UFUK KUTLUANA, NEVİN ORUÇ, Selma DİNÇER TEKEKOĞLU, Neşe ÇALLI DEMİRKAN, Beyza AKDAĞ, Mustafa YILMAZ, Nadir YÖNETÇİ, Ömer ÖZÜTEMİR

Leflunomid Methotrexat'a bağlı karaciğer toksisitesini önleyebilir mi?

GİRİŞ ve AMAÇ: Uzun dönem Methotrexat kullanımı artmış karaciğer hasarı ve fibrozis riski ile ilişkilidir. Leflunomid hastalık modifiye edici bir ilaçtır. Leflunomid nükleer faktör kappa B aktivasyonunun güçlü bir inhibitörüdür. Aynı zamanda anti-oksidan aktivitesi de vardır. Bu deneysel çalışmada Methotrexat'ın neden olduğu karaciğer toksisitesinde Leflunomid tedavisinin etkinliği araştırılmıştır. YÖNTEM ve GEREÇLER: 39 rat 4 gruba ayrılmıştır. Methotrexat'a bağlı karaciğer toksisitesi tek doz 20mg/kg Methotrexat'ın periton içine injeksiyonu ile oluşturulmuştur. Ardından Leflunomid 5 gün boyunca 10 mg/kg dozda verilmiştir. Ardından serum örnekleri ve homojenize karaciğer örnekleri toplanmıştır. Serum alanin aminotransferaz, alkalin fosfataz, superoxide dismutaz, myeloperoxidaz aktivitesi, glutatyon düzeyleri çalışılmış ve histopatolojik değerlendirme yapılmıştır. BULGULAR: Leflunomid tedavisi tedavi almayan gruba göre karaciğer semikantitatif skalaya bağlı histopatolojik değerlendirmede anlamlı düzelme sağlamıştır (Patolojik skor 1.1+0.7 ve 5.1+2, p<0,01). Leflunomid tedavisi Kuppfer hücre aktivasyonunu anlamlı derecede iyileştirmiştir. (Aktive Kuppfer hücre skorunda yükselme 0.2+0.6 ve 2.5+1.01, p = 0.001). Leflunomid tedavisi alan grupta Methotrexat toksisite grubuna göre serum alanin aminotransferaz, alkalin fosfataz düzeyleri düşük, glutatyon seviyesi, superoxide dismutaz ve myeloperoxidaz aktivitesi benzer bulunmuştur. TARTIŞMA ve SONUÇ: Bu deneysel modelde Leflunomid tedavisi Methotrexat'a bağlı karaciğer toksisitesini iyileştirmektedir.

Anahtar Kelimeler:

Leflunomid, methotrexat, karaciğer toksisitesi

Can Leflunomide prevent Methotrexate induced liver toxicity?

INTRODUCTION: Long-term clinical use of Methotrexate is to connect with a raised risk of liver injury and fibrosis. Leflunomide is a is a disease-modifying drug. Leflunomide has a powerful inhibitory effect on nuclear factor kappa B activation. Leflunomide also presents antioxidant activity. In this experimental study, we aimed to investigate the effects of Leflunomide treatment on Methotrexate -induced hepatotoxicity. METHODS: Thirty-nine rats were divided into 4 groups. A single dose of 20mg/kg Methotrexate was injected intraperitoneally for Methotrexate-induced hepatotoxicity. After induction, Leflunomide (10 mg/kg) was administered into the stomach for consecutive 5 days. Then, serum samples and homogenated liver tissues were collected for analyzed serum alanine aminotransferase, alkaline phosphatase, superoxide dismutase activity, myeloperoxidase activity, glutathione levels and assessment of histopathology. RESULTS: Leflunomide treatment significantly ameliorated total histopathologic score according to semiquantitative scale compared to the untreated group, (Pathological score 1.1+0.7 versus 5.1+2 respectively, p<0,01). Leflunomide treatment significantly ameliorated Kuppfer cell activation. (Elevation of the activated Kupffer cells score were 0.2+0.6 and 2.5+1.01 respectively, p = 0.001). The serum alanine aminotransferase, alkaline phosphatase levels were lower and glutathione levels, myeloperoxidase activity, and superoxide dismutase activity were similar between Leflunomide treated and untreated Methotrexate toxicity groups. DISCUSSION AND CONCLUSION: Leflunomide treatment ameliorated Methotrexate induced liver toxicity in an experimental model.

Keywords:

Leflunomide, methotrexate, liver toxicity,

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