Inhibitor Report for: Theophylline

BACKGROUND: There is accumulating evidence that theophylline has anti-inflammatory or immunomodulatory effects. This may be, in part, mediated via an upregulation in the production of the anti-inflammatory cytokine interleukin (IL)-10. We determined whether low-dose theophylline (LDT) would increase the production of IL-10, and attenuate the production of proinflammatory cytokines by alveolar macrophages.
METHODS: In a double-blind, placebo-controlled, crossover study involving 15 steroid-free patients with mild asthma, fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed at the end of the treatment and placebo periods. Alveolar macrophages were cultured in vitro, and we measured their release of IL-10, GM-CSF, and TNF-alpha. We also measured IL-10 production in whole blood together with the number of monocytes and T cells expressing intracellular IL-10 by flow cytometry.
RESULTS: LDT did not increase the production of IL-10, or attenuate the production of GM-CSF or TNF-alpha by alveolar macrophages. However, after theophylline treatment, there was a significant reduction in mean (SD) (95% CI) BAL eosinophil number from 3.4 (1.7)% (95% CI 2.4-4.4) to 1.7 (1.0)% (95% CI 1.1-2.3) compared with placebo (P<0.05). Similarly, there was no increase in whole-blood IL-10 release or in the number of monocytes and T cells expressing intracellular IL-10 after treatment.
CONCLUSIONS: LDT has an anti-inflammatory effect in asthma; however, this effect is not mediated via the production of IL-10 or the attenuation of GM-CSF or TNF-alpha. The mechanisms of theophylline activity remain to be determined.

AIM: The aim of the study was to evaluate the pharmacokinetics of theophylline administered alone, and in combination with donepezil HCl, following multiple-dose administration of both drugs in healthy volunteers.
METHODS: This was an open-label, randomized, two-period crossover study in healthy male volunteers (n=12). During each treatment period, subjects received either titrated-dose theophylline alone, or in combination with donepezil (5 mg, once daily) for 10 consecutive days. On day 10 of each treatment period, serial blood samples for the determination of theophylline concentrations in plasma were measured up to 24 h. Treatment periods were separated by a 3-week, drug-free washout. Plasma concentrations of theophylline were determined by HPLC with UV detection.
RESULTS: No statistically significant differences in theophylline pharmacokinetics (Cmax, AUC or tmax) were observed between theophylline administered alone and in combination with donepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed in any subject during any treatment period.
CONCLUSIONS: Concurrent administration of donepezil HCl does not alter the pharmacokinetic profile of theophylline following multiple-dose administration of both drugs in healthy volunteers. These findings suggest that donepezil may be safely co-administered with theophylline without a need for dose modification or additional monitoring procedures.

BACKGROUND: There is accumulating evidence that theophylline has anti-inflammatory or immunomodulatory effects. This may be, in part, mediated via an upregulation in the production of the anti-inflammatory cytokine interleukin (IL)-10. We determined whether low-dose theophylline (LDT) would increase the production of IL-10, and attenuate the production of proinflammatory cytokines by alveolar macrophages.
METHODS: In a double-blind, placebo-controlled, crossover study involving 15 steroid-free patients with mild asthma, fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed at the end of the treatment and placebo periods. Alveolar macrophages were cultured in vitro, and we measured their release of IL-10, GM-CSF, and TNF-alpha. We also measured IL-10 production in whole blood together with the number of monocytes and T cells expressing intracellular IL-10 by flow cytometry.
RESULTS: LDT did not increase the production of IL-10, or attenuate the production of GM-CSF or TNF-alpha by alveolar macrophages. However, after theophylline treatment, there was a significant reduction in mean (SD) (95% CI) BAL eosinophil number from 3.4 (1.7)% (95% CI 2.4-4.4) to 1.7 (1.0)% (95% CI 1.1-2.3) compared with placebo (P<0.05). Similarly, there was no increase in whole-blood IL-10 release or in the number of monocytes and T cells expressing intracellular IL-10 after treatment.
CONCLUSIONS: LDT has an anti-inflammatory effect in asthma; however, this effect is not mediated via the production of IL-10 or the attenuation of GM-CSF or TNF-alpha. The mechanisms of theophylline activity remain to be determined.

AIM: The aim of the study was to evaluate the pharmacokinetics of theophylline administered alone, and in combination with donepezil HCl, following multiple-dose administration of both drugs in healthy volunteers.
METHODS: This was an open-label, randomized, two-period crossover study in healthy male volunteers (n=12). During each treatment period, subjects received either titrated-dose theophylline alone, or in combination with donepezil (5 mg, once daily) for 10 consecutive days. On day 10 of each treatment period, serial blood samples for the determination of theophylline concentrations in plasma were measured up to 24 h. Treatment periods were separated by a 3-week, drug-free washout. Plasma concentrations of theophylline were determined by HPLC with UV detection.
RESULTS: No statistically significant differences in theophylline pharmacokinetics (Cmax, AUC or tmax) were observed between theophylline administered alone and in combination with donepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed in any subject during any treatment period.
CONCLUSIONS: Concurrent administration of donepezil HCl does not alter the pharmacokinetic profile of theophylline following multiple-dose administration of both drugs in healthy volunteers. These findings suggest that donepezil may be safely co-administered with theophylline without a need for dose modification or additional monitoring procedures.

It has been suggested that theophylline may possess anti-inflammatory actions which underlie its antiasthma properties. We examined whether theophylline could inhibit the bronchoconstriction and the bronchial hyperresponsiveness induced by inhaled platelet-activating factor (PAF) in eight nonasthmatic subjects in a double-blind, cross-over study. After oral theophylline (6 mg.kg-1), plasma theophylline at 1 h was 10.4 +/- 1.8 mg.ml-1 (mean +/- SEM) compared to 0.39 +/- 0.19 mg.ml-1 on the placebo day (p less than 0.005). PAF, inhaled in five successive doses every 15 min, caused a 56 +/- 11% fall in Vp30 (flow at 30% of vital capacity from a partial expiratory manoeuvre) after the first dose at 5 min, and diminishing responses with successive doses. Theophylline had no significant effect on PAF-induced bronchoconstriction. PAF caused a significant decrease in PC40 (the concentration of methacholine needed to cause 40% fall in baseline Vp30) from a baseline of 12.8 mg.ml-1 (geometric standard error of mean (GSEM) 1.98) to 7.9 (1.79) mg.ml-1 on day 3 and 6.9 (1.74) on day 7 (p less than 0.02). There was no significant difference when mean PC40 values on corresponding days after PAF were compared between placebo and theophylline treatment periods. Our results suggest that theophylline has negligible influence on the airway effects of PAF.

The protective effects of oxyphenonium bromide, terbutaline and theophylline were compared in 8 asthmatic patients by determination of the degree of non-specific airway reactivity after 1 week of oral treatment according to a fixed dose scheme in a double-blind random order: oxyphenonium bromide 3 X 10 mg; terbutaline 3 X 5 mg; theophylline 2 X 300 mg and placebo. Controlled, standardized inhalation provocation tests were carried out with histamine, acetylcholine and propranolol. The study was monitored by measuring blood concentrations of the 3 drugs, and their effect on the plasma cAMP concentration was also determined. Significant protection by oxyphenonium bromide against the bronchial obstructive effects of acetylcholine and propranolol was observed, but not against the effect of inhaled histamine. The other two drugs provided no significant protection against the inhaled agents. The absence of any protective effect of terbutaline and theophylline might have resulted from too low a blood concentration. The observed differences in protection could not be explained by changes in pulmonary function. The study suggests dissociation between the bronchodilating effect of a drug and its protective effect against inhaled substances.

On the dog isolated right ventricular muscle, experiments were carried out in order to elucidate the characteristics of the cholinergic antagonism against the positive inotropic action (PIA) induced via different subcellular mechanisms. The relationship between cyclic AMP and cyclic GMP levels, and contractile force during cholinergic antagonism was assessed. Carbachol (10 microM) by itself decreased only slightly the tension developed, but inhibited prominently the PIAs of isoprenaline, histamine, glucagon, theophylline and papaverine. The action of dibutyryl cyclic AMP was inhibited less than PIAs of other agents mentioned above. In contrast, carbachol did not affect the PIAs of calcium and g-strophanthin. The antagonism by carbachol of PIAs of isoprenaline, histamine, glucagon, theophylline and papaverine was accompanied by a reduction of the intracellular cyclic AMP level elevated previously by these agents, and by an elevation of the intracellular cyclic GMP level. A good correlation was found between changes in the tension developed, and cyclic AMP and cyclic GMP levels during the cholinergic antagonism of PIAs induced by these agents in the dog ventricular myocardium.

This study concerns the effects of theophylline on nerve-muscle transmission of the frog; it was of particular interest to evaluate the facilitatory actions of theophylline at the postsynaptic sites. At concentrations of up to 5 mM, theophylline exerted negligible effects on the end-plate resting potential or on the passive membrane characteristics. The major effects of theophylline (0.5--5.0 mM) were exerted on the end-plate potentials (EPPs), miniature EPPs, acetylcholine (ACh) potentials, and on the end-plate current. The amplitude of these parameters was markedly increased; furthermore, the half-decay time of the EPP and, particularly, of the end-plate current were markedly affected. On the other hand, the time course of the ACh potentials was not significantly affected by theophylline. Spontaneous and evoked release of ACh were not affected by theophylline (0.5--5 mM). Altogether, these results indicate that, in amphibia, the neuromyal facilitation induced by theophylline is mainly due to its postsynaptic actions. Furthermore, some of these data as well as results of others indicate that these effects of theophylline are not due to its anticholinesterase properties. It is suggested that theophylline may act directly on the cholinergic receptor or ionic conductance modulator and that it may stabilize the ACh-receptor complex.