Medications for MS: addressing blood flow

August 22, 2013 at 12:16pm

With the growth of research into the connection of MS to cerebral blood flow,  we've seen an interest in exploring new ways to address hypoperfusion (slowed blood flow), endothelial dysfunction (damaged blood vessels) and  brain atrophy (loss of brain tissue).

Why is this?  Because MS specialists, neurologists and advocacy groups are much more comfortable designing, testing and recommending a drug for MS, rather than encouraging healthy lifestyles and treating venous malformations.  You cannot monetize or patent a diet, exercise and angioplasty.  It's impossible to have a placebo-controlled clinical trial for lifestyle.  But you can develop a drug and make a lot of money selling it to a population with a chronic and degenerative disease.  

Please note that I am not recommending these specific drugs at all, I'm just pointing out how MS research is slowly shifting.  

We saw this paradigm change happen with the Vitamin D.  Six years ago, Jeff's neuro chuckled when I asked to have his D3 levels tested. But slowly, with independent research funded by patient advocacy groups like Direct MS,  the research paradigm has changed. And now, neurologists are testing their new patients' vitamin D levels, and adding supplementation accordingly. I believe we will see this shift continue with drug approaches to reducing hypoperfusion. 

This is tacet proof that blood flow matters in MS.  But you will not hear that from neurologists-yet.   They will discuss cerebral blood flow with their patients when they have a prescription they can write.  

Here's some info on a few of these new medications which target blood flow, currently in clinical trials.

Ibudilast (MN-166)

Clinical trials in progressive MS patients to be lead by Dr. Robert Fox and the Cleveland Clinic with the NMSS.  Dr. Fox received NMSS money to study CCSVI, and after finding new venous malformations in the jugular veins of people with MS, he has moved on to a clinical trial using a vasodilating and neuroprotective drug.  Is this coincidental?

http://finance.yahoo.com/news/medicinova-announces-initiation-cooperative-phase-230000864.html

MN-166 has been marketed in Japan and Korea since 1989 to treat cerebrovascular disorders, including post-stroke complications, and bronchial asthma. MediciNova licensed MN-166 (ibudilast), from Kyorin Pharmaceutical for potential utility in MS.

Lisinopril 

An inexpensive blood pressure medication and ACE inhibitor which modulates angiotensin.  This drug opens up blood vessels and allows blood to flow more easily. This older drug is being developed to treat MS by Dr. Lawrence Steinman of Stanford University School of Medicine.  (Dr. Steinman is also one of the inventors of Tysabri--which he has since spoken out against as a first line treatment for MS.) 

... angiotensin immediately causes blood vessels to constrict. “That raises your blood pressure so when you stand up to get out of a chair, you don’t fall down and faint,” said Steinman, who is also the George A. Zimmerman Professor in the medical school. But angiotensin overactivity causes chronic hypertension. Lisinopril controls blood pressure by blocking an enzyme that converts angiotensin’s precursor into the active hormone. The drug also appears to have certain anti-inflammatory properties.

http://med.stanford.edu/ism/2009/august/lisinopril.html

Here is info on the current study:

 In these studies, lisinopril reduced molecular measures of inflammation that accompany MS, yet it did not inhibit overall immune function.

link 

Statins

Although these cholesterol-lowering drugs failed in earlier trials for RRMS, they are now being brought back to life to address brain atrophy in progressive MS.  

Gray matter atrophy in MS

December 8, 2011 at 1:05pm

For those who want more background on the importance of loss of gray matter in MS disease progression, here are some recent papers with explanation.

Gray matter atrophy means the loss of gray matter in the brain.  

It is a "wasting away" or death of the axons which make up brain tissue. This can be seen on MRI.  The death of gray matter is directly related to disease progression and disability levels in MS.

What's most important to understand is that gray matter atrophy happens independent of white matter lesions.  That's why Jeff has over 20 white matter lesions, but has had a reversal of gray matter atrophy since his CCSVI venoplasty almost 3 years ago.  His gray matter is plumper on his last MRI---it actually looks "normal."  And that gives us reason to celebrate.

People with MS should ask their neurologists "How does my gray matter look?"

If disease progression and disability are more closely linked to the rate of gray matter atrophy, it will give patients a better understanding of their own disease progression.

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From the Cleveland Clinic in 2008--a 4 year longitudinal study of gray matter atrophy.

To determine gray matter (GM) atrophy rates in multiple sclerosis (MS) patients at all stages of disease, and to identify predictors and clinical correlates of GM atrophy.

METHODS:

MS patients and healthy control subjects were observed over 4 years with standardized magnetic resonance imaging (MRI) and neurological examinations. Whole-brain, GM, and white matter atrophy rates were calculated. Subjects were categorized by disease status and disability progression to determine the clinical significance of atrophy. MRI predictors of atrophy were determined through multiple regression.

RESULTS:

Subjects included 17 healthy control subjects, 7 patients with clinically isolated syndromes, 36 patients with relapsing-remitting MS (RRMS), and 27 patients with secondary progressive MS (SPMS). Expressed as fold increase from control subjects, GM atrophy rate increased with disease stage, from 3.4-fold normal in clinically isolated syndromes patients converting to RRMS to 14-fold normal in SPMS. In contrast, white matter atrophy rates were constant across all MS disease stages at approximately 3-fold normal. GM atrophy correlated with disability. MRI measures of focal and diffuse tissue damage accounted for 62% of the variance in GM atrophy in RRMS, but there were no significant predictors of GM atrophy in SPMS.

INTERPRETATION:

Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disabillity. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. These findings demonstrate the clinical relevance of gray matter atrophy in MS, and underscore the need to understand its causes.

http://www.ncbi.nlm.nih.gov/pubmed/18661561

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Here's a study on gray matter loss in clinically isolated syndrome (CIS), or patients that have had one MS event, but are not officially diagnosed.  

Iron in the Brain or the Immune System

September 17, 2009 at 9:36am

Many disease modifying treatments use the reduction of immune activated lesions as shown on MRI as proof a treatment is "working" in MS. This has baffled me, since we know that the number of lesions does not correlate to level of disease progression. Someone like my husband can have 20 brain lesions and function quite well. Someone else can have one or two lesions and be wheelchair-bound. Also, at a certain point, lesion progression stops when MS turns progressive. There must be another mechanism of injury, along with the immune system, at work in the MS brain.

In Bologna, Dr. Mark Haacke addressed another means of measuring brain tissue injury in MS. Susceptibility Weighted MRI. What SWI MRI shows us, is that iron deposited in the brain is a bio marker for MS progression.

What is different in SWI-MRI, according to Dr. Haacke, is that brain damage shown due to iron deposition actually CORRESPONDS to disability in MS.

The more iron deposed in the brain, the more disability, the more progressive MS is. This is different than the usual measuring of hyperintense lesions on MRI, which have no specific correlation to disease severity.

Here's the rub:
Pharma companies use the lesions shown on MRI as "proof" that their particular drug is working. Look! We've reduced hyperintensities on MRI! Our amaze-a-bub is slowing MS! Stock prices go up, investors are happy, and MS patients continue to decline.

If we look at the TRUE cause of disability- the only measurement in the brain that correlates to disability is iron deposition and brain atrophy.

This is why my husband had 20 lesions at his diagnosis and could mountain bike, and someone with one lesion is in a wheelchair. It's not just about the white matter lesions.

If we understand that the macrophages and immune system are activated as janitors to clean up the cellular death in the brain, we understand that the lesions we see on standard MRI may be secondary--just as they are a stroke patient, or someone with an ischemic brain ijury.

Thank goodness for Dr. Haacke, and other scientists who are speaking out.  It is not simply about the lesions on MRI. We will be told it is, because we can be sold drugs that halt these lesions---but that has not stopped MS progression.  There is no drug to stop reflux, iron deposition and hypoxic injury in the brain, and this is why it has not been explored since TJ Putnam in the 1940s, and will be fought.