Recent research

[HarryZ]

This is some recently published research that looks at the possible mechanism of what happens when Tysabri is used. Interesting to say the least.

Harry

________________

Vol. 63 No. 10, October 2006
Arch Neurol. 2006;63:1383-1387.


Altered CD4+/CD8+ T-Cell Ratios in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis

Background Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an 41 integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection.

Objective: To test the effect of natalizumab treatment on the CD4+/CD8+ T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.

Design Prospective longitudinal study.

Setting Academic and private multiple sclerosis centers.

Patients Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus–infected patients.

Main Outcome Measures CD4+ and CD8+ T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound 4 integrin on peripheral blood CD4+ and CD8+ T cells was analyzed before and after natalizumab therapy.

Results: Natalizumab therapy decreased the CSF CD4+/CD8+ ratio of patients with MS to levels similar to those of human immunodeficiency virus–infected patients. CD4+/CD8+ ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4+/CD8+ ratios normalized. The expression of unbound 4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4+ vs CD8+ T cells.

Conclusions Natalizumab treatment alters the CSF CD4+/CD8+ ratio. Lower expression of unbound 4 integrin on CD4+ T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.

[bromley]

HarryZ,

I wondered where you had gone. You've obviously spent the week trawling the internet for a bad Tysabri story.

Interesting to say the least

- does this mean it's interesting to you because it's a bad Tysabri story?


The bottom line is that sufferers have to watch themselves physically and/or mentally deteriorate or take a new drug which might result in death or them being the equivalent of an HIV patient. I know you are trying to provide the sufferer with more information but what would you do if you had MS and was faced with such a decision? Sufferers are caught between a rock and a hard-place and stories like this just make the situation even harder.

I know you mean well, but I have to wonder how this contribution helps for sufferers already making difficult decisions.

Ian

[HarryZ]

Ian,

I wondered where you had gone. You've obviously spent the week trawling the internet for a bad Tysabri story.

Some researchers were obviously looking to obtain some objective scientific data on what Tysabri does to one's immune system. They published their findings in a medical journal. Why do you consider this as a "bad" story?! It is scientific data.

Interesting to say the least - does this mean it's interesting to you because it's a bad Tysabri story?

It's interesting because of what they discovered since nobody has published this info before. It's interesting because they found that Tysabri has the ability to reduce one's immune system level to that of one having HIV. It's interesting because it is new information which can only help MS patients in the long run by providing the docs and patients additional scientific data that was not available before.

The bottom line is that sufferers have to watch themselves physically and/or mentally deteriorate or take a new drug which might result in death or them being the equivalent of an HIV patient. I know you are trying to provide the sufferer with more information but what would you do if you had MS and was faced with such a decision? Sufferers are caught between a rock and a hard-place and stories like this just make the situation even harder.

I have some understanding what MS patients have to put up with every day of their lives but this has nothing to do with trying to make it more difficult for any of them. Are you suggesting that this kind of research be kept from MS patients and that only the "good" information be released? Good grief, Ian, we already have Biogen/Elan doing that!!! I think that the vast majority of MS patients have the ability to read both sides of the issue and then make a decision, in consultation with their doctor, on whatever medication they wish to try. Let's give the patient some credit here and not censor what they should or should not be able to read.

Take care.

Harry

[bromley]

HarryZ,

Are you suggesting that this kind of research be kept from MS patients and that only the "good" information be released? Good grief, Ian, we already have Biogen/Elan doing that!!!

I think this says it all Harry. Your postings on Tysabri are much more to do with your personal issues with the companies behind this drug. I'm in no way suggesting that there should be any censorship, but I also think that posts should remain unbiased. You only ever post negative stories about this drug, even though you know that some on this site with the condition have taken the difficult decision to have this treatment.

I'm sick of hearing the excuse that you are providing sufferers with additional information to help them with their decision making. Do you really think that telling those who are having Tysabri now that their immune system will be the equivalent of an HIV patient helps? No doubt they can all sleep better in their bed tonight because of your helpfulness!

If you posted a range of articles on Tysabri I might buy into your "I'm giving sufferers information to help themselve decide" story. But from the very start it has all been the bad news. What do you hope to achieve? That sufferers with few other treatment options come off Tysabri / don't start? Who gains then?

And we all know that further PML cases will arise and that a certain someone will make sure that the data is posted as quickly as possible. All under the guise of being Mr Helpful. Why don't you shock us an come up with a positive Tysabri story to show you are unbiased? You must come across some on your visits to various MS sites.

A new more efective treatment should be a celebration, even knowing that increased effectiveness brings bigger risks. How anyone could get pleasure from keep dashing peoples' hopes by bringing a constant stream of negative stories beggars belief. Let the dust settle and let's see how those on Tysabri do after six months.

Ian

[retired_at_40_01]

I noticed about 5 eastern that the pain, numbness(sp) in my legs are almost gone.

The people that made us wait for Ty had no idea what this drug means. If given a choice between the chance of death and staying the same as when this was removed from the shelves, I would have taken my chances. Signed whatever.

Somebody making choices for me. That's to full of oneself.(sp) Get a grip. I, we, don't need a big brother. It's my life, not your's!

G. Bush has some set, going against the house and senate to veto stem cells. Watch, that's where CURES are. If you don't agree, don't use them. Tell me how discarding them are different from using them for research? Dead is dead. Go figure. Yes, I'm angry and venting. People have to suffer from diseases that could be helped. All for the sake of one man's belief. Now we wait for '08. Hopefully then, the NIH will get the money they need.

I'm lucky, Ty work's for me.
Pete

PS: this was a message sent by me. Ty= Tysabri (the drug) NIH= National Institute of Health

Harry, take notice, many people are informed and are willing to take a chance rather than live with no hope.

[bromley]

Pete,

I'm glad you are seeing some benefit.


HarryZ,

It is with a heavy heart that I have to inform you that following a meeting with my fellow owners of this site (yes I have to declare that I own 80% of the company which owns / finances this website), that you are no longer welcome at this website. We have no intention of removing this ban. This site is about hope for those living with this devastating condition. It is not a mouthpiece for individual's with gripes against drugs companies or MS treatments. I have allowed you to continue posting for too long and your posts are eating away at the hope that this site aims to give people.

Please do not post any more on our website - you have made your views clear and it is time that we moved on. I'm sure many users of the site wish to thank you for the contribution you have made. But we are entering a new dawn where new treatments will radically alter the outlook for those with this condition.

I did not want to censor you but there is light at the end of the tunnel and your posts bring a constant shadow that none of us need.

I understand that you also visit other MS websites, and no doubt you will continue your anti-Tysabri, anti-hope campaign. PLEASE DO NOT POST ON THIS SITE AGAIN. Please respect our wishes.

Ian Frederick Anderton, majority owner of Mynsyd Corporation (private company), the company which owns and finances the thisisms website.

[TheTysabriBull]

First of all, a clinically diagnosed, treatment naive MSer has too many infiltrating or cascading WBCs in their CSF. An AIDs patient has a severely degraded immune system and poor immune suveillance in their CNS! Natalizumab's novel mechanism of action IS to mitigate and dampen the cascade of these errant Tcells migrating across the blood brain barrier and inherently causing the inflammation and subsequent CNS damage in MS. Transiently and safely reducing an MS patient's CSF WBC to 5 or less per ml is highly desirable to mitigate the inflammatory cascade in MS!

In HIV/AIDs, the CD4/CD8 ratio is inately and humoraly depleted by the activated HIV virus which INFECTS most all available mature and immature CD4 helper cells, replicates in them, and then kills those infected Tcells! If any CD4 helper cell is dead, it CANNOT transmigrate the blood brain barrier(BBB) to assist in CNS immune surveillance. The activation of JCV to PML viremia is theorized to occur in IMMUNE COMPRIMISED patients when an JCV infected B cell or activated JCV pathogen enters the brain parenchyma or oligodendrocytes. With a reduced CD4/CD8 ratio, immune surveillance of the CNS compartment is severely compromised and risk of infection from viruses and pathogens such as JCV is increased.

Natalizumab's biological half life is 11 days plus or minus 4 days. Upon infusion into the blood the natalizumab selective adhesion molecule(SAM) affixes itself to the very late antigen 4 receptor proteins expressed on the surface of most Tcells except neutrophils. Biological clearance of natalizumab is time dependent on the average biological lifespan of all Tcells expressing VLA4 that exist and circulate in the blood serum at time of infusion. Assuming no simultaneous biologic or pharmakinetic clearance reduction, just before the next infusion of natalizumab at end of day 27 and using a conservative range of 15 days as clinical biological half life, natalizumab serum trough concentration would be 15 days/15 days (1/2) X 12 days/15 days(1/2) or .5 X .8 (.5) or 20% of the original serum concentration from the previous infusion. Therefore it can be conservatively assumed that 80% of the Tcells or circulating immune cells that were bound by the natalizumab SAM and blockaded from transmigrating the BBB have been cleared by natural life cycle and replaced by newly activated and mature Tcells expressing VLA4.

Although natalizumab therapy given to an MS patient may IDEALLY and TRANSIENTLY reduce the available CD4 and CD8 cell's ability to respond and transmigrate the blood brain barrier for immune surveillance of the CNS, it is not a degraded chronic condition such as HIV/AIDs which AGGRESSIVELY infects and KILLS Tcells necessary for healthy immune surveillance of the CNS. This chronic unhealthy condition allows for a much higher occurrence of other infectious diseases as well as PML. AIDs patients are known to suffer from more frequent occurences of PML than other immune comprimised individuals.

I conclude that those TEVA funded medical experts who did that study used misleading terminology to maliciously correlate an UNHEALTHY comprimised and damaged immune condition caused solely by the AIDs pathogen to a much SAFER and HEALTHIER TRANSIENT blockade of Tcells which effectively mitigates the undesireable inflammatory cascade and immune response mechanism of MS during monthly natalizumab therapy. AIMHO

Adios Harry Z.

[HarryZ]

Ian,

I think this says it all Harry. Your postings on Tysabri are much more to do with your personal issues with the companies behind this drug. I'm in no way suggesting that there should be any censorship, but I also think that posts should remain unbiased. You only ever post negative stories about this drug, even though you know that some on this site with the condition have taken the difficult decision to have this treatment.

There are a number of people on this forum and other forums who only post press releases from Biogen/Elan that depict Tysabri in a totally favorable way. Are you suggesting that they be unbiased and post the other side of the story to "balance" their messages?

I post messages giving the readers the "other" side of the story so they can read not only the pros but cons about this drug. Why do you continually equate other information like I posted with this research article as being "negative". It's the result of science, Ian...it isn't negative. If a MS patient was going to make a decision about whether to use Tysabri or not wouldn't he/she want to know EVERYTHING they could about it before making their decision. If you had your way, they would only read what Biogen/Elan would want them to read and wouldn't be totally informed, would they?

I'm sick of hearing the excuse that you are providing sufferers with additional information to help them with their decision making. Do you really think that telling those who are having Tysabri now that their immune system will be the equivalent of an HIV patient helps? No doubt they can all sleep better in their bed tonight because of your helpfulness!

If you have an issue with the research paper that was published then perhaps you should contact the authors and explain to them that current or potential Tysabri users don't want to read their science. I can't believe that you are suggesting that this information not be posted because the feelings of some MS patients may get hurt!!!

I always get private messages from readers here as well as other MS forums encouraging me to continue to give the "other view" about Tysabri and other medications with MS so the readers get the full picture.

If you posted a range of articles on Tysabri I might buy into your "I'm giving sufferers information to help themselve decide" story. But from the very start it has all been the bad news. What do you hope to achieve? That sufferers with few other treatment options come off Tysabri / don't start? Who gains then?

There are more than enough posters here and on other MS forums that post several articles of various types involving Tysabri or other medications. I choose to present the "other side" so readers can be well informed. Do you think I'm interested in becoming part of a popularity contest in providing MS patients only one side of the issue?!

Ian, you have tried to suggest on several occasions that I stop informing MS patients about the dangers and potential problems of some MS medications. I am going to respectfully ask you to stop "beating a dead horse" and let the readers here decide what they want to read and listen to. I can relate to your frustrations with this lousy disease but please, give the readers some credit here....most of them are quite capable of making their own decisions.

Why don't you shock us an come up with a positive Tysabri story to show you are unbiased?

Because I have a strong opinion that Tysabri is a MS medication that was simply rushed into the market place without proper research in order for Biogen/Elan to make a lot of money. Because of this and all of the resulting problems associated with re-introducing this drug, MS patients have had to endure needless frustrations and suffering.

A new more efective treatment should be a celebration, even knowing that increased effectiveness brings bigger risks. How anyone could get pleasure from keep dashing peoples' hopes by bringing a constant stream of negative stories beggars belief. Let the dust settle and let's see how those on Tysabri do after six months.

So according to your wishes, Tysabri patients should not be told any scientific information about Tysabri that casts some real concerns about it....let's keep them in the dark and hope that these problems don't materialize. And if they do, we can always tell them that we wanted to make them "feel better" and not tell them about some of these dangers!!

Tysabri may very well be of great benefit to some MS patients just as other medications have helped. But there is still a lot of research to do with this drug and I have a concern that the general MS population are going to be the "research subjects".

Take care.

Harry

[HarryZ]

Pete,

Harry, take notice, many people are informed and are willing to take a chance rather than live with no hope.

That's great and YOU have made the choice to do what you think is best for you. I have never had a problem with a MS or any other patient having the right to make their own decisions on their health care. The more informed the patient, the better the decision making process.

Harry

[HarryZ]

Ian,

Nice try!

Harry

[lyndacarol]

Please don't drive away from this site anyone who has a connection with MS, who wants to contribute, and who may have opinions that differ from general consensus--wait, that's a description of ME!

I read everything here, whether I personally agree with the hypothesis or not. I might learn from anything, since I recognize my inadequacies. I think there can be value for someone in all knowledge. Let it all, good and bad, be out there so that I can weigh it all in my decision-making.

[TheTysabriBull]

Harry,

The conflicted and biased research study you refered to was ORIGINALLY and COINCIDENTALLY presented just prior to the Tysabri FDA AC meeting in March. It's old F.U.D which I think was sponsored or funded by TEVA, owners of the Copaxone for MS franchise in a pitiful attempt to slow or even halt FDA re-approval of Tysabri.

[HarryZ]

Harry,

The conflicted and biased research study you refered to was ORIGINALLY and COINCIDENTALLY presented just prior to the Tysabri FDA AC meeting in March. It's old F.U.D which I think was sponsored or funded by TEVA, owners of the Copaxone for MS franchise in a pitiful attempt to slow or even halt FDA re-approval of Tysabri.

Regardless of who sponsored it, (the CRAB drug makers have been in a marketing "war" among themselves for many months now, all trying to ensure they keep their lucrative market $hare) the research was done and the results published. This particular article I came across just yesterday so I have no idea when it was originally published.

We have heard from Biogen for months and months through press releases how absolutely great Tysabri is. But we have also heard from other researchers and docs about the possible dangers that are associated with this drug. I post these messages of caution so the readers can learn as much as possible about this medication and if they decide to use it, at least they have can make an informed decision.

Take care.

Harry

[HarryZ]

I conclude that those TEVA funded medical experts who did that study used misleading terminology to maliciously correlate an UNHEALTHY comprimised and damaged immune condition caused solely by the AIDs pathogen to a much SAFER and HEALTHIER TRANSIENT blockade of Tcells which effectively mitigates the undesireable inflammatory cascade and immune response mechanism of MS during monthly natalizumab therapy. AIMHO

Adios Harry Z.

Well, I guess MS patients can rest easily now that you have made your conclusion

Here is something that Dr. Lawrence Steinman wrote(one of the inventors of Tysabri....


Steinman said he was thrilled with the trial results and began to question his own predictive powers regarding the drug's potential side effects. Nonetheless, he continued to voice his concerns at medical meetings and in scientific journals.

In June 2004 review article in Science magazine, he wrote that this approach to treatment carried "at least a theoretical concern that recipients of the therapy would become generally compromised in their ability to fight infection."

Still, the FDA was so impressed with the trial results that it approved the drug in November 2004 under an accelerated process. Analysts predicted the drug—the first new drug for M.S. in eight years—would have a $2 billion market within two years.

At the time of the drug's approval, it had only been tested in a few thousand patients, Steinman noted.

"I worried that when it becomes the blockbuster everyone expected, what would happen when we had 50,000 patient-years of experience?" he asked. "And sure enough, after only a few thousand patient-years of experience, the drug gets pulled because it causes two people to develop a horrendous disease, and one is already dead."

__________________________

So you see, there are experts in the field who have differing opinions. The readers here can look at both and decide which ones they want to give more credibility. That's what these forums are all about.....different views, different opinions. Some people, however, believe we shouldn't be allowed to post these different opinions and views..... I, however,don't happen to be one of them.

Harry

[bromley]

Harry,

You just can't stop yourself. This was something you said when Tysabri got approved in Canada:

Interesting that Dr. O'Connor of the St. Michael's MS Clinic in Toronto was the spokesman for this announcement. He has a reputation of being a very eager MS drug prescriber for his patients.

This sort of sums up your position regarding drug treatments - what do you expect Dr O'Connor to do - not to precribe drugs to MS patients?

Your interest on these boards is to wind up people so that a flurry of e-mails will follow. You have had clashes with a number of people with MS about Tysabri. It's always scientific data to you if it is negative, and you undermine positive data by suggesting that the drugs companies fiddle the results.

Please don't treat us as idiots - we know people die from PML, we know that more effective drugs have major downsides. But people without hope may be prepared to take the risks for improvements in their life.

There must be hundreds of MS sites you can go on. Just leave this one alone - we're about research breakthroughs, new treatments and hope. And all you say is the CRABs are useless, chemo treatments muck up your immune system, and you are a full-time anti-Tysabri campaigner. You never seem to understand the hope issue and seem determined to keep nibbling away. So if your efforts turn people away from Tysabri what then for them? They are on Tysabri because the first line treatments have failed. They are on Tysabri because they are sick and tired of disabling relapses and are scared stiff that the next one will rob them of thier sight or put them in a wheelchair. I'm at home following a very bad relapse. My MS nurse said that her patients on Tysabri generally saw good benefit. One young woman went down hill after Tysabri was halted and is now in a wheelchair.

This isn't a hobby Harry, or a place for a pseudo-intellectual debate. Playing around with trials data is a waste of time. You do not have MS, your wife is not likely to be prescribed Tysabri given that she has progressive MS. Why keep posting the negative stuff for those where this may be the only treatment option?

And don't keeep playing the censorship, freedom of speech stuff. I posted some research on the increase in MS in Canadian women. A few of us tried to come up with possible reasons for this - amateurs as we are. Where were you on this post - you're Canadian and say you have knowledge of MS over 4-5 decades?

You're starting to turn me off this site for the simple reason that you are killing peoples' hope. The Rituximab Phase II trial data should be out soon (Biogen one of the drugs companies). You better ask Arron to set up a Rituximab thread so you can undermine all the results etc. And shock horror, if it proves to be an effective treatment Dr O'Connor might start prescribing it and we wouldn't want him to do that would we Harry!