Μg In Patients Research Articles

P261 Tiotropium Safety And Performance In Respimat(R) (tiospir ): Safety And Efficacy In Patients Naive To Treatment With Anticholinergics

Introduction The TIOSPIR™ trial showed similar safety and exacerbation efficacy profiles for tiotropium Respimat ® and HandiHaler ® in patients with chronic obstructive pulmonary disease (COPD). We present here the results for patients who were naive to anticholinergic treatment at baseline. Methods TIOSPIR™ (n = 17,135), a 2–3 year, randomised, double-blind, parallel-group, event-driven trial, compared safety and efficacy of once-daily tiotropium Respimat ® 5 and 2.5 µg with HandiHaler ® 18 µg in patients with COPD. Primary endpoints were time to death (noninferiority of Respimat ® 5 or 2.5 μg versus HandiHaler ® ) and time to first COPD exacerbation (superiority of Respimat ® 5 μg versus HandiHaler ® ). Safety, including cardiovascular safety, was assessed. Results Overall, 6966 patients from TIOSPIR™, naive to anticholinergic treatment at baseline, were randomised and treated (n = 2345, n = 2312 and n = 2309 for tiotropium Respimat ® 2.5 and 5 µg and HandiHaler ® 18 µg). There was similar risk of death (vital status follow up) (measured as time to death) for the Respimat ® groups versus HandiHaler ® (Respimat ® 5 µg: hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.75–1.17; Respimat ® 2.5 µg: HR, 1.05; 95% CI, 0.84–1.30) with similar results for the on-treatment sensitivity analysis (Respimat ® 5 µg: HR, 0.91; 95% CI, 0.71–1.17; Respimat ® 2.5 µg: HR, 1.11; 95% CI, 0.87–1.40). Risk of exacerbation was also similar for the Respimat ® groups versus HandiHaler ® (measured as time to first exacerbation) (Respimat ® 5 µg: HR, 0.99; 95% CI, 0.90–1.08; Respimat ® 2.5 µg: HR, 1.04; 95% CI, 0.95–1.14). Risk of major adverse cardiovascular event (MACE) or fatal MACE were similar for the Respimat ® groups versus HandiHaler ® (MACE: Respimat ® 5 µg: HR, 1.20; 95% CI, 0.88–1.63; Respimat ® 2.5 µg: HR, 1.11; 95% CI, 0.81–1.51; fatal MACE: Respimat ® 5 µg: HR, 1.14; 95% CI, 0.75–1.71, Respimat ® 2.5 µg: HR, 1.12; 95% CI, 0.75–1.69). Conclusions Analogous to the global analysis, patients naive to anticholinergic treatment and treated with tiotropium Respimat ® 2.5 or 5 µg or HandiHaler ® in the TIOSPIR™ trial exhibited similar safety and exacerbation efficacy profiles.

Effects of Moderate Hepatic Impairment on the Pharmacokinetic Properties and Tolerability of Umeclidinium and Vilanterol in Inhalational Umeclidinium Monotherapy and Umeclidinium/Vilanterol Combination Therapy: An Open-Label, Nonrandomized Study

BackgroundThe long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a monotherapy, and in combination with the long-acting β2-agonist vilanterol (VI), as a once-daily inhaled maintenance bronchodilator therapy for chronic obstructive pulmonary disease in the US and EU; they are not indicated for the treatment of asthma. Preclinical and clinical data suggest that UMEC and VI are predominantly eliminated by the liver. ObjectivesThe objectives of the study were to evaluate the effects of moderate hepatic impairment on the plasma and urinary pharmacokinetic properties of each drug, and on the tolerability of inhalational UMEC/VI 125/25 µg and UMEC 125 µg. MethodsThis open-label, nonrandomized study was conducted in patients with moderate hepatic impairment (Child-Pugh score, 7–9) and in healthy volunteers (control). Patients and volunteers were administered a single dose of UMEC/VI 125/25 µg, and, after a 7- to 14-day washout period, repeat-dose UMEC 125 µg once daily for 7 days. Primary end points were the plasma pharmacokinetic properties of single- and repeat-dose UMEC and VI. Secondary end points were the urinary pharmacokinetic properties of UMEC, and the tolerability of each treatment. ResultsAll 18 enrolled patients and volunteers (12 men, 6 women; mean age, 53.6 years) completed the study. Mean systemic exposures of UMEC and VI were similar or numerically lower in patients with moderate hepatic impairment compared with those in healthy volunteers, but the differences were not clinically significant. UMEC accumulations with 7-day dosing of UMEC were similar between patients with moderate hepatic impairment and healthy volunteers. UMEC/VI 125/25 µg and UMEC 125 µg were well-tolerated, with no safety concerns identified. ConclusionsThe administration of UMEC/VI 125/25 µg or UMEC 125 µg in patients with moderate hepatic impairment did not result in clinically relevant increases in UMEC or VI exposures compared with those in healthy volunteers. Based on these findings, no dose adjustment for UMEC/VI or UMEC is warranted in patients with moderate hepatic impairment.

Differential pharmacology and clinical utility of emerging combination treatments in the management of COPD--role of umeclidinium/vilanterol.

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. Bronchodilator therapy is the cornerstone in COPD treatment. Bronchodilation in COPD is mainly achieved via administration of long- and ultralong-acting β2-agonists and with long-acting muscarinic antagonists. New combinations of bronchodilators with dual-acting muscarinic antagonist and β2-agonist properties have been licensed, and others are currently being developed with the aim of achieving once-daily dosing, and therefore may improve the likelihood of treatment compliance. These combination bronchodilators include glycopyrronium bromide/indacaterol maleate, umeclidinium (UMEC) bromide/vilanterol trifenatate (VI), aclidinium bromide/formoterol and tiotropium bromide/olodaterol (Boehringer Ingelheim, Germany). This review will focus mainly on studies and clinical trials involving the novel fixed-dose combination of UMEC/VI at doses of 125/25 μg and 62.5/25 μg in patients with COPD. Data from large clinical trials involving more than 4,500 COPD patients indicate that UMEC/VI is an effective once-daily treatment in COPD with improved pulmonary function. Future studies assessing the impact of this combination on exacerbations, delay in disease progression, and health status in patients with COPD are warranted.

Umeclidinium–vilanterol: First once-daily dual bronchodilator for COPD

Umeclidinium–vilanterol: First once-daily dual bronchodilator for COPD

Comparison of 75 and 150 µg doses of intrathecal morphine for postoperative analgesia after transurethral resection of the prostate under spinal anesthesia

The administration of single dose intrathecal (IT) morphine with local anesthetics during spinal anesthesia produces an effective postoperative analgesia. In this study, we evaluated the efficacy and safety of two different doses of IT morphine with bupivacaine for postoperative analgesia after transurethral resection of prostate (TURP). Prospective, randomized study. Urology Department. Sixty patients who were scheduled to undergo TURP with spinal anesthesia. Patients were allocated to receive IT morphine (75 μg) with bupivacaine heavy (group I) and IT morphine (150 μg) with bupivacaine heavy (group II). Postoperative pain was evaluated by Visual Analogous Scale during 24 hours. The need for rescue analgesia, adverse effects and patient satisfaction were recorded. Groups were comparable with respect to demographic data. VAS scores were similarly low in both groups. However, the request for analgesia was significantly higher in group I (27 percent) than group II (7 percent; p = 0.04). The incidence of postoperative nausea was similarly low in both groups. No patients reported pruritis in group I where as six patients (20 percent) reported mild pruritis not necessitating treatment in group II (p = 0.036) Patients satisfaction was similarly high in both the groups. IT morphine 150 μg reduced the need for rescue analgesia compared to IT morphine 75 μg in patients undergoing TURP under spinal anesthesia. As the incidence of pruritis was low with no treatment, IT morphine 150 μg may be a suitable dose for postoperative analgesia for patients undergoing TURP under spinal anesthesia.

Tiotropium Respimat Inhaler and the Risk of Death in COPD

BackgroundTiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.MethodsIn this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a once-daily dose of 18 μg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 μg or 2.5 μg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 μg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease.ResultsDuring a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 μg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups.ConclusionsTiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.)

ACCORD COPD II: A Randomized Clinical Trial to Evaluate the 12-Week Efficacy and Safety of Twice-Daily Aclidinium Bromide in Chronic Obstructive Pulmonary Disease Patients

Aclidinium bromide is a long-acting muscarinic antagonist approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). This 12-week phase III study evaluated efficacy and tolerability of aclidinium 200 or 400 μg in patients with moderate-to-severe COPD. In this double-blind study, 544 patients with COPD were randomized to placebo or twice-daily aclidinium 200 or 400 μg administered by Genuair(®)/Pressair(®). Lung function, health status [measured by the St. George's Respiratory Questionnaire (SGRQ)], dyspnea [measured using the Transition Dyspnea Index (TDI)], and safety were assessed throughout the study. Mean changes from baseline in morning trough forced expiratory volume in 1 s (FEV(1)) at week 12 (primary endpoint) were significantly higher for aclidinium than for placebo (200 μg, 51 mL; 400 μg, 72 mL; both p < 0.05). Aclidinium also significantly improved other lung function outcomes. At week 12, improvements from baseline were observed with aclidinium in SGRQ total score (200 μg, -6.0; 400 μg, -5.4) and TDI focal score (200 μg, 1.0; 400 μg, 1.3). Furthermore, clinically important improvements in SGRQ total and TDI focal scores were achieved by 45 and 51 % of patients, respectively, who received aclidinium 400 μg, with a significant difference versus placebo for TDI (p < 0.05). Anticholinergic-related adverse events (e.g., dry mouth) were infrequent, occurring <2 % for any event in any treatment group. Both aclidinium doses were well tolerated. This study demonstrates efficacy and safety of aclidinium in COPD patients. Unexpected baseline imbalances between treatment groups may have impacted the aclidinium treatment benefit in this study.

Pooled subpopulation analyses of the effects of roflumilast on exacerbations and lung function in COPD

This post-hoc analysis examined the impact of roflumilast on chronic obstructive pulmonary disease (COPD) exacerbations and lung function in patients with COPD who received concomitant long-acting β2-agonists (LABA) with or without prior inhaled corticosteroid (ICS) and the influence of various demographic and clinical characteristics on these outcomes. Data were pooled from 2 double-blind, placebo-controlled, 52-week studies of once-daily roflumilast 500μg in patients with COPD. Endpoints were mean rate of exacerbations and change from baseline in pre- and postbronchodilator FEV1. In this pooled analysis (N=3091), addition of roflumilast to LABAs for 1 year in patients who discontinued ICS prior to study entry (n=945) significantly reduced the risk of COPD exacerbations vs. placebo by 19.2% (p<0.05) and significantly improved pre- and postbronchodilator FEV1 by 40mL and 34mL, respectively (both, p<0.01). Similar improvements were observed in patients who received concomitant LABAs but were not taking ICS prior to study entry (n=597). A significant reduction in COPD exacerbation risk with roflumilast vs. placebo was observed regardless of age or smoking status, and in patients who had severe or very severe COPD. Significantly improved lung function was observed with roflumilast in all the subgroups (p<0.05), with the exception of patients with moderate COPD. Roflumilast reduced exacerbation rates and improved lung function in patients with COPD who received concomitant LABA, regardless of prior ICS use, and across various patient subgroups regardless of age and smoking status. NCT00297102 (M2-124) and NCT00297115 (M2-125).

A novel model-based approach for dose determination of glycopyrronium bromide in COPD

BackgroundGlycopyrronium bromide (NVA237) is an inhaled long-acting muscarinic antagonist in development for treatment of COPD. This study compared the efficacy and safety of once-daily (OD) and twice-daily (BID) glycopyrronium bromide regimens, using a novel model-based approach, in patients with moderate-to-severe COPD.MethodsDouble-blind, randomized, dose-finding trial with an eight-treatment, two-period, balanced incomplete block design. Patients (smoking history ≥10 pack-years, post-bronchodilator FEV1 ≥30% and <80% predicted, FEV1/FVC <0.7) were randomized to one of 16 independent sequences for 28 days. Primary endpoint: mean trough FEV1 at Day 28.Results385 patients (mean age 61.2 years; mean post-bronchodilator FEV1 53% predicted) were randomized; 88.6% completed. All OD and BID dosing regimens produced dose-dependent bronchodilation; at Day 28, increases in mean trough FEV1 versus placebo were statistically significant for all regimens, ranging from 51 mL (glycopyrronium bromide 12.5 μg OD) to 160 mL (glycopyrronium bromide 50 μg BID). Pharmacodynamic steady-state was reached by Day 7. There was a small separation (≤37 mL) between BID and OD dose–response curves for mean trough FEV1 at steady-state in favour of BID dosing. Over 24 hours, separation between OD and BID regimens was even smaller (FEV1 AUC0-24h maximum difference for equivalent daily dose regimens: 8 mL). Dose–response results for FEV1 at 12 hours, FEV1 AUC0-12h and FEV1 AUC0-4h at steady-state showed OD regimens provided greater improvement over placebo than BID regimens for total daily doses of 25 μg, 50 μg and 100 μg, while the reverse was true for OD versus BID regimens from 12–24 hours. The 12.5 μg BID dose produced a marginally higher improvement in trough FEV1 versus placebo than 50 μg OD, however, the response at 12 hours over placebo was suboptimal (74 mL). Glycopyrronium bromide was safe and well tolerated at all doses.ConclusionsGlycopyrronium bromide 50 μg OD provides significant bronchodilation over a 24 hour period, and in terms of FEV1 AUC0-24h is not significantly different than the same total daily dose administered BID. Importantly, OD dosing may confer better patient adherence. The results are consistent with previous glycopyrronium bromide studies and support once-daily dosing of glycopyrronium bromide 50 μg in patients with moderate-to-severe COPD.Trial registrationClinicalTrials.gov: NCT01119950

The Efficacy and Safety of the Novel Long-Acting β2 Agonist Vilanterol in Patients With COPD: A Randomized Placebo-Controlled Trial

Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD. Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV(1) on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests. VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels. VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo.

PTU-152 Significant improvements in abdominal pain and bowel symptoms in a phase 3 trial of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a European perspective

IntroductionLinaclotide, a minimally absorbed guanylate cyclase-C agonist, was evaluated in a Phase 3 trial. To fulfil EMA submission requirements, the efficacy, safety and effects of withdrawal of linaclotide 290 μg...

Onset of Action of Formoterol versus Salmeterol via Dry Powder Inhalers in Moderate Chronic Obstructive Pulmonary Disease

Bronchodilator therapy is central to the symptomatic management of chronic obstructive pulmonary disease (COPD), and treatment with short-acting bronchodilators is recommended in patients with mild COPD. This study aimed to evaluate the onset of effect of single-dose formoterol 9 μg versus single-dose salmeterol 50 μg in patients with moderate COPD. In this multicentre, double-blind, double-dummy, placebo-controlled, three-way single-dose crossover study, patients ≥40 years of age with moderate COPD were randomized to single-dose formoterol 9 μg via Turbuhaler® plus placebo via Diskus®, single-dose salmeterol 50 μg via Diskus® plus placebo via Turbuhaler® or placebo via Turbuhaler® and Diskus® (washout period 2-7 days). Terbutaline 0.5 mg/actuation via Turbuhaler® was used as reliever medication throughout. The primary endpoint was forced expiratory volume in 1 second (FEV₁) at 5 minutes post-dose. Secondary endpoints included proportion of patients achieving ≥12% increase in FEV₁ at 5 minutes post-dose. 109 patients were randomized, and 108 completed the study. The increase in FEV₁ 5 minutes post-dose versus pre-dose was 7.2% for formoterol, 4.1% for salmeterol and 0.7% for placebo, and significantly greater for formoterol versus salmeterol (ratio of treatment effects: 1.030; 95% CI 1.008, 1.052; p = 0.009), for formoterol versus placebo (1.064, 95% CI 1.041, 1.087; p < 0.001) and for salmeterol versus placebo (1.033, 95% CI 1.011, 1.056; p = 0.003). The proportions of patients with ≥12% increase in FEV₁ 5 minutes post-dose were 23.1%, 9.2% and 6.4% for formoterol, salmeterol and placebo, respectively; this was statistically significantly larger after formoterol than salmeterol (p = 0.008) or placebo (p < 0.001). All treatments were well tolerated. In COPD patients, formoterol 9 μg has an onset of bronchodilatory effect that is more rapid than salmeterol 50 μg based on FEV₁ at 5 minutes post-dose. Clinicaltrials.gov identifier: NCT01048333; AstraZeneca study code: D5127C00001.

Sevoflurane vs. propofol in patients with coronary disease undergoing mitral surgery: a randomised study

Myocardial ischemic damage is reduced by volatile anaesthetics in patients undergoing low-risk coronary artery bypass graft surgery; few and discordant results exist in other settings. We therefore performed a randomised controlled trial (sevoflurane vs. propofol) to compare cardiac troponin release in patients with coronary disease undergoing mitral surgery. Patients with coronary artery disease undergoing mitral surgery were randomly allocated to receive either sevoflurane (50 patients) or propofol (50 patients) as main hypnotic. The primary endpoint of the study was peak post-operative cardiac troponin release defined as the maximum value among the post-operative values measured at intensive care unit arrival, 4 h later, on the first and second post-operative day. There was no significant difference in post-operative peak troponin release, the median (25th-75th percentiles) values being 14.9 (10.1-22.1) ng/ml and 14.5 (8.8-17.6) ng/ml in the sevoflurane and propofol groups, respectively (P = 0.4). Fentanyl administration was different between the two groups: 1347 ± 447 μg in patients receiving sevoflurane and 1670 ± 469 μg in those receiving propofol, P = 0.002. The 1-year follow-up identified two patients who died in the propofol group (one myocardial infarction and one low cardiac output syndrome) and one in the sevoflurane group (myocardial infarction). In this study, patients with coronary artery disease undergoing mitral surgery did not benefit from the cardioprotective properties of halogenated anaesthetics. Sevoflurane anaesthesia was not associated to lower cardiac troponin release when compared with propofol anaesthesia.

Sustained 24-hour efficacy of once daily indacaterol (300 μg) in patients with chronic obstructive pulmonary disease: A randomized, crossover study

Purpose Indacaterol is a novel, once daily, inhaled ultra-long-acting β 2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). Here we compared the 24-h spirometry profile of once daily indacaterol 300 μg with that of placebo and twice daily salmeterol 50 μg in patients with COPD. Methods This randomized, multicenter, placebo-controlled, crossover study comprised three 14-day treatment periods (with 14-day washouts). Patients (male/female ≥40 years) with moderate-to-severe COPD were randomized to receive double-blind indacaterol 300 μg or placebo once daily, or open-label salmeterol 50 μg twice daily. The primary outcome measure was 24-h post-dose (trough) FEV 1 (mean of FEV 1 at 23 h 10 min and 23 h 45 min post-indacaterol dose) after 14 days. FEV 1 was assessed at multiple time points on Days 1 and 14 of each treatment period. Safety and tolerability were also monitored. Results Of 68 randomized patients, 61 completed. Trough FEV 1 (primary endpoint) on Day 14 for indacaterol was 200 mL higher than placebo ( p < 0.001), exceeding the prespecified minimum clinically important difference (120 mL), and was 90 mL higher than for salmeterol ( p = 0.011). After Day 1, trough FEV 1 for indacaterol was 150 mL higher than placebo ( p < 0.001). Indacaterol provided superior bronchodilation compared with placebo ( p < 0.001) across the full 24-h assessment period on Days 1 and 14. In addition, on both days, indacaterol provided superior FEV 1 compared with salmeterol ( p < 0.05) at many post-baseline time points, including 5 min post-dose. All treatments were well tolerated. Conclusions Once daily indacaterol 300 μg produced effective sustained 24-h bronchodilation from the first dose, an efficacy profile superior to placebo and twice daily salmeterol. Given its effective bronchodilation with once daily dosing, indacaterol is likely to be a useful treatment option for patients with moderate-to-severe COPD.

Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients

NVA237 is a novel once-daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability and bronchodilator efficacy of two doses of NVA237 (100 and 200 μg), versus placebo, in patients with moderate-to-severe COPD (forced expiratory volume in 1 s [FEV 1] ≥ 30% and <80% predicted and FEV 1/forced vital capacity [FVC] < 0.7, 30 min after inhalation of 80 μg ipratropium bromide). After appropriate washout periods, patients were randomized to treatment with NVA237 100 μg ( n = 92), NVA237 200 μg ( n = 98) or placebo ( n = 91) for 28 days. The primary objective was evaluation of safety, with efficacy measures included as secondary objectives. NVA237 was generally well tolerated and associated with a frequency and distribution of adverse events similar to placebo. Serious adverse events were uncommon and there was no evidence of adverse cardiovascular effects or unexpected events. Trough FEV 1 was significantly higher in those receiving NVA237 compared with placebo. For NVA237 100 μg the differences were 131 and 161 mL on Days 1 and 28, respectively ( p < 0.05), and for NVA237 200 μg the differences were 146 and 151 mL on Days 1 and 28, respectively ( p < 0.05). Peak FEV 1, FEV 1 at all timepoints up to 24 h after dosing, and FEV 1 area under the curve during 5 min–5 h post-dosing were also significantly higher in both NVA237 groups, compared with placebo. Patients receiving NVA237 required fewer daily puffs of rescue medication and had a higher percentage of days on which rescue medication was not required. Overall, the present study provides further evidence of the safety, tolerability and bronchodilator efficacy of once-daily treatment with NVA237 100 and 200 μg in patients with moderate-to-severe COPD.

The acute antipanic and anxiolytic activity of aerobic exercise in patients with panic disorder and healthy control subjects

Regular physical activity is anxiolytic in both healthy subjects and patients with panic disorder. In contrast, acute exercise may induce acute panic attacks or increase subjective anxiety in patients with panic disorder more than in other people. The effects of quiet rest or an aerobic treadmill exercise (30 min at an intensity of 70% of the maximal oxygen uptake, VO 2max) on cholecystokinin tetrapeptide (CCK-4) induced panic attacks were studied in a crossover design in 12 patients with panic disorder and 12 matched healthy subjects. The effects of CCK-4 (25 μg in patients and 50 μg in control subjects) were measured with the Acute Panic Inventory (API) score, comparing panic attack frequencies, total score, and subscores for anxiety and somatic symptoms. CCK-4-induced panic attacks were less frequent after prior exercise: they occurred in 15 (62.5%) subjects after rest (9 patients and 6 control subjects), but only 5 (20.8%) subjects after exercise (4 patients and 1 control subject). In both conditions, CCK-4 administration induced a significant increase in the total API score and the anxiety and somatic symptoms subsores. However, compared to prior rest, exercise resulted in a significantly reduced CCK-4-induced increase of the total API score and the anxiety subscore. In patients with panic disorder exercise increased the total API score and the somatic symptoms subscale but not the anxiety subscore. Patients with panic disorder showed increased somatic but not anxiety symptoms after an acute bout of exercise. Severity of CCK-4-induced panic and anxiety, on the other hand was reduced by exercise. These findings suggest that in addition to exercise training an acute bout of exercise may be used to reduce anxiety and panic attack frequency and intensity in panic disorder patients.

Formoterol used as needed improves health-related quality of life in asthmatic patients uncontrolled with inhaled corticosteroids

Clinical benefits have been shown to occur when using the long-acting β 2-agonist formoterol 4.5 μg for as-needed medication rather than terbutaline 500 μg in patients with unstable asthma taking an inhaled corticosteroid. This study compared their effects on health-related quality of life and the relation with conventional clinical indices in the same population. 362 asthmatics were randomized to use either formoterol 4.5 μg or terbutaline 500 μg as needed, both inhaled via Turbuhaler ®. The Asthma Quality of Life Questionnaire (AQLQ) was practised at enrolment and completed by 341 patients after randomization and at 4, 8, and 12 weeks. Clinical indices were measured at the same time points. Mean overall AQLQ scores were comparable at baseline, being 4.90 in the formoterol and 4.82 in the terbutaline group and improved during treatment by 0.41 and 0.17 units, respectively (mean difference 0.24, 95% CI 0.08, 0.39, P<0.005). Mean improvement in the symptom domain was 0.49 units when using formoterol. Correlations between changes in clinical indices and changes in AQLQ scores during the 12-week period were weak (maximum r value=0.37). When used for as-needed medication, formoterol 4.5 μg provided an improvement in asthma-specific quality of life and to a somewhat greater extent than the widely used terbutaline 500 μg. The symptom domain in AQLQ showed almost 0.5 units improvement after formoterol, a change that is considered to be clinically relevant.

Complex Abnormalities in Baroreflex Function in Patients with Monogenic Hypertension and Neurovascular Contact

P53 We have shown that autosomal-dominant hypertension with brachydactyly regularly features brainstem neurovascular compression (NVC). To seek mechanisms by which NVC could influence blood pressure, we conducted extensive autonomic tests in 5 affected persons (18-34 yrs.). Cold pressor testing, hand-grip testing, and upright posture all increased BP excessively. Baseline muscle sympathetic nerve activity was 15±4.6 bursts/min in patients, 12±6 bursts/min in normotensive controls, and 14±9 bursts/min in borderline hypertensive controls (ns). The increase in nerve traffic during cold pressor testing was not excessive. Urinary norepinephrine excretion was 19±4.0 μg/24 hours (normal range 23-105 μg/ 24 hours). Blood pressure during ganglionic blockade was134±4.9/ 82±4.1 mmHg in patients and 90±6/49±2.4 mmHg in controls (p&lt;0.05). In patients, plasma vasopressin concentration changed from 0.47±0.03 pg/ml at baseline to 0.84±0.23 pg/ml during ganglionic blockade. In contrast, in control subjects, plasma vasopressin concentration increased profoundly from 1.6±0.17 pg/ml at baseline to 39±13 pg/ml during ganglionic blockade. The phenylephrine dose that increased SBP 12.5 mmHg was 8.0±2.0 μg in patients and 135±35 μg in control subjects before ganglionic blockade (p&lt;0.01). During ganglionic blockade, the dose of phenylephrine that increased SBP 12.5 mmHg was 5.4±0.4 μg in patients and 13±4.8 μg in control subjects. The baroreflex slope was 9.4±1.6 msec/mmHg. We conclude that in these patients, basal BP was increased even during interruption of sympathetic and parasympathetic nerve traffic. However, sympathetic stimuli caused an excessive increase in BP. This excessive response cannot be explained by increased sympathetic nerve traffic or increased vascular sensitivity. Instead, we suggest that the ability of the baroreflex to buffer changes in blood pressure is severely impaired despite retained heart rate control.