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TPI 1020, a novel anti-inflammatory, nitric oxide donating compound, potentiates the bronchodilator effects of salbutamol in conscious guinea-pigs.

Abstract
Inhaled corticosteroids are regularly co-administered with beta(2)-adrenoceptor agonists. This study evaluates in conscious guinea-pigs the bronchodilator effect, alone or combined with salbutamol, of TPI 1020, a novel anti-inflammatory corticosteroid and nitric oxide (NO) donor derived from budesonide. Guinea-pigs received inhaled histamine (3 mM) and specific airway conductance (sG(aw)) measured. Responses to histamine were measured before and on the next day 15 min after a 15 min inhalation of vehicle, salbutamol, TPI 1020, budesonide, the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP), or combinations of these drugs. Salbutamol and TPI 1020 caused concentration-dependent bronchodilatation measured as inhibition of histamine-induced bronchoconstriction. TPI 1020-induced bronchodilatation was blocked by the guanylyl cyclise inhibitor, ODQ, indicating cGMP-dependence through released NO. While salbutamol at 80 microM did not exert significant bronchodilatation, significant inhibitions were observed when co-administered with TPI 1020, 0.11 and 0.33 mM. The combined effects of TPI 1020 and salbutamol lasted significantly longer than either drug alone. Inhaled budesonide was a weak bronchodilator and when co-administered with salbutamol there was enhanced bronchodilatation. Addition of the NO-donor, SNAP (0.1 mM), to the budesonide/salbutamol combination, also improved the inhibition of histamine-induced bronchoconstriction. This study has shown that TPI 1020 potentiates the bronchodilator activity of salbutamol, and their combination lasted longer than either drug administered individually. Both the corticosteroid and NO-releasing activities of TPI 1020 appear to be required for the potentiation of salbutamol. Combination of TPI 1020 with a beta(2)-adrenoceptor agonist may therefore be useful against acute bronchoconstriction episodes in asthma, and may offer an opportunity for reducing doses of inhaled beta(2)-adrenoceptor agonists.
AuthorsDawn L Turner, Nicolay Ferrari, William R Ford, Emma J Kidd, Luc Paquet, Paulo Renzi, Kenneth J Broadley
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 641 Issue 2-3 Pg. 213-9 (Sep 1 2010) ISSN: 1879-0712 [Electronic] Netherlands
PMID20639142 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright (c) 2010 Elsevier B.V. All rights reserved.
Chemical References
  • Adrenergic beta-Agonists
  • Anti-Inflammatory Agents
  • Bronchodilator Agents
  • NCX 1020
  • Nitric Oxide Donors
  • Receptors, Adrenergic, beta-2
  • Nitric Oxide
  • Budesonide
  • S-Nitroso-N-Acetylpenicillamine
  • Histamine
  • Cyclic GMP
  • Albuterol
Topics
  • Administration, Inhalation
  • Adrenergic beta-Agonists (pharmacology)
  • Albuterol (administration & dosage, pharmacology, therapeutic use)
  • Animals
  • Anti-Inflammatory Agents (pharmacology, therapeutic use)
  • Asthma (drug therapy)
  • Bronchoconstriction (drug effects)
  • Bronchodilator Agents (administration & dosage, pharmacology, therapeutic use)
  • Budesonide (analogs & derivatives, pharmacology, therapeutic use)
  • Consciousness
  • Cyclic GMP (pharmacology, therapeutic use)
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Guinea Pigs
  • Histamine (pharmacology, therapeutic use)
  • Male
  • Nitric Oxide (pharmacology, therapeutic use)
  • Nitric Oxide Donors (pharmacology, therapeutic use)
  • Receptors, Adrenergic, beta-2 (therapeutic use)
  • S-Nitroso-N-Acetylpenicillamine (pharmacology)

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