Pharmacodynamics of GSK961081, a bi-functional molecule,in patients with COPD

GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β₂-agonism (MABA) properties.This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV₁) at 24 h on Days 1 and 14.MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV₁ over 24 h. Mean (95% CI) 24 h trough FEV₁ (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only.GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.     

Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design

BackgroundThe drug development process can be streamlined by combining the traditionally separate stages of dose-finding (Phase IIb) and confirmation of efficacy and safety (Phase III) using an adaptive seamless design. This approach was used in a clinical study of indacaterol, a novel once-daily (od) inhaled long-acting β₂-adrenoreceptor agonist bronchodilator for the treatment of COPD (chronic obstructive pulmonary disease).MethodsThe study comprised a dose-finding stage with dose selection after 14 days of treatment, and a second stage evaluating efficacy and safety during 26 weeks of treatment. The dose-finding stage included seven randomized treatment arms: double-blind indacaterol 75 μg, 150 μg, 300 μg or 600 μg od, the β₂-adrenoceptor agonist formoterol 12 μg twice-daily or placebo, or the anticholinergic tiotropium 18 μg od open-label. An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician. The sponsor, investigators and patients remained blinded to the results. The indacaterol doses were selected using pre-set efficacy criteria for trough (24-h post-dose) and early (1–4 h post-dose) bronchodilator effect after 14 days, and all safety data. To qualify for selection, the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol, whichever was the highest value. Selected doses were continued into the second, 26-week stage. The two other indacaterol doses not selected, and formoterol, were discontinued following dose selection.Results801 patients with moderate-to-severe COPD were evaluated. Indacaterol 150 μg was the lowest effective dose, exceeding criteria for trough FEV₁ (reference value 140 mL vs placebo) and FEV₁ AUC_1–4h (reference value 220 mL vs placebo). No safety signal was observed with any dose of indacaterol. Thus, indacaterol 150 and 300 μg were selected to continue into the second, 26-week stage.ConclusionThe adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial.     

24-hour bronchodilation following a single dose of the novel β(2)-agonist olodaterol in COPD

Background

Current guidelines recommend long-acting bronchodilators as maintenance therapy in COPD when symptoms are not adequately controlled with short-acting agents. Olodaterol is a novel long-acting β₂-adrenoceptor agonist with a pre-clinical profile that suggests 24-h bronchodilation may be achieved with once-daily administration.

Objective

To assess dose- and time-response in terms of bronchodilator efficacy, and to evaluate pharmacokinetics, safety and tolerability of single doses of olodaterol administered via Respimat^® Soft Mist™ Inhaler in COPD patients.

Methods

A single-center, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry (FEV₁, FVC), safety, tolerability and pharmacokinetics (in a subset of patients) following dosing of olodaterol 2 μg, 5 μg, 10 μg and 20 μg; the washout period between test-days was at least 14 days. Primary endpoint of the study was the 24-h post-dosing FEV₁. Patients participating in the pharmacokinetic assessments continued in an open-label extension phase to establish pharmacokinetics of olodaterol 40 μg.

Results

36 patients were assigned to treatment; mean baseline prebronchodilator FEV₁ was 1.01 L (37% predicted normal). All doses of olodaterol provided significantly greater bronchodilation compared to placebo in 24-h FEV₁ post-dose (p < 0.001); a clear dose–response relationship was observed, with values ranging from 0.070 L for olodaterol 2 μg to 0.119 L for olodaterol 20 μg. Similarly, olodaterol was superior to placebo (p < 0.001) in peak FEV₁ (0.121 L to 0.213 L) and average FEV₁ both during the daytime (0–12 h; ranging from 0.099 L to 0.184 L) and night-time (12–24 h; ranging from 0.074 L to 0.141 L). FVC results were consistent with those observed for FEV₁. Pharmacokinetic evaluation of the peak plasma concentrations and renal excretion suggested no obvious deviation from dose-proportionality over the investigated dose range of 2 μg–40 μg; in most patients, no plasma levels could be detected following the 2 μg dose. All treatments were well tolerated with no apparent dose relation in terms of adverse events.

Conclusions

Olodaterol appears to be a promising long-acting β₂-adrenoceptor agonist,with bronchodilation maintained over 24 h that offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy for the management of COPD symptoms.     

Stepping-across controlled asthmatic patients to extrafine beclometasone/formoterol combination

BackgroundAsthma management focuses on achieving and maintaining asthma control. Few studies have assessed whether complete and sustained asthma control is maintained in clinical practice after stepping-across ICS/LABA fixed combinations. Aim of this double-blind, double-dummy, randomized, parallel group, controlled study was to demonstrate clinical equivalence between equipotent doses of extrafine beclometasone/formoterol (BDP/F) pMDI and fluticasone/salmeterol (FP/S) Diskus^® in maintaining lung function and asthma control.MethodsA total of 416 asthmatic patients already controlled with FP/S 500/100 μg/day (Diskus^®, pMDI or separate inhalers) were randomized to a 12-week treatment with extrafine BDP/F 400/24 μg/day pMDI or FP/S 500/100 μg/day Diskus^®. Pre-dose 1-s forced expiratory volume (FEV₁) was the primary efficacy variable; secondary variables included asthma control questionnaire (ACQ-7) and FEV₁0-1 h area under the curve (FEV₁AUC_0–1h). Safety was assessed through adverse events monitoring and vital signs.ResultsAfter 12 weeks of treatment, pre-dose FEV₁ did not differ between treatments (difference between means 0.01 L; 95% CI –0.03–0.06 L) with no significant changes from baseline in both groups (p = 0.726 and p = 0.783 in BDF/F arm and FP/S, respectively). ACQ-7 score showed that control was maintained after stepping-across to extrafine BDP/F. FEV₁AUC_0–1h was significantly higher in BDP/F arm at the beginning (p = 0.004) and at the end of the 12-week treatment period (p = 0.019). No safety issues were reported in both groups.ConclusionsPatients previously controlled with FP/S in any device formulation can effectively step-across to extrafine BDP/F pMDI, maintaining lung function and asthma control with a 5-min onset of action.     

Aclidinium bromide provides long-acting bronchodilation in patients with COPD

Aclidinium bromide is a novel, long-acting, muscarinic antagonist in phase III development for the maintenance treatment of COPD. This phase IIb study investigated the efficacy and safety of aclidinium for the treatment of moderate to severe COPD to establish the optimal dose for phase III studies. A total of 464 patients with moderate to severe stable COPD were randomised to double-blind, once-daily treatment with aclidinium (25, 50, 100, 200, or 400 μg), placebo, or open-label tiotropium (18 μg) for 4 weeks. Spirometric measurements were performed at 22–24 h after the first dose and then at weekly intervals, and from 0.5 to 6 h post-dose on day 1 and day 29. Compared with placebo, aclidinium 200 μg and 400 μg significantly increased trough FEV₁ on day 29 versus baseline. During the first 6 h post-dose, the bronchodilatory effect of aclidinium (all doses) on day 1 was comparable to that on day 29. Time to peak FEV₁ was 3 h for aclidinium 100–400 μg. Aclidinium was well tolerated, with no dose-dependent effect on ECG, laboratory parameters, or adverse events. The incidence of AEs was generally comparable to placebo. Aclidinium produced sustained bronchodilation over 24 h and was well tolerated during this short-term study. Based on these data, aclidinium 200 μg was selected as the investigational dose for future clinical trials in COPD.     

Bronchodilator efficacy of tiotropium–formoterol via single pressurized meter dose inhaler (pMDI) versus tiotropium alone in COPD

BackgroundBronchodilators form the main stay of treatment for COPD. When symptoms are not adequately controlled with one bronchodilator, addition of another bronchodilator is recommended. We have recently developed a combination of tiotropium and formoterol in a single pressurized metered dose inhaler (pMDI) (Cipla Ltd., India). The aim of this study was to compare the bronchodilator effects of a single dose of 18 mcg of tiotropium versus a single dose of a combination of 18 mcg tiotropium plus 12 mcg formoterol administered via a pMDI in subjects with moderate-to-severe COPD.Study design44 COPD subjects were enrolled in this randomized, double-blind, multi-centre, cross-over study. 18 mcg tiotropium and 18 mcg tiotropium plus 12 mcg formoterol were administered via pressurized metered dose inhalers on two separate days. FEV₁, FVC and Inspiratory capacity (IC) were measured before, 15, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24 h after the study drugs were administered.ResultsCompared with tiotropium alone, a combination of tiotropium plus formoterol showed a faster onset of bronchodilator response (p < 0.01 for FEV1 and FVC), a greater mean maximum change in FEV1 (p = 0.01) and FVC (p = 0.008) and greater AUC_0–24h values for FEV₁, FVC and IC. Trough FEV₁ and FVC values were also greater in the combination group.ConclusionA combination of tiotropium plus formoterol administered via a single inhaler produced a superior bronchodilator response than tiotropium alone over a period of 24 h.     

Vilanterol trifenatate,a novel inhaled long-acting beta2 adrenoceptor agonist,is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD

Vilanterol (VI; GW642444M) is a novel inhaled long-acting β2-agonist with inherent 24 h activity in vitro in development as a combination with the inhaled corticosteroid fluticasone furoate for both COPD and asthma. These studies were conducted to determine the safety, tolerability, pharmacodynamics and pharmacokinetics of VI in healthy subjects and subjects with mild to moderate persistent asthma and moderate to severe COPD.Single doses of VI (25–100 μg) were given once daily to subjects with asthma and COPD and repeat doses once daily for 14 days to healthy subjects. Adverse events (AEs), vital signs, ECGs, pharmacodynamic endpoints, FEV₁ and VI plasma pharmacokinetics (AUC, Cmax and Tmax) were determined following dosing.VI (25–100 μg) was well tolerated. The incidence and severity of AEs were comparable to placebo. Following VI administration there were no clinically significant abnormalities in vital signs, 12-lead ECG, Holter ECG, blood glucose or potassium. There were no statistically significant effects on QTc of single and repeat VI doses up to 50 μg; some differences were seen following the 100 μg VI dose after single and repeat dose in healthy subjects and single dose in asthmatic subjects. All VI doses produced increases in FEV₁ from as early as 5 min after dosing which were maintained up to 24 h post-dose in subjects with asthma and COPD. In all subjects VI was rapidly absorbed (healthy subjects median Tmax at 5 min; asthma and COPD subjects median Tmax at 10 min) with systemic exposure increasing in an approximately dose proportional manner across the VI dose range. Marginal accumulation was seen on repeat dosing.Single doses of inhaled VI in subjects with asthma and COPD and repeat doses in healthy subjects were well tolerated with no clinically significant unwanted systemic effects. VI produced a rapid and prolonged bronchodilation over 24 h suggesting the potential for once daily administration.     

Plasma renalase levels are associated with the development of acute pancreatitis

Background/objectivesSevere acute pancreatitis is associated with significant morbidity and mortality. Identifying factors that affect the risk of developing severe disease could influence management. Plasma levels of renalase, an anti-inflammatory secretory protein, dramatically decrease in a murine acute pancreatitis model. We assessed this response in hospitalized acute pancreatitis patients to determine if reduced plasma renalase levels occur in humans.MethodsPlasma samples were prospectively and sequentially collected from patients hospitalized for acute pancreatitis. Two forms of plasma renalase, native (no acid) and acidified, were measured by ELISA and RNLS levels were compared between healthy controls and patients with mild and severe disease (defined as APACHE-II score ≥7) using nonparametric statistical analysis.ResultsControl (33) and acute pancreatitis (mild, 230 (76.7%) and severe, 70 (23.3%) patients were studied. Acidified RNLS levels were lower in pancreatitis patients: Control: 10.1 μg/ml, Mild 5.1 μg/ml, Severe 6.0 μg/ml; p < 0.001. Native RNLS levels were increased in AP: Control: 0.4 μg/ml, Mild 0.9 μg g/ml, Severe 1.2 μg/ml p < 0.001; those with severe AP trended to have higher native RNLS levels than those with mild disease (p = 0.056). In patients with severe AP, higher APACHE-II scores at 24 h after admission correlated with lower acid-sensitive RNLS levels on admission (r = ?0.31, p = 0.023).ConclusionLow plasma acidified RNLS levels, and increased native RNLS levels are associated with AP. Additional studies should assess the clinical correlation between plasma RNLS levels and AP severity and outcomes.     

Faster onset of action of formoterol versus salmeterol in patients with chronic obstructive pulmonary disease: A multicenter,randomized study

BackgroundChronic obstructive pulmonary disease (COPD) is a growing public health problem that has increased in recent years. It similarly affects men and women, especially those who smoke. The goals of COPD pharmacotherapy are to improve lung function, reduce symptoms, prevent exacerbations, and improve patients' health status. Bronchodilators are the foundation of treatment for COPD, and the long-acting β₂-agonists formoterol and salmeterol are both indicated for regular use by patients with stable COPD.ObjectiveA clinical study was conducted to compare the onset of bronchodilator effects following treatment with formoterol 12 μg administered twice-daily (BID) or salmeterol 50 μg BID. The trial also assessed whether the bronchodilator effects of treatment resulted in significant differences in clinical response.MethodsThis was a randomized, multicenter, open-label, parallel-group study of formoterol 12 μg BID versus salmeterol 50 μg BID, both administered for 28 days. Patients were current or previous smokers aged ≥40 years, with a diagnosis of stable COPD. The primary efficacy variable was change from baseline in forced expiratory volume in 1 s (FEV₁) 5 min after drug administration on day 28. Secondary efficacy variables included changes from baseline in the 6-min walk test (6MWT) and rescue medication use. The primary variable was assessed by analysis of covariance, with baseline FEV₁ as the covariate.ResultsA total of 270 patients were randomized to formoterol 12 μg BID (n = 137) or salmeterol 50 μg BID (n = 133). In the intent-to-treat population the least square (LS) mean change from baseline in FEV₁ at 5 min postdose on day 28 was 0.13 L in the formoterol group compared with 0.07 L in the salmeterol group (P = 0.022). At 30 min postdose on day 28, the LS mean change from baseline in FEV₁ was 0.17 L in the formoterol group compared with 0.07 L in the salmeterol group (P < 0.001). Similar changes were reported at 60 min postdose (0.19 L for the formoterol group versus 0.13 L for the salmeterol group, P = 0.069). Patients in the formoterol group walked longer distances in the 6MWT and used less rescue medication compared with patients in the salmeterol group, although the differences were not statistically significant.ConclusionsSignificantly greater improvements from baseline in FEV₁ were observed at 5 and 30 min postdose with formoterol 12 μg compared with salmeterol 50 μg after 28 days of treatment. Numeric improvements in the 6MWT and rescue medication use were also observed with formoterol.     

Airway responsiveness to adenosine after a single dose of fluticasone propionate discriminates asthma from COPD

BackgroundRegular treatment with inhaled corticosteroids (ICS) is known to reduce airway hyperresponsiveness (AHR) to adenosine 5′-monophosphate (AMP) in asthma even after a single dose of fluticasone propionate (FP).AimTo determine whether this rapid protective effect of a single dose of FP is also present in COPD.Methods23 mild asthmatic and 24 COPD subjects with documented AHR to both AMP and methacholine took part in a randomized, double-blind, placebo-controlled, crossover study to measure AHR to inhaled AMP and methacholine 2 h after either 1000 μg FP or matched placebo.ResultsIn subjects with asthma, 1000 μg FP in a single dose significantly attenuated the constrictor response to AMP, geometric mean (range) PC20AMP values increasing from a 19.2 (1.3–116.3) to 81.5 (9.6–1600.0) (p < 0.001; post-placebo vs post-FP) mg/ml. Change in the airways response to inhaled AMP after FP was well within test variability in patients with COPD, with PC20AMP values 59.6 (11.3–183.9) and 76.3 (21.0–445.3) (p = 0.022; post-placebo vs post-FP) mg/ml. Additionally, FP failed to significantly attenuate the bronchial response to methacholine in both asthma and COPD subjects. A change in doubling dilution, between placebo and following a single dose of FP, in AMP had a better sensitivity and specificity of 95.8% and 65.2%, compared to methacholine of 79.2% and 43.5% respectively in delineating between COPD and asthma.ConclusionA single dose of 1000 μg FP rapidly improves AHR to AMP in asthmatics but not in COPD subjects. This may provide a convenient way by which provocation challenge with inhaled AMP may help in discriminating asthma from COPD.     

Levothyroxine dose adjustment in hypothyroid patients following gastric sleeve surgery

IntroductionEuthyroid patients show decreased TSH level following sleeve gastrectomy. However, studies of levothyroxine absorption after bariatric surgery reported contradictory results and data on levothyroxine dose adjustment according to weight are sparse. The aim of this study was to evaluate levothyroxine dose adjustment during weight loss following sleeve surgery.MethodThis retrospective study assessed change in levothyroxine dose in patients undergoing sleeve gastrectomy at the university hospital center of Nîmes (France) between January 2010 and March 2016. Patients were receiving standard bariatric surgery follow-up with levothyroxine therapy for hypothyroidism.ResultsFifty-two of the 271 patients who underwent sleeve gastrectomy (19.2%) were being treated with levothyroxine. Among these patients, 31 were followed up for 12 months, including 12 who were followed up for 24 months. Mean weight loss was 35 ± 11 kg at 12 months and 41.8 ± 10.2 kg at 24 months. Daily levothyroxine dose decreased from 108 [88–144] μg/day to 94 [63–125] μg/day at 12 months and 69 [44–134] μg/day at 24 months, with positive correlation between dose and weight loss at 12 months (P = 0.03). Weight-adjusted dose was 1.04 [0.81–1.24] μg/kg/day at baseline, 1.14 [0.85–1.66] μg/kg/day at 12 months, and 0.85 [0.53–2.10] μg/kg/day at 24 months, showing no correlation with weight loss. Median TSH level dropped to 1.30 [0.63–2.27] mIU/l at 12 months and 1.48 [1.08–2.42] mIU/l at 24 months.ConclusionDespite a decrease in daily levothyroxine dose correlating with weight loss at 12 months, the absence of correlation with weight-adjusted dose suggests the involvement of confounding factors such as poor levothyroxine absorption or altered thyroid function. Further studies are required to elucidate the absorption of levothyroxine.     

The contribution of sublingual immunotherapy to the achievement of control in birch-related mild persistent asthma: A real-life randomised trial

BackgroundAsthma control represents the main goal of asthma management and different strategies aim to avoid the long term downsides of inhaled corticosteroids. We investigated in real-life conditions the contribution of sublingual immunotherapy in achieving the control of birch-related mild persistent asthma compared to two usual step-up therapeutic options.MethodsA three-year open randomised study included 84 asthmatics, uncontrolled during the previous birch pollen season, despite a treatment with budesonide 400 μg/day. Patients randomly received budesonide 800 μg/day, budesonide 1600 μg/day, budesonide 400 μg/day plus montelukast 10 μg/day and budesonide 400 μg/day plus carbamylated allergoid of betulaceae pre-coseasonally. Asthma Control test, combined allergy symptoms and medications score, albuterol consumption, lung function, nasal eosinophils and nasal steroids usage were assessed as changes from the first to last pollen season.ResultSeventy-six patients concluded the study. All options, except budesonide 800 μg/day, produced an improvement of mean monthly Asthma Control test (p < 0.05). Patients undergoing low-dose budesonide plus immunotherapy achieved, after three years, an appreciable control (ACT mean score 24). A significant improvement was seen in all groups for allergy symptoms plus medications and bronchial reactivity. Albuterol consumption and lung function improved in all but the first group. Only budesonide plus immunotherapy reduced nasal eosinophils and nasal steroids usage. Two mild self-resolving adverse events were reported.ConclusionsFor patients with respiratory allergy due to birch pollen and mild persistent asthma, sublingual immunotherapy added to low-dose inhaled corticosteroids appears effective in maintaining long-term seasonal asthma control, representing a safe opportunity to reduce the cumulative amount of delivered corticosteroids.     

Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity

BackgroundGuidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms.MethodsA post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = ‘less dyspnoea’; scores ≥2 = ‘more dyspnoea’). Outcomes were assessed after 26 weeks.ResultsThe analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose (‘trough’) forced expiratory volume in 1 s (FEV₁), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV₁ and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV₁, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV₁, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated.ConclusionsIn patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness.     

Formoterol

Abstract

Inhaled formoterol is a long-acting selective β₂-adrenoceptor agonist, with an onset of action of 5 minutes postdose and a bronchodilator effect that lasts for at least 12 hours.Statistically significant and clinically relevant (> 120ml) improvements in lung function [assessed using standardized/normalized area under the forced expiratory volume in 1 second (FEV₁) versus time curve (AUC FEV₁)] were observed with inhaled formoterol 12μg twice daily (the approved dosage in the US) compared with placebo in 12-week and 12-month, randomized, double-blind trials in patients with chronic obstructive pulmonary disease (COPD).The bronchodilator efficacy of formoterol 12μg twice daily was greater than that of oral slow-release theophylline (individualized dosages) in a 12-month trial or inhaled ipratropium bromide 40μg four times daily in a 12-week trial. Improvement in AUC FEV₁ with formoterol, but not theophylline, compared with placebo was observed in patients with irreversible or poorly-reversible airflow obstruction. Formoterol also significantly improved health-related quality of life compared with ipratropium bromide or placebo and significantly reduced symptoms compared with placebo. Combination therapy with formoterol 12μg twice daily plus ipratropium bromide 40μg four times daily was significantly more effective than albuterol (salbutamol) 200μg four times daily plus the same dosage of ipratropium bromide in a 3-week, randomized, double-blind, double-dummy, crossover trial.Inhaled formoterol was well tolerated in clinical trials. The incidence of investigator-determined drug-related adverse events with inhaled formoterol 12μg twice daily was similar to that with placebo and inhaled ipratropium bromide 40μg four times daily but lower than that with oral slow-release theophylline (individualized dosages). Importantly, there were no significant differences between formoterol and placebo or comparator drugs in cardiovascular adverse events in patients with COPD and corrected QT interval values within the normal range.In conclusion, inhaled formoterol improved lung function and health-related quality of life and reduced symptoms relative to placebo in clinical trials in patients with COPD. The drug had greater bronchodilator efficacy than oral slow-release theophylline or inhaled ipratropium bromide and showed efficacy in combination with ipratropium bromide. The adverse events profile (including cardiovascular adverse events) with formoterol was similar to that with placebo. Thus, inhaled formoterol may be considered as a first-line option for the management of bronchoconstriction in patients with COPD who require regular bronchodilator therapy for the management of symptoms.

Pharmacodynamic Properties

Inhaled formoterol is a long-acting selective β₂-adrenoceptor agonist (β₂-agonist); it has a rapid onset of action (5 minutes in single- and multiple-dose studies) and, like salmeterol, maintains a bronchodilator effect for at least 12 hours. The onset of postdose bronchodilator action was faster with formoterol 12μg than with salmeterol 100μg in a double-blind, randomized, placebo-controlled trial.Formoterol 6 to 24μg improved forced expiratory volume in 1 second (FEV₁) compared with baseline and placebo in single-dose crossover trials in patients with chronic obstructive pulmonary disease (COPD), and was at least as effective as salmeterol 50 or 100μg or albuterol (salbutamol) 400μg at improving FEV₁. Mean peak FEV₁ was reached 1 hour after inhalation of formoterol 12μg; values for this parameter were 1 hour after albuterol 200μg, and 2 to 5 hours after salmeterol 50μg.Formoterol 4.5 to 18μg twice daily for 1 week prolonged the time to exhaustion on a bicycle ergometer test compared with placebo; results were similar to those for ipratropium bromide 80μg three times daily.All β₂-agonists have the potential to increase heart rate and plasma glucose concentrations, and to decrease plasma potassium concentrations, through effects on extrapulmonary β₂ receptors. Dose-dependent increases in heart rate, corrected QT (QTc) interval and plasma glucose concentrations, and dose-dependent decreases in plasma potassium concentrations, were observed with inhaled formoterol 24 to 96μg or salmeterol 100 to 400μg in a double-blind, placebo-controlled, crossover trial in 16 healthy volunteers. In patients with COPD, pre-existing mild to moderate cardiac arrhythmias and hypoxemia [PaO₂ (arterial oxygen pressure) <60mm Hg], formoterol 12μg had similar systemic effects to salmeterol 50μg. Complex ventricular arrhythmias were observed in formoterol 12 and 24μg recipients, but not in salmeterol 50μg or placebo recipients.

Pharmacokinetic Properties

The maximum plasma concentration (92 ng/L) of formoterol was reached within 5 minutes of inhalation of a single supraoptimal dose (120μg) in 12 healthy volunteers. Urinary excretion data suggest that absorption was linear with inhaled formoterol 12 to 96μg in ten healthy volunteers. In vitro plasma protein binding of formoterol was 61 to 64% at concentrations 0.1 to 100 μg/L.Mean plasma concentrations of the drug at 10 minutes to 6 hours postinhalation were 4.0 to 8.8 ng/L and 8.0 to 17.3 ng/L, respectively, after multiple doses of formoterol 12 or 24μg administered twice daily for 12 weeks in patients with COPD, with some evidence of accumulation of formoterol in the plasma (accumulation index 1.19 to 1.38).Formoterol is metabolized primarily in the liver by four cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6). These enzymes were not inhibited by the drug at therapeutic concentrations. Following inhalation of formoterol 12 or 24μg by 18 patients with COPD, 7% of the total dose was excreted in the urine as unchanged drug and 6 to 9% of the total dose was eliminated as direct conjugates of formoterol. The mean terminal elimination half-life was determined to be 10 hours (based on plasma concentrations) following inhalation of single-dose formoterol 120μg by 12 healthy volunteers.Currently, there are no pharmacokinetic data for the use of formoterol in patients with hepatic or renal impairment or in elderly individuals.

Therapeutic Efficacy

Inhaled formoterol has been evaluated as monotherapy or combination therapy for the management of patients with COPD. In clinical trials, COPD was diagnosed using the American Thoracic Society guidelines.The bronchodilator effect [measured as normalized area under the FEV₁ versus time curve (AUC FEV₁)] with formoterol 12μg twice daily (n = 194) was significantly greater than that with ipratropium bromide 40μg four times daily (n = 194; p = 0.001) or placebo (n = 200; p < 0.001) in a randomized, double-blind, 12-week trial in patients with COPD. Significant improvements were also observed in mean morning premedication peak expiratory flow (PEF; p < 0.001) and health-related quality of life [all three subsections of the St. George’s Respiratory Questionnaire (SGRQ); p ≤ 0.036], and significant reductions were reported for the use of rescue medication (p ≤ 0.014) and the percentage of ‘bad days’ (days with at least two individual symptom scores of ≥2 and/or a reduction in PEF from baseline of >20%; p < 0.001) in formoterol compared with ipratropium bromide recipients. The differences in health-related quality of life between the two treatments were clinically relevant (exceeding 4 points) for the Activity and the Impacts domains of the SGRQ.Compared with oral slow-release theophylline (individualized dosages targeted at plasma concentrations of 8 to 20 mg/L), formoterol 12μg twice daily significantly increased standardized AUC_12h FEV₁ (primary end-point; p = 0.026) and mean morning premedication PEF (p ≤ 0.020) and reduced the percentage of ‘bad days’ (p ≤ 0.035) in a randomized, double-blind (with the exception of the theophylline arm), 12-month trial. A subgroup analysis in this trial indicated that at 3 (p = 0.007) and 12 months (p = 0.002), formoterol (n = 118), but not oral slow-release theophylline (n = 105), produced significant bronchodilation compared with placebo (n = 117) in patients with irreversible or poorly-reversible airflow obstruction (i.e. patients whose FEV₁ values increased <15% after receiving albuterol). Both formoterol (p ≤ 0.026) and oral slow-release theophylline (p ≤ 0.013) were significantly more effective than placebo at managing COPD during the night (measured as morning premedication FEV₁).In these two monotherapy trials, inhaled formoterol 24μg twice daily did not provide any additional benefit over the 12μg twice daily dosage in patients with COPD.The combined efficacy of inhaled formoterol 12μg twice daily plus inhaled ipratropium bromide 40μg four times daily for 3 weeks has been compared with that of albuterol 200μg four times daily for 3 weeks via a pressurized metered-dose inhaler plus inhaled ipratropium bromide 40μg four times daily in a randomized, double-blind, double-dummy, crossover trial in 172 patients with COPD. Formoterol combination therapy was significantly more effective than albuterol combination therapy at increasing mean morning premedication PEF (primary endpoint; p = 0.0003). Combination therapy with formoterol was also more effective according to secondary endpoints, significantly increasing postmedication FEV₁ to 6 hours (p< 0.0001), peak postmedication FEV₁ (p < 0.0001) and AUC FEV₁ (p < 0.0001) and improving symptoms of COPD (measured as mean total symptoms score, p = 0.0042) and the SGRQ symptoms score (p = 0.0408) relative to albuterol combination therapy.

Tolerability

Inhaled formoterol was well tolerated in clinical trials in patients with COPD. The percentage of patients experiencing at least one adverse event with inhaled formoterol 12μg twice daily was similar to that with placebo, inhaled ipratropium bromide 40μg four times daily or oral slow-release theophylline (individualized dosages targeted at plasma concentrations of the drug of 8 to 20 mg/L) in randomized, double-blind, comparative trials of 12 weeks’ and 12 months’ duration. Viral infection, exacerbation of COPD, bronchitis, upper respiratory tract infection, dyspnea and headache were the most commonly reported adverse events (i.e. occurring in >5% of formoterol 12μg twice daily recipients); however, the incidence of these events was not significantly different compared with oral slow-release theophylline or placebo.Drug-related adverse events, serious adverse events and events leading to withdrawal from the study occurred with a similar incidence with inhaled formoterol, placebo or ipratropium bromide. In contrast, drug-related adverse events and withdrawal because of adverse events occurred with a higher incidence in patients receiving oral slow-release theophylline in the 12-month trial.There were no significant differences in the incidence of cardiovascular adverse events with inhaled formoterol (0.5% of patients) compared with inhaled placebo (2.5%) or ipratropium bromide (2.6%) after 12 weeks’ treatment or in the incidence of serious cardiovascular adverse events with inhaled formoterol (2.4% of patients) compared with placebo (0.9%) or oral slow-release theophylline (2.4%) after 12 months’ treatment in patients with COPD and QTc interval values within the normal range; heart rate and rhythm disorders were infrequent. The incidences of QTc interval prolongation (>0.46s), ECG abnormalities or clinically relevant changes in serum potassium or fasting plasma glucose concentrations were similar with inhaled formoterol 12μg twice daily compared with placebo, inhaled ipratropium bromide or oral slow-release theophylline in clinical trials.

Dosage and Administration

Formoterol, inhaled orally using an Aerolizer?1 inhaler, is indicated in the US for the long-term maintenance treatment of bronchoconstriction associated with COPD (including chronic bronchitis and emphysema). The recommended dosage of formoterol in this patient group is 12μg twice daily approximately 12 hours apart; the total daily dose should not exceed 24μg.Formoterol should be used with caution in patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias or hypertension), convulsive disorders or thyrotoxicosis, or hypersensitivity to sympathomimetic amines. Extreme caution is advised if formoterol is used concomitantly with monoamine oxidase inhibitors, tricyclic antidepressants or drugs that are known to prolong the QTc interval, and caution is recommended with the concomitant use of formoterol and non-potassium-sparing diuretics.

     

Early detection of anastomotic leakage after pancreatoduodenectomy with microdialysis catheters: an observational Study

BackgroundMicrodialysis catheters can detect focal inflammation and ischemia, and thereby have a potential for early detection of anastomotic leakages after pancreatoduodenectomy. The aim was to investigate whether microdialysis catheters placed near the pancreaticojejunostomy can detect leakage earlier than the current standard of care.MethodsThirty-five patients with a median age 69 years were included. Two microdialysis catheters were placed at the end of surgery; one at the pancreaticojejunostomy, and one at the hepaticojejunostomy. Concentrations of glucose, lactate, pyruvate, and glycerol were analyzed hourly in the microdialysate during the first 24 h, and every 2–4 h thereafter.ResultsSeven patients with postoperative pancreatic fistulae (POPF) had significantly higher glycerol levels (P < 0.01) in the microdialysate already in the first postoperative samples. Glycerol concentrations >400 μmol/L during the first 12 postoperative hours detected patients with POPF with a sensitivity of 100% and a specificity of 93% (P < 0.001). After 24 h, lactate and lactate-to-pyruvate ratio were significantly higher (P < 0.05) and glucose was significantly lower (P < 0.05) in patients with POPF.ConclusionHigh levels of glycerol in microdialysate was an early detector of POPF. The subsequent inflammation was detected as increase in lactate and lactate-to-pyruvate ratio and a decrease in glucose (NCT03627559).     

Comparison of intermittent versus continuous-infusion vancomycin for treating severe patients in intensive care units

PurposeThe aim of this study was to compare pharmacokinetic characteristics between intermittent infusion and continuous infusion of vancomycin for critically ill patients admitted to intensive care units.MethodsIntermittent therapy was administered for 60 minutes and prescribed as a loading dose of 30 mg/kg and continued with 15 mg/kg q12 h. Continuous infusion was prescribed as a loading dose of 30 mg/kg followed by 30 mg/kg on constant infusion pump. Blood samples from vancomycin intermittent infusion group were collected 1 h before third dose, 1 h, 8 h and 24 h after third dose infusion. Blood samples from vancomycin continuous infusion group were collected 1 h after loading dose, 12 h, 24 h, 36 h, and 48 h after continuous infusion initiation.ResultsMedian serum concentration of continuous infusion group at 24-hour was 23.59 μg/mL [14.52–28.97], while of intermittent infusion group at 23-hour was 12.30 μg/mL [7.27–18.12] and on 25-hour was 17.58 μg/mL [12.5–22.5]. Medians AUC_24–48h were 357.2 mg.h/L and 530.2 mg.h/L for intermittent infusion and continuous infusion groups, respectively (p = 0.559).ConclusionVancomycin CI reached steady state earlier, which guaranteed therapeutic levels from the first day and made it possible to manage therapeutic drug monitoring faster.     

Clinical outcomes of pleural drainage on pneumothorax and hydrothorax in critically ill patients with COVID-19: A case series with literature review

BackgroundFor patients with COVID-19, pneumothorax and hydrothorax are suggested to be negative prognostic indicators. However, the management of these two conditions has rarely been discussed. We aimed to describe the clinical outcomes of pleural drainage in critically ill patients with COVID-19.MethodsA total of 17 pleural drainages were performed in 11 critically ill patients with pneumothorax or hydrothorax. Either chest tubes or central venous catheters (CVCs) were used. The clinical outcomes, including respiratory and circulation indicators at 24 h and 1 h before the procedure and 24 h and 48 h after the procedure, were retrospectively recorded.Results(1) Following pleural drainage, there was a 19.1% improvement in the PaO₂/FiO₂ ratio from 147.4 mmHg (-1 h) to 175.5 mmHg (24 h), while the mean positive end expiratory pressure (PEEP) decreased from 10.7 cmH₂O (-1 h) to 8.9 cmH₂O (24 h) and 8.1 cmH₂O (48 h). The A-a gradients decreased from 313.3 mmHg (-1 h) to 261.3 mmHg (24 h). (2) The dosage of norepinephrine increased from 0.15 μg/kg/min (-1 h) to 0.40 μg/kg/min (24 h). (3) No haemorrhagic or infectious complications were observed. (4) A total of 41.6% of CVCs were partially or fully obstructed, while no chest tubes were obstructed.ConclusionFor critically ill patients with COVID-19, pleural drainage leads to a significant improvement in oxygenation and gas exchange, but the deterioration of circulation is not reversed. It is safe to perform pleural drainage even though anticoagulation therapy and glucocorticoids are widely used. Chest tubes rather than CVCs are recommended.     

Preclinical efficacy of THRX-200495, a dual pharmacology muscarinic receptor antagonist and β(2)-adrenoceptor agonist (MABA)

Combinations of a muscarinic receptor antagonist (MA) and a β₂-adrenoceptor agonist (BA) improve bronchodilation in COPD patients to a greater extent than drugs with either mechanism alone. Here, using an in vivo model of bronchoprotection in guinea pigs, we characterize a single agent with dual-acting MA and BA activity, THRX-200495 (MABA). THRX-200495 was compared to a fixed-dose combination of a short-acting muscarinic receptor antagonist (SAMA) and a β₂-adrenoceptor agonist (SABA). The SAMA/SABA combination consisted of a 1:5.7 ratio of ipratropium and albuterol (the components of Combivent®). Conscious guinea pigs received aqueous nebulized solutions of vehicle or test compound by aerosol exposure. Bronchoprotective potency was estimated in anesthetized, tracheotomized and ventilated guinea pigs at predetermined time points after aerosol exposure by measuring changes in ventilation pressure. The individual (MA, BA) and composite (MABA) pharmacologies were assessed by determining protection against bronchoconstrictor responses induced by methacholine in the presence of propranolol (for MA activity), histamine (for BA activity) or methacholine (MABA activity). Bronchoprotection was calculated as percent inhibition of methacholine or histamine response relative to the vehicle group. THRX-200495 exhibited matched MA (ID₅₀ = 11.4 μg/mL) and BA (ID₅₀ = 11.2 μg/mL) potency and potent dual pharmacology (MABA ID₅₀ = 3.5 μg/mL) that persisted for over 24 h. The combination of ipratropium/albuterol exhibited bronchoprotective activity that was 2.6-fold more potent as a BA (ID₅₀ = 5.7 μg/mL) than as an MA (ID₅₀ = 14.6 μg/mL) at 0.5 h post-dose and 37-fold more potent as an MA (ID₅₀ = 4.3 μg/mL) than a BA (ID₅₀ = 159 μg/mL) at 1.5 h post aerosol exposure. Under MABA pharmacological conditions, ipratropium/albuterol produced potent bronchoprotective activity (ID₅₀ = 2.0/11.4 μg/mL) and an apparent additive effect of the two pharmacologies. In conclusion, a dual-acting prototypical MABA, THRX-200495, demonstrated potent, balanced and long-lasting bronchodilation in a guinea pig model of bronchoprotection that was greater than either the MA or BA mechanisms alone.     

Effectiveness of 0.05% oxymetazoline (Vicks Sinex Micromist®) nasal spray in the treatment of objective nasal congestion demonstrated to 12 h post-administration by magnetic resonance imaging

IntroductionThis study aimed to assess the qualitative and quantitative utility of MRI imaging to illustrate the magnitude and duration of the effect of a standard 100 μg dose of oxymetazoline in a commercially available formulation that also contains aromatic oils.MethodsThis was a randomized, open label, single dose, parallel group study in 21 adult male and female subjects who reported moderate to severe nasal congestion due to acute upper respiratory tract infection or hay fever. MRI scans were acquired using a 3T Philips Achieva scanner with a 16 channel head receive coil. High resolution MRI scans of the nasal turbinates were obtained immediately prior to dosing (baseline) and at approximately 1, 8, 10, 11, and 12 h after dosing. The efficacy variables of primary interest were inferior turbinate total volume at 8 and 12 h post-dosing. The secondary efficacy variables analysed were inferior turbinate total volume at 1, 10, and 11 h post-dosing, middle turbinate total volume at 1, 8, 10, 11, and 12 h post-dosing.ResultsChanges from baseline volumes measured for the inferior and middle turbinates of subjects receiving the oxymetazoline formulation showed significant (P < 0.05) decreases at all times up to and including 12 h post-administration. No significant decreases from baseline were detected in subjects receiving a sham ‘spray’ (untreated control – spray bottles with no spray solution). Statistical ANCOVA results of inferior and middle turbinate volume indicated significant differences (P < 0.05) at all measurement points up to and including 12 h post-administration between the oxymetazoline treatment group and the untreated control with the only exception the middle turbinate volume at 10 h (P = 0.0896). The significant changes were likely to be clinically relevant though this was not measured in the study. No AEs were reported during this study and no other safety evaluations were made.ConclusionsThis study showed that MRI assessment of nasal congestion in human volunteers is a robust, repeatable and viable measurement technique. The application of a 100 μg Vicks Sinex Micromist^® nasal decongestant (0.05% oxymetazoline solution) delivered a highly significant reduction in inferior and middle turbinate volumes compared with the application of a control, measurable by the MRI method up to and including a 12 h post-dose scan.     

Detection of carbapenemase-producing Pseudomonas aeruginosa: Evaluation of the carbapenem inactivation method (CIM)

IntroductionThe carbapenem inactivation method (CIM) is a cost-effective assay for detecting carbapenemases. However, its interpretation is unclear for Pseudomonas spp. We evaluate its accuracy when meropenem is changed to imipenem.MethodsWe analyzed 266 P. aeruginosa isolates. The CIM method consists of: resuspend bacterial colonies (a full 10 μL loop) in 400 μL water, in which a 10 μg disk of meropenem/imipenem is immersed. After 2 h of incubation (35 °C), remove the disk, place it onto a Mueller-Hinton agar plate previously inoculated with Escherichia coli (ATCC 25922), and incubate at 35 ̊C between 18-24 h. Interpretation criteria (mm of inhibition zone): ≤19 mm, positive; ≥25 mm negative; 20–24 mm, undetermined.ResultsImipenem improves the sensitivity and specificity of CIM when compared to meropenem (99.4% and 98.9%, vs. 91.9% and 94.7%, respectively).ConclusionsThe accuracy of CIM for carbapenemase detection in P. aeruginosa is increased with the use of imipenem.