Efficacy and Safety of Fixed-Dose Combination of Efonidipine and Telmisartan in Stage II Hypertensive Patients: Results from Randomized Clinical Trial

Aim: The aim of this study was to evaluate the anti-hypertensive efficacy of a fixed-dose combination (FDC) of Efonidipine 40 mg and Telmisartan 40 mg in Stage II hypertensive patients. Study Design: Multicentric, randomized, double-blind, parallel, comparative Phase III clinical trial. Methodology: This clinical trial was conducted at six geographically distributed sites across India and enrolled 240 Stage II hypertensive patients. They were randomized into two groups in a ratio of 1:1 using computer-generated block randomization to receive E+T (FDC of Efonidipine 40 mg + Telmisartan 40mg) or C+T (FDC of Cilnidipine 10 mg + Telmisartan 40 mg) group intervention once daily for a period of 90 days. The study site staff, investigator and patients were blinded to the treatment allocation. The primary endpoint of the study evaluated the mean reduction in sitting systolic BP (SBP) and diastolic BP (DBP) from baseline to day 90 whereas the secondary endpoints assessed were mean reduction in BP from baseline to day 30 & 60, patients achieving target BP (<140/90 mmHg) and the safety and tolerability of the investigational products based on the incidences of adverse events (AEs) reported. Results: A total of 118 subjects were randomized to the E+T group wherein the mean (±SD) SBP and DBP at baseline was 167.25 ± 4.68/107.26 ± 5.19 mmHg. After 30 days of treatment with the E+T group, the mean reduction in SBP/DBP of 29.37/18.06 mmHg was observed whereas at Day 60 reduction of 38.55/22.69 mmHg was seen from the baseline. At Day 90, SBP/DBP decreased to 119.41±14.99/81.67±4.29 mmHg with a mean reduction of 47.94/25.89 mmHg in the E+T group. During the study period, the difference in systolic blood pressure between the treatments with E+T and C+T was -0.48 mmHg, with the two-sided 95% confidence interval (CI) ranging from -4.54 to 3.58?mmHg. The corresponding difference in diastolic blood pressure was -0.77 (95% CI: -2.60 to 1.06) mm?Hg. The upper boundary of the 95% CI was below the margin of 10?mmHg, confirming the non-inferiority of E+T to C+T. A total of 92% of patients who had been assigned to E+T treatment achieved their target BP goal. Only one patient reported an adverse event with E+T treatment. No unexpected AEs were reported in the E+T group suggesting its good safety and tolerability. Overall, the E+T treatment was effective, safe and well-tolerated by the patients for 90 days. Conclusion: It was concluded that the FDC of Efonidipine 40 mg and Telmisartan 40 mg was efficacious in the management of Stage II hypertension.

Azilsartan causing metabolic encephalopathy

Angiotensin II receptor blockers (ARBs) are the antihypertensive drugs associated with side effects, majorly such ascough and electrolyte disturbance. Azilsartan is a newly marketed ARB in India, not even having a well-establishedadverse effect profile. Here, we present a 58-year-old female who was admitted to the emergency department showingsigns and symptoms of delirium, disorientation, and vomiting for 4 days. The patient is known to have coronaryartery disease so that she underwent coronary artery bypass grafting. She was recently started on azilsartan for herchronic hypertension, along with other drugs. The presence of electrolyte imbalance in laboratory reports and currentsymptoms suggested azilsartan-induced encephalopathy. The patient was recovered after discontinuation of azilsartan.This case enlightens the clinical characteristics, possible mechanism, and treatment strategy opted to correct thecondition.

Efficacy of drugs in controlling microalbuminuria of diabetic nephropathy.

Background: Benefi cial effect in reducing microalbuminuria of diabetic nephropathy with angiotensin converting enzyme (ACE) inhibitor and angiotensin II receptor blockers (ARB) is proven. This study has directly compared the renoprotective effects of ARB and ACE inhibitors in persons with type-2 diabetes. Methods: In this prospective, double-blind, controlled trial, 100 patients with type 2 diabetes mellitus were chosen and randomly assigned to either receive ACE inhibitor (ramipril 5 mg, 50 patients) or ARB (losartan 50 mg, 50 patients). The endpoint was a reduction in 24 hrs urine microalbuminuria after a period of 3 months treatment. Results: At the end of 3 months treatment, the mean reduction of 24 hrs urine microalbuminuria in the ramipril group was 25 mg as compared to 38 mg in the losartan group; (t value=1.11, p=0.27). There was no statistical difference in the mean reduction when compared between the two groups. Signifi cant reduction of blood pressure especially systolic blood pressure was noted in the losartan group as compared to those who received ramipril. Conclusion: Losartan was not inferior to ramipril in providing renoprotection in subjects with type 2 diabetes and early nephropathy. Losartan showed a signifi cant reduction in systolic blood pressure, though not much reduction was seen with ramipril. Despite this, both drugs have shown a reduction in microalbuminuria, which supports the fact that reduction in microalbuminuria is independent of the antihypertensive action of ramipril or losartan.

Gastrointestinal tract injury Associated with Aspirin and Other Drugs: Data Mining of the FDA Adverse Event Reporting System, FAERS / 医薬品情報学

<b>Objective: </b>To examine the signal of gastrointestinal tract injury induced by aspirin and other drugs, we analyzed the US FDA Adverse Event Reporting System (FAERS).<br><b>Methods: </b>After deleting duplicate submissions, we analyzed the reports involving gastrointestinal tract injury associated with aspirin, H2-receptor antagonists (H2RAs), proton pump inhibitors (PPIs), ACE inhibitors, angiotensin II receptor blockers (ARBs), and antiplatelet and antithrombotic drugs.  The reporting odds ratio (ROR), a recognized pharmacovigilance tool, was used for the quantitative detection of signals.<br><b>Results: </b>Based on 29,017,485 co-occurrences, i.e., drug-adverse event pairs, found in 1,645,605 reports from 2004 to 2009, the ROR-associated gastrointestinal tract injury for aspirin alone, aspirin with H2RAs, aspirin with PPIs, aspirin with ACE inhibitors, aspirin with ARBs, and aspirin with antiplatelet and antithrombotic drugs were 2.88, 1.42, 1.46, 1.00, 1.05, and 2.98-8.26, respectively.  The following summarizes the types of listed reports: 86 reports described the daily aspirin doses, and 36/86 were between 75 and 100 mg; 343 reports described the periods between the start-date for aspirin and the date when gastrointestinal tract injury occurred, of which 128/343 were within one month while 215/343 were over one month; additionally, 78 reports described the total cumulative doses of aspirin, and 17/78 were between 1 and 5 g.<br><b>Conclusion: </b>The data suggest that H2RAs, PPIs, ACE inhibitors, and ARBs may reduce gastrointestinal tract injury associated with aspirin in possibility.

Preventive Effects of the Angiotensin-II Receptor Blocker on Atrial Remodeling in an Ischemic Heart Failure Model of Rats

BACKGROUND AND OBJECTIVES: It is widely known that angiotensin-II receptor blockers (ARBs) have reverse remodeling effects in atrium. Although atrial fibrillation is frequent in ischemic heart failure clinically, experiments to demonstrate ARB's effects on atrial remodeling in a heart failure model are rare. MATERIALS AND METHODS: A heart failure model and a sham-operated group were formed in 25 Sprague-Dawley male rats of roughly 260 g in weight. Ischemic heart failure models were obtained via ligation of the left anterior descending coronary artery. In the ARB group, 30 mg/kg of losartan was administrated over a day for 4 weeks. Echocardiography was performed to measure left ventricle ejection fraction and left atrial diameter (LAD) at the baseline and 4 weeks after the operation. 4 weeks later, histologic and immunohistochemical evaluation were performed. RESULTS: Groups were divided into the sham group, heart failure group, and heart failure-ARB group. We maintained 5 rats in each group for 4 weeks after operation. The decrease of left ventricular ejection fraction in the heart failure-ARB group was less than that in the heart failure group (p=0.023). The increase of LAD in the heart failure-ARB group was less than that in the heart failure group (p=0.025). Masson's trichrome stain revealed less fibrosis in the heart failure-ARB group. Immunohistochemical stain and western blot for connexin 43 showed less expression in the heart failure-ARB group. CONCLUSION: In the ischemic heart failure model of rats, structurally and histologically, the ARB, losartan, has atrial reverse-remodeling effects. However, electrically, its role as an electrical stabilizer should be studied further.

Lithium Intoxication Induced by Angiotensin II Receptor Blocker/Thiazide Combination Agent

No abstract available.

Angiotensin II Inhibits Insulin Binding to Endothelial Cells

BACKGROUND: Insulin-mediated glucose uptake in insulin target tissues is correlated with interstitial insulin concentration, rather than plasma insulin concentration. Therefore, insulin delivery to the interstitium of target tissues is very important, and the endothelium may also play an important role in the development of insulin resistance. METHODS: After treating bovine aortic endothelial cells with angiotensin II (ATII), we observed the changes in insulin binding capacity and the amounts of insulin receptor (IR) on the cell membranes and in the cytosol. RESULTS: After treatment of 10(-7)M ATII, insulin binding was decreased progressively, up to 60% at 60 minutes (P<0.05). ATII receptor blocker (eprosartan) dose dependently improved the insulin binding capacity which was reduced by ATII (P<0.05). At 200 microM, eprosartan fully restored insulin binding capacity, althogh it resulted in only a 20% to 30% restoration at the therapeutic concentration. ATII did not affect the total amount of IR, but it did reduce the amount of IR on the plasma membrane and increased that in the cytosol. CONCLUSION: ATII decreased the insulin binding capacity of the tested cells. ATII did not affect the total amount of IR but did decrease the amount of IR on the plasma membrane. Our data indicate that ATII decreases insulin binding by translocating IR from the plasma membrane to the cytosol. The binding of insulin to IR is important for insulin-induced vasodilation and transendothelial insulin transport. Therefore, ATII may cause insulin resistance through this endothelium-based mechanism.

Angiotensin II Receptor Blocker Induced Inhibition of Cellular Hypertrophy and Differential Expression of Cyclin-dependent Kinase Inhibitors in Cultured Podocytes Stimulated by Long-term High Glucose / 대한신장학회잡지

BACKGROUND: Hypertrophy of podocytes is observed in type 2 diabetic patients. Cellular hypertrophy requires combined effects of various mitogen- induced entry into the cell cycle and subsequent cell cycle arrest at the G1/S interphase. This cell cycle arrest is mediated by various cyclin-dependent kinase inhibitors (CKIs). We investigated the effect of angiotensin II receptor blocker (ARB) treatment on podocyte hypertrophy and CKIs expression in cultured podocytes stimulated by long-term high glucose. METHODS: Immortalized mouse podocytes were cultured in media containing 5.6 mM normal glucose (NG), 30 mM high glucose (HG), or NG+angiotensin II (AII, 10(-7)M) for 7 days with or without ARB (L-158,809, 10(-6)M). Cellular hypertrophy was assessed by measurement of cellular protein/cell counts, and CKIs mRNA and protein expression were assessed by reverse-transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. RESULTS: Cellular hypertrophy was induced in podocytes exposed to HG or AII compared to NG cells and this HG-induced cellular hypertrophy was inhibited with ARB treatment by 70% (p<0.05). In addition, there were 1.5-fold and 2.0 fold increases in p27Kip1 mRNA and protein expression, respectively, in HG-stimulated podocytes compared to NG- treated cells (p<0.05). p27Kip1 mRNA and protein expression were also increased in cultured podocytes stimulated by AII by 156% and 199%, respectively (p<0.05). ARB treatment ameliorated HG-induced increase in p27Kip1 mRNA by 75% and protein expression by 70% (p<0.05). In contrast, there were no significant changes in p21Cip1 and p57Kip2 protein expression in cultured podocytes exposed to HG or AII. CONCLUSION: High glucose induced significant cellular hypertrophy and increased p27Kip1 mRNA and protein expression in cultured mouse podocytes, and these changes were effectively inhibited by ARB treatment.

Angiotensin II Receptor Blocker Induced Inhibition of Cellular Hypertrophy and Differential Expression of Cyclin-dependent Kinase Inhibitors in Cultured Podocytes Stimulated by Long-term High Glucose / 대한신장학회잡지

BACKGROUND: Hypertrophy of podocytes is observed in type 2 diabetic patients. Cellular hypertrophy requires combined effects of various mitogen- induced entry into the cell cycle and subsequent cell cycle arrest at the G1/S interphase. This cell cycle arrest is mediated by various cyclin-dependent kinase inhibitors (CKIs). We investigated the effect of angiotensin II receptor blocker (ARB) treatment on podocyte hypertrophy and CKIs expression in cultured podocytes stimulated by long-term high glucose. METHODS: Immortalized mouse podocytes were cultured in media containing 5.6 mM normal glucose (NG), 30 mM high glucose (HG), or NG+angiotensin II (AII, 10(-7)M) for 7 days with or without ARB (L-158,809, 10(-6)M). Cellular hypertrophy was assessed by measurement of cellular protein/cell counts, and CKIs mRNA and protein expression were assessed by reverse-transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. RESULTS: Cellular hypertrophy was induced in podocytes exposed to HG or AII compared to NG cells and this HG-induced cellular hypertrophy was inhibited with ARB treatment by 70% (p<0.05). In addition, there were 1.5-fold and 2.0 fold increases in p27Kip1 mRNA and protein expression, respectively, in HG-stimulated podocytes compared to NG- treated cells (p<0.05). p27Kip1 mRNA and protein expression were also increased in cultured podocytes stimulated by AII by 156% and 199%, respectively (p<0.05). ARB treatment ameliorated HG-induced increase in p27Kip1 mRNA by 75% and protein expression by 70% (p<0.05). In contrast, there were no significant changes in p21Cip1 and p57Kip2 protein expression in cultured podocytes exposed to HG or AII. CONCLUSION: High glucose induced significant cellular hypertrophy and increased p27Kip1 mRNA and protein expression in cultured mouse podocytes, and these changes were effectively inhibited by ARB treatment.

Renoprotective Effect of the Combined Use of Steroid and Angiotensin II Receptor Blocker in IgA Nephropathy / 대한신장학회잡지

BACKGROUND: Several studies have examined the role of angiotensin II receptor blocker (ARB) or steroid treatment in decreasing proteinuria and preserving renal function in IgA nephropathy (IgAN). METHODS: We designed a prospective, randomized trial to assess the effects of combination therapy of steroid (daily high-dose for 6 months) and ARB in IgAN patients with proteinuria >or=1.0 g/d and serum creatinine (SCr)or=1.4 mg/dL at the last visit had older age and higher proteinuria level at 6 mo than those with SCror=1g/d that the combination of ARB and prednisolone was more effective in preserving renal function as well as in decreasing proteinuria than the ARB alone therapy.

Effect of combination of ACEI and ARB on left ventricle in pressure-overloaded hypertrophy rats / 中国临床药理学与治疗学

AIM:To explore the effect of the combination of ACEI and ARB on left ventricle in pressure-overloaded hypertrophy rats, and also the relationship between left ventricular hypertrophy (LVH) and cytokines, matrix metalloproteinases, apoptosis, and apoptosis genes. METHODS: IL-6, IL-10, MMP-2 and MMP-9 were evaluated by ELISA method. TNF-alpha was measured with radioimmunoassays. Flow cytometer was used to measure the apoptosis ratio and the expression of Fas, Bcl-2 and Bax. RESULTS: 6 weeks after abdominal aortic coarctation operation, the weight of the left ventricle ( 0.983 ? 0.316 g ) and heart weight/body weight ( 0.382 ? 0.154 ) were significantly increased in control group compared with the sham operated group. And also IL-6 ( 208.71 ? 84.51 pg?ml -1 ), TNF-? ( 1.983 ? 0.842 ng?ml -1 ), MMP-2 ( 74.63 ? 37.62 ), MMP-9 ( 57.74 ? 25.61 ), apoptosis ratio ( 8.47 ? 4.18 ) and apoptosis genes (fas, bax, bcl-2, bcl-2/bax) expression were increased, but IL-10 ( 86.23 ? 40.13 pg?ml -1 ) was decreased compared with sham operated group. The 3 groups with drugs (CP, LT, CP+LT) decreased the increasing weight of LV and ventricular weight/body weight and inhibited the changes of influencing factors (IL-6, IL-10, TNF-?, MMP-2, MMP-9, apoptosis ratio and apoptosis genes expression), especially in the group of combination of 2 drugs. CONCLUSION: LVH might be related with many influencing factors. ACEI and ARB may have the positive importance in the treatment and prevention of LVH.

Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes

VEGF expressed in glomerular podocytes, is known to increase vascular permeability to macromolecules. Angiotensin II can stimulate the release of VEGF, and the protective effects of angiotensin II antagonist against diabetic glomerular injury suggest that the angiotensin II-induced VEGF is an important pathogenetic mechanism in the development of proteinuria during diabetic nephropathy although this mechanism is not fully understood. In this study, the changes of VEGF expression was examined in the experimental diabetic nephropathy to determine whether these changes were modified by renoprotective intervention by blockers of angiotensin II receptors. The streptozotocin- induced diabetic rats were treated with L-158,809, a blocker of angiotensin II receptors, for 12 weeks. Age-matched rats with L-158,809 served as controls. RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of VEGF. A progressive increase in urinary protein excretion was observed in diabetic rats. Glomerular VEGF expression was significantly higher in diabetic rats than in the control groups, with a significant reduction in glomerular VEGF expression and proteinuria in L-158,809- treated diabetic rats. VEGF mRNA was also significantly higher in diabetic kidneys than in the control groups, with a significant reduction in VEGF mRNA in L-158,809-treated diabetic kidneys. These results demonstrates that VEGF expression is significantly increased in diabetic podocytes, and angiotensin II receptor antagonist attenuated these changes in VEGF expression and prevented the development of proteinuria in vivo. Attenuation of increased VEGF expression in podocytes could contribute to the renoprotective effects of angiotensin II receptor antagonists in diabetic nephropathy.

A case of angioedema associated with losartan / 천식및알레르기

Angioedema is a non-pitting edema that occurs in the skin and mucus membranes. It is known that major etiologies include hereditary deficiency of C1 esterase inhibitor, temperature extreme, trauma, food sensitivity, and medications such as penicillin, aspirin, NSAIDS and ACE inhibitors. ACE inhibitors are blocking the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and increasing local levels of bradykinin, a potent vasodilator. This increased bradykinin has been theorized to cause angioedema and cough in patients on ACE inhibitors. However, there has been very few causes of angioedema induced by angiotensin II receptor blocker. This is the first report of a patient presenting angioedema induced by losartan -angiotensin II receptor blocker- in this century.

Effect of Combined Treatment of Steroid and Angiotensin II Receptor Blocker (ARB) in Proteinuric IgA Nephropathy / 대한신장학회잡지

BACKGROUND: It has been reported that prednisolone (PDL) therapy favorably influences proteinuria and renal function in the patients with IgAN in whom ARB as well as ACE inhibitor has an anti- proteinuric effect. Therefore, we did a controlled prospective trial to test the effect of treatment with PDL (daily high-dose for 6 months) and ARB in proteinuric adult patients with IgAN. METHODS: Forty-two patients with proteinuria > or =1.0 g/day and serum Cr < or =2.0 mg/dL were randomized to treatment with PDL and ARB and to that with ARB alone. RESULTS: The follow-up period lasted 15.4+/-3.5 months in combination group (n=18) and 19.8+/-7.4 months in ARB group (n=20). Proteinuria was significantly reduced in the both groups (ARB group: from 4.31+/-2.85 g to 1.38+/-1.09 g vs. combination group: from 4.67+/-5.33g to 0.78+/-0.99 g). The rate of complete remission was 10% in ARB group and 44% in combination group at the final follow-up (p<0.05). There were no differences of mean serum Cr between groups before and after treatment. The number of patient with aggravation in renal function was five (25%) in ARB group and one (5%) in combination group. CONCLUSION: This study shows that the urinary protein excretion was effectively reduced by both groups and the rate of complete remission was higher in combination group than in ARB group. Long- term follow-up may be helpful to define the effect on the renal function in IgAN patients.

A Clinical Study on Anti-Hypertensive Effect and Safety of Candesartan Cilexetil (Atacand) in Mild to Moderate Hypertensive Patients

BACKGROUND AND OBJECTIVES: Candesartan cilexetil (Atacand ), a selective type I angiotensin II receptor blocker, has recently been introduced as a new antihypertensive agent. We evaluated its anti-hypertensive effect and safety in mild to moderate hypertensive patients. MATERIALS AND METHODS: Candesartan cilexetil, 8 mg or 16 mg, was administered once a day over 8 weeks period in the patients with mild to moderate hypertension (25 male, 26 female, mean age: 53.5+/-1.2 years). For safety evaluation, laboratory tests were performed before and after treatment with candesartan cilexetil. Changes in blood pressure, heart rate and electrocardiogram were also observed. RESULTS: 1) The mean blood pressures in the sitting position were systolic 164.1+/-2.1 mmHg and diastolic 106.3+/-0.8 mmHg before treatment, which were lowered to 135.4+/-2.0 mmHg and 89.1+/-1.1 mmHg, repectively after 8 weeks of treatment (p0.05). 4) Laboratory tests revealed no significant abnormality by the treatment with candesartan cilexetil. 5) Left ventricular hypertrophy by ECG criteria detected in 3 cases disappeared after treatment with candesartan cilexetil. 6) No significant side effects were observed during the treatment period. CONCLUSION: Candesartan cilexetil, 8 mg or 16 mg, once a day is an effective and well tolerated antihypertensive treatment. It has a significant dose-dependent antihypertensive effect.

The Clinical Effects of Losartan (Cozaar) on Hypertensive Patients

BACKGROUND: Losartan potassium, one of an orally active, selective type 1 angiotensin II receptor blocker, has been introduced recently as an antihypertensive agent. METHOD: Losartan, angiotensin II receptor blocker, was administrated as an initial antihypertensive agent over 12 weeks in 30 patients (11 male, 19 female, 60.1+/-7.2 years) with stage 1 to 3 hypertension in order to observe the clinical effects. Changes in quality of life, side effects, electrocardiogram and left ventricular function were also evaluated before and after losartan therapy. RESULTS: 1) After 12 weeks treatment with 50 to 100 mg of losartan, blood pressure was lowered markedly in 18 (60%), moderately in 9 (30%) and mildly in 1 (3%) out of 30 patients studied. The average of blood pressures of the 30 subjects were systolic 159.0+/-13.2 mmHg and diastolic 100.7+/-9.4 mmHg before treatment, which were lowered to 130.7+/-15.6 and 85.9+/-9.1 mmHg respectively after 12 weeks (p<0.005). 2) Heart rates were not changed with losartan. 3) Quality of life including general well-being, physical symptom, sleep and sexual dysfunction improved markedly in 2 (7%) and slightly in 17 (57%) out of 30 subjects. 4) Laboratory findings revealed no significant changes. 5) In electrocardiographic and echocardiographic follow-up 1 patient with ST-T abnormality and 2 patients with mild LV systolic dysfunction improved to normal. 6) Undesirable side effects were observed in 2 cases with dizziness, 1 dry cough, 1 skin rash, 1 leg edema and 1 epigastric discomfort, among whom one with dizziness stopped losartan. 7) In the final clinical assessment according to the scores of hypotensive effect, quality of life, LV function and side effect, losartan was very useful in 3 (10%), useful in 18 (60%) and slightly useful in 3 (10%) out of 30 hypertensive patients. CONCLUSION: Losartan can be used as an effective initial agent for the treatment of hypertension of various severities with the improvement of quality of life and low side effects.