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1 Itraconazole =Abstract= Therapeutic Effect of Itraconazole in Seborrheic Dermatitis Eun Joo Park, Chul Woo Kim, Kwang Ho Kim, Kyu Joong Ahn* and Kwang Joong Kim Department of Dermatology, College of Medicine, Hallym University, Anyang, Korea Department of Dermatology, College of Medicine, Konkuk University*, Seoul, Korea Background: Seborrheic dermatitis is a very common chronic inflammatory disease. The causal factor of the disease is still unknown, but early investigators focused on the role of Malassezia yeasts. These yeasts are also normal skin commensals, thus their importance as pathogens in this disorder came to be doubted. However, it was subsequently found that treatment of seborrheic dermatitis with an antifungal agent not only resulted in clinical improvement but also reduced the number of Malassezia yeasts on the skin. Object: The purpose of this study is to confirm relationship between seborrheric dermatits and Malassezia yeast, and to evaluate the therapeutic efficacy of oral itraconazole in the seborrheic dermatitis. Methods: Using the scrub-wash technique in the glabella and swabbing technique in the scalp, the number of cultured Malassezia yeasts were counted in 30 patients with seborrheic dermatitis and 20 control persons. The patients took itraconazole, 100mg/day, during 4weeks. The clinical and mycologic score were measured at the initial evaluation, followed after 2weeks and 4weeks Result: The number of Malassezia yeasts in patient with seborrheic dermatits were significantly higher than in normal control group. There was statistically significant decrease in the clinical and mycological score after a 4 week trial of oral itraconazole in the seborrheic dermatitis group. Conclusion: This study indicates that Malassezia yeast may be one of the important causative factor of seborrheic dermatitis and itraconazole plays an important role in the treatment of seborrheic dermatitis Key Words: Seborrheic dermatitis, Malassezia yeasts, Itraconazole (031) , Fax: (031) , kkj51818@hallym.or.kr

2 Itraconazole Malassezia Malassezia Malassezia Malassezia Malassezia itraconazole Smith Seborrhea Area and Severity index (SASI) (Table 1) 0, mild 1, moderate 2, severe 3 scrubwash technique swabbing technique (cm) Malassezia 1L gycerol monostearate (BDH) 0.5g,bacteriological pepton (Oxoid) 10g,glucose (Oxoid) 5g, yeast extract (Oxoid) 0.1g, ox bile (Merck) 4g, agar No. 1 (Oxoid) 12g, Tween 60 (Yakuri) 0.5ml, glycerol (Tedia) 1ml 15psi 20 Table 1. Seborrhea Area and Severity Index* 1. The area or degree of involvement of the face and scalp are independently rated on a scale of 0~6 as follows: Degree of Involvement Rating < 1% % % % % % % 6 Area of Face involved (AF) Area of Scalp involved (AS) 2. The erythema and scaling of the face and scalp are rated independently according to the following scale: Severity of the condition: None Very Mild Mild Moderate Severe Rating FACE: Erythema (EF) Scaling (SF) SCALP: Erythema (EF) Scaling (SF) 3. The area and severity ratings above are combined in accordance with the following formular to obtain the SASI score for the patient: SASI = 0.5(AF)(EF+SF)+0.5(AS)(ES+SS) SASI = (maximum score = 48) * Quaotation from Altern Med Rev. 2002; 7:

3 cycloheximide (Sigma) 200mg, chloramphenicol(sigma) 50mg 5ml Petri dish NaH2PO4 2H2O 1.17g 100ml 85ml Na2HPO4 10.6g 100ml 915ml ph 7.9 1ml Triton Scrub-wash technique cm 2 1ml 1 1ml swabbing technique 3cm 5 0.9ml (Vortem mixer) 30 Malassezia 0.1ml 1/2 0.9ml 0.1ml Leeming- Notman (cm 2 ) Malassezia (colony-forming units:cfu/cm 2 ) /4.409 swab Malassezia (CFU/swab) Parker Q Ink 15% KOH 1:1 30% H2O2 catalase 0.5% Tween % Tween 80 2% glucose/ 1% pepton 37 Gueho (Table 2) itraconazole (Sporanox 100mg/day 4 2 student t-test Table 2. Key to species of the genus Malassezia 7 Type species : Malassezia furfur (Robin) Baillon 1889 On glucose/pepton agar - Growth M. pachydermatis - No growth - Catalase reaction negative M. restricta - Catalase reaction positive On glucose/peptone agar with 0.5% Tween 60 - No growth Long cylindrical cells; growth at 37 M. obtusa Spherical cells; usually no growth at 37 M. globosa - Growth On glucose/peptone agar with 0.1% Tween 80 - No growth M. slooffiae - Growth - Sympodial budding M. sympodialis - Bud on a broad base, filament formation M. furfur

2005.1.14 1:51 PM 페이지225 mac1 175sepc2 박은주 등: 지루피부염에서 Itraconazole의 치료 효과 p값이 0.05 미만인 경우를 통계학적으로 의미가 있는 경우로 판정하였다. 결 과 1.

4 :51 PM 페이지225 mac1 175sepc2 박은주 등: 지루피부염에서 Itraconazole의 치료 효과 p값이 0.05 미만인 경우를 통계학적으로 의미가 있는 경우로 판정하였다. 결 과 1.지루피부염 환자군과 정상인에서 Malassezia 효모균의 수의 비교 지루 피부염환자 30명과 정상인 20명을 대상 으로 미간과 두피에서 각각 scrub-wash technique과 swabbing technique을 이용한 배양검사를 시행하여 피부 단위면적 (cm2)당 Malassezia 효모균수를 측 정한 결과 환자군에서의 미간에서 ± , 정상 대조군의 미간에서는 470.5±435.7로 유의한 차이를 보였으며 (p< 0.05), 환자군에서의 두피에서 ±5574.7, 정상 대조군의 두피에 서는 ±4640.0로 감소는 하였으나 통계학적 인 유의한 차이를 보이지는 않았다 (p>0.05) (Table 3). Table 3. The population density of Malassezia yeasts from the scalp and face in seborrheic dermatitis and control group Control (N=20) Patients (N=30) Scalp Face Scalp Malassezia Face Density (Mean±SD) ± ± ±435.7 ± face 임상증상과 Malassezia 효모균수의 관계 환자군에서 임상증상이 심한 환자일수록 미간 과 두피에서 배양된 Malassezia 효모균수가 증가 하는 경향을 보였으며, 임상증상과 균수와의 유 의한 상관관계 (미간에서의 상관계수=0.726, 두 피에서의 상관계수=0.477)를 나타내었다 (Fig. 1). 3. 환자군에서 itraconazole 치료전, 후의 임상증 상지수의 비교 지루피부염 환자군에서 itraconazole을 4주간 투 여한 후, 투약전과 2주 후, 4주 후의 Seborrhea Area and Severity index (SASI)는 투약전에는 11.8± 4.7, 2주 후에는 9.7±3.0, 4주 후에는 3.4±1.0로 유 의하게 감소하였고 (p<0.05), 소양증도 투약전에 는 1.9±4.7, 2주 후에는 1.3±0.5, 4주 후에는 0.7± 0.5로 유의한 감소를 보였다 (p<0.05). 투약과 관 련된 부작용은 없었다 (Table 4). 4. 환자군에서 itraconazole 치료전, 후의 Malass- ezia 효모균수의 비교 지루피부염 환자군에서 itraconazole을 4주간 투 여한 후, 투약 전과 2주 후, 4주 후의 Malassezia scalp Malassezia density 4단락 Clinical score 30 Fig. 1. The relationship between the Malassezia density and clinical scores of the face and scalp in seborrheic dermatitis group (Pearson correlation of face=0.726 / Pearson correlation of scal p=0.477). 효모균의 수는 미간에서 투약전에는 ± 개, 2주 후에는 ±1755.4개, 4주 후에는 ±876.0개로 유의하게 감소하였으며 (p<0.05), 두 피에서 투약전에는 ±5574.7개, 2주후에는 ±2926.3개, 4주 후에는 810.0±2277.8개로 유 의하게 감소하였다 (p<0.05) (Table 4). 5. 지루피부염 병변에서 배양된 Malassezia 균종 의 종류 미간에서 배양된 Malassezia 균종을 분류한 본 연구에서 총 30예 중 26예(86.6%)에서 Malassezia 효모균이 단독으로 배양되었는데 M. restricta가 18 예 (60%), M. globosa가 7예 (23.3%), M. furfur가 1예 (3.3%)이었다. 나머지 4예 (13.4%)에서는 M. restricta와 M. globosa가 함께 배양되었다. 또한 두 피에서 배양된 Malassezia 균종은 총 30예 중 27 예(90%)에서 Malassezia 효모균이 단독으로 배양되

5 Table 4. The population density of Malassezia yeast of scalp and face in seborrheic dermatitis group before and after treatment with itraconazole Before 2 weeks 4 weeks Clinical score Malassezia density SASI Pruritus SASI Pruritus Table 5. The Malassezia species cultured from the lesion Malassezia species Scalp Face M. restricta 24 ( 80%) 18 ( 60 %) M. globosa 3 ( 10%) 7 ( 23.3%) M. furfur 0 ( 0%) 1 ( 3.3%) M. restricta / M. globosa 3 ( 10%) 4 ( 13.4%) Total 30 (100%) 30 (100 %) M. restricta 24 (80%) M. globosa 3 (10%) 4 (13.4%) M. restricta M. globosa (Table 5). 1~3% 3~5% Malassezia Malassezia Malassezia fufur Gueho Malassezia Malassezia Malassezia Malassezia Sohnle Collins Malassezia classic, alternative pathway Faergemann Malassezia Bergbrant Malassezia ELISA Malassezia IgG Soeprono Malassezia Malassezia M- alassezia colony

6 Itraconazole colony itraconazole 4 colony Malassezia Williamson Kligman scrubwash technique swabbing technique Malassezia itraconazole Malassezia Malassezia M. restricta M. restricta M. restricta 51.4% 56.8% M. restricta Malassezia Malassezia Itraconazole triazole cytochrome P450 heme lanosterol a-14 demethylation ergosterol a- 14 methyl sterols IL-8 Malassezia itraconazole 100mg 4 Masataro 1 150mg 200mg 2~3 Caputo 7 200mg/day 1 Baysal 7 200mg/day mg/day 100mg 4 colony Itraconazole 0.3~0.5% Malassezia itraconazole Malassezia colony

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Sheu HM, et al., British J Dermatol 1997; 136:884-890 Kao JS, et al., J Invest Dermatol 03; 1:446-464 1 10 0 3 Day Normal MLE Lotion Lotion MLE Cream Cream 80 7 70 6 3 Day Normal MLE Lotion Lotion MLE