Combined uterorelaxant effect of magnesium sulfate and terbutaline: Studies on late pregnant rat uteri in vitro and in vivo.

INTRODUCTION: Preterm delivery and its complications are among the biggest challenges and health risks in obstetrical practice. Several tocolytic agents are used in clinical practice, although the efficacy and side effect profiles of these drugs are not satisfying. The aim of this study was to investigate the uterus relaxant effect of the coadministration of ß2 -mimetic terbutaline and magnesium sulfate (MgSO4 ) in an isolated organ bath and to perform in vivo smooth muscle electromyographic (SMEMG) studies in pregnant rats. In addition, we also investigated whether the tachycardia-inducing effect of terbutaline can be reduced by the presence of magnesium, due to the opposite heart rate modifying effects of the two agents. MATERIAL AND METHODS: In the isolated organ bath studies, rhythmic contractions of 22-day- pregnant Sprague-Dawley rats were stimulated with KCl, and cumulative dose-response curves were constructed in the presence of MgSO4 or terbutaline. The uterus-relaxing effects of terbutaline were also investigated in the presence of MgSO4 in both normal buffer and Ca2+ -poor buffer. The in vivo SMEMG studies were carried out under anesthesia with the subcutaneous implantation of an electrode pair. The animals were treated with MgSO4 or terbutaline alone or in combination in a cumulative bolus injection. The implanted electrode pair also detected the heart rate. RESULTS: Both MgSO4 and terbutaline reduced uterine contractions in vitro and in vivo, furthermore, the administration of a small dose of MgSO4 significantly enhanced the relaxant effect of terbutaline, especially in the lower range. However, in Ca2+ -poor environment, MgSO4 was not able to increase the effect of terbutaline, indicating the role of MgSO4 as a Ca2+ channel blocker. In the cardiovascular studies, MgSO4 significantly decreased the tachycardia-inducing effect of terbutaline in late pregnant rats. CONCLUSIONS: The combined application of MgSO4 and terbutaline may have clinical significance in tocolysis, which must be confirmed in clinical trials. Furthermore, MgSO4 could substantially reduce the tachycardia-inducing side effect of terbutaline.

Terbutaline for acute tocolysis prior to emergency caesarean delivery for suspected foetal compromise.

INTRODUCTION: Terbutaline has been used as a foetal resuscitation measure to improve the intrapartum foetal heart rate abnormalities and neonatal outcome for suspected foetal compromise. Unfortunately, till date, the available data are limited to draw any recommendation. MATERIAL AND METHODS: This was a double-blind, placebocontrolled trial conducted among women planned for emergent caesarean delivery for suspected foetal compromise where 100 were randomised to receive subcutaneous terbutaline or placebo. The primary outcomes were the neonatal acid-base status, while the 5- minute Apgar score, admission to the intensive care unit and the maternal outcomes were recorded as secondary outcomes. RESULTS: Data from a total of 96 women were analysed and showed a lower incidence of neonatal acidemia (4.4% vs 10.4%) and fewer neonates born with umbilical artery pH of less than 7.20 (12.5% vs 27.1%) and 7.10 (4.2% vs 6.2%) after terbutaline injection. However, the difference in the incidence of neonatal acidaemia, mean cord pH and base excess, Apgar score or admission to the intensive care unit did not differ significantly. No difference was seen in the maternal mean arterial pressure, estimated blood loss or haematocrit after the surgery between the study groups. The only significant maternal effect was tachycardia which was more common after terbutaline injection (54.2% vs 25.0 %, p=0.003). CONCLUSION: The study shows that acute tocolysis with subcutaneous terbutaline prior to caesarean delivery has the potential to improve the neonatal outcome in suspected intrauterine foetal compromise and should be further investigated.

Safety of SABA Monotherapy in Asthma Management: a Systematic Review and Meta-analysis.

INTRODUCTION: Short-acting ß2-agonist (SABA) reliever overuse is common in asthma, despite availability of inhaled corticosteroid (ICS)-based maintenance therapies, and may be associated with increased risk of adverse events (AEs). This systematic literature review (SLR) and meta-analysis aimed to investigate the safety and tolerability of SABA reliever monotherapy for adults and adolescents with asthma, through analysis of randomized controlled trials (RCTs) and real-world evidence. METHODS: An SLR of English-language publications between January 1996 and December 2021 included RCTs and observational studies of patients aged ≥ 12 years treated with inhaled SABA reliever monotherapy (fixed dose or as needed) for ≥ 4 weeks. Studies of terbutaline and fenoterol were excluded. Meta-analysis feasibility was dependent on cross-trial data comparability. A random-effects model estimated rates of mortality, serious AEs (SAEs), and discontinuation due to AEs (DAEs) for as-needed and fixed-dose SABA treatment groups. ICS monotherapy and SABA therapy were compared using a fixed-effects model. RESULTS: Forty-two studies were identified by the SLR for assessment of feasibility. Final meta-analysis included 24 RCTs. Too few observational studies (n = 2) were available for inclusion in the meta-analysis. One death unrelated to treatment was reported in each of the ICS, ICS + LABA, and fixed-dose SABA groups. No other treatment-related deaths were reported. SAE and DAE rates were < 4%. DAEs were reported more frequently in the SABA treatment groups than with ICS, potentially owing to worsening asthma symptoms being classified as an AE. SAE risk was comparable between SABA and ICS treatments. CONCLUSIONS: Meta-analysis of data from RCTs showed that deaths were rare with SABA reliever monotherapy, and rates of SAEs and DAEs were comparable between SABA reliever and ICS treatment groups. When used appropriately within prescribed limits as reliever therapy, SABA does not contribute to excess rates of mortality, SAEs, or DAEs.

Innovative pulmonary targeting of terbutaline sulfate-laded novasomes for non-invasive tackling of asthma: statistical optimization and comparative in vitro/in vivo evaluation.

Asthma represents a globally serious non-communicable ailment with significant public health outcomes for both pediatrics and adults triggering vast morbidity and fatality in critical cases. The ß2-adrenoceptor agonist, terbutaline sulfate (TBN), is harnessed as a bronchodilator for monitoring asthma noising symptoms. Nevertheless, the hepatic first-pass metabolism correlated with TBN oral administration mitigates its clinical performance. Likewise, the regimens of inhaled TBN dosage forms restrict its exploitation. Consequently, this work is concerned with the assimilation of TBN into a novel non-phospholipid nanovesicular paradigm termed novasomes (NVS) for direct and effective TBN pulmonary targeting. TBN-NVS were tailored based on the thin film hydration method and Box-Behnken design was applied to statistically optimize the formulation variables. Also, the aerodynamic pattern of the optimal TBN-NVS was explored via cascade impaction. Moreover, comparative pharmacokinetic studies were conducted using a rat model. TBN elicited encapsulation efficiency as high as 70%. The optimized TBN-NVS formulation disclosed an average nano-size of 223.89 nm, ζ potential of -31.17 mV and a sustained drug release up to 24 h. Additionally, it manifested snowballed in vitro lung deposition behavior in cascade impactor with a fine particle fraction of 86.44%. In vivo histopathological studies verified safety of intratracheally-administered TBN-NVS. The pharmacokinetic studies divulged 3.88-fold accentuation in TBN bioavailability from the optimum TBN-NVS versus the oral TBN solution. Concisely, the results proposed that NVS are an auspicious nanovector for TBN pulmonary delivery with integral curbing of the disease owing to target specificity.

The Impact of Terbutaline as Adjuvant Therapy in the Treatment of Severe Asthma in the Pediatric Emergency Department.

METHODS: Patients were identified using a retrospective cohort analysis from a single, tertiary care, urban children's hospital. Patients presenting directly to our emergency department aged 2 to 18 years were included if they had a diagnosis of severe asthma exacerbation, defined by an initial Respiratory Clinical Score (RCS) of 9 or higher. A total of 787 patients were identified during the study timeframe (December 16, 2017, to December 31, 2018), and of those, 651 patients met study criteria and were included in the analysis. The χ2 test was used to establish P values for categorical variables. For normally distributed variables, a t test was used. For nonnormally distributed variables, the Kruskal-Wallis test was used. A P value of 0.05 or less was interpreted as statistically significant. RESULTS: Patients who received terbutaline had an increased risk of admission to the PICU (P < 0.001). This association was lost after controlling for age, sex, continuous albuterol use, and intramuscular epinephrine use (P = 0.362). Patients receiving terbutaline in the emergency department also had a higher risk of admission to the hospital (odds ratio, 1.55; confidence interval, 1.08-2.22; P = 0.020) as compared with their nonterbutaline counterparts. Overall, patients in the terbutaline group had a higher initial RCS at presentation. Upon further analysis, patients with the same RCS at presentation were more likely to be admitted if they received terbutaline than those who did not. There was no statistically significant difference in length of stay (P = 0.298) and BiPAP/CPAP use (P = 0.107). The patients on terbutaline were relatively more likely to require oxygen (P = 0.003) and intramuscular epinephrine (P = 0.010) than the patients not on terbutaline. CONCLUSIONS: Terbutaline administration given to pediatric patients experiencing a severe asthma exacerbation was not associated with decreased PICU or general hospital floor admission. The study is limited given that it was a retrospective analysis. Further randomized controlled trials are needed to assess the role of terbutaline in severe acute asthma exacerbations in pediatric patients.

Efficacy and Safety of As-Needed Budesonide-Formoterol in Adolescents with Mild Asthma.

BACKGROUND: Medication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed short-acting beta2-agonists, similar to the reduction with maintenance budesonide. OBJECTIVE: This post hoc pooled analysis of Symbicort Given as-needed in Mild Asthma (SYGMA) 1 and 2 assessed the efficacy and safety of as-needed BUD-FORM in adolescents. METHODS: SYGMA 1 and 2 were 52-week, double-blind studies (NCT022149199; NCT02224157) in patients 12 years or older with mild asthma. Patients were randomized to twice-daily placebo + as-needed BUD-FORM 200/6 µg, twice-daily BUD 200 µg + as-needed terbutaline (BUD maintenance), or twice-daily placebo + as-needed terbutaline 0.5 mg (SYGMA 1 only). Annualized severe exacerbation rates, maintenance treatment adherence, and safety (including change in height) were compared between treatment groups in adolescents (aged ≥12 to <18 years). RESULTS: Severe exacerbation rate was similar with as-needed BUD-FORM and BUD maintenance (pooled analysis: 0.08 vs 0.07/y; P = .634), and was significantly lower with as-needed BUD-FORM versus as-needed terbutaline (SYGMA 1: 0.04 vs 0.17/y; P = .005). Median adherence was 73% in SYGMA 1 and 51% in SYGMA 2. Change in height from baseline in adolescents aged ≥12 years to <14 years was significantly greater with as-needed BUD-FORM (4.8 cm) versus BUD maintenance (3.9 cm) (pooled: P < .046), and was similar between as-needed BUD-FORM (4.5 cm) and as-needed terbutaline (4.1 cm) (SYGMA 1: P = .500). No new or unexpected safety concerns were identified. CONCLUSIONS: In adolescents with mild asthma, as-needed BUD-FORM was superior to as-needed terbutaline for severe exacerbation reduction, with similar efficacy to BUD maintenance. As-needed BUD-FORM provides an alternative treatment option for adolescents with mild asthma, without needing daily treatment.

Clinical value of N-acetylcysteine combined with terbutaline sulfate in elderly patients with chronic obstructive pulmonary disease and its effect on apoptosis/anti-apoptosis mechanism.

BACKGROUND: The pathogenesis of chronic obstructive pulmonary disease (COPD) is complex. Our study aimed to investigate the clinical value of N-acetylcysteine (NAC) combined with terbutaline sulfate in the treatment of COPD in elderly people, and its effect on the apoptosis/anti-apoptosis mechanism. METHODS: A total of 126 elderly COPD patients in our hospital from December 2017 to June 2019 were recruited and divided into 3 groups. On the basis of conventional treatment, control group A was treated with NAC, control group B with terbutaline sulfate, and combined group with both drugs. Lung function, apoptosis/anti-apoptosis related indexes, oxidative stress indexes, COPD assessment test (CAT) score, 6-min walk distance (6MWD), blood gas indexes, and adverse reactions were measured. RESULTS: The levels of forced vital capacity (FVC), maximum mid-expiratory flow rate (MMF), peak expiratory flow (PEF), oxygenation index (OI), and blood oxygen saturation (SaO2) in 3 groups were increased after treatment, and were the highest in the combined group. The level of carbon dioxide partial pressure (PaCO2) was decreased, and was the lowest in the combined group. After 2 weeks of treatment, the 6MWD had increased in all 3 groups and was longest in the combined group. The CAT score was decreased and the extent of decrease was the highest in the combined group. After treatment, the levels of Fas receptor/apoptosis antigen 1 (Fas/APO-1), soluble Fas (sFas), malondialdehyde (MDA), and reactive oxygen species (ROS) in the three groups were decreased, and their levels were decreased most markedly in the combined group. Meanwhile, the levels of superoxide dismutase (SOD) and glutathione peroxide enzyme (GSH-PX) were increased after treatment, and their levels were the highest in the combined group. The incidence of dizziness, chest tightness, constipation, and nasal congestion in the combination group were not significantly different from the other two groups. CONCLUSIONS: The combined use of terbutaline sulfate and NAC in the treatment of elderly patients with COPD can effectively improve their lung function and blood gas status, which can strengthen athletic ability, reduce the oxidative stress response, and regulate apoptotic cytokines.

Combination budesonide/formoterol inhaler as sole reliever therapy in Maori and Pacific people with mild and moderate asthma.

AIM: In the PRACTICAL study, as-needed budesonide/formoterol reduced the rate of severe exacerbations compared with maintenance budesonide plus as-needed terbutaline. In a pre-specified analysis we analysed the efficacy in Maori and Pacific peoples, populations with worse asthma outcomes. METHOD: The PRACTICAL study was a 52-week, open-label, parallel group, randomised controlled trial of 890 adults with mild to moderate asthma, who were randomised to budesonide/formoterol Turbuhaler 200/6mcg one actuation as required or budesonide Turbuhaler 200mcg one actuation twice daily and terbutaline Turbuhaler 250mcg two actuations as required. The primary outcome was rate of severe exacerbations. The analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable. RESULTS: Seventy-two participants (8%) identified as Maori, 36 participants (4%) as Pacific ethnicity. There was no evidence that ethnicity was an effect modifier for severe exacerbations (P interaction 0.70). CONCLUSION: The reduction in severe exacerbation risk with budesonide-formoterol reliever compared with maintenance budesonide was similar in Maori and Pacific adults compared with New Zealand European/Other.

What matters most to patients when choosing treatment for mild-moderate asthma? Results from a discrete choice experiment.

BACKGROUND: An as-needed combination preventer and reliever regimen was recently introduced as an alternative to conventional daily preventer treatment for mild asthma. In a subgroup analysis of the PRACTICAL study, a pragmatic randomised controlled trial of budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild asthma, we recently reported that about two-thirds preferred as-needed combination preventer and reliever therapy. The aim of this study was to determine the relative importance of attributes associated with these two asthma therapies in this subgroup of participants who indicated their preferred treatment in the PRACTICAL study. METHODS: At their final study visit, a subgroup of participants indicated their preferred treatment and completed a discrete choice experiment using the Potentially All Pairwise RanKings of all possible Alternatives method and 1000minds software. Treatment attributes and their levels were selected from measurable study outcomes, and included: treatment regimen, shortness of breath, steroid dose and likelihood of asthma flare-up. RESULTS: The final analysis dataset included 288 participants, 64% of whom preferred as-needed combination preventer and reliever. Of the attributes, no shortness of breath and lowest risk of asthma flare-up were ranked highest and second highest, respectively. However, the relative importance of the other two attributes varied by preferred therapy: treatment regimen was ranked higher by participants who preferred as-needed treatment than by participants who preferred maintenance treatment. CONCLUSIONS: Knowledge of patient preferences for treatment attributes together with regimen characteristics can be used in shared decision-making regarding choice of treatment for patients with mild-moderate asthma. TRIAL REGISTRATION NUMBER: ACTRN12616000377437.

Terbutaline and aminophylline as second-line therapies for status asthmaticus in the pediatric intensive care unit.

OBJECTIVE: Asthma is the most common chronic disease of childhood. Although asthma admissions to the pediatric intensive care unit (PICU) are increasing, there are no evidence-based guidelines on preferred escalation of therapies for patients with status asthmaticus who fail to respond to inhaled bronchodilators and systemic corticosteroids. The purpose of this study was to assess outcomes of PICU patients receiving aminophylline versus terbutaline as second-tier therapies for status asthmaticus. DESIGN: Retrospective cohort study using Pediatric Health Information System from 2016-2019. SETTING: Fifty-three tertiary children's hospitals. SUBJECTS: Children aged 2 to 18 years admitted to the PICU in children's hospitals contributing data to the Pediatric Health Information System with a primary diagnosis of status asthmaticus. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 11 133 pediatric patients treated for status asthmaticus in the PICU during the study period, 1144 received either terbutaline or aminophylline. There was no difference in intubation and mechanical ventilation between patients who received aminophylline and those who received terbutaline. However, in African American patients, those who received terbutaline had a significantly higher odds of intubation and mechanical ventilation compared to those who received aminophylline (OR, 12.41; 95%CI, 1.61,95). CONCLUSIONS: The use of aminophylline is associated with lower odds of intubation and mechanical ventilation in African American patients with status asthmaticus as compared to terbutaline.

Possible Propofol-Induced Priapism Following Cardiac Catheter Ablation in a Teenager.

BACKGROUND Priapism is rarely reported as a potential complication after the cardiac ablation procedure. We report the case of a teenager admitted for atrial flutter ablation who developed priapism following the procedure. CASE REPORT A 16-year-old male with episodic atrial flutter came to our hospital for an electrophysiological study and catheter ablation. During the procedure, he was given IV propofol for anesthesia and IV heparin for anticoagulation. After the procedure, nursing noted that he had an erection, which persisted for 5 h, with complaints of discomfort. There was no known history of sickle cell disease or trauma to the perineum, nor did he endorse any prior prolonged erections. On physical examination, he had a circumcised phallus with rigid and non-tender corpora cavernosa. He was given 5 mg terbutaline PO, without improvement. Three hours later, a second dose of terbutaline was given. In addition, a penis corporal venous blood gas was taken, and the result was consistent with an ischemic priapism. He had detumescence 1-2 min later. The total duration of his priapism was 8 h. There was no swelling, pain, or any sequelae after detumescence. CONCLUSIONS Although priapism rarely occurs as a complication following catheter ablation procedures due to propofol use, prolonged priapism can result in corporal fibrosis and cause future erectile dysfunction. Recognition and treatment of priapism in the postoperative period may be delayed due to a patient's hesitance to express concerns. To prevent future erectile dysfunction, signs of priapism should be included in routine postoperative evaluation in male patients.

DETECTION OF SKUNK ADENOVIRUS 1 IN TWO NORTH AMERICAN PORCUPINES (ERETHIZON DORSATUM) WITH RESPIRATORY DISEASE.

Adenoviruses have been reported to affect a broad range of host species, tend to be species specific, and often affect the respiratory system. This report describes the isolation of an adenovirus from deep nasal swabs of two wild North American porcupines (Erethizon dorsatum) with respiratory diseases that presented to a wildlife hospital. Partial sequences of the deoxyribonucleic acid polymerase gene of the isolated virus were identical to skunk adenovirus (SkAdV-1), also known as pygmy marmoset adenovirus. Both porcupines survived and were released back to the wild after successful medical treatment and rehabilitation. The significance of the adenovirus isolated from these porcupines is unknown; however, this is the first report of an adenovirus in porcupines, and the first report of SkAdV-1 in a rodent.

Response to bronchodilator and clinical, pathophysiological features in patients with nonasthmatic eosinophilic bronchitis.

INTRODUCTION: Whether nonasthmatic eosinophilic bronchitis (NAEB) shows response to bronchodilator (RB) remains unclear. OBJECTIVES: To investigate the RB and its relationship with clinical and pathophysiological features in NAEB. METHODS: Fifty-one patients with NAEB were assigned in a 2:1 ratio to receive oral bambuterol hydrochloride (n = 34, 10 mg, once daily, for 3 days) or matched placebo (n = 17) randomly, of whom 48 patients (32 with bronchodilator and 16 with placebo) completed the study. Sputum induction, spirometry and cough reflex sensitivity were measured. RB was considered when cough Visual analogue scale (VAS) score decreased 30% or more after treatment. Cough reflex sensitivity was defined as the lowest concentration of capsaicin inducing five coughings or more (C5), and presented as Log C5. RESULTS: The responsive rate of patients with bronchodilator was significantly higher than that with placebo (34.4% vs 6.3%, P < 0.05). The VAS score decreased significantly in patients with bronchodilator (median: 6.0-3.0, P < 0.01). There was a significantly higher median Log C5 (2.7 vs 1.3, P < 0.05), and a higher trend of decline in FEV1 % predicted and MMEF% predicted after bronchial provocation in patients with RB as compared with patients without RB. No significant differences in baseline percentages of sputum eosinophil were found between patients with RB and that without RB. CONCLUSIONS: One third of patients with NAEB respond well to bronchodilator treatment, which are related with lower cough reflex sensitivity and increased airway responsiveness. The relationship between NAEB and asthma needs to be investigated further.

Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial.

BACKGROUND: In adults with mild asthma, a combination of an inhaled corticosteroid with a fast-onset long-acting ß-agonist (LABA) used as reliever monotherapy reduces severe exacerbations compared with short-acting ß-agonist (SABA) reliever therapy. We investigated the efficacy of combination budesonide-formoterol reliever therapy compared with maintenance budesonide plus as-needed terbutaline. METHODS: We did a 52-week, open-label, parallel-group, multicentre, superiority, randomised controlled trial at 15 primary care or hospital-based clinical trials units and primary care practices in New Zealand. Participants were adults aged 18-75 years with a self-reported doctor's diagnosis of asthma who were using SABA for symptom relief with or without maintenance low to moderate doses of inhaled corticosteroids in the previous 12 weeks. We randomly assigned participants (1:1) to either reliever therapy with budesonide 200 µg-formoterol 6 µg Turbuhaler (one inhalation as needed for relief of symptoms) or maintenance budesonide 200 µg Turbuhaler (one inhalation twice daily) plus terbutaline 250 µg Turbuhaler (two inhalations as needed). Participants and investigators were not masked to group assignment; the statistician was masked for analysis of the primary outcome. Six study visits were scheduled: randomisation, and weeks 4, 16, 28, 40, and 52. The primary outcome was the number of severe exacerbations per patient per year analysed by intention to treat (severe exacerbations defined as use of systemic corticosteroids for at least 3 days because of asthma, or admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids). Safety analyses included all participants who had received at least one dose of study treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616000377437. FINDINGS: Between May 4, 2016, and Dec 22, 2017, we assigned 890 participants to treatment and included 885 eligible participants in the analysis: 437 assigned to budesonide-formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. Severe exacerbations per patient per year were lower with as-needed budesonide-formoterol than with maintenance budesonide plus terbutaline as needed (absolute rate per patient per year 0·119 vs 0·172; relative rate 0·69, 95% CI 0·48-1·00; p=0·049). Nasopharyngitis was the most common adverse event in both groups, occurring in 154 (35%) of 440 patients receiving as-needed budesonide-formoterol and 144 (32%) of 448 receiving maintenance budesonide plus terbutaline as needed. INTERPRETATION: In adults with mild to moderate asthma, budesonide-formoterol used as needed for symptom relief was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline. The findings support the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid-formoterol reliever therapy is an alternative regimen to daily low-dose inhaled corticosteroid for patients with mild asthma. FUNDING: Health Research Council of New Zealand.

Ventilation following established ARDS: a preclinical model framework to improve predictive power.

BACKGROUND: Despite advances in understanding the pathophysiology of acute respiratory distress syndrome, effective pharmacological interventions have proven elusive. We believe this is a consequence of existing preclinical models being designed primarily to explore biological pathways, rather than predict treatment effects. Here, we describe a mouse model in which both therapeutic intervention and ventilation were superimposed onto existing injury and explored the impact of ß-agonist treatment, which is effective in simple models but not clinically. METHODS: Mice had lung injury induced by intranasal lipopolysaccharide (LPS), which peaked at 48 hours post-LPS based on clinically relevant parameters including hypoxaemia and impaired mechanics. At this peak of injury, mice were treated intratracheally with either terbutaline or tumour necrosis factor (TNF) receptor 1-targeting domain antibody, and ventilated with moderate tidal volume (20 mL/kg) to induce secondary ventilator-induced lung injury (VILI). RESULTS: Ventilation of LPS-injured mice at 20 mL/kg exacerbated injury compared with low tidal volume (8 mL/kg). While terbutaline attenuated VILI within non-LPS-treated animals, it was ineffective to reduce VILI in pre-injured mice, mimicking its lack of clinical efficacy. In contrast, anti-TNF receptor 1 antibody attenuated secondary VILI within pre-injured lungs, indicating that the model was treatable. CONCLUSIONS: We propose adoption of a practical framework like that described here to reduce the number of ultimately ineffective drugs reaching clinical trials. Novel targets should be evaluated alongside interventions which have been previously tested clinically, using models that recapitulate the (lack of) clinical efficacy. Within such a framework, outperforming a failed pharmacologic should be a prerequisite for drugs entering trials.

Differential effects of inhaled R- and S-terbutaline in ovalbumin-induced asthmatic mice.

Inhaled terbutaline is commercially available ß2-agonist which consists of equivalent amount of R- and S-enantiomer. In this study, we aimed to investigate the effects of single enantiomers of terbutaline and its racemate in an ovalbumin (OVA)-induced mouse model of asthma via. seven days inhalation and the potential mechanisms involved. In a standard experimental asthma model, BALB/c mice were sensitized and challenged with OVA. R-terbutaline (R-ter), S-terbutaline (S-ter) or racemic terbutaline (rac-ter) was given via. nose-only inhalation for one week. Airway responsiveness to methacholine was measured by the plethysmography in conscious mice. Eosinophils counts in blood and bronchoalveolar (BAL) fluid were determined. The OVA-sIgE in plasma and inflammatory cytokines and mediators in BAL fluid or lung tissue were analyzed by ELISA, qRT-PCR or western blotting. Airway inflammation and remodeling were evaluated with hematoxylin and eosin (HE), periodic acid-Schiff (PAS), and Masson staining. Drug distribution and deposition after inhalation were determined by LC-MS/MS. Our data showed that R-ter efficiently ameliorated asthma responses, including airway hyperresponsiveness, eosinophils influx and IL-5 in BALF, plasma OVA-sIgE and significantly reduced pulmonary inflammation, peribronchial smooth muscle layer thickness, goblet cell hyperplasia, and deposition of collagen fibers, as well as downregulation of p38 MAPK phosphorylation and NF-κB expression. Racemic mixture exhibited diminished effects while S-ter enhanced airway responsiveness to methacholine and exerted pro-asthmatic effects.

Terbutaline alleviates the lung injury in the neonatal rats exposed to endotoxin: Potential roles of epithelial sodium channels.

Intrauterine inflammation generates inflammatory mediators that damage the developing bronchoalveolar epithelium, resulting in neonatal lung injury. Lung fluid transport disorders are the main reasons for the development of pulmonary edema, an important pathology of lung injury. Previous studies suggested that epithelial sodium channels (ENaCs) play an important role in lung fluid transport. Here, we investigated whether changes in the expression of ENaCs were observed when neonatal rat lung injury was induced by maternal exposure to endotoxin. We also examined the therapeutic effect of terbutaline nebulizer inhalation on this injury. The results showed that maternal exposure to endotoxin increased the levels of TNF-α and IL-1ß in bronchoalveolar lavage fluid, suppressed α-, ß-, γ-ENaC in the neonatal rat lung, and resulted in the formation of pulmonary edema on postnatal days 1 and 7. Terbutaline up-regulated the expression of ß- and γ-ENaC in the distal lung after 7 days of treatment. The potential signal molecules cAMP, PKA, and CREB expressions were increased after terbutaline treatment. In summary, maternal exposure to endotoxin decreased the expression of ENaCs in neonatal rats which, in turn, may exacerbate pulmonary edema. Inhalation of the ß2-adrenergic receptor agonist terbutaline improved lung liquid clearance. By increasing the expression of sodium ion channels, the effective removal of alveolar fluid provides a new way for the prevention and treatment of neonatal lung injury.