Angiotensin-converting Enzyme Inhibitor Ramipril Research Articles

ACE Inhibitor Boosts Walking Times in Peripheral Artery Disease

ACE Inhibitor Boosts Walking Times in Peripheral Artery Disease

Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies

BackgroundLixisenatide is a glucagon-like peptide-1 analog which stimulates insulin secretion and inhibits glucagon secretion and gastric emptying. We investigated cardioprotective effects of lixisenatide in rodent models reflecting the clinical situation.MethodsThe acute cardiac effects of lixisenatide were investigated in isolated rat hearts subjected to brief ischemia and reperfusion. Effects of chronic treatment with lixisenatide on cardiac function were assessed in a modified rat heart failure model after only transient coronary occlusion followed by long-term reperfusion. Freshly isolated cardiomyocytes were used to investigate cell-type specific mechanisms of lixisenatide action.ResultsIn the acute setting of ischemia-reperfusion, lixisenatide reduced the infarct-size/area at risk by 36% ratio without changes on coronary flow, left-ventricular pressure and heart rate. Treatment with lixisenatide for 10 weeks, starting after cardiac ischemia and reperfusion, improved left ventricular end-diastolic pressure and relaxation time and prevented lung congestion in comparison to placebo. No anti-fibrotic effect was observed. Gene expression analysis revealed a change in remodeling genes comparable to the ACE inhibitor ramipril. In isolated cardiomyocytes lixisenatide reduced apoptosis and increased fractional shortening. Glucagon-like peptide-1 receptor (GLP1R) mRNA expression could not be detected in rat heart samples or isolated cardiomyocytes. Surprisingly, cardiomyocytes isolated from GLP-1 receptor knockout mice still responded to lixisenatide.ConclusionsIn rodent models, lixisenatide reduced in an acute setting infarct-size and improved cardiac function when administered long-term after ischemia-reperfusion injury. GLP-1 receptor independent mechanisms contribute to the described cardioprotective effect of lixisenatide. Based in part on these preclinical findings patients with cardiac dysfunction are currently being recruited for a randomized, double-blind, placebo-controlled, multicenter study with lixisenatide.Trial registration(ELIXA, ClinicalTrials.gov Identifier: NCT01147250)

Antihypertensive efficacy of the angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril

Drug therapy often fails to control hypertension. Azilsartan medoxomil (AZL-M) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability. This double-blind, controlled, randomised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril (RAM) in patients with clinic systolic blood pressure (SBP) 150–180 mm Hg. Patients were randomised (n=884) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks, then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks. The primary endpoint was change in trough, seated, clinic SBP. Mean patient age was 57±11 years, 52.4% were male, 99.5% were Caucasian. Mean baseline BP was 161.1±7.9/94.9±9.0 mm Hg. Clinic SBP decreased by 20.6±0.95 and 21.2±0.95 mm Hg with AZL-M 40 and 80 mg vs12.2±0.95 mm Hg with RAM (P<0.001 for both AZL-M doses). Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg (2.4% and 3.1%, respectively) than with RAM (4.8%). These data demonstrated that treatment of stage 1–2 hypertension with AZL-M was more effective than RAM and better tolerated.

Renal Antifibrotic Effect of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in Diabetic Rats

Background and Aim: Diabetic nephropathy is the main cause of end-stage renal disease. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a physiological tetrapeptide hydrolyzed by the angiotensin-converting enzyme (ACE), has antifibrotic effects in the cardiovascular system and in the kidney in experimental models of hypertension, heart failure and renal disease. The aim of the study was to evaluate the effect of Ac-SDKP in diabetic nephropathy and the potential additive effect of Ac-SDKP, when compared to ACE inhibitors alone, on the development of renal fibrosis. Method: Diabetes was induced in 28 Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. Control rats (n = 10) received only buffer solution. An ACE inhibitor (ramipril, 3 mg/kg/day) was administered to 11 diabetic rats. After 2 months, Ac-SDKP (1 mg/kg/day) was administered by osmotic minipumps for 8 weeks to 7 diabetic rats and to 6 diabetic rats treated with ramipril. Osmotic minipumps delivered saline solution in the corresponding sham-treated rats (diabetic rats, n = 10, and ramipril-treated diabetic rats, n = 5). Results: Diabetic rats showed a significant increase in blood glucose level, urinary albumin excretion and renal fibrosis, and a reduction of glomerular nephrin expression with respect to control rats. Ac-SDKP administration significantly reduced renal fibrosis in diabetic rats, without significantly reducing urinary albumin excretion. Ramipril treatment caused a significant decrease in albuminuria and renal fibrosis and restored glomerular nephrin expression. Administration of Ac-SDKP, in addition to ramipril, further reduced renal fibrosis with respect to ramipril alone, while it did not improve the antiproteinuric effect of ramipril. Conclusion: Ac-SDKP administration reduces renal fibrosis in diabetic nephropathy. Addition of Ac-SDKP to ACE inhibition therapy improves the reduction of renal fibrosis with respect to ACE inhibition alone, suggesting a beneficial effect of this pharmacological association in diabetic nephropathy.

Implication of atrial size and function in adults with repaired Tetralogy of Fallot and the effect of treatment by ramipril: the APPROPRIATE randomised trial

Background Background: Patients with repaired tetralogy of Fallot (rtoF) are at risk of supra-ventricular tachycardia due to atrial dilatation. To date, the impact of atrial size and function has been poorly studied in this population. Angiotensin-converting enzyme (ACE ) inhibitor are known for their beneficial effects on atrial and ventricular remodelling in patients with cardiomyopathy. A previous study (APPROPRIATE study) has demonstrated their beneficial effect on ventricular longitudinal contraction in patients with rtoF. We aimed to study first the impact atria volume and function and second, the effect of ACE inhibitor ramipril in adults with rtoF. Methods

The best-laid plans

The best-laid plans

Antihypertensive Efficacy of Olmesartan Medoxomil and Ramipril in Elderly Patients with Mild to Moderate Hypertension Grouped According to Renal Function Status

The objective of this study was to compare the antihypertensive efficacy and safety of the angiotensin II antagonist olmesartan medoxomil and the ACE inhibitor ramipril in elderly patients with mild to moderate essential hypertension, grouped according to renal function. We performed a post hoc analysis of pooled data from two randomized, double-blind, parallel-group, multicentre studies. After a 2-week placebo wash-out period, 1453 mild to moderate hypertensive subjects were randomized to a 12-week treatment with olmesartan medoxomil 10 mg/day or ramipril 2.5 mg/day. After 2 and 6 weeks, doses were increased up to a maximum of 40 mg/day (olmesartan medoxomil) and 10 mg/day (ramipril) in non-normalized subjects (office systolic blood pressure [SBP] ≥ 140 mmHg or diastolic blood pressure [DBP] ≥90 mmHg in non-diabetic subjects and office SBP ≥ 130 mmHg or DBP ≥80 mm Hg in diabetic patients). Office blood pressure (BP) was measured at 0, 2, 6 and 12 weeks, 24-hour ambulatory BP at 0 and 12 weeks. 284 patients treated with olmesartan medoxomil 40 mg/day at the end of the double-blind period entered a 36-week, open-label follow-up. Renal function (Cockroft-Gault equation) was evaluated as normal or increased estimated glomerular filtration rate (eGFR) [≥90 mL/min/1.73 m(2)], mild eGFR reduction (60-90 mL/min/1.73 m(2)) and moderate or severe eGFR reduction (<60 mL/min/1.73 m(2)). 181 (12.7%) subjects had normal or increased eGFR, 840 (58.9%) mild eGFR reduction, and 405 (28.4%) moderate or severe eGFR reduction. Baseline-adjusted office BP reductions were superior with olmesartan medoxomil than with ramipril in normal or increased (olmesartan medoxomil - ramipril difference SBP: 5.0 mmHg [95% CI 9.1, 0.9], p = 0.018; DBP: 2.7 mmHg [4.8, 0.6], p = 0.011) and mildly reduced eGFR patients (SBP: 1.6 mmHg [3.5, 0.2], p = 0.080; DBP: 1.2 mmHg [2.3, 0.2], p = 0.022). In the group with moderately or severely reduced eGFR the two treatments were comparable (SBP: 1.9 mmHg [4.6, 0.9], p = 0.185; DBP: 0.8 mmHg [2.3, +0.7]; p = 0.296). At 12 weeks, the rate of normalized patients was 46.1 % with olmesartan medoxomil versus 23.9% with ramipril (p = 0.002) in the normal, and 49.9% versus 42.7% (p = 0.037) in the mild eGFR reduction group. No significant differences in normalization rate were observed in the moderately or severely reduced eGFR group (olmesartan medoxomil 49.5% vs ramipril 46.3%, p = 0.519). eGFR did not show any significant change during treatment. Olmesartan medoxomil provides a more effective BP control, similar if not superior to that of ramipril, independently from the patient's renal function status.

Antihypertensive Efficacy and Safety of Olmesartan Medoxomil and Ramipril in Elderly Mild to Moderate Essential Hypertensive Patients With or Without Metabolic Syndrome

Two recent identically designed trials (one Italian and one European multinational) have compared the head-to-head efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil and the angiotensin converting enzyme inhibitor ramipril, in elderly patients with essential hypertension. The aim of the present study was to assess the antihypertensive efficacy of olmesartan and ramipril in elderly patients with hypertension, with or without metabolic syndrome, by performing a pooled analysis of data from the two head-to-head trials. After a 2-week, placebo wash-out, 1,453 treated or untreated elderly hypertensive patients aged 65-89 years [with sitting office diastolic blood pressure (DBP) 90-109 mmHg and/or sitting office systolic BP (SBP) 140-179 mmHg] were randomized to 12-weeks of double-blind treatment with olmesartan 10 mg or ramipril 2.5 mg once daily. Treatment could be up-titrated to 20 and 40 mg for olmesartan, and 5 and 10 mg for ramipril, after the first 2 and 6 weeks, respectively, in patients with inadequately controlled BP (BP ≥ 140/90 mmHg for non-diabetics and ≥ 130/80 mmHg for diabetics). Office BP was measured at randomization and after 2, 6 and 12 weeks of treatment. 24-h ambulatory BP recordings were obtained at randomization and after 12 weeks. Of the 1,426 patients in the intent-to-treat analysis, 735 (51.5 %) had metabolic syndrome (olmesartan, n = 372; ramipril, n = 363). After 12 weeks of treatment, baseline-adjusted office BP reductions were greater (p < 0.05) with olmesartan (SBP 17.0 mmHg; 95% CI 18.4, 15.6; DBP 9.6 mmHg; 95% CI 10.4, 8.8) than with ramipril (SBP 14.7 mmHg; 95% CI 16.1, 13.2; DBP 8.4 mmHg; 95% CI 9.2, 7.6) in patients with metabolic syndrome. In these patients, BP normalization rates were also greater with olmesartan than with ramipril (46.0 vs. 35.8%, p < 0.01). Similarly, in patients without metabolic syndrome, the antihypertensive efficacy of olmesartan was also significantly (p < 0.05) better than that of ramipril. In the subgroup of patients with valid ambulatory BP (ABP) recordings and metabolic syndrome (olmesartan, n = 182; ramipril, n = 170), the reduction in mean 24-h ABP was greater with olmesartan (SBP 10.2 mmHg; 95% CI 11.8, 8.6; DBP 6.6 mmHg; 95% CI 7.5, 5.6) than with ramipril (SBP 8.5 mmHg; 95% CI 10.2, 6.9; DBP 4.7 mmHg; 95% CI 5.7, 3.7), with a statistically significant (p < 0.01) difference for the DBP comparison. The proportion of patients experiencing drug-related adverse events was comparable in patients with (olmesartan 2.4 % vs. ramipril 2.8 %) and without (3.5 vs. 3.7 %) metabolic syndrome. Olmesartan provides more effective BP control than ramipril in elderly hypertensive patients with and without metabolic syndrome.

Suits you? A qualitative study exploring preferences regarding the tailoring of consumer medicines information

To explore participants' opinions and preferences on tailored written medicines information. Forty-five participants were recruited to eight focus groups, run concurrently in Australia (23 participants in four groups) and the UK (22 participants in four groups). Participants were provided with exemplar leaflets for a cardiovascular medicine based on the angiotensin-converting enzyme (ACE) inhibitor ramipril, which was tailored for a man aged 55 with hypertension. Reference to other indications of the medicine, children's doses, pregnancy and breast-feeding information were removed. A topic guide directed the discussion and explored preferences and opinions on tailored leaflets. Focus group discussions were recorded, transcribed verbatim and content analysed using adapted cross-case study analysis. Participants welcomed the concept of tailored information, desiring shorter and more relevant information. Information tailored to their condition or disease was most sought-after, followed by tailoring by age or gender. However, some participants voiced concerns about the potential for the wrong information being given to patients who would be unable to recognise that it was incorrect. Other concerns included how tailoring might impact upon the quality of information available and the feasibility of delivery, especially regarding the legal implications (Australia) and the cost (UK). A key finding was the participants' desire for a truly individualised approach to tailoring medicines information, as opposed to the generalised tailored information provided in the study. Participants said they would value having spoken communication with a healthcare professional at the same time as they received tailored leaflets. Most participants welcomed tailored leaflets but overall valued a more personalised approach than the generalised tailored information we provided. Despite concerns about quality and delivery, many felt tailoring written medicines information could improve the relevance of the information to the individual and potentially encourage them to value it.

Patients Who Seem Sick and Tired Usually Are

Patients Who Seem Sick and Tired Usually Are

Administration-Time Differences in Effects of Hypertension Medications on Ambulatory Blood Pressure Regulation

Specific features of the 24-h blood pressure (BP) pattern are linked to progressive injury of target tissues and risk of cardiovascular disease (CVD) events. Several studies have consistently shown an association between blunted asleep BP decline and risk of fatal and nonfatal CVD events. Thus, there is growing focus on ways to properly control BP during nighttime sleep as well as during daytime activity. One strategy, termed chronotherapy, entails the timing of hypertension medications to endogenous circadian rhythm determinants of the 24-h BP pattern. Significant and clinically meaningful treatment-time differences in the beneficial and/or adverse effects of at least six different classes of hypertension medications, and their combinations, are now known. Generally, calcium channel blockers (CCBs) are more effective with bedtime than morning dosing, and for dihydropyridine derivatives bedtime dosing significantly reduces risk of peripheral edema. The renin-angiotensin-aldosterone system is highly circadian rhythmic and activates during nighttime sleep. Accordingly, evening/bedtime ingestion of the angiotensin-converting enzyme inhibitors (ACEIs) benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril exerts more marked effect on the asleep than awake systolic (SBP) and diastolic (DBP) BP means. Likewise, the bedtime, in comparison with morning, ingestion schedule of the angiotensin-II receptor blockers (ARBs irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with the additional benefit, independent of drug terminal half-life, of converting the 24-h BP profile into a more normal dipping pattern. This is the case also for the bedtime versus upon-awakening regimen of combination ARB-CCB, ACEI-CCB, and ARB-diuretic medications. The chronotherapy of conventional hypertension medications constitutes a new and cost-effective strategy for enhancing the control of daytime and nighttime SBP and DBP levels, normalizing the dipping status of their 24-h patterning, and potentially reducing the risk of CVD events and end-organ injury, for example, of the blood vessels and tissues of the heart, brain, kidney, and retina. (Author correspondence: rhermida@uvigo.es)

876 Anti-proliferative and anti-inflammatory effects of Ramiprilat-coated stent in a porcine coronary overstretch restenosis model

Background: The angiotensin-converting enzyme inhibitor ramiprilat has been previously demonstrated to protect myocardium from ischemia/reperfusion injury. Objectives: The aim of this study was to examine the anti-proliferative and anti-inflammatory effects of ramiprilat-coated stent in a porcine coronary overstretch restenosis model. Methods: Pigs were randomized into two groups in which the coronary arteries (16 pigs, 16 coronaries in each group) had either a ramiprilat-coated MAC stent or control MAC stent (AMG, Munich, Germany). Stents were deployed with oversizing (stent/artery ratio 1.3:1) in porcine coronary arteries, and histopathologic analysis was assessed at 28 days after stenting. Results: There were no significant differences in the neointima area normalized to injury score and inflammation score between the two groups (1.58 ± 0.43, 1.60 ± 0.39 in ramiprilat stent group vs. 1.60 ± 0.57, 1.62 ± 0.49 in control stent group, respectively). In neointima, most inflammatory cells were lymphohistiocytes. Overall, significant positive correlations were found between the lymphohistiocyte count and the neointima area (r = 0.567, p < 0.001) and between the lymphohistiocyte count and the percent area stenosis (r = 0.478, p < 0.001). Although lymphohistiocyte count (170 ± 121 cells vs. 162 ± 83 cells) and fibrin scores (0.15 ± 0.06 vs. 0.17 ± 0.07, p = 0.8) were not different between both groups, there was a strong trend of smaller neointima area (1.06 ± 0.51 mm2 vs. 1.28 ± 0.35 mm2, p = 0.083) and percent area stenosis (18.9 ± 8.7% vs. 22.8 ± 7.2%, p = 0.088) in the ramiprilat stent group compared with control group. Conclusions: Ramiprilat-coated stent showed a trend of more inhibitory effects on neointimal hyperplasia without differences in effects on inflammatory cell infiltration and arterial healing compared with control stent in a porcine coronary restenosis model.

Priminary observations of the effects of ACE inhibitor ramipril in patients with Stargardt's disease

AbstractPurpose to assess the effect of Ramipril 2% eyedrops on visual function in patients with Stargardt’s disease.Methods We conducted a prospective, interventional, open label pilot study. 12 eyes of 6 consecutive patients in whom Stargardt’s disease had been diagnosed were treated with Ramipril 2%, one drop three times a day in both eyes. Four follow‐up visits were performed over 3 months. Retinal imaging workup was performed at baseline to confirm diagnosis. During follow up, best corrected visual acuity, fundus examination, static perimetry and electroretinogram were performed to assess safety and efficacy.Results Treatment was well‐tolerated in all cases. Mean BCVA improved from 40 +/‐ 20 letters to 51 +/‐ 17. Mean sensitivity improved from 20.6 +/‐ 3.2 dB to 22.5 +/‐ 3.7dB.Conclusion Ramipril demonstrated a good local and systemic safety profile as well as efficiency in terms of BCVA improvement and retinal sensitivity in patients with Stargardt’s disease. These results encourage us to further describe the effects of Ramipril used as a NO‐donating and antioxidative drug in ophthalmology. Commercial interest

Abstract 147: The AMP-Activated Protein Kinase (AMPK) -Dependent Regulation of Endothelial Cell Angiotensin-Converting Enzyme (ACE) Expression Involves p53 and MicroRNA-143/145

High ACE-levels are associated with cardiovascular disease development, but little is known about its expressional regulation. ACE is a target of the miR143/145-cluster in murine vascular smooth muscle cells and can also be affected by AMPK activation in monocytes. Since shear stress activates AMPK in endothelial cells, we determined whether flow alters ACE expression and the involvement of AMPK and miR143/145. Shear stress decreased ACE expression in human endothelial cells, an effect prevented by downregulating (siRNA) the AMPK α2 subunit, but not AMPKα1.Pharmacological AMPK activation also suppressed endothelial ACE expression and AMPKα2 -/- (not AMPK α 1 -/- ) mice expressed significantly higher ACE levels in different arteries than wild-type littermates. While basal blood pressure was comparable in AMPKα2 +/+ and AMPKα2 -/- mice, AMPKα2 -/- mice were more sensitive to the hypotensive effect of the ACE-inhibitor ramipril and demonstrated an impaired bradykinin-induced hindlimb-vasodilatation. The suppressive effect of the miR-143/145-cluster on human endothelial ACE was confirmed by overexpression of pre-miR143/145 and AMPKα2 downregulation decreased miR143/145-levels . Since f low increased mature and pre-miR-143/145 levels, but not pri-miR143/145 levels, we focused on the post-transcriptional regulation of miR143/145 by AMPK via p53 . Indeed, p53 expression and phosphorylation (Ser15) increased in response to shear stress, and were sensitive to treatment with AMPK α 2 (but not AMPK α 1) siRNA. The data indicate that, AMPKα2 suppresses endothelial ACE expression via p53 activation and upregulation of miR143/145. Since AMPK (and p53) dysregulation is associated with several diseases (e.g. diabetes, cancer), their effect on miRNA143/145 and ACE might mediate disease-associated cardiovascular disorders.

Comparison Between Zofenopril and Ramipril in Combination With Acetylsalicylic Acid in Patients With Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction: Results of a Randomized, Double‐Blind, Parallel‐Group, Multicenter, European Study (SMILE‐4)

Angiotensin-converting enzyme inhibitors (ACEIs) are largely employed for treating patients with left ventricular dysfunction (LVD), but their efficacy may be negatively affected by concomitant administration of acetylsalicylic acid (ASA), with some difference among the different compounds. The interaction between ASA and the two ACEIs zofenopril and ramipril may result in a different impact on survival of cardiac patients, due to differences in the pharmacological properties of the two ACEIs. This phase IIIb, randomized, double-blind, parallel-group, multicenter, European study compared the safety and efficacy of zofenopril (60 mg/day) and ramipril (10 mg/day) plus ASA (100 mg/day), in 771 patients with LVD (clinical signs of heart failure or a left ventricular ejection fraction <45%) following acute myocardial infarction (AMI). The primary study end point was 1-year combined occurrence of death or hospitalization for cardiovascular causes. In the intention-to-treat population, the primary outcome was significantly reduced by zofenopril (n = 365) vs ramipril (n = 351) (odds ratio [OR]: 0.70, and 95% confidence interval [CI]: 0.51-0.96; P = 0.028) as a result of a decrease in cardiovascular hospitalization (OR: 0.64,95% CI: 0.46-0.88; P = 0.006). Mortality rate was not significantly different between the 2 treatments (OR: 1.51, 95% CI: 0.70-3.27; P = 0.293). Blood pressure values did not significantly change during the 1-year follow-up. N-terminal pro-brain natriuretic peptide levels were progressively reduced during the study, with no statistically significant between-treatment differences. Proportion of patients with deterioration of renal function during the study was similar between the 2 groups. Drug safety profile was comparable between treatments. In patients with LVD following AMI, the efficacy of zofenopril associated with ASA was superior to that of ramipril plus ASA, indicating some important clinical implications for the future use of ACEIs in patients with LVD or overt heart failure.

Peptidomic profiles of post myocardial infarction rats affinity depleted plasma using matrix‐assisted laser desorption/ionization time of flight (MALDI‐ToF) mass spectrometry

BackgroundDespite major advances in drug development, effective cardiovascular therapies and suitable cardiovascular biomarkers remain limited. The aim of this study was to leverage mass spectrometry (MS) based peptide profiling strategies to identify changes that occur in peptidomic profiles of rat plasma following coronary artery ligation generated myocardial infarction (MI).MethodsOne week after MI, rats were randomized to receive either an ACE inhibitor (ramipril, Ram-1 mg/kg/day), or vehicle (Veh) for 12 weeks. Echocardiography and hemodynamic measurements were made before sacrifice and plasma collection. High abundance proteins were depleted with affinity capture before MS profiling. Differentially expressed peptide ions were identified using proprietary software (ClinProtTools).ResultsMI increased heart/body weight (18%), lung/body weight (56%), and left ventricular (LV) end diastolic pressure (LVEDP, 247%); and significantly reduced percentage fractional shortening (FS, 75%) and rate of pressure rise in the LV (dP/dtmax, 20%). Ram treatment significantly attenuated the changes in LVEDP (61%) and FS (27%). Analysis of MALDI-ToF generated mass spectra demonstrated that peptide ions 1271, 1878, 1955, 2041 and 2254 m/z were consistently decreased by Ram treatment (p < 0.001) and thus may be associated with the agent’s therapeutic effects. Among peptides that were significantly changed, synapsin-2, adenomatous polyposis coli protein and transcription factor jun-D were identified as significantly reduced by Ram treatment.ConclusionsThis approach allows us to screen for potential biomarkers in a window of the blood proteome that previously has been difficult to access. The data obtained from such an approach may potentially useful in prognosis, diagnosis, and monitoring of treatment response.

A Spectrophotometric Method for the Determination of Ramipril in Solid Dosage Forms

Purpose: To develop a simple and cost effective spectrophotometer method for the determination of ACE inhibitor ramipril in dosage forms. Methods: UV spectrophotometry was used to develop and validate a simple method for the assay of ramipril in solid dosage form at λmax of 210 nm, as per International Conference on Harmonization (ICH) guidelines. Aqueous methanol (5 %) was used as the blank solvent. The method was validated for linearity, recovery, accuracy, precision, specificity in the presence of excipients, and also for inter-day stability under laboratory conditions. Results: Validation results showed linearity in the range 1 – 38 μg/ml; recovery accuracy 101.55%; regression equation Y = 0.0256X + 0.0697, R² of 0.9942; precision RSD < 2.00 %; and negligible interference from common excipients and colorants. The method was accurate (95 % confidence limit) compared to standard liquid chromatography (LC) method, with comparable reproducibility when used to assay a commercial product (Ramitace®, 2 and 5 mg tablets). Conclusion: The validated data were within allowable limits and therefore, the proposed method is recommended for routine quality control (QC) analysis Keywords: Ramipril, Spectrophotmetric assay, Validation, Solid dosage forms

Double blockade of angiotensin II (AT1)‐receptors and ACE does not improve weight gain and glucose homeostasis better than single‐drug treatments in obese rats

Combination therapies are becoming increasingly important for the treatment of high blood pressure. Little is known about whether double blockade of angiotensin II (AT(1) ) receptors and angiotensin-converting enzyme (ACE) exert synergistic metabolic effects. Spontaneously hypertensive rats were allowed to choose between palatable chocolate bars and standard chow and were simultaneously treated with the AT(1) blocker telmisartan (8 mg·kg(bw) (-1) ·day(-1) ), the ACE inhibitor ramipril (4 mg·kg(bw) (-1) ·day(-1) ) or a combination of the two (8 + 4 mg·kg(bw) (-1) ·day(-1) ) for 12 weeks. Although food-dependent energy intake was increased by telmisartan and telmisartan + ramipril compared with ramipril or controls, body weight gain, abundance of fat and plasma leptin levels were decreased. Increased insulin levels in response to an oral glucose tolerance test were comparably attenuated by telmisartan and telmisartan + ramipril, but not by ramipril. During an insulin tolerance test, glucose utilization was equally as effectively improved by telmisartan and telmisartan + ramipril. In response to a stress test, ACTH, corticosterone and glucose increased in controls. These stress reactions were attenuated by telmisartan and telmisartan + ramipril. The combination of telmisartan + ramipril was no more efficacious in regulating body weight and glucose homeostasis than telmisartan alone. However, telmisartan was more effective than ramipril in improving metabolic parameters and in reducing body weight. The association between the decrease in stress responses and the diminished glucose levels after stress supports our hypothesis that the ability of telmisartan, as an AT(1) receptor blocker, to alleviate stress reactions may contribute to its hypoglycaemic actions.

Ramipril and Telmisartan Exhibit Differential Effects in Cardiac Pressure Overload-Induced Hypertrophy Without an Additional Benefit of the Combination of Both Drugs

We aimed to characterize different cellular effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 1 (AT1) receptor blockers (ARBs) as mono- or combination therapy in cardiac pressure overload. Methods and C57B1/6 mice received either the ACEI ramipril (2.5 mg/kg body weight), the ARB telmisartan (20 mg/kg body weight), or the combination. In all groups, pressure overload was induced by transverse aortic constriction (TAC). Cardiac hypertrophy (heart weight/tibia length) induced by TAC was reduced in all 3 treatment groups, with the most pronounced effect in the telmisartan group. The cardiomyocyte short-axis diameter and cardiac fibrosis were increased by TAC and similarly reduced by ACEI, ARB, and the combination therapy. The TAC-induced increase in the number of proliferating Ki67(pos) cardiomyocytes and noncardiomyocytes was reduced more potently by ACEI than by ARB. Four days of drug treatment induced a significant increase in Scal(pos)/VEGFR1(pos) endothelial progenitor cells (EPCs) in all animals in the treated SHAM groups. After 1 day of aortic constriction, only ramipril increased EPC numbers; after 5 weeks, telmisartan monotherapy did not change the EPC levels compared to vehicle or the combination therapy but raised it compared to ramipril. Neither TAC nor one of the therapies changed the number of cardiac capillaries per cardiomyocytes. ACE inhibition and AT1 receptor blockade have beneficial effects in remodeling processes during cardiac pressure overload. There are small differences between the 2 therapeutical approaches, but the combination therapy has no additional benefit.

Angiotensin Receptor Blockers in Clinical Practice — Implications of the ONTARGET Study

Hypertension and cardiovascular disease remain the major causes of premature morbidity and mortality. Following a diagnosis of hypertension, treatment with antihypertensive medication will almost invariably be lifelong. Even when prescribed treatment, many patients remain above blood pressure goals, and this is particularly common in patients at high risk of cardiovascular events due to the presence of other risk factors such as diabetes mellitus. An important cause of this failure is medication nonadherence, which is particularly common with treatments that have side-effects. Antihypertensive drugs do not make the patient feel better in the short term, but side-effects often occur immediately. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) is highly relevant to clinical practice because it demonstrated that the angiotensin receptor blocker (ARB) telmisartan is as effective as the proven angiotensinconverting enzyme inhibitor ramipril in preventing cardiovascular events in high-risk patients, while being better tolerated. Evidence of the advantages of telmisartan in the management of cardiovascular morbidity suggest, therefore, that it might be a better treatment option for hypertensive patients and that switching to generic ARBs may not always be best.