新一代血管紧张素受体阻断剂奥美沙坦酯

奥美沙坦酯是一种新型的血管紧张素Ⅱ受体ATl的阻断剂，是一种前体药物，它通过阻止血管紧张素Ⅱ与ATl受体结合，使血管平滑肌放松，从而使血压降低。临床上用于治疗各种类型的高血压，不良反应较少。综述了奥美沙坦酯的作用机制、药代动力学及临床评价。     

Clinical and experimental aspects of olmesartan medoxomil, a new angiotensin II receptor antagonist

Olmesartan medoxomil is a new orally active angiotensin II (Ang II) type 1 receptor antagonist. It is a prodrug and is rapidly de-esterified during absorption to form olmesartan, the active metabolite. Olmesartan is a potent, competitive and selective Ang II type 1 receptor antagonist. Olmesartan is not metabolized by the cytochrome P-450 and has a dual route of elimination, by kidneys and liver. In patients with essential hypertension olmesartan medoxomil administered once daily at doses of 10-80 mg dose-dependently reduced diastolic blood pressure (DBP). Troughto-peak ratios for both DBP and systolic blood pressure (SBP) were above 50%. At the recommended once-daily starting doses, olmesartan medoxomil (20 mg) was more effective than losartan (50 mg), valsartan (80 mg) or irbesartan (150 mg) in reducing cuff DBP in patients with essential hypertension. The results of cuff SBP and mean 24-h DBP and SBP were similar to those of cuff DBP measurement. In mild-to-moderate hypertensive patients the recommended starting dose of olmesartan medoxomil was as effective as that of amlodipine besylate (5 mg/day) in reducing both cuff and 24-h blood pressure. In lowering DBP olmesartan medoxomil, at 10-20 mg/day, was as effective as atenolol at 50-100 mg/day. In mild-to-moderate hypertensive patients, olmesartan medoxomil, at 5-20 mg once daily, was more effective than captopril at 12.5-50 mg twice daily. At 20-40 mg once daily olmesartan medoxomil was as effective as felodipine, at 5-10 mg once daily. Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions. Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models. Future investigation should reveal whether these beneficial effects of olmesartan medoxomil are applicable to human diseases.     

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.     

Pharmacological and clinical profile of telmisartan, a selective angiotensin II type-1 receptor blocker

Telmisartan (Micardis) is a potent, long-lasting, nonpeptide angiotensin II type-1 (AT(1)) receptor blocker (ARB) that is indicated for the treatment of essential hypertension. In receptor binding studies, telmisartan showed a high affinity and selectivity for the human AT(1) receptors compared with AT(2) receptors and a slower dissociation rate from the human AT(1) receptor than those of ARBs. In isolated aorta rings, telmisartan was shown to be an insurmountable antagonist of AII-induced contractions. The inhibitory effects of telmisartan on AII-induced contraction persisted even after wash-out procedures. In animal models such as spontaneous hypertension rats and renovascular hypertensive rats, telmisartan produced the consistent reduction of blood pressure. Furthermore, there were no rebound phenomenon and no tolerance to the drug developed in the repeated oral administration. Telmisartan has a longer terminal elimination half-life (about 24 h) than the other ARBs. In patients with mild-moderate hypertension, trough/peak ratios for telmisartan were above 80%. In Japanese patients with mild-moderate hypertension, telmisartan produced a significant reduction in blood pressure (effective rate: 76.0%) with a good safety profile. Therefore, telmisartan is expected to be effective in the treatment of hypertension, producing sustained 24-h blood pressure control.     

Hydrolysis of angiotensin II receptor blocker prodrug olmesartan medoxomil by human serum albumin and identification of its catalytic active sites.

In the present study, we investigated the esterase-like activity of human serum albumin (HSA) and the mechanism by which it hydrolyzes, and thereby activates, olmesartan medoxomil (CS-866), a novel angiotensin II receptor antagonist. CS-866 has previously been shown to be rapidly hydrolyzed in serum in which HSA appeared to play the most important role in catalyzing the hydrolysis. We found that the hydrolysis of CS-866 by HSA followed Michaelis-Menten kinetics. Compared with the release of p-nitrophenol from p-nitrophenyl acetate (PNPA), CS-866 showed lower affinity to HSA and a lower catalytic rate of hydrolysis. Thermodynamic data indicated that PNPA has a smaller value of activation entropy (deltaS) than CS-866; consequently, PNPA is more reactive than CS-866. Ibuprofen and warfarin acted as competitive inhibitors of hydrolysis of CS-866, whereas dansyl-L-asparagine, n-butyl p-aminobenzoate, and diazepam did not. These findings suggest that the hydrolytic activity is associated to parts of site I and site II for ligand binding. All chemically modified HSA derivatives (Tyr-, Lys-, His-, and Trp-modifications) had significantly lower reactivity than native HSA; Lys-HSA and Trp-HSA had especially low reactivity. All the mutant HSAs tested (K199A, W214A, and Y411A) exhibited a significant decrease in reactivity, suggesting that Lys-199, Trp-214, and Tyr-411 play important roles in the hydrolysis. Results obtained using a computer docking model are in agreement with the experimental results, and strongly support the hypotheses that we derived from the experiments.     

Effects of olmesartan medoxomil as an angiotensin II-receptor blocker in chronic hypoxic rats

We established a rat chronic alveolar hypoxia in vivo model to evaluate the efficacy against hypoxic pulmonary hypertension of a new angiotensin II-receptor I blocker, olmesartan medoxomil. Three groups of rats were established: rats exposed for 2-6 weeks to 10% oxygen atmosphere in a normobaric chamber; hypoxic rats treated with olmesartan medoxomil oral administration (5 mg/day) every day; and control rats fed in a normoxic condition. After hypoxia treatment, the presence, etiology and severity of pulmonary hypertension, was echocardiographically evaluated, and expressions of brain natriuretic peptide (BNP), transforming growth factor (TGF-beta) and endothelin-1 genes measured by both immunohistochemical assay and real-time polymerase chain reaction. Olmesartan medoxomil significantly reduced the induction of hypoxic cor pulmonale not only on echocardiographical observations but also in BNP, TGF-beta and endothelin gene expressions in molecular studies. However, systolic blood pressure was independent of olmesartan medoxomil. The present study clearly indicates that the angiotensin II-type I-receptor blocker olmesartan medoxomil has significant efficacy for hypoxic cor pulmonale.     

Antihypertensive, insulin-sensitising and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models

The pharmacological profile of a novel angiotensin II type 1 receptor blocker, azilsartan medoxomil, was compared with that of the potent angiotensin II receptor blocker olmesartan medoxomil. Azilsartan, the active metabolite of azilsartan medoxomil, inhibited the binding of [(125)I]-Sar(1)-I1e(8)-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24h. ID(50) values were 0.12 and 0.55 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In conscious spontaneously hypertensive rats (SHRs), oral administration of 0.1-1mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24h after dosing. Oral administration of 0.1-3mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24h after dosing. ED(25) values were 0.41 and 1.3mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1-1mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3-3mg/kg olmesartan medoxomil. In a 2-week study in SHRs, azilsartan medoxomil showed more stable antihypertensive effects than olmesartan medoxomil and improved the glucose infusion rate, an indicator of insulin sensitivity, more potently (≥ 10 times) than olmesartan medoxomil. Azilsartan medoxomil also exerted more potent antiproteinuric effects than olmesartan medoxomil in Wistar fatty rats. These results suggest that azilsartan medoxomil is a potent angiotensin II receptor blocker that has an attractive pharmacological profile as an antihypertensive agent.     

Pharmacological profiles and clinical effects of azelnidipine, a long-acting calcium channel blocker

Azelnidipine (Calblock) is a newly developed dihydropyridine-type calcium antagonist for the treatment of hypertension. In hypertensive animals, a single oral administration of azelnidipine caused a slowly developed and long-lasting hypotensive effect with a little reflex tachycardia. The extent of tachycardia was less with azelnidipine than with other agents of the same class. Long-term administrations of azelnidipine produced a stable antihypertensive effect with a slight decrease in heart rate. The hypotensive effect was preceded by an increase in plasma drug concentration and it persisted even after plasma drug concentration declined to very low levels. In the isolated arteries, the calcium blocking action developed gradually after treatment with azelnidipine and survived for a long period of time after the drug was removed from the bathing solution. These data suggest that the high affinity to vascular tissue contributes to the long-lasting hypotensive effects of this agent. The results from clinical studies in hypertensive patients indicated that once daily administration of azelnidipine achieved stable, 24-h control of blood pressure with no change or a slight decrease in heart rate. Clinical studies also showed a low incidence of adverse events such as headache, facial flush, dizziness, and palpitations. These characteristics make azelnidipine a new generation calcium antagonist that can be used for the treatment of hypertension.     

Comparative cost effectiveness of angiotensin II receptor blockers in a US managed care setting: olmesartan medoxomil compared with losartan,valsartan, and irbesartan

OBJECTIVE: To compare the cost effectiveness of the angiotensin II receptor blockers (ARBs) olmesartan medoxomil, losartan, valsartan and irbesartan for the treatment of hypertension, from the perspective of a US managed care setting. METHODS: The evaluation was based on a recently completed, prospective, randomised, double-blind clinical trial comparing the antihypertensive efficacy of these agents. Differences in diastolic blood pressure reductions among the comparative agents were used to estimate reductions in the annualised risk of cardiovascular (CV) and cerebrovascular events using the Framingham model. These annualised risks were translated into reductions in healthcare expenditures associated with treating CV events covered by managed care in the US. Data sources included: the recently published clinical trial of ARB antihypertensive efficacy, the Framingham Heart Study and a managed care database. Actual reimbursed amounts were used. RESULTS: Based on antihypertensive efficacy data versus irbesartan, the use of olmesartan medoxomil is expected to reduce the number of new cases of CV disease, resulting in a first-year reduction in cost in a cohort of 100,000 patients of 906,000 US dollars. Similarly, a reduction in new cases of coronary heart disease (CHD) resulted in a cost reduction of 701,000 US dollars; a cost reduction of 196,000 US dollars for fewer myocardial infarctions (MI); and a cost reduction of 28,000 US dollars for fewer strokes. Over 5 years, these estimates increase to 5,410,000 US dollars for fewer cases of CV disease; 3,975,000 US dollars for fewer cases of CHD; 1,430,000 US dollars for fewer MI; and 497,000 US dollars for fewer strokes. Compared with valsartan, the use of olmesartan medoxomil is estimated to reduce by 3,397,000 US dollars the expected cost of treating a cohort of 100 000 patients in the first year for fewer cases of CV disease; by 2,426,000 US dollars for fewer cases of CHD; by 565,000 US dollars for fewer MI; and by 124,000 US dollars for fewer strokes. Over 5 years, these estimates increase to 16,231,000 US dollars for CV disease; 11,955,000 US dollars for CHD; 4,505,000 US dollars for MI; and 1,741,000 dollars for stroke. Compared with losartan, the estimated reduction in first-year cost is 2,969,000 US dollars for CV disease for the cohort of 100,000 patients; 2,163,000 US dollars for CHD; 732,000 US dollars for MI; and 124,000 US dollars for stroke. Over 5 years, these estimates increase to 15,149,000 US dollars for CV disease; 11,107,000 US dollars for CHD; 4,057,000 US dollars for MI; and 1,437,000 dollars for stroke. CONCLUSION: Based on comparative antihypertensive efficacy data, treatment of hypertensive patients with olmesartan medoxomil instead of the other leading ARBs has the potential to reduce overall cost of medical care in a US managed care setting.     

Preclinical and clinical profile of Valsartan,a selective angiotensin II type-1 receptor blocker

Valsartan (Diovan) is a potent, orally active, specific, and highly selective blocker for the AT1-receptor subtype. The antihypertensive effects of oral treatment with valsartan were preclinically demonstrated in the sodium-depleted marmosets, renal hypertensive rats (2K1C), spontaneous hypertensive rats (SHR) and stroke-prone SHR. Moreover, valsartan had protective effects against hypertensive end-organ damage such as cardiac hypertrophy and renal disease. In an investigation of pharmacokinetics and pharmacodynamics in normotensive male volunteers, valsartan was rapidly absorbed with the maximal plasma concentration occurring 2-3 h after oral administration. The elimination half-life was about 4-6 h, valsartan was poorly metabolized, and most of the drug was excreted via feces. Valsartan produced persistent reductions of blood pressure in patients with mild to moderate essential hypertension and had a good safety profile with a wide therapeutic window between the effective pharmacological doses and the toxic doses. Therefore, valsartan is expected to be a safe and effective antihypertensive agent for the treatment of essential and severe hypertension.     

Pharmacological profiles of CS-622, a novel angiotensin converting enzyme inhibitor

CS-622 is a prodrug type ACE inhibitor with a thiazepin ring. Its active form, CS-622 diacid, was slightly more potent than enalaprilat in inhibiting ACE isolated from rabbit lung. The inhibitory potency of CS-622 diacid on isolated rat aorta was 3 times that of enalaprilat. The inhibitory action of enalaprilat was abolished quickly by washing the aortic strip with drug-free solution, whereas that of CS-622 diacid was abolished only slowly. This difference suggests that CS-622 diacid binds to vascular ACE more firmly than enalaprilat. By oral administration, CS-622 was 3 times more potent than enalapril, and its onset of action was faster than that of enalapril, suggesting that the conversion of CS-622 to its active diacid occurs faster than the conversion of enalapril. Although CS-622 diacid was only slightly more potent than enalaprilat by intravenous administration, it had a longer duration than enalaprilat. Elimination of renal excretory function potentiated the action of captopril but not that of CS-622, suggesting that unlike captopril, only a small portion of CS-622 is excreted through the kidney.     

Fimasartan, a novel angiotensin II receptor antagonist

Fimasartan (Kanarb?), an angiotensin II receptor antagonist with selectivity for the AT1 receptor subtype, is a pyrimidinone-related heterocyclic compound that was developed by Boryung Pharm. Co., Ltd. Among numerous synthetic derivatives, fimasartan was chosen as a new drug candidate through in vitro and in vivo screening studies. Pharmadynamic-pharmacokinetic properties and safety profiles were determined in a series of nonclinical and clinical studies. Fimasartan is a new angiotensin receptor blocker, and the first new molecular entity acting on cardiovascular system approved by Korean Food and Drug Administration for the treatment of essential hypertension in September 2010. Further development process for combination therapy and overseas registration is currently ongoing.     

Pharmacological and pharmacokinetic study of olmesartan medoxomil in animal diabetic retinopathy models

A close relationship between the renin-angiotensin system and the pathophysiology of diabetic retinopathy has been suggested, several angiotensin II type 1 receptor (angiotensin AT1 receptor) antagonists being effective in animal models. Therefore, we examined the efficacy of an angiotensin AT1 receptor antagonist, olmesartan medoxomil (CS-866), in animal retinopathy models. In diabetic stroke-prone spontaneously hypertensive (SHRSP) rats, 4-week treatment with CS-866 prevented the elongation of oscillatory potential peaks dose-dependently which almost normalized at 3 mg/kg/day. Next, in oxygen-induced retinopathy mice, CS-866 at 1 mg/kg significantly prevented the retinal neovascularization. In these animal models, plasma concentrations of CS-866 were comparable to the in vitro IC50 value of the angiotensin AT1 receptor. In summary, our data demonstrated that CS-866 was effective in early and late stage retinopathy models through the inhibition of the angiotensin AT1 receptor. These findings suggest the possibility of CS-866 as a therapeutic agent for diabetic retinopathy.     

Pharmacological characterization of the novel nonpeptide angiotensin II receptor antagonist, BIBR 277.

1. The pharmacological profile of BIBR 277, 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl ]- [1,1'-biphenyl]-2-carboxylic acid, a novel, nonpeptide angiotensin II receptor antagonist has been investigated by use of receptor binding studies, enzymatic assays, functional in vitro assays in rabbit aorta as well as in vivo experiments in pithed, anaesthetized and conscious rats. 2. BIBR 277 potently interacted with rat AT1 receptors (Ki 3.7 nM). Competitive receptor interaction was shown by radioligand saturation experiments performed in the presence of BIBR 277. The failure to inhibit radioligand binding to AT2 sites demonstrates the selectivity of BIBR 277 for AT1 receptors. This is further substantiated by the findings that BIBR 277 neither interacted with other receptor systems investigated nor affected the activity of components of the human renin-angiotensin system, such as plasma renin or serum converting enzyme. 3. In rabbit aorta, BIBR 277 had no agonistic properties and was shown to be an insurmountable antagonist of angiotensin II-induced contractions (KB 0.33 nM). The antagonistic effect persisted even after several wash-out procedures. However, this interaction was not irreversible since the insurmountable antagonism was concentration-dependently reversed when BIBR 277 (0.1 microM) and the surmountable antagonist, losartan (0.1 and 1.0 microM) were incubated simultaneously. The specificity of BIBR 277 for the AT1 receptor was further substantiated in this preparation since micromolar concentrations of BIBR 277 neither affected potassium chloride and noradrenaline-induced contractions nor acetylcholine-mediated tissue relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of cognitive decline in mice fed a high-salt and cholesterol diet by the angiotensin receptor blocker, olmesartan

The metabolic syndrome is closely related to dietary habits and seems to be associated with impairment of cognitive function in humans. Angiotensin receptor blockers are widely used with the expectation of preventing cardiovascular events and stroke and potential amelioration of the metabolic syndrome. We examined the diet-induced changes of cognitive function in mice treated with a high-salt and high-cholesterol diet. C57BL/6J mice were fed a high-salt (2% NaCl in drinking water) and high-cholesterol (1.25% cholesterol, 10% coconut oil) diet (HSCD) or a normal diet (ND), and subjected to 20 trials of a passive avoidance task every week from 8 weeks of age. An age-dependent decline of the avoidance rate starting from 10 weeks of age was observed in HSCD mice, whereas the avoidance rate gradually increased in the ND group. Oral administration of an angiotensin receptor blocker, olmesartan, at a dose of 3 mg/kg per day in drinking water from 8 weeks of age prevents this decline of avoidance rate in HSCD mice (49% vs. 82% at 12 weeks of age). Treatment with olmesartan significantly decreased serum glucose and cholesterol levels in HSCD mice, with a slight decrease in blood pressure. Administration of olmesartan in HSCD-fed mice showed a 1.6-fold increase in mRNA expression of a neuroprotective factor, MMS2, compared to HSCD-fed mice without olmesartan. Olmesartan attenuated the increase in superoxide anion production detected by dihydroethidium staining in the brain of HSCD mice. Our results suggest that olmesartan could be therapeutically effective in preventing the impairment of quality of life in persons on a high-fat and high-salt diet.     

OATP1B1, OATP1B3, and mrp2 are involved in hepatobiliary transport of olmesartan, a novel angiotensin II blocker.

Hepatic uptake and biliary excretion of olmesartan, a new angiotensin II blocker, were investigated in vitro using human hepatocytes, cells expressing uptake transporters and canalicular membrane vesicles, and in vivo using Eisai hyperbilirubinemic rats (EHBR), inherited multidrug resistance-associated protein (mrp2)-deficient rats. The uptake by human hepatocytes reached saturation with a Michaelis constant (K(m)) of 29.3 +/- 9.9 microM. Both Na(+)-dependent and Na(+)-independent uptake of olmesartan by human hepatocytes were observed. The uptake by Na(+)-independent human liver-specific organic anion transporters OATP1B1 and OATP1B3 expressed in Xenopus laevis oocytes was also saturable, with K(m) values of 42.6 +/- 28.6 and 71.8 +/- 21.6 microM, respectively. The Na(+)-dependent taurocholate-cotransporting polypeptide expressed in HEK 293 cells did not transport olmesartan. The cumulative biliary excretion in EHBR was one-sixth compared with that in Sprague-Dawley rats. ATP-dependent uptake of olmesartan was observed in both human canalicular membrane vesicles (hCMVs) and MRP2-expressing vesicles. An MRP inhibitor, MK-571 ([[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid) completely inhibited the uptake of olmesartan by hCMVs. In conclusion, the hepatic uptake and biliary excretion of olmesartan are mediated by transporters in humans. OATP1B1 and OATP1B3 are involved in hepatic uptake, at least in part, and MRP2 plays a dominant role in the biliary excretion.     

Clinical profile of eprosartan: a different angiotensin II receptor blocker

Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity.     

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

1. We studied the effect of a new angiotensin II type 1 (AT(1)) receptor antagonist, olmesartan medoxomil (olmesartan), on the fibrogenic responses in rat hepatic stellate cells (HSCs) and liver fibrogenesis. 2. Olmesartan (1 mg kg(-1) per day) was orally administered to fibrotic rats, induced by bile duct ligation. Liver hydroxyproline content, the mRNA expression of collagen alpha1(I) and alpha-smooth muscle actin (alpha-SMA), and plasma levels of transforming growth factor-beta1 (TGF-beta1) were significantly reduced by olmesartan treatment, suggesting that olmesartan improved liver fibrosis. Interestingly, AT(1) receptors were found to be expressed in alpha-SMA-positive cells in the fibrotic area of livers in bile duct-ligated rats by immunohistochemical analysis. Olmesartan treatment reduced the number of these cells. 3. In vitro experiments showed that angiotensin II (Ang II) treatment induced proliferation and collagen synthesis, and upregulated the profibrogenic cytokines, TGF-beta1 and connective tissue growth factor (CTGF), in rat primary HSCs. Olmesartan blocked all these effects of Ang II. 4. Based on these results, since activated HSCs were found to express AT(1) receptors and Ang II is thought to play an important role in the pathogenesis of liver fibrosis by binding to these receptors, olmesartan may act as a potent antifibrotic drug to suppress the proliferation, collagen synthesis and the expression of profibrogenic cytokines in activated HSCs by blocking these receptors.     

Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects

CS-866, a novel angiotensin II receptor blocker, is rapidly and completely metabolized to RNH-6270, its active metabolite. The pharmacokinetics of RNH-6270 following oral CS-866 or intravenous RNH-6270 administration was determined in 104 healthy male volunteers. The pharmacokinetics of RNH-6270 was linear over dose ranges of 1 to 32 mg (intravenous RNH-6270 administration) and 10 to 160 mg (oral CS-866 administration). The time to maximum plasma concentration of RNH-6270 after oral CS-866 administration ranged from 1.4 to 2.8 hours, and the terminal elimination half-life ranged from 12 to 18 hours. Absolute bioavailability of RNH-6270 after oral administration of CS-866 was 26%. Administration of CS-866 once daily for 10 days did not result in drug accumulation. When administered intravenously, RNH-6270 has a volume of distribution of 15 to 25 L. Approximately 35% to 50% of RNH-6270 is excreted unchanged in the urine. CS-866 was safe and well tolerated at doses of up to 160 mg/day.