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Byline: Abdurrahman Karaman (1), Mustafa Iraz (2), Hale Kirimlioglu (3), Nese Karadag (3), Erkan Tas (1), Ersin Fadillioglu (4) Keywords: Leflunomide; Extrahepatic cholestasis; Impaired bile flow; Bile duct ligation; Oxidative stress; Lipid peroxidation Abstract: Cholestasis, or impaired bile flow, occurs in a wide variety of liver diseases and causes hepatic damage by retention and accumulation of toxic hydrophobic bile salts inducing persistent inflammation and oxidative stress. In the present research, we studied the effect of leflunomide, a novel immunosuppressive and anti-inflammatory agent against autoimmune disease, on hepatic damage produced by double ligature of the extrahepatic biliary duct in Wistar Albino rats. Cholestasis was done by double ligature and section of the extrahepatic biliary duct (BDL). Leflunomide was given i.g. 10 mg/kg/day. The severity of cholestasis and hepatic injury was determined by changes in the plasma enzyme activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and levels of direct bilirubin. Malondialdehyde (MDA), protein carbonyl (PC), nitric oxide (NO), catalase (CAT) and superoxide dismutase (SOD) were determined to the oxidative status in the liver tissue. Myeloperoxidase (MPO) activity and levels of tissue hydroxyproline (HPR) were determined to neutrophil activation and collagen accumulation, respectively. Further, histological changes were studied. Treatment with leflunomide markedly reduced serum transaminase activities as compared to BDL rats. At the same time leflunomide significantly inhibited increases in liver MDA, PC and NO levels and also attenuated the depletion of CAT and SOD in the liver after bile duct ligation. Similarly, increase in tissue MPO activity and HPR due to BDL was also attenuated by leflunomide treatment. These findings were supported by histopathological findings. These findings suggested that leflunomide can attenuate hepatic damage in extrahepatic cholestasis by prevention of oxidative stress and inflammatory process. Author Affiliation: (1) Department of Pediatric Surgery, Turgut Ozal Medical Center, Faculty of Medicine, Inonu University, 44280, Malatya, Turkey (2) Department of Pharmacology, Turgut Ozal Medical Center, Faculty of Medicine, Inonu University, Malatya, Turkey (3) Department of Pathology, Turgut Ozal Medical Center, Faculty of Medicine, Inonu University, Malatya, Turkey (4) Department of Physiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey Article History: Registration Date: 10/07/2006 Accepted Date: 10/07/2006 Online Date: 05/08/2006

Byline: Hong Wei Yao (1,2), Jun Li (2), Ji Qiang Chen (1), Shu Yun Xu (2) Keywords: leflunomide; A771726; lipopolysaccharide; cytokines; Kupffer cells; hepatocytes Abstract: This study was conducted to investigate the importance of direct contact between Kupffer cells (KCs) and hepatocytes (HCs) during the hepatic inflammatory responses, and the effect of leflunomide's active metabolite, A771726, on cytokines in KCs and HCs (DC cocultures) and KC cultures using an in vitro approach. Lipopolysaccharide (LPS)-induced inflammatory response in monocultures of rats HCs and KCs were compared with DC cocultures. Tumor necrosis factor-[alpha] (TNF-[alpha]) and interleukin-1 (IL-1) concentrations of different culture supernatants were measured with ELISA. TNF-[alpha] and IL-1 mRNA in KCs of inflammatory liver injury was analyzed with reverse transcription polymerase chain reaction (RT-PCR). Our data showed that DC cocultures exhibited the highest production of TNF-[alpha] and IL-1 compared with other cultures, and these cytokines were mainly produced by KCs, in particular activated KCs. Time course studies revealed an increased production of TNF-[alpha] preceding the IL-1 production, suggesting that increased TNF-[alpha] levels could be involved in the increased IL-1 production. Leflunomide's active metabolite, A771726, has significantly inhibitory effect on TNF-[alpha] and IL-1 at protein and transcription levels, and reduced production of IL-1 by A771726 was associated with inhibitory action of A771726 on TNF-[alpha]. These results provided evidence that leflunomide significantly inhibited TNF-[alpha] and IL-1 from KCs. Author Affiliation: (1) School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China (2) Zhejiang Respiratory Drugs Research Laboratory of State Drugs Administration of China, Medical School of Zhejiang University, Hangzhou, People's Republic of China Article History: Registration Date: 28/09/2004

Byline: Vandana. Mehta, Saurav. Kisalay, C. Balachandran Introduction Leflunomide is an isoxazole immuno-modulatory agent which belongs to DMARD (Disease Modifying Antirheumatic Drug) class of drugs. It is an inhibitor of [...]

ABSTRACT: The newer therapies have shown increased effectiveness in rheumatoid arthritis, but they may also have adverse effects. Adverse GI reactions to leflunomide occur within the first weeks of therapy [...]