Why They Should Treat ALL Phenotypes

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Why They Should Treat ALL Phenotypes

Post by 1eye »

PMID:
27145057
DOI:
10.1089/jir.2015.0177

[PubMed - in process]

J Interferon Cytokine Res. 2016 Jun;36(6):347-57. doi: 10.1089/jir.2015.0177. Epub 2016 May 4.
Abstract

Axon regeneration in the mature mammalian central nervous system (CNS) is extremely limited after injury. Consequently, functional deficits persist after spinal cord injury (SCI), traumatic brain injury, stroke, and related conditions that involve axonal disconnection. This situation differs from that in the mammalian peripheral nervous system (PNS), where long- distance axon regeneration and substantial functional recovery can occur in the adult. Both extracellular molecules and the intrinsic growth capacity of the neuron influence regenerative success. This chapter discusses determinants of axon regeneration in the PNS and CNS.

1 Introduction

Central nervous system (CNS) axons do not spontaneously regenerate after injury in adult mammals. In contrast, peripheral nervous system (PNS) axons readily regenerate, allowing recovery of function after peripheral nerve damage. Aguayo and colleagues demonstrated that at least some mature CNS neurons retain the capacity to regenerate when provided with a permissive peripheral nerve graft (Richardson et al. 1980, 1984; David and Aguayo, 1981; Benfey and Aguayo, 1982). This work suggested that the PNS environment is stimulatory and/or that the CNS environment is inhibitory for axon growth. Subsequent studies identified both growth- promoting factors in the PNS and growth- inhibiting factors in the CNS. Inhibitors of regeneration include specific proteins in CNS myelin and molecules associated with the astroglial scar. In addition, slower debris clearance in the CNS relative to the PNS may impede axonal re-growth. The cell-autonomous failure of the cell of axotomized CNS neurons to induce those growth- promoting genes, which are highly upregulated by injured PNS neurons also limits brain and spinal cord repair. An understanding of factors which influence axon growth is critical for the development of therapeutics to promote CNS regeneration.
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Re: Why They Should Treat ALL Phenotypes

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OK I got the paper wrong: for those who were wondering what it had to do with my title: what I was talking about was a study that shows fty720/finglimod/Gilenya helps regenerate nerve tissue. I don't know what the excuse was for limiting prescription of Gilenya to relapsing MS, other than saving money at the expense of progressive patients, but the difference between EDSS 5.5 and 6.0, commonly given as reason to believe a patient is SPMS, and the reason why I was taken out of a study on fty720/Gilenya, has to do with the ability to walk. Peripheral nerves. Now it is shown that fty720 affects the remyelination of peripheral nerves. The study I quoted in the previous posting was interesting, but not the one I had in mind.

The one I had in mind was:
J Neuroinflammation. 2016; 13: 143.
Published online 2016 Jun 10. doi: 10.1186/s12974-016-0612-9
PMCID: PMC4901498
Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
Fabian Szepanowski,corresponding author Angelika Derksen, Irina Steiner, Gerd Meyer zu Hörste, Thomas Daldrup, Hans-Peter Hartung, and Bernd C. Kieseier
Author information ► Article notes ► Copyright and License information ►

Abstract
Background

The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P1 receptor on lymphocytes with the immunomodulatory drug fingolimod has proven effective in the treatment of multiple sclerosis. An emerging body of experimental evidence points to additional direct effects on cells of the central and peripheral nervous system. Furthermore, fingolimod has been reported to reduce LPA synthesis via inhibition of the lysophospholipase autotaxin. Here we investigated whether modulation of particular signaling aspects of S1P as well as LPA by fingolimod might propagate peripheral nerve regeneration in vivo and independent of its anti-inflammatory potency.
Methods

Sciatic nerve crush was performed in wildtype C57BL/6, in immunodeficient Rag1−/− and Foxn1−/− mice. Analyses were based on walking track analysis and electrophysiology, histology, and cAMP formation. Quantification of different LPA species was performed by liquid chromatography coupled to tandem mass spectrometry. Furthermore, functional consequences of autotaxin inhibition by the specific inhibitor PF-8380 and the impact of fingolimod on early cytokine release in the injured sciatic nerve were investigated.
Results

Clinical and electrophysiological measures indicated an improvement of nerve regeneration under fingolimod treatment that is partly independent of its anti-inflammatory properties. Fingolimod treatment correlated with a significant elevation of axonal cAMP, a crucial factor for axonal outgrowth. Additionally, fingolimod significantly reduced LPA levels in the injured nerve. PF-8380 treatment correlated with improved myelin thickness. Sciatic nerve cytokine levels were not found to be significantly altered by fingolimod treatment.
Conclusions

Our findings provide in vivo evidence for direct effects of fingolimod on cells of the peripheral nervous system that may propagate nerve regeneration via a dual mode of action, differentially affecting axonal outgrowth and myelination by modulating relevant aspects of S1P and LPA signaling.

Keywords: Fingolimod, Sphingosine-1-phosphate, Lysophosphatidic acid, PF-8380, Peripheral nerve regeneration
Why nobody has started selling the "Chinese nostrum" that fty720 is derived from, at a lower price, to poorer pwMS, I can only attribute to control of the supply, exercised by the patent holder, to maximize profits. Chinese people could be making a lot of money right soon, by selling directly to progressive MS patients. Or maybe they'll try the ET-game/electric-car trick and bury all of it in the desert.
Last edited by 1eye on Thu Jul 07, 2016 2:14 pm, edited 1 time in total.
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Re: Why They Should Treat ALL Phenotypes

Post by 1eye »

It ain't just me. It's all my friends who have been classified as SPMS and PPMS sufferers. This drug could help us walk again! It could help me play guitar again! This is a national and international disgrace: first limiting the prescriptions to RR patients, and then not doing any more research to show it works, (regenerating peripheral nerves) on more than just RR patients. I would be ashamed to be an MS doctor, or sell Gilenya. Very ashamed.

And what about those with peripheral nerve damage from traumatic and other causes? They found this out by crushing the nerves of mice!!!
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Re: Why They Should Treat ALL Phenotypes

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Here's another substance mentioned in the report above, that has potential uses in treatment of both MS and cancer...
J Pharmacol Exp Ther. 2010 Jul;334(1):310-7. doi: 10.1124/jpet.110.165845. Epub 2010 Apr 14.
A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation.
Gierse J1, Thorarensen A, Beltey K, Bradshaw-Pierce E, Cortes-Burgos L, Hall T, Johnston A, Murphy M, Nemirovskiy O, Ogawa S, Pegg L, Pelc M, Prinsen M, Schnute M, Wendling J, Wene S, Weinberg R, Wittwer A, Zweifel B, Masferrer J.
Author information
Abstract

Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), and it is up-regulated in many inflammatory conditions, including but not limited to cancer, arthritis, and multiple sclerosis. LPA signaling causes angiogenesis, mitosis, cell proliferation, and cytokine secretion. Inhibition of autotaxin may have anti-inflammatory properties in a variety of diseases; however, this hypothesis has not been tested pharmacologically because of the lack of potent inhibitors. Here, we report the development of a potent autotaxin inhibitor, PF-8380 [6-(3-(piperazin-1-yl)propanoyl)benzo[d]oxazol-2(3H)-one] with an IC(50) of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role in producing LPA in plasma and at the site of inflammation was tested in a rat air pouch model. The specific inhibitor PF-8380, dosed orally at 30 mg/kg, provided >95% reduction in both plasma and air pouch LPA within 3 h, indicating autotaxin is a major source of LPA during inflammation. At 30 mg/kg PF-8380 reduced inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen. Inhibition of plasma autotaxin activity correlated with inhibition of autotaxin at the site of inflammation and in ex vivo whole blood. Furthermore, a close pharmacokinetic/pharmacodynamic relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound for elucidating LPA's role in inflammation.

PMID:
20392816
DOI:
10.1124/jpet.110.165845
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Re: Why They Should Treat ALL Phenotypes

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Neuroinflammation. 2016; 13: 143.
Published online 2016 Jun 10. doi: 10.1186/s12974-016-0612-9
PMCID: PMC4901498
Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
Fabian Szepanowski

I have seen many people on ThisIsMS complain about foot drop. Peripheral nerve damage, in the hand and foot, is the single reason why I can't walk. This is ironic since it is also the single reason why I have been classified SPMS (my doctor merely said "you use a cane, don't you?"), and the single reason why I was not allowed to join the fingolimod trial by that same neurologist. Now we know that, in mice anyway, it restores peripheral nerve function, in animals that have had deliberate damage done to their peripheral nerves. So why aren't they giving it, open label, to everybody with MS who has peripheral nerve damage?

Oh, yes, we have to have another human trial. Meanwhile many people may die accidental deaths at the hand of pwMS who have peripheral nerve damage. What price FDA approval? Unnecessary death, suffering and paralysis. Why? Because a few doctors want to wait until they have more proof. They may be scientists, but I question their humanity. In fact I question the humanity of anyone who delays this treatment in humans, and not just MS sufferers. This treatment may help people who have lived for years with traumatic nerve damage. All because Novartis wants their t's crossed. They will continue to charge the earth, making it out of reach for large percentages of humanity. Why? Well, they have as much right as anyone to get rich off of the suffering of their fellow humans. Who cares if it means inhumanity towards their fellow humans? Cash is cash.
J Neuroinflammation. 2016; 13: 143.
Published online 2016 Jun 10. doi: 10.1186/s12974-016-0612-9
PMCID: PMC4901498
Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
Fabian Szepanowski,corresponding author Angelika Derksen, Irina Steiner, Gerd Meyer zu Hörste, Thomas Daldrup, Hans-Peter Hartung, and Bernd C. Kieseier

Abstract
Background

The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P1 receptor on lymphocytes with the immunomodulatory drug fingolimod has proven effective in the treatment of multiple sclerosis. An emerging body of experimental evidence points to additional direct effects on cells of the central and peripheral nervous system. Furthermore, fingolimod has been reported to reduce LPA synthesis via inhibition of the lysophospholipase autotaxin. Here we investigated whether modulation of particular signaling aspects of S1P as well as LPA by fingolimod might propagate peripheral nerve regeneration in vivo and independent of its anti-inflammatory potency.
Methods

Sciatic nerve crush was performed in wildtype C57BL/6, in immunodeficient Rag1−/− and Foxn1−/− mice. Analyses were based on walking track analysis and electrophysiology, histology, and cAMP formation. Quantification of different LPA species was performed by liquid chromatography coupled to tandem mass spectrometry. Furthermore, functional consequences of autotaxin inhibition by the specific inhibitor PF-8380 and the impact of fingolimod on early cytokine release in the injured sciatic nerve were investigated.
Results

Clinical and electrophysiological measures indicated an improvement of nerve regeneration under fingolimod treatment that is partly independent of its anti-inflammatory properties. Fingolimod treatment correlated with a significant elevation of axonal cAMP, a crucial factor for axonal outgrowth. Additionally, fingolimod significantly reduced LPA levels in the injured nerve. PF-8380 treatment correlated with improved myelin thickness. Sciatic nerve cytokine levels were not found to be significantly altered by fingolimod treatment.
Conclusions

Our findings provide in vivo evidence for direct effects of fingolimod on cells of the peripheral nervous system that may propagate nerve regeneration via a dual mode of action, differentially affecting axonal outgrowth and myelination by modulating relevant aspects of S1P and LPA signaling.

Keywords: Fingolimod, Sphingosine-1-phosphate, Lysophosphatidic acid, PF-8380, Peripheral nerve regeneration
Why nobody has started selling the "Chinese nostrum" that fty720 is derived from, at a lower price, to poorer pwMS, I can only attribute to control of the supply, exercised by the patent holder, to maximize profits. Chinese people could be making a lot of money right soon, by selling directly to progressive MS patients. Or maybe they'll try the ET-game/electric-car trick and bury all of it in the desert.
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Re: Why They Should Treat ALL Phenotypes

Post by ElliotB »

The answer to the problem at hand is not a simple one, there are many legal and ethical reasons that some into play (and of course monetary which may tie in directly with the legal reasons).

"This drug could help us walk again!"

Perhaps. And perhaps it could harm you as well. While the 'safeguards' may appear to inhibit the introduction of drugs to the market place, in some cases it has saved lives.
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Re: Why They Should Treat ALL Phenotypes

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The answer to the problem at hand (which seems to be fine if you have enough money and no progressive MS), is to prescribe fingolimod/Gilenya/fty720 to people who want it, after informing them and securing their consent. It's much easier to say no, and let people suffer and die. Plenty of skin left on my nose.
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Re: Why They Should Treat ALL Phenotypes

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1eye: I understand your passion and frustration, but I disagree with you on many points

For one thing, fingolimod has already failed misreably in a progressive multiple sclerosis trial, demonstrating absolutely no benefit against placebo (1). I think doctors would consider it to be unethical to prescribe a patient a medication with potentially serious side effects (PML, bradycardia, disseminated shingles) just because the patient wants it.

Literally hundreds of substances have been shown to have benefit in experimental autoimmune encephalitis and other animal studies, but almost all of these substances are ineffective in treating humans with multiple sclerosis. The study you linked really has nothing to do with humans with multiple sclerosis. the peripheral nervous system is different than the central nervous system. Crush injuries are different than inflammatory/degenerative injuries. If we jump for joy at every animal study with rough resemblance to a human disease, we will have 1000 ineffective treatments for every 1 effective treatment. We will be lost in a sea of nonsense. This isn't some conspiracy of drug companies or physicians.

By the way, progressive multiple sclerosis has nothing to do with the current degree of disability. some people with progressive multiple sclerosis have very low disability, and some people with relapsing multiple sclerosis have very high disability. "Progression" is just a clinical term which refers to an insidious clinical decline. The term causes a lot of confusion among both patients and physicians.

One of the reasons that patients with EDSS >/= 6 are excluded from the trials is for practical reasons-because if you are already at EDSS >/= 6, the EDSS score becomes very static, and it is difficult to determine if the drug has an effect on disability. This is unfortunate in my opinion, and hopefully they will come up with new clinical trial outcomes. EDSS is a lousy measure in my opinion. I am with you on this.

As always, I wish you the best of luck. Remember to always make the best of your situation. Enjoy life, and make a positive contribution to the world

sources:

1: Lublin, F. et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 387, 12–18 (2016).
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Re: Why They Should Treat ALL Phenotypes

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I understand your passion and frustration.
No you don't.
experimental autoimmune encephalitis
Hard to believe you read the paper. This was not EAE, nor had it anything much in common with MS, progressive or not. The mice were immunodeficient probably to prove the effect had nothing to do with immunity!
Sciatic nerve crush was performed in wildtype C57BL/6, in immunodeficient Rag1−/− and Foxn1−/− mice
Is the sciatic nerve considered peripheral in mice? Humans?

Please don't lecture me about MS, progression, EDSS, etc.
"You use a cane, don't you?"
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Re: Why They Should Treat ALL Phenotypes

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Who said anything about <EDSS 6.0? I am probably 5.0 since my CCSVI procedure. I don't think I have progressed since 2010. I do 20 km on my electric trike regularly. I only use the motor to climb hills and to keep up with a big-wheel bike. I have 20" wheels. Don't need the motor, even though the back wheel is much heavier than it used to be. I did bicep curls, tricep curls, flys and other exercises with dumbells this morning, standing up. My main problems are dizziness, foot drop and grip strength, both on my left side. I can play George Harrison and Bob Dylan's, "I'd Have You Anytime", among many others, on the piano. I use a lightweight walker. I fold and unfold it and store and remove it from the car myself.

I would keep it light, but I see pwMS used as guinea pigs and maimed or killed by MS drugs. They are treated as so many children by a lot of people. I myself am referred to by neurologists and other doctors in the third person as if I, or my brains, are not there. I was a victim of a delayed mitoxantrone heart attack. Life for a lot of pwMS is infinitely worse than it is for me. Some of them commit suicide. Doctors regularly take their god-complexes and deny, deny, deny. I think it is sometimes the only fun they have.

The INFORMS study said:
By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively
I'm no statistician, but it sounds to me as if the fingolimod group had a lot less confirmed disability progression than the placebo group. Could this be because of the effect of fingolimod on peripheral nerves?

I believe there were a lot more trials, period, and therefore more evidence in the non-progressive MS investigations. Maybe this is because of bias on the part of the investigators? Maybe Novartis didn't want to spend the money? I think in general doctors care less about progressive MS patients.

What about PASAT? The progressive MS trial I was on used PASAT as well. Maybe cognition is not important in progressive MS patients, especially when enough money has already been spent, and is already being made, on non-progressive MS patients. Maybe some standardization in these trials would help.
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Re: Why They Should Treat ALL Phenotypes

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1eye wrote:Hard to believe you read the paper. This was not EAE, nor had it anything much in common with MS, progressive or not. The mice were immunodeficient probably to prove the effect had nothing to do with immunity!
Again, this has nothing to do with multiple sclerosis in humans. the sciatic nerve is part of the peripheral nervous system (in both mice and humans)
1eye wrote:I would keep it light, but I see pwMS used as guinea pigs and maimed or killed by MS drugs.
So why are you are you demanding medication that has no evidence of efficacy in your condition if you are so concerned about side effects? Fingolimod has side effects: bradycardia/heart block, afib, disseminated shingles, PML, shortness of breath, macular edema, and so forth. In one sentence you are saying that drugs are horrible toxins, and in the next sentence, you think that the drugs are even better than the clinical trials show them to be.
The INFORMS study said: By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively
There were 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. The percentage with confirmed disability progression was 66.4% vs 69.4% which was not statistically significant. This is miserable failure.
I'm no statistician, but it sounds to me as if the fingolimod group had a lot less confirmed disability progression than the placebo group.
nope
Could this be because of the effect of fingolimod on peripheral nerves?
Nope. Multiple sclerosis is a central nervous system disease.
I believe there were a lot more trials, period, and therefore more evidence in the non-progressive MS investigations. Maybe this is because of bias on the part of the investigators? Maybe Novartis didn't want to spend the money? I think in general doctors care less about progressive MS patients.
No; no; no no. Doctors and drug companies always want their trials to be successful. Doctors want to become famous for being the primary investigator for a landmark trial. Drug companies want to sell more drugs and make more money. It is ludicrous to assume they were biased in favor of the trial failing. The opposite is true.
What about PASAT? The progressive MS trial I was on used PASAT as well. Maybe cognition is not important in progressive MS patients, especially when enough money has already been spent, and is already being made, on non-progressive MS patients. Maybe some standardization in these trials would help.
The PASAT is certainly a legitimate outcome measure. I don't think it was included in this trial. I suppose you can only have so many outcome measures or else people won't want to participate. Standardization would be nice. The real reason that drug companies generally don't want to pursue progressive MS trials is because they know there it is a good chance that they won't be successful. It is easier to spend money on marketing to convince people to take/prescribe ineffective drugs than to gamble on new endeavors. It seems that this marketing has been wonderfully successful.
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Re: Why They Should Treat ALL Phenotypes

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centenarian100 wrote:
1eye wrote:Hard to believe you read the paper. This was not EAE, nor had it anything much in common with MS, progressive or not. The mice were immunodeficient probably to prove the effect had nothing to do with immunity!
Again, this has nothing to do with multiple sclerosis in humans. the sciatic nerve is part of the peripheral nervous system (in both mice and humans)
I wasn't the one who brought up EAE. I don't believe EAE has anything to do with MS either.
So why are you are you demanding...
I make no demands. My bed is made. fty-720 probably works better in the original 'nostrum' form.

You seem to have a thing about Central vs Peripheral. Why not try it? If you had been a quadriplegic for 40 years, you might want to.
The PASAT is certainly a legitimate outcome measure. I don't think it was included in this trial. I suppose you can only have so many outcome measures or else people won't want to participate. Standardization would be nice. The real reason that drug companies generally don't want to pursue progressive MS trials is because they know there it is a good chance that they won't be successful. It is easier to spend money on marketing to convince people to take/prescribe ineffective drugs than to gamble on new endeavors. It seems that this marketing has been wonderfully successful.
Gosh nobody has been prescribing me any drugs at all. They don't seem to want to treat my MS. No chance of any ineffective drugs. They wouldn't even prescribe ones that were effective, except the one that gave me the heart attack. Copaxone use was unilaterally withdrawn by the MS clinic even though it was still working, and specifically approved by the doctor in charge of my MS chemotherapy. The MS clinic decided it had priority. They told the pharmacist not to sell it to me. Later (too late for me) a paper came out that said that copaxone was synergistic with the chemo drug. I am still off copaxone (glatiramer acetate), not by my own choice.

There seems to be a general belief on the part of some MS neurologists that informed consent means "we informed the MS patient as much as they need to be informed. Any other information they may have is irrelevant, unnecessary, and they consent by default to anything we do for them or to them." Some even believe that since MS neurologists are all-knowing, they are the only ones who need to be informed or consent to anything. They believe that they are the final arbiters of what goes in a patient's mouth, or arm, or under their skin. That may or may not protect them from lawsuits, but it is not the case, nor should it be. But MS neurologists think they are gods, or at least gods where MS patients are concerned. I think that belief is what really matters to them, not whether drugs are effective. That, and how much money they make, through channels licit or not. MS patients are sub-human to them, nothing but puppets for their self-aggrandizement.

The MS population has been divided and conquered very successfully along actuarial lines. Effort is not spent on the generally older progressive patient. The trials on these patients have presumed conclusions because diagnose and adios is more lucrative for the ineffective specialist and costs the government less, while still keeping the presses rolling.

P.S. If the peripheral nervous system is so different in MS, perhaps it is because it has no Blood Brain Barrier, which is part of blood vessel walls, and will not prevent a drug from working in the PNS. Maybe fty-720 would work more effectively in the CNS if it were delivered across the BBB. As it is, its only known action is to sequester T Cells. Maybe it has other tricks up its sleeve.
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Re: Why They Should Treat ALL Phenotypes

Post by frodo »

Yes. They should treat all phenotypes, But not all of them in the same way.

There are common things (neurodegeneration) that can be treated equally for everybody. I think Ibudilast is a neuroprotector, and probably will work for everybody. In non-inflammatory cases, like yours seem to be, neuroprotection should be the way to treat it.

There are other things that are specific. For example, pattern II MS shows specific circulating autoantibodies, and therefore they can be cleaned with plasmapheresis. Other patterns do not show these antibodies, and therefore it makes no sense to undertake a plasmapheresis with no expected results.
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Re: Why They Should Treat ALL Phenotypes

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frodo wrote:Yes. They should treat all phenotypes, But not all of them in the same way.

There are common things (neurodegeneration) that can be treated equally for everybody. I think Ibudilast is a neuroprotector, and probably will work for everybody. In non-inflammatory cases, like yours seem to be, neuroprotection should be the way to treat it.

There are other things that are specific. For example, pattern II MS shows specific circulating autoantibodies, and therefore they can be cleaned with plasmapheresis. Other patterns do not show these antibodies, and therefore it makes no sense to undertake a plasmapheresis with no expected results.
I think we will never figure out what MS even is until we stop paying attention to differences and find out what is common to all MS patients. And treat it. With something that works for everyone. Until we stop trying to slice up the problem into ever-finer bits, and stop believing the malarkey that different things cause all the phenotypes, numbered, named, classifed, refined, defined, confined, selected, rejected, neglected, inspected, infected and democratically elected. Once it's stopped, the human body can repair itself.
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Re: Why They Should Treat ALL Phenotypes

Post by frodo »

and find out what is common to all MS patients. And treat it. With something that works for everyone
I really do not understand your point. Do you mean that we should stop treating responsive patients with, for example, plasmapheresis just because it doesn't work for eveybody? Even if they are improving?
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