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Olmesartan is the best solution Unique Olmesartan Property Olmesartan 40mg Organ Protection

Hypertension Vol. 62(3):444-449 August 14, 2013 The components of the renin–angiotensin–aldosterone system and the multiple redundant pathways for generating angiotensin II (Ang II). ACE2 indicates angiotensin-converting enzyme 2; AGTG, angiotensinogen; AMN, aminopeptidases (angiotensinases); AT-1 and AT-2, type I and type II angiotensin II receptors; Chym, chymase; mas, receptor for Ang 1-7; NEP, neutral endopeptidase (neprilysin); PEP/PCP, prolyl endopeptidase and prolyl carboxypeptidase; and (P)RR, prorenin receptor.

Unique effect of Olmesartan on plasma Ang II levels in hypertensive patients Ichikawa S. Hypertens Res 2001; 24:641-646)

The metabolism of Angiotensin II ACE Angiotensin I Angiotensin II ACE2 Angiotensin-(1-7) Angiotensin II會被ACE2代謝成Angiotensin (1-7)，2005年，Ferrario教授指出，olmesartan可以加速ACE2的作用。 Angiotensin (1-7)又有甚麼作用呢？ 註： Angiotensin I 由 10個胜肽組成 (angiotensin 1- 10) Angiotensin II 由 8個胜肽組成 (angiotensin 1- 8) Ferrario et al. Am J Physiol Heart Circ Physiol 289: H2281-H2290，2005

Olmesartan up-regulate ACE2 Angiotensin-(1-5) ACE Angiotensin I Angiotensin II ACE2 Angiotensin-(1-7) Angiotensin II會被ACE2代謝成Angiotensin (1-7)，2005年，Ferrario教授指出，olmesartan可以加速ACE2的作用。 Angiotensin (1-7)又有甚麼作用呢？ 註： Angiotensin I 由 10個胜肽組成 (angiotensin 1- 10) Angiotensin II 由 8個胜肽組成 (angiotensin 1- 8) AT1-R Ferrario et al. Am J Physiol Heart Circ Physiol 289: H2281-H2290，2005

Hypertension Vol. 62(3):444-449 August 14, 2013 The components of the renin–angiotensin–aldosterone system and the multiple redundant pathways for generating angiotensin II (Ang II). ACE2 indicates angiotensin-converting enzyme 2; AGTG, angiotensinogen; AMN, aminopeptidases (angiotensinases); AT-1 and AT-2, type I and type II angiotensin II receptors; Chym, chymase; mas, receptor for Ang 1-7; NEP, neutral endopeptidase (neprilysin); PEP/PCP, prolyl endopeptidase and prolyl carboxypeptidase; and (P)RR, prorenin receptor.

Opposing effects of Angiotensin-(1-7)  PAI-1/ thrombosis Vasodilation Ang-(1-7)  Platelet aggregation Reduce SNS activity  Superoxide production Anti-proliferative No effect on Aldosterone  Myocyte growth  Collagen Angiotensin (1-7)的作用非常類似Angiotensin II與AT2 receptor結合後的效果，對於血管有擴張的作用，也具有抗發炎、改善內皮細胞的功能等等的降血壓與血管保護作用。 所以，隨著RAA system研究的不斷發現，我們可以更明白olmesartan確實是與眾不同的ARB。 Vasopressin  Endothelin Reverse Remodeling 必 SNS = Sympathetic nervous system Ferrario et al. Am J Physiol Heart Circ Physiol 289: H2281-H2290，2005

Vascular protection effect by Olmesartan Anti-inflammatory Olmesartan 40 mg Vascular Protection Anti-Atherosclerosis Vascular Hypertrophy Angiotensin II本身就是發炎物質，而atheroslerosis可視為一個發炎反應的過程。因此身為AT1R blocker且還能促進angiotensin Ⅱ代謝的olmesartan自然就具備了心血管保護的作用。 從EUTOPIA實驗中我們看到了olmesartan可降低inflammatory marker的產生。 VIOS實驗中，olmesartan 加到40mg的情況下，我們看到了血管壁的異常增厚減少了。 MORE study中，olmesartan具有獨立於降壓能力之外的減少plaque volume的功能。 OLIVUS實驗中，我們也看到了olmesartan帶來的atheroma regression的現象。 由於olmesartan這樣的特性，減少了atheroma，在OLIVUS 4 year extension中，我們還看到了olmesartan組重大心血管事件的減少! 效果甚至比statin的使用更好。 Atheroma Regression 必

2 4 6

2046 2 – Double chain domain 0 – 0 AT1 Activation 4 – 4 binding sites 6 – Best BP Lowering efficacy beyond other 6 ARBs

2046 2 – Double chain domain 0 – 0 AT1 Activation 4 – 4 binding sites 6 – Best BP Lowering efficacy beyond other 6 ARBs

Chemical Structure of ARBs Losartan Exp3174 Valsartan Imidazole C l C l N O N CH OH 2 COOH N COOH N N Biphenyl N N Tetrazole N N N N N N H N H N N H N Candesartan Olmesartan Hydroxyl 談到Olmetec的降壓能力必須從結構談起, 我們知道結構上的小小差異會影響到藥物動力學和葯效學上的改變 簡單的向各位醫師報告一下ARB間結構的不同 Tetrazole是ARB的基本配備, 有Carboxyl side chain的ARB結合力會強一些, 所以<我們知道 losartan因為有了 Exp 3174這個活性代謝物, 所以降壓能力才能追上Valsartan Olmetec就不一樣了, 多了Hydroxyl side chain. 這就是本公司一直強調的”Olmetec獨特的雙鍵結構 (double chain domain)” 日本的 Miura教授的研究指出, Olmetec除了一般ARB所擁有的carboxyl group之外, 其所特有的hydroxyl group可以與AT1 receptor結合更鞏固, 而且可以對AT1 receptor發生反向催化的作用, 因此, 降壓效果最為顯著 O H N N a-carboxyl COOH M e O COOH M e N N N N N N N N H N N H Miura S, et al. Curr Hypertens Rev. 2005

decreases Inverse Agonist effect Lack of Hydroxyl Group decreases Inverse Agonist effect 　 Double-Chain Domain is important for inverse agonism (%) IP Production of AT1-F11A/N111G Mutant Receptor 120 （Marker of Endogenous Activation） * : P<0.05 vs Olmesartan w/o OH 100 80 Inositol phosphate production * 60 40 20 這個比較更有趣 Miura教授將 Olmetec結構中的 –OH拿掉, 果然, Inverse agonist的作用就消失了 再次證明Hydroxyl group (-OH)側枝才是Inverse agonist作用的關鍵 所以Inverse agonist的作用是 Olmetec所特有的 None Olmesartan Olmesartan w/o OH N COOH H OH M e CH 3 N COOH H M e CH 3 -OH Miura S et al.:JBC 281(28):19228 - 19295,2006

2046 2 – Double chain domain 0 – 0 AT1 Activation 4 – 4 binding sites 6 – Best BP Lowering efficacy beyond other 6 ARBs

2046 2 – Double chain domain 0 – 0 AT1 Activation 4 – 4 binding sites 6 – Best BP Lowering efficacy beyond other 6 ARBs

What is an Inverse Agonist? [R*WT] Full active state agonists Partial active state [R’WT] Neutral antagonists Spontaneous and Consititutive Activity Inactive state Inverse agonists [RWT] Ligand (Log A) (Miura S, et al. Curr Hypertens Rev. 2005)

2046 2 – Double chain domain 0 – 0 AT1 Activation 4 – 4 binding sites 6 – Best BP Lowering efficacy beyond other 6 ARBs

2046 2 – Double chain domain 0 – 0 AT1 Activation 4 – 4 binding sites 6 – Best BP Lowering efficacy beyond other 6 ARBs

Model of interactions between AT1 receptor and Angiotensin II or ARB Olmesartan Ang II Double-chain domain OH COOH Biphenyl- tetrazol group Cytoplasm AT1 Receptor Ligand Pocket

G protein-coupled receptor (GPCR)

Signal activation via structural changes of AT1 receptor Mechanical Stress Mechanical Stress A II ARB Ca Olmetec L type Channel AT1 AT1 G PLC IP3 Ca Ca2+-sensitive kinase (Pyk2, Src etc) ↑ SR Ca ARB是抑制AT1 receptor的作用, 所以得先看看AT1是怎樣作用的 AT1發生作用會受到兩種因子, 一種是化學性的刺激, 就是Angiotensin的結合, 另一種是物理性的刺激, 就是如血壓變化等機械性的壓力 搞糊塗了嗎, 舉個例子可能大家會比較清楚, 武俠片中常見的讓人昏倒有兩種方法, 一種是施放迷魂香, 另一種是從後腦杓敲下去, 兩種方法都有一樣的結果 回到主題, AT1 receptor受刺激後(不管是化學性的或是物理性的), 會引起一連串的反應來促使血管收縮, 血壓上升 <以下參考資料有興趣的人看一看就好> AT1被活化後, 會透過 G蛋白傳遞訊息, 活化一些和鈣離子相關的激酶如PYK2 (prolinerich tyrosine kinase 2), PyK2會很快受到磷酸化, 進而促進細胞內氧化物的提昇及Src 的活化, 而引起鈣離子增加, 最後透過ERK(Extracellular Signal Regulated Kinase, 胞外信號調節酶)傳遞, 而促進血管平滑肌 (VSMC, Vascular Smooth Muscle Cell)增生 (記得 VIOS study 嗎? 血管變厚是引起高血壓的原因) 另一個途徑是, AT1被活化後, 透過 G蛋白活化磷脂酶 C (Phospolipase C, PLC) , 進而活化 肌醇三磷酸酶 (Inositol triphosphatase, IP3), 而打開鈣離子通道, 將鈣離子從 SR (Sarcoplasmic Reticulum, 胞漿間質網組織)中釋放出來, 增加細胞內鈣離子的濃度而促進血管收縮 (肌肉收縮必須仰賴大量的鈣離子) Ca ERK Akt ↑ Ca ↑ Ca Ca↑ in Cell VSMC proliferation

2046 2 – Double chain domain 0 – 0 AT1 Activation 4 – 4 binding sites 6 – Best BP Lowering efficacy beyond other 6 ARBs

2046 必 2 – Double chain domain 0 – 0 AT1 Activation 4 – 4 binding sites 6 – Best BP Lowering efficacy beyond other 6 ARBs 必

Systematic review of the antihypertensive activity of ARBs: BP reduction over 24 hours Placebo Losartan Valsartan Irbesartan Candesartan Telmisartan Eprosartan Olmesartan -2 -4 Change in SBP (mmHg) -6 -8 -10 -12 -14 Olmesartan 具有ARB中非常好的降壓能力 -2 Change in DBP (mmHg) -4 -6 -8 -10 Independent meta-analysis of 47 randomised studies of BP changes measured by ABPM Fabia et al. J Hypertension 2007;25:1327–1336.

Olmesartan is the best solution Unique Olmesartan Property Olmesartan 40mg Organ Protection

Left ventricular hypertrophy Left ventricular (LV) hypertrophy (LVH) is an independent cardiovascular risk factor in the general population.

Background Ang II stimulates LVH and fibrosis in HF patients, whereas Ang II blockade prevents development of LVH. The objective of this study was, therefore, to investigate the effects on LVH in HF patients of a changeover from other ARBs to olmesartan. Heart Vessels. 2016 Oct 8.

Methods Participants enrolled in this prospective trial were 64 outpatients with stable HF who had been treated with ARBs other than olmesartan for more than 1 year at Kobe University Hospital between December 2013 and March 2016. The primary end point was defined as a change in Left ventricular mass index (LVMI) between baseline and 6 months after the start of administration of olmesartan. The secondary end points comprised a change in brain natriuretic peptide (BNP), E/A, e′ and E/e′ between baseline and 6 months after the start of administration of olmesartan. Heart Vessels. 2016 Oct 8.

Results Heart Vessels. 2016 Oct 8.

Stable antihypertensive effect Results Stable antihypertensive effect Inhibitory effect on cardiac hypertrophy Heart Vessels. 2016 Oct 8.

Ann Thorac Cardiovasc Surg Advance Published Date: April 18, 2016

Background The RAAS is activated after cardiac surgery. After cardiac surgery, suppressing RAAS activity inhibited target organ damage and improving the long-term prognosis. Switching from candesartan to olmesartan significantly reduced angiotensin II and aldosterone levels, as well as significantly reducing the left ventricular mass index(LVMI) after 6 months and 1 year of treatment. Azilsartan and olmesartan have both been shown to increase angiotensin-(1–7) in animal experiments. Sezai A, et al.

Methods The subjects were outpatients with essential hypertension who were clinically stable after cardiac surgery. Sixty patients were randomized to receive either azilsartan or olmesartan for 1 year and were switched to the other drug for the following 1 year. If the early morning home blood pressure exceeded 140/90 mmHg, a calcium antagonist was used as add-on therapy. The primary endpoints were plasma renin activity, plasma angiotensin II, and plasma aldosterone. Sezai A, et al.

CHAOS study Olmesartan is more reliable on HBP control vs azilsartan! Number of patients After 1 year treatment, HBP exceeded 140/90 mmHg in 12 patients from the azilsartan group versus 4 patients from the olmesartan group, with the number being significantly higher in the azilsartan group. Number of patients Sezai A, et al.

CHAOS study Olmesartan is a better choice than azilsartan! Olmesartan significantly reduce angiotensin 2 and aldsterone concentration than azilsartan. More over, left ventricular mass index is significantly smaller in olmesartan group than azilsartan group after 1 year treatment. Sezai A, et al.

Olmesartan VS Azilsartan Couclusion Olmesartan VS Azilsartan Reduced angiotensin II and aldosterone levels Stable antihypertensive effect Inhibitory effect on cardiac hypertrophy

Vascular protection effect by Olmesartan Anti-inflammatory Vascular Protection Anti-Atherosclerosis Vascular Hypertrophy Angiotensin II本身就是發炎物質，而atheroslerosis可視為一個發炎反應的過程。因此身為AT1R blocker且還能促進angiotensin Ⅱ代謝的olmesartan自然就具備了心血管保護的作用。 從EUTOPIA實驗中我們看到了olmesartan可降低inflammatory marker的產生。 VIOS實驗中，olmesartan 加到40mg的情況下，我們看到了血管壁的異常增厚減少了。 MORE study中，olmesartan具有獨立於降壓能力之外的減少plaque volume的功能。 OLIVUS實驗中，我們也看到了olmesartan帶來的atheroma regression的現象。 由於olmesartan這樣的特性，減少了atheroma，在OLIVUS 4 year extension中，我們還看到了olmesartan組重大心血管事件的減少! 效果甚至比statin的使用更好。 Atheroma Regression 必

Olmesartan is the best solution Unique Olmesartan Property Olmesartan 40mg Organ Protection