Evaluation of two novel co-processed excipients for direct compression of orodispersible tablets and mini-tablets.

Pediatric, geriatric, and other patients who suffer from swallowing difficulties represent a special patient group, where an increased need in appropriate formulation development is required. To overcome these mostly swallowability linked issues, orodispersible tablets (ODTs) and orodispersible mini-tablets (ODMTs) can be seen as a suitable alternative to improve compliance. Orodispersible tablets are oral solid dosage forms which rapidly disintegrate after contact with saliva, leaving a liquid dispersion, which can be easily swallowed. To fulfil the required quality criteria and optimize the formulations regarding tensile strength and disintegration time, co-processed excipients (CPE) based on mannitol are frequently used in the manufacturing of orodispersible tablets. This study aimed to systematically compare two new CPEs, namely Granfiller-D® and Hisorad® and evaluate their potential in future OD(M)T formulations with already marketed products. The performance of the CPEs was examined in combination with three different APIs. Disintegration time, sufficient mechanical strength and content uniformity for low dosed formulation were chosen as main quality aspects. Conventionally sized tablets (9 mm) with 50% drug load of ibuprofen and paracetamol were produced with each CPE. Low dosed OD(M)Ts with a drug load of 4% enalapril maleate were manufactured to study content uniformity. Large differences were visible in the formulations containing ibuprofen and only Hisorad® allowed to compress ODT fulfilling the specifications of Ph.Eur. and FDA regarding disintegration times (180 s and 30 s, respectively). For the poorly binding model drug paracetamol, none of the studied excipients showed a satisfactory performance, with maximum tensile strengths < 1 MPa. To reach content uniformity in low dosed ODMTs, Ludiflash® seems to be the most preferable alternative, as the formulation showed the lowest acceptance values (AV) according to Ph.Eur. (<4) as well as the smallest coefficient of variation (CV) in API content (CV < 2%). In conclusion, the study revealed that none CPE is the ideal choice for all approaches, but different CPEs should be selected dependent on different challenges during formulation development of OD(M)Ts.

Sacubitril/valsartan versus enalapril on exercise capacity in patients with heart failure with reduced ejection fraction: A randomized, double-blind, active-controlled study.

Sacubitril/valsartan reduces mortality in patients with heart failure with reduced ejection fraction (HFrEF) when compared with enalapril. However, it is unknown the effect of both treatments on exercise capacity. We compared sacubitril/valsartan versus enalapril in patients with HFrEF based on peak oxygen consumption (VO2) and 6-minute walk test (6-MWT). METHODS: We included 52 participants with HFrEF with a left ventricular ejection fraction <40% to receive either sacubitril/valsartan (target dose of 400 mg daily) or enalapril (target dose of 40 mg daily). Peak VO2 was measured by using cardiopulmonary exercise testing. Six-minute walk test was also performed. RESULTS: At 12 weeks, the sacubitril/valsartan (mean dose 382.6 ± 57.6 mg daily) group had increased peak VO2 of 13.1% (19.35 ± 0.99 to 21.89 ± 1.04 mL/kg/min) and enalapril (mean dose 34.4 ± 9.2 mg daily) 5.6% (18.58 ± 1.19 to 19.62 ± 1.25 mL/kg/min). However, no difference was found between groups (P = .332 interaction). At 24 weeks, peak VO2 increased 13.5% (19.35 ± 0.99 to 21.96 ± 0.98 mL/kg/min) and 12.0% (18.58 ± 1.19 to 20.82 ± 1.18 mL/kg/min) in sacubitril/valsartan (mean dose 400 ± 0 mg daily) and enalapril (mean dose 32.7 ± 11.0 mg daily), respectively. However, no differences were found between groups (P= .332 interaction). At 12 weeks, 6-MWT increased in both groups (sacubitril/valsartan: 459 ± 18 to 488 ± 17 meters [6.3%] and enalapril: 443 ± 22 to 477 ± 21 meters [7.7%]). At 24 weeks, sacubitril/valsartan increased 18.3% from baseline (543 ± 26 meters) and enalapril decreased slightly to 6.8% (473 ± 31 meters), but no differences existed between groups (P= .257 interaction). CONCLUSIONS: Compared to enalapril, sacubitril/valsartan did not substantially improve peak VO2 or 6-MWT after 12 or 24 weeks in participants with HFrEF. (NEPRIExTol-HF Trial, ClinicalTrials.gov number, NCT03190304).

A Randomized Crossover Pilot Study Examining the Effect of Carvedilol and Terazosin plus Enalapril on Urinary Symptoms of Patients with Hypertension and Benign Prostatic Hyperplasia.

PURPOSE: The present study aims to assess and compare the effects of carvedilol and terazosin plus enalapril on lower urinary tract symptoms (LUTS), the urine flow, and blood pressure (BP) in patients with moderate hypertension (HTN) and benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: In this randomized crossover trial, a total of 40 men with HTN and LUTS symptoms were enrolled. The first group was treated with carvedilol, and the second one received terazosin plus enalapril. After eight weeks of treatment, the patients experienced a one-month washout period, and the treatments changed and continued for eight weeks. To diagnose BPH in the study, the international prostate symptom score (IPSS) questionnaire was used. Moreover, the prostate-specific antigen (PSA), the post-void residual (PVR) urine volume, and the maximum urinary flow rate (Q-max using the uroflowmetry test) were measured. RESULTS: Effect assessment results in this crossover trial illustrated neither carryover effects nor significant treatment effects on all primary outcomes (P > 0.05). Moreover, the results for the period effect indicated a significant reduction in BP (systolic and diastolic), PVR, and IPSS, yet a significant raise in Qmax. CONCLUSION: The effects of carvedilol are similar to those of the combination of terazosin and enalapril in patients with moderate HTN and BPH in controlling LUTS. Carvedilol could be used as an appropriative drug in patients with moderate HTN and cardiac problems with LUTS of BPH. Further studies are recommended to be conducted to investigate and compare the efficacy of carvedilol with that of other alpha-blockers with a larger sample size and over a longer period of time.

[Antiproteinuric action of amiloride in paediatric patient with corticoresistant nephrotic syndrome]. / Acción antiproteinúrica del amiloride en el paciente pediátrico con síndrome nefrótico corticorresistente.

INTRODUCCION: In nephrotic syndrome, increased podocyturia accompanies pathologic proteinuria. The therapeutic regimen with enalapril, losartan and amiloride could reduce both variables. OBJETIVES: Evaluate the anti-proteinuric effect of 2 non-immunological therapeutic regimens, the quantitative relationship between podocyturia and proteinuria. MATERIAL AND METHODS: We included children aged 4 to 12 years with corticoresistant nephrotic syndrome, using 2 different schemes: group A, enalapril+losartan, and group B, enalapril+losartan+amiloride. RESULTS: In group A, 17 patients completed the study, the initial mean proteinuria was 39mg/m2/h and mean proteinuria at the end was 24mg/m2/h, while in group B 14 patients were treated and the initial average proteinuria was 36mg/m2/h and the end average proteinuria was 13mg/m2/h. The paired T test showed significant differences in the decrease in proteinuria, for patients in group B without variation in podocyturia. The 2 factors associated with an increase in proteinuria were podocyturia and the time elapsed from the diagnosis of cortico-resistant nephrotic syndrome to the start of treatment anti-proteinuric. CONCLUSIONS: The use of amiloride decreased proteinuria, without significantly modifying podocyturia; we did not observe a positive relationship between both variables.

Clinical Characteristics and Outcomes of Patients With Heart Failure With Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease: Insights From PARADIGM-HF.

Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Blocker-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non-COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta-blockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13-1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05-1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94-1.30), or all-cause mortality (HR, 1.14; 95% CI, 0.99-1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05-1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29-1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions In PARADIGM-HF, COPD was associated with lower use of beta-blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high-risk subgroup. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255.

Effects of sacubitril/valsartan on ventricular remodeling in patents with left ventricular systolic dysfunction following acute anterior wall myocardial infarction.

OBJECTIVE: The aim of this study was to investigate the effect of sacubitril/valsartan (Sal/Val) on left ventricular (LV) remodeling in patients with LV systolic dysfunction following acute anterior wall myocardial infarction (AAMI). METHODS: AAMI patients with LV systolic dysfunction were enrolled in this study. All patients underwent percutaneous coronary intervention. After hemodynamic stabilization, patients were randomly assigned either to group T (Sal/Val treatment) or group C (enalapril treatment). Changes in echocardiographic parameters and plasma biochemical markers were used to evaluate the effects of Sal/Val on LV remodeling and cardiac function. The incidence of major cardiac adverse events (MACEs) and adverse reactions during follow-ups was also recorded. RESULTS: In total, 137 eligible patients were prospectively included. Compared to group C, LV ejection fraction significantly improved (P < 0.05), while the LV end-systolic volume index and wall motion score index showed a tendency to decrease in group T. There was no difference in the LV end-diastolic volume index between groups. During follow-ups, the plasma N-terminal pro-B-type natriuretic peptide and soluble suppression of tumorigenesis-2 levels in both groups decreased (all P < 0.05), and the change was more prominent in group T. Additionally, drug-related adverse effects were similar between the two groups (P > 0.05); however, the incidence of MACEs was lower in group T than in group C (39.71% vs. 53.62%, P = 0.103), although the difference was insignificant. CONCLUSION: Sac/Val attenuated LV remodeling and dysfunction and was safe and effective in LV systolic dysfunction patients post AAMI.

Relationship of visceral adiposity index with new-onset proteinuria in hypertensive patients.

BACKGROUND & AIMS: Visceral adiposity index (VAI) is a sex-specific surrogate marker of adipose tissue distribution and function. Little is known about the longitudinal relationship between VAI and proteinuria. This study aimed to examine the prospective relationship of baseline VAI with new-onset of proteinuria in hypertensive patients without major cardiovascular diseases. METHODS: A total of 10 699 hypertensive patients without proteinuria (negative urine dipstick reading) at baseline from the renal sub-study of the China Stroke Primary Prevention Trial (CSPPT) were included. Participants were randomly assigned to a double-blind daily treatment with 10 mg enalapril and 0.8 mg folic acid or 10 mg enalapril alone. Participants were followed every 3 months after randomization. The primary outcome was new-onset proteinuria, defined as a urine dipstick reading of ≥1+ at the exit visit. The secondary outcome was progression of proteinuria, defined as a urine dipstick reading of trace or ≥1+ at the exit visit. RESULTS: During a median follow-up duration of 4.4 years, a total of 396 (3.7%) participants developed new-onset proteinuria, while 1236 (11.6%) participants met progression of proteinuria. When VAI was categorized into quartiles, compared with participants in quartile 1-3 (<2.99), a significantly higher risk of new-onset proteinuria (OR, 1.43; 95%CI: 1.07-1.91) and progression of proteinuria (OR, 1.23; 95%CI: 1.03-1.46) was found in those in quartile 4 (≥2.99). Moreover, the positive association was consistent in participants with or without general obesity, abdominal obesity, and dyslipidemia (all P-interactions > 0.05). CONCLUSIONS: There was a positive association between VAI levels and the risk of new-onset proteinuria in hypertensive patients.

Angiotensin Receptor-Neprilysin Inhibition Based on History of Heart Failure and Use of Renin-Angiotensin System Antagonists.

BACKGROUND: The PIONEER-HF (comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode) trial demonstrated the efficacy and safety of sacubitril/valsartan (S/V) in stabilized patients with acute decompensated heart failure (HF) and reduced ejection fraction. OBJECTIVES: The study sought to determine whether and how prior HF history and treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) affected the results. METHODS: The PIONEER-HF trial was a prospective, multicenter, double-blind, randomized clinical trial enrolling 881 patients with an ejection fraction ≤40%. Patients were randomly assigned 1:1 to in-hospital initiation of S/V (n = 440) versus enalapril (n = 441). Pre-specified subgroup analyses were performed based on prior HF history (i.e., de novo HF vs. worsening chronic HF) and treatment with an ACE inhibitor or ARB (i.e., ACE inhibitor or ARB-yes vs. ACE inhibitor or ARB-no) at admission. RESULTS: At enrollment, 303 (34%) patients presented with de novo HF and 576 (66%) patients with worsening chronic HF. A total of 421 (48%) patients had been treated with an ACE inhibitor or ARB, while 458 (52%) had not been treated with an ACE inhibitor or ARB. N-terminal pro-B-type natriuretic peptide declined significantly in all 4 subgroups (p < 0.001), with greater decreases in the S/V versus the enalapril arm (p < 0.001). There was no interaction between prior HF history (p = 0.350) or ACE inhibitor or ARB treatment (p = 0.880) and the effect of S/V versus enalapril on cardiovascular death or rehospitalization for HF. The incidences of adverse events were comparable between S/V and enalapril across all 4 subgroups. CONCLUSIONS: Among patients admitted for acute decompensated HF, S/V was safe and well tolerated, led to a significantly greater reduction in N-terminal pro-B-type natriuretic peptide, and improved clinical outcomes compared with enalapril irrespective of previous HF history or ACE inhibitor or ARB treatment. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).

Lipospheres for Simultaneous Controlled Release and Improved Pharmacokinetic Profiles of Saxagliptin-Enalapril: Formulation, Optimization, and Comparative In Vitro-In Vivo Evaluation.

The current study aims at formulating and optimizing lipospheres (LS) by the Box-Behnken design (BBD) from safe biodegradable carnauba wax (CW) to co-administer saxagliptin (SG) and enalapril (EP) for co-existing chronic hypertensive diabetes in order to overcome inadequacies of conventional modes of drug administration. Optimized liposphere formulation (OLF) was selected by a numerical optimization procedure and a comparative in vivo pharmacokinetic study of OLF and commercial brands was also performed. Discrete, free-flowing, spherical, smooth-surface LS having a size range of 5-10 µm and zeta potential of - 20 to - 30 mV were successfully formulated. Compatibility studies by FTIR and DSC proved the lack of interaction of components while XRD suggested the transformation of crystalline drugs to amorphous form. Outcomes of dependent optimizing variables like percentage yield (30-90%), EP-release (32-92%), and SG-release (28-95%) followed a polynomial quadratic model. Pharmacokinetics studies indicated a significantly lower Cmax of EP (125.22 ± 6.32) and SG (75.63 ± 3.85) and higher mean Tmax values (9.4 h for EP and 10.73 h for SG) from OLF in comparison with reference brands of EP (257.54 ± 8.23 ng/mL) and SG (393.66 ± 2.97 ng/mL). Additionally, a potential rise in half-life and MRT of SG and EP was achieved reaching approximately 2- to 3-fold higher than noted for reference brands. Importantly, the enhanced Tmax and AUC0-24 specified the achievement of enhanced bioavailability of both drugs from LS. Consequently, such an innovative approach could not only control drug release in both in vitro and in vivo analyses but also maintain plasma drug concentration for a longer time without maximizing Cmax leading towards effective management of chronic illnesses.

New Orodispersible Mini Tablets of Enalapril Maleate by Direct Compression for Pediatric Patients.

BACKGROUND: In many countries, hypertension in the pediatric population is considered a serious risk of mortality and morbidity. In this respect, it is central to design and develop new pharmaceutical forms for pediatric patients with hypertension. The development of Orodispersible Mini-Tablets (ODMTs) for pediatric use has gained importance in recent years. Therefore, regulations for developing suitable and palatable dosage forms for pediatric patients have been established by WHO authorities. OBJECTIVE: This study aimed to design and develop orodispersible mini tablets of enalapril maleate (EnM ODMTs) for pediatric use. METHODS: Five pharmaceutical formulations (A, B, C, D and E, shown in Table 1) were designed. The effects of different co-processed excipients and active pharmaceutical ingredients at different doses were studied. Lactose co-processed excipients selected were the following: Tablettose® 80, Microce- Lac® 100 and StarLac®. The micromeritic properties for all the physical mixtures were examined. The mini tablets were obtained by direct compression. Quality control parameters were determined in accordance with US Pharmacopeia. RESULTS: Three OMDTs with StarLac® showed good results of hardness, flow ability and fast disintegration. The formulation with 0.1 mg of enalapril maleate presented the best results for the official parameters of hardness (4.0 kp), friability (< 1%), disintegration time (28 s), drug content uniformity (103.6 %), and wetting time (23 s). CONCLUSION: The three OMDTs with StarLac® showed good quality parameters, according to official requirements. Formulation A exhibited the best wetting time, complying with the dose recommended for pediatric patients. This formulation could be considered eligible for being manufactured at industrial scale.

Relationship of Body Mass Index and Waist Circumference With Risk of New-Onset Proteinuria in Hypertensive Patients.

CONTEXT: The association of the combination of body mass index (BMI) and waist circumference (WC) with the risk of proteinuria has previously not been comprehensively investigated and results have been inconclusive. OBJECTIVE: To examine BMI and WC in relation to new-onset proteinuria in Chinese hypertensive patients. DESIGN AND SETTING: Post hoc analysis of the renal substudy of the China Stroke Primary Prevention Trial (CSPPT). PATIENTS: 10 805 hypertensive patients without proteinuria at baseline. MAIN OUTCOME MEASURE: The primary outcome was new-onset proteinuria, defined as a urine dipstick protein reading ≥ 1 + at the exit visit, after a median follow-up duration of 4.4 years. RESULTS: When analyzed separately, increased BMI (≥ 28 kg/m2, quartile 4; odds ratio [OR], 1.36; 95% confidence interval [CI], 1.08-1.72), or increased WC (≥ 91cm for females, quartile 4; OR, 1.35; 95% CI, 1.01-1.80; and ≥ 79 cm for males, quartile 2-4; OR, 1.60; 95% CI, 1.03-2.50) were each significantly associated with higher risk of new-onset proteinuria. When analyzed jointly, participants without increased BMI and increased WC had the lowest risk, while those with both increased BMI and increased WC had the highest risk of proteinuria (OR, 1.61; 95% CI, 1.21-2.13). Notably, participants with only increased WC also had significantly increased risk of proteinuria (OR, 1.39; 95% CI, 1.04-1.85). CONCLUSION: In Chinese hypertensive patients, increased BMI and increased WC were individually and jointly associated with a higher risk of new-onset proteinuria, underscoring the value of monitoring both BMI and WC in assessing proteinuria risk.

Relative Bioavailability of Enalapril Administered as Orodispersible Minitablets in Healthy Adults.

The angiotensin-converting enzyme inhibitor enalapril is commonly used to treat chronic heart failure in children. Because some children are unable to swallow capsules or tablets, a new, age-appropriate, orodispersible minitablet (ODMT) containing 1 mg of enalapril was developed within the EU-funded LENA (Labeling of Enalapril from Neonates up to Adolescents) consortium. In order to support the clinical evaluation of this new formulation in children, a relative bioavailability study was performed in healthy adults, comparing the bioavailability of enalapril in the ODMT with that of a reference product (RP) Renitec, a registered standard enalapril tablet formulation. In this open-label, randomized 3-way crossover study, 24 healthy subjects received a 10-mg enalapril dose administered as (1) 2 × 5-mg tablets of the RP swallowed with water, (2) 10 × 1-mg ODMT swallowed with water, and (3) 10 × 1 mg ODMT dispersed on the tongue. When the relative bioavailability of the ODMT formulation swallowed with water was compared with that of the RP, the estimated 90%CIs for the ratio of area under the concentration-time curve (AUC0-∞ ) and or peak concentration (Cmax ) of enalapril were 92.34% to 106.49% and 91.28% to 115.72%, respectively, which are within the accepted bioequivalence limits of 80% to 125%. Following dispersion of the ODMT in the mouth, a slightly higher Cmax for enalapril was observed as compared with the RP with an upper 90%CI of 127.57%, slightly exceeding the bioequivalence limit. Taken together, it was demonstrated that the method of administration of the ODMT, swallowed or dispersed, did not significantly affect the bioavailability of enalapril.

Cost-effectiveness of sacubitril/valsartan for the treatment of patients with heart failure with reduced ejection fraction in Portugal.

Objectives: This study assesses the cost-effectiveness of sacubitril/valsartan versus enalapril in patients with symptomatic heart failure with reduced ejection fraction (HFrEF).Methods: We used a previously developed Markov model calibrated with patient-level data from the PARADIGM-HF trial, adapted to the Portuguese setting. The model considers two health states (alive or dead) and uses regression analyzes to estimate hospitalizations and deaths over time. A panel of experts estimated resource consumption in the outpatient setting. To estimate resource consumption with hospitalizations, the National Health Service Diagnosis Related Groups database was used. Unit costs were based on national legislation, and on the Infomed database. The model considers a societal perspective, a time horizon of 30-years, and a 5% annual discount rate. Sensitivity analyses assessed the robustness of results.Results: Sacubitril/valsartan increases life expectancy by 0.5 life-years, corresponding to 0.4 incremental quality adjusted life-years (QALY) versus enalapril. The estimated incremental cost-effectiveness ratio (ICER) is 22,702€/QALY. Sensitivity analysis shows that results are robust, but sensitive to the parameter estimates of the cardiovascular survival curve.Conclusion: Sacubitril/valsartan is a cost-effective therapeutic option in the treatment of Portuguese patients with HFrEF and translate into significant health gains and increased life expectancy versus the current standard of care.

Effect of bilateral sympathectomy in a rat model of dilated cardiomyopathy induced by doxorubicin.

OBJECTIVE: The study objective was to evaluate the effect of bilateral sympathectomy on ventricular remodeling and function in a rat model of dilated cardiomyopathy induced by doxorubicin. METHODS: Dilated cardiomyopathy was induced in male Wistar rats by weekly intraperitoneal injection of doxorubicin (2 mg/kg) for 9 weeks. Animals were divided into 4 groups: dilated cardiomyopathy; bilateral sympathectomy, submitted on day 15 of the protocol to bilateral sympathectomy; angiotensin-converting enzyme inhibitor, treated with enalapril through day 15 until the end of the experimental protocol; and sham, nonsubmitted through doxorubicin protocol, with weekly intraperitoneal injections of saline solution (0.9%). The left ventricular function was assessed, and the heart was collected for posterior analyses. RESULTS: The dilated cardiomyopathy group presented a significant decrease in the myocardial efficiency when compared with the sham group (33.4% vs 71.2%). Only the bilateral sympathectomy group was able to preserve it (57.5%; P = .0001). A significant dilatation in the left ventricular chamber was observed in the dilated cardiomyopathy group (15.9 µm2) compared with the sham group (10.2 µm2; P = .0053). Sympathectomy and enalapril prevented ventricular remodeling (9.5 and 9.6 µm2, respectively; P = .0034). There was a significant increase in interstitial myocardial fibrosis in the dilated cardiomyopathy group (14.8%) when compared with the sham group (2.4%; P = .0001). This process was significantly reduced with sympathectomy and enalapril (8.7 and 3.9%, respectively; P = .0001). CONCLUSIONS: Bilateral sympathectomy was effective in preventing remodeling and left ventricular dysfunction in a rat model of dilated cardiomyopathy induced by doxorubicin.

Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial.

BACKGROUND: In the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by postrandomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril. METHODS: There were 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (ejection fraction ≤35%) randomized to receive starting doses (5-10 mg/day) of placebo (n = 1284) or enalapril (n = 1285). At day 14, both study drugs were blindly up-titrated to the target dose (20 mg/day). Overall, 96% (2458/2569) of the patients returned for dose up-titration, which was achieved in 59% (1444/2458), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated. RESULTS: HRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14 days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06), respectively. Corresponding HRs (95% CIs) at 30 days were 0.82 (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68), respectively. The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose. CONCLUSION: These data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug.

Improving the use of intravenous antihypertensive medications in the hospital setting: a quality improvement initiative for patient safety.

Intravenous (IV) hydralazine, enalapril and labetalol are oftentimes used without indication for the treatment of asymptomatic hypertension in the hospital setting and have been shown to have substantial adverse effects that are associated with increased morbidity and mortality, as well as longer length of stay. Their use is also associated with greater monetary costs. In this project, we studied the frequency of use and consequences of these medications before and after a series of education cycles which clarified when and when not to use intravenous antihypertensives (IVAHs). Our initial aim was to decrease the unindicated use of IVAH by at least 25% in the setting of asymptomatic hypertension in our community hospital within a 1-year period after introducing education on the topic. Multidisciplinary involvement throughout three Plan-Do-Study-Act (PDSA) cycles yielded favourable results. We focused on education towards a hospital-wide knowledge gap stemming from a lack of guidelines regarding the treatment of asymptomatic hypertension, as well as the guideline indications for IVAH. After three cycles of education targeting different groups, the unindicated use of IVAH fell by a total of 66%, decreasing patient exposure by approximately 248 cases over the total course of the study and ultimately, yielding a 52% increase in patient safety. Secondary outcome included a reduction in cost. It was noted that IV drugs cost more than their oral counterparts. The culture change in switching away from IVAH unless otherwise indicated was driven by repetitive education and group discussion to close the gap created by a lack of guidelines.

New orodispersible mini-tablets for paediatric use - A comparison of isomalt with a mannitol based co-processed excipient.

The development of orodispersible mini-tablets (ODMTs) for paediatric use has gained importance within recent years as European authorities set up regulations for developing suitable and palatable dosage forms for paediatric patients. Polyols like mannitol and isomalt are frequently used in the manufacture of tablets where sensory properties have to be taken into account. In literature, ODTMs based on a commercialized co-processed excipient based on mannitol (Ludiflash®) have been already described. Isomalt is known for its pleasant sensory properties and therefore appears to be a good candidate for ODMTs. The feasibility of the direct compression grade of isomalt for the manufacture of ODMTs was assessed and compared to Ludiflash®. Hydrochlorothiazide and enalapril maleate were chosen as model drugs and compressed to 2 mm mini-tablets. ODMTs could be obtained fulfilling the criteria of Ph.Eur. with disintegration times of 180 s or even the FDA limit of 30 s. Dissolution studies and mass variation were fulfilled for all mini-tablets. Acceptance values (AV) ≤ 15 were achieved for formulations based on both isomalt and Ludiflash®. Stability data showed the change of disintegration time and tensile strength as a function of storing time, condition and excipient. Both excipients showed their potential for ODMTs for paediatric use.

Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial.

BACKGROUND: A fixed-dose combination therapy (polypill strategy) has been proposed as an approach to reduce the burden of cardiovascular disease, especially in low-income and middle-income countries (LMICs). The PolyIran study aimed to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan for primary and secondary prevention of cardiovascular disease. METHODS: The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50 045 participants aged 40-75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation. We used a balanced randomisation algorithm, considering block sizes of 20 and balancing for cluster size or natural log of the cluster size (depending on the skewness within strata). Randomisation was done at a fixed point in time (Jan 18, 2011) by statisticians at the University of Birmingham (Birmingham, UK), independent of the local study team. The non-pharmacological preventive interventions (including educational training about healthy lifestyle-eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12·5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome-occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)-was centrally assessed by the GCS follow-up team, who were masked to allocation status. We did intention-to-treat analyses by including all participants who met eligibility criteria in the two study groups. The trial was registered with ClinicalTrials.gov, number NCT01271985. FINDINGS: Between Feb 22, 2011, and April 15, 2013, we enrolled 6838 individuals into the study-3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. 1761 (51·5%) of 3421 participants in the polypill group were women, as were 1679 (49·1%) of 3417 participants in the minimal care group. Median adherence to polypill tablets was 80·5% (IQR 48·5-92·2). During follow-up, 301 (8·8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5·9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0·66, 95% CI 0·55-0·80). We found no statistically significant interaction with the presence (HR 0·61, 95% CI 0·49-0·75) or absence of pre-existing cardiovascular disease (0·80; 0·51-1·12; pinteraction=0·19). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0·43, 95% CI 0·33-0·55). The frequency of adverse events was similar between the two study groups. 21 intracranial haemorrhages were reported during the 5 years of follow-up-ten participants in the polypill group and 11 participants in the minimal care group. There were 13 physician-confirmed diagnoses of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group. INTERPRETATION: Use of polypill was effective in preventing major cardiovascular events. Medication adherence was high and adverse event numbers were low. The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in LMICs. FUNDING: Tehran University of Medical Sciences, Barakat Foundation, and Alborz Darou.

Associations between Blood Pressure Indices and Brachial-ankle Pulse Wave Velocity in Treated Hypertensive Adults: results from the China Stroke Primary Prevention Trial (CSPPT).

Brachial-ankle pulse wave velocity (baPWV), as a marker of arterial stiffness, has been demonstrated to be associated with blood pressure (BP) and onset of hypertension. However, little information is available on the associations between baPWV and BP indices [systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), mean arterial pressure (MAP)] in treated hypertensive patients. We aimed to assess the associations between BP indices and baPWV. In this cross-sectional study, 14,598 hypertensive patients from China Stroke Primary Prevention Trial (CSPPT) at the exit visit of the trial were analyzed. Elevated baPWV was defined as ≥18.3 m/s. Multivariate linear and logistic regression analyses were performed to evaluate the associations of BP indices with baPWV and elevated baPWV. Moreover, the smooth curve fitting (penalized spline method) was conducted. Multivariate linear regression analyses showed that continuous SBP, DBP, PP and MAP were independently and positively associated with baPWV (ß = 0.081, 0.084, 0.078 and 0.115, respectively, all P < 0.001). Compared with controlled SBP group (<140 mm Hg), uncontrolled SBP (≥140 mm Hg) was significantly associated with higher baPWV [ß = 2.234, 95% confidence interval (CI): 2.137-2.332]. Similarly, compared with controlled DBP group (<90 mm Hg), uncontrolled DBP (≥90 mm Hg) was significantly associated with higher baPWV (ß = 1.466, 95%CI: 1.341-1.590). Multiple logistic analyses also showed that SBP, DBP, PP and MAP were significantly and positively associated with elevated baPWV (OR = 1.056, 1.049, 1.052, and 1.075, respectively, all P < 0.001). The fully-adjusted smooth curve fitting presented a linear association between BP indices with baPWV. In conclusion, among treated hypertensive patients, SBP, DBP, PP and MAP levels were independently and positively associated with baPWV and elevated baPWV, suggesting that baPWV might be a way to predict uncontrolled BP.