The treatment of multiple sclerosis with inosine.
OBJECTIVE
The objective of this study is to evaluate the safety and tolerability of inosine in patients with relapsing-remitting multiple sclerosis (RRMS). The secondary objectives are to assess the effects of inosine administration on serum urate (UA) levels, the progression of neurologic disability, the cumulative number of new, active lesions on magnetic resonance imaging (MRI), and changes in serum levels for markers of inflammation.


METHODS
Oral administration of inosine was used to raise serum levels of the natural peroxynitrite scavenger UA in 16 patients with RRMS during a 1-year randomized, double-blind trial.


METHODS
The endpoints studied were relapse rate, disability assessed by the Kurtzke Expanded Disability Status Scale (EDSS), MRI, and analysis of serum levels of nitrotyrosine, and oxidative and pro-inflammatory makers.


RESULTS
Increased serum UA levels correlated with a significant decrease in the number of gadolinium-enhanced lesions and improved EDSS. A number of MRI intensity-based parameters were altered by inosine treatment, in certain cases correlating with changes in serum UA levels. In a patient with low serum UA and high lesion activity, raising UA levels by inosine treatment decreased serum nitrotyrosine while increasing the ratio of Th2 to Th1 cytokines in circulating cells. The only side-effect correlated with inosine treatment was kidney stone formation in 4/16 subjects.


CONCLUSIONS
These data suggest that the use of inosine to raise serum UA levels may have benefits for at least some MS patients. The effect of this treatment is likely to be a consequence of inactivation of peroxynitrite-dependent free radicals. Close monitoring of serum UA levels as well as other measures are required to avoid the potential development of kidney stones.
Markowitz
Clyde E
CE
Neurology Department, University of Pennsylvania, Philadelphia, PA, USA.
Spitsin
Sergei
S
Zimmerman
Vanessa
V
Jacobs
Dina
D
Udupa
Jayaram K
JK
Hooper
D Craig
DC
Koprowski
Hilary
H
D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000284:Administration, Oral; D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D018791:CD4 Lymphocyte Count; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology; D018592:Cross-Over Studies; D016207:Cytokines / Q000378:metabolism; D004185:Disability Evaluation; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007288:Inosine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007669:Kidney Calculi; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D018417:Th1 Cells; D018418:Th2 Cells; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood; D014527:Uric Acid / Q000097:blood*; D055815:Young Adult
D000276:Adjuvants, Immunologic; D016207:Cytokines; D014527:Uric Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D007288:Inosine