Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis.
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.
Parry
Gareth J
GJ
Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55414, USA. parry001@umn.edu
Rodrigues
Cecilia M P
CM
Aranha
Marcia M
MM
Hilbert
Sarah J
SJ
Davey
Cynthia
C
Kelkar
Praful
P
Low
Walter C
WC
Steer
Clifford J
CJ
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid* / Q000188:drug therapy*; D000704:Analysis of Variance; D001647:Bile Acids and Salts / Q000097:blood / Q000134:cerebrospinal fluid; D001812:Blood-Brain Barrier / Q000187:drug effects; D002756:Cholagogues and Choleretics / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid* / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid* / Q000494:pharmacology / Q000627:therapeutic use*
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid