Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(+/-)-1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116, Candesartan) and its active metabolite 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974) are specific nonpeptide angiotensin AT1 receptor antagonists. In the present study, the inhibitory potency of these two antagonists on the angiotensin II-induced responses in aortic vascular smooth muscle cells from Wystar Kyoto rats was investigated. The specific binding of 125I-angiotensin II to cells was inhibited by CV-11974 and TCV-116 with a half-maximal inhibitory concentration (IC50) of 3 x 10(-11) M and 1 x 10(-9) M, respectively. CV-11974 and TCV-116 inhibited the angiotensin II-induced increase in [3H]thymidine incorporation with an IC50 of 3 x 10(-10) and 5 x 10(-9) M, respectively. Both CV-11974 and TCV-116 (10(-7) M) completely blocked the angiotensin II-induced increase in c-fos mRNA. The inhibitory potency of the metabolite CV-11974 was about 30-100-fold higher than that of the prodrug TCV-116.
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PMID:Effects of TCV-116 and CV-11974 on angiotensin II-induced responses in vascular smooth muscle cells. 762 17

Many previous studies have demonstrated that angiotensin II (AII) type I (ATI) receptor antagonists remarkably reduced intimal lesions in rats following balloon injury. Using vascular smooth muscle cells (VSMC) in culture, we tested the hypothesis that other classical growth factors may enhance AII effects on VSMC growth, and ATI receptor antagonists may inhibit these effects. AII, platelet-derived growth factor-BB (PDGF-BB), and epidermal growth factor (EGF) caused a 3426 +/- 262%, 277 +/- 69%, and 1568 +/- 62% increase in [3H]thymidine incorporation in VSMC (mean +/- SD, n = 3), respectively. The exposure of the cells to AII in combination with PDGF-BB or EGF resulted in an approximately 2-fold or 1.5-fold elevation of the AII-dependent effect, respectively. 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole-7- carboxylic acid (CV-11974), the active metabolite of the specific nonpeptide AT1 receptor antagonist (+/-)-1-cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole- 7-carboxylate (TCV-116, Candesartan), suppressed the effect of AII down to basal values, as well as reducing the synergistic effect of PDGF or the additive effect of EGF on AII-induced [3H]thymidine incorporation. AII and PDGF-BB per se induced 57 +/- 19 and 70 +/- 14% increase in VSMC number. Combination of both agonists resulted in a 2-fold increase of the AII effect on cell number. Again, CV-11974 blocked the effect of AII, as well as the additive effect of PDGF-BB on cell number. From these findings, it may be concluded that AT1 receptor antagonists may reduce or prevent the development of intimal lesions following vascular injury through inhibition of direct and indirect growth-promoting effects of AII in VSMC.
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PMID:CV-11974, the active metabolite of TCV-116 (Candesarten), inhibits the synergistic or additive effect of different growth factors on angiotensin II-induced proliferation of vascular smooth muscle cells. 867 95

The present study describes the influence of carbocyclic thromboxane A2 on the proliferative effects of angiotensin II on vascular smooth muscle cells. Angiotensin II (10(-7) M) and carbocyclic thromboxane A2 (10(-6) M) per se caused an increase in [3H]thymidine incorporation and cell number. The exposure of cells to both agonists resulted in a 2.5-fold elevation of the angiotensin II dependent effect on DNA synthesis and a 1.6-fold increase in cell number. 2-Ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid (CV-11974), the active metabolite of the specific non-peptide angiotensin AT1 receptor antagonist (+/-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylate (TCV-116, Candesartan) suppressed the effect of angiotensin II on cell growth as well as reduced the synergistic effect of carbocyclic thromboxane A2. Simultaneous cell stimulation with carbocyclic thromboxane A2 and angiotensin II for 30 min resulted in a 26 +/- 9% elevation of the angiotensin II-induced increase of c-fos mRNA (100%).
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PMID:Carbocyclic thromboxane A2 enhances the angiotensin II-induced DNA synthesis in smooth muscle cells. 883 Nov 14

Candesartan cilexetil is rapidly and completely hydrolysed to the active compound candesartan during absorption from the gastrointestinal tract. Candesartan is a potent, long-acting, selective angiotensin II AT1 receptor blocker. The pharmacokinetics of candesartan were investigated after single and repeated once-daily doses of candesartan cilexetil in the dose range 2-16 mg in both younger (19-40 years) and elderly (65-78 years) healthy volunteers in five studies. Blood pressure, heart rate, and hormones associated with the renin-angiotensin system, and safety of candesartan cilexetil administration were also assessed. Placebo comparisons were made in four studies. Frequent blood samples were collected after the first single dose of candesartan cilexetil, and during the last dosing interval after 1 week repeated once-daily administration. Serum and plasma were analysed for candesartan cilexetil, candesartan and its inactive metabolite, CV-15959, as well as angiotensin I and II, aldosterone, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) activity. The AUC and Cmax of candesartan showed dose-proportional increases in the dose range of 2-16 mg candesartan cilexetil after both single and repeated once-daily tablet intake, indicating linear pharmacokinetics in both younger and elderly healthy subjects. The pharmacokinetics did not change on repeated dosing and, as expected from the half-life of candesartan of approximately 9 h in younger subjects, there was almost no accumulation after repeated once-daily dosing. The time to peak candesartan concentrations after tablet intake was consistently approximately 4 h at all dose levels. Both Cmax and AUC of candesartan were increased after single and repeated once-daily dosing in the elderly compared to younger subjects by approximately 50%. However, no accumulation after repeated once-daily dosing were seen in the elderly. The half-life of candesartan in the elderly (9-12 h) was somewhat longer than in the younger healthy adult volunteers (approximately 9 h) and no gender-related differences in the disposition of candesartan were observed. Serum concentrations of CV-15959 were much lower than candesartan, and reached peak serum concentrations later, about 4-9 h after dose intake. The elimination of CV-15959 was somewhat slower than that of candesartan. Candesartan cilexetil, the prodrug to candesartan, was not measurable in serum. No differences in ACE activity or serum aldosterone concentrations were observed between subjects receiving candesartan cilexetil and placebo tablets. Plasma angiotensin I and II concentrations and PRA were augmented after single doses and further increased after 1 week repeated candesartan cilexetil dosing. Single and repeated doses of candesartan cilexetil were well tolerated in the younger and elderly volunteers. Only mild adverse events were recorded, with 'headache' as the most commonly reported event, and no increase in the number of reported adverse events was observed with higher doses of candesartan cilexetil. No clinically significant changes in respect to vital signs, physical examination, ECG, and clinical laboratory tests were observed.
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PMID:Pharmacokinetics of candesartan after single and repeated doses of candesartan cilexetil in young and elderly healthy volunteers. 933 Oct

Candesartan is a potent and selective angiotensin II type 1 receptor blocker which binds tightly to and dissociates slowly from the AT1 receptor. It is administered orally as the prodrug candesartan cilexetil, which is rapidly and completely converted to the active compound, candesartan, during gastrointestinal absorption. In hypertensive patients, candesartan cilexetil dose-dependently lowers diastolic and systolic blood pressure (BP) over the 24-h dose interval and it maintains its antihypertensive effects in the long term. Clinical trials indicate that a once-daily dose of 4-16 mg provides a clinically relevant reduction in BP. The usual maintenance doses of candesartan cilexetil are expected to be 8 mg and 16 mg once-daily and dosage adjustment does not appear to be necessary in elderly patients or those with mild to moderate renal or hepatic impairment. Adverse events during treatment with candesartan cilexetil occur at a similar low incidence as with placebo and no dose-dependent events or adverse metabolic effects have been noted. As once-daily monotherapy, candesartan cilexetil 8 mg is as effective as enalapril 10-20 mg, amlodipine 5 mg or hydrochlorothiazide 25 mg, and candesartan cilexetil 16 mg is more effective than losartan 50 mg. The trough to peak ratio for the reduction in BP with candesartan cilexetil has been shown to be in the order of 80-100%, confirming the smooth 24-h BP-lowering profile of the drug. Combined treatment with candesartan cilexetil and hydrochlorothiazide or amlodipine provides an enhanced BP-lowering effect that is useful in patients with inadequate response to initial treatment after step-up titration. Candesartan cilexetil is similarly well tolerated as placebo, both when given as monotherapy, and in combination for example with hydrochlorothiazide. Candesartan cilexetil with its flexible dosage regimen therefore appears to offer an effective and well-tolerated alternative to other established agents in the treatment of a wide range of hypertensive patients.
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PMID:Candesartan cilexetil: a new, long-acting, effective angiotensin II type 1 receptor blocker. 933 Oct 18

The effects of the nonpeptide angiotensin II AT1 receptor antagonist candesartan on responses to angiotensin II were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II caused dose-related increases in perfusion pressure that were reduced by candesartan in doses of 3, 10, and 30 microg/kg i.v.. After administration of the AT1 receptor antagonist in a dose of 3 microg/kg i.v., the dose-response curve for angiotensin II was shifted to the right in a parallel manner, whereas the administration of higher doses resulted in nonparallel rightward shifts of the angiotensin II dose-response curves. The duration of the inhibitory actions of candesartan were dependent on dose, and the AT1 receptor antagonist did not alter responses to norepinephrine, U46619, vasopressin, neuropeptide Y, BAY K8644, endothelin-1, alpha,beta-methylene ATP, adenosine, acetylcholine, and bradykinin. Treatment with the AT2 receptor antagonist PD123,319 or with sodium meclofenamate did not alter the inhibitory effects of candesartan on responses to angiotensin II. Candesartan also decreased pressor responses to angiotensin III and IV with a parallel shift at the low dose and a nonparallel shift to the right of the dose-response curve at the high dose. These results indicate that candesartan is a potent, selective, long-acting AT1 receptor antagonist that, depending on dose, can produce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV.
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PMID:Analysis of the effects of candesartan in the mesenteric vascular bed of the cat. 936 85

The effects of the nonpeptide angiotensin II AT1 receptor antagonist candesartan on responses to angiotensin II were investigated in the hindquarters vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Candesartan in a dose of 3 micrograms/kg i.v. decreased vasoconstrictor responses to angiotensin II in a competitive manner. However, at doses of 10-1000 micrograms/kg i.v., candesartan shifted the dose-response curve to angiotensin II to the right in a nonparallel manner, suggesting a noncompetitive blockade. The inhibitory effects of candesartan on responses to angiotensin II were long in duration, and the AT1 receptor antagonist had little effect on baseline pressures. Candesartan was without effect on vasoconstrictor responses to norepinephrine, U46619, PGF2 alpha, and BAY K8644; on biphasic responses to endothelin-1; and on vasodilator responses to acetylcholine. Candesartan significantly attenuated hindquarters vasoconstrictor responses to angiotensin III and IV with a parallel shift at the 3 micrograms/kg iv dose and a nonparallel shift to the right at the high dose of the AT1 receptor antagonist. The results of the present study indicate that candesartan is a potent angiotensin AT1 receptor antagonist that can induce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV n the hindquarters vascular bed of the cat.
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PMID:Inhibitory effects of candesartan on responses to angiotensin peptides in the hindquarters vascular bed of the cat. 963 51

The main goal of the treatment of hypertension is to decrease cardiovascular morbidity and mortality. Since this has been demonstrated for betablocker and diuretics only, other antihypertensive agents should be recommended for initial single-drug therapy only if they demonstrate that their antihypertensive potency, and their tolerability is at least comparable to that of the other established drug classes. From this latter perspective AT1 blockers should become one of the most favored anti-hypertensive drugs, since it can be shown that their efficacy is comparable to all other classes of antihypertensive drugs and their tolerability is undoubtedly better. Candesartan seems to be the most efficient AT1 blocker with regard to molar potency. Moreover, it has been shown that Candesartan achieves an impressively long duration of action presumably due to its special receptor binding properties with a peak trough ratio of more than 0.9. An other advantage of this special AT1 blocker may be its dose response curve which demonstrates a continuous increase of efficacy between 2 and 16 mg daily.
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PMID:Clinical efficacy of a new AT1 blocker. 983 63

We studied cerebral blood flow autoregulation by laser Doppler flowmetry, and expression of brain angiotensin II AT1 receptors by quantitative autoradiography, after administration of an angiotensin AT1 receptor antagonist, CV-11974 (Candesartan, 0.5 or 1.0 mg/kg.day) for two weeks via subcutaneously implanted osmotic pumps in adult normotensive Wistar Kyoto and spontaneously hypertensive male rats (SHR). In SHR, the autoregulation curve was shifted towards higher blood pressures, when compared with that of normotensive Wistar Kyoto rats. Administration of CV-11974 shifted the autoregulation curve toward lower blood pressures in both Wistar Kyoto and SHR, partially normalizing the autoregulation curve in SHR. CV-11974 treatment markedly decreased the expression of AT1 receptors in Wistar Kyoto rats, both in areas outside the blood brain barrier (subfornical organ, 95% decrease) and inside the blood brain barrier (nucleus of the tractus solitarius, 87% decrease, and paraventricular nucleus, 96% decrease). Our results demonstrate that blockade of AT1 receptors tends to normalize the shift to higher pressures in the autoregulation curve of genetically hypertensive rats, and has a profound modulatory role in brain angiotensin II AT1 receptors.
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PMID:The angiotensin AT1 receptor antagonist CV-11974 regulates cerebral blood flow and brain angiotensin AT1 receptor expression. 983 66

The effects of the nonpeptide angiotensin II (AngII) AT1 receptor blocker candesartan on responses to AngII were investigated in the hindquarters vascular bed of the cat. Under constant-flow conditions, injections of AngII into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Candesartan in a dose of 3 microg/kg intravenously (i.v.) decreased vasoconstrictor responses to AngII in a surmountable manner. At doses of 30 and 300 microg/kg i.v., candesartan shifted the dose-response curve to AngII to the right in an insurmountable manner, indicating an insurmountable blockade of AT1 receptors. The inhibitory effects of the larger doses of candesartan on responses to AngII were long in duration, and the AT1 receptor blocker had little effect on baseline pressures. Candesartan was without effect on vasoconstrictor responses to norepinephrine, U46619, PGF2alpha, vasopressin, BAY K8644; biphasic responses to endothelin-1; or on vasodilator responses to acetylcholine, albuterol, or levcromakalim. These results indicate that candesartan is a potent and selective angiotensin AT1 receptor blocker that can induce both surmountable and insurmountable AT1 receptor blockade and provide support for the hypothesis that there are "spare" AT1 receptors in the hindquarters vascular bed of the cat.
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PMID:Analysis of the effects of candesartan on responses to angiotensin II in the hindquarters vascular bed of the cat. 989 49


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