: a gel or 0.05 percent retinoic acid cream. Cutis 1979;23:856–9.
multicenter, double-blind, randomized, paral el-group study. 40. Montes LF. Acne vulgaris: treatment with topical benzoyl peroxide acetone gel. Cutis 1977;19:681–5.
23. Leyden J, Lowe N, Kakita L, Draelos Z. Comparison of 41. Mil s O, Thornsberry C, Cardin CW, et al. Bacterial resistance treatment of acne vulgaris with alternate-day applications of and therapeutic outcome fol owing three months of topical tazarotene 0.1% gel and once-daily applications of adapalene acne therapy with 2% erythromycin gel versus its vehicle. Acta 0.1% gel: a randomized trial. Cutis 2001;67(6 Suppl):10–6.
24. Pariser D, Colon LE, Johnson LA, Gottschalk RW. Adapalene 42. Bernstein JE, Shalita AR. Topical y applied erythromycin in in- 0.1% gel compared to tazarotene 0.1% cream in the treatment flammatory acne vulgaris. J Am Acad Dermatol 1980;2:318–21.
of acne vulgaris. J Drugs Dermatol 2008;7:S18–23.
43. Jones EL, Crumley AF. Topical erythromycin vs blank vehicle 122 JCOM March 2009 Vol. 16, No. 3
in a multiclinic acne study. Arch Dermatol 1981;117:551–3.
63. Piette WW, Taylor S, Pariser D, et al. Hematologic safety of 44. Prince RA, Busch DA, Hepler CD, Feldick HG. Clinical trial of dapsone gel 5% for topical treatment of acne vulgaris. Arch topical erythromycin in inflammatory acne. Drug Intel Clin 64. Cunliffe WJ, Hol and KT, Bojar R, Levy SF. A randomized, 45. Dobson RL, Belknap BS. Topical erythromycin solution in double-blind comparison of a clindamycin phosphate/benzoyl acne: results of a multiclinic trial. J Am Acad Dermatol 1980;3: peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topi- 46. Lesher JL, Chalker DK, Smith JG, et al. An evaluation of a 2% cal treatment of acne vulgaris. Clin Ther 2002;24:1117–33.
erythromycin ointment in the topical therapy of acne vulgaris. 65. Mil s OH, Kligman AM. Treatment of acne vulgaris with topi- J Am Acad Dermatol 1985;12:526–31.
cal y applied erythromycin and tretinoin. Acta Dermatovener 47. Pochi PE, Bagatel FK, El is CN, et al. Erythromycin 2 percent gel in the treatment of acne vulgaris. Cutis 1988;41:132–6.
66. Richter JR, Forstrom LR, Ki stala UO, Jung EG. Efficacy of 48. Becker LE, Bergstresser PR, Whiting DA, et al. Topical clinda- the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel mycin therapy for acne vulgaris: a cooperative clinical study. formulation (Velac®) and a proprietary 0.025% tretinoin gel for- mulation (Aberela®) in the topical control of facial acne. J Eur 49. Kuhlman DS, Cal en JP. A comparison of clindamycin phos- Acad Dermatol Venereol 1998;11:227–33.
phate 1 percent topical lotion and placebo in the treatment of 67. Zouboulis CC, Derumeaux L, Decroix J, et al. A multicentre, acne vulgaris. Cutis 1986;38:203–6.
single-blind, randomized comparison of a fixed clindamycin 50. El is CN, Gammon WR, Stone DZ, Heezen-Wehner JL. A com- phosphate/tretinoin gel formulation (Velac®) applied once parison of Cleocin T solution, Celocin T gel, and placebo in the daily and a clindamycin lotion formulation (Dalacin T®) ap- treatment of acne vulgaris. Cutis 1988;42:245–7.
plied twice daily in the topical treatment of acne vulgaris. Br J 51. Leyden JJ, Shalita AR, Saatjian GD, Sefton J. Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution in 68. Leyden JJ, Krochmal L, Yaroshinsky A. Two randomized, acne vulgaris. J Am Acad Dermatol 1987;16:822–7.
double-blind, control ed trials of 2219 subjects to compare the 52. Shahlita AR, Smith EB, Bauer E. Topical erythromycin v combination clindamycin/tretinion hydrogel with each agent clindamycin therapy for acne. A multicenter, double-blind alone and vehicle for the treatment of acne vulgaris. J Am comparison. Arch Dermatol 1984;120:351–5.
53. Thomas DR, Raimer S, Smith EB. Comparison of topical 69. Wolf JE, Kaplan D, Kraus SJ, et al. Efficacy and tolerability of erythromycin 1.5 percent solution versus topical clindamycin combined topical treatment of acne vulgaris with adapalene phosphate 1.0 percent solution in the treatment of acne vul- and clindamycin. A multicenter, randomized, investigator- garis. Cutis 1982;29:624–5, 28–32.
blinded study. J Am Acad Dermatol 2003;49:S211–7.
54. Simonart T, Dramaix M. Treatment of acne with topical anti- 70. Shahlita AR, Rafal ES, Anderson DN, et al. Compared efficacy biotics: lessons from clinical studies. Br J Dermatol 2005;153: and safety of tretinoin 0.1% microsphere gel alone and in com- bination with benzoyl peroxide 6% cleanser for the treatment 55. Zander E, Weisman S. Treatment of acne vulgaris with salicylic of acne vulgaris. Cutis 2003;72:167–72.
acid pads. Clin Ther 1992;14:247–53.
71. Thiboutot DM, Weiss J, Bucko A, et al. Adapalene-benzoyl 56. Cunliffe WJ, Hol and KT. Clinical and laboratory studies on peroxide, a fixed-dose combination for the treatment of acne treatment with 20% azelaic acid cream for acne. Acta Derm vulgaris: results of a multicenter, randomized double-blind, Venereol (Stockh) 1989;143(Suppl):31–4.
control ed study. J Am Acad Dermatol 2007;57:791–9.
57. Katsambas A, Graupe K, Stratigos J. Clinical studies of 20% 72. Lookingbil DP, Chalker DK, Lindholm JS, et al. Treatment of azelaic acid cream in the treatment of acne vulgaris. Acta Derm acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel, and 58. Hjorth N, Graupe K. Azelaic acid for the treatment of acne. A vehicle gel. Combined results of two double-blind investiga- clinical comparison with oral tetracycline. Acta Derm Venereol tions. J Am Acad Dermatol 1997;37:590–5.
73. Tschen EH, Katz EI, Jones TM, et al. A combination benzoyl 59. Cavicchini S, Caputo R. Long-term treatment of acne with 20% peroxide and clindamycin topical gel compared with benzoyl azelaic acid cream. Acta Derm Venereol 1989;143(Suppl):40–4.
peroxide, clindamycin phosphate, and vehicle in the treatment 60. Draelos ZD, Carter E, Maloney JM, et al. Two randomized of acne vulgaris. Cutis 2001;67:165–9.
studies demonstrate the efficacy and safety of dapsone gel, 5% 74. Leyden JJ, Hickman JG, Jarratt MT, et al. The efficacy and for the treatment of acne vulgaris. J Am Acad Dermatol 2007; safety of a combination benzoyl peroxide/clindamycin topi- cal gel compared with benzoyl peroxide alone and a benzoyl 61. Raimer S, Maloney JM, Bourcier M, et al. Efficacy and safety peroxide/erythromycin combination product. J Cut Med Surg of dapsone gel 5% for the treatment of acne vulgaris in adoles- 75. Chalker DK, Shahlita AR, Smith JG, Swann RW. A double- 62. Lucky AW, Maloney JM, Roberts J, et al. Dapsone gel 5% for blind study of the effectiveness of a 3% erythromycin and the treatment of acne vulgaris: safety and efficacy of long-term 5% benzoyl peroxide combination in the treatment of acne (1 year) treatment. J Drugs Dermatol 2007;6:981–7.
vulgaris. J Am Acad Dermatol 1983;9:933–6.
Vol. 16, No. 3 March 2009 JCOM 123
76. Krakowski AC, Stendardo S, Eichenfield LF. Practical consid- 95. Lucky AW, Henderson TA, Olson WH, et al. Effectiveness of erations in acne treatment and the clinical impact of topical norgestimate and ethinyl estradiol in treating moderate acne combination therapy. Pediatr Dermatol 2008;25(Suppl):1–14.
vulgaris. J Am Acad Dermatol 1997;37:746–54.
77. Garner SE, Eady EA, Popescu C, et al. Minocycline for acne 96. Thiboutot D, Archer DF, Lemay A, et al. A randomized, con- vulgaris: efficacy and safety. Cochrane Database Syst Rev trol ed trial of a low-dose contraceptive containing 20 µg of ethinyl estradiol and 100 µg of levonorgestrel for acne treat- 78. Lane P, Wil iamson DM. Treatment of acne vulgaris with tetra- ment. Fertil Steril 2001;76:461–8.
cycline hydrochloride: a double-blind trial with 51 patients. Br 97. Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a random- 79. Blaney DJ, Cook CH. Topical use of tetracycline in the treatment ized, placebo-control ed trial. Obstet Gynecol 1997;89:615–22.
of acne: a double-blind study comparing topical and oral tetra- 98. Maloney JM. Use of low-dose oral contraceptive containing cycline therapy and placebo. Arch Dermatol 1976;112:971–3.
norethindrone acetate and ethinyl estradiol in the treatment of 80. Anderson RL, Cook CH, Smith DE. The effect of oral and topi- moderate acne vulgaris. Clin J Women Health 2001;1:123–31.
cal tetracycline on acne severity and on surface lipid composi- 99. Carlborg L. Cyproterone acetate versus levonorgestrel com- tion. J Invest Dermatol 1976;66:172–7.
bined with ethinyl estradiol in the treatment of acne: results of a 81. Smith JG Jr, Chalker DK, Wehr RF. The effectiveness of topical multicenter study. Acta Obstet Gynecol Scand 1986;134:29–32.
and oral tetracycline for acne. South Med J 1976;69:695–7.
100. Worret I, Arp W, Zahradnik HP, et al. Acne resolution rates: re- 82. Gratton D, Raymond GP, Guertin-Larochel e S, et al. Topical sults of a single-blind, randomized, control ed, paral el phase clindamycin versus systemic tetracycline in the treatment of III trial with EE/CMA (Belara®) and EE/LNG (Microgynon®). acne: results of a multiclinic trial. J Am Acad Dermatol 1982;7: 101. Dieben TO, Vromans L, Theeuwes A, Bennink HJ. The effects of 83. Braathen LR. Topical clindamycin versus oral tetracycline and CTR-24, a biphasic oral contraceptive combination, compared to placebo in acne vulgaris. Scand J Infect Dis Suppl 1984;43:71–5.
Diane-35 in women with acne. Contraception 1994;50:373–82.
84. Katsambas A, Towarky AA, Stratigos J. Topical clindamycin 102. Charoenvisal C, Thaipisuttikul Y, Pinjaroen S, et al. Effects on phosphate compared with oral tetracycline in the treatment of acne of two oral contraceptives containing desogestrel and acne vulgaris. Br J Dermatol 1987;116:387–91.
cyproterone acetate. Int J Fert 1996;41:423–9.
85. Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracy- 103. Vartiainen M, de Gezel e H, Broekmeulen CJ. Comparison of clines in the treatment of acne vulgaris: a review. Br J Dermatol the effect on acne with a combiphasic desogestrel-containing oral contraceptive and a preparation containing cyproterone 86. Harrison PV. A comparison of doxycycline and minocycline acetate. Eur J Contracept Reprod Health Care 2001;6:46–53.
in the treatment of acne vulgaris. Clin Exp Dermatol 1988;13: 104. Palatsi R, Hirvensalo E, Liukko P, et al. Serum total and un- bound testosterone and sex hormone binding globulin (SHBG) 87. Gammon WR, Meyer C, Lantis S, et al. Comparative efficacy of in female acne patients treated with two different oral contra- oral erythromycin versus oral tetracycline in the treatment of ceptives. Acta Derm Venereol 1984;64:517–23.
acne vulgaris: a double-blind study. J Am Acad Dermatol 1986; 105. Rosen MP, Breitkopf DM, Nagamani M. A randomized con- trol ed trial of second- versus third-generation oral contracep- 88. Ross JI, Snel ing AM, Carnegie E, et al. Antibiotic-resistant tives in the treatment of acne vulgaris. Am J Obstet Gynecol acne: lessons from Europe. Br J Dermatol 2003;148:467–78.
89. Hersle K. Trimethoprim-sulphamethoxazole in acne vulgaris: 106. Thorneycroft IH, Stanczyk FZ, Bradshaw KD, et al. Effect of a double-blind study. Dermatologica 1972;187–91.
low-dose contraceptives on adrogenic markers and acne. Con- 90. Jen I. A comparison of low dosage trimethoprim/ sulfamethoxazole with oxytetracycline in acne vulgaris. Cutis 107. Winkler UH, Ferguson H, Mulders JA. Cycle control, quality of life and acne with two low-dose oral contraceptives containing 91. Cotteril JA, Cunliffe WJ, Forster RA, et al. A comparison of 20 µg ethinylestradiol. Contraception 2004;69:469–76.
trimethoprim-sulphamethoxazole with oxytetracycline in acne 108. Thorneycroft IH, Gol nick H, Schnel schmidt I. Superiority of a vulgaris. Br J Dermatol 1971;84:366–9.
combined contraceptive containing drospirenone to a triphasic 92. Bottomley WW, Cunlifee WJ. Oral trimethoprim as a third-line preparation containing norgestimate in acne treatment. Cutis antibiotic in the management of acne vulgaris. Dermatology 109. van Vloten WA, van Haselen CW, van Zuuren EJ, et al. The effect 93. Bardazzi F, Savoia F, Parente G, et al. Azithromycin: a new of 2 combined oral contraceptives containing either drospire- therapeutic strategy for acne in adolescents. Dermatol Online J none or cyproterone acetate on acne and seborrhea. Cutis 2002; 94. Leyden J, Shahlita A, Hordinsky M, et al. Efficacy of a low- 110. Halbe HW, de Melo NR, Bahamondes L, et al. Efficacy and dose oral contraceptive containing 20 µg of ethinyl estradiol acceptability of two monophasic oral contraceptives contain- and 100 µg of levonorgestrel for the treatment of moderate ing ethinylestradiol and either desogestrel or gestodene. Eur J acne: a randomized, placebo-control ed trial. J Am Acad Der- Contracept Reprod Health Care 1998;3:113–20. 111. Koetsawang S, Charoenvisal C, Banharnsupawat L, et al. 124 JCOM March 2009 Vol. 16, No. 3
Multicenter trial of two monophasic oral contraceptives con- in acne patients treated with isotretinoin: a systematic review. taining 30 mcg ethinylestradiol and either desogestrel or ges- Semin Cutan Med Surg 2007;26:210–20.
todene in Thai women. Contraception 1995;51:225–9.
130. Azoulay L, Blais L, Koren G, et al. Isotretinoin and the risk 112. Mango D, Ricci S, Manna P, et al. Clinical and hormonal effects of depression in patients with acne vulgaris: a case-crossover of ethinylestradiol combined with gestodene and desogestrel study. J Clin Psychiatry 2008;69:526–32.
in young women with acne vulgaris. Contraception 1996;53: 131. Bigby M. Does isotretinoin increase the risk of depression? 113. Monk BE, Almeyda JA, Caldwel IW, et al. Efficacy of low-dose 132. Nader S, Rodriguez-Rigau LJ, Smith KD, Steinberger E. Acne cyproterone acetate compared with minocycline in the treat- and hyperandrogenism: impact of lowering androgen levels ment of acne vulgaris. Clin Exp Dermatol 1987;12:319–22.
with glucocorticoid treatment. J Am Acad Dermatol 1984;11: 114. George R, Clarke S, Thiboutot D. Hormonal therapy for acne. Semin Cutan Med Surg 2008;27:188–96.
133. Rebel o D. Intralesional triamcinoilone acetonide in skin dis- 115. Micromedex® Healthcare Series [internet database]. Available eases other than psoriasis. Br J Dermatol 1962;74:358–60.
at www.micromedex.com. Accessed 19 Jan 2009.
134. Leeming JA. Intralesional triamcinolone in the treatment of 116. Muhlemann MF, Carter GD, Cream JJ, Wise P. Oral spirono- cystic acne. S Afr Med J 1965;39:567–71.
lactone: an effective treatment for acne vulgaris in women. Br 135. Levine RM, Rasmussen JE. Intralesional corticosteroids in the treatment of modulocystic acne. Arch Dermatol 1983;119:480–1.
117. Goodfel ow A, Alaghband-Zadeh J, Carter G, et al. Oral 136. Potter RA. Intralesional triamcinolone and adrenal suppres- spironolactone improves acne vulgaris and reduces sebum sion in acne vulgaris. J Invest Dermatol 1971;57:364–70.
excretion. Br J Dermatol 1984;111:209–14.
137. Atzori L, Brundu MA, Orru A, Biggio P. Glycolic acid peel- 118. Hatwal A, Bhatt RP, Agrawal JK, et al. Spironolactone and ing in the treatment of acne. J Eur Acad Dermatol Venereol cimetidine in treatment of acne. Acta Derm Venereol 1988;68: 138. Lee HS, Kim IH. Salicylic acid peels for the treatment of acne 119. Shaw JC. Low-dose adjunctive spironolactone in the treatment vulgaris in Asian patients. Dermatol Surg 2003;29:1196–9.
of acne in women: a retrospective analysis of 85 consecutively 139. Kim SW, Moon SE, Kim JA, Eun HC. Glycolic acid versus treated patients. J Am Acad Dermatol 2000;43:498–502.
Jessner’s solution: which is better for facial acne patients? 120. Strauss JS, Stranieri AM. Changes in long-term sebum produc- A randomized prospective clinical trial of split-face model tion from isotretinoin therapy. J Am Acad Dermatol 1982;6: therapy. Dermatol Surg 1999;25:270–3.
140. Wang CM, Huang CL, Hu CT, Chan HL. The effect of glycolic 121. Peck GL, Olsen TG, Butkus D, et al. Isotretinoin versus placebo acid on the treatment of acne in Asian skin. Dermatol Surg in the treatment of cystic acne. J Am Acad Dermatol 1982;6: 141. Grimes PE. The safety and efficacy of salicylic acid chemical 122. Jones DH, King K, Mil er AJ, Cunliffe WJ. A dose-response peels in darker racial-ethnic groups. Dermatol Surg 1999;25: study of 13-cis-retinoic acid in acne vulgaris. Br J Dermatol 142. Taub AF. Procedural treatments for acne vulgaris. Dermatol 123. Strauss JS, Rapini RP, Shahlita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am 143. Lowney ED, Witkowski J, Simons HM, Zagula ZW. Value of comedo extraction in treatment of acne vulgaris. JAMA 124. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004; 144. Enshaieh S, Jooya A, Siadat AH, Iraji F. The efficacy of 5% 125. Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotretinoin for topical tea tree oil gel in mild to moderate acne vulgaris: acne vulgaris—10 years later: a safe and successful treatment. a randomized, double-blind placebo-control ed study. Indian J Dermatol Venereol Leprol 2007;73:22–5.
126. Stainforth JM, Layton AM, Taylor JP, Cunliffe WJ. Isotretinoin 145. Bassett IB, Pannowitz DL, Barnetson RS. A comparative study for the treatment of acne vulgaris: which factors may predict of tea-tree oil versus benzoylperoxide in the treatment of acne. the need for more than one course? Br J Dermatol 1993; 146. Paranjpe P, Kulkarni PH. Comparative efficacy of four Ay- 127. Strauss JS, Leyden JJ, Lucky AW, et al. A randomized trial of urvedic formulations in the treatment of acne vulgaris: a the efficacy of a new micronized formulation versus a standard double-blind radomised placebo-control ed clinical evalua- formulation of isotretinoin in patients with severe recalcitrant tion. J Ethnopharmacol 1995;49:127–32.
nodular acne. J Am Acad Dermatol 2001;45:187–95.
147. Lal a JK, Nandedkar SY, Paranjape MH, Talreja NB. Clinical 128. Strauss JS, Leyden JJ, Lucky AW, et al. Safety of a new micron- trials of ayurvedic formulations in the treatment of acne vul- ized formulation of isotretinoin in patients with severe recalci- garis. J Ethnopharmacol 2001;78:99–102.
trant nodular acne: a randomized trial comparing micronized 148. Hughes H, Brown BW, Lawlis GF, Fulton JE Jr. Treatment of isotretinoin with standard isotretinoin. J Am Acad Dermatol acne vulgaris by biofeedback relaxation and cognitive imag- ery. J Psychoso Res 1983;27:185–91.
129. Marqueling AL, Zane LT. Depression and suicidal behavior 149. Seaton ED, Charakida A, Mouser PE, et al. Pulsed-dye laser Vol. 16, No. 3 March 2009 JCOM 125
treatment for inflammatory acne vulgaris: randomised con- therapy with topical 5-aminolevulinic acid and intense pulsed trol ed trial. Lancet 2003;362:1347–52.
light versus intense pulsed light alone in the treatment of acne 150. Orringer JS, Kang S, Hamilton T, et al. Treatment of acne vul- vulgaris: comparative study. Dermatol Surg 2005;31:910–5.
garis with a pulsed dye laser: a randomized control ed trial. 163. Hongcharu W, Taylor CR, Chang Y, et al. Topical ALA-photo- dynamic therapy for the treatment of acne vulgaris. J Invest 151. Baugh WP, Kucaba WD. Nonablative phototherapy for acne vulgaris using the KTP 532 nm laser. Dermatol Surg 2005;31: 164. Pol ock B, Turner D, Stringer MR, et al. Topical aminolaevu- lanic acid-photodynami therapy for the treatment of acne 152. Orringer JS, Kang S, Maier L, et al. A randomized, control ed, vulgaris: a study of clinical efficacy and mechanism of action. split-face clinical trial of 1,320-nm Nd:YAG laser therapy in the treatment of acne vulgaris. J Am Acad Derm 2007;56:432–8.
165. Goldman MP, Boyce SM. A single-center study of aminolevu- 153. Paithankar DY, Ross EV, Saleh BA, et al. Acne treatment with a linic acid and 417 nm photodynamic therapy in the treatment 1,450 nm wavelength laser and cryogen spray cooling. Lasers of moderate to severe acne vulgaris. J Drugs Dermatol 2003;2: 154. Wang SQ, Counters JT, Flor ME, Zelickson BD. Treatment of 166. Rojanamatin J, Choawawanich P. Treatment of inflammatory inflammatory facial acne with the 1,450 nm diode laser alone facial acne vulgaris with intense pulsed light and short contact versue microdermabrasion plus the 1,450 nm laser: a random- of topical 5-aminolevulinic acid: a pilot study. Dermatol Surg ized, split-face trial. Dermatol Surg 2006;32:249–55.
155. Jih MH, Friedman PM, Goldberg LH, et al. The 1450-nm diode 167. Alexiades-Armenakas M. Long-pulsed dye laser-mediated laser for facial inflammatory acne vulgaris: dose-response and photodynamic therapy combined with topical therapy for 12-month fol ow-up study. J Am Acad Dermatol 2006;55:80–7.
mild to severe comedonal, inflammatory, or cystic acne. J Drugs 156. Papageorgious P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660) light in the treatment of acne vul- 168. Wiegal SR, Wulf HC. Photodynamic therapy of acne vulgaris garis. Br J Dermatol 2000;142:973–8.
using methyl aminolaevulinate: a blinded, randomized, con- 157. Elman M, Slatkine M, Harth Y. The effective treatment of acne trol ed trial. Br J Dermatol 2006;154:969–76.
vulgaris by a high-intensity, narrow band 405-420nm light 169. Wiegel SR, Wulf HC. Photodynamic therapy of acne vulgaris source. J Cosmet Laser Ther 2003;5:111–7.
using 5-aminolevulinic acid versus methyl aminoluvulinate. 158. Sigurdsson V, Knulst AC, van Weelden H. Phototherapy of J Am Acad Dermatol 2006;54:647–51.
acne vulgaris with visible light. Dermatol 1997;194:256–60.
170. Horfelt C, Funk J, Frohm-Nilsson M, et al. Topical methyl ami- 159. Gold MH. A multicenter clinical evaluation of the treatment of nolaevulinate photodynamic therapy for treatment of facial mild to moderate inflammatory acne vulgaris of the face with acne vulgaris: results of a randomized, control ed study. Br J visible blue light in comparison to topical 1% clindamycin antibiotic solution. J Drugs Dermatol 2005;4:64–70.
171. Yeung CK, Shek SY, Bjerring P, et al. A comparative study of 160. Tzung TY, Wu KH, Huang ML. Blue light phototherapy in the intense pulsed light alone and its combination with photody- treatment of acne. Photodermatol Photoimmunol Photomed namic therapy for the treatment of facial acne in Asian skin. 161. Na JI, Suh DH. Red light phototherapy alone is effective for 172. Haedersdal M, Togsverd-Bo K, Wiegel SR, Wulf HC. Long- acne vulgaris: randomized, single-blinded clinical trial. Der- pulsed dye laser versus long-pulsed dye laser-assisted photo- dynamic therapy for acne vulgaris: a randomized control ed 162. Santos AV, Belo VG, Santos G. Effectiveness of photodynamic trial. J Am Acad Dermatol 2008;58:387–94.
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126 JCOM March 2009 Vol. 16, No. 3
Collaborating on Utterances with a Spoken Dialogue SystemUsing an ISU-based Approach to Incremental Dialogue Managementbrief pause”. As discussed by Clark (1996), thisdevice is an efficient solution to the problem posedby uncertainty on the side of the speaker whethera reference is going to be understood, as it checksfor understanding in situ, and lets the conversationoverlapping turn-taki