Long-acting beta(2)-agonist in addition to tiotropium versus either tiotropium or long-acting beta(2)-agonist alone for chronic obstructive pulmonary disease

BackgroundLong-acting bronchodilators comprising long-acting beta(2)-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta2-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear.ObjectivesTo assess the relative effects of treatment with tiotropium in addition to long-acting beta(2)-agonist compared to tiotropium or long-acting beta2-agonist alone in patients with chronic obstructive pulmonary disease.Search methodsWe searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012.Selection criteriaWe included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta2-agonist against tiotropium or long-acting beta2-agonist alone for patients with chronic obstructive pulmonary disease.Data collection and analysisTwo review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.Main resultsFive trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta(2)-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta2-agonist (formoterol) alone. Two studies used the long-acting beta2-agonist indacaterol, two used formoterol and one used salmeterol.Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long-acting beta2-agonist resulted in a slightly larger improvement in the mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) MD -1.61; 95% CI -2.93 to -0.29). In the control arm, tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with both treatments the improvement was a fall of 6.1 units from baseline (on average). High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator FEV1 showed a small mean increase with the addition of long-acting beta2-agonist (MD 0.07 L; 95% CI 0.05 to 0.09) over the control arm, which showed a change from baseline ranging from 0.03 L to 0.13 L on tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There were wide confidence intervals around these outcomes and moderate heterogeneity for both exacerbations and withdrawals.The results from the one trial comparing the combination of tiotropium and long-acting beta2-agonist to long-acting beta2-agonist alone (417 participants) were insufficient to draw firm conclusions for this comparison.Authors' conclusionsThe results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta2-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta(2)-agonists to tiotropium. There were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta2-agonist compared to long-acting beta2-agonist alone. There were insufficient data to make comparisons between the different long-acting beta2-agonists when used in addition to tiotropium

Cardiac safety of tiotropium in patients with cardiac events: a retrospective analysis of the UPLIFT® trial.

BackgroundTiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, we re-evaluated the safety of tiotropium HandiHaler® in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study.MethodsA post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT® and who completed the study. Descriptive analyses were performed.ResultsMost patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan-Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler® versus placebo. Patients who experienced a cardiac event and continued in UPLIFT® were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo.ConclusionsRisk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler® in patients with COPD

Chronic toxicity of inhaled thymol in lungs and respiratory tracts in mouse model.

Epinephrine HFA (Primatene® Mist) is a newly formulated asthma metered dose inhaler developed to replace the previous Primatene® Mist CFC. The formulation of Epinephrine HFA contains thymol, a substance recognized to be safe by the FDA. Although the content of thymol contained in Epinephrine HFA is much lower compared to many common foods and medications available, there are no known nonclinical data about the chronic toxicity of thymol through inhalation. Two sequential 6-month studies of identical design were conducted to assess the chronic toxicity of inhaled thymol in mice. Four treatment groups, (a) Air; (b) vehicle control; (c) Article-1 (thymol 0.1%); and (d) Article-2 (thymol 0.5%) were assessed in 128 mice for 26 weeks. The mice were sacrificed at the end of the treatment period and a histopathologic evaluation was performed with respect to lungs, bronchial lymph nodes, nasal passages/nasopharynx, and trachea. Forty-five pathologic assessment parameters (PAPs) were evaluated. In total, 5591 data points from 487 mouse organs were assessed. Chronic toxicity index was calculated for 16 PAPs that had multiple histopathologic abnormal observations. The t tests were conducted for these 16 PAPs (Articles-1 and 2 versus Air and vehicle control, respectively), and all P-values were greater than .05 indicating no significant differences between all treatment groups. An evaluation was also conducted for 25 PAPs that had only a very small number of pathologic abnormalities. No significant differences for chronic toxicity were found when comparing mice under long-term repeated exposure of high doses of inhaled thymol and mice that inhaled no thymol

Working Capital Management and Solvency of the Industries in Bangladesh

The goal of a firm is to maximize its wealth maximization and it is important for the financial manager to take the right decision to utilize its investment efficiently and effectively. One of the crucial decisions is the working capital management which is made by the financial manager. The challenge is that every firm should maintain the optimum working capital management by which the shareholders’ wealth can be maximized. This study focused on the working capital management of different types of industries in Bangladesh and covers the difference between the solvencies of different industries. Moreover, it also represents the profitability of different industries in compare with the working capital management. It is important to manage the working capital management; otherwise, the firm may suffer in insolvency which may result in bankruptcy. Keywords: Working Capital Management, Liquidity, Solvency, Profitability, Cash Conversion Cycle

Capital Structure and Financing Decision: Industry-Base Debt-Equity Ratio in Bangladesh

This study covers the significance of capital structure for the organization which differs on the basis of the industry. The reasons behind the various debt-equity ratios for different industry are also discussed in this study. This study also mainly focused on the use of debt and equity for financing the various types of industry in Bangladesh. It is important to evaluate any particular industry of any country by considering their financing decision which has an impact on capital structure. Bangladesh is a developing country and has an opportunity to attract the foreign investors and also the domestic investors to invest in the country. For this reason, it is essential to assess the capital structure before investing in the industry of this country. Keywords: Capital Structure, Financial Distress Cost, Weighted Average Cost of Capital, Debt-Equity Ratio, Tax Benefit

Preventing and managing exacerbations in COPD – critical appraisal of the role of tiotropium

The course of COPD is punctuated by acute exacerbations that are associated with an increase in the morbidity and mortality related to this chronic disease and may contribute to its rate of progression. Therefore, preventing and treating exacerbations are major goals of COPD management. The role of tiotropium in the prevention of exacerbations has been investigated in several placebo-controlled randomized clinical trials varying in duration from 3 months to 4 years in patients with moderate to very severe COPD. In all of these trials, tiotropium has uniformly reduced the proportion of patients experiencing at least one exacerbation and delayed the time to the first exacerbation compared with placebo. In the longer trials (≥6 months’ duration) tiotropium has also reduced the exposure-adjusted incidence rate of exacerbations. In trials of at least 1 year in duration, tiotropium either significantly reduced the risk of hospitalization for an exacerbation and/or the proportion of patients with an exacerbation-related hospitalization. In a meta-analysis that included 15 trials of tiotropium vs either placebo (n = 13) and/or a long-acting beta-agonist (LABA; n = 4), tiotropium significantly reduced the odds of experiencing an exacerbation compared to placebo as well as a LABA. The potential additive benefits of tiotropium to those of a LABA and/or inhaled corticosteroid in reducing exacerbations require further investigation. The mechanism whereby tiotropium reduces exacerbations is not due to an anti-inflammatory effect but more likely relates to its property of causing a sustained increase in airway patency and reduction in hyperinflation, thereby counteracting the tendency for respiratory insults to worsen airflow obstruction and hyperinflation. For the management of acute exacerbations, an increase in short-acting inhaled bronchodilators is recommended as needed, while the potential role of long-acting bronchodilators, such as tiotropium, in conjunction with short-acting agents, is unclear and warrants further study

Pharmacokinetic study of thymol after intravenous injection and high-dose inhalation in mouse model.

Thymol is generally recognized as a safe substance by the FDA and has been widely used in the pharmaceutical, food, and cosmetic industries. Pharmacokinetic (PK) studies of thymol have been previously conducted for oral administration, but there has been no PK study for inhalation administration or intravenous (IV) injection. This study aims at exploring and comparing the inhalation and IV PK profile of thymol in a mouse model. The inhalation PK for mouse model was corrected with fur/skin absorption. Thirty-two male CD-1 mice were randomized into two study arms, Arm-A for intravenous (n = 16) and Arm-B for inhalation (n = 16). The amount of thymol in the mouse serum was measured for Arm-A and for Arm-B at the highest dose. Furthermore, 48 mice were utilized for fur/skin absorption of thymol. In total, 320 mouse serum samples for thymol were analyzed by LC/MS method. After inhalation, the peak concentration of thymol in mouse serum was 42.3 ng/mL (Cmax ) and occurred at 2 minutes (tmax ). The AUC of the inhaled thymol at 0-60 minutes (AUC0-60) was 464 ng/mL/min. From 10-60 minutes post-dose, the PK inhalation curve appeared to be higher than that for the IV injection. This is likely attributed to the effect of absorption of thymol through the fur/skin of mice. After an adjustment by fur/skin absorption, the PK profile for net inhalation closely matched the two-compartment model. In fact, the bioavailability for the net inhalation of thymol was 74% and 77% relative to that for IV injection per AUC0-60min and AUC0-infinite, respectively

Effect of smoking status on lung function, patient-reported outcomes, and safety among COPD patients treated with glycopyrrolate inhalation powder: pooled analysis of GEM1 and GEM2 studies.

BackgroundSmoking is a major risk factor for COPD and may impact the efficacy of COPD treatments; however, a large proportion of COPD patients continue to smoke following diagnosis.MethodsThis post-hoc analysis of pooled data from the replicate 12-week, placebo-controlled GEM1 and GEM2 studies assessed the impact of smoking status on the efficacy and safety of glycopyrrolate 15.6 μg twice daily vs placebo in patients with moderate-to-severe COPD. Data from 867 patients enrolled in GEM1 and GEM2 were pooled for analysis and grouped by smoking status (57% current smokers, 43% ex-smokers). Forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 12 h, trough FEV1, forced vital capacity, St George's Respiratory Questionnaire (SGRQ) total score, COPD assessment test (CAT) score, transition dyspnea index (TDI) focal score, daily symptom scores, and rescue medication use were assessed in current smokers and ex-smokers. Incidences of adverse events (AEs) and serious AEs (SAEs) were also assessed.ResultsTreatment with glycopyrrolate resulted in significant improvements in all lung function measures, independent of smoking status. In both current and ex-smokers, changes from baseline in trough FEV1 were less marked in patients taking inhaled corticosteroids (ICS) than those not receiving ICS. Changes from baseline in SGRQ total score and rescue medication use were significantly greater with glycopyrrolate compared with placebo, regardless of smoking status. Changes in the CAT score, TDI focal score, and daily symptom scores significantly improved versus placebo, but only in current smokers. Improvements in patient-reported outcomes (PROs) with glycopyrrolate relative to placebo were numerically greater in current smokers than ex-smokers. The incidences of AEs and SAEs were similar regardless of smoking status.ConclusionsIn this post-hoc analysis of GEM1 and GEM2, glycopyrrolate use led to significant improvements in lung function, independent of baseline smoking status; improvements were less marked among patients receiving background ICS, regardless of baseline smoking status. Improvements in PROs were greater with glycopyrrolate than placebo, and the magnitude of changes was numerically greater among current smokers. The safety profile of glycopyrrolate was comparable between current smokers and ex-smokers

Benefit:Risk Profile of Budesonide in Obstructive Airways Disease

Airway inflammation is a major contributing factor in both asthma and chronic obstructive pulmonary disease (COPD) and represents an important target for treatment. Inhaled corticosteroids (ICS) as monotherapy or in combination therapy with long-acting β2-agonists or long-acting muscarinic antagonists are used extensively in the treatment of asthma and COPD. The development of ICS for their anti-inflammatory properties progressed through efforts to increase topical potency and minimise systemic potency and through advances in inhaled delivery technology. Budesonide is a potent, non-halogenated ICS that was developed in the early 1970s and is now one of the most widely used lung medicines worldwide. Inhaled budesonide's physiochemical and pharmacokinetic/pharmacodynamic properties allow it to reach a rapid and high airway efficacy due to its more balanced relationship between water solubility and lipophilicity. When absorbed from the airways and lung tissue, its moderate lipophilicity shortens systemic exposure, and its unique property of intracellular esterification acts like a sustained release mechanism within airway tissues, contributing to its airway selectivity and a low risk of adverse events. There is a large volume of clinical evidence supporting the efficacy and safety of budesonide, both alone and in combination with the fast- and long-acting β2-agonist formoterol, as maintenance therapy in patients with asthma and with COPD. The combination of budesonide/formoterol can also be used as an as-needed reliever with anti-inflammatory properties, with or without regular maintenance for asthma, a novel approach that is already approved by some country-specific regulatory authorities and currently recommended in the Global Initiative for Asthma (GINA) guidelines. Budesonide remains one of the most well-established and versatile of the inhaled anti-inflammatory drugs. This narrative review provides a clinical reappraisal of the benefit:risk profile of budesonide in the management of asthma and COPD