TOPICAL NICOTINAMIDE COMPARED WITH CLINDAMYCIN GEL IN THE TREATMENT OE INELAMMATORY ACNE VULGARIS

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1 International Journal of Dermatology, VoL 34, No. 6, June 1995 PHARMACOLOGY AND THERAPEUTICS TOPICAL NICOTINAMIDE COMPARED WITH CLINDAMYCIN GEL IN THE TREATMENT OE INELAMMATORY ACNE VULGARIS ALAN R. SHALITA, M.D., J. GRAHAM SMITH, M.D., LAWRENCE CHARLES PARISH, M.D., MICHAEL S. SOFMAN, M.D., AND DAN K. CHALKER, M.D. other antimicrobials, is associated with emergence of resistant microorganisms, is a desirable alternative treatment for acne vulgaris. Int J Dermatol 1995; 34: Abstract Background. Systemic and topical antimicrobials are effective in the treatment of inflammatory acne vulgaris; however, widespread use of these agents is becoming increasingly associated with the emergence of resistant pathogens raising concerns about microorganism resistance and highlighting the need for alternative nonantimicrobial agents for the treatment of acne. Nicotinamide gel provides potent antiinflammatory activity without the risk of inducing bacterial resistance. Systemic and topically applied antimicrobial agents have been widely prescribed for the treatment of inflammatory acne vulgaris for over 30 years. Although these agents generally continue to be effective,^"^ their widespread use has also been associated with the emergence of resistant strains of Staphylococi and Propionibacterium.^"^ As early as 1976, samples of cutaneous propionibacterium microorganisms taken from over 1000 acne patients were uniformly sensitive to antibiotics.'" In contrast, 17 years later, 40% of the 468 acne patients studied in England carried Propionibacteria strains that were resistant to one or more antibiotics." As a result, guidelines were proposed to restrict the use of antimicrobial agents for the treatment of acne. Propionibacteria resistance should be considered as a cause of antimicrobial therapeutic failure. These observations have spawned renewed interest in the development of alternative therapy for acne providing the therapeutic characteristics of antimicrobial agents without the problem of bacterial resistance. Nicotinamide has potent antiinflammatory properties,^^"^^ and the compound has been used both topically and systemically in a variety of cutaneous inflammatory disorders."*"^" The present study was conducted to determine the efficacy and safety of topically applied 4% compared to 1%, in treating inflammatory acne vulgaris. Methods. In our double-biind investigation, the safety and efficacy of topically applied 4% was compared to 1% for the treatment of moderate inflammatory acne vulgaris. Seventy-six patients were randomly assigned to apply either 4% (n = 38) or 1% (n = 38) twice daily for. Efficacy was evaluated at 4 and using a Physician's Global Evaluation, Acne Lesion Counts, and an Acne Severity Rating. Results. After, both treatments produced comparable (P = 0.19) beneficial results in the Physician's Global Evaluation of Inflammatory Acne; 82% of the patients treated with and 68% treated with clindamycin gel were improved. Both treatments produced statistically similar reductions in acne lesions (papules/pustules; -60%, nicotinamide vs. -43%, clindamycin, P = 0.168), and acne severity (-52% nicotinamide group vs. -38% clindamycin group, P = 0.161). Conclusions. These data demonstrate that 4% nicotinamide gel is of comparable efficacy to 1% in the treatment of acne vulgaris. Because topical clindamycin, like From the Department of Dermatology, State University of New York, College of Medicine, Brooklyn, New York, the Division of Dermatology, University of South Alabama, School of Medicine, Mobile, Alabama; the Department of Dermatology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, and the Department of Dermatology, Medical College of Georgia, Augusta, Georgia. Materials and Methods A multicenter, double-blind, randomized, parallel, active-control study was conducted for up to 12 weeks. Data compiled during the first from all centers were analyzed, whereas two of the centers followed patients for a period of 12 weeks. Unfortunately there was an insufficient number of patients studied to allow meaningful analyses in the longer treatment period. Seventy-six men and women, aged 13 to 35 years, with moderate inflammatory acne vulgaris enrolled in this study. Moderate inflammatory acne was defined by the presence of at least 15 papules and/or pustules on the face. Patients with predominately comedonal acne were excluded. All concomi- Supported in part by Genderm Corporation, Lincolnshire, IL. Address for correspondence: Alan R. Shalita, M.D., Department of Dermatology, SUNY Health Sciences Center, Box 46, 450 Clarkson Avenue, Brooklyn, NY

2 Nicotinamide Gel in Acne Vulgaris Shalita et ai. tant treatments were withdrawn according to the following schedule: topical acne preparations, topical antimicrobial agents, medicated cosmetics, soaps, or shampoos, and radiation therapy, topical corticosteroids, and investigational drugs at least 2 weeks before entry; systemic antimicrobials corticosteroids at least 12 weeks before entry; and oral isotretinoin at least 2 years before entry. The only concomitant medications permitted were oral contraceptives, if they had been used continuously for at least 3 months before entry and the dosage schedule was not expected to change during the study period. Exclusion criteria included: pregnant or lactating women; patients with more than three nodular lesions on the face; patients with any active skin diseases other than inflammatory acne vulgaris; patients with a history of allergy to study-medications; patients with a previous history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis. Prior to enrollment, a signed informed consent was obtained. At the initial qualifying visit, a medical history was obtained and patients were given a dermatologic examination to determine eligibility for study, A lesion count of the entire face was taken, noting the number of papules, pustules, and cysts (baseline only). Additionally, the investigator determined an acne severity grade using Allen and Smith's^^ modification of the Cook et al,^^ procedure (Table 1). Patients who met all eligibility criteria were assigned to receive either 4% or 1% clindamycin phosphate gel in a double-blind, randomized manner. Each patient was instructed to apply the medication to the face twice a day. Patients were supplied with adequate quantities of Ivory soap and Suave shampoo to be used exclusively for facial and hair cleansing during the course of the study. Each patient was required to return for follow-up visits after 4 and of therapy to assess clinical improvement and to elicit information regarding adverse effects. At each follow-up visit, the investigator repeated the Acne Severity Rating and Acne Lesion Count, and also rated the overall improvement of acne compared to pre-treatment examination using a Physician's Global Evaluation of Inflammatory Acne: +3 = much better; +2 = moderately better, +1 = slightly better, 0 = no change, -1 = worse. Demographic data were analyzed using Student's T-test. The Cochran-Mantel Haenszel (CMH) chi-square test with riditassigned scores was used for analysis of the Physician's Global Evaluation, Percent change from baseline in the Acne Severity Rating and the Acne Lesion Count were analyzed using analysis of covariance. All statistical tests were two-tailed and statistical significance was defined as P < 0,05, Results are expressed as Mean ± SEM. RESULTS Seventy-six patients, 23 men and 53 women, age 13 to 35 years (mean age 21,3 years) were enrolled in the study. There were no significant demographic differences between the two treatment groups. Seventeen patients failed to complete the study; nine in the nicotinamide treatment group and eight in the clindamycin group. Reasons for premature withdrawal included adverse experience (nicotinamide 2), lost to follow-up (nicotinamide 7, clindamycin 5), tion-medical reasons (clindamycin 2) or condition unchanged/worsened from baseline (clindamycin 1), Efficacy results were based on 49 evaluable subjects (nicotinamide 2 1, clindamycin 28), who participated in at least one evaluation during the treatment period with no protocol violations. Both clindamycin and nicotinarnide treatment was associated with a progressive reduction in acne severity after 4 and of therapy (Fig. 1). At baseline, the mean acne severity rating for the nicotinamide treatment group (4,78 ± 0,19) was nearly identical to the rating for the clindamycin-treated patients (4,84 ± 0.19), After of therapy, the acne severity ratings decreased to 2,48 ± 0.39 in nicotinamide-treated patients ( %) and to 3.07 ± 0.33 in clindamycin-treated patients (-38,4 ± 6,1%), No significant differences between nicotinamide- and clindamycin-treated patients were evident. Similarly, nicotinamide and clindamycin produced comparable reductions in the number of acne lesions (papules and pustules) after of therapy. The acne lesion count decreased from 27,6 ± 2,1 to 13,5 + 2,8 (-59,5 ± 9,0%) in the nicotinamide treatment group compared c -20 d) CO a> -40 < Tahle 1, Acne Severity Rating Grade 0 Grade 2 Grade 4 Grade 6 Grade 8 Facial skin is clear or a few scattered comedones or papules are visible on close examination. About one-fourth of face is involved with small papules (6 to 10) and comedones, A few pustules or prominent papules may he present. About one-half of the face is involved with small papules and comedones, A few pustules or prominent papules are usually present. About three-fourths of the face is involved with papules and/or large open comedones. Numerous pustules are usually present. I -60 p=0.16 p= Figure 1. Acne Severity Rating: percent reduction in acne severity compared to baseline. Practically all of the face is involved with highly inflammatory lesions. 435

3 International Journal of Dermatology Vol. 34, No. 6, June 1995 cologic agent, nicotinamide has been used for its antiinflammatory properties in such cutaneous disorders as bullous pemphigoid,'** necrobiosis lipoidica," and dermatitis herpetiformis.^^ In our investigation, we found, presumably acting through an antiinflammatory mechanism of action, to be equivalent in efficacy to topical clindamycin for the treatment of acne vulgaris. The precise mechatiism(s) by which nicotinamide exerts a therapeutic effect in acne vulgaris is unclear. Nicotinamide has been shown to blunt potassium iodide-induced inflammation in human volunteers'^ and markedly suppress 12-O-tetradecanoyl-phorbol13-acetate-induced cutaneous inflammation in mice.'^ Nicotinamide may exert an antiitiflamrnatory action through inhibition of mast cell histamine release,''' inhibition of neutrophil chemotaxis and secretion of inflammatory mediators,'^ blockade of histamine receptors,'^ or suppression of lymphocyte transformatioti.'^ Nicotinamide has other diverse actions such as electron scavenging,^^ inhibition of phosphodiesterase activity,^'' or increased synthesis of serotonin^^ which may also contribute to the pharmacologic activity of this compound. Some or all of these pharmacologic effects of nicotinamide may contribute to the resolution and prevention of inflammatory acne lesions ~ O O <D p=0,06 T p=0,17-80 Figure 2. Acne Lesion Count: percent reduction in the number of acne lesions (papules and pustules) compared to baseline. to a reduction from 29.3 ± 2.0 to 17.0 ± 2.4 (-42.7 ± 7.8%) in the clindamycin treatment group (Fig. 2). Finally, there were no significant differences in the Physician's Global Evaluation of Inflammatory Acne for overall change in acne condition from baseline between the nicotinamide- and clindamycin-treated patients at any time during the study (Fig. 3). At Week 4, 36% of the patients being treated with nicotinamide were rated as either moderately or much better compared to 40% of the clindamycin group. After of treatment, the response rate increased to 86% for nicotinamide compared to 68% for clindamycin (P = 0.19). The frequency of adverse reactions was similar in both treatment groups (10 nicotinamide-treated patients and nine clindamycin-treated patients) and consisted entirely of local application-site reactions. Localized mild to moderate pruritus and production of excessive oiliness at the application site were reported with topical clindamycin, whereas mild stinging or burning at the site of application was reported with topical nicotinamide. Application site reactions with topical treatment of acne vulgaris have been attributed to vehicle components in previous studies.''-^ After of therapy, 4% nicotinamide and 1% s were equivalent in efficacy for the treatment of inflammatory acne vulgaris as shown by Physician's Global Evaluation, Acne Lesion Count, and Acne Severity Rating. Unlike topical clindamycin,^ 100 DISCUSSION Nicotinamide is the physiologically active form of niacin and is the source of vitamin B3 found in a majority of multivitamin products. Nicotinamide serves as a precursor in the synthesis of the coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). AS a pharma- Figure 3. Physicians Global Evaluation of Inflammatory Acne: percent of patients whose acne condition was rated as moderately better or much better. 436

4 Nicotinamide Gel in Acne Vutgaris Shalita et al. topical nicotinamide use is not associated with the emergence of resistant strains of microorganisms nor with pseudomembranous colitis. Caution regarding the use of topical and systemic antimicrobial agents, such as clindamycin, erythromycin, and tetracycline, is now commonly advised due to concern about antimicrobial resistance.'^ propionibacteria in acne: need for policies to modify antibiotic usage. BMJ 1993; 306: Bernstein JE, Lorincz AL. The effects of topical nicotinamide, tetracycline and dapsone on potassium iodideinduced inflammation. J Invest Dermatol 1980; 74: Ludwig A, Dietel M, Schafter G, et al. Nicotinamide and nicotinamide analogues as tumor promoters in mouse skin. Gancer Res 1990; 50: Bekier E, Wyczolkowska J, Szyc H, Maslinski GZ. The inhibitory effect of nicotinamide on asthma-like symptoms and eosinophilia in guinea pigs, anaphylactic mast cell degranulation in mice, and histamine release from isolated peritoneal mast cells by compound 48/80. Int Arch Allergy 1974; 47: Bakier E, Maslinski GZ. Antihistaminic action of nicotinamde. Agents Actions 1974; 4: Berk MA, Lorincz AL. The treatment of bullous pemphigoid with tetracycline and niacinamide. Arch Dermatol 1986; 2: DRUG NAMES clindamycin phosphate gel 1%: Cleocin : Papulex REFERENCES 1. Stoughton RB. Topical antibiotics for acne vulgaris: Current usage. Arch Dermatol 1979; tt5: Resh W, Stoughton RB. Topically applied antibiotics in acne vulgaris: clinical response and suppression of Corynebacterium acnes in open comedones. Arch Dermatol 1976; 112: Burger DR, Wandenbark AA, Daves D, et al. Nicotinamide: suppression of lymphocyte transformation with a component identified in human transfer factor. J Immunol 1976; 117: Leyden JJ, Shalita AR, Saatjian GD, Sefton J. Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution in acne vulgaris. J Am Acad Dermatol 1987; 16: Fivenson DP, Breneman DL, Rosen GB, et al. Nicotinamide and tetracycline therapy of bullous pemphigoid. Arch Dermatol 1994; 130: Bernstein JE, Shalita AR. Topically applied erythromycin in inflammatory acne vulgaris. J Am Acad Dermatol 1980; 2: Handfield-Jones S, Jones S, Peachey R. High dose nicotinamide in the treatment of necrobiosis lipoidica. BrJ Dermatol 1988; 118: Grawford WW, Grawford IP, Stoughton RB, Gornell RG. Laboratory induction and clinical occurrence of combined clindamycin and erythromycin resistance in Corynebacterium acnes. J Invest Dermatol 1979; 238: Zemtsov J, Neldner KH. Successful treatment of dermatitis herpetiformis with tetracycline and nicotinamide in a patient unable to tolerate dapsone. J Am Acad Dermatol 1993; 28: Allen BS, Smith JG. Various parameters for grading acne vulgaris. Arch Dermatol 1982; 118: Gook GH, Gentner RL, Michaels SE. An acne grading method using photographic standards. Arch Dermatol 1979; 115: Wilson GL, Patton NJ, McGord JM, et al. Mechanisms of streptozotocin and nicotinamide. Diabetologia 1974; 10: Shimoyama M, Kawai M, Hoshi Y, Ueda I. Nicotinamide inhibition of 3', 5"-CAMP phosphodiesterase in vitro. Biochem Biophys Res Gomm 1972; 49: Hoffer A. Mega vitamin B-3 therapy for schizophrenia. Gan Psychiatr Assoc J 1971; 16: Milstone EB, McDonald AJ, Scholhamer GF. Pseudomembranous colitis after topical application of chndamycin. Arch Dermatol 1981; 117: Leyden JJ, McGinley KJ, Gavalieri S, et al. Propionibacterium acnes resistance to antibiotics in acne patients. J Am Acad Dermatol 1983; 8: Eady EA, Gove JH, Holland KT, Gunliffe WJ. Erythromycin-resistant propionibacteria in antibiotic treated acne patients: association with therapeutic failure. Br J Dermatol 1989; 121: Pearson TA, Braine HG, Rathbun HK. Gorynebacterium sepsis in oncology patients. Predisposing factors, diagnosis, and treatment. JAMA 1977; 238: Schoenbaum SG, Gardner P, Shilito J. Infections of cerebrospinal fluid shunts: epidermiology, clinical manifestations and therapy. J Infect Dis 1975; 131: Leyden JJ. Antibiotic resistant acne. Gutis 1976; 17: Eady EA, Jones GE, Tipper JL, et al. Antibiotic-resistant 437 Parry MF, Rha GK. Pseudomembranous colitis caused by topical clindamycin phosphate. Arch Dermatol 1986; 122:

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