Comparison of increasing doses of olmesartan medoxomil, losartan potassium, and valsartan in patients with essential hypertension.

This 12-week, randomized, double-blind, forced-titration study compared the efficacy of 3 angiotensin receptor blockers. Patients received olmesartan medoxomil 20 mg, losartan potassium 50 mg, valsartan 80 mg, or placebo once daily. At week 4, doses were titrated to 40, 100, and 160 mg once daily for olmesartan, losartan, and valsartan, respectively. At week 8, losartan was increased to 50 mg twice daily and valsartan increased to 320 mg once daily (olmesartan remained at 40 mg once daily). The primary end point was mean change from baseline in seated diastolic blood pressure (SeDBP) at week 8. All 3 medications significantly reduced mean SeDBP from baseline compared with placebo at weeks 4, 8, and 12 (P<.001). At week 8, olmesartan reduced mean SeDBP more than losartan (P<.001); more patients in the olmesartan medoxomil group achieved a blood pressure goal of <140/90 mm Hg (P<.001). Olmesartan did not reduce mean SeDBP significantly compared with valsartan, although more patients attained blood pressure goal with olmesartan (P=.031). At week 12, all agents lowered blood pressure equivalently.

Use of 24-h ambulatory blood pressure monitoring to assess blood pressure control: a comparison of olmesartan medoxomil and amlodipine besylate.

OBJECTIVE: Olmesartan medoxomil is an angiotensin II receptor blocker with similar antihypertensive efficacy as the calcium channel blocker amlodipine besylate in patients with mild-to-moderate hypertension. In addition to a drug's ability to lower blood pressure, the effectiveness of the agent in enabling patients to achieve specific blood pressure targets is an important clinical consideration. This secondary analysis of a randomized, double-blind study compared the efficacy of olmesartan medoxomil with that of amlodipine besylate in achieving ambulatory blood pressure goals among patients with mild-to-moderate hypertension. METHODS: Following a 4-week placebo run-in, 440 study participants aged >or=18 years were randomized to olmesartan medoxomil (20 mg/day), amlodipine besylate (5 mg/day), or placebo for 8 weeks. The proportion of participants achieving specific systolic and diastolic ambulatory blood pressure goal levels was calculated by dividing the number of participants who had achieved a particular blood pressure goal by the total number of patients in the intent-to-treat population. RESULTS: After 8 weeks of treatment, a mean 24-h ambulatory blood pressure of <130/80 or <130/85 mmHg was achieved by significantly more participants in the olmesartan medoxomil group (18.1 and 30.4%, respectively) than in the amlodipine besylate (7.0 and 14.0%, respectively) or placebo (1.9% for both) groups. The target daytime ambulatory blood pressure of <135/85 mmHg was achieved by more participants in the olmesartan medoxomil group than in the amlodipine besylate group (15.8 vs. 5.8%, respectively; P<0.01). CONCLUSION: In a previous publication of the same study, we demonstrated that starting doses of olmesartan medoxomil and amlodipine besylate produced similar mean reductions in blood pressure. In this subanalysis of the blood pressure data from that primary publication, however, olmesartan medoxomil therapy was shown to result in a greater proportion of patients achieving specific ambulatory blood pressure goals than therapy with amlodipine besylate. As blood pressure goal attainment may be of more direct clinical relevance than numerical blood pressure lowering, the achievement of blood pressure goals should be a key efficacy parameter assessed in clinical trials of antihypertensive medications.

A review of the structural and functional features of olmesartan medoxomil, an angiotensin receptor blocker.

The angiotensin II (A-II) type 1 (AT1) receptor-mediated effects of A-II play a key role in the pathophysiology of hypertension. Effective inhibition of A-II is provided by the latest class of antihypertensive medications, the AT1 receptor blockers (ARBs). These orally available agents were developed around a common imidazole-based structural core. The most recent member of this drug class to be approved by the Food and Drug Administration, olmesartan medoxomil, contains unique features that may explain its clinical efficacy. Key structural elements of olmesartan medoxomil include a hydroxyalkyl substituent at the imidazole 4-position and a hydrolyzable ester group at the imidazole 5-position. Inter- and intramolecular hydrogen bonding involving these groups may contribute to the potentiation of antagonist activity. After oral administration, olmesartan medoxomil is deesterified in the intestinal tract to produce the active metabolite olmesartan, which undergoes no additional metabolic change. The marked antihypertensive efficacy of olmesartan medoxomil may result from a unique pharmacological interaction of the drug with the AT1 receptor, resulting in a potent, long-lasting, dose-dependent blockade of A-II. This review article characterizes the structural features of olmesartan that may be responsible for its clinical efficacy. Inferential pharmacological studies compare and contrast the effects of olmesartan to those of other ARBs in comparable preclinical animal models.

Role of angiotensin receptor blockers as monotherapy in reaching blood pressure goals.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure emphasizes the urgent need to lower blood pressure (BP) to a goal of <140/90 mm Hg in patients with uncomplicated hypertension and to <130/80 mm Hg in high-risk patients, such as those with diabetes mellitus or chronic kidney disease, to prevent cardiovascular disease morbidity and mortality. Consequently, a meaningful measure of the efficacy of an antihypertensive therapy is its ability to achieve BP reduction to below the recommended BP goals. Angiotensin II receptor blockers (ARB) are highly effective antihypertensive agents with excellent tolerability profiles similar to those of placebo. A literature search using MEDLINE, EMBASE, and BIOSIS to identify studies reporting data on the percentage of patients attaining BP goals found that monotherapy with an ARB can generally result in the attainment of the diastolic BP (DBP) goal of <90 mm Hg in approximately 50% of hypertensive patients. However, to our knowledge, the attainment of the systolic BP (SBP) and combined SBP/DBP goals with ARB monotherapy has not been reported. Therefore, a secondary analysis of BP efficacy data from a published study that directly compared recommended starting doses of four currently marketed ARB was performed to assess combined SBP and DBP goal attainment. This analysis showed that the percentage of patients achieving the combined SBP/DBP goal rate of <140/90 mm Hg was highest with olmesartan medoxomil (32.4%) compared with recommended starting doses of losartan potassium (16.1%), valsartan (14.5%), or irbesartan (25.9%). Optimal ARB monotherapy can achieve recommended BP goals in a significant proportion of hypertensive patients. However, the majority of hypertensive patients will require combination therapy with two or more antihypertensive agents.

Phosphatidylinositide 3-kinase regulates angiotensin II-induced cytosolic phospholipase A2 activity and growth in vascular smooth muscle cells.

Angiotensin (Ang) II via the AT(1) receptor acts as a mitogen in vascular smooth muscle cells (VSMC) through stimulation of multiple signaling mechanisms, including tyrosine kinases and mitogen-activated protein kinase (MAPK). In addition, cytosolic phospholipase A(2)(cPLA(2))-dependent release of arachidonic acid (AA) is linked to VSMC growth and we have reported that Ang II stimulates cPLA(2) activity via the AT(1) receptor. The coupling of Ang II to the activation of cPLA(2) appears to involve mechanisms both upstream and downstream of MAPK such that AA stimulates MAPK activity which phosphorylates cPLA(2) to further enhance AA release. However, the upstream mechanisms responsible for activation of cPLA(2) are not well-defined. One possibility includes phosphatidylinositide 3-kinase (PI3K), since PI3K has been reported to participate in the upstream signaling events linked to activation of MAPK. However, it is not known whether PI3K is involved in the Ang II-induced activation of cPLA(2) or if this mechanism is associated with the Ang II-mediated growth of VSMC. Therefore, we used cultured rat VSMC to examine the role of PI3K in the Ang II-dependent phosphorylation of cPLA(2), release of AA, and growth induced by Ang II. Exposure of VSMC to Ang II (100 nM) increased [(3)H]thymidine incorporation, cell number, and the release of [(3)H]AA. Also, using Western analysis, Ang II increased the phosphorylation of MAPK and cPLA(2) which were blocked by the MAPK kinase inhibitor PD98059 (10 microM/L). Similarly, the PI3K inhibitor LY294002 (10 microM/L) abolished the Ang II-mediated increase in MAPK phosphorylation, as well as phosphoserine-PLA(2). Further, inhibition of PI3K blocked the Ang II-induced release of AA and VSMC mitogenesis. However, exogenous AA was able to restore VSMC growth in the presence of LY294002, as well as reverse the inhibition of MAPK and cPLA(2) phosphorylation by LY294002. Thus, it appears from these data that Ang II stimulates the PI3K-sensitive release of AA which stimulates MAPK to phosphorylate cPLA(2) and enhance AA release. This mechanism may play an important role in the Ang II-induced growth of VSMC.