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AN EXPLANATION OF CIRCADIAN RHYTHM FOR THEOPHYLLINE AND OTHER DRUGS
570
(bronchodilators) will have a less fundamental effect on the disease. Most probably it is the bronchial inflammatory changes that accompany the late reaction which account for its effects on airways reactivity.3 Accordingly the development of the whole of the
unequivocal support for the hypothesis. And the hypothesis is unlikely to provide more than a partial explanation for the natural history of perennial asthma. It fails, for example, to take account of the likely importance of intercurrent infection as a cause of
be must reaction inhibited; simple reversal of the bronchoconstriction which is its most readily observed feature is insufficient. This corollary is easier to test clinically than is the hypothesis itself, and with this objective we have been collaborating for the past two years in a series of clinical investigations designed to determine the effects of sodium cromoglycate on bronchial hyperreactivity to allergic and non-allergic stimuli in seasonal and perennial asthmatic patients. Not all of these studies have yet been fully reported, but the data which are available and the results of other studies in the literature do support the hypothesis that it is only drugs that prevent the development of the late reaction which prevent the development of bronchial hyperreactivity.44 Thus most studies in which sodium cromoglycate has been given for three weeks or more have demonstrated reductions in nonspecific airways hyperreactivity,5-9 though two of the most recently reported placebo-controlled studies have found an effect of the drug only on specific hyperreactivity-to antigen in one caseio and to eucapnic hyperventilation with cold air in the other.ll Bronchodilators, as predicted, on the limited evidence available, do not appear to affect airways hyperreactivity.12,13 Corticosteroids, which do inhibit the late reaction, have been variously reported, mainly in open assessment studies, to reduce bronchial hyperto have no effect upon it,15-17 or to increase it.l8 Methodological problems probably account for many of the apparent contradictions in these results, and on balance the data do seem to support Cockcroft’s hypothesis, though the case must still be regarded as "not proven". There is, therefore, much direct and indirect4evidence of the importance of the late reaction to antigen in the pathogenesis of bronchial hyperreactivity. The considerable technical difficulties which surround clinical work in this area, and to which Cockcroft alluded, mean that we are still some way from providing
bronchial
reactivity,13,
3 Gleich
GJ. The late phase of the immunoglobulin E-mediated reaction: a link between anaphylaxis and common allergic disease? J Allergy Clin Immunol 1982; 70: 160-69.
4.
Auty RM. Pharmacologic modulation of bronchial hyperreactivity. Immunol All Pract
5.
Altounyan REC. Changes in histamine and atropine responsiveness as a guide to diagnosis and evaluation of therapy in obstructive airways disease. In: Pepys J, Frankland AW, eds. Disodium cromoglycate in allergic airways disease. London:
1983; 5: 78-85.
Butterworth, 1970: 47.
one-year’s trial of IntalR compound in 24 children with severe asthma. In: Pepys J, Frankland AW, eds. Disodium cromoglycate in allergic airways disease. London: Butterworth, 1970: 105. 7. Szmidt M, Gorski P, Rozniecki J, Rychlicka I. Ocena zaleznosci miedzy wragliwoscia oskrzeli na wziewana histamine a histaminemia u chorych na astme atopowa podczas leczenia Intalem (DSCG). Pneumonal Pol 1979; 47: 517-22. 8. Bierman CW, Pearson WE, Shapiro GG, Kraemer MJ, Auty RM, Furukawa CT. Theophylline versus cromolyn sodium in outpatient management of childhood asthma: A double blind clinical trial. Proceedings of the XI International Congress of Allergology and Clinical Immunology. New York: Macmillan, 1982: 707. 9. Rak S, Millqvist E, Lowhagen O. Therapeutic modification of non-specific hyperreactivity by sodium cromoglycate. Presented at Meeting of American Academy of Allergy and Immunology, Florida, March, 1983. 10. Bleecker ER, Britt EJ, Maston PL. The effect of cromolyn on antigen and methacholine airways reactivity during ragweed season in allergic asthma. Chest 1982; 82: 227. 11. Griffin MP, MacDonald N, McFadden ER. Effects of cromolyn sodium on the airway reactivity of asthmatics. Am Rev Resp Dis 1982; 125: 61. 12. Peel ET, Gibson GJ. Effects of long-term inhaled salbutamol therapy on the provocation of asthma by histamine. Am Rev Resp Dis 1980; 121: 973-78. 13. Juniper EF, Firth PA, Hargreave FE. Long-term stability of non-specific airway responsiveness to histamine and effect of beclomethasone. Am Rev Resp Dis 1980; 121 (suppl): 76, and Aust NJ J Med 1981; 11: 93. 14. Clarke PS. The effect of beclomethasone diproprionate on bronchial hyperreactivity. J Asthma 1982; 19: 91-93. 15. Tiffeneau R, Dunoyer P. Action de la cortisone sur l’hypersensibilité cholinergique pulmonaire de l’asthmatique. Presse Méd 1956; 64: 719-21. 16. Woolfe JD, Rosenthal RR, Bleecker E, Lauise B, Norman PS, Permutt S. The effect of corticosteroids on cholinergic hyperreactivity. J Allergy Clin Immunol 1979; 63: 162. 17. Easton JG. Effect of an inhaled corticosteroid on methacholine airway reactivity. J Allergy Clin Immunol 1981; 67: 388-90. 18. Arkins JA, Schleuter DP, Fink JN. The effect of corticosteroids on methacholine inhalation in symptomatic bronchial asthma. J Allergy 1968; 41: 209-16. 6. Dickson W. A
hyperreactivity’9 and so of exacerbations of the disease.
Similarly exercise,an agonist clearly different
from antigen, has been reported to cause "late" bronchoconstrictive reactions,2and the effects on bronchial reactivity of these and many of the other hazards to which the asthmatic patient is exposed have yet to be investigated.
occasionally
Pharmaceutical Division, Fisons plc, Loughborough, Leicestershire LE11 0RH
R. M. AUTY A. CHAMBERS
AN EXPLANATION OF CIRCADIAN RHYTHM FOR THEOPHYLLINE AND OTHER DRUGS
SiR,—Dr Jonkman and Dr van der Boon (June 4, p 1278), in commenting on Dr Primrose’s observations (April 23, p 927) on possible differences in nocturnal and daytime theophylline levels, report that trough values depend on the time of day at which they t 3 In particular, are taken. This has been confirmed elsewhere. Giacona and associates report no significant differences in metabolic clearances.3This is similar to our observation that paediatric age dependent theophylline clearance does not exhibit metabolic 4 age The paediatric age dependency of drug clearance was suggested to be a function of micturition frequency and urine volume output. Theophylline is resorbed from the bladder,s and the dominant factors governing resorption are drug concentration, volume of urine, and time. With the use of these parameters variability in urinary excretion has been successfully predicted for several drugs. Accordingly it is predicted that, in general, trough levels of the drug should be slightly higher in the early morning, since bladder retention time is normally greater overnight than during the day with normal activities and fluid intake. Overnight urine volumes are also generally less than for a corresponding daytime period. Both the micturition frequency and the volume output would normally result in greater overnight resorption of the drug into the general circulation. Diurnal variations can be expected with these drugs. Indeed, some temporal oscillations in plasma level normally assumed to result from biliary recycle may result from the bladder recycle to venous blood and lymph. Only drugs which are difficult to absorb from the gastrointestinal tract may be expected to exhibit minimal recycle potential. Drugs absorbable by oral administration may be expected to recycle in part or even completely until metabolised to possess sufficient polarity to minimise this capability. When any temporal variations in drug level are observed they should be first correlated with micturition frequency, volume of output, and urine concentration to determine whether they can explain the observed effects.
dependency.4
.
Department of Pharmacy and Pharmaceutics and Department of Pediatrics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23233, USA
19.
20. 1. 2. 3.
JOHN H. WOOD LORNE K. GARRETTSON
Empey EW, Laitinen LA, Jacobs L, Gold EM, Nadel JA. Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection Am Rev Resp Dis 1976; 113: 131-39. Bierman CW, Spiro SG, PetheramI. Late response in exercise-induced asthma (EIA) J Allergy Clin Immunol 1980; 65: 206. Lesko LJ, Brousseau D, et al. Temporal variations in trough serum theophylline concentration at steady state. J Pharm Sci 1980; 69: 358-59. Reed RC, Schwartz HJ. Circadian variation in trough theophylline concentrations Drug Intell Clin Pharm 1983; 17: 444. Giacona N, Elvin AT, et al. Diurnal variation in theophylline elimination Drug Intell
Clin Pharm 1983; 17: 452. LK, Wood JH, Leonard TW. Age dependent changes in theophylline elimination. In: Hunt V, Smith MK, Worth D, eds. Environmental effects on maturation: Banbury report. New York: Cold Spring Harbor Laboratory, 1982 197-505. 5. Wood JH, Leonard TW. Kinetic implications of drug resorption from the bladder Drug Metab Rev 1983; 14: 407-23.
4. Garrettson
(bronchodilators) will have a less fundamental effect on the disease. Most probably it is the bronchial inflammatory changes that accompany the late reaction which account for its effects on airways reactivity.3 Accordingly the development of the whole of the
unequivocal support for the hypothesis. And the hypothesis is unlikely to provide more than a partial explanation for the natural history of perennial asthma. It fails, for example, to take account of the likely importance of intercurrent infection as a cause of
be must reaction inhibited; simple reversal of the bronchoconstriction which is its most readily observed feature is insufficient. This corollary is easier to test clinically than is the hypothesis itself, and with this objective we have been collaborating for the past two years in a series of clinical investigations designed to determine the effects of sodium cromoglycate on bronchial hyperreactivity to allergic and non-allergic stimuli in seasonal and perennial asthmatic patients. Not all of these studies have yet been fully reported, but the data which are available and the results of other studies in the literature do support the hypothesis that it is only drugs that prevent the development of the late reaction which prevent the development of bronchial hyperreactivity.44 Thus most studies in which sodium cromoglycate has been given for three weeks or more have demonstrated reductions in nonspecific airways hyperreactivity,5-9 though two of the most recently reported placebo-controlled studies have found an effect of the drug only on specific hyperreactivity-to antigen in one caseio and to eucapnic hyperventilation with cold air in the other.ll Bronchodilators, as predicted, on the limited evidence available, do not appear to affect airways hyperreactivity.12,13 Corticosteroids, which do inhibit the late reaction, have been variously reported, mainly in open assessment studies, to reduce bronchial hyperto have no effect upon it,15-17 or to increase it.l8 Methodological problems probably account for many of the apparent contradictions in these results, and on balance the data do seem to support Cockcroft’s hypothesis, though the case must still be regarded as "not proven". There is, therefore, much direct and indirect4evidence of the importance of the late reaction to antigen in the pathogenesis of bronchial hyperreactivity. The considerable technical difficulties which surround clinical work in this area, and to which Cockcroft alluded, mean that we are still some way from providing
bronchial
reactivity,13,
3 Gleich
GJ. The late phase of the immunoglobulin E-mediated reaction: a link between anaphylaxis and common allergic disease? J Allergy Clin Immunol 1982; 70: 160-69.
4.
Auty RM. Pharmacologic modulation of bronchial hyperreactivity. Immunol All Pract
5.
Altounyan REC. Changes in histamine and atropine responsiveness as a guide to diagnosis and evaluation of therapy in obstructive airways disease. In: Pepys J, Frankland AW, eds. Disodium cromoglycate in allergic airways disease. London:
1983; 5: 78-85.
Butterworth, 1970: 47.
one-year’s trial of IntalR compound in 24 children with severe asthma. In: Pepys J, Frankland AW, eds. Disodium cromoglycate in allergic airways disease. London: Butterworth, 1970: 105. 7. Szmidt M, Gorski P, Rozniecki J, Rychlicka I. Ocena zaleznosci miedzy wragliwoscia oskrzeli na wziewana histamine a histaminemia u chorych na astme atopowa podczas leczenia Intalem (DSCG). Pneumonal Pol 1979; 47: 517-22. 8. Bierman CW, Pearson WE, Shapiro GG, Kraemer MJ, Auty RM, Furukawa CT. Theophylline versus cromolyn sodium in outpatient management of childhood asthma: A double blind clinical trial. Proceedings of the XI International Congress of Allergology and Clinical Immunology. New York: Macmillan, 1982: 707. 9. Rak S, Millqvist E, Lowhagen O. Therapeutic modification of non-specific hyperreactivity by sodium cromoglycate. Presented at Meeting of American Academy of Allergy and Immunology, Florida, March, 1983. 10. Bleecker ER, Britt EJ, Maston PL. The effect of cromolyn on antigen and methacholine airways reactivity during ragweed season in allergic asthma. Chest 1982; 82: 227. 11. Griffin MP, MacDonald N, McFadden ER. Effects of cromolyn sodium on the airway reactivity of asthmatics. Am Rev Resp Dis 1982; 125: 61. 12. Peel ET, Gibson GJ. Effects of long-term inhaled salbutamol therapy on the provocation of asthma by histamine. Am Rev Resp Dis 1980; 121: 973-78. 13. Juniper EF, Firth PA, Hargreave FE. Long-term stability of non-specific airway responsiveness to histamine and effect of beclomethasone. Am Rev Resp Dis 1980; 121 (suppl): 76, and Aust NJ J Med 1981; 11: 93. 14. Clarke PS. The effect of beclomethasone diproprionate on bronchial hyperreactivity. J Asthma 1982; 19: 91-93. 15. Tiffeneau R, Dunoyer P. Action de la cortisone sur l’hypersensibilité cholinergique pulmonaire de l’asthmatique. Presse Méd 1956; 64: 719-21. 16. Woolfe JD, Rosenthal RR, Bleecker E, Lauise B, Norman PS, Permutt S. The effect of corticosteroids on cholinergic hyperreactivity. J Allergy Clin Immunol 1979; 63: 162. 17. Easton JG. Effect of an inhaled corticosteroid on methacholine airway reactivity. J Allergy Clin Immunol 1981; 67: 388-90. 18. Arkins JA, Schleuter DP, Fink JN. The effect of corticosteroids on methacholine inhalation in symptomatic bronchial asthma. J Allergy 1968; 41: 209-16. 6. Dickson W. A
hyperreactivity’9 and so of exacerbations of the disease.
Similarly exercise,an agonist clearly different
from antigen, has been reported to cause "late" bronchoconstrictive reactions,2and the effects on bronchial reactivity of these and many of the other hazards to which the asthmatic patient is exposed have yet to be investigated.
occasionally
Pharmaceutical Division, Fisons plc, Loughborough, Leicestershire LE11 0RH
R. M. AUTY A. CHAMBERS
AN EXPLANATION OF CIRCADIAN RHYTHM FOR THEOPHYLLINE AND OTHER DRUGS
SiR,—Dr Jonkman and Dr van der Boon (June 4, p 1278), in commenting on Dr Primrose’s observations (April 23, p 927) on possible differences in nocturnal and daytime theophylline levels, report that trough values depend on the time of day at which they t 3 In particular, are taken. This has been confirmed elsewhere. Giacona and associates report no significant differences in metabolic clearances.3This is similar to our observation that paediatric age dependent theophylline clearance does not exhibit metabolic 4 age The paediatric age dependency of drug clearance was suggested to be a function of micturition frequency and urine volume output. Theophylline is resorbed from the bladder,s and the dominant factors governing resorption are drug concentration, volume of urine, and time. With the use of these parameters variability in urinary excretion has been successfully predicted for several drugs. Accordingly it is predicted that, in general, trough levels of the drug should be slightly higher in the early morning, since bladder retention time is normally greater overnight than during the day with normal activities and fluid intake. Overnight urine volumes are also generally less than for a corresponding daytime period. Both the micturition frequency and the volume output would normally result in greater overnight resorption of the drug into the general circulation. Diurnal variations can be expected with these drugs. Indeed, some temporal oscillations in plasma level normally assumed to result from biliary recycle may result from the bladder recycle to venous blood and lymph. Only drugs which are difficult to absorb from the gastrointestinal tract may be expected to exhibit minimal recycle potential. Drugs absorbable by oral administration may be expected to recycle in part or even completely until metabolised to possess sufficient polarity to minimise this capability. When any temporal variations in drug level are observed they should be first correlated with micturition frequency, volume of output, and urine concentration to determine whether they can explain the observed effects.
dependency.4
.
Department of Pharmacy and Pharmaceutics and Department of Pediatrics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23233, USA
19.
20. 1. 2. 3.
JOHN H. WOOD LORNE K. GARRETTSON
Empey EW, Laitinen LA, Jacobs L, Gold EM, Nadel JA. Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection Am Rev Resp Dis 1976; 113: 131-39. Bierman CW, Spiro SG, PetheramI. Late response in exercise-induced asthma (EIA) J Allergy Clin Immunol 1980; 65: 206. Lesko LJ, Brousseau D, et al. Temporal variations in trough serum theophylline concentration at steady state. J Pharm Sci 1980; 69: 358-59. Reed RC, Schwartz HJ. Circadian variation in trough theophylline concentrations Drug Intell Clin Pharm 1983; 17: 444. Giacona N, Elvin AT, et al. Diurnal variation in theophylline elimination Drug Intell
Clin Pharm 1983; 17: 452. LK, Wood JH, Leonard TW. Age dependent changes in theophylline elimination. In: Hunt V, Smith MK, Worth D, eds. Environmental effects on maturation: Banbury report. New York: Cold Spring Harbor Laboratory, 1982 197-505. 5. Wood JH, Leonard TW. Kinetic implications of drug resorption from the bladder Drug Metab Rev 1983; 14: 407-23.
4. Garrettson