Minimal effects after a massive intravenous terbutaline overdose in a child.

A 22-kg female in early childhood with a history of reactive airway disease presented to a paediatric emergency department with acute shortness of breath, tachypnoea and wheezing. Despite treatment with albuterol and corticosteroids, her bronchospasm persisted, prompting the administration of terbutaline. The patient received 220 mcg (10 mcg/kg) terbutaline intravenously, followed immediately by an inadvertent supratherapeutic intravenous dose of 10 000 mcg (454.5 mcg/kg). The patient's laboratory results obtained minutes after the medication error were notable for: potassium, 3.1 mmol/L, lactate, 2.6 mmol/L and troponin I, 0.30 ng/mL (normal <0.03 ng/mL). Over the next 48 hours, serial serum troponin values decreased. The patient was discharged home approximately 72 hours after the initial presentation and she remained well based on follow-up calls over the next several months. Given the timing and trend of troponin concentrations, we do not believe the terbutaline overdose to be responsible for the myocardial injury.

The use of injectable subcutaneous terbutaline and topical nitroglycerin ointment in the treatment of peripheral vasopressor extravasation in 3 dogs.

OBJECTIVE: To describe the clinical course and treatment of 3 dogs with peripheral vasopressor extravasation. CASE SERIES SUMMARY: Although vasopressor extravasation (VE) is a well-documented complication in human medicine, literature describing VE and its management in veterinary patients is sparse. VE increases patient morbidity by causing local tissue injury and necrosis. The gold standard treatment for VE, phentolamine, has been periodically limited in supply in human medicine and is not consistently available for use in veterinary medicine. An alternative protocol proposed for use in people with VE combines topical nitroglycerin application with subcutaneous terbutaline infiltration. In this report, a treatment protocol utilizing these therapies was used to treat 3 dogs with VE and secondary tissue injury. NEW OR UNIQUE INFORMATION PROVIDED: This report describes 3 cases of VE-induced tissue injury in dogs. In addition, this report describes the use of perivascular terbutaline infiltration and topical nitroglycerin application as therapeutic management for VE in dogs.

Azithromycin sequential therapy plus inhaled terbutaline for Mycoplasma Pneumoniae pneumonia in children: a systematic review and meta-analysis.

BACKGROUND: An improper host immune response to Mycoplasma pneumoniae generates excessive inflammation, which leads to the impairment of pulmonary ventilation function (PVF). Azithromycin plus inhaled terbutaline has been used in the treatment of Mycoplasma pneumoniae pneumonia (MPP) in children with impaired pulmonary function, but previous randomized controlled trials (RCTs) showed inconsistent efficacy and safety. This study is aimed to firstly provide a systematic review of the combined therapy. METHODS: This study was registered at the International Prospective Register of Systematic Reviews (PROSPERO CRD42023452139). A PRISMA-compliant systematic review and meta-analysis was performed. Six English and four Chinese databases were comprehensively searched up to June, 2023. RCTs of azithromycin sequential therapy plus inhaled terbutaline were selected. The revised Cochrane risk of bias tool for randomized trials (RoB2) was used to evaluate the methodological quality of all studies, and meta-analysis was performed using Stata 15.0 with planned subgroup and sensitivity analyses. Publication bias was evaluated by a funnel plot and the Harbord' test. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation recommendations. RESULTS: A total of 1,938 pediatric patients from 20 RCTs were eventually included. The results of meta-analysis showed that combined therapy was able to significantly increase total effectiveness rate (RR = 1.20, 95%CI 1.15 to 1.25), forced expiratory volume in one second (SMD = 1.14, 95%CIs, 0.98 to 1.29), the ratio of forced expiratory volume in one second/forced vital capacity (SMD = 2.16, 95%CIs, 1.46 to 2.86), peak expiratory flow (SMD = 1.17, 95%CIs, 0.91 to 1.43). The combined therapy was associated with a 23% increased risk of adverse reactions compared to azithromycin therapy alone, but no significant differences were found. Harbord regression showed no publication bias (P = 0.148). The overall quality of the evidence ranged from moderate to very low. CONCLUSIONS: This first systematic review and meta-analysis suggested that azithromycin sequential therapy plus inhaled terbutaline was safe and beneficial for children with MPP. In addition, the combined therapy represented significant improvement of PVF. Due to lack of high-quality evidence, our results should be confirmed by adequately powered RCTs in the future.

Effect of Humidified High-Flow Nasal Cannula Oxygen Therapy with a Pulmonary Infection Control Window as a Ventilation Switching Indication in Combination with Atomizing Inhalation of Terbutaline on the Lung Function of Patients with Acute Exacerbation of COPD.

We investigated how humidified high-flow nasal cannula oxygen therapy (HFNC) with a pulmonary infection control (PIC) window as a ventilation switching indication in combination with atomizing inhalation of terbutaline affects the lung function of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We examined 140 hospitalized AECOPD patients randomized to control and observation groups. Conventional supportive therapy and invasive mechanical ventilation with tracheal intubation were conducted in both groups, with a PIC window as the indication for ventilation switching. Noninvasive positive pressure ventilation (NIPPV) plus atomizing inhalation of terbutaline was used in the control group. In the observation group, HFNC combined with atomizing inhalation of terbutaline was used. Compared to the control group, after 48-hr treatment and treatment completion, the observation group had significantly increased levels of lung function indicators (maximal voluntary ventilation [MVV] plus forced vital capacity [FVC], p<0.05) and oxygen metabolism indicators (arterial oxygen partial pressure [PaO2], arterial oxygen content [CaO2], and oxygenation index, p<0.05). The comparison of the groups revealed that the levels of airway remodeling indicators (matrix metalloproteinase-2 [MMP-2], tissue inhibitor of metalloproteinase 2 [TIMP-2] plus MMP-9) and inflammatory indicators (interferon gamma [IFN-γ] together with interleukin-17 [IL-17], IL-10 and IL-4) were significantly lower after 48 h of treatment as well as after treatment completion (both p<0.05). These results demonstrate that HFNC with a PIC window as the indication for ventilation switching combined with atomizing inhalation of terbutaline can relieve the disorder of oxygen metabolism and correct airway hyper-reactivity.

Comparison of terbutaline and atosiban as tocolytic agents in intrauterine repair of myelomeningocele: a retrospective cohort study.

BACKGROUND: Myelomeningocele (MMC) is a neural tube defect disease. Antenatal repair of fetal MMC is an alternative to postnatal repair. Many agents can be used as tocolytics during the in utero fetal repair such as ß2-agonists and oxytocin receptor antagonists, with possible maternal and fetal repercussions. This study aims to compare maternal arterial blood gas analysis between terbutaline or atosiban, as tocolytic agents, during intrauterine MMC repair. METHODS: Retrospective cohort study. Patients were divided into two groups depending on the main tocolytic agent used during intrauterine MMC repair: atosiban (16) or terbutaline (9). Maternal arterial blood gas samples were analyzed on three moments: post induction (baseline, before the start of tocolysis), before extubation, and two hours after the end of the surgery. RESULTS: Twenty-five patients were included and assessed. Before extubation, the terbutaline group showed lower arterial pH (7.347 ± 0.05 vs. 7.396 ± 0.02 for atosiban, p = 0.006) and higher arterial lactate (28.33 ± 12.76 mg.dL-1 vs. 13.06 ± 6.35 mg.dL-1, for atosiban, p = 0.001) levels. CONCLUSIONS: Patients who received terbutaline had more acidosis and higher levels of lactate, compared to those who received atosiban, during intrauterine fetal MMC repair.

Ambulatory electrocardiography, heart rate variability, and pharmacologic stress testing in cats with subclinical hypertrophic cardiomyopathy.

The utility of ambulatory electrocardiography (AECG) to evaluate cats with subclinical hypertrophic cardiomyopathy (HCM) for arrhythmias and heart rate variability (HRV) is not well defined but may provide information regarding risk stratification. This prospective study used AECG to evaluate ectopy and HRV in subclinical HCM cats compared to healthy controls and is the first to implement a pharmacologic cardiac stress test. Twenty-three purpose-bred, Maine coon cross cats (16 HCM, 7 control) underwent 48-h of continuous AECG. Terbutaline (0.2-0.3 mg/kg) was administered orally at 24 and 36 h. Heart rate, ectopy frequency and complexity and HRV parameters, including standard deviation of normal R-R intervals (SDNN), were compared pre-terbutaline and post-terbutaline and across phenotype, genotype and sex. Genotype for an HCM-causative mutation was significantly associated with the frequency of supraventricular (P = 0.033) and ventricular (P = 0.026) ectopy across all cats. Seven HCM cats and zero healthy cats had a sinus arrhythmia. Mean heart rate was significantly higher post-terbutaline (p < 0.0001). HCM cats had significantly greater HRV compared to controls (SDNN: p = 0.0006). Male cats had significantly higher HRV (SDNN: p = 0.0001) and lower mean heart rates (p = 0.0001). HRV decreased post-terbutaline (SDNN: p = 0.0008) and changes in HRV observed between sexes were attenuated by terbutaline.

[Effect of Storage of Tulobuterol Tapes after Package Opening and Liner Peeling on Their Formulation Properties].

Although tulobuterol tape is provided to patients in an inner package, information regarding the stability of the tape after opening the packaging may be requested by patients. This study was performed to generate underlying data on the storage stability after package opening or liner peeling with package opening. Tulobuterol tapes were stored at 25℃, 60% relative humidity (RH); 40℃, 75%RH; or in a refrigerator (2-4℃, 10-30%RH) for 1 day or 3 days. In a peel adhesive strength test after package opening, storage at 25℃, 60%RH had a low effect on the adhesive strength of the tape. Storage after liner peeling with package opening resulted in variable adhesive strength of the tape. Regarding drug release properties, for storage after package opening, the f2 values of tapes stored in the three different conditions were over 50, except for tapes stored at 25℃, 60%RH for 3 days. For the tapes stored at 25℃, 60%RH or 40℃, 75%RH after liner peeling with package opening, the release rate and the ratio of drug released at 24 h may be decreased because the drug content decreased due to drug sublimation. This study suggested that tulobuterol tapes can be stored after package opening at 25℃, 60%RH for 1 d.

Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma.

BACKGROUND: Asthma affects 350 million people worldwide including 45% to 70% with mild disease. Treatment is mainly with inhalers containing beta2-agonists, typically taken as required to relieve bronchospasm, and inhaled corticosteroids (ICS) as regular preventive therapy. Poor adherence to regular therapy is common and increases the risk of exacerbations, morbidity and mortality. Fixed-dose combination inhalers containing both a steroid and a fast-acting beta2-agonist (FABA) in the same device simplify inhalers regimens and ensure symptomatic relief is accompanied by preventative therapy. Their use is established in moderate asthma, but they may also have potential utility in mild asthma. OBJECTIVES: To evaluate the efficacy and safety of single combined (fast-onset beta2-agonist plus an inhaled corticosteroid (ICS)) inhaler only used as needed in people with mild asthma. SEARCH METHODS: We searched the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 19 March 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over trials with at least one week washout period. We included studies of a single fixed-dose FABA/ICS inhaler used as required compared with no treatment, placebo, short-acting beta agonist (SABA) as required, regular ICS with SABA as required, regular fixed-dose combination ICS/long-acting beta agonist (LABA), or regular fixed-dose combination ICS/FABA with as required ICS/FABA. We planned to include cluster-randomised trials if the data had been or could be adjusted for clustering. We excluded trials shorter than 12 weeks. We included full texts, abstracts and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We analysed dichotomous data as odds ratios (OR) or rate ratios (RR) and continuous data as mean difference (MD). We reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence. Primary outcomes were exacerbations requiring systemic steroids, hospital admissions/emergency department or urgent care visits for asthma, and measures of asthma control. MAIN RESULTS: We included six studies of which five contributed results to the meta-analyses. All five used budesonide 200 µg and formoterol 6 µg in a dry powder formulation as the combination inhaler. Comparator fast-acting bronchodilators included terbutaline and formoterol. Two studies included children aged 12+ and adults; two studies were open-label. A total of 9657 participants were included, with a mean age of 36 to 43 years. 2.3% to 11% were current smokers. FABA / ICS as required versus FABA as required Compared with as-required FABA alone, as-required FABA/ICS reduced exacerbations requiring systemic steroids (OR 0.45, 95% CI 0.34 to 0.60, 2 RCTs, 2997 participants, high-certainty evidence), equivalent to 109 people out of 1000 in the FABA alone group experiencing an exacerbation requiring systemic steroids, compared to 52 (95% CI 40 to 68) out of 1000 in the FABA/ICS as-required group. FABA/ICS as required may also reduce the odds of an asthma-related hospital admission or emergency department or urgent care visit (OR 0.35, 95% CI 0.20 to 0.60, 2 RCTs, 2997 participants, low-certainty evidence). Compared with as-required FABA alone, any changes in asthma control or spirometry, though favouring as-required FABA/ICS, were small and less than the minimal clinically-important differences. We did not find evidence of differences in asthma-associated quality of life or mortality. For other secondary outcomes FABA/ICS as required was associated with reductions in fractional exhaled nitric oxide, probably reduces the odds of an adverse event (OR 0.82, 95% CI 0.71 to 0.95, 2 RCTs, 3002 participants, moderate-certainty evidence) and may reduce total systemic steroid dose (MD -9.90, 95% CI -19.38 to -0.42, 1 RCT, 443 participants, low-certainty evidence), and with an increase in the daily inhaled steroid dose (MD 77 µg beclomethasone equiv./day, 95% CI 69 to 84, 2 RCTs, 2554 participants, moderate-certainty evidence). FABA/ICS as required versus regular ICS plus FABA as required There may be little or no difference in the number of people with asthma exacerbations requiring systemic steroid with FABA/ICS as required compared with regular ICS (OR 0.79, 95% CI 0.59 to 1.07, 4 RCTs, 8065 participants, low-certainty evidence), equivalent to 81 people out of 1000 in the regular ICS plus FABA group experiencing an exacerbation requiring systemic steroids, compared to 65 (95% CI 49 to 86) out of 1000 FABA/ICS as required group. The odds of an asthma-related hospital admission or emergency department or urgent care visit may be reduced in those taking FABA/ICS as required (OR 0.63, 95% CI 0.44 to 0.91, 4 RCTs, 8065 participants, low-certainty evidence). Compared with regular ICS, any changes in asthma control, spirometry, peak flow rates (PFR), or asthma-associated quality of life, though favouring regular ICS, were small and less than the minimal clinically important differences (MCID). Adverse events, serious adverse events, total systemic corticosteroid dose and mortality were similar between groups, although deaths were rare, so confidence intervals for this analysis were wide. We found moderate-certainty evidence from four trials involving 7180 participants that FABA/ICS as required was likely associated with less average daily exposure to inhaled corticosteroids than those on regular ICS (MD -154.51 µg/day, 95% CI -207.94 to -101.09). AUTHORS' CONCLUSIONS: We found FABA/ICS as required is clinically effective in adults and adolescents with mild asthma. Their use instead of FABA as required alone reduced exacerbations, hospital admissions or unscheduled healthcare visits and exposure to systemic corticosteroids and probably reduces adverse events. FABA/ICS as required is as effective as regular ICS and reduced asthma-related hospital admissions or unscheduled healthcare visits, and average exposure to ICS, and is unlikely to be associated with an increase in adverse events. Further research is needed to explore use of FABA/ICS as required in children under 12 years of age, use of other FABA/ICS preparations, and long-term outcomes beyond 52 weeks.

Detecting asthma exacerbations using daily home monitoring and machine learning.

OBJECTIVE: Acute exacerbations contribute significantly to the morbidity of asthma. Recent studies have shown that early detection and treatment of asthma exacerbations leads to improved outcomes. We aimed to develop a machine learning algorithm to detect severe asthma exacerbations using easily available daily monitoring data. METHODS: We analyzed daily peak expiratory flow and symptom scores recorded by participants in the SAKURA study (NCT00839800), an international multicentre randomized controlled trial comparing budesonide/formoterol as maintenance and reliever therapy versus budesonide/formoterol maintenance plus terbutaline as reliever, in adults with persistent asthma. The dataset consisted of 728,535 records of daily monitoring data in 2010 patients, with 576 severe exacerbation events. Data post-processing techniques included normalization, standardization, calculation of differences or slopes over time and the use of smoothing filters. Principal components analysis was used to reduce the large number of derived variables to a smaller number of linearly independent components. Logistic regression, decision tree, naïve Bayes, and perceptron algorithms were evaluated. Model accuracy was assessed using stratified cross-validation. The primary outcome was the detection of exacerbations on the same day or up to three days in the future. RESULTS: The best model used logistic regression with input variables derived from post-processed data using principal components analysis. This had an area under the receiver operating characteristic curve of 0.85, with a sensitivity of 90% and specificity of 83% for severe asthma exacerbations. CONCLUSION: Asthma exacerbations may be detected using machine learning algorithms applied to daily self-monitoring of peak expiratory flow and asthma symptoms.

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.

Serotonin Syndrome Following Terbutaline Administration in a Heart Transplant Patient on Multiple Inotropic Agents: A Case Report.

The significance of serotonin syndrome due to drug-drug interactions has emerged as a prominent consideration when the effects of polypharmacy are reviewed. The emergence of the selective serotonin reuptake inhibitors has most likely fueled the increased reporting of serotonin syndrome in the literature, leading to increased awareness of this phenomenon. However, their presence is not necessarily inclusive to a case and the utilization of agents precipitating an occurrence may be unavoidable. We report a case of serotonin syndrome occurring in a heart transplant patient without the presence of any of the usual suspect agents involved. In the postoperative course, the patient developed cardiogenic shock with vasoplegia requiring continuation of inotropic therapy along with vasopressor support of epinephrine. Oral terbutaline was begun for hemodynamic improvement. The patient's tenuous mental status rapidly deteriorated after addition of the terbutaline, with symptoms consistent with serotonin syndrome. Administration of cyproheptadine, a known reversal agent for serotonin toxicity, rapidly alleviated the adverse symptoms.

Outcomes following acute tocolysis prior to emergency caesarean section.

AIM: To determine if a policy recommending administration of terbutaline prior to emergency caesarean section improved arterial umbilical cord pH. MATERIALS AND METHODS: This was a prospective audit between February 2018 and June 2019 among women who underwent a category one or two caesarean section. Neonatal cord gas results and perinatal outcomes were compared before and after the introduction of a policy recommending subcutaneous terbutaline prior to emergency caesarean section. RESULTS: Among 423 women in the pre-policy change cohort and 253 post-policy change, there was no difference in arterial cord pH (median pH = 7.24 before the policy and median pH = 7.24 after the policy was introduced, P = 0.88). There was no statistically significant difference in any perinatal outcome, apart from the median arterial cord lactate which was higher in the post-treatment group (4.2 mmol/L vs 3.9 mmol/L, P = 0.006). Maternal heart rate was higher (median 110 vs 95, P < 0.0001) in the post-treatment group. Breastfeeding was more common in the post-treatment group (99% vs 95%, P = 0.005). There was no difference in estimated blood loss or rate of post-partum haemorrhage. A post hoc analysis according to treatment received, limited to caesarean section when the indication was suspected fetal compromise, demonstrated that among women who received terbutaline the rate of low pH (<7.1) was 3.8% (5/130) when terbutaline was given, compared with 6.6% (18/272) when terbutaline was not given (χ21  = 1.3, P = 0.26). CONCLUSION: Changing our labour ward policy to recommending terbutaline prior to all category one and category two caesarean sections did not change arterial cord pH.

Cold Flow Evaluation in Transdermal Drug Delivery Systems by Measuring the Width of the Oozed Adhesive.

The objective of this study was to develop a simpler and more practical quantitative evaluation method of cold flow (CF) in transdermal drug delivery systems (TDDSs). CF was forcibly induced by loading a weight on a punched-out sample (bisoprolol and tulobuterol tapes). When the extent of CF was analyzed using the area of oozed adhesive as following a previously reported method, the CF profiles were looked different between the samples 12 mm in diameter subjected to a 0.5-kg weight and samples 24 mm in diameter subjected to a 2.0-kg weight despite an equal load per unit area (4.42 g/mm2). The width of oozed adhesive around the original sample was suggested to be an index that properly describes the relationship between the load per unit area and the extent of CF. Further, it was clarified that the average CF width over the entire circumference of the sample was the same whether the samples were round or square as long as the sample area and load were the same. We also observed a linear relationship between the CF width and the aspect ratio of oval and rectangular samples. These results indicated that the CF properties of typical TDDS products lacking CF-proof processing at the edges could be determined by testing samples cut from the product rather than the whole TDDS patch. The proposed width measuring method was simple and useful for optimizing the composition of the adhesive and for testing the quality of the product.

Comparison of Nitroglycerin and Terbutaline for External Cephalic Version in Women Who Received Neuraxial Anesthesia: A Retrospective Analysis.

External cephalic version is a technique that decreases the need for cesarean delivery in patients with breech presentation. Several techniques exist to increase the success of external cephalic version; however, there are no studies comparing different tocolytics in patients who also received neuraxial anesthesia. We, therefore, performed a review of 198 patients who presented for external cephalic version and compared their success rates based on the tocolytic medication utilized. The external cephalic version success rate for patients who received terbutaline was significantly higher than for those who received nitroglycerin (N [%]: 57 [65.6] terbutaline group versus 40 [36.0] nitroglycerin group; P < .001).

A novel nanogel loaded with chitosan decorated bilosomes for transdermal delivery of terbutaline sulfate: artificial neural network optimization, in vitro characterization and in vivo evaluation.

The objective of the present work was to formulate, optimize, and evaluate transdermal terbutaline sulfate (TBN)-loaded bilosomes (BLS) in gel, compared to conventional oral TBN solution and transdermal gel loaded with free TBN, aiming at evading the hepatic first-pass metabolism. A face-centered central composite design was adopted to observe the effects of different formulation variables on TBN-BLS, and artificial neural network (ANN) modeling was employed to optimize TBN-BLS. TBN-BLS were prepared by a thin film hydration method integrating soybean phosphatidylcholine and cholesterol as a lipid phase and sodium deoxycholate (SDC) as a surfactant with or without the coating of chitosan (CTS). After being subjected to physicochemical characterization, TBN-BLS were enrolled in a histopathological study and pharmacokinetic investigation in a rat model. The optimized TBN chitosan-coated bilosomes (TBN-CTS-BLS) were spherical vesicles (245.13 ± 10.23 nm) with adequate entrapment efficiency (65.25 ± 5.51%) and good permeation characteristics (340.11 ± 22.34 µg/cm2). The TBN-CTS-BLS gel formulation was well-tolerated with no inflammatory signs manifested upon histopathological evaluation. The pharmacokinetic study revealed that the optimized TBN-CTS-BLS formulation successively enhanced the bioavailability of TBN by about 2.33-fold and increased t1/2 to about 6.21 ± 0.24 h as compared to the oral solution. These findings support the prospect use of BLS as active and safe transdermal carrier for TBN in the treatment of asthma. Graphical Abstract.

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.

Effect of beta2 -adrenergic agonist and resistance training on maximal oxygen uptake and muscle oxidative enzymes in men.

While beta2 -adrenoceptor stimulation has been shown to increase lean mass and to alter metabolic properties of skeletal muscle, adaptations in muscle oxidative enzymes and maximal oxygen uptake ( V ˙ O2max ) in response to beta2 -adrenergic agonist treatment are inadequately explored in humans, particularly in association with resistance training. Herein, we investigated beta2 -adrenergic-induced changes in V ˙ O2max , leg and arm composition, and muscle content of oxidative enzymes in response to treatment with the selective beta2 -adrenergic agonist terbutaline with and without concurrent resistance training in young men. Forty-six subjects were randomized to 4 weeks of lifestyle maintenance (n = 23) or resistance training (n = 23). Within the lifestyle maintenance and resistance training group, subjects received daily terbutaline (8 × 0.5 mg) (n = 13) or placebo (n = 10) treatment. No apparent treatment by training interactions was observed during the study period. Terbutaline increased leg and arm lean mass with the intervention, whereas no treatment differences were observed in absolute V ˙ O2max and incremental peak power output (iPPO). Treatment main effects were observed for V ˙ O2 -reserve (P < .05), V ˙ O2max relative to body mass (P < .05), V ˙ O2max relative to leg lean mass (P < .01), and iPPO relative to leg lean mass, in which terbutaline had a negative effect compared with placebo. Furthermore, content of electron transport chain complex I-V decreased by 11% (P < .05) for terbutaline compared with placebo. Accordingly, chronic treatment with the selective beta2 -adrenergic agonist terbutaline may negatively affect V ˙ O2max and iPPO in relative terms, but not in absolute.

Real-life effectiveness of inhaler device switch from dry powder inhalers to pressurized metred-dose inhalers in patients with asthma treated with ICS/LABA.

BACKGROUND AND OBJECTIVE: Mixed inhaler device use for asthma is associated with worse inhaler technique and outcomes. Given that relievers are commonly prescribed as pressurized metred-dose inhalers (pMDI), changing preventers from dry powder inhalers (DPI) to pMDI may improve asthma outcomes. This study aimed to assess the persistence and effectiveness of switching from DPI to pMDI for inhaled corticosteroid and long-acting ß2 -agonist combination therapy (ICS/LABA). METHODS: This was a historical cohort study using Ajou University Hospital (Korea) patient records. Persistence of switch was defined as receiving ≥1 pMDI and no DPI after the switch. Effectiveness of switch was assessed as the proportion without severe asthma exacerbation and the proportion achieving risk domain asthma control (RDAC; no asthma-related hospitalization, antibiotics without upper respiratory diagnosis or acute course of oral corticosteroids) and overall asthma control (OAC; RDAC and ≤ 200 µg salbutamol/≤500 µg terbutaline average daily dose) comparing 1 year after and before the switch. RESULTS: Within 85 patients who switched from DPI to pMDI and persisted for a year, higher proportion were free from asthma exacerbation after the switch (mean difference in proportion = 0.129, 95% CI: 0.038-0.220). Switching to pMDI was also associated with better RDAC (75.3% vs 57.7%, P = 0.001) and OAC (57.7% vs 45.9%, P = 0.021). From the entire 117 patients who switched to fixed-dose combination (FDC)/ICS LABA pMDI, 76.1% (95% CI: 69.0-100.0%) patients persisted in the following 6 months. CONCLUSION: Switching to and persisting with pMDI was associated with decreased asthma exacerbations and improved asthma control. The majority of patients persisted with the switch to pMDI for ICS/LABA treatment.

Astragalus membranaceus improves therapeutic efficacy of asthmatic children by regulating the balance of Treg/Th17 cells.

Astragalus membranaceus may be a potential therapy for childhood asthma but its driving mechanism remains elusive. The main components of A. membranaceus were identified by HPLC. The children with asthma remission were divided into two combination group (control group, the combination of budesonide and terbutaline) and A. membranaceus group (treatment group, the combination of budesonide, terbutaline and A. membranaceus). The therapeutic results were compared between two groups after 3-month therapy. Porcine peripheral blood mononuclear cells (PBMCs) were isolated from venous blood by using density gradient centrifugation on percoll. The levels of FoxP3, EGF-ß, IL-17 and IL-23 from PBMCs and serum IgE were measured. The relative percentage of Treg/Th17 cells was determined using flow cytometry. The main components of A. membranaceus were calycosin-7-O-glucoside, isoquercitrin, ononin, calycosin, quercetin, genistein, kaempferol, isorhamnetin and formononetin, all of which may contribute to asthma therapy. Lung function was significantly improved in the treatment group when compared with a control group (P < 0.05). The efficacy in preventing the occurrence of childhood asthma was higher in the treatment group than the control group (P < 0.05). The levels of IgE, IL-17 and IL-23 were reduced significantly in the treatment group when compared with the control group, while the levels of FoxP3 and TGF-ß were increased in the treatment group when compared with the control group (P < 0.05). A. membranaceus increased the percentage of Treg cells and reduced the percentage of Th17 cells. A. membranaceus is potential natural product for improving the therapeutic efficacy of combination therapy of budesonide and terbutaline for the children with asthma remission by modulating the balance of Treg/Th17 cells.