Beta adrenergic is enough? John W. Jenne,
agents-how
M.D. Hines, 111.
The article by Weber, Petty, and Nelson appearing in this issue of the JOURNAL is not only a precise and useful comparison of the dose of inhaled isoproterenol and terbutaline by several method of administration, but is also a reminder to us that the log-dose response curve extends far beyond the 20% improvement conventionaliy used for diagnosis when the dose is pushed. This prompts the questions: “Under what circumstances should the dose of beta agonists be pushed?” “How much is too much?” Certainly the issue is being forced upon us by the often successful use in some quarters of isoproterenol intravenously in children as a last-ditch pharmacologic effort in status asthmaticus before resorting to assisted ventilation with its own set of hazards. Moreover, the optimum use of inhaled and oral beta agents is far from settled. What information do we have at this date bearing on these questions? If we limit the questions to the effects on bronchospasm, I believe that we are indeed narrowing the areas of uncertainty. Evidence comes from both in vitro and in vivo studies. We should recall the study of Paterson, Courtenay Evans, and Prime2 in their comparison of doubling doses of, first, intravenous isoproterenol and, then, salbutamol, on the FEVi and pulse rate in stable but severe asthmatics. The abrupt cessation of the salbutamol drip was followed by “rebound bronchoconstriction” (more severe than that originally present) in 4 of the 15 subjects. Two of these failed to respond to recommencement of salbutamol at high doses, but dramatically responded to intravenous aminophylline. This is precisely the type of study needed to clarify this issue, and we are fortunate that it is in the literature. First, the unexpected result of “rebound bronchoconstriction” strongly indicts beta receptor fatigue or tachyphylaxis during intense beta stimulation. Perhaps endogenous catecholamines, responding to such a crisis, contributed to this stimulation as well. Second, aminophylline is demonstrated to be literally indispensable in such circumstances. The behavior of bronchial smooth muscle beta reReprint requests to: John W. Jenne, M.D., Center, Hines, IL 60141.
Vol. 63, No. 2, pp. 74-76
much
Hines VA Medical
ceptors has been studied in vitro. Work with rat trachea,3 guinea pig trachea,4 and human bronchial segments” shows that considerable tachyphylaxis can be produced by as little as 25 to 30 minutes’ incubation with ten times the initially effective concentration of isoproterenol or terbutaline, with the production of cross-tolerance. The mechanism appears to involve, in part at least, a reduction in affinity of the beta receptors for the beta agonist. A reduction in the number of binding sites may also be involved.6 The original response can be restored by increasing the concentration of beta agonist, but at the likely cost of producing even more tachyphylaxis. Significantly, muscle relaxants not involving the beta receptor continue to work effectively on the tachyphylactic muscle.3, 4 Moreover, the identical in vitro tracheal condition can be produced in the rat by preceding doses of isoproterenol or terbutaline in vivo.7 These results are very likely to be relevant to the problem of pushing the dose of beta agonist in the treatment of status asthmaticus. They also are consistent with the clinical study of Paterson, Courtenay Evans, and Prime2 and the early work by Conolly and co-workers* and provide a basis for the observed relief by aminophylline. The importance of steroids in the treatment of bronchospasm is becoming clearer. The studies of Ellul-Micallef, Borthwick, and McHardy’ are particularly illuminating. In stable asthmatics, 40 mg of oral prednisolone by itself produced significant bronchodilation at 3 hr, peaking at 9 hr. This may have been an enhancement of bronchial beta receptor sensitivity to circulating catecholamines. A startling augmentation of bronchodilator response to 200 pg of inhaled isoproterenol was observed one hour following the intravenous injection of 40 mg prednisolone in certain otherwise unresponsive patients. lo The reason for their unresponsiveness was not discussed, but Tattersfield and Holgate” suspect that tolerance to inhaled adrenergic agents had been induced by prior therapy. These investigators have demonstrated that very appreciable tolerance to inhaled salbutamol can be produced in normal subjects using doses of salbutamol aerosol exceeding 200 Fg four times daily.12 In their studies, responsiveness was completely re-
0091-6749/79/020074+03$00.30/0
@ 1979 The C. V. Mosby
Co.
VOLUME NUMBER
63 2
stored by the intravenous administration of 200 mg of hydrocortisone three to five hours prior to the inhaled salbutamol. In our laboratory, Stephan, Chick, and Jenne’” worked with methacholine-induced bronchospasm in dogs. The protection conferred by isoproterenol nebulized by intermittent positive pressure was markedly diminished 105 min following a period of repeated applications of isoproterenol at 5-min intervals. The response was preserved, however, when preceded by methyprednisolone an hour earlier. Thus, by whatever mechanism will finally emerge, steroids seem to restore sensitivity to receptors that have become tolerant to beta agents. This may simply be due to a Favorable shift in the dose-response curve, but the mechanisms remain to be elucidated. The evidence seems clear that the inhaled application of beta agonists in frequently used doses leads to a predictable degree of tachyphylaxis. This is consistent with the experience of Trautlein, Allegra, and Gillin’-’ using fenoterol in recommended doses, and extends the experience of Van Metre,‘,’ Reisman,‘” and Keighley” with a certain portion of asthmatics on isoproterenol.* Steroids seem to mitigate this effect. Yet, if beta agonists by the inhaled route were a serious problem, it is difficult to believe that this potential complication would not have been appreciated by practitioners in European and other countries in which inhaler delivery is the mainstay of treatment. Perhaps the concomitant use of inhaled steroids in the more severe cases prevents development of tolerance. The confusion over the question of tolerance to oral maintenance doses of beta agents is clearing somewhat. Although there is continuing adequate bronchodilation in divided doses,‘* when pre-existing tolerance to oral agents is avoided and the bronchodilator response is compared from the same baseline values, definite development of tolerance or subsensitivity can be demonstrated.‘“, Z’ This is at least of academic interest, and possibly is important during exacerbations of asthma or abrupt discontinuation of therapy. Thus, there is good evidence, both in vitro and in vivo, that inhaled, oral, or intravenous administration of beta agonists can lead to a degree of tachyphylaxis “Note added in proof: Kneussl and Richardson (Alpha-
adrenergic receptors in human and canine tracheal and bronchial smooth muscle, J Appl Physiol 42:307. 1978) have described an augmented alpha receptor response in the bronchi of diseased lungs including some with bron-
chitis. Whether this is a factor in the reduced. or even “paradoxic.” response lo isoproterenol. particularly in the presence of beta tachyphylaxis, remains to be determined.
Beta adrenergic agents 75 or tolerance. There is still the problem of individual variation of beta response, both in the native and the partially tolerant state. Commonly prescribed doses of beta agonists may be insufficient for some patients and excessive for others. We know little of these individual characteristics of the bronchial smooth muscle beta receptors or how they might fluctuate during various clinical circumstances. We are far more cognizant of individual variations in peripheral tremor, up to eightfold, to the beta-2 agents. Interesting studies are emerging purporting to show that a combination of suboptimal doses of oral theophylline and beta agonists provides adequate bronchodilation without the threat of that rare but severe toxicity that hangs over the head of the practitioner who is being urged to use the larger doses of theophylline but who may not have easy access to serum theophylline levels to guide him. In my opinion, there is considerable room for research in the drug combination area. There are a number of studies of single, acute doses of drugs in combination compared to their single use. Seldom do the investigators state the previous therapy, with its potential for influencing the response to the beta agonist. There are far fewer studies of drug combinations during chronic maintenance therapy. Here, the need is to allow a sufficient length of time to equilibrate both drug levels and the effects of drug tolerance, the latter requiring at least two weeks for the beta receptors. The study of acute single-dose combinations by Wolfe and co-worker?’ is suggestive that 200 mg of aminophylline combined with 2.5 mg of terbutaline will produce bronchodilation equal to 400 mg of aminophylline or 5.0 mg of terbutaline given alone. Unfortunately, previous adrenergic drug therapy is not specified. Application of the results to a chronic maintenance situation is hazardous for the reasons specified. A study of maintenance therapy by Sims, doPico, and ReedZ2takes the above precautions into consideration, showing that 130 mg of theophylline combined with 25 mg of ephedrine and phenobarbital on a four times daily schedule is more efficacious after two weeks than either bronchodilator alone. Here, rising theophylline levels on chronic therapy appeared to compensate for increasing tolerance to ephedrine, but the ephedrine still augmented the theophylline response. In the classic study by Weinberger and Bronsky’” in children on chronic therapy, the patients were sicker. Larger doses of theophylline, adjusted to give mean levels of 13 pg/ml, gave as much bronchodilation by themselves as when combined with huge doses of ephedrine. Since ephedrine is known to be associated with considerable tolerance,
76 Jenne
by largely different mechanisms than purely betaspecific compounds, this type of study should be repeated in a population of severe asthmatics with the beta-2 agents. Thus, the answers to the question, “How much beta adrenergic drug is enough?” depend on the patient, the severity and nature of his asthma, the presence of other drugs, and undoubtedly factors yet unrecognized. In the mild to moderate case, it probably matters little whether the patient or his doctor chooses to rely on the inhaled or oral beta agonists, oral theophylline compounds, or some combination. Refinements in their optimal use should emerge-but, in the more severe asthmatic, whether on chronic therapy or in the acute emergency, particularly if beta adrenergic agents are being pushed to their limit, there are compelling reasons for the simultaneous use of theophylline in the “therapeutic range,” along with steroids. This is only clinical common sense based on experience and the necessary judgment to recognize the dangerous attack. It is comforting, however, to know that, in that black box that we call the patient, the simultaneous use of these agents is beginning to rest firmly on experimental evidence.
J ALLERGY
7.
8.
9.
10.
11. 12.
13.
14.
IS. 16. 17.
REFERENCES 1. Weber RW, Petty WE, Nelson HS: Aerosolized terbutaline in asthmatics: Comparison of dosage strength, schedule, and method of administration. J ALLERGY CLIN IMMUNOL 63: , 1979. 2. Paterson JW, Courtenay Evans RJ, Prime FJ: Selectivity of bronchodilator action of salbutamol in asthmatic patients, Br J Dis Chest 65:21, 1971. 3. Lin CS, Hurwitz L, Jenne JW, Avner BP: Mechanism of isoproterenol-induced desensitization of tracheal smooth muscle, J Pharmacol Exp Ther 203: 12, 1977. 4. Douglas JS, Lewis AJ, Ridgeway P, Brink C, Bouhuys A: Tachyphylaxis to /3-adrenoreceptor agonists in guinea pig airway smooth muscle in vivo and in vitro, Eur J Pharmacol 42195, 1977. 5. Avner, BP, Noland BJ, Jenne JW: Desensitization of human bronchial smooth muscle to P-receptor agonists, Proc West Pharmacol Sot 20:25, 1977. 6. Galant SP, Duriseti L, Underwood S, Insel PA: Decreased
18.
19.
20.
21.
22.
23.
CLIN. IMMUNOL. FEBRUARY 1979
beta-adrenergic receptors on polymorphonuclear leukocyte\ after adrenergic therapy, N Engl J Med 299:933, 197X. Avner BP, Noland BJ: In vivo desensitization to p receptor mediated bronchodilator drugs in the rat: Decreased fl receptor affinity, J Pharmacol Exp Ther 207~23. 1978. Conolly ME, Davies DS, Dollery CT, George CF: Resistance to p-stimulants (a possible explanation for the rise in asthma deaths), Br J Pharmacol 43:389, 197 I. Ellul-Micallef R, Borthwick RC, McHardy GJR: The time course of response to prednisolone in chronic bronchial asthma, Clin Sci Molec Med 47: 105, 1974. Ellul-Micallef R, French FF: Effect of intravenous prednisolone in asthmatics with diminished adrenergic responsiveness, Lancet 2: 1269, 1975. Tattersfield AE, Holgate ST: Intravenous prednisolone in asthma, Lancet 1:422, 1976. Holgate ST, Baldwin CJ, Tattersfield AE: /3-adrenergic agonist resistance in normal human airways, Lancet 2:375, 1977. Stephan W, Chick T, Jenne JW: Tachyphylaxis to nebulized isoproterenol in dogs, Am Rev Respir Dis 117: 182, 1978. (Abst.) Trautlein J, Allegra J, Gillin M: A long term study of low-dose aerosolized terbutaline sulfate, J Clin Pharmacol 16361, 1976. Van Metre TE: Death in asthmatics, Trans Am Clin Climatol Assoc 78:58, 1967. Reisman R: Asthma induced by adrenergic aerosols, J ALLERGY 46:162, 1970. Keighley JF: Iatrogenic asthma associated with adrenergic aerosols, Ann Intern Med 65~985, 1966. Wilson AF, Novey HS, Cloninger P, Davis J, White D: Cardiopulmonary effects of long-term bronchodilator administration, J ALLERGY CLIN IMMUNOL S&204, 1976. Jenne JW, Chick TW, Strickland RD, Wall FJ: Subsensitivity of beta responses during therapy with a long-acting beta-2 preparation, J ALLERGY CLIN IMMUNOL 59:383, 1977. Nelson HS, Raine D, Doner HC, Posey WC: Subsensitivity to the bronchodilator action of albuterol produced by chronic administration, Am Rev Respir Dis 116~871, 1977. Wolfe JD, Tashkin DP, Calvarese B, Simmons M: Bronchodilator effects of terbutaline and aminophylline alone and in combination in asthmatic patients, N Engl J Med 298~363, 1978. Sims JA, doPico GA, Reed CE: Bronchodilating effect of oral theophylline-ephedrine combination, J ALLERGY CLIN IMMUNOL 62: 15, 1978. Weinberger MM, Bronsky E: Evaluation of oral bronchodilator therapy in asthmatic children, J Pediatr 84:421, 1974.
agents-how
M.D. Hines, 111.
The article by Weber, Petty, and Nelson appearing in this issue of the JOURNAL is not only a precise and useful comparison of the dose of inhaled isoproterenol and terbutaline by several method of administration, but is also a reminder to us that the log-dose response curve extends far beyond the 20% improvement conventionaliy used for diagnosis when the dose is pushed. This prompts the questions: “Under what circumstances should the dose of beta agonists be pushed?” “How much is too much?” Certainly the issue is being forced upon us by the often successful use in some quarters of isoproterenol intravenously in children as a last-ditch pharmacologic effort in status asthmaticus before resorting to assisted ventilation with its own set of hazards. Moreover, the optimum use of inhaled and oral beta agents is far from settled. What information do we have at this date bearing on these questions? If we limit the questions to the effects on bronchospasm, I believe that we are indeed narrowing the areas of uncertainty. Evidence comes from both in vitro and in vivo studies. We should recall the study of Paterson, Courtenay Evans, and Prime2 in their comparison of doubling doses of, first, intravenous isoproterenol and, then, salbutamol, on the FEVi and pulse rate in stable but severe asthmatics. The abrupt cessation of the salbutamol drip was followed by “rebound bronchoconstriction” (more severe than that originally present) in 4 of the 15 subjects. Two of these failed to respond to recommencement of salbutamol at high doses, but dramatically responded to intravenous aminophylline. This is precisely the type of study needed to clarify this issue, and we are fortunate that it is in the literature. First, the unexpected result of “rebound bronchoconstriction” strongly indicts beta receptor fatigue or tachyphylaxis during intense beta stimulation. Perhaps endogenous catecholamines, responding to such a crisis, contributed to this stimulation as well. Second, aminophylline is demonstrated to be literally indispensable in such circumstances. The behavior of bronchial smooth muscle beta reReprint requests to: John W. Jenne, M.D., Center, Hines, IL 60141.
Vol. 63, No. 2, pp. 74-76
much
Hines VA Medical
ceptors has been studied in vitro. Work with rat trachea,3 guinea pig trachea,4 and human bronchial segments” shows that considerable tachyphylaxis can be produced by as little as 25 to 30 minutes’ incubation with ten times the initially effective concentration of isoproterenol or terbutaline, with the production of cross-tolerance. The mechanism appears to involve, in part at least, a reduction in affinity of the beta receptors for the beta agonist. A reduction in the number of binding sites may also be involved.6 The original response can be restored by increasing the concentration of beta agonist, but at the likely cost of producing even more tachyphylaxis. Significantly, muscle relaxants not involving the beta receptor continue to work effectively on the tachyphylactic muscle.3, 4 Moreover, the identical in vitro tracheal condition can be produced in the rat by preceding doses of isoproterenol or terbutaline in vivo.7 These results are very likely to be relevant to the problem of pushing the dose of beta agonist in the treatment of status asthmaticus. They also are consistent with the clinical study of Paterson, Courtenay Evans, and Prime2 and the early work by Conolly and co-workers* and provide a basis for the observed relief by aminophylline. The importance of steroids in the treatment of bronchospasm is becoming clearer. The studies of Ellul-Micallef, Borthwick, and McHardy’ are particularly illuminating. In stable asthmatics, 40 mg of oral prednisolone by itself produced significant bronchodilation at 3 hr, peaking at 9 hr. This may have been an enhancement of bronchial beta receptor sensitivity to circulating catecholamines. A startling augmentation of bronchodilator response to 200 pg of inhaled isoproterenol was observed one hour following the intravenous injection of 40 mg prednisolone in certain otherwise unresponsive patients. lo The reason for their unresponsiveness was not discussed, but Tattersfield and Holgate” suspect that tolerance to inhaled adrenergic agents had been induced by prior therapy. These investigators have demonstrated that very appreciable tolerance to inhaled salbutamol can be produced in normal subjects using doses of salbutamol aerosol exceeding 200 Fg four times daily.12 In their studies, responsiveness was completely re-
0091-6749/79/020074+03$00.30/0
@ 1979 The C. V. Mosby
Co.
VOLUME NUMBER
63 2
stored by the intravenous administration of 200 mg of hydrocortisone three to five hours prior to the inhaled salbutamol. In our laboratory, Stephan, Chick, and Jenne’” worked with methacholine-induced bronchospasm in dogs. The protection conferred by isoproterenol nebulized by intermittent positive pressure was markedly diminished 105 min following a period of repeated applications of isoproterenol at 5-min intervals. The response was preserved, however, when preceded by methyprednisolone an hour earlier. Thus, by whatever mechanism will finally emerge, steroids seem to restore sensitivity to receptors that have become tolerant to beta agents. This may simply be due to a Favorable shift in the dose-response curve, but the mechanisms remain to be elucidated. The evidence seems clear that the inhaled application of beta agonists in frequently used doses leads to a predictable degree of tachyphylaxis. This is consistent with the experience of Trautlein, Allegra, and Gillin’-’ using fenoterol in recommended doses, and extends the experience of Van Metre,‘,’ Reisman,‘” and Keighley” with a certain portion of asthmatics on isoproterenol.* Steroids seem to mitigate this effect. Yet, if beta agonists by the inhaled route were a serious problem, it is difficult to believe that this potential complication would not have been appreciated by practitioners in European and other countries in which inhaler delivery is the mainstay of treatment. Perhaps the concomitant use of inhaled steroids in the more severe cases prevents development of tolerance. The confusion over the question of tolerance to oral maintenance doses of beta agents is clearing somewhat. Although there is continuing adequate bronchodilation in divided doses,‘* when pre-existing tolerance to oral agents is avoided and the bronchodilator response is compared from the same baseline values, definite development of tolerance or subsensitivity can be demonstrated.‘“, Z’ This is at least of academic interest, and possibly is important during exacerbations of asthma or abrupt discontinuation of therapy. Thus, there is good evidence, both in vitro and in vivo, that inhaled, oral, or intravenous administration of beta agonists can lead to a degree of tachyphylaxis “Note added in proof: Kneussl and Richardson (Alpha-
adrenergic receptors in human and canine tracheal and bronchial smooth muscle, J Appl Physiol 42:307. 1978) have described an augmented alpha receptor response in the bronchi of diseased lungs including some with bron-
chitis. Whether this is a factor in the reduced. or even “paradoxic.” response lo isoproterenol. particularly in the presence of beta tachyphylaxis, remains to be determined.
Beta adrenergic agents 75 or tolerance. There is still the problem of individual variation of beta response, both in the native and the partially tolerant state. Commonly prescribed doses of beta agonists may be insufficient for some patients and excessive for others. We know little of these individual characteristics of the bronchial smooth muscle beta receptors or how they might fluctuate during various clinical circumstances. We are far more cognizant of individual variations in peripheral tremor, up to eightfold, to the beta-2 agents. Interesting studies are emerging purporting to show that a combination of suboptimal doses of oral theophylline and beta agonists provides adequate bronchodilation without the threat of that rare but severe toxicity that hangs over the head of the practitioner who is being urged to use the larger doses of theophylline but who may not have easy access to serum theophylline levels to guide him. In my opinion, there is considerable room for research in the drug combination area. There are a number of studies of single, acute doses of drugs in combination compared to their single use. Seldom do the investigators state the previous therapy, with its potential for influencing the response to the beta agonist. There are far fewer studies of drug combinations during chronic maintenance therapy. Here, the need is to allow a sufficient length of time to equilibrate both drug levels and the effects of drug tolerance, the latter requiring at least two weeks for the beta receptors. The study of acute single-dose combinations by Wolfe and co-worker?’ is suggestive that 200 mg of aminophylline combined with 2.5 mg of terbutaline will produce bronchodilation equal to 400 mg of aminophylline or 5.0 mg of terbutaline given alone. Unfortunately, previous adrenergic drug therapy is not specified. Application of the results to a chronic maintenance situation is hazardous for the reasons specified. A study of maintenance therapy by Sims, doPico, and ReedZ2takes the above precautions into consideration, showing that 130 mg of theophylline combined with 25 mg of ephedrine and phenobarbital on a four times daily schedule is more efficacious after two weeks than either bronchodilator alone. Here, rising theophylline levels on chronic therapy appeared to compensate for increasing tolerance to ephedrine, but the ephedrine still augmented the theophylline response. In the classic study by Weinberger and Bronsky’” in children on chronic therapy, the patients were sicker. Larger doses of theophylline, adjusted to give mean levels of 13 pg/ml, gave as much bronchodilation by themselves as when combined with huge doses of ephedrine. Since ephedrine is known to be associated with considerable tolerance,
76 Jenne
by largely different mechanisms than purely betaspecific compounds, this type of study should be repeated in a population of severe asthmatics with the beta-2 agents. Thus, the answers to the question, “How much beta adrenergic drug is enough?” depend on the patient, the severity and nature of his asthma, the presence of other drugs, and undoubtedly factors yet unrecognized. In the mild to moderate case, it probably matters little whether the patient or his doctor chooses to rely on the inhaled or oral beta agonists, oral theophylline compounds, or some combination. Refinements in their optimal use should emerge-but, in the more severe asthmatic, whether on chronic therapy or in the acute emergency, particularly if beta adrenergic agents are being pushed to their limit, there are compelling reasons for the simultaneous use of theophylline in the “therapeutic range,” along with steroids. This is only clinical common sense based on experience and the necessary judgment to recognize the dangerous attack. It is comforting, however, to know that, in that black box that we call the patient, the simultaneous use of these agents is beginning to rest firmly on experimental evidence.
J ALLERGY
7.
8.
9.
10.
11. 12.
13.
14.
IS. 16. 17.
REFERENCES 1. Weber RW, Petty WE, Nelson HS: Aerosolized terbutaline in asthmatics: Comparison of dosage strength, schedule, and method of administration. J ALLERGY CLIN IMMUNOL 63: , 1979. 2. Paterson JW, Courtenay Evans RJ, Prime FJ: Selectivity of bronchodilator action of salbutamol in asthmatic patients, Br J Dis Chest 65:21, 1971. 3. Lin CS, Hurwitz L, Jenne JW, Avner BP: Mechanism of isoproterenol-induced desensitization of tracheal smooth muscle, J Pharmacol Exp Ther 203: 12, 1977. 4. Douglas JS, Lewis AJ, Ridgeway P, Brink C, Bouhuys A: Tachyphylaxis to /3-adrenoreceptor agonists in guinea pig airway smooth muscle in vivo and in vitro, Eur J Pharmacol 42195, 1977. 5. Avner, BP, Noland BJ, Jenne JW: Desensitization of human bronchial smooth muscle to P-receptor agonists, Proc West Pharmacol Sot 20:25, 1977. 6. Galant SP, Duriseti L, Underwood S, Insel PA: Decreased
18.
19.
20.
21.
22.
23.
CLIN. IMMUNOL. FEBRUARY 1979
beta-adrenergic receptors on polymorphonuclear leukocyte\ after adrenergic therapy, N Engl J Med 299:933, 197X. Avner BP, Noland BJ: In vivo desensitization to p receptor mediated bronchodilator drugs in the rat: Decreased fl receptor affinity, J Pharmacol Exp Ther 207~23. 1978. Conolly ME, Davies DS, Dollery CT, George CF: Resistance to p-stimulants (a possible explanation for the rise in asthma deaths), Br J Pharmacol 43:389, 197 I. Ellul-Micallef R, Borthwick RC, McHardy GJR: The time course of response to prednisolone in chronic bronchial asthma, Clin Sci Molec Med 47: 105, 1974. Ellul-Micallef R, French FF: Effect of intravenous prednisolone in asthmatics with diminished adrenergic responsiveness, Lancet 2: 1269, 1975. Tattersfield AE, Holgate ST: Intravenous prednisolone in asthma, Lancet 1:422, 1976. Holgate ST, Baldwin CJ, Tattersfield AE: /3-adrenergic agonist resistance in normal human airways, Lancet 2:375, 1977. Stephan W, Chick T, Jenne JW: Tachyphylaxis to nebulized isoproterenol in dogs, Am Rev Respir Dis 117: 182, 1978. (Abst.) Trautlein J, Allegra J, Gillin M: A long term study of low-dose aerosolized terbutaline sulfate, J Clin Pharmacol 16361, 1976. Van Metre TE: Death in asthmatics, Trans Am Clin Climatol Assoc 78:58, 1967. Reisman R: Asthma induced by adrenergic aerosols, J ALLERGY 46:162, 1970. Keighley JF: Iatrogenic asthma associated with adrenergic aerosols, Ann Intern Med 65~985, 1966. Wilson AF, Novey HS, Cloninger P, Davis J, White D: Cardiopulmonary effects of long-term bronchodilator administration, J ALLERGY CLIN IMMUNOL S&204, 1976. Jenne JW, Chick TW, Strickland RD, Wall FJ: Subsensitivity of beta responses during therapy with a long-acting beta-2 preparation, J ALLERGY CLIN IMMUNOL 59:383, 1977. Nelson HS, Raine D, Doner HC, Posey WC: Subsensitivity to the bronchodilator action of albuterol produced by chronic administration, Am Rev Respir Dis 116~871, 1977. Wolfe JD, Tashkin DP, Calvarese B, Simmons M: Bronchodilator effects of terbutaline and aminophylline alone and in combination in asthmatic patients, N Engl J Med 298~363, 1978. Sims JA, doPico GA, Reed CE: Bronchodilating effect of oral theophylline-ephedrine combination, J ALLERGY CLIN IMMUNOL 62: 15, 1978. Weinberger MM, Bronsky E: Evaluation of oral bronchodilator therapy in asthmatic children, J Pediatr 84:421, 1974.
