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170 Adenosine-theophylline interactions in canine tracheal smooth muscle (CTSM) strips
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The Bronchodilator Effects and Pharmacokinetics of Caffeine in Asthma. A.B.Becker, M.D., F.E.R. Simons, M.D., K.J.Simons,Ph.D. C.A. Gillespie,R.N., Winnipeg,Manitoba Caffeine (C) 10 mg/kg and theophylline (T) 5 mg/kg were compared in a double-blind, single-dose study. Fourteen patients, age 8-18 yrs, abstained from C and T-containing substances for 48 hrs and from other bronchodilators for 8 hr before study. FVC, FEVl, FEFZS-75% and flow at 50 and 25% of vital . capacity (V50 and $25) were obtained before the dose and 1, 1 l/2,2,2 l/2,3,4,5 & 6 hrs after. Physical examination results and vital signs were recorded hourly. Blood samples were obtained pre-dose, then half-hourly for 6 hrs. Serum C and T concentrations were measured by HPLC. The C and T groups did not differ significantly in degree of bronchial obstruction before the study, FEF25-75% being 22514 and 35212% predicted respectively. Decreased wheezing and significant (~(0.05) fmprovement in FVC, FEVl, FEVlX, FEFZT-75%, V50 and $25 were found after both C & T from 1-6 hrs, and were maximal at 2 hrs. The bronchodilator effect of C did not differ significantly from T. Peak serum levels of C (13.122.5 mg/L) were seen at 1.1+0.5 hrs. The mean serum half-life value for C-was 3.7+2.1 hrs. All patients receiving C metabolizgd it to T and had a mean T level of 3.6iC.8 mg/L at 6 hrs. Transient, mild shakiness was seen in 70% of patients after C and 33% after T. Vital signs did not change significantly in either group. We conclude that C, a commonly used chemical, is an effective bronchodilator in young patients with asthma.
ADENOSINE-THEOPHYLLINE INTERACTIONS IN CANINE TRACHEAL SMOOTH MUSCLE (CTSM) STRIPS. g Krzanowski, Ph.D., J.B. Polson, Ph.D., Meredith McPherson, Antonio Urdaneta-Bohorquez, M.D., A. Szentivanyi, M.D., Tampa, Florida Observations reported from other laboratories in quinea pig trachea showing that adenosine contracts this smooth muscle and the knowledge that theophylline blocks adenosine receptors contributed to the suggestion that theophylline is effective as a consequence of inhibition of adenosine receptors. This hypothesis was tested in CTSM bathed in Krebs-Ringer (pH 7.4, 38") utilizing Grass force-displacement transducers to measure teysion. Dose response curves to adenosine (lo10e3M) resulted in no alteration of yasal tension. Strips placed in tone with lo- M methacholine relaxed when a enosine was added to the f M, n=8) bath (EC50=3.28~10and this response was reduced by the adenosine uptake inhibitor dipyridamole. Interaction between theophylline and adenosine was tested by generating dose response curves to theophylline on methacholine contracted strips in the absence and presence of adenosine (10V7-lo-4M). Comparisons of EC50's and dose response curves to theophylline with adenosine did not give evidence of any changes which would suggest that theophylline and adenosine interact in inducing CTSM relaxation. Conclusions: 1) Adenosine does not alter basal tone of CTSM strips. '2) Adenosine produces relaxation of methacholine-contracted canine tracheal smooth muscle. 3) Theophylline-induced relaxation of CTSM does not depend on inhibition of or interaction with adenosine receptors.
171
EFFECT OF ERYTHROMYCINBASE ON THEOPHYLLINE PHARMACOKINETICS IN ASTHMATIC CHILDREN: 6. F. Leorce, M. F.Miller, A. Kaliskar, Denver,
Colorado
A study was undertaken to invesitgate the effect of erythromycin base (EB) on theophylline pharmacokinetics in children with chronic asthma in a residential treatment program. Ten children with chronic asthma (ages 9-18) were given an intravenous bolus of aminophylline before and after a one-week course of EB (dose = Pharmacokinetic data was calculat1 gram/day). ed from serial serum theophylline and erythromytin levels drawn after each aminophylline bolus. Assuming a one compartment open model, we calculated theophylline clearance rate (TCR) and serum half-life (tQ. Steady state volume of distribution (VDSS) was also determined for a noncompartmental model. Liver functions were measured before and after EB administration. There was a 30.6 f 21.0% (mean + S.D.) reduction in TCR after administration of EB (p< .05). The mean t$ increased from 4.9 to 6.3 hours after EB administration. This represents a 36.1 + 35.3% (mean + S.D.) prolongation of t$ (p< There was a 14.7% reduction in VDSS (p .OOOl). There was no correlation between peak < .025). serum erythromycin level achieved and change in TCR (r= -0.20) or t+ (r= 0.34). There were no significant changes in liver functions. This data confirms our previous observation that erythromycin has a significant effect on theophylline metabolism in children with Such patients run a considerchronic asthma. able risk of theophylline toxicity when theophylline and EB are coadministered.
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COMPUTER-ASSISTED PHARMACOKINETIC EVIDENCE 'IHAT THEOPRYLLINE INDUCED BRONCHODILATORYRESPONSE VARIES WITH, BUT LAGS BEHIND FLUCTUATIONS IN SERUM THEOPHYLLINE LEVELS IN THE THERAPEUTIC RANGE. James Baker, M.D., Lester Lennert, M.S., Laurie Smith, M.D., Richard Summers, M.D. and Carl Peck, M.D., Washington, D.C., Bethesda, Md In an attempt to examine the usefulness of optimizing and-maintaining stable levels of theophylline in the treatment of asthma, Bayesian computer-assisted pharmacokinetic analysis was employed to study the relationship hetween serum theophylline levels (STL) and pulmonary functions (PFT) in asthma. Individualized, single doses of anhydrous theophylline elixir (TE) were designed such that they could he substituted for a dose of the patient's usual theophylline medication and raise the subject from lcw to maximal therapeutic STL. Ten asthmatic adults were studied on 14 occasions with STL and PFT's measured at baseline, 1, 2, 3, 4, 5 and 6 hrs. post dose of TE. STL rose from 8.1k3.2 (SD) to 17.6k2.6 rig/ml, peaking at 76.5k28.6 min. post ingestion. FEVl (% predicted) rose and fell progressively with changes in STL, and went from a baseline level of 73.2220.9 (SD) to a peak of 83.1+18.4% at 146.4i68.7 min. This resulted in a time lag of 69.9519.8 (SEM) min. (p
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The Bronchodilator Effects and Pharmacokinetics of Caffeine in Asthma. A.B.Becker, M.D., F.E.R. Simons, M.D., K.J.Simons,Ph.D. C.A. Gillespie,R.N., Winnipeg,Manitoba Caffeine (C) 10 mg/kg and theophylline (T) 5 mg/kg were compared in a double-blind, single-dose study. Fourteen patients, age 8-18 yrs, abstained from C and T-containing substances for 48 hrs and from other bronchodilators for 8 hr before study. FVC, FEVl, FEFZS-75% and flow at 50 and 25% of vital . capacity (V50 and $25) were obtained before the dose and 1, 1 l/2,2,2 l/2,3,4,5 & 6 hrs after. Physical examination results and vital signs were recorded hourly. Blood samples were obtained pre-dose, then half-hourly for 6 hrs. Serum C and T concentrations were measured by HPLC. The C and T groups did not differ significantly in degree of bronchial obstruction before the study, FEF25-75% being 22514 and 35212% predicted respectively. Decreased wheezing and significant (~(0.05) fmprovement in FVC, FEVl, FEVlX, FEFZT-75%, V50 and $25 were found after both C & T from 1-6 hrs, and were maximal at 2 hrs. The bronchodilator effect of C did not differ significantly from T. Peak serum levels of C (13.122.5 mg/L) were seen at 1.1+0.5 hrs. The mean serum half-life value for C-was 3.7+2.1 hrs. All patients receiving C metabolizgd it to T and had a mean T level of 3.6iC.8 mg/L at 6 hrs. Transient, mild shakiness was seen in 70% of patients after C and 33% after T. Vital signs did not change significantly in either group. We conclude that C, a commonly used chemical, is an effective bronchodilator in young patients with asthma.
ADENOSINE-THEOPHYLLINE INTERACTIONS IN CANINE TRACHEAL SMOOTH MUSCLE (CTSM) STRIPS. g Krzanowski, Ph.D., J.B. Polson, Ph.D., Meredith McPherson, Antonio Urdaneta-Bohorquez, M.D., A. Szentivanyi, M.D., Tampa, Florida Observations reported from other laboratories in quinea pig trachea showing that adenosine contracts this smooth muscle and the knowledge that theophylline blocks adenosine receptors contributed to the suggestion that theophylline is effective as a consequence of inhibition of adenosine receptors. This hypothesis was tested in CTSM bathed in Krebs-Ringer (pH 7.4, 38") utilizing Grass force-displacement transducers to measure teysion. Dose response curves to adenosine (lo10e3M) resulted in no alteration of yasal tension. Strips placed in tone with lo- M methacholine relaxed when a enosine was added to the f M, n=8) bath (EC50=3.28~10and this response was reduced by the adenosine uptake inhibitor dipyridamole. Interaction between theophylline and adenosine was tested by generating dose response curves to theophylline on methacholine contracted strips in the absence and presence of adenosine (10V7-lo-4M). Comparisons of EC50's and dose response curves to theophylline with adenosine did not give evidence of any changes which would suggest that theophylline and adenosine interact in inducing CTSM relaxation. Conclusions: 1) Adenosine does not alter basal tone of CTSM strips. '2) Adenosine produces relaxation of methacholine-contracted canine tracheal smooth muscle. 3) Theophylline-induced relaxation of CTSM does not depend on inhibition of or interaction with adenosine receptors.
171
EFFECT OF ERYTHROMYCINBASE ON THEOPHYLLINE PHARMACOKINETICS IN ASTHMATIC CHILDREN: 6. F. Leorce, M. F.Miller, A. Kaliskar, Denver,
Colorado
A study was undertaken to invesitgate the effect of erythromycin base (EB) on theophylline pharmacokinetics in children with chronic asthma in a residential treatment program. Ten children with chronic asthma (ages 9-18) were given an intravenous bolus of aminophylline before and after a one-week course of EB (dose = Pharmacokinetic data was calculat1 gram/day). ed from serial serum theophylline and erythromytin levels drawn after each aminophylline bolus. Assuming a one compartment open model, we calculated theophylline clearance rate (TCR) and serum half-life (tQ. Steady state volume of distribution (VDSS) was also determined for a noncompartmental model. Liver functions were measured before and after EB administration. There was a 30.6 f 21.0% (mean + S.D.) reduction in TCR after administration of EB (p< .05). The mean t$ increased from 4.9 to 6.3 hours after EB administration. This represents a 36.1 + 35.3% (mean + S.D.) prolongation of t$ (p< There was a 14.7% reduction in VDSS (p .OOOl). There was no correlation between peak < .025). serum erythromycin level achieved and change in TCR (r= -0.20) or t+ (r= 0.34). There were no significant changes in liver functions. This data confirms our previous observation that erythromycin has a significant effect on theophylline metabolism in children with Such patients run a considerchronic asthma. able risk of theophylline toxicity when theophylline and EB are coadministered.
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131
COMPUTER-ASSISTED PHARMACOKINETIC EVIDENCE 'IHAT THEOPRYLLINE INDUCED BRONCHODILATORYRESPONSE VARIES WITH, BUT LAGS BEHIND FLUCTUATIONS IN SERUM THEOPHYLLINE LEVELS IN THE THERAPEUTIC RANGE. James Baker, M.D., Lester Lennert, M.S., Laurie Smith, M.D., Richard Summers, M.D. and Carl Peck, M.D., Washington, D.C., Bethesda, Md In an attempt to examine the usefulness of optimizing and-maintaining stable levels of theophylline in the treatment of asthma, Bayesian computer-assisted pharmacokinetic analysis was employed to study the relationship hetween serum theophylline levels (STL) and pulmonary functions (PFT) in asthma. Individualized, single doses of anhydrous theophylline elixir (TE) were designed such that they could he substituted for a dose of the patient's usual theophylline medication and raise the subject from lcw to maximal therapeutic STL. Ten asthmatic adults were studied on 14 occasions with STL and PFT's measured at baseline, 1, 2, 3, 4, 5 and 6 hrs. post dose of TE. STL rose from 8.1k3.2 (SD) to 17.6k2.6 rig/ml, peaking at 76.5k28.6 min. post ingestion. FEVl (% predicted) rose and fell progressively with changes in STL, and went from a baseline level of 73.2220.9 (SD) to a peak of 83.1+18.4% at 146.4i68.7 min. This resulted in a time lag of 69.9519.8 (SEM) min. (p