In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol

被引:27
作者
Aziz, I
Lipworth, BJ [1 ]
机构
[1] Univ Dundee, Ninewells Hosp & Med Sch, Dept Clin Pharmacol & Therapeut, Dundee DD1 9SY, Scotland
[2] Univ Dundee, Ninewells Hosp & Med Sch, Dept Resp Med, Dundee DD1 9SY, Scotland
关键词
asthma; bronchoprotection; antagonism; airways; methacholine; albuterol; salmeterol; formoterol; polymorphism;
D O I
10.1016/S0091-6749(99)70425-2
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: It has been shown in vitro that prior treatment with salmeterol and formoterol antagonizes the relaxant effect of albuterol in carbachol-contracted human bronchi. Objectives: The primary aim of this study was to evaluate whether there is a potential in vivo interaction between long- and short-acting beta(2)-agonists in the presence of increased airway tone induced by methacholine, In addition,a post hoc analysis was made, to evaluate the effects of beta(2)-adrenoceptor polymorphisms. Methods: Sixteen asthmatic subjects (mean age [+/-SD], 39 [13] years; FEV1, 81% [17%] of predicted value), all taking inhaled corticosteroids and having methacholine PD20 values of less than 500 mu g, were randomized in double-blind, double-dummy, cross-over fashion to receive single doses of inhaled placebo, inhaled formoterol 12 mu g, or inhaled salmeterol 50 mu g followed 12 hours later by a single dose of inhaled albuterol 400 mu g (low dose) or 1600 mu g (high dose). Methacholine challenges were performed on each of 6 separate occasions 1 hour after albuterol, Results: There was a greater numerical difference in geometric mean PD20 values between low- and high-dose albuterol after placebo dosing (671 mu g vs 1080 mu g, a 1.61-fold difference; P < .05) compared with low- and high-dose albuterol after formoterol dosing (660 mu g vs 799 mu g, a 1.21-fold difference; P = .4). or after salmeterol dosing (568 mu g vs 847 mu g, a 1.49-fold difference; P = .055). PD20 values with high-dose albuterol in combination with formoterol or salmeterol were numerically Lower than those found with high-dose albuterol in combination with placebo, but they were not significantly different, There was a significant difference between PD20 values with low-dose albuterol after dosing with formoterol (PD20 = 660 mu g, a 1.6-fold difference; P < .05) or with salmeterol (PD20 = 568 mu g, a 19-fold difference; P < .05) compared with PD20 with high-dose albuterol after placebo dosing (PD20 = 1080 mu g). Post hoc polymorphism analysis for pooled pretreatment with formoterol and salmeterol (excluding placebo pretreatment) showed significantly (P < .05) lower PD20 values with homozygous glycine-16 compared with heterozygous glycine/arginine-16 and significantly (P < .05) lower PD20 values with homozygous glutamate-27 compared with either heterozygous glutamate/glutamine-27 or homozygous glutamine-27, Conclusion: Compared with placebo, both salmeterol and formoterol caused a significant degree of antagonism of albuterol-induced bronchorelaxation in methacholine-contracted bronchi in vivo. This interaction could be caused by prolonged occupancy of airway beta(2)-adrenoceptors by long-acting beta(2)-agonists or by early tachyphylaxis 12 hours after a single-dose exposure. The degree of albuterol protection was also related to beta(2)-adrenoceptor polymorphism.
引用
收藏
页码:816 / 822
页数:7
相关论文
共 27 条
[1]  
[Anonymous], 1987, AM REV RESPIR DIS, V136, P225
[2]  
[Anonymous], 1987, Am Rev Respir Dis, V136, P1285
[3]   MEASUREMENT OF AIRWAY RESPONSIVENESS TO METHACHOLINE - RELATIVE IMPORTANCE OF THE PRECISION OF DRUG DELIVERY AND THE METHOD OF ASSESSING RESPONSE [J].
BEACH, JR ;
YOUNG, CL ;
AVERY, AJ ;
STENTON, SC ;
DENNIS, JH ;
WALTERS, EH ;
HENDRICK, DJ .
THORAX, 1993, 48 (03) :239-243
[4]   LONG-TERM EFFECTS OF A LONG-ACTING BETA-2-ADRENOCEPTOR AGONIST, SALMETEROL, ON AIRWAY HYPERRESPONSIVENESS IN PATIENTS WITH MILD ASTHMA [J].
CHEUNG, D ;
TIMMERS, MC ;
ZWINDERMAN, AH ;
BEL, EH ;
DIJKMAN, JH ;
STERK, PJ .
NEW ENGLAND JOURNAL OF MEDICINE, 1992, 327 (17) :1198-1203
[5]   The glutamine 27 beta(2)-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families [J].
Dewar, JC ;
Wilkinson, J ;
Wheatley, A ;
Thomas, NS ;
Doull, I ;
Morton, N ;
Lio, P ;
Harvey, JF ;
Liggett, SB ;
Holgate, ST ;
Hall, IP .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1997, 100 (02) :261-265
[6]  
Dewar JC, 1998, CLIN EXP ALLERGY, V28, P442
[7]   Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment [J].
Drotar, DE ;
Davis, EE ;
Cockcroft, DW .
ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY, 1998, 80 (01) :31-34
[8]   Adenosine monophosphate and histamine induced bronchoconstriction: Repeatability and protection by terbutaline [J].
Egbagbe, E ;
Pavord, ID ;
Wilding, P ;
ThompsonCoon, J ;
Tattersfield, AE .
THORAX, 1997, 52 (03) :239-243
[9]   ADDED SALMETEROL VERSUS HIGHER-DOSE CORTICOSTEROID IN ASTHMA PATIENTS WITH SYMPTOMS ON EXISTING INHALED CORTICOSTEROID [J].
GREENING, AP ;
IND, PW ;
NORTHFIELD, M ;
SHAW, G .
LANCET, 1994, 344 (8917) :219-224
[10]   Evaluation of the beta(2) adrenoceptor agonist antagonist activity of formoterol and salmeterol [J].
Grove, A ;
Lipworth, BJ .
THORAX, 1996, 51 (01) :54-58