Selective Beta-blockers Research Articles

Abstract 11571: Beneficial Effect of Early Infusion of Landiolol; A Very Short Acting Beta1 Adrenergic Receptor Blocker, on Reperfusion Status in Acute Myocardial Infarction

Introduction: Landiolol is the beta-1 selective receptor blocker and its half-life elimination is 4 minutes. The safety and efficacy of landiolol started before coronary reperfusion in patients with ST-segment elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) remains unclear. We assessed the hypothesis that very early use of landiolol promotes optimal reperfusion without increasing adverse events for those patients. Methods: We conducted a prospective, single-group trial of landiolol during the pPCI for a STEMI. Landiolol was started intravenously just before the pPCI with 3 μg/kg/min. The reperfusion status and clinical outcomes in 55 treated patients were compared with those in 60 historical control patients treated without landiolol. The optimal reperfusion was assessed by an ST-segment resolution (STR), coronary flow, myocardial brush grade (MBG) and peak creatine kinase (CK) after reperfusion. Result: Time from admission to starting landiolol was 35±23min in landiolol group. Age, sex, coronary risk factors, culprit lesion, SYNTAX score and reperfusion time did not differ between landiolol group and control group (all NS). Those in the landiolol group achieved a higher rate of an STR (64% vs. 42%, p =0.023) and MBG 2/3 (64% vs. 45%, p =0.045), whereas coronary flow and peak CK were comparable between the two groups. A multivariate analysis showed that landiolol use was an independent predictor of an STR (OR 2.99, 95% CI 1.25-7.16, p =0.014). The incidence of non-sustained ventricular tachycardia (27% vs. 50%, p =0.014), hypotension (15% vs. 32%, p =0.046) and progression to Killip class grade III or IV (0% vs. 10%, p =0.028) during admission were lower in the landiolol group. Within 12 months after the admission, the rate of worsening heart failure (0vs7%, p=0.07) tended to be lower in landiolol group. Left ventricular ejection fraction and end-diastolic volume index in 12 months after the admission did not differ between the two groups (landiolol group vs control group: 59±11%vs56±15%, p=0.23; 60±14vs63±30ml/m 2 , p=0.62). Conclusion: In patients with STEMI, intra-procedural landiolol in pPCI may attenuate myocardial reperfusion injury and reduce adverse events.

PP.13.16] EFFECTS OF COMBINATION OF ANGIOTENSIN II RECEPTOR ANTAGONIST WITH CALCIUM ANTAGONIST IN HYPERTENSIVE PATIENTS WITH CORONARY HEART DISEASE AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE.

Objective: To evaluate the effects of valsartan/amlodipine (V/A) fixed combination for standard therapy of arterial hypertension (AH) and coronary heart disease (CHD) in smokers with chronic obstructive pulmonary disease (COPD) Design and method: 36 smoker male with AH (DBP 90–110 mmHg and/or SBP 140 −180 mmHg), CHD and COPD were randomized into 2 groups (gr): I gr (n = 18, 55,8 ± 5,9 yrs) which received angiotensin-converting enzyme inhibitor and II gr (n = 18, 58,0 ± 4,9 yrs) which treated with the fixed combination V/A (160 mg/5–10 mg). All pts received selective beta-blockers, 16.7% of pts I and II grs - diuretics. The duration of the study was 4 months. The trail includes bicycle exercise stress test (PE); echocardiography; spirometry (forced vital capacity, FVC; forced expiratory volume in 1 second, FEV1); 24-hour ambulatory BP monitoring; questionnaires as SGRQ and Quality of Life SF-36. Results: Treatment with V/A significant (p < 0.001) decreased of office SBP (−39.2 ± 9.7 mmHg), DBP (−16.9 ± 5,7 mmHg), pulse BP (−22.2 ± 5.9 mmHg) vs the absence of such dynamics in pts of I gr. Also the average 24 h SBP/DBP was reduced by −10.6/9.3% (p < 0.001), daytime SBP/DBP by −11.6/9.8% (p < 0.01), nighttime SBP/DBP by −9.6/8.4% (p < 0.01). After V/A therapy there was observed increasing of the duration of the PE (22.2%, p < 0.01), threshold power (23.6%, p < 0.01), time before the development of angina pectoris (8.6%, p < 0.05) and myocardial ischemia (8.3%, p < 0.05). In pts of I gr there was a decrease of the duration of the PE (−10.2%, p < 0.05) and time to the development of angina pectoris (−29%, p < 0.05). In II gr we have found positive changes in structural parameters of the heart and decrease of mean pulmonary artery pressure. After V/A therapy there was increase of FVC (by 14.8%, p < 0.05), prebronchodilator FEV1 (by 11.7%, p < 0.05) and FEV1 after administration of salbutamol (by 12.5%, p < 0.05). After V/A therapy there was the improvement of psychological status and quality of life. Conclusions: Combination therapy with V/A have complementary mechanisms of action, effectively decreases the levels of office and ambulatory BP, mean pulmonary artery pressure, respiratory symptoms, improves exercise tolerance, and health-related quality of life in smokers with co-morbidities.

Influence of Beta Blockers on Complications of Cirrhosis

INTRODUCTION: Histologically cirrhosis, a chronic liver disease is characterized by fibrosis and the alteration of normal liver architecture into abnormal nodules. In the west, it is the leading cause of mortality, particularly affecting the productive age population. In our country, an estimated 188,575 cirrhosis related death in 2010 which is 18.3% of the universal burden of the disease. And the deaths due to cirrhosis increased globally from 2005 to 2015, whereas age-standardized cirrhosis mortality rates fell during the same period. The economic burden, the disease poses on the family of the patient and the patient’s loss of productive life has been overseen largely. The complications of cirrhosis are protean including portal hypertension, ascites, hepatorenal syndrome, hepatic encephalopathy, portal vein thrombosis, hepatocellular carcinoma and eventually death. Besides the complications that are disease driven, certain complications are worsened by the therapies instituted for the management of cirrhosis, of which beta blockers which have been used for managing portal hypertension since the 1980s when Lebrec et al. first demontsrated the usefulness of non selective beta blockers in a randomized controlled trial involving 74 patients with variceal bleeding, has recently drawn the interest of researchers and hepatologists worldwide, when concerns of its safety in advanced cirrhosis was raised by Serste. AIM OF THE STUDY: Aimed to analyze the impact of beta blockers on the following complications in cirrhosis: 1. Spontaneous bacterial peritonitis (SBP), 2. Refractory ascites, 3. Hepatorenal syndrome (HRS) and 4. Hepatic encephalopathy (HE). In patients who did or did not take non-selective beta blockers and thereby to test the null hypothesis that beta blockers cause worsening of the above mentioned complications. MATERIALS AND METHODS: Study Design: Single centre, case control retrospective study. Study centre: Department Of Digestive Health and Diseases, Kilpauk Medical College and Hospital, Kilpauk Medical College, Chennai. Period of Study: 2 years (January 2015 to January 2017). Study population: In Patients and Outpatients having cirrhosis and portal hypertension who were registered with the Department of Digestive Health and Disease between the period January 2009 to January 2016. Inclusion criteria: Patients having cirrhosis with portal hypertension. Exclusion criteria : Patients who had significant cardiovascular disease, extrahepatic malignancy, intrinsic renal disease and those not willing to provide consent were excluded from this study. METHODOLOGY Patients were identified from a prospectively collected data base. The following parameters were recorded at the time of enrollment to study: age, sex, duration of disease, number of hospital admissions for cirrhosis related illnesses, history of diabetes, history of upper gastrointestinal bleeding, presence of cirrhotic cardiomyopathy, portal vein thrombosis. Biochemical parameters such as complete blood count, renal function test, and liver function test were done. The MELD[5] and CTP[6,7] score were calculated based on the bilirubin, creatinine, PT/INR, albumin, presence of ascites and Hepatic Encephalopathy. RESULTS: A total of 82 patients were included in this study. The mean age of the entire cohort was 47.91 years. Predominantly our cohort had male patients (n=65, 79.3%). The overall mean duration of disease was 1.5 years. The common etiology for liver cirrhosis was ethanol (n = 61, 74.39%), followed by Chronic viral Hepatitis B (n = 9, 10.97%) cryptogenic, non alcoholic steatohepatitis and Hepatitis C. Four patients had both Hepatitis B and significant alcohol consumption. CONCLUSIONS: In this study , no significant statistical association was found between the NSBB group versus the non NSBB group in terms of the following 4 complications of cirrhois: 1. Spontaneous Bacterial peritonitis, 2. Refractory Ascites, 3. Hepatorenal syndrome, 4. Hepatic encephalopathy, To conclude, in this study non selective beta blockers are neither protective nor a risk factor for spontaneous bacterial peritonitis, refractory ascites, hepatorenal and hepatic encephalopathy. And therefore, we suggest that beta blockers can be continued safely in cirrhotics.

Respiratory effect of beta-blocker eye drops in asthma: population-based study and meta-analysis of clinical trials.

To measure the prevalence of beta-blocker eye drop prescribing and respiratory effect of ocular beta-blocker administration in people with asthma. We measured the prevalence of ocular beta-blocker prescribing in people with asthma and ocular hypertension, and performed a nested case-control study (NCCS) measuring risk of moderate exacerbations (rescue steroids in primary care) and severe exacerbations (asthma hospitalization) using linked data from the UK Clinical Practice Research Datalink. We then performed a systematic review and meta-analysis of clinical trials evaluating changes in lung function following ocular beta-blocker administration in people with asthma. From 2000 to 2012, the prevalence of non-selective and selective beta-blocker eye drop prescribing in people with asthma and ocular hypertension fell from 23.0% to 13.4% and from 10.5% to 0.9% respectively. In the NCCS, the relative incidence (IRR) of moderate exacerbations increased significantly with acute non-selective beta-blocker eye drop exposure (IRR 4.83, 95% CI 1.56-14.94) but not with chronic exposure. In the meta-analysis, acute non-selective beta-blocker eye drop exposure caused significant mean falls in FEV1 of -10.9% (95% CI -14.9 to -6.9), and falls in FEV1 of ≥20% affecting one in three. Corresponding values for selective beta-blockers in people sensitive to ocular non-selective beta-blockers was -6.3% (95% CI -11.7 to -0.8), and a non-significant increase in falls in FEV1 of ≥20%. Non-selective beta-blocker eye drops significantly affect lung function and increase asthma morbidity but are still frequently prescribed to people with asthma and ocular hypertension despite safer agents being available.

Hemodynamic Effects, Safety, and Feasibility of Intravenous Esmolol Infusion During Takotsubo Cardiomyopathy With Left Ventricular Outflow Tract Obstruction: Results From A Multicenter Registry.

Left ventricular outflow tract obstruction (LVOTO) may complicate an episode of Takotsubo cardiomyopathy (TTC), potentially leading to cardiogenic shock. Beta-blockers are considered the most suitable treatment for such complication. The objective of this study was to evaluate the hemodynamic effects, safety, and feasibility of a selective beta-blocker (β1) with a short half-life, esmolol, in subjects with a TTC episode. Ninety-six consecutive patients with TTC were enrolled in a multicenter registry. The hemodynamic and echocardiographic effects of esmolol (0.15-0.3mg/kg/min) were analyzed in nine consecutive patients with LVOTO. Clinical course of patients, hemodynamics, days of hospitalization, LV function, and adverse events at follow-up were recorded. Left ventricular outflow tract obstruction was present in 10 (10.4%) of 96 patients. Patients with LVOTO were older and had higher values of troponin-I at admission. LV ejection fraction at admission (36.1±8.4%) significantly improved at discharge (51.4±6.9%, P=0.001). Among patients treated with esmolol infusion, LVOT pressure gradient before treatment was 47.6±16.6mmHg and after 18.2±2.3mmHg (P=0.0091). Systolic blood pressure decreased from 123.8±29.1 to 112.6±12.7mmHg (P=0.1537). Mean hospital stay was 9±2days. No adverse events were observed during hospitalization and at follow-up. Esmolol infusion was temporally associated with reduction in intraventricular gradient and systemic blood pressure in patients with TTC and LVOTO. Further controlled studies are warranted to confirm these preliminary findings.

Present trends and controversies in the use of beta-blockers in cardiovascular diseases

In this paper we summarize present trends and controversies in the use of beta-blockers in cardiovascular diseases. Beta-blockers are catecolamine competitive inhibitors and act through alpha and beta adrenergic receptors blockade. Different agents have a dose-dependent affinity for different beta adrenergic receptors (beta 1, beta 2, beta 3) which is less with higher doses. The most important therapeutic effects of beta-blockers are on cardiovascular system, where they act as negative chronotropic and inotropic agents, lowering cardiac work and improving oxygen demand /supply ratio. Clinical indications are numerous. For their anti-ischemic activity beta-blockers are used as anti-anginal drugs and in acute and previous myocardial infarction for preventing total and cardiovascular mortality. Combined use of beta-blockers and ACE inhibitors slows down heart failure progression and reduces cardiovascular mortality. Beta-blockers are useful in treating focal atrial tachycardia and supra ventricular paroxysmal tachycardia, by reducing sinus node automaticity and delay atrio-ventricular conduction; they also prevent sudden cardiac death and ventricular tachycardia associated with increased sympathetic activity. There is no indication in treating primary non-complicated hypertension with beta-blockers as first-line drugs. Different metabolic effects of selective and non-selective beta-blockers are actually debated. In conclusion, beta-blockers have indication in the treatment of many cardiovascular diseases. Further studies are needed for better understanding the differences in cardiac and peripheral beta-blockers effects depending on their selectivity.

Blood pressure lowering efficacy of beta-1 selective beta blockers for primary hypertension.

Beta blockers are commonly used to treat hypertension. The blood pressure reading is the primary tool for physicians and patients to assess the efficacy of the treatment. The blood pressure lowering effect of beta-1 selective blockers is not known. To quantify the dose-related effects of various doses and types of beta-1 selective adrenergic receptor blockers on systolic and diastolic blood pressure versus placebo in people with primary hypertension. We searched the Database of Abstracts of Reviews of Effectiveness (DARE) for related reviews.We searched the following databases for primary studies: the Cochrane Hypertension Specialised Register (All years to 15 October 2015), CENTRAL via the Cochrane Register of Studies Online (2015, Issue 10), Ovid MEDLINE (1946 to 15 October 2015), Ovid EMBASE (1974 to 15 October 2015) and ClinicalTrials.gov (all years to 15 October 2015).The Hypertension Group Specialised Register includes controlled trials from searches of CAB Abstracts, CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, Food Science and Technology Abstracts (FSTA), Global Health, LILACS, MEDLINE, ProQuest Dissertations & Theses, PsycINFO, Web of Science and the WHO International Clinical Trials Registry Platform (ICTRP).Electronic databases were searched using a strategy combining the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity-maximizing version (2008 revision) with selected MeSH terms and free text terms. No language restrictions were used. The MEDLINE search strategy was translated into CENTRAL, EMBASE, the Hypertension Group Specialised Register and ClinicalTrials.gov using the appropriate controlled vocabulary as applicable. Full strategies are in Appendix 1. Randomised, double-blind, placebo-controlled parallel or cross-over trials. Studies had to contain a beta blocker monotherapy arm with fixed dose. People enrolled into the studies had to have primary hypertension at baseline. Duration of studies had to be between 3 weeks to 12 weeks. Drugs in this class of beta blockers are atenolol, betaxolol, bevantolol, bisoprolol, esmolol, metoprolol, nebivolol, pafenolol, practolol. Two authors confirmed the inclusion of studies and extracted the data independently. Review Manager (RevMan) 5.3.5 was used to synthesise data. We identified 56 RCTs (randomised controlled trials) that examined the blood pressure (BP) lowering efficacy of beta-1 selective blockers (beta-1 blocker) in 7812 primary hypertensive patients. Among the included trials, 26 RCTs were parallel studies and 30 RCTs were cross-over studies, examining eight beta-1 blockers. Overall, the majority of beta-1 blockers studied significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP). In people with mild to moderate hypertension, beta-1 selective blockers lowered BP by an average of -10/-8 mmHg and reduced heart rate by 11 beats per minute. The maximum BP reduction of beta-1 blockers occurred at twice the starting dose. Individual beta-1 blockers did not exhibit a graded dose-response effect on SBP and DBP over the recommended dose range.Most beta-1 blockers tested significantly lowered heart rate. A graded dose-response of beta-1 blockers on heart rate was evident. Higher dose beta-1 blockers lowered heart rate more than lower doses. Individually and overall beta-1 blockers did not affect pulse pressure, which distinguishes them from other classes of drugs. This review provides low quality evidence that in people with mild to moderate hypertension, beta-1 selective blockers lowered BP by an average of -10/-8 mmHg and reduced heart rate by 11 beats per minute as compared to placebo. The effect of beta-1 blockers at peak hours, -12/-9 mmHg, was greater than the reduction at trough hours, -8/-7 mmHg. Beta-1 selective blockers lowered BP by a greater magnitude than dual receptor beta-blockers and partial agonist beta-blockers, lowered BP similarly to nonselective beta-blockers. Beta-1 selective blockers lowered SBP by a similar degree and lowered DBP by a greater degree than diuretics, angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Because DBP is lowered by a similar extent to SBP, beta-1 selective blockers do not reduce pulse pressure.

PS062 - Prevalence of Cardiomyopathy and Impact of the use of Non Selective Beta Blockers in End-Stage Liver Disease

PS062 - Prevalence of Cardiomyopathy and Impact of the use of Non Selective Beta Blockers in End-Stage Liver Disease

Beta-1-Selective Beta-Blockers and Cognitive Functions in Patients With Coronary Artery Disease: A Cross-Sectional Study.

The association between current beta-1-selective beta-blocker use and cognitive function was evaluated in 722 patients with coronary artery disease without dementia. Beta-1-selective beta-blocker use was associated with worse incidental learning independently of sociodemographic characteristics, clinical coronary artery disease severity, and depression/anxiety.

Preparation of Biological Samples Containing Metoprolol and Bisoprolol for Applying Methods for Quantitative Analysis

Abstract Arterial hypertension is a complex disease with many serious complications, representing a leading cause of mortality. Selective beta-blockers such as metoprolol and bisoprolol are frequently used in the management of hypertension. Numerous analytical methods have been developed for the determination of these substances in biological fluids, such as liquid chromatography coupled with mass spectrometry, gas chromatography coupled with mass spectrometry, high performance liquid chromatography. Due to the complex composition of biological fluids a biological sample pre-treatment before the use of the method for quantitative determination is required in order to remove proteins and potential interferences. The most commonly used methods for processing biological samples containing metoprolol and bisoprolol were identified through a thorough literature search using PubMed, ScienceDirect, and Willey Journals databases. Articles published between years 2005-2015 were reviewed. Protein precipitation, liquid-liquid extraction and solid phase extraction are the main techniques for the extraction of these drugs from plasma, serum, whole blood and urine samples. In addition, numerous other techniques have been developed for the preparation of biological samples, such as dispersive liquid-liquid microextraction, carrier-mediated liquid phase microextraction, hollow fiber-protected liquid phase microextraction, on-line molecularly imprinted solid phase extraction. The analysis of metoprolol and bisoprolol in human plasma, urine and other biological fluids provides important information in clinical and toxicological trials, thus requiring the application of appropriate extraction techniques for the detection of these antihypertensive substances at nanogram and picogram levels.

Abstract 9815: Nadolol Seems to Be Superior to Selective Beta Blockers in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia: Is a Smaller Arrhythmic Window Part of the Explanation?

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable arrhythmogenic disease, and typically presents as syncope or sudden cardiac death during exercise. Beta blockers are first choice therapy but little is known about antiarrhythmic effects of different beta blockers in CPVT. Nadolol has shown superior antiarrhythmic effect in other cardiomyopathies. Hypothesis: We hypothesized that nadolol is superior to selective beta blockers in arrhythmia protection in CPVT patients. Methods: We included 34 CPVT patients (age 34±19 yrs, 44% female, 88% RYR2 mutation positive). We serially performed 2 bicycle exercise tests in each patient; 1)&gt;6 weeks on maximum tolerated dose of selective beta blockers. 2)&gt;6 weeks on maximum tolerated dose of nadolol. We recorded resting and maximum heart rate (HR), HR at first arrhythmia and the most severe arrhythmia occurring. Arrhythmic window was defined as the difference between maximum HR and HR at first arrhythmia. Severity of arrhythmias was scored as arrhythmic score: no arrhythmias (0point), single ventricular extra systoles (1point), bigemini (2points), couplets (3points) and nonsustained VT (4points). Results: Resting HR was similar on nadolol and selective beta blockers (54±10bpm vs. 56±14bpm, p=0.50), while maximum heart rate was lower on nadolol (122±21bpm vs. 139±24bpm, p&lt;0.01). First arrhythmias occurred at similar HR at both exercise tests (113±21bpm vs. 113±19bpm, p=1.0). Consequently, arrhythmic window was smaller during nadolol treatment (17±10bpm vs. 32±26bpm, p=0.03) (Figure) and also the arrhythmic score was lower than on selective beta blockers (1.1±1.2 vs. 2.4±0.9, p&lt;0.01). Conclusion: Arrhythmic score was lower on nadolol compared to selective beta blockers. Also, arrhythmic window, representing the span of heart rates where arrhythmias may occur and progress in severity, was smaller. This suggests that nadolol should be the beta blocker of choice in CPVT patients.

Abstract 10337: Using Landiolol During Primary Percutaneous Coronary Intervention Attenuates Myocardial Reperfusion Injury in Patients With ST-segment Elevation Acute Myocardial Infarction

Introduction: Landiolol is the beta-1 selective receptor blocker and its half-life elimination is 4 minutes. The safety and efficacy of landiolol started before coronary reperfusion in patients with ST-segment elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) remains unclear. We assessed the hypothesis that early use of landiolol promotes optimal reperfusion without increasing adverse events for those patients. Methods: We recruited 220 consecutive patients with STEMI performed pPCI. Patients with heart rate&lt;50, Killip class≧2, old myocardial infarction and 2 or 3 degree of AV-block on admission were excluded. 60 patients were non-landiolol group with conventional treatment admitted from October 2010 to September 2012. 55 patients were landiolol group admitted from October 2012 to September 2014. Administration of landiolol was started before pPCI with 3 μg/kg/min and stopped within 12 hours when oral beta-blockers were administered. ST-segment resolution (STR) was defined as more than 70% resolution of sum of ST-segment elevation at the J point between at the time of admission and just after pPCI. Result: Time form admission to stating landiolol was 35±23min in landiolol group. Age, sex, coronary risk factors, culprit lesion, SYNTAX score (19±10vs18±10) and reperfusion time did not differ between the two groups (all NS). The rate of non-sustained ventricular tachycardia (27vs50%, p=0.013), worsening heart failure (0vs8%, p=0.029) and shock (15vs31%, p=0.030) within 12 hours after the admission was lower in landiolol group. Although, at the time of finishing pPCI, systric blood pressure did not differ between the two groups (117±21vs124±24mmHg, p=0.09), heart rate was lower (66±11vs77±14/min, p&lt;0.01) and the rate of STR was higher (61vs42%, p=0.023) in landiolol group. Multivariate analysis showed that landiolol use was an independent predictor of STR (OR2.51, p=0.045). Within 6 months after the admission, the rate of worsening heart failure (0vs7%, p=0.07), target vessel revasculization (5vs10%, p=0.17) was lower in landiolol group. Conclusion: In low risk patients with STEMI, using landiolol during pPCI may attenuate myocardial reperfusion injury and reduce adverse events.

Blood pressure lowering efficacy of dual alpha and beta blockers for primary hypertension.

Drugs with combined alpha and beta blocking activity are commonly prescribed to treat hypertension. However, the blood pressure (BP) lowering efficacy of this class of beta blockers has not been systematically reviewed and quantified. To quantify the dose-related effects of various types of dual alpha and beta adrenergic receptor blockers (dual receptor blockers) on systolic and diastolic blood pressure versus placebo in patients with primary hypertension. We searched the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ClinicalTrials.gov for randomized controlled trials up to October 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Group's Specialised Register. Randomized double blind placebo controlled parallel or cross-over trials. Studies contained a beta blocker monotherapy arm with a fixed dose. Patients enrolled in the studies had primary hypertension at baseline. Duration of the studies was from three to 12 weeks. Drugs in this class of beta blockers are carvedilol, dilevalol and labetalol. Two review authors (GW and AL) confirmed the inclusion of studies and extracted the data independently. RevMan 5.3 was used to synthesize data. We included eight studies examining the blood pressure lowering efficacy of carvedilol and labetalol in 1493 hypertensive patients. Five of the included studies were parallel design; three were cross-over design. The two largest included studies were unpublished carvedilol studies. The estimates of BP lowering effect (systolic BP/diastolic BP millimeters of mercury; SPB/DBP mm Hg) were -4 mm Hg (95% confidence intervals (CI) -6 to -2)/-3 mm Hg (95% CI -4 to -2) for carvedilol (>1000 subjects) and -10 mm Hg (95% CI -14 to -7)/-7 mm Hg (95% CI -9 to -5) for labetalol (110 subjects). The effect of labetalol is likely to be exaggerated due to high risk of bias. Carvedilol, within the recommended dose range, did not show a significant dose response effect for SBP or DBP. Carvedilol had little or no effect on pulse pressure (-1 mm Hg) and did not change BP variability. Overall, once and twice the starting dose of carvedilol and labetalol lowered BP by -6 mm Hg (95% CI -7 to -4) /-4 mm Hg (95% CI -4 to -3) (low quality evidence) and lowered heart rate by five beats per minute (95% CI -6 to -4) (low quality evidence). Five studies (N = 1412) reported withdrawal due to adverse effects; the risk ratio was 0.88 (95% CI 0.54 to 1.42) (moderate quality evidence). This review provides low quality evidence that in patients with mild to moderate hypertension, dual receptor blockers lowered trough BP by an average of -6/-4 mm Hg and reduced heart rate by five beats per minute. Due to the larger sample size from the two unpublished studies, carvedilol provided a better estimate of BP lowering effect than labetalol. The BP lowering estimate from combining carvedilol once and twice the starting doses is -4/-3 mm Hg. Doses higher than the recommended starting dose did not provide additional BP reduction. Higher doses of dual receptor blockers caused more bradycardia than lower doses. Based on indirect comparison with other classes of drugs, the blood pressure lowering effect of dual alpha- and beta-receptor blockers is less than non-selective, beta1 selective and partial agonist beta blockers, as well as thiazides and drugs inhibiting the renin angiotensin system. Dual blockers also had little or no effect on reducing pulse pressure, which is similar to the other beta-blocker classes, but less than the average reduction of pulse pressure seen with thiazides and drugs inhibiting the renin angiotensin system. Patients taking dual receptor blockers were not more likely to withdraw from the study compared to patients taking placebo.

Clinical impact of selective and nonselective beta-blockers on survival in patients with ovarian cancer.

Preclinical evidence has suggested that sustained adrenergic activation can promote ovarian cancer growth and metastasis. The authors examined the impact of beta-adrenergic blockade on the clinical outcome of women with epithelial ovarian, primary peritoneal, or fallopian tube cancers (collectively, epithelial ovarian cancer [EOC]). A multicenter review of 1425 women with histopathologically confirmed EOC was performed. Comparisons were made between patients with documented beta-blocker use during chemotherapy and those without beta-blocker use. The median age of patients in the current study was 63 years (range, 21-93 years). The sample included 269 patients who received beta-blockers. Of those, 193 (71.7%) were receiving beta-1-adrenergic receptor selective agents, and the remaining patients were receiving nonselective beta antagonists. The primary indication for beta-blocker use was hypertension but also included arrhythmia and postmyocardial infarction management. For patients receiving any beta-blocker, the median overall survival (OS) was 47.8 months versus 42 months for nonusers (P =.04). The median OS based on beta-blocker receptor selectivity was 94.9 months for those receiving nonselective beta-blockers versus 38 months for those receiving beta-1-adrenergic receptor selective agents (P<.001). Hypertension was associated with decreased OS compared with no hypertension across all groups. However, even among patients with hypertension, a longer median OS was observed among users of a nonselective beta-blocker compared with nonusers (38.2 months vs 90 months; P<.001). Use of nonselective beta-blockers in patients with EOC was associated with longer OS. These findings may have implications for new therapeutic approaches. Cancer 2015;121:3435-43. © 2015 American Cancer Society.

Effect of Intravenous Intraoperative Esmolol on Pain Management Following Lower Limb Orthopedic Surgery.

BackgroundLack of proper control of acute postoperative pain often leads to lingering or chronic pain. Several studies have emphasized the role of beta-blockers in reducing postoperative pain. Esmolol is a selective short-acting beta-blocker that produces few side effects. The purpose of this study was to examine the effect of intravenous intraoperative esmolol on postoperative pain reduction following orthopedic leg fracture surgery.MethodsIn a clinical trial, 82 patients between 20-65 years of age with tibia fractures and American Society of Anesthesiologists (ASA) physical status I & II who underwent surgery were divided into two groups. Group A received esmolol and group B received normal saline. Postoperative pain was measured at three time points: entering the recovery unit, and at 3 h and 6 h following surgery, using the Visual Analogue Scale (VAS). A P value of < 0.05 was considered significant.ResultsMean VAS scores at all three time points were significantly different between the two test groups (P = 0.02, P = 0.0001, and P = 0.0001, respectively). The consumption of pethidine was lower in group A than in group B (P = 0.004) and the duration of its effect was significantly longer in time (P = 0.026).ConclusionsIntravenous intraoperative esmolol is effective in the reduction of postoperative pain following leg fracture surgery. It reduced opioid consumption following surgery and delayed patient requests for analgesics.

Сучасне лікування пацієнтів з артеріальною гіпертензією в умовах економічного сьогодення: фокус на дієві комбінації вітчизняного виробництва

Мета. Відомо, що ефективність препаратів, призначених як монотерапія, або їх комбінації різна. Метою цього дослідження було порівняння ефективності терапії на підставі комбінації високоселективного бета-адреноблокатора бісопрололу та гідрохлортіазиду («Б + ГХТ») із дієвою фіксованою комбінацією вітчизняного виробництва — інгібітору ангіотензинперетворюючого ферменту (іАПФ) лізиноприлу та гідрохлортіазиду («Ліз + ГХТ»).Матеріали і методи. У дослідження було включено 59 пацієнтів із помірною та тяжкою артеріальною гіпертензією (АГ) (середній рівень систолічного (САТ)/діастолічного (ДАТ) артеріального тиску (АТ) — 171,3 ± 2,1/98,6 ± 1,3 мм рт.ст.). Усім пацієнтам на початку дослідження та на етапах лікування проводили такі дослідження: вимірювання маси тіла та зросту, офісного САТ, ДАТ та частоти серцевих скорочень (ЧСС), добове моніторування АТ (ДМАТ), визначення швидкості поширення пульсової хвилі по артеріях еластичного (ШППХе) та м’язового (ШППХм) типів, центрального САТ (цСАТ), біохімічне дослідження крові, електрокардіографію. Пацієнтам призначали або фіксовану комбінацію «Ліз + ГХТ» у добовій дозі 40 мг та 25 мг відповідно (n = 32) або нефіксовану комбінацію бісопрололу 10 мг та гідрохлортіазиду 25 мг (n = 27). Якщо рівень АТ через 1 місяць лікування становив понад 140/90 мм рт.ст., то додавали амлодипін 5 мг, дозу якого збільшували до 10 мг при неефективності терапії на 2-му місяці. Через 3 місяці, за необхідності, додавали доксазозин 2–4 мг.Результати. Відбулося достовірно однакове зниження офісних рівнів САТ/ДАТ як у групі «Ліз + ГХТ», так і в групі «Б + ГХТ» (44,5 ± 1,9/19,0 ± 2,1 мм рт.ст. та 42,4 ± 2,1/18,8 ± 2,5 мм рт.ст. у кожній групі відповідно, Р = НД для різниці між групами). Кількість пацієнтів, які досягли цільового АТ, становила 31,2; 53,1; 84,4 і 93,8 % у групі «Ліз + ГХТ» та 22,2; 48,1; 85,2 і 92,6 % — у групі «Б + ГХТ» на 1, 2, 3 та 6-му місяці відповідно. Показники 24САТ/24ДАТ у групі «Ліз + ГХТ» знизилися на 19,0 ± 3,3/19,3 ± 2,8 мм рт.ст., у групі «Б + ГХТ» — на 24,1 ± 1,8/16,9 ± 1,2 мм рт.ст. Крім того, ми спостерігали достовірне зниження середньодобової ЧСС у цій групі. Зниження цСАТ у групі «Ліз + ГХТ» було достовірно більшим, ніж у групі комбінації бісопрололу та гідрохлортіазиду (25,9 ± 2,9 мм рт.ст. проти 15,4 ± ± 2,9 мм рт.ст. відповідно; Р &lt; 0,05 для різниці ступеня зниження цСАТ між групами). У групі «Б + ГХТ» відбулося достовірне збільшення індексу аугментації (від 19,7 ± 1,7 % до 24,6 ± 1,5 %; Р &lt; 0,05), у групі «Ліз + ГХТ» індекс достовірно не змінився. Достовірної динаміки ШППХе та ШППХм в жодній групі не спостерігалося. У групі «Ліз + ГХТ» ШППХе знизилася на 1,2 ± 0,08 м/с, у групі «Б + ГХТ» — на 0,63 ± 0,09 м/с, різниця між групами була достовірною (Р &lt; 0,001). Спостерігалося достовірне зниження рівня креатиніну на 6-му місяці лікування у групі «Ліз + ГХТ» (від 88,9 ± 3,7 мкмоль/л до 74,7 ± 3,8 мкмоль/л; Р &lt; 0,05), у той час як на фоні застосування комбінації бісопрололу та гідрохлортіазиду цей показник знизився від 88,6 ± 3,2 мкмоль/л до 83,3 ± 2,5 мкмоль/л (Р = НД). Висновки. Незважаючи на майже еквівалентне зниження рівня брахіального АТ за результатами як офісного вимірювання, так і добового моніторування, терапія на основі комбінації «Ліз + ГХТ» достовірно краще впливала на зниження цСАТ. Крім того, лише у цій групі ми спостерігали достовірне зниження концентрації креатиніну сироватки наприкінці дослідження.

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Objective: Evaluate the possibility of identifying of the patients with high risk of bronchoobstruction due to beta-blockers (BB) with acute test with single dose of bisoprolol 1,25 mg and assessed reproducibility of this test. Design and method: 47 patients (mean age 61,1 ± 9,1 years) with broncoobstructive and cardiovascular diseases (CVD) were included in the study and received single dose selective BB (bisoprolol) 1.25 mg. The FEV1 and FVC were assessed initially, after 30, 90, 150, 240 min after BB and after 30 min of salbutamol 400 mcg (Test1). 15 patients (aged 58,9 ± 7,0 years) with AH and COPD (n = 5) or BA (n = 10) underwent repeat this Test 2 weeks after Test1 employing the same technique. Measurements were compared between tests using correlation and Bland-Altman plots. Results: Initially FEV1 was 74,0 ± 20,6%, FVC79,1 ± 21,7% and didn’t change significantly after 30, 90, 150 and 240 min. Minimal FEV1 in one patient was after 90 min, in 4 patients – after 150 min, in 5 patients – after 240 min. In two patients after 240 min FEV1 decreased on 10% and 200 ml compared with initial FEV1. After use of salbutamol there was significant increase of FEV1.The FVC did not significantly change. 15 patients had FEV1 initially was 72,9 ± 24,3% at Test1 and 73,1 ± 25,6% at Test2. In 30, 90, 150 and 240 min FEV1 and FVC didn’t chanced significantly in both tests. After administration of salbutamol increase of FEV1 up to 78,3 ± 22,7% at Test1 and 77,2 ± 23,3% at Test2 was registered. There was excellent correlation between tests: r = 0.98, p < .001. Bland-Altman plots showed no association between difference. Conclusions: Despite that on the average in patients with broncoobstructive and CVD had no significant decrease of FEV1 after the single dose of bisoprolol in maximum number of the patients with maximum decrease of FEV1 was after 240 min after BB and 4% of patients the fall was more than 10% and 200 ml. FEV1 and FVC were highly reproducible over time. This allows to recommend the 4-hours acute test with bisoprolol to identified the patients with possible bronchoobstruction.

Long-Term Use of Antihypertensive Agents and Risk of Breast Cancer: A Population-Based Case-Control Study.

IntroductionTo evaluate the risk of breast cancer associated with long-term use of antihypertensive agents (AHs) in Taiwanese women with hypertension.MethodsA search of the Taiwan National Health Insurance Research Database identified 330,699 patients with hypertension who were treated with antihypertensive drugs between January 1, 1998 and December 31, 2011. Logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) between the use of AHs and breast cancer risk, adjusted for other types of antihypertensive drugs, statins and co-morbidities.ResultsAmong the AHs used to treat the hypertensive women enrolled in our study, our analysis revealed that those treated with one specific particular class of beta-blockers (beta-1 selective beta-blockers) had an increased risk for breast cancer. We also found that the ever-use of calcium channel blockers (CCBs; i.e. for 13 years) was associated with breast cancer in an adjusted model (OR 1.09; 95% CI 1.03–1.16). However, the use of nonselective beta-blockers, selective and nonselective alpha-blockers, angiotensin-converting enzyme inhibitors and angiotensin II antagonists were not associated with breast cancer risk.ConclusionBased on the results of our analysis, long-term use of CCBs or beta-1 selective beta-blockers are likely to be associated with the risk of breast cancer. Further large comprehensive population-based studies to support our findings are required for confirmation of this conclusion.

Landiolol Hydrochloride Ameliorates Liver Injury in a Rat Sepsis Model by Down Regulating Hepatic TNF-a

Aims: The effects of a beta blocker, especially an ultra-short acting selective beta blocker, such as landiolol hydrochloride on the organ protection in sepsis are unclear. The present study aimed to investigate whether acute (early hours) liver injury in a rat model of sepsis induced by lipopolysaccharide (LPS) administration: a) can be corrected by administering landiolol and b) whether landiolol’s effects on liver injury is accomplished by diminishing the elevated expression of inflammatory cytokine, such as tumor necrosis factor (TNF)-α and a vaso constrictor peptide, such as endothelin (ET)-1. Methods: Eight (8)-week-old male Wistar rats were administered for three hours with either LPS (n=12), or continuously with LPS plus landiolol (n=11). Control rats were treated with saline only in a similar manner as the treatment group during the relevant time points (n=13). Results: Following LPS administration, blood gas and hemodynamic parameters were significantly altered compared to control rats at 3 h. Also, At 3 h after LPS administration, circulatory levels of ALT, AST, TNF-α and ET-1 were significantly increased. In addition, at 3 h after LPS administration significant features of hepatic injuries at morphological levels were also evident. Co-treatment of rats with LPS and landiolol ameliorated hepatic injury at 3 h post-treatment, as well as reversed elevated circulatory levels of factors associated with liver injury back to normal levels, such as AST and ALT, and local hepatic levels of TNF-α. Conclusion: Based on the current findings, it can be stated that landiolol may exert protective effects on liver injury in septic rats by normalizing local expression levels of inflammatory cytokine, such as TNF-α.

INSTRUMENTAL AND DIAGNOSTIC CRITERIA OF HEMODYNAMIC DISORDERS AND ENDOTHELIAL DYSFUNCTION CORRECTION IN PREGNANTS WITH ARTERIAL HYPERTENSION

&lt;p&gt;&lt;strong&gt;Background&lt;/strong&gt;. According to the WHO, hypertension is associated with 20-33 % of maternal death during pregnancy within extragenital pathology statistics. There are complications of the fetus and newborn associated with hypertension at 140/90 mm Hg and higher.&lt;br /&gt;&lt;strong&gt;Objective.&lt;/strong&gt; A comparative analysis of antihypertensive therapy effectiveness in pregnants with arterial hypertension was performed using modern clinical and instrumental methods of endothelial function diagnostic, central and utero-placental hemodynamic estimation.&lt;br /&gt;&lt;strong&gt;Methods.&lt;/strong&gt; We examined 63 pregnant women with hypertension at 28 to 32 weeks of gestation. Women were randomized into three groups:group I (control group – 20 women), that included pregnant women with hypertension treated with basic antihypertensive therapy as recommended by Health Ministry of Ukraine standards (metildofa and nifedipin); group II – 21 pregnant women receiving metildofa and metoprolol; group III (22 pregnant women) receiving metildofa and nebivolol.&lt;br /&gt;&lt;strong&gt;Conclusions.&lt;/strong&gt; It was found that the brachial artery ultrasound measuring and occlusive plethysmography procedure by Dietz is an early and safe method of endothelial dysfunction diagnostic in pregnants with hypertension. Doppler ultrasound of blood flow in uterine, umbilical arteries, and middle cerebral arteries of the fetus allows timely diagnosis of the side effect of antihypertensive drugs on the fetus. The therapy of choice for pregnants with Stage II Arterial Hypertension should be based on methyldopa and calcium channel antagonists or selective beta-blockers combination. Highly selective beta-blockers with vasodilative effect (nebivolol hydrochloride) and L-arginine (Tivortin) allow to prevent perinatal adverse effects of antihypertensive therapy, to correct hemodynamic disorders and endothelial dysfunction in pregnants with arterial hypertension.&lt;/p&gt;&lt;p&gt;&lt;br /&gt;&lt;strong&gt;KEY WORDS:&lt;/strong&gt; arterial hypertension, uterine-placental hemodynamics, endothelial dysfunction&lt;/p&gt;