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The article presents a case-control study which examines the association of fenoterol, a beta2-adrenergic agonist, with multiple sclerosis (MS) risk. The study was conducted to 578 individuals with MS in Taiwan and a conditional logistic regression method was performed to analyze the drug administration. Findings show that patients who used fenoterol have lesser risk of MS than their counterparts.

Highlights: [•] Fenoterol derivatives display stereoselective activity as β2-AR agonists. [•] A full stereochemical characterization of fenoterol derivatives is crucial. [•] A combined ECD and TD-DFT analysis was performed on fenoterol stereoisomers. [•] TD-DFT calculations confirm the stereochemistry of fenoterol stereoisomers. [•] DFT geometries reveal different conformational patterns among diastereomers. [Copyright &y& Elsevier]

β-Adrenoceptor agonists have recently been introduced for the symptomatic treatment of the overactive bladder syndrome. As such treatment is not curative, long-term treatment is anticipated to be required. As the susceptibility of β-adrenoceptors to undergo agonist-induced desensitization is cell type- and tissue-dependent, we have explored whether pre-treatment with a β-adrenoceptor agonist will attenuate subsequent relaxation responses to freshly added agonist using rat urinary bladder as a model. We have used the prototypical β-adrenoceptor agonist isoprenaline, the β-selective fenoterol and the β-selective CL 316,243 and mirabegron as well as the receptor-independent bladder relaxant forskolin. We show that a 6-h pre-treatment with agonist can significantly reduce subsequent relaxation against KCl-induced smooth muscle tone, but agonist-induced desensitization was also observed with longer pre-treatments or against passive tension. The agonist-induced desensitization was prominent for the β component of rat bladder relaxation but much weaker or even absent for the β component. Moreover, β-adrenoceptor agonist pre-treatment reduced contractile responses to the muscarinic agonist carbachol and the receptor-independent stimulus KCl. Taken together these data do not support the hypothesis that the long-term clinical efficacy of β-adrenoceptor agonists in the treatment of the overactive bladder syndrome will be limited by receptor desensitization. Rather they raise the possibility that such treatment may not only cause smooth muscle relaxation but also may attenuate hyper-contractility of the bladder. [ABSTRACT FROM AUTHOR]

Abstract: (R,R′)-4′-Methoxy-1-naphthylfenoterol (MNF) promotes growth inhibition and apoptosis of human HepG2 hepatocarcinoma cells via cannabinoid receptor (CBR) activation. The synthetic CB1R inverse agonist, AM251, has been shown to block the anti-mitogenic effect of MNF in these cells; however, AM251 is also an agonist of the recently deorphanized, lipid-sensing receptor, GPR55, whose upregulation contributes to carcinogenesis. Here, we investigated the role of MNF in GPR55 signaling in human HepG2 and PANC-1 cancer cell lines in culture by focusing first on internalization of the fluorescent ligand Tocrifluor 1117 (T1117). Initial results indicated that cell pretreatment with GPR55 agonists, including the atypical cannabinoid O-1602 and l-α-lysophosphatidylinositol, dose-dependently reduced the rate of cellular T1117 uptake, a process that was sensitive to MNF inhibition. GPR55 internalization and signaling mediated by O-1602 was blocked by MNF in GPR55-expressing HEK293 cells. Pretreatment of HepG2 and PANC-1 cells with MNF significantly abrogated the induction of ERK1/2 phosphorylation in response to AM251 and O-1602. Moreover, MNF exerted a coordinated negative regulation of AM251 and O-1602 inducible processes, including changes in cellular morphology and cell migration using scratch wound healing assay. This study shows for the first time that MNF impairs GPR55-mediated signaling and, therefore, may have therapeutic potential in the management of cancer. [Copyright &y& Elsevier]

Abstract: The β2-adrenergic receptor (β2-AR) agonist [3H]-(R,R′)-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (K i values) of the stereoisomers of a series of 4′-methoxyfenoterol analogs in which the length of the alkyl substituent at α′ position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [3H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC50 values, were determined in HEK293 cells expressing the β2-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α′ position. The results also indicate that the K i values obtained using [3H]-(R,R′)-methoxyfenoterol as the marker ligand modeled the EC50 values obtained from cAMP stimulation better than the data obtained using [3H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β2-AR conformation probed by [3H]-(R,R′)-4′-methoxyfenoterol. The CoMFA model of the agonist-stabilized β2-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β2-AR is governed to a greater extend by steric effects than binding to the [3H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role. [Copyright &y& Elsevier]

Fenoterol, a fast-acting β 2-adrenergic agonist, is used in the therapy of obstructive pulmonary diseases and for the inhibition of premature labour obstetrics. Doping control for β 2-agonists, which are prohibited in sports by the World Anti-Doping Agency, is commonly performed by liquid chromatography/mass spectrometry after hydrolysis of phase II metabolites. The continuing development of analytical procedures has led to direct injection of urine samples without sample preparation becoming a viable tool. For the detection of substances without sample preparation, including hydrolysis, detailed information of the phase II metabolism of the substances is essential. In this study, human S9 fractions of different tissues and two recombinant sulfotransferases were investigated for their potential to form fenoterol sulfoconjugates, which were characterised in detail. Two mono-sulfoconjugates and one bis-sulfoconjugate were synthesised and their structures confirmed by liquid chromatography–high-resolution/high-accuracy mass spectrometry. All of the metabolites were identified as esterified phenolic compounds. Excretion studies with orally and inhalatively administered fenoterol proved the occurrence of the sulfoconjugates in vivo. Inhalatively administered fenoterol resulted in the detection of the two mono-sulfoconjugates in low amounts in urine due to the lower inhalation dose of fenoterol compared to the oral dose. After oral uptake of fenoterol, the two mono-sulfoconjugates and a fenoterol bis-sulfoconjugate were detected in urine. This is the first report of the bis-sulfoconjugate. [ABSTRACT FROM AUTHOR]

The β adrenergic receptor (β-AR) has become a model system for studying the ligand recognition process and mechanism of the G protein coupled receptors activation. In the present study stereoisomers of fenoterol and some of its derivatives ( N = 94 molecules) were used as molecular probes to identify differences in stereo-recognition interactions between β-AR and structurally similar agonists. The present study aimed at determining the 3D molecular models of the fenoterol derivative-β-AR complexes. Molecular models of β-AR have been developed by using the crystal structure of the human β-AR T4 lysozyme fusion protein with bound ( S)-carazolol (PDB ID: 2RH1) and more recently reported structure of a nanobody-stabilized active state of the β-AR with the bound full agonist BI-167107 (PDB ID: 3P0G). The docking procedure allowed us to study the similarities and differences in the recognition binding site(s) for tested ligands. The agonist molecules occupied the same binding region, between TM III, TM V, TM VI and TM VII. The residues identified by us during docking procedure (Ser203, Ser207, Asp113, Lys305, Asn312, Tyr308, Asp192) were experimentally indicated in functional and biophysical studies as being very important for the agonist-receptor interactions. Moreover, the additional space, an extension of the orthosteric pocket, was identified and described. Furthermore, the molecular dynamics simulations were used to study the molecular mechanism of interaction between ligands (( R, R')- and ( S, S')-fenoterol) and β-AR. Our research offers new insights into the ligand stereoselective interaction with one of the most important GPCR member. This study may also facilitate the design of improved selective medications, which can be used to treat, prevent and control heart failure symptoms. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the effectiveness of intrapartum acute tocolysis for nonreassuring fetal heart rate tracing in decreasing the incidence of cesarean delivery. Secondary outcomes included modes of delivery other than cesarean delivery, successful acute tocolysis, time-to-delivery interval, and short-term perinatal outcomes., Data Sources: Searches were performed in MEDLINE/PubMed, Embase, Scopus, the Cochrane Central Register of Controlled Trials and Reviews, ClinicalTrials.gov, and the International Clinical Trials Registry Platform from the inception of each database until February 2022., Study Eligibility Criteria: Selection criteria included randomized controlled trials of laboring patients with singleton gestations randomized to receive intrapartum acute tocolysis for nonreassuring fetal heart rate tracing, as defined by the original trial., Methods: All analyses were done using an intention-to-treat approach, evaluating women according to the treatment group to which they were randomly allocated in the original trials. A frequentist network-meta-analysis was performed., Results: Four randomized clinical trials were eligible, including 605 patients with nonreassuring fetal heart rate tracing and singleton gestations at gestational ages >32 weeks. The cesarean delivery rate was similar among patients managed with different types of acute tocolysis. Acute tocolysis, compared with emergency delivery, was associated with improved neonatal acid-base status (notably decreasing the prevalence of base deficit >12 mmol/L [beta-2 agonists odds ratio, 0.61; 95% confidence interval, 0.37-0.99] and the rate of neonatal intensive care unit admission [beta-2 agonists odds ratio, 0.42; 95% confidence interval, 0.22-0.78]) and with an increase in the time-to-delivery interval (beta-2 agonists mean difference, 17.62 minutes; 95% confidence interval, 15.66-19.58); there was no reduction of cesarean delivery rate, showing an increased rate with atosiban and beta-2 agonists., Conclusion: The cesarean delivery rate was not reduced by acute tocolysis when used for nonreassuring fetal heart rate tracing during labor. Acute tocolysis is associated with improved short-term fetal outcomes and safely increases the time-to-delivery interval., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Highlights: [•] Developed an LC–MS/MS method for the determination of fenoterol enantiomers. [•] Improved quantitation limit from 2ng/ml to 50pg/ml over existing methods. [•] Enantioselective competitive interaction affects fenoterol presystemic sulfation. [Copyright &y& Elsevier]

In the determination of nine β-agonists including salbutamol, terbutaline, cimaterol, fenoterol, clorprenaline, ractopamine, tulobuterol, clenbuterol and penbuterol in porcine, bovine, lamb and chicken muscle, liver and urine samples with LC-MS/MS, calibration curves prepared in solvent (SC) were compared with those prepared in each matrix (MC) for all analytes. Significant differences (P ＜ 0.05) between SC and each MC for most analytes indicated the existence of matrix effects and the necessity of using MC for quantitation to compensate MEs. Then MC in each muscle, liver and urine sample was compared with the select potential representative matrix, followed by validating the recoveries of nine analytes calculated through the MC in the potential representative matrix and MC in their corresponding matrices, respectively. The results suggested that porcine muscle could be selected as a representative matrix to calibrate β-agonist residues in bovine, lamb and chicken muscle samples. [ABSTRACT FROM AUTHOR]

Organic cation transporter 1 (OCT1) is a membrane transporter that affects hepatic uptake of cationic and weakly basic drugs. OCT1 transports structurally highly diverse substrates. The mechanisms conferring this polyspecificity are unknown. Here, we analyzed differences in transport kinetics between human and mouse OCT1 orthologs to identify amino acids that contribute to the polyspecificity of OCT1. Following stable transfection of HEK293 cells, we observed more than twofold differences in the transport kinetics of 22 out of 28 tested substrates. We found that the β2-adrenergic drug fenoterol was transported with eightfold higher affinity but at ninefold lower capacity by human OCT1. In contrast, the anticholinergic drug trospium was transported with 11-fold higher affinity but at ninefold lower capacity by mouse Oct1. Using human-mouse chimeric constructs and site-directed mutagenesis, we identified nonconserved amino acids Cys36 and Phe32 as responsible for the species-specific differences in fenoterol and trospium uptake. Substitution of Cys36 (human) to Tyr36 (mouse) caused a reversal of the affinity and capacity of fenoterol but not trospium uptake. Substitution of Phe32 to Leu32 caused reversal of trospium but not fenoterol uptake kinetics. Comparison of the uptake of structurally similar β2-adrenergics and molecular docking analyses indicated the second phenol ring, 3.3 to 4.8 Å from the protonated amino group, as essential for the affinity for fenoterol conferred by Cys36. This is the first study to report single amino acids as determinants of OCT1 polyspecificity. Our findings suggest that structure-function data of OCT1 is not directly transferrable between substrates or species., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: In vivo solid-phase microextraction (SPME) can be used to sample the circulating blood of animals without the need to withdraw a representative blood sample. In this study, in vivo SPME in combination with liquid–chromatography tandem mass spectrometry (LC–MS/MS) was used to determine the pharmacokinetics of two drug analytes, R,R-fenoterol and R,R-methoxyfenoterol, administered as 5mgkg−1 i.v. bolus doses to groups of 5 rats. This research illustrates, for the first time, the feasibility of the diffusion-based calibration interface model for in vivo SPME studies. To provide a constant sampling rate as required for the diffusion-based interface model, partial automation of the SPME sampling of the analytes from the circulating blood was accomplished using an automated blood sampling system. The use of the blood sampling system allowed automation of all SPME sampling steps in vivo, except for the insertion and removal of the SPME probe from the sampling interface. The results from in vivo SPME were compared to the conventional method based on blood withdrawal and sample clean up by plasma protein precipitation. Both whole blood and plasma concentrations were determined by the conventional method. The concentrations of methoxyfenoterol and fenoterol obtained by SPME generally concur with the whole blood concentrations determined by the conventional method indicating the utility of the proposed method. The proposed diffusion-based interface model has several advantages over other kinetic calibration models for in vivo SPME sampling including (i) it does not require the addition of a standard into the sample matrix during in vivo studies, (ii) it is simple and rapid and eliminates the need to pre-load appropriate standard onto the SPME extraction phase and (iii) the calibration constant for SPME can be calculated based on the diffusion coefficient, extraction time, fiber length and radius, and size of the boundary layer. In the current study, the experimental calibration constants of 338.9±30mm−3 and 298.5±25mm−3 are in excellent agreement with the theoretical calibration constants of 307.9mm−3 and 316.0mm−3 for fenoterol and methoxyfenoterol respectively. [Copyright &y& Elsevier]

Abstract: Fenoterol has been reported to be a potent and selective β2-adrenoceptor agonist and is currently used clinically to treat asthma. Electrical field stimulation (EFS) of isolated urinary bladder mimics the voiding contraction by stimulating parasympathetic nerves, resulting in neurogenic contractions. To determine if stimulation of β2-adrenoceptors can inhibit this response, fenoterol was tested against EFS-induced contractions in human isolated urinary bladder and compared with mouse and rat. Bladder strips were mounted in organ baths and reproducible contractions induced by EFS. Fenoterol was added cumulatively in the presence of the β2-adrenoceptor antagonist ICI118551 or the β3-adrenoceptor antagonist L-748337. Fenoterol inhibited neurogenic contractions in all three species in a concentration-dependent manner with pEC50 values of 6.66±0.11, 6.86±0.06 and 5.71±0.1 in human, mouse and rat respectively. In human bladder strips ICI118551 (100nM) did not affect responses to fenoterol, while L-748337 (0.3–3μM) produced rightward shifts of the concentration-response curves with a pA2 value of 8.10. In mouse bladder strips ICI118551 (30nM) blocked the inhibitory effect of fenoterol (pA2=8.80), while L-748337 (10μM) inhibited the response with a pA2 of 5.79. In rat bladder ICI118551 (30nM) was without effect, while L-748,337 (10μM) inhibited the response to fenoterol with a pA2 of 5.40. From these results it is clear that fenoterol potently activates β3-adrenoceptors in human isolated urinary bladder to inhibit EFS-induced contractions. Fenoterol also activates β3-adrenoceptors in rat, but β2-adrenoceptors in mouse bladder to inhibit EFS-induced contractions. [Copyright &y& Elsevier]

Purpose: To compare the efficacy of nifedipine and fenoterol in the management of threatened preterm labor (TPL). Methods: A randomized and multicenter study assessing the tocolytic effect of nifedipine versus fenoterol in patients admitted to the participating maternity units with a diagnosis of TPL and a cost-savings study for economic assessment. For a power of 80% and an α error equal to 0.05, 132 consecutive patients were recruited during the study period; 66 patients were assigned to each group. A χ2 analysis and a mean differences test were performed according to variable types and survival curves per intention-to-treat. Results: Demographics were similar in both groups. The latency period was similar in both groups (26.7 vs. 25.6; p = 0.3). There were no differences in the results obtained. Nifedipine failed more frequently to obtain tocolysis when used as a first-line agent (80 vs. 90%, p = 0.0001). The group treated with fenoterol showed more drug adverse events (57.8 vs. 19.0%, p = 0.0001). The economic assessment did not evidence a significant difference in terms of cost savings between groups treated with either drug. Conclusion: The present study failed to demonstrate either clinical or economic superiority of any of the two drugs used in TPL management. The highest failure percentage of nifedipine when used as a first-line agent should encourage further research. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to determine if transdermal penetration of fenoterol, a β-agonist drug, could be enhanced and controlled by formulation modification and formulation of transdermal patches. Pre-formulation studies were performed to determine the feasibility of a transdermal dosage form of fenoterol. Penetration of fenoterol was determined using the hairless guinea pig skin with unjacketed Franz diffusion cell. Transdermal patches were formulated using drug in-adhesive technique. Several enhancers were investigated for fenoterol skin penetration. Transcutol–oleic acid co-solvent gives the highest drug flux among all tested liquid formulations. Pretreatment of the skin with oleic acid 2h before patch application significantly increases drug diffusion. Cis-oleic acid gives best results compared to oleic acid. Azone derivative (1-dodecyl-2-pyrrolidinone) gives the highest drug diffusion amongst all tested enhancers. Results of this study show the feasibility of using fenoterol formulated in transdermal delivery system in the treatment of chronic asthma to improve patient compliance, bioavailability and reduce the inter-subject variability. [Copyright &y& Elsevier]

Purpose: A salutary effect of β adrenergic receptor (AR) agonist, fenoterol has been demonstrated in a rat model of post-myocardial infarction (MI) dilated cardiomyopathy (DCM). Recent reports on single cardiomyocyte experiments suggested that out of two enantiomers, RR and SS, that constitute a racemic mixture of fenoterol, only RR-enantiomer is an active component that might be a promising new drug for treatment of chronic heart failure. The objective of this study was to compare the efficacy of the RR enantiomer of fenoterol with efficacy of racemic fenoterol, and SS, an inactive enantiomer, in whole animal experimental models of DCM. Methods: Two weeks after induction of MI by permanent ligation of the anterior descending coronary artery early cardiac remodeling and MI size were assessed via echocardiography and rats were divided into treatment groups. Treatment (placebo, racemic fenoterol, RR- or SS-enantiomers of fenoterol) continued for 6 months while progression of DCM was followed by serial echocardiography. Results: Compared with untreated rats, rats treated with racemic fenoterol demonstrated previously described attenuation of LV remodeling, functional decline and the arrest of the MI expansion during the first 2 months of treatment. On the contrary, the treatment with either RR-, or with SS-enantiomers of fenoterol was completely ineffective. Conclusion: The conclusion drawn on the basis of previous experiments with single cardiomyocytes that RR-enantiomer of fenoterol represents an active component of racemic fenoterol and can be further investigated as a new drug for treatment of chronic heart failure was not confirmed in the whole animal model of DCM. [ABSTRACT FROM AUTHOR]

Fenoterol HBr is a bronchodilator known to be subject to first pass effect after oral administration. The aim of this study was to prepare and evaluate fenoterol HBr suppositories. Suppositories were prepared by a fusion method using different fatty bases, viz. Witepsol H15, Witepsol E75, Suppocire AP, and Suppocire BM, as well as different hydrophilic bases, viz. polyethylene glycol and poloxamer bases. In vitro release studies revealed a greater release of the drug from hydrophilic bases than from fatty bases. The effect of incorporating different types and concentrations of non-ionic surfactants (Tween 60 and Span 20) on the release rate of the drug from Witepsol H15, as a model fatty base, was investigated. Results showed an enhanced release at low surfactant concentrations. A very fast 100% drug release was achieved when the drug was incorporated as an aqueous solution in Witepsol H15 (F17). This formula was selected to test the effect of fenoterol HBr suppositories on histamine-induced bronchospasms in Guinea pigs. No dyspnea of the animals was recorded for up to 30 min. In addition, thermogel liquid suppositories of different poloxamer 188 and poloxamer 407 proportions in the presence of sodium alginate as a mucoadhesive polymer were prepared. The different formulations behaved similarly concerning sustainment of drug release, however, only the formula containing 15% poloxamer 188 and 25% poloxamer 407 (F20) showed optimal gelation at body temperature. In conclusion, among the studied suppository bases there are bases suitable for fast release of the drug like F17 and hydrophilic bases especially polyethylene glycol, as well as other bases for sustained release applications of fenoterol HBr like fatty and thermogel bases. [ABSTRACT FROM AUTHOR]

Cannabinoid and adrenergic receptors belong to the class A (similar to rhodopsin) G protein coupled receptors. Docking of agonists and antagonists to CB and CB cannabinoid receptors revealed the importance of a centrally located rotamer toggle switch and its possible participation in the mechanism of agonist/antagonist recognition. The switch is composed of two residues, F3.36 and W6.48, located on opposite transmembrane helices TM3 and TM6 in the central part of the membranous domain of cannabinoid receptors. The CB and CB receptor models were constructed based on the adenosine A receptor template. The two best scored conformations of each receptor were used for the docking procedure. In all poses (ligand-receptor conformations) characterized by the lowest ligand-receptor intermolecular energy and free energy of binding the ligand type matched the state of the rotamer toggle switch: antagonists maintained an inactive state of the switch, whereas agonists changed it. In case of agonists of βAR, the ( R,R) and ( S,S) stereoisomers of fenoterol, the molecular dynamics simulations provided evidence of different binding modes while preserving the same average position of ligands in the binding site. The ( S,S) isomer was much more labile in the binding site and only one stable hydrogen bond was created. Such dynamical binding modes may also be valid for ligands of cannabinoid receptors because of the hydrophobic nature of their ligand-receptor interactions. However, only very long molecular dynamics simulations could verify the validity of such binding modes and how they affect the process of activation. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Short-acting β2-adrenoreceptor agonist (SABA) is the major asthma reliever as indicated in the GINA guidelines. Regulated on activation, normal T expressed and secreted (RANTES) is a chemokine that attracts eosinophils, mast cells, and basophils toward site of allergic inflammation. Interferon γ-inducible protein (IP)-10 is a Th1-related chemokine that is also important in asthmatic inflammation and also involved in our immune defense against pathogens. Bronchial epithelial cells are first-line barrier against invasive pathogen and also have immunomodulatory function. However, whether albuterol and fenoterol (two SABAs) have modulatory effects on RANTES and IP-10 expression in bronchial epithelial cells is unknown. The human bronchial epithelial cell lines, BEAS-2B cells, were pre-treated with different concentrations of albuterol, fenoterol or dibutyryl-cAMP (a cyclic AMP analog) before polyinosinic-polycytidylic acid (poly I:C) stimulation. In some condition, BEAS-2B cells were pre-treated with ICI-118551, a selective β2-adrenoreceptor antagonist, 30 min before albuterol or fenoterol treatment. The levels of RANTES and IP-10 were measured by ELISA. Intracellular signaling was investigated using cAMP assay, mitogen-activated protein kinase (MAPK) inhibitor, nuclear factor (NF)-κB inhibitor, and western blot. Albuterol and fenoterol suppressed poly I:C-induced RANTES and IP-10 expression of BEAS-2B cells. ICI-118551 could partly reverse the suppressive effects of albuterol and fenoterol on RANTES and IP-10 expression. Albuterol and fenoterol increased intracellular cAMP levels. Dibutyryl- cAMP conferred the similar effects of albuterol and fenoterol. Western blot revealed that albuterol suppressed p-ERK, p-JNK and pp38, and also their associated kinase expression. Albuterol had no effect on pp65 expression. Albuterol and fenoterol could suppress poly I:C-induced RANTES and IP-10 expression in human bronchial epithelial cells via at least partly the β2-adrenoreceptor-cAMP and the MAPK pathways, implicating that albuterol and fenoterol could exert anti-inflammatory effect and benefit asthmatic patients by suppressing RANTES and IP-10 expression. However, these suppressive effects of albuterol and fenoterol may inhibit the defense against viral infection. [ABSTRACT FROM AUTHOR]

sensitive, simple and rapid spectrofluorimetric method has been developed for the determination of both Fenoterol hydrobromide ( FNT) and Ritodrine hydrochloride ( RTH) in pure and dosage forms. The method is based on derivatization using dansyl chloride (DNS-Cl) as fluorogenic agent and measuring the fluorescence of the products at emission wavelengths of 517 and 515 nm after excitation at 348 and 343 nm for FNT and RTH, respectively. Different experimental parameters affecting the fluorescence intensities were carefully studied and optimized. The relation between fluorescence intensities and drug concentrations were rectilinear over the concentration range of 0.25-6.0 μg/mL for both drugs with a minimum detectability of 0.065 and 0.045 μg/mL for FNT and RTH, respectively. The percentage recoveries ±SD were 100.1 ± 0.9, 99.9 ± 0.6 for FNT and RTH respectively. The proposed method was successfully applied to the determination of both drugs in their commercial dosage forms. The obtained results were statistically validated and agreed well with those obtained with reference methods. A suggestion for the reaction pathway with DNS-Cl was postulated. [ABSTRACT FROM AUTHOR]

Abstract: Background: Limited evidence is available on the use of budesonide inhalation suspension (BIS) for the treatment of mild to severe acute asthma exacerbations (AAE) in adults in an inpatient setting. This study was conducted to evaluate the efficacy of a five-day course of BIS compared with oral prednisolone (OP) in the management of adults with AAE. Methods: A retrospective study examined the response of 28 patients hospitalized with mild to severe acute asthma exacerbation from January 2003 to December 2003. These patients, who were steroid free ≥1 yr, were administered a five-day course of BIS (2 × 2 mg bid) or OP (2 × 15 mg bid). PEF, FEV1 and asthma symptom scores were recorded daily. Results: The BIS (n = 13) and OP (n = 15) treatment groups were comparable at baseline for demographic characteristics and prebronchodilator (fenoterol) FEV1 of 52.4% predicted normal value and 54.6% predicted normal value, respectively. Mean change of morning PEF was 152 L/min during BIS treatment and 130 L/min for OP treatment; the mean changes of morning forced expiratory volumes in 1 s (FEV1) were 1.0 and 0.7 L, respectively. The mean change in daytime symptom scores were −1.6 and −1.3 in the BIS and the OP groups, respectively. Improvements in PEF, FEV1 and daytime symptom scores were significantly different between baseline and after treatment in each treatment group (p < 0.05). However, improvements in both BIS and OP groups were similar. Conclusion: Budesonide inhalation suspension may be an alternative treatment of acute asthma exacerbation in adults who are at risk for systemic corticosteroids. [Copyright &y& Elsevier]

Abstract: The binding thermodynamics of the stereoisomers of fenoterol, (R,R′)-, (S,S′)-, (R,S′)-, and (S,R′)-fenoterol, to the β2-adrenergic receptor (β2-AR) have been determined. The experiments utilized membranes obtained from HEK cells stably transfected with cDNA encoding human β2-AR. Competitive displacement studies using [3H]CGP-12177 as the marker ligand were conducted at 4, 15, 25, 30 and 37°C, the binding affinities calculated and the standard enthalpic (ΔH°) and standard entropic (ΔS°) contribution to the standard free energy change (ΔG°) associated with the binding process determined through the construction of van’t Hoff plots. The results indicate that the binding of (S,S′)- and (S,R′)-fenoterol were predominately enthalpy-driven processes while the binding of (R,R′)- and (R,S′)-fenoterol were entropy-driven. All of the fenoterol stereoisomers are full agonists of the β2-AR, and, therefore, the results of this study are inconsistent with the previously described “thermodynamic agonist–antagonist discrimination”, in which the binding of an agonist to the β-AR is entropy-driven and the binding of an antagonist is enthalpy-driven. In addition, the data demonstrate that the chirality of the carbon atom containing the β-hydroxyl group of the fenoterol molecule (the β-OH carbon) is a key factor in the determination of whether the binding process will be enthalpy-driven or entropy-driven. When the configuration at the β-OH carbon is S the binding process is enthalpy-driven while the R configuration produces an entropy-driven process. [Copyright &y& Elsevier]

Abstract: Regular use of β2-adrenoceptor agonists may enhance non-specific airway responsiveness and inflammation. In earlier experimental studies, we showed that prolonged in vitro fenoterol exposure induced airway sensitization via perturbed epithelial regulation of bronchoconstriction. The aim of the present work was to examine the involvement of inflammatory mediator genes and proinflammatory cells and to investigate the role of the bronchial epithelium in these untoward effects. Bronchial tissues were surgically removed from 17 ex-smokers. Bronchial rings and primary cultures of bronchial epithelial cells were incubated with 0.1μM fenoterol for 15h. Levels of mRNA-expression were analyzed using a real-time quantitative reverse transcription-polymerase chain reaction array. Bronchial rings were contracted with endothelin-1 and immune cell infiltration was assessed by immunohistochemistry. Compared to paired controls, fenoterol up-regulated the mRNAs of cytokines/proteins implicated in the recruitment of T and B cells or the activation and proliferation of bronchial epithelial cells (CCL20/MIP-3α, FOXA2, PPAR-γ) in isolated bronchi and in cultured epithelial cells. Fenoterol exposure significantly enhanced CD8+-T and differentiated CD138+-B-cells infiltration into the bronchi, especially the subepithelial area. Increase in CD8 or CD138 labeling-intensity strongly correlated with rise in maximal contraction to endothelin-1 induced by fenoterol exposure. In summary, our results show that fenoterol modulates the T and B cells chemotaxis possibly via the epithelial chemokine secretion in isolated bronchi from ex-smokers. They also suggest that the infiltration of resident T and B cells into the subepithelial area is associated with an increase in airway responsiveness due to fenoterol exposure. [Copyright &y& Elsevier]

Metal complexes of fenoterol (FEN) drug are prepared and characterized based on elemental analyses, IR, 1H NMR, magnetic moment, molar conductance, and thermal analyses (TG and DTA) techniques. From the elemental analyses data, the complexes are formed in 1:2 [Metal]:[FEN] ratio and they are proposed to have the general formula [Cu(FEN)2]·2H2O; [M(FEN)2(H2O)2]· yH2O (where M = Mn(II) ( y = 2), Co(II) ( y = 4), Ni(II) ( y = 4), and Zn(II) ( y = 0) and [Cr(FEN)2(H2O)2]Cl·H2O. The molar conductance data reveal that all the metal chelates are non-electrolytes except Cr(III) complex, having 1:1 electrolyte. IR spectra show that FEN is coordinated to the metal ions in a uninegative bidentate manner with ON donor sites of the aliphatic –OH and secondary amine –NH. From the magnetic moment measurements, it is found that the geometrical structures of these complexes are octahedral (Cr(III), Mn(II), Co(II), Ni(II), and Zn(II)) and square planar (Cu(II)). The thermal behavior of these chelates is studied using thermogravimetric and differential thermal analyses (TG and DTA) techniques. The results obtained show that the hydrated complexes lose water molecules of hydration followed immediately by decomposition of the coordinated water and ligand molecules in the successive unseparate steps. The FEN drug, in comparison to its metal complexes is also screened for their antibacterial activity against bacterial species ( Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Salmonella typhi), Yeasts ( Candida albicans and Saccharomyces cervisiae), and Fungi ( Aspergillus niger and Aspergillus flavus). The activity data show that the metal complexes have antibacterial activity like that of the parent FEN drug against one or more species. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the β2-adrenergic receptor. Results: Out of 21 computationally designed structures 6 compounds were synthesized and characterized for β2-AR binding affinities, subtype selectivities and functional activities. Conclusion: the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with K iβ2-AR=0.28μm, K iβ1-AR/K iβ2-AR=573, EC50cAMP =3.9nm, EC50cardio =16nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure. [Copyright &y& Elsevier]

AbstractAim:To investigate the molecular mechanism and signaling pathway by which fenoterol, a β2-adrenergic receptor (β2-AR) agonist, produces anti-inflammatory effects.Methods:THP-1, a monocytic cell line, was used to explore the mechanism of β2-AR stimulation in LPS-induced secretion of inflammatory cytokines and changes of toll-like receptors (TLRs). We labeled TLR4 and CD14 using monoclonal anti-TLR4 PE-conjugated and anti-CD14 FITC-conjugated antibodies in THP-1 cells stimulated by β2-AR in the presence or absence of lipopolysaccharide (LPS) and small, interfering RNA (siRNA)-mediated knockdown of β-arrestin-2, and then analyzed their changes in distribution by flow cytometry, Western blotting and confocal analysis.Results:LPS-induced membrane-bound CD14, TLR4/CD14 complex levels and elevation of inflammatory cytokines were all significantly reduced by pre-incubation of fenoterol (P<0.05). However, the total level of CD14 and TLR4 was not significantly changed. Interestingly, confocal microscopy revealed redistribution of CD14 and TLR4/CD14 complex under β2-AR stimulation. Furthermore, siRNA-mediated knockdown of β-arrestin-2 eliminated the anti-inflammatory effects and redistribution of CD14 and TLR4/CD14 complex stimulated by β2-AR.Conclusion:β2-AR agonist exerts its anti-inflammatory effects by down-regulating TLR signaling in THP-1 cells, potentially resulting from β-arrestin-2 mediated redistribution of CD14 and TLR14/CD14 complex. [ABSTRACT FROM AUTHOR]

We investigated longitudinally the behavioral development in the rat following exposure to β-agonists and glucocorticoids (GC). Neonatal rats received either 1 mg/kg fenoterol (FEN), 0.3 mg/kg betamethasone (BET), or saline (SAL). Weanling and young adult rats were tested in the open field, the elevated-plus maze, and the water maze. FEN-treated as well as BET-treated animals displayed increased anxiety-like behavior. Furthermore, BET-treated adult animals showed a reduced locomotor activity. An enhanced 24-h memory in the water maze in both treatment groups may be facilitated by emotional arousal due to the increased anxiety levels. The possible neurobiological underpinnings are discussed in detail. [ABSTRACT FROM AUTHOR]

Summary: Background: The bronchodilation test is used to detect reversible airways obstruction, considered important for diagnosing asthma. However, little is known about the effects of age on the bronchodilation response. The aim of this study was to evaluate the effects of age on the bronchodilation response by determining changes in the 1-second forced expiratory volume (FEV1) in a Chinese population. Methods: All patients underwent pulmonary function testing to evaluate forced vital capacity, peak expiratory flow, and FEV1. We assessed bronchodilation by measuring the change in FEV1 (ΔFEV1) before and after inhalation of 0.4mg of fenoterol (two puffs) delivered by a metered-dose inhaler with a spacer. Results: Of the 1,616 patients tested in the clinic, the 333 (21%) who had a positive bronchodilator test, defined as ΔFEV1 > 12% and 200mL, were enrolled in the study. For this population, the ΔFEV1 was +360.8 ± 138.6mL (mean ± standard deviation) or + 21.0% ± 9.1%. In a multiple linear regression model, the absolute ΔFEV1 (expressed in milliliters) was independently and negatively predicted by age (p < 0.001), and baseline peak expiratory flow (p < 0.001), but positively predicted by height (p < 0.001). Conclusion: Age was an important determinant for response to bronchodilation as determined by the absolute change in FEV1. [Copyright &y& Elsevier]