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.

Adsorption of terbutaline ß-agonists from wastewater by mechano-synthesized iron oxide nanoparticles modified copper (II) isonicotinate metal-organic framework.

Frequent detection of terbutaline in wastewater highlights its potential risks to human health associated in the environment. Exposure to terbutaline through contaminated water sources or food chain have adverse effects to human health. This work emphasized on the removal of terbutaline from wastewater using adsorption technology. Mechanochemically synthesized [Cu(INA)2] metal-organic frameworks (MOFs) and its magnetic composite ([Cu(INA)2]-MOF@Fe3O4) are designed with higher specific surface areas and tailored features to accommodate the molecular size and structure of terbutaline. Thus, batch experiment has been conducted using the [Cu(INA)2]-MOF and [Cu(INA)2]-MOF@Fe3O4 for the terbutaline adsorption. The adsorption efficiency achieved by the MOFs was 91.8% and 99.3% for the Cu(INA)2]-MOF and [Cu(INA)2]-MOF@Fe3O4 respectively. The optimum for the adsorption study included terbutaline concentration of 40 mg/L, adsorbent dose of 5 mg/L, pH of 11, temperature of 25 °C and equilibrium time of 40 min. The kinetics and isotherms have been described by pseudo-second order and Langmuir models, while the thermodynamics revealed the exothermic and spontaneous nature of the process. The promising performance of the MOFs is manifested on the ease of regeneration and reusability, achieving adsorption efficiency of 85.0% and 94.7% by the Cu(INA)2]-MOF and [Cu(INA)2]-MOF@Fe3O4, respectively at five consecutive cycles. The higher performance of the MOFs demonstrates their excellent potentialities for the terbutaline adsorption from the aqueous solution.

Predicting the Strength of Cohesive and Adhesive Interparticle Interactions for Dry Powder Inhalation Blends of Terbutaline Sulfate with α-Lactose Monohydrate.

Grid-based systematic search methods are used to investigate molecule-molecule, molecule-surface, and surface-surface contributions to interparticle interactions in order to identify the crystal faces that most strongly affect particle behavior during powder blend formulation and delivery processes. The model system comprises terbutaline sulfate (TBS) as an active pharmaceutical ingredient (API) and α-form lactose monohydrate (LMH). A combination of systematic molecular modeling and X-ray computed tomography (XCT) is used to determine not only the adhesive and cohesive interparticle energies but, also the agglomeration behavior during manufacturing and de-agglomeration behavior during delivery after inhalation. This is achieved through a detailed examination of the balance between the adhesive and cohesive energies with the XCT results confirming the blend segregation tendencies, through the particle-particle de-agglomeration process. The results reveal that the cohesive interaction energies of TBS-TBS are higher than the adhesive energies between TBS and LMH, but that the cohesive energies of LMH-LMH are the smallest between molecule and molecule, molecule and surface, and surface and surface. This shows how systematic grid-search molecular modeling along with XCT can guide the digital formulation design of inhalation powders in order to achieve optimum aerosolization and efficacy for inhaled medicines. This will lead to faster pharmaceutical design with less variability, higher quality, and enhanced performance.

Investigating the Effect of Silver Nanoparticles on the Fluorescence Intensity of Bambuterol and its Active Metabolite Terbutaline Using FRET.

Silver nanoparticles (AgNPs) were found to significantly quench the fluorescence of bambuterol hydrochloride (BAM) and its active metabolite terbutaline sulfate (TER). The intrinsic fluorescence intensity of each of BAM (at 264/292 nm) and TER (at 276/306 nm) decreased by the gradual addition of AgNPs. Quenching of the steady state fluorescence of BAM and TER probably resulted from the energy transfer to the photo-excited state of AgNPs. The estimated Stern-Volmer quenching constant at several temperature settings proved that the quenching mechanism of the two drugs was dynamic quenching in case of BAM while it was static quenching in case of TER. The number of binding sites, binding constants, and corresponding thermodynamic parameters depending on the interaction system were estimated at 293, 313, and 333 °K and the results obtained were interpreted.

Mechanical loading alleviated the inhibition of ß2-adrenergic receptor agonist terbutaline on bone regeneration.

The long-term use of adrenergic medication in treating various conditions, such as asthma, increases the chances of bone fracture. Dynamic mechanical loading at a specific time is a method for improving bone quality and promoting healing. Therefore, we hypothesized that precisely controlling the mechanical environment can contribute to the alleviation of the negative effects of chronic treatment with the common asthma drug terbutaline, which is a ß2-adrenergic receptor agonist that facilitates bone homeostasis and defect repair through its anabolic effect on osteogenic cells. Our in vitro results showed that terbutaline can directly inhibit osteogenesis by impairing osteogenic differentiation and mineralization. Chronic treatment in vivo was simulated by administering terbutaline to C57BL/6J mice for 4 weeks before bone defect surgery and mechanical loading. We utilized a stabilized tibial defect model, which allowed the application of anabolic mechanical loading. During homeostasis, chronic terbutaline treatment reduced the bone formation rate, the fracture toughness of long bones, and the concentrations of bone formation markers in the sera. During defect repair, terbutaline decreased the bone volume, type H vessel, and total blood vessel volume. Terbutaline treatment reduced the number of osteogenic cells. Periostin, which was secreted mainly by Prrx1+ osteoprogenitors and F4/80+ macrophages, was inhibited by treating the bone defect with terbutaline. Interestingly, controlled mechanical loading facilitated the recovery of bone volume and periostin expression and the number of osteogenic cells within the defect. In conclusion, mechanical loading can rescue negative effects on new bone accrual and repair induced by chronic terbutaline treatment.

Assessment of High-Power Electronic Nicotine Delivery System as an Alternative Aerosol Device for Terbutaline Delivery.

PURPOSE: The performance of new-generation high-power electronic nicotine delivery system (ENDS) for the administration of inhaled terbutaline was assessed. METHODS: The formulation of e-liquid was carried out using terbutaline in combination with 1, 3- propanediol. Several terbutaline concentrations (from 0.3125 to 2.500 mg / mL) and power levels (from 15 to 35 W) were assessed using a box type ENDS. The respirable drug dose was determined using a Glass Twin Impinger and quantified by liquid chromatography coupled with a UV-detector. The Next Generation Impactor and the Dekati Low Pressure Impactor were used to measure the aerosol particle size distribution in drug mass. The results were compared with a jet nebulizer (Cirrus TM 2) similar to the usual clinical conditions (2 mL at [terbutaline] of 2.5 mg / mL). RESULTS: The optimal conditions to maximize terbutaline delivery using ENDS are a drug concentration at 1 mg/mL, and a power level at 30 W, to reach a respirable dose of 8.73 ± 0.90 µg/puff. By contrast, during a 5 min nebulization, the respirable dose of terbutaline was 1040 ± 33 µg whatever the cascade impactors and the aerosol devices used. The mass median aerodynamic diameter (MMAD) remains similar for jet nebulizer and ENDS in the 1.74-2.07 µm range. CONCLUSION: Compared to the jet nebulizer, a same respirable dose of terbutaline at the same range of aerosol size distribution was delivered by ENDS if 120 puffs were performed. The ENDS can be considered as an alternative aerosol device for terbutaline delivery.

Micelle-enhanced spectrofluorimetric method for the rapid determination of bronchodilator terbutaline and its prodrug bambuterol: application for content uniformity test.

A novel, simple and sensitive spectrofluorimetric approach for determination of terbutaline sulphate (TER) and its prodrug bambuterol (BAM) in their pure and pharmaceutical dosage forms was developed. The suggested approach depends on enhancing the native fluorescence of either TER or BAM at 315 and 297.2 nm after excitation at 277 and 259 nm, respectively, using sodium dodecyl sulphate (SDS) as a micellar medium. In the presence of 0.7% w/v SDS, ~1.38-fold and 1.18-fold enhancement is achieved in the relative fluorescence intensity (RFI) of TER and BAM, respectively. The fluorescence-concentration curves were rectilinear over the concentration range 0.8-16 µg ml-1 , with detection limits (LOD) of 0.252 and 0.26 (µg ml-1 ), quantitation limits (LOQ) of 0.76 and 0.79 (µg ml-1 ), determination coefficients (r2) of 0.9981, and slopes of 45.92 and 10.44 for TER and BAM, respectively. The suggested approach was validated in accordance with International Council for Harmonisation criteria and was effectively applied in the analysis of the studied drugs in their commercial tablets. The high sensitivity of the proposed approach allows its application in evaluating the content uniformity testing of the studied drugs in their tablets through using the official United States Pharmacopeia criteria. Statistical analogies of the findings with that of the reported methods showed really good harmony and indicated no major differences in precision and accuracy.

Electrospun nanofibers modified with zeolitic imidazolate framework-8 for electrochemiluminescent determination of terbutaline.

For the first time it is demonstrated that zeolitic imidazolate framework-8 electrospun nanofibers (ZIF-8 NF) could serve as electrochemiluminescence (ECL) accelerator for the facile detection of terbutaline residual. A novel ECL sensor for the determination of terbutaline was fabricated based on ZIF-8 NF. The ZIF-8 NF were successfully prepared according to electrospinning and in-situ growth method. First, chitosan was modified on the surface of the electrode, and then the ZIF-8 NF was modified onto the upper layer of the chitosan. Taking advantages of chitosan and ZIF-8 NF in conductivity and electrocatalysis, the modified electrode presents obvious ECL phenomenon in 0.2 M PBS solution (pH 10.0) containing 0.025 M luminol. After the addition of terbutaline, ECL intensity decreased significantly, and the decreasing value showed a linear relationship with the logarithm of terbutaline concentration. The linear range was from 2.0 × 10-10 to 2.0 × 10-5 M, and the detection limit was 1.41 × 10-11 M (3σ/m). The method had high sensitivity, good stability, and good applicability to actual pork samples.

Terbutaline attenuates LPS-induced injury of pulmonary microvascular endothelial cells by cAMP/Epac signaling.

Acute lung injury (ALI), characterized by an acute onset of severe hypoxemia, is a common and devastating syndrome usually triggered by lipopolysaccharide (LPS) infection from bacteria. This study is intended to explore whether terbutaline can alleviate LPS-induced human pulmonary microvascular endothelial cell (HPMVEC) injury through cAMP/Epac signaling. LPS was utilized to induce ALI in HPMVECs, and after exposure of LPS-induced HPMVECs to terbutaline, the cellular functions including cell viability and apoptosis were measured by cell counting kit-8 and terminal deoxynucleotidyl transferase dUTP nick-end labeling. The protein expression related to cAMP/Epac signaling, apoptosis, and that of tight junction and inflammatory factors were evaluated at the same time. The effects of terbutaline on cellular functions were confirmed again after the addition of antagonists of cAMP and Epac, respectively. The levels of both cAMP and Epac reduced by LPS was concentration-dependently increased by terbutaline. The apoptosis and endothelial cell permeability damage of LPS-induced HPMVECs were enhanced after the addition of KT-5720 and ESI-09. The beneficial effects of terbutaline on alleviating the inflammation and apoptosis in HPMVECs injured by LPS are mediated by cAMP/Epac signaling, and this evidence would demonstrate the potential of terbutaline in the treatment of ALI.

Separation of terbutaline enantiomers in capillary electrophoresis with neutral cyclodextrin-type chiral selectors and investigation of the structure of selector-selectand complexes using nuclear magnetic resonance spectroscopy.

The major goal of this study was to determine the affinity pattern of the terbutaline (TB) enantiomers toward α-, ß-, γ-, and heptakis(2,3-di-O-acetyl)-ß-cyclodextrins and using NMR spectroscopy for the understanding of the fine mechanisms of interaction between the cyclodextrins (CD) and TB enantiomers. It was shown once again that CE in combination with NMR spectroscopy represents a sensitive tool to study the affinity patterns and structure of CD complexes with chiral guests. Opposite affinity patterns of TB enantiomers toward native α- and ß-CDs were associated with significant differences between the structure of the related complexes in solution. In particular, the complex between TB enantiomers and α-CD was of the external type, whereas an inclusion complex was formed between TB enantiomers and ß-CD. One of the possible structures of the complex between TB and heptakis(2,3-di-O-acetyl)-ß-CD (HDA-ß-CD) was quite similar to that of TB and ß-CD, although the chiral recognition pattern and enantioselectivity of TB complexation with these two CDs were very different.

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.

Novel lipid-polymer hybrid nanoparticles incorporated in thermosensitive in situ gel for intranasal delivery of terbutaline sulphate.

AIM: The present work aimed to improve the bioavailability of terbutaline sulphate (TS) and to prolong its nasal residence time for the treatment of asthma. METHODS: Chitosan/pectin polyelectrolyte complex nanoparticles (CS/PC) were prepared by ionic gelation method and coated with phospholipid (PL) and then incorporated into optimised thermosensitive in situ gel. RESULTS: The optimal PL-coated nanoparticle formulation (LP1) showed the smallest particle size (345.5 nm), the highest zeta potential (32.9 mV) and the greatest percent drug released after 6 h (71%). The optimum in situ gel loaded with LP1 (NG3) showed three times greater permeation through nasal mucosa than aqueous solution of TS and revealed about 94% and 92% of the effect of IV injection of drug solution on tidal volume and peak expiratory flow in histamine treated rats, respectively. CONCLUSION: The developed PL-coated CS/PC/in situ gel could be considered as a promising intranasal formulation of TS for asthma management.

Anti-inflammatory effect of ß2 adrenergic stimulation on circulating monocytes with a pro-inflammatory state in high-fat diet-induced obesity.

Obesity is a chronic condition associated with low-grade inflammation, and it also involves alterations of the function of the hypothalamic-pituitaryadrenal axis and the sympathetic nervous system. Adrenergic agonists such as catecholamines are important immunoregulatory molecules that are involved in modulating both metabolism and most of the mechanisms of the immune response. The first objective of this study was to determine whether the systemic inflammatory state associated with obesity is also manifested in the inflammatory profile and phenotype of circulating monocytes; and the second objective was to evaluate the effects of ß2 adrenergic stimulation on the inflammatory profile and phenotype of monocytes in obesity, and whether this response could be different from that in lean individuals. C57BL/6J mice were randomly allocated to one of two diets for 18 weeks: high-fat diet in order to obtain an experimental model of obesity, and standard diet in the control lean group. Circulating monocyte expression of inflammatory cytokines (MCP-1, TNF-α, IL-8, IL-6, IL-10, and TGF-ß), surface membrane marker Ly6C, inducible nitric oxide synthase and arginase-1, and Toll-like receptor 4 were evaluated through flow cytometry in the presence or absence of selective ß2 adrenergic receptor agonist terbutaline. Monocytes from high-fat diet-induced obese animals presented higher expression levels of all pro-inflammatory cytokines and a higher percentage of monocytes with a pro-inflammatory phenotype than those from lean animals. ß2 adrenergic stimulation induced a shift towards an anti-inflammatory activity profile and phenotype in obese mice, whereas it induced a shift towards a pro-inflammatory activity profile and phenotype in lean mice. In conclusion, ß2 adrenergic stimulation in monocytes was anti-inflammatory only in obese animals, which presented a pro-inflammatory state at baseline.

Spectrofluorimetric investigation with green analytical procedures for estimation of bambuterol and terbutaline: Application to pharmaceutical dosage forms and content uniformity testing.

Bambuterol (BAM) and terbultaline (TER) are well known and effective bronchodilators. In this article highly sensitive, green and cost-effective spectrofluorimetric methods are designed to determine low concentrations of such drugs. The proposed methods are based on an investigation of the native fluorescence properties of aqueous solutions of BAM at 298 nm after excitation at 263 nm and of TER at 313 nm after excitation at 275 nm. Under optimum conditions, the plots of the relative fluorescence intensity versus concentration were rectilinear over the range 0.1-1.2 µg/mL for BAM and 0.05-0.5 µg/mL for TER with a limit of quantitation of 0.067 µg/mL for BAM and 0.018 µg/mL for TER. The methods are simple and hence suitable for application to the quantification of BAM and TER in syrups and tablets without interference from common excipients. Furthermore, based on United States Pharmacopeia (USP) guidelines, the application was extended to determine the content uniformity of the cited drugs in low dose tablets. The developed methods were fully validated according to the guidelines of the International Conference on Harmonization (ICH).

The Effect of Dexamethasone, Adrenergic and Cholinergic Receptor Agonists on Phospholipid Metabolism in Human Osteoarthritic Synoviocytes.

Phospholipids (PLs) possess the unique ability to contribute to synovial joint lubrication. The aim of our study was to determine for the first time the effect of dexamethasone and some adrenergic and cholinergic agonists on the biosynthesis and release of PLs from human fibroblast-like synoviocytes (FLS). Osteoarthritic human knee FLS were treated with dexamethasone, terbutaline, epinephrine, carbachol, and pilocarpine, or the glucocorticoid receptor antagonist RU 486. Simultaneously PL biosynthesis was determined through the incorporation of stable isotope-labeled precursors into PLs. Radioactive isotope-labeled precursors were used to radiolabel PLs for the subsequent quantification of their release into nutrient media. Lipids were extracted and quantified using electrospray ionization tandem mass spectrometry or liquid scintillation counting. Dexamethasone significantly decreased the biosynthesis of phosphatidylcholine, phosphatidylethanolamine (PE), PE-based plasmalogen, and sphingomyelin. The addition of RU 486 abolished these effects. A release of PLs from FLS into nutrient media was not recognized by any of the tested agents. None of the adrenergic or cholinergic receptor agonists modulated the PL biosynthesis. We demonstrate for the first time an inhibitory effect of dexamethasone on the PL biosynthesis of FLS from human knees. Moreover, our study indicates that the PL metabolism of synovial joints and lungs are differently regulated.

RP-HPLC-UV method development and validation for simultaneous determination of terbutaline sulphate, ambroxol HCl and guaifenesin in pure and dosage forms.

OBJECTIVE: The objective of the present work was to develop and validate a simple, sensitive, rapid and stable reverse-phase high performance liquid chromatography (RP-HPLC) method for a combination of Terbutaline sulphate (TSL), Ambroxol hydrochloride (AML) and Guaifenesin (GFN). METHOD: The combination of these drugs was analyzed by using Shimadzu LC 2010 CHT high performance liquid chromatography (HPLC). Successful separation was achieved by isocratic elution on a reverse-phase C18 column (sun fire) (250mm, 4.6mm, 5µ), using a mobile phase consisting of buffer: acetonitrile in the ratio 80: 20 (buffer - 0.1% v/v triethyleamine pH-3.0) followed by 1.0mL/min flow rate. The wavelength of detection was at 220nm. RESULT: The chromatographic retention times were consistent at 3.0, 10.5 and 13.8minutes for TSL, AML and GFN respectively. For these three compounds, the lower limit of detection was 1.0, 1.25, and 1.5µg/mL and lower limit of quantification was 3.3, 4.1 and 5.0µg/mL respectively. The linearity concentrations established for TSL, AML and GFN were 1.0-7.0, 1.5-7.5 and 4.0-14.0µg/mL respectively. The correlation coefficients for all the drugs were found to be greater than 0.999. The relative standard deviation of inter- and intra-day were less than 2.0%. CONCLUSION: This method provides a necessary tool for quantification of the selected drugs for their assay. The proposed method is simple, accurate, reproducible and applied successfully to analyze three compounds in pure as well dosage form.

Chronic ß2 -adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men.

KEY POINTS: While several studies have investigated the effects of exercise training in human skeletal muscle and the chronic effect of ß2 -agonist treatment in rodent muscle, their effects on muscle proteome signature with related functional measures in humans are still incompletely understood. Herein we show that daily ß2 -agonist treatment attenuates training-induced enhancements in exercise performance and maximal oxygen consumption, and alters muscle proteome signature and phenotype in trained young men. Daily ß2 -agonist treatment abolished several of the training-induced enhancements in muscle oxidative capacity and caused a repression of muscle metabolic pathways; furthermore, ß2 -agonist treatment induced a slow-to-fast twitch muscle phenotype transition. The present study indicates that chronic ß2 -agonist treatment confounds the positive effect of high intensity training on exercise performance and oxidative capacity, which is of interest for the large proportion of persons using inhaled ß2 -agonists on a daily basis, including athletes. ABSTRACT: Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, ß2 -agonists are frequently used to counteract exercise-induced bronchoconstriction, but the effects ß2 -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomly assigned 21 trained men to 4 weeks of high intensity training with (HIT+ß2 A) or without (HIT) daily inhalation of ß2 -agonist (terbutaline, 4 mg dose-1 ). Of 486 proteins identified by mass-spectrometry proteomics of muscle biopsies sampled before and after the intervention, 32 and 85 were changing (false discovery rate (FDR) ≤5%) with the intervention in HIT and HIT+ß2 A, respectively. Proteome signature changes were different in HIT and HIT+ß2 A (P = 0.005), wherein ß2 -agonist caused a repression of 25 proteins in HIT+ß2 A compared to HIT, and an upregulation of 7 proteins compared to HIT. ß2 -Agonist repressed or even downregulated training-induced enrichment of pathways related to oxidative phosphorylation and glycogen metabolism, but upregulated pathways related to histone trimethylation and the nucleosome. Muscle contractile phenotype changed differently in HIT and HIT+ß2 A (P ≤ 0.001), with a fast-to-slow twitch transition in HIT and a slow-to-fast twitch transition in HIT+ß2 A. ß2 -Agonist attenuated training-induced enhancements in maximal oxygen consumption (P ≤ 0.01) and exercise performance (6.1 vs. 11.6%, P ≤ 0.05) in HIT+ß2 A compared to HIT. These findings indicate that daily ß2 -agonist treatment attenuates the beneficial effects of high intensity training on exercise performance and oxidative capacity, and causes remodelling of muscle proteome signature towards a fast-twitch phenotype.

Enantioselective resolution of Rac-terbutaline and evaluation of optically pure R-terbutaline hydrochloride as an efficient anti-asthmatic drug.

Terbutaline is a ß2 -adrenoceptor agonist for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Among the two isomers of terbutaline (TBT 2), R-isomer was found to be the potent enantiomer in generating therapeutic effect, while S-isomer has been reported to show side effects. In this study, R-terbutaline hydrochloride (R-TBH 6) was synthesized through chiral resolution from the racemic terbutaline sulfate (rac-TBS 1) with 99.9% enantiomeric excess (ee) in good overall yield (53.6%). Further, R-TBH 6 nebulized solution was prepared in half dosage of Bricanyl®, which is a marketed product of racemic terbutaline and evaluated in vitro aerosol performance and in vivo anti-asthmatic effect on guinea pigs via. pulmonary delivery. From the investigation, it is evident that R-TBH 6 nebulized solution of half dosage performed similar fine aerosol characteristics and anti-asthmatic effect with Bricanyl®.

Preparation of a Sustained-Release Nebulized Aerosol of R-terbutaline Hydrochloride Liposome and Evaluation of Its Anti-asthmatic Effects via Pulmonary Delivery in Guinea Pigs.

An aerosolized liposome formulation for the pulmonary delivery of an anti-asthmatic medication was developed. Asthma treatment usually requires frequent administration of medication for a sustained bronchodilator response. Liposomes are known for their sustained drug release capability and thus would be a suitable delivery system for prolonging the therapeutic effect of anti-asthmatic medication. Liposomes prepared by thin film hydration were loaded with a model drug, R-terbutaline hydrochloride(R-TBH), using an ammonium sulfate-induced transmembrane electrochemical gradient. This technique provided an encapsulation efficiency of up to 71.35% and yielded R-TBH liposomes with a particle size of approximately 145 ± 20 nm. According to stability studies, these R-TBH liposomes should be stored at 4°C before usage. Compared to R-TBH solution, which showed 90.84% release within 8 h, liposomal R-TBH had a cumulative release of 73.53% at 37°C over 192 h. A next generation impactor (NGI) was used to analyze the particle size distribution in the lungs of R-TBH liposome aerosol in vitro at 5°C. The therapeutic efficacy of the nebulized aerosol of the R-TBH liposomes was assessed via pulmonary delivery in guinea pigs. The results showed that, compared to the R-TBH solution group, the R-TBH liposome group had a prolonged anti-asthma effect.

R- and S-terbutaline activate large conductance and Ca2+ dependent K+ (BKCa) channel through interacting with ß2 and M receptor respectively.

This study investigated the effect of the ß2 receptor agonist terbutaline on the single channel activity of BKCa channel. The effects of racemate and two isomers of terbutaline were all assessed. ß2 adrenoceptors were stably overexpressed on HEK293 cells by lentiviral transduction method and chicken BKCa channels were transiently expressed on normal HEK293 cell line or HEK293 cells overexpressing ß2 receptors. Data showed that terbutaline significantly increased the single channel open probability of BKCa channel within 10min. The channel activating effects of terbutaline are stereoselective and mainly stay with the R-enantiomers. The opening probability of BKCa channel at 10min after drug application normalized to that just before drug application (Po10/Po0s) for R- and S-terbutaline were 7.85±3.20 and 1.06±0.45 respectively at 1µM concentration, corresponding to 28.37±9.96 and 2.68±1.09 at the higher concentration of 10µM. ICI 118551 blocked the effect of R- but not S-terbutaline (10µM), whereas atropine blocked the channel activating effects of S-terbutaline of higher concentration. In addition, the muscarinic receptor agonist carbachol increased the BKCa channel activity in an atropine-sensitive manner as an positive control experiment, which indicate the involvement of M receptor in the channel activating effect of S-terbutaline.