Min J-H, et al. • Oral Ursodeoxycholic Acid Therapy in Amyotrophic Lateral Sclerosis 3. Hagey LR, Crombie DL, Espinosa E, Carey MC, Igimi H, Hofmann AF. Ursodeoxycholic acid in the Ursidae: biliary bile acids of bears, pandas, and related carnivores. J Lipid Res 1993; 34: 1911-7. 4. Leuschner U, Fischer H, Kurtz W, Güldütuna S, Hübner K, Hellstern A, Gatzen M, Leuschner M. Ursodeoxycholic acid in primary biliary cir- rhosis: results of a controlled double-blind trial. Gastroenterology 1989; 97: 1268-74. 5. Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders.’ J Hepatol 2001; 35: 134-46. 6. Rodrigues CM, Steer CJ. The therapeutic effects of ursodeoxycholic acid as an anti-apoptotic agent. Expert Opin Investig Drugs 2001; 10: 1243-53. 7. Rodrigues CM, Stieers CL, Keene CD, Ma X, Kren BT, Low WC, Steer CJ. Tauroursodeoxycholic acid partially prevents apoptosis induced by 3-ni- tropropionic acid: evidence for a mitochondrial pathway independent of the permeability transition. J Neurochem 2000; 75: 2368-79. 8. Solá S, Castro RE, Laires PA, Steer CJ, Rodrigues CM. Tauroursodeoxy- cholic acid prevents amyloid-beta peptide-induced neuronal death via a phosphatidylinositol 3-kinase-dependent signaling pathway. Mol Med 2003; 9: 226-34. 9. Solá S, Castro RE, Kren BT, Steer CJ, Rodrigues CM. Modulation of nu- clear steroid receptors by ursodeoxycholic acid inhibits TGF-beta1-in- duced E2F-1/p53-mediated apoptosis of rat hepatocytes. Biochemistry 2004; 43: 8429-38. 10. Ramalho RM, Borralho PM, Castro RE, Solá S, Steer CJ, Rodrigues CM. Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Al- zheimer’s disease mutant neuroblastoma cells. J Neurochem 2006; 98: 1610-8. 11. Amaral JD, Castro RE, Solá S, Steer CJ, Rodrigues CM. p53 is a key mo- lecular target of ursodeoxycholic acid in regulating apoptosis. J Biol Chem 2007; 282: 34250-9. 12. Duan WM, Rodrigues CM, Zhao LR, Steer CJ, Low WC. Tauroursode- oxycholic acid improves the survival and function of nigral transplants in a rat model of Parkinson’s disease. Cell Transplant 2002; 11: 195-205. 13. Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. Tau- roursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington’s disease. Proc Natl Acad Sci U S A 2002; 99: 10671-6. 14. Rodrigues CM, Spellman SR, Solá S, Grande AW, Linehan-Stieers C, Low WC, Steer CJ. Neuroprotection by a bile acid in an acute stroke model in the rat. J Cereb Blood Flow Metab 2002; 22: 463-71. 15. Rodrigues CM, Sola S, Nan Z, Castro RE, Ribeiro PS, Low WC, Steer CJ. Tauroursodeoxycholic acid reduces apoptosis and protects against neu- rological injury after acute hemorrhagic stroke in rats. Proc Natl Acad Sci U S A 2003; 100: 6087-92. 16. Bellentani S. Immunomodulating and anti-apoptotic action of ursode- oxycholic acid: where are we and where should we go? Eur J Gastroen- terol Hepatol 2005; 17: 137-40. 17. Serviddio G, Pereda J, Pallardó FV, Carretero J, Borras C, Cutrin J, Ven- demiale G, Poli G, Viña J, Sastre J. Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress. Hepatology 2004; 39: 711-20. 18. Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol Suppl 1994; 204: 1-15. 19. Park IH, Kim MK, Kim SU. Ursodeoxycholic acid prevents apoptosis of mouse sensory neurons induced by cisplatin by reducing P53 accumula- tion. Biochem Biophys Res Commun 2008; 377: 1025-30. 20. Thao TD, Ryu HC, Yoo SH, Rhee DK. Antibacterial and anti-atrophic effects of a highly soluble, acid stable UDCA formula in Helicobacter py- lori-induced gastritis. Biochem Pharmacol 2008; 75: 2135-46. 21. Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neu- rology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyo- troph Lateral Scler Other Motor Neuron Disord 2000; 1: 293-9. 22. Appel V, Stewart SS, Smith G, Appel SH. A rating scale for amyotrophic lateral sclerosis: description and preliminary experience. Ann Neurol 1987; 22: 328-33. 23. Haverkamp LJ, Appel V, Appel SH. Natural history of amyotrophic later- al sclerosis in a database population. Validation of a scoring system and a model for survival prediction. Brain 1995; 118: 707-19. 24. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 1999; 169: 13-21. 25. Czaplinski A, Yen AA, Appel SH. Forced vital capacity (FVC) as an indi- cator of survival and disease progression in an ALS clinic population. J Neurol Neurosurg Psychiatry 2006; 77: 390-2. 26. Lange DJ, Murphy PL, Diamond B, Appel V, Lai EC, Younger DS, Appel SH. Selegiline is ineffective in a collaborative double-blind, placebo-con- trolled trial for treatment of amyotrophic lateral sclerosis. Arch Neurol 1998; 55: 93-6. 27. Grizzle JE. The two-period change-over design an its use in clinical trials. Biometrics 1965; 21: 467-80. 28. Miller RG, Moore DH 2nd, Gelinas DF, Dronsky V, Mendoza M, Barohn RJ, Bryan W, Ravits J, Yuen E, Neville H, Ringel S, Bromberg M, Petajan J, Amato AA, Jackson C, Johnson W, Mandler R, Bosch P, Smith B, Graves M, Ross M, Sorenson EJ, Kelkar P, Parry G, Olney R; Western ALS Study Group. Phase III randomized trial of gabapentin in patients with amyo- trophic lateral sclerosis. Neurology 2001; 56: 843-8. 29. Traynor BJ, Zhang H, Shefner JM, Schoenfeld D, Cudkowicz ME; NEALS Consortium. Functional outcome measures as clinical trial endpoints in ALS. Neurology 2004; 63: 1933-5. 30. Parry GJ, Rodrigues CM, Aranha MM, Hilbert SJ, Davey C, Kelkar P, Low WC, Steer CJ. Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic acid in patients with amyotrophic lateral sclerosis. Clin Neuropharmacol 2010; 33: 17-21. 206 http://jkms.org http://dx.doi.org/10.3346/jkms.2012.27.2.200