Efficacy and safety of a budesonide/formoterol reliever therapy regimen in mild-moderate asthma: A randomised controlled trial

<p>Background Inhaled corticosteroids taken regularly reduce exacerbation risk in patients with mild asthma. In clinical practice however, adherence to inhaled corticosteroids is poor and the burden of disease from exacerbations is substantive. In this thesis I explore an alternative approach, that of an inhaled corticosteroid/formoterol combination used as sole reliever therapy, that potentially overcomes the problem of poor adherence. I report the results of my research, known as the PeRsonalised Asthma Combination Therapy: with Inhaled Corticosteroid And fast-onset Long acting beta agonist (PRACTICAL) study. Research aims To investigate the efficacy and safety of as-needed budesonide/formoterol, an inhaled corticosteroid (ICS)/fast-onset long-acting beta agonist (LABA) combination, as compared with maintenance budesonide (ICS) plus as-needed terbutaline, a short-acting beta-agonist (SABA), in adult patients with mild-moderate asthma. Methods This research was performed as a 52-week, open-label, parallel-group, multicentre, phase III randomised controlled trial of adults aged 18-75 with mild to moderate asthma using SABA for symptom relief, with or without low to moderate doses of maintenance ICS in the previous 12 weeks. Participants were randomly assigned (1:1) to either: (i) budesonide/formoterol Turbuhaler, an ICS/fast-onset LABA, 200/6 micrograms (μg), one inhalation as needed for relief of symptoms, or (ii) budesonide Turbuhaler, an ICS, 200µg, one inhalation twice daily, plus terbutaline Turbuhaler, a SABA, 250µg, two inhalations as needed. Participants and investigators were not masked to group assignment. Participants were seen for six study visits: randomisation, and at weeks 4, 16, 28, 40 and 52. The primary outcome was rate of severe exacerbations per patient per year, with severe exacerbations defined as the use of systemic glucocorticoids for at least three days because of asthma, or a hospitalisation or emergency department visit because of asthma requiring systemic glucocorticoids. Findings Between May 4, 2016 and Dec 22, 2017, 890 participants were assigned to treatment. The analysis included 885 of 890 randomised participants; 437 assigned to budesonide/formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. 70% of participants were using ICS at entry. The annualised severe exacerbation rate was lower with as-needed budesonide/formoterol than with maintenance budesonide (absolute rate 0.119 vs 0.172; relative rate, 0.69 [95% confidence interval [CI], 0.48 to 1.00]; p=0.049). The Asthma Control Questionnaire-5 score with budesonide/formoterol was not significantly different from budesonide maintenance (mean difference, 0.06; 95% CI -0.005 to 0.12). Conclusion This research has demonstrated that in adults with mild to moderate asthma in the real-world setting, budesonide/formoterol reliever therapy was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline without a clinically important worsening in asthma control. The evidence presented in this thesis supports the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid/formoterol reliever therapy is an alternative regimen to maintenance low-dose inhaled corticosteroid and SABA reliever for the prevention of severe exacerbations for patients with mild to moderate asthma.</p>

Efficacy and safety of a budesonide/formoterol reliever therapy regimen in mild-moderate asthma: A randomised controlled trial

<p>Background Inhaled corticosteroids taken regularly reduce exacerbation risk in patients with mild asthma. In clinical practice however, adherence to inhaled corticosteroids is poor and the burden of disease from exacerbations is substantive. In this thesis I explore an alternative approach, that of an inhaled corticosteroid/formoterol combination used as sole reliever therapy, that potentially overcomes the problem of poor adherence. I report the results of my research, known as the PeRsonalised Asthma Combination Therapy: with Inhaled Corticosteroid And fast-onset Long acting beta agonist (PRACTICAL) study. Research aims To investigate the efficacy and safety of as-needed budesonide/formoterol, an inhaled corticosteroid (ICS)/fast-onset long-acting beta agonist (LABA) combination, as compared with maintenance budesonide (ICS) plus as-needed terbutaline, a short-acting beta-agonist (SABA), in adult patients with mild-moderate asthma. Methods This research was performed as a 52-week, open-label, parallel-group, multicentre, phase III randomised controlled trial of adults aged 18-75 with mild to moderate asthma using SABA for symptom relief, with or without low to moderate doses of maintenance ICS in the previous 12 weeks. Participants were randomly assigned (1:1) to either: (i) budesonide/formoterol Turbuhaler, an ICS/fast-onset LABA, 200/6 micrograms (μg), one inhalation as needed for relief of symptoms, or (ii) budesonide Turbuhaler, an ICS, 200µg, one inhalation twice daily, plus terbutaline Turbuhaler, a SABA, 250µg, two inhalations as needed. Participants and investigators were not masked to group assignment. Participants were seen for six study visits: randomisation, and at weeks 4, 16, 28, 40 and 52. The primary outcome was rate of severe exacerbations per patient per year, with severe exacerbations defined as the use of systemic glucocorticoids for at least three days because of asthma, or a hospitalisation or emergency department visit because of asthma requiring systemic glucocorticoids. Findings Between May 4, 2016 and Dec 22, 2017, 890 participants were assigned to treatment. The analysis included 885 of 890 randomised participants; 437 assigned to budesonide/formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. 70% of participants were using ICS at entry. The annualised severe exacerbation rate was lower with as-needed budesonide/formoterol than with maintenance budesonide (absolute rate 0.119 vs 0.172; relative rate, 0.69 [95% confidence interval [CI], 0.48 to 1.00]; p=0.049). The Asthma Control Questionnaire-5 score with budesonide/formoterol was not significantly different from budesonide maintenance (mean difference, 0.06; 95% CI -0.005 to 0.12). Conclusion This research has demonstrated that in adults with mild to moderate asthma in the real-world setting, budesonide/formoterol reliever therapy was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline without a clinically important worsening in asthma control. The evidence presented in this thesis supports the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid/formoterol reliever therapy is an alternative regimen to maintenance low-dose inhaled corticosteroid and SABA reliever for the prevention of severe exacerbations for patients with mild to moderate asthma.</p>

The Mechanisms of Sevoflurane-Induced Neuroinflammation

Sevoflurane is one of the most commonly used inhaled anesthetics due to its low blood gas coefficient, fast onset, low airway irritation, and aromatic smell. However, recent studies have reported that sevoflurane exposure may have deleterious effects on cognitive function. Although neuroinflammation was most widely mentioned among the established mechanisms of sevoflurane-induced cognitive dysfunction, its upstream mechanisms have yet to be illustrated. Thus, we reviewed the relevant literature and discussed the most mentioned mechanisms, including the modulation of the microglial function, blood–brain barrier (BBB) breakdown, changes in gut microbiota, and ease of cholinergic neurotransmission to help us understand the properties of sevoflurane, providing us new perspectives for the prevention of sevoflurane-induced cognitive impairment.

Antidepressant-Like Effects of Chronic Guanosine in the Olfactory Bulbectomy Mouse Model

Major depressive disorder (MDD) leads to pervasive changes in the health of afflicted patients. Despite advances in the understanding of MDD and its treatment, profound innovation is needed to develop fast-onset antidepressants with higher effectiveness. When acutely administered, the endogenous nucleoside guanosine (GUO) shows fast-onset antidepressant-like effects in several mouse models, including the olfactory bulbectomy (OBX) rodent model. OBX is advocated to possess translational value and be suitable to assess the time course of depressive-like behavior in rodents. This study aimed at investigating the long-term behavioral and neurochemical effects of GUO in a mouse model of depression induced by bilateral bulbectomy (OBX). Mice were submitted to OBX and, after 14 days of recovery, received daily (ip) administration of 7.5 mg/kg GUO or 40 mg/kg imipramine (IMI) for 45 days. GUO and IMI reversed the OBX-induced hyperlocomotion and recognition memory impairment, hippocampal BDNF increase, and redox imbalance (ROS, NO, and GSH levels). GUO also mitigated the OBX-induced hippocampal neuroinflammation (IL-1, IL-6, TNF-α, INF-γ, and IL-10). Brain microPET imaging ([18F]FDG) shows that GUO also prevented the OBX-induced increase in hippocampal FDG metabolism. These results provide additional evidence for GUO antidepressant-like effects, associated with beneficial neurochemical outcomes relevant to counteract depression.

Topical Refrigerant Spray for IVs: Patient/Provider Responses - Prospective, Double-blind, Randomized Study

Painful procedures are common. Patients prefer analgesia for painful procedures. Studies indicate that use of a topical refrigerant spray (TRS) prior to needlestick procedures decreases needlestick pain. TRS is easy to apply, inexpensive, has fast onset, and avoids needlestick pain and anxiety, and needlestick injury risk. Patient and health care provider (HCP) acceptance of any technique is essential before it is adopted. This study evaluated the decrease in pain with TRS and the patient and HCP satisfaction and acceptance of TRS for peripheral intravenous (PIV) placement. Adults (N = 300) randomized to placebo or TRS and HCPs (N = 300) placing PIVs answered questionnaires. Patients had significantly less pain than with prior PIVs, and were satisfied with and would use TRS in the future (P < 0.001). HCP felt that patients had significantly (P < 0.001) less pain with TRS than the placebo, and were satisfied with the TRS, and would use TRS in the future. Registered at Clinicaltrials.gov NCT01670487

Abstract 15505: Aortic Stiffening in L-NAME Treated C57bl6 Mice Precedes Peripheral Hypertension and Cardiac Hypertrophy: Early Endothelial Dysfunction Shifts to Late-term Vascular Smooth Muscle Cell Disease

Introduction: Endothelial dysfunction (ED) acts as a common player in most cardiovascular (CV) risk factors (e.g. hypertension, smoking) underlining its importance in CV ageing. Therefore, this study aims to characterize ex vivo aortic function changes in Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) treated mice. Methods: C57Bl6 mice (male, n=10) received 0.5 mg/mL L-NAME through the drinking water for 1, 2, 4, 8, and 16 weeks, followed by in-depth ex vivo thoracic aorta isometric reactivity studies and arterial stiffness (Peterson modulus, Ep) measurements in the Rodent Oscillatory Tension set-up for Arterial Compliance (ROTSAC). In addition, peripheral blood pressure (BP, Coda), aortic pulse wave velocity (aPWV, Vevo2100), and echocardiography (Vevo2100) were measured in vivo . (Data are represented as mean±SEM) Results: L-NAME treated mice display fast-onset aortic stiffening after 1-week L-NAME (Fig. A, B), followed by the development of peripheral hypertension (Fig. C) and cardiac disease (Fig. D-F) after 4-weeks L-NAME. Ex vivo aorta studies reveal different stages of disease. Early on (1-4 weeks), mice show elevated phenylephrine (PE) contractions (Fig. G) and impaired acetylcholine (ACh) relaxations (Fig. H), consistent with L-NAME related ED. After 8 weeks, endothelial function and PE contractions normalize. Relaxations to exogenous NO remain unaltered (Fig. I). In contrast to the recovery of ACh relaxations, stiffness analysis in the ROTSAC reveals constantly reduced basal NO levels (Fig. J), and a late-term shift (16 weeks) towards vascular smooth muscle cell (VSMC) disease. This involves basal cytoplasmic calcium loading (Fig. K) and a sharply increasing contribution of voltage-gated calcium channels (Fig. L). Conclusions: NOS inhibition by L-NAME treatment causes a distinct time-dependent aortic disease phenotype, underlying fast-onset arterial stiffening which precedes peripheral hypertension and cardiac disease.

Development of Lidocaine-Loaded Dissolving Microneedle for Rapid and Efficient Local Anesthesia

Lidocaine is a local anesthetic agent used in the form of injection and topical cream. However, these formulation types have limitations of being either painful or slow-acting, thereby hindering effective and complete clinical performance of lidocaine. Dissolving microneedles (DMNs) are used to overcome these limitations owing to their fast onset time and minimally invasive administration methods. Using hyaluronic acid and lidocaine to produce the drug solution, a lidocaine HCl encapsulated DMN (Li-DMN) was fabricated by centrifugal lithography. The drug delivery rate and local anesthetic quality of Li-DMNs were evaluated using the pig cadaver insertion test and Von Frey behavior test. Results showed that Li-DMNs could deliver sufficient lidocaine for anesthesia that is required to be utilized for clinical level. Results from the von Frey test showed that the anesthetic effect of Li-DMNs was observed within 10 min after administration, thus confirming fast onset time. A toxicity test for appropriate clinical application standard was conducted with a microbial limit test and an animal skin irritation test, showing absence of skin irritation and irritation-related microorganisms. Overall, Li-DMN is a possible alternative drug delivery method for local anesthesia, meeting the requirements for clinical conditions and overcoming the drawbacks of other conventional lidocaine administration methods.