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Enprofylline in chronic asthma
Br. J. Dis. Chest (1988) 82, 354
ENPROFYLLINE B. J. CHAPMAN,
IN CHRONIC
ASTHMA
C. MCDONALD, S. CAPEWELL, M. H. FRAME* AND G. K. CROMPTON
Respiratory Diseases Unit, Northern General Hospital, Edinburgh and Departments of Medicine and Respiratory Medicine, University of Edinburgh; *Asha Clinical Research Unit, 10 York Place, Edinburgh
Summary
A double-blind crossover study has been performed in 14 patients with moderately severe chronic asthma to compare the bronchodilator efficacy of two dosage regimens of intravenous enprofylline (high dose=2 mg/kg bolus and 1 mg/kg/hour infusion; low dose=1 mg/kg bolus and 500 pg/kg/hour infusion) with aminophylline (5 mg/kg/bolus and 500 pg/kg/hour infusion) and placebo. The bolus injections were given over 20 minutes and infusion over 160 minutes. Twelve subjects completed the study. High dose enprofylline was more effective than aminophylline in increasing PEF (P=O.OOS) and FEV, (P=O.O04). Low dose enprofylline and aminophylline were of similar efficacy. Sideeffects, notably headaches and nausea, were more common with enprofylline; three out of 14 subjects receiving the high dose regimen developed severe nausea. The plasma enprofylline levels achieved with the high dose regimen were greater than anticipated. Further studies are required in acute severe asthma to clarify the therapeutic role of intravenous enprofylline and the most appropriate dosage regimen. INTRODUCTION Theophylline (1,3-dimethylxanthine) is an effective bronchodilator but to obtain an optimum therapeutic effect with minimum unwanted effects requires judicious prescribing and treatment monitoring (1, 2). Variable hepatic metabolism may lead to unpredictable plasma concentrations, and its narrow therapeutic index can result in toxic effects at plasma levels just above or even within the ‘therapeutic range’. The most common unwanted effects are headaches, nausea and vomiting but potentially fatal reactions, including convulsions and cardiac dysrhythmias, can also occur (3-5). Enprofylline (3-propylxanthine) is a novel xanthine derivative which seems to lack many of the unwanted effects of theophylline (6-8). It was developed from structureactivity studies of a great number of xanthines (9) and has been reported to be five times more potent a bronchodilator than theophylline, while lacking its CNS-stimulant behavioural effects and diuretic actions (10). This is considered to be due to enprofylline’s lack of adenosine receptor antagonistic activity (7, 9). In experimental animals, it is without seizure activity and the lethal infused dose is twice that of theophylline (11). Correspondence to: Dr G. K. Crompton, Respiratory Unit, Northern General Hospital, Ferry Road, Edinburgh EH5 2DQ.
CHAPMAN,
MCDONALD,
CAPEWELL
ET AL.:
ENPROFYLLINE
IN CHRONIC
ASTHMA
355
Enprofylline is eliminated by the kidney without prior metabolism (12). It may be possible, therefore, to predict plasma levels in patients with normal renal function. Enprofylline administered intravenously has been shown to be an effective bronchodilator in asthmatics (13,14) but the optimum dosage regimen compared with aminophylline has not yet been studied. We have, therefore, performed a double-blind, placebocontrolled, crossover study comparing the bronchodilator effects of two dose levels of enprofylline given as a bolus followed by a constant rate infusion with a standard aminophylline bolus plus infusion in patients with moderately severe asthma. This patient group was selected because of their high potential reversibility, combined with their availability for study under controlled conditions on more than one occasion. The study was approved by the hospital’s Ethics Committee and all patients studied gave written informed consent. Patients and Methods Patients Eleven male and three post-menopausal female subjects were entered into the study. They had a mean age of 43 years (range 19-72). All had chronic bronchial asthma without evidence of any other disease. The morning peak expiratory flow (PEF) and forced expiratory volume in one second (FEVi) were between 25 and 50% of predicted value for each patient, and improved by at least 20% after inhalation of 2 mg terbutaline via a ‘Nebuhaler’. None was receiving oral bronchodilator therapy of any kind. Methods Each subject attended the clinic on 4 days at 0900 hours when the following treatment regimens were given using a Latin square design to determine treatment order. 1. 2. 3. 4.
Enprofylline-low dose (EL): 1 mg/kg bolus+SM lug/kg/hour infusion; Enprofylline-high dose (EH): 2 mg/kg bolus+ 1 mg/kg/hour infusion; Aminophylline: 5 mg/kg bolus+500 ,ug/kg/hour infusion.; Normal saline: normal saline bolus and infusion.
The bolus injection over 20 minutes and infusion over the next 160 minutes were delivered with a ‘TREONIC IP4’ syringe pump. At the end of the infusion, 4 mg of inhaled terbutaline was administered via a ‘Nebuhaler’ to establish maximum reversibility. Prior to each study, inhaled bronchodilators were prohibited for 5 hours and tea/coffee/cola for 12 hours. Baseline PEF on the 4 days did not vary by more than 15%. The PEF, FEVi and vital capacity (VC), each best of three, heart rate and blood pressure were measured at 0,20,40,60,90,120,150,180 and 210 minutes from the beginning of the bolus injection. Plasma theophylline and enprofylline levels were measured at 0, 20,40, 60, 150 and 180 minutes. Side-effects were recorded as they were reported. Statistics A two-way analysis of variance followed by paired t-tests were performed for each comparison. To correct for multiple t-tests, a significance level of P~O.009 was taken (15).
RESULTS Twelve patients completed the study. One withdrew for personal reasons and one was withdrawn because of severe nausea with high dose enprofylline.
356
BR.
J. DIS.
CHEST:
VOL.
82 NO.
4
Spirometry
The mean PEF and FEV, for the four treatment regimens are shown in Fig. 1. For statistical analysis of PEF, FEV, and VC, the area under the curve above the baseline from 0 to 180 minutes was determined for each patient. Enprofylline (high dose) and aminophylline both produced a significantly greater increase in PEF, FEV, and VC than placebo (P
. Enpmfyllmek~wl Enpmfyllme(highi o Ammophyllme 360, .‘-- Placebo q
PEFR I I /mm1 320,
7 2LOO.
l Enpmfylllne (low) q Enprofyllme I hlghl D Ammophyllw --- Placebo
FEVl [ml)
1600
0
al
60
90
180
2x)
MINUTES
Fig. 1. Mean PEFR and FEVl (k 1 SEM) on the 4 study days Plasma concentrations
The aminophylline regimen gave a steady-state mean plasma theophylline concentration of 10 mg/litre (Fig. 2). The low dose enprofylline infusion gave a steady-state enprofylline level of 2 mg/litre (Fig. 2). With high dose enprofylline, however, the plasma concentration continued to rise throughout the study (Fig. 2).
CHAPMAN,
MCDONALD,
CAPEWELL
ET AL.:
ENPROFYLLINE
IN CHRONIC
ASTHMA
357
20 ENPROFYLLINE hKJ/l) -
IS
THEOFliYLLlNf lmgll) -
3 utes
Fig. 2. Mean plasma enprofylline and theophylline levels (+l SEM) on the active treatment study days Adverse effects (Table I)
Headache was the commonest adverse effect reported, but this was generally mild and tolerable. The most troublesome unwanted effect was nausea which was severe enough to precipitate termination of the infusion on three occasions during the infusion of the high dose of enprofylline. The study was also discontinued in one patient during the low dose enprofylline infusion on account of nausea and headache, although he had previously been treated with the high dose regimen without any adverse effects. There were no significant differences in heart rate, systolic blood pressure or diastolic blood pressure between the 4 study days. No cardiac dysrhythmias were observed during continuous cardiac monitoring throughout all study days. Table I. Side-effects on the 4 study days
No. of subjects Headache Nausea Vomiting Warm/clammy Light-headed Urinary frequency
Enprojjdine
Enprofylline
(high dose)
Aminophylline
Placebo
(low dose) 12 5 1 0 0 0 0
14 4 6 1 3 2 0
12 1 0 0 0 0 2
12 1 0 0 0 0 0
DISCUSSION Enprofylline is a new xanthine derivative with potential value in the management of reversible obstructive airways disease. Its lack of adenosine receptor antagonist activity should be an advantage, reducing the likelihood of CNS side-effects such as insomnia, restlessness, anxiety and, in the most severe cases, seizures. Since adenosine may be an important negative feedback modulator of sympathetic stimulation of the heart, enprofylline may offer therapeutic advantages over theophylline (16, 17).
358
BR.
J. DIS.
CHEST:
VOL.
82 NO. 4
This study confirms that enprofylline is an effective bronchodilator and lends support to the pharmacological findings that at equivalent bronchodilator effect, enprofylline plasma levels are one-fifth of theophylline plasma levels (10). Side-effects, predominantly headache and nausea, were more common with enprofylline than with aminophylline, and were greater in number and variety following the higher dose of enprofylline. The general lack of side-effects with aminophylline is surprising, but may be explained by patient sellction. Most patients had previously received intravenous aminophylline for treatment of acute exacerbations of their asthma. Since, prior to giving informed consent, all patients were told that they would receive aminophylline on one day, it is possible that those who had previously suffered side-effects from aminophylline declined to participate in this study. The main side-effects associated with enprofylline in our study, i.e. headache and nausea, have been reported previously (8,13,18). In one study these effects were related to plasma concentrations greater than 2.9 mg/litre. The low dose and high dose enprofylline regimens in our study were designed to give steady-state plasma levels of 2 mg/litre and 4 mg/litre, respectively. The initial plasma concentration produced by the high dose regimen was as anticipated, but plasma concentrations then slowly increased to levels higher than predicted, suggesting infusion of enprofylline at too high a dose rate following the initial bolus. The predicted renal clearance used in our dose calculations was based on estimations obtained from young healthy volunteers (12). Recent pharmacokinetic data from asthmatic patients, however, suggests that their renal clearance of the drug is lower and also that it is dose-dependent (19). On the basis of this new information, a 2 mg/kg bolus followed by a 0.8 mg/kg/hour infusion should, in theory, produce a steady-state plasma level of 4 mg/litre. The undoubted bronchodilator efficacy of intravenous enprofylline and apparent lack of serious side-effects have to be set against a relatively high incidence of headache and nausea in this study. The patient population chosen, however, would not normally receive intravenous therapy unless their asthma became acutely severe. Patients with acute severe asthma may be less susceptible to enprofylline-induced headache and nausea than patients with chronic asthma. Boe et al. (20), in a study of patients with acute severe asthma, reported only one case of headache in 20 patients treated with a 1 mg/kg bolus of enprofylline, although a 2 mg/kg bolus produced three cases of nausea (one accompanied by dizziness and one by vomiting) in 14 patients. Maintenance infusions were not used in these patients following the initial bolus. Similarly, Haahtela et al. (21) found few sideeffects with a 1 mg/kg bolus of enprofylline when administered to 20 patients, namely nausea in one and dry mouth in another. Further studies are required in a larger population of patients with acute severe asthma in order to clarify the therapeutic role of intravenous enprofylline, and the most appropriate intravenous dosage regimen.
ACKNOWLEDGEMENTS We wish to thank Dr Jan Jonkman for analyses of plasma enprofylline and theophylline. Dr Brian Tiplady for statistical analyses, Miss Carolyn Paterson for assistance with drug preparation and administration and Miss Isabel McCall for typing this manuscript.
CHAPMAN,
MCDONALD,
CAPEWELL
ET AL.:
ENPROFYLLINE
IN CHRONIC
ASTHMA
359
REFERENCES 1. Jenne JW, Wyze E, Rood FS, MacDonald FM. Pharmacokinetics of theophylline. Application to adjustment of the clinical dose of aminophylline. Clin Pharmac Ther 1972;13:349-60. 2. Editorial. Theophylline benefits and difficulties. Lancet 1983;ii:607-8. 3. Jacobs MH, Senior RM, Kessler G. Clinical experience with theophylline. Relationships between dosage, serum concentration and toxicity. JAMA 1976;235:1983-6. 4. Hendeles L, Bighley L, Richardson RH et al. Frequent toxicity from IV infusions of aminophylline in critically ill patients. Drug Intel1 Clin Pharm 1977;11:12-18. 5. Woodcock AA, Johnson MA, Geddes DM. Theophylline prescribing, serum concentrations, and toxicity. Lancet 1983;ii:610-13. 6. Persson CGA, Kjellin G. Enprofylline, a principally new antiasthmatic xanthine. Acta Pharmac Toxic01 1981;49:313-16. 7. Persson CGA, Erjefalt I, Karlsson J-A. Adenosine antagonism, aless desirable characteristic of xanthine asthma drugs? Acta Pharmac Toxic01 1981;49:317-20. 8. Lunell E, Svedmyr N, Andersson K-E et al. Effects of enprofylline, a xanthine lacking adenosine antagonism, in patients with reversible obstructive lung disease. Eur J Clin Pharmac 1982;22:395-402. 9. Persson CGA, Karlsson J-A, Erjefalt I. Differentiation between bronchodilation and universal adenosine antagonism among xanthine derivatives. Life Sci 1982;30:2181-9. 10. Lunell E, Svedmyr N, Andersson K-E, Persson CGA. A novel bronchodilator xanthine apparently without adenosine receptor antagonism and tremorogenic effect. Eur J Resp Dis 1983;64:333-9. 11. Persson CGA, Erjefalt I. Seizure activity in animals given enprofylline and theophylline, two xanthines with partly different mechanisms of action. Arch Int Pharmacodyn Ther 1982;258:267-82.
12. Borga 0, Andersson K-E, Edholm L-E et al. Enprofylline kinetics in healthy subjects after single doses. Clin Pharmac Ther 1983;34:799-804. 13. Laursen LC, Johannesson N, Sondergaard I, Weeke B. Maximally effective plasma concentrations of enprofylline and theophylline during constant infusion. Br J Clin Pharmac 1984$8:591-S. 14. Lunell E, Andersson K-E, Persson CGA, Svedmyr N. Intravenous enprofylline in asthma patients. Eur J Resp Dis 1984;65:2834. 15. Pocock SJ. Clinical trials, a practical approach. Chichester: John Wiley & Sons, 1983: 231. 16. Persson CGA, Erjefalt I, Andersson K-E. Positive inotropic and chronotrophic effects and coronary vasodilation in vitro by two antiasthmatic xanthines with different abilities to antagonise adenosine. J Cardiovasc Pharmac 1983;5:778-85. 17. Conradson T-B. Bronchodilating plasma concentrations of enprofylline and theophylline have minor cardiovascular effects in man. Acta Pharmac Toxic01 1986;58:204-8. 18. Laursen LC, Johannesson N, Weeke B. Continuous treatment of asthmatic patients with enprofylline and theophylline. Eur J Resp Dis 1984;65:504-8. 19. Borga 0. Enprofylline: summary of human pharmacokinetics and bioavailability. Data on file, AB Draco, Sweden, 1986. 20. Boe J, Eriksson G, Ljungholm, K. Efficacy of a new bronchodilating xanthine, enprofylline, in acute asthma. Ann Allergy 1987$9:155-g. 21. Haahtela T, Venho K, Eriksson G. Comparison of enprofylline and theophyllim For intravenous treatment of acute asthma. Allergy 1986;41:160-2.
Date accepted 4 August
1987
ENPROFYLLINE B. J. CHAPMAN,
IN CHRONIC
ASTHMA
C. MCDONALD, S. CAPEWELL, M. H. FRAME* AND G. K. CROMPTON
Respiratory Diseases Unit, Northern General Hospital, Edinburgh and Departments of Medicine and Respiratory Medicine, University of Edinburgh; *Asha Clinical Research Unit, 10 York Place, Edinburgh
Summary
A double-blind crossover study has been performed in 14 patients with moderately severe chronic asthma to compare the bronchodilator efficacy of two dosage regimens of intravenous enprofylline (high dose=2 mg/kg bolus and 1 mg/kg/hour infusion; low dose=1 mg/kg bolus and 500 pg/kg/hour infusion) with aminophylline (5 mg/kg/bolus and 500 pg/kg/hour infusion) and placebo. The bolus injections were given over 20 minutes and infusion over 160 minutes. Twelve subjects completed the study. High dose enprofylline was more effective than aminophylline in increasing PEF (P=O.OOS) and FEV, (P=O.O04). Low dose enprofylline and aminophylline were of similar efficacy. Sideeffects, notably headaches and nausea, were more common with enprofylline; three out of 14 subjects receiving the high dose regimen developed severe nausea. The plasma enprofylline levels achieved with the high dose regimen were greater than anticipated. Further studies are required in acute severe asthma to clarify the therapeutic role of intravenous enprofylline and the most appropriate dosage regimen. INTRODUCTION Theophylline (1,3-dimethylxanthine) is an effective bronchodilator but to obtain an optimum therapeutic effect with minimum unwanted effects requires judicious prescribing and treatment monitoring (1, 2). Variable hepatic metabolism may lead to unpredictable plasma concentrations, and its narrow therapeutic index can result in toxic effects at plasma levels just above or even within the ‘therapeutic range’. The most common unwanted effects are headaches, nausea and vomiting but potentially fatal reactions, including convulsions and cardiac dysrhythmias, can also occur (3-5). Enprofylline (3-propylxanthine) is a novel xanthine derivative which seems to lack many of the unwanted effects of theophylline (6-8). It was developed from structureactivity studies of a great number of xanthines (9) and has been reported to be five times more potent a bronchodilator than theophylline, while lacking its CNS-stimulant behavioural effects and diuretic actions (10). This is considered to be due to enprofylline’s lack of adenosine receptor antagonistic activity (7, 9). In experimental animals, it is without seizure activity and the lethal infused dose is twice that of theophylline (11). Correspondence to: Dr G. K. Crompton, Respiratory Unit, Northern General Hospital, Ferry Road, Edinburgh EH5 2DQ.
CHAPMAN,
MCDONALD,
CAPEWELL
ET AL.:
ENPROFYLLINE
IN CHRONIC
ASTHMA
355
Enprofylline is eliminated by the kidney without prior metabolism (12). It may be possible, therefore, to predict plasma levels in patients with normal renal function. Enprofylline administered intravenously has been shown to be an effective bronchodilator in asthmatics (13,14) but the optimum dosage regimen compared with aminophylline has not yet been studied. We have, therefore, performed a double-blind, placebocontrolled, crossover study comparing the bronchodilator effects of two dose levels of enprofylline given as a bolus followed by a constant rate infusion with a standard aminophylline bolus plus infusion in patients with moderately severe asthma. This patient group was selected because of their high potential reversibility, combined with their availability for study under controlled conditions on more than one occasion. The study was approved by the hospital’s Ethics Committee and all patients studied gave written informed consent. Patients and Methods Patients Eleven male and three post-menopausal female subjects were entered into the study. They had a mean age of 43 years (range 19-72). All had chronic bronchial asthma without evidence of any other disease. The morning peak expiratory flow (PEF) and forced expiratory volume in one second (FEVi) were between 25 and 50% of predicted value for each patient, and improved by at least 20% after inhalation of 2 mg terbutaline via a ‘Nebuhaler’. None was receiving oral bronchodilator therapy of any kind. Methods Each subject attended the clinic on 4 days at 0900 hours when the following treatment regimens were given using a Latin square design to determine treatment order. 1. 2. 3. 4.
Enprofylline-low dose (EL): 1 mg/kg bolus+SM lug/kg/hour infusion; Enprofylline-high dose (EH): 2 mg/kg bolus+ 1 mg/kg/hour infusion; Aminophylline: 5 mg/kg bolus+500 ,ug/kg/hour infusion.; Normal saline: normal saline bolus and infusion.
The bolus injection over 20 minutes and infusion over the next 160 minutes were delivered with a ‘TREONIC IP4’ syringe pump. At the end of the infusion, 4 mg of inhaled terbutaline was administered via a ‘Nebuhaler’ to establish maximum reversibility. Prior to each study, inhaled bronchodilators were prohibited for 5 hours and tea/coffee/cola for 12 hours. Baseline PEF on the 4 days did not vary by more than 15%. The PEF, FEVi and vital capacity (VC), each best of three, heart rate and blood pressure were measured at 0,20,40,60,90,120,150,180 and 210 minutes from the beginning of the bolus injection. Plasma theophylline and enprofylline levels were measured at 0, 20,40, 60, 150 and 180 minutes. Side-effects were recorded as they were reported. Statistics A two-way analysis of variance followed by paired t-tests were performed for each comparison. To correct for multiple t-tests, a significance level of P~O.009 was taken (15).
RESULTS Twelve patients completed the study. One withdrew for personal reasons and one was withdrawn because of severe nausea with high dose enprofylline.
356
BR.
J. DIS.
CHEST:
VOL.
82 NO.
4
Spirometry
The mean PEF and FEV, for the four treatment regimens are shown in Fig. 1. For statistical analysis of PEF, FEV, and VC, the area under the curve above the baseline from 0 to 180 minutes was determined for each patient. Enprofylline (high dose) and aminophylline both produced a significantly greater increase in PEF, FEV, and VC than placebo (P
. Enpmfyllmek~wl Enpmfyllme(highi o Ammophyllme 360, .‘-- Placebo q
PEFR I I /mm1 320,
7 2LOO.
l Enpmfylllne (low) q Enprofyllme I hlghl D Ammophyllw --- Placebo
FEVl [ml)
1600
0
al
60
90
180
2x)
MINUTES
Fig. 1. Mean PEFR and FEVl (k 1 SEM) on the 4 study days Plasma concentrations
The aminophylline regimen gave a steady-state mean plasma theophylline concentration of 10 mg/litre (Fig. 2). The low dose enprofylline infusion gave a steady-state enprofylline level of 2 mg/litre (Fig. 2). With high dose enprofylline, however, the plasma concentration continued to rise throughout the study (Fig. 2).
CHAPMAN,
MCDONALD,
CAPEWELL
ET AL.:
ENPROFYLLINE
IN CHRONIC
ASTHMA
357
20 ENPROFYLLINE hKJ/l) -
IS
THEOFliYLLlNf lmgll) -
3 utes
Fig. 2. Mean plasma enprofylline and theophylline levels (+l SEM) on the active treatment study days Adverse effects (Table I)
Headache was the commonest adverse effect reported, but this was generally mild and tolerable. The most troublesome unwanted effect was nausea which was severe enough to precipitate termination of the infusion on three occasions during the infusion of the high dose of enprofylline. The study was also discontinued in one patient during the low dose enprofylline infusion on account of nausea and headache, although he had previously been treated with the high dose regimen without any adverse effects. There were no significant differences in heart rate, systolic blood pressure or diastolic blood pressure between the 4 study days. No cardiac dysrhythmias were observed during continuous cardiac monitoring throughout all study days. Table I. Side-effects on the 4 study days
No. of subjects Headache Nausea Vomiting Warm/clammy Light-headed Urinary frequency
Enprojjdine
Enprofylline
(high dose)
Aminophylline
Placebo
(low dose) 12 5 1 0 0 0 0
14 4 6 1 3 2 0
12 1 0 0 0 0 2
12 1 0 0 0 0 0
DISCUSSION Enprofylline is a new xanthine derivative with potential value in the management of reversible obstructive airways disease. Its lack of adenosine receptor antagonist activity should be an advantage, reducing the likelihood of CNS side-effects such as insomnia, restlessness, anxiety and, in the most severe cases, seizures. Since adenosine may be an important negative feedback modulator of sympathetic stimulation of the heart, enprofylline may offer therapeutic advantages over theophylline (16, 17).
358
BR.
J. DIS.
CHEST:
VOL.
82 NO. 4
This study confirms that enprofylline is an effective bronchodilator and lends support to the pharmacological findings that at equivalent bronchodilator effect, enprofylline plasma levels are one-fifth of theophylline plasma levels (10). Side-effects, predominantly headache and nausea, were more common with enprofylline than with aminophylline, and were greater in number and variety following the higher dose of enprofylline. The general lack of side-effects with aminophylline is surprising, but may be explained by patient sellction. Most patients had previously received intravenous aminophylline for treatment of acute exacerbations of their asthma. Since, prior to giving informed consent, all patients were told that they would receive aminophylline on one day, it is possible that those who had previously suffered side-effects from aminophylline declined to participate in this study. The main side-effects associated with enprofylline in our study, i.e. headache and nausea, have been reported previously (8,13,18). In one study these effects were related to plasma concentrations greater than 2.9 mg/litre. The low dose and high dose enprofylline regimens in our study were designed to give steady-state plasma levels of 2 mg/litre and 4 mg/litre, respectively. The initial plasma concentration produced by the high dose regimen was as anticipated, but plasma concentrations then slowly increased to levels higher than predicted, suggesting infusion of enprofylline at too high a dose rate following the initial bolus. The predicted renal clearance used in our dose calculations was based on estimations obtained from young healthy volunteers (12). Recent pharmacokinetic data from asthmatic patients, however, suggests that their renal clearance of the drug is lower and also that it is dose-dependent (19). On the basis of this new information, a 2 mg/kg bolus followed by a 0.8 mg/kg/hour infusion should, in theory, produce a steady-state plasma level of 4 mg/litre. The undoubted bronchodilator efficacy of intravenous enprofylline and apparent lack of serious side-effects have to be set against a relatively high incidence of headache and nausea in this study. The patient population chosen, however, would not normally receive intravenous therapy unless their asthma became acutely severe. Patients with acute severe asthma may be less susceptible to enprofylline-induced headache and nausea than patients with chronic asthma. Boe et al. (20), in a study of patients with acute severe asthma, reported only one case of headache in 20 patients treated with a 1 mg/kg bolus of enprofylline, although a 2 mg/kg bolus produced three cases of nausea (one accompanied by dizziness and one by vomiting) in 14 patients. Maintenance infusions were not used in these patients following the initial bolus. Similarly, Haahtela et al. (21) found few sideeffects with a 1 mg/kg bolus of enprofylline when administered to 20 patients, namely nausea in one and dry mouth in another. Further studies are required in a larger population of patients with acute severe asthma in order to clarify the therapeutic role of intravenous enprofylline, and the most appropriate intravenous dosage regimen.
ACKNOWLEDGEMENTS We wish to thank Dr Jan Jonkman for analyses of plasma enprofylline and theophylline. Dr Brian Tiplady for statistical analyses, Miss Carolyn Paterson for assistance with drug preparation and administration and Miss Isabel McCall for typing this manuscript.
CHAPMAN,
MCDONALD,
CAPEWELL
ET AL.:
ENPROFYLLINE
IN CHRONIC
ASTHMA
359
REFERENCES 1. Jenne JW, Wyze E, Rood FS, MacDonald FM. Pharmacokinetics of theophylline. Application to adjustment of the clinical dose of aminophylline. Clin Pharmac Ther 1972;13:349-60. 2. Editorial. Theophylline benefits and difficulties. Lancet 1983;ii:607-8. 3. Jacobs MH, Senior RM, Kessler G. Clinical experience with theophylline. Relationships between dosage, serum concentration and toxicity. JAMA 1976;235:1983-6. 4. Hendeles L, Bighley L, Richardson RH et al. Frequent toxicity from IV infusions of aminophylline in critically ill patients. Drug Intel1 Clin Pharm 1977;11:12-18. 5. Woodcock AA, Johnson MA, Geddes DM. Theophylline prescribing, serum concentrations, and toxicity. Lancet 1983;ii:610-13. 6. Persson CGA, Kjellin G. Enprofylline, a principally new antiasthmatic xanthine. Acta Pharmac Toxic01 1981;49:313-16. 7. Persson CGA, Erjefalt I, Karlsson J-A. Adenosine antagonism, aless desirable characteristic of xanthine asthma drugs? Acta Pharmac Toxic01 1981;49:317-20. 8. Lunell E, Svedmyr N, Andersson K-E et al. Effects of enprofylline, a xanthine lacking adenosine antagonism, in patients with reversible obstructive lung disease. Eur J Clin Pharmac 1982;22:395-402. 9. Persson CGA, Karlsson J-A, Erjefalt I. Differentiation between bronchodilation and universal adenosine antagonism among xanthine derivatives. Life Sci 1982;30:2181-9. 10. Lunell E, Svedmyr N, Andersson K-E, Persson CGA. A novel bronchodilator xanthine apparently without adenosine receptor antagonism and tremorogenic effect. Eur J Resp Dis 1983;64:333-9. 11. Persson CGA, Erjefalt I. Seizure activity in animals given enprofylline and theophylline, two xanthines with partly different mechanisms of action. Arch Int Pharmacodyn Ther 1982;258:267-82.
12. Borga 0, Andersson K-E, Edholm L-E et al. Enprofylline kinetics in healthy subjects after single doses. Clin Pharmac Ther 1983;34:799-804. 13. Laursen LC, Johannesson N, Sondergaard I, Weeke B. Maximally effective plasma concentrations of enprofylline and theophylline during constant infusion. Br J Clin Pharmac 1984$8:591-S. 14. Lunell E, Andersson K-E, Persson CGA, Svedmyr N. Intravenous enprofylline in asthma patients. Eur J Resp Dis 1984;65:2834. 15. Pocock SJ. Clinical trials, a practical approach. Chichester: John Wiley & Sons, 1983: 231. 16. Persson CGA, Erjefalt I, Andersson K-E. Positive inotropic and chronotrophic effects and coronary vasodilation in vitro by two antiasthmatic xanthines with different abilities to antagonise adenosine. J Cardiovasc Pharmac 1983;5:778-85. 17. Conradson T-B. Bronchodilating plasma concentrations of enprofylline and theophylline have minor cardiovascular effects in man. Acta Pharmac Toxic01 1986;58:204-8. 18. Laursen LC, Johannesson N, Weeke B. Continuous treatment of asthmatic patients with enprofylline and theophylline. Eur J Resp Dis 1984;65:504-8. 19. Borga 0. Enprofylline: summary of human pharmacokinetics and bioavailability. Data on file, AB Draco, Sweden, 1986. 20. Boe J, Eriksson G, Ljungholm, K. Efficacy of a new bronchodilating xanthine, enprofylline, in acute asthma. Ann Allergy 1987$9:155-g. 21. Haahtela T, Venho K, Eriksson G. Comparison of enprofylline and theophyllim For intravenous treatment of acute asthma. Allergy 1986;41:160-2.
Date accepted 4 August
1987