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Hypertrophic Scars and Keloids, Part 2: Newer and Investigational Therapies Andrea D

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Hypertrophic Scars and Keloids, Part 2: Newer and Investigational Therapies Andrea D Review Hypertrophic Scars and Keloids, Part 2: Newer and Investigational Therapies Andrea D. Maderal, BA; Jennifer C. Tang, MD; Alejandra C. Vivas, MD; Martha H. Viera, MD Hypertrophic scars (HTSs) and keloids are benign proliferative scar tissues that represent a dysregulation in the wound healing process. These lesions not only result in disfigurement but also can cause symp- toms such as pain and pruritus. Although treatments for HTSs and keloids have been extensively studied, even the most successfully proven methods can be ineffective for some patients. To treat patients refrac- tory to more conventional therapies, newer therapies constantly are being investigated for these recal- citrant lesions. Some of these modalities employ new uses for old drugs, such as angiotensin-converting enzyme inhibitors and verapamil, while others, such as gene therapy, represent cutting-edge treatments. In part 2 ofCOS this series we highlight various new DERMand investigational therapies; although they are not yet available for use, these therapies demonstrate exciting and promising potential for successfully manag- ing HTSs and keloids. Do Not CopyCosmet Dermatol. 2012;25:373-379. here are many emerging and innovative fibroblast growth factor (bFGF), and botulinum toxin modalities that are in different phases of type A (BTX-A). investigational study and already have shown promising results as potential treat- ANGIOTENSIN-CONVERTING ment options for hypertrophic scars (HTSs) ENZYME INHIBITORS Tand keloids that are refractory to more conventional Angiotensin-converting enzyme inhibitors are best known therapies. Some of these therapies include angiotensin- for their use in the treatment of cardiovascular disorders. converting enzyme inhibitors, verapamil, tamoxifen Angiotensin-converting enzyme is responsible for the citrate, calcineurin inhibitors, mitomycin-C, ima- conversion of angiotensin I to angiotensin II, a vasoactive tinib mesylate, adenovirus-mediated gene therapy, hormone that mediates many of its effects through the transforming growth factor b (TGF-b), IL-10, basic renin-angiotensin system.1 Angiotensin II has been found to support tissue repair in many different organ systems (ie, vasculature, heart, brain, lung, kidney, liver, skin)2-4 From the Department of Dermatology and Cutaneous Surgery, Miller by increasing collagen production, cell migration, and School of Medicine, University of Miami, Florida. promotion of growth factors and cytokines.2 The ability The authors report no conflicts of interest in relation to this article. of angiotensin-converting enzyme inhibitors to prevent This article is the last of a 2-part series. remodeling and collagen deposition in postinfarction Correspondence: Andrea D. Maderal, BA, 1321 NW 14th St, UMH, cardiac tissue, which correlates with improvement of ven- West Bldg, Ste 505, Miami, FL 33136 ([email protected]). tricular function, has been well studied.5-7 More recently, www.cosderm.com VOL. 25 NO. 8 • AUGUST 2012 • Cosmetic Dermatology® 373 Copyright Cosmetic Dermatology 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. HypertropHic ScarS and KeloidS the role of angiotensin II in cutaneous wound healing verapamil was comparable to intralesional triamcinolone and pathologic scarring also has been revealed.3 It has acetonide in the treatment of HTSs and keloids. Both been found that angiotensin II has similar properties in were found to produce similar end results (reduction dermal tissue, as it causes increased proliferation, migra- of scar vascularity, pliability, height, and width), with tion, and matrix production in human fibroblasts.8,9 Bond intralesional triamcinolone achieving these effects faster et al10 studied the mechanism of fibroblast migration by but with a greater incidence of adverse reactions than angiotensin II and found that it increased migration by intralesional verapamil.22 Intralesional verapamil alone increasing expression of nonmuscle myosin II, the princi- and in conjunction with intralesional triamcinolone has pal motor protein in fibroblasts.11 Bond et al10 also found been observed to decrease viability and proliferation of that angiotensin II receptor 1 inhibitors suppressed this fibroblasts in HTSs despite no changes in scar weight as increase in migration. compared with intralesional saline.19 Angiotensin-converting enzyme inhibitors have been found to be beneficial in the treatment of keloids and TAMOXIFEN CITRATE HTSs in animals and humans. Captopril was found to Tamoxifen citrate is a nonsteroidal agent and selec- effectively prevent HTS development in New Zealand tive estrogen receptor modulator used in the treat- white rabbits.12 In one study, treatment of a hyperten- ment of breast cancer.23,24 It affects keloid fibroblasts sive patient with low doses of enalapril (10 mg once through alterations in transcription, delay, or arrest in the daily) and hydrochlorothiazide (3 mg once daily) coin- Gap1 (G1) phase of the cell cycle, as well as inhibition of cided with nearly complete recovery of a keloid scar different growth factors.25 Specifically, tamoxifen citrate after 15 days as well as complete disappearance of decreases TGF-b production in a dose-dependent man- cesarean section scars of 25 and 30 years’ duration after ner.26 It also has been shown to inhibit proliferation in 3 to 4 months of treatment. Another patient who followed keloid fibroblasts.27 the same treatment regimen also showed good results after Mousavi et al24 conducted a double-blind, randomized, 6 months.13 Application of captopril solution 5% in cold controlled trial of 300 patients with a history of HTSs who cream twiceCOS daily for 6 weeks led to marked improvement DERM were undergoing surgical operations to assess the efficacy in a postburn keloid lesion, including reduction in scar of tamoxifen citrate in preventing the development of height and erythema as well as elimination of pruritus. postsurgical HTSs. The patients were randomly split into This topical application was not associated with any noted the treatment or control groups 1 month following surgery. side effects.14 The treatment group was administered 10 mg of tamoxifen citrate twice daily for 2 months, while the control group VERAPAMIL received a placebo. The authors found that only 52% of Verapamil is a phenylalkylamine calcium channel blocker patients in the treatment group developed HTSs compared Do Not Copy24 that alters fibroblast shape (from bipolar to spherical), with 92% of the control group. It has been reported induces procollagenase expression, and reduces proteins that topical application of tamoxifen citrate 0.1% leads to that make up extracellular matrices.15 Increased levels smaller and less erythematous HTSs.28 A prospective study of cytokines IL-6 and vascular endothelial growth factor of 46 burn patients with HTSs who applied tamoxifen (VEGF) have been shown to be expressed in fibroblasts citrate 0.1% noted improvement of all scars after 6 months from keloids, contributing to matrix abnormalities and of treatment.29 Adverse reactions to treatment with tamoxi- cell proliferation.16,17 In cell cultures, verapamil has been fen citrate have been reported, most commonly flushing observed to decrease IL-6 and VEGF production in central and occasionally nausea and urinary retention.30 keloid fibroblasts, translating to decreased cell prolifera- tion and increased apoptosis.18 In addition, intralesional CALCINEURIN INHIBITORS verapamil appears to increase the expression of decorin, Tacrolimus is a macrolide lactone derived from an inhibitor of fibroblast proliferation and migration.19,20 Streptomyces tsukubaensis that binds to the immunophilin In a prospective study of 45 earlobe keloids, the applica- FKBP-12 that inhibits calcineurin and its phosphatase tion of intralesional verapamil 7 to 14 days following sur- activity to suppress IL-2 production. Tacrolimus also gical keloid excision and again at 1 month postprocedure, inhibits the expression of tumor necrosis factor a, a if necessary, combined with the use of pressure earrings profibrotic cytokine. An elevated expression of glioma- for at least 6 months resulted in resolution of 22 keloids associated oncogene homologue gli-1 has been docu- (55%; 40 keloids were included in follow-up) at an aver- mented in scars and keloids31; gli-1 also has been age follow-up interval of 28 months.21 A single-blind, observed as a target of tacrolimus, which justifies the parallel-group study demonstrated that intralesional application of this drug in the treatment of keloids. 374 Cosmetic Dermatology® • AUGUST 2012 • VOL. 25 NO. 8 www.cosderm.com Copyright Cosmetic Dermatology 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. HypertropHic ScarS and KeloidS In clinical practice, tacrolimus ointment 0.1% has been demonstrated 0% recurrence 8 months after surgery. investigated in an open-label pilot study in which it was Successful results also were achieved with topical applica- applied to keloids twice daily for 12 weeks. Although the tion on earlobe keloids following surgical excision.43 results were not statistically significant, tacrolimus was Intralesional mitomycin-C appears to cause negative observed to decrease induration, tenderness, pruritus, effects, such as severe pain, erythema, blistering, necrosis, and erythema in the treated keloids.32 In another clinical and ulceration. Other side
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