Prospective Clinical Trial Comparing IV Esmolol to IV Metoprolol in CT Coronary Angiography: Effect on Hemodynamic, Technical Parameters and Cost.

BACKGROUND: Intravenous [IV] esmolol, an alternative to IV metoprolol for coronary computed tomography angiography [CCTA], has shorter half-life that decreases the risk of prolonged hypotension. The primary aim was to prospectively compare IV esmolol alone to IV metoprolol alone for effectiveness in achieving heart rate [HR] of 60 beats per minute[bpm] during CCTA. The secondary aim was to compare hemodynamic response, image quality, radiation dose and cost. MATERIALS AND METHODS: Institutional Review Board approved prospective randomized study of 28 CCTA patients medicated in a 1:1 blinded match with IV esmolol or IV metoprolol to achieve HR of 60 bpm. Serial hemodynamic response was measured at 6 specified times. Two cardiac radiologists independently scored the image quality. RESULTS: Both IV esmolol and IV metoprolol achieved the target HR. IV esmolol resulted in significantly less profound and shorter duration of reduction in systolic blood pressure [BP] than IV metoprolol with a difference of -10, -14 and -9 mm Hg compared to -20, -26 and -25 mmHg at 2, 15 & 30 min respectively. No significant difference in HR at image acquisition, exposure window, radiation dose and image quality. Although IV esmolol was expensive, the overall cost of care was comparable to IV metoprolol due to shortened post CCTA observation period consequent to faster restoration of hemodynamic status. CONCLUSION: Comparison of IV esmolol and IV metoprolol demonstrate that both are effective in achieving the target HR but significantly faster recovery of HR and BP in patients who receive IV esmolol was found.

Assessment of Haemodynamic Response to Nonselective Beta-Blockers in Portal Hypertension by Phase-Contrast Magnetic Resonance Angiography.

A significant unmet need exists for accurate, reproducible, noninvasive diagnostic tools to assess and monitor portal hypertension (PHT). We report the first use of quantitative MRI markers for the haemodynamic assessment of nonselective beta-blockers (NSBB) in PHT. In a randomized parallel feasibility study in 22 adult patients with PHT and a clinical indication for NSBB, we acquired haemodynamic data at baseline and after 4 weeks of NSBB (propranolol or carvedilol) using phase-contrast MR angiography (PC-MRA) in selected intra-abdominal vessels. T1 mapping of liver and spleen was undertaken to assess changes in tissue composition. Target NSBB dose was achieved in 82%. There was a substantial reduction from baseline in mean average flow in the superior abdominal aorta after 4 weeks of NSBB therapy (4.49 ± 0.98 versus 3.82 ± 0.86 L/min, P = 0.03) but there were no statistically significant differences in flow in any other vessels, even in patients with >25% decrease in heart rate (47% of patients). Mean percentage change in liver and spleen T1 following NSBB was small and highly variable. In conclusion, PC-MRA was able to detect reduction in cardiac output by NSBB but did not detect significant changes in visceral blood flow or T1. This trial was registered with the ISRCTN registry (ISRCTN98001632).

Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

Clinical status and outcome of Japanese heart failure patients with reduced or preserved ejection fraction treated with carvedilol.

The effect of beta-blockers in treating Japanese heart failure (HF) patients with preserved left ventricular (LV) ejection fraction (EF) is unclear. This prospective observational study enrolled 1,682 Japanese HF patients who received carvedilol for the first time. Patients were followed for a mean of 1.6 years. The 1,492 patients with baseline LVEF measurements were allocated to the following groups: reduced EF (LVEF < 40%; n = 724), borderline EF (LVEF 4050%; n = 355), and preserved EF (LVEF ≥ 50%; n = 413). Baseline characteristics, New York Heart Association (NYHA) class, change in B-type natriuretic peptide (BNP) level, and long-term outcome were compared among the groups. Patients with preserved EF were more likely to be older, female, and have ischemic etiology and hypertension than patients with reduced EF. Carvedilol maintenance dosage was lower in patients with preserved EF (7.9 mg/day versus 6.6 mg/ day). NYHA class and BNP level were lower in patients with preserved EF at baseline but improved to the same level in all groups at 6 months. After adjusting for baseline characteristics, the hazard ratio for death or hospitalization due to cardiovascular disease in patients with preserved EF versus those with reduced EF was 1.031 (P = 0.847). This study elucidated the characteristics of HF patients given carvedilol in "real world" clinical settings. A comparative controlled study is necessary to elucidate whether the improvements in NYHA and BNP as well as the outcome profile observed in patients with preserved EF were caused by the favorable effects of carvedilol.

Persistence with nebivolol in the treatment of hypertension: a retrospective claims analysis.

OBJECTIVE: Examine drug persistence by evaluating the hazard of discontinuation and of switching to different antihypertensive drugs in patients initiating treatment with a recently approved ß-blocker, nebivolol, versus other ß-blockers. METHODS: This retrospective analysis included all patients diagnosed with hypertension in the MarketScan Database (January 2007 - December 2008) with at least two medical claims and no prior ß-blocker prescriptions within 6 months of the initial prescription date. Multivariate Cox proportional hazard models (adjusted for baseline differences in demographics, previous use of other antihypertensive medications, initial doses and supply of medication, and number of distinct prescriptions at baseline) were used to assess the hazard of discontinuation, defined as the first prescription gap of ≥30 days, and to assess the hazard of switching to another antihypertensive drug, defined as a prescription fill for another antihypertensive drug within 15 days before and 30 days after discontinuation of the initial ß-blocker. RESULTS: Of the 173,200 patients included in the study population, the adjusted hazard of discontinuation for nebivolol-initiated patients was 8-20% lower than that of patients who initiated treatment with atenolol (hazard ratio [HR] 0.82, p < 0.001), metoprolol (HR 0.91, p < 0.001), carvedilol (HR 0.92, p < 0.001), or other ß-blockers (HR 0.80, p < 0.001). The adjusted hazard of nebivolol-treated patients switching to a different antihypertensive medication was 12-22% lower than that of the other four ß-blocker cohorts (atenolol: HR 0.80, p < 0.001; metoprolol: HR 0.86, p < 0.001; carvedilol: HR 0.88, p < 0.001; other ß-blockers: HR 0.78, p < 0.001). Sensitivity analyses defined discontinuation as prescription gaps of ≥45 days and ≥60 days and showed a lower hazard of discontinuation among patients initiating nebivolol than among patients initiating all other drug cohorts (p < 0.001). LIMITATIONS: Comparisons of non-randomized treatment groups may be confounded by unobserved differences in patients' baseline characteristics. CONCLUSIONS: Initiation with nebivolol was associated with greater persistence than initiation with atenolol, carvedilol, metoprolol, or other ß-blockers.

Final amended report on safety assessment on aminomethyl propanol and aminomethyl propanediol.

Aminomethyl propanol and aminomethyl propanediol are substituted aliphatic alcohols that function as pH adjusters in cosmetic products at concentrations less than 10%; additionally, aminomethyl propanediol is a fragrance. Extensive oral toxicity data are reviewed, with fewer inhalation toxicity data. Dermal toxicity data are presented that demonstrate, for example, that a mascara with 1.92% aminomethyl propanediol does not cause dermal irritation or allergic contact sensitization, suggesting that the maximum reported use concentration of 2% in mascara would be safe. Although these ingredients are primary amines that are not substrates for N-nitrosation, they may contain secondary amines as impurities in finished products that may undergo N-nitrosation. These ingredients should not be included in cosmetic formulations containing N-nitrosating agents. The Cosmetic Ingredient Review Expert Panel concludes that aminomethyl propanol and aminomethyl propanediol are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.

Hypotensive anesthesia with esmolol. Assessment of hemodynamics, consumption of anesthetic drugs, and recovery.

OBJECTIVE: To assess the effect of esmolol added to propofol-remifentanil combination for hypotensive anesthesia on hemodynamic conditions, consumption of anesthetic drugs, and recovery, during elective septorhinoplasty. METHODS: This prospective, randomized study was carried out at Gazi University, Faculty of Medicine, Ankara, Turkey in 2005. Following Institutional Ethical Committee approval, 40 American Society of Anesthesiologists (ASA) I patients were divided into 2 equal groups group remifentanil infusion RP and group esmolol infusion (RP-E). After anesthesia induction with propofol (2-2.5 mg/kg), the mean arterial pressure was aimed to be between 50 mm Hg and 65 mm Hg for controlled hypotensive anesthesia in both groups. In group RP, a remifentanil infusion of 0.1-0.5 microg/kg/min was titrated, following a bolus of 1 microg/kg; for group RP-E, an esmolol infusion of 100-300 mg/kg/min was titrated, following a bolus of 500 microg/kg; to achieve a target blood pressure. In addition, propofol was infused according to depth of anesthesia to maintain anesthesia in both groups. Electrocardiography, heart rate, blood pressure, cardiac output, and consumption of anesthetic drugs were recorded. Postoperatively, recovery times, visual analog pain scores, and side effects were observed. RESULTS: The decrease in the intraoperative heart rate was more significant in group RP-E than in group RP. The remifentanil consumption was much lower in group RP-E. The recovery times were similar in both groups. CONCLUSION: Addition of esmolol to propofol-remifentanil combination leads to a decrease in remifentanil consumption, without a decrease in cardiac output during hypotensive anesthesia.

Use and risk management of carvedilol for the treatment of heart failure in the community in England: results from a modified prescription-event monitoring study.

BACKGROUND: In the UK, the licence for carvedilol was extended in 1998 to include symptomatic heart failure (New York Heart Association [NYHA] class II and III heart failure) with the recommendation that initiation and up-titration should be under the supervision of a hospital physician. A post-marketing surveillance study was conducted to address the UK regulatory authority's request for monitoring the use and safety of carvedilol prescribed for heart failure in clinical practice. AIM: To investigate adherence to risk management recommendations for the use of carvedilol for heart failure, monitor how patients' subsequent care was managed and collect event data to evaluate the safety profile of carvedilol used for the treatment of heart failure. METHODS: An observational cohort study using a modified prescription-event monitoring technique identified patients from dispensed primary care prescriptions in England (August 1999 to June 2001). An eligibility questionnaire was used to identify patients who had been prescribed carvedilol for heart failure for the first time after 31 July 1999. Up to three follow-up questionnaires were sent to the prescribers of eligible patients, requesting demographic information, dosage, supervision of treatment, status of cardiac failure and event information. RESULTS: 2311 patients met the eligibility criteria. For 1666 patients, one or more valid follow-up questionnaires were returned: 68.5% were male; male median age 66 years; female median age 72 years; the observation period was up to 3 years. Hospital physicians supervised initiation of treatment and first up-titration in 85.6% and 61.4% of patients, respectively. 49.2% of patients were prescribed the recommended starting dosage of carvedilol (6.25 mg/day). Approximately 25% of patients started on a lower dose than recommended, and the same proportion were prescribed a higher dose. NYHA status of cardiac failure between starting treatment and the third questionnaire improved for 39.5% of patients, deteriorated for 10.9%, and 11.7% of those for whom NYHA status was given died. Adverse drug reactions (ADRs) were reported for 2.4% of patients; the most commonly reported ADR was malaise/lassitude. Overall, 27.1% of patients stopped taking carvedilol. None of the 163 deaths were attributed to carvedilol. CONCLUSIONS: Regulatory guidelines for the use and risk management of carvedilol in heart failure were mostly followed, and most patients appeared to benefit from treatment with carvedilol for heart failure. Malaise/lassitude was the main reason for discontinuing treatment. Further investigations may be warranted to examine the prescribing of carvedilol at lower than recommended doses.

Is urethane-chloralose anaesthesia appropriate for pharmacokinetic-pharmacodynamic assessment? Studies with carvedilol.

INTRODUCTION: The aim of the work was to establish the impact of urethane-chloralose anaesthesia on pharmacokinetic-pharmacodynamic (PK-PD) properties of carvedilol in control rats and L-NAME hypertensive animals. METHODS: Male Wistar Rats were randomly divided into: control (n=12) with tap water to drink and L-NAME rats (n=12) with L-NAME solution (40 mg/kg/day) to drink for 2 weeks. Effects of carvedilol (1 mg kg(-1), i.v.) on blood pressure and heart rate were recorded during 3 h in conscious and urethane (500 mg kg(-1), i.p.) - chloralose (50 mg kg(-1), i.p.) anaesthetized rats. Carvedilol plasma pharmacokinetics was studied by means of traditional blood sampling. PK-PD modeling of carvedilol was made by means of an effect compartment model. RESULTS: Neither urethane-chloralose nor L-NAME modified estimation of pharmacokinetic parameters of carvedilol. Although urethane-chloralose did not modify potency of carvedilol comparing with awake animals in control and hypertensive group, maximal negative chronotropic response was significantly greater in anaesthetized L-NAME rats in comparison to awake animals. Conversely, anaesthesia did not modify maximal chronotropic response to carvedilol in control rats. Whilst no differences were found in the estimated potency of carvedilol hypotensive response comparing control and L-NAME rats in both awake and anaesthetized conditions, maximal hypotensive effect of carvedilol was significantly greater in anaesthetized control and L-NAME animals in comparison to conscious rats. L-NAME rats showed a greater maximal hypotensive response comparing to control group. DISCUSSION: Urethane-chloralose anaesthesia is an acceptable experimental condition for the evaluation of PK-PD properties of carvedilol, considering that it does not affect the potency of carvedilol for its chronotropic and hypotensive effect. Conclusions obtained from urethane-chloralose anaesthetized animals, regarding the impact of l-NAME treatment on PK-PD properties of carvedilol, did not differ from those obtained from conscious animals. Anaesthesia did not modify pharmacokinetic behaviour of carvedilol in both normotensive and L-NAME hypertensive rats.

Appropriate dose transition to a controlled-release formulation of carvedilol in patients with hypertension.

Few patients with hypertension meet recommended target blood pressure goals, and most hypertensive patients require at least 2 antihypertensive medications from different pharmacologic classes to adequately lower blood pressure. beta-Blockers are guideline-recommended for the treatment of hypertension with compelling indications. beta-Blockers differ with respect to pharmacology (particularly receptor biology and ancillary properties), hemodynamic effects, and tolerability. In clinical practice, the choice of beta-blockers for individual patients with hypertension is often based on practical issues such as convenience and cost. However, given the pharmacologic and clinical trial data demonstrating differences, the choice of beta-blocker for the treatment of high-risk hypertension should be evidence-based. Vasodilating beta-blockers, such as carvedilol, decrease blood pressure without the concerning hemodynamic, renal, and metabolic responses associated with most beta-blockers. The use of carvedilol CR (once daily) may be preferable to a twice-daily regimen.

Three-dimensional echocardiographic and magnetic resonance assessment of the effect of telmisartan compared with carvedilol on left ventricular mass a multicenter, randomized, longitudinal study.

BACKGROUND: The hypothesis that left ventricular hypertrophy regression in hypertension relates to blood pressure (BP) control and to non-antihypertensive activity of some drugs was tested by comparing the effects of telmisartan and carvedilol on 24-h mean ambulatory BP and left ventricular mass (LVM) regression, measured using three-dimensional echocardiography (3-DECHO) and magnetic resonance imaging (MRI). METHODS: A total of 82 patients with mild-to-moderate hypertension and an optimal echocardiographic acoustic window were randomized to receive once-daily telmisartan 80 mg or carvedilol 25 mg for 44 weeks. RESULTS: Ten patients withdrew from the study because office diastolic BP remained >90 mm Hg. The 24-h mean ambulatory systolic/diastolic BP reductions were similar in both treatment groups (telmisartan, from 159.6 +/- 10.2/97.8 +/- 5.4 to 128.6 +/- 6.5/78.2 +/- 5.8 mm Hg; carvedilol, from 157.8 +/- 11.1/95.7 +/- 11.9 to 128.2 +/- 5.6/78.7 +/- 5.2 mm Hg). However, night-time and last 6-h mean BP reductions were nonsignificantly greater with telmisartan. Using 3-DE, telmisartan (P< .001) and carvedilol (P< .001) progressively reduced LVM index by 21.97 +/- 5.84 (15.7%) and 12.31 +/- 3.14 (9.1%) g/m2, respectively, at week 44. Similar magnitudes of reductions were observed using MRI (15.5% and 9.6%, respectively). Reductions in LVM index achieved with telmisartan were statistically superior to carvedilol (P< or = .001). CONCLUSIONS: The superior LVM regression with telmisartan versus carvedilol suggests telmisartan has a mechanism that may be beyond that of lowering BP in hypertensive patients.

Comparative assessment of the effects of alfentanil, esmolol or clonidine when used as adjuvants during induction of general anaesthesia.

BACKGROUND AND OBJECTIVE: This randomized, double-blinded, prospective study compared the effects of clonidine, esmolol or alfentanil on the level of hypnosis and haemodynamic responses to intravenous induction of anaesthesia and endotracheal intubation. METHODS: Forty-five patients scheduled for elective surgery were allotted to one of three groups. They were given either alfentanil 3 microg kg(-1) min(-1) (n = 15); esmolol 1 mg kg(-1) min(-1) (n = 16) or clonidine 3 microg kg(-1) (n = 14) as a 10 min infusion. The infusions of alfentanil and esmolol, but not of clonidine, were maintained during endotracheal intubation. Anaesthesia was induced with midazolam (2 mg) and thiopental as required to suppress the eyelash reflex. Atracurium (0.5 mg kg(-1)) was given to produce neuromuscular block. Mean arterial pressure, heart rate, and bispectral index were recorded on arrival (baseline), after study drug infusion, after injecting midazolam and thiopental, as well as after endotracheal intubation. ANOVA and chi2-test were used for analysis. RESULTS: Blood pressure, heart rate and the bispectral index were unaltered by the study drugs, but thiopental requirements were reduced by alfentanil and clonidine (P < 0.014). Mean arterial pressure values (mean +/- standard error of mean) in the alfentanil, esmolol and clonidine groups were: baseline: 107.8 +/- 3.8; 106.6 +/- 3.9; 103.4 +/- 3.7 mmHg; after thiopental: 74.0 +/- 4.2; 85.6 +/- 4.3; 94.2 +/- 4.1 mmHg and after endotracheal intubation: 91.7 +/- 5.3; 114.1 +/- 6.9; 123.6 +/- 5.6 mmHg, respectively (two-way ANOVA, P < 0.001). Mean arterial pressure changed significantly after intubation from baseline (P < 0.001) after alfentanil (-15%) and clonidine (+20%) but not after esmolol (+7%), while the changes between pre- and postintubation values were similar in all groups (24-33% increase). The bispectral index indicated that all patients had an adequate level of hypnosis, but the variability was higher in the esmolol group (P < 0.002). CONCLUSIONS: None of the study drugs blocked the increase in mean arterial pressure induced by endotracheal intubation, but esmolol provided better overall haemodynamic stability. All groups had an adequate level of hypnosis.

Cost-effectiveness of differing perioperative beta-blockade strategies in vascular surgery patients.

OBJECTIVES: To determine the incremental value of different strategies of both oral and intravenous beta-blockade during the perioperative period in high-risk vascular patients in reducing costs and improving outcomes. DESIGN: Decision analytic model incorporating costs from provider's perspective INTERVENTIONS: Five perioperative strategies in patients undergoing abdominal aortic aneurysm surgery: (1). no routine beta-blockade, (2). preoperative oral bisoprolol for 7 days followed by perioperative intravenous metoprolol and oral bisoprolol based on preoperative titration, (3). immediate preoperative atenolol with postoperative intravenous then oral atenolol, (4). intraoperative esmolol and postoperative intravenous then oral atenolol, and (5). intraoperative and 18 hours of postoperative esmolol then atenolol. MEASUREMENTS AND MAIN RESULTS: Perioperative death was associated with a net increase of US dollars 21909 in charges to Medicare, whereas sustaining a perioperative myocardial infarction was associated with a net increase in charges of US dollars 15000. There is a net hospital saving of US dollars 500 using a strategy of titration of an oral beta-blocker medication for a minimum of 7 days, with a net increase in efficacy of 0.0304. All of the strategies involving acute perioperative blockade were associated with a net cost savings and increase in efficacy, although less than the strategy involving preoperative oral titration. CONCLUSION: Perioperative beta-blockade is both cost effective as well as efficacious from a short-term provider perspective. The optimal strategy of treatment for patients who do not present to surgery already on beta-blockers requires further study, although all strategies save money even accounting for pharmaceutical costs.

Esmolol versus diltiazem in the treatment of postoperative atrial fibrillation/atrial flutter after open heart surgery.

BACKGROUND: Supraventricular tachyarrhythmias are common after open heart surgery. Possible causative factors for these arrhythmias include operative trauma, atrial ischemia, electrolyte imbalances, pericardial irritation, and excess catecholamines. Two agents commonly used to control ventricular rate in atrial fibrillation or atrial flutter (AF/AFL) are beta-blockers and calcium channel blockers. METHODS AND RESULTS: This randomized study was designed to compare the safety and efficacy of intravenous diltiazem versus intravenous esmolol in patients with postoperative AF/AFL after coronary bypass surgery and/or valve replacement surgery. A comparative cost analysis was also performed. Thirty patients received either esmolol (n = 15) or diltiazem (n = 15) for AF/AFL. During the first 6 hours of treatment, 66.6% of esmolol-treated patients converted to sinus rhythm compared with 13.3% of the diltiazem-treated patients (P <.05). At 24 hours, 66.6% of the diltiazem group converted to SR compared with 80% of the esmolol group (not significant). Drug-induced side effects, time to rate control (<90 beats/min), number of patients requiring cardioversion, and length of hospitalization were similar for the two groups. The drug cost/successfully treated patient for esmolol versus diltiazem was $254 versus $437 at 6 hours and $529 versus $262 at 24 hours. CONCLUSIONS: Although this is a small study, it suggests that esmolol is more effective in converting patients to normal sinus rhythm than diltiazem during the initial dosing period. No differences in conversion rates were observed between the two groups after 24 hours. Additional studies are needed to confirm whether esmolol is the initial drug of choice in patients with postoperative AF/AFL after coronary bypass surgery.

Assessment of bronchial effects following topical administration of butylamino-phenoxy-propanol-acetate, an oculoselective beta-adrenoceptor blocker in asthmatic subjects.

1. Butylamino-phenoxy-propanol-acetate (BPPA) is a new topical oculoselective beta-adrenoceptor blocker for the reduction of intraocular pressure (IOP) in man. Its potency on the airways of normal subjects was identical with that of placebo. A study was carried out to determine the potential of BPPA to cause bronchoconstriction in mild asthmatics (FEV1 greater than or equal to 60% predicted) with normal IOP. 2. Twelve nonsmoking outpatients who bronchoconstricted to 0.25 or 0.50% of timolol eye drops (fall in FEV1 23.33 +/- 1.20% (mean +/- s.e. mean), range 16-30) were investigated in this double-masked, randomized, 3-period, crossover study. On three different occasions six incremental concentrations of BPPA (range: 0.1-2%; maximum cumulative concentration 4%), timolol (0.1-1%; 2%), and placebo were administered bilaterally until bronchoconstriction (decrease in FEV1 greater than or equal to 20% and in specific airway conductance (sGaw) greater than or equal to 35% simultaneously) or the maximum cumulative concentration was reached. 3. Airway response was measured as change in FEV1 and sGaw and dose-response curves to timolol, BPPA and placebo were performed. IOP was measured 3 h after the highest concentration of each study day. 4. Timolol caused dose-dependent falls in FEV1 and sGaw as well as clinical symptoms of respiratory distress in all subjects. The median cumulative concentrations of timolol required to decrease FEV1 by 20% and sGaw by 35% were 0.98% and 1.53%. Neither placebo (P greater than 0.05) nor BPPA (P greater than 0.05) caused a significant change in sGaw. A fall in FEV1 by 20% not accompanied by a simultaneous fall in sGaw by 35% was found in four subjects following BPPA and in five subjects following placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of histamine receptors on basal left ventricular contractile tone in humans: assessment using the H2 receptor antagonist famotidine and the beta-adrenoceptor antagonist esmolol as pharmacologic probes.

Histamine has a positive inotropic action in humans. Recent controversial data have suggested that histamine2 (H2) receptor blockade depresses overall left ventricular systolic performance in healthy volunteers. To explore the possibility that H2 receptors positively influence basal left ventricular contractile tone, 10 normal subjects were studied by using imaging and Doppler echocardiography and calibrated subclavian pulse data in a blinded, randomized, two-period crossover trial with measurements obtained at the end of each 7-day period. Oral drug administration consisted of either the potent H2 antagonist famotidine (40 mg/day) or placebo. Left ventricular circumferential end-systolic wall stress-rate-corrected velocity of fiber shortening (Vcfc) relations were generated over a range of loads with methoxamine. Contractility was assessed by using Vcfc at a common end-systolic wall stress. During each study, data were obtained before and during high dose intravenous esmolol administration to determine the contributions, if any, of sympathetic reflex responses. Famotidine did not alter blood pressure, left ventricular percent fractional shortening, circumferential end-systolic wall stress, stroke volume index, cardiac index, total vascular resistance or ventricular contractile state in comparison with placebo but did decrease heart rate by 3 beats/min (p less than 0.05). With beta-adrenergic blockade, no differences in contractility were evident between esmolol alone and famotidine plus esmolol. Thus, H2 receptor blockade with famotidine does not alter myocardial mechanics or cardiac sympathetic tone, suggesting that in humans basal left ventricular contractile state is not physiologically dependent on the H2-mediated effects of histamine.

Assessment of beta-1 selectivity of bisoprolol and atenolol by means of their influence on the lipolytic response to an infusion of terbutaline.

We have investigated the beta-1 selectivity of a new beta-blocker, Bisoprolol, by comparing its effect on lipolysis induced by intravenous terbutaline infusion with that of Atenolol. At a dose of 5 mg, Bisoprolol had virtually no beta-2 blocking activity as measured by free fatty acid (FFA) release during terbutaline infusion. At a dose of 10 mg, Bisoprolol had a small but statistically insignificant effect on FFA release similar to 50 mg Atenolol. At a dose of 20 mg, Bisoprolol had significant beta-2 blocking activity. At lower doses, therefore, Bisoprolol is a very selective beta-blocker.

Assessment of beta-blocking activity of low-dose bupranolol.

In the present study an investigation was made on the pharmacodynamic effect of the beta-blocking agent bupranolol in the low-dose range. Bupranolol is usually given in doses of 100 mg twice daily in the treatment of hypertension, however the dose range between 20 and 100 mg was studied using graded isoproterenol injections in healthy volunteers. A significant beta-1-blocking activity was observed for the 20 mg dose already. This effect was reduced after a treatment of 10 days. The effect increased with the higher doses, there might be a linear correlation between the logarithm of the dose and the reduction of the tachycardia after the isoproterenol injections in the low-dose range. It was concluded that using the safe and sensitive isoproterenol injection method, the clinical effect of very low doses of bupranolol may be demonstrated. The low dose might be useful to reduce the reflex tachycardia seen in the treatment of hypertension with vasodilating drugs.