Science behind olmesartan (Benicar)

Patients on the Marshall Protocol (MP) take olmesartan (Benicar)Medication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor., a drug whose actions are fully known, every six hours. A substantial body of research supports the use of olmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. as a part of a curative therapy for chronic disease. In general, olmesartan tends to be prescribed for its antihypertensive properties due to the fact that is an angiotensin receptor blocker.

For the purposes of the MP, olmesartan has two primary actions: it reduces inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. by blocking the Nuclear Factor-kappaB cytokineAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. pathway and it is an agonist of the Vitamin D ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. (VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response.). As a VDR agonistA substance such as olmesartan (Benicar) or 1,25-D which activates the Vitamin D Receptor and transcribes the genes necessary for a proper innate immune response., olmesartan activates the innate immune responseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease.. Research supports the safety of the doses used by MP patients. Olmesartan has minimal interactions with other drugs and is one of the safest drugs on the market.

Ample research supports the fact that olmesartan is one of the safest and has the most gentle side effects profiles of almost any drug on the market.

Olmesartan is classified as an Angiotensin II Receptor Blocking (ARB) drug. When olmesartan binds and blocks the Angiotensin Receptor, it prevents fibrotic tissue from forming and decreases levels of Nuclear Factor Kappa B, a protein that stimulates the release of inflammatory cytokinesAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. - proteins that generate pain and fatigue. These cytokines include interferon gamma and TNF-alpha. The drop in cytokines results in less inflammation and oxidative stress. As inflammation drops, the antibiotics can also perfuse the tissues more effectively.

Working at a higher level than the cytokines or chemokines, olmesartan 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 such as Remicade and Enbrel.

The drop in inflammation stimulated by olmesartan can affect patients in two, sometimes simultaneously occurring, ways.

In some cases, the olmesartan can make patients feel better, allowing them to more easily tolerate the increase in symptoms generated by bacterial die-off. In fact, if patients feel that their immunopathologyA temporary increase in disease symptoms experienced by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed. is too strong, they can take extra olmesartan in order to help palliate the inflammatory response.

Olmesartan has both an affinity for the Vitamin D Receptor and a molecular structure which lends itself to easy activation of the receptor. The low level of interaction olmesartan has with the other nuclear receptorsIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affect transcription. makes it even better than 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol., the endogenous or native nuclear receptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription. for the VDR.

In other circumstances, the reduction in inflammation that olmesartan promotes allows better tissue perfusion of the antibiotics and, as a consequence, greater immunopathology. Without an olmesartan blockade it is difficult to get enough antibiotic into the tissues to kill off all the recalcitrant pathogens.

Olmesartan's action as VDR agonist makes it a critical component of the Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis.. This is evident in patients taking MP antibiotics who do not begin killing bacteria until they take olmesartan. For this reason, olmesartan meets the definition of an antibacterial.

To us, olmesartan is not a “medication.” It is a method of turning-on your body’s Vitamin D Receptor. This is a key part of the immune system, and transcribes over 1,000 genes which affect body processes from calcium homeostasis to cancer metastasis.

Trevor Marshall, PhD

The ribosome blockades initiated by the Marshall Protocol antibiotics weaken the Th1 pathogens but are unable to actually kill the pathogens. For this reasons, patients on the MP take olmesartan, which activates the innate immune response. In this respect, olmesartan is distinct from other ARBs such as telmisartan, which has been shown to be a strong VDR antagonistA substance such as 25-D or certain bacterial ligands which inactivates the Vitamin D Receptor the receptor which transcribes the genes necessary for a proper innate immune response..¹ Molecular modeling has revealed that olmesartan binds and activates the Vitamin D Receptor among others. This action is validated by in silicoExperiment technique performed on computer or via computer emulation. data.²

Because the VDR itself is in constant motion and it 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.

Benicar docks into several different cellular receptors to provide a variety of actions, luckily all beneficial.

The Vitamin D Receptor is relatively insensitive to changes in concentration of competing ligands. At some points in the curve, it takes a five-fold change in concentration to increase the amount of the drug docking at the VDR by only 10%.

Other ARBs also bind the same nuclear receptors as olmesartan but fail to activate them at the correct level.

Like other ligands, olmesartan binds to nuclear receptors above a certain concentration. For this reason MP patients do not use time-release tablets of olmesartan. The affinity for the VDR of olmesartan is low, which explains the need for a higher concentration. Although Benicar closes off the Angiotensin II Receptor (AT2R) at below 20mg/day, MP patients 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.

The pharmacodynamic half life of Benicar is not the same as the pharmacokinetic half-life because there is a disassociation constant involved. That means olmesartan 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 approximately 13 hours of the plasma half-life.

Incidentally, this is also why Marshall Protocol patients are advised to avoid sustained-release versions of Benicar.

Olmesartan docked in the PXR superimposed on a PXR agonist, SR12813. This emulation by Trevor Marshall, PhD suggests that olmesartan activates the PXR.

Many patients who have begun the MP find that their levels of 1,25-D drop dramatically in the first weeks. This can be explained by pointing to olmesartan's ability to activate both the VDR (discussed previously) and, quite possibly, the Pregnane X Nuclear Receptor (PXR).

Based on [an in silico] model published more recently I would today opine that Benicar is more likely a PXR agonist at this point, as it is active in the same PXR residues as the known agonist SR12813. The gene SR12813 is confirmed to transcribe is that for CYP3A4 [an enzyme which breaks down 1,25-D].

Trevor Marshall, PhD

Given that 1,25-D tends to be higher than normal in patients with chronic disease and that high levels of 1,25-D interfere with the actions of other nuclear receptors, a reduction in 1,25-D can contribute to a certain amount of symptom relief.

Olmesartan may also exert its palliative effects through binding other key receptors.

Examples of some of the documented protective effects of ARBs include the ability to:

• decrease the incidence and progression of Alzheimer's disease and dementia³
• prevent migraines⁴
• inhibit liver fibrosis and aid liver healing⁵
• reduce insulin resistance in rats⁶
• protect the mitochondria from age-associated damage from oxidation⁷
• reduce liver fibrosis⁸
• treatment of anxiety and stress-related disorders⁹

Olmesartan and other ARBs have been used to block various bad effects of Angiotensin II, including heart failure. In this regard, olmesartan has been shown to:

• protect the heart from damage from inflammation in myocarditis¹⁰
• ameliorate acute experimental autoimmuneA condition or disease thought to arise from an overactive immune response of the body against substances and tissues normally present in the body myocarditis, in rats, suppressing cytotoxic myocardial injury ¹¹
• prevent acute left ventricular dysfunction¹²
• lower C-reactive protein, one of the acute phase proteins that increase during systemic inflammation¹³
• act as an antiarrhythmic¹⁴
• block the production of Angiotensin II, thus improving mortality rates in heart failure patients¹⁵
• reduces the volume of atherosclerotic plaques^{16 17}

Olmesartan has also been shown to mildly reduce the risk of stroke in people at high risk for strokes (cerebrovascular events).¹⁸

Pharmacotherapy targeting the renin-angiotensin system [the mechanism of the ARBs] is one of the most effective means of reducing hypertension and cardiovascular morbidity.^{19 20}

Nien-Chen Li et al.²¹

A number of studies have found that olmesartan and other ARBs possess various ways of protecting the kidneys from the effects of inflammation and cytokine damage.

In August 2002, Trevor Marshall and Frances (Liz) Marshall published a NetPrint about valsartan (Diovan), in which they reported that the once daily dosing of the ARB caused psychedelic dreams and psychotic events in two sarcoidosis patients. On the theory that these symptoms were caused by changes in plasma concentration, the frequency of the dosing of ARB was increased, which ended up reducing symptoms of disease including psychedelic dreams. This early insight into ARBs anti-inflammatory effects led Marshall to conclude that for an ARB to provide symptomatic relief, it was necessary to use more frequent dosing than typical. Marshall would later go on to recommend frequent dosing of another ARB, olmesartan, as a part of the Marshall Protocol.