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Biological actions of formoterol isomers
Sepracor Inc, Marlborough, MA, USA.
Sepracor Inc, Marlborough, MA, USA.
Sepracor Inc, Marlborough, MA, USA.
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA.
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2002 (English)In: Pulmonary Pharmacology & Therapeutics, ISSN 1094-5539, E-ISSN 1522-9629, Vol. 15, no 2, 135-145 p.Article in journal (Refereed) Published
Abstract [en]

Racemic β2 agonists, composed of equal amounts of (R)- and (S)-isomers, can display anomalous actions that compromise their effectiveness as asthma therapies. Loss of efficacy during regular use is characteristic of isoprenaline, albuterol and terbutaline and has in part been attributed to the biological effects of the (S)-isomer. This hypothesis was applied to the (R,R)- and (S,S)-isomers of formoterol. (R,R)-formoterol had 1000-times greater affinity (2.9 nm) to the human β2 adrenoceptor than (S,S)-formoterol (3100 nm), with receptor binding modulating intracellular cAMP levels. The minimum lethal intravenous (IV) dose was determined to be 100 mg/kg for (R,R)- and 50 mg/kg for (S,S)-formoterol, suggesting that the toxicity of (S,S)-formoterol may not be related to the binding of β2 adrenoceptors. In tissues pretreated with (S,S)-formoterol but not with (R,R)- or racemic formoterol contractions to high concentrations of carbachol were exaggerated. In vivo experiments with sensitized guinea pigs demonstrated that (R,R)-formoterol inhibited both histamine and antigen-induced bronchoconstriction with greater potency than (R,R/S,S)-formoterol while (S,S)-formoterol was ineffective. Metabolic radiolabeling experiments of (R,R)-, (S,S)- or (R,R/S,S)-formoterol with crude human liver phenolsulfotransferase (PST) determined the Vmax/Km values to be (0.151), (0.74) and (0.143), respectively. The reciprocal plot illustrates a 2-fold reduction in sulfation rate when (R,R)-formoterol is present as a single isomer. The data presented here suggest that (R,R)-formoterol binds to the β2 adrenoceptor and inhibits the contraction of bronchial tissues by spasmogens. However, (S,S)-formoterol exhibits properties inconsistent as an asthma therapeutic and may antagonize the actions of (R,R)-formoterol.

Place, publisher, year, edition, pages
2002. Vol. 15, no 2, 135-145 p.
Keyword [en]
ß2 adrenoceptor, Asthma, Formoterol, Isomers, Tracheal tissue
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26775DOI: 10.1006/pupt.2001.0327Local ID: 11379OAI: oai:DiVA.org:liu-26775DiVA: diva2:247325
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-15Bibliographically approved
In thesis
1. Bronchial hyperresponsiveness of ß-adrenoceptor agonists and antagonists in guinea pig airways
Open this publication in new window or tab >>Bronchial hyperresponsiveness of ß-adrenoceptor agonists and antagonists in guinea pig airways
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Asthma is one of the most common diseases in the industrialised countries. The underlying mechanisms are complex and still not fully understood although inflammation of the airways plays an important role. There are to day several types of drugs used in the treatment of asthma such as anti-inflammatory drugs, specific antagonists for inflammatory mediators and bronchodilators. Beta-agonists are the main choice for relaxing airway constriction, however unwanted effects of beta-agonists on patients with asthma has been reported. The betaantagonists that are used for treatment of hypertension and various other conditions also is shown to be deleterious in asthmatics. In the present study we have used guinea pig airways to examine the proposed deleterious effects of beta-agonists and antagonists. We have shown that the (S)-enantiomeric forms of salbutamol and formoterol are able to potentiate cholinergic stimuli and we have shown that the potentiation was indomethacin sensitive in airway preparations of sensitised guinea pigs. We also showed and confirmed that the (R)-enantiomeric forms of salbutamol and formoterol were more potent in relaxing airway smooth muscle contracted with different stimuli compared to the (S)-enantiomers. The betaantagonists propranolol and pindolol were shown to be able to contract tracheal preparations if they had been pre-treated with a beta-agonist and the contraction was not simply a blockade of the beta-adrenoceptor induced relaxation. Propranolol contraction was stereo-selective and (S)-propranolol was more effective in inducing contraction than (R)-propranolol. Moreover, atenolol a betacselective antagonist induced significantly smaller contractions compared to general beta-antagonists. This indicates that the beta2-adrenocepor probably is involved in the beta-antagonist induced contraction. The cyclooxygenase inhibitor indomethacin, the 5-lipoxygenase inhibitor MK886 and a thromboxane A2 antagonist as well as capsaicin reduced the beta-antagonist induced contraction. This indicates that several arachidonic acid products as well as neuropeptides may be involved in the beta-antagonistinduced contraction.

The worsening of asthma by beta-antagonists is well known and the risks associated with beta-agonists are discussed, but the mechanisms behind these effects need further clarification. In this thesis some of the possible mechanism have been discussed, further studies are needed in order to get more safe and effective asthma treatment regime.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 66 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 780
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27499 (URN)12153 (Local ID)91-7373-541-8 (ISBN)12153 (Archive number)12153 (OAI)
Public defence
2003-04-10, Viktoriasalen, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-15Bibliographically approved

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Andersson, RolfJohansson, Fredrik

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