Gilenya (ie Fingolimod/ S1P) and Veins?

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Gilenya (ie Fingolimod/ S1P) and Veins?

Postby CureOrBust » Wed Jul 06, 2011 2:40 am

OK, not throwing any wild allegations here, I just found it interesting when I came across this small relation.

http://en.wikipedia.org/wiki/Smooth_muscle_tissue
Smooth muscle tissue. WIKI wrote:Stretch
Recent research indicates that sphingosine-1-phosphate (S1P) signaling is an important regulator of vascular smooth muscle contraction. When transmural pressure increases, sphingosine kinase 1 phosphorylates sphingosine to S1P, which binds to the S1P2 receptor in plasma membrane of cells. This leads to a transient increase in intracellular calcium, and activates Rac and Rhoa signaling pathways. Collectively, these serve to increase MLCK activity and decrease MLCP activity, promoting muscle contraction. This allows arterioles to increase resistance in response to increased blood pressure and thus maintain constant blood flow. The Rhoa and Rac portion of the signaling pathway provides a calcium-independent way to regulate resistance artery tone.


http://en.wikipedia.org/wiki/Vein
Sphingosine-1-phosphate WIKI wrote:Although S1P is of importance in the entire human body, it is a major regulator of vascular and immune systems.... In the vascular system, S1P regulates angiogenesis, vascular stability, and permeability. In the immune system, it is now recognized as a major regulator of trafficking of T- and B-cells. S1P interaction with its receptor S1PR1 is needed for the egress of immune cells from the lymphoid organs (such as thymus and lymph nodes) into the lymphatic vessels. Inhibition of S1P receptors was shown to be critical for immunomodulation.


Interesting that something found to be effective on MS, also affects the smooth muscle's found in veins. :?
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Postby MegansMom » Wed Jul 06, 2011 6:06 am

My understanding that this drug Gilenya has a major action in that it
"traps" lymphocytes , making them unable to do their role. (of course the immune theory believers think that this is a good thing)

But honestly if the immune system (35% of all WBCs are lymphocytes) are tasked with tissue repair, debridement and clean up of damaged or dead tissue, then those with CCSVI would need all of the lymphocytes, in fact they could use drugs that enhance the immune system, not depress it, especially after



LDN seems a much more appropriate drug treatment post venoplasty to me.
But this is just my opinion.
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My 35 yo daughter is newly dx 8/19/10 (had 12 symptoms)
Dx with Type A CCSVI- 1 IJV & double "candy wrapper" appearance of her Azygos
Venoplasty done Sept 21, 2010
Doing extremely well-
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Re: Gilenya (ie Fingolimod/ S1P) and Veins?

Postby Cece » Wed Jul 06, 2011 7:44 am

CureOrBust wrote:Interesting that something found to be effective on MS, also affects the smooth muscle's found in veins. :?

That really is interesting.

The question is if it is working because of the impact on the immune system or the vascular system or both combined.

Great find.
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Postby cheerleader » Wed Jul 06, 2011 9:24 am

Interesting find, Cure! When a compound targets the endothelium, the response can be vascular, immune, or coagulation, since the endothelium controls all of these....
Researchers can only posit what Fingolimod is actually affecting....notice how they say "targets may include" because S1P receptors are endothelial receptors. S1P maintains endothelial integrity.

Fingolimod targets sphingosine 1-phosphate (S1P) receptors, of which the mRNA is widely expressed in immune, vascular and neural cells. The expression levels of the five S1P receptor subtypes in cell membranes versus cytoplasmic compartments may vary considerably depending on the activation and differentiation stage of the cells and the tissue levels of the ligand S1P48. Relevant targets of fingolimod may include cell membrane-expressed S1P1 on T and B cells38, 55, S1P1 and S1P3 on astrocytes114, 115 and, perhaps, S1P1 on neurons102, S1P1 and S1P5 on oligodendrocytes (OGCs)101, 109, and S1P1 on endothelial cells of the blood–brain barrier48. S1P receptors modulate the actin cytoskeleton of cells, thereby affecting pseudopodia formation and migration of lymphocytes, process outgrowth and retraction in neural cells, junctional communication between those cells, endothelial cell migration, and angiogenesis and endothelial permeability barriers48. IFN, interferon; IL, interleukin; MHC class II, major histocompatibility complex class II; MMPs, matrix metalloproteinases; NO, nitric oxide; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor.

http://www.nature.com/nrd/journal/v9/n1 ... 48_F1.html

They only posit that it's the lymphocyte migration...but what if it's the angiogenesis property (like LDN) or the BBB permeabiity which is the real target? They don't really know. This drug has many side effects. I'd stay clear of it. There are much safer and cheaper ways to increase nitric oxide and help strengthen the endothelium.
http://www.ccsvi.org/index.php/helping- ... ial-health

cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby 1eye » Wed Jul 06, 2011 9:38 am

Both combined. The action of the drug is to make T-cells go dormant into the lymphatic system. In the earliest document I read about it, researchers were excited because they had watched fluorescent mouse T-cells on a TV screen migrate into the mouse's spleen. Apparently they can continue to survey the blood for pathogens from there, so your immune system is not fully suppressed.

I think I am more interested in vasodilation to keep on top of heat sinking, but what do I know? Do users report heat sensitivity decreases?
"Try - Just A Little Bit Harder" - Janis Joplin
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Postby CureOrBust » Thu Jul 07, 2011 6:23 am

cheerleader wrote:Interesting find, Cure!
I personally would hardly call it a find, the fact is hard to miss (after I stumbled across it). I was very surprised no one had brought this to my attention (or I missed it)

cheerleader wrote:Researchers can only posit what Fingolimod is actually affecting....notice how they say "targets may include" because S1P receptors are endothelial receptors. S1P maintains endothelial integrity.
A lot of articles I have read on this compound usually state that it also has some kind of unknown beneficial effect on the CNS. I don't think too many people think they truly understand all the effects of this relatively new compound.

cheerleader wrote:This drug has many side effects. I'd stay clear of it.
Some of us do not have the luxury of that as the best option.

cheerleader wrote:There are much safer and cheaper ways to increase nitric oxide and help strengthen the endothelium.
http://www.ccsvi.org/index.php/helping- ... ial-health
Already doing most of these things, and as for cost, it has been recommended by the govt board to be subsidised by the Govt, so cost should be no issue. I would hazard a guess of around $30 / month

1eye wrote:Do users report heat sensitivity decreases?
Just read a users post, complaining they were still sensitive to the heat.

MegansMom wrote:... then those with CCSVI would need all of the lymphocytes...
Don't forget, the CCSVI - MS relationship is still in its early stages. I have had two treatments, with no real effect on my MS so far. I had CCSVI, the last ultrasound did not find any issues.

MegansMom wrote:LDN seems a much more appropriate drug treatment post venoplasty to me.
Admittedly before venoplasty, but LDN did nothing for me.
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Postby 1eye » Thu Jul 07, 2011 5:25 pm

MegansMom wrote:
LDN seems a much more appropriate drug treatment post venoplasty to me.
Admittedly before venoplasty, but LDN did nothing for me.

Not sure what anybody means anymore :?: I don't have the luxury of taking it on account of cost. I would if I could but I can't. They say it won't work because I have SPMS, but I really don't see that argument. Has it ever been tested for SPMS?

I think the while thing is a big racket. I don't need no stinkin nurolojist. Plus the grapes are too sour.
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Re: Gilenya (ie Fingolimod/ S1P) and Veins?

Postby CureOrBust » Sun Dec 04, 2011 3:17 am

While doing some more searching on info on Fingolimod, I came accross this article. Although not specifically the BBB, it does hold some interest I think. They also deal with variants of FTY720, but I think its because the original has some similar effects to begin with.
Given these observations of S1P and FTY720, we explored the barrier-regulatory capacity of several novel, synthetic analogues of FTY720. We now demonstrate the similar, but not identical, barrier-regulatory mechanisms of these analogues to S1P and FTY720, with one class of analogues producing significant barrier disruption despite structural similarities. Finally, our in vivo data demonstrate that the representative (S)-phosphonate analogue of FTY720 significantly reduces LPS-induced vascular leak in a murine model of inflammatory lung injury. These studies advance our understanding of pulmonary vascular permeability and characterize four novel FTY720 analogues that may potentially act as improved therapeutic tools for prevention and reversal of vascular leak.

http://jpet.aspetjournals.org/content/early/2008/12/31/jpet.109.153544.full.pdf
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Gilenya (Fingolimod) post CCSVI syndrome procedure

Postby MarkW » Mon Dec 05, 2011 4:31 am

Gilenya (Fingolimod) is on my list of possible drugs to use post CCSVI syndrome procedure. Unfortunately it is not approved for use in UK and I cannot find a clinical trial offering it. One the plus side it is oral and the side effects are low risk. I support treating MS as a multifactorial disease, so altering the immune system and/or BBB is worth a go in my view. Interesting find of the theory Cure but let's keep in mind that how these drugs work is not defined (if they work for you then go for it).
Kind regards,
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Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: Gilenya (ie Fingolimod/ S1P) and Veins?

Postby CureOrBust » Mon Dec 05, 2011 4:42 am

I have been on it for a couple of weeks, and can not say I have noticed any difference as far as my MS goes. I have also not had any side effects either. My next step is to actually check its effects on my Lymphocyte counts.

If your interested in using it, and can afford to pay for it, the UK probably has a similar policy that we have in Australia. A few years ago I wanted to try Aimspro, which was not available in Aus, and had not even been through trials like FTY720 has. I got approval for a personal medical import on compassionate grounds. If your serious, it may be worth a look.
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