Keratolytic Treatment

Transcription

1 Keratolytic Treatment Ali Alikhan and Howard I. Maibach 54 Contents 54.1 Introduction Benzoyl Peroxide Retinoids: Tretinoin, Tazarotene, Adapalene Tretinoin Isotretinoin Tazarotene Adapalene Azelaic Acid Salicylic Acid Sulfur Glycolic Acid Resorcinol In vivo Keratolytic Potential of Benzoyl Peroxide, Retinoic Acid, and Salicylic Acid Conclusions References Core Messages This chapter examines keratolytic agents utilized in acne treatment. Despite varying mechanisms of action, these agents target aberrant desquamation and proliferation of keratinocytes. Keratolytic agents have long been the cornerstone of acne therapy, coming in a variety of formulations and potencies. Though novel retinoid agents have expanded our therapeutic arsenal, established treatments like benzoyl peroxide still play a prominent role in acne therapy. Controlled trials have established effective keratolytic regimens and dosages for various acne presentations. Laboratory research has more precisely defined how keratolytic agents function. A colorimetric protein assay utilizing the tape strip method will be of invaluable use in measuring keratolytic efficacy and extending their value. Adapted with permission from Alikhan A, Maibach HI. Acne: Keratolytic Treatment. Cosmetics and Toiletries. 2010;11(10): A. Alikhan (*) H.I. Maibach Department of Dermatology, University of California, 110 Surge Bldg., 90 Medical Center Way, San Francisco, CA, USA alialikhan1@yahoo.com; maibachh@derm.ucsf.edu 54.1 Introduction Topical keratolytic agents have long been employed for acne treatment. Shalita et al. state that the first histologically visible change in acne is a disruption in the normal pattern of keratinization, resulting in dense, coherent squamae of C.C. Zouboulis et al. (eds.), Pathogenesis and Treatment of Acne and Rosacea, DOI / _54, Springer-Verlag Berlin Heidelberg

2 398 keratinous material that accumulate to form a plug in the orifice of the follicle, leading to formation of the microcomedo (precursor acne lesion). Furthermore, these aberrancies in proliferation, adhesion, and differentiation of the keratinocytes obstruct the infundibulum and the sebaceous duct, paving the way for excessive sebum secretion, bacterial overgrowth, and inflammatory response due to release of bacterial and cellular products. Under light microscopy, microcomedones are visualized as layers of horny cells surrounding a sebum and bacteria core [ 1 ]. Keratolytic agents are thought to function by relaxing the cohesiveness of the stratum corneum layer, which serves as a crucial, life-sustaining barrier, keeping hydration in and harmful foreign agents out. The mechanism of action A. Alikhan and H.I. Maibach does not involve keratin lysis as the name implies, but rather disintegration of desmosomes and hemidesmosomes, which link keratinocytes and bind them to the extracellular matrix respectively [ 2 ]. In this manner, these agents modulate and correct abnormal follicular keratinization. Currently many classes of keratolytics exist (Table 54.1 ). Available in varying concentrations and vehicles, they may be specifically indicated depending on the type, duration, and severity of acne. The proceeding text covers widely available topical and oral keratolytics, controlled trials comparing keratolytic agents, and in vivo keratolytic protein assays. Uncontrolled trials and older acne treatments are discussed briefly. Table 54.1 Keratolytics currently used in the USA Name Class First introduced Concentration(s), % Vehicle(s) Salicylic acid β-hydroxy acid 2.0 Bar, foam Glycolic acid α-hydroxy acid Benzoyl peroxide Organic peroxide 1920s 2.5, 3.0, 4.0, 5.0, 6.0, Gel, liquid, bar 8.0, 8.5, 9, 10 Tretinoin Retinoid , 0.05, 0.1, 0.01, 0.025, 0.05, 0.04 Cream, gel, liquid Isotretinoin Retinoid mg, 20 mg, 30 mg, Oral 40 mg Tazarotene Retinoid , 0.05, 0.5 Gel, cream Adapalene Retinoid-like Gel, cream, pledgets, solution Azelaic acid Dicarboxylic acid 15.0, 20.0 Cream, gel Sulfur Sulfur 10.0 Bar Urea Urea Resorcinol Phenol Clindamycin/benzoyl peroxide Antibiotic 1.0/5.0 Gel combination Erythromycin/benzoyl peroxide Antibiotic 3.0/5.0 Gel combination Sulfur/sodium salfacetamide Antibiotic combination 5.0/10.0 Tube, gel, cream, lotion Benzoyl peroxide/urea Keratolytic 4.5/10.0, 8.5/10.0 Liquid, gel combination Sulfur/benzoyl peroxide Keratolytic combination 2.0/5.0, 5.0/10.0 Lotion Table derived from: TP Habif, Skin Disease: Diagnosis and Treatment, 2nd edition. Elsevier Mosby, Philadelphia

3 54 Keratolytic Treatment 54.2 Benzoyl Peroxide Benzoyl peroxide (BPO), a mainstay treatment of mild-to-moderate acne for decades, has antimicrobial, anti-inflammatory, and anti- comedogenic effects. Acting through oxidation and formation of free radicals, its bacteriostatic activity is superior even to that of topical antibiotics [ 3 ]. It decreases inflammation by killing PMNs, preventing the release of reactive oxygen species [ 4 ] and was recently shown to be a keratolytic in vivo. Unfortunately, oxidative destruction of the stratum corneum may deplete cutaneous vitamin E, resulting in oxidation of surface lipids and proteins; this may predispose to skin dryness and desquamation [ 5 ]. BPO is absorbed effectively into the epidermis and converted to benzoic acid, with approximately 2 % entering the systemic circulation [ 6 8 ]. Its lipophilicity allows it to enter and accumulate in the lipid-rich pilosebaceous units and subcutaneous fat [ 4 ]. It is an FDA Pregnancy Category C agent, with little known about potential fetal harm or breast milk excretion, and positive in the rodent photocarcinogenicity assay. It is widely available, both over the counter and by prescription, and comes in different concentrations, ranging from 2.5 to 10 %. Adverse effects include dryness, peeling, burning, and redness of skin, with contact allergy in 1 2 % of patients [ 3 ]. Additionally, the water-based formulations may exert less drying, scaling, burning, and erythema than the alcohol-based formulations [ 3, 9 ]. Of note, an oxidizing agent, BPO can bleach hair, clothes, and colored fabrics. It may also inactivate tretinoin if both are applied concurrently [ 10 ]; in contrast, adapalene and tazarotene remain stable in the presence of BPO [ 6 ]. The 2.5 % formulation may be as effective as the 5 % and 10 % formulations in reducing inflammatory lesions and producing positive global ratings, while causing fewer adverse reactions than the 10 % solution [ 11 ]. Compared to vehicle, 2.5 % BPO significantly decreased inflammatory lesions and improved global 399 ratings; by the end of the 8-week study, the only significant adverse effect was peeling [ 11 ]. In a split-face, double-blind trial, a combination of BPO 5 %/urea 8 % lotion was not more efficacious in diminishing acne than BPO 5 % lotion alone; the combination took longer to dry and was stickier according to subjects [ 12 ]. Despite disappointing results with urea, combination therapy with topical antibiotics and BPO may be more effective than BPO alone. Both the clindamycin/bpo and the erythromycin/bpo formulations have shown superior efficacy when compared to either the antibiotic or BPO alone [ 13 ]. Three welldesigned, randomized, double-blind, vehiclecontrolled, multicenter clinical trials comparing the clindamycin/bpo gel with each individual agent and vehicle demonstrated significantly superior efficacy in inflammatory lesion reduction after weeks [ 4 ]. In two of the trials, global improvement assessments demonstrated significantly greater improvement in the combination group. Furthermore, the side-effect profile (dry skin, peeling, and erythema) of combination therapy is comparable to that of BPO alone [ 4 ] (Table 54.2 ). Leyden et al. compared clindamycin/bpo and erythromycin/bpo demonstrating statistically equivalent lesion reduction and global improvement, with similar tolerability [ 14 ] (Table 54.3 ). Additionally, a vehicle-controlled, randomized trial examining a 5 % BPO/1 % clindamycin combination gel in acne rosacea demonstrated significant improvement in papules/pustules and flushing/blushing after just a few weeks [ 15 ]. These results suggest a viable alternative to traditional rosacea treatments, which can produce systemic side effects. In vivo data suggest that the increased efficacy of a BPO/antibiotic combination may have an immunologic basis, as demonstrated by decreased antioxidant enzyme activities in leukocytes after month-long combination treatment [ 16 ]. Additionally, this combinatory approach may prevent the evolution of resistant P. acnes strains [ 17 ].

4 Retinoids: Tretinoin, Tazarotene, Adapalene Topical retinoids encompass a group of powerful, comedolytic, anti-comedogenic, and antiinflammatory agents. They are powerful keratolytics, targeting both primary and secondary prevention of comedones [ 6 ]. Retinoids exert their effects through nuclear receptor families RAR (retinoic acid receptors) and RXR (retinoic X receptors), subsequently inducing retinoic acid-responsive target gene expression [ ]. Both receptor families are ligand-dependent transcription factors and consist of three receptor subtypes (α, β, and γ), encoded by three separate genes [ 21 ]. Although RARα is ubiquitous in embryonic skin, RARγ is the most abundant RAR in human epidermis, cultured keratinocytes, and dermal fibroblasts [ 21, 22 ]. Retinoids also inhibit expression of certain genes by downregulating other transcription factors, notably AP-1 and NF-IL6 [ 19 ]. This inhibitory action may be partly responsible for the anti-proliferative and anti- inflammatory actions of retinoids [ 21 ]. Prior to binding with nuclear RARs, retinoids must first bind to intracellular proteins. Cellular retinoic acid proteins (CRABP I and II) are present in the skin. Intracellular retinoid concentrations are dependent upon CRABP, primarily type II [ 19 ]. However, CRABP II is not essential for biologic retinoid activity as adapalene does not bind to it; interestingly, it may play a role in retinoid- induced epidermal irritation [ 21 ]. Through this genetic regulation, retinoids are thought to affect cellular differentiation and proliferation [ 20 ]. Experimental studies, some using primary neonatal mouse epidermal keratinocyte cultures, have confirmed this concordant decrease in keratinocyte differentiation and proliferation [ 23 ]. Retinoids also regulate activity of keratinocyte adhesion and cohesion molecules, resulting in breakdown and obliteration of the horny plug [ 22 ]. Mechanisms of action are numerous and include normalization of epidermal proliferation and differentiation, inhibition of neutrophil chemotaxis, expression of TLRs involved in A. Alikhan and H.I. Maibach immunomodulation, and anti-inflammatory effects via inhibition of prostaglandins, leukotrienes, and IFN-gamma release. Retinoids may exert an anti- inflammatory response by inhibiting the release of proinflammatory cytokines (interleukins 12 and 8 and tumor necrosis factor) via downregulation of monocyte Toll-like receptors (TLR) [ 24, 25 ]. Interestingly, P. acnes acts through TLR-2 to stimulate proinflammatory cytokine production [ 21, 26 ]. Combination therapy involving topical retinoids and antimicrobials allows targeting of different pathophysiologic factors in acne vulgaris [ 19 ]. This combination approach is optimal in patients with both inflammatory and comedonal lesions given the different but complementary mechanisms of action present in both agents [ 19 ]. Additionally, topical retinoid therapy, by weakening the horny layer barrier, may increase skin permeability, enhancing penetration of antimicrobial agents. Increased cell turnover of follicular epithelium enables greater access of antibiotic into the canal which houses P. acnes. A large retrospective, vehicle-controlled study of inflammatory acne (mild/moderate to severe) demonstrated clinically significant improvements with tazarotene 0.1 % gel and 0.1 % cream, adapalene 0.1 % gel, and tretinoin 0.1 % microsponge treatment [ 25 ]. These treatments along with tretinoin % gel produced significant improvement in global acne response [ 25 ]. Among these, tazarotene 0.1 % cream and 0.1 % gel showed a greater frequency of clinically significant improvement when compared to adapalene or tretinoin gel [ 25 ]. Between-retinoid comparisons demonstrated tazarotene to have the greatest efficacy on the overall inflammatory acne severity and global response scales [ 25 ] (Table 54.2 ). The major drawback of topical retinoids is local skin irritation and acne exacerbation, also termed retinoid flare, which may occur during the first month of treatment and last several weeks [ 6 ]. This flare-up may be secondary to release of follicular inflammatory factors after topical retinoid treatment [ 27 ]. Another limiting factor of retinoids, particularly oral agents, is their teratogenicity, resulting in severe fetal malformations if exposure occurs

5 54 Keratolytic Treatment during the first trimester. Malformations include microtia/anotia, conotruncal heart defects and aortic-arch abnormalities, thymic defects, and central nervous system malformations [ 28 ]. Several case reports suggest these effects may not be limited to oral retinoid therapy, with limb reduction defects and ear malformations reported with maternal use of topical retinoids [ 29, 30 ]. However, Jick et al., in a retrospective study, did not substantiate this suggestion, and the clinical issue remains sub judice [ 31 ] Tretinoin The first topical retinoid to be studied, tretinoin binds with high activity to all three RAR subtypes and to CRABP, and with low activity to RXRs. It is an effective comedolytic agent, which increases epithelial cell turnover and modulates abnormal keratinization (that leads to microcomedone formation). It also acts in an anticomedogenic manner, preventing formation of microcomedones [ 21 ]. Mills and Kligman, using a cyanoacrylate follicular biopsy technique, demonstrated a profound microcomedone reduction in 8 and 12 weeks [ 32 ]. From an immunological perspective, in vitro studies have demonstrated that tretinoin downregulates and decreases surface expression of TLR-2 and CD14 mrna, preventing secretion of interleukins (perhaps IL-1α, 12, and 8), tumor necrosis factor, and interferon-γ, as well as production of free radicals [ 22, 24 ]. In a large multicenter trial, % tretinoin cream significantly reduced inflammatory and non-inflammatory acne lesions compared with vehicle by week 12; side effects included eruption, dry skin, and exfoliation [ 33 ]. Polyolprepolymer-2, which localizes drug molecules in upper skin layers, preventing deep penetration, may diminish adverse cutaneous reactions [ 33 ]. A large study demonstrated earlier favorable global assessments with % tretinoin with PP-2 cream vs. a % tretinoin cream, but no significant difference in side effects [ 33 ]. PP-2 forms a liquid reservoir of polymer and solubilized drug on the skin surface, slowing percutaneous absorption and transcellular cutaneous diffusion, potentially 401 targeting folliculo- infundibular delivery in the process [ 34 ]. Some clinical trials have demonstrated reduced irritation as less drug penetrates the skin [ 34 ] (Table 54.2 ). The Microsponge Delivery System found in 0.1 % microsphere gel also helps reduce drug release rate and increase drug retention in the SC, inhibiting deeper penetration [ 6 ]. Tretinoin is trapped within porous copolymer microspheres, which selectively localize to the follicle, releasing tretinoin over time and producing less irritation (than the standard % cream) due to reduced concentration on the skin [ 22 ]. A study examining tretinoin gel microsphere 0.04 % compared to vehicle demonstrated significant reduction in total, inflammatory, and noninflammatory acne by week 12 [ 24 ]. About 90 % of subjects reported none or only mild adverse events; there were no significant differences in tolerability between the treatment and control groups at week 12 [ 24 ]. Moreover, tretinoin 0.1 % microsphere gel significantly reduces facial shine at 3 and 6 h posttreatment when compared with tretinoin % cream [ 35 ]. Numerous trials have demonstrated the efficacy of tretinoin in various forms of acne. Patience is advised as full effect may take 2 4 months; adherence is essential as tretinoin serves to control rather than cure acne. Recently, a hydrogel containing 1 % clindamycin and % tretinoin was found to be more efficacious in treating inflammatory and noninflammatory acne lesions than either agent alone or vehicle [ 36 ]. These results were confirmed by two large studies; adverse effects were similar in frequency and severity to tretinoin alone [ 36 ]. Furthermore, a BPO 6 % cleanser tretinoin 0.1 % microsphere gel demonstrated significantly greater inflammatory lesion reduction than tretinoin alone [ 37 ]. In a split-face ultrastructural study comparing 0.1 % tretinoin to emollient cream, an 80 % decrease in microcomedones was demonstrated on the tretinoin side at 12 weeks [ 1 ]. Employing the technique of skin surface biopsy, microscopic examination of comedones showed progressive loss of the cohesiveness and significant alterations in epithelial structure; thick keratinous

6 402 A. Alikhan and H.I. Maibach Table 54.2 Controlled clinical trials comparing keratolytic agents in acne vulgaris treatment Authors Comparison Lesions Placebo Results: brief Lucky et al. (1998) Cunliffe et al. (1998) Bershad et al. (2002) Lookingbill et al. (1997) Shalita et al. (1999) Leyden et al. (2005) Leyden et al. (2005) Galvin et al. (1998) % tretinoin gel vs % tretinoin gel containing polyolprepolymer-2 vs. vehicle over 12 weeks Meta-analysis of five 12-week-long randomized trials comparing 0.1 % adapalene gel vs % tretinoin gel 12-week trial comparing 0.1 % tazarotene gel once daily vs. 0.1 % tazarotene gel twice daily in short-contact (<5 min) application vs. vehicle twice daily Combined results of two double-blind, 11-weeklong, randomized trials comparing 1 % clindamycin/5%benzoyl peroxide gel, 1 % clindamycin gel, 5 % benzoyl peroxide gel, and vehicle Multicenter, controlled, 12-week-long trial comparing 0.05 % tazarotene gel vs. 0.1 % tazarotene gel vs. vehicle Retrospective, vehicle-controlled, photographic assessment comparing tazarotene 0.1 % gel, adapalene 0.1 % gel, tretinoin 0.1 % microsponge, tretinoin % gel, and tazarotene 0.1 % cream Combined results of two double-blind, randomized, 12- or 15-week-long trials comparing % tretinoin/1 % clindamycin hydrogel with each agent alone and vehicle Two controlled, randomized studies comparing 0.1 % adapalene gel with a total of six different tretinoin formulations and petrolatum in terms of tolerability after 3 weeks All types Vehicle Both treatments significantly more effective than vehicle. Polyolprepolymer-2 treatment has significantly less peeling and drying. All types Vehicle only in one study Both treatments had equivalent efficacy in reducing lesion count; adapalene works more rapidly with greater tolerability. All types Vehicle Both groups were comparable and significantly more efficacious than vehicle All types Vehicle All three treatments were significantly better than vehicle. Combination gel was significantly superior to two individual agents in global improvement and reduction of inflammatory lesions; it was also better than clindamycin in treating noninflammatory lesions. All types Vehicle At 12 weeks, both tazarotene gels produced significant success rates and decreased total and non-inflammatory lesions. Only 0.1 % gel significantly reduced inflammatory lesions; it was also significantly more efficacious than 0.05 % gel, with decrease of total and non-inflammatory lesions and success rates Inflammatory Vehicle All treatments had significant improvement in global response compared to vehicle. All except tretinoin gel had clinically significant improvement in inflammatory acne. Between-retinoid comparisons demonstrated tazarotene to have significantly greater incidences of clinically significant improvement compared to adapalene or tretinoin gel. All types Vehicle All treatments were more efficacious than vehicle. Combination treatment was more efficacious in treating inflammatory and non-inflammatory lesions compared to either agent alone, and its side-effect profile was similar to tretinoin. Petrolatum Adapalene had a better tolerability profile than tretinoin 0.1 % cream, tretinoin 0.05 % cream, tretinoin % cream, tretinoin 0.01 % gel, tretinoin % gel, and tretinoin 0.1 % gel microsphere, and an equivalent tolerability to petrolatum.

7 54 Keratolytic Treatment 403 Chalker et al. (1987) Multicenter, controlled study comparing Iso 0.05 % gel twice daily for up to 14 weeks with its vehicle Mills et al. Three double-blind, 8-week-long studies comparing 2.5 % benzoyl peroxide, 5 % benzoyl peroxide, 10 % benzoyl peroxide, and vehicle Katsambas et al. (1989) 3 month double-blind study comparing 20 % azelaic acid cream to its vehicle Shalita (1981) 12-week trial comparing 0.5 % salicylic acid in an alcoholic detergent solution (Stri-Dex medicated pads) vs. placebo (pads soaked in buffered water) Spellman et al. (1998) 12-week double-blind, randomized trial comparing azelaic acid 20 % cream glycolic acid solution with tretinoin % cream and vehicle lotion Thiboutot et al. (2007) 12-week randomized, double-blind trial comparing combination adapalene 0.1 % gel BPO 2.5 % gel vs. adapalene 0.1 % gel vs. BPO 2.5 % gel vs. vehicle Thiboutot et al. (2006) 12-week randomized vehicle-controlled study comparing 0.3 % adapalene gel to 0.1 % adapalene gel Mild to moderate acne Mild to moderately severe inflammatory acne Moderate inflammatory acne Mild to moderate acne Mild to moderate acne Inflammatory and noninflammatory Inflammatory and noninflammatory Vehicle Iso gel was significantly more effective in reducing inflammatory lesions after 5 weeks, and non- inflammatory lesions and acne severity grade after 8 weeks. Two Iso patients dropped out due to skin irritation. Vehicle 2.5 % BPO formulation was more effective than vehicle and equivalent to 5 % and 10 % concentrations in reducing the number of inflammatory lesions; 2.5 % formulation had less desquamation, erythema, and burning than the 10 % preparation, but tolerability was equivalent to the 5 % gel. Vehicle At 2 and 3 months, azelaic acid showed significant improvement in reducing inflammatory lesions compared to its vehicle. Azelaic acid showed significant comedone reduction compared to its vehicle in all visits. There was also a significant difference in overall evaluation. The only significant side-effect difference was burning sensation. Vehicle The treatment group experienced significant reductions in inflammatory lesions and open comedones compared to the placebo group. The treatment group also had significantly more good or excellent responses than the placebo group. Vehicle Both groups experienced significant lesion reduction and global improvement compared to vehicle. The combination treatment was significantly better in decreasing inflammatory lesions than tretinoin, while producing significantly fewer adverse effects. Both treatments had equivalent non-inflammatory lesion reduction. Vehicle The combination was significantly more effective than the monotherapies in investigator s global assessment and reduction of inflammatory, non-inflammatory, and total lesions. Tolerabililty of combination treatment was similar to adapalene monotherapy. Vehicle Adapalene 0.3 % gel was significantly superior to 0.1 % gel in various efficacy assessments, total lesion reduction, and inflammatory lesion reduction. Tolerability profile was similar in both concentrations.

8 404 plugs infested with bacteria were transformed into a few wispy layers of keratin with few bacteria [ 1 ]. Using transmission electron microscopy, it was possible to track microcomedones with compact, adherent stratum corneum morphing into spongy, loosely adherent layers of corneocytes [ 1 ]. From a combination therapeutic standpoint, the alteration in SC integrity incurred during tretinoin treatment may enhance penetration of other agents such as BPO and topical antibiotics (see paragraph above) [ 1 ]. Surprisingly, topical tretinoin has poor percutaneous absorption and does not alter systemic retinoid levels, which stay constant despite application [ 6 ]. Side effects include peeling, erythema, dryness, burning, and itching [ 6, 22 ]. Pustular eruptions may occur initially, but are alleviated with concomitant erythromycin [ 22 ]. Additionally, tretinoin may bring out the postinflammatory darkening which occurs in healing acne of darkerskinned patients [ 27 ]. Tretinoin- induced skin irritation may be explained by a flexible chemical structure, resulting in nonselective action and the ability to activate numerous pathways, resulting in various biological effects [ 21 ]. Applying a moisturizing cream along with topical tretinoin or oral tretinoin significantly improves skin dryness, roughness, and desquamation, increasing subjective skin comfort [ 38 ]. Adverse effects are exacerbated by sunlight, extremes in weather, oxygen, and comedogenic skincare products. They can be reduced by spacing out applications and/or diminishing frequency and concentration of the product [ 22 ]. Additionally, tretinoin should not be used with BPO (an oxidizing agent), which can result in degradation and deactivation. Despite some evidence to the contrary, topical tretinoin is not advised during pregnancy and lactation. Potential for systemic exposure and excretion in breast milk has not been adequately studied Isotretinoin Introduced in the late 1970s, oral isotretinoin (Iso) remains a mainstay for severe, recalcitrant nodulocystic acne unresponsive to topical therapy and systemic antibiotics [ 19 ] (see relevant Chap. 63 ). Its efficacy extends beyond correction of hyperkeratinization to include actions on the sebaceous gland (decreases size and secretion), anti-comedogenic properties, and reduction of P. acnes via creation of an unfavorable follicular environment [ 39 ] Tazarotene A. Alikhan and H.I. Maibach Tazarotene, a topical acetylenic retinoid indicated in both psoriasis and acne vulgaris, is hydrolyzed by keratinocyte esterases to tazarotenic acid, its active metabolite [ 19 ]. It binds all three RARs but activates gene expression only in RAR β and γ; downregulation of AP-1 and lack of RXR binding are observed [ 19, 21, 40 ]. In doing so, it normalizes the keratinization pattern and decreases coherence of follicular keratinocytes, manifesting both comedolytic and anti- comedogenic properties [ 20 ]. Tazarotene also has anti-inflammatory properties [ 20 ]. In the systemic circulation, tazarotenic acid is rapidly converted to inactive sulfur-oxidized forms, resulting in limited exposure [ 40 ]. A randomized, double-blind, vehiclecontrolled study demonstrated that 0.05 % and 0.1 % tazarotene gels significantly decrease total lesions, decrease non-inflammatory lesions, and produce a higher success rate than vehicle at 12 weeks [ 20 ]. Moreover, 0.1 % gel was significantly more efficacious than 0.05 % gel and demonstrated a significant decrease in inflammatory acne at 12 weeks [ 20 ]. A more recent randomized trial comparing tazarotene 0.1 % cream to adapalene 0.1 % cream demonstrated tazarotene to be significantly and rapidly more effective in reducing comedone count and producing global improvement, with no significant difference in side effects at 12 weeks [ 20 ]. Although only noninflammatory lesions could be compared in this study, other studies have demonstrated efficacy in inflammatory lesions as well [ 41 ]. Furthermore, a large clinical trial suggests that even short- contact application (>5 min) once daily for 12 weeks produces significant reduction in both inflammatory and non-inflammatory acne lesions [ 42 ]. With our armament of acne medications, standard acne treatment now involves using multiple

9 54 Keratolytic Treatment agents, each with its own mechanism of action. To that end, a multicenter, double-blind, randomized trial found a daily BPO 5 %/clindamycin 1 % gel tazarotene 0.1 % cream regimen to be more effective than daily tazarotene monotherapy in reducing comedo count and inflammatory lesion count (in those with 25 baseline inflammatory lesions), with a similar, if not slightly improved, tolerability profile [ 43 ]. Currently, only the 0.1 % formulation of tazarotene is approved by the FDA for acne; it is primarily used in cases of acne refractory to tretinoin and adapalene treatment [ 6 ]. Nonetheless, animal studies have demonstrated that tazarotene has low systemic absorption with no toxic effects even at high topical doses [ 40 ]. Additionally, after 12 weeks of normal tazarotene application, serum samples from 22 subjects demonstrated limited systemic exposure with most below the quantifiable limit (<0.05 ng/ml) [ 20 ]. Local side effects typically occur; these include itching, burning, irritation, and erythema [ 6, 20 ]. In fact, tazarotene is thought to be the most irritating of the topical retinoids. In the Bershad study cited above, half of patients applying tazarotene for only 2 10 min daily reported local skin irritation. These side effects are most common during the first 2 weeks of therapy; cream formulations, alternate-day application, and short-contact therapy can curtail side effects [ 22 ]. Despite little evidence of fetal malformations or spontaneous abortions, topical tazarotene is an FDA Pregnancy Category X drug; little is known about its excretion in breast milk. Of all topical retinoids in acne treatment, it is the only one requiring sufficient contraception in women of childbearing age [ 22 ] Adapalene Adapalene, a derivative of retinoic acid, binds selectively to RAR β and γ in vitro but can activate gene expression through all three RARs; it does not bind CRABP II, but increases CRABP II mrna [ 19, 21 ]. It has comedolytic, anti- proliferative, and anti-inflammatory properties [ 21 ]. Its anti-inflammatory action stems 405 from inhibitory effects on PMN chemotactic response, free radical production, and Toll-like R2 receptors expressed by perifollicular monocytes [ 22 ]. It also inhibits production of leukotrienes by 5- and 15-lipoxygenase pathways [ 21, 22 ]. Furthermore, adapalene may have a dosedependent response, with 0.3 % statistically superior to 0.1 % in several different measures, while demonstrating equivalent tolerability [ 44 ]. A meta-analysis of five large randomized trials (composed of 900 patients) demonstrated equivalent acne reduction, quicker onset of action (significant at 1 week), and fewer side effects in 0.1 % adapalene gel compared to % tretinoin gel [ 45 ]. Side-effect profile was significantly better in regard to scaling, erythema, dryness, immediate and persistent burning, and immediate pruritus [ 45 ]. With its three aromatic rings, adapalene demonstrates higher stability than tretinoin in the presence of light, dark, and BPO [ 10 ]. In a study comparing the chemical stability of 0.1 % adapalene gel/10 % BPO and % tretinoin gel/10 % BPO after 24 h of actinic light exposure, approximately 100 % of adapalene remained intact versus only 20 % of tretinoin [ 46 ]. In a study examining two 21-day-long trials, adapalene 0.1 % gel demonstrated greater tolerability and significantly less irritation than tretinoin 0.1 % cream, tretinoin 0.05 % cream, tretinoin % cream, tretinoin 0.01 % gel, tretinoin % gel, and tretinoin 0.1 % gel microsphere [ 47 ]. Furthermore, in both studies, adapalene 0.1 % gel was no more irritating than the petrolatum control [ 47 ]. Favorable tolerability to adapalene may be explained by its receptor specificity, neutral molecular structure, and lack of breakdown products. A study comparing 0.1 % adapalene gel, 5 % BPO, and a 0.1 % adapalene/5 % BPO combination demonstrated no significant difference between the groups in efficacy or side effects (erythema, dryness, or burning) [ 48 ]. Additionally, all three treatments were significantly effective in reducing inflammatory and non-inflammatory acne lesions [ 48 ]. Adapalene reduced non-inflammatory lesion counts by %, inflammatory lesion counts by %, and total lesion counts by % [ 48 ]. A more recent study testing a

10 % adapalene/2.5 % BPO combination gel against vehicle and individual monotherapies demonstrated combination therapy to have faster onset of action, significantly greater reductions in all lesion types, and no increase in adverse effects compared to monotherapy [ 26 ]. Adapalene s particle size (diameter between 3 and 10 microns), along with its lipophilic properties, results in optimal follicular duct penetration [ 21 ]; furthermore, after 5 min of exposure, 14-C-labeled adapalene applied to human skin in vitro demonstrates radiosensitivity in the pilosebaceous units, with sparse activity in the SC and epidermis [ 10 ]. Adverse effects, including erythema, scaling, dryness, pruritus, and burning, occur mainly during the first month and decrease thereafter [ 10 ]. Nevertheless, in comparative trials, adapalene demonstrates a more favorable side-effect profile than its relative, tretinoin. Cyanoacrylate strip data suggest that application of adapalene 0.1 % gel every other day may be effective maintenance therapy in microcomedone reduction, resulting in decreased exposure [ 49 ] Azelaic Acid Azelaic acid, a naturally occurring, saturated C9-dicarboxylic acid, modifies epidermal keratinization (cytostatic), combats both aerobic and anaerobic bacteria (reducing P. acnes proliferation), and exhibits anti-inflammatory activity [ 19, 50 ]. This anti-inflammatory activity may potentially be mediated through inhibition of hydroxyland superoxide radical production by neutrophils [ 51 ]. Contributing to its anti-inflammatory properties, in vitro, azelaic acid is an oxygen-free radical scavenger, inhibiting hydroxylation of aromatic compounds and arachidonic acid peroxidation [ 50, 52 ]. To date no published reports of azelaic acid bacterial resistance have surfaced. In their review article, Fitton and Goa describe that azelaic acid, in vivo, affects differentiation of human keratinocytes by decreasing synthesis of filaggrin (keratin filament aggregating protein) [ 52 ]. This results in alterations of epidermal keratinization, including reductions in the number A. Alikhan and H.I. Maibach and size of keratohyaline granules and tonofilament bundles in the SC, abnormal tonofilament arrangements, intercellular edema, swollen mitochondria, enlargement of RER, and reductions in the thickness of the horny layer in infundibular areas [ 52, 53 ]. Azelaic acid functions in a cytostatic, anti-proliferative manner on keratinocytes, affecting both early and terminal phases of keratinocyte differentiation, with primary effects on mitochondria and RER [ 53 ]. In only 2 weeks of topical treatment, 200 μl of 20 % azelaic acid attenuated tetradecaneinduced comedo formation in the rabbit ear, a model of follicular epithelial hyperplasia [ 52, 54 ]. These microscopic and experimental findings indicate keratolytic and anti-comedogenic properties for azelaic acid via normalization of disordered keratinization of the follicular infundibulum. This is further evidenced by reduction in non-inflammatory acne lesions after topical treatment (see studies below). Cyanoacrylate skin surface biopsies have demonstrated significant reductions (>50 %) in comedo count after 4 months of twice-daily 20 % azelaic acid treatment when compared to vehicle [ 55 ]. Additionally, comedone reduction was similar in magnitude to that of 0.05 % retinoic acid cream [ 55 ]. Azelaic acid has demonstrated significant inflammatory and non-inflammatory acne reduction in numerous studies, even when compared to tretinoin, BPO, erythromycin, and tetracycline [ 50, 51 ]. Comparing 20 % azelaic acid to 0.05 % tretinoin over 6 months, one group found statistically equivalent comedone and total lesion reduction and similar overall improvement [ 56 ]. However, tretinoin use led to increased erythema, scaling, and irritation-induced discontinuation than did azelaic acid [ 56 ]. Another trial comparing 20 % azelaic acid with 5.0 % BPO demonstrated a more rapid initial effect with BPO but similar results for global response and inflammatory lesion reduction by 4 months [ 57 ]. Keeping with the theme, azelaic acid demonstrated milder, more transient adverse events than BPO [ 57 ]. Pooling together results of four trials, Mackrides et al. determined that after 6 months of treatment, 65 85% of patients experienced a 50% decrease in number of lesions (good-toexcellent clinical response) (Table 54.3 ).

11 54 Keratolytic Treatment 407 Table 54.3 Uncontrolled clinical trials comparing keratolytic agents in acne vulgaris treatment Authors Comparison Lesions Placebo Results Akman et al. Moderate and None (2007) severe Leyden et al. (2001) Katsambas et al. (1989) Cavicchini et al. (1989) Korkut et al. (2005) Tanghetti et al. (2006) Isotretinoin for first 10 days of each month for 6 months vs. each day in first month and first 10 days of each month for 5 months vs. daily for 6 months 10-week trial comparing 5 % benzoyl peroxide/1 % clindamycin, 5 % benzoyl peroxide, and 5 % benzoyl peroxide/3 % erythromycin 6-month trial comparing 20 % azelaic acid cream and 0.05 % tretinoin cream 6-month single-blind trial comparing 20 % AA cream vs. 5 % BPO gel Open-labeled, prospective study comparing 0.1 % adapalene gel, 5 % BPO lotion, or combination of 0.1 % adapalene gel +5 % BPO treatment Multicenter, randomized, 12-week-long trial comparing tazarotene 0.1 % cream once daily vs. tazarotene 0.1 % cream once daily + clindamycin 1 %/BPO 5 % gel once daily Moderate to moderately severe Comedonal but patients had both Papulopustular acne Non-inflammatory and inflammatory Moderate-tosevere inflammatory acne Acne scores were significantly lower for all groups posttreatment. No difference in groups for total lesions but daily was more effective than intermittent for severe acne. Daily treatment also demonstrated significantly greater SE profile. None All treatments had significantly reduced non-inflammatory acne reduction. BPO/ clindamycin had significantly greater reduction in inflammatory lesions and greater overall improvement rated by physicians and patients compared to BPO. Efficacy was statistically similar to BPO/erythromycin. SE of BPO/ clindamycin similar to BPO alone. None Similar decreases in comedone and total lesion count as well as overall response rate. AA had significantly fewer side effects. None BPO more rapid initially but by 4 months equal inflammatory lesion reduction and overall response; additionally, BPO had more intense and longer-lasting side effects None All three treatments were effective in treating non- inflammatory and inflammatory lesions, but there was no significant difference between them in efficacy or side effects. None Combination therapy resulted in significantly greater comedone reduction than tazarotene alone. In patients with >25 inflammatory lesions, combination therapy also resulted in a significant inflammatory lesion reduction. Both were equally well tolerated. A 12-week controlled study of azelaic acid 20 % vs. vehicle demonstrated significant improvement in mild-to-moderate acne [ 56 ]. During the 3 months, inflammatory lesions decreased by 72 %, comedones by 55.6 %, and 64 % of treated patients had good-to-excellent improvement [ 56 ]. Symptomatic improvement is typically observed within 4 weeks of commencing therapy [ 6 ]. Transient side effects lasting 2 4 weeks have been described [ 50 ]. These include burning, erythema, dryness, scaling, pruritus, and hypopigmentation. Nonetheless, there is some evidence that azelaic acid may improve the overall wearability (feel, smoothness, evenness, and ease of application) of a facial foundation [ 51 ]. After application of azelaic acid, 3 5 % remains on the SC, up to 10 % penetrates into the epidermis and dermis, and 4 % is absorbed systemically (although this can double with gel formulations) [ 6 ]. Nevertheless, baseline serum and urine levels are not altered by topical usage and are primarily dependent on dietary intake of whole grain cereals and animal products [ 6 ]. It is

12 408 an FDA Pregnancy Category B drug as animal studies have shown favorable results; meaningful human studies are lacking. Despite efficacy as a monotherapy, a large randomized trial demonstrated that azelaic acid functions better in combination [ 51 ] Salicylic Acid A core component in many OTC acne treatments, salicylic acid (SA) is a widely available topical keratolytic agent. It may have a profound structural effect on the SC, resulting in disruption of intercorneocyte cohesion and subsequent desquamation [ 58 ]. Dissolution of intercellular cement is further supported by scanning electron microscopy, which has demonstrated marked squamous cell separation in salicylic acid-treated human skin [ 59 ]. Bashir et al. demonstrated the keratolytic properties of salicylic acid using a novel tape stripping/protein assay method described later (see Table 54.4 ). Mills and Kligman using cyanoacrylate follicular biopsy demonstrated significant decreases in microcomedone count. Although various concentrations exist ( %), 2 % is the maximum strength allowed by the FDA in OTC products. In five human subjects, microcomedo formation was induced via 10 % coal tar distillate ointment at four sites on the back; formation was confirmed by cryanoacrylate biopsy [ 60 ]. At each site, subjects were treated with one of three different concentrations of SA (0.5 %, 1 %, and 2 %) twice daily for 2 weeks and one site was left untreated [ 60 ]. Ultimately, lesions were rebiopsied and examined microscopically; all three concentrations displayed tremendous comedolytic activity, with the 2 % preparation superior to the lower concentrations [ 60 ]. Microcomedo quantitative reduction reached nearly 50 % in the 2 % SA group [ 60 ]. Two 12-week studies comparing 0.5 % and 2 % SA pads to placebo pads demonstrated significant efficacy in reducing inflammatory acne, non-inflammatory acne, and total lesions, while producing significantly higher proportions of good-to-excellent overall treatment assessments Table 54.4 Studies using colorimetric protein assay to measure keratolytic potential Authors Drug Result Bashir et al. (2004) Waller et al. (2005) Aqueous solution 2 % salicylic acid 3 formulations Aqueous solutions of 0.05 % all-trans RA, 2 % BPO, and 2 % SA A. Alikhan and H.I. Maibach Statistically significant mass of SC removed after 6 h and 20 tape strips in all three experimental groups (salicylic acid ph 3.3, salicylic acid ph 3.3 w/menthol, salicylic acid ph 6.95) compared to vehicle, untreated, and untreated but occluded groups. Statistically significant mass of SC removed after 6 h and 25 tape strips in all three experimental groups compare to vehicle, untreated, and occluded groups. The first ten tape strips from SA group removed more protein than the other groups; at strips, treatments were comparable; at strips, protein removed from BP sites was greatest. [ 60 ]. In one study, 60 % of patients using 2 % and 0.5 % SA pads experienced a % decrease in total lesion count, compared to 2 % of patients receiving placebo [ 60 ]. In both studies side effects were minimal and well tolerated [ 60 ]. In a study comparing medicated pads with 0.5 % salicylic acid in an alcoholic detergent (Stridex ) to placebo (pads soaked in buffered water), the treatment group experienced a 54 % reduction in inflammatory acne compared to 29 % in the placebo group [ 61 ]. Reductions of open comedones and total lesions were also significant compared to placebo [ 61 ]. A 12-week study found 2 % SA cream superior to 5 % BPO cream in reducing closed comedones, open comedones, inflammatory lesions, and total lesions [ 60 ]. A 4-week crossover study comparing a 2 % SA acne cleanser to a 10 % BPO wash demonstrated that only patients treated with the SA cleanser had a significant decrease in comedonal lesions [ 62 ]. Stated differently, both groups demonstrated significant improvement in comedonal count when treated with SA, whereas

13 54 Keratolytic Treatment BPO treatment either worsened or insignificantly improved comedonal quantity [ 62 ]. Recently, a small study comparing a 2 % SA/1 % clindamycin combination with placebo demonstrated a significant reduction in inflammatory and noninflammatory lesions, with 71 % of subjects reporting improvement after 8 weeks (compared to 11 % of placebo group) [ 63 ]. Salicylic acid is well absorbed as evidenced by numerous studies; its bioavailability in topical application varies according to duration of contact [ 8, 64 ]. One study estimated bioavailabilities for topically applied SA at 57.6 and 44.0 % for hydroalcoholic and cream delivery vehicles, respectively [ 65 ]. The same study also demonstrated the hydroalcoholic vehicle to have superior peak plasma SA concentrations and earlier time to peak when compared with a cream vehicle [ 65 ]. In a related study, absorption was enhanced significantly in a mineral oil/petrolatum ointment compared to an ointment containing polyethylene glycol, glycerol, petrolatum, and 10 % urea (Kerasal) [ 66 ]. New chemical peels using 30 % salicylic acid in polyethylene glycol vehicle have demonstrated efficacy and safety, with marked reductions in comedones and papules [ 67 ]. Polyethylene glycol may be a more tolerable vehicle than the commonly used ethyl alcohol in salicylic acid chemical peels [ 67 ]. Although local skin irritation (e.g., peeling) at concentrations >2 % is common, systemic toxicity is rare [ 6 ]. However, if applied to large areas of the body for prolonged periods of time, salicylate toxicity, toxic inner ear damage, and hypersensitivity reactions are plausible [ 6 ]. To that end, these manifestations are uncommon in appropriate acne therapy. Like several other keratolytic agents, salicylic acid is an FDA Pregnancy Category C agent, with unknown effects on breastfeeding Sulfur Sulfur, a yellow nonmetallic element, has many dermatological indications, including but not limited to acne vulgaris, rosacea, seborrheic dermatitis, and dandruff [ 68 ]. Once a very 409 common ingredient in acne treatments, sulfur has recently fallen out of favor, partly due to its pungent odor [ 69 ]. In the acne arena, sulfur is thought to be keratolytic and bacteriostatic. After application to skin, sulfur reacts with cysteine in the SC, resulting in reduction to hydrogen sulfide [ 68 ]. Hydrogen sulfide is thought to break down keratin and inhibit growth of P. acnes [68 ]. Appearing in a variety of vehicles (lotions, creams, soaps, ointments), it appears to be more efficacious when used in combination with other drugs, namely, BPO and sodium sulfacetamide [ 6 ]. Clinical trials have demonstrated that lotions containing sulfur 5 % with sodium sulfacetamide 10 % have resulted in reduction of inflammatory lesions, comedones, and seborrhea [ 68 ]. Interestingly, this combination is also effective in acne rosacea, an inflammatory skin disorder involving the cheeks, nose, and forehead [ 68 ]. In clinical trials, sulfur and sulfur/sodium sulfacetamide have demonstrated superiority in reducing overall severity and inflammatory lesion count when compared to Metronidazole gel and oral Tetracycline [ 68 ]. Sulfur penetrates skin; it is detectable in the epidermis at 2 h, throughout the skin in 8 h, and completely undetectable by 24 h [ 68 ]. Additionally, there is no evidence of systemic absorption in intact skin [ 68 ]. Early studies, using human and animal subjects, demonstrated that elemental sulfur, while having a positive role in diminishing papules and pustules, may possibly induce comedone formation [ 68, 70 ]. Later studies did not confirm these results despite identical treatment conditions [ 68, 71 ]. Rare, transient side effects include dryness, itching, and malodorous skin. Nonetheless, given a lack of knowledge, it is an FDA Pregnancy Class C drug with nothing known regarding breast milk excretion Glycolic Acid Glycolic acid, a naturally occurring organic acid (α-hydroxy acid), is a component in many cosmetic formulations. In the context of acne, research has been conducted examining glycolic acid chemical peels. Superficial chemical peels may serve as valuable adjuvant therapy in acne.

14 410 Various chemical preparations have been employed, all of which result in a partialthickness skin injury, or peel [ 72 ]. Comedones are removed after only two or three peels, and the procedure may be repeated every 2 or 3 weeks [ 73 ]. Between peels, low concentrations of glycolic acid may be used as a daily cleanser to prevent re-occlusion of follicles [ 73 ]. Glycolic acid, a hydrophilic compound with keratolytic properties, is present in many peel formulations due to its desquamating efficacy. According to Kessler et al., this desquamation reduces corneocyte cohesion, keratinocyte plugging, and enables the extrusion of inflammatory contents. Glycolic acid mainly effects deeper, newly forming levels of SC, leading to a sheet-like separation [ 74 ]. The exact mechanism of action may be due to inhibition of ionic bond forming enzymes involved in creating sulfated and phosphorylated mucopolysaccharides, glycoproteins, sterols, and lipid phosphatides [ 74 ]. This results in fewer electronegative groups on the outer walls of keratinocytes and corneocytes, effectively diminishing cohesion forces [ 74 ]. This diminished cohesion loosens keratinocytes in the follicular epithelium, resulting in breakdown of comedones, inhibition of comedone formation, and unroofing of pustules [ 73 ]. A randomized split-face prospective clinical trial comparing glycolic acid to Jessner s solution (salicylic acid, lactic acid, and resorcinol) demonstrated significant acne improvement in both after three treatment sessions. Furthermore, glycolic acid was associated with significantly less exfoliation than Jessner s solution, resulting in more facile makeup application and suggesting a more favorable side-effect profile [ 75 ]. In a similar study comparing glycolic acid and salicylic acid peels, both were equally effective by the second treatment; however, salicylic acid demonstrated greater sustained effectiveness and a more favorable side-effect profile [ 72 ]. A study examining 35 % and 50 % glycolic acid peels on Asian patients found significant resolution of comedones, papules, and pustules, decreased follicular pore size, acne scar improvement, and few side effects [ 76 ]. A combination of azelaic acid 20 % cream glycolic acid lotion was compared with tretinoin % in a 12-week, vehicle-controlled study [ 27 ]. The azelaic acid glycolic acid treatment produced significantly greater inflammatory lesion reduction and equivalent non- inflammatory lesion reduction, while causing less dryness, scaling, and erythema than tretinoin [ 27 ] Resorcinol A. Alikhan and H.I. Maibach Due to limited information about resorcinol, all of the following information was extracted from a review article by Karam in 1993 [ 77 ]. No longer significantly used in the USA, resorcinol, an isomer of hydroquinone and a relative of phenol, is soluble in water, ether, and alcohol. It is a reducing agent with antibacterial and keratolytic properties. Even at low concentrations, it can disrupt hydrogen bonds of keratin. A 50 % resorcinol paste is used in other countries for chemical peels. It is used to treat the postinflammatory hyperpigmentation, erythema, and shallow scars resulting from facial, chest, upper back, and buttocks acne. Contraindications include pregnancy and skin type VI, due to inadequate data regarding complications. Side effects include burning sensation and paresthesia, which can be felt anywhere from 2 to 30 min after application. Burning intensity increases initially, stopping after 1 h; despite discomfort, pain is usually tolerable. Additionally, subsequent resorcinol applications cause more intense burning sensation, prompting shorter exposure. Corticoid creams and cold compresses may provide some relief. Dizziness immediately after the peel may last min and is probably secondary to flushing related to resorcinol application In vivo Keratolytic Potential of Benzoyl Peroxide, Retinoic Acid, and Salicylic Acid The SC desquamating effect of three keratolytics will be presented in table format (see Table 54.4 ) using data obtained from colorimetric protein assays described by Dreher et al. in 1998 [ 78 ].