This Is MS Multiple Sclerosis Community: Knowledge & Support

This topic started in the autoimmune section with a post by OddDuck (Deb) and her research and theories are now posted as a headline article here on ThisIsMS..

My post is just some more info on Desipramine and its relationship to MS..

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First let me say thanks to Deb for all her research and non conformist thinking to provide everyone with this great overview and well thoughtout and prepared documentation.

One thing is certain, until someone else steps forward, Deb is so far the only example of the interaction of Desipramine and someone with MS, and with that known, we are at the mathmatical conjecture "if one in a given, two is an absolute", so hopefully that other "absolute" will appear and add more to this extremely interesting subject.

I read Debs information several times, and I found it to be very conclusive in all areas as per specifics of her purpose, and as it is obvious she has spent a great deal of time in checking and rechecking all aspects of Desipramine, perhaps first it would be good to see how it is decribed:

Desipramine : Brand Names Norpramin, Pertofrane

http://www.mentalhealth.com/drug/p30-n03.html

As can be seen on this page there are several areas of specific concern, everyone should read these areas thouroughly. But as to the concerns, the actual negative aspects are not truely stated as per volume of dosage.

DESIPRAMINE HYDROCHLORIDE

http://www.rxlist.com/cgi/generic2/desipram.htm
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While looking over the chemical makeup of DESIPRAMINE, I noticed the word Monohydrochloride, with a definition here:

http://www.online-medical-dictionary.or ... rochloride

Quinpirole Monohydrochloride
A dopamine D2/D3 receptor agonist.

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Pertaining to the use of Desipramine ( or should I say lack of) in regards to MS, at this site, under Pain/Altered Sensation (Dysaesthesia) you will see Desipramine listed..

http://www.mult-sclerosis.org/mstreatments.html

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Once again we find Desipramine mentioned in an article on MS, it is mentioned in the area of pain relief:

MS usually causes severe pain in over 60% of patients. The pain itself is a strong stressor instigating flare-up (relapse) of MS. Treatment with anticonvulsants such as Tegretol (non-generic), Klonopin® (non-generic), and Depakote help in the management of severe pain. Analgesic antidepressant treatment with Trazodone or Desipramine (not Amitriptyline), opioid antagonists, Tramadol (Ultram) are the minimum requirements.

http://www.rsdrx.com/Multiple%20Sclerosis.htm

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And here as to be used for emotional areas..

Emotional disorders (depression, mood swings) 25-50% amitriptyline (Elavil)
desipramine (Norparmin, Pertofrane) imipramine (Tofranil)

http://imaginis.com/multiple-sclerosis/ ... for-ms.asp

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And here again for the emotional aspects :

... The authors con- cluded that desipramine is beneficial for MS patients experi- encing serious depression, but the ... Symptomatic therapy of multiple sclerosis.

Note:** The below link will take you to a pdf document..

http://www.cpa-apc.org/Publications/Arc ... odgers.pdf

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So, with all these references to desipramine and MS in regards to pain & psycological, one would assume that at sometime,somewhere, it would have been used, maybe not.
We know what desipramine has done for Deb, so now it would be wonderful to find others and see what thier experiance was, I suspect, and this is purely my thoughts, that perhaps due to the stated side effects and other negatives, perhaps Doctors shyed away from it, or it was used and never looked at as what was "actually" helping, as it was used for other aspects of MS..

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Deb, Thank you for your hard work, you are a great example of what needs to be done in situations like this, I am so glad you stepped up and posted this, and we can hope you have set an example for everyone to not hesitate to let everyone know about "anything" that might be of help to others in dealing with this Disease or any disease.

Philip

I printed out and read Deb's interesting post about desipramine. I have a series of comments about it and the reactions from mscaregiver and the NMSS. I am going to go from the general to the specific in my list. This is a tough review, but I fully intend it to be fair and ultimately constructive. Deb, if you want to have an impact you'll get to work on Version 2.0 of your piece.

1. I'm really glad it worked for Deb. I am in favor of anything that works.

2. Deb did an impressive survey of the information out there, but I am afraid she is destined to be ignored by medical professionals. My issues aren't with Deb's work, but with her interpretation and presentation of what she collected. On the interpretation side of things, I think she hasn't substantiated her evident conclusion that desipramine affects the disease process. I further think that her presentation diminishes, rather than enhances her case. I offer specifics below.

3. I tend to agree with the NMSS and miscaregiver that desipramine is best viewed as a treatment for the symptoms of MS as opposed to something that will affect the disease process. I say "tend to" agree because the specifics of Deb's argument on its impact on the disease process were murky, an issue I will get into below.

4. It would appear that desipramine is already used, or at least listed, as an MS treatment. Perhaps the neuros should give it more attention, but other than that I'm not sure what, if any, problem Deb has solved. (On the other hand, if desipramine works that well but is hardly ever used, then spreading the word about an underutilized treatment for symptoms is certainly worthwhile.)

5. Specifics on her presentation:

• There's no abstract, nor is there a conclusion. So, while I can surmise that she regards desipramine as something that affects the MS disease process, there is no statement to that effect. It lends an air of disorganization to her piece. To put it differently, Deb needs to reconsider her specific goals with respect to desipramine and the article she has written. The way to do this, Deb, is to sit down with a blank sheet of paper and write down the three or so things you want to say. No more than once sentence per idea. Trust me, this will help.
  
• Her writing style will appeal to the alternative medicine crowd, but it is far too promotional, colloquial and personal for a readership of medical professionals. Some examples: Capitalized words, exclamation points, personal references, misuse of quotation marks, the use of the term miracle drug. These are the sorts of things that will cause medical professionals not to take someone very seriously. Frankly, I think the NMSS person bent over backwards to be kind to Deb in his response.
  
  Every writer must write for the reader. All professions communicate in codes, and if you want to talk to people you must use that code. Is it fair? Actually, I think it is. "Codes" of the sort I'm referring to make for efficient transfer of information. By departing from the medical research "code," Deb has virtually insured that her work won't get the attention it deserves within the medical community.
  
  I must ask whether Deb either consciously or unconsciously intended her work to be ignored by established professionals. After all, she mentions having read numerous research reports. I wonder how she would have regarded one written in the style she's written hers.
  
• The main body of her piece is a laundry list of acronyms. It badly needs footnotes. For the purposes of general readership, those footnotes should explain the acronyms and concepts cited. Otherwise, all she's really accomplished is the dazzling of her readers. Some of them will be taken in, but many cirical readers will see it as a device intended to forestall rather than encourage real thinking. How can I really read Deb's article without attached explanations?
  
  For the purposes of technical readership, the footnotes should cite specific publications. Medical professionals will not take her meta-analysis seriously without citations. Period.
  
• In one section, she referred to her "findings." She has no findings; she did what I believe is called a "meta-analysis," i.e., a survey of other people's work. This is perfectly legitimate. It's done all the time. But there can be no "findings" in such work, because it doesn't involve original research.
  
• She mentions a "fairly extensive" side effect profile of desipramine. This screams for a footnote for general readers.
  
• She mentions in fairly rapid order the drugs Keppra, levetiracetam, Rolipram and Norpramin without really comparing or contrasting them in a way that I, a general reader, could find useful.
  
• Let me end this section on a hopeful note: All of the deficiencies I have cited could be corrected if Deb would simply rewrite her piece. She needs to write for two audiences: Medical professionals and interested laymen. This will make it a longer piece than if it was just directed to the medical professional community, but it can be accomplished. Deb needs to reconsider her specific goals; to add an abstract, a conclusion and footnotes; to remove promotional, personal and colloquial references; to tighten the focus in the section on the biochemical action of desipramine and in the section on the other drugs.

6. I think the NMSS reacted appropriately. I was intrigued by Timothy C.'s wording in his first paragraph, "... your many interesting messages related to desipramine ...". This begs the question, Deb: How many letters have you sent to these people?

7. mscaregiver makes an excellent point when noting that Deb is the only one who's reported such a dramatic effect. It would be interesting to know if others have done so.

8. I see that desipramine is, among other things, an anti-depressant. Naltrexone, in low doses (i.e., LDN), stimulates the production of endorphins. I can't help wondering if the enthusiasm for these drugs might come from their anti-depressant and/or euphoric effects, especially in people whose MS is either fairly mild to begin with or mainly cognitive in its expression.

Hi, Willy.

Yes, all valid points. I've been in law for over 30 years, and am a paralegal. I wrote that piece in the presentation format that I did on purpose. Frankly, it was done in a hurry, too (and I hate footnotes anyway), so I had two reasons for not putting them in - speed and laziness. (Terrible, aren't I?)

Two: It was originally written for my neurologist (on a dare), whom I didn't want to insult by providing footnotes etc. for points I knew he would be (or should have already been) aware of as individual points. (Shoot, as it was, he was always harping on me for talking "down" to him, so I didn't DARE make it appear like he wouldn't already know what I was saying! HAH!) My whole purpose was simply compilation of results, nothing else. That's why I wrote in there that it was over-simplified in presentation. Believe me, my neuro hated to read anything lengthy (matter of fact, I think he hated to read at all). But he asked me to provide him with the compilation, so I did. I asked him later if he wanted me to provide the substantive materials (because I hated footnotes), and he said "no", because he did understand what I was saying without them, and knew me well enough to know that if I said I had it, I had it. There was no need to do so much "convincing" to someone who was more educated and had a PhD in Pharmacology/Toxicology. He knew all this stuff. Some of it was his own research, or the research done by his colleagues whom he had worked directly with for many years, as a matter of fact. He recognized it all. Plus, as I got going, I had SO much substantive material that it got overwhelming, and I did stop organizing it all.

Three: My original purpose was not to have to send it on any further than my personal neurologist. After we had our falling out (unrelated to this research), I simply moved on with it. I didn't change the presentation at that point because why insult an expert's intelligence? If they did NOT already know what I was talking about, or did not know where I got my information, then that should tell them something (and us!). Come on.....they make their livings supposedly knowing all about MS and the theories, etc. that their colleagues are working on......uh....don't they? I'd HATE it if someone compiled legal issues for presentation to me, and they included a lot of substantive material and footnotes for basic legal knowledge that I am well aware of. It would make me feel insulted....as if they thought I was stupid or something. Nothing in what I provided to the NMSS was that complex anyway. It's all really basic stuff. If I had come across something that was unlikely for them to have been already aware of, I would have put in a footnote.

So....you are correct once more about your point about writing it in layperson's terms. It was NOT written for the layperson, I suppose. But I will admit that I do have trouble knowing how much a "layperson" knows. I base it on my own knowledge, I guess. Am I aiming too high for the average Joe? I certainly didn't think so. (Maybe I don't give myself enough credit, then? Hey...that's flattering!) But it still is VERY basic for a clinical researcher. If I can understand it, then they must! Perhaps I just read too much and too fast. Again, I did not rewrite my findings for posting on this website for the general public, because can you imagine the LENGTH it would be to try to REALLY explain everything? It would end up being 100 pages long. There's a lot of information crammed into just a couple of pages there. Shoot....as you can see, I'm "wordy" enough as it is! I like the way Arron said it in this website's intro; the real point is that there are people out here trying to make a difference. Plus, from what I gathered from the short time I've been perusing this website, it appeared to me that everyone here was VERY highly educated and knowledgeable about MS and the prevailing research theories, etc., so the thought of rewriting it for this website came and went through my mind fairly quickly, also. My thoughts (perhaps again mistakenly) would be that MSers (who are all highly knowledeable in my mind) and/or MS experts, etc., would be the prevailing audience for my compilation, anyway.

You're absolutely correct again, though, about this next point. I would have to narrow it down to one or two "points" if my purpose was really to get the NMSS to grant funds. I'll let whomever clinical researcher who understands what I put together make that determination, if s/he wants to look into desipramine. That's hard for me to do, though, simply because there are so many valid theories circulating right now, and with desipramine's likely broad spectrum of action, which two or three would you choose? Hard to say. It would take a roundtable brainstorming session with a few others to debate that one. And for now, it's only little ole me. I'll leave that to the experts, too. Hey, I included all of their lab research conclusions in my presentation. If you notice closely, the top people (who receive some of the highest grants from the NMSS - some of whom are on the panels at the NMSS) had their conclusions added to my research. So, if Dr. Calabresi could only relate to his findings and my reference that desipramine may prove effective for reduction of ion potassium, that's all he would need to check out. Dr. Rodriguez is currently concentrating on killer T cells, so again, that's where he would focus. And on and on. See what I mean? Each one of them would only pay attention to the particular hypothesis I included in my presentation that would directly relate to their line of research anyway. So, in my mind, I didn't know (or care) which researcher to choose as my favorite, so I figured I'd just include all the laboratory results, and simply correlate them to each researcher's line of specialty.

And my other strategy was to spur the experts into researching and double-checking my "findings" themselves (which in legal terms means exactly that.....those are my findings) and prove what I found wrong. I never claimed that any of it was my original discovery. That's a different meaning altogether. To me, the medical world must define the word "findings" as meaning original "discovery". That is my mistake, then. I will try to be more vigilant in the future. (I tend to be very literal. Law makes you that way, I guess.)

I've learned in legal writing that sometimes you need to place emphasis in your writing or it is misunderstood. Especially if you are communicating solely via email to someone you have never met, who then is unable to factor in body language or voice tone to what you are saying. Things can become drastically miscommunicated that way. But, yes, it is written very informally.....I recognize that.

Did I CONSIDER re-writing it in a more formal manner? Yes, I did. But......again, when I thought about, I discarded the idea based on what my overall strategy was in the first place, etc., as I explained above. It would actually in most ways have defeated my purpose. Besides, did they REALLY spend all that much time critiqueing my writing technique? If they did, then that tells me where their head is really at, also.

I didn't write formal "letters" to the man at the NMSS......we had informal written conversations with each other. (And respectfully asking, why does that matter?) As you can see, we were on a first name basis. (I tend to speak to everyone as friends anyway.) I work at the headquarters of an international union, and am used to speaking familiarly with many political leaders, officials, etc. I consider everyone my equal.....don't you? I believe this man does, also. Why should I have felt that I might need to "beg" for his respect for my credibility? I told him exactly who I was, where I worked, etc. And we treated each other with mutual respect and friendliness right from the start. I work for a union.........I tend to be a tad on the assertive and self-confident side due to the world I live in, I suppose. (Maybe that's putting it mildly?)

And I believe I DID say (in writing here on this website) that the NMSS was very nice. Based on how I'm reading your comment (which I could be misunderstanding, of course), where did you get the idea that anyone thought that the NMSS was NOT nice or responsive to us MSers, or that their answer to me was taken for granted? You didn't get that idea from me. But I don't feel that they should NOT have responded to me, either. That's just plain and simple RUDENESS and total unprofessionalism for anyone to ever NOT respond to anyone else! No matter who they are.

And my "conclusion" was stated. My conclusion is that there is far and above enough evidence out there to take desipramine to clinical trial. Bottom line. That's my point, without a clinical trial, there IS no way right now to "prove" desipramine's effect on the disease process. That's the whole point of suggesting a clinical trial, and for asking that someone else (with more knowledge and grant funds than me) to at least research my preliminary synopsis and tell us whether it might work for MS therapy or not. Even THAT much has never been done. Right now, we're stuck - unless or until a clinical researcher with a little moxie, as they say, moves on this themselves. I could do it myself, but again.........tell me why? Aren't they there to help us? If not, why are we raising money for them to continue researching for our benefit?

Willy, I take absolutely no offense whatsoever with your comments, because as I said you are absolutely correct in "almost" all of your points.

And I hope I haven't come across as sounding "defensive", because that's not the tone with which I am speaking at all. I'm simply explaining portions of my true intent, which of course, how would anyone know? They don't know me or all of the circumstances surrounding and/or leading up to this journey of mine. I'm guilty of making mistaken assumptions from time to time myself. It's only human.

Thanks Willy! Good points!

Oh....and anyone is welcome at any time to take any one of my points, research it to prove me incorrect and let me know. That's what discussion and debate is all about. Let's get people thinking on their own. Let's tickle their "need to know". I call it "grassroots mobilization".

Best always,

Deb

Oh.....sorry...one last thing.

With TCA antidepressants, you have to take about 5 or more times the dosage that I'm on for it to affect your "mood" at all. To get anti-depressant effects, it takes a high dose, which I am not on.

I think I mentioned how efficacy for MS would probably show itself at a pretty low dose of desipramine.

And if anyone knows anything about TCAs, they don't really provide a "euphoric" feeling.....those are the SSRIs that do that, because they only act on and increase serotonin alone. Those are the "feel good" drugs. TCAs affect so many other physiological processes, and most of the time do NOT give a person that euphoric feeling, that that's why they were put on the shelf for a while once the newer "feel good" drugs came out.

If you want to obtain that euphoric feeling, don't take a TCA.....take an SSRI.



Deb

Thanks for not going batsh*t on me. Seriously!


This helps me understand where you were coming from, but I still think you should re-write it. The NMSS isn't your neurologist and neither is anyone else who'll read it. Prior to my disability I had a long background in writing, and the very first rule is to write for your reader -- who is no longer your neurologist.


This will sound really strange, but writing it in medical research code allows the professionals to skip over a lot of what they don't want to read. It's a bit like an investment prospectus, which typically runs for dozens of pages but rarely gets read in its entirety. But the reader of only 10 pages demands that the other 50 pages be there or he won't believe any of what he does read. That's because one investor's meaningless financial statement footnote is another investor's telltale clue.

In fact, if anything's missing, the S.E.C. won't allow it to be published. If by some quirk it got through the S.E.C., the investors would toss it in the wastebasket, including the investors who otherwise would have bought the shares without reading the document. Does that mean form trumps content? Not at all. It means that if you want someone's money you'll give them the right words, in the format that he expects. If you can't do it, you could be offering shares in the second coming of Jesus Christ and you won't get in the door.

Paradoxical? Unfair? Silly? Yup, just like a whole lot in life. Think of it this way: You're out to send a message, not to reform the subcultures that define the means of delivering it effectively.


Once again, the audience is no longer your neuro.


You truly have my sympathy, honest you do. Some good things about footnotes nowadays: 1) Word processing software has done a great job of automating the creation and placement, 2) It's perfectly o.k. to put the footnotes at the end of the piece, and 3) you can put Internet links in your footnotes. Another approach would be to restrict footnotes to publication citations and use an Appendix at the back for rehashing concepts for the layperson.


From my perspective as a reader, I don't care if your original purpose was to howl at the moon. When I'm the reader I am in charge. Your original purpose and a buck and a half can be exchanged for a good cup of coffee out here in Seattle.


Really? What if you came across a Supreme Court opinion that wasn't footnoted? The first thing I'd do is wonder whether it was a Supreme Court opinion at all. Then I'd check to see which justice wrote it.


Think of your layperson as a bright 12th grader with little background in the subject. All those acronyms and concepts gave me a severe case of MEGO (My Eyes Glaze Over) Syndrome. Those terms and concepts need to be defined. If you do Version 2.0 I think you'll be surprised at the challenge you'll face in being informative but concise. Footnoting isn't an excuse to take your reader over the woods and through the hills to grandma's house.


Without footnotes? Absolutely.


See my comment above about footnotes not being an excuse to inject air into the hamburger bun. As for the length, there are some ways to handle it. One is to have an abstract at the top. Then make the document itself downloadable. Use an early version of Word for Windows.

Within the document, use the following technique: 30-3-30, which refers to writing something that can be read in 30 seconds, three minutes or 30 minutes. You do this with a document title, a table of contents, an abstract and headlines. Often, the same reader is a 30-second reader and later a 30-minute reader. It's a challenge, but it's a very effective means of expressing complex ideas.


I think you could do it in 25 pages with space left over for a review of The Decline and Fall of the Roman Empire. 20-25 pages sounds like a lot, but what you wrote already took up 6 pages when I pasted it into Word and printed it out. If two-thirds was footnotes and/or appendices, you could preserve the structure of your narrative for the experts while accomodating the laypeople.


I disagree. One of my complaints about some medical websites is that you get the feeling of joining a party that started a long time ago. People can be intelligent but not have the information to follow your argument. Why not accomodate them? Hell, you already did all that work; by contrast, writing it effectively ought to be duck soup in terms of the time spent.


Please tell me you didn't send that to the NMSS as part of a grant application. Even if you didn't, a concise and focused argument understandable to professionals and laymen alike is a good thing, wouldn't you say? As it now stands, I am completely unable to weigh your fundamental arguments because you lost me in the tall grass of your acronyms and medical concepts.


You don't have to provide the answers to everything. You need to make an articulate case for what you want investigated further.


I can't speak for Calabresi and Rodriguez, but I think those kinds of people would look at your paper in its current form and not get very far. That's unfortunate, because I think you present ideas that ought to be considered. And, as a layman who has MS, it would be nice to be able to follow the issue.


I may well be wrong about that point, but I don't think so. And remember, it's their code, not yours.


I'd lay off the capitalization. If it were me, and I felt the urge to emphasize, I'd use italics. Capitalization is the trailer park of written expression.


No, they did not spend time on your technique. I argue that they looked at what you wrote and said, in effect, this is a semi-crank wanna-be researcher and who has the time? It's not just about what you say, but also about how you say it. That's especially the case when you're an outsider.


I consider everyone my equal as a human being. But, as a union employee, surely you'll understand me when I say that if I want to persuade someone of something, then I will take careful note of who the target is and what approaches will be most effective. For instance, it is unlikely that I will persuade a German by stating my argument in Mandarin Chinese, no matter how impassioned or well-reasoned it might be.


I'm not advising anyone to beg for anything.


There have been some others around here who have been taking shots at them. This might have been reflected in what I wrote. My error.


It's really not stated unambiguously and clearly. There's no identifiable "conclusion" section to your piece.


Well, that would take some persuasion, wouldn't it? And if you want to persuade, then you must speak in your target's language. You have two kinds of targets: Medical researchers and interested laymen. I think your piece largely misses both audiences.

That's the bad news. The good news is that you missed your targets not on account of a lack of substance but because of the format and manner of expression. Those are problems that can be fixed. Remember, revision is the soul of good writing. Oh, and ellipses consist of three periods, not five or eight. They are used to indicate a gap in a quotation, not a pause in a narrative or to signal a mood of wistful reflection.


A little, but not too much. I was pretty blunt, and it's only human to want to defend one's self. But I think you've been remarkably non-crazy in response to me, and I want you to know that I notice it and very much appreciate it. If you can keep your cool after this picky and sometimes sarcastic (or was it just curmudgeonly and condescending?) rebuttal, then your name will be sent to Rome for future beatification. It's really refreshing to be able to have such a direct exchange without personal brickbats.

All the best, and I really hope you'll take a whack at a Version 2.0 sometime. You've got a lot to say, and I'd hate to see this wither on the vine.


Thanks for clearing that up.

Willy,

Touche!

(or....I could have said "and your point is?", but I couldn't decide between the two).

You know the one major point I did relate to totally in your feedback? Personally, that is? (And I had to chuckle.) The one that said something about how I was writing to an audience somewhere in the middle between the medical professionals and the laypeople. Hey, I think I live that way!

..."curmudgeonly and condescending?" Naw, I'd never think that! Besides, Willy, you haven't met my boss! HAH!

Seriously, I do appreciate your feedback. And I thank you. I don't have to like what someone has to say to appreciate it, respect it, and give it the consideration it deserves. If a person can't take constructive criticism, then don't try to play the game, I say. Besides, not once did I ever hear or get the feeling that you were trying to attack me personally, or even attack me at all. I even think I recognize a few traits of yours in myself! (I bet THAT statement - yes, all in caps - scares ya! hehehe...) And my interpretation of those traits is integrity, not sarcasm.

Thank you for your support, Willy. I recognize and appreciate that, also.

Talk at ya'll later! Willy wore me out today!

Deb

Oh..geez. I forgot to log in with my last post!

It has been a looooooooong day!

Deb

Hey Deb, wanna know what I really think?

Darn, Willy!

That was a good one! Why didn't I think of that? hahahahahahaha.....

Hey, you have a great night. I gotta go eat. Keep my strength up!

Deb

Hey, folks. I stumbled onto something again (fairly new stuff - at least for me), and it relates directly to desipramine again. This time I'm going to post the actual abstracts I found, highlight the "connections" I made, and try to be as concise as possible. (This also uncannily lends some support to the statement I just posted on here yesterday about how I thought a lower dose of desipramine might work best for MS.)

Here we go. I hope I know how to highlight, etc. LOL

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PUBLIC RELEASE DATE: 27-MAY-2004
[ Print This Article | Close This Window ]

Contact: Jacqueline Weaver
jacqueline.weaver@yale.edu
203-432-8555
Yale University

Researchers identify basis for irreversible damage in multiple sclerosis
New Haven, Conn. -- Yale researchers and collaborators have identified
molecules that underlie nerve fiber degeneration in patients with secondary progressive multiple sclerosis (MS), a disease that cripples nearly three million people worldwide. The new findings are the first observations in humans of molecules that contribute to degeneration of nerve fibers. Researchers at Yale, the Veterans Administration (VA) and University College London examined postmortem spinal cord tissue from patients with a progressive form of MS in a project supported by the Department of Veterans Affairs, National MS Society, Paralyzed Veterans of America, and the United Spinal Association. Using biomarkers of the damaged nerve fibers, they looked for molecular abnormalities and found a strong link between nerve damage and the presence of two molecules, Nav. 1.6 and NCX, a sodium channel and a sodium-calcium exchanger.

Located on the surface of most nerve fibers, Nav.1.6 controls the flow of sodium into the cell, which in turn triggers the activation of NCX, a molecule that, if unchecked, imports abnormal levels of calcium into the nerve fiber that ultimately lead to its death. "These results are extremely exciting because they provide, for the first time, important clues about the molecular basis for permanent and irreversible damage in MS," said Stephen Waxman, M.D., the lead investigator, chair of neurology and director of the VA Rehabilitation Research and Development Center in West Haven. "We hope to use these results
to design new therapies that will protect vulnerable nerve fibers."
MS is an inflammatory disease of the central nervous system in which myelin, the insulation that surrounds the nerve fibers, is damaged in multiple regions, leaving scars that hinder the relay of nerve signals from the brain to the rest of the body. One of the hallmark features of MS is a relapsing-remitting course in some patients. There is molecular rebuilding of nerve fibers, relay of nerve signals even in the absence of myelin, and recovery of previously lost functions such as the ability to see or walk, as the disease remits. Patients with the relapsing-remitting form of MS are neurologically normal between relapses, and do not develop permanent disability. However, in progressive forms of the disease, entire lengths of the nerve fibers begin to degenerate, resulting in permanent and irreparable damage, a steady worsening of symptoms and accumulation of disability.

Co-authors included Matthew Craner, M.D., and Joel Black of Yale and the VA.
The three researchers are part of Yale-London Collaboration on Nervous
System Injury and Repair.
Citation: PNAS, May 17, 2004, 10.1073/pnas.0402765101 (Early Edition)
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COMMENT FROM DEB: Ok. Let's start our correlations. The main thing here to remember is the need to try to maintain sodium density and reduce calcium influx. Ok....next:

PUBLIC RELEASE DATE: 23-MAY-2004

Contact: Natalie Frazin or Paul Girolami
301-496-5924
NIH/National Institute of Neurological Disorders and Stroke

Combination therapy dramatically improves function after spinal cord injury in rats.

A combination therapy using transplanted cells plus two experimental drugs significantly improves function in paralyzed rats, a new study shows. The results suggest that a similar therapy may be useful in humans with spinal cord injury. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, and appears in the June 2004 issue of Nature Medicine.*

About 10,000 people in the United States suffer spinal cord injuries each
year. Studies in animals during the past decade have shown that supporting cells from nerves outside the brain and spinal cord, called Schwann cells, can be used to make a "bridge" across the damaged spinal cord that encourages nerve fibers to regrow. Other research has suggested that a substance called cyclic AMP (cyclic adenosine monophosphate) can turn on growth factor genes in nerve cells, stimulating growth and helping to overcome signals that normally inhibit regeneration. This study is the first to try a combination of the two approaches in an animal model of spinal cord injury.

In the new study, Mary Bartlett Bunge, Ph.D., Damien Pearse, Ph.D., and
colleagues at the Miami Project to Cure Paralysis at the University of Miami School of Medicine, found that spinal cord injury triggers a loss of cAMP in the spinal cord and in some parts of the brain. They then transplanted Schwann cells into the spinal cords of rats in a way that bridged the damaged area. The researchers also gave the rats a form of cAMP and a drug called rolipram, which prevents cAMP from being broken down. Treatment with the triple-combination therapy preserved and even elevated cAMP levels in nerve cells after injury. It also preserved many of the myelinated nerve fibers in treated animals, compared to untreated rats and
those that did not receive the triple combination, the researchers found.
Myelin is a fatty substance that insulates the nerve fibers and improves
transmission of signals. The treated rats also grew back many more nerve fibers than untreated rats or rats that received only one or two of the therapies. The regenerated nerve fibers included many that carry the
nerve-signaling chemical serotonin, which is important for locomotion.
Rats that received the triple therapy had much better locomotion and
coordination 8 weeks after treatment than control rats. "The behavioral improvements in the rats receiving the triple therapy are dramatically better than those reported previously using Schwann cell bridges or cAMP strategies in spinal cord-injured animals," says Naomi Kleitman, Ph.D., the NINDS program director for spinal cord injury research.
Previous studies using Schwann cells found that nerve fibers from cells
above the injury could travel onto the Schwann cell bridge, but they did not leave the bridge, she explains. The triple therapy "punches the cells into overdrive and helps them get off the bridge." The therapies tested in this study were selected for their likely feasibility in humans, Dr. Kleitman adds. Rolipram has already been tested in clinical trials for other disorders, and Schwann cells can be grown from patients' own peripheral nerves. The researchers are now planning follow-up studies to confirm their results and to try to learn more about how the triple therapy works, Dr. Bunge says. Their studies might also lead to the development of better drugs to prevent the breakdown of cAMP, she adds.

The NINDS is a component of the National Institutes of Health within the
Department of Health and Human Services and is the nation's primary
supporter of biomedical research on the brain and nervous system.
*Pearse DD, Pereira FC, Marcillo AE, Bates ML, Berrocal YA, Filbin MT, Bunge MB. "cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury." Nature Medicine, June 2004, Vol. 10, No. 6, DOI:
10.1038/nm1056 (http://dx.doi.org/10.1038/nm1056).
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COMMENT FROM DEB: Ok. Let's start comparing in our minds my previous research and statements regarding desipramine's actions with the above theories.

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Acta Pharmacol Sin. 2003 Oct;24(10):996-1000. Related Articles, Links

Cytoprotective effect is one of common action pathways for antidepressants.

Li YF, Liu YQ, Huang WC, Luo ZP.

Institute of Pharmacology and Toxicology, Academy of Military Medical
Sciences, Beijing 100850, China. LYF619@yahoo.com.cn

AIM: To explore the possible common action mechanism of antidepressants. METHODS: The cell viability was detected by MTT assay. The intracellular Ca2+ concentration ([Ca2+]i) was measured by Fura 2-AM fluorescence labeling assay. Using RT-PCR, the mRNA level of nerve growth factor (NGF) was also detected. RESULTS: High concentration of corticosterone (0.2 mmol/L) was incubated with PC12 cells to simulate the lesion state of brain neurons in depressive illness. Three main kinds of antidepressants used in clinic [(1) tricyclic antidepressants (TCAs), such as desipramine (DIM) 0.625-10
micromol/L; (2) selective serotonin reuptake inhibitors (SSRIs), such as
fluoxetine (FLU) 0.625-10 micromol/L; (3) monoamine oxidase inhibitors
(MAOIs), such as moclobemide (MOC) 2.5-40 micromol/L] protected cells from the lesion induced by corticosterone. While antipsychotic drug
chlorpromazine or anxiolytic agent diazepam 0.4-50 micromol/L had no such effect. Moreover, DIM 1, 5 micromol/L or FLU 1, 5 micromol/L attenuated the [Ca2+]i overload induced by corticosterone 0.1 mmol/L for 48 h in PC12 cells. Furthermore, treatment with DIM or FLU 10 micromol/L for 48 h elevated the NGF mRNA expression in PC12 cells. CONCLUSION: Despite a remarkable structural diversity, the cytoprotective effect can be viewed as the common action pathway of the antidepressants. Moreover, attenuation of the intracellular Ca2+ overload and elevation of neurotrophic factor (such as NGF) expression is one of the mechanisms of cytoprotective effect of antidepressants.

PMID: 14531941 [PubMed - in process]

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COMMENT FROM DEB: The above mainly introduces how antidepressants affect calcium and provide cytoprotective effects. Hang in there, we are quickly reaching a conclusion.

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Neurochem Res. 1999 Mar;24(3):391-8. Related Articles, Links

High concentrations of tricyclic antidepressants increase intracellular Ca2+ in cultured neural cells.

Joshi PG, Singh A, Ravichandra B.

Department of Biophysics, National Institute of Mental Health and
Neurosciences, Bangalore, India.

We examined the effect of tricyclic antidepressants on intracellular Ca2+ signalling in cultured cells of neuronal and glial origin. High concentrations of amitriptyline and desipramine increased the intracellular Ca2+ in PC-12 and U-87 MG cells. In PC-12 cells amitriptyline induced a biphasic rise in intracellular Ca2+. A rapid and transient increase due to release of Ca2+ from intracellular pools was followed by sustained elevation of [Ca2+]i due to influx from the extracellular medium. Desipramine evoked the Ca2+ release from intracellular pools but the influx of Ca2+ was not elicited. In U-87 MG cells both the drugs induced Ca2+ release from intracellular pools, however amitriptyline also induced a transient influx of Ca2+. To delineate the mechanisms involved in mobilization of Ca2+ by the
drugs pharmacological agents that inhibit IP3 formation in cells and Ca2+
channel blockers were used and changes in [Ca2+]i and membrane potential were monitored. The results show that both the drugs release Ca2+ from IP3 sensitive pools by activation of phospholipase C and amitriptyline in addition activates a non specific cation channel in the plasma membrane of cells. Paradoxically at relatively lower concentrations (< 50 microM) amitriptyline and desipramine inhibited the Ca2+ signal induced by adenosine triphosphate in both the cell types. Our data demonstrate that tricyclic antidepressants at different doses may have inhibitory or stimulatory effects on cellular Ca2+ signalling.

PMID: 10215513 [PubMed - indexed for MEDLINE]
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COMMENT FROM DEB: Ok...going back to the beginning of this compilation of data, we started with wanting to maintain sodium density and reduce calcium influx, and hopefully raise levels of cAMP; and WHY we might want to do that (i.e. as a possible therapy for progressive MS.) Based on what we have found here and my previous research, does desipramine appear to be something to investigate?

These are the same type of correlations I found time and again in conjunction with my research on desipramine and its possible (or should I say "probable") effectiveness for MS (for which I have no footnotes). And now it appears that perhaps desipramine may even prove some effectiveness for progressive MS (it may need to be used in a combination therapy approach, which I also speculated the same thing), and the tricky thing again that my intuition has always bothered me about, was that the dosage of desipramine in MS would be crucial. Do these abstracts not indicate something very similar? How the dosage of desipramine appears to make a big difference (and perhaps the lower the better?)

And so far, how many treatments, etc., clinical trials, or newly mentioned drugs claim that they might be useful for progressive MS? I always see that the press releases relate to therapies for RRMS. As it is now, what and/or how many options do progressives have?

Is it POSSIBLE this avenue might be a treatment option? That's all I'm asking from the scientific world. Who's looking into this? And if nobody is, then why not?

Thanks everyone for your time and attention.

Deb

Deb, thank you so much for writing such a great article, putting it out there on This is MS, and following up with even more info. As far as I’m concerned, this is what it’s really all about and another sterling example of ideas and contributions people with MS can make.

Now, I have no scientific background and am really not in a position to comment on your great research on the possibility of desipramine as a potential treatment for MS. What does strike me though is that this is an anti-depressant used to treat depression, a mental illness.

Contrary to popular belief, mental illnesses are brain disorders and not the result of a bad childhood or whatever people generally conjure up about mental illnesses. So, in essence, since desipramine is a drug used to treat an existing brain disorder, i.e., the mental illness of depression, and since MS is also a disorder that affects the brain, it seems to me that it’s quite feasible just from that perspective alone to think that it could be useful for MS as well.

But, I think there is at least one expert who combines MS and depression who says more about that connection quite nicely. In Montel Williams book, Climbing Higher, Dr. Adam Kaplin, Chief Psychiatric Consultant to the MS Center at Johns Hopkins University, states the following:



My personal interpretation of those statements is that they really support your research. Wouldn't it be wonderful if someone from Johns Hopkins would consider being your champion as NMSS has suggested? You never know! At the very least, if you haven't already shared it with Johns Hopkins, you could write and ask your question, "Why not?"

And, I plan to share a copy of your article with a psychopharmacologist I work with who might have some comments or information about the drug itself. I'll certainly post any useful stuff I might glean from that.

Thank you again Deb.

Sharon

I don't think this argument has any validity at the moment. Depression as a brain disorder is a hotly debated topic, not a fact, as they have yet to identify biological markers or idenitifiable pathology in the brains of depressed patients. More importantly, antidepressants are mood-altering drugs...meaning that if they help with MS, then we should also try Cocaine and Ectacsy as MS treatments.

If I've read the previous material correctly, this particular antidepressant appears to have a specific mechanism that may help with MS. It looks like a reasonable enough hypothesis to explore to me! But I don't think that arguing that since antidepressants affect mood via the brain, those drugs might also help in the treatment of demyelination, is a valid argument at this point.

Sharon and Daunted:

Thank you for your hope and encouragement!

Yes, I did send this to Johns Hopkins and to the Montel Williams MS Foundation. To date, the only people I have heard back from was the NMSS.

My PCP (who is also a geneticist and works closely with the Vanderbilt group) is seriously investigating what I've stumbled onto, also.

Any and all whom we can get involved and elicit opinions or activism from is certainly welcomed and encouraged!!

Thank you for your support and willingness to pass this on to others.

You never know what may come of serendipitous discoveries. Why leave any stone unturned?

And by the way, everyone, if I haven't expressed this to anyone before, I have been remiss. May I take this moment to sincerely say that I hope everyone here is doing well with your health (and/or the health of your loved ones).

All the best,

Deb

This drug is prescribed for neuropathic pain (which many of us have), so I think it would be fairly easy to get your neurologist to prescribe it. Question, though, what would be the problem with combining it with interferons? Surely, neurologists are doing this.

Like most people, I didn't really understand what I was reading when I read your article. A synopsis would have been useful for us laypeeps.

No, I don't think neurologists are doing that (combining desipramine with interferons) - not as a first-line medication, that is. TCAs are very strong, and they DO affect the immune system drastically and directly. [All the terms I referred to in my research with the IL in front of them are all individual pieces (interleukins/cytokines) that make up your immune system as a whole.] Your immune system consists of the innate immune system and the adaptive immune system.

If you do a direct breakdown comparison of what "ILs" the interferons affect and in which direction they affect them (i.e. either by increasing or reducing them) and compare that to which ILs desipramine affects, you'll understand what I mean - they overlap. The hard part is dissecting the immune system down to such a minute presentation. To get down that far, took a LOT of dissection and literally weeks of research!

Anyway, since the interferons directly affect LPS and the immune system, and so does desipramine, you have to be extremely careful about prescribing the two together. You could get toxic effects. Desipramine tends to accumulate in your system over time and takes a while to reach its steady state in your system, also, so you do need to be careful what you take with it, because some drugs will cause desipramine to raise to overdose levels in your system (without you even having to increase the dose you are taking of desipramine. The drug itself will elevate in your body on its own.) I'm not saying it's "impossible" to prescribe desipramine with an interferon, just that extreme caution and consideration should be applied before doing so. (Frankly, I wouldn't do it!)

Now.......the AEDs (anti-epileptic) medications that are prescribed in conjunction with the interferons for pain and spasticity do not interact directly and/or with much potency with the immune system or with the interferons. I would sincerely doubt that you would notice a neurologist prescribing a tri-cyclic to someone who is on an interferon. (And if so, stop them and have them re-evaluate doing that.)

Now, an SSRI anti-depressant - yes. Again, that's because an SSRI is sort of "stripped down" (in layman's terms) and is not such a broad spectrum drug as the TCAs. SSRIs do not affect norepinephrine, only serotonin and sometimes dopamine. They are what some people call the "feel good" drugs. Norepinephrine has been studied and is thought to be another probable integral problem in people with MS, and regulation or modulation of norepinephrine by any drug will produce a cascade of events that affect MS (not all negative, though, if done correctly, but you don't want to play around with norepinephrine haphazzardly). And again, I did compare desipramine with the other TCAs/anti-depressants (a new one being Bupropion) and again, this new anti-depressant (although not a true TCA, it does weakly affect norepinephrine) does not affect as many physiological processes in the same manner as desipramine. Desipramine proved to be an entirely different "puppy" from all of the rest of the TCAs. Completely. MUCH stronger..........has effects on MANY more physiological processes - a huge broad spectrum of action. It's in a class by itself, practically. The good thing, though, is it is still a reduction in potency and side effect profile than its parent drug is/was (imipramine).

Desipramine mainly (as far as being prescribed for neurological pain) was prescribed sometimes for neurological pain for people with diabetes, not MS. I know it shows up on MS lists as a possible drug treatment, but that was before interferons came on the scene, and I speculate that it has just stayed on the list now. If you do a survey of MS folks, though, I truly believe you will find most of them on either an AED (Trileptal, Keppra, etc.) or Neurontin, Baclofen, etc. or is taking a pain medication (Tramadol, for instance) for MS pain and spasticity - or is taking something simpler, such as Valium or is adding an NSAID (ibuprofen - which is used in combination with the interferons to help reduce side-effects). But not desipramine. I myself am not taking desipramine for neurological pain. I take Keppra for that purpose.

Or people are on an SSRI for MS associated depression....again not on a TCA. I myself researched heavily any possible interaction in taking desipramine in connection with Keppra (levetiracetam) before I did it. The fact that levetiracetam is a new AED, and does NOT metabolize in the liver at ALL (in conjunction with other facts I uncovered - such as levetiracetam does not affect the immune system, etc., and only affects the receptors that desipramine does not and vice versa) was the only reason why I myself decided to try the combination together. Otherwise, I would have only taken desipramine alone. As you will note from my research, even some vitamins interact with desipramine (such as C and E). Vitamin C decreases desipramine's efficacy, and vitamin E inhibits desipramine's lysosomal cellular uptake, and with ceramide being possibly something you want to beneficially regulate in MS, also, my thought recently is that you do not want to inhibit desipramine's lysosomal uptake. But the jury is still out on that one. (Another LONG and boring story.)

Desipramine used alone, though, (or with another drug that is closely researched before combining the two) in as low a dose as I am claiming would prove helpful for MS, has very little side effects to it. (I am only taking 25 mg. once a day, which wouldn't even TOUCH or be beneficial to treat someone with clinical depression, and with the above additional research that I posted on this thread earlier, there is supporting expert material that supports my theory on that - that the dose of desipramine does very different things. To be effective for depression itself, the average dose begins at anywhere from 100 to 150 mg. per day! Yes, at that dose, the side effects might be extreme, and now we know why. Desipramine affects a lot of things! I speculate that the dose for depression had to be so high with desipramine precisely BECAUSE it's not a "feel good" drug, unless it's taken in higher concentrations.) The last dose that I was on before was only 50 mg. per day. Again, I had no noticeable side effects from that dosage and I did experience huge neurological improvement and stabilization. Since I combined desipramine with levetiracetam this time, I started even lower with desipramine. And apparently, my intuition proved to probably be correct.

Over the past several years, the tri-cyclics were put on the shelf for more favorable and less side-effect profiles of the newer drugs for depression. Fluoxetine being one of them.

I'll clarify here a couple other things. Desipramine's actions on the immune system is not the only mechanism of action it exhibits. Effects on the immune system is only ONE of many actions desipramine has. It also has effects on physiological and cellular/neuronal processes that have nothing to do with the immune system. GAP43 is unassociated with the immune system, also (referring back to one of my statements in my original research.) Desipramine shows effects on the immune system, on growth processes, on neuronal communications, ion channels, antigen presenting cells (APC), MHC II (which affects sodium densities and APC), the blood/brain barrier, caspase 3 (the same as minocycline does), sulfatide (which has direct effects on the survival of oligodendrocytes), etc. etc.

So, anyway.............we need clinical trials on this.

Deb