Publication: Fare Psoriasis Modelinde Topikal 4'4 Diamino Difenil Sülfon (Dapson) Jelin Tedaviye Etkisi
Abstract
Giriş ve Amaç: Psoriasis toplumda %2 sıklıkta görülen, etiyolojisinde genetik ve çevresel faktörlerin rol oynadığı kronik inflamatuar bir deri hastalığıdır. Tedavisinde topikal, sistemik tedaviler ve fototerapi kullanılmaktadır. Dapson (4,4'-diaminodifenilsülfon) 1940'larda sentezlenen bir sülfon bileşiği olup antiinflamatuar ve antimikrobiyal özelliklere sahiptir. Antiinflamatuar etkileri nedeniyle püstüler psoriasiste sınırlı vakada denenmiş olup bu vakalarda çoğunlukla faydalı bulunmuştur. Literatürde topikal dapsonun psoriasisteki etkisini değerlendiren randomize kontrollü çalışma bulunmamaktadır. Bu çalışmada fare psoriasis modelinde topikal dapsonun etkinliğini topikal kortikosteroidler ile klinik, histopatolojik ve ELISA yöntemi aracılığıyla sitokin düzeyleri yönünden karşılaştırmayı hedefledik. Gereç ve Yöntem: Çalışmada ortalama 6-8 haftalık olan ve canlı ağırlıkları 32-33 gram arasında değişen 20 dişi, 20 erkek olmak üzere toplam 40 adet Balb/c ırkından fare deney materyalini oluşturdu. Tüm hayvanlar her bir grupta 4 erkek 4 dişi olacak şekilde 5 eşit gruba ayrıldı. Topikal kremlerin uygulama yeri olarak sırt ve kulak derisi seçildi. Ketamin ve ksilazin anestezisi altında sırt dorsal bölge tıraşlandı ve başlangıç kulak kalınlıkları ölçüldü. İlk gruba 14 gün boyunca sadece 62,5 mg dozda imikimod krem (Aldara) uygulandı. İkinci, üçüncü ve dördüncü gruplara 7 gün boyunca sadece 62,5 mg dozda imikimod krem (Aldara) uygulandı. Yedinci günden sonra aynı bölgeye önce imikimod krem, 6 saat sonra ise ikinci gruba 62,5 mg/kg dozda dapson jel (Acnewell), üçüncü gruba 125 mg/kg dozda dapson jel (Acnewell) ve dördüncü gruba 50 mg dozda betametazon valerat krem (Betnovate) topikal uygulamaları yapıldı. Beşinci gruba ise 14 gün boyunca Acnewell jelde çözücü olarak kullanılan dietilen glikol monoetil eter (Merck) topikal olarak uygulandı. Yedinci gün sadece klinik değerlendirme yapıldı. On dördüncü gün ise klinik değerlendirme yapıldıktan sonra farelere anestezi altında ötanazi işlemi yapılarak sırt derilerinden bistüri yardımıyla histopatolojik inceleme ve sitokin ölçümleri için deri örnekleri alındı. Elde edilen sonuçlar gruplar arasında karşılaştırıldı. Bulgular: Deney grupları ağırlık ve cinsiyet dağılımı açısından incelendiğinde gruplar arasında anlamlı fark bulunmadı (p>0,05). Kulak kalınlıklarının değişimleri incelendiğinde tüm gruplarda 0. gün ve 14. günler arasında anlamlı farklılıklar tespit edildi. (p<0,05). Psoriasis alan şiddet skorlarındaki (PASI) değişimler incelendiğinde 0. gün ve 7. gün arasında tüm gruplarda anlamlı farklılıklar tespit edilirken, 7.gün ile 14. günler arasında ise birinci grup dışındaki tüm gruplarda anlamlı farklılıklar tespit edildi (p<0,05). Deney sonunda 14. günde yapılan histopatolojik değerlendirmede Kogoj püstülleri ve Munro mikroapseleri bulguları dışındaki tüm parametrelerde gruplar arasında anlamlı farklılıklar tespit edildi (p<0,05). Histopatolojik incelemede, yüksek doz (125 mg/kg) dapson ve betametazon valerat kullanılan grupların total histopatolojik skor ortalamaları birbirine yakın olarak izlendi. ELISA testi ile sitokin ölçümleri yapıldığında üç sitokin (TNF-α, IL-17A ve IL-23A) düzeyinde de gruplar arasında anlamlı farklılıklar tespit edildi. Farklılıklar çoğunlukla dietilen glikol monoetil eter kullanılan beşinci gruptan kaynaklandı. Tartışma ve Sonuç: Çalışmanın sonunda hayvan kaybı yaşanmamıştır. Kulak kalınlığı ölçümleri, PASI ve histopatolojik değerlendirme incelendiğinde yüksek doz (125 mg/kg) dapson uygulanan grup betametazon valerat uygulanan grupla benzer sonuçlar elde etmiştir. Düşük doz (62,5 mg/kg) dapson tedavisi, yüksek doz (125 mg/kg) dapson tedavisine göre klinik ve histopatolojik iyileşme açısından daha başarısız bulunmuştur. Bu durum topikal dapsonun tedavide başarısının doza bağımlı olduğunu göstermiştir. ELISA yöntemi aracılığıyla ölçülen sitokin düzeyleri (TNF-α, IL-17A ve IL-23A) incelendiğinde dapson uygulanan her iki grubun da sadece imikimod uygulanan birinci grupla benzer sitokin düzeylerine sahip olduğu saptanmıştır. Bu durum topikal dapson tedavisinin TNF-α, IL-17A ve IL-23A sitokin düzeylerine etkisinin zayıf olduğunu göstermiştir. Sonuç olarak topikal dapson tedavisi fare psoriasis modelinde etkili ve güvenilir bulunmakla birlikte insanlar üzerinde aynı etkiyi gösterip göstermeyeceğini öğrenmek için ileri faz çalışmalarına ihtiyaç vardır.
Introduction and Aim: Psoriasis is a chronic inflammatory skin disease with a prevalence of 2% in the general population, with genetic and environmental factors playing a role in its aetiology. Topical and systemic treatments and phototherapy are used in the treatment of psoriasis. Dapsone (4,4'-diaminodiphenylsulfone) is a sulfone compound synthesised in the 1940s that has anti-inflammatory and antimicrobial properties. Due to its anti-inflammatory effects, it has been tried in limited cases of pustular psoriasis and has mostly been beneficial in these cases. In this study, we aimed to compare the efficacy of topical dapsone with topical corticosteroids in a murine psoriasis model in terms of clinical, histopathological and cytokine levels by ELISA. Materials and Methods: A total of 40 Balb/c mice (20 male and 20 female) with an average age of 6-8 weeks and body weight between 32-33 grams were used as experimental material. All animals were divided into 5 equal groups with 4 males and 4 females in each group. Topical creams were applied to the back and ear skin. The dorsal region was shaved under ketamine and xylazine anaesthesia and the initial ear thickness was measured. The first group received only imiquimod cream (Aldara) at a dose of 62.5 mg for 14 days. The second, third and fourth groups received only imiquimod cream (Aldara) at a dose of 62.5 mg for 7 days. After the seventh day, imiquimod cream was first applied to the same area, followed 6 hours later by dapsone gel (Acnewell) at a dose of 62.5 mg/kg in the second group, dapsone gel (Acnewell) at a dose of 125 mg/kg in the third group and betamethasone valerate cream (Betnovate) at a dose of 50 mg in the fourth group. The fifth group received topical application of diethylene glycol monoethyl ether (Merck), used as a solvent in Acnewell gel, for 14 days. On the seventh day, only clinical evaluation was performed. On day 14, after the clinical evaluation, the mice were euthanised under anaesthesia and skin samples were taken from the dorsal skin with a scalpel for histopathological evaluation and cytokine measurements. The results were compared between groups. Results: When the experimental groups were analysed in terms of weight and sex distribution, no significant difference was found between the groups (p>0.05). When the changes in ear thickness were analysed, significant differences were found between day 0 and day 14 in all groups (p<0.05). When analysing the changes in psoriasis area severity scores (PASI), significant differences were found between day 0 and day 7 in all groups, while significant differences were found between day 7 and day 14 in all groups except the first group (p<0.05). Histopathological evaluation on day 14 at the end of the experiment showed significant differences between groups in all parameters except Kogoj pustules and Munro microabscesses (p<0.05). On histopathological examination, the mean total histopathological scores of the high dose (125 mg/kg) dapsone and betamethasone valerate groups were close to each other. When cytokines were measured by ELISA, significant differences were found between the groups for all three cytokine levels (TNF-α, IL-17A and IL-23A). The differences were mainly due to the fifth group using diethylene glycol monoethyl ether. Discussion and Conclusion: There were no animal losses at the end of the study. When ear thickness measurements, psoriasis area severity score (PASI) and histopathological evaluation were analysed, the high dose (125 mg/kg) dapsone group achieved similar results to the betamethasone valerate group. Low-dose (62.5 mg/kg) dapsone treatment was less successful than high-dose (125 mg/kg) dapsone treatment in terms of clinical and histopathological improvement. This showed that the success of topical dapsone treatment was dose dependent. When cytokine levels (TNF-α, IL-17A and IL-23A) measured by ELISA were analysed, it was found that both groups treated with dapsone had similar cytokine levels to the first group treated with imiquimod alone. This showed that topical dapsone treatment had a weak effect on TNF-α, IL-17A and IL-23A cytokine levels. In conclusion, although topical dapsone treatment was found to be effective and safe in the murine psoriasis model, further phase studies are needed to find out whether it will have the same effect in humans.
Introduction and Aim: Psoriasis is a chronic inflammatory skin disease with a prevalence of 2% in the general population, with genetic and environmental factors playing a role in its aetiology. Topical and systemic treatments and phototherapy are used in the treatment of psoriasis. Dapsone (4,4'-diaminodiphenylsulfone) is a sulfone compound synthesised in the 1940s that has anti-inflammatory and antimicrobial properties. Due to its anti-inflammatory effects, it has been tried in limited cases of pustular psoriasis and has mostly been beneficial in these cases. In this study, we aimed to compare the efficacy of topical dapsone with topical corticosteroids in a murine psoriasis model in terms of clinical, histopathological and cytokine levels by ELISA. Materials and Methods: A total of 40 Balb/c mice (20 male and 20 female) with an average age of 6-8 weeks and body weight between 32-33 grams were used as experimental material. All animals were divided into 5 equal groups with 4 males and 4 females in each group. Topical creams were applied to the back and ear skin. The dorsal region was shaved under ketamine and xylazine anaesthesia and the initial ear thickness was measured. The first group received only imiquimod cream (Aldara) at a dose of 62.5 mg for 14 days. The second, third and fourth groups received only imiquimod cream (Aldara) at a dose of 62.5 mg for 7 days. After the seventh day, imiquimod cream was first applied to the same area, followed 6 hours later by dapsone gel (Acnewell) at a dose of 62.5 mg/kg in the second group, dapsone gel (Acnewell) at a dose of 125 mg/kg in the third group and betamethasone valerate cream (Betnovate) at a dose of 50 mg in the fourth group. The fifth group received topical application of diethylene glycol monoethyl ether (Merck), used as a solvent in Acnewell gel, for 14 days. On the seventh day, only clinical evaluation was performed. On day 14, after the clinical evaluation, the mice were euthanised under anaesthesia and skin samples were taken from the dorsal skin with a scalpel for histopathological evaluation and cytokine measurements. The results were compared between groups. Results: When the experimental groups were analysed in terms of weight and sex distribution, no significant difference was found between the groups (p>0.05). When the changes in ear thickness were analysed, significant differences were found between day 0 and day 14 in all groups (p<0.05). When analysing the changes in psoriasis area severity scores (PASI), significant differences were found between day 0 and day 7 in all groups, while significant differences were found between day 7 and day 14 in all groups except the first group (p<0.05). Histopathological evaluation on day 14 at the end of the experiment showed significant differences between groups in all parameters except Kogoj pustules and Munro microabscesses (p<0.05). On histopathological examination, the mean total histopathological scores of the high dose (125 mg/kg) dapsone and betamethasone valerate groups were close to each other. When cytokines were measured by ELISA, significant differences were found between the groups for all three cytokine levels (TNF-α, IL-17A and IL-23A). The differences were mainly due to the fifth group using diethylene glycol monoethyl ether. Discussion and Conclusion: There were no animal losses at the end of the study. When ear thickness measurements, psoriasis area severity score (PASI) and histopathological evaluation were analysed, the high dose (125 mg/kg) dapsone group achieved similar results to the betamethasone valerate group. Low-dose (62.5 mg/kg) dapsone treatment was less successful than high-dose (125 mg/kg) dapsone treatment in terms of clinical and histopathological improvement. This showed that the success of topical dapsone treatment was dose dependent. When cytokine levels (TNF-α, IL-17A and IL-23A) measured by ELISA were analysed, it was found that both groups treated with dapsone had similar cytokine levels to the first group treated with imiquimod alone. This showed that topical dapsone treatment had a weak effect on TNF-α, IL-17A and IL-23A cytokine levels. In conclusion, although topical dapsone treatment was found to be effective and safe in the murine psoriasis model, further phase studies are needed to find out whether it will have the same effect in humans.
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