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Foundation Staff
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Posted: Thu Jan 6th, 2005 05:45 |
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How does Benicar work?
Classification
Benicar is an Angiotensin Receptor Blocker (ARB). It is a designer drug whose method of action is fully known. Its interaction with the body has been extensively studied and it is believed to do only one thing - block off the receptors for Angiotensin II which exist in the inflamed tissue and elsewhere throughout your body. This reduces the Angiotensin II produced by your inflammation and that stops fibrotic tissue from forming (fibrosis). See The Need for a Benicar Blockade.
Actions
Benicar has two actions, a palliative action by blocking the Nuclear Factor-kappaB cytokine pathway, and an action whereby it activates the VDR and gets the innate immune system working again. The initial palliative action of Benicar is can be profound, but it will fade with time.
The cytoplasm of a cell, where the Th1 pathogens have their metagenomic communities, also consists of literally thousands of proteins drifting around, bumping into other proteins, other peptides, drugs, bonding with the ones which have sufficient attractive force. Then those bonds are in turn broken by higher affinity bonding to a different protein which comes by, or by 'conduction' into receptor binding pockets.
When I simulated how 1,25-D was pulled into the binding pocket of the VDR, I began to realize how mind-boggling is the number of molecular interactions which never evolve into anything biologically useful. You might wonder why you need to take Benicar so frequently. Once it is in the binding pocket of the VDR, surely it will stay there for ever? No - firstly the VDR itself is in constant motion - second, that motion is affected by the forces on the VDR from adjacent molecules. Olmesartan has an ability to stay in that binding pocket for only a few hours before it is either ejected, or the VDR itself is pulled apart by outside forces. ..Trevor..
Benicar docks into several different cellular receptors to provide a variety of actions, luckily all beneficial.
Benicar stops TNF-alpha from being released from the macrophages. It also blocks the other cytokines released during an inflammatory reaction. It does not bind to just any TNF-alpha floating around so it doesn't interfere with the function of the immune system like the TNF-antagonists (Remicade or Enbrel). Benicar works at a higher level than the cytokines or chemokines and is obviously a superior way to go. This enables the immune system to 'see' and kill the bacteria.
Benicar is an antibacterial (but not really an antibiotic) because its actions on the Vitamin D Receptor in the nucleus of cells activates the innate immune system (the body's last line of defense), which enables the immune system to kill the intracellular bactera. Benicar might also act as an antibacterial by binding to pathogenic proteins.
Benicar's structure is described here:
http://www.fda.gov/medwatch/SAFETY/2004/nov_PI/Benicar_Tab_PI.pdf
The reduction in inflammation that Benicar promotes allows better tissue perfusion of the antibiotics. Without a Benicar blockade it is difficult to get enough antibiotic into the tissues to kill off all the recalcitrant pathogens.
Benicar has a number of actions on a variety of key immune receptors. Activating the VDR is just one key function, and it occurs at relatively low doses. At higher doses Benicar affects other receptors which provide a degree of immunosuppression, and palliation (pain reduction and feeling-good).
In fact, taking additional Benicar as needed will allow you to, in effect, tell your immune system to 'slow down' when it might otherwise kill more bugs than you are comfortable killing.
Effect of Benicar on the bacterial genome
The job of benicar is to lower the initial levels of cytokines, especially the level of intracellular 1,25-D; so that the immune system can manufacture the proteins it needs to fight the bacterial pathogens. The same effect also makes most folks feel better. Some, however, find that their immune system immediately starts recognizing and attacking the pathogens when they start taking Benicar, without needing the assistance of antibiotics. Partly this is because of the lowered 1,25-D and partly it is because Benicar also disrupts the bacteria themselves. Here are the first few sentences from a paper I wrote:
"Whenever administering an antibiotic it is important to be aware of the drug’s effect not only on the bacterial genome, but also on the genome of the patient. Some antibiotics, such as streptomycin, have excellent antibacterial activity, but ‘side-effects’ are a problem. The reverse is also true - that drugs being administered to the patient may have a direct effect on the parasitic organisms. Some Angiotensin Receptor Blockers (ARBs) act in just this way, as ligands on bacterial proteins, and, if dosed correctly, have utility as a new class of antibacterials."
..Trevor..
Impact of Benicar on symptoms
Benicar (and the antibiotics) do not cause symptoms; they merely make Th1 inflammation evident. The cause of symptom exacerbation is the inflammatory disease. Symptoms that are subclinical without the Marshall Protocol, will remain and get worse unless Th1 inflammation is resolved.
Benicar has two roles. It selectively suppresses the immune system to reduce inflammatory symptoms. And it activates the Vitamin D receptor to enable the immune system to kill intracellular bacteria resulting in immunopathology, indirectly increasing symptoms.
Benicar is superior to other ARBs
This JOIMR website page uses stick-figures of each of the sartan molecules to illustrate how different each ARB is. This is the logical reason why we have found that Benicar works better than others.
Palliative effect
Benicar also has palliative effect. It works with other nuclear receptors to reduce cytokines generated when intracellular bacteria are killed. This provides symptomatic relief.
As you increase the dose of Benicar, it provides a more effective blockade of those receptors for which it does not have a super-high affinity. Angiotensin II is fully-blockaded at quite low doses. Higher doses are needed to make the VDR work better, and even higher to exert the palliative actions.
Benicar lowers the level of 1,25-D to reduce organ and joint damage. It also keeps the level of 1,25-D in check when you take antibiotics and immunopathology causes a temporary flare of 1,25-D. This prevents an exacerbation of existing organ damage.
As we recover and the innate immune system becomes more active, 1,25-D will recommence its role as VDR agonist. At some point the immunosuppressive action of Benicar (and it's ability to reduce symptoms) becomes dominant over its role in activation of the VDR (which is so critically important at the start of treatment).
Pharmacodynamics
I used to think that a steady baseline concentration of Benicar (olmesartan) would be the best way to provide an effective inflammatory blockade. But while I was computing the molecular genomics, it occurred to me that the pulses of concentration which result from taking discrete, rather than time-release tablets, also have a function. It is the pulses that will dislodge any other ligands docked into the receptors, and put the Benicar in place to do its job.
The pharmacodynamic half life of Benicar is not the same as the pharmacokinetic half-life because there is a disassociation constant involved. That means Benicar loses its affinity for the A-II receptor more quickly than it decays from the bloodstream. So the effective useful lifetime is 6-8 hours rather than the approx. 13 hours of the plasma half-life.
The affinity for the VDR of Benicar is low. That's why we need to use a higher concentration. Although Benicar closes off the Angiotensin II Receptor (AT2R) at below 20mg/day, we need a much higher dose to properly activate the VDR. Thus the displacement of ligands from the VDR is easier to control by dosage than its blockade of the AT2R.
Additionally, if you take Benicar with a big meal, the data presented to the FDA by Sankyo show it can take 3-4 hours for Benicar to enter the bloodstream.
The total effect is not 24 hours. That is a marketing fallacy. Sankyo's own studies show a dis-assocation constant in the 4 hour region, and we find that the drug has to be dosed every 4-8 hours for a proper blockade.
Therefore, you need both timed release and some standard tablets. You will want a few standard tablets to use as a 20-40mg bolus. Use them when you feel a drop in their effect occasionally and need a bit more blockade to tide you over to the next 40-80mg TR dose.
The affinity for the VDR of Benicar is low. That's why we need to use a higher concentration.
Although Benicar closes off the Angiotensin II Receptor (AT2R) at below 20mg/day, we need a much higher dose to properly activate the VDR. Thus the displacement of ligands from the VDR is easier to control by dosage than its blockade of the AT2R.
A really high affinity VDR ligand, like the ANTAGONIST Telmisartan (which you don't want to take under any circumstances) only requires a fraction of a tablet to block the action of multiple Benicar tablets for 24 hours or so...
The FDA has a mantra "It's all a matter of Dose." The agonist effect of Olmesartan occurs at higher doses, and the degree of effect can be adjusted by adjusting the dose.
Whereas with a drug which is too high an affinity, like Telmisartan as an antagonist, you cannot adjust the dose to modulate the degree of the effect.
So Olmesartan is able to displace 1,25-D, or capnine, from the VDR LBP in a controlled manner, dependent on Olmesartan dose (and the concentration of capnine or 1,25-D).
This is called "homologous displacement" in most pharmacology texts. It follows a characteristic S-shaped curve. ..Trevor..
Long-term use
As you heal, you will find the amount needed will drop, although it waxes and wanes as different bug 'colonies' are addressed every few months or so. Eventually you find your need drops the point where you forget to take the tablets.
Dosage
See Benicar dosage and schedules
Side effects
To us, Benicar is not a "medication." It is a method of turning-on your body's VDR (Vitamin D Receptor). This is a key part of the immune system, and transcribes over 1000 genes which affect body processes from calcium homeostasis to cancer metastasis. We know that the VDR is blocked from operating properly by the intraphagocytic microbiota.
When you take Benicar, and your VDR is activated again, your body may have difficulty dealing with the consequences. As for using the word "side effects," the FDA would laugh. In healthy people this drug has no side effects. It is one of the safest in the US formulary. 'Side effects' are artifacts of the illness, and will need to be faced in order to recover.
See Benicar 'side effects'
Benicar and potassium
Medications that decrease urine potassium excretion increase serum potassium. These include ACE inhibitors, ARBs (including Benicar), NSAIDs, potassium-sparing diuretics such as spironolactone (Aldactone), triamterene (Dyrenium), and trimethoprim-sulfamethoxazole (Bactrim). See My potassium is elevated. What should I do?
Dr. Marshall's latest paper on molecular modeling indicates that all of the ARBs have potential to modulate the immune system to some extent:
Common Angiotensin Receptor Blockers may directly modulate the immune system via VDR, PPAR and CCR2b
Theor Biol Med Model. 2006 Jan 10;3(1):1
PMID: 16403216 [PubMed - as supplied by publisher]
http://tinyurl.com/8wqk5
Our newest paper, although 33 pages long, details the link between the immune system and the Angiotensin Receptor Blockers. You may print off a copy from URL
http://www.tbiomed.com/content/pdf/1742-4682-3-1.pdf
......................
Last edited on Mon Nov 3rd, 2008 18:20 by Foundation Staff
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Foundation Staff
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Posted: Wed Aug 6th, 2008 06:07 |
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[filelink]
Benicar 'side effects'
"To us, Benicar is not a "medication." It is a method of turning-on your body's VDR (Vitamin D Receptor). This is a key part of the immune system, and transcribes over 1000 genes which affect body processes from calcium homeostasis to cancer metastasis. We know that the VDR is blocked from operating properly by the intraphagocytic microbiota.
When you take Benicar, and your VDR is activated again, your body may have difficulty dealing with the consequences. As for using the word "side effects," the FDA would laugh. In healthy people this drug has no side effects. It is one of the safest in the US formulary. 'Side effects' are artifacts of the illness, and will need to be faced in order to recover.
When we visited the US FDA in Washington in April 2007, we were told that "Benicar is the safest drug in the US formulary." At the upcoming 6th International Congress on Autoimmunity in September, Captain Tom Perez will be presenting our study success data. Tom is a member of the US Commissioned Corps of the Dept of Health and Human Services, and has spent a lifetime in the FDA, both in the Center for Drug Evaluation and in Headquarters Staff. He has personally reviewed the adverse events files for Benicar, and for many other drugs.
If you review the literature you see will lots of studies with Olmesartan, but I can't remember one in which any "side effects" were noted at any rate above placebo. The exception is dizziness.
I myself have gone through all the studies submitted to the FDA as apart of the certification of Benicar for sale in the USA. The file is available on the web and I recommend you look through it:
http://www.fda.gov/cder/foi/nda/2002/21-286_Benicar.htm
Benicar, when given to healthy people, causes a very mild depression in blood pressure (the FDA has told us that it is the least effective of all the pressor drugs) and no side effects beyond dizziness. But when given to sick people, as we have found, it has a profound effect, due to the immunopathology.
So I am at a loss to understand what the "side effects of benicar " might be. I have been looking for them for six years, and all I can find is epidemic Th1 disease, and a consequent reaction to Benicar when folks' immune systems are activated to recognize the pathogens 
If blood pressure becomes too low, it is as a result of the disease, the immunopathology, as the drug doesn't have much pressor effect in healthy people (max 12 mm Hg)
The decision to kill the Th1 metagenomic microbiota, rather than try to suppress its effects, is life-altering. It might take 3-5 years to get back to a point where the individual can function well in their families and workplace again. Luckily that recovery is incremental, but it is slow.
You need to be very careful when looking at reported side efects of a drug. Those side effects are reported, in many cases, by people who have no idea what they are talking about. The only way to sort the competent from the incompetent is to look through the raw FDA files, which are confidential, and most of us don't get the opportunity to do so... I take the word of those who have had this opportunity..."
Dr. Trevor Marshall, Ph.D
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