Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Olmesartan medoxomil is a new non-peptide angiotensin (A) II antagonist under development for treating hypertension. It is a pro-drug containing an ester moiety that, after oral administration, is rapidly cleaved to release the active form olmesartan (RNH-6270). In vitro, olmesartan is a highly potent, competitive and selective All AT1 receptor antagonist with almost no antagonistic activity on AT2 and AT4 receptors. Olmesartan produces selective insurmountable inhibition of All-induced contractions of the guinea-pig aorta and is much more potent than losartan in reducing maximal responses. In vivo, intravenous olmesartan produces a rapid and long-lasting inhibition of All-induced pressor responses in conscious rats. Oral olmesartan medoxomil also inhibits All-pressor response but onset of the action is slower compared with intravenous administration. Following oral administration, olmesartan has a faster onset but similar potency when compared with candesartan cilexetil, and clearly exceeds losartan in both respects. Oral olmesartan medoxomil exhibits dose-dependent antihypertensive effects in several rat and dog models, with the most marked effects seen in high plasma renin models, when compared with normal or low renin types. Haemodynamic studies in spontaneously hypertensive rats and normotensive dogs showed intravenous olmesartan selectively reduces renal vascular resistance, which suggests that vasodilatation in the renal vascular bed contributes most to the antihypertensive action of the drug. Long-term treatment with olmesartan medoxomil exhibits, beside antihypertensive effects, beneficial effects in animal models of various types of nephrosis and heart failure, and anti-atherogenic effects in hyperlipidaemic animals. Olmesartan medoxomil is worthy of clinical development in essential and renal hypertension, particularly where renal function is threatened by underlying diabetic disease.
 ...
PMID:In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT1 receptor antagonist. 1145 Dec 12

The therapeutic profile of olmesartan medoxomil, which is a recently developed angiotensin II (A II) receptor blocker, has been compared with four commonly used antihypertensive therapeutic drugs (atenolol, captopril, felodipine and losartan) in five separate multicentre, randomised, double-blind, parallel-group, phase III trials. The trials were designed to compare the efficacy of individually optimised dosages of olmesartan medoxomil and the comparator agent. The primary efficacy variable in all trials was the mean change from baseline to week 12 in trough mean sitting diastolic blood pressure (DBP). Olmesartan medoxomil (10-20 mg once daily (o.d.)) showed similar efficacy to atenolol (50-100 mg o.d.), both in patients with mild-to-moderate hypertension and, when given together with hydrochlorothiazide (HCTZ) 25 mg o.d., in patients with moderate-to-severe hypertension. Olmesartan medoxomil (20-40 mg o.d.) was also similar in efficacy to felodipine (5-10 mg o.d.) in reducing BP in patients with mild-to-moderate hypertension. Compared with captopril (12.5-50 mg twice daily (b.i.d.)) and losartan (50-100 mg o.d.), in patients with mild-to-moderate hypertension, olmesartan medoxomil (5-20 mg o.d. and 10-20 mg o.d., respectively) was significantly superior in terms of lowering DBP from baseline to week 12. In terms of the secondary efficacy variable, which was mean change from baseline to week 12 in trough mean sitting systolic BP, olmesartan showed significant superiority to atenolol, captopril and losartan in patients with mild-to-moderate hypertension. In the longer term, compared with losartan, a lower percentage of olmesartan-treated patients required concomitant HCTZ after 12 weeks of therapy. Olmesartan was well tolerated in all studies.
 ...
PMID:Antihypertensive efficacy of olmesartan compared with other antihypertensive drugs. 1196 29

To evaluate the efficacy of angiotensin II receptor blockers (ARBs) for use in the treatment of diabetic nephropathy, we examined the effects of olmesartan medoxomil (olmesartan), an angiotensin II type 1 (AT1) specific ARB, on the progression of nephropathy in Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes. We used 2 doses of olmesartan, a sub-antihypertensive dose and an antihypertensive dose, to specifically examine whether the drug exerts beneficial effects on the kidney without lowering blood pressure. Olmesartan mixed in the diet at a concentration of 0.001% (approximately 0.6 mg/kg/day) or 0.01% (approximately 6 mg/kg/day) was administered for 19 weeks starting from 12 weeks of age, when the animals developed microalbuminuria. Lean non-diabetic rats served as controls. ZDF rats had hyperglycemia, hyperinsulinemia, and moderate hypertension as compared to lean control rats. Plasma glucose and insulin concentrations were not affected by olmesartan, and blood pressure was lowered only by the high dose of olmesartan. Progressive proteinuria in ZDF rats was greatly (about 70%) suppressed by the high dose of olmesartan and moderately (about 30%) suppressed by the low dose that did not significantly lower blood pressure. ZDF rats exhibited hyperlipidemia and hypoalbuminemia, both of which were substantially corrected by treatment with olmesartan. The histological evidence of glomerular and tubular damage in the ZDF rats was also reduced by the drug. These results indicate that AT1 receptor blockade with olmesartan retards the progression of nephropathy associated with type 2 diabetes without affecting glucose metabolism, and that this renal protective effect is at least partly independent of the antihypertensive effect of the drug.
 ...
PMID:Renoprotective effects of blockade of angiotensin II AT1 receptors in an animal model of type 2 diabetes. 1204 43

The present study explored the possibility that estrogen may enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker on neointima formation in vascular injury, and investigated the signaling mechanism involved in their actions. Polyethylene cuff placement around the femoral artery of mice induced neointima formation and increased bromodeoxyuridine (BrdU) incorporation into vascular smooth muscle cells. These changes were significantly smaller in female mice than in male mice. Ovariectomy enhanced neointima formation and BrdU incorporation in the injured artery, which were reversed by 17beta-estradiol (80 microg/kg per day) replacement. Treatment with a selective AT1 receptor blocker, olmesartan (3 mg/kg per day), significantly inhibited neointima formation and BrdU incorporation, whereas the inhibitory effects of olmesartan were more marked in intact female mice than in male or ovariectomized mice. Phosphorylation of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription (STAT) 1, and STAT3 was increased in the injured artery. These increases were significantly smaller in intact female mice than in male or ovariectomized mice. Olmesartan or estrogen attenuated the phosphorylation of ERK and STAT in the injured artery, whereas these inhibitory effects were greater in intact female mice. Lower doses of olmesartan (0.5 mg/kg per day) or 17beta-estradiol (20 microg/kg per day) did not influence neointima formation, BrdU incorporation, and ERK and STAT phosphorylation in ovariectomized mice, whereas coadministration of olmesartan and 17beta-estradiol at these doses attenuated these parameters. These results indicate that estrogen and an AT1 receptor blocker synergistically attenuate vascular remodeling, which is at least partly via inhibition of ERK and STAT activity.
Hypertension 2002 Oct
PMID:Effect of estrogen and AT1 receptor blocker on neointima formation. 1236 46

Prevention or retardation of diabetic nephropathy (DN) includes anti-hypertensive treatment with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) on the premises that these drugs have an added protective effect beyond their influence on BP. The present study used a strain of spontaneously hypertensive/NIH-corpulent rats [SHR/NDmc-cp (fat/fat)] as a model of type II DN to unravel the renoprotective effects of anti-hypertensive drugs. Olmesartan (1 or 5 mg/kg per d), an ARB, and hydralazine (5mg/kg per d), an anti-hypertensive drug without effect on the renin-angiotensin system (RAS), were given for 20 wk. BP, renal function, glucose and insulin levels, and proteinuria were monitored. Glomerular lesions and kidney pentosidine content were assessed at the end of the study. Olmesartan (1 and 5 mg) significantly reduced BP and kidney pentosidine content and improved histologic renal damage and proteinuria. The changes were dose-dependent. The effect of hydralazine (5 mg) was similar to that of olmesartan (1 mg) but reached statistical significance only for kidney pentosidine content. The similarity of both drugs' effects on kidney damage and proteinuria suggest that renoprotection does not hinge on manipulation of RAS in these rats. By contrast, the inhibition of renal pentosidine formation assessed both by immunohistochemistry and HPLC suggests a critical role of advanced glycation end product (AGE) formation together with hypertension in the genesis of diabetic nephropathy. This view is supported by the correlation found between renal pentosidine content and proteinuria. The unsuspected AGE-lowering effect of hydralazine was further confirmed in vitro and elucidated; it is due to both reactive carbonyl compounds trapping and modifications of the oxidative metabolism. It is concluded that AGE inhibition should be included in the therapeutic strategy of DN.
 ...
PMID:Anti-hypertensive agents inhibit in vivo the formation of advanced glycation end products and improve renal damage in a type 2 diabetic nephropathy rat model. 1270 91

Olmesartan medoxomil is a new angiotensin-II receptor antagonist for the treatment of hypertension. Olmesartan medoxomil is a pro-drug that is de-esterified to the active metabolite, olmesartan. Olmesartan has a dual method of elimination, with about 60% eliminated by the liver and the remainder by the kidney. In situations of impaired renal or hepatic function, the alternative excretion pathway can compensate for the compromised one. Olmesartan is not metabolized by the cytochrome P450 enzyme system and therefore has a low potential for metabolic drug interactions, a feature that may be of importance when treating patients on multiple drug regimens, such as the elderly. Olmesartan is well tolerated and has an excellent safety profile that is comparable to that of placebo. In addition, olmesartan provides 24-h blood pressure control with a once-daily dosing. In head-to-head studies, olmesartan delivered superior blood pressure reduction when compared with other angiotensin-II receptor antagonists at their recommended doses.
 ...
PMID:Clinical efficacy of olmesartan medoxomil. 1292 7

Olmesartan is an angiotensin II receptor antagonist indicated for the treatment of essential hypertension. Angiotensin II is an important hormonal effector and end-product of the renin-angiotensin system. When it binds to its endogenous receptor sites, it causes widespread vasoconstriction and a subsequent increase in blood pressure. Olmesartan works by selectively binding to AT(1) against the pathophysiologic events leading to diabetic nephropathy and cardiovascular morbidity/mortality. This end-organ protection is independent of olmesartan's blood pressure lowering properties and is therefore thought to be mediated by different mechanisms. In summary, olmesartan has an efficacy profile superior to other available antihypertensive agents, with a tolerability profile comparable to that of placebo. In addition, the convenience of its once-daily dosing means that olmesartan should be considered not only as an alternative, but also as a first-line treatment for patients with mild to severe essential hypertension. Thus, olmesartan appears to be a very promising new therapy for the treatment of hypertension.
 ...
PMID:Olmesartan, an AT1-selective antihypertensive agent. 1466 30

Recent studies have indicated that both endothelin (ET) and angiotensin (Ang) II stimulate oxidative stress, which contributes to the development of hypertension. Here, we examined the effects of Ang II type 1 (AT1) receptor blockade on reactive oxygen species (ROS) formation in ET-dependent hypertension. Chronic ET-1 infusion (2.5 pmol/kg/min, i.v., n=7) into rats for 14 days increased systolic blood pressure from 113+/-1 to 141+/-2 mmHg. ET-1-infused rats showed greater plasma renin activity (8.1+/-0.8 Ang I/ml/h), and greater Ang I (122+/-28 fmol/ml) and Ang II levels (94+/-13 fmol/ml) than vehicle (0.9% NaCl)-infused rats (3.1+/-0.6 Ang I/ml/h, 45+/-8 and 47+/-7 fmol/ml, respectively, n=6). Angiotensin converting enzyme and AT1 receptor expression in aortic tissues were similar between the vehicle- and ET-1-infused rats. Vascular superoxide anion (O2-) production and plasma thiobarbituric acid-reactive substance (TBARS) levels were greater in ET-1-infused rats (27+/-1 counts per minutes [CPM]/mg dry tissue weight and 8.9+/-0.8 micromol/l, respectively) than vehicle-infused rats (16+/-1 CPM/mg and 5.1+/-0.1 micromol/l, respectively). The ET-1-induced hypertension was prevented by simultaneous treatment with a new AT1 receptor antagonist, olmesartan (0.01% in chow, 117+/-5 mmHg, n =7), or hydralazine (15 mg/kg/day in drinking water, 118+/-4 mmHg, n=6). Olmesartan prevented ET-1-induced increases in vascular O2- production (15+/-1 CPM/mg) and plasma TBARS (5.0+/-0.1 micromol/l). Vascular O2- production and plasma TBARS were also decreased by hydralazine (21+/-1 CPM/mg and 7.0+/-0.3 micromol/l, respectively), but these levels were significantly higher than in vehicle-infused rats. These data suggest that ET-dependent hypertension is associated with augmentation of Ang II levels and ROS formation. The combined effects of the elevations in circulating ET-1 and Ang II, as well as the associated ROS production, may contribute to the development of hypertension induced by chronic ET-1 infusion.
 ...
PMID:Olmesartan improves endothelin-induced hypertension and oxidative stress in rats. 1530 86

Olmesartan medoxomil is a new angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. Olmesartan medoxomil is a pro-drug that is converted to the active metabolite olmesartan. Olmesartan does not undergo further metabolism and does not interact with cytochrome P450 enzymes. Olmesartan is a potent ARB with high selectivity for the type 1 (AT(1)) receptor subtype and shows insurmountable antagonism against the AT(1) receptor in vascular tissues. This antagonistic mode, which could be attributed to tight binding of this drug to the receptor, would underlie the potent and persistent action of olmesartan medoxomil in vivo. In fact, oral administration of olmesartan medoxomil produces a potent and long-lasting antihypertensive action without inducing tachycardia. 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.
 ...
PMID:[Pharmacological profiles and clinical effects of olmesartan medoxomil, a novel angiotensin II receptor blocker]. 1546 59

Olmesartan medoxomil (Belsar, Olmetec) developed by Sankyo Pharma and proposed by Sankyo Pharma but also Menarini is a new angiotensin II ATI receptor blocker. Its indication is the treatment of hypertension. Olmesartan is indeed an antihypertensive agent with an efficacy dependent on the dose from 10 to 40 mg. It is taken once a day, because of a long duration of action. This prodrug has a dual elimination pathway (biliary and renal). The contraindications are the same as for the other sartans. One of its main advantage, besides its rapidly observed efficacy to lower high blood pressure, is its relatively low cost within this family. It has also cardiovascular and renal protective effects. The recommended usual dosage is 20 mg/day.
 ...
PMID:[The drug of the month: Olmesartan medoxomil]. 1562 83


1 2 3 4 5 6 7 8 9 Next >>