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  • Handley, Dean A.Sepracor Inc, Marlborough, MA, USA (author)

Biological actions of formoterol isomers

  • Article/chapterEnglish2002

Publisher, publication year, extent ...

  • Elsevier BV,2002
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-26775
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-26775URI
  • https://doi.org/10.1006/pupt.2001.0327DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

Subject headings and genre

  • ß2 adrenoceptor
  • Asthma
  • Formoterol
  • Isomers
  • Tracheal tissue
  • MEDICINE
  • MEDICIN

Added entries (persons, corporate bodies, meetings, titles ...)

  • Senanayake, Chris HSepracor Inc, Marlborough, MA, USA (author)
  • Dutczak, WilliamSepracor Inc, Marlborough, MA, USA (author)
  • Benovic, Jeffrey LDepartment of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA (author)
  • Walle, ThomasDepartment of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, USA (author)
  • Penn, Raymond B.Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, USA (author)
  • Wilkinson, H. ScottSepracor Inc, Marlborough, MA, USA (author)
  • Tanoury, Gerald J.Sepracor Inc, Marlborough, MA, USA (author)
  • Andersson, Rolf,1943-Linköpings universitet,Farmakologi,Hälsouniversitetet(Swepub:liu)rolan40 (author)
  • Johansson, FredrikLinköpings universitet,Farmakologi,Hälsouniversitetet(Swepub:liu)frejo29 (author)
  • Morley, JohnSackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine and Allergy, Guys, King's and St Thomas' School of Medicine, Denmark Hill, London, UK (author)
  • Sepracor Inc, Marlborough, MA, USADepartment of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA (creator_code:org_t)

Related titles

  • In:Pulmonary Pharmacology & Therapeutics: Elsevier BV15:2, s. 135-1451094-55391522-9629

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