Clinical trial design for assessing hypertension medications: are critical circadian chronopharmacological principles being taking into account?

INTRODUCTION: Clinical hypertension trials typically rely on homeostatic principles, including single time-of-day office blood pressure (BP) measurements (OBPM), rather than circadian chronopharmacological principles, including ambulatory monitoring (ABPM) done around-the-clock to derive the asleep systolic BP (SBP) mean and sleep-time relative SBP decline - jointly the strongest prognosticators of cardiovascular disease (CVD) risk and true definition of hypertension - to qualify participants and assess outcomes. AREAS COVERED: Eight chronopharmacological elements are indispensable for design and conduct of hypertension medication trials, mainly those on ingestion-time differences in effects, and also a means of rating quality of investigations. Accordingly, we highlight the findings and shortcomings of: (i) 155 such ingestion-time trials, 83.9% finding at-bedtime/evening treatment more beneficial than conventional upon-awakening/morning treatment; (ii) HOPE and ONTARGET CVD outcomes investigations assessing in the former add-on ramipril at-bedtime and in the latter telmisartan, ramipril, or both in combination in the morning; and (iii) pragmatic TIME CVD outcomes trial. EXPERT OPINION: Failure to incorporate chronopharmacological principals - including ABPM to derive asleep SBP and SBP dipping to qualify subjects as hypertensive and assess CVD risk - results in deficient study design, dubious findings, and unnecessary medical controversy at the expense of advances in patient care.

Evaluation of the efficacy of hydro-alcoholic extract of Evolvulus alsinoides L. for the treatment of primary hypertension - A randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Evolvulus alsinoides L. (Sankhaholi) has been traditionally used in Unani (Greco-Arabic) medicine to treat diverse cardiovascular disorders. Notably, preclinical and clinical investigations have substantiated its remarkable potential as an antihypertensive agent. AIM OF THE STUDY: The aim of this study was to compare the efficacy of hydroalcoholic extract of Evolvulus alsinoides L. and ramipril in treating hypertension using a higher dose of the test drug within the recommended limit. MATERIALS AND METHODS: In this open-label randomized controlled trial, 57 participants (29 in the test group, 28 in the control group) completed the 42-day study. The test group received 630 mg of dried hydro-alcoholic extract of Evolvulus alsinoides L. in capsule form orally once daily, while the control group received 5 mg of Ramipril orally once daily. Participants in both groups were advised to adhere to the Dietary Approaches to Stop Hypertension (DASH) eating plan in terms of diet and lifestyle adjustments recommended by JNC-8. The primary outcome measures were changes in systolic and diastolic blood pressure as well as changes in plasma levels of hsCRP and IL6. Secondary outcome measures included changes in symptoms such as palpitations, giddiness, headaches, fatigue and shortness of breath. Headaches, palpitations, and giddiness were assessed using a customized Visual Analog Scale (VAS) graded as "none," "mild," "moderate," and "severe". Fatigue was assessed on a binary scale as either absent or present, and dyspnea was assessed using the modified Medical Research Council (mMRC) scale for breathlessness. Both primary and secondary outcomes were assessed at baseline and each follow-up visit (2nd week, 4th week, and 6th week) until the completion of the trial. RESULTS: At the end of the trial, the mean differences for the primary outcomes were as follows:SBP:-1.8895%CI:-4.82,1.05,p=0.203,d=0.33, DBP: -2.8395%CI:-4.67,-0.10,p=0.003,d=0.8, hsCRP: -1.4095%CI:-2.80,-0.003,p=0.49,d=0.53, and IL6: -88.6795%CI:-148.90,-28.43,p=0.005,d=0.78. No statistically significant differences were observed between the two groups for any of the secondary outcomes. CONCLUSIONS: Based on the preliminary results, it can be inferred that the hydro-alcoholic extract of Evolvulus alsinoides L. exhibits significant antihypertensive potential, comparable to that of ramipril. Furthermore, it appears that Evolvulus alsinoides L. may be more effective than ramipril in reducing the biochemical markers of inflammation associated with primary hypertension. However, additional research is required to validate these findings.

Appraisal of anti-inflammatory and immunomodulatory potential of ramipril against Freund's adjuvant-provoked arthritic rat model.

Because of evident role of renin-angiotensin system in the etiology of rheumatoid arthritis, the current study's objective was to assess the anti-arthritic efficacy of ramipril through CFA-instigated arthritic model. The drug has been shown to have anti-inflammatory potential. CFA-instigated arthritic model assessed the anti-arthritic efficacy of ramipril by estimating different parameters, including paw volume, arthritic index scoring, haematological and biochemical attributes, histological and radiographic analyses, and various cytokines level. Ramipril significantly (p < 0.001) reduced paw volume and the arthritic index especially at the dose of 4mg/kg. The biochemical and haematological changes were likewise restored to normal by ramipril administration with an increase in anti-inflammatory cytokines while reducing pro-inflammatory cytokines level. Ramipril's ability to prevent arthritis by preserving the normal architecture of arthritis-induced joints is further supported by radiographic and histological investigation. The study's findings demonstrated ramipril's considerable anti-arthritic activity. To identify the precise mechanism of action, however, thorough mechanistic studies are still needed.

Supplementation of antihypertensive drug regimen with vitamin E ameliorates alterations of primary haemodynamic parameters and total antioxidant capacity in ovariectomised rats.

OBJECTIVES: Ovariectomy induces heightened response to vasoconstrictors, alters vasorelaxation and consequently causes hypertension due to increased oxidative stress in rats. METHODS: This study evaluated the ameliorative effects of ramipril and vitamin E, on primary haemodynamic parameters and cardiac antioxidant defence status, in ovariectomised rats using 64 adult female rats of the Wistar strain randomly divided as follows: Control (sham); Ovariectomised (OVX); OVX plus Ramipril; OVX plus vitamin E; and OVX plus Ramipril plus vitamin E. RESULTS: The plasma level of oestrogen was significantly lower (p<0.05), in the ovariectomised rats compared with the sham. The systolic, diastolic and mean arterial blood pressure of ovariectomised rats increased significantly (p<0.05), but the alteration was significantly reduced by the administration of ramipril alone or in combination with vitamin E. Significant decrease (p<0.05) was observed in the serum level of nitric oxide in OVX group compared with Sham. Also, analysed markers of oxidative stress: Malondialdehyde (MDA) contents and hydrogen peroxide (H2O2) generated decreased significantly (p<0.05), but systemic antioxidants: reduced glutathione (GSH) contents; glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities increased significantly (p<0.05) in the ovariectomised rats treated with ramipril and vitamin E compared with untreated ovariectomised rats. The study concludes that alteration, in the primary haemodynamic parameters, associated with ovariectomy in rats is potently ameliorated by co-administration of the antihypertensive drug ramipril and vitamin E. CONCLUSIONS: The supplementation of antihypertensive regimen with antioxidants such as vitamin E in the treatment of hypertension is therefore justifiable especially in ovariectomised or hypogonadal patients.

Angiotensin-Converting Enzyme Inhibitor Reduces Radiation-Induced Periprosthetic Capsular Fibrosis.

BACKGROUND: The capsular contracture is one of the main complications after radiotherapy in patients with implant-based reconstruction. The aim of this study is to evaluate the efficacy of ramipril for the prevention of radiation-induced fibrosis around the silicone implant. MATERIALS AND METHODS: Thirty Wistar rats in 5 groups were used. Group 1: implant; group 2: implant + radiation; group 3: ramipril + implant; group 4: ramipril + implant + radiation; group 5: sham. Ramipril treatment was started 5 d before surgery and continued for 12 wk after surgery. A mini silicone implant was placed in the back of the rats. A single fraction of 21.5 Gy radiation was applied. Tissues were examined histologically and immunohistochemically (TGF-ß1, MMP-2, and TIMP-2 expression). The alteration of plasma TGF-ß1 levels was examined before and after the experiment. RESULTS: After applying implant or implant + radiation, capsular thickness, percentage of fibrotic area, tissue and plasma TGF-ß1 levels significantly increased, and MMP-2/TIMP-2 ratio significantly decreased compared with the sham group. In ramipril-treated groups, the decrease in capsular thickness, fibrosis, TGF-ß1 positivity, and an increase in MMP-2/TIMP-2 ratio were found significant. In the ramipril + implant + radiation group, the alteration values of TGF-ß1 dramatically decreased. CONCLUSIONS: Our results show that ramipril reduces radiation-induced fibrosis and contracture. The results of our study may be important for the design of the clinical trials required to investigate the effective and safe doses of ramipril, which is an inexpensive and easily tolerated drug, on humans.

Preparation and Evaluation of '3 Cap' Pulsatile Drug Delivery System of Ramipril.

BACKGROUND: Chronotherapeutics, the drug delivery based on circadian rhythm, is recently gaining much attention worldwide. Various diseases like asthma, hypertension, and arthritis show the circadian variation that demands time scheduled drug release for effective drug action. Therefore, the pulsatile drug delivery system has been designed to confer preprogrammed drug delivery. OBJECTIVE: In the present study, a '3 Cap' pulsatile drug delivery system has been developed, optimized, and characterized in order to achieve the floating and pulsatile release of ramipril. METHODS: An optimal response surface design was employed to investigate the effect of isopropanol: formaldehyde vapors for varying time on drug release from the capsules. '3 Cap' pulsatile drug delivery system was evaluated in terms of floating time, density, the effect of gastric flow rate, and type of dissolution apparatus on drug release. RESULTS: Independent variables exhibited a significant effect on the drug release of the prepared formulations. Results showed that time between the release of fractions of dose increased with an increase in formaldehyde: isopropanol ratio and duration of exposure to formaldehyde vapors with no effect of gastric flow rate. CONCLUSION: The results of the designed system revealed that an optimum exposure of 1:2 of isopropanol: formaldehyde vapors for sixty minutes resulted in the desired release of second pulse of dose after a predetermined lag time of 5 hours as desired. '3Cap' system was successful in achieving floating and pulsed release of hypertensive drug opening a 'new lease of life' to the existing drug molecule.

Impact of renin-angiotensin system inhibitors on clinical outcomes and ventricular remodelling after transcatheter aortic valve implantation: rationale and design of the RASTAVI randomised multicentre study.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) as a treatment in severe aortic stenosis (AS) is an excellent alternative to conventional surgical replacement. However, long-term outcomes are not benign. Renin-angiotensin system (RAS) blockade has shown benefit in terms of adverse remodelling in severe AS and after surgical replacement. METHODS AND ANALYSIS: The RAS blockade after TAVI (RASTAVI) trial aims to detect if there is a benefit in clinical outcomes and ventricular remodelling with this therapeutic strategy following the TAVI procedure. The study has been designed as a randomised 1:1 open-label study that will be undertaken in 8 centres including 336 TAVI recipients. All patients will receive the standard treatment. The active treatment group will receive ramipril as well. Randomisation will be done before discharge, after signing informed consent. All patients will be followed up for 3 years. A cardiac magnetic resonance will be performed initially and at 1 year to assess ventricular remodelling, defined as ventricular dimensions, ejection fraction, ventricular mass and fibrosis. Recorded events will include cardiac death, admission due to heart failure and stroke. The RASTAVI Study will improve the management of patients after TAVI and may help to increase their quality of life, reduce readmissions and improve long-term survival in this scenario. ETHICS AND DISSEMINATION: All authors and local ethics committees have approved the study design. All patients will provide informed consent. Results will be published irrespective of whether the findings are positive or negative. TRIAL REGISTRATION NUMBER: NCT03201185.

Clinical efficacy of African traditional medicines in hypertension: A randomized controlled trial with Combretum micranthum and Hibiscus sabdariffa.

Medicinal plants are widely used as a first-line therapy for hypertension, often without comparative clinical data. A prospective, randomized controlled trial was conducted to assess efficacy of Combretum micranthum (kinkeliba) and Hibiscus sabdariffa (bissap), in the galenic form of capsules of plant powder, on blood pressure in adult patients with non-complicated hypertension ( > 140/90 mm Hg). One hundred and twenty five patients were randomly allocated into group 1 (kinkeliba leaves 190 mg × 2/day), or group 2 (bissap calyx 320 mg × 2/day), or group 3 (ramipril 5 mg /day) during four consecutive weeks. Blood and urinary samples were collected on day 0 and 28 while patients' blood pressure was measured weekly. In all three groups SBP and DBP decreased over 3 weeks of treatment (P < 0.001). For SBP, mean decrease was higher with ramipril (-16.7 ± 8.4 mm Hg) than with kinkeliba (-12.2 ± 6.6 mm Hg, P = 0.016) and bissap (-11.2 ± 3.3 mm Hg, P = 0.001). For DBP, mean decrease with ramipril (-6.7 ± 3.6 mm Hg) was more important than with kinkeliba (-5.0 ± 3.0 mm Hg, P = 0.011) but not statistically different to bissap group (-6.0 ± 4.7 mm Hg, P = 0.271). A significant natriuretic effect was observed in the kinkeliba and bissap groups but not in patients under ramipril treatment. At the end of the four weeks, 39% [95% CI: 25.7-54.3] of patients in the ramipril group, 37% [95% CI: 23.6-51.9] of patients in the kinkeliba group and 21% [95% CI: 11.7-35.9] of those taking bissap had normalized their BP.

Effect of ethanolic extract of Cyperus rotundus L. against isoprenaline induced cardiotoxicity.

Interruption of blood supply to the heart results in acute myocardial infarction (AMI), and further damages the heart muscles. Available drugs for the treatment MI have one or other side effects, and there is a need for development of better alternative drugs from herbal sources. Here, we evaluated cardioprotective effect of Cyperus rotundus on isoprenaline- induced myocardial infarction. Thirty five Wistar rats, aged 60-100 days with body wt. 150-200 g, pretreated with ethanolic extract of Cyperus rotundus L. (@ 250 and 500 mg/kg body wt.) orally before induction of myocardial necrosis by administrating isoprenaline (85 mg/kg, s.c.) on 19th and 20th day of the pretreatment period. The treated rats were examined for gross functioning of heart, heart weight/body wt. Ratio, and also observed histopathologically. Further, activities of various cardiac enzymes such as aspartate transaminase, alanine transaminase, creatinine kinase-myoglobulin, lactate dehydrogenase, and the gold marker troponin-I were also determined. The levels altered by isoproterenol were found to be restored significantly by the test extracts especially at higher dose. Biochemical observations viz., serum ALT (P <0.0001), AST (P <0.0001), creatine kinase-myoglobulin (CK-MB) (P <0.0001), LDH (P <0.0001) demonstrated significant cardioprotective activity of the ethanolic extract of C. rotundus (500 mg/kg body wt.), against isoprenaline induced myocardial infarction. These results were also substantiated by physical parameters and histopathological observations. All these results were comparable with that of two standard drugs metoprolol (10 mg/kg/day), ramipril (3 mg/kg/day) as well as polyherbal formulation Abana (50 mg/kg/day).

[Ramipril plus amlodipine and lisinopril plus amlodipine fixed dose combinations and patient's adherence]. / A ramipril/amlodipin és a lisinopril/amlodipin fix kombinációk a terápiahuség tükrében.

INTRODUCTION: Patient's adherence has a great significance to reach target blood pressure values. The risk of cardiovascular adverse events decreases when patients are on target blood pressure. AIM: The aim of the authors was to investigate the one-year persistence of the ramipril/amlodipine and lisinopril/amlodipine fixed dose combination in hypertensive patients. METHOD: National Health Insurance Found prescriptions database of Hungary on pharmacy-claims between October 1, 2012 and September 30, 2013 was analyzed. The authors identified patients who filled prescriptions for fixed dose combinations of ramipril and amlodipine, and lisinopril and amlodipine prescribed for the first time, for the therapeutic indication of hypertension. Patients have not received antihypertensive therapy with similar active substances during one year before the study. To model the persistence, the apparatus of survival analysis was used, where "survival" was the time to abandon the medication. As it was available to month precision, discrete time survival analysis was applied: a generalized linear model was estimated with complementary log-log link function with the kind of drug being the only explanatory variable. RESULTS: During the study period, fixed dose combination antihypertensive therapy with ramipril plus amlodipine and lisinopril plus amlodipine was started in 10,449 and 20,276 patients, respectively. One-year persistence rate in patients taking ramipril and amlodipine as a fixed dose combination was 54%, whereas 36% in those on the fixed lisinopril and amlodipine combination. Considering only the 360-day study period, the mean duration of persistence was 271 days in patients on the ramipril based and 211 days on lisinopril based fixed dose combination. Analyzing persistence on treatment with these combinations showed that the actual rate of discontinuation was about twice higher during treatment with the lisinopril and amlodipine fixed dose combination compared with the use of the ramipril and amlodipine fixed dose combination (hazard ratio = 1.79, p<0.001). CONCLUSIONS: There is a significant difference between the one-year persistence of ramipril plus amlodipine and lisinopril plus amlodipine fixed dose combination in patients with hypertension. The result demonstrated that ramipril and amlodipine fixed dose combination has a favourable patients' adherence as compared to lisinopril and amlodipine fixed dose combination.

Ramipril/amlodipine single pill - effectiveness, tolerance and patient satisfaction with antihypertensive therapy in relation to nutritional status.

BACKGROUND: Overweight and obesity decrease the effectiveness of antihypertensive therapy despite the more frequent use of polytherapy. One method for improving therapy effectiveness is by decreasing non-compliance with the use of fixed-dose combinations (FDC). The aim of this study was to assess the effectiveness, tolerance, and satisfaction with ramipril/amlodipine FDC antihypertensive therapy in relation to nutritional status. METHODS: The survey enrolled 24,240 hypertensive patients recently switched to ramipril/amlodipine FDC (EGIRAMLON) at the same doses as previously prescribed separate pills. RESULTS: The effectiveness of antihypertensive therapy increased during follow-up from 32.9% to 76.5%. Overweight and obesity were associated with the increased risk of not attaining the recommended BP values [adjusted for age OR=0.74 (95% CI 0.67-0.83) and 0.70 (0.61-0.81) for overweight; 0.54 (0.47-0.60) and 0.49 (0.42-0.57) for obese, at the first and the second examination, respectively]. "Very good" or "good" the FDP tolerance was reported by 98.8%, 97.6% and 96.4%, respectively. Adverse events (AE) were reported in 0.35% of patients regardless of nutritional status. High levels of satisfaction with the FDC were reported by 57.0% of patients with normal weight, 54.5% of overweight, and 50.6% with obesity. Effectiveness and convenience were the most important for patients. CONCLUSIONS: The effectiveness of therapy with ramipril/amlodipine FDC in the study population was high, but slightly lower in overweigh and obese. This FDC was well tolerated and a significant number of patients satisfied with the therapy regardless of nutritional status. Although the perceived tolerance and satisfaction with treatment were lower in obese and overweight than in normal weight patients; the incidence of AE and perceived benefit from the use of a single-pill, compared to multiple tablets, were comparable irrespective of nutritional status.

Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V).

Background McArdle disease (Glycogen Storage Disease type V) is caused by an absence of muscle phosphorylase leading to exercise intolerance,myoglobinuria rhabdomyolysis and acute renal failure. This is an update of a review first published in 2004.Objectives To review systematically the evidence from randomised controlled trials (RCTs) of pharmacological or nutritional treatments for improving exercise performance and quality of life in McArdle disease.Search methods We searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE on 11 August 2014.Selection criteria We included RCTs (including cross-over studies) and quasi-RCTs. We included unblinded open trials and individual patient studies in the discussion. Interventions included any pharmacological agent or nutritional supplement. Primary outcome measures included any objective assessment of exercise endurance (for example aerobic capacity (VO2) max, walking speed, muscle force or power and fatigability). Secondary outcome measures included metabolic changes (such as reduced plasma creatine kinase and a reduction in the frequency of myoglobinuria), subjective measures (including quality of life scores and indices of disability) and serious adverse events.Data collection and analysis Three review authors checked the titles and abstracts identified by the search and reviewed the manuscripts. Two review authors independently assessed the risk of bias of relevant studies, with comments from a third author. Two authors extracted data onto a specially designed form.Main results We identified 31 studies, and 13 fulfilled the criteria for inclusion. We described trials that were not eligible for the review in the Discussion. The included studies involved a total of 85 participants, but the number in each individual trial was small; the largest treatment trial included 19 participants and the smallest study included only one participant. There was no benefit with: D-ribose,glucagon, verapamil, vitamin B6, branched chain amino acids, dantrolene sodium, and high-dose creatine. Minimal subjective benefit was found with low dose creatine and ramipril only for patients with a polymorphism known as the D/Dangiotens in converting enzyme(ACE) phenotype. A carbohydrate-rich diet resulted in better exercise performance compared with a protein-rich diet. Two studies of oral sucrose given at different times and in different amounts before exercise showed an improvement in exercise performance. Four studies reported adverse effects. Oral ribose caused diarrhoea and symptoms suggestive of hypoglycaemia including light-headedness and hunger. In one study, branched chain amino acids caused a deterioration of functional outcomes. Dantrolene was reported to cause a number of adverse effects including tiredness, somnolence, dizziness and muscle weakness. Low dose creatine (60 mg/kg/day) did not cause side-effects but high-dose creatine (150 mg/kg/day) worsened the symptoms of myalgia.Authors' conclusions Although there was low quality evidence of improvement in some parameters with creatine, oral sucrose, ramipril and a carbohydrate rich diet, none was sufficiently strong to indicate significant clinical benefit.

Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: a randomized controlled trial. Journal of the American Medical Association 2013; 309: 453-460.

STUDY OBJECTIVE: The objective of the trial was to examine whether ramipril, an angiotensin-converting enzyme (ACE), improves walking distance and health-related quality of life in patients with peripheral artery disease (PAD) associated with claudication. STUDY POPULATION: The study enrolled 212 patients with risk factors and symptoms of PAD treated by conventional therapies at three centers in Australia. All patients had an ankle-brachial index (ABI) of less than 0.90 at rest and intermittent claudication in at least one leg, which were stable for at least 6 preceding months along with the medication regimen. The patients were excluded if blood pressure was not controlled (brachial blood pressure of 160/100 mmHg or greater); if there was current or recent use of either ACE inhibitors or angiotensin II receptor blockers, potassium-sparing diuretics, or potassium supplements; renal failure (serum creatinine level 2.3 mg/dL or greater [200 µmol/L]); renal artery stenosis; previous coronary or peripheral artery revascularizations, recent myocardial infarction and other health conditions other than PAD that could adversely influence walking ability at the time of screening and for 1 year thereafter. DESIGN AND METHODS: This was a randomized, placebo-controlled, triple blinded study of ramipril at the high daily dose (10 mg) for 6 months. Primary outcomes were pain-free and maximum walking times assessed by a standard treadmill exercise test. Secondary outcomes were ABI changes; symptoms and functional status assessed by the Walking Impairment Questionnaire (WIQ)(1); health-related quality of life assessed by the Short-Form 36 Health Survey (SF-36)(2); and stenosis severity assessed by duplex ultrasound of the lower limb arteries. At baseline and at follow-up, pain-free and maximum walking distances were assessed by the standard constant load treadmill exercise test performed at a speed of 3.2 km/h and a grade of 12%.(3) ABI was calculated in both legs. Duplex ultrasonography was used to determine stenosis in lower-limb vessel segments. Functional changes per WIQ, and perceived disability assessed on the Physical Component Summary and the Mental Component Summary of the SF-36 were self-reported. Sample size was calculated as 100 patients per each group needed to provide a power of 80% at an α of 0.05 to detect a 120-second change in walking time and a 65-second change in pain-free walking time. A two-sided p-value of less than 0.05 was considered significant. Baseline variables were compared using the χ(2) test and one-way analysis of variance. The analysis of covariance model with baseline and post-treatment values after 6 months used Kruskal-Wallis analysis of variance. Imputations for missing 6-month data were performed. Data were analyzed on the intention-to-treat basis. RESULTS: Of 921 potential participants screened, 212 eligible participants were randomized into equal-sized ramipril and placebo groups where baseline parameters were not different. Compliance was monitored by pill count and adverse effects were monitored through interval clinical assessments, laboratory tests, and telephone calls. There was a 100% adherence rate to the study medications among 200 patients who completed the study. Ramipril was associated with a 75-second increase in mean pain-free and a 255-second increase in maximum walking time. There was a modest (less than 5 mmHg) blood pressure reduction and a small (0.1) ABI increase at rest and after exercise compared to placebo. The maximum walking time increase after ramipril therapy compared to placebo was greater in the subgroup of patients with femoropopliteal disease (286 seconds) than in those with aortoiliac disease (127 seconds). Patients treated with ramipril showed improvement of the median distance, speed and stair climbing scores on the WIQ, as well as of the Physical, but not the Mental, Component Summary score on the SF-36. The most frequent side effect was dizziness, more common in the ramipril (8.5%) than in the placebo (2.8%) group. Persistent cough occurred in 6.6% of patients on ramipril, causing their withdrawal from the study.

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.

[Direct antiatherosclerotic therapy: possible approaches, results of clinical trials].

The paper discusses the main approaches to slowing the progression and epy regression of atherosclerosis. Lipid and non-lipid treatment of atherosclerosis described. The results of clinical studies of the effect of antiatherosclerotic agents are analyzed. The main indicator is the thickness of the intima-media complex of the carotid arteries as measured by ultrasonography.

Comparison of risk factor reduction and tolerability of a full-dose polypill (with potassium) versus low-dose polypill (polycap) in individuals at high risk of cardiovascular diseases: the Second Indian Polycap Study (TIPS-2) investigators.

BACKGROUND: A daily single capsule (polycap) of 3 blood pressure (BP) lowering drugs (hydrochlorthiazide, 12.5 mg; atenolol, 50 mg; ramipril, 5 mg) at low doses, simvastatin (20 mg), and aspirin (100 mg) has been demonstrated to be well tolerated and to reduce BP and low-density lipoprotein cholesterol. We examined the incremental effects of 2 (full dose) plus K(+) supplementation versus single polycap (low dose) on risk factors and tolerability. METHODS AND RESULTS: After a run-in period, 518 individuals with previous vascular disease or diabetes mellitus from 27 centers in India were randomly assigned to a single-dose polycap or to 2 capsules of the polycap plus K(+) supplementation for 8 weeks. The effects on BP, heart rate (HR), serum lipids, serum and urinary K(+), and tolerability were assessed using an intention-to-treat analysis. The full-dose polycap (plus K(+) supplementation) reduced BP by a further 2.8 mm Hg systolic and 1.7 mm Hg diastolic, compared with that observed with the low-dose polycap (P=0.003; P=0.001), but there were no differences in HR (0.1 bpm). The differences in total and low-density lipoprotein cholesterol between the full-dose and low-dose polycap was 7.2 mg/dL (P=0.014) and 6.6 mg/dL (P=0.006), respectively, but there were no differences in high-density lipoprotein cholesterol or triglycerides. The rates of discontinuation of the study drug after randomization were similar in the 2 groups (6.9% low dose versus 7.8% full dose). CONCLUSIONS: The full-dose polycap (plus K(+) supplementation) reduces BP and low-density lipoprotein cholesterol to a greater extent compared with the low dose, with similar tolerability. Therefore, the full-dose polycap should potentially lead to larger benefits. Clinical Trial Registration- URL: http://www.ctri.nic.in. Unique identifier: CTRI/2010/091/000054.

Coenzyme Q10 attenuates diastolic dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes.

AIMS/HYPOTHESIS: An increase in the production of reactive oxygen species is commonly thought to contribute to the development of diabetic cardiomyopathy. This study aimed to assess whether administration of the antioxidant coenzyme Q(10) would protect the diabetic heart against dysfunction and remodelling, using the db/db mouse model of type 2 diabetes. Furthermore, we aimed to compare the efficacy of coenzyme Q(10) to that of the ACE inhibitor ramipril. METHODS: Six-week-old non-diabetic db/+ mice and diabetic db/db mice received either normal drinking water or water supplemented with coenzyme Q(10) for 10 weeks. Endpoint cardiac function was assessed by echocardiography and catheterisation. Ventricular tissue was collected for histology, gene expression and protein analysis. RESULTS: Untreated db/db diabetic mice exhibited hyperglycaemia, accompanied by diastolic dysfunction and adverse structural remodelling, including cardiomyocyte hypertrophy, myocardial fibrosis and increased apoptosis. Systemic lipid peroxidation and myocardial superoxide generation were also elevated in db/db mice. Coenzyme Q(10) and ramipril treatment reduced superoxide generation, ameliorated diastolic dysfunction and reduced cardiomyocyte hypertrophy and fibrosis in db/db mice. Phosphorylation of Akt, although depressed in untreated db/db mice, was restored with coenzyme Q(10) administration. We postulate that preservation of cardioprotective Akt signalling may be a mechanism by which coenzyme Q(10)-treated db/db mice are protected from pathological cardiac hypertrophy. CONCLUSIONS/INTERPRETATION: These data demonstrate that coenzyme Q(10) attenuates oxidative stress and left ventricular diastolic dysfunction and remodelling in the diabetic heart. Addition of coenzyme Q(10) to the current therapy used in diabetic patients with diastolic dysfunction warrants further investigation.

Combination delapril/manidipine as antihypertensive therapy in high-risk patients.

The majority of patients with hypertension, and in particular high-risk patients or those with diabetes mellitus or renal dysfunction, are likely to require combination therapy with at least two antihypertensive agents (from different classes) to achieve their blood pressure (BP) target. The delapril/manidipine fixed-dose combination consists of two antihypertensive agents with different, yet complementary, mechanisms of action. Delapril/manidipine has demonstrated short- and long-term antihypertensive efficacy in a number of clinical studies in patients with hypertension with an inadequate response to monotherapy. Comparative studies have demonstrated that delapril/manidipine is as effective as enalapril/hydrochlorothiazide (HCTZ) in patients with hypertension with an inadequate response to monotherapy, and as effective as irbesartan/HCTZ, losartan/HCTZ, olmesartan medoxomil/HCTZ, ramipril/HCTZ and valsartan/HCTZ in reducing BP in patients with hypertension and diabetes, or in obese patients with hypertension. Therapy with delapril/manidipine also appears to exert beneficial effects that extend beyond a reduction in BP, including nephroprotective activity and an improvement in fibrinolytic balance, supporting its value as a treatment option in these patient populations at high or very high cardiovascular risk because of the presence of organ damage, diabetes or renal disease.