Albuterol add on therapy

[Cvfactor]

Another article

Here is another recent article that describes how current drugs that have an effect on the nervous/immune system interaction may be used as add on therapies for MS:

http://www.ncbi.nlm.nih.gov/pubmed/23074017

The Albuterol trial is mentioned in this paper. As discussed this route of treatment is not likely to become mainstream but there does seem to be a lot of valid science behind it.

[Cvfactor]

University of Chicago

It seems researchers at the University of Chicago investgated the use of beta2-agonists for use in MS a while ago and obtained a patent about their work:

http://www.google.com/patents/US5264459

It's interesting that one of the patentees (Dr. Arnason) was a teacher of Dr. Howard Weiner of Harvard who was an author on the Albuterol trial.

Dr. Arnason (as well as Dr. Weiner) are some of the most respected MS researchers there are, so this does not look like a Zamboni-like discovery:

http://www.nationalmssociety.org/Abo...ch-Goes-To-Pro

It seems the research is there but there is no incentive by pharma to pursue this which is a shame.

[Cvfactor]

Update

I talked to my primary care physician about adding Albuterol to Copaxone and showed him the phase 2 trial results from the researchers at Harvard.

He had no issues with prescribing this. I think PCP's are more open to this as they have experience with the drug as apposed to neurologist s who probably tend to stick to FDA guidelines for ms medications.

At any rate both my neurologist and PCP are on board with it doing it this way.

I've been on it for 2 days and don't notice any I'll effects. One thing I have noticed is my blood pressure is normal again. Prior to this during the height of my relapse my blood pressure was varying quite a bit.

I guess it will take a while to determine if this halts my disease activity but I am happy to be trying this alternative as there seems to be a lot of valid data behind it.

[AMFADVENTURES]

I would guess any result will take some time to show up but am anxious to hear how it goes.

What Rx dosage?

Could not agree more, I have gone through a lot of neurologists and in the end had better luck getting what I want from my PCP.

[Cvfactor]

dosage

The dosage is 4mg/day in tablet form. This is the exact dosage that was used in the trial.

If you compare this to the maximum daily dosage for asthma which is 32mg it is a small amount which is probably why my PCP was not concerned about prescribing this.

Historically my relapses happen in the winter months so I will have to see how it goes next winter, but from the trial data the relapse rate was expected to be once every 11.1 years (on average extrapolated from the trial data) with this combination. If that's the case I'm happy.

[Cvfactor]

Antigen Tolerance

One final thing I should say about the Albuterol add on therapy is that it might show the effectiveness using a combination of Copaxone + Albuterol and might be different if Albuterol was used alone or with another DMD.

It seems Copaxone is an synthetic antigen mimic of myelin basic protein which is the protective covering around the nerves in the CNS.

In the past it was suspected that autoimmune diseases could be cured by giving bits of the protein (antigen) that was suspected to be targeted in the disease to induce tolerance.

In my mind this is like getting allergy shots containing cat protein to tolerize your body to cats.

At any rate, there have been trials of this tolerance induction method for MS as well as rheumatoid arthritis including many different routes of antigen administration including through the oral route.

These studies have not been pursued due to lack of efficacy in the trials. However it seems that if Albuterol is added along with the tolerizing antigen, tolerance is induced in the mouse model of disease (rheumatoid arthritis in this case) even after the disease process was started which has never been seen before.

http://m.jimmunol.org/content/169/9/5028.full

I suspect Copaxone was chosen specifically for this trial evaluation.

[Suebee]

CVFActor, this is really intriguing stuff. It makes sense to me based on the information you provided that copaxone was used. I am pretty sure it is the only MS drug that Has demonstrated it reduces T cells from pro-inflammatory Th1 cells and increases regulatory Th2 cells that suppress the inflammatory response. The synthetic Meylin apparently in acting as a decoy triggers this reaction.

[Suebee]

Here is link to one paper discussing ithttp://www.pnas.org/content/100/24/14157.full.pdf

[Suebee]

CVFactor. The last article you cited talks about the affect of timing in administration of immunization anti antigen and add on. It made me wonder if this an issue with Copaxone , which is daily , and active MS disease process.
-
---"Interestingly, our data show that salbutamol only potentiated tolerance induction during an ongoing immune response and not when salbutamol was coadministered with the Ag before immunization (Fig. 4⇑). Moreover, coadministration of salbutamol before immunization did not further modulate cytokine production by splenocytes as determined on day 9 after immunization of the animals (Fig. 7⇑). Therefore, we conclude that β2-adrenergic stimulation is only effective in potentiating tolerance induction in the context of an activated immune system. One possible explanation for this phenomenon would be that immunization increases the sensitivity of the β2-AR on immune cells."-----
What do you think? Am I misunderstanding mechanism?

[Cvfactor]

Repetitive Self Epitopes

Suebee,

I think Copaxone may show its efficacy because it is a low dose self epitope (or auto-antigen) that is administered on a frequent basis. I think it has been shown in the mouse model of MS that this can induce tolerance.

Albuterol may provide additional benefit by shifting the immune system further to an anti-inflamitory state would be my assumption.

Here is an article that describes this better:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667816/

"Induction of antigen specific tolerance based on the persistence of antigen can be achieved after injection of high-dose antigen or repeated injections of low dose soluble antigens [3], [4], [5]. T cell deletion, anergy mechanisms and active suppression by regulatory cells constitute essential factors in the maintenance of tolerance induced by these means [3], [6]. Active suppression represents one of the dominant mechanisms in the control of autoreactivity characterized by deviation of the immune response via the secretion of suppressive cytokines [7], [8].

The use of multivalent antigens represents an useful approach to deal with the dose/concentration of the antigen required to induce tolerance [9], [10], [11]. As an example, the synthetic repetitive Copolymer-1 (Glatiramer Acetate), approved as a therapy for relapsing remitting multiple sclerosis [12], contains sequences that cross react with the myelin basic protein [13], [14] and produce immunomodulatory effects involving the induction of specific T suppressor cells and bystander suppression mechanisms [15]. Despite several therapies for multiple sclerosis exist, their efficacy is very limited and most of the drugs slow the progression of the disease and reduce the number of relapses, however no complete cure is achieved [16], [17]."

[Cvfactor]

Autoreactive T cells

One other thing is that autoreactive T cells such as those that are believed to react to myelin are present in healthy individuals to the same extent that they are in people with MS.

This being the case it makes you consider what is the cause of ms. It may not be that autoreactive cells are present in MSers but rather the surrounding environment that these cells are in when they are activated.

Here is an article that explains this:

http://www.ncbi.nlm.nih.gov/pubmed/10686174

[Suebee]

CVfactor, ok then without further studies based effectiveness with albuterol as add on do you think it is too big a leap to say it would be better to stay on a daily injection of 20mg copaxone with daily add on of albuterol vs taking 40 mg copaxone three times weekly with add on? Interestingly, at my last visit my neuro offered 3x weekly, but noted the studies were not extensive as to whether increased dose less frequently was as effective as lower dose daily. Clearly the graph you posted shows the dramatic decrease in relapse using an addon. Thanks so much for sharing this info. I was unfamiliar with it and will pursue. it gives me hope!

[Cvfactor]

Suebee,

I cannot say if the benefits seen in the add on trial will work with the 40mg formulation as well as it did with the 20mg.

I guess that is the big question is if the two formulations are exactly the same. There should have been a head to head trial of the two formulations but I guess this was to risky to Teva if the 20mg performed better than the 40mg.

For me personally I am staying with the 20mg formulation because I don't have any issues taking it every day.

But if I had difficulty with the daily shot I think I would try the 40mg + Albuterol add on.

Good luck.

[Suebee]

Thanks CVFactor! Good luck to you too. I will be interested to hear updates on how the albuterol add-on is helping. I found another interesting thing about this concept. An inverse relationship between asthma and multiple sclerosis has been documented and highlighted as potentially having the key to getting upregulation of beneficial T cells for treatment. I wish we could get more review of existing medical documentation of clinical outcomes of MS / asthma patients on dual copaxone and albuterol treatments. It would seem to show if the inverse relationship was actually because of use of albuterol with Copaxone ( as opposed to another DM drug). Suebee

[Suebee]

http://www.ncbi.nlm.nih.gov/m/pubmed/19259620/