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In-depth research into the precise evaluation of enzymatic digestion efficiency and the selection of a suitable deuterium-labelled internal standard remains a gap in the accurate determination of β 2 -agonists in animal-derived food by isotope dilution-liquid chromatography/tandem mass spectrometry (ID-LC-MS/MS). In this study, the enzymatic digestion conditions were optimized by monitoring the presence of β 2 -agonist conjugates in positive samples, which proved to be reliable for ensuring complete enzymatic digestion. Comparative analysis of deuterium-labelled internal standards for salbutamol (SAL), ractopamine (RAC), and clenbuterol (CLB) revealed that CLB-D 6 and SAL-D 9 were less effective in compensating for matrix effects due to hydrogen‑deuterium exchange during MS fragment formation. Consequently, SAL-D 3 , RAC-D 3 and CLB-D 9 were chosen for the implementation of ID-LC-MS/MS. The developed method demonstrates high accuracy and precision, with the average recoveries ranging from 93.8% to 107.3% with RSD <6.1%, which can provide higher-order measurement results for β 2 -agonists in pork. [Display omitted] • A high-accuracy measurement procedure for β 2 -agonists in pork was established. • Enzymatic digestion was optimized via monitoring conjugates in positive sample. • Hydrogen‑deuterium exchange was found for CLB-D 6 and SAL-D 9 during MS fragmentation. • CLB-D 6 and SAL-D 9 were less effective in correcting for matrix effects for IDMS. • An ID-LC-MS/MS method was developed using appropriate 2H-labelled internal standards. [ABSTRACT FROM AUTHOR]

CMS are a heterogeneous group of disorders caused by mutations in genes that encode proteins essential for neuromuscular transmission. CMS are rare disorders of which DOK7 is one of the most common. DOK7 CMS typically presents with limb girdle weakness in early childhood and is associated with slowly progressive weakness over decades. Misdiagnosis is therefore not uncommon. We describe two patients who presented in adulthood but misdiagnosed with seronegative MG and treated as such over decades, with progressive weakness and seemingly immunosuppressant resistant disease. 57-year-old lady with a 25 year-history of seronegative MG manifest as proximal limb weakness and ptosis, transferred for consideration of rituximab in the setting of acute severe generalised MG requiring ICU, not responding to pyridostigmine, immunosuppression and rescue therapies. Specialist review including detailed history and clinical improvement on weaning pyridostigmine prompted genetic testing which confirmed DOK7 CMS. The patient was weaned off all immunosuppression and is improving on salbutamol treatment. 68-year-old gentleman with a 20 year-history of seronegative MG manifest as limb girdle weakness and ptosis, reviewed for second opinion following protracted hospital admission with severe generalised MG requiring gastrostomy and non-invasive ventilation, on a background of a 3-year decline. Poor response to multiple previous immunosuppressants and rescue therapies and prescribed rituximab, IVIG, prednisolone and pyridostigmine at time of assessment. Detailed history revealed ptosis present since early childhood and prompted genetic screening which confirmed DOK7 CMS. Pyridostigmine and immunotherapy weaned as salbutamol introduced with good effect. These cases highlight the importance of considering a CMS diagnosis in antibody negative myasthenia and the significance of taking an extensive early life and family history. Additional red flags include immunotherapy refractory disease or worsening with pyridostigmine. [ABSTRACT FROM AUTHOR]

Congenital myopathy is a heterogenous group of neuromuscular disorders, with no cure in the pipeline. Case reports describe potential effect with oral salbutamol. There is a lack of clinical trials proving this. We hypothesize that oral salbutamol improves muscle strength in congenital myopathy. We are currently running COMPIS (NCT05099107) a prospective, randomised-controlled study to test this theory. Here we report 3 independent cases of severe RYR1 myopathy treated outside the study. All three children were diagnosed and are followed at our site with severe autosomal recessive form of RYR1 myopathy. We present clinical, muscle morphological and genetic data, as well as their response to treatment with oral salbutamol. Two siblings with severe muscle weakness, gastrostomy for nutrition and tracheostomy with home ventilation, started salbutamol treatment at the ages of 8 and 3 years, respectively. Upon treatment, the older sibling started to lift his arms, control his neck and head, and developed small movements in his legs. The younger sibling with no voluntary movements before treatment, developed antigravitational movements in all extremities, opened her eyes and started to talk. The third patient had severe muscle weakness since birth with sparse voluntary movements, breathing and feeding difficulties. Salbutamol treatment was initiated at 3 months of age and currently at 11 months of age, she sits unassisted, roll over, swallow food, and has unaided respiratory function. We hypothesize that oral salbutamol increased muscle strength in these individuals, leading to obtained motor milestones. Our randomized-controlled study, expected to be completed in Q1 2025, is designed to further test this hypothesis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Developed a proof-of-concept scFv-based immunochromatographic (IAC) assay to detect a widely misused substance, salbutamol. • The IAC assay demonstrated the application of moderate-affinity antibodies for high-sensitivity detection platforms. Widespread misuse of salbutamol as an athletic performance enhancer and livestock growth promoter necessitates its detection in biological matrices. Antibodies remain important immunodiagnostic reagents in the detection of salbutamol. Previously, a novel anti-salbutamol chicken scFv (clone OP2B1C4) was generated from a SAL-KLH-immunized chicken antibody phage display library. This scFv (K D = ∼0.592 μM) was used to develop an indirect competitive (ic) ELISA capable of detecting salbutamol at the high ng/mL to low μg/mL levels for human doping urinalysis but was incapable of low ng/mL detection. In this study, the same scFv OP2B1C4 was used to develop a prototype immunoaffinity chromatographic (IAC) adsorbent for higher sensitivity applications. The scFv was immobilized on CNBr-activated Sepharose 4B and the scFv-IAC was profiled for its binding capacity and recovery. From three consecutive runs, estimated binding capacity was > 7 μg with elution recoveries of 59.43 %, 69.34 % and 73.8 %. When used as a clean-up SPE prior to LC-MS/MS analysis, the scFv-IAC could isolate salbutamol at a concentration of 1 ng/mL (∼100-fold lower than ic-ELISA LOD) in salbutamol-spiked porcine urines with relative recoveries ranging from 76.96 % − 99.85 %. The results highlight the potential of often-neglected moderate-affinity antibodies for high-sensitivity applications through extension onto IAC-based immunodiagnostic platforms. [ABSTRACT FROM AUTHOR]

• Novel paper-based MOF/MIPs chip strategy was successfully proposed by the boron-functionalized MOF as scaffold. • A new fluorescence strip detection of SAL can be accomplished within 30 min with the LOD as low as 0.095 μg kg-1. • The interaction between RhB and SAL was clarified and approved to be effective and applicable for fluorescence detection. Mimetic recognition materials for rapid and selective analysis of foodborne contamination from complex foodstuff becomes a hot research topic in the field of food safety. In this work, borate-affinity-functionalized MOF/molecularly imprinted polymer paper-based microfluidic chips (FSU-BA@MIP) were prepared by growing functionalized MOFs on paper surface with 3-carboxyphenylboronic acid (3-CPBA) as the ligands, followed by coating of a MIP layer of salbutamol (SAL) through a borate-affinity surface imprinting strategy. Using the obtained paper-based chip as a mimetic recognition and specific enrichment module, the fluorescence sensing platform achieved visual rapid quantitative analysis of SAL with a linear range of 0.1 × 10−2–5.0 mg L−1. The limits of detection and quantification were calculated to be 0.095 and 0.290 μg kg−1, respectively, and the sample loading via lateral flow aid could be completed within 30 min. The obtained MOFs/MIPs paper chips provide an effective way for the rapid analysis of harmful contaminants from different animal-derived foods. [ABSTRACT FROM AUTHOR]

Beta-2 agonists are the standard of care for asthmatic patients. Racemic albuterol and levalbuterol are two of the most commonly used bronchodilators in this category. Although their efficacy has been tested excessively, their effects on heart rate remain debatable in the medical literature. This review aims to summarize all available data in the literature concerning the effects of Racemic Albuterol versus Levalbuterol on heart rate in asthmatic children. Our search covered five different databases: PubMed, SCOPUS, Wiley Online Library, Web of Science, and Cochrane Library. We included clinical trials investigating heart rate in asthmatic pediatric patients, either as a primary or secondary outcome. The primary outcome was heart rate changes. Secondary outcomes were respiratory rate, FEV1 peak percent changes, potassium serum levels, SpO2 peak changes, asthma score, and adverse effects. Eight clinical trials were included; seven of them were eligible for meta-analysis. In a dosing ratio of levalbuterol: albuterol =1:4, levalbuterol showed better outcomes on heart rate changes when compared with racemic albuterol (mean difference = −5.97, p = 0.02). However, this difference was dose-dependent as it vanished with equivalent dosing of levalbuterol: albuterol = 1:2. Levalbuterol also had a better effect on FEV1 changes (mean difference = 3.72, p = 0.003). However, there was no statistically significant difference between the two drugs regarding changes in respiratory rate, SpO2, asthma score, or adverse effects. In conclusion, levalbuterol and racemic albuterol have almost the same effect on heart rate in asthmatic children when they are used in equivalent dosing. • Pharmacological and adverse effects of levalbuterol and racemic albuterol have been debatable in the literature. • The cardiac side effects of levalbuterol and racemic albuterol seem to be dose-dependent. • Levalbuterol and racemic albuterol have almost the same effects of heart rate when they are used in equivalent dose. [ABSTRACT FROM AUTHOR]

RationaleAlbuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.ObjectivesTo identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.MethodsWe performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.Measurements and main resultsWe identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P

BackgroundAsthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited.MethodsWe studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids.ResultsThe rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06).ConclusionsIn children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

BackgroundThere are limited data regarding the comparability of medication exposure information during pregnancy from maternal report and medical records, including for rheumatoid arthritis and asthma-related medications.MethodsThis study included pregnant women with rheumatoid arthritis (n = 216) and asthma (n = 172) enrolled in the MothertoBaby Pregnancy Studies (2009-2014). Women reported types and dates of medications used through semi-structured telephone interviews up to three times during pregnancy and once after delivery, and medical records were obtained. We calculated Cohen's kappa coefficients and 95% confidence intervals (CIs) and per cent agreement for agreement between report and records.ResultsFor rheumatoid arthritis, prednisone was reported most frequently (53%). During pregnancy, kappa coefficients for rheumatoid arthritis medications ranged from 0.32 (95% CI 0.15, 0.50) for ibuprofen, with 84.3% agreement, to 0.90 (95% CI 0.84, 0.96) for etanercept with 95.4% agreement, and was 0.44 (95% CI 0.33, 0.55) for prednisone, with 71.3% agreement. For asthma, albuterol was reported most frequently (77.9%). During pregnancy, kappa coefficients for asthma medications ranged from 0.21 (95% CI 0.08, 0.35), with 64.5% agreement for albuterol to 0.84 (95% CI 0.71, 0.96) for budesonide/formoterol, with 96.5% agreement. Where kappas for any use during pregnancy were less than excellent (i.e. ≤0.80), medication use was more frequently captured by report than record.ConclusionsAgreement was higher for medications typically used continuously than sporadically. Information on medication use from medical records alone may not be adequate when studying the impact of intermittently used medications during pregnancy on perinatal outcomes.

Introduction: Although bronchiolitis is a common reason for infant hospitalization, significant heterogeneity persists in its management. The American Academy of Pediatrics currently recommends that inhaled albuterol not be used in routine care of children with bronchiolitis. Our objective was to identify factors associated with pre-admission (e.g., emergency department or primary care) use of albuterol among infants hospitalized for bronchiolitis. Methods: We analyzed data from a 17-center observational study of 1,016 infants (age

Asthma is a common inflammatory disease of the lungs. The prevalence of asthma is increasing worldwide, and the tendency indicates that the number of asthma sufferers will soar in the coming years for several reasons, in particular, the lifestyles we have adopted that expose us to risk factors. Salbutamol is the first selective short-acting β2-agonist (SABA) used as an alternative reliever in the treatment of asthma. Its therapeutic effect is based on its potent smooth muscle relaxant properties, which allow the inhibition of bronchial smooth muscle contraction and subsequent bronchodilation. Salbutamol can be administered orally, intravenously (IV), intramuscularly (IM), subcutaneously, or by inhalation. For this reason, the pharmacokinetic (PK) parameters—absorption, distribution, metabolism, and elimination—are highly diverse and, consequently, the efficacy and adverse effects also differ between each formulation. Here, we review the pharmacological profile of different salbutamol formulations, focusing on their efficacy and adverse effects for its original application, asthma. [ABSTRACT FROM AUTHOR]

OBJECTIVES: A bronchiolitis integrated care pathway (BICP) proved useful in reducing the use of unnecessary medications at a local level. The aim of this study was to reduce overtreatment by scaling up the BICP across our regional health service in the 2019 and 2020 bronchiolitis season. METHODS: We conducted a quality improvement (QI) initiative in 115 primary care (PC) centers and 7 hospitals in the Basque Country, Spain, from October 2019 to March 2020. The primary outcome measure was the percentage of children prescribed salbutamol comparing the rate to that in the previous bronchiolitis season (October 2018--March 2019). Secondary outcomes were the use of other medications. Balancing measures were hospitalization and unscheduled return rates. RESULTS: We included 8153 PC visits, 3424 emergency department (ED) attendances, and 663 inpatient care episodes, of which 3817 (46.8%), 1614 (47.1%), and 328 (49.4%) occurred in the postintervention period, respectively. Salbutamol use decreased from 27.1% to 4.7%, 29.5% to 3.0%, and 44.4% to 3.9% (P < .001) in PC centers, Eds, and hospital wards, respectively. In PC, corticosteroid and antibiotic prescribing rates fell from 10.1% to 1.7% and 13.7% to 5.1%, respectively (P < .001). In EDs and hospital wards, epinephrine use rates fell from 14.2% to 4.2% (P < .001) and 30.4% to 19.8% (P = .001), respectively. No variations were noted in balancing measures. CONCLUSIONS: The scaling up of the BICP was associated with significant decreases in the use of medications in managing bronchiolitis across a regional health service without unintended consequences. [ABSTRACT FROM AUTHOR]

Background: Albuterol by inhalation (IH) is a common treatment for hyperkalemia in humans but its effect on blood potassium concentrations in dogs is unknown. Objective: Determine whether albuterol (IH) decreases blood potassium concentrations in healthy normokalemic dogs and if effects are dose‐dependent. Animals: Ten healthy dogs. Methods: Prospective, crossover experimental study. Albuterol sulfate was administered at a low‐dose (90 μg) in phase I and, 7 days later, high‐dose (450 μg) in phase II. Blood potassium and glucose concentrations (measured via blood gas analyzer) and heart rates were obtained at baseline and then 3, 5, 10, 15, 30, 60, 90, 120, 180, and 360 minutes after inhaler actuation. Results: Blood potassium concentrations decreased rapidly after albuterol delivery with a significant reduction compared to baseline within 30 minutes in both phases (P =.05). The potassium nadir concentration of phase I occurred at 60 minutes (mean, SD; 4.07 mmol/L, 0.4) and was significantly decreased from baseline, (4.30 mmol/L, 0.3; t(9) = 2.40, P =.04). The potassium nadir concentration of phase II occurred at 30 minutes (mean, SD; 3.96 mmol/L, 0.39) and was also significantly decreased from baseline, (4.33 mmol/L, 0.4; t(9) = 2.22, P =.05). The potassium nadir concentration decreased by 0.1 mmol/L for each 10 μg/kg increase in dose of albuterol (P =.01). Five dogs had ≥1 hyperglycemic measurement (ie, >112 mg/dL). No median heart rate was tachycardic nor was any mean blood glucose concentration hyperglycemic at any time point. Conclusion and Clinical Importance: Albuterol IH decreases blood potassium concentrations in a dose‐dependent manner without clinically meaningful alterations to heart rate or blood glucose concentrations in healthy dogs. The mean decrease in potassium concentration at the high‐dose of albuterol was modest (0.38 mmol/L). [ABSTRACT FROM AUTHOR]

BACKGROUND: Standardized acute asthma management with score-based, respiratory therapist (RT)--driven pathways and protocols improves outcomes including decreased length of stay (LOS) and time on continuous albuterol therapy. Limited data are available for the safety of continuous albuterol used outside of pediatric ICU (PICU). We use a modified pediatric asthma score (PAS) for the asthma pathway at our institution. The safety and effectiveness of using PAS to initiate/stop continuous albuterol as part of a score-based, RT-driven asthma pathway were evaluated. METHODS: A retrospective review of children ≥ 2 y admitted for asthma exacerbation to the PICU and step-down unit who received continuous albuterol as part of the asthma pathway during 2017-2019 was completed. Demographic and clinical data were extracted including PAS, dose and duration of continuous albuterol, LOS, and complications. Outcomes of subjects admitted to the PICU and step-down unit were compared. RESULTS: Results are expressed as median (interquartile range). The study included 412 children (61% male, 59.9% Black, 92.7% non-Hispanic, 44.9% moderate persistent asthma) with age and weight of 6.4 (4.0-10.0) y and 24.8 (17.3-39.5) kg, respectively. Most children were admitted to step-down unit (71.1%). Initial albuterol dose, duration, and LOS were 15 (10-20) mg/h, 9.1 (5.7-16.0) h, and 1.4 (0.9-2.3) d, respectively. Respiratory support was required by 29% of subjects. Need to restart therapy (2.9%), transfer to PICU (1.7%), and intubation (0.5%) were infrequent. No pneumothoraces or deaths were reported. Emergency department visits (3.9%) or readmissions (0.7%) within 30 d of discharge were low. Subjects admitted to the PICU were sicker and required more therapies and respiratory support than those admitted to the step-down unit. CONCLUSIONS: Use of an RT-driven, score-based pathway for initiation and discontinuation of continuous albuterol for treatment of pediatric asthma exacerbation was safe and effective in the PICU and step-down unit. [ABSTRACT FROM AUTHOR]

Background: There is inconclusive evidence on the role of nebulized magnesium sulphate (MgSO4) in the management of acute asthma in paediatric population.Objectives: Whether the use of nebulized salbutamol with or without MgSO4 in the management of acute asthma results in clinically significant improvement in lung function in Indian children? The primary outcome measure was to assess improvements in peak expiratory flow rate (PEFR), heart rate, respiratory rate and SpO2.Methods: This was a single centre; prospective double-blind randomized control trial conducted in paediatric intensive care unit of a tertiary care centre. Ninety children of 6-14 years with acute exacerbations of bronchial asthma were enrolled to receive either inhaled magnesium sulphate (95 mg) with salbutamol (5 mg) or inhaled salbutamol (5 mg) alone. All patients got three nebulizations done during the first hour at 20 min intervals, two nebulizations during the second hour at 30 min intervals, hourly for the next 2 h and then at 24 and 48 h.Results: Eighty-five patients were finally analysed as per protocol analysis. The trial showed that PEFR increased gradually in both groups over the study duration, but it was statistically not significant. Heart rate decreased significantly in both groups over the study duration. Respiratory rate decreased significantly between the groups at 24 and 48 h only. SpO2 improved too in both groups but was not significant statistically.Conclusion: The addition of nebulized MgSO4 to salbutamol does not seem to result in improvement in lung function in the management of acute asthma in Indian children. [ABSTRACT FROM AUTHOR]

Background: Suboptimal use of pressurized metered dose inhaler (pMDI) remains a major barrier to inhaled therapy success. Verbal inhaler technique training (VT) fails to maintain patients' good pMDI use, thus training tools might help. Trainhaler® (THR device) and Flo-Tone® CR (FTCR device), two novel pMDI technique training tools, were evaluated and compared in terms of relative lung and systemic bioavailability and oropharyngeal deposition of salbutamol inhaled from Ventolin® Evohaler® (GlaxoSmithKline) either alone following THR or connected to FTCR. Methods: Sixteen healthy adults inhaled 2 × 100 μg salbutamol puffs (1 minute apart) from Ventolin using the THR device or FTCR device in a two-period, randomized crossover study. A 7-day washout separated THR and FTCR approaches. Immediately after each puff inhalation, each subject gargled with 20 mL water for oropharyngeal deposition determination. Urine samples were collected 0.5 hour (pre-inhalation) and 0.5, 1.0, and 2.0 hours post-inhalation. Urine was then pooled till 24-hour post-inhalation. The relative lung bioavailability (0- to 0.5-hour urinary salbutamol excretion—USAL0.5) and relative systemic bioavailability (0- to 24-hour urinary excretion of salbutamol and its metabolite—USALMET24) were determined. Results: The mean (standard deviation [SD]) USAL0.5 of the THR and FTCR groups was 5.70 (6.43) and 11.39 (9.67) μg, respectively. The mean (SD) oropharyngeal deposition was 11.11 (4.37) and 6.09 (1.89) μg, respectively. The THR and FTCR devices were statistically significantly different in USAL0.5 and oropharyngeal deposition (p < 0.001), whereas there was no statistically significant difference in USALMET24. Conclusion: The THR device and the FTCR device showed positive impact on inhaled pMDI delivery. Indeed, the FTCR device doubled the relative lung bioavailability and minimized the unwanted oropharyngeal deposition of inhaled salbutamol. In practice, these pMDI trainers would complement and maintain VT. Study Registration: The study was registered on the ISRCTN registry (Reference: ISRCTN88332465-06/12/2017 [Prospectively Registered]). [ABSTRACT FROM AUTHOR]

[Display omitted] More than fifty years after the commercialization of the Ventolin metered-dose inhaler (MDI), its constituent active ingredient, salbutamol sulfate (SS), remains the most prescribed short-acting beta agonist for the first-line treatment of acute asthma attacks and the metered-dose inhaler remains its primary dosage form. The first generation of Ventolin MDI was developed at a time when environmental and regulatory concerns were less stringent than today. The MDI industry is now on the verge of a second major reformulation effort in response to environmental concerns. This paper serves to illustrate how modern computational modeling of molecular interactions can aid the reformulation process. By way of a case study, computational modeling was performed to compare poly(ethylene glycol) 400 (PEG400) and, separately, isopropyl myristate (IPM) as substitutes for the ethanol used in some generic salbutamol sulfate suspension-based hydrofluoroalkane MDIs. PEG400 and IPM were investigated as potential alternative cosolvents to ethanol in HFA134a-based SS suspension MDI formulations. Density functional theory (DFT) molecular dynamics simulations were used to evaluate the compatibility of the candidate cosolvents with the formulation's components. Corresponding physical formulations were filled into polyethylene terephthalate (PET) and, separately, aluminium canisters. In-vitro pharmaceutical product performance and macroscopic visual appearance were assessed and compared to the results of the simulation studies. The simulation studies indicated that PEG400 would be a good candidate as a replacement for ethanol whereas IPM would not. The in-vitro and visual assessments support the predicted outcome of the simulation studies. This work suggests that molecular dynamics simulations may provide a useful tool to aid the selection of compatible excipients when reformulating MDI suspension-based products, thereby reducing the time and cost associated with manufacturing and testing of physical samples. [ABSTRACT FROM AUTHOR]

Pediatric patients receiving respiratory support with heated flow nasal cannula (HFNC) systems frequently receive inhaled medications. Most available data have been obtained with vibrating mesh nebulizers that are expensive. Data are lacking regarding the feasibility of using less expensive devices such as continuous output jet nebulizers. The characteristics of the aerosols generated by jet nebulizers operated at different conditions (6 and 9 L/min) were studied alone and connected to a HFNC system and different size cannulas using a cascade impactor and spectrophotometry (276 nm). Aerosol characteristics changed while traveling through the HFNC system. Initial size selection occurred at the exit of the circuit (before connecting to the cannula) with all aerosol <5 µm. Nasal cannula size further selected aerosols and reduced drug delivery. The operating flow of the nebulizer did not affect the delivered mass but higher flows generated smaller particle size aerosols. The addition of supplemental flow significantly reduced the delivered mass. The measured aerosol characteristics would likely result in intrapulmonary deposition. The delivery of aerosolized albuterol generated by a continuous output nebulizer placed in the inlet of a HFNC system and connected to large or XXL cannulas is feasible. [ABSTRACT FROM AUTHOR]

Pediatric morbidity due to unintentional poison exposure is a significant burden on public health. We prospectively characterize patterns of unintentional poison exposure in a single pediatric emergency department, using a detailed computerized questionnaire for all unintentional injuries admitted during 2009 to 2017. Out of 71,765 visits due to unintentional injuries, 252 children were admitted due to unintentional poison exposure. Most (198/252, 79%) were between 1 and 3 years of age. The majority of events (209/252, 82.9%) occurred at the patient's home and 81% (205/255) were classified as exploratory ingestion. In 41/252 (14%) cases, exposure to more than one substance was reported. Most events 231/293 (79%) involved medications and 21% were due to domestic products. Four medications account for 45% of the events (Paracetamol, Salbutamol, Antihypertensive, and Antidepressants). Opioids were responsible for only 1.7%. By, collaboration between government, public health, educational institutions and commercial companies, can the burden of pediatric unintentional poison exposure be reduced. [ABSTRACT FROM AUTHOR]

Background: Paediatric asthma usually presents with acute exacerbation and requires hospital admission and emergency management. The objective of this study was to compare the peak expiratory flow rate (PEFR) with salbutamol plus ipratropium bromide versus salbutamol alone in acute asthma in children in Lahore, Pakistan. Material & Methods: This randomized controlled trial was undertaken at The Children’s Hospital and The Institute of Child Health, Lahore, Pakistan from 14-04-2017 to 17-10-2017. One hundred children with acute asthma with age 2-12 years were enrolled. Fifty patients each were randomly assigned to experimental and control groups by lottery method. At presentation, PEFR was measured by using a peak flow meter. Experimental group received three doses of 2.5 mg salbutamol and 500 mcg of ipratropium at 20 minutes intervals. Control group received three doses of 2.5 mg salbutamol alone. PEFR was again measured after 60 minutes. Results: Mean age in experimental group was 9.60±2.86 years, whereas it was 8.68±3.28 years in control group, almost similar. Mean weight in experimental group was 29.50±8.26 kg, whereas it was 28.24±10.07 kg in control group, almost similar. Baseline mean PEFR% was 43.18±4.25 in experimental, while it was 42.48±4.82 in control group. Mean PEFR% at 60 minutes after intervention was 82.88±7.54 in experimental, while it was 60.04±6.05 in control group. PEFR% was higher in experimental group showing its better effect than the control group (p<.00001). Conclusion: The peak expiratory flow rate was higher with salbutamol plus ipratropium bromide versus salbutamol alone in acute asthma in children in Lahore, Pakistan. [ABSTRACT FROM AUTHOR]

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6-Nitrodopamine (6-ND) is an endogenous modulator of the contractility in the rat isolated epididymal vas deferens (RIEVD) and considered to be the main peripheral mediator of the emission process. Use of selective and unselective β-adrenergic receptor antagonists has been associated with ejaculatory failure. Here, the effects of selective β1- and β1/β2-adrenergic receptor antagonists on RIEVD contractions induced by 6-ND, dopamine, noradrenaline, adrenaline, and electric-field stimulation (EFS) were investigated. The selective β1-adrenergic receptor antagonists atenolol (0.1 and 1 µM), betaxolol (1 µM), and metoprolol (1 µM) and the unselective β1/β2-adrenergic receptor antagonists propranolol (1 and 10 µM) and pindolol (10 µM) caused significant rightward shifts of the concentration–response curve to 6-ND (pA2 6.41, 6.91, 6.75, 6.47, and 5.74; for atenolol, betaxolol, metoprolol, propranolol, and pindolol), but had no effect on dopamine-, noradrenaline-, and adrenaline-induced contractions. The effects of selective β1- and β1/β2-adrenergic receptor antagonists at a higher concentration (atenolol 1 µM, betaxolol 1 µM, metoprolol 1 µM, propranolol 10 µM, and pindolol 10 µM) also reduced the EFS-induced RIEVD contractions in control, but not in RIEVD obtained from L-NAME-treated animals. The selective β1-adrenoceptor agonist RO-363, the selective β2-adrenoceptor agonist salbutamol, and the selective β3-adrenoceptor agonist mirabegron, up to 300 µM, had no effect on the RIEVD tone. The results demonstrate that β1- and β1-/β2-adrenoceptor receptor antagonists act as 6-ND receptor antagonists in RIEVD, further confirming the main role of 6-ND in the RIEVD contractility. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis and osteoarthritis overlap many molecular mechanisms of cartilage destruction. Wear and tear in cartilage is chondrocyte-mediated, where chondrocytes act both as effector and target cells. In current study, role ofβ2-AR was studied in chondrocytes both in vitro and in vivo. High grade inflammation in vitro and in vivo diseasemodels led to decline in anti-inflammatoryβ2-AR signaling and use of ß2-AR agonist attenuated arthritis symptoms. Detailed analysis in chondrocytes revealed that Isoprenaline (ISO) and Salbutamol (SBT) increased cell viability and relative Bcl-2 expression, meanwhile, decreased proteins levels of TNF-a, IL-6andIL-8 in arthritic chondrocytes when compared with control, respectively. SBT preserved physiological concentration of antioxidant enzymes (CAT, POD, SOD and GSH) in cartilage homogenates and ISO inhibited IL-1ß-mediated genotoxicity in arthritic chondrocytes. Moreover, β2-AR agonist increased mitochondrial biogenesis and proteoglycan biosynthesis by upregulating the gene expression of PGC1-a, NRF2 and COL2A1, Acan, respectively. ISO and SBT inhibited extracellular matrix (ECM) degradation by downregulating the gene expression of MMP1, MMP3, MMP9 and ADAMTS5 in vitro and in vivo study. In mechanism, β2-AR agonists decreasedβ-arrestin and GRK2 pathway, and as a resultmice receiving SBT did not exhibit severe disease. Hence our data suggestβ2-AR agonist administered at disease onset can inhibit receptor internalization by downregulating the expression ofβ-arrestin and GRK2 in chondrocytes. [ABSTRACT FROM AUTHOR]

Background: The circadian rhythm controls multiple biological processes, including immune responses; however, its impact on cutaneous adaptive immune response remains unclear. Methods: We used a well‐established cutaneous type IV allergy model, contact hypersensitivity (CHS). We induced CHS using dinitrofluorobenzene (DNFB). Mice were sensitized and elicited with DNFB in the daytime or at night. Results: In mice, a nocturnally active animal, we found that ear swelling increased when mice were sensitized at night compared with in the daytime. In addition, cell proliferation and cytokine production in the draining lymph nodes (LNs) were promoted when sensitized at night. We hypothesized that these differences were due to the oscillation of leukocyte distribution in the body through the circadian production of adrenergic hormones. Administration of a β2‐adrenergic receptor (β2AR) agonist salbutamol in the daytime decreased the number of immune cells in blood and increased the number of immune cells in LNs. In contrast, a β2AR antagonist ICI18551 administration at night increased the number of immune cells in blood and decreased the number of immune cells in LNs. Accordingly, the severity of CHS response was exacerbated by salbutamol administration in the daytime and attenuated by ICI18551 administration at night. Conclusion: Our study demonstrated that the magnitude of adaptive CHS response depends on the circadian rhythm and this knowledge may improve the management of allergic contact dermatitis (ACD) in humans. [ABSTRACT FROM AUTHOR]

Introduction: Despite the step-up step-down approach of asthma management suggested by the Global Initiative for Asthma (GINA), control of asthma continues to be poor. It was hypothesized that a new "Step-in Step-down approach" could prove to be a better alternative. The present study was carried out with the objective to assess the efficacy and adverse effects of this new approach in the control of asthma. Materials and Methods: All treatment-naïve asthma patients were randomly allocated to either Group I (patients received budesonide 400 µg + formoterol 6 µg twice daily via dry powder inhalation device along with as-needed salbutamol) or Group II (patients received stepwise treatment as per GINA guidelines, 2017). Patients were monitored on a fortnightly basis for control of symptoms, spirometry, and complications if any. Asthma Control Questionnaire (ACQ-7) was used to assess control of asthma. Adverse effects, if any, were recorded and managed appropriately. Step-down was attempted on achieving sustained control of asthma, i.e., ACQ score of <0.75 on two consecutive fortnight assessments in both the groups. In Group I patients, long-acting ß2-agonist was withdrawn first. Subsequently, a dose of budesonide was also reduced. In Group II patients, the treatment was decreased to the next lower step medicines as per the GINA guidelines. Results: After exclusions, a total of 787 patients were randomized to either Group I or II. The demographic profile of patients in the two groups was similar. Patients on "step-in step-down" approach had a statistically significant advantage over those on conventional step-up step-down approach in terms of (a) time to the first control (271 vs. 98 within first 4 weeks), (b) need for rescue steroids (two patients in Group 1 vs. 40 in Group 2), (c) number of exacerbations (30 vs. 232), and (d) use of rescue SABA (Only 30 patients in group I required > 5 inhalations per week as compared to all in group II). Adverse reactions were not observed in any of the patients in either group. Conclusion: We conclude that step-in step-down approach is a more robust and safer approach for control of asthma. [ABSTRACT FROM AUTHOR]

Background: Although studies on epileptic seizures occurring during acute asthma attacks are limited, there is widespread belief among families and physicians that salbutamol causes seizures. Aims: To investigate whether salbutamol triggers seizures in patients with epilepsy and asthma. Study Design: A retrospective cohort study. Methods: Epilepsy and asthma in patients aged 2-18 years who were admitted to the pediatric emergency department because of asthma attacks between January 2016 and December 2016 in a university hospital were evaluated retrospectively. The inclusion criteria were age 2-18 years, previous diagnosis of epilepsy and asthma, and admission to the pediatric emergency department due to asthma attacks. Results: 276 medical records were evaluated. The seizure group had a longer period of diagnosis for epilepsy than the seizure absent group in the pediatric emergency department (5.4 years and 3.1, respectively). According to the logistic regression analysis, the duration of seizures in the emergency department, duration of asthma diagnosis, duration of epilepsy diagnosis, uncontrolled asthma, and severity of asthma attack in the pediatric emergency department have significantly increased the possibility of having a seizure during an asthma attack in our study population. Conclusion: This study shows that patients using salbutamol have a lower risk of epileptic seizures than those who do not use salbutamol. This result should be verified by studies containing a large number of patients. [ABSTRACT FROM AUTHOR]