Related article: Recent research into Celiac disease
Some patients and healthcare providers have expressed concerns about the safety of higher than typical doses of olmesartan (Benicar).
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 – as opposed to Benicar HCT, which contains a thiazide and is harmful.
I feel there are simply no adverse reactions or negative side effects that I need to worry about while taking the Marshall Protocol medications. It is an extremely safe approach. Personally, I believe overtreating this condition is preferable than undertreating as the side effects of both antibiotics and Benicar are so minimal compared to the risk of [disease] recurrence.
Greg Blaney, M.D.
For those with gastric issues, it is recommended that the pill be crushed and mixed with applesauce or similar to reduce impact on gastric lining.
Although they do so for many other drugs, the U.S. Food and Drug Administration has set no unsafe upper limit for olmesartan. The FDA bases its safety data on “post-marketing experience” - how many dose-related adverse events have been linked to the drug – and for olmesartan, they are negligible. The FDA has consequently set no unsafe dosage level for Olmesartan.
According to the FDA's full prescribing information for Benicar:
A 2001 study published in the Journal of of Pharmacology found olmesartan to be safe and well tolerated at doses of up to 160 mg/day.1)
CS-866 [olmesartan] was safe and well tolerated at doses of up to 160 mg/day…. [Olmesartan] has no serious adverse effects.
Lee R. Schwocho, PhD and Harvey N. Masonson, MD 2)
Animal studies in mice, with olmesartan doses up to 480 times the human dose of 40 mg per day (relative to body weight), showed that olmesartan is not carcinogenic.
The label for olmesartan states that the drug is well-tolerated. Adverse events were similar to those experienced by the placebo group – a group of patients who were not given the drug at all. Adverse events were generally “mild, transient and not related to dose.” The frequency of adverse events also had no relationship to the dose of olmesartan.
From a MPStudySite topic
a Member recently reported “taking a whole days worth of Benicar into my mouth and they were down before I could stop them. Had forgotten I hadn't just put the one 6 a.m. dose in the container…. no adverse effects.
Peleg and Nguyen observed that in the absence of an agonist such as 1,25-D, the VDR suffers from polyubiquitination and proteasome-mediated degradation in relatively short course – in the sub-4 hour region, and certainly in the sub-24hour region.3) This study offers some support for why sick patients need more frequent dosing than their healthy counterparts.
Recent published reports on the dynamics of VDR recruitment to promoters of target genes in cultured cells demonstrate that the time course for maximal recruitment of the 1,25D3–VDR complex to the promoter of the CYP24 gene in osteoblasts is 3 h, whereas the time course for maximal recruitment of the VDR to the promoter of this gene in IECs is only 30 min [Kim et al., 2005; Meyer et al., 2006].
S. Peleg and C. V. Nguyen 4)
In placebo-controlled trials, the only side effect that occurred in more than 1 percent of olmesartan-treated patients vs. placebo-treated patients was dizziness (3 percent vs. 1 percent). The label does state that olmesartan should not be used during pregnancy or breast-feeding, but since pregnant women are not allowed to do the Marshall Protocol, the warning is of little concern for those using the medicine to recover from Th1 disease.
According to the report:
In the dose-finding study, 792 patients were randomized to olmesartan (2.5-80 mg) or placebo once daily…. The results of the clinical studies in >3000 patients receiving olmesartan showed that the frequency and profile of adverse events with olmesartan were generally similar to those with placebo; the frequency of adverse events was not dose related. Olmesartan, with or without hydrochlorothiazide, was well tolerated over two years of treatment.
Hans R. Brunner, MD 5)
In April 2007, the staff of Autoimmunity Research FoundationNon-profit foundation dedicated to exploring a pathogenesis and therapy for chronic disease. had a high-level meeting at the FDA in Maryland. One of the topics on the agenda was how to put an end to concerns physicians express about the safety of olmesartan.
Those present included the head of CDER's Cardio-Renal Drug Products Division at the time olmesartan was approved, Dr. Robert Temple.
He [Dr. Temple] is expert on the drug’s behavior and is currently the medical director at the Food and Drug Administration division that evaluates drugs. He made it clear that the hypotensive effect of olmesartan is already in full effect at a low dose (less than 40 mg) and there is a graph in the package insert showing that beyond that 40mg the dose really doesn’t affect BP any more. Second, he pointed out that the FDA has set no toxic level for olmesartan, because its safety is not in question, and certainly not at the levels we are using.
Trevor Marshall, PhD
Additional papers on the general safety of olmesartan state:
Frequency of adverse events is not dose related.6)
Peak plasma concentrations of olmesartan occur 1-3 hours after administration, after which concentrations decrease with an elimination half-life of 10-15 hours… Frequencies of adverse events during treatment with olmesartan medoxomil and placebo are similar, with no evidence of a dose response. There are no clinically significant effects on laboratory parameters, and the drug-interaction potential of olmesartan medoxomil is low.7)
High-dose ARB treatment in patients with chronic renal disease is not associated with any clinically significant long-term negative effects on serum creatinine or potassium and is thus an important therapeutic modality with which to achieve further reductions in urinary protein excretion.8)
The results of this pilot study suggest that supramaximal doses of ARBs are safe and well tolerated in patients with chronic kidney disease, while reducing both blood pressure and proteinuria.9)
Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions. Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models.10)
Just as some patients mistakenly assume they're allergic to antibiotics, patients may mistake certain symptoms brought about by olmesartan use for harmful side effects.
The most common reason that patients who begin the Marshall Protocol incorrectly assume that they are suffering from side effects of olmesartan is that they mistakenly attribute the hormonal adjustments that accompany the onset of a olmesartan blockade to side effects of the drug. These hormonal changes occur because in most patients with Th1 disease, the body has become accustomed to a higher than normal level of the hormone 1,25-D, which rises as part of the immune system’s reaction to bacteria.
But the olmesartan blockade quickly and dramatically lowers 1,25-D - by as much as half in just two weeks. Since 1,25-D is a powerful hormone that affects nearly every cell in the body, and interacts with all the body’s major hormones, myriad other hormones are forced to adjust their levels according to the new lower level of 1,25-D. This often causes temporary neurological-type symptoms such as (but not limited to) fatigue, dizziness, headache, photosensitivityAbnormal sensitivity to sunlight and bright lights. Also referred to as "sun flare" or "light flare.", irritability, sleep disturbances, brain fogThe loss of intellectual functions such as reasoning; memory loss; and other neurological abilities that is severe enough to interfere with daily functioning., etc. As the body adjusts to this hormonal shift these symptoms dissipate, usually in a week or two.
Patients should not confuse the rise in symptoms that occurs due to immunopathology with side effects of olmesartan. Immunopathology is absolutely necessary to make progress on the MP.
The ability to accept and tolerate a certain level of immunopathology is a requisite of continuing with the Marshall Protocol and is not always predictable. Usually symptoms wax and wane, but they can also be constant for varying periods of time. Immnopathology-generated symptoms often mimic a patient’s disease symptoms but they can also be surprisingly new, pointing to areas of previously undetected inflammation.
Meg Mangin
Olmesartan has a number of protective effects. For one, it's a potent anti-inflammatory. Since the anti-inflammatory actions of olmesartan actually protect organs, the medication will reduce damage to the body from immunopathology.
Olmesartan is designed to reduce the impact on the tissues of the inflammatory substances released by the immune system as part of the immunopathological reaction.
Other protective effects include:
olmesartan reduced angiotensin II and aldosterone levels more effectively than azilsartan, resulting in a stable antihypertensive effect. Olmesartan also had an inhibitory effect on cardiac hypertrophy. Accordingly, it may be effective for patients with increased RAAS activity after cardiac surgery or patients with severe cardiac hypertrophy. 15)
angiotensin II and aldosterone are decreased in a change-over from candesartan to olmesartan
With the halt of reimbursement of olmesartan, there was a decrease in the prescription of ARB in France. When olmersartan was replaced by another ARB, a worse blood pressure control was observed in treated hypertensive patients. 16)
The incidence of this adverse drug reaction is not entirely clear, although it is thought to be rare. 17)
Seven cases (2.8%) reported recurrence of symptoms after restarting olmesartan 18)
Although enteropathy is rare, clinicians should remain vigilant of this potential adverse event even years after medication initiation. 19)
results suggest that SMEEDS formulation improves dissolution and oral bioavailability of OM while reducing adverse effects (celiac-like enteropathy or diarrhea ). 20)
Collagenous enteritis is an uncommon small intestinal injury pattern with unclear pathogenesis.
All subjects with biopsy-proven collagenous enteritis diagnosed between 2002 and 2015 were identified from 2 tertiary care medical centers. Human leukocyte antigen (HLA)-DQ genotyping was performed by polymerase chain reaction on archived tissue. Celiac disease serology, past medical history, medications, smoking history, demographics, histology, clinical management, and follow-up were recorded. A total of 32 subjects were included. In contrast to celiac disease, subjects with collagenous enteritis were mostly elderly (median age at diagnosis, 69 y; range, 33 to 84 y). Seventy percent of collagenous enteritis subjects harbored celiac disease susceptibility alleles HLA-DQ2/DQ8; however, only 1 subject had elevated serum levels of celiac disease-associated autoantibodies while on a gluten-containing diet. Furthermore, 56% of subjects were taking nonsteroidal anti-inflammatory drugs, 36% proton-pump inhibitors, 28% statins, and 32% olmesartan at the time of diagnosis. Discontinuation of olmesartan and treatments with steroids and/or gluten-free diet resulted in symptomatic and histologic improvement. 21)
Olmesartan was not associated with intestinal malabsorption or significant body weight loss in the general Korean population. 22)