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Safety, Tolerability, and Cerebrospinal Fluid Penetration of Ursodeoxycholic Acid in Patients With Amyotrophic Lateral Sclerosis

Parry, Gareth J. MD*; Rodrigues, Cecilia M.P. PhD; Aranha, Marcia M. MSc; Hilbert, Sarah J. MS*; Davey, Cynthia MS§; Kelkar, Praful MD*; Low, Walter C. PhD; Steer, Clifford J. MD¶#

doi: 10.1097/WNF.0b013e3181c47569
Original Articles

Objective: Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration.

Methods: Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly.

Results: Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner.

Conclusions: These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.

From the Department of *Neurology, University of Minnesota Medical School, Minneapolis, MN; †iMed.UL, ‡Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal; §Biostatistical Design and Analysis Center, University of Minnesota Academic Health Center; and Departments of ∥Neurosurgery, ¶Medicine, and #Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN.

Address correspondence and reprint requests to Gareth J. Parry, MD, University of Minnesota, 717 Delaware St SE, MC 1932, Minneapolis, MN 55414; E-mail: parry001@umn.edu

G.J. Parry and C.M.P. Rodrigues contributed equally to this work.

This project was supported by a grant from Axcan Pharma Inc, Mont-Saint-Hilaire, Quebec, Canada. M.M.A. was a recipient of PhD fellowship SFRH/BD/28429/2006 from Fundação para a Ciência e a Tecnologia, Portugal.

The authors report no conflicts of interest.

© 2010 Lippincott Williams & Wilkins, Inc.