Rolipram Trial Terminated

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Rolipram Trial Terminated

Postby OddDuck » Sun Sep 26, 2004 5:59 am

THIS IS JUST INTERESTING FURTHER JUSTIFICATION FOR MY PERSONAL OPINION THAT DESIPRAMINE NEEDS TO BE PUT INTO CLINICAL TRIAL:

I was perusing the NMSS's list of Clinical Trials for Summer/Fall 2004, and the current results, etc., and lo and behold I ran across the results of the Rolipram clinical trial.

Did I call it or what? I had said in my original research that the reason that Rolipram had not been looked at sooner for MS was because the dose required to effectuate any viable use for MS would have to be way too high. It doesn't surprise me one bit that they terminated the trial early because it showed no effectiveness. The reason being, I'm sure, is as I suspected they'd find (like they found originally in their lab). You can't go high enough on the dose. The side effects would be too much for a patient. But they tried it anyway - at the dose that a patient could safely take, but not at a dose that would work. I'll give them credit for that, I suppose. I was sort of surprised that they were going to try it, though, especially since they already knew they wouldn't be able to go high enough on dose, but..........whatever.

If you'll go back and look at my original research paper or peruse it again online (I even went and got it myself to see exactly what it was I said), I predicted that desipramine would be a better drug to try, because one of the beneficial effects it had was the same thing as Rolipram (which could be helpful in MS), and it was via a different pathway than Rolipram, and the dose you would take of desipramine would be far less with far less possible adverse consequences. I specifically said that in my opinion, based on the available data I found, desipramine would/should prove to be better than Rolipram. (Not to mention the broader spectrum of effectiveness desipramine appears to have for MS that Rolipram never showed.) You know, I bet they could combine a small dose of Rolipram with desipramine and find it synergistic, too. I just throw that out there, but it's not fully thought out.

Well, my credibility just increased a tad, huh? Not to mention my "gut feelings" appear to be as reliable as I always claimed. Talk about timing! JUST before I take my research to Dr. Moses, one of my predictions, or should I say hypotheses, (based on my detailed research) pans out.

I know I'm sort of "tickled". Especially after the Auckland guys stole my thunder! HAH! (Oh, I should post what the "Auckland" thing is all about. You might find it funny. It was actually an article that was posted on this website, I believe, too.) See below (this is an email I wrote right after the Auckland article came out). :wink:

Deb
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7/14/04

Ok....I can't believe this one! I JUST saw this article today! This is touted as a "breakthrough", how "exciting", etc., and this may sound sarcastic, but once you read this article (below) you'll totally understand why I feel this way:

All I can say is "DUH, you Auckland guys!"

I've been saying this for months. And if someone would listen to me, we won't have to wait "ten years" to try it!!

They found........gee........a "neuro-protector" (i.e. an anti-convulsant called NBQX) in combination with a growth factor stimulator (glypromate) MIRACULOUSLY helps to reverse MS damage! And combine that with a little immune regulation! "How exciting!" "IF it works in people", they say?

Duh...........I'm taking that combination NOW! In two simple drugs already on the market. And MINE are simple oral medications! And they do MORE (broader range of probable effectiveness)! HAH!

Do you blame me for being just a "tad" upset? (I'm upset, but laughing at the same time.) For heavens sake!

TOO funny! I'm attaching the news article along with a couple of abstracts (as always) where I've highlighted the "duh" parts. Of course, when I dug just a hair deeper (which only took me about two seconds), this all links back to what I've been blabbing about over the last weeks/months.........Ca2, Gaba, glutamate, cytokines, antibodies, caspase 3, on and on............so I stopped right there. No need to go further.

Ten years? They've got to be kidding! And they SOLD it, it looks like? They have patents?? You mean I could be RICH? (No matter.........I'm not trying to make any money.........I'm just trying to get someone to listen, is all.)

Best always, guys. I'm gonna go home now and lick my wounds. *smile*

Deb

P.S. I don't know........maybe I'm missing something (?) Shoot, maybe I SHOULD present this as a money-making proposition instead of an altruistic one. *sigh* Nope...that's out...it's just not in me. Altruism, it is.

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HERE'S THE ARTICLE. Below this are a couple of my comments via highlighted abstracts, so please scroll on through, if you would. Thanks.

Auckland researchers make MS treatment breakthrough

15 July 2004

Scientists have developed a treatment which may eventually rescue multiple sclerosis victims from what is often an inexorable slide towards a wheelchair.

The treatment, pioneered at the Auckland Medical School, produced a complete recovery in mice which had been paralysed by a similar disease.

If it also works in people, it could transform the lives of 2.5 million people who now suffer from multiple sclerosis (MS) around the world, 3000 of them in New Zealand.

The mystery disease makes the body's immune system attack the protective coating around its own nerve cells, causing bouts of blurred eyesight, balance problems and eventually paralysis which get worse with every new attack.

Paralysed Aucklander sufferer Carolyn Ryan called the breakthrough "really exciting".

"It sounds to me as though it's a very special thing, because as far as I know, no one has come up with a way to actually treat people who already have got damaged nerves," she said. "It's really revolutionary."

Auckland medical researcher Dr Tom Miller, research director of the MS Society until recently, said the new treatment was the first time anyone had been able to reverse the deterioration in the health of an MS victim, rather than just slow it down.

Associate Professor Geoff Krissansen, who led the research team, said existing treatments all attacked only one part of the problem.

His team's approach, published in the Oxford journal Brain, combines two elements:

An antibody that prevents white blood cells of the immune system from breaking into the body's central nervous system when they get confused.

Two "neuroprotectors", a widely used chemical NBQX and a molecule, glypromate, which is part of a growth factor occurring naturally in the body, which protect individual nerve cells from attack and allow the body to rebuild the nerves' protective coatings.

"It's the combination of the two neuroprotectors which seems to be critical, because both the neurons and the cells that repair them have to be protected," Dr Krissansen said.

"You can actually see the new myelin (protective coating) being laid down."

The treatment requires a continuous injection of the two neuroprotectors and injection of the antibodies every two or three days.

Dr Krissansen, a molecular researcher who also studies cancer and other diseases, has worked on MS for the past seven years.

He said progress was slow until Indian scientist Dr Jagat Kanwar, "an extremely good experimentalist", joined the team soon after moving to New Zealand with his wife Dr Rupinder Kanwar, who is also part of the team.

The project got another boost when the Royal Society awarded Dr Krissansen a rare James Cook Fellowship to work on the research fulltime in 1998-99, followed by a Marsden grant from 2000 to 2002.

Patents for the treatment have been given to Neuren Pharmaceuticals (formerly Neuronz), based in the medical school's Liggins Institute.

Neuren chief scientist Dr Peter Gluckman said the company hoped to start phase one clinical trials of glypromate next year, but he said NBQX would never enter clinical trials.

"It's not clear that the combination does require both. There are many drug companies working on this," he said.

"But we will, in time, develop trials for the combination if it makes sense."

Dr Krissansen said it would be at least 10 years before the treatment got through all the trials required for general use with MS patients.

MS Society medical director Dr Ernie Willoughby said patients were often frustrated by the need to wait, but would be encouraged by the fact that the society was helping to fund such cutting-edge research in New Zealand.

"It's kind of exciting that we can get work done here that's innovative and interesting," he said.

"Not all the treatments or effects in the animal model have always worked out in humans. It's too early to say whether it's going to be a breakthrough in human MS. But it's potentially exciting."

Original article can be found here: http://www.stuff.co.nz/stuff/0,2106,2971969a11,00.html

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Here's what I found when I researched it further.

Brain. 2004 Jun;127(Pt 6):1313-31. Epub 2004 May 06.

Simultaneous neuroprotection and blockade of inflammation reverses autoimmune encephalomyelitis.

Kanwar JR, Kanwar RK, Krissansen GW.

Department of Molecular Medicine & Pathology, Faculty of Medicine and Health Science, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand.

In multiple sclerosis, the immune system attacks the white matter of the brain and spinal cord, leading to disability and/or paralysis. Myelin, oligodendrocytes and neurons are lost due to the release by immune cells of cytotoxic cytokines, autoantibodies and toxic amounts of the excitatory neurotransmitter glutamate. Experimental autoimmune encephalomyelitis (EAE) is an animal model that exhibits the clinical and pathological features of multiple sclerosis. Current therapies that suppress either the inflammation or glutamate excitotoxicity are partially effective when administered at an early stage of EAE, but cannot block advanced disease. In a multi-faceted approach to combat EAE, we blocked inflammation with an anti-MAdCAM-1 (mucosal addressin cell adhesion molecule-1) monoclonal antibody and simultaneously protected oligodendrocytes and neurons against glutamate-mediated damage with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate antagonist 2,3-dihydroxy-6-nitro-7- sulfamoylbenzo(f)quinoxaline (NBQX) and the neuroprotector glycine-proline-glutamic acid (GPE; N-terminal tripeptide of insulin-like growth factor). Remarkably, administration at an advanced stage of unremitting EAE of either a combination of NBQX and GPE, or preferably all three latter reagents, resulted in amelioration of disease and repair of the CNS, as assessed by increased oligodendrocyte survival and remyelination, and corresponding decreased paralysis, inflammation, CNS apoptosis and axonal damage. Each treatment reduced the expression of nitric oxide and a large panel of proinflammatory and immunoregulatory cytokines, in particular IL-6 which plays a critical role in mediating EAE. Mice displayed discernible improvements in all physical features examined. Disease was suppressed for 5 weeks, but relapsed when treatment was suspended, suggesting treatment must be maintained to be effective. The above approaches, which allow CNS repair by inhibiting inflammation and/or simultaneously protect neurons and oligodendrocytes from damage, could thus be effective therapies for multiple sclerosis.

PMID: 15130951 [PubMed - indexed for MEDLINE]

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COMMENT (albeit just a hair sarcastic) FROM DEB: No kidding, Aukland?

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Pediatr Res. 2004 Jun 16 [Epub ahead of print]

Brain Injury Induced by Intracerebral Injection of Interleukin-1beta and Tumor Necrosis Factor-alpha In the Neonatal Rat.

Cai Z, Lin S, Pang Y, Rhodes PG.

Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216, U.S.A.

To examine the possible role of inflammatory cytokines in mediating neonatal brain injury, we investigated effects of intracerebral injection of IL-1beta (IL-1beta) or tumor necrosis factor-alpha (TNFalpha) on brain injury in the neonatal rat. A stereotaxic intracerebral injection of IL-1beta or TNFalpha (10 ng per pup) was performed in postnatal day 5 (P5) SD rats. Although no necrosis of neurons was found, increased astrogliosis, as indicated by GFAP positive staining was observed 24 and 72 h following the injection of IL-1beta or TNFalpha. IL-1beta induced apoptotic cell death in the rat brain 24 h after the injection, as indicated by increases in positive TUNEL staining and caspase-3 activity, and apoptotic cell death was partially blocked by systemic administration of NBQX, an antagonist of the AMPA glutamate receptor. IL-1beta also significantly reduced the number of developing oligodendrocytes (OLs) 24 h after the injection and this impairment was not prevented by NBQX. On the contrary, TNFalpha induced a much smaller increase in the number of TUNEL positive cells and did not reduce the number of developing OLs. By P8, myelin basic protein (MBP) was clearly detected in the control rat brain, while MBP positive staining was very weak, if any, in the IL-1beta treated rat brain. MBP expression in the TNFalpha treated rat brain was less affected. The overall results indicate that IL-1beta may directly cause injuries to developing OLs and impair myelination in the neonatal rat brain and TNFalpha may have different roles in mediating brain injury.

PMID: 15201401 [PubMed - as supplied by publisher]

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COMMENT FROM DEB: Based on the above, it looks like my suggested drug treatments are better,........so there, Auckland!
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Postby bromley » Sun Sep 26, 2004 6:10 am

OddDuck,

You are either mad or a genius (the line is fine between the two). I enjoy reading your entries but could you provide a one para idiot guide so that lesser mortal such as I can understand what you are saying / have found.

Regards

Bromley
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Postby OddDuck » Sun Sep 26, 2004 6:13 am

Bromley,

Hey, that's what my last neuro said! hahahahahahahahaha.....

Hey, don't blame me totally. The NMSS keeps encouraging me! :lol:

Well, that's why I highlight stuff. I "think" if you follow the main highlighted text, it makes more common sense. Or at least I hope so.

Deb
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Postby treez » Sun Sep 26, 2004 8:40 am

OddDuck,

How does the NMSS keep encouraging you? I quit even visiting the site because it seems so "behind the times" with just about every aspect of MS. This site has MUCH more up to date info. all in one place

Curious..............

Treez
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Postby OddDuck » Sun Sep 26, 2004 8:53 am

Treez,

I'm in direct contact with them via personal email. I've developed sort of a "professional" friendship, I guess you would say, with one of the Research Directors there. We stay in touch with each other, and he keeps encouraging me. REALLY nice guy!

Deb
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Postby OddDuck » Sun Sep 26, 2004 8:58 am

Oh, and actually, they're not as behind as you'd think. They just don't jump the gun on what/where they support (research-wise). It's a fine line that they have to walk.

If you look at the grants they've given out closely, though, you'll see where they aren't doing too bad. They're financing research programs all over the board, as I put it. From genetics to immunotherapy to proteins to infectious causes to patterns of disease, on and on.

Deb
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Postby treez » Sun Sep 26, 2004 9:16 am

OddDuck,

I guess I understand their caution. Besides their funding could also be a risk if they were to jump the gun. Also, that site is geared to the average Joe who isn't interested in all the medical "mumbo jumbo" presented here. I personally have alot of medical background info to learn to better understand, but most people could care less. they just want to know current research in a nutshell I guess.

I personally want to know as much as I can! I'm starting to believe the answer may already be out there. there are just so many pieces of the puzzle to sort though. Like looking for ten needles scattered in 100 different haystacks?

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Postby OddDuck » Sun Sep 26, 2004 9:19 am

Ditto, treez!!

:wink:

Deb
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