ORIGINAL ARTICLE Neuroscience http://dx.doi.org/10.3346/jkms.2012.27.2.200 • J Korean Med Sci 2012; 27: 200-206 Oral Solubilized Ursodeoxycholic Acid Therapy in Amyotrophic Lateral Sclerosis: A Randomized Cross-Over Trial Ju-Hong Min1, Yoon-Ho Hong2, Jung-Joon Sung3, Sung-Min Kim3, Jung Bok Lee4, and Kwang-Woo Lee3 1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; 2Department of Neurology, Seoul Metropolitan Goverment Boramae Medical Center, Seoul National University College of Medicine, Seoul; 3Department of Neurology, Clinical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul; 4Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Received: 23 August 2011 Accepted: 11 November 2011 Address for Correspondence: Kwang-Woo Lee, MD Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea Tel: +82.2-2072-3215, Fax: +82.2-3672-7553 E-mail: kwoo@plaza.snu.ac.kr This study was supported by a grant of the Seoul National University Hospital (20054179). To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) with oral solubilized formula in amyotrophic lateral sclerosis (ALS) patients, patients with probable or definite ALS were randomized to receive oral solubilized UDCA (3.5 g/140 mL/day) or placebo for 3 months after a run-in period of 1 month and switched to receive the other treatment for 3 months after a wash-out period of 1 month. The primary outcome was the rate of progression, assessed by the Appel ALS rating scale (AALSRS), and the secondary outcomes were the revised ALS functional rating scale (ALSFRS-R) and forced vital capacity (FVC). Fifty-three patients completed either the first or second period of study with only 16 of 63 enrolled patients given both treatments sequentially. The slope of AALSRS was 1.17 points/month lower while the patients were treated with UDCA than with placebo (95% CI for difference 0.08-2.26, P = 0.037), whereas the slopes of ALSFRS-R and FVC did not show significant differences between treatments. Gastrointestinal adverse events were more common with UDCA (P < 0.05). Oral solubilized UDCA seems to be tolerable in ALS patients, but we could not make firm conclusion regarding its efficacy, particularly due to the high attrition rate in this cross-over trial. Key Words: Amyotrophic Lateral Sclerosis; Ursodeoxycholic Acid; Cross-Over Trial INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neu- rodegenerative disease that primarily affects upper and lower motor neurons, resulting in death three to five years after symp- tom onset in the majority of patients (1). The pathomechanism of ALS is largely unknown, but research efforts have been focused on several hypothetical models such as glutamate excitotoxicity, oxidative damage, mitochondrial dysfunction, inflammation and apoptosis (2). Numerous clinical trials have been performed, but unfortunately all failed to demonstrate any beneficial effects on the disease progression or survival, with the exception of rilu- zole. Ursodeoxycholic acid (3α, 7β-dihydroxy-5β-cholanic acid, UDCA), a hydrophilic tertiary bile acid, is a major component of black bear bile that was used in traditional Chinese medicine (3). It is the current mainstay of treatment of primary biliary cirrho- sis as the only drug approved by the US FDA, and has been in- creasingly used for the treatment of various cholestatic liver dis- eases such as primary sclerosing cholangitis and progressive fa- milial intrahepatic cholestasis (4, 5). Although the mechanisms of action is not completely understood, UDCA and its taurine- conjugated derivative (TUDCA) have been shown to strongly inhibit apoptosis in different type of cells by either stabilizing the mitochondrial membrane, or modulating the expression of specific upstream targets of apoptosis (6-11). TUDCA improved the survival and function of nigral transplants in a rat model of Parkinson’s disease (12), and the neuroprotective effect was also reported in a transgenic mouse model of Huntington’s disease (13), and rat models of ischemic and hemorrhagic stroke (14, 15). ALS must be such a complex disease with numerous factors contributing to the degeneration of motor neurons, that an ap- proach targeting a single molecule or process may not be effec- tive (2). In this respect, UDCA may be a promising therapeutic candidate because of its multiple mechanisms of cytoprotective actions which may include antiapoptotic, immunomodulatory and antioxidant effects (6, 16, 17). Despite these therapeutic po- tentials, however, clinical application of UDCA has been limited to the hepatobiliary disorders exclusively. This is because of its unique pharmacokinetic properties which prevent the molecule © 2012 The Korean Academy of Medical Sciences. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. pISSN 1011-8934 eISSN 1598-6357