- Email: [email protected]
Clinical Effects of Inhaled Corticosteroids: Results of a Questionnaire Survey of Asthma Specialists
Clinical adverse effects of inhaled corticosteroids: results of a questionnaire survey of asthma specialists William W Storms, MD and Charity Theen
Background: Inhaled corticosteroids are recognized as the mainstay of prophylactic anti-inflammatory therapy in patients with persistent asthma. In large multiclinic trials, the clinical adverse event profiles have been not significantly different than patients treated with placebo or other medications; however, in small studies evaluating very sensitive in vitro measurements of the hypothalamic pituitary adrenal axis there have been adverse laboratory events noted with moderate and high doses of inhaled steroids. Objective: To survey asthma specialists in North America with regard to their personal clinical experience of adverse events with the use of inhaled corticosteroids. Methods: Two hundred thirteen physicians specializing in the treatment of asthma responded to questionnaires asking their experiences with specific adverse clinical events that have the potential to occur after the use of inhaled corticosteroids (see appendix A for questionnaire). Results: There was a 67% response rate for the questionnaire. Eighty percent of the respondents were allergists/immunologists and 20% were pulmonologists. The average length of time they had been in practice was 16 years. In general, side effects from inhaled steroids were seen very infrequently in the hands of these physicians in spite of the fact that they were primarily secondary or tertiary referral physicians for the treatment of asthma. The local oropharyngeal adverse events were seen 48% of the time on an occasional basis but only 3% of the time on a frequent basis. When spacers were used the oropharyngeal symptoms were reduced significantly. Skin changes such as bruising or thin skin were seen frequently 6% of the time and occasionally 24% of the time only. In general, these skin changes were found in elderly or middle-aged individuals. Weight gain was very unusually seen, as were adverse effects on bone (osteoporosis, fractures, growth problems, etc.). Hypothalamic pituitary axis abnormalities were seen quite infrequently and primarily in patients who had also received oral corticosteroids. Conclusions: This study shows that inhaled corticosteroids are generally safe in the treatment of asthma and are rarely associated with systemic side effects, as detected in routine clinical practice. Ann Allergy Asthma Immunol 1998;80:391– 4.
INTRODUCTION Inhaled corticosteroids have been used in the treatment of asthma for almost 20 years. They were originally prescribed for use in patients who required oral corticosteroids for control Asthma & Allergy Associates, PC, Colorado Springs, Colorado. Received for publication January 6, 1998. Accepted for publication in revised form February 26, 1998.
VOLUME 80, MAY, 1998
of asthma, but their clinical use expanded to prophylactic treatment in patients who had chronic persistent asthma and usage in this manner has been shown to result in reduced frequency of emergency room visits, hospitalizations, oral steroid bursts, and other parameters indicating severe asthma. In recent years multiple inhaled corticosteroid products have appeared on the market, and there have been a number of studies evaluating
the potential side effects of the various drugs.1–15 In the large multiclinic trials, which have been used for regulatory approval of these compounds, side effects have infrequently been noted with their use. Some patients have had local side effects in the oropharynx including dysphonia, candidiasis, and hoarseness. Some patients have had morning serum cortisol readings less than the normal range but clinical adverse consequences of these lowered serum cortisols have not been identified. There have been many recent studies with small groups of patients in which very sensitive tests of the hypothalamic pituitary adrenal axis (HPA axis) have been performed showing that inhaled corticosteroids may suppress HPA function.4,6,9,10 The question is whether or not these clinical laboratory changes are reflected in true clinical adverse events. Concerns about inhaled corticosteroids have also been raised in regard to potential problems with cataracts, glaucoma, and growth in children. The current study was undertaken in order to attempt to shed some light on this issue. STUDY DESIGN A questionnaire (Appendix A) was designed that identified potential adverse clinical events which had been described as possibly associated with inhaled corticosteroids. These included oropharyngeal events, bone changes, skin changes, eye changes, HPA axis abnormalities, short stature in children, and weight gain. The questionnaire was mailed to asthma specialists in North America and each physician was asked to record the frequency with which he/she had observed these adverse events in his/her clinical experi-
391
ence. The names of 320 asthma specialists were chosen from the membership directories of the American Thoracic Society, American College of Chest Physicians, American College of Allergy, Asthma & Immunology, and the American Academy of Allergy, Asthma & Immunology by one of the authors (W.S.) based on his knowledge of the fact that the physicians to whom the questionnaires were sent met the criteria of having a clinical practice (whether or not they worked at an academic center) and having had at least 10 years of experience in treating patients with asthma. The physicians who were questioned included adult and pediatric allergists/ pulmonologists and adult and pediatric pulmonologists. The questionnaire did not request specific information on the age of patients treated by individual physicians. The one page questionnaire was sent back by mail or fax to the authors and the data was then summarized and analyzed. RESULTS Two hundred thirteen physicians returned the questionnaire for a response rate of 67%. Of these, 80% were allergists/immunologists and 20% were pulmonologists. The 213 physicians reported that they had been in practice for an average of 16 years each; this computed to a total experience of 3,408 physician-years for the data collected from the questionnaires.
The results are described in Table 1. In general, side effects were seen “rarely” and “occasionally.” Oropharyngeal adverse events were seen occasionally in 48% of physician’s practices and seen frequently in 3%. The questionnaire asked whether or not spacers were beneficial for these oropharyngeal symptoms and two-thirds of the physicians indicated that spacers resolved these local side effects. Skin changes, such as bruising or thin skin, were noted frequently in 6% of practices, occasionally in 24% of practices, and rarely or never in 70%. The respondents were asked to break this down by age groups: 55% of these skin changes were found in elderly individuals, 33% in middle-aged, and less than 10% in children. Weight gain was seen occasionally in 8% and never or rarely in 91%. Questions regarding bone metabolism, growth, and HPA axis function were included on the questionnaire to try to obtain information from those physicians who might include those in their evaluations, knowing full well that this would probably be reserved for the academic asthma specialists in tertiary referral settings. The frequency of measurement of these tests was not quantitated in any manner, but these questions were included to try to gain some extra information from those physicians who measured these parameters. Adverse effects on bone were not seen frequently. There were 1% of
Table 1. Percent of Physicians Responding to Frequency of Side Effects in Each Individual Category Occasional Frequent Local side effects Oropharyngeal symptoms Skin changes (bruising/thin skin) Weight gain Bone metabolism Osteoporosis or fractures Short stature in children Abnormal bone markers Hypothalamic pituitary axis changes Reduced/serum urine cortisol Blunted ACTH stimulation Hypoadrenalism Cataracts
392
Never
Rare
Occasional
Frequent
1% 36% 50%
48% 34% 41%
48% 24% 8%
3% 6% 1%
89% 83% 82%
10% 15% 14%
1% 1% 3%
0% 1% 1%
71% 76% 86% 75%
20% 18% 11% 24%
8% 5% 2% 1%
1% 1% 1% 0%
physicians who saw osteoporosis or fractures occasionally, and 3% saw abnormal bone markers occasionally. The strong majority either never saw these changes or saw them very rarely. Some physicians who responded to the questionnaire indicated that these side effects were actually attributed to oral steroids since most of these patients had received oral steroids in the past. This was probably due to the fact that the physicians responding to the questionnaire tended to be asthma specialists who were seeing patients primarily on a referral basis; in many cases they were in tertiary referral centers for asthma. Changes in the HPA were seen quite infrequently. In those practices in which some of these changes were noted, the patients had also been on oral steroids. Cataracts were not seen frequently or occasionally but only rarely. DISCUSSION Inhaled corticosteroids have been used for the treatment of asthma for almost 20 years. Studies of sensitive markers of the HPA and of bone metabolism have shown that inhaled corticosteroids may adversely effect these parameters, indicating definite systemic activity. These recent findings have led some authors to conclude that inhaled steroids might have dangerous clinical side effects. In some cases, these clinical laboratory adverse events have been used by pharmaceutical companies to try to make their product look better than the competitors. The end result of these “steroid wars” may lead to an underutilization of inhaled steroids in the American market, and the 1997 Expert Panel II Report on asthma recommends increased usage of inhaled steroids, especially in newly diagnosed asthma. Concerns have been raised regarding possible effects of inhaled steroids on growth in children and their possible association with cataracts and glaucoma.7,8,9,11–13 The current study was designed in order to shed some light on the true issue of clinical adverse events from inhaled steroids since most of the
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
data that was being published addressed laboratory adverse events. The response rate from the physicians involved in this study was excellent and we appreciate the fact that the responding physicians took the time out of their busy practices to fill out the questionnaire and return it. There was no compensation for this whatsoever. The results clearly show that oropharyngeal side effects are occasionally seen but in most situations these side effects can be resolved by using a spacer. Systemic side effects from inhaled steroids are either never seen or rarely
seen in most physician practices. In those cases in which they are seen there usually is some other extenuating circumstance: (1) elderly patients on high dose steroids may have bruising of the skin; (2) some children may show weight gain but in most instances they also had received oral steroids in the past; or (3) osteoporosis and fractures have been seen in some patients who were also on oral steroids. The percentage of physician responses who were treating pediatric as compared with adult asthma patients was not identified; therefore the results may reflect some bias towards either
pediatric or adult patients and associated adverse events. CONCLUSION The results of this study show that inhaled corticosteroids are generally safe in the treatment of asthma and are rarely associated with systemic side effects as detected in routine clinical practice, even in the hands of physicians who see more severe asthma patients. ACKNOWLEDGEMENTS The efficient and knowledgeable assistance of Kay Bailey was invaluable for the preparation of this manuscript.
APPENDIX A QUESTIONNAIRE ON THE USE OF INHALED CORTICOSTEROIDS IN PATIENTS WITH ASTHMA These questions relate only to patients with asthma and only to patients you have seen yourself. 1. How many years have you been in practice? years. 2. Have you seen the clinical complications (adverse effects) listed below from inhaled corticosteroids? A. Oral/pharyngeal symptoms: Hoarseness, sore throat of candida of the throat Did a spacer resolve the problem? Yes No
Never
Rare
Occasional
Frequent
Were these patients also on oral steroids? Yes
No
B. Osteoporosis or fractures: C. Skin changes (bruising/thin skin): If yes, check age groups: child adult elderly D. Weight Gain: If yes, check age groups: child adult elderly E. Short stature in children: F. Cataracts: G. Lab abnormalities: 1. Reduced serum/urine cortisol 2. Blunted ACTH stimulation 3. Abnormal bone markers H. Hypoadrenalism: Name Date Your specialty: Allergy/Immunology Pulmonary disease Please mail or Fax to William W. Storms, M.D. Fax 719-630-3658
VOLUME 80, MAY, 1998
Other (
)
393
REFERENCES 1. Johnson M. Pharmacodynamics and pharmacokinetics of inhaled glucocorticoids. J Allergy Clin Immunol 1996; 97:169 –76. 2. Hanania NA, Chapman KR, Kesten S. Adverse effects of inhaled corticosteroids. Am J Medicine 1995;98: 196 –208. 3. Padfield PL, Teelucksingh S. Inhaled corticosteroids: the endocrinologist’s view. Eur Respir Rev 1993;3(15): 494 –500. 4. Grove A, Allam C, McFarlane LC. A comparison of the systemic bioactivity of inhaled budesonide and fluticasone propionate in normal subjects. Br J Clin Pharm 1994;38:527–32. 5. Dogterom P, Oosterhuis B, Ebels JT, Jonkman JHG. Inhaled fluticasone propionate induces greater cortisol suppression compared to budesonide. A dose response study using pressurized metered dose inhalers (PMDI’s) [Abstract]. Eur Resp J 1995;8(Suppl 19):303s. 6. Clark DJ, Grove A, Cargill RI. Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients. Thorax 1996;51:262– 6.
394
7. Wolthers OD, Pedersen S. Short term growth during treatment with inhaled fluticasone propionate and beclomethasone dipropionate. Arch Dis Child 1993;68(5):673– 6. 8. Price JF. Asthma, growth and inhaled corticosteroids. Respir Med 1993; 87(Suppl A):23– 6. 9. Lipworth BJ. Airway and systemic effects of inhaled corticosteroids asthma: dose response relationship. Pulmonary Pharmacology 1996;9:19 –27. 10. Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997;52:55– 8. 11. Agertoft L, Pedersen S, et al. Shortterm knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose response study. Eur Respir J 1997;10:1507–12. 12. Kamada AK, et al. Issues in the use of inhaled glucocorticoids. Am J Respir Crit Care Med 1996;153:1739 – 48. 13. Garbe E, et al. Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma. JAMA 1997;277:722–7.
14. Wolthers OD, et al. Knemometry, urine cortisol excretion, and measures of the insulin-like growth factor axis and collagen turnover in children treated with inhaled glucocorticosteroids. Pediatr Res 1997;41:44 –50. 15. Grove A, et al. Effects of short-term exposure to high-dose inhaled corticosteroids on novel markers of bone metabolism. Eur J Clin Pharmacol 1996; 50:275–7. 16. Corren J, Rachelefsky G, Hochhaus G, et al. A five-way parallel randomized study to compare the safety profile of beclomethasone dipropionate (BDP), budesonide (BUD), flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TA) in healthy male volunteers [Abstract]. Chest 1996;110(4):83S. 17. Guidelines for the diagnosis and management of asthma. NIH 97-4051, 1997.
Request for reprints should be addressed to: William W Storms, MD 2709 N Tejon St Colorado Springs, CO 80907 email: [email protected]
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Background: Inhaled corticosteroids are recognized as the mainstay of prophylactic anti-inflammatory therapy in patients with persistent asthma. In large multiclinic trials, the clinical adverse event profiles have been not significantly different than patients treated with placebo or other medications; however, in small studies evaluating very sensitive in vitro measurements of the hypothalamic pituitary adrenal axis there have been adverse laboratory events noted with moderate and high doses of inhaled steroids. Objective: To survey asthma specialists in North America with regard to their personal clinical experience of adverse events with the use of inhaled corticosteroids. Methods: Two hundred thirteen physicians specializing in the treatment of asthma responded to questionnaires asking their experiences with specific adverse clinical events that have the potential to occur after the use of inhaled corticosteroids (see appendix A for questionnaire). Results: There was a 67% response rate for the questionnaire. Eighty percent of the respondents were allergists/immunologists and 20% were pulmonologists. The average length of time they had been in practice was 16 years. In general, side effects from inhaled steroids were seen very infrequently in the hands of these physicians in spite of the fact that they were primarily secondary or tertiary referral physicians for the treatment of asthma. The local oropharyngeal adverse events were seen 48% of the time on an occasional basis but only 3% of the time on a frequent basis. When spacers were used the oropharyngeal symptoms were reduced significantly. Skin changes such as bruising or thin skin were seen frequently 6% of the time and occasionally 24% of the time only. In general, these skin changes were found in elderly or middle-aged individuals. Weight gain was very unusually seen, as were adverse effects on bone (osteoporosis, fractures, growth problems, etc.). Hypothalamic pituitary axis abnormalities were seen quite infrequently and primarily in patients who had also received oral corticosteroids. Conclusions: This study shows that inhaled corticosteroids are generally safe in the treatment of asthma and are rarely associated with systemic side effects, as detected in routine clinical practice. Ann Allergy Asthma Immunol 1998;80:391– 4.
INTRODUCTION Inhaled corticosteroids have been used in the treatment of asthma for almost 20 years. They were originally prescribed for use in patients who required oral corticosteroids for control Asthma & Allergy Associates, PC, Colorado Springs, Colorado. Received for publication January 6, 1998. Accepted for publication in revised form February 26, 1998.
VOLUME 80, MAY, 1998
of asthma, but their clinical use expanded to prophylactic treatment in patients who had chronic persistent asthma and usage in this manner has been shown to result in reduced frequency of emergency room visits, hospitalizations, oral steroid bursts, and other parameters indicating severe asthma. In recent years multiple inhaled corticosteroid products have appeared on the market, and there have been a number of studies evaluating
the potential side effects of the various drugs.1–15 In the large multiclinic trials, which have been used for regulatory approval of these compounds, side effects have infrequently been noted with their use. Some patients have had local side effects in the oropharynx including dysphonia, candidiasis, and hoarseness. Some patients have had morning serum cortisol readings less than the normal range but clinical adverse consequences of these lowered serum cortisols have not been identified. There have been many recent studies with small groups of patients in which very sensitive tests of the hypothalamic pituitary adrenal axis (HPA axis) have been performed showing that inhaled corticosteroids may suppress HPA function.4,6,9,10 The question is whether or not these clinical laboratory changes are reflected in true clinical adverse events. Concerns about inhaled corticosteroids have also been raised in regard to potential problems with cataracts, glaucoma, and growth in children. The current study was undertaken in order to attempt to shed some light on this issue. STUDY DESIGN A questionnaire (Appendix A) was designed that identified potential adverse clinical events which had been described as possibly associated with inhaled corticosteroids. These included oropharyngeal events, bone changes, skin changes, eye changes, HPA axis abnormalities, short stature in children, and weight gain. The questionnaire was mailed to asthma specialists in North America and each physician was asked to record the frequency with which he/she had observed these adverse events in his/her clinical experi-
391
ence. The names of 320 asthma specialists were chosen from the membership directories of the American Thoracic Society, American College of Chest Physicians, American College of Allergy, Asthma & Immunology, and the American Academy of Allergy, Asthma & Immunology by one of the authors (W.S.) based on his knowledge of the fact that the physicians to whom the questionnaires were sent met the criteria of having a clinical practice (whether or not they worked at an academic center) and having had at least 10 years of experience in treating patients with asthma. The physicians who were questioned included adult and pediatric allergists/ pulmonologists and adult and pediatric pulmonologists. The questionnaire did not request specific information on the age of patients treated by individual physicians. The one page questionnaire was sent back by mail or fax to the authors and the data was then summarized and analyzed. RESULTS Two hundred thirteen physicians returned the questionnaire for a response rate of 67%. Of these, 80% were allergists/immunologists and 20% were pulmonologists. The 213 physicians reported that they had been in practice for an average of 16 years each; this computed to a total experience of 3,408 physician-years for the data collected from the questionnaires.
The results are described in Table 1. In general, side effects were seen “rarely” and “occasionally.” Oropharyngeal adverse events were seen occasionally in 48% of physician’s practices and seen frequently in 3%. The questionnaire asked whether or not spacers were beneficial for these oropharyngeal symptoms and two-thirds of the physicians indicated that spacers resolved these local side effects. Skin changes, such as bruising or thin skin, were noted frequently in 6% of practices, occasionally in 24% of practices, and rarely or never in 70%. The respondents were asked to break this down by age groups: 55% of these skin changes were found in elderly individuals, 33% in middle-aged, and less than 10% in children. Weight gain was seen occasionally in 8% and never or rarely in 91%. Questions regarding bone metabolism, growth, and HPA axis function were included on the questionnaire to try to obtain information from those physicians who might include those in their evaluations, knowing full well that this would probably be reserved for the academic asthma specialists in tertiary referral settings. The frequency of measurement of these tests was not quantitated in any manner, but these questions were included to try to gain some extra information from those physicians who measured these parameters. Adverse effects on bone were not seen frequently. There were 1% of
Table 1. Percent of Physicians Responding to Frequency of Side Effects in Each Individual Category Occasional Frequent Local side effects Oropharyngeal symptoms Skin changes (bruising/thin skin) Weight gain Bone metabolism Osteoporosis or fractures Short stature in children Abnormal bone markers Hypothalamic pituitary axis changes Reduced/serum urine cortisol Blunted ACTH stimulation Hypoadrenalism Cataracts
392
Never
Rare
Occasional
Frequent
1% 36% 50%
48% 34% 41%
48% 24% 8%
3% 6% 1%
89% 83% 82%
10% 15% 14%
1% 1% 3%
0% 1% 1%
71% 76% 86% 75%
20% 18% 11% 24%
8% 5% 2% 1%
1% 1% 1% 0%
physicians who saw osteoporosis or fractures occasionally, and 3% saw abnormal bone markers occasionally. The strong majority either never saw these changes or saw them very rarely. Some physicians who responded to the questionnaire indicated that these side effects were actually attributed to oral steroids since most of these patients had received oral steroids in the past. This was probably due to the fact that the physicians responding to the questionnaire tended to be asthma specialists who were seeing patients primarily on a referral basis; in many cases they were in tertiary referral centers for asthma. Changes in the HPA were seen quite infrequently. In those practices in which some of these changes were noted, the patients had also been on oral steroids. Cataracts were not seen frequently or occasionally but only rarely. DISCUSSION Inhaled corticosteroids have been used for the treatment of asthma for almost 20 years. Studies of sensitive markers of the HPA and of bone metabolism have shown that inhaled corticosteroids may adversely effect these parameters, indicating definite systemic activity. These recent findings have led some authors to conclude that inhaled steroids might have dangerous clinical side effects. In some cases, these clinical laboratory adverse events have been used by pharmaceutical companies to try to make their product look better than the competitors. The end result of these “steroid wars” may lead to an underutilization of inhaled steroids in the American market, and the 1997 Expert Panel II Report on asthma recommends increased usage of inhaled steroids, especially in newly diagnosed asthma. Concerns have been raised regarding possible effects of inhaled steroids on growth in children and their possible association with cataracts and glaucoma.7,8,9,11–13 The current study was designed in order to shed some light on the true issue of clinical adverse events from inhaled steroids since most of the
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
data that was being published addressed laboratory adverse events. The response rate from the physicians involved in this study was excellent and we appreciate the fact that the responding physicians took the time out of their busy practices to fill out the questionnaire and return it. There was no compensation for this whatsoever. The results clearly show that oropharyngeal side effects are occasionally seen but in most situations these side effects can be resolved by using a spacer. Systemic side effects from inhaled steroids are either never seen or rarely
seen in most physician practices. In those cases in which they are seen there usually is some other extenuating circumstance: (1) elderly patients on high dose steroids may have bruising of the skin; (2) some children may show weight gain but in most instances they also had received oral steroids in the past; or (3) osteoporosis and fractures have been seen in some patients who were also on oral steroids. The percentage of physician responses who were treating pediatric as compared with adult asthma patients was not identified; therefore the results may reflect some bias towards either
pediatric or adult patients and associated adverse events. CONCLUSION The results of this study show that inhaled corticosteroids are generally safe in the treatment of asthma and are rarely associated with systemic side effects as detected in routine clinical practice, even in the hands of physicians who see more severe asthma patients. ACKNOWLEDGEMENTS The efficient and knowledgeable assistance of Kay Bailey was invaluable for the preparation of this manuscript.
APPENDIX A QUESTIONNAIRE ON THE USE OF INHALED CORTICOSTEROIDS IN PATIENTS WITH ASTHMA These questions relate only to patients with asthma and only to patients you have seen yourself. 1. How many years have you been in practice? years. 2. Have you seen the clinical complications (adverse effects) listed below from inhaled corticosteroids? A. Oral/pharyngeal symptoms: Hoarseness, sore throat of candida of the throat Did a spacer resolve the problem? Yes No
Never
Rare
Occasional
Frequent
Were these patients also on oral steroids? Yes
No
B. Osteoporosis or fractures: C. Skin changes (bruising/thin skin): If yes, check age groups: child adult elderly D. Weight Gain: If yes, check age groups: child adult elderly E. Short stature in children: F. Cataracts: G. Lab abnormalities: 1. Reduced serum/urine cortisol 2. Blunted ACTH stimulation 3. Abnormal bone markers H. Hypoadrenalism: Name Date Your specialty: Allergy/Immunology Pulmonary disease Please mail or Fax to William W. Storms, M.D. Fax 719-630-3658
VOLUME 80, MAY, 1998
Other (
)
393
REFERENCES 1. Johnson M. Pharmacodynamics and pharmacokinetics of inhaled glucocorticoids. J Allergy Clin Immunol 1996; 97:169 –76. 2. Hanania NA, Chapman KR, Kesten S. Adverse effects of inhaled corticosteroids. Am J Medicine 1995;98: 196 –208. 3. Padfield PL, Teelucksingh S. Inhaled corticosteroids: the endocrinologist’s view. Eur Respir Rev 1993;3(15): 494 –500. 4. Grove A, Allam C, McFarlane LC. A comparison of the systemic bioactivity of inhaled budesonide and fluticasone propionate in normal subjects. Br J Clin Pharm 1994;38:527–32. 5. Dogterom P, Oosterhuis B, Ebels JT, Jonkman JHG. Inhaled fluticasone propionate induces greater cortisol suppression compared to budesonide. A dose response study using pressurized metered dose inhalers (PMDI’s) [Abstract]. Eur Resp J 1995;8(Suppl 19):303s. 6. Clark DJ, Grove A, Cargill RI. Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients. Thorax 1996;51:262– 6.
394
7. Wolthers OD, Pedersen S. Short term growth during treatment with inhaled fluticasone propionate and beclomethasone dipropionate. Arch Dis Child 1993;68(5):673– 6. 8. Price JF. Asthma, growth and inhaled corticosteroids. Respir Med 1993; 87(Suppl A):23– 6. 9. Lipworth BJ. Airway and systemic effects of inhaled corticosteroids asthma: dose response relationship. Pulmonary Pharmacology 1996;9:19 –27. 10. Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997;52:55– 8. 11. Agertoft L, Pedersen S, et al. Shortterm knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose response study. Eur Respir J 1997;10:1507–12. 12. Kamada AK, et al. Issues in the use of inhaled glucocorticoids. Am J Respir Crit Care Med 1996;153:1739 – 48. 13. Garbe E, et al. Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma. JAMA 1997;277:722–7.
14. Wolthers OD, et al. Knemometry, urine cortisol excretion, and measures of the insulin-like growth factor axis and collagen turnover in children treated with inhaled glucocorticosteroids. Pediatr Res 1997;41:44 –50. 15. Grove A, et al. Effects of short-term exposure to high-dose inhaled corticosteroids on novel markers of bone metabolism. Eur J Clin Pharmacol 1996; 50:275–7. 16. Corren J, Rachelefsky G, Hochhaus G, et al. A five-way parallel randomized study to compare the safety profile of beclomethasone dipropionate (BDP), budesonide (BUD), flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TA) in healthy male volunteers [Abstract]. Chest 1996;110(4):83S. 17. Guidelines for the diagnosis and management of asthma. NIH 97-4051, 1997.
Request for reprints should be addressed to: William W Storms, MD 2709 N Tejon St Colorado Springs, CO 80907 email: [email protected]
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY