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Posted: Tue Feb 1st, 2005 07:00 |
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In April 2007, Meg, Belinda and I, had a high-level meeting at the FDA in Maryland. One of the topics on the agenda was how we put an end to concerns physicians are expressing about the safety of Benicar.
Those present included the head of the Cardiovascular division when Benicar was approved who is an 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 Benicar 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 beyond 40mg the dose really doesn't affect BP any more.
Second, he pointed out that the FDA has set no toxic level for Benicar, because its safety is not in question, and certainly not at the levels we are using.
The issue of exactly what the drug does is less clear. As you know, we have shown that the ARBs, as a class, have a wide range of activity in the Nuclear Receptors, quite distinct from their intended target, the Angiotensin II receptor. The Nuclear Receptors are responsible for transcription of genes which are active in the immune system. Others have now confirmed my work on PPAR activity, and I have gone on to specifically show that benicar is a strong agonist of the VDR nuclear receptor, which is at the heart of innate immunity.
On the other hand, we know how the drug works, and I can guarantee that many potential linkages are not seen by the FDA. For example, when I was in Perth, Western Australia, a hospital anesthesiologist commented that he now understood why patients who were using ARBs were more likely to have an adverse reaction to certain pre-op IV antibiotics he gave them (immunopathology ). If the FDA doesn't understand what a drug is doing it can't properly assess the effects of that drug.
It is our understanding of Benicar's actions which allows the moderators to select a dosing which is an effective compromise between safety (with all things considered) and efficacy.
The best plan seems to be to maintain blockade with a 40mg dose every 6-8 hours and use a 20mg bolus as needed or increase to 40mg every 4 hours to control additional symptoms.
Benicar protects organs, and reduces damage to the body from immunopathology. Any assessment of 'safety' has to take that into account.
That is why I say that no dose is too high; well, certainly no dose up to an average 40mg every 2 hours. We have no data indicating problems up to this level. I have personally tried this level for a day or two at a time without any obvious adverse events, acute or chronic. It is better to minimize damage from the immunopathology, IMO.
"it is not fair to ask me if there are any risks involved in ARB therapy. I can tell you that statistics show that I would be dead if the Marshall Protocol had not worked for me (mean survival post cardiac-sarcoidosis diagnosis is 5 years). You need to figure out what your life is worth to you, I guess.
Nobody can guarantee you will recover, nobody can guarantee you that the ARBs or antibiotics will not harm you in some obscure way. All I can do is tell you what we have observed so far in the several hundred patients who are already on the Marshall Protocol, and what is known from trials of the same drugs in a healthy population."
Adverse reactions in FDA studies were likely due to immunopathology
Q- I have fluid on my lungs and my doctor suspects Benicar because there were 3 cases of this in the FDA studies.
A- There is a failure in the medical community to recognize how serious the Th1 diseases really are. Even when a patient is close to suicide, Doc often cannot understand why the patient is complaining, a tragic lack of understanding.
Even after diagnosis, there is no recognition of the systemic nature of these diseases, nor is the FDA certification process set up to find things like we discovered with the MP. Those 3 patients out of several thousand who had fluid on their lungs during the Benicar trials may have seemed quite healthy to the Doctors, yet in actuality may have been severely ill with Th1 disease. There is just no way to tell, as no such record-keeping is required by the FDA yet. They don't track the health of folks subsequent to their having taken part in safety-trials. Those three folks may all have died from pulmonary insuffiency within a year, there is no requirement to report such things.
The hypotension experienced by Th1 patients is experienced as a result of their disease. There is no way they can avoid this symptom as they heal.
The dizzyness almost certainly is not the result of the hypotension, but is also related to disease processes, and so it occurs concurrently with the hypotension.
The Th1 syndromes are profound chronic diseases. By the time patients get a diagnosis they are usually very ill indeed. The least of their worries should be their dizzyness, yet the neuroses which are concomitant with the physical syndromes aften make the patients quite scared of dizzyness, when they really need to sit or lie down as first response, rather than worry excessively.
Dr. Trevor Marshall, Ph.D
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Foundation Staff
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Posted: Sat Feb 5th, 2005 06:50 |
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[filelink]
Evidence that taking Benicar at the MP recommended doses is safe
When we visited the FDA they made it clear that there is no safety limit set for Benicar; that no dose had been detected that results in an adverse event. During the studies on Benicar the animals were subjected to doses equivalent to 2000 times 'normal' levels. The FDA bases its safety data on 'post-marketing experience' - how many adverse events have been linked to the drug - and they are negligable.
The label for Benicar is at http://tinyurl.com/asyfc
This prescribing information for Benicar indicates that:
Benicar dosing must be individualized.
Point out that FDA guidelines allow the "40mg Q8hr dosage":and state that the "Dosage must be individualized" and "The overall frequency of adverse events was not dose-related".
http://tinyurl.com/9pfvz
This study shows that Benicar (CS-866) was safe and well tolerated at doses of up to 160 mg/day.
Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects.
http://tinyurl.com/bspq8
Benicar was well-tolerated in safety evaluations. Adverse events were similar to a placebo. Adverse events generally were mild, transient and not related to dose.
The frequency of adverse events had no relationship to the dose of Benicar.
In placebo-controlled trials, the only side effect that occurred in more than 1 percent of Benicar-treated patients vs. placebo-treated patients was dizziness (3 percent vs. 1 percent).
Animal studies in mice, with Benicar doses up to 480x the human dose of 40 mg per day, showed Benicar was not carcinogenic.
Tell your doctor that the New England Journal of Medicine published an article in Nov 2003 which describes how treatment of MI might need a higher dosing schedule: Angiotensin Blockade-A Matter of Dose
Here are studies that may convince your doctor of the safety of high dose ARBs (Benicar is an ARB):
Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus.
Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria.
Pharmacokinetics and pharmacodynamics of irbesartan in healthy subjects.
The angiotensin II receptor blockers: opportunities across the spectrum of cardiovascular disease.
Rev Cardiovasc Med. 2002 Fall;3(4):183-91. Review.
PMID: 12556752 [PubMed - indexed for MEDLINE]
Full Text http://tinyurl.com/8noek
Side effect cannot be differentiated from placebo.
Therapeutic role of angiotensin II receptor blockers in the treatment of heart failure.
Mayo Clin Proc. 2003 Mar;78(3):334-8. Review.
PMID: 12630586 [PubMed - indexed for MEDLINE]
From the Mayo Clinic:
"As a class, ARBs are well tolerated and have a good safety profile."
Point out that higher doses of ARBs are needed to effectively block the Angiotensin II in sarcoidosis. This is a non-pressor effect of the medicine, and higher doses do not significantly affect blood pressure. These ARBs have been approved to treat nephropathy and migraines so if you have those problems that will help.
This study about higher doses of ARBs to treat renal disease reports "Data from many studies strongly support the use of the higher doses of ACE inhibitors or ARBs to reduce proteinuria. All studies of kidney disease progression demonstrate benefit on slowing only when blood pressure is reduced when using higher doses."
How High Should an ACE Inhibitor or Angiotensin Receptor Blocker Be Dosed in Patients with Diabetic Nephropathy?
See ARBs: Benefits Beyond Blood Pressure Lowering? for a noted cardiologist's opinion that ARBs are more effective at higher doses.
These papers explain why the two hormones 1,25-dihydroxyvitamin-D and Angiotensin II are critical in sarcoidosis, and why an angiotensin blockade significantly reduces immunopathology symptoms.
http://tinyurl.com/mcqa
Here is a study showing the safety of doses higher than 40mg a day:
Antihypertensive efficacy of olmesartan medoxomil, a new angiotensin II receptor antagonist, as assessed by ambulatory blood pressure measurements.
http://tinyurl.com/53qz6
This study shows the rationale of higher dosing for sarcoidosis patients: Angiotensin II receptor on BALF macrophages from Japanese patients with active sarcoidosis.
Am J Nephrol. 2004 May-Jun;24(3):340-5. Epub 2004 Jun
Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study.
Patients received candesartan titrated to a targeted dosage of 160 mg/day (5 times above the currently approved maximum dose) and remained at that dosage for the subsequent 4 weeks. RESULTS: Candesartan was well tolerated with no serious drug-related adverse events reported.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.
http://tinyurl.com/4mspw
When Doc is concerned with Benicar & blood pressure. >> This is the graph to show Doc (there is a copy taped to every package of Benicar your Pharmacy gets)
Clinical efficacy and tolerability of olmesartan
Clin Ther. 2004;26 Suppl A:A28-32.
PMID: 15291377 [PubMed - in process]
http://tinyurl.com/3qa5c
The report says:
"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 2 years of treatment."
See High-dose exposure to valsartan with suicidal intention
This report demonstrates the effect/side effect profile of valsartan (ARB similar to olmesartan) when taken at a high dose, not achievable in a clinical trial.
Benicar/Olmesartan General Safety Articles
Clinical and experimental aspects of olmesartan medoxomil, a new angiotensin II receptor antagonist.
Cardiovasc Drug Rev. 2004 Winter;22(4):285-308.
PMID: 15592575 [PubMed - in process]
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.
Clinical efficacy and tolerability of olmesartan.
Clin Ther. 2004;26 Suppl A:A28-32. Review.
PMID: 15291377 [PubMed - indexed for MEDLINE]
Frequency of adverse events is not dose related.
The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview.
J Hum Hypertens. 2002 May;16 Suppl 2:S13-6. Review.
PMID: 11967728 [PubMed - indexed for MEDLINE]
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.
Testing a therapeutic dose range of 40-80 mg daily
The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interaction.
J Hypertens Suppl. 2001 Jun;19 Suppl 1:S21-32.
PMID: 11451211 [PubMed - indexed for MEDLINE]
Elimination is 40 % via kidneys, the remainder being excreted in faeces, following secretion in bile. Renal clearance was independent of dose.
Safe and well tolerated at doses up to 160 mg per day
Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects.
J Clin Pharmacol. 2001 May;41(5):515-27.
PMID: 11361048 [PubMed - indexed for MEDLINE]
Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease: Nonhemodynamic Renal Protection.
J Am Soc Nephrol. 2007 Feb 7; Yu C, Gong R, Rifai A, Tolbert EM, Dworkin LD. Division of Renal Disease, Department of Medicine, and Department of Pathology, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island; and Department of Nephrology, Zhongshan Hospital, School of Medicine, Fudan University, Shanghai, China.
Recent evidence suggests that higher-than-usual antihypertensive dosages of renin-angiotensin-aldosterone system blockers may provide additional protection from progression of chronic renal disease;... These findings suggest that candesartan has dosage-dependent, anti-inflammatory effects that are mediated by suppression of NF-kappaB activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.
PMID: 17287430 [PubMed - as supplied by publisher]
See also:
Effects of Higher-Dose Angiotensin Receptor Blockers on Humans
Effects of Higher-Dose Angiotensin Receptor Blockers in Animal Disease Models
Last edited on Wed Mar 5th, 2008 02:02 by Foundation Staff
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Foundation Staff
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Posted: Fri Feb 11th, 2005 22:25 |
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[filelink]
Frequently Asked Questions About Benicar
Benicar dosage and schedules
Where to purchase Benicar for self pay members
Why do we need a Benicar blockade?
How does Benicar work?
How does Benicar act on the Vitamin D Receptor (VDR)?
What is a therapeutic probe?
What hormonal changes result from the reduction in 1,25D-hydroxyvitamin-D caused by Benicar?
Why does Benicar work so well? See:
Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b
Trevor G Marshall, Robert E Lee, Frances E Marshall
Theoretical Biology and Medical Modelling 2006, 3:1 (10 January 2006)
[Abstract] [Full Text] [PDF] [PubMed] [Related articles]
How does Benicar activate the immune system? See Dr Marshall's Karolinksa presentation:
http://www.marshallprotocol.com/forum39/5940.html
http://www.marshallprotocol.com/forum39/6362.html
How can I obtain my insurance benefit for the full dose of Benicar?
Benicar is not available in my country. I cannot afford Benicar. Is there an acceptable substitute?
How much is an adequate emergency supply of Benicar to keep on hand?
My blood pressure is already low. Can I take Benicar?
Why shouldn’t we ramp up the dose of Benicar?
I just started Benicar. Why do I feel worse? What should I do?
Does Benicar cause dizziness?
Does Benicar raise serum potassium?
Why am I dizzy and/or fainting? What should I do?
Why is my blood pressure high? Why does it fluctuate?
My immune system seems to be responding to Benicar alone. Why?
How long should I stay on Benicar only? Why don't I feel better? When should I start minocycline?
How to make Benicar act faster
Do I need to take extra salt because of Benicar?
Should I take less Benicar if my bodyweight is low?
Do I have to wean off Benicar?
Where can I learn about Benicar used for applications beyond anti-hypertension?
We need to know who has been refused Benicar by Medco
Related topic threads:
BENICAR questions
Benicar for Aussies has the recent Rx Information
Medicare Drug Plans
Insurance Coverage of Benicar
My MP doctor wants to modify the Marshall Protocol. Is that okay?
Last edited on Fri Apr 11th, 2008 10:41 by Foundation Staff
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Posted: Tue Apr 5th, 2005 04:00 |
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Benicar Applications Beyond Hypertension
Click on this link for studies providing evidence that Benicar is effective in treating other conditions besides hypertension.
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Posted: Wed Nov 30th, 2005 07:11 |
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(filelink)
The right kind of Benicar
Check your Benicar tablets to make sure that you have the right kind. There are two types of Benicar and it is CRITICAL that you have the right kind, which is just plain Benicar.
These are the right kind of Benicar:
40 mg tabs which have C-15 written on them
20 mg tabs which have C-14 written on them
There is also a form of Benicar which includes Hydrochlorothiazide (HCT), a diuretic. You do NOT want this kind. Hydrochlorothiazide (HCT) is too hard on the kidneys and liver, and these are organs in which people with Th1 disease may have undetected problems. You can read the precautions about HCT on the internet drug index.
Here are photos of Benicar. Votum from Germany may not have the Sankyo name.
How to identify Benicar from Sankyo
We use benicar without HCT and these tablets are white.
The Benicar we use has an identification stamp on the tablet saying "C15" for the 40mg tablets or "C14" for the 20mg tablets. The stamp "Sankyo" is on the other side of the correct tablet.
Benicar with HCT has orange color, like these
these colored tabs we MUST NOT USE.
How much is an adequate emergency supply of Benicar to keep on hand?
The answer depends on your pharmaceutical supply source. If you are dependant on an overland or overseas mailorder source for Benicar which can lead to delays in refills, estimate the time of a possible delay in delivery. If your insurance company is likely to balk at refilling your Benicar order, estimate the length of time you might be without it while you appeal their denial.
Often reordering any medication the moment it is due for a refill will provide you will a few extra pills each refill. "This tactic over the past two years has give me a nice supply of extra minocycline and Benicar for 'emergencies'. I haven't needed it until last month when my insurer unexpectedly decided to deny my claim and it took three weeks to get my Benicar refill."
The doctor's office is a good source of Benicar samples if you do run out. They don't prescribe it very often and Sankyo is promoting it so they usually will have a good supply and they can give you some to tide you over if necessary. Ask them for samples each time you make an office visit to help you create a stockpile. "I used the delay in prescription refill as an excuse to ask my doctor for samples and add to my emergency supply."
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