International Journal of Dermatology, VoL 34, No. 6, June 1995

PHARMACOLOGY AND THERAPEUTICS

TOPICAL NICOTINAMIDE COMPARED WITH CLINDAMYCINGEL 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.

AbstractBackground. Systemic and topical antimicrobials are ef-fective in the treatment of inflammatory acne vulgaris;however, widespread use of these agents is becoming in-creasingly associated with the emergence of resistantpathogens raising concerns about microorganism resis-tance and highlighting the need for alternative nonantimi-crobial agents for the treatment of acne. Nicotinamide gelprovides potent antiinflammatory activity without the riskof inducing bacterial resistance.

Methods. In our double-biind investigation, the safety andefficacy of topically applied 4% nicotinamide gel was com-pared to 1% clindamycin gel for the treatment of moderateinflammatory acne vulgaris. Seventy-six patients were ran-domly assigned to apply either 4% nicotinamide gel (n = 38)or 1% clindamycin gel (n = 38) twice daily for 8 weeks. Effi-cacy was evaluated at 4 and 8 weeks using a Physician'sGlobal Evaluation, Acne Lesion Counts, and an Acne Sever-ity Rating.

Results. After 8 weeks, both treatments produced compa-rable (P = 0.19) beneficial results in the Physician's GlobalEvaluation of Inflammatory Acne; 82% of the patients treat-ed with nicotinamide gel and 68% treated with clindamycingel were improved. Both treatments produced statisticallysimilar reductions in acne lesions (papules/pustules; -60%,nicotinamide vs. -43%, clindamycin, P = 0.168), and acneseverity (-52% nicotinamide group vs. -38% clindamycingroup, P = 0.161).

Conclusions. These data demonstrate that 4% nicotinamidegel is of comparable efficacy to 1% clindamycin gel in thetreatment of acne vulgaris. Because topical clindamycin, like

From the Department of Dermatology, State University ofNew York, College of Medicine, Brooklyn, New York, theDivision of Dermatology, University of South Alabama,School of Medicine, Mobile, Alabama; the Department ofDermatology, Jefferson Medical College, Thomas JeffersonUniversity, Philadelphia, Pennsylvania, and the Department ofDermatology, Medical College of Georgia, Augusta, Georgia.

Supported in part by Genderm Corporation, Lincolnshire, IL.

Address for correspondence: Alan R. Shalita, M.D., Depart-ment of Dermatology, SUNY Health Sciences Center, Box46, 450 Clarkson Avenue, Brooklyn, NY 11203.

other antimicrobials, is associated with emergence of resis-tant microorganisms, nicotinamide gel is a desirable alterna-tive treatment for acne vulgaris.

Int J Dermatol 1995; 34:434-437

Systemic and topically applied antimicrobial agentshave been widely prescribed for the treatment of in-flammatory acne vulgaris for over 30 years. Althoughthese agents generally continue to be effective,̂ "^ theirwidespread use has also been associated with the emer-gence of resistant strains of Staphylococi and Propioni-bacterium.^"^ As early as 1976, samples of cutaneouspropionibacterium microorganisms taken from over1000 acne patients were uniformly sensitive to antibi-otics.'" In contrast, 17 years later, 40% of the 468acne patients studied in England carried Propionibacte-ria strains that were resistant to one or more antibi-otics." As a result, guidelines were proposed to restrictthe use of antimicrobial agents for the treatment ofacne. Propionibacteria resistance should be consideredas a cause of antimicrobial therapeutic failure.

These observations have spawned renewed interestin the development of alternative therapy for acne pro-viding the therapeutic characteristics of antimicrobialagents without the problem of bacterial resistance.Nicotinamide has potent antiinflammatory proper-ties,̂ ^"^^ and the compound has been used both topical-ly and systemically in a variety of cutaneous inflamma-tory disorders."*"^" The present study was conducted todetermine the efficacy and safety of topically applied4% nicotinamide gel compared to 1% clindamycin gel,in treating inflammatory acne vulgaris.

Materials and MethodsA multicenter, double-blind, randomized, parallel, active-con-trol study was conducted for up to 12 weeks. Data compiledduring the first 8 weeks from all centers were analyzed,whereas two of the centers followed patients for a period of12 weeks. Unfortunately there was an insufficient number ofpatients studied to allow meaningful analyses in the longertreatment period.

Seventy-six men and women, aged 13 to 35 years, withmoderate inflammatory acne vulgaris enrolled in this study.Moderate inflammatory acne was defined by the presence ofat least 15 papules and/or pustules on the face. Patients withpredominately comedonal acne were excluded. All concomi-

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Nicotinamide Gel in Acne VulgarisShalita et ai.

tant treatments were withdrawn according to the followingschedule: topical acne preparations, topical antimicrobialagents, medicated cosmetics, soaps, or shampoos, and radi-ation therapy, topical corticosteroids, and investigationaldrugs at least 2 weeks before entry; systemic antimicrobialscorticosteroids at least 12 weeks before entry; and oralisotretinoin at least 2 years before entry. The only concomi-tant medications permitted were oral contraceptives, if theyhad been used continuously for at least 3 months beforeentry and the dosage schedule was not expected to changeduring the study period. Exclusion criteria included: preg-nant or lactating women; patients with more than threenodular lesions on the face; patients with any active skindiseases other than inflammatory acne vulgaris; patientswith a history of allergy to study-medications; patients witha previous history of regional enteritis, ulcerative colitis, orantibiotic-associated colitis. Prior to enrollment, a signed in-formed consent was obtained.

At the initial qualifying visit, a medical history was ob-tained and patients were given a dermatologic examinationto determine eligibility for study, A lesion count of the en-tire face was taken, noting the number of papules, pustules,and cysts (baseline only). Additionally, the investigator de-termined 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 toreceive either 4% nicotinamide gel or 1% clindamycin phos-phate gel in a double-blind, randomized manner. Each pa-tient was instructed to apply the medication to the facetwice a day. Patients were supplied with adequate quantitiesof Ivory® soap and Suave® shampoo to be used exclusivelyfor facial and hair cleansing during the course of the study.

Each patient was required to return for follow-up visitsafter 4 and 8 weeks of therapy to assess clinical improve-ment and to elicit information regarding adverse effects. Ateach follow-up visit, the investigator repeated the AcneSeverity Rating and Acne Lesion Count, and also rated theoverall improvement of acne compared to pre-treatmentexamination using a Physician's Global Evaluation of In-flammatory 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 ridit-assigned scores was used for analysis of the Physician'sGlobal Evaluation, Percent change from baseline in theAcne Severity Rating and the Acne Lesion Count were ana-lyzed using analysis of covariance. All statistical tests weretwo-tailed and statistical significance was defined as P <0,05, Results are expressed as Mean ± SEM.

Tahle 1, Acne Severity Rating

Grade 0 Facial skin is clear or a few scattered comedonesor papules are visible on close examination.

Grade 2 About one-fourth of face is involved with smallpapules (6 to 10) and comedones, A few pustulesor prominent papules may he present.

Grade 4 About one-half of the face is involved with smallpapules and comedones, A few pustules orprominent papules are usually present.

Grade 6 About three-fourths of the face is involved withpapules and/or large open comedones. Numerouspustules are usually present.

Grade 8 Practically all of the face is involved with highlyinflammatory lesions.

RESULTS

Seventy-six patients, 23 men and 53 women, age 13 to35 years (mean age 21,3 years) were enrolled in thestudy. There were no significant demographic differ-ences between the two treatment groups. Seventeen pa-tients failed to complete the study; nine in the nicoti-namide treatment group and eight in the clindamycingroup. Reasons for premature withdrawal included ad-verse experience (nicotinamide 2), lost to follow-up(nicotinamide 7, clindamycin 5), tion-medical reasons(clindamycin 2) or condition unchanged/worsened frombaseline (clindamycin 1), Efficacy results were based on49 evaluable subjects (nicotinamide 21, clindamycin28), who participated in at least one evaluation duringthe treatment period with no protocol violations.

Both clindamycin and nicotinarnide treatment wasassociated with a progressive reduction in acne severityafter 4 and 8 weeks of therapy (Fig. 1). At baseline, themean acne severity rating for the nicotinamide treat-ment group (4,78 ± 0,19) was nearly identical to therating for the clindamycin-treated patients (4,84 ±0.19), After 8 weeks of therapy, the acne severity rat-ings decreased to 2,48 ± 0.39 in nicotinamide-treatedpatients (-51.6 + 7.0%) and to 3.07 ± 0.33 in clin-damycin-treated patients (-38,4 ± 6,1%), No signifi-cant differences between nicotinamide- and clin-damycin-treated patients were evident. Similarly,nicotinamide and clindamycin produced comparable re-ductions in the number of acne lesions (papules andpustules) after 8 weeks of therapy. The acne lesioncount decreased from 27,6 ± 2,1 to 13,5 + 2,8 (-59,5 ±9,0%) in the nicotinamide treatment group compared

•c -20

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<-40

I -60

-80

p=0.16 p=0.16

nicotinamide gel

clindamycin gel

4 weeks 8 weeks

Treatment Period

Figure 1. Acne Severity Rating: percent reduction in acneseverity compared to baseline.

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International Journal of DermatologyVol. 34, No. 6, June 1995

-20-

•~ O -40-O <D

-60

-80

p=0,06 Tp=0,17

4 weeks 8 weeks

nicotinamide gel

clindamycin gel

Treatment Period

Figure 2. Acne Lesion Count: percent reduction in the num-ber 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). Fi-nally, there were no significant differences in the Physi-cian's Global Evaluation of Inflammatory Acne foroverall change in acne condition from baseline betweenthe nicotinamide- and clindamycin-treated patients atany time during the study (Fig. 3). At Week 4, 36% ofthe patients being treated with nicotinamide were ratedas either moderately or much better compared to 40%of the clindamycin group. After 8 weeks of treatment,the response rate increased to 86% for nicotinamidecompared to 68% for clindamycin (P = 0.19).

The frequency of adverse reactions was similar inboth treatment groups (10 nicotinamide-treated patientsand nine clindamycin-treated patients) and consisted en-tirely of local application-site reactions. Localized mildto moderate pruritus and production of excessive oili-ness at the application site were reported with topicalclindamycin, whereas mild stinging or burning at thesite of application was reported with topical nicoti-namide. Application site reactions with topical treat-ment of acne vulgaris have been attributed to vehiclecomponents in previous studies.''-^

DISCUSSION

Nicotinamide is the physiologically active form ofniacin and is the source of vitamin B3 found in a ma-jority of multivitamin products. Nicotinamide serves asa precursor in the synthesis of the coenzymes, nicoti-namide adenine dinucleotide (NAD) and nicotinamideadenine dinucleotide phosphate (NADP). AS a pharma-

cologic agent, nicotinamide has been used for its anti-inflammatory properties in such cutaneous disorders asbullous pemphigoid,'** necrobiosis lipoidica," and der-matitis herpetiformis.^^ In our investigation, we foundnicotinamide gel, presumably acting through an antiin-flammatory mechanism of action, to be equivalent inefficacy to topical clindamycin for the treatment ofacne vulgaris.

The precise mechatiism(s) by which nicotinamideexerts a therapeutic effect in acne vulgaris is unclear.Nicotinamide has been shown to blunt potassiumiodide-induced inflammation in human volunteers'^and markedly suppress 12-O-tetradecanoyl-phorbol-13-acetate-induced cutaneous inflammation in mice.'^Nicotinamide may exert an antiitiflamrnatory actionthrough inhibition of mast cell histamine release,''' in-hibition of neutrophil chemotaxis and secretion of in-flammatory mediators,'^ blockade of histamine recep-tors,'^ or suppression of lymphocyte transformatioti.'^Nicotinamide has other diverse actions such as elec-tron scavenging,^^ inhibition of phosphodiesterase ac-tivity,^'' or increased synthesis of serotonin^^ whichmay also contribute to the pharmacologic activity ofthis compound. Some or all of these pharmacologic ef-fects of nicotinamide may contribute to the resolutionand prevention of inflammatory acne lesions.

After 8 weeks of therapy, 4% nicotinamide and 1%clindamycin gels were equivalent in efficacy for thetreatment of inflammatory acne vulgaris as shown byPhysician's Global Evaluation, Acne Lesion Count, andAcne Severity Rating. Unlike topical clindamycin,^

100

4 weeks 8 weeks

nicotinamide gel

clindamycin gel

Treatment Period

Figure 3. Physicians Global Evaluation of InflammatoryAcne: percent of patients whose acne condition was rated asmoderately better or much better.

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Nicotinamide Gel in Acne VutgarisShalita et al.

topical nicotinamide use is not associated with theemergence of resistant strains of microorganisms norwith pseudomembranous colitis. Caution regarding theuse of topical and systemic antimicrobial agents, suchas clindamycin, erythromycin, and tetracycline, is nowcommonly advised due to concern about antimicrobialresistance.'^

DRUG NAMES

clindamycin phosphate gel 1%: Cleocinnicotinamide gel: Papulex

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