Permethrin 5% Cream versus Metronidazole 0.75% Gel for the Treatment of Papulopustular Rosacea

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1 Pharmacology and Treatment Dermatology 2002;205: DOI: / Received: May 14, 2001 Acceted: Aril 5, 2002 Permethrin 5% Cream versus Metronidazole 0.75% Gel for the Treatment of Pauloustular Rosacea A Randomized Double-Blind Placebo-Controlled Study Mukadder Koçak a Salime Yağlı b Güler Vahaoğlu b Meral Ekşioğlu b a Deartment of Dermatology, Kırıkkale University, Faculty of Medicine, Kırıkkale, and b Deartment of Dermatology, Ankara Education and Research Hosital, Ministry of Health, Ankara, Turkey Key Words Rosacea W Demodex W Permethrin W Metronidazole W Placebo Abstract Background: Permethrin 5% cream used against human ectoarasites suggests that it may be effective in auloustular rosacea. Methods: This study included 63 atients diagnosed as having auloustular rosacea based on the clinical and histological findings. Patients were randomly assigned into ermethrin (n = 23), metronidazole (n = 20) and lacebo (n = 20) grous. Scores of erythema, telangiectasia, edema and rhinohyma and the numbers of aules, ustules, inflammatory nodules and Demodex folliculorum were determined. Twentythree atients were given ermethrin 5% cream (Zalvor 5% skin cream ), 20 atients metronidazole 0.75% gel (Roza gel ) and 20 atients lacebo cream (Basis cream ), in ackages looking identical to those of metronidazole and ermethrin creams, and were recommended to aly them to their faces twice a day. All atients were also given SPF 20 cream for rotection against sunlight. Two months of treatment were lanned, and the atients were invited to the clinic for fortnightly controls. Scores of erythema, telangiectasia, edema and rhinohyma and the numbers of aules, ustules, inflammatory nodules and D. folliculorum were recorded at each visit. The mean scores of erythema and the mean numbers of aules, ustules and D. folliculorum were determined at baseline and on days 15, 30, 45 and 60. Side effects were also detected. Results: The effect of ermethrin 5% cream on D. folliculorum was suerior to that of metronidazole 0.75% gel. The effect of ermethrin 5% cream on erythema and aules was found to be more effective than lacebo and as effective as metronidazole 0.75% gel. However, it had no effect on telangiectasia, rhinohyma and ustules. Conclusion: It can be concluded that the alication of ermethrin 5% cream twice daily for 2 months can be as effective and reliable as metronidazole in the treatment of rosacea and a greater benefit can be gained when it is combined with other systemic and/or toical treatments. Introduction Coyright 2002 S. Karger AG, Basel Rosacea is a chronic dermatological disorder characterized by ersistent symmetrical erythema, edema, telangiectasia, aules and ustules on the face, esecially on the nose, cheeks, chin and forehead. Although the etiology of the disease is not fully understood, a genetic redisosition, gastrointestinal diseases, changes in weather conditions, sychogenic factors, seborrhea, changes in vascular mediating mechanisms, mediators such as substance P, ABC Fax karger@karger.ch S. Karger AG, Basel /02/ $18.50/0 Accessible online at: Mukadder Koçak, MD Filistin caddesi, İzci sokak 26/2 TR GOP Ankara (Turkey) Tel , Fax , husnukocak@ttnet.net.tr

2 histamine, serotonin or rostaglandin and Demodex folliculorum have been incriminated as causing rosacea [1 8]. In view of the fact that no factors incriminated in the etioathogenesis of the disease are definitely established and that the disease shows recurrences, the effectiveness of available treatment modalities and their side effects should be evaluated. Permethrin is a toical drug active against mites, ticks, lice, fleas and other arthroods. Since the long-term use of ermethrin in lants and animals was observed to be safe, its formulation was modified for use against human ectoarasites. At resent, ermethrin is used for the treatment of scabies and ediculosis. Although large studies showed that ermethrin had low toxicity in mammals, active ermethrin could not be detected in blood and urine in some studies conducted on volunteers. This drug was reorted to be used also in rosacea deending on the results of the studies on facial demodicidosis and diseases associated with other mites [9 11]. The aim of this study was to comare the effect of ermethrin 5% cream with those of metronidazole 0.75% gel and lacebo in the treatment of auloustular rosacea and to investigate whether ermethrin could be an alternative in the toical treatment of auloustular rosacea. atients were given ermethrin 5% cream (Zalvor 5% skin cream ), 20 atients metronidazole 0.75% gel (Roza gel ) and 20 atients lacebo cream (Basis cream ) in ackages looking identical to those of metronidazole and ermethrin creams; they were recommended to aly them to their faces in a thin layer twice a day. All atients were also given SPF 20 cream (a unique commercial rearation) for rotection against sunlight. They were instructed not to take antibiotics or aly any other toical agents. Two months of treatment were lanned, and the atients were invited twice monthly for control. Scores of erythema, telangiectasia, edema and hyma and the numbers of aules, ustules, inflammatory nodules and D. folliculorum were recorded. Side effects were evaluated. The mean erythema scores and the mean numbers of aules, ustules and D. folliculorum were determined. Primary comarisons were based on the change in the resonse variable from baseline to day 60 with additional analyses comaring resonses at each of the assessment visits (i.e. on days 15, 30, 45 and 60). Descritive statistics are exressed as means B SEM (standard error of the mean). The mean erythema scores and the mean numbers of aules, ustules and D. folliculorum were comared with Kruskal-Wallis one-way ANOVA (analysis of variance) in each grou. When there was a significant difference between the grous, they were comared 2 by 2 using the Mann-Whitney U Wilcoxon rank sum W test with Bonferroni correction. Changes in values over time were analyzed with the Friedman test. When the Friedman test showed a significant difference, a Wilcoxon rank sum W test with Bonferroni correction was used to determine the times when there were changes in values. Quantitative variables were analyzed with nonarametric tests instead of ANOVA because the distribution of values was not even. Material and Methods This study included 63 atients, aged years, resenting to the Outatient Clinic of Dermatology at Ankara Education and Research Hosital between 1999 and 2000 and diagnosed as having auloustular rosacea based on clinical and histoathological findings. Patients were eligible when they had at least 10 inflammatory aules or ustules, did not have erythematotelangiectatic rosacea, did not receive systemic treatment for involvement of the eyes or oral anticoagulants and had no diagnosis of fulminant rosacea. The study rotocol was aroved by the Ethical Committees of the Ankara Education and Research Hosital and the Ministry of Health. Having been informed about the aim, duration, effects and side effects of the treatments, the atients acceted to articiate in the study. They were randomly assigned to three grous to receive ermethrin (n = 23), metronidazole (n = 20) and lacebo (n = 20). History was taken from all atients. They were subjected to hysical and dermatological examinations. On dermatological examination, manual counting of aules, ustules and inflammatory nodules was erformed. Assessment of erythema was made on a scale, where 0 = none, 1 = mild, 2 = moderate and 3 = severe. Telangiectasia, edema and rhinohyma were rated as 0 = absent and 1 = resent. To determine the number of D. folliculorum, 3 scraings were obtained from a square lesion of 1 cm 2 on the cheek by the same dermatologist using a blunt scalel (No. BA 161 N). Materials obtained by scraing were laced onto slides, 1 dro of glycerin was added and counting of D. folliculorum was erformed under the microscoe. Twenty-three Results This study included 63 atients, of whom 48 were women and 15 men, aged years (mean 51). The duration of the disease ranged from 0.17 to 15 years (mean 2.9 years). No local comlication due to ermethrin, metronidazole or lacebo was observed. One atient comlained about lacrimation and burning sensation in the eyes due to the rotective cream against sunlight. No change was observed in telangiectasia and rhinohyma, and inflammatory nodules and edema were detected in few atients. The mean erythema scores and the mean numbers of aules, ustules and D. folliculorum obtained on days 0, 15, 30, 45 and 60 are shown in table 1. There was no significant difference between grous in the scores of erythema and the number of aules, ustules and D. folliculorum obtained before treatment (table 2). The mean difference in the erythema score between baseline and day 60 was B (Z = , = ) in atients assigned into the ermethrin grou and B (Z = , = ) in those assigned to metronidazole. The mean erythema score in 266 Dermatology 2002;205: Koçak/Yağlı/Vahaoğlu/Ekşioğlu

3 Table 1. Erythema scores and the numbers of aules, ustules and D. folliculorum at baseline and on days 15, 30, 45 and 60 in the ermethrin, metronidazole and lacebo grous (means B SEM) Baseline Day 15 Day 30 Day 45 Day 60 Permethrin Erythema score 2.60B B B B B0.71 Paules 6.04B B B B B2.20 Pustules 2.30B B B B B1.27 D. folliculorum 2.20B B B B B0.71 Metronidazole Erythema score 2.85B B B B B0.68 Paules 8.00B B B B B2.80 Pustules 4.90B B B B B3.10 D. folliculorum 2.60B B B B B0.56 Placebo Erythema score 2.65B B B B B0.50 Paules 4.85B B B B B3.80 Pustules 2.60B B B B B3.10 D. folliculorum 2.70B B B B B0.92 Table 2. Effect of treatment on erythema, aules, ustules and D. folliculorum obtained from each grou Day Permethrin/metronidazole/ lacebo Permethrin/metronidazole Permethrin/lacebo Metronidazole/lacebo 2 Z Z Z Effect of treatment on erythema Effect of treatment on aules Effect of treatment on ustules Effect of treatment on D. folliculorum = When there was no significant difference following analysis with Kruskal-Wallis one-way ANOVA, 2 by 2 comarisons could not be done. Permethrin 5% Cream versus Metronidazole 0.75% Gel for the Treatment of Pauloustular Rosacea Dermatology 2002;205:

4 atients assigned to lacebo was B ( 2 = , = ) before treatment and did not change after treatment so we did not comare the mean erythema scores in atients receiving lacebo with the mean scores of atients receiving ermethrin or metronidazole. The significant differences in the erythema scores of atients in the ermethrin, metronidazole and lacebo grous between baseline and days 15, 30, 45 and 60 are shown in table 2. The mean difference in the number of aules between baseline and day 60 was B (Z = , = ) in atients receiving ermethrin, B (Z = , = ) in atients receiving metronidazole and B ( 2 = , = ) in atients receiving lacebo. The mean number of aules obtained from each grou was comared with each other, and the significant differences in the mean number of aules in atients receiving ermethrin, metronidazole and lacebo between baseline and days 15, 30, 45 and 60 are shown in table 2. The mean difference in the number of ustules between baseline and day 60 was B ( 2 = 2.953, = ) in the ermethrin grou, B (Z = , = ) in the metronidazole grou and B ( 2 = , = ) in the lacebo grou following 2 months treatment. The mean number of ustules obtained from each grou was comared with each other and the significant differences in the number of ustules between baseline and days 15, 30, 45 and 60 are shown in table 2. The mean difference in the number of D. folliculorum between baseline and day 60 was B (Z = , = ) in the ermethrin grou, B (Z = , = ) in the metronidazole grou and B ( 2 = 3.123, = ) in the lacebo grou. The mean values of the three grous were comared and the significant differences in the number of D. folliculorum between baseline and days 15, 30, 45 and 60 are shown in table 2. Discussion Rosacea is a skin disease involving the face symmetrically and characterized by flashing eisodes, erythema, telangiectasia, recurrent inflammatory aules and ustules. The fact that rosacea and other diseases due to Demodex mites show imrovement following treatment with acaricides has led to investigations of many treatment alternatives [1 4]. In their study in 1993, Forton and Seys [2] determined the mite density in 49 atients with rosacea and controls using standardized skin surface biosy and found that the Demodex density is higher in auloustular rosacea than in controls. However, the increase in Demodex density in erythematotelangiectatic rosacea was not significant. Therefore, they suggested that Demodex could lay a role in the formation of aules and ustules and that vascular changes initiated a auloustular comonent by redisosing to an increase in Demodex mites and/or by allowing their enetration into the dermis. Dominey et al. [12] reorted imrovement in 5 atients with ityriasis folliculorum after treatment with toical tretinoin and toical Á-benzene hexachloride 1% and imrovement in 1 atient, not resonding to the treatment mentioned above, after treatment with oral isotretinoin 0.5 mg/kg daily for 14 weeks followed by ermethrin rinse cream 1% daily for 2 weeks. Shelley et al. [3] reorted imrovement with long-term toical alication of crotamiton in 1 atient with unilateral rosacea due to Demodex. Sahn and Sheridan [13] reorted that facial demodicidosis develoing in an infant with acute lymhoblastic lymhoma imroved with ermethrin 5% cream alied once. Ivy et al. [14] reorted demodicidosis in 11 children with acute lymhoblastic leukemia treated with ermethrin once a week for 3 weeks, and the Demodex density was brought under control in 5 atients after treatment. In 1995, Signore and Park [15] observed a moderate clinical imrovement on both sides of the face in 5 atients with rosacea treated on one side by toical 5% ermethrin cream and on the other side by 0.75% metronidazole for 9 weeks; they noted no variation in the Demodex oulation. In 1998, in one study of 34 atients, the acaricidal actions of metronidazole 2% cream, ermethrin 1% rinse cream, sublimed sulfur 10%, Á-benzene hexachloride 1%, crotamiton 10% and benzyl benzoate 10% on auloustular rosacea, erythematotelangiectatic rosacea or demodicidosis were investigated. Alication of ermethrin 1% rinse cream for 10 min once every 2 days for 45 days was found to decrease the Demodex density based on the results of standardized skin surface biosy, but the acaricidal action of ermethrin was not statistically significant. It was suggested that further studies were necessary to investigate the effect of ermethrin 5% cream [16]. In the resent study, skin scraings were erformed to determine the mean number of D. folliculorum. Because, although standardized skin surface biosy is more accurate and sensitive, we lanned to obtain material 5 times, we referred skin scraing, a less invasive method, and obtained material from the same area each time (at base- 268 Dermatology 2002;205: Koçak/Yağlı/Vahaoğlu/Ekşioğlu

5 line and on days 15, 30, 45 and 60). So, the result we obtained (the mean mite count /cm 2 ) seemed not to be consistent with the results of recent studies (mean mite count 49.8, range 2 158/6! a circle 1.5 cm in diameter [17], mean mite count 49.9/10.5 cm 2 [18], mean mite count B SD B [19], mean mite count 10.9/cm 2 [2]). In this study, auloustular rosacea was treated with ermethrin 5% cream, metronidazole 0.75% gel and lacebo. No comlication occurred due to ermethrin, metronidazole or lacebo. Since no change occurred in telangiectasia and rhinohyma, we thought that ermethrin 5% cream and metronidazole 0.75% gel had no effect on telangiectasia and rhinohyma and, therefore, did not make any statistical analysis of telangiectasia and rhinohyma scores. Our finding that metronidazole 0.75% gel did not have any effect on telangiectasia and rhinohyma was consistent with the results of revious studies [4, 20 29]. The effect of ermethrin 5% cream on erythema, aule, ustule and D. folliculorum arameters showing changes at the end of the treatment was comared with those of metronidazole 0.75% gel and lacebo. The scores of erythema and the number of D. folliculorum obtained at baseline started to decrease on day 15 with a statistical significance. Comared to lacebo, ermethrin 5% cream was observed to initiate a significant effect on erythema on day 15, aules on day 45 and on D. folliculorum within the fifteenth to thirthieth days of treatment. This significant effect of ermethrin on erythema, aules and D. folliculorum continued until the end of the treatment. Its effect on ustules was not found to be significant excet that on day 60. As far as we know, there is no controlled study on the effect of ermethrin on erythema, aules, ustules and D. folliculorum. The study by Signore and Park [15] was based on the comarison of the Demodex revalence and was only erformed on 2 atients: in this context it is difficult, in our view, to draw a valuable conclusion, so we could not comare our results with those of the latter study since the effect of ermethrin was evaluated based on the global imrovement scores of rosacea in their study. Comared to lacebo, metronidazole 0.75% gel was found to have a significant effect on erythema within the second 15 days of treatment, on D. folliculorum between the forty-fifth and sixtieth days of treatment, although Guarrera et al. [30] reorted that toical metronidazole 1% vanishing cream did not have any effect on UVBinduced erythema. We suggest that toical metronidazole may reduce erythema severity scores in rosacea since it is also ossible that UVA-mediated mechanisms may well contribute to erythema in rosacea; metronidazole has hotorotective effects, esecially with regard to UVA. The effectiveness of metronidazole continued until the end of the treatment. Although Forton et al. [16], reorted no acaricidal effect of metronidazole 2% cream twice daily for 45 days on rosacea and diseases due to Demodex mites, Patrizi et al. [31] treated 8 children suffering from demodicidosis with toical metronidazole 1% for 4 6 weeks; at the end of the treatment, D. folliculorum scraings erformed in 4 atients were negative, and they obtained a 100% recovery without relase after a 1- to 3-year follow-u. We observed a significant decrease in the number of D. folliculorum in atients treated with metronidazole 0.75% gel on the sixtieth day of treatment. This may be exlained by the fact that metronidazole 0.75% gel was alied for longer eriods of time. Our finding is in contradiction to the results of a study revealing that Demodex mites remained viable desite high in vitro metronidazole concentrations of 1 mg/ml [22]. To sum u, ermethrin 5% cream was more effective on erythema and aules than lacebo and as effective as metronidazole 0.75% gel. In addition, ermethrin was more effective on D. folliculorum than metronidazole 0.75% gel and lacebo. We should mention the fact that our study suorts the athogenic role of D. folliculorum in rosacea. It can be concluded that alication of ermethrin 5% cream twice daily for 2 months can be as effective and reliable as metronidazole in the treatment of rosacea and a greater benefit can be gained when it is combined with other systemic and/or toical treatments. Acknowledgments The authors thank Glaxo-Wellcome for their contributions to ackaging the two drugs and the lacebo in identical boxes. Permethrin 5% Cream versus Metronidazole 0.75% Gel for the Treatment of Pauloustular Rosacea Dermatology 2002;205:

6 References 1 Wilkin JK: Rosacea: Pathohysiology and treatment. Arch Dermatol 1994;130: Forton F, Seys B: Density of Demodex folliculorum in rosacea: A case-control study using standardized skin-surface biosy. Br J Dermatol 1993;128: Shelley WB, Shelley ED, Burmeister V: Unilateral demodectic rosacea. J Am Acad Dermatol 1989;20: Jansen T, Plewig G: Rosacea: Classification and treatment. J R Soc Med 1997;90: Hirsch RJ, Weinberg JM: Rosacea Cutis 2000;66: Bamford JTM, Tilden RL: Effect of treatment of Helicobacter ylori infection on rosacea. Arch Dermatol 1999;135: Son SW, Kim IH, Oh CH, Kim JG: The resonse of rosacea to eradication of Helicobacter ylori. Br J Dermatol 1999;140: Maddin S: A comarison of toical azelaic acid 20% cream and toical metronidazole 0.75% cream in the treatment of atients with auloustular rosacea. J Am Acad Dermatol 1999; 40: Tali D, Meinking LT, Porcelain SL: Permethrin 5% dermal cream: A new treatment for scabies. J Am Acad Dermatol 1986;15: Forstinger C, Kittler H, Binder M: Treatment of rosacea-like demodicidosis with oral ivermectin and toical ermethrin cream. J Am Acad Dermatol 1999;41: Paasch U, Haustein UF: Management of endemic outbreaks of scabies with allethrin, ermethrin and ivermectin. Int J Dermatol 2000; 39: Dominey A, Tschen J, Rosen T, Batres E, Stern JK: Pityriasis folliculorum revisited. J Am Acad Dermatol 1989;21: Sahn E, Sheridan D: Demodicidosis in a child with leukemia. J Am Acad Dermatol 1990;27: Ivy SP, Mackall CL, Gore L, Gress RE, Hartley H: Demodicidosis in childhood acute lymhoblastic leukemia: An oortunistic infection occurring with immunosuression. J Pediatr 1995;127: Signore RJ, Park T: A ilot study of 5 ercent ermethrin cream versus 0.75 ercent metronidazole gel in acne rosacea. Cutis 1995;56: Forton F, Seys P, Marchal JL, Song M: Demodex folliculorum and toical treatment: Acaricidal action evaluated by standardized skin surface biosy. Br J Dermatol 1998;138: Bonnar E, Eustace P, Powell FC: The Demodex mite oulation in rosacea. J Am Acad Dermatol 1993;28: Abd-El-Al AM, Bayoumy AM, Abou Salem EA: A study on Demodex folliculorum in rosacea. J Egyt Soc Parasitol 1997;27: Erbağcı Z, Özgöztaşı O: The significance of Demodex folliculorum density in rosacea. Int J Dermatol 1998;37: Eriksson G, Nord CE: Imact of toical metronidazole of the skin and colon microflora in atient rosacea. Infection 1987;1: Miyachi Y, Imamura S, Niwa Y: Anti-oxidant action of metronidazole: A ossible mechanism of action in rosacea. Br J Dermatol 1986; 114: Persi A, Rebora A: Metronidazole and Demodex folliculorum. Acta Derm Venereol (Stockh) 1981;61: Gamborg Nielsen P: Treatment of rosacea 1% metronidazole cream: A double blind study. Br J Dermatol 1983;108: Gamborg Nielsen P: A double-blind study of 1% metronidazole cream versus systemic oxytetracycline theray for rosacea. Br J Dermatol 1983;109: Gamborg Nielsen P: The relase rate for rosacea after treatment with either oral tetracycline or metronidazole cream. Br J Dermatol 1983; 109: Gamborg Nielsen P: Metronidazole treatment in rosacea. Int J Dermatol 1988;27: Lowe NJ, Henderson T, Millikan LE, Smith S, Truk K, Parker F: Toical metronidazole for severe and recalcitrant rosacea: A rosective oen trial. Cutis 1989;43: Aranson IK, Rumsfield JA, West DP, Alexander J, Fisher JH, Paloucek FP: Evaluation of toical metronidazole gel in acne rosacea. Drug Intell Clin Pharm 1987;21: Bleicher PA, Charles JH, Sober JA: Toical metronidazole theray for rosacea. Arch Dermatol 1987;123: Guarrera M, Brusati C, Rebora A: Toical metronidazole does not abate UVB-induced erythema. Dermatology 2001;203: Patrizi A, Neri I, Chieregato C, Misciali M: Demodicidosis in immunocometent young children: Reort of eight cases. Dermatology 1997;195: Dermatology 2002;205: Koçak/Yağlı/Vahaoğlu/Ekşioğlu