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1.
Carvedilol versus propranolol effect on hepatic venous pressure gradient at 1 month in patients with index variceal bleed: RCT.
Gupta, V, Rawat, R, Shalimar, , Saraya, A
Hepatology international. 2017;(2):181-187
Abstract
BACKGROUND AND AIMS Endoscopic variceal ligation (EVL) plus beta blocker is the mainstay treatment after index bleed to prevent rebleed. Primary objective of this study was to compare EVL plus propranolol versus EVL plus carvedilol on reduction of HVPG after 1 month of therapy. METHODS Patients of cirrhosis presenting with index esophageal variceal bleed received standard treatment (Somatostatin therapy f/b EVL) following which HVPG was measured and patients were randomized to propranolol or carvedilol group if HVPG was >12 mmHg. Standard endotherapy protocol was continued in both groups. HVPG was again measured at 1 month of treatment. RESULTS Out of 129 patients of index esophageal variceal bleed, 59 patients were eligible and randomized into carvedilol (n = 30) and propranolol (n = 29). At 1 month of treatment, decrease in heart rate, mean arterial blood pressure (MAP) and HVPG was significant within each group (p = 0.001). Percentage decrease in MAP was significantly more in carvedilol group as compared to propranolol group (p = 0.04). Number of HVPG responders (HVPG decrease >20 % or below 12 mmHg) was significantly more in carvedilol group (22/29) as compared to propranolol group (14/28), p = 0.04. CONCLUSION Carvedilol is more effective in reducing portal pressure in patients with cirrhosis with esophageal bleed. Though a larger study is required to substantiate this, the results in this study are promising for carvedilol. Clinical trials online government registry (CTRI/2013/10/004119). Trial registration number CTRI/2013/10/004119.
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2.
Drug-Excipient Interactions in the Solid State: The Role of Different Stress Factors.
Gressl, C, Brunsteiner, M, Davis, A, Landis, M, Pencheva, K, Scrivens, G, Sluggett, GW, Wood, GPF, Gruber-Woelfler, H, Khinast, JG, et al
Molecular pharmaceutics. 2017;(12):4560-4571
Abstract
Understanding properties and mechanisms that govern drug degradation in the solid state is of high importance to ensure drug stability and safety of solid dosage forms. In this study, we attempt to understand drug-excipient interactions in the solid state using both theoretical and experimental approaches. The model active pharmaceutical ingredients (APIs) under study are carvedilol (CAR) and codeine phosphate (COP), which are known to undergo esterification with citric acid (CA) in the solid state. Starting from the crystal structures of two different polymorphs of each compound, we calculated the exposure and accessibility of reactive hydroxyl groups for a number of relevant crystal surfaces, as well as descriptors that could be associated with surface stabilities using molecular simulations. Accelerated degradation experiments at elevated temperature and controlled humidity were conducted to assess the propensity of different solid forms of the model APIs to undergo chemical reactions with anhydrous CA or CA monohydrate. In addition, for CAR, we studied the solid state degradation at varying humidity levels and also under mechano-activation. Regarding the relative degradation propensities, we found that variations in the exposure and accessibility of molecules on the crystal surface play a minor role compared to the impact of molecular mobility due to different levels of moisture. We further studied drug-excipient interactions under mechano-activation (comilling of API and CA) and found that the reaction proceeded even faster than in physical powder mixtures kept at accelerated storage conditions.
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3.
Pharmacological interventions for treating heart failure in patients with Chagas cardiomyopathy.
Martí-Carvajal, AJ, Kwong, JS
The Cochrane database of systematic reviews. 2016;(7):CD009077
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Abstract
BACKGROUND Chagas disease-related cardiomyopathy is a major cause of morbidity and mortality in Latin America. Despite the substantial burden to the healthcare system, there is uncertainty regarding the efficacy and safety of pharmacological interventions for treating heart failure in people with Chagas disease. This is an update of a Cochrane review published in 2012. OBJECTIVES To assess the clinical benefits and harms of current pharmacological interventions for treating heart failure in people with Chagas cardiomyopathy. SEARCH METHODS We updated the searches in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 1), MEDLINE (Ovid; 1946 to to February Week 1 2016), EMBASE (Ovid; 1947 to 2016 Week 07), LILACS (1982 to 15 February 2016), and Web of Science (Thomson Reuters; 1970 to 15 February 2016). We checked the reference lists of included papers. We applied no language restrictions. SELECTION CRITERIA We included randomised clinical trials (RCTs) that assessed the effects of pharmacological interventions to treat heart failure in adult patients (18 years or older) with symptomatic heart failure (New York Heart Association classes II to IV), regardless of the left ventricular ejection fraction stage (reduced or preserved), with Chagas cardiomyopathy. We did not apply limits to the length of follow-up. Primary outcomes were all-cause mortality, cardiovascular mortality at 30 days, time-to-heart decompensation, disease-free period (at 30, 60, and 90 days), and adverse events. DATA COLLECTION AND ANALYSIS Two authors independently performed study selection, 'Risk of bias' assessment and data extraction. We estimated relative risk (RR) and 95% confidence intervals (CIs) for dichotomous outcomes. We measured statistical heterogeneity using the I² statistic. We used a fixed-effect model to synthesize the findings. We contacted authors for additional data. We developed 'Summary of findings' (SoF) tables and used GRADE methodology to assess the quality of the evidence. MAIN RESULTS In this update, we identified one new trial. Therefore, this version includes three trials (108 participants). Two trials compared carvedilol against placebo and another assessed rosuvastatin versus placebo. All trials had a high risk of bias.Meta-analysis of two trials showed a lower proportion of all-cause mortality in the carvedilol groups compared with the placebo groups (RR 0.69; 95% CI 0.12 to 3.88, I² = 0%; 69 participants; very low-quality evidence). Neither of the trials reported on cardiovascular mortality, time-to-heart decompensation, or disease-free periods.One trial (30 participants) found no difference in hospital readmissions (RR 1.00; 95% CI 0.31 to 3.28; very low-quality of evidence) or reported adverse events (RR 0.92; 95% CI 0.67 to 1.27; very low-quality of evidence) between the carvedilol and placebo groups.There was very low-quality evidence from two trials of inconclusive effects on quality of life (QoL) between the carvedilol and placebo groups. One trial (30 participants) assessed QoL with the Minnesota Living With Heart Failure Questionnaire (21 items; item scores range from 0 to 5; a lower MLHFQ score is better). The MD was -14.74; 95% CI -24.75 to -4.73. The other trial (39 participants) measured QoL with the Medical Outcomes Study 36-item short-form health survey (SF-36; item scores range from 0 to 100; higher SF-36 score is better). Data were not provided.One trial (39 participants) assessed the effect of rosuvastatin versus placebo. The trial did not report on any primary outcomes or adverse events. There was very low-quality evidence of uncertain effects on QoL (no data were provided). AUTHORS' CONCLUSIONS This first update of our review found very low-quality evidence for the effects of either carvedilol or rosuvastatin, compared with placebo, for treating heart failure in people with Chagas disease. The three included trials were underpowered and had a high risk of bias. There were no conclusive data to support or reject the use of either carvedilol or rosuvastatin for treating Chagas cardiomyopathy. Unless randomised clinical trials provide evidence of a treatment effect, and the trade-off between potential benefits and harms is established, policy-makers, clinicians, and academics should be cautious when recommending or administering either carvedilol or rosuvastatin to treat heart failure in people with Chagas disease. The efficacy and safety of other pharmacological interventions for treating heart failure in people with Chagas disease remains unknown.
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Randomized Control of Sympathetic Drive With Continuous Intravenous Esmolol in Patients With Acute ST-Segment Elevation Myocardial Infarction: The BEtA-Blocker Therapy in Acute Myocardial Infarction (BEAT-AMI) Trial.
Er, F, Dahlem, KM, Nia, AM, Erdmann, E, Waltenberger, J, Hellmich, M, Kuhr, K, Le, MT, Herrfurth, T, Taghiyev, Z, et al
JACC. Cardiovascular interventions. 2016;(3):231-240
Abstract
OBJECTIVES This study sought to evaluate the role of esmolol-induced tight sympathetic control in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Elevated sympathetic drive has a detrimental effect on patients with acute STEMI. The effect of beta-blocker-induced heart rate mediated sympathetic control on myocardial damage is unknown. METHODS The authors conducted a prospective, randomized, single-blind trial involving patients with STEMI and successful percutaneous intervention (Killip class I and II). Patients were randomly allocated to heart rate control with intravenous esmolol for 24 h or placebo. The primary outcome was the maximum change in troponin T release as a prognostic surrogate marker for myocardial damage. A total of 101 patients were enrolled in the study. RESULTS There was a significant difference between patients allocated to placebo and those who received sympathetic control with esmolol in terms of maximum change in troponin T release: the median serum troponin T concentration increased from 0.2 ng/ml (interquartile range [IQR] 0.1 to 0.7 ng/ml) to 1.3 ng/ml (IQR: 0.6 to 4.7 ng/ml) in the esmolol group and from 0.3 ng/ml (IQR: 0.1 to 1.2 ng/ml) to 3.2 ng/ml (IQR: 1.5 to 5.3 ng/ml) in the placebo group (p = 0.010). The levels of peak creatine kinase (CK), CK subunit MB (CK-MB), and n-terminal brain natriuretic peptide (NT-proBNP) were lower in the esmolol group compared with placebo (CK 619 U/l [IQR: 250-1,701 U/l] vs. 1,308 U/l [IQR: 610 to 2,324 U/l]; p = 0.013; CKMB 73.5 U/l [IQR: 30 to 192 U/l] vs. 158.5 U/l [IQR: 74 to 281 U/l]; p = 0.005; NT-proBNP: 1,048 pg/ml (IQR: 623 to 2,062 pg/ml] vs. 1,497 pg/ml [IQR: 739 to 3,318 pg/ml]; p = 0.059). Cardiogenic shock occurred in three patients in the placebo group and in none in the esmolol group. CONCLUSIONS Esmolol treatment statistically significantly decreased troponin T, CK, CK-MB and NT-proBNP release as surrogate markers for myocardial injury in patients with STEMI. (Heart Rate Control After Acute Myocardial Infarction; DRKS00000766).
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A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates.
Cosman, F, Gilchrist, N, McClung, M, Foldes, J, de Villiers, T, Santora, A, Leung, A, Samanta, S, Heyden, N, McGinnis, JP, et al
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2016;(1):377-86
Abstract
UNLABELLED In women with osteoporosis treated with alendronate for >12 months and oral bisphosphonates for >3 of the last 4 years, switching to MK-5442, a calcium receptor antagonist, stimulated endogenous parathyroid hormone (PTH) secretion and increased bone turnover marker levels, but produced a decline in bone mineral density (BMD) at all sites. INTRODUCTION This study assessed the effects of switching from long-term oral bisphosphonate therapy to the calcium-sensing receptor antagonist MK-5442 on BMD and bone turnover markers (BTMs) in post-menopausal women with osteoporosis. METHODS This randomized, active and placebo-controlled, dose-ranging study enrolled 526 postmenopausal women, who had taken alendronate (ALN) for ≥12 months preceding the trial and any oral bisphosphonate for ≥3 of the preceding 4 years and had spine or hip BMD T-scores ≤-2.5 or ≤-1.5 with ≥1 prior fragility fracture. Women were randomized to continue ALN 70 mg weekly or switch to MK-5442 (5, 7.5, 10, or 15 mg daily) or placebo. RESULTS Switching from ALN to MK-5442 produced a dose-dependent parathyroid hormone (PTH) pulse of threefold to sixfold above baseline at 1 h, with PTH levels that remained twofold to threefold above baseline at 4 h and returned to baseline by 24 h. Switching to MK-5442 or placebo increased BTM levels compared to baseline within 3 months and MK-5442 10 mg increased BTM levels compared to placebo by 6 months. With all MK-5442 doses and placebo, spine and hip BMD declined from baseline, and at 12 months, BMD levels were below those who continued ALN (all groups P < 0.05 vs ALN). There was also a dose-dependent increase in the incidence of hypercalcemia with MK-5442. CONCLUSION Switching from ALN to MK-5442 resulted in a pulsatile increase in PTH and increases in BTMs, but a decline in BMD compared with continued ALN. MK-5442 is not a viable option for the treatment of osteoporosis.
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Mechanisms and Treatment of Intradialytic Hypertension.
Van Buren, PN, Inrig, JK
Blood purification. 2016;(1-3):188-93
Abstract
BACKGROUND Intradialytic hypertension is a condition where there is an increase in blood pressure (BP) from pre- to post-hemodialysis; this condition has been recently identified as an independent mortality risk factor in hypertensive hemodialysis patients. The mechanisms and management of intradialytic hypertension have been explored in numerous research studies over the past few years. SUMMARY Patients with intradialytic hypertension have been found to be more chronically volume overloaded compared to other hemodialysis patients, although no causal role has been established. Patients with intradialytic hypertension have intradialytic vascular resistance surges that likely explain the BP increase during dialysis. Acute intradialytic changes in endothelial cell function have been proposed as etiologies for the increase in vascular resistance, although it is unclear if endothelin-1 or some other vasoconstrictive peptide is responsible. There is an association between dialysate to serum sodium gradients and BP increase during dialysis in patients with intradialytic hypertension, although it is unclear if this is related to endothelial cell activity or acute osmolar changes. In addition to probing the dry weight of patients with intradialytic hypertension, other management strategies include lowering dialysate sodium and changing antihypertensives to include carvedilol or other poorly dialyzed antihypertensives. KEY MESSAGES Hemodialysis patients with intradialytic hypertension have an increased mortality risk compared to patients with modest decreases in BP during dialysis. Intradialytic hypertension is associated with extracellular volume overload in addition to acute increases in vascular resistance during dialysis. Management strategies should include reevaluation of dry weight and modification of both the dialysate prescription and medication prescription.
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Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation.
Driver, BE, Debaty, G, Plummer, DW, Smith, SW
Resuscitation. 2014;(10):1337-41
Abstract
INTRODUCTION We compare the outcomes for patients who received esmolol to those who did not receive esmolol during refractory ventricular fibrillation (RVF) in the emergency department (ED). METHODS A retrospective investigation in an urban academic ED of patients between January 2011 and January 2014 of patients with out-of-hospital or ED cardiac arrest (CA) with an initial rhythm of ventricular fibrillation (VF) or ventricular tachycardia (VT) who received at least three defibrillation attempts, 300mg of amiodarone, and 3mg of adrenaline, and who remained in CA upon ED arrival. Patients who received esmolol during CA were compared to those who did not. RESULTS 90 patients had CA with an initial rhythm of VF or VT; 65 patients were excluded, leaving 25 for analysis. Six patients received esmolol during cardiac arrest, and nineteen did not. All patients had ventricular dysrhythmias refractory to many defibrillation attempts, including defibrillation after administration of standard ACLS medications. Most received high doses of adrenaline, amiodarone, and sodium bicarbonate. Comparing the patients that received esmolol to those that did not: 67% and 42% had temporary return of spontaneous circulation (ROSC); 67% and 32% had sustained ROSC; 66% and 32% survived to intensive care unit admission; 50% and 16% survived to hospital discharge; and 50% and 11% survived to discharge with a favorable neurologic outcome, respectively. CONCLUSION Beta-blockade should be considered in patients with RVF in the ED prior to cessation of resuscitative efforts.
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Addition of N-acetyl cysteine to carvedilol decreases the incidence of acute renal injury after cardiac surgery.
Ozaydin, M, Peker, T, Akcay, S, Uysal, BA, Yucel, H, Icli, A, Erdogan, D, Varol, E, Dogan, A, Okutan, H
Clinical cardiology. 2014;(2):108-14
Abstract
BACKGROUND Oxidative stress and inflammation during cardiac surgery may be associated with acute renal injury (ARI). N-acetyl cysteine (NAC) and carvedilol have antioxidant and anti-inflammatory properties. HYPOTHESIS A combination of carvedilol and NAC should decrease the incidence of ARI more than metoprolol or carvedilol. METHODS Patients undergoing cardiac surgery were randomized to metoprolol, carvedilol, or carvedilol plus NAC. End points were occurrence of ARI and change in preoperative to postoperative peak creatinine levels. RESULTS ARI incidence was lower in the carvedilol plus NAC group compared with the metoprolol (21.0% vs 42.1%; P = 0.002) or carvedilol (21.0% vs 38.6%; P = 0.006) groups, but was similar between the metoprolol and carvedilol groups (P = 0.62). Preoperative and postoperative day 1 creatinine levels were similar among the metoprolol (1.02 [0.9-1.2] and 1.2 [0.92-1.45]) the carvedilol (1.0 [0.88-1.08] and 1.2 [0.9-1.5]) and the carvedilol plus NAC groups (1.06 [0.9-1.18] and 1.1 [1.0-1.21] mg/dL; all P values >0.05). Postoperative day 3, day 5, and peak creatinine levels were lower in the carvedilol plus NAC group (1.11 [1.0-1.23], 1.14 [1.0-1.25] and 1.15 [1.0-1.25]) as compared with the metoprolol (1.4 [1.3-1.49], 1.3 [1.0-1.54] and 1.3 [1.0-1.54]) or carvedilol groups (1.2 [1.0-1.52], 1.25 [1.0-1.52] and 1.25 [1.0-1.55] mg/dL; all P values <0.05), but were similar between the metoprolol and carvedilol groups (all P values >0.05). CONCLUSIONS Combined carvedilol and NAC decreased ARI incidence as compared with carvedilol or metoprolol. No difference was detected between carvedilol and metoprolol.
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Protective effect of esmolol on myocardial ischemic injury during open heart surgery in children.
Gui, P, Wu, Q, Wu, J, Yao, S
Paediatric anaesthesia. 2013;(3):217-21
Abstract
OBJECTIVES To investigate the efficacy of esmolol in protecting the myocardium from ischemia during pediatric cardiac surgery. BACKGROUND Esmolol, an ultra-short acting beta 1-adrenoceptor blocker, reduces myocardial injury in adult cardiac operations. However, this technique is rarely used in pediatric cardiac surgery. METHODS Thirty children with ventricular septal defect were randomly allocated to the esmolol group and the control group. Patients received intravenous esmolol (0.05 mg·kg(-1) ·min(-1) after tracheal intubation, 0.3 mg·kg(-1) ·min(-1) during cardiopulmonary bypass (CPB) and 0.03-0.05 mg·kg(-1) ·min(-1) until the end of surgery) or placebo, respectively. RESULTS Plasma levels of creatine kinase-MB, cardiac troponin I in the esmolol group 2 min after completion of CPB, at the end of surgery, 4 h after surgery, and the first postoperative day were significantly lower than those in the control group. Values of heart rate 10 min after induction, 2 min before institution of CPB, 2 min after completion of CPB, and at the end of surgery were significantly lower in the esmolol group; however, mean arterial pressure, CPB time, cross-clamp time, and the rate of heart spontaneous rebeating were not statistically different between two groups. Cumulative postoperative dosage of dopamine in the esmolol group (100.1 ± 53.1 mg) was significantly less than that in the control group (171.4 ± 92.1 mg). CONCLUSIONS Esmolol can protect the myocardium from ischemic injury during CPB in children and significantly reduce the use of inotropic drug.
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Metoprolol vs. carvedilol or carvedilol plus N-acetyl cysteine on post-operative atrial fibrillation: a randomized, double-blind, placebo-controlled study.
Ozaydin, M, Icli, A, Yucel, H, Akcay, S, Peker, O, Erdogan, D, Varol, E, Dogan, A, Okutan, H
European heart journal. 2013;(8):597-604
Abstract
AIMS: Carvedilol and N-acetyl cysteine (NAC) have antioxidant and anti-inflammatory properties. Aim was to evaluate the efficacy of metoprolol, carvedilol, and carvedilol plus NAC on the prevention of post-operative atrial fibrillation (POAF). METHODS AND RESULTS Patients undergoing cardiac surgery (n = 311) were randomized to metoprolol, carvedilol, or carvedilol plus NAC. Baseline characteristics were similar. The incidence of POAF was lower in the carvedilol plus NAC group compared with the metoprolol group (P < 0.0001) or the carvedilol group (P = 0.03). There was a borderline significance for lower POAF rates in the carvedilol group compared with the metoprolol group (P = 0.06). Duration of hospitalization was lower in the carvedilol plus NAC group compared to the metoprolol group (P = 0.004). Multivariate independent predictors of POAF included left-atrial diameter, hypertension, bypass duration, pre-randomization and pre-operative heart rates, carvedilol plus NAC group vs. metoprolol group, and carvedilol plus NAC group vs. carvedilol group. CONCLUSION Carvedilol plus NAC decreased POAF incidence and duration of hospitalization compared with metoprolol and decreased POAF incidence compared with carvedilol.