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Biol Pharm Bull. 2008 Jul; 31(7): 1356-61
Yayama K, Miyagi R, Sugiyama K, Sugaya T, Fukamizu A, Okamoto H
Angiotensin II (Ang II) is an important mediator stimulating liver fibrosis after liver injury. However, it is not known whether Ang II plays a role in liver regeneration. Here, we investigate the effects of Ang II type 1 (AT(1)) receptor blocker (ARB), angiotensin-converting enzyme inhibitor (ACEI), systemic infusion of Ang II, and genetic deficiency of the AT(1a) receptor (AT1a-KO) on the hepatic regenerative response to partial hepatectomy (PH) in mice. Administration of ARB (candesartan cilexetil and losartan) or ACEI (enarapril and lisinopril) enhanced 5-bromo-2'-deoxyuridine (BrdU) incorporation into hepatocyte nuclei in remnant liver as well as the restoration of liver weight after PH. Systemic infusion of Ang II (100 ng/kg/min) suppressed the PH-induced BrdU incorporation and the restoration of liver weight. In contrast to Ang II infusion, these hepatic responses to PH were significantly greater in AT1a-KO mice than in wild-type mice. The PH-induced increases in hepatic levels of hepatocyte growth factor (HGF) mRNA and plasma HGF concentrations were greater in candesartan- and enarapril-treated mice or in AT1a-KO mice than in vehicle-treated mice or wild-type mice, respectively, whereas they were less in Ang II-infused mice than in vehicle-infused mice. In contrast to HGF, blockades of the renin-angiotensin system or Ang II infusion produced opposite effects on the PH-induce increases in hepatic transforming growth factor (TGF)-beta 1 mRNA and plasma TGF-beta 1 levels. These studies suggest that Ang II plays a role in the liver regeneration as a suppressor of hepatocyte proliferation via the AT(1) receptor-mediated control of growth factor production.
J Hypertens. 2008 Jul; 26(7): 1435-45
Liu H, Kitazato KT, Uno M, Yagi K, Kanematsu Y, Tamura T, Tada Y, Kinouchi T, Nagahiro S
BACKGROUND: Angiotensin II type 1 (AT1) receptor blockers decrease ischemia by mechanisms dependent on and independent of arterial blood pressure in hypertensive rats and AT1-R knockout mice, respectively. However, the detailed mechanisms underlying the effects of AT1 receptor blockers remain unclear. AIMS: To elucidate the systemic and focal effects of AT1 receptor blockers against cerebral ischemia in in-vivo and in-vitro studies. METHODS: Normotensive Wistar rats were treated for 2 weeks with 0.5 or 1 mg/kg candesartan cilexetil and then subjected to 2-h middle cerebral artery occlusion-reperfusion. Human umbilical endothelial cells were stimulated with the active form of candesartan and angiotensin II in the absence and presence of an angiotensin II type 2 (AT2) receptor antagonist. RESULTS: In candesartan-pretreated hypotensive and nonhypotensive rats, blood pressure was moderately increased during middle cerebral artery occlusion and fell gradually to the baseline after the reperfusion; it remained elevated in the control even after the reperfusion occlusion. Candesartan treatment resulted in a decrease in the cortical infarct volume and oxidative damage, the hypoxic status was improved, and the expression of repair-associated and growth-associated proteins in the cortical penumbra was augmented. Candesartan also increased the eNOS mRNA level and the lumen size of the middle cerebral artery. In human umbilical endothelial cells, candesartan increased the eNOS protein level AT2-R dependently, inhibited the expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and angiotensin II-induced intracellular reactive oxygen species and nitric oxide, and promoted the extracellular release of nitric oxide, suggesting that it augmented the bioavailability of nitric oxide. CONCLUSION: Among the mechanisms candesartan exerts in its protection against cerebral ischemia, restoration of endothelial function may represent an attractive therapeutic goal to address cerebral ischemia.
Olmesartan medoxomil : a review of its use in the management of hypertension.
Drugs. 2008; 68(9): 1239-72
Scott LJ, McCormack PL
Olmesartan medoxomil (Olmetec((R)), Benicar((R))) is an angiotensin II type 1 (AT(1)) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system, which plays a key role in the pathogenesis of hypertension. Oral olmesartan medoxomil 10-40 mg once daily is recommended for the treatment of adult patients with hypertension. In those with inadequate BP control using monotherapy, fixed-dose olmesartan medoxomil/hydrochlorothiazide (HCTZ) [Olmetec plus((R)), Benicar-HCT((R))] combination therapy may be initiated.Extensive clinical evidence from several large well designed trials and the clinical practice setting has confirmed the antihypertensive efficacy and good tolerability profile of oral olmesartan medoxomil, as monotherapy or in combination with HCTZ, in patients with hypertension, including elderly patients with isolated systolic hypertension (ISH). Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 4 hours of this period. In clinical trials, olmesartan medoxomil monotherapy provided better antihypertensive efficacy than losartan, candesartan cilexetil or irbesartan monotherapy, and was at least as effective as valsartan treatment, with a faster onset of action than other ARBs in terms of reductions from baseline in diastolic BP (DBP) and, in most instances, systolic BP (SBP). Combination therapy with olmesartan medoxomil plus HCTZ was superior to that with benazepril plus amlodipine, as effective as that with losartan plus HCTZ, noninferior to that with atenolol plus HCTZ, but less effective than that with telmisartan plus HCTZ, in individual trials. Data from ongoing clinical outcome trials are required to more fully determine the relative position of olmesartan medoxomil therapy in the management of hypertension. In the meantime, the consistent antihypertensive efficacy during the entire 24-hour dosage interval and good tolerability profile of olmesartan medoxomil, with or without HCTZ, make it a valuable option for the treatment of adult patients with hypertension, including the elderly.
J Obstet Gynaecol Res. 2008 Apr; 34(2): 242-6
Kato K, Okuda M, Ishikawa H, Takahashi T, Hirahara F
Administration of an angiotensin II receptor antagonist (ARB) during the second trimester of pregnancy is known to cause irreversible renal damage in the fetus. We report a case in which ARB was given to the mother from the first trimester until 26 weeks' gestation. The patient had diabetic nephropathy with accompanying nephrotic syndrome. At 8 weeks' gestation, she was started on candesartan cilexetil (an ARB). At 26 weeks' gestation, she was transferred to our center. Severe oligohydramnios was noted. The pregnancy was terminated, and she delivered at 27 weeks' gestation. The neonate weighed 884 g and died 1 h after birth. Autopsy revealed that the lung/bodyweight ratio was 0.0096 (>0.015) and pulmonary hypoplasia was noted. Histological examination of the kidneys showed tubular dysgenesis with poor differentiation of the proximal tubules.
MMW Fortschr Med. 2008 Jan 17; 149 Suppl 4: 172-81
Bramlage P, Schönrock E, Odoj P, Wolf WP, Funken C
BACKGROUND: The treatment of arterial hypertension in Germany is, compared to international control rates, not adequate. In particular patients having additional cardiac risk factors like diabetes mellitus, dyslipidemia, increased waist circumference as well as concomitant diseases like myocardial infarction, heart- as well as kidney failure would benefit from an effective antihypertensive therapy. Aim of the present study was therefore to investigate in more detail blood pressure control in patients receiving a fixed combination of 16 mg Candesartan and 12.5 mg hydrochlorothiazide (HCTZ). METHODS: The present studywas performed as a non-interventional observational study. Included were patients with previously uncontrolled hypertension with at least one further risk factor. Primary variable was the blood pressure reduction over a time period of 8 weeks; secondary variables were the achievement of blood pressure targets and the tolerability of Candesartan/HCTZ. RESULTS: Between August 2006 and February 2007 3,787 patients in 893 physicians' offices in Germany were included. Patients were 62.2 +/- 11.3 years old, 48.1% were female, 97.5% had at least one additional risk factor, 29.8% a cardiovascular event. The risk to die from cardiovascular disease within the next 10 years was 7.4% according to the SCORE Score. By prescribing patients a fixed combination of 16 mg Candesartan/12.5 mg HCTZ a mean blood pressure reduction of -27.2/-13.4 mmHg was achieved (p < 0.001), pulse pressure was reduced by 13.8 mmHg (p
Clin Exp Nephrol. 2008 Mar 5;
Tamura Y, Kosuga M, Yamashita M, Tomioka S, Sasaki M, Hikita T, Nakajima H, Kojima K, Uchida S
BACKGROUND: To investigate the renoprotective effects and safety of angiotensin II receptor blocker (ARB) for patients with stage 4-5 chronic kidney disease. METHODS: An ARB, candesartan cilexetil, was administered to 13 patients (ARB group, n = 7; control group, n = 6) with a serum creatinine level of 2.52-5.95 mg/dl whose blood pressure had been maintained below 140/90 mmHg by the use of drugs other than ARBs. Routine measurements were conducted for 48 weeks, and renal survival analysis was observed for up to 3 years with the endpoints being doubling of the serum creatinine level, entry to hemodialysis, or death. The results were compared with those of the control group that was not treated with ARB. RESULTS: No significant changes were observed in the blood pressure in either group. Proteinuria significantly decreased from 0.95 +/- 0.51 to 0.39 +/- 0.12 g/day (paired t test, P = 0.033) in the ARB group, but did not change in the control group. Creatinine clearance in the control group decreased significantly from 16.2 +/- 5.7 to 10.4 +/- 4.8 ml/min per 1.73 m(2) (paired t test, P = 0.011), but did not change in the other group. Thus, the slopes of the reciprocal serum creatinine values became less steep in the ARB group as compared with the control (-0.002 +/- 0.015 vs. -0.025 +/- 0.015 dl/mg per month; unpaired t test, P = 0.019). Kaplan-Meier analysis revealed that ARB exhibited more favorable renal outcome at 3 years (log-rank, P = 0.025). No serious adverse events were noted in the study. CONCLUSION: These results show that ARB reduces proteinuria and protects renal function even in the advanced renal failure.
Clin Exp Nephrol. 2008 Feb; 12(1): 33-40
Mori-Takeyama U, Minatoguchi S, Murata I, Fujiwara H, Ozaki Y, Ohno M, Oda H, Ohashi H
BACKGROUND: Proteinuria and hypertension are predictors of poor renal outcome in chronic glomerulonephritis (CGN). At the same level of blood pressure (BP) control, we evaluated which is superior, dual blockade of the rennin-angiotensin system (RAS) with both angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 (AT-1) receptor blockade (ARB) or single blockade of ARB to reduce proteinuria and to preserve renal function in patients with CGN. METHODS: In this prospective, parallel, open study of 86 patients with CGN, we compared the effects on proteinuria and renal functions of 36 months with comparable blood pressure (BP) control achieved by candesartan cilexetil (candesartan, 4-12 mg/day) or benazepril hydrochrolide (benazepril, 2.5-10 mg/day) with candesartan (4 mg/day). Aiming at BP 125/75 mmHg or less, the dose of candesartan (single blockade) or benazepril (dual blockade) was increased. RESULTS: Dual blockade decreased proteinuria more than single blockade with ARB (-42.3 vs. -60.5%, P < 0.01). Renal plasma flow (RPF) and glomerular filtration fraction (GFR) did not change significantly in either group. The filtration fraction (FF) decreased dual blockade more than single blockade (-1.7 vs. -19.0%, P < 0.05). Decreased FF was associated with the reduction of proteinuria (P < 0.05). Six percent of patients with dual blockade were not able to continue the study because of a dry cough. CONCLUSION: Long-term dual blockade decreased proteinuria more than single blockade with ARB. Although ARB and ACEI have a glomerular size-selective function for proteinuria, a greater antiproteinuric effect may depend on renal hemodynamics, especially FF. Increased levels of bradykinin after ACEI can decrease FF and ameliorate proteinuria. Dry cough is a significant adverse effect of ACE inhibitor.
Clin Interv Aging. 2006; 1(4): 357-66
Ripley TL, Chonlahan JS, Germany RE
Candesartan cilexetil is a nonpeptide selective blocker of the angiotensin II receptor sub-type 1. It is a prodrug that is converted to its active metabolite during its variable absorption. It is highly protein bound with a small volume of distribution and a nine-hour half-life. Candesartan is one of two angiotensin receptor blockers approved for use in heart failure. MEDLINE was searched using OVID and PubMed to evaluate the evidence for using candesartan in patients with heart failure. Pharmacologic and pharmacokinetic evaluations, as well as clinical trials, were selected and are presented in this review. Clinical evidence supports the indication for use in systolic heart failure. Results for use in patients with diastolic heart failure were non-significant. Candesartan was well tolerated in the trials, with hyperkalemia, renal dysfunction, and hypotension being the most common adverse events. Use of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors needs further study; however, candesartan appears to provide added benefit in this setting. Candesartan is a safe and effective option for patients with systolic heart failure. Data regarding other angiotensin receptor blockers is underway.
Fertil Steril. 2007 Nov 12;
Ata B, Yakin K, Alatas C, Urman B
OBJECTIVE: To evaluate the effectiveness and safety of dual renin-angiotensin system (RAS) blockage together with total embryo cryopreservation for prevention of ovarian hyperstimulation syndrome (OHSS) in overstimulated patients undergoing IVF. DESIGN: Retrospective case series. SETTING: A private tertiary care hospital assisted reproduction program. PATIENT(S): Ten women at high risk for OHSS (mean E(2) level 9401 +/- 585 pg/mL on the day of hCG administration). INTERVENTION(S): Cancellation of ET and dual RAS blockage with an angiotensin receptor blocker (candesartan cilexetil) and an angiotensin-converting enzyme inhibitor (enalapril) starting from day 1 after oocyte retrieval. Embryos were cryopreserved and transferred in subsequent cycles. MAIN OUTCOME MEASURE(S): Development of OHSS and pregnancy and live birth rates after frozen-thawed ETs. RESULT(S): While eight women did not develop OHSS, two women (20%) developed severe OHSS requiring hospitalization. Subsequent frozen-thawed ETs resulted in an 80% clinical pregnancy rate and 40% live birth rate. CONCLUSION(S): Dual RAS blockage with total embryo cryopreservation is a relatively new strategy that was proposed for use in patients at high risk for OHSS. It should be stressed that complete elimination of the syndrome is not possible with this treatment. Subsequent pregnancy rates with the transfer of frozen-thawed embryos are high.
Dig Dis Sci. 2008 May; 53(5): 1206-10
Huang W, Wu YL, Zhong J, Jiang FX, Tian XL, Yu LF
Angiotensin II (Ang II) has been reported to promote tumor progression, tumor growth and angiogenesis in many cancers. We previously observed that angiotensin II type 1 receptors (AT1R) were upregulated in human gastric cancer and may be involved in the progression of gastric cancer. We studied the effects of AT1R antagonist on angiogenesis and growth in gastric cancer xenografts to observe the mechanism action of AT1R in the gastric cancer. The results showed that the growth of gastric cancer cells was significantly suppressed by treatment with AT1R antagonist. In vivo, TCV-116, at doses of both 2 and 5 mg/kg/day, significantly suppressed tumor growth in mice (47.3 and 70.2%). Microvessel density was significantly decreased by TCV-116 (3.4 +/- 0.9 and 2.8 +/- 0.5 per field) compared with the control group (12.9 +/- 1.1 per field), and VEGF expression was significantly suppressed by AT1R antagonist. These results demonstrate that AT1R plays an important role in the progression of gastric cancer. Suppression tumor angiogenesis could be one of the mechanisms by which AT1R antagonist suppresses the growth of gastric cancer. These findings also provide a theoretical basis for the future clinical application of AT1R antagonist against gastric cancer.