Effect of theophylline administered intratracheally as a dry powder formulation on bronchospasm and airway microvascular leakage in the anesthetized guinea-pig.
The effect of theophylline (a non-selective phosphodiesterase (PDE) inhibitor), dosed intratracheally (it) as a dry powder, on histamine- and platelet activating factor (Paf)-induced bronchospasm and antigen (ovalbumin, OA)-, histamine- and Paf-induced microvascular leakage (MVL) in the airways, was studied in the anaesthetized guinea-pig. Bronchospasm was measured as the increase in pulmonary inflation pressure (PIP). MVL was assessed by fluorometric assay of fluorescein isothiocyanate dextran (FITC-dextran) content in airway tissues and tracheobronchial lavage fluid. OA (200 micrograms), histamine (60 nmol) and Paf (4 nmol), all given it, significantly increased MVL by up to 350% over levels in undosed unchallenged animals. Theophylline (50-500 micrograms it, n = 5-6) inhibited histamine-induced bronchospasm (30% inhibitory dose, ID30: 258 +/- 30 micrograms), and Paf-induced bronchospasm (ID30: 190 +/- 80 micrograms). An inhibition of 40-50% of maximal bronchospasm was the largest attained. Theophylline, at approximately the bronchospasm ID30 dose (200 micrograms it, n = 4-8), inhibited MVL induced by all agents by 30-80% in airway tissues and in lavage fluid samples. Theophylline (50-500 micrograms it, n = 3) produced plasma drug levels of 0.13 +/- 0.07 to 0.83 +/- 0.39 microgram/ml 10 min after dosing. Plasma levels were the same 60 min after dosing, suggesting retention of theophylline in the airways. The local concentration of theophylline retained in the airways should be sufficient to inhibit PDE activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Raeburn
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Rhône-Poulenc Rorer Ltd., Dagenham Research Centre, Essex, UK.
Woodman
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VR
D000704:Analysis of Variance; D000758:Anesthesia; D000818:Animals; D001980:Bronchi / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D001986:Bronchial Spasm / Q000139:chemically induced / Q000517:prevention & control*; D002199:Capillary Permeability / Q000187:drug effects; D003911:Dextrans / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006632:Histamine; D007442:Intubation, Intratracheal; D008297:Male; D010047:Ovalbumin; D011208:Powders; D013806:Theophylline / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014132:Trachea / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism
D003911:Dextrans; D011208:Powders; C015219:fluorescein isothiocyanate dextran; D006632:Histamine; D010047:Ovalbumin; D013806:Theophylline; D016650:Fluorescein-5-isothiocyanate