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Abstract: An on-line immunoextraction and liquid chromatography/mass spectrometry (LC/MS) method was developed and validated for the determination of R,R′-fenoterol, R,R′-methoxyfenoterol and R,S′-naphthylfenoterol in rat plasma. Sample preparation involved immunoextraction of analytes using an antibody raised against R,R′- and R,S′-aminofenoterol that was immobilized onto chromatographic support. LC was performed on a Waters hydrophilic interaction chromatography (HILIC) column (150mm×2.1mm), using an isocratic mobile phase of methanol:ammonium acetate (10mM, pH 6.8) (90:10, v/v) at a flow rate of 0.2ml/min. The MS was operated in the single ion monitoring mode (m/z 304.2 for R,R′-fenoterol, m/z 318.1 for R,R′-methoxyfenoterol, and m/z 339.2 for R,S′-naphthylfenoterol). Optimization of analytes desorption process from the immunoextraction column was performed by factorial analysis and the sample calibration curves were made with spiked rat plasma samples containing 0.5–100ng/ml of drugs. The cross-selectivity studies of the antibody were determined and the results suggested high selectivities toward R,R′-fenoterol, R,R′-methoxyfenoterol and R,S′-naphthylfenoterol. The accuracy of assay was more than 96% while intra- and inter-day precision of assay were less than 12.4%. Stability studies (2h benchtop, freeze/thaw, and autosampler stability) were conducted and the analytes were stable through out studies. The validated method was used to determine the plasma concentration–time profiles of drugs after oral administration to rats of R,R′-fenoterol, R,R′-methoxyfenoterol and R,S′-naphthylfenoterol. [Copyright &y& Elsevier]

• AC obtained by of plum seeds using water vapor is suitable for use in human medicine. • The PSC has a high adsorption capacity for fenoterol, and it is 337.8 mg/g. • The process of adsorption of fenoterol on PSC is thermodynamically favorable. • The application of ultrasound has a favorable of adsorption of fenoterol on PSC. The aim of the study was to preliminarily investigate the possibility of using active carbon (AC) of the shell of plum seeds (PSC) in cases of acute poisoning by excessive oral intake of fenoterol. It was found that the PSC surface is characterized by a large specific area, 1680 m2/g, high Langmuir monolayer capacity, 337.8 mg/g without ultrasound (US) and 351 mg/g with US. The Langmuir, Flory–Huggins, pseudo second order and intraparticular diffusion model, follow the experimental results well, R2 = 0.99 was in all cases. According to Boyd's criterion, a combination of diffusion of solute through the film and through the pores, limiting steps for fenoterol adsorption onto PSC are. The contribution of US was positive in this study. This was shown by the adsorption rate constant of the pseudo-second-order which, without application of US it was 298 g/mg·min and with the application of US was 347 g/mg·min. The Gibbs free energy ΔG values, −27.25 kJ/mol, −27.93 kJ/mol and −28.58 kJ/mol, obtained by Langmuir constant K L , were negative at all operating temperatures, verifying that the adsorption of fenoterol was spontaneous and thermodynamically favorable. PSC has been shown to be a highly effective adsorbent that can be used in acute oral fenoterol poisoning and US is not contraindicated, on the contrary. [ABSTRACT FROM AUTHOR]

Abstract: A fast and specific liquid chromatography–mass spectrometry method for the determination of (R,R)-fenoterol ((R,R)-Fen) in rat plasma has been developed and validated. (R,R)-Fen was extracted from 125μl of plasma using solid phase extraction and analyzed on Atlantis HILIC Silica 3μm column. The mobile phase was composed of acetonitrile:ammonium acetate (pH 4.1; 20mM) (85:15, v/v), at a flow rate of 0.2ml/min. The lower limit of detection (LLOD) was 2ng/ml . The procedure was validated and applied to the analysis of plasma samples from rats previously administered (R,R)-Fen in an intravenous bolus. [Copyright &y& Elsevier]

Siedlecka U, Arora M, Kolettis T, Soppa GK, Lee J, Stagg MA, Harding SE, Yacoub MH, Terracciano CM. Effects of clenbuterol on contractility and Ca2 homeostasis of isolated rat ventricular myocytes. Am J Physiol Heart Circ Physiol 295: H1917-H1926, 2008. First published September 5, 2008; doi: 10.1152/ajpheart.00258.2008.-Clenbuterol, a compound classified as a β2-adrenoceptor (AR) agonist, has been employed in combination with left ventricular assist devices (LVADs) to treat patients with severe heart failure. Previous studies have shown that chronic administration of clenbuterol affects cardiac excitation-contraction coupling. However, the acute effects of denbuterol and the signaling pathway involved remain undefined. We investigated the acute effects of clenbuterol on isolated ventricular myocyte sarcomere shortening, Ca[sup2+] transients, and L-type Ca[sup2+] current and compared these effects to two other clinically used 132-AR agonists: fenoterol and salbutamol. Clenbuterol (30 μM) produced a negative inotropic response, whereas fenoterol showed a positive inotropic response. Salbutamol had no significant effects. Clenbuterol reduced Ca[sup2+] transient amplitude and L-type Ca[sup2+] current. Selective β1-AR blockade did not affect the action of clenbuterol on sarcomere shortening but significantly reduced contractility in the presence of fenoterol and salbutamol (P < 0.05). Incubation with 2 μg/ml pertussis toxin significantly reduced the negative inotropic effects of 30 μM clenbuterol. In addition, overexpression of inhibitory G protein (G[subi]) by adenoviral transfection induced a stronger clenbuterol-mediated negative inotropic effect, suggesting the involvement of the G, protein. We conclude that clenbuterol does not increase and, at high concentrations, significantly depresses contractility of isolated ventricular myocytes, an effect not seen with fenoterol or salbutamol. In its negative inotropism, clenbuterol predominantly acts through G[subi], and the consequent downstream signaling pathways activation may explain the beneficial effects observed during chronic administration of clenbuterol in patients treated with LVADs. [ABSTRACT FROM AUTHOR]

Abstract: Capillary electrophoresis (CE) with UV detection for the simultaneous and short-time analysis of clenbuterol, salbutamol, procaterol, fenoterol is described and validated. Optimized conditions were found to be a 10mmoll−1 borate buffer (pH 10.0), an separation voltage of 19kV, and a separation temperature of 32°C. Detection was set at 205nm. Under the optimized conditions, analyses of the four analytes in pharmaceutical and human urine samples were carried out in approximately 1min. The interference of the sample matrix was not observed. The LOD (limits of detection) defined at S/N of 3:1 was found between 0.5 and 2.0mgl−1 for the analytes. The linearity of the detector response was within the range from 2.0 to 30mgl−1 with correlation coefficient >0.996. [Copyright &y& Elsevier]

Objectives: In countries with high income, tocolytic therapy with β-mimetic agents is a cost-effective strategy compared to placebo. In our study, the cost-effectiveness of two β-mimetic agents, ritodrine and fenoterol, used in the management of preterm labor was compared in the setting of a low–middle-income transitional country, Serbia & Montenegro. Methods: This case study was conducted at the Gynecology-Obstetrics Clinic, Clinical Center “Kragujevac,” in Kragujevac, Serbia & Montenegro, between October 2004 and January 2006. In total, 235 pregnant patients with threatened preterm labor were enrolled, but 35 were lost to follow-up. Of the remaining 200 patients, 85 were given ritodrine, and 115 fenoterol. The perspective of Republic Institute for Health Insurance in Serbia was taken into account. Only direct costs were calculated; primary outcomes of the study were length of pregnancy (in weeks), time passed from the onset of uterine contractions to delivery (in weeks), and score on modified Flanagan's quality-of-life scale for chronic diseases, measured after discharge from hospital. Results: Prolongation of pregnancy was significantly longer in the fenoterol group (12.7 ± 8.4 weeks) than in the ritodrine group (11.6 ± 7.1 weeks). The mean duration of hospitalization was shorter in the fenoterol group (11.9 ± 8.8 days) than in the ritodrine group (14.9 ± 11.3 days). The treatment with fenoterol was less costly and more cost-effective than the treatment with ritodrine, but the difference in cost-effectiveness was not statistically significant. The cost of treatment per gained week of pregnancy prolongation was 3345.51 ± 7668.04 CSD in the fenoterol group, and 4181.96 ± 12,069.83 CSD in the ritodrine group. Conclusions: The observed differences in treatment costs and duration of hospitalization per patient did not translate into significant differences in cost-effectiveness ratios, because of low costs of hospitalization and human labor in Serbian health system. Nevertheless, fenoterol treatment still has a tendency to be more cost-effective, and its lower acquisition cost is an advantage to this treatment option. [ABSTRACT FROM AUTHOR]

An increase in asthma mortality in 1960s noted by British authors stirred a debate about the use of beta-adrenergic therapy that has persisted in the medical literature. The cause appears to be isoproterenol and fenoterol overuse. A second debate evolved around the possible deleterious, pro-inflammatory effects, of the albuterol distomer. Most clinical studies showed improved bronchodilatation, but limited benefits from using levalbuterol. Recently, genotyping has uncovered a single nucleotide polymorphism at codon 16 that appears to affect the long term response to both regular and as needed use of albuterol, calling for a new genotype based therapeutic approach in asthma. [ABSTRACT FROM AUTHOR]

Abstract: Sphingosine 1-phosphate (S1P), a lysophospholipid mediator that signals through G protein-coupled receptors, regulates a wide plethora of biological responses such as angiogenesis and immune cell trafficking. Detection and quantification of S1P in biological samples is challenging due to its unique physicochemical nature and occurrence in trace quantities. In this report, we describe a new method to selectively enrich S1P and dihydro-S1P from biological samples by the Fe3+ gel immobilized metal affinity chromatography (IMAC). The eluted S1P from IMAC was dephosphorylated, derivatized with o-phthalaldehyde (OPA), and detected by high-performance liquid chromatography (HPLC) coupled to a fluorescence detector. IMAC purification of S1P was linear for a wide range of S1P concentration. Using this assay, secretion of endogenous S1P from endothelial cells, fibroblasts and colon cancer cells was demonstrated. We also show that dihydro-S1P was the major sphingoid base phosphate secreted from HUVEC over expressed with Sphk1 cDNA. Pharmcological antagonists of ABC transporters, glyburide and MK-571 attenuated endogenous S1P release. This assay was also used to demonstrate that plasma S1P levels were not altered in mice deficient for ABC transporters, Abca1, Abca7 and Abcc1/Mrp1. IMAC-based affinity-enrichment coupled with a HPLC-based separation and detection system is a rapid and sensitive method to accurately quantify S1P. [Copyright &y& Elsevier]

The article reports on the results of a study of the effects of short-acting bronchodilators added to maintenance tiotropium therapy. A description of study methods is presented. The study concluded that short-acting bronchodilator classes were effective when added to maintenance treatment with tiotropium. Also, beta2-adrenergic fenoterol provided greater additional bronchodilation than the short-acting anticholinergic ipratropium.

The structure of fenoterol, a 2-adrenoceptor agonist used in therapy, has been joined with furoxan NO-donor moieties to give new NO-donor 2-agonists. The furazan analogues, devoid of the property to release NO, were also synthesized for comparison. All the compounds retained 2-agonistic activity at micromolar or submicromolar concentration when tested on guinea pig tracheal rings precontracted with carbachol. Among the furoxan derivatives, the NO contribution to trachea relaxation was evident with product 15bat micromolar concentrations. All the new NO-donor hybrids were able to dilate rat aortic strips precontracted with phenylephrine. Both furoxan and furazan derivatives displayed antioxidant activity greater than that of fenoterol. [ABSTRACT FROM AUTHOR]

Stimulating the β-adrenoceptor (β-AR) signaling pathway can enhance the functional repair of skeletal muscle after injury, but long-term use of β-AR agonists causes β-AR downregulation, which may limit their therapeutic effectiveness. The aim was to examine β-AR signaling during early regeneration in rat fast-twitch [extensor digitorum longus (EDL)] and slow-twitch (soleus) muscles after bupivacaine injury and test the hypothesis that, during regeneration, β-agonist administration does not cause β-AR desensitization. Rats received either the β-AR agonist fenoterol (1.4 mg·kg-1day-1 ip) or saline for 7 days postinjury. Fenoterol reduced β-AR density in regenerating soleus muscles by 42%. Regenerating EDL muscles showed a threefold increase in β-AR density, and, again, these values were 43% lower with fenoterol treatment. An amplified adenylate cyclase (AC) response to isoproterenol was observed in cell membrane fragments from EDL and soleus muscles 7 days postinjury. Fenoterol attenuated this increase in regenerating EDL muscles but not soleus muscles. β-AR signaling mechanisms were assessed using AC stimulants (NaF, forskolin, and Mn2+). Although β-agonist treatment reduces β-AR density in regenerating muscles, these muscles can produce large cAMP responses relative to healthy (uninjured) muscles. Desensitization of β-AR signaling in regenerating muscles is prevented by altered rates of β-AR synthesis and/or degradation, changes in G protein populations and coupling efficiency, and altered AC activity. These mechanisms have important therapeutic implications for modulating β-AR signaling to enhance muscle repair after injury. [ABSTRACT FROM AUTHOR]

Abstract: Fenoterol and salbutamol were determined by electrogenerated chemiluminescence (ECL) coupled with flow injection analysis (FIA), using Ru(bpy)3 2+ as the luminescent substance. Fenoterol and salbutamol oxidize together with the ruthenium 2,2-bipyridyl at a platinum electrode, which leads to an increase in the luminescent intensity, and this increase is proportional to the analyte concentration. For fenoterol a linear calibration curve within the range from 1.0×10−5 to 1.0×10−4 moll−1 was obtained with a correlation coefficient of 0.998 (n =5) and for salbutamol the linear analytical curve was also obtained in this range with a correlation coefficient of 0.995 (n =5). The relative standard deviation was estimated as ≤2.5% for 3×10−5 moll−1 for fenoterol solution and as ≤1.3% for 5.0×10−5 moll−1 salbutamol solution for 15 successive injections. The limit of detection for fenoterol was 2.4×10−7 moll−1 and for salbutamol was 4.0×10−7 moll−1. Fenoterol and salbutamol were successfully determined in drug tablets and the soluble components of the matrix did not interfere in the luminescent emission. The results obtained using the luminescent methodology were not statistically different from those obtained by UV-spectrophotometry at 95% confidence level. [Copyright &y& Elsevier]

Stereoisomers of fenoterol and six fenoterol derivatives have been synthesized and their binding affinities for the 2adrenergic receptor (Ki2-AR), the subtype selectivity relative to the 1-AR (Ki1-AR/Ki2-AR) and their functional activities were determined. Of the 26 compounds synthesized in the study, submicromolar binding affinities were observed for (R,R)-fenoterol, the (R,R)-isomer of the p-methoxy, and (R,R)- and (R,S)-isomers of 1-naphthyl derivatives and all of these compounds were active at submicromolar concentrations in cardiomyocyte contractility tests. The Ki1-AR/Ki2-AR ratios were >40 for (R,R)-fenoterol and the (R,R)-p-methoxy and (R,S)-1-naphthyl derivatives and 14 for the (R,R)-1-napthyl derivative. The binding data was analyzed using comparative molecular field analysis (CoMFA), and the resulting model indicated that the fenoterol derivatives interacted with two separate binding sites and one steric restricted site on the pseudo-receptor and that the chirality of the second stereogenic center affected Ki2and subtype selectivity. [ABSTRACT FROM AUTHOR]

Abstract: Albuterol is a β2-adrenoceptor agonist prescribed for the treatment of bronchial asthma; it exists as a racemate and its bronchodilator activity resides in the (R)-isomer or levalbuterol. The aim of this study was to determine a methodology that would separate the enantiomers of albuterol by preferential crystallization after a conglomerate is identified within its derivatives. We found that albuterol sulfate behaves as a conglomerate showing the characteristic α x-value=2 (mole fraction solubility ratio of racemate vs enantiomer), the V-shaped ternary phase diagram and the preferential crystallization by seeding with the pure enantiomer. On the basis of these characteristics, we separated the enantiomers by entrainment, and crystallizing out a saturated methanolic solution of albuterol sulfate at 15°C. [Copyright &y& Elsevier]

In rat ventricular cardiomyocytes β2-adrenoceptors (AR) couple to Gs- and Gi-protein, and evidence has accumulated that β2-AR agonists can differentially activate either Gs- or Gs- and Gi-protein.In this study, in isolated adult rat ventricular cardiomyocytes, we assessed the effects of pertussis toxin (PTX) on β2-AR agonist (terbutaline (TER), salbutamol (SAL) and fenoterol (FEN)) evoked inhibition of phenylephrine (PE)-induced increase in the rate of protein synthesis (assessed as [3H]phenylalanine incorporation) to find out which β2-AR agonist activates selectively Gs- or Gs- and Gi-protein.PE (1 μM) increased the rate of protein synthesis from 100% to 130±2% (n=34). FEN, TER and SAL (1 nM–10 μM) inhibited PE-induced increase in the rate of protein synthesis concentration-dependently. FEN inhibited PE effects almost completely (from 132±3 to 101±1%), whereas TER and SAL caused only partial inhibition (from 131±2 to 114±2 and 129±1 to 111±2%, respectively).Pretreatment of cardiomyocytes with PTX (250 ng ml−1 for 16 h at 37°C) did not affect FEN effects, but converted TER- and SAL-evoked partial inhibition into complete inhibition.Inhibitory effects of the three β2-AR agonists were markedly attenuated by β1-AR selective antagonist CGP 20712A (CGP) (300 nM); in contrast, β2-AR selective antagonist ICI 118,551 (55 nM) inhibited the inhibitory effects of the three β2-AR agonists only in PTX-pretreated cardiomyocytes,with β1-AR blocked by CGP.We conclude that, in adult rat ventricular cardiomyocytes, FEN activates selectively the Gs protein-pathway, while TER and SAL activate the Gs- and Gi-protein pathways. Part of the effects of these three β2-AR agonists appears to be mediated by β1-AR.British Journal of Pharmacology (2006) 147, 714–719. doi:10.1038/sj.bjp.0706674; published online 6 February 2006 [ABSTRACT FROM AUTHOR]

Abstract: Background:: Drugs that stimulate the β2-adrenergic receptor have been reported to prolong the QT interval corrected for heart rate (QTc interval), a potential mechanism for cardiac toxicity. Objective:: This study evaluated whether β2-adrenergic agonist drugs prolong the QTc interval when different correction formulas for the effect of heart rate are used. Methods:: Healthy subjects of both sexes aged 19 to 33 years were recruited with advertisements. In pilot studies, subjects took a preparation containing the β2-agonist ephedrine, or they participated in a postural study of the effect of endogenous β-agonists. The study-drug group took 3 pills of the ephedra preparation per day for 2 days and then 6 pills per day for the next 2 days. Electrocardiograms (ECGs) were recorded before and at 1, 3, and 82 hours after the first study-drug dose and both before and after standing in the standing-up group. QT intervals obtained by automatic measurement were corrected for heart rate with 3 formulas: Bazett (QTc[B]), Framingham (QTc[F]), and Fridericia (QTc[Fr]). For the literature review, PubMed was searched using the search terms β2-agonist drugs, QT, QTc, EKG, ECG, or electrocardiogram for studies that reported prolongation of the QTc by β2-agonist drugs. We analyzed the method by which 11 different studies corrected QT interval for heart rate after the use of formoterol, salmeterol, terbutaline, salbutamol, and fenoterol. Results:: The ephedra study included 20 healthy subjects (35% men; mean [SD] age, 25 [4] years). Two hours after the last dose, QTc(B) had increased significantly from baseline by 19 ms (P = 0.02). QTc(F) and QTc(Fr) did not change significantly. In the postural study, 19 healthy subjects (68% men; mean [SD] age, 32 [8] years) stood up and QTc(B) increased by a mean (SD) of 8 (15) ms (P = 0.03). In these subjects, the QTc(B)/RR regression slope was significantly different from 0 (r = 0.60, P = 0.002), and the Bazett formula did not eliminate the dependence of QTc on heart rate. However, QTc(F) and QTc(Fr) did not change significantly, meaning that these formulas eliminated the dependence of QTc on heart rate. Eleven publications reported prolongation of QTc(B) by 5 β2-adrenergic agonists for asthma. The change in QTc(B) interval from these publications was still dependent on the change in heart rate (r = 0.63, P = 0.004), but this dependence was eliminated after using QTc(F) and QTc(Fr). The increase in QTc(B) would have been up to 30 ms less if QTc(F) or QTc(Fr) had been reported instead. Conclusions:: The Bazett correction is the one typically reported by computerized ECG machines and the medical literature. This review suggests that QTc(B) may overestimate QTc when heart rate increases. Because the β2-adrenergic agonist drugs increase heart rate, a systematic bias may have implicated these drugs in prolongation of cardiac repolarization. Prospective, large studies with a placebo and active control group are needed to evaluate the effect of β2 agonists on QTc using formulas other than Bazett. [Copyright &y& Elsevier]

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Abstract: Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 μM) of fenoterol decreased isoprenaline-induced maximal relaxation (E max) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the β2-adrenoceptor. Preincubation with 1 μM of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) caused a small but significant decrease in isoprenaline-induced E max, indicating activated PKC-mediated heterologous β2-adrenoceptor desensitization. To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 μM PMA and 1 μM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E max of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the β2-adrenergic receptor can be enhanced by PKC activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to β2-adrenoceptor agonists in patients with asthma during a severe exacerbation. [Copyright &y& Elsevier]

Purpose: The new β2 radioligand (R,R)(S,S) 5-(2-(2-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylethylamino)-1-hydroxyethyl)-benzene-1,3-diol ([18F]FE-fenoterol; [18F] FEFE), a fluoroethylated derivative of racemic fenoterol, was evaluated in vivo and ex vivo using a guinea pig model. Methods: Dynamic PET studies over 60 min with [18F]FEFE were performed in nine Hartley guinea pigs in which a baseline (group 1, n=3), a predose (group 2, n=3; 2 mg/kg fenoterol 5 min prior to injection of [18F]FEFE) or a displacement study (group 3, n=3; 2 mg/kg fenoterol 5 min post injection of [18F]FEFE) was conducted. Results: In all animal groups, the lungs could be visualised and semi-quantified separately by calculating uptake ratios to non-specific binding in the neck area. Premedication with non-radioactive fenoterol and displacement tests showed significant reduction of lung uptake, by 94% and 76%, respectively. Conclusion: These data demonstrate specific binding of the new radioligand to the pulmonary β2-receptors in accordance with ex vivo measurements. Therefore, [18F]FEFE seems to be suitable for the in vivo visualisation and quantification of the pulmonary β2-receptor binding in this animal model. [ABSTRACT FROM AUTHOR]

Abstract: A simple method for the simultaneous detection of four β2-agonists (salbutamol, fenoterol, clorprenaline, and clenbuterol) using ion chromatography (IC) with direct conductivity detection (CD) based on their ionization in acidic medium without chemical suppression is presented. The mixture of 1.8mM HNO3 and 2% (v/v) acetonitrile was used as eluent. The method could be applied to the determination of the β2-agonists in pharmaceutical preparations. The recovery of salbutamol and clenbuterol in tablets was more than 97% (n =3) and the relative standard deviation (n =11) less than 2.8%. With the proposed method, salbutamol could also be successfully detected in human plasma. In a single chromatographic run, the four β2-agonists can be separated and determined in less than 8min. The linear ranges were of 7.0–1.4×103 ng/ml for salbutamol, 34–7.8×103 ng/ml for fenoterol, 8.0–1.6×103 ng/ml for clorprenaline, and 25–7.5×103 ng/ml for clenbuterol. The detection limits were 2.0ng/ml for salbutamol, 10ng/ml for fenoterol, 3.0ng/ml for clorprenaline, and 10ng/ml for clenbuterol. [Copyright &y& Elsevier]

Purpose. The compatibility, pH, and osmolality of N-acetylcysteine (NAC) nebulizing solution in the presence of ipratropium bromide or fenoterol hydrobromide were studied. Methods. Portions (400 μL) of each mixture were sampled immediately upon mixing and one, two, three, four, five, six, and seven hours after mixing and assayed by high-performance liquid chromatography. Osmolality was measured by sampling 100 μL from the filling cup at a five-minute interval during nebulization and by the freezing-point-depression method. Results. Adding NAC solution to fenoterol solution raised the pH from 3.20 to 7.90 and the osmolality to a mean ± S.D. of 1400.67 ± 4.51 mOsm/kg. Fenoterol concentrations decreased to 93.71% and NAC concentrations to 92.54% of initial concentrations after seven hours. Mixing ipratropium with NAC solution raised the pH from 3.74 to 7.95 and the osmolality to a mean ± S.D. of 1413 ± 11.79 mOsm/kg. The initial ipratropium concentration declined 7.39% and 10.91% one and two hours after mixing with NAC solution, respectively. Conclusion. NAC and ipratropium were stable in nebulizing solution within one hour of mixing. NAC and fenoterol were compatible for at least seven hours. [ABSTRACT FROM AUTHOR]

Asthma and chronic obstructive pulmonary disease (COPD) can be effectively treated by the use of bronchodilator therapies delivered by inhalation. Berodual® is a fixed combination of the anticholinergic agent ipratropium bromide (IB) and the β2-adrenergic agonist fenoterol hydrobromide (FEN). IB/FEN has been available for the treatment of asthma and COPD in a pressurised metered dose inhaler (MDI) [pMDI] formulation for many years. The pMDI is the most widely used device for the delivery of inhaled medications, such as IB/FEN. However, most conventional pMDIs contain chlorofluorocarbon (CFC) propellants, which are currently being withdrawn because of their detrimental effects on the environment. This has resulted in alternative methods of drug delivery being developed. Respimat® Soft Mist™ Inhaler (SMI) is a new generation, propellant-free inhaler that generates a fine, slow-moving cloud (the Soft Mist™) which can be easily inhaled. Scintigraphic studies have shown that this improves deposition of drugs in the lung and results in less oropharyngeal deposition than the CFC-MDI. A clinical development programme has been conducted to compare the efficacy and safety of IB/FEN delivered via Respimat® SMI with that of IB/FEN via CFC-MDI in the treatment of patients with asthma or COPD. Five clinical studies (two phase II and three phase III) investigated dosages of IB/FEN 5/12.5μg to 320/800μg via Respimat® SMI in single and multiple dose administration regimens. Four of the trials were conducted in patients with asthma (three in adults and one in children), while one phase III trial was conducted in patients with COPD. In phase III, 2058 patients participated, with a total of 1112 patients treated with IB/FEN via Respimat® SMI. In the phase III studies, each dose from Respimat® SMI was given in one actuation compared with two actuations with the CFC-MDI. In the paediatric asthma phase III study, all CFC-MDI doses were delivered via a spacer device. The results of the trials demonstrated that IB/FEN via Respimat® SMI allows a reduction in the nominal dose of IB/FEN, while offering similar therapeutic efficacy and safety to a CFC-MDI. In children, Respimat® SMI obviates the need for a spacer. [ABSTRACT FROM AUTHOR]

Objective: To characterise the phytotherapeutic tocolytic Bryophyllum pinnatum in vitro versus the conventional betamimetic, fenoterol, in human myometrium. Study design: Contractility (endpoints: area under the curve (AUC), amplitude and frequency of isometric force development) was measured in strips of term myometrium biopsied at caesarean section in 14 women and exposed to increasing concentrations of B. pinnatum versus fenoterol±oxytocin 1 U/l. Results: Inhibition of spontaneous contraction by B. pinnatum was concentration-dependent: 16% at maximum concentration (104 mg/l), or 53% that with fenoterol 5×10−8 mol/l. B. pinnatum increased contraction frequency by 91% at constant amplitude and inhibited oxytocin-stimulated contractions by 20% (AUC) at constant amplitude with slightly decreased frequency. Fenoterol decreased contraction AUC by 50% with a significant decrease in frequency. Conclusion: Our in vitro data confirm the tocolytic activity of B. pinnatum observed in alternative medicine centres and may justify further clinical studies. [Copyright &y& Elsevier]

Objective: In critically ill patients adrenergic agonists are used to treat haemodynamic disorders. Their metabolic actions should be considered in controlling metabolic homeostasis. Dopexamine has assumed effects on carbohydrate, fat and protein metabolism. The aim of this study was to define its metabolic actions and compare these with those of fenoterol by using a stable isotope dilution technique.Design: Prospective, randomized experimental study.Setting: Experimental section of a university anaesthesiology department.Participants: Twenty-seven healthy male volunteers in three groups with nine participants each.Interventions: Participants received a 4-h infusion of dopexamine (2.25 microg/kg per min), fenoterol (at least 0.025 microg/kg per min) or saline.Measurements and Results: Before and every 80 min during drug infusion, we measured endogenous glucose production and the plasma appearance rates for leucine and urea. In addition, we measured plasma concentrations of glucose, lactate, free fatty acids (FFAs), noradrenaline, adrenaline, insulin, glucagon and potassium. Endogenous glucose production did not differ among the groups. Glucose plasma concentration and glucose clearance remained constant during the dopexamine infusion. Fenoterol increased glucose plasma concentration and decreased glucose clearance. Lactate, FFAs, insulin and noradrenaline plasma concentrations were increased and the rate of leucine appearance was decreased by both drugs. The rate of urea appearance did not differ from the control group.Conclusions: Dopexamine has no or only weak effects on carbohydrate metabolism, its effects on fat and protein metabolism are comparable to those of fenoterol. This metabolic profile may be advantageous in increasing cardiac output in patients with impaired glucose tolerance. [ABSTRACT FROM AUTHOR]

The β2-adrenoceptor agonist (β2-agonist) fenoterol has potent anabolic effects on rat skeletal muscle. We conducted an extensive dose-response study to determine the most efficacious dose of fenoterol for increasing skeletal muscle mass in adult rats and used this dose in testing the hypothesis that fenoterol may have therapeutic potential for ameliorating age-related muscle wasting and weakness. We used adult (16-month-old) rats that had completed their growth and development, and old (28-month-old) rats that exhibited characteristic muscle wasting and weakness, and treated them daily with either fenoterol (1.4 mg kg-1, I.P), or saline vehicle, for 4 weeks. Following treatment, functional characteristics of fast-twitch extensor digitorum longus (EDL) and predominantly slow-twitch soleus muscles of the hindlimb were assessed in vitro. Untreated old rats exhibited a loss of skeletal muscle mass and a decrease in force-producing capacity, in both fast and slow muscles, compared with adult rats (P < 0.05). However, there was no age-associated decrease in skeletal muscle β-adrenoceptor density, nor was the muscle response to chronic β-agonist stimulation reduced with age. Thus, muscle mass and forceproducing capacity of EDL and soleus muscles from old rats treated with fenoterol was equivalent to, or greater than, untreated adult rats. The increase in mass and strength was attributed to a non-selective increase in the cross-sectional area of all muscle fibre types, in both the EDL and soleus. Fenoterol treatment caused a small increase in fatiguability due to a decrease in oxidative metabolism in both EDL and soleus muscles, with some cardiac hypertrophy. Further studies are needed to fully separate the desirable effects on skeletal muscle and the undesirable effects on the heart. Nevertheless, our results demonstrate that fenoterol is a powerful anabolic agent that can restore muscle mass... [ABSTRACT FROM AUTHOR]

Although many β1-receptor antagonists and β2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of β-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of human β-adrenergic receptors in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three β-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the β-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three β-receptor subtypes. In particular, a number of β2- or β3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, β1-receptor antagonists with agonistic activity at β2- and β3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. [ABSTRACT FROM AUTHOR]

Background: Formoterol is a long-acting (≥12 hours) beta2-receptor agonist with a rapid onset of action (1–3 minutes). It is approved in the United States, delivered via a single-dose dry-powder inhaler (DPI), for use in combination with anti-inflammatory therapy for the maintenance treatment of asthma and for the prevention of exercise-induced bronchospasm. Potential exposure of patients to higher doses than are currently approved is an important consideration in assessing the safety profile of formoterol.Objective: This article reviews data from clinical trials investigating the effects of short-term use (4–48 hours) of high doses of formoterol (maximum, 228 μg).Methods: Comparative and noncomparative studies of the effects of short-term, high-dose formoterol, inhaled via metered-dose inhaler (MDI) or single-dose DPI, were identified through searches of the literature indexed on MEDLINE, EMBASE, Current Contents, and Science Citation Index from their inception through August 15, 2003.Results: This review included 1 open-label noncomparative study of high-dose formoterol in 12 healthy volunteers (mean age, 29 years), 1 placebo-controlled dose-escalation study of formoterol in 20 patients with asthma (mean age, 30 years), and 3 comparative studies of formoterol and short-acting beta2-agonists. The latter included a dose-escalation study in 13 patients with asthma (mean age, 47.2 years), a high-dose study in 12 healthy volunteers (mean age, 27 years), and a dose-escalation study in 9 children with asthma (mean age, 10 years). In the study in healthy volunteers, the metabolic and cardiovascular effects of high single doses of formoterol (maximum, 120 μg) were small and had no clinical consequences. In the placebo-controlled dose-escalation study in patients with asthma, however, the metabolic effects of formoterol at doses from 24 to 96 μg and the cardiovascular effects of formoterol at doses from 48 to 96 μg differed significantly from those of placebo (P < 0.05 to P <0.001) but were unlikely to result in clinically significant adverse effects. In the studies comparing formoterol with short-acting beta2-agonists in patients with stable asthma, the cardiovascular and metabolic effects of short-term, high-dose formoterol (cumulative dose, up to 228 μg) were comparable to those of high-dose albuterol (salbutamol) (cumulative dose, up to 3800 μg). Studies of high-dose formoterol delivered via multidose DPI (not available in the United States) have reported a safety profile similar to those of high-dose terbutaline and albuterol.Conclusion: In studies of the short-term use of high-dose formoterol delivered via an MDI or single-dose DPI, this agent had a safety profile comparable to that of short-acting beta2-agonists. [Copyright &y& Elsevier]

A sensitive and rapid spectrophotometric procedure has been investigated for the determination of fenoterol either per se or in pharmaceutical preparations. The proposed procedure is based on the reaction between the drug and 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) at pH 7.2, using borate buffer, to produce a yellow adduct. The latter has maximum absorbance at 400 nm and obeys Beer''s law within the concentration range 5–30 μg/ml. Regression analysis of the calibration data showed a good correlation coefficient (r=0.9996) with minimum detection limit of 0.24 μg/ml (6.2×10−8 M). The proposed procedure has been successfully applied to the determination of this drug in its tablets and in syrup, the mean percent recoveries were 97.45±0.59 and 98.7±0.64%, respectively. The results obtained are in good agreement with those given using a reference method. The pharmaceutical additives other than active ingredient did not interfere. A proposal of the reaction pathway has been postulated. [Copyright &y& Elsevier]

Objectives. Respimat® (RMT) soft mist inhaler (SMI) is a novel, propellant-free alternative to chlorofluorocarbon metered-dose inhalers (CFC-MDIs). The aim of this study was to evaluate the safety and establish the equipotent dose of fenoterol delivered by RMT SMI vs. a conventional MDI. DESIGN: Double-blind, randomized, crossover, comparative study between fenoterol inhaled via RMT (either 50 µg/actuation, RMT50; or 100 µg/actuation, RMT100) and MDI (100 µg/actuation; MDI100). Patients and interventions. A total of 41 asthma patients received cumulative doses of fenoterol 600 µg (RMT50) or 1200 µg (RMT100 and MDI100) on 3 test days. Measurements and results. The bronchodilator response (forced expiratory volume in 1 second [FEV1]) was considered therapeutically equivalent (i.e., noninferior) if the 95% confidence intervals for the difference in their mean changes from baseline were within limits of ± 0.15 L. Systemic exposure was evaluated from plasma fenoterol levels. Adverse events (AEs) were recorded. RMT50 and RMT100 produced noninferior bronchodilatation to MDI100 from 30 minutes after the first dose. RMT50 showed equivalent safety and tolerability to MDI100, whereas RMT100 produced a higher incidence of AEs, a significantly greater plasma potassium reduction and a significant increase in pulse rate. Fenoterol plasma levels were twice as high with RMT100 as with RMT50 or MDI100. CONCLUSIONS: The nominal dose of fenoterol administered via RMT SMI can be at least halved to achieve equivalent efficacy, safety, and tolerability to a MDI. [ABSTRACT FROM AUTHOR]

The 18F-labeled β2-adrenergic receptor ligand (R,R)(S,S) 5-(2-(2-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylethylamino)-1-hydroxyethyl)-benzene-1,3-diol, a derivative of the original highly selective racemic fenoterol, was synthesized in an overall radiochemical yield of 20% after 65 min with a radiochemical purity higher than 98%. The specific activity was in the range of 50–60 GBq/μmol. In vitro testing of the non-radioactive fluorinated fenoterol derivative with isolated guinea pig trachea was conducted to obtain an IC50 value of 60 nM. Preliminary ex vivo organ distribution and in vivo experiments with positron emission tomography (PET) on guinea pigs were performed to study the biodistribution as well as the displacement of the radiotracer to prove specific binding to the β2-receptor. [Copyright &y& Elsevier]

The present study investigates the population of [beta]2-receptors on lymphocytes in pregnant women with premature labor between the 29th and 34th week of pregnancy. The population of receptors on lymphocytes correlates with that on the myometrium,which is not accessible for study during pregnancy. Fourteen patients received a pulsatile tocolysis,while ten women received a continuous tocolysis with Fenoterol. Assuming an equal population of receptors in both groups before commencement of therapy, the numbers of receptors in the patients with continuous tocolysis fell to about 35% of the initial value after 72 hours.Under pulsatile tocolysis,the numbers of receptors remained unchanged for a period of three days and was still only just below 70% of the initial value by the seventh day. Our data demonstrate that continuous administration of the shortacting [beta]2-agonist Fenoterol resulted in asubstantial loss of [beta]2-adrenoceptors on lymphocytes. In contrast, intermittent administration of the same [beta]2-adrenergic agonist prevented the onset of receptor downregulation in pregnant women with preterm labor. Further studies are required to investigate the impact of the decreased loss of [beta]2-adrenoceptor density on the good clinical experience with intermittent tocolysis. [ABSTRACT FROM AUTHOR]

Objective: To compare the maternal and fetal side effects of transdermal nitroglycerin and intravenous fenoterol combined with magnesium sulfate in a prospective randomised study. Study design: Fifty pregnant women between 27 and 35 weeks of gestation with preterm labour were treated with either nitroglycerin (0.4–0.8 mg/h) or fenoterol (60 – 120 μg/h). Outcome parameters were (1) the effects on fetal and maternal heart frequency (FHF / MHF) and blood pressure, and (2) subjective experiences of adverse effects assessed by utilising a questionnaire. Results: In the fenoterol group, elevated mean MHF, FHF and systolic blood pressure were recorded compared to nitroglycerin. Fewer maternal side effects were reported in the nitroglycerin group. Palpitations (82%), tremor (68%) and restlessness (64%) were most common in the fenoterol group (two drop-outs), whereas nitroglycerin caused headaches in 71% of the cases (four drop-outs). Conclusion: Transdermal nitroglycerin appears to be a safe therapy for the mother and fetus and is a promising new option for the treatment of preterm labour. [Copyright &y& Elsevier]

We investigated whether fenoterol was able to enhance contractile responsiveness to neurokinin A (NKA) on the guinea-pig isolated trachea. We then studied the effects of two inhibitors of nuclear factor kappa B (NFκB), gliotoxin and pyrrolidine dithiocarbamate, and of the tachykinin NK1, NK2 and NK3 receptor antagonists, SR 140333, SR 48968 and SR 142801 and determined whether tachykinin receptor gene expression was up-regulated in the trachea after exposure to fenoterol. Fenoterol (0.1 μM, 15 h, 21 °C) induced an increased contractile response to NKA (mean of difference in maximal tension between control and fenoterol ± S.E.M; +0.47 ± 0.14 g, n = 26, P < 0.01). This hyperresponsiveness was strongly reduced by co-incubation with gliotoxin (0.1 μg/ml) or pyrrolidine dithiocarbamate (0.1 mM) and abolished by SR 140333 (0.1 μM) and SR 142801 (0.1 μM). SR 48968 (0.1 μM) diminished the tracheal contractility to NKA but failed to reduce the hyperreactivity induced by fenoterol. Tachykinin NK1 receptor (NK1R), NK2 receptor (NK2R) and NK3 receptor (NK3R) gene expression was analyzed by semiquantitative RT–PCR. Compared to control tissues, NK1R and NK2R mRNA expression was increased by about 1.6-fold and 1.4-fold, respectively, in tissues treated with fenoterol. We were unable to detect the presence of NK3R mRNA in the guinea-pig trachea. In conclusion, fenoterol induces tracheal hyperresponsiveness to NKA and an up-regulation of NK1R and NK2R gene expression. The hyperresponsiveness implicates the NFκB pathway and is abolished by tachykinin NK1 (SR 140333) and NK3 (SR 142801) receptor antagonists. [Copyright &y& Elsevier]

Potential treatments for skeletal muscle wasting and weakness ideally possess both anabolic and ergogenic properties. Although the β[sub 2]-adrenoceptor agonist clenbuterol has well-characterized effects on skeletal muscle, less is known about the therapeutic potential of the related β[sub 2]-adrenoceptor agonist fenoterol. We administered an equimolar dose of either clenbuterol or fenoterol to rats for 4 wk to compare their effects on skeletal muscle and tested the hypothesis that fenoterol would produce more powerful anabolic and ergogenic effects. Clenbuterol treatment increased fiber cross-sectional area (CSA) by 6% and maximal isometric force (P[sub o]) by 20% in extensor digitorum longus (EDL) muscles, whereas fiber CSA in soleus muscles decreased by 3% and Po was unchanged, compared with untreated controls. In the EDL muscles, fenoterol treatment increased fiber CSA by 20% and increased Po by 12% above values achieved after clenbuterol treatment. Soleus muscles of fenoterol-treated rats exhibited a 13% increase in fiber CSA and a 17% increase in Po above that of clenbuteroltreated rats. These data indicate that fenoterol has greater effects on the functional properties of rat skeletal muscles than clenbuterol. [ABSTRACT FROM AUTHOR]

Background: Chronic exposure to fenoterol (FEN), a β[sub 2] -adrenergic receptor (β[sub 2] -AR) agonist, was shown to induce both airway hyperresponsiveness and airway remodeling in experimental animals. Objective: We wanted to know the effects of chronic exposure to procaterol (PRO), a β[sub 2] -AR agonist, on airway function and structure, because this agent is widely used as a bronchodilator in Japan. For comparison, the effects of FEN were also examined. Methods: Aerosolized PRO (0.1 or 1 mg/ml), FEN (1 mg/ml) or vehicle (0.9% NaCl) was given to guinea pigs 3 times a day for 6 weeks. Sublaryngeal deposition of these agents was calculated using radioisotopes. At 72 h after the last inhalation of PRO, FEN or vehicle, the dose-response relationship between lung resistance (R[sub L] ) and intravenously administered acetylcholine (ACh) was measured. After measuring R[sub L] , histological changes in noncartilaginous airway dimensions were evaluated. Results: The amount of sublaryngeal deposition of 0.1 mg/ml PRO in the present study was speculated to be 100 times larger than that of therapeutic dose. ACh concentrations causing 2-fold, 10-fold and maximal increases in R[sub L] were not different in 4 groups tested. In the smaller membranous airways (<0.4 mm in diameter), but not the larger ones, thickening of adventitial areas was significantly greater in animals treated with β[sub 2] -AR agonists than in control animals (23 and 25, and 96% higher in animals treated with 0.1 and 1 mg/ml PRO or 1 mg/ml FEN, respectively). The degree of the increase was significantly less in PRO-treated animals than in FEN-treated animals (p < 0.01). Conclusion: Our results did not provide any evidence that regular inhalation of PRO at the therapeutic dose might induce bronchial hyperresponsiveness. In addition, huge amounts of PRO only caused a mild thickening of the adventitial areas, suggesting that PRO may be a weak inducer of airway remodeling compared with FEN.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A new kind of silica-based restricted-access material (RAM) has been tested in pre-columns for the on-line solid-phase extraction (SPE) of basic drugs from directly injected plasma samples before their quantitative analysis by reversed-phase liquid chromatography (LC), using the column switching technique. The outer surface of the porous RAM particles contains hydrophilic diol groups while sulphonic acid groups are bound to the internal surface, which gives the sorbent the properties of a strong cation exchanger towards low molecular mass compounds. Macromolecules such as proteins have no access to the internal surface of the pre-column due to their exclusion from the pores and are then flushed directly out. The retention capability of this novel packing material has been tested for some hydrophilic basic drugs, such as atropine, fenoterol, ipratropium, procaine, sotalol and terbutaline, used as model compounds. The influence of the composition of the washing liquid on the retention of the analytes in the pre-column has been investigated. The elution profiles of the different compounds and the plasma matrix as well as the time needed for the transfer of the analytes from the pre-column to the analytical column were determined in order to deduce the most suitable conditions for the clean-up step and develop on-line methods for the LC determination of these compounds in plasma. The cationic exchange sorbent was also compared to another RAM, namely RP-18 ADS (alkyl diol silica) sorbent with respect to retention capability towards basic analytes. [Copyright &y& Elsevier]

A new method for the determination of fenoterol is described, which uses HPLC separation with fluorescence detection. Dobutamine is employed as an internal standard. The separation was achieved on a short reversed phase column with a mobile phase consisting of water, acetonitrile and methanol. Prior to chromatography both analytes are derivatized with 9-chloroformyl-carbazole. Isolation of the analytes from plasma is carried out by liquid–liquid extraction into 2-butanol after protein precipitation with acetonitrile. The method is capable of estimating fenoterol concentrations in the sub-nanogram per ml range with sufficient accuracy and precision. The determination of fenoterol can now be carried out in the average laboratory without radiolabelled material. [Copyright &y& Elsevier]

Objectives: To compare the efficacy and tolerability of formoterol (12 or 24µg twice daily) alone with combined ipratropium bromide and fenoterol in the treatment of chronic obstructive pulmonary disease (COPD). Design and Setting: Randomised, parallel-group, open-label study in 10 German centres. Patients: 101 patients with COPD. Interventions: The patients were randomised to receive either formoterol 12µg twice daily or a combination of ipratropium bromide 20µg plus fenoterol 50µg three times daily for 4 weeks. Dosages could be doubled if required. Results: Morning pre-dose airway resistance (R) decreased significantly from 0.87 to 0.66 kPa·L·s with formoterol and from 0.81 to 0.66 kPa·L·s with combined ipratropium bromide and fenoterol (p = ns). The treatment groups were similar with respect to other lung function parameters, daily clinical symptom scores and salbutamol rescue medication. Adverse events occurred in 7/52 (13.5%) of the formoterol and 11/49 (22.4%) of the combination therapy group, and were the reason for study discontinuation in one (1.9%) versus seven (14.3%) patients. The overall discontinuation rate was 5.8% (3/52) with formoterol and 20.4% (10/49) with ipratropium bromide/fenoterol (p = 0.038). Conclusions: The efficacy of formoterol monotherapy was comparable with that of combined ipratropium bromide and fenoterol in the treatment of COPD. Formoterol had a better adverse event profile and a lower rate of discontinuations resulting from adverse events. [ABSTRACT FROM AUTHOR]

A series of phenylethanolamines bearing a 2-[1-phenylpropyl] substituent on the nitrogen atom was evaluated in vitro for activity at β[sub 1] - and β[sub 2] -adrenoceptors. As previously observed, the presence of 3,4-dihydroxy substitution on phenylethanolamine is required for potent activation of both subtypes, whereas the 3,5-dihydroxy analog showed selectivity for the β[sub 2] -subtype. Replacement by a carboxyl group of the 4-hydroxyl group on the aralkyl nitrogen substituent produced only a small reduction in β[sub 1] potency (5-fold), whereas β[sub 2] potency was reduced by more than 100-fold. Hence this structural class includes agonists having either a β[sub 1] , nonselective β[sub 1] /β[sub 2] or β[sub 2] selectivity profile.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]