Coste-efectividad de la polipíldora CNIC frente a los monocomponentes separados en prevención secundaria cardiovascular en España / Cost-effectiveness of the CNIC-Polypill versus separate monocomponents in cardiovascular secondary prevention in Spain

Introducción y objetivos A pesar de los avances en el tratamiento, la enfermedad cardiovascular es la segunda causa de muerte en España. El objetivo de este estudio fue determinar el coste-efectividad de la estrategia polipíldora CNIC (ácido acetilsalicílico 100mg, atorvastatina 20/40mg, ramipril 2,5/5/10mg) comparada con los mismos monocomponentes por separado para la prevención secundaria de eventos cardiovasculares recurrentes en adultos en España. Materiales y métodos Se adaptó un modelo Markov considerando 4 estados de salud (estable, evento cardiovascular adverso mayor posterior, ictus isquémico posterior y muerte) y la ecuación de riesgo SMART con un horizonte temporal de toda la vida desde la perspectiva del Sistema Nacional de Salud español. La estrategia polipíldora CNIC se comparó con monocomponentes en una cohorte hipotética de 1.000 pacientes en prevención secundaria.Los datos de efectividad, epidemiológicos, de costes y de utilidades se obtuvieron del estudio NEPTUNO, de bases de datos oficiales y de la literatura. Los resultados fueron los costes (en euros de 2021) por año de vida (AV) ganados y por años de vida ajustados por calidad (AVAC) ganados. Se aplicó una tasa de descuento del 3%. Se realizaron análisis de sensibilidad determinísticos univariantes y probabilísticos para evaluar la solidez del modelo. Resultados La estrategia polipíldora CNIC, en prevención secundaria, produce más ganancias de AV (13,22) y AVAC (11,64) a un coste inferior que los monocomponentes. La polipíldora CNIC es dominante y ahorra 280,68euros por paciente en comparación con los monocomponentes por separado. El análisis de sensibilidad probabilístico muestra que el 82,4% de las simulaciones están por debajo del umbral de 25.000euros por AVAC ganado (AU)

Introduction and objectives Despite advances in treatment, cardiovascular disease is the second leading cause of death in Spain. The objective of this study was to determine the cost-effectiveness of the CNIC-Polypill strategy (acetylsalicylic acid 100mg, atorvastatin 20/40mg, ramipril 2.5/5/10mg) compared with the same separate monocomponents for the secondary prevention of recurrent cardiovascular events in adults in Spain. Materials and methods A Markov cost-utility model was adapted considering four health states (stable, subsequent major adverse cardiovascular event, subsequent ischemic stroke and death) and the SMART risk equation over a lifetime horizon from the perspective of the Spanish National Healthcare System. The CNIC-Polypill strategy was compared with monocomponents in a hypothetical cohort of 1000 secondary prevention patients. Effectiveness, epidemiological, cost and utilities data were obtained from the NEPTUNO study, official databases and literature. Outcomes were costs (in 2021euros) per life-year (LY) and quality-adjusted LY (QALY) gained. A 3% discount rate was applied. Deterministic one-way and probabilistic sensitivity analyses evaluated the robustness of the model. Results The CNIC-Polypill strategy in secondary prevention results in more LY (13.22) and QALY (11.64) gains at a lower cost than monocomponents. The CNIC-Polypill is dominant and saves €280.68 per patient compared with monocomponents. The probabilistic sensitivity analysis shows that 82.4% of the simulations are below the threshold of €25,000 per QALY gained. Conclusions The CNIC-Polypill strategy in secondary cardiovascular prevention is cost-effective compared with the same separate monocomponents, resulting in a cost-saving strategy to the Spanish National Healthcare System (AU)

The bioequivalence of fixed-dose combination tablets of bisoprolol and ramipril and its drug-drug interaction potential.

Chronic antihypertensive treatment often includes combination of two or more therapies with complementary mechanism of action targeting different blood pressure (BP) control system. If available, these components are recommended to be administered as a fixed-dose combination (FDC) to reduce tablet burden, improve adherence and thus BP control. A combination of ramipril (RAMI) and bisoprolol (BISO) is one of the options used in clinical practice and is supported by therapeutic guidelines. The clinical program for a novel BISO/RAMI FDC consisted of two randomized, open-label, bioequivalence (BE) studies and one drug-drug interaction (DDI) study. The BE was examined between two FDC strengths of BISO/RAMI (10/10 and 10/5 mg) and the individual reference products administered concomitantly at respective doses after a single oral dose under fasting conditions. In both BE studies, 64 healthy subjects were randomized according to a two-way crossover design. The DDI study evaluated a potential pharmacokinetic (PK) interaction between BISO 10 mg and RAMI 10 mg following their single or concomitant administrations in 30 healthy subjects under fasting condition. BE for BISO/RAMI 10/5 mg and absence of a clinically relevant PK DDI between BISO and RAMI was demonstrated as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for area under the concentration time curve (AUC) and maximum concentration (Cmax ) remained within the acceptance range of 80.00 to 125.00%. However, BE for BISO/RAMI 10/10 mg was not demonstrated, as the lower bound of the 90% CI of Cmax for RAMI was outside the acceptance range of BE. Both drugs administered alone or combined were well-tolerated. No PK interaction was observed between BISO and RAMI/ramiprilat, since the co-administration of BISO and RAMI 10 mg single doses resulted in comparable rate and extent of absorption for BISO and RAMI when compared to their individual products.

Impact of the COVID-19 pandemic on the management of chronic heart failure.

The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented challenge. Meeting this has resulted in changes to working practices and the impact on the management of patients with heart failure with reduced ejection fraction (HFrEF) is largely unknown. We performed a retrospective, observational study contrasting patients diagnosed with HFrEF attending specialist heart failure clinics at a UK hospital, whose subsequent period of optimisation of medical therapy was during the COVID-19 pandemic, with patients diagnosed the previous year. The primary outcome was the change in equivalent dosing of ramipril and bisoprolol at 6-months. Secondary outcomes were the number and type of follow-up consultations, hospitalisation for heart failure and all-cause mortality. In total, 60 patients were diagnosed with HFrEF between 1 December 2019 and 30 April 2020, compared to 54 during the same period of the previous year. The absolute number of consultations was higher (390 vs 270; p = 0.69), driven by increases in telephone consultations, with a reduction in appointments with hospital nurse specialists. After 6-months, we observed lower equivalent dosing of ramipril (3.1 ± 3.0 mg vs 4.4 ± 0.5 mg; p = 0.035) and similar dosing of bisoprolol (4.1 ± 0.5 mg vs 4.9 ± 0.5 mg; p = 0.27), which persisted for ramipril (mean difference 1.0 mg, 95% CI 0.018-2.09; p = 0.046) and bisoprolol (mean difference 0.52 mg, 95% CI -0.23-1.28; p = 0.17) after adjustment for baseline dosing. We observed no differences in the proportion of patients who died (5.0% vs 7.4%; p = 0.59) or were hospitalised with heart failure (13.3% vs 9.3%; p = 0.49). Our study suggests the transition to telephone appointments and re-deployment of heart failure nurse specialists was associated with less successful optimisation of medical therapy, especially renin-angiotensin inhibitors, compared with usual care.

Investigating the beneficial effect of aliskiren in attenuating neuropathic pain in diabetic Sprague-Dawley rats.

Objectives: Worldwide, diabetic neuropathy (DN) is a major complication of diabetes mellitus. The direct renin inhibitor aliskiren is recognized as a treatment for cardiovascular disease in diabetic patients, but little is known about its potential benefits in cases of diabetic neuropathy. Accordingly, we investigated the effects of aliskiren (ALIS) and gliclazide (GLZ) and their combination therapy on peripheral neuropathy in streptozotocin-induced diabetic rats. Methods: In total, 112 adult Sprague-Dawley rats were used for this study. Diabetes was induced using streptozotocin (STZ), whereas the control group was treated with an equal volume of citrate buffer. The diabetic rats were divided randomly into six groups according to the proposed treatment regime: diabetic control (DC), gliclazide (GLZ), aliskiren (ALIS), ramipril (RAM), (GLZ + ALIS) and (GLZ + RAM). Behavioural responses to thermal (hot-plate) and mechanical (tail-pinch) pain were evaluated. After eight weeks of daily treatments, the animals were fasted and sacrificed. The blood samples were collected, with the serum separated and subjected to various biochemical and enzyme analyses so as to assess the effect of the treatments on diabetic peripheral neuropathy. Results: After 8 weeks, aliskiren alone and in combination with gliclazide therapy had a significant effect (P < .001) in reducing blood glucose levels and showed increased hot-plate and tail-flick latencies compared with the diabetic control group. The threshold of mechanical hyperalgesia was also significantly elevated (P < .001). Conclusions/Interpretations: These data suggest that either aliskerin alone or in combination with gliclazide can protect against the development and progression of diabetic neuropathy.

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.

RAMIC: Design of a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of ramipril in patients with COVID-19.

BACKGROUND AND AIMS: Retrospective studies have shown that angiotensin-converting-enzyme (ACE) inhibitors are associated with a reduced risk of complications and mortality in persons with novel coronavirus disease 2019 (COVID-19). Thus, we aimed to examine the efficacy of ramipril, an ACE-inhibitor, in preventing ICU admission, mechanical ventilation and/or mortality while also minimizing the risk of transmission and use of personal protective equipment (PPE). METHODS: RAMIC is a multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial comparing the efficacy of treatment with ramipril 2.5 mg orally daily compared to placebo for 14 days. The study population includes adult patients with COVID-19 who were admitted to a hospital or assessed in an emergency department or ambulatory clinic. Key exclusion criteria include ICU admission or need for mechanical ventilation at screening, use of an ACE inhibitor or angiotensin-receptor-II blocker within 7 days, glomerular filtration rate < 40 mL/min or a systolic blood pressure (BP) < 100 mmHg or diastolic BP < 65 mmHg. Patients are randomized 2:1 to receive ramipril (2.5 mg) or placebo daily. Informed consent and study visits occur virtually to minimize the risk of SARS-CoV-2 transmission and preserve PPE. The primary composite endpoint of ICU admission, invasive mechanical ventilation and death are adjudicated virtually. CONCLUSIONS: RAMIC is designed to assess the efficacy of treatment with ramipril for 14 days to decrease ICU admission, mechanical ventilator use and mortality in patients with COVID-19 and leverages virtual study visits and endpoint adjudication to mitigate risk of infection and to preserve PPE (ClinicalTrials.gov, NCT04366050).

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.

Use of the Cardiovascular Polypill in Secondary Prevention of Cerebrovascular Disease: A Real-Life Tertiary Hospital Cohort Study of 104 Patients.

BACKGROUND: The use of the cardiovascular polypill, a fixed-dose combination treatment, is conceived to improve adherence. However, randomized controlled trials (RCTs) may overestimate it. Studies focusing on cerebrovascular disease and real-life efficacy compared with conventional treatment are lacking. METHODS: This is a retrospective, hospital-based cohort study of acute ischaemic stroke patients who were prescribed a polypill (aspirin 100 mg, atorvastatin 20/40 mg, ramipril 2.5/5/10 mg) versus conventional treatment (aspirin 100 mg and other blood pressure/lipid-lowering agents) in secondary prevention (2017-2018). Clinical records were reviewed 90 days after discharge for stroke recurrence, vascular risk factor control, and safety. Adherence was assessed using the adapted Morisky-Green scale. RESULTS: A total of 104 patients were included (61% male; mean age 69.7 ± 13.9 years); 54 were treated with the polypill and 50 with conventional treatment. No baseline differences in clinical or demographic variables were detected. No recurrences were registered in the polypill group, compared to 1 recurrence in the conventional treatment group. A significant reduction of systolic blood pressure (SBP) was achieved in the polypill group (12.1 mm Hg) compared to the conventional treatment group (6.8 mm Hg) (p = 0.002). No significant differences were detected regarding the goal of LDL cholesterol ≤70 mg/dL (41 vs. 44%). The adverse events were mild and their frequency was similar in the two groups (9 vs. 2%, ns). Adherence was similarly good in the two groups (93 vs. 88%, ns). Polypill group adherence was similar to that reported in a previous meta-analysis of RCTs (93 vs. 84%, ns). CONCLUSION: In our experience, the cardiovascular polypill achieved a higher reduction in SBP levels and was well tolerated. Adherence was similar to that found in the previous literature, which is remarkable given the real-life setting of our study.

Drug Testing for Residual Progression of Diabetic Kidney Disease in Mice Beyond Therapy with Metformin, Ramipril, and Empagliflozin.

BACKGROUND: Progression of CKD in type 2 diabetes, despite dual inhibition of sodium-glucose transporter-2 and the renin-angiotensin system, remains a concern. Bromoindirubin-3'-oxime (BIO), previously reported to promote podocyte survival and regeneration, is a candidate additional drug to elicit renoprotective effects beyond therapy with metformin, ramipril, and empagliflozin (MRE). Evaluating a drug with standard therapeutics more closely mimics the clinical setting than evaluating the drug alone. METHODS: Uninephrectomized BKS-Lepr-/- (db/db) mice treated with or without MRE served as a model of progressive CKD in type 2 diabetes. Mice on or off MRE were randomized to only 4 weeks of add-on BIO or vehicle. The primary end point was slope of GFR (ΔGFR). RESULTS: Four weeks of MRE treatment alone did not affect ΔGFR, but significantly attenuated hyperglycemia, albuminuria, and glomerulosclerosis and increased podocyte filtration slit density, as assessed by STED super-resolution microscopy upon tissue clearing. BIO alone improved albuminuria, podocyte density in superficial and juxtamedullary nephrons, and podocyte filtration slit density. MRE+BIO combination therapy had additive protective effects on ΔGFR, glomerulosclerosis, podocyte density in juxtamedullary nephrons, and filtration slit density. CONCLUSIONS: Add-on treatment with BIO for only 4 weeks attenuates progression of CKD beyond MRE therapy in mice with type 2 diabetes. Additional drug combinations may help to further delay ESKD in type 2 diabetes.

The development and validation of a quality by design based process analytical tool for the inline quantification of Ramipril during hot-melt extrusion.

Continuous processing is superseding conventional batch processing as a means of manufacturing within the pharmaceutical research/industry. This paradigm shift has led to the implementation of Process Analytical Technology (PAT) as a semi-automatic, predictive tool offering real-time quality control that can be built into the production line. However, PAT tools have been mainly utilised to monitor a single process (e.g. powder blending, synthesis of biopharmaceuticals and small molecules) rather than a full continuous manufacturing process. In addition, there is a paucity of guidance documents that consider the continuous and dynamic conditions of real-time measurements for validation purposes. In this study, the feasibility of developing and validating a predictive and reliable Raman method based on quality by design (QbD) and PAT frameworks for the real-time quantification of Ramipril (RMP) during hot-melt extrusion (HME) were investigated. Through QbD, a design space elucidating the quality attributes of RMP stability was successfully identified based on offline HPLC measurements. Process temperature and powder feeding rate were the main quality attributes to affect the stability of RMP during HME. The optimum combination of process and formulation variables were extracted from the validated design space and used to extrude RMP at a concentration range of 2.5-12.5 %w/w. Three calibration models were established using PLS regression analysis. The developed PLS calibration models showed excellent linearity (R2 = 0.989, 0.995, 0.992), accuracy (RMSEcv = 0.31, 0.26, 0.30%) and specificity (PC1 = 81, 85, 89%) for models 1, 2 and 3, respectively. Furthermore, the developed QbD-PAT model was able to predict the quantity of RMP at varied process feed rate (10, 35 rpm) operating under long processing time (60 min). The output of this study allows in-process optimisation of formulation and process variables to control the quality and quantity of RMP during HME. Furthermore, it allows the implementation of PAT tools as routine methods of analysis within the laboratory.

Multicap to improve adherence after acute coronary syndromes: results of a randomized controlled clinical trial.

BACKGROUND: Adherence to treatment after a myocardial infarction (MI) is poor, even in the early postinfarction period. Combining evidence-based drugs into a multicap could improve adherence in this population. No previous randomized trial assessing fixed-dose combination therapy has included patients early after a MI. We aimed to assess if a multicap containing four secondary prevention drugs increases adherence to treatment at 6 months after MI hospitalization. The study was designed as a randomized, parallel, open-label, controlled trial. METHODS: Patients were randomized within 7 days of a MI to either multicap or control group. The multicap group received a capsule containing aspirin, atenolol, ramipril, and simvastatin. The control group received each drug in separate pills. The primary outcome was adherence at 6 months. We also measured blood pressure, heart rate, serum cholesterol levels, C-reactive protein, and platelet aggregation. RESULTS: The study was stopped prematurely when 100 patients were included for futility. At 6 months, 92 (95.8%) patients were adherent to medical treatment: 98.0% in the multicap group and 93.5% in the control group [relative risk (RR) 1.05; 95% confidence interval (CI) 0.96-1.14; p = 0.347]. There were no differences between groups in systolic blood pressure (p = 0.662), diastolic blood pressure (p = 0.784), heart rate (p = 0.533), total cholesterol (p = 0.760), LDL-c (p = 0.979), C-reactive protein (p = 0.399), or in the proportion of patients with adequate platelet aggregation inhibition (p = 0.600). CONCLUSIONS: The study did not find any improvement in the adherence at 6 months after a MI with a multicap-based strategy (Multicap for Increase Adherence After Acute Myocardial Infarction; [ ClinicalTrials.gov identifier: NCT02271178]).

Association of egg intake with blood lipids, cardiovascular disease, and mortality in 177,000 people in 50 countries.

BACKGROUND: Eggs are a rich source of essential nutrients, but they are also a source of dietary cholesterol. Therefore, some guidelines recommend limiting egg consumption. However, there is contradictory evidence on the impact of eggs on diseases, largely based on studies conducted in high-income countries. OBJECTIVES: Our aim was to assess the association of egg consumption with blood lipids, cardiovascular disease (CVD), and mortality in large global studies involving populations from low-, middle-, and high-income countries. METHODS: We studied 146,011 individuals from 21 countries in the Prospective Urban Rural Epidemiology (PURE) study. Egg consumption was recorded using country-specific validated FFQs. We also studied 31,544 patients with vascular disease in 2 multinational prospective studies: ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial) and TRANSCEND (Telmisartan Randomized Assessment Study in ACEI Intolerant Subjects with Cardiovascular Disease). We calculated HRs using multivariable Cox frailty models with random intercepts to account for clustering by study center separately within each study. RESULTS: In the PURE study, we recorded 14,700 composite events (8932 deaths and 8477 CVD events). In the PURE study, after excluding those with history of CVD, higher intake of egg (≥7 egg/wk compared with <1 egg/wk intake) was not significantly associated with blood lipids, composite outcome (HR: 0.96; 95% CI: 0.89, 1.04; P-trend = 0.74), total mortality (HR: 1.04; 95% CI: 0.94, 1.15; P-trend = 0.38), or major CVD (HR: 0.92; 95% CI: 0.83, 1.01; P-trend = 0.20). Similar results were observed in ONTARGET/TRANSCEND studies for composite outcome (HR 0.97; 95% CI: 0.76, 1.25; P-trend = 0.09), total mortality (HR: 0.88; 95% CI: 0.62, 1.24; P-trend = 0.55), and major CVD (HR: 0.97; 95% CI: 0.73, 1.29; P-trend = 0.12). CONCLUSIONS: In 3 large international prospective studies including ∼177,000 individuals, 12,701 deaths, and 13,658 CVD events from 50 countries in 6 continents, we did not find significant associations between egg intake and blood lipids, mortality, or major CVD events. The ONTARGET and TRANSCEND trials were registered at clinicaltrials.gov as NCT00153101. The PURE trial was registered at clinicaltrials.gov as NCT03225586.

The N-AcetylCysteine and RAMipril in Takotsubo Syndrome Trial (NACRAM): Rationale and design of a randomised controlled trial of sequential N-Acetylcysteine and ramipril for the management of Takotsubo Syndrome.

BACKGROUND: Takotsubo Syndrome(TTS), contrary to historical reports, is now increasingly recognised to be associated with substantial mortality and morbidity, both in the short- and long-term. Although TTS is often precipitated by a catecholamine "pulse", in-hospital hypotension is a common occurrence, increasing the risk of mortality. Furthermore, despite the transient catecholamine stimulus, there is increasing evidence that there are significant long term sequelae, including persistently impaired left ventricular(LV) systolic dysfunction, myocardial oedema with fibrosis, as well as persistent impairment of quality of life. A definitive therapeutic option to limit the extent of initial myocardial injury, and to accelerate recovery in TTS is therefore justified. However to date, there has been a lack of prospective studies in this area. DESIGN AND RATIONALE: NACRAM is a multi-centre, randomised, placebo-controlled trial, sequentially testing early use of intravenous N-acetylcysteine(NAC), followed by/or oral ramipril for 12 weeks. The rationale for utilising these agents is related to their effects on limiting nitrosative stress and expression of the inflammasome activator thioredoxin interacting protein(TXNIP); both processes fundamental to the pathogenesis of TTS. END POINTS: NACRAM is assessing resolution of myocardial oedema on cardiac magnetic resonance imaging(CMR), improvements in LV systolic function as measured by global longitudinal strain(GLS) on echocardiography, quality of life, and inflammatory markers. DISCUSSION: To the best of our knowledge, NACRAM will be the first prospective study to help definitively evaluate a therapeutic option in acute attacks of TTS.

The effect of topical ramipril and losartan cream in inhibiting scar formation.

The renin-angiotensin system (RAS) plays an important role in scar formation. We have previously shown that oral administration of ramipril and losartan could inhibit scarring. For easier application, here we developed a series of topical ramipril and losartan creams in different concentrations and formulations to explore the effect on scar formation in a C57BL/6 mouse scar model. The harvested scar tissues were analyzed with H&E staining, Masson staining and immunohistochemical staining. We found the group treated with 0.2% losartan urea cream (Prep. 1) or 0.1% ramipril cream (Prep. 2) had significantly smaller scars compared to the negative control, while the proliferation of fibroblasts was less active and the collagen fibers were more regular; both groups showed similar efficacy with the positive control (triamcinolone acetonide urea). We also found that drug transdermalness couldn't directly determine the efficacy. Our findings indicate that local application of angiotensin converting enzyme inhibitor drugs (ACEIs) and angiotensin receptor blocker drugs (ARBs) can reduce scarring by reducing the expression of collagen I, collagen III, phosphorylated small mothers against decapentaplegic 3 (p-Smad3) and transforming growth factor-ß 1 (TGF-ß1). This may provide new insight on scar treatment in clinic.

A Comparative Study on the Memory-Enhancing Actions of Oral Renin-Angiotensin System Altering Drugs in Scopolamine-Treated Mice.

This study was designed to evaluate the spatial working memory (as studied in Y-maze) or short-term and long-term spatial memory (assessed in radial 8 arms-maze task), in a scopolamine-induced memory deficits model in mice, by the oral administration of 2 angiotensin-converting enzyme inhibitors-captopril and ramipril and also the effects of the AT1 receptor antagonist, losartan. The present article was initiated as a reaction to the clinical setting of hypertensive disease, which involves lifelong administration of antihypertensive drugs, dietary or lifestyle constraints, and aging, which all take a toll on the higher functions of the nervous system. Most of the patients with cognitive decline suffer of various metabolic imbalances, hypertension, cardiac and kidney disease, many of them which are treated with oral administration of Renin-angiotensin aldosterone system-altering agents like those presented above. Our results showed a protective effect of captopril, ramipril, and losartan prescopolamine administration on spontaneous alternation in Y-maze task, as compared to scopolamine-alone treated mice, as well as decreased number of working memory errors and reference memory errors in radial-arm maze for both losartan + scopolamine and ramipril + scopolamine groups versus scopolamine alone. This could have a therapeutical relevance, especially since oral administration was preferred in our report, as it is used in the therapeutic procedures in humans, further enhancing the similarities with the clinical conditions.

Ramipril and resveratrol co-treatment attenuates RhoA/ROCK pathway-regulated early-stage diabetic nephropathy-associated glomerulosclerosis in streptozotocin-induced diabetic rats.

Clinical studies have shown that hyperglycemia can induce early-stage diabetic nephropathy (DN). Furthermore, oxidative stress, tubular epithelial-mesenchymal transition and extracellular matrix accumulation promote the progression of DN to chronic kidney disease and tubulointerstitial fibrosis. It is necessary to initiate treatment at the early stages of DN or even during the early stages of diabetes. In this work, rats with streptozotocin (STZ)-induced diabetes mellitus (DM) presented early DN symptoms within 45 days, and collagen accumulation in the glomerulus of the rats was primarily mediated through the RhoA/ROCK pathway instead of the TGF-ß signaling pathway. Resveratrol (15 mg/kg/day) and ramipril (10 mg/kg/day) co-treatment of STZ-induced DN rats showed that glomerulosclerosis in early-stage DN was reversible (P < .05 compared with that in STZ-induced DM rats). The results of this study support early intervention in diabetes or DN as a more efficient therapeutic strategy.

Effects of Sevelamer Carbonate in Patients With CKD and Proteinuria: The ANSWER Randomized Trial.

RATIONALE & OBJECTIVE: Hyperphosphatemia is associated with increased risk for chronic kidney disease (CKD) progression and reduced antiproteinuric effects of renin-angiotensin system (RAS) blockers. We investigated whether the phosphate binder sevelamer carbonate may enhance the antiproteinuric effect of RAS inhibitors in patients with CKD. STUDY DESIGN: Phase 2, randomized, controlled, open-label, crossover trial. SETTING & PARTICIPANTS: Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs)>15mL/min/1.73m2 and residual proteinuria with protein excretion≥0.5g/24h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy. INTERVENTION: After stratification by serum phosphate level, ≤4 or>4mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600mg thrice daily) treatment followed by 3 months without sevelamer separated by a 1-month washout period or 3 months without sevelamer followed by 3 months with sevelamer, also separated by a 1-month washout period. OUTCOMES: The primary outcome was 24-hour proteinuria (n=49patients). Secondary outcomes included measured GFR (using iohexol plasma clearance), office blood pressure (BP), serum lipid levels, levels of inflammation and bone metabolism biomarkers, urinary electrolyte levels, and arterial stiffness. RESULTS: Changes in proteinuria during the 3-month treatment with (from 1.36 [IQR, 0.77-2.51] to 1.36 [IQR, 0.77-2.60] g/24h) or without (from 1.36 [IQR, 0.99-2.38] to 1.48 [IQR, 0.81-2.77] g/24h) sevelamer were similar (P=0.1). Sevelamer reduced urinary phosphate excretion without affecting serum phosphate levels. Sevelamer reduced C-reactive protein (CRP), glycated hemoglobin, and total and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol levels without affecting levels of office BP, measured GFR, fibroblast growth factor 23, klotho, intact parathyroid hormone, serum vitamin D, or other urinary electrolytes. Results were similar in the low- and high-phosphate groups. Sevelamer was well tolerated. Adverse events were comparable between treatment periods. One case of transient hypophosphatemia was observed during treatment with sevelamer. LIMITATIONS: Short treatment duration, lower pretreatment proteinuria than expected. CONCLUSIONS: 3-month sevelamer treatment did not reduce proteinuria in patients with CKD on maximal RAS blockade. Amelioration of inflammation and dyslipidemia with sevelamer treatment raises the possibility that it may confer benefit in patients with CKD beyond reduction of proteinuria. FUNDING: Sanofi (Milan, Italy). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01968759.

Assessment of a guideline-based heart substructures delineation in left-sided breast cancer patients undergoing adjuvant radiotherapy : Quality assessment within a randomized phase III trial testing a cardioprotective treatment strategy (SAFE-2014).

BACKGROUND AND PURPOSE: In our institute, breast cancer patients undergoing adjuvant treatment are included in a protocol aimed to reduce cardiovascular morbidity (SAFE-2014, NCT2236806), assessing preclinical heart damage with heart speckle-tracking ultrasound. To develop a dose constraint related to subclinical heart damage, a reliable delineation of heart substructures based on a pre-existing guideline was made. PATIENTS AND METHODS: Heart substructures of 16 left-sided breast cancer patients included in the SAFE protocol were delineated by five operators. For each substructure, a multi-contour delineation based on a majority vote algorithm (MCD) was created. A consensus-based delineation (CBD) was developed by an independent team of two blinded operators. Dice similarity coefficients (DSC) between volumes delineated by different operators and the MCD were collected and reported, as well as DSC between CBD and MCD. RESULTS: Mean DSCs between heart chambers delineated by each operator and the corresponding MCDs ranged between 0.78 and 0.96. Mean DSC between substructures delineated by all single operators and the corresponding MCD ranged between 0.84 and 0.94. Mean DSC between CBD and the corresponding MCD ranged from 0.89 to 0.97. CONCLUSION: Results showed low inter-observer variability of heart substructure delineation. This constitutes an external validation of the contouring atlas used, allowing a reliable dosimetric assessment of these volumes within the SAFE-2014 trial.

ACE-inhibitor/calcium antagonist combination: is this the first-choice therapy in arterial hypertension?

The 2018 ESH/ESC guidelines indicate that the first-choice therapy in the majority of hypertensive patients should be a fixed combination of a drug that blocks the renin-angiotensin-aldosterone system and a calcium antagonist or a diuretic. Evidence from the meta-analysis of controlled clinical trials, however, indicates that the classes of drugs that block the renin-angiotensin-aldosterone system should not be considered equivalent as ACE inhibitors have been clearly shown to outperform AT-1 antagonists in preventing myocardial infarction and total mortality. Moreover, studies such as ASCOT and ACCOMPLISH demonstrate a superiority of the ACE-inhibitor/calcium antagonist association over beta-blocker/diuretic associations and especially towards the ACE-inhibitor/diuretic combination, whereas there is no scientific evidence of efficacy with respect to cardiovascular events on the part of AT-1 antagonist/calcium antagonist combinations. Drugs such as ramipril and amlodipine are undoubtedly the reference molecules within their respective classes as numerous controlled clinical studies have demonstrated their effectiveness on cardiovascular events. It is therefore obvious that the availability of a fixed combination with both molecules is a great opportunity for the therapy of the hypertensive patient, considering also the availability of studies that demonstrate its effectiveness on intermediate endpoints associated with high tolerability. So, in accordance with the 2018 ESH/ESC guidelines, the fixed combination ramipril/amlodipine represents a first choice therapy for hypertension.