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Teresa Green
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Posted: Thu Oct 15th, 2009 23:58 |
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I have been researching the molecular processes behind the formation of L-Form biofilms and the mechanisms that biofilms use to survive. The research has revealed what could be the “silver bullet” for defeating bio-films.
It appears that in the process of L-Form biofilm creation a number of genes are dramatically up regulated. The genes that are over expressed can be broken down into the following categories:
1.) Envelope Stress
2.) DNA repair
3.) Iron Homeostasis
4.) Efflux pumps.
The following study goes into more detail about this:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752164/
Of particular note from the study is the over expression of genes belonging to the categories of Iron Homeostasis and Efflux pumps. The particular gene in Iron Homeostasis that is over expressed is the fur (Ferric uptake regulator) gene. This gene is fundamental in maintaining the iron homeostasis of the biofilm. This would help to explain why people with Th1 illness usually present with low iron. The biofilms directly impact host iron homeostasis.
But of greater importance and note is the dramatic up regulation of genes associated with Efflux pumps. Efflux pumps are employed by both bacteria and L-Forms to rid themselves of toxins which can include waste products and antibiotics. The Efflux pumps are the mechanism employed by biofilms to develop resistance against endogenous anti microbial peptides (AMP’s) and exogenous antibiotics.
http://content.karger.com/ProdukteDB/produkte.asp?Doi=219377
By targeting the Efflux pumps it is possible to effectively kill of L-Form biofilms. There are a number of known EPI’s (Efflux Pump Inhibitors) that are used for this exact purpose. When these EPI’s are used in conjunction with normal antibiotics, the killing of biofilms is increased dramatically. The following study demonstrates this:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592912/
What is also of particular note is the fact that the EPI’s are derived from compounds that are used for many of the psychotropic drugs in use today, such as SSRI’s. This would help explain the antimicrobial activity effect associated with SSRI’s. The following study elaborates on this effect:
http://www.ijaaonline.com/article/PIIS0924857999001545/abstract
The question remains would the inclusion of Efflux Pump Inhibitors improve the efficacy of the Marshall Protocol?
Teresa
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Joyful
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Posted: Fri Oct 16th, 2009 10:41 |
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Teresa,
As a general observation, it is often much, much harder to lower the level of die-off once the innate immune system kicks into gear.
At any point in time, for every person on the MP who is working on getting their immune system to awaken and go after the pathogens, there are probably two others who are trying to figure out how to slow down their awakened immune system!
It is possible that some of the information you have identified would be helpful in refining the MP science and clinical application, but the critical factor to never lose sight of is that our body's immune response can be unbelievably powerful in it's own right.
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Teresa Green
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Posted: Mon Oct 19th, 2009 00:11 |
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Joyful,
The ultimate goal for anyone on the Marshall protocol is full health with a fully restored innate immune system capable of dealing with any challenge by future pathogens.
Having a full understanding of the mechanisms employed by L-Form biofilms to resist conventional and endogenous antimicrobial agents gives us some insight into the journey from initial full health to chronic illness. It also paves the roadmap for recovery from chronic illness to full health.
The road we take to recovery has many pathways. The Marshall protocol relies on stimulating and re-awakening the innate immune system to go on the attack against intracellular L-form pathogens, bludgeoning them into submission. Unfortunately stimulating the innate immune system has the draw back of causing an increase in the inflammatory response and so the die-off needs to be managed.
If it were possible to defeat intracellular L-Form pathogens through more conventional means without over stimulating innate immunity, such as using Efflux pump inhibitors to bring down L-form defences, then die-off could be increased and the time taken to lower the pathogenic load dramatically reduced. The pathway to full recovery would be shorter and more tolerable.
Regards
Teresa
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Jigsaw
Health Professional
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Posted: Mon Oct 19th, 2009 01:13 |
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"then die-off could be increased and the time taken to lower the pathogenic load dramatically reduced. The pathway to full recovery would be shorter and more tolerable."
The increased die-off releases more PAMPS (Pathogen-Associated Molecular Patterns), ie recognisable bits of dead bugs, which trigger the innate immune system through pre-programmed TLRs (Toll-like receptors) and hence lead to the immunopathology.
I don't see an easy way to avoid this other than killing them slowly.
Last edited on Mon Oct 19th, 2009 01:16 by Jigsaw
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MP1.Arthritis30+yrs.3/98>3X50mgdoxy/wk.6/06 limitation.9/06:Noirs.11/06:25-D,15;1,25-D,29.4.20/07:25-D.7.
2/2/07:Beni40mg,Q6H.20/2:Mino25mg,Q2-3D.3/6:Beni40,Q8H.3/8Mino50Q2-3D.3/24Mino75Q2-3D.4/16Mino100Q2D.4/29,pH2.
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ChrisMavo
Member in Phase 2
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Posted: Mon Oct 19th, 2009 03:46 |
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Teresa,
I fail to see how " ... using Efflux pump inhibitors to bring down L-form defences, then die-off could be increased and the time taken to lower the pathogenic load dramatically reduced." ... would help with immunopathology. As Jigsaw mentions above... you would still have to deal with the effects of the IP when the pathogenic die-off is increased.
But, by all means if there is a pathway to full recovery that is shorter and more tolerable ... please let us know! The only thing that comes to mind would be a two-pronged approach.. one to kill the pathogens.. and two to suppress the immune response somehow while STILL killing the pathogens. This would entail finding a way to kill the pathogens directly without the immune system having to do the job. In a perfect world we would have already discovered such a protocol. But, at this time I doubt there are any shortcuts to full recovery though!
Chris Mavo
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PLS/ALS, speech difficulty, dizziness, leg weakness, overly emotional, Ph1Aug2609, 11/09: 25D-20, 9/09: 25D-27, 7/09: 25D-38, 1,25D-46, Mod Ph2Oct09, 100mg Mino + 150mg Clindy
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Joyful
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Posted: Mon Oct 19th, 2009 04:46 |
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The first dilemma a chronically ill person faces is convincing their healthcare provider that they in fact have an illness that is (1) real, (2) persistent, and (3) life-disrupting.
Perhaps they will succeed in finding a believing and willing healthcare provider to partner with them in discovering the cause of their illness, and hopefully find suitable ways to address either the symptoms or maybe (!) the source of the problem.
Most healthcare providers have no concept of persistent, difficult to culture pathogens such as the L-forms. Not to mention biofilm-like communities of pathogens that appear to cooperate at some level to maintain persistance.
Therefore they have little basis for seeing the need for the off-label use of common medications to not only restore normal function of the immune system, but also many of the hormonal processes that are shut down by the compromise of a significant portion of the body's VDR (nuclear receptors).
If the total number of genes identified to date that require a functioning VDR to be transcribed is greater than 900 (Wang, et al.), then restoring VDR function must remain a key objective of the restoring long term health. The handful of genes related to anti-microbial peptides seems to me to be a very small part of the picture.
I doubt anyone would mind finding ways to make the process shorter and/or less unpleasant. The many warnings we post to "take it slow", back off if the IP is too much, etc. seem to fail to have any impact on a person who is newly aware that they are hosting a high load of pathogenic microbiota in their bodies. Our instinctive first response is to, in fact, want to bludgeon to death whatever it is, that is "not us" with a heavy hand even if we are horribly miserable in the process.
For alternative approaches that hold the greatest promise, I would think that finding a way to signal to the pathogens to "become harmless and leave the building" would be the gentlest method. I know of nothing that comes close to this right now.
Those who claim to have something to do anything near to the above (leave w/o damage) method charge great amounts of money for their treatments. When I researched treatments in 2006/2007, I found that these plans are never as simple as one would expect for what they claim to do. And the number of people being helped was far to small to assure me that it would be money well spent.
To me on the MP, that the Benicar provides important anti-inflammatory activity (alongside other actions), is what makes the therapy tolerable. I'm not sure what your experience has been.
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MP Stories | Bacteriality | MP Search | MP Knowledge Base
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Teresa Green
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Posted: Fri Jan 15th, 2010 02:24 |
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All,
Whatever happened to this thread?
Teresa
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marysue
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Posted: Sun Jan 17th, 2010 21:40 |
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Teresa,
I read this thread several times and hadn't posted my thoughts since three others have shared similar views. I didn't see any reason to be redundant. But since you asked, I'll add my input:
The studies you refer to are interesting and certainly help add to our understanding of the mechanisms involved in the life of biofilms. But I for one would not even consider taking anything that is known to kill off more bacteria "faster". And that's what you seem to be proposing. If I am wrong about that, correct me. As was also previously mentioned, there does not seem to be any way to prevent the IP that occurs in response to the die off of the bacteria.
Pre-MP, I became very sick when I took anything that increased the die-off process. Not surprisingly, when I started the MP I had more IP than I could tolerate on just Benicar alone. After nearly 9 months, I have had numerous improvements and am still experiencing enough IP to keep me from taking anything (including antibiotics) that would increase the rate of die-off.
IMO, if there is ever a place for targeting the 4 areas you listed in your original post, including EPIs, it would only come long after one has recovered their health. At that point it could be used as a means of halting future growth and production of biofilms. But to pursue the possibility of using them in conjunction with the MP would be a recipe for disaster since so many people already have to be careful to keep IPs tolerable. As Joyful said, there are more people needing to put the brakes on and control the die off than people attempting to "rev it up."
Marysue
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Thanks Dr. Marshall and staff for all the support!
CFS/FM '95; infert/endomet '02; hypotension; cardiac IP; start light restrict. Oct08; 125D=70 25D=30 (Feb09); Benicar26Apr09; NoIRs, low light, no sun; 25D=10 (Jun09); 25D=5 (Nov09)
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ChrisMavo
Member in Phase 2
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Posted: Mon Jan 18th, 2010 07:20 |
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Marysue,
I would second your observation in your previous post. I am currently backing off the abx's after the neurological IP became a bit too scary for me at this time! Unless the IP can be addressed, killing more pathogens faster is probably not going to be possible for most people.
Chris
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PLS/ALS, speech difficulty, dizziness, leg weakness, overly emotional, Ph1Aug2609, 11/09: 25D-20, 9/09: 25D-27, 7/09: 25D-38, 1,25D-46, Mod Ph2Oct09, 100mg Mino + 150mg Clindy
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mdimock
Member in Phase 3
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Posted: Sat Jan 30th, 2010 01:18 |
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Dr. Marshall,
My course on the MP has been one of 3 steps forward 2 steps back. I am now under the care of Dr. Greg Blaney and making slow but steady progress against my sarcoidosis, diagnosed 3 years ago (MP started 3 years ago, now in Ph3).
I just saw the post about Klonopin.. . I have been on 1mg the entire time I've been on the MP and am concerned that it may be blocking the effectiveness of my treatment. I use it with two other pain meds for facial pain (topamirate and amitriptyline). I am preparing to wean down the klonopin and wean up some other benzo since your post seemed to indicate that it was ONLY Klonopin that seemed to be a problem for the cohort members. However, since the post is a year old, I thought I'd check to see if any new information has come in since then. I'd hate to put myself through this only to find that ALL benzos are suspect. I'm curious if there's any explanation why Klonopin particularly interferes and the others don't seem to. . . Sincerely, Marti Dimock
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Sarcoidosis/facial neuropathy hypothy 125D65 25D9 Ph1Apr07 Mod P2Sept07 P2Dec 07 ModP2 Aug08 P3 1/09; Aug09 125D:15; Nov09 25D12; thyroid Klonopin amitriptyline topamax gaba NOIRs, cover up|
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Dr Trevor Marshall
Foundation Staff
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Posted: Sat Jan 30th, 2010 16:46 |
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Marti,
Interference between drugs is an area of medicine which still has not been properly studied. The brand-name Valium (with the V in the center of the tablet) do not interfere with the MP, but the generic valium does. Klonopin has been a real problem for us. Weaning is very difficult for some members.
All drugs affect multiple receptors, enzymes and proteins in the body. Some drugs have isomers, which different manufacturing processes may allow in greater concentrations than others.
If you take a statin it will interfere with your recovery, as it will block receptors which the Benicar needs to activate in order for your immune system to work properly. Other drugs we have not investigated so closely - we just say that ANY DRUG is likely to affect your progress, with the exception of a very few (Guaifenesin, low-dose aspirin, paracetamol, opioids, etc). Some affect progress only a little (eg some NSAIDS) and it is still a reasonable compromise to use them. Some (eg Tramadol) we have conflicting data upon, they affect different members differently.
The list is changing all the time, as we get more and more members getting closer to 'total' recovery it becomes easier to see what interferes with what..
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mdimock
Member in Phase 3
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Posted: Sat Jan 30th, 2010 17:07 |
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Dr. Marshall,
THANK YOU for your reply. I am preparing myself to wean off Klonopin, but probably will substitute another drug to ease my neuropathic facial pain. Since brand name Valium is so expensive, I'm wondering if some other benzo, such as lorazepam would have pain relieving qualities without blocking the MP. Have you had any input on this?
Marti
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Sarcoidosis/facial neuropathy hypothy 125D65 25D9 Ph1Apr07 Mod P2Sept07 P2Dec 07 ModP2 Aug08 P3 1/09; Aug09 125D:15; Nov09 25D12; thyroid Klonopin amitriptyline topamax gaba NOIRs, cover up|
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Dr Trevor Marshall
Foundation Staff
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Posted: Sat Jan 30th, 2010 17:18 |
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Marti,
I said that only brand-name Valium has been reported as OK. For everything else, you are on your own.
You may find that the pain becomes less when you wean the Klonopin. It is easy to become dependent on these drugs, and often they often don't work as they should. You will have to try it for yourself.
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Aunt Diana
Moderator
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Posted: Sun Jan 31st, 2010 01:29 |
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Marti,
I have been using lorazepam instead of Valium to relieve some neurological symptoms (such as anxiety or throbbing sensations); and it works quite well for me. It also helps me to fall asleep. (Valium has no effect on me) But I have never noticed lorazepam relieve pain. I didn't even know it was intended for that.
The painkillers that work best for me (for joint and muscle pain) are oxycontin or hydrocodone.
As Dr. Marshall says, different things work for different people. You need to experiment a bit to find out what works.
Best of luck.
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Lyme 1987, neuro cardio fatigue achiness brain fog depression, anxiety. Pacemaker, D.1,25 32; D <5; 12/07 <6, hydrocodone, lorazapam, benedryl, zantac, colase, Noirs, cover-up or avoid sun, house <30lux. Feb 08 Phase 3. 6/08 D <4, D1,25
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mdimock
Member in Phase 3
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Posted: Sun Jan 31st, 2010 18:54 |
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Aunt Diana,
Thanks for your comments. I have neuropathic pain in my face, and worked with a pain doctor for a year to come up with a workable pain cocktail. Opioids (oxycodone/hydrocodone) don't seem to work for neuropathic pain, but interestingly, the drugs that work for anxiety (and also for seizures) also work for neuro pain. It doesn't take it away, but it cuts it down to tolerable.
I also have muscle and joint pain (or aching and stiffness, more of the time), but nothing compared to the facial pain, so I tend not to medicate for that.
The best thing for neuro pain, I've found, is sleep, and lots of it. I sleep about 11 or 12 hours a night, and the first hour after I wake up, if I don't rub my face or eat or drink anything, I am pain-free! After that, the pain curve starts up and by evening is quite uncomfortable. The drugs are spread through the day to make daytime as tolerable as possible. Taking a nap helps interrupt it and restarts the curve. I also use two topical agents: capsacin during the day, and a 5% Lidoderm (lidocaine) patch to get me to sleep and into the night.
This has worked for many months but now I am going to try to get off Klonopin, with or without the substitution of another benzodiazapine.
Wish me luck.
Marti
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Sarcoidosis/facial neuropathy hypothy 125D65 25D9 Ph1Apr07 Mod P2Sept07 P2Dec 07 ModP2 Aug08 P3 1/09; Aug09 125D:15; Nov09 25D12; thyroid Klonopin amitriptyline topamax gaba NOIRs, cover up|
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Dr Trevor Marshall
Foundation Staff
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Posted: Sun Jan 31st, 2010 19:50 |
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Marti,
As the Benicar starts to return your body to normal your neuropathy (and neuropathic pain) will disappear. Medications which affect your body by altering the metabolite balance will not necessarily continue to work in the same way...
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jcwat101
Research Professional
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Posted: Mon Feb 1st, 2010 03:59 |
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Different people have different experiences. I have been on and off a small dosage of Klonopin for many years as a sleep aid. I have been on and off it at various times on the MP and have not noticed it affecting my IP. Though, of course, I can't know for sure if it has negatively affected my rate of progress, at least it hasn't caused the MP to fail in my case.
So, if you can get off of it, great, but my experience would indicate that it is still possible to progress despite being on it (in case you are unable to do without it).
BTW, I don't need it now on a daily basis. Although, occasionally I take a tiny bit for sleep.
Joyce Waterhouse
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20 yrs with CFS/FM/Lyme/IBS, food sensitivities; 1,25D/25D 8/04:64/11 http://SynergyHN.com
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mdimock
Member in Phase 3
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Posted: Mon Feb 1st, 2010 04:31 |
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Joyce,
Thanks for the feedback.
I'd like to hear from any other members who have used it specifically for neuropathic pain. I remember reading a book about trigeminal neuralgia shortly after this came on three years ago (gladly I don't have classic TN), but atypical facial pain (which is what mine is often classified as). Atypical facial pain is often is mentioned in the same sentence with "but this drug or that drug doesn't generally work very well to suppress this sort of pain." Clonozepam (Klonopin) was really one of the only medications that was listed as having much effectiveness with this kind of "background" pain. And that's been my experience, which is why I've kept using it so far.
But my progress on the MP has been spotty and difficult to track over the three years I've been on it, so I am motivated to clear any obstacles to my progress. My supervising doctor suggests I substitute a different benzo BEFORE weaning the klonopin to ameliorate the withdrawal effects. This may be what I'll do. I'm still curious about why this benzo alone seems to be the one that gives MP patients so much trouble.
Regards,
Marti
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Sarcoidosis/facial neuropathy hypothy 125D65 25D9 Ph1Apr07 Mod P2Sept07 P2Dec 07 ModP2 Aug08 P3 1/09; Aug09 125D:15; Nov09 25D12; thyroid Klonopin amitriptyline topamax gaba NOIRs, cover up|
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jcwat101
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Posted: Mon Feb 1st, 2010 16:22 |
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Perhaps someone else will respond. But if not, you might do some searching of the site for other discussions of klonopin and benzos (in the realm of 1 to 3 years ago). We don't really have systematic data on it, to my knowledge. It might even be that klonopin seems worse because more people have been on it for longer periods of time and come to depend on it. I know for some it can be hard to get off.
For myself, over the years, I have substituted Ambien at times for sleep and it seemed to do as well for that purpose (but may be different for your situation).
My experience with klonopin was that there were times when I could gradually work down the dosage and other times that I needed more and would raise it some. I tended to go up and down on it a lot. By always working it down when I could, it kept me always at a fairly low level (I never had to go over a full .5 mg tablet and most of the time was under 1/2 tablet). I would take as little as I thought I could get away with and if it wasn't enough take a fraction of a tablet more until I could get to sleep.
Joyce Waterhouse
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20 yrs with CFS/FM/Lyme/IBS, food sensitivities; 1,25D/25D 8/04:64/11 http://SynergyHN.com
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MnD
Guests visiting Phase 1/2/3
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Posted: Tue Feb 2nd, 2010 10:09 |
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If I may ask what is the difference between brand diazepam and generic. I have been taking generic 2.5 mg diazepam for sleep last 4 days.First two days it helped me fall asleep and on the 3rd day when I waked up I felt so dehydrated with headache and bitter taste in mouth , nose one nostril clogged,one ear full of fluid. Than I go to bathroom I expelled maybe more than one liter orange, terrible smelling urine.Drunk 1.5 liter water and had 3 times diarrhea.On 4th day when I took 2.5 mg generic diazepam my herx was so strong that I couldn't sleep cause of headache.
What do they put in generic diazepam if it is causing problem to th1 patients and brand name diazepam does not.
I also found some article: Suppressive effect of diazepam on IFN-γ production by human T cells http://tinyurl.com/ybxjepb It says that diazepam could modulate immune response through interaction with peripheral benzodiazepine receptors (PBRs).Diazepam inhibited interferon gamma production by human peripheral blood mononuclear cells (PBMCs) induced by anti-CD3 in dose-dependent manner.They also showed that diazepam could inhibit the frequency of Interferon gamma-producing CD4+ and CD8+ T cells.
Now knowing that cytokine interferon gamma catalyzes conversion of inactive vit D. to active 30x times , what effect would have diazepam in Th1 patients who already have elevated interferon gamma.Any ideas ?Last edited on Tue Feb 2nd, 2010 10:16 by MnD
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