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i think i would be interested in participating in this study, if i didn't think they would make me stop all my other supplements so as not to cloud the results!

The Journal of Immunology, 2000, 164: 1013-1019.
Copyright © 2000 by The American Association of Immunologists

Inosine Inhibits Inflammatory Cytokine Production by a Posttranscriptional Mechanism and Protects Against Endotoxin-Induced Shock1
György Haskó2, David G. Kuhel, Zoltán H. Németh, Jon G. Mabley, Robert F. Stachlewitz, László Virág, Zsolt Lohinai, Garry J. Southan, Andrew L. Salzman and Csaba Szabó
Inotek Corp., Beverly, MA 01915

Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia. In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-, IL-1, IL-12, macrophage-inflammatory protein-1, and IFN-, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor B, and elevation of intracellular cAMP. Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.

Vol. 96, Issue 23, 13486-13490, November 9, 1999
Neurobiology
Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury
Larry I. Benowitz*,,,§, David E. Goldberg*, Joseph R. Madsen*,, Deepa Soni*, and Nina Irwin*,
* Department of Neurosurgery, Children's Hospital, Program in Neuroscience, and Department of Surgery, Harvard Medical School, Boston, MA 02115

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved September 16, 1999 (received for review July 19, 1999)

The purine nucleoside inosine has been shown to induce axon outgrowth from primary neurons in culture through a direct intracellular mechanism. For this study, we investigated the effects of inosine in vivo by examining whether it would stimulate axon growth after a unilateral transection of the corticospinal tract. Inosine applied with a minipump to the rat sensorimotor cortex stimulated intact pyramidal cells to undergo extensive sprouting of their axons into the denervated spinal cord white matter and adjacent neuropil. Axon growth was visualized by anterograde tracing with biotinylated dextran amine and by immunohistochemistry with antibodies to GAP-43. Thus, inosine, a naturally occurring metabolite without known side effects, might help to restore essential circuitry after injury to the central nervous system.

The uric acid connection with MS, like the vitamin D one, has been very under-explored by researchers. That is my frustration with the state of MS research: when there is highly suggestive epidemiology data, and supporting animal data, it still does not quickly ead to more definitive human trials even if the safety profile for the intervening agent is known - vitamin D and inosine are by no means new drugs. I'm like jimmylegs, Anecdote, and others, I would rather try something that is supported by some science and take my chances, than wait 20-30+ years, if ever, for the research to finally grind through some FDA-approved clinical study.

The abstract below is probably posted elsewhere on this site, but below is a PubMed abstract which addressed both aspects of uric acid, both animal and human epidemiology. Notably the authors searched through more than 20 million patient records and found that MS and gout (characterized by high uric acid) appeared to be almost mutually exclusive diseases. This number of patient records provides a lot of statistical power. The article can be viewed for free online. I remember reading an abstract of an older German study (can't remember authors) in which the authors noted that in a series of MS patients, they also saw none with gout, even though gout was common in the general population from which the patients came from.

I am glad lyndacarol reported that an early trial is ongoing for this. I think someone posted earlier that these Philadelphia researchers had been wanting to do a human study with inosine for some time, but it was a matter of funding. An OTC supplement can't become a trillion dollar blockbuster, no matter how good it is.

Lisa

^^^^^^^^^^^^^^^
Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):675-80. Related Articles, Links


Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis.

Hooper DC, Spitsin S, Kean RB, Champion JM, Dickson GM, Chaudhry I, Koprowski H.

Center for Neurovirology, Thomas Jefferson University, Philadelphia, PA 19107-6799, USA. dchooper@reddil.uns.tju.edu

Uric acid, the naturally occurring product of purine metabolism, is a strong peroxynitrite scavenger, as demonstrated by the capacity to bind peroxynitrite but not nitric oxide (NO) produced by lipopolysaccharide-stimulated cells of a mouse monocyte line. In this study, we used uric acid to treat experimental allergic encephalomyelitis (EAE) in the PLSJL strain of mice, which develop a chronic form of the disease with remissions and exacerbations. Uric acid administration was found to have strong therapeutic effects in a dose-dependent fashion. A regimen of four daily doses of 500 mg/kg uric acid was required to promote long-term survival regardless of whether treatment was initiated before or after the clinical symptoms of EAE had appeared. The requirement for multiple doses is likely to be caused by the rapid clearance of uric acid in mice which, unlike humans, metabolize uric acid a step further to allantoin. Uric acid treatment also was found to diminish clinical signs of a disease resembling EAE in interferon-gamma receptor knockout mice. A possible association between multiple sclerosis (MS), the disease on which EAE is modeled, and uric acid is supported by the finding that patients with MS have significantly lower levels of serum uric acid than controls. In addition, statistical evaluation of more than 20 million patient records for the incidence of MS and gout (hyperuricemic) revealed that the two diseases are almost mutually exclusive, raising the possibility that hyperuricemia may protect against MS.

PMID: 9435251 [PubMed - indexed for MEDLINE]

Bit of a random link, but i just noticed the cross-over.

From the article (http://www.thisisms.com/article124.html) IL-10 may help to reduce BBB permeability, however above, inosine does not increase IL-10.

jimmylegs wrote:but failed to alter the production of the anti-inflammatory cytokine IL-10

I have been using inosine for quite some time (1000mg/day for 6+months), and cant say I noticed the difference. Except that my uric acid (froom blood tests) has gone from below normal, to within the normal range.

hey cure, glad your levels are back in the normal range. mine are normal too, luckily.

okay all here's another instalment:

High-dose Methylprednisolone Therapy in Multiple Sclerosis Increases Serum Uric Acid Levels
--------------------------------------------------------------------------------
Author(s): Gordana Toncev | Biljana Milicic | Slavco Toncev | Goran Samardzic

Uric acid, which is the final product of purine nucleoside metabolism, is a strong peroxynitrite scavenger. Several studies report on lower serum uric acid levels in multiple sclerosis. In this study, we investigated serum uric acid levels before and after high-dose methylprednisolone treatment (intravenous 1 g/day/5 days) in multiple sclerosis patients. Blood samples from 25 definite multiple sclerosis patients (11 male and 14 female) before and after methylprednisolone treatment (days 0, 6 and 30) and from 20 healthy donors (9 male and 11 female) were analyzed. Serum uric acid levels were measured using a quantitative enzymatic assay (Elitech diagnostics, Sees, France) according to the manufacturer's protocol, and the results were standardized using a commercial uric acid standard solution. We observed significantly increased serum uric acid levels 1 day after the termination of the therapy (day 6). These differences were sustained for 30 days after starting treatment (during remission period). Mean serum uric acid levels were significantly higher in the control group. These results suggest that increasing the uric acid concentration may represent one of the possible mechanisms of action of methylprednisolone in multiple sclerosis.


next bit is from "http://en.wikipedia.org/wiki/Methylprednisolone"

Methylprednisolone (molecular weight 374.48) is a synthetic glucocorticoid drug which is usually taken orally. It's chemical name is pregna-1,4-diene-3,20 -dione, 11,17,21-trihydroxy-6-methyl-,(6α, 11β)- and its chemical formula is C22H30O5.

Like most adrenocortical steroids, methylprednisolone is typically used for its anti-inflammatory purposes. However, glucocorticoids have a wide range of effects, including changes to metabolism and immune responses. The list of medical conditions for which methlyprednisolone is rather large, and is similar to other corticosteroids such as prednisolone. Common uses includes arthritis therapy and short-term treatment of bronchial inflammation due to various respiratory diseases. It is used both in the treatment of acute periods and long-term controlling of autoimmune diseases, most notably SLE.

Methylprednisolone has serious side effects if taken long-term, including weight gain, glaucoma, osteoporosis and psychosis, especially when overdosed. The most serious side effect occurs after the kidneys cease natural production of cortisone, which methylprednisolone will replace. Abrupt cessation of the drug after this occurs can result in a condition known as Addisonian crisis, which can be fatal. To prevent this, the drug is usually prescribed with a tapering dosage, including a pre-dosed "dose pack" detailing a specific number of pills to take as designated times over a six day period.

Alternative treatments to many of the conditions currently indicated for methlyprednisolone are actively being researched. Additionally, new drugs such as budesonide are being created, which provide similar benefits but without the adrenal suppression problems.

***jimmy wonders if this is why liver extract has been used in some earlier ms treatment protocols...***

These results were just added to pubmed. I'm not sure if this is one of the inosine studies that's been widely reported on, but it's at least a new abstract discussing some promising results.



Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis.

Vojnosanit Pregl. 2006 Oct;63(10):879-82.
Toncev G.
Clinical Center Kragujevac, Center of Neurology, Kragujevac, Srbija.

BACKGROUND/AIM: Uric acid was successfully used in both, prevention and treatment of the animal model of multiple sclerosis (MS). Recently it has been shown that inosine, a ribosylated precursor of uric acid, might be used to elevate serum uric acid levels in MS patients. The aim of this study was to evaluate the safety and efficacy of oral inosine as a single drug treatment in patients with MS.

METHOD: We administered inosine orally to 32 MS patients from 2001-2004 year at doses from 1-2 g daily (given twice) depending on the pretreatment serum uric acid levels. The mean follow-up interval was 37.69+/-6.55 months. The other 32 MS patients, without any treatment except for a relapse period (matched by age, sex, duration of disease and functional disability), were used as controls. The follow-up interval of these patients was 36.39 +/- 2.68 months. The neurological disability was evaluated by the Expanded Disability Status Scale score (EDSS).

RESULTS: During the observed period the treated MS patients were found to have the lower relapses rate than the non-treated MS patients (Chi-square test, p = 0.001). None of the patients have showed any adverse effect of inosine treatment. The non-treated MS patients were found to have a higher increasing in the mean EDSS score than the treated ones (two-way ANOVA-repeated measures/factor times, p = 0.025).

CONCLUSION: Our results suggested that the treatment approaches based on the elevation of serum uric acid levels might prove beneficial for some MS patients.

<shortened url>

It would also be good to know what the actual reduction in relapse is so as to compare to other treatments.

Great post. I think some of the earlier thread refered to a phase II trial "Treatment of Multiple Sclerosis Using Over the Counter Inosine" funded by NCCAM. That study is showing as completed as of June 2006, I can't find any published results (I'll keep looking)

I think G Toncev's other research on uric acid is interesting, specifically, that methylprednisolone therapy increases uric acid levels (i.e that may be its method of activity on ms)

Also: my source for Jarrow Inosine ended and in fact I haven't been able to locate on www. Has anyone else in USA or Canada been able to purchase (there are other suppliers but Jarrow was highly recommended.)

I have been using Source Naturals which I purchase over the net from iHerb. They have 500mg Tablets.
In what way was jarrow expressed to be better than the others?

these guys seem to think they still have some (Jarrow) in stock http://www.lef.org/newshop/items/item00155.html "life extention" is jarrow isnt it.

Ignore this....

Hey, I got a copy of the full article, but its a really bad fax/pdf. I'm glad to email to anyone (until I find a site I can post these docs to). FYI the dose given was 1-2 gram daily with the goal of exceeding (not meeting) normal blood serum level. And, as Dignan's abstract pointed out, not only were there fewer relapses in the treated group, but within the treated group those with higher levels did best of all. Most impressively, 20/32 treated patients - or 62% - had NO RELAPSE or progression on EDSS scale over the test period. Unfortunately the study was not double blind/placebo-controlled, nor was the research group able to use MRI pre/post study to confirm impact on lesion activity. Taking all in mind, I'm definitely increasing my inosine supplements. ps. not only methylprednisone but also copaxone increases uric acid levels.

here is the article ljm spoke of, I don't know how long it will last up here, so grab it quick if you want it.


http://www.sendspace.com/file/9e55mu

All---

Here’s a nice article (free access) on uric acid that contains several references to uric acid and MS. Some new info seems to be that UA can also protect against glutamate toxicity (and not just peroxynitrite formation).

Altered Uric Acid Levels and Disease States

Some select quotes…..from page 18

UA acts upon astroglia and upregulates protein levels of EAAT-1, a glutamate transporter, to protect spinal cord neurons from glutamate induced toxicity.

There is an abundance of evidence that suggests that low UA levels are associated with the development and progression of a variety of diseases. A number of studies have found an independent negative correlation between serum UA levels and MS (Spitsin et
al., 2001b; Toncev et al., 2002; Rentzos et al., 2006).

(P 20) Furthermore, a recent clinical study found that the administration of inosine, a UA precursor, stopped the progression of MS in all 11 patients that received the drug and improved some of the symptoms of the disease in 3 of the patients (Spitsin et al., 2001a).

(P 21) because both decreased as well as elevated UA levels may contribute to the development and progression of a number of disease states, significant alterations in UA levels that result in above or below normal serum UA concentrations should be minimized.

(P 6) the normal range of UA concentration falls somewhere between 120 µmol/L and 380 µmol/L, varying slightly depending on gender.

If you’re interested in inosine as a supplement I think it’s worth the read. Some of it is even understandable.

Take care all--

Sharon

Uric Acid With Multiple Sclerosis And Other Neurological Diseases
Uric Acid Research From Mult Scler. 2007 Oct 17; [Epub ahead of print]

Serum uric acid levels of patients with multiple sclerosis and other neurological diseases.
Peng F, Zhang B, Zhong X, Li J, Xu G, Hu X, Qiu W, Pei Z.

Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, People’s Republic of China.

The serum uric acid (UA) levels were measured in 112 patients with multiple sclerosis (MS) and 794 patients with different types of other neurological diseases (OND) or healthy control group. Serum UA levels, along with relevant clinical parameters of MS and OND, were also investigated.

MS patients had significantly lower UA levels than those with

Transient ischemia attack (344.6+/-130.6 micromol/L, P=0.000)
Cerebral hemorrhage (311.9+/-104.7 micromol/L, P=0.000)
Cerebral infarction (291.3+/-101.6 micromol/L, P=0.014)
Healthy control group (312.1+/-92.8 micromol/L, P=0.000)

MS patients had significantly higher serum UA levels than those with:

Cryptococcus meningitis or meningoencephalitis (178.9+/-107.0 micromol/L, P=0.000)
Tuberculous meningitis or meningoencephalitis patients (175.7+/-99.9 micromol/L, P=0.000)

There were no significant differences in UA levels between patients with MS and those with:

Facial neuritis
Viral meningitis or encephalitis
Pulmonary tuberculosis
Polymyositis or dermatomyositis
Myasthenia gravis
Subarachnoid hemorrhage
Migraine
Guillain-Barre syndrome
Myelitis

In addition, uric acid levels were independently correlated with gender and duration of MS, but neither with MRI activity, disability nor subtypes of the disease in MS patients.

Our data suggest that UA has two biphasic functions: neuroprotective and injurious. Our studies may help physicians to deal with conditions having abnormal UA levels.

Multiple Sclerosis 2007; 00: 00-00. http://msj.sagepub.com.

PMID: 17942520 [PubMed - as supplied by publisher]

Has anyone seen/found the results to this study?


http://clinicaltrials.gov/ct2/show/NCT00067327

Estimated Enrollment: 30
Study Start Date: February 2002
Estimated Study Completion Date: September 2005

Detailed Description:
Uric acid is a natural inhibitor of certain chemistries associated with peroxynitrite, a product of inflammation. In animal models of multiple sclerosis (MS), these chemical reactions have been associated with breakdown of the blood-brain barrier and CNS tissue damage. In addition, MS patients have serum uric acid levels that are lower than age- and sex- matched healthy individuals. The primary purpose of this study to determine whether raising low serum uric acid levels by daily oral administration of its precursor inosine has an effect on the cumulative number of newly active lesions on magnetic resonance imaging (MRI) and to evaluate the safety and tolerability of inosine in patients diagnosed with relapsing remitting and secondary progressive MS.