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Health Maintenance and Olmesartan

with additional studies

Clinical studies have demonstrated that some antihypertensive agents provide renoprotection independent of BP lowering. 1)

Although uncontrolled confounding might still exist, (this was a short term study) olmesartan does not seem to increase cardiovascular risk compared with losartan. 2)

The ROADMAP study will answer the question whether an ARBA drug which is an angiotensin receptor blocker. One of the ARBs is olmesartan (Benicar). Not all ARBs activate the Vitamin D Receptor. can prevent or delay the onset of microalbuminuria and whether this translates into protection against cardiovascular events and renal disease. 3)

Benefits of RAS blockade with olmesartan treatment are sustained after study discontinued. 4)

Olmesartan and Bay11-7082 inhibit the MCF-7 cells growth indicating RAS and NF-kappaBA protein that stimulates the release of inflammatory cytokines in response to infection pathway blockade lead to cytotoxicity and apoptosis induction against tumour cells. (in breast cancer)5)

Data demonstrate potential benefits of reducing the heart rate of type 2 diabetes patients, and indicate that olmesartan could, in particular, reduce the risk of microalbuminuria in patients with low heart rate. 6)

Administration of olmesartan suppressed the accumulation of macrophages in brachiocephalic atherosclerotic plaque. (in mice) 7)

Olmesartan significantly reduced myocardial infarct size and improved LV contractility at a dose (3 mg/kg) with systemic vasodilating effects but not at a lower dose (0.3 mg/kg) without hemodynamic effects.(in rat) 8)

Olmesartan medoxomil reverses left ventricle hypertrophy and reduces inflammatory cytokineAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. IL-6 in the renovascular hypertensive rats. 9)

Replacing candesartan with olmesartan decreased LVMI in association with a sustained decrease of plasma Ang II over a 12-month period without changing blood pressure or plasma aldosterone in patients with essential hypertension. 10)

Inhibition of renin-angiotensin system attenuates periadventitial inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. and reduces atherosclerotic lesion formation. 11)

Therapeutic and supratherapeutic OLM doses had no clinically significant effect on cardiac repolarization and were well tolerated. 12)

In conclusion, there is no robust signal for harm with olmesartan use. 13)

General research on aging

Holistic vitamin D supplementation with or without calcium is unlikely to be an effective primary prevention strategy for falls or fracture. There has also been high-quality evidence that vitamin D, daily or as a bolus, does not reduce the risk of cardiovascular events. 14)

When using off-label Olmesartan, patients are observed to need fewer other pharmaceutical preparations to maintain and improve health status. Falls studies have determined that taking ≥ 4 drugs is associated with an increased incidence of falls, recurrent falls, and injurious falls. 15)

Some of the documented protective effects of ARBs

include the ability to:

  • decrease the incidence and progression of Alzheimer's disease and dementia16)
  • prevent migraines17)
  • inhibit liver fibrosis and aid liver healing18)
  • reduce insulin resistance in rats19)
  • 6 mg/kg olmesartan reduces the inflammatory process and bone loss in rats20)
  • protect the mitochondria from age-associated damage from oxidation21)
  • play a protective role against proliferative diabetic retinopathy 22)
  • reduce liver fibrosis23)
  • treatment of anxiety and stress-related disorders24)
  • reduce oxidative damage25) and limit aging 26) 27)

Olmesartan and other ARBs have been used

to block various bad effects of Angiotensin II, including heart failure. In this regard, olmesartan has been shown to:

  • protect the heart from damage from inflammation in myocarditis28)
  • prevent acute left ventricular dysfunction30)
  • lower C-reactive protein, one of the acute phase proteins that increase during systemic inflammation31)
  • act as an antiarrhythmic32)
  • block the production of Angiotensin II, thus improving mortality rates in heart failure patients33)
  • This study demonstrated that 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. 34)
  • Conclusion: In the present study, left ventricular hypertrophy and on arterial compliance were inhibited by a decrease in angiotensin II and aldosterone due to the change-over to olmesartan. In the future, protective effects on organs will be clarified by long-term observations. 35) 36)

Dosage

80mg single dose vs 6hrlydosing
4 hourly compared to 6 hourly dosing

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

In rats, Olmesartan at 6 mg/kg optimally reduced the inflammatory process and bone loss37). That would be 9-10 tablets of Olmetec daily for a 64 Kg human

Olmesartan has also been shown to

  • prevent or delay left ventricular remodeling and hypertrophy in patients with type 2 diabetes 38)
  • reduce the volume of atherosclerotic plaques39) 40)
  • mildly reduce the risk of stroke in people at high risk for strokes (cerebrovascular events).41)
  • significantly remodel and destiffen the arterial wall material during long-term treatment 42)

A number of studies have found

that olmesartan possesses various ways of protecting the kidneys from the effects of inflammation and cytokine damage:

  • in circadian rhythms between HR and MAP in CKD: Synchronization between the two rhythms was progressively lost as renal function deteriorated, and Olmesartan partly restored the synchronization 43)
  • in hypertensive patients with CKD, olmesartan add-on therapy improves the ambulatory BP profile via a preferential reduction in nighttime BP with concomitant renal injury inhibition 44)
  • results suggest olmesartan can help decrease plasma AGE levels in patients on Hemodialysis 45)
  • renal protective effects of olmesartan may be better than those of other ARBs 46)
  • olmesartan may uniquely increase urinary ACE2 level, which could offer additional renoprotective effects 47)

Studies also showed

  • treatment with olmesartan inhibited bone loss 48)
  • olmesartan protects endothelial cells against oxidative stress-mediated cellular injury 49)
  • decreases viability of malignant cell lines50)
  • carotid IMT and BP decreased similarly with olmesartan and atenolol; but only olmesartan reduced the volume of larger atherosclerotic plaques 51)
  • improvement of Plasma Biomarkers after switching stroke patients from other Angiotensin II Type I Receptor Blockers to Olmesartan 52)
  • improvement of glycemic control & insulin resistance was only observed in olmesartan group 53)
  • OLM substantially delayed the development of left ventricular remodeling in type 2 diabetes 54)
  • prevention of microalbuminuria in patients with type 2 diabetes and hypertension 55)

Long term treatment

Patients receiving the highest dose of olmesartan (40 and 80 mg) had an inward carotid remodeling and were shifted toward a lower elastic modulus at a given circumferential wall stress, indicating an improvement in the intrinsic elastic properties of the carotid artery wall material. These data suggest that 40 and 80 mg olmesartan were able to significantly remodel and destiffen the arterial wall material during long-term treatment, partly independently of blood pressure, compared with 20 mg.

hyper.ahajournals.org/content/early/2014/07/07/HYPERTENSIONAHA.114.03282.reprint 56)

1)
Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering.
Izuhara Y, Nangaku M, Inagi R, Tominaga N, Aizawa T, Kurokawa K, van Ypersele de Strihou C, Miyata T
J Am Soc Nephrol16p3631-41(2005 Dec)
3)
Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.
Haller H, Viberti GC, Mimran A, Remuzzi G, Rabelink AJ, Ritz E, Rump LC, Ruilope LM, Katayama S, Ito S, Izzo JL Jr, Januszewicz A
J Hypertens24p403-8(2006 Feb)
6)
The Effect of Resting Heart Rate on the New Onset of Microalbuminuria in Patients With Type 2 Diabetes: A Subanalysis of the ROADMAP Study.
Schmieder RE, Bramlage P, Haller H, Ruilope LM, Böhm M
Medicine (Baltimore)95pe3122(2016 Apr)
7)
AT1 blockade attenuates atherosclerotic plaque destabilization accompanied by the suppression of cathepsin S activity in apoE-deficient mice.
Sasaki T, Kuzuya M, Nakamura K, Cheng XW, Hayashi T, Song H, Hu L, Okumura K, Murohara T, Iguchi A, Sato K
Atherosclerosis210p430-7(2010 Jun)
10)
Comparison of the long-term effects of candesartan and olmesartan on plasma angiotensin II and left ventricular mass index in patients with hypertension.
Tsutamoto T, Nishiyama K, Yamaji M, Kawahara C, Fujii M, Yamamoto T, Horie M
Hypertens Res33p118-22(2010 Feb)
12)
A thorough QTc study demonstrates that olmesartan medoxomil does not prolong the QTc interval.
Mendell J, Matsushima N, O'Reilly TE, Lee J
J Clin Pharmacol56p484-91(2016 Apr)
14)
The vitamin D and calcium controversy: an update.
Lewis JR, Sim M, Daly RM
Curr Opin Rheumatolp(2018 Dec 27)
16)
Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis.
Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B
BMJ340pb5465(2010 Jan 12)
17)
Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial.
Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G
JAMA289p65-9(2003 Jan 1)
20) , 37)
Olmesartan decreases IL-1β and TNF-α levels; downregulates MMP-2, MMP-9, COX-2, and RANKL; and upregulates OPG in experimental periodontitis.
Araújo AA, Lopes de Souza G, Souza TO, de Castro Brito GA, Sabóia Aragão K, Xavier de Medeiros CA, Lourenço Y, do Socorro Costa Feitosa Alves M, Fernandes de Araújo R Jr
Naunyn Schmiedebergs Arch Pharmacol386p875-84(2013 Oct)
21)
Enalapril and losartan attenuate mitochondrial dysfunction in aged rats.
de Cavanagh EM, Piotrkowski B, Basso N, Stella I, Inserra F, Ferder L, Fraga CG
FASEB J17p1096-8(2003 Jun)
22)
Olmesartan blocks advanced glycation end products (AGEs)-induced angiogenesis in vitro by suppressing receptor for AGEs (RAGE) expression.
Yamagishi S, Matsui T, Nakamura K, Inoue H, Takeuchi M, Ueda S, Fukami K, Okuda S, Imaizumi T
Microvasc Res75p130-4(2008 Jan)
23)
Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis.
Oakley F, Teoh V, Ching-A-Sue G, Bataller R, Colmenero J, Jonsson JR, Eliopoulos AG, Watson MR, Manas D, Mann DA
Gastroenterology136p2334-2344.e1(2009 Jun)
24)
Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists.
Saavedra JM, Ando H, Armando I, Baiardi G, Bregonzio C, Juorio A, Macova M
Regul Pept128p227-38(2005 Jun 30)
25)
Effect of olmesartan on oxidative stress in hypertensive patients: mechanistic support to clinical trials derived evidence.
Cal LA, Maso LD, Caielli P, Pagnin E, Fusaro M, Davis PA, Pessina AC
Blood Press20p376-82(2011 Dec)
26)
Angiotensin receptors as determinants of life span.
Cassis P, Conti S, Remuzzi G, Benigni A
Pflugers Arch459p325-32(2010 Jan)
27)
Role of renin-angiotensin system in inflammation, immunity and aging.
Capettini LS, Montecucco F, Mach F, Stergiopulos N, Santos RA, da Silva RF
Curr Pharm Des18p963-70(2012)
29)
Olmesartan, a novel AT1 antagonist, suppresses cytotoxic myocardial injury in autoimmune heart failure.
Yuan Z, Nimata M, Okabe TA, Shioji K, Hasegawa K, Kita T, Kishimoto C
Am J Physiol Heart Circ Physiol289pH1147-52(2005 Sep)
30)
Unequal effects of renin-angiotensin system inhibitors in acute cardiac dysfunction induced by isoproterenol.
Ohta T, Hasebe N, Tsuji S, Izawa K, Jin YT, Kido S, Natori S, Sato M, Kikuchi K
Am J Physiol Heart Circ Physiol287pH2914-21(2004 Dec)
31)
C-reactive protein (CRP)-lowering agents.
Prasad K
Cardiovasc Drug Rev24p33-50(2006 Spring)
33)
Angiotensin II in the failing heart. Short communication.
Schulz R, Heusch G
Kidney Blood Press Res28p349-52(2005)
38) , 54)
Prevention of electrocardiographic left ventricular remodeling by the angiotensin receptor blocker olmesartan in patients with type 2 diabetes.
Raff U, Ott C, Ruilope LM, Menne J, Haller H, Schmieder RE
J Hypertens32p2267-76; discussion 2276(2014 Nov)
39) , 51)
Carotid intima-media thickness and plaque volume changes following 2-year angiotensin II-receptor blockade. The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study.
Stumpe KO, Agabiti-Rosei E, Zielinski T, Schremmer D, Scholze J, Laeis P, Schwandt P, Ludwig M
Ther Adv Cardiovasc Dis1p97-106(2007 Dec)
40)
Impact of olmesartan on progression of coronary atherosclerosis a serial volumetric intravascular ultrasound analysis from the OLIVUS (impact of OLmesarten on progression of coronary atherosclerosis: evaluation by intravascular ultrasound) trial.
Hirohata A, Yamamoto K, Miyoshi T, Hatanaka K, Hirohata S, Yamawaki H, Komatsubara I, Murakami M, Hirose E, Sato S, Ohkawa K, Ishizawa M, Yamaji H, Kawamura H, Kusachi S, Murakami T, Hina K, Ohe T
J Am Coll Cardiol55p976-82(2010 Mar 9)
41)
A systematic review of angiotensin receptor blockers in preventing stroke.
Lu GC, Cheng JW, Zhu KM, Ma XJ, Shen FM, Su DF
Stroke40p3876-8(2009 Dec)
43)
Angiotensin receptor blockers regulate the synchronization of circadian rhythms in heart rate and blood pressure.
Sato R, Mizuno M, Miura T, Kato Y, Watanabe S, Fuwa D, Ogiyama Y, Tomonari T, Ota K, Ichikawa T, Shirasawa Y, Ito A, Yoshida A, Fukuda M, Kimura G
J Hypertens31p1233-8(2013 Jun)
44)
The angiotensin II type 1 receptor blocker olmesartan preferentially improves nocturnal hypertension and proteinuria in chronic kidney disease.
Yanagi M, Tamura K, Fujikawa T, Wakui H, Kanaoka T, Ohsawa M, Azushima K, Maeda A, Kobori H, Umemura S
Hypertens Res36p262-9(2013 Mar)
47)
Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker.
Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, Shibata S, Tanaka M, Watanabe Y, Akasaka H, Ohnishi H, Yoshida H, Takizawa H, Saitoh S, Ura N, Shimamoto K, Miura T
Am J Hypertens28p15-21(2015 Jan)
48)
Effect of angiotensin II receptor blocker, olmesartan, on turnover of bone metabolism in bedridden elderly hypertensive women with disuse syndrome.
Aoki M, Kawahata H, Sotobayashi D, Yu H, Moriguchi A, Nakagami H, Ogihara T, Morishita R
Geriatr Gerontol Int15p1064-72(2015 Aug)
49)
Olmesartan protects endothelial cells against oxidative stress-mediated cellular injury.
Kadowaki D, Anraku M, Sakaya M, Hirata S, Maruyama T, Otagiri M
Clin Exp Nephrol19p1007-14(2015 Dec)
50)
The role of ROS and NF-κB pathway in olmesartan induced-toxicity in HeLa and mcf-7 cell lines.
Bakhtiari E, Hosseini A, Mousavi SH
Biomed Pharmacother93p429-434(2017 Sep)
52)
Improvement of Plasma Biomarkers after Switching Stroke Patients from Other Angiotensin II Type I Receptor Blockers to Olmesartan.
Tada Y, Yagi K, Uno M, Matsushita N, Kanematsu Y, Kuwayama K, Shimada K, Nishi K, Hirasawa M, Satomi J, Kitazato KT, Kageji T, Matsuura E, Nagahiro S
J Stroke Cerebrovasc Dis24p1487-92(2015 Jul)
55)
Prevention of microalbuminuria in patients with type 2 diabetes and hypertension.
Menne J, Izzo JL Jr, Ito S, Januszewicz A, Katayama S, Chatzykirkou C, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G, Haller H
J Hypertens30p811-8; discussion 818(2012 Apr)
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