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Postby HarryZ » Fri Jul 02, 2004 8:36 pm

Sharon,

Shayk wrote:To me this is just a single example that reinforces your remark that we need to look outside the envelope for answers to the MS puzzle. There may or may not be any information in this example that would help solve the MS puzzle, but I'd like to at least think the scientific experts have taken a good hard look at these findings asking, "Is there something here to help solve the MS puzzle or not?" They can do a yeah or nay and move on appropriately.

It's my personal impression quite a few pieces of the MS puzzle are still missing.


You make a number of very logical comments that seem a practical way to proceed but we have seen absolutely no interest in the NMSS to even consider some of these ideas.

Elaine Delack, the inventor of Prokarin, tried to sit down with the NMSS and explain the science behind why Prokarin had some decent success on MS patients' fatigue. And this was done after the completion of her double-blind clinical trial which was published by The MS Journal. The NMSS refused to listen to her theory, wanted no part of examining Prokarin, wrote a very derogatory press release on the trial results and told her to basically "go fly a kite"! They also squashed a proposed national news item on the trial by ABC news. So when you make suggestions that MS needs to be looked at from a different perspective, the last people on earth that we can count on to do this is the NMSS!! How sad!
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Postby OddDuck » Fri Jul 02, 2004 8:39 pm

Harry,

That's really interesting! I didn't realize all that about Prokarin and the NMSS. How odd! And disconcerting.

I wonder what the problem was? Did the NMSS ever really say WHY they didn't support the findings? (I apologize for my ignorance in knowing anything about this.)

IS it possible that the encouraging response I received did come from someone within the NMSS who is more open minded? How curious!

Deb
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Postby HarryZ » Sat Jul 03, 2004 5:38 am

Deb,

I believe the main reason the NMSS had no interest in Prokarin is because, like LDN, the theory behind how it works was contrary to the decades old auto-immune theory. Anything that might work that opposes this theory gets a very cold shoulder from the NMSS.

The first press release from the NMSS came on the same day that The MS Journal made public the Prokarin clinical trial. The NMSS didn't even have a final draft of the trial but one point of their release mentions the fact that the patients' reduction in fatigue was likely due to the caffeine component of the medication. Of course the NMSS made no attempt whatsover to contact EDMS (Prokarin company) nor did they try and obtain any clinical data at all before making their statement. What they would have discovered is the fact that at the end of the 3 month trial period, the placebo group had higher blood serum caffeine levels than did the patients who were actually on the Prokarin. Also ignored was the fact that applying two patches of Prokarin over a 16 hour period was the equivalent of sipping one cup of coffee over the same 16 hour period....hardly something that would give anyone the level of energy the NMSS inferred. The caffeine citrate in Prokarin is used to slow down and regulate the metabolism of the histamine diphosphate in your system. Otherwise, histamine, which has a half life of only 50 minutes, would leave your system very quickly and little benefit would be obtained from the medication.

The NMSS also published in their Info magazine that histamine treatment was proven to be ineffective against treating MS symptoms. They quoted a horribly designed and applied study done in California in the 80's which had 20 participants as proof of this. Yet, the NMSS complained to EDMS that the 29 participants in their clinical trial was far too small a number to be taken seriously!! They also went after Dr. Silverberg, the editor of The MS Journal for publishing the trial. Ironically, he was on the Board of Directors of the NMSS and purposely did not tell them about the trial results, likely knowing their reaction. He told them that if he had to do it all over again, he would publish the trial again because of what The MS Journal Board of Directors called "good science" involved in the trial.

So like I've said in the past, the NMSS will talk out of both sides of their mouth and apply a double standard in order to substantiate their beliefs when it comes to MS.

One other interesting result found in the Prokarin trial... the radiologist involved took MRS scans of the patients' brains during the trial and found the level of N-acetylaspartate had increased substantially in the participants that were on the Prokarin. He went on to state that normally the increased level of this important brain chemical took many months to show up under normal circumstances. He was very surprised to find the level went up so quickly after only 3 months of Prokarin use. Researchers have since stated that this brain chemical is greatly reduced in MS patients and accounts for a lot of problems found in these patients.

Harry
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Postby OddDuck » Sat Jul 03, 2004 6:29 am

Yep, Harry......I'm familiar with MRS. As a matter of fact, that's one of the points I made in one my emails to the NMSS AND I suggested to my own former neuro that we should do MRS and Elispot testing (at the very least) on me to see what was going on in more detail. He only wanted to do an MRI alone, once every six months. I'm sorry, I thought that was just totally insufficient. I noticed when researching clinical trials and the tests that were used in them, how MRS and Elispot tests (just to mention a couple), were not even utilized! So....I noticed the same thing as you mention. Why aren't some of the newer tests being used in clinical trials (along with the old)? If I were to design a clinical trial, I'd use as many tests, and as many of the newer tests, as I could. Of course, clinical trial designs are proposed by the researcher and not by the NMSS.

I still get an underlying feeling, though (and have no real proof, of course), that someone might be trying to effectuate some changed attitudes within the NMSS. Their most recent "call" for research proposals stressed (more than usual, I believe) that they wanted to see proposals with new and more innovative ways of measurement and testing, also. (Indicating to me, that someone might be getting tired of seeing the same old type of proposals.)

I did visit the Cochrane Group website you provided. VERY interesting! And you know what is funny? (I swear!) In my vast research on the CRABs, I ran across the same information the Cochrane Group must have come across, because I had reached very similar conclusions. I know it may be unpopular, and it's just my opinion, but I just couldn't find anything regarding Copaxone that convinced me that real efficacy was ever really exhibited, either. (And Copaxone increases IL4, and if you'll notice from my research statements, what I found when researching IL4 in MS, was that you really might want to decrease IL4, not increase it and I explained why.) I found the same type of controversy (if you will) regarding the interferons. As a matter of fact, I found definite indication where after 18 mos. to 2 yrs. of use, the interferons will often change from being anti-inflammatory to being pro-inflammatory! There was some speculation that PDE IV might need to be prescribed with the interferons to see if that might keep that change from happening. (And we won't even go into the development of antibodies to the injectables.) All in all, I just didn't feel there was enough evidence in favor of the injectables to suit me personally. I realize that they help some people, and that's great. I totally support that. We're all individual with our disease presentation of MS. It just seems a little "disconcerting" that we are beginning to hear more often lately, how folks either have to switch from one injectable to another quite often, or have to add another therapy with an injectable.

The Mayo not long ago, even publicly announced that they do NOT recommend anymore putting MSers on injectable treatments right away. I didn't bookmark the publication (it might even have been on the Mayo website itself, as a matter of fact), but others from another board who were being treated at the Mayo were told the same thing.

There is such a lack of a consistency standard right now in MS! Unless you dig REAL deep, and research for WEEKS all across the board on just about every subject - both pros and cons, and weigh as much available evidence as possible, a person would have very little other than trust and faith to go on in trying to make possible life-altering decisions for their medical treatment. It's a shame there is this much confusion.

It puts patients at a real disadvantage. And if you are so ill, emotionally drained or upset, and fatigued, who can really take on the added stress of having to dig that deep for information? I describe it as being in layers. There's the top layer of information that seems quite lacking in detail, etc., and then it gets a little clearer, etc., the farther down you dig.

Maybe I should have been an archeologist! :wink:

Yes, my former neuro and I heatedly discussed the pure auto-immune theory. I do keep running up against the strict "it's auto-immune" theory time and again. What I found slightly hilarious, though, was when the mentor of my neuro finally changed HIS opinion about MS being purely auto-immune, and he was the one who had originally helped convince my neuro that it was strictly auto-immune in the first place. I don't think my neuro even knew that his mentor had published his changed attitude toward MS! I'm open to there being what I describe in layman's terms as a cascade effect in MS. One thing gets out of balance, and then everything else starts to cascade....just like dominoes.

I'm not familiar with Prokarin itself or what its proposal for use was, but I certainly cannot throw stones at anything you've just mentioned about it, Harry. Simply because I have personally experienced the same type of attitudes here and there from the medical field as you just described the Prokarin folks did. Based on what you mentioned, the comments from the NMSS regarding caffeine and histamine don't appear on the surface to make much real sense, do they? Is it possible that it's something isolated within the NMSS where someone is strictly "shooting from the hip" when they issue press statements?

Deb
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Postby HarryZ » Sat Jul 03, 2004 6:56 am

Deb,

OddDuck wrote:Is it possible that it's something isolated within the NMSS where someone is strictly "shooting from the hip" when they issue press statements?



Your message was MOST interesting to read. Both you and Elaine Delack, the Prokarin inventor, have much the same ideas when it comes to the interferons. She has been researching MS for about 10 years now and her theories are not something that were thought about yesterday. I would be interested in your response to reading about Prokarin and how they think it works. Go to www.edmsllc.com Click on the "research" button and then on the "professional" explanation. It is much more detailed than the "layman's" explanation and with your background, you will be able to understand what is being said.

One of the problems between Elaine and the NMSS stems from the attitude of Dr. Reingold. Let's just say that since Prokarin first appeared on the horizon back in 1998, there has been a "history" involved here. Reingold has gone out of his way to oppose Prokarin and I guess only he knows why. The meetings between him and Elaine have been anything but cordial.

But like you said, perhaps things may be changing within the NMSS as more and more MS researchers are starting to question the whole auto-immune theory and lack of progress against MS for so many years. I guess only time will tell.

Harry
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Postby Shayk » Sat Jul 03, 2004 8:35 am

Wonderful discussion.

One idea I have for all of us (more so for those who understand the science and research in MS more than I do) is to do a mental check when we're reading something and ask "Does this support MS as an auto-immune disease or not, or, is it neutral (silent) on the topic?"

As an FYI I've found some MS and gender findings that I think are consistent with not auto-immune only because I asked myself that question when I was reading the report.

I'm hoping to have time to post it on the not auto-immune thread in the near future. Not biggies, but certainly interesting.

Have a nice week end all.

Sharon
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Postby OddDuck » Sat Jul 03, 2004 10:06 am

Harry,

I did a quick once over on Prokarin. I'll have to think further on everything they are stating, but yes, I do see some similarities in what they found and what I found.

The problem I immediately identified, though, is the histamine theory itself. Histamine and its effects on MS are HIGHLY controversial and even then, don't really apply to the actual first-line problems or the pathogenesis of MS - only to secondary problems arising from MS. Take myself for example, part of my symptomatic problems relate to the fact that I produce an overabundance of histamine that I need to reduce, not increase. (My struggles with fatigue are not histamine related at all. Long story...I'll just ask you to trust me on this one.) An overabundance of histamine can possibly produce just as devastating effects on how a person with MS feels, as too little does. Hence, before taking Prokarin, I'd say histamine levels would need to be definitely ascertained first before even trying Prokarin. And I'd say off the top of my head, that combining Prokarin with other meds would have to be carefully considered. So, can a general boiler-plate supportive statement be issued that Prokarin is helpful for fatigue in ALL MS patients? I'd say No.

As for whether histamine itself affects energy levels? Of course...it directly affects energy levels. When you have a cold or an allergy, and have to take allergy medications (i.e. anti-histamines), what's the one "precaution" you find on the label? That it may cause drowsiness. So......if you ARE already deficient in histamine on your own, then yes, you very well may be experiencing fatigue symptoms of some sort.

As for anything else, right now I don't want to address them definitively without thinking things through a little more. There's a LOT of information posted on that website, even though it appears to be fairly light in information load. But that's a little deceiving in and of itself to a layperson who may not be totally educated on what they are reading. Believe me, there's a LOT of information they've put on that website. Most of which I recognize as being truthful, but it's the connections they make that I'd have to think about long and hard before expressing a hard-core opinion.

Take Vitamin E for example. Which type of Vitamin E are they referring to? D-alpha tycopherol, dl-alpha tycopherol, and gamma tycopherol are all very different forms of vitamin E and affect the body totally differently! Some forms of vitamin E interact with certain physiological processes and some do not. Some forms of vitamin E, though, mainly only affect IL-6 in the immune system. For one example right off the top of my head, I might beg to differ that vitamin E has any affect whatsoever on IL-10 or TNFa! You do have to be careful with vitamin E in the overall scheme of things, because it's a fat soluble vitamin and is pretty tricky, but again, it depends on which form of vitamin E you are talking about when making references. That whole paragraph I read on their website about the interactions of vitamin E, fatty acids, suppressed immune system, etc. was pretty vague and severely lacking in detail. It's not anywhere NEAR as simple as they voiced. Not at all! Lipids in MS and their interactions, etc., are EXTREMELY complex....extremely.

You can't make any type of blanket statement about the immune system in MS. What are they targeting? The innate immune system or the adaptive immune system? Some of the interleukins/cytokines they mention are pro-inflammatory, and some are anti-inflammatory. IL-1, for example needs to be broken down even farther.....i.e. IL1-b, etc. (there are other IL-1 breakdowns also).......are they talking about IL-1b or another breakdown of IL-1? And in MS, you want to increase IL-10. That's an anti-inflammatory cytokine and also helps to counteract the breakdown of the blood/brain barrier. But some of the other ILs you want to decrease in MS. You want to be careful WHICH ILs and which divisions of the immune system (innate or adaptive) that you mess with. In MS, when and if the immune system becomes out of balance (say for example during an exacerbation when inflammation goes rampant), you want to try to flip the immune system from a TH1 predominate response to a TH2 response. There are several ways to do that. All extremely complex.

Again, it also depends on how much inflammation you are actually experiencing, or how much of the immune system your particular pattern or stage of MS actually involves. If you are experiencing axonal degeneration and are suffering the symptoms from that process, that probably doesn't involve your immune system much at all, so you want to be careful what you introduce into your system.

Off the top of my head, though, you know what immediate thought I had about what the NMSS's reaction to this was really all about? The fact that this is only a type of symptomatic treatment (similar to taking tylenol for a headache), and not really anything that shows indication would change the disease course of MS at all. The NMSS appears to want something bigger in scope to look at, i.e. disease modification. Neither wrong nor right.........just that that appears, in my sole opinion, to be the possible basis for the real struggle between Prokarin and the NMSS. Histamine is not something that can be solely attributable in MS as anything that really can make MS better or worse overall in the big scheme of things.

BUT.....on the other side of the coin, I saw nothing that really was WAY out of line, but I will say I got the feeling that the claims that histamine itself had a direct affect on myelin to be a little "stretched".

Again, they are basically correct in their quotes about parts of the immune system, and the role of lipids in MS, but...........again, it appeared to be just slightly skewed. I repeat, though - I'm saying this purely from just a cursory review and stating simply what caught my attention first.

Sometimes in MS, also, it may depend on where someone has suffered neurological damage. As I said, in my case, I over produce histamine. And that's highly determinable to be due to where my permanent damage is located: in my brainstem.

Do the Prokarin folks have some good points? Yes. Is Prokarin worth some folks giving it a try? Sure, but not without knowing for certain first that they ARE deficient in histamine. I would not recommend anyone "trying" it without determining that first. Otherwise, go for it! As for their claims regarding fats in your diet? Again, it's the combination of what they are recommending that holds the key. It's not anywhere near as "simple" as is sort of implied or "indicated" on their website. And what bothers me most, I suppose, is that their website isn't about pushing for clinical trial of Prokarin......they jumped right to trying to sell it without FDA approval. Which might be ok, except for the fact that their claims invite and may very well REQUIRE FDA intervention and approval first. From a legal standpoint, I'd have to say that's pushing the envelope just a hair.

Frankly, though, and call me crazy, but in my opinion, I can see right away where the problem really was between them and the NMSS. It's in the substantiation of their claims. Not that anything is a falsehood by any means.......just that it's sort of slightly (although not too badly) convoluted in a way. Hence, why the NMSS wouldn't back it. Truthfully, if I were the NMSS, I wouldn't either. Not without the proper clinical trials and FDA approval, anyway. NOT because it's a quackery form of symptomatic treatment, but because that's all it is, i.e. just a possible treatment for one main single "symptom" - i.e. fatigue. If Elaine was pushing for NMSS support WITHOUT clinical trial and FDA approval first, that would put the NMSS off right away, I'd bet.

What is lacking in their theories is not really whether or not histamine affects myelin, but the "how" does it do so that is severely missing (from my first once over, that is). And here's the rub. I believe they might have a real hard time proving that one. (But AGAIN, I have to go over all their information again with a fine tooth comb; their claims and references; which I haven't done yet.)

Should it be put into clinical trial as a possible treatment for SOME types of fatigue (there are many causes of fatigue in MS)........sure! Absolutely! I say let somebody prove them wrong! I'm always supportive of that!

As for any further details than what I've just provided above? Again, I'd really have to think further and analyze deeper before I can give any further opinion on it. And remember, this is just my off the cuff impressions.

Hey, thanks for flattering me in asking for my comments!

Deb

P.S. I had to add something here that bothered me. Harry, I didn't see any indication that they did an actual clinical trial on Prokarin. They only did a 12 week "study". That's a totally different thing. Perhaps that's also where some confusion comes in (?)
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Postby OddDuck » Sat Jul 03, 2004 6:13 pm

Ok....I did a little more research. Here tis:

Here’s a little of what I found regarding histamine that I personally would suggest that MSers should be mindful of before supplementing their system with histamine.

Miscellaneous tidbits:

Histamine does not raise BDNF (which is something we do want to do in MS).

Histamine (too much production) is mainly connected with reactions of the skin (itching, hives, etc.) and is associated with allergens and allergies.


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Cataplexy-Active Neurons in the Hypothalamus
Implications for the Role of Histamine in Sleep and Waking Behavior

Joshi John1, 2, Ming-Fung Wu2, Lisa N. Boehmer1, 2 and Jerome M. Siegel , 1, 2, 3, ,

1 Department of Psychiatry, University of California, Los Angeles, Los Angeles, CA 90095, USA
2 Neurobiology Research (151A3), Veterans Administration Greater Los Angeles Healthcare System, North Hills, CA 91343, USA
3 Brain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA

Received 7 October 2003; Revised 24 December 2003; accepted 29 March 2004 Published: May 26, 2004 Available online 26 May 2004.

Abstract

Noradrenergic, serotonergic, and histaminergic neurons are continuously active during waking, reduce discharge during NREM sleep, and cease discharge during REM sleep. Cataplexy, a symptom associated with narcolepsy, is a waking state in which muscle tone is lost, as it is in REM sleep, while environmental awareness continues, as in alert waking. In prior work, we reported that, during cataplexy, noradrenergic neurons cease discharge, and serotonergic neurons greatly reduce activity. We now report that, in contrast to these other monoaminergic "REM-off" cell groups, histamine neurons are active in cataplexy at a level similar to or greater than that in quiet waking. We hypothesize that the activity of histamine cells is linked to the maintenance of waking, in contrast to activity in noradrenergic and serotonergic neurons, which is more tightly coupled to the maintenance of muscle tone in waking and its loss in REM sleep and cataplexy.

Corresponding author. Correspondence: Jerome M. Siegel, (818) 891-8612 (phone), (818) 895-9575 (fax)
*************************************
COMMENT FROM DEB: Histamine alone is associated with mental alertness and not actually body fatigue. In cataplexy (such as I, and many other MSers, experience), you can feel perfectly “awake”, but you totally lose muscle tone, etc. You feel like you’ve been hit by a mack truck! I refer to it as my whole body is trying to shut down. Hence my former reference to different types of fatigue. If you have histamine related fatigue, you feel “sleepy”, but your body isn’t necessarily giving out on you. If you have fatigue associated with noradrenaline (aka norepinephrine) or serotonin cessation or depletion, your mind is totally awake – you don’t feel “sleepy” – but your body just suddenly won’t work anymore. You are mentally awake just fine (for the most part), but you can’t control your body. You have an overwhelming “fatigue”.
So again, I would reiterate my original assumption that before supplementing your system with histamine, that you are very careful that it is a lack of histamine that is causing your fatigue in the first place.


*****************************************
Pathol Int. 2004 Jul;54(7):465-74. Related Articles, Links

Acute inflammatory reactions caused by histamine via
monocytes/macrophages chronically participate in the initiation and progression of atherosclerosis.

Kimura S, Wang KY, Tanimoto A, Murata Y, Nakashima Y, Sasaguri Y.

Department of Pathology and Cell Biology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.

Previously we demonstrated that histidine decarboxylase (HDC), which produces histamine from l-histidine, was detected in monocytes/macrophages located in human atherosclerotic lesions. As monocytic migration is a key event of atherogenesis, we investigated whether histamine induces monocytic expression of monocyte chemoattractant protein (MCP)-1 and its receptors CCR2-A and -B, and also endothelial expression of ICAM-1 and VCAM-1. Furthermore, we studied the effect of interleukin (IL)-4, which inhibits the HDC expression, on the expression of MCP-1 and CCR2. Histamine stimulated monocytes, but not macrophages, to express MCP-1 and CCR2-A and -B. The expression of MCP-1 was inhibited by histamine H2 blocker. In contrast, IL-4 enhanced CCR2 expression but not MCP-1. Histamine stimulated endothelial cells to express ICAM-1 and VCAM-1. These results indicate that histamine and IL-4, which are both synthesized in the arterial intima, chronically participates in the pathogenesis of atherosclerosis via the enhanced expression of monocytic MCP-1, CCR2 and endothelial adhesion molecules.

PMID: 15189499 [PubMed - in process]
****************************************

COMMENT FROM DEB: That above is just another “caution” regarding supplementation of histamine, in addition to surprisingly providing further credence to my previous theories that if anything, you want to decrease IL-4, not increase it. The goal of Antegren in helping MS is the fact that it inhibits VCAM-1. Histamine tends to INCREASE VCAM-1, which is definitely something we might want to reconsider doing.

*********************************************

Neurosci Lett. 2004 May 6;361(1-3):159-62. Related Articles, Links

Histamine-induced Ca(2+) influx via the PLA(2)/lipoxygenase/TRPV1 pathway in rat sensory neurons.

Kim BM, Lee SH, Shim WS, Oh U.

Sensory Research Center, National Creative Research Initiatives, College of Pharmacy, Seoul National University, San 56-1, Shinlim, Kwanak-Gu, Seoul 151-742, South Korea.

Histamine is known to excite a subset of C-fibers and cause itch sensation. Despite its well-defined excitatory action on sensory neurons, intracellular signaling mechanisms are not understood. Previously, we demonstrated that bradykinin excited sensory neurons by activating TRPV1 via the phospholipase A(2) (PLA(2)) and lipoxygenase (LO) pathway. We, thus, hypothesized that histamine excited sensory neurons via the PLA(2)/LO/TRPV1 pathway. Application of histamine elicited a rapid increase in intracellular Ca(2+) ([Ca(2+)](i)) that desensitized slowly in cultured dorsal root ganglion neurons. Histamine-induced [Ca(2+)](i) was dependent on extracellular Ca(2+) and inhibited by capsazepine and by SC0030, competitive antagonists of TRPV1. Quinacrine and nordihydroguaiaretic acid, a PLA(2) and an LO inhibitor, respectively, blocked the histamine-induced Ca(2+) influx in sensory neurons, while indomethacin (a cyclooxygenase inhibitor) did not. We thus conclude that histamine activates TRPV1 after stimulating the PLA(2)/LO pathway, leading to the excitation of sensory neurons. These results further provide an idea for potential use of TRPV1 antagonists as anti-itch drugs.

PMID: 15135918 [PubMed - in process]
***********************************************
COMMENT FROM DEB: Now, the above is where we could possibly run into some problems if you are suffering with progressive MS or axonal degeneration and you increase histamine in your system. Histamine will INCREASE cellular calcium influx (not to mention its affects on PLA2), which may prove itself to be detrimental in progressive MS (via possibly promoting axon degeneration). (As I have referred to previously in my other research.)

**********************************************

Cytokine. 2004 May 7;26(3):122-30. Related Articles, Links

IL-9 increases the expression of several cytokines in activated mast cells, while the IL-9-induced IL-9 production is inhibited in mast cells of histamine-free transgenic mice.

Wiener Z, Falus A, Toth S.

Department of Genetics, Cell and Immunobiology, Semmelweis University of Medicine, Nagyvarad ter 4, Budapest 1089, Hungary.

Histamine and IL-9 are suspected to play an important role in the pathogenesis of asthmatic and allergic reactions. Mast cells store a large amount of histamine in their granules and are capable of producing different cytokines upon stimulation. In this study we show that mast cells stimulated by IL-9 and ionomycin or IL-9 and antigen-specific IgE/antigen express several cytokines at mRNA level, among them are IL-5, IL-4, IL-10, IL-9, IL-13, IL-1beta, IL-1Ra, IL-6 and MIF. Furthermore, both IL-9 and ionomycin are needed for the production of these cytokines in great quantities, which is mediated through the production of IL-1beta. Histamine-free mast cells respond by a markedly decreased IL-9 expression to this stimulation. Our results show that this IL-9-induced IL-9 production may result in a positive feedback loop in mast cells and the lack of histamine disturbs this loop, which may serve as an explanation for the reduced asthmatic symptoms, observed in histamine-free mice. Copyright 2004 Elsevier Ltd.

PMID: 15135806 [PubMed - in process]
*************************************
COMMENT FROM DEB: If you have MS and also suffer from any type of allergies or asthma, extreme caution should be exercised regarding introducing additional histamine into your system. You could trigger a severe asthmatic attack or exacerbate your existing allergies.

****************************************
I’m certainly not trying to debunk Prokarin at all. I personally found Elaine’s research to be very thorough.

Actually, I’d have to say that I probably stand by my original post and my comments posted therein. I would personally reiterate that in my opinion, the use of Prokarin in MS would depend on the TYPE of fatigue that you suffer from and the reasons behind it.

To put it simply, just be sure that you don’t suffer from existing allergies or asthma; I would advise using EXTREME caution in taking Prokarin if you are diagnosed with progressive MS; and be certain that you truly are suffering from a lack of histamine in the first place before supplementation with Prokarin.

Other than that, again, I think my original thoughts regarding their research, etc., still holds true in my mind. Their statements that histamine is a receptor that can affect quite a few physiological processes is certainly true. It’s just not very simple in its application in MS.

And I'd say it needs actual clinical trials.


Well, that’s my two cents!

Deb
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Postby HarryZ » Sat Jul 03, 2004 7:11 pm

Deb,

When I asked for comments I certainly did get "comments" :D

The information that is posted on the Prokarin website is a very condensed amount of data that Elaine has accumulated over the years. During one of her seminars in Toronto 4 years ago, Dr. George Gilson, who was involved in the trial, went into a huge amount of detail on how histamine worked in your system.

The one thing that you have to be careful about is the difference between the H1 and H2 receptors that histamine produces. The H1 are the "bad ones" which cause all the allergy problems etc and have nothing to do with the H2 receptors that are produced by Prokarin. The H2 receptors are the neurotransmitters and very important in proper cell function within your system.

You mentioned that having too much histamine in your system is bad and that is true but very few people have this problem. And testing for histamine levels, from what I've been told, is not all that accurate. One thing about Prokarin...if you overdose, your MS symptoms will become worse for a number of hours.

From the very beginning, Elaine and EDMS have stated that Prokarin was for the treatment of MS symptoms and was in no way associated with a cure. That misinformation came from some media people and of course, the NMSS jumped on that and stated that Elaine was making false claims.
You mentioned that it would be a good idea to obtain FDA approval for Prokarin on the treatment of MS. That will likely never happen, simply because of the cost. These days, the minimum cost for FDA drug approval is around $ 50 million! All of the drugs these days that are used for MS symptom treatment are used on an "off label" basis and none of these drugs have FDA approval for MS.

Elaine's only request from the NMSS was to list Prokarin as another possible treatment for MS symptoms. They list Provigil which is a level 4 substance and possibly addictive and Cylert which is banned in Canada because of the danger of severe liver damage. At first the NMSS complained that no clinical trials had been done on Prokarin and when one was finally done, you read how the NMSS reacted to it. And yes, it was a 3 month, full double-blind clinical trial with a control group. The trial had to go through the typical regulatory procedure and approvals along the way and was peer reviewed by The MS Journal who eventually published it. I don't know how much you know about statistical mumbo jumbo on these trials but within the Prokarin user group, the power benefit was .00008 and between the Prokarin users and placebo group, it was .02. The FDA demands at least a level of .050 or lower so from that standpoint, the effect of the drug during the trial was significant.

The MS Journal stated that because trial results were decent, further studies were warranted. But, as usual, these trials are very, very expensive and EDMS simply doesn't have the kind of money needed to do large, multi-centre studies.

It is also interesting to note that Dr. Jonez, back in the late 40's and early 50's, treated thousands of MS patients with IV histamine and got positive results from 85% of the patients treated. Nobody supposedly had any horrible side effects from the drug, despite the difficulty in applying the correct dosage of histamine using the IV method. Dr. Jonez died suddenly in 1952 and all of his research came to an abrupt end, never to be done again.

The dangers of Prokarin are extremely minimal because of the small dosage of histamine that is being applied. And yes, there are some conditions that would prevent you from using it...like severe asthma with being on long term, anit-histamine use.

Prokarin helps about 2/3 of the people that use it. 1/3 get multiple symptom relief, 1/3 get one or two symptoms relieved and 1/3 have nothing happen to them at all. But like you said, MS is such a complex disease with so many variables there is nothing available that helps everyone.....and I believe it's going to be some time yet before any major accomplishment is done.

Take care.

Harry
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Postby OddDuck » Sat Jul 03, 2004 8:11 pm

LOL......I guess you'll think twice before asking me anything next time, huh? :wink: Gee....and I thought I was being brief! hehehe....(that's a legal person for ya, huh?)

Yes, I realized the differences with H1, H2, and H3 histamine receptors. I tried to concentrate only on H2, also. It's still pretty complex and not easy to break down physiologically. If you read on the EDMS website under "layman", they explain also how H2 histamine does correlate directly with H1 - one aspect ends up affecting the other eventually. Elaine also explains how H2 histamine affects exactly the same physiological processes I concentrated on. She and I are on the same page. She explains like I did, just in different words and presentation, how H2 affects skin, melatonin (i.e. sleep cycles, etc.), neurotransmitters (cyclic AMP, calcium influx, etc.) I'm on the same page as she is. My references were all about the same things, just from a different angle, is all.

I see what you mean regarding the trials, the FDA, etc. Actually, that sort of goes along with where my head was at, also, (i.e. about the clinical trial aspect, etc.), and even where the NMSS's perspective might have been coming from. I get the feeling they just aren't concentrating that closely on purely symptomatic relief these days. I know.....a person just can't afford to conduct a clinical trial without either grant funding or support from a *gulp* pharmaceutical corporation! (And you have to appeal to a pharma's pocketbook, market share, and profit margin, to get them on board, I believe.) I know that personally. :wink:

The thing that strikes me as sort of strange in a way, is that even though Elaine may not have intended it to come across this way, I have to say that I myself had the distinct impression that their website was inferring that Prokarin was something that may affect actual MS disease modification, not simply symptomatic relief. Might that be a potential difficulty, also? The mistaken "impression" that is perhaps accidentally being presented?

I can imagine it would be difficult to get the NMSS to put any drug on their list of symptomatic treatments for MS. That's practically like an unspoken "endorsement", I would think. That's neither here nor there, but just a supposition about their possible perspective on it.

The majority of drugs used off-label, though, Harry, have FDA approval for use - just not always for use directly in MS. There are government regulations that dictate when and how (under what conditions) a physician may legally prescribe an FDA approved drug for "off label" use. My impression was that Prokarin has NO FDA approval at all for use. Have they attempted to gain approval from the FDA as an "orphan drug"? Even that might help, if Prokarin qualifies.

Yep...........I completely agree with you, Harry, that unfortunately, it may be some time before any real accomplishment will be seen. Let's hope we're wrong on that one.

I do wish Elaine and her company all the best in their quest! As I said before, I support as many options available to MSers as is possible, be it via actual disease modification, or via symptomatic relief.

Whatever works!

Have a terrific weekend! GREAT discussion, by the way! Thanks for all the new info!

Deb
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Postby willysnout1 » Sun Jul 04, 2004 8:32 am

HarryZ, correct me if I am wrong, but my reading of this site tells me that the Prokarin issue is the one where you went to the MS conference and found one person who told you the "inside workings" of the NMSS. From that, you've confabulated all kinds of things about the alleged motives of the NMSS. As I've said before, this style of exposition leaves me quite cold toward your idea. My mind is a lot more open than you think, but the challenger has the implicit duty to lay his cards -- all of them -- face up on the table.

A cornerstone of your complaint is the NMSS's "deregoatory press release" about Prokarin. Here is a link to the bullein. People can decide for themselves whether it is "derogatory," as you have characterized it, or "cautionary," as I would characterize it. The design of the Prokarin study is certainly not one to fill an objective observer with confidence in the results.

In any case, MS fatigue is one of a variety of symptoms. I have fatigue to a major degree and have tried a bunch of things and settled on ritalin. It works well enough to get me through a light day. Would Prokarin be better? Who knows. In any case, the NMSS is not preventing me from trying it nor are they preventing anyone from selling it. Harry, you're bitter that the NMSS isn't endorsing Prokarin -- and make no mistake about it, listing it as a possible treatment option is an endorsement. From my viewpoint, if they had endorsed Prokarin the NMSS would have been irresponsible. I don't want them hopping on bandwagons without first investigating them thoroughly.

As for the wider question of histamines and MS, it would be interesting to see something about it that was objective and readable in layman's terms.
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Postby willysnout1 » Sun Jul 04, 2004 8:57 am

HarryZ wrote:I guess it depends on what one may consider is a significant proportion of people. In reading Dr. P. Behan's large summary study of MS research over the decades, he says that the benefit for MS patients from the CRABs is about 33% of the users obtaining a reduction of about 1/3 in the number of exacerbations. He also states that the placebo effect for these trials is pretty much a constant 30% and wonders if the CRABs even give as much an effect as the companies state.

The interpretation of survey results is something I rely on other people to do. I lack the statistical background, and the cognitive skills, to be confident in my evaluation of the results. I do read the studies, but I am extremely hesitant to draw conclusions pro or con. If something really catches my eye I will ask others whose skill and objectivity I trust to read the study and give me their evaluation. Maybe that's a chickens--- approach but it's an honest one; I've reached that stage in life where the words "I don't know" aren't so scary as they once were.

Now, to the specifics all I can really say is that there appears to be plenty of evidence for the overall efficacy of the ABCRs. The problem is that the efficacy is sufficiently low that there's no way to predict what these drugs will do in any individual case. Not only that, but the test of efficacy is maddening: The absence of progression, or progression that's slower than it otherwise would have been. Makes it difficult, if not impossible, to say whether the Avonex I am taking works for me.

I choose to live with all of that for the following reasons: First, the FDA has reviewed the data and approved the drug. Second, my cousin with MS has neglected to comply with his Betaseron regimen and has progressed, and it's a scary thing. If I progress, I want to be able to tell myself that I did what I could do based on the best information at hand. Third, for me Avonex's side effects are tolerable and I can live with the injections. Fourth, there is a substantial group of people who have been taking these drugs without ill effect, so I can be pretty confident that they're safe. Finally, my insurance will pay for it.

No one is forced to take an ABCR drug, and no one is kept from using something promoted by the alt-med crowd. If Dr. Behan dissents, that's fine. Dissent is part of the picture and it should be. But I'm not going to allow it to freeze me in place or induce me to follow the many quacks who prey upon people with MS and other serious, incurable chronic illnesses. We do the best we can.

HarryZ wrote:do MS patients really care that the number of lesions are dropping if they continue to become worse?

No, we don't. But that's not the only issue. If we become worse at a slower rate than we would have, that's a good thing.

HarryZ wrote:I would think that symptom relief and general well being without disease progression is the prime goal and the CRABs, in my opinion, have really not done this to any meaningful degree.

The research would tend to differ with you, and so would many MSers.

HarryZ wrote:When asked if researchers could state if Betaseron was responsible for the changes or simply the disease doing what it wanted he replied "we don't know!"

A frustrating situation, for certain. HarryZ, if you don't want to take one of the ABCRs I don't see anything forcing you to do it.

HarryZ wrote:the NMSS seems to go out of its way to "skewer" anything that comes along that doesn't fit their line of thinking.

They didn't endorse your favorites du jour. I guess the NMSS won't be getting any contributions from you! :)
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Postby HarryZ » Sun Jul 04, 2004 10:01 am

Willy,

willysnout1 wrote:The interpretation of survey results is something I rely on other people to do. I lack the statistical background, and the cognitive skills, to be confident in my evaluation of the results. I do read the studies, but I am extremely hesitant to draw conclusions pro or con. If something really catches my eye I will ask others whose skill and objectivity I trust to read the study and give me their evaluation. Maybe that's a chickens--- approach but it's an honest one; I've reached that stage in life where the words "I don't know" aren't so scary as they once were.


I'm much in the same boat as you when it comes to statistics. Sometimes I can't even count properly :D What has happened in the past year or so is some MS researchers, like Dr. Behan, have looked at all the stats involved with various CRAB trials, lumped them all together and come out with less than supportive comments on these drugs. Dr. Ben Thrower, another MS researcher in the US, has commented on the Cochrane Group's press release on Copaxone (scathing to say the least) and politely said that they shouldn't have combined all the statistical results into one "bag" when they issued their statement. Who's right and who's wrong? I suppose it depends on just where you may be as a researcher and who is employing you.

willysnout1 wrote:Now, to the specifics all I can really say is that there appears to be plenty of evidence for the overall efficacy of the ABCRs. The problem is that the efficacy is sufficiently low that there's no way to predict what these drugs will do in any individual case. Not only that, but the test of efficacy is maddening: The absence of progression, or progression that's slower than it otherwise would have been. Makes it difficult, if not impossible, to say whether the Avonex I am taking works for me.


I suppose what peope feel about the CRAB drugs really depends on how they may view your comment and apply it to themselves. Some users will agree while others state that they simply can't stand the side effects or feel the daily aggravation isn't worth the end result.

willysnout1 wrote:I choose to live with all of that for the following reasons: First, the FDA has reviewed the data and approved the drug. Second, my cousin with MS has neglected to comply with his Betaseron regimen and has progressed, and it's a scary thing. If I progress, I want to be able to tell myself that I did what I could do based on the best information at hand. Third, for me Avonex's side effects are tolerable and I can live with the injections. Fourth, there is a substantial group of people who have been taking these drugs without ill effect, so I can be pretty confident that they're safe. Finally, my insurance will pay for it.


I'm thinking it's impossible to determine if your cousin not taking the Beaseron had anything to do with his progression. I know of two people personally who have used Betaseron with one progressing so quickly it brought me to tears and the other having just suffered a huge attack that left her in the hospital for 5 weeks! But like you said, each person has to decide for him/herself based on their experience.

willysnout1 wrote: But I'm not going to allow it to freeze me in place or induce me to follow the many QuackeryRelatedTopics who prey upon people with MS and other serious, incurable chronic illnesses. We do the best we can.


Absolutely. But I think most readers on this forum and other MS forums have the ability to determine the difference between quackery and alternative medicines.

willysnout1 wrote:The (MS)research would tend to differ with you, and so would many MSers.


I guess it depends on what researchers' comments one would tend to believe. In reading the various MS forums for the past few years, the level of acceptance for the CRABs has dropped compared to what it has been previously. I'm thinking that the MS patients that have the ability to browse the internet and look up various aspects of MS research, are thinking twice before starting on a CRAB. This is only a personal opinion and based on what I have read.

willysnout1 wrote:A frustrating situation, for certain. HarryZ, if you don't want to take one of the ABCRs I don't see anything forcing you to do it.


I'm very fortunate in that I don't suffer from MS...my wife has for over 30 years. I obviously look at the disease from a different set of eyes than what the MS patient does. One interesting note though.....my wife, who worked in medicine for many, many years, has refused the CRABs from the very beginning. I suppose she knew more about these drugs from a general point of view and wanted nothing to do with them. Fortunately, she went about 20 years without any major attacks by taking nothing. Now that she is on the Prokarin and LDN, she has not had any disease progression of her SPMS for over 4 years now....quite a feat for someone who has this level of MS. But like you said, you go with what works for you.

Willysnout1 wrote:They didn't endorse your favorites . I guess the NMSS won't be getting any contributions from you! :)


I'm not totally anti MS Society....I do give both time-wise and monetarily to the local chapter which does great work here in London, Canada. :D

Harry
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Postby HarryZ » Sun Jul 04, 2004 11:32 am

Willy,

willysnout1 wrote:HarryZ, correct me if I am wrong, but my reading of this site tells me that the Prokarin issue is the one where you went to the MS conference and found one person who told you the "inside workings" of the NMSS. From that, you've confabulated all kinds of things about the alleged motives of the NMSS. As I've said before, this style of exposition leaves me quite cold toward your idea. My mind is a lot more open than you think, but the challenger has the implicit duty to lay his cards -- all of them -- face up on the table.


The issues I have with the NMSS have come from various sources and not just this one incident that you are referring to. The comment from the person that you mention had solely to do with the NMSS going around the country and following the Prokarin seminars and then posting a news article the very next day in each city....stating that all the info about Prokarin given at the seminar was not correct. If a person tells me something about the NMSS in confidence, then that information will get related generally. If the information has been made public then I will give specifics like I have.



willysnout1 wrote:A cornerstone of your complaint is the NMSS's "deregoatory press release" about Prokarin. People can decide for themselves whether it is "derogatory," as you have characterized it, or "cautionary," as I would characterize it. The design of the Prokarin study is certainly not one to fill an objective observer with confidence in the results


The comments that you see on the NMSS website about Prokarin are not the same ones that were originally posted. I'm not sure if I have the original posting copied somewhere but it wasn't until EDMS complained to the NMSS and Dr. Silverberg of The MS Journal defended his publication of the trial that the NMSS changed the information.

The design of the trial was approved by two different protocol boards at the University of Washington and accepted by The MS Journal. I'm not sure if you were able to tread the entire study or an abstract which wouldn't tell you all that much. Perhaps there is a question that I can answer for you about Prokarin.

willysnout1 wrote:In any case, MS fatigue is one of a variety of symptoms. I have fatigue to a major degree and have tried a bunch of things and settled on ritalin. It works well enough to get me through a light day. Would Prokarin be better? Who knows. In any case, the NMSS is not preventing me from trying it nor are they preventing anyone from selling it. Harry, you're bitter that the NMSS isn't endorsing Prokarin -- and make no mistake about it, listing it as a possible treatment option is an endorsement. From my viewpoint, if they had endorsed Prokarin the NMSS would have been irresponsible. I don't want them hopping on bandwagons without first investigating them thoroughly.


My dislike about the NMSS goes a way beyond what you have isolated in the above paragraph. That is but one of many episodes about what I have seen in how they operate.

Per their own statement, the NMSS does not endorse or recommend any one particular medication. They list the drugs and the patient and their doctor are responsible to determine if they will use it. So, by merely listing Prokarin (and they don't) they would not giving it any kind of "endorsement". Don't forget, they list Cylert which is banned in Canada due to the possibility of severe liver damage. Does this make them irresponsible?

You mention that you would hope that the NMSS would investigate a particular medication before they would issue any kind of comment on it. I agree with you 110%. But that is my point....when they were approached by EDMS on several occasions, they made it very clear that they wanted no part in listening to what Elaine Delack (and other doctors who worked on the initial stages of Prokarin) had to say. They had face to face meetings and the result was always the same....don't bother us! They posted inaccurate information about the trial and convinced ABC news not to run a story about the trial. At one point, they mentioned that a better reception might take place if EDMS provided some "benefits" in the NMSS's direction!! That last episode put the "frosting on the cake" as far as EDMS was concerned. This is part of the reason why I have such a dislike of the NMSS.

willysnout1 wrote:As for the wider question of histamines and MS, it would be interesting to see something about it that was objective and readable in layman's terms.


I can only suggest you go to www.edmsllc.com and click on the "research" button. Then click on "layman's" explanation. Of course this is a theory as to how Prokarin works but in the world of MS medicine, everything is a theory and nobody has been able to prove anything.

Does Prokarin work for everyone?....not on your life! But it does work for many people who use it. The trial scientifically proved that. Unfortunately, the possibility of multi-center trials won't happen for one reason....the lack of money! And when it comes to the world of medicine, several trials are needed.

Harry
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Postby willysnout1 » Sun Jul 04, 2004 11:42 am

HarryZ wrote:Who's right and who's wrong? I suppose it depends on just where you may be as a researcher and who is employing you.

This is why the integrity of the FDA is so important. I worry quite a bit about breaches in the FDA's integrity at the behest of the pharmaceutical companies. I am similarly apprehensive when the alt-med advocates push for acceptance and endorsement of their treatments without full study.

To me, this only weakens the review process. Today the FDA is very separate from the alternative medicines, but what happens if, for example, a pharmaceutical conglomerate takes a look at the alt-med sector's rapid growth and decides to push their more questionable substances through that route? I think it's important for people to take a step back and look at the overall picture. Alternatives that are marketed as treatments for specific conditions should have to go through the FDA review process.

HarryZ wrote:Some users will agree while others state that they simply can't stand the side effects or feel the daily aggravation isn't worth the end result.

I'm a pretty firm advocate of the ABCRs because of the data surrounding them. But the decision is ultimaely up to the individual. What worries me is that some people won't take an ABCR for what are essentially political reasons, i.e., as a form of rebellion against the big bad corporations. This is one way in which the alt-med "bandwagon" can be harmful.

HarryZ wrote:I'm thinking it's impossible to determine if your cousin not taking the Beaseron had anything to do with his progression.

I totally agree with you. There is no way to apply the generalization that the ABCRs slow progression to anyone's individual case. But, given the studies showing a significant slowing of lesion accumulation in people who take the ABCRs, I think it's reasonable for me to have the attitude I do. So you know, I never have and never will "blame" my cousin for his progression, but I am absolutely determined to stay on an approved drug as recommended by my neurologist.

HarryZ wrote:I think most readers on this forum and other MS forums have the ability to determine the difference between quackery and alternative medicines.

Like other entities that tell people what they want to hear, that part of alt-med that is sheer quackery can be very persuasive. A long time ago, a friend of mine died of AIDS after he decided that AZT was "poison" and decided to listen to some quack "naturopath" instead. My friend was a medical doctor. It was just tragic.

HarryZ wrote:In reading the various MS forums for the past few years, the level of acceptance for the CRABs has dropped compared to what it has been previously. I'm thinking that the MS patients that have the ability to browse the internet and look up various aspects of MS research, are thinking twice before starting on a CRAB. This is only a personal opinion and based on what I have read.

I don't know what the level of support was and is. I suspect that the opponents are more vocal than the supporters, myself notwithstanding, and that some people had unrealistic expectations for the ABCR drugs. The manufacturers and doctors have not been guilty of fueling those expectations. I was diagnosed two years ago, and everyone has been rigorously careful to tell me that it's a crapshoot.

But people want to get better, which is of course a good thing. When they don't get better, some of them get disillusioned. And others just can't tolerate the side effects.


HarryZ wrote:Fortunately, she went about 20 years without any major attacks by taking nothing. Now that she is on the Prokarin and LDN, she has not had any disease progression of her SPMS for over 4 years now....quite a feat for someone who has this level of MS. But like you said, you go with what works for you.

Sounds to me as if your wife is cursed with MS but also blessed with a relatively mild case of it. I sure hope so, anyway. I feel no need to use the alternatives, but I am not dead-set against them. I just want everyone to be honest about what they are. I think the standard therapies have been marketed in an honest way; not because the drug companies are saintly, but because they are pretty carefully regulated by the law.
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