Effects of cyclosporin A administered into the airways against antigen-induced airway inflammation and hyperreactivity in the rat.
The immunosuppressant cyclosporin A given orally has anti-asthma properties but carries an undesirable risk of systemic effects. We administered cyclosporin A to Brown Norway rats either orally (p.o.) or topically by intratracheal (i.t.) instillation into the airways before inhaled antigen. Cyclosporin A suppressed the antigen-induced accumulation of activated (CD25+) CD4+ T lymphocytes and eosinophils in the lung, interleukin-5 mRNA expression in lung tissue and airway hyperreactivity. Intratracheal cyclosporin A suppressed cell accumulation at a 10-fold lower dose than that required orally. Minimum effective doses were 3 mg x kg(-1) i.t. and 30 mg x kg(-1) p.o. Intratracheal administration reduced the plasma concentration and systemic exposure compared with an equieffective oral dose, but the reduction (4-5-fold) was not as large as anticipated. Our data suggests that although topical administration to asthmatics would provide some potential for an improved safety margin, it may not offer any major advantage over existing oral therapy. However, the data clearly demonstrate that a novel immunosuppressant with similar anti-inflammatory properties but reduced potential for systemic effects would offer an attractive therapy for severe asthma.
Underwood
S L
SL
Aventis Pharma, Pharmacology Department, Dagenham Research Centre, Rainham Road South, Essex RM10 7XS, Dagenham, UK. stephen.underwood@aventis.com
McMillan
S
S
Reeves
R
R
Hunt
J
J
Brealey
C J
CJ
Webber
S
S
Foster
M
M
Sargent
C A
CA
D000280:Administration, Inhalation; D000818:Animals; D000941:Antigens / Q000008:administration & dosage*; D019540:Area Under Curve; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D001991:Bronchitis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D018801:CD2 Antigens / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000473:pathology; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015848:Interleukin-5 / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D015375:Receptors, Interleukin-2 / Q000032:analysis
D000941:Antigens; D018801:CD2 Antigens; D015704:CD4 Antigens; D007166:Immunosuppressive Agents; D015848:Interleukin-5; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D016572:Cyclosporine