Benicar Applications Beyond Hypertension - Marshall Protocol FAQs (Required Reading) - ABOUT THE MARSHALL PROTOCOL

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Benicar Applications Beyond Hypertension

Antiinflammatory

Anti-inflammatory properties of drugs acting on the renin-angiotensin system.
Anti-inflammatory properties of drugs acting on the renin-angiotensin system.
Drugs Today (Barc). 2005 Sep;41(9):609-22.
PMID: 16341292 [PubMed - in process]
"Blocking the RAS by inhibiting Ang II generation or blocking angiotensin receptors reduces the morbidity and mortality associated with cardiovascular and renal disease beyond the levels due to the lowering of blood pressure, and these benefits are at least partially due to the reduction/prevention of both local and systemic inflammatory processes."

Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation.
Circulation. 2004 Aug 31;110(9):1103-7. Epub 2004 Aug 16.
PMID: 15313950 [PubMed - indexed for MEDLINE]
“We measured a panel of vascular inflammation markers, including high-sensitivity C-reactive protein, and lipid levels during 12 weeks of therapy with olmesartan (n=100) or placebo (n=99) in a prospective double-blind multicenter study… Angiotensin II receptor blockade significantly reduces vascular microinflammation in patients with essential hypertension by as early as week 6 of therapy. This antiinflammatory action of angiotensin II receptor antagonists may contribute to their beneficial cardiovascular effects.”

Protective Effects of Angiotensin II Interruption: Evidence for Antiinflammatory Actions

Nigel J. Dagenais, B.Sc.(Pharm.); Fakhreddin Jamali, Ph.D.

Angiotensin II, the major effector molecule produced from the renin-angiotensin-aldosterone axis, is a vasoconstrictor contributing to hypertension. Evidence indicates, however, that angiotensin II also is a potent proinflammatory mediator with growth and remodeling effects. In vitro and in vivo studies have shown that angiotensin II blockade significantly reduces concentrations of proinflammatory mediators and oxidative stress products in numerous inflammatory models. Interruption of angiotensin II activity with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been beneficial for patients with inflammatory diseases.

Much of this benefit occurs independent of the antihypertensive effect of angiotensin II interruption, suggesting a distinctive protective mechanism. Angiotensin II receptor blockers may represent a novel class of antiinflammatory drugs with indications far beyond cardiovascular diseases.

All drugs are developed with a certain indication in mind, but widespread use can often expand beyond the initial indication. For example, acetylsalicylic acid was originally marketed as an analgesic and antipyretic agent in the late 19th century.[1] However, documented antiplatelet activity of aspirin many years later expanded its use as a valuable agent for preventing heart attacks and strokes.[2] Similar off-label indications may be expanded to angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), which were originally developed for treatment of hypertension by blocking the vasoconstrictive effect of angiotensin II.

Recent human trials have shown that angiotensin II interruption has benefit in cardiovascular disease, diabetes mellitus, and heart failure, often independent of the antihypertensive effect. In vitro and in vivo data suggest that this special benefit may be due to a novel antiinflammatory effect, and this is supported by evidence that angiotensin II is a proinflammatory mediator.

Arthritis

Angiotensin II type 1 receptor as a novel therapeutic target in rheumatoid arthritis: in vivo analyses in rodent models of arthritis and ex vivo analyses in human inflammatory synovitis.
Arthritis Rheum. 2007 Feb;56(2):441-7.
PMID: 17265479 [PubMed - indexed for MEDLINE]

Angiotensin receptor blockers suppress antigen-specific T cell responses and ameliorate collagen-induced arthritis in mice.
Arthritis Rheum. 2005 Jun 2;52(6):1920-1928 [Epub ahead of print]
PMID: 15934096 [PubMed - as supplied by publisher]

Liver Fibrosis

An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells.

Br J Pharmacol. 2003 Jul;139(6):1085-94
Kurikawa N, Suga M, Kuroda S, Yamada K, Ishikawa H.

Neurological

Trophic effect of olmesartan, a novel AT1R antagonist, on spinal motor neurons in vitro and in vivo.
Neurol Res. 2002 Jul;24(5):468-72.
PMID: 12117316 [PubMed - indexed for MEDLINE]
"These in vitro and in vivo studies showed that Olmesartan has a neurotrophic effect on spinal motor neurons. Our data suggest a potential therapeutic use of Olmesartan in treating diseases that involve degeneration and death of motor neurons, such as motor neuropathy and amyotrophic lateral sclerosis."

Oxidative Stress

Olmesartan improves endothelin-induced hypertension and oxidative stress in rats.
Hypertens Res. 2004 Jul;27(7):493-500.
PMID: 15302986 [PubMed - indexed for MEDLINE]

Preventing Organ Damage

[Pharmacological profiles and clinical effects of olmesartan medoxomil, a novel angiotensin II receptor blocker]
Nippon Yakurigaku Zasshi. 2004 Oct;124(4):257-69. Japanese.
PMID: 15467259 [PubMed - indexed for MEDLINE]
“The preventive effects of olmesartan medoxomil on end-organ damage in the kidney, heart, and blood vessels have been demonstrated in various animal models. In clinical studies, olmesartan medoxomil is shown to be well tolerated and have an excellent safety profile that is comparable to that of placebo. Head-to-head comparisons with other ARBs (losartan, valsartan, irbesartan, and candesartan cilexetil) conducted in the United States and Europe have revealed that olmesartan medoxomil is superior to these other ARBs in lowering blood pressure. These facts suggest that olmesartan medoxomil would be beneficial for the treatment of hypertension and other end-organ diseases.”

Raynaud’s Syndrome

Current Treatment Options in Raynaud's Phenomenon.
Curr Treat Options Cardiovasc Med. 2003 Apr;5(2):147-161.
PMID: 12686012 [PubMed - as supplied by publisher]

Retinopathy

Pharmacological and pharmacokinetic study of olmesartan medoxomil in animal diabetic retinopathy models.
Eur J Pharmacol. 2005 Apr 11;512(2-3):239-46.
PMID: 15840410 [PubMed - in process]

Vitamin D Receptor

Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b

This paper on ARB metabolism states "Valsartan is known to be excreted largely as unchanged compound and is minimally metabolized in man. Although CYP2C9 is involved in valsartan metabolism, CYP-mediated drug-drug interaction between valsartan and other co-administered drugs would be negligible."

In other words, CYP enzymes have no effect on excretion. Olmesartan acts directly on the VDR in a manner CYP2C9 does not affect.

Angiotensin II Receptor Blocker

This fascinating study of a murine model shows that administering Angiotensin II to rats causes a shift to a Th1 cytokine profile and that Benicar blocks this effect.

Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury

Shao J, Nangaku M, Miyata T, Inagi R, Yamada K, Kurokawa K, Fujita T. Hypertension. 2003 Jul;42(1):31-8. Epub 2003 May 27.

Angiotensin II Receptor Blockade
(A collection of Medscape articles on the benefits of ARBs other than hypertension.

This article, Angiotensin Receptor Blockers, includes information about the Renin-Angiotensin System (RAS).

Last edited on Mon Sep 1st, 2008 05:01 by Foundation Staff.

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Migraines

Prophylactic Treatment of Migraine With an Angiotensin II Receptor Blocker

Norwegian research gives hope for migraine sufferers

First study to show the potential for effective prevention of migraine with and AT1 receptor blocker

See also Migraine pain control

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Kidney disease

Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study.

Am J Nephrol. 2004 May-Jun;24(3):340-5. Epub 2004 Jun 10.
Weinberg AJ, Zappe DH, Ashton M, Weinberg MS.
College of Arts and Sciences, Boston University, Boston, Mass, USA.

BACKGROUND: The progression of renal disease is ameliorated by drugs that inhibit the renin-angiotensin system (RAS). The doses used to slow the progression of renal disease may not completely suppress the RAS for 24 h and may explain why some patients do not obtain optimal renoprotective benefits from therapy. This pilot study was initiated to determine the safety and tolerability of using higher doses, than currently approved by the Food and Drug Administration, for the angiotensin-receptor blocker (ARB) candesartan cilexetil in patients with chronic kidney disease. We hypothesized that higher doses will be safe and well tolerated. Consequently, this should be a viable strategy for larger clinical trials evaluating the preservation of renal function. METHODS: Twelve patients (10 males; age = 57 +/- 14 years) with a history of diabetic or non-diabetic chronic kidney disease were enrolled in an 8-week open-label trial. 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. The safety and tolerability of the higher doses were determined by measures of blood pressure, serum creatinine and potassium. RESULTS: Candesartan was well tolerated with no serious drug-related adverse events reported. Serum creatinine concentrations throughout the study were not different (p > 0.05) from baseline levels (2.0 +/- 0.5 mg/dl). Plasma potassium concentrations at 160 mg/day candesartan
(4.9 +/- 0.7 mEq/l) were similar (p > 0.05) to those at baseline (4.8 +/- 0.5 mEq/l). CONCLUSIONS: 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. This study demonstrates the need to further investigate the optimal dosing strategy for ARBs in reducing the progression of renal disease. Copyright 2004 S. Karger AG, Basel
http://tinyurl.com/4mspw

Renoprotective effects of an ultrahigh dose of olmesartan

Hypertens Res. 2006 Mar;29(3):169-78.

Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan.
" Fan YY, Baba R, Nagai Y, Miyatake A, Hosomi N, Kimura S, Sun GP, Kohno M, Fujita M, Abe Y, Nishiyama A.
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
Recent studies have suggested that aldosterone plays a role in the pathogenesis of renal injury. In this study, we investigated whether local angiotensin II (Ang II) activity contributes to the progression of renal injury in aldosterone/salt-induced hypertensive rats. Uninephrectomized rats were treated with 1% NaCl in a drinking solution and one of the following combinations for 6 weeks: vehicle (2% ethanol, s.c.; n=9), aldosterone (0.75 mug/h, s.c.; n=8), aldosterone+Ang II type 1 receptor blocker olmesartan (10 mg/kg/day, p.o.; n=8), or aldosterone+olmesartan (100 mg/kg/day, p.o.; n=9). Aldosterone/salt-treated hypertensive rats exhibited severe proteinuria and renal injury characterized by glomerular sclerosis and tubulointerstitial fibrosis. Aldosterone/salt-induced renal injury was associated with augmented expression of angiotensin converting enzyme and Ang II levels in the renal cortex and medullary tissues. Renal cortical and medullary mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) as well as the collagen contents were increased in aldosterone/salt-treated hypertensive rats. Treatment with olmesartan (10 or 100 mg/kg/day) had no effect on blood pressure but attenuated proteinuria in a dose-dependent manner. Olmesartan at 10 mg/kg/day tended to decrease renal cortical and medullary Ang II levels, TGF-beta and CTGF expression, and collagen contents; however, these changes were not significant. On the other hand, an ultrahigh dose of olmesartan (100 mg/kg/day) significantly decreased these values and ameliorated renal injury. These data suggest that augmented local Ang II activity contributes, at least partially, to the progression of aldosterone/salt-dependent renal injury.
PMID: 16755152 [PubMed - indexed for MEDLINE

Benicar and Kidney Function published articles on the renoprotective effects

Renoprotective Properties of Angiotensin Receptor Blockers beyond Blood Pressure Lowering.
Renoprotective Properties of Angiotensin Receptor Blockers beyond Blood Pressure Lowering.
J Am Soc Nephrol. 2005 Dec;16(12):3631-41. Epub 2005 Oct 19.
PMID: 16236804
"These observations confirm unique renoprotective properties of ARB, independent of BP lowering but related to decreased oxidative stress (hydroxyl radicals scavenging and inhibition of the Fenton reaction), correction of chronic hypoxia, and inhibition of advanced glycation end product formation and of abnormal iron deposition. These benefits of ARB may contribute to the renoprotection observed beyond BP lowering."

The renal protective effects of angiotensin II receptor blockers in type 2 diabetes mellitus.
Ann Pharmacother. 2004 Oct;38(10):1731-8. Epub 2004 Sep 7. Review.
PMID: 15353571 [PubMed - indexed for MEDLINE]
“ARBs have extensive data showing their renal protective benefits in hypertensive type 2 diabetic patients with microalbuminuria or proteinuria. The benefits are over and above that of blood pressure reduction alone and extend to normotensive diabetic patients as well. Maximizing the ARB dose before adding additional therapies or another renal-protecting agent (angiotensin-converting enzyme [ACE] inhibitor or non-dihydropyridine calcium-channel blocker) may be superior to adding another class of antihypertensive, even if similar blood pressures can be achieved.”

Angiotensin Receptor Blockers (as a class of drugs) have a renoprotective effect. See Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering.

The ARBs seem to provide long-term beneficial effects, according to this report on Chronic Kidney Disease.

This study found that the reno-protective effects of olmesartan were dose-dependent in animals models of diabetes.

The latest research, reported at the November 12th (2005) 28th Annual Meeting and Scientific Exposition of the American Society of Nephrology(ASN) includes this: "Olmesartan Improves Insulin Resistance in Chronic Kidney Disease Patients: Presented at ASN." The study participants were non-diabetic CKD patients.

See also:

My kidney function tests are worse since I started the MP. What should I do?

ARBs treat chronic kidney disease

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Diabetes

Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes.
J Am Soc Nephrol. 2005 Apr;16(4):1135-40. Epub 2005 Feb 16.
PMID: 15716329 [PubMed - in process]
“Chronic angiotensin II subtype 1 receptor blockade decreases (intra)renal vascular resistance and increases renal perfusion despite significant BP reduction. In addition, it significantly reduces oxidative stress. These effects of angiotensin II receptor antagonists may contribute to their beneficial long-term renal effects in patients with type 2 diabetes.”

Insulin Resistance
Olmesartan Improves Insulin Resistance in Chronic Kidney Disease Patients: Presented at American Society of Nephrology November, 2005.

Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity.
J Hypertens. 2004 Oct;22(10):1977-82.
PMID: 15361770 [PubMed - indexed for MEDLINE]

Olmesartan medoxomil, an angiotensin II receptor blocker ameliorates insulin resistance and decreases triglyceride production in fructose-fed rats.

Okada K, Hirano T, Ran J, Adachi M. Hypertens Res. 2004 Apr;27(4):293-9. First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.

Although angiotensin II receptor blockers (ARBs) have been recommended as a first line of anti-hypertensive agents in patients with diabetes, it remains unclear whether ARBs have a favorable effect on insulin action and triglyceride (TG) metabolism, both of which are impaired in type 2 diabetes. In this study we addressed this issue by investigating how a newly developed ARB, olmesartan medoxomil, influenced insulin sensitivity and TG metabolism in fructose-fed rats, a representative animal model of insulin resistance. Olmesartan was administrated as a 0.01% drinking solution ad libitum to rats either fed normal chow or fructose-enriched chow (60%) for 21 days. Olmesartan treatment markedly decreased both systolic and diastolic blood pressure in both chow-fed and fructose-fed animals. The area under the curve of insulin (AUCI) was substantially greater in fructose-fed rats in the intravenous glucose tolerance test, and olmesartan treatment significantly reduced the AUCI. Olmesartan significantly improved the insulin sensitivity index in fructose-fed rats assessed by Bergman's minimal model without affecting insulin-independent glucose disposal. Olmesartan significantly decreased plasma TG and non-esterified fatty acid levels in fructose-fed rats without affecting lipoprotein lipase mass. The TG secretion rate determined by the triton WR1339 technique was two-fold higher in fructose-fed rats, but olmesartan restored the TG secretion to a normal rate. Olmesartan did not affect plasma parameters, insulin sensitivity or TG metabolism in chow-fed rats. Olmesartan ameliorates insulin resistance and overproduction of TG in fructose-fed rats, and these effects appear to be independent of its hypotensive action.

Valsartan (is an ARB) protects against Diabetes
By Ed Susman

SAN FRANCISCO, CA -- May 19, 2005 -- A new analysis of a major clinical trial shows that hypertensive patients treated with the angiotensin receptor blocker valsartan have a reduced risk of developing diabetes compared with patients who receive the calcium channel blocker amlodipine. The findings were presented here May 17^th at the 20^th Annual Scientific Meeting and Exposition of the American Society of Hypertension.

"These new results should help physicians as they select anti-hypertensive agents for their patients, especially for those at higher risk of developing diabetes," said Kenneth Jamerson, MD, professor of internal medicine at the University of Michigan in Ann Arbor, Michigan, United States. "Since we know from other studies that other hypertension medications such as diuretics come with a higher risk of diabetes, this result is especially interesting."

In comparing valsartan (Diovan) against the calcium channel blocker amlodipine (Norvasc), Dr. Jamerson and colleagues determined that patients taking valsartan had a 23% lower risk of developing diabetes during the four or more years of the study. The two drugs had previously been shown to be roughly equivalent in reducing the risk of heart attack and stroke.

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) study enrolled 15,313 patients at 942 sites in 31 countries. Approximately 10,000 of these patients were non-diabetic at the start of the trial. All patients were hypertensive, over age 50, and at high risk for having a cardiac event.

By the end of four or more years of follow-up, 11.5% of the patients taking valsartan had developed diabetes, compared with 14.5% of patients taking amlodipine. According to Dr. Jamerson, the difference represented a relative risk reduction of 23%, and that difference reached statistical significance at the P < .0001 level.

The new in-depth analysis of data from the two groups of patients shows that the difference in diabetes onset risk appears to be attributable to valsartan and not to other underlying factors, said Dr. Jamerson.

But the researchers did determine that certain risk factors made some patients more likely to develop diabetes; the more of these risk factors a patient had, the more protective was the effect of valsartan.

Hyperglycemia, faster heart rate, high body mass index, the concurrent use of a diuretic drug and beta blocker drug, non-white race, and younger age were all associated with a higher risk of developing diabetes in all VALUE participants. But after all these variables were taken into account, patients who took valsartan had a lower chance of developing diabetes.

"We know many factors increase the risk of diabetes, but valsartan appears to be important in that it provides protection against diabetes," said Dr. Jamerson. "Many patients with hypertension are also obese and have other risk factors that predispose them to develop diabetes. This trial adds to the armamentarium that physicians can choose from when treating patients with high diabetes risk."

The trial was sponsored by Novartis, which markets Diovan.

[Presentation title: Effects of Valsartan Preventing the Development of Type 2 Diabetes in High Risk Hypertensive Patients: Analysis From the VALUE Trial.]

Efficacy and Safety of Angiotensin II Receptor Blockade in Elderly Patients With Diabetes

Wolfgang C. Winkelmayer, MD, SCD, Zhongxin Zhang, PHD, Whahnaz Shahinfar, MD, Mark E. Cooper, MD, PHD, Jerry Avorn, MD, Barry M Brenner, MD.

Conclusions- Elderly patients had the same level of benefits and risks as younger patients from treatment with losartan. Underuse of ACEI and ARB therapy in elderly because of the perceived lack of efficacy or a greater risk of adverse events appears unjustified.

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Cardiac

Vascular Remodeling

Olmesartan inhibits the expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha and improves vascular remodeling after vascular injury in mouse.
Chin J Traumatol. 2004 Feb;7(1):56-61.
PMID: 14728822 [PubMed - in process]

Heart Failure

Angiotensin II in the failing heart. Explains how elevated levels of Angiotensin II are related to clinical signs of heart failure. Angiotensin receptor blockers block production of Angiotensin II and can improve mortality rates in heart failure patients.

Do all angiotensin II type 1 receptor blockers have the same beneficial effects? Notes that ARBs have been used to block various bad effects of Angiotensin II, including heart failure and discusses how ARBs have differing molecular characteristics.

Olmesartan, a Novel Angiotensin II Receptor Type 1 Antagonist, Suppressed Cytotoxic Myocardial Injury in Autoimmune Heart Failure.
Am J Physiol Heart Circ Physiol. 2005 May 6; [Epub ahead of print]
PMID: 15879491 [PubMed - as supplied by publisher]
“Olmesartan ameliorates acute experimental autoimmune myocarditis (EAM) in rats. The cardioprotection of olmesartan may be due to suppression of inflammatory cytokines as well as to suppressive effects for cytotoxic myocardial injury in addition to the hemodynamic modifications.”

Unequal effects of renin-angiotensin system inhibitors in acute cardiac dysfunction induced by isoproterenol.
Am J Physiol Heart Circ Physiol. 2004 Dec;287(6):H2914-21. Epub 2004 Aug 5.
“In conclusion, acute LV (left ventricular) dysfunction and beta-adrenergic desensitization induced by excess isoproterenol administration were almost totally prevented by ARB (angiotensin receptor blockade) but only partially prevented by ACEI (angiotensin converting enzyme inhibitor). These differences were attributable at least in part to bradykinin pathways activated by ACEI administration in acute LV dysfunction.”

Beneficial effects of olmesartan, a novel angiotensin II receptor type 1 antagonist, upon acute autoimmune myocarditis.
Mol Cell Biochem. 2004 Apr;259(1-2):217-22.
PMID: 15124927 [PubMed - in process]

C-Reactive Protein Reduction

C-reactive protein (CRP)-lowering agents.
Cardiovasc Drug Rev. 2006 Spring;24(1):33-50. Review.
PMID: 16939632 [PubMed - indexed for MEDLINE]
"Angiotensin receptor blockers (ARBs) (valsartan, irbesartan, olmesartan, telmisartan) markedly reduce serum levels of CRP."

Antiarrhythmic

Targeting the renin–angiotensin–aldosterone system in atrial fibrillation: from pathophysiology to clinical trials
J Hum Hypertens. 2005 Nov;19(11):855-9.
PMID: 16094406 [PubMed - indexed for MEDLINE]

Old and new antiarrhythmic drugs for converting and maintaining sinus rhythm in atrial fibrillation: comparative efficacy and results of trials.
Am J Cardiol. 2003 Mar 20;91(6A):15D-26D. Review.
PMID: 12670638 [PubMed - indexed for MEDLINE]
"Some data exist suggesting that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can prevent AF [atrial fibrillation] either by preventing atrial dilation and stretch-induced arrhythmias or by blocking the renin-angiotensin system."

Myocarditis

Effect of the angiotensin II receptor blocker olmesartan on the development of murine acute myocarditis caused by coxsackievirus B3.

Clin Sci (Lond). 2006 Mar;110(3):379-86.
PMID: 16336207 [PubMed - indexed for MEDLINE]

Olmesartan significantly decreased myocardial inflammation compared with controls, whereas hydralazine significantly increased this. Olmesartan significantly decreased the expression of IFN-gamma (interferon-gamma), FasL (Fas ligand), iNOS (inducible nitric oxide synthase) and PFP (pore-forming protein) in myocardial tissue, indicating that olmesartan suppressed the activation of infiltrating killer lymphocytes. Olmesartan also decreased the expression of CVB3 genomes in myocardial tissue as well as serum levels of 8-OHdG (8-hydroxy-2'-deoxyguanosine), a biomarker of oxidative-stress-induced DNA damage. The findings suggest that olmesartan prevents myocardial damage and may improve the prognosis of patients with acute myocarditis; however, further investigations are needed before clinical use.

Atherosclerosis

Olmetec(R) Is First Angiotensin Receptor Blocker (ARB) To Suggest Atherosclerosis Regression (In Hypertensives With Cardiovascular Risk), UK

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Benicar is an antibacterial agent

Benicar is an antibacterial by binding to pathogenic proteins. It can directly activate the innate immune system, and so it is an antibacterial for that reason. Its structure is in here:
http://www.fda.gov/medwatch/SAFETY/2004/nov_PI/Benicar_Tab_PI.pdf

Benicar is an antibacterial, but not really an antibiotic.

Putative Antibacterial Mechanisms for Angiotensin II Receptor Blockers
Authors: Trevor G Marshall, PhD, Belinda Fenter, BS, and Frances E Marshall, GradDipPharm, RPh
May 9, 2004

Benicar affects 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 disprupts the bacteria themselves. Here are the first few sentences from a paper I recently wrote for an upcoming conference:

"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..

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Angiotensin Receptor Blockers: Benefits Beyond Blood Pressure Lowering?

Angiotensin II Receptor Blockade Expert Column

Michael A. Weber, MD

Medscape Cardiology. 2007; ©2007 Medscape
Posted 06/26/2007

Editor's Note
Michael A. Weber, MD, is Professor of Medicine in the Cardiology Division at the State University of New York (SUNY) Downstate Medical College of Medicine (Brooklyn, New York). Dr. Weber's main areas of interest are hypertension and preventive cardiology, and he has been involved in numerous clinical trials in patients with hypertension and those at high risk for cardiovascular events or recurrent strokes. He is also an active participant in trials involving patients with diabetic and nondiabetic nephropathy. Dr Weber currently serves on the steering committees of several national and international clinical outcomes trials. He has published numerous research articles and has authored/edited 16 books. He was one of the founders of the American Society of Hypertension (ASH) and has served as President of the Society. He has also served on the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration.

ARBs vs ACE Inhibitors
Medscape: What do we currently know about the effects of angiotensin receptor blockers (ARBs) beyond blood pressure lowering? Do we know that they differ from angiotensin-converting enzyme (ACE) inhibitors, or are ARBs just ACE inhibitors without the side effects of cough, etc?

Dr. Weber: To date it has been difficult to fully separate ARBs from ACE inhibitors. ACE inhibitors have been around almost 15-20 years longer than ARBs, so they have built up a strong list of credentials in terms of cardiovascular and metabolic effects. For example, we know that ACE inhibitors, beyond their ability to lower blood pressure, improve outcomes and survival in patients with heart failure, people with prior myocardial infarction (MI), and patients with type 1 diabetes and kidney disease. With ARBs we expect that there might be similar but potentially also different results when we analyze outcomes, because of their different mechanism of action. They act very specifically by blocking the renin-angiotensin system, and particularly by preventing angiotensin II from having its effects at the so-called AT1 receptor. ACE inhibitors, on the other hand, have a mechanism of action that is not as precise. In fact, they may only partly prevent formation of angiotensin II and so not completely block the renin-angiotensin system. On the other hand, ACE inhibitors reduce breakdown of bradykinin, which may have beneficial effects. So from a pharmacologic point of view, it is very reasonable to assume that the 2 drug classes -- ACE inhibitors and ARBs -- may produce different outcomes.

Having said all that, we now know that ARBs have very comparable beneficial effects to ACE inhibitors in patients with heart failure,^[1-5] and almost identical benefits in patients who have had an MI with residual left ventricular dysfunction.^[6] We also have very strong data with ARBs in patients with diabetic nephropathy, where we see, quite independent of their blood pressure effects, significant protection for those patients in preventing progression to end-stage renal disease.^[7-10] That is a subtle but potentially interesting difference between ACE inhibitors and ARBs: The data with ACE inhibitors were obtained in patients with type 1 diabetes and kidney disease, and now for the first time we have compelling data in patients with type 2 diabetes and kidney disease, but only in studies with ARBs.

Medscape: The studies that demonstrate the non-blood-pressure-lowering effects of ARBs have usually only been carried out with 1 or 2 drugs. Would the results of these studies hold for the entire ARB drug class?

Dr. Weber: We always assume the possibility that what is true for one ARB will be true for others. For instance, in heart failure we have definitive data with valsartan and candesartan. Valsartan was used in the Valsartan Heart Failure Trial (Val-HeFT)^[1] and candesartan in the Candesartan in Heart Failure -- Assessment of Mortality and morbidity (CHARM) trial.^[2-5] In both studies, the ARB showed significant benefits and both of these ARBs are now indicated for the treatment of heart failure. Valsartan was also shown in the Valsartan in Acute Myocardial Infarction Trial (VALIANT)^[6] to be at least as good as the ACE inhibitor captopril in patients with left ventricular dysfunction following an MI. That was really a major study; and at this point valsartan is the only ARB able to claim that kind of benefit in those patients. Other ARBs might have the same effect, but we do not have any data as of yet. So it is tempting always to talk about class effects, but at the same time one ought to be cautious.

Slowing the Progression of New-Onset Diabetes
Medscape: One effect of antihypertensive drugs that always gives rise to a lot of debate is the one on new-onset diabetes mellitus. Do ARBs really have a better protective effect than other drug classes, as suggested in a recent meta-analysis?^[11] Do we know anything about the mechanism of this effect?

Dr. Weber: I would say that at this time, both ACE inhibitors and ARBs can be said to be useful in preventing or delaying progression of nondiabetic patients into type 2 diabetes. So far, neither drug class, nor any single drug, has stood out. Most of the studies in which an ACE inhibitor or an ARB has appeared beneficial have been in comparison with drugs known to have potentially deleterious effects on progression to diabetes such as diuretics and beta-blockers. However, in a substudy of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial,^[12] valsartan was shown to be superior to the calcium channel blocker (CCB) amlodipine at preventing new-onset diabetes. This is interesting, because amlodipine itself is somewhat beneficial in terms of improving glucose metabolism, so for valsartan to be superior to amlodipine is quite noteworthy. Whether other ARBs could do the same remains to be examined.

It is important, though, that when we talk about preventing new-onset diabetes, we face the rather sad truth that these drugs are not completely preventing new-onset diabetes. It is more accurate to think of them as slowing down the rate of progression to true diabetes. So in the end, most patients destined to become diabetic will still become diabetic, but if they are taking valsartan they will do so at a later time, which, of course, is very useful, clinically and economically. The longer we can delay diabetes, the better off are our patients, and ARBs are very effective in that way.

Medscape: What will the ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial tell us about ARBs and incident diabetes?

Dr. Weber: NAVIGATOR is using the oral antidiabetic agent nateglinide and the ARB valsartan in high-risk patients with impaired glucose tolerance. The primary endpoint of the trial is the occurrence of a major cardiovascular outcome, and I think we are all hoping to be pleased by what we might see. But a key secondary endpoint of NAVIGATOR is new-onset diabetes, and that will allow us to learn whether valsartan performs the way we predict. We expect to hear the first results of NAVIGATOR in 2008.

The Importance of Long-term Follow-up
Medscape: In the recently reported Diabetes Reduction Approaches With Ramipril and Rosiglitazone Medications (DREAM) study,^[13] the use of ramipril for 3 years did not significantly reduce the incidence of diabetes in patients with impaired fasting glucose or impaired glucose tolerance over 3 years. Does this result have any implications for ARBs?

Dr. Weber: Every clinical trial inevitably seems to create its own cluster of controversies, and in the case of DREAM some people at first sight felt that the ramipril arm was something of a disappointment. There was actually a significant improvement in the patients brought into the study with so-called prediabetes (impaired glucose tolerance) back into normoglycemia; so quite a few people who appeared to have been on the brink of diabetes were rescued and returned to normal status. As far as preventing new-onset diabetes was concerned, although there was no significant benefit associated with ramipril, there was a trend in that direction. It was unfortunate that for the first year or two of the study, ramipril had no effect whatsoever in preventing new-onset diabetes; but as the study continued, the effect appeared and was getting stronger and wider with each passing month. When the study was finally stopped, the effect of the drug was not yet statistically significant, but the investigators running the study are now being criticized for stopping it too early. So there is always a story and there is always a controversy with trials; but having seen the data, I remain confident that ramipril is a useful antidiabetes drug. It may not be the best, however; there may be others, perhaps some of the ARBs, that are more effective.

Medscape: How long would a clinical trial with an ARB, or another drug, need to run to show when the effects on new-onset diabetes, diabetic nephropathy, etc, would start translating into a reduction of events?

Dr. Weber: That is such a difficult question. There was an Italian study of new-onset diabetes, not the most robust or authoritative of studies, but it indicated that the effect of new-onset diabetes on clinical events did not emerge for at least 5 years.^[14] It was only because these patients were followed for 15 years that the investigators were able to get some sense of the importance of drug-induced diabetes in hypertension in leading to events.

So I believe there is a benefit in terms of event reduction if you can prevent new-onset diabetes, but it will not be apparent within 3-5 years; it may take a long time. This is a very long-term investment and I do not think that many clinical trialists could get the support or, frankly, would have the patience to follow patients for 12-15 years to see whether preventing new-onset diabetes really does prevent events. Most of us accept that preventing diabetes will have long-term benefits, but we are not likely to see authoritative proof.

Animal Studies
Medscape: What do animal studies tell us about how ACE inhibitors or ARBs prevent diabetes? For instance, there have been studies in mice suggesting that blockade of the renin-angiotensin system affects pancreatic beta cells, etc.

Dr. Weber: That is fascinating. The renin-angiotensin system seems to mediate a number of adverse events in the islets of the pancreas, and there are at least 2 ways in which angiotensin could predispose to diabetes. First, angiotensin stimulates growth factors in the islets, such as transforming growth factor beta-1 (TGF- beta 1), that increase fibrosis in the islets, which in time has the effect of damaging and engulfing the beta cells that actually produce the insulin. Second, there seems to be a direct effect of angiotensin within the islets on the beta cells themselves, and this effect seems to hasten so-called apoptosis, the permanent death of those cells. So there are several reasons to assume that effective blockade of the renin-angiotensin system would directly support the function of the pancreas, and it has been demonstrated in animal models. It would be more difficult, obviously, to show it in humans.

Medscape: A recent animal study has suggested that another benefit of ARBs might be to prevent diabetes-associated sexual dysfunction.^[15]

Dr. Weber: That is something that needs to be explored. There have been some superficial clinical studies, including one in which valsartan was compared with atenolol. The people on valsartan reported better sexual activity, with atenolol having a negative effect.^[16]

Protecting Against Myocardial Infarction
Medscape: There has recently been a lot of discussion, some of it contentious, about the effect of ARBs and MI.

Dr. Weber: The discussion has been about whether blockers of the renin-angiotensin system are as good at preventing MIs as we would have predicted based on our knowledge of the renin-angiotensin system and our belief that it is a major contributor to coronary events. The most recently published meta-analysis of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC)^[17] concluded that ACE inhibitors are truly efficacious at preventing MIs and perhaps superior to other drug classes in doing so. Usually there are so many variables in this sort of statement, because blood pressure reductions and many other factors that could affect the likelihood of MIs must be accounted for. In the hands of this very experienced group, however, there seemed to be evidence that the ACE inhibitors are truly beneficial and perhaps more so than other classes.

So where does this leave the ARBs? There has been some concern, perhaps driven by poorly understood data from a few of the major trials, that ARBs may be less efficacious than other drug classes in preventing heart attacks.^[18-21] This has now been firmly refuted, and in their latest review the BPLTTC says quite categorically that there is no evidence whatsoever to justify any concern about ARBs, but rather that they are just as effective as any other classes of antihypertensive drugs in protecting against MIs. The group even adds that there are not yet enough data to take the analysis further and examine whether ARBs could even be superior to certain other drug classes used for treating hypertension. It is again important to recognize that the data are not yet strong enough and the experience not yet broad enough for any conclusion along those lines to be properly examined; but even so, it is promising, and ongoing studies may reveal more about this.

Important additional information in this discussion will come from the results of a very large trial, scheduled to finish at the end of 2007, which will probably be announced in March 2008. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)^[22] is a perfect study to answer the questions that we are considering here. It is a head-to-head comparison of a well-established ACE inhibitor, ramipril, which was very effective in providing survival and endpoint benefits in high-risk cardiovascular patients in the Heart Outcomes Prevention Evaluation (HOPE) trial,^[23] vs telmisartan, which is a powerful, long-acting ARB. ONTARGET is basically a repeat of the HOPE study in high-risk cardiovascular patients, but now comparing an ARB and an ACE inhibitor. That will give us fascinating information and should resolve many of these issues once and for all. ONTARGET is also examining the combination of the ACE inhibitor and the ARB, and that may turn out to be most effective at improving survival and reducing major endpoints. If so, then this sort of combination treatment may become a standard approach for people with high-risk cardiovascular status.

Medscape: With respect to the HOPE trial, there was some discussion as to whether the risk reduction seen for stroke and cardiovascular endpoints in the HOPE study were really greater than could be accounted for by the small reduction in measured blood pressure.^[24-27]

Dr. Weber: That is a very relevant point, because many people did believe and still do believe that some of the benefit of ramipril in the HOPE study was because it had a blood pressure-lowering effect, and even the authors of the study themselves have acknowledged that as much as 50% of the supposed benefit of the ACE inhibitor could be attributed to its blood pressure- lowering effects.^[28-30] Of course, there are many people who say that they do not care whether there was a blood pressure effect or not. The point is, the trial asked whether -- on top of all the other treatments that patients with high cardiovascular risk were supposed to be taking -- would adding an ACE inhibitor provide a benefit compared with adding placebo? The answer was, yes, it provided a very strong benefit. Perhaps blood pressure lowering was a part of that, but there was nothing to stop people in the placebo arm from getting whatever antihypertensive drugs they needed to help reduce their blood pressure. So if you take the point of view that this was a true intent to treat, a full exposure of patients to the best available therapies, then however ramipril worked, and however it achieved its results, it did so. The same question will come up with the ONTARGET trial, because telmisartan is probably a better blood pressure-lowering drug than ramipril. All the ONTARGET investigators have been told to ensure that they treat any hypertension effectively, so hopefully there will not be a blood pressure story to confound the results. If there is, however, I would take the view that it is largely irrelevant if there is a blood pressure inequality, because investigators were told to do everything they could to prevent this inequality. Frankly, at this point, we have to put blood pressure behind us and see what the real results are.

Expanding Indications
Medscape: What is the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trial?

Dr. Weber: TRANSCEND is a trial being done in parallel with ONTARGET, and it is an important study. It is a comparative study of an ARB, again telmisartan, vs placebo in patients who are intolerant of ACE inhibitors. So this is a situation where it was perfectly ethical in high-risk cardiovascular patients to compare an ARB with placebo. That study is also well advanced, and I believe the results will be announced later in 2008.

Medscape: What is your opinion about the effect of ARBs on diastolic dysfunction? The results of the Valsartan In Diastolic Dysfunction (VALIDD) trial,^[31,32] announced at the recent American College of Cardiology meeting, did not show any benefit for an ARB-based regimen over aggressive blood pressure lowering with a regimen of non-renin-angiotensin system-inhibiting drugs in prehypertensive adults with diastolic dysfunction, as measured by tissue Doppler imaging.

Dr. Weber: Diastolic dysfunction in difficult to study. A long-term study is needed if it is going to be events-driven, rather than just depending on studies of function. There was an intriguing finding in the CHARM-Preserved study of a borderline benefit in preventing hospitalizations for heart failure compared with placebo on top of all other treatments, although there was no mortality benefit.^[5] The currently ongoing Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE)^[33] trial, a true large-scale, robust, well-designed comparison of irbesartan with all other drugs that are not renin-angiotensin system blockers in patients with diastolic dysfunction, will be the definitive study in this area. However, the fact that diastolic dysfunction has not responded particularly well to ACE inhibitors or to ARBs up to this point leads me to suspect that the etiology of the dysfunction, which is obviously related to the abnormal tissue properties of the left ventricle, is not being driven primarily by the renin-angiotensin system. I think we are going to have to wait for some rather innovative pharmacologies to truly address what is happening in those left ventricles.

Medscape: ARBs have also been reported to have a benefit in preventing stroke.

Dr. Weber: There have been several studies on ARBs and stroke, including the Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES)^[34] trial, the Study on Cognition and Prognosis in the Elderly (SCOPE)^[35] trial, and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE)^[36,37] study. In all of these trials, an ARB was better than other drugs at preventing strokes. In the LIFE study, the ARB was compared with the beta-blocker atenolol; but even if one is skeptical about a beta-blocker as a comparator, the MOSES study, which was a small but well-conducted, relatively rigorous trial, compared an ARB with a CCB, nitrendipine, which is widely used in Europe, and which has powerful antistroke credentials of its own. Nitrendipine was the drug used, for example, in the Systolic Hypertension in Europe (Syst-Eur)^[38] trial, in which it showed dramatic benefits in stroke prevention.^[38] In MOSES, nitrendipine and the ARB eprosartan achieved identical blood pressure effects in patients who had had previous ischemia; but by the time the study was over, eprosartan was associated with a 25% relative reduction in new strokes. That raises an issue as to whether there is something special about ARBs.

Pharmacologists have hypothesized that the ARBs do not just block the renin-angiotensin system, but they do it in such a selective way that they actually enhance the effect of angiotensin on the AT2 receptor, which may have a protective effect on nerve tissue. This has been shown in animals, but whether that is a mechanism for why these drugs may have a stroke benefit in humans is another question that has yet to be explored. Of course, the ONTARGET study will address that question as well. It will be fascinating to see whether the ARB and the ACE inhibitor combination have the same stroke effects or whether one is better than the other.

Medscape: ARBs have also been associated with a reduced risk of developing new-onset atrial fibrillation.

Dr. Weber: We are tantalized at the moment by the atrial fibrillation story. We know, particularly from meta-analyses,^[39-41] that ACE inhibitors can be shown to prevent new-onset atrial fibrillation, and the same is true for ARBs.^[42-45] There were some very nice data from the LIFE study,^[42] and even though people are a little critical now of that study -- because atenolol is not regarded as an optimal comparator -- you would nonetheless assume that a beta-blocker should be effective at protecting against atrial fibrillation. Yet in that particular study, the patients who received losartan had about a one-third reduction in the incidence of new-onset atrial fibrillation. To me that was compelling information, and there are now some exciting mechanistic studies being done by electrophysiologists that seem to show that there are angiotensin receptors that activate -- or at least in some ways regulate -- the flow of cardiac electrical impulses. Such findings lead one to believe that drugs that block the renin-angiotensin system, perhaps particularly ARBs, could potentially be good anti-atrial fibrillation drugs. We are a long way off from making such a strong assertion, but it is a beguiling thought.

Dosing and Future Outlook

Medscape: If patients were to benefit from all these non-blood-pressure-lowering effects of ARBs, would the highest approved dose be sufficient, or do you think that they would need an even higher dose?

Dr. Weber: This is a difficult issue. With all these drugs, not only the ARBs, but also the ACE inhibitors, the CCBs, etc, we tend to achieve some sort of a belief in doses based on the first major indication for which these drugs are tested, which is often hypertension. So we learn what the best doses for ACE inhibitors and ARBs are for treating high blood pressure, and we assume that when we have reached a dose of drug beyond which you get no further reduction in blood pressure, that we have maximized the dose range. That is correct, but only for high blood pressure. There may be a totally different dose range needed to protect the kidney or to protect the myocardium. For instance, as far as the kidney is concerned, if we use the so-called maximum dose of an ARB and measure its effect on proteinuria, we will typically see about a one-third reduction in proteinuria. With so-called super doses, however, such as valsartan 640 mg instead of 160 mg or 320 mg, even though there is no further reduction in blood pressure, there is a significant further reduction in proteinuria. Likewise with irbesartan: Instead of stopping at 300 mg, if we go to 600 mg and 900 mg we see better and better proteinuria effects. So this is teaching us that just because we have reached the maximum dose for blood pressure, it does not mean that we have reached the maximum dose for what these drugs might do at other tissues, regulating other cardiovascular outcomes of interest.

Medscape: How will physicians prescribing for blood pressure control feel about these additional benefits? Maybe they do not have enough time to worry about them because they just want to get the blood pressure down to targets with the approved doses?

Dr. Weber: Your statement is absolutely accurate at the moment. The doctor treating high blood pressure will be satisfied when the blood pressure is brought under control. If there is some reason to suspect that other things are going on, such as kidney involvement or heart failure, then there might be a reason to think about alternatives. No one has done definitive studies with "super dosing" of the ARBs or the ACE inhibitors. It is a pity, because these drugs are well tolerated and it would probably be possible to go up to 2, 4, 8, or even 12 times what is now regarded as the top dose without producing major adverse effects. However, we do not have that information as yet, and so it is not possible to advise administering any dose in excess of what is currently the maximum recommended dose.

Medscape: When do you think we will have answers about these benefits beyond blood pressure lowering with ARBs?

Dr. Weber: It is an exciting time at the moment and a good time to raise these questions. I predict that by the end of 2008 we will know a lot more about these effects of ARBs.

Supported by an independent educational grant from Novartis

References

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Pfeffer MA, McMurray JJ, Velazquez EJ, et al; Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-1906. Abstract
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Parving H-H, Lehnert H, Bröchner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-878. Abstract
Viberti G, Wheeldon NM; MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672-678. Abstract
Elliott WJ, Meyer PM. Incidence diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:201-207. Abstract
Kjeldsen SE, Julius S, Mancia G, et al; VALUE Trial Investigators. Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: the VALUE trial. J Hypertens. 2006;24:1405-1412. Abstract
The DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551-1562. Abstract
Verdecchia P, Reboldi G, Angeli F, et al. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension. 2004;43:963-969. Abstract
Nomura M, Nishii H, Ozaki Y, et al. An angiotensin II receptor blocker increases sexual behavior in type 2 diabetic mice. Physiol Behav. 2007;91:223-228. Abstract
Fogari R, Preti P, Derosa G, Marasi G, et al. Effect of antihypertensive treatment with valsartan or atenolol on sexual activity and plasma testosterone in hypertensive men. Eur J Clin Pharmacol. 2002;58:177-180. Abstract
Blood Pressure Lowering Treatment Trialists' Collaboration; Turnbull F, Neal B, Pfeffer M, et al. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25:951-958. Abstract
Strauss MH, Verma S. Inhibition of the reninangiotensin system in cardiovascular protection: is it important to watch your C'ARB' intake? Can J Cardiol. 2005;21:577-580.
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Staessen JA, Thijs L, Birkenhager WH. VALUE: analysis of results. Lancet. 2004;364:931.
Verdecchia P, Angeli F, Gattobigio R, Reboldi G. Do angiotensin II receptor blockers increase the risk of myocardial infarction. Eur Heart J 2005;26:2381-2386.
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Muhlhauser I. Blood pressure and cardiovascular risk in the HOPE study. Lancet. 2002;359:2118. [Letter] Abstract
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Sleight P, Pogue J, Yusef S. Blood pressure and cardiovascular risk in the HOPE study. Author's reply. Lancet. 2002;359:2118.
Conundrum of the HOPE study: Time of taking ramipril may account for lack of relation between blood pressure and outcome. BMJ. 2003;327:681-682.
Svensson P, de Faire U, Sleight P, et al. Comparative effects of ramipril on ambulatory and office blood pressures: A HOPE substudy. Hypertension. 2001;38;28-32.
Sleight P, Yusuf S, Pogue J, et al. Blood pressure reduction and cardiovascular risk in HOPE study. Lancet. 2001;358: 2130-2131. Abstract
Bosch J, Yusuf S, Pogue J, et al. Effect of ramipril in preventing stroke: double blind randomised trial. BMJ. 2002;324:699-702. Abstract
Janardhanan R, Daley WL, Naqvi TZ, et al. Rationale and design: The VALsartan In Diastolic Dysfunction (VALIDD) Trial: Evolving the management of diastolic dysfunction in hypertension. Am Heart J. 2006;152:246-252. Abstract
Solomon SD, Janardhanan R, Verma R, et al. The influence of angiotensin receptor blockers and blood pressure lowering on diastolic function in patients with hypertension and diastolic dysfunction. Program and abstracts of ACC.07: 56th Scientific Session of the American College of Cardiology. Late-Breaking Clinical Trials I. Abstract 402-11.
Schrader J, Luders S, Kulschewski A, et al; MOSES Study Group. Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. 2005;36:1218-1226. Abstract
Lithell H, Hansson L, Skoog I, et al; SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875-886. Abstract
Dahlof B, Devereux RB, Kjeldsen SE, et al; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003. Abstract
Kizer JR, Dahlöf B, Kjeldsen SE, et al. Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the Losartan Intervention For Endpoint reduction in hypertension study. Hypertension. 2005;45:46-52. Abstract
Staessen JA, Fagard R, Thijs L, et al; The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757-764. Abstract
Carson P, Massie BM, McKelvie R, et al; for the I-PRESERVE Investigators. The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design. J Card Fail. 2005;11:576-585. Abstract
Madrid AH, Peng J, Javier Zamora J, et al. The role of angiotensin receptor blockers and/or angiotensin converting enzyme inhibitors in the prevention of atrial fibrillation in patients with cardiovascular diseases. Pacing Clin Electrophysiol. 2004;27:1405-1410. Abstract
Healey JS, Baranchuk A, Crystal E, Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol. 2005;45:1832-1839. Abstract
Anand K, Mooss AN, Hee TT, Mohiuddin SM. Meta-analysis: inhibition of renin-angiotensin system prevents new-onset atrial fibrillation. Am Heart J. 2006;152:217-222. Abstract
Wachtell K, Hornestam B, Lehto M, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: The Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol. 2005;45:712-719. Abstract
Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: Results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J. 2005;149:548-557. Abstract
Ducharme A, Swedberg K, Pfeffer MA, et al; CHARM Investigators. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J. 2006;152:86-92. Abstract
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Michael A. Weber, MD, Professor of Medicine, Cardiology Division, State University of New York (SUNY) Downstate Medical College of Medicine, Brooklyn, New York

Disclosure: Michael Weber, MD, has disclosed that he has served as a consultant for Boehringer Ingelheim, Daiichi-Sankyo, Forest, Gilead, Merck & Co., Inc., Novartis, and Takeda. Dr. Weber has also disclosed that he was a speaker for Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Forest, GlaxoSmithKline, Merck & Co., Inc., Novartis, Pfizer, and sanofi-aventis.

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Posted: Fri Feb 1st, 2008 06:08

(filelink)
New Data Show Olmesartan, An Angiotensin Receptor Blocker (ARB) Has Significant Anti-atherosclerotic And Vascular Protective

Article Date: 06 Sep 2007 - 3:00 PST
From: Medical News Today Online

Vascular protection data presented at the European Society of Cardiology's (ESC) 2007 Annual Congress in Vienna have shown that Daiichi-Sankyo's angiotensin-receptor blocker (ARB), olmesartan, can prevent and reverse atherosclerotic processes including: oxidative stress,1 endothelial inflammation,2 remodelling of cardiac vascular tissues,3,4 development of atherosclerotic lesions5 and reduction of large plaques.6,7 These additional vascular protective effects appear to be independent of olmesartan's blood-pressure-reducing function.6,7

The Multicentre Olmesartan Atherosclerosis Regression Evaluation (MORE) study6,7 sought to clarify whether two-year treatment with olmesartan could reverse atherosclerotic plaque progression, and used the beta-blocker, atenolol, as a direct comparator. Preliminary findings look set to show:

-- in patients with larger plaque volumes olmesartan can significantly reduce plaque volume compared to atenolol
-- olmesartan's regressive effects could be evident from week 28 onwards
-- blood pressure reductions are similar in both groups

Olmesartan's vascular protective effects have also been assessed in a series of previous clinical studies including EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis (EUTOPIA) study8 and Vascular Improvement with Olmesartan Medoxomil Study (VIOS).4

EUTOPIA showed that olmesartan produced significantly greater reductions in inflammatory atherosclerosis markers after 6 weeks compared with placebo.8 VIOS showed that olmesartan can reverse the hypertension-associated changes in small vascular structure compared with atenolol. After one year of treatment, olmesartan reduced the wall:lumen ratio of small resistance arteries from baseline (14.9%) to a value (11.1%) similar to that seen in a group of normotensive control patients (11.0%).4

Professor Enrico Agabiti-Rosei, Department of Medical and Surgical Sciences, University of Brescia, Italy, and one of the MORE study lead investigators said: "The olmesartan portfolio of vascular protective studies including EUTOPIA and VIOS show that in patients with hypertension, olmesartan is not only highly effective in reducing blood pressure but it appears also to possess additional cardiovascular protection. The MORE study shows that olmesartan is the first ARB to significantly reduce large atherosclerotic plaque volume. In light of published data and preliminary MORE study findings, olmesartan's additional vascular protective benefits should be considered seriously when prescribing an anti-hypertensive agent in patients with vascular damage."

About CVD

Annually, nearly 50 per cent of all deaths in Europe are due to cardiovascular disease (CVD).9 Atherosclerosis, or the formation of plaques, is a clear risk factor of CVD and it is believed that atherosclerosis and thrombosis leading to blockage of cardiac and cerebral arteries are the main causes of cardiovascular events.10

About Olmesartan

Olmesartan medoxomil, Olmetec, is an orally active, selective angiotensin II receptor (type AT1) antagonist, which is one of a class of agents known more commonly as angiotensin-receptor blockers (ARBs). Olmetec is indicated for the treatment of essential hypertension (hypertension with no readily identifiable cause).11 In clinical trials, Olmetec showed a placebo like side-effect profile. Clinical indications for Olmetec may vary from one country to another.

About Daiichi-Sankyo

Through the merger of two major pharmaceutical companies with Japanese origin, completed in April 2007, Daiichi-Sankyo has strengthened its position as the number one pharmaceutical company by sales in Japan and as one of the 20 leading global pharmaceutical concerns.12 On the way to become a "Global Pharma Innovator", the business strategy is to focus on the company's research activities to develop and commercialise innovative first and/or best in class products.

The current Daiichi-Sankyo product range is focused on the treatment of cardiovascular diseases and diabetes.

Daiichi-Sankyo facts

Number one pharmaceutical company by sales in the Japanese market. First company to develop a statin for hyperlipidaemia. First company to develop a glitazone for diabetes. 6,4 billion of worldwide net sales. 17 % global net sales invested in R&D. One of the 20 leading global pharmaceutical companies. 15,400 employees around the world. 1,800 employees in Europe.

http://www.daiichi-sankyo.eu

References

1. Tsuda M, Iwai M et al. Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress. Hypertension. 2005;45(4):545-51. Epub 2005 Feb 21

2. Takai S, Kim S et al. Mechanisms of angiotensin II type 1 receptor blocker for anti-atherosclerotic effect in monkeys fed a high-cholesterol diet. J Hypertens. 2003;21(2):361-9

3. Min LJ, Mogi M et al. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ Res. 2005;97(5):434-42.Epub 2005 Aug 4

4. Smith RD, Yokoyama H et al. The protective effects of angiotensin II blockade with olmesartan medoxomil on resistance vessel remodelling (VIOS study): rationale and baseline characteristics. Am J Cardiovasc Drugs. 2006;6(5):335-42

5. Kato M, Sada T et al. Severity of hyperlipidemia does not affect antiatherosclerotic effect of an angiotensin II receptor antagonist in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 2006;47(6):764-9

6. Agabiti-Rosei E. Proving effects beyond blood pressure lowering on vascular protection. Satellite symposium presentation held during the ESC Congress 1-5 Sept 2007

7. Stumpe KO. J Hypertens 2006; 24(Suppl.6): 414

8. Fliser D, Buchholz K et al. Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation 2004;110(9):1103-7.Epub 2004 Aug 16

9. European Heart Network. CVD Statistics. Statistical data about cardiovascular disease in Europe. Available at http://www.ehnheart.org/content/sectionintro.asp?level0=1457. Accessed August 2007

10. National Heart, Lung, and Blood Institute. Diseases and Conditions: Atherosclerosis. Available here. Accessed on 22 August 2007

11. Olmetec film-coated tablets SPC. Last updated 14 November 2006. Available here.Accessed August 2007

12. IMS Midas 2006

Olmetec(R) Is First Angiotensin Receptor Blocker (ARB) To Suggest Atherosclerosis Regression (In Hypertensives With Cardiovascular Risk), UK

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Posted: Wed Apr 23rd, 2008 01:20