Theophylline Exposure Research Articles

Current status and usefulness of therapeutic drug monitoring implementation of theophylline in elderly patients based on a nationwide database study and modeling approach.

Theophylline is used in the treatment of chronic obstructive pulmonary disease but readily causes symptoms of intoxication and exhibits high risks in elderly patients. However, there have only been a few recent reports on the significance of therapeutic drug monitoring (TDM) implementation, especially in elderly patients. To examine the usefulness of theophylline TDM, we evaluated the current status of prescriptions containing theophylline and its side effects and assessed the influence of aging, sex, drug formulation, and concurrent drugs use on theophylline exposure using data from various nationwide databases and a pharmacokinetic modeling approach. We utilized sampling data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Using the data of patients aged ≥80 years, we conducted an association analysis of theophylline and concurrent drugs. The transition in plasma theophylline concentration levels of elderly patients was estimated based on a previously reported physiological-based pharmacokinetic model. Altogether, 3973 patients using theophylline were registered in our dataset, and about 50% were over 70 years old and used theophylline. Therapeutic drug monitoring implementation was confirmed in only 1.13% of patients. The association analysis confirmed a frequent co-occurrence with allopurinol and famotidine, which increase theophylline exposure, in elderly patients aged ≥80 years. The physiologically based pharmacokinetic model indicated that theophylline trough concentrations were 1.65-fold higher in elderly patients aged 80 years compared to those aged 30 years and 1.35-fold higher in females compared to males. This study effectively combined information on the nationwide health care database and modeling approach, indicating the importance of proactive TDM and dose justification for female and elderly patients.

Application of a Physiologically Based Pharmacokinetic Approach to Predict Theophylline Pharmacokinetics Using Virtual Non-Pregnant, Pregnant, Fetal, Breast-Feeding, and Neonatal Populations.

Perinatal pharmacology is influenced by a myriad of physiological variables that are changing dynamically. The influence of these covariates has not been assessed systemically. The objective of this work was to use theophylline as a model drug and to predict its pharmacokinetics before, during (including prediction of the umbilical cord level), and after pregnancy as well as in milk (after single and multiple doses) and in neonates using a physiological-based pharmacokinetic (PBPK) model. Neonatal theophylline exposure from milk consumption was projected in both normal term and preterm subjects. Predicted infant daily doses were calculated using theophylline average and maximum concentration in the milk as well as an estimate of milk consumption. Predicted concentrations and parameters from the PBPK model were compared to the observed data. PBPK predicted theophylline concentrations in non-pregnant and pregnant populations at different gestational weeks were within 2-fold of the observations and the observed concentrations fell within the 5th−95th prediction interval from the PBPK simulations. The PBPK model predicted an average cord-to-maternal plasma ratio of 1.0, which also agrees well with experimental observations. Predicted postpartum theophylline concentration profiles in milk were also in good agreement with observations with a predicted milk-to-plasma ratio of 0.68. For an infant of 2 kg consuming 150 ml of milk per day, the lactation model predicted a relative infant dose (RID) of 12 and 17% using predicted average (Cavg,ss) and maximum (Cmax,ss) concentration in milk at steady state. The maximum RID of 17% corresponds to an absolute infant daily dose of 1.4 ± 0.5 mg/kg/day. This dose, when administered as 0.233 mg/kg every 4 h, to resemble breastfeeding frequency, resulted in plasma concentrations as high as 3.9 (1.9–6.8) mg/L and 2.8 (1.3–5.3) (5th−95th percentiles) on day 7 in preterm (32 GW) and full-term neonatal populations.

Acute theophylline exposure modulates breathing activity through a cervical contusion

Cervical spinal contusion injuries are the most common form of spinal cord injury (>50%) observed in humans. These injuries can result in the impaired ability to breathe. In this study we examine the role of theophylline in the rescue of breathing behavior after a cervical spinal contusion. Previous research in the C2 hemisection model has shown that acute administration of theophylline can rescue phrenic nerve activity and diaphragmatic EMG on the side ipsilateral to injury. However, this effect is dependent on intact and uninjured pathways. In this study we utilized a cervical contusion injury model that more closely mimics the human condition. This injury model can determine the effectiveness of therapeutic interventions, in this case theophylline, on the isolated contused pathways of the spinal cord. Three weeks after a 150kD C3/4 unilateral contusion subjects received a 15mg/kg dose of theophylline prior to a contralateral C2 hemisection. Subjects that received theophylline were able to effectively utilize damaged pathways to breathe for up to 2min, while subjects treated with saline were unable to support ventilation. Through these experiments, we demonstrate that theophylline can make injured pathways that mediate breathing more effective and therefore, suggest a potential therapeutic role in the critical time points immediately after injury.

Demographic and Clinical Characteristics of Theophylline Exposures between 1993 and 2011

Acute and chronic exposure to theophylline can cause serious signs and symptoms of poisoning. Additionally, with a narrow therapeutic range, toxicity could be observed even with therapeutic doses of theophylline. Epidemiological data on theophylline exposures in our country are extremely limited. The results of our study may improve the clinical management of theophylline poisoning in our country and elsewhere. To present aetiological and demographic features, clinical findings and treatment attempts with regard to theophylline exposures reported to Dokuz Eylül University Drug and Poison Information Center (DPIC), between 1993 and 2011. Descriptive study. The data regarding demographics, date, time, type of exposure, route of and reason for exposure, signs and symptoms upon admission, clinical management and outcome were retrospectively evaluated. The DPIC recorded 88,562 poisoning calls between 1993 and 2011; 354 (0.4%) of them were due to theophylline exposure. The mean age of all cases was 24.1±15.4 (range between 1 month and 90 years). Females dominated all age groups (72.6%, 257 females). Intentional exposure was significantly higher in women than in men (88.2% vs. 68.2% for all age groups; p<0.001 for children; p<0.001 for adults; p<0.001 for all age groups). While 60.5% of the cases had no symptoms, severe signs of toxicity were present in 1.9% of theophylline exposure cases during the telephone inquiry. Signs and symptoms were found to be significantly more prevalent in adults than in children (p<0.01). The serum theophylline level was regarded as toxic in 74% (65 toxic levels) of theophylline measured cases. Clinical signs and symptoms were found to be significantly prevalent in cases with toxic theophylline levels (p<0.001). The rate of gastrointestinal decontamination procedures was higher than that of recommended gastrointestinal decontamination procedures by DPIC (83% and 66%, respectively). There were two fatalities (4.6%) associated with chronic theophylline toxicity and theophylline overdose in an acute setting for suicide (a 90 year-old and 25 year-old, respectively). Although most of the theophylline exposure cases had no symptoms, some reported serious signs and symptoms of poisoning such as hypokalaemia, tachycardia and hyperglycaemia. DPICs have an important role in the management of theophylline exposure without unnecessary gastrointestinal decontamination procedures.

A multi-endpoint in vivo larval zebrafish (Danio rerio) model for the assessment of integrated cardiovascular function

IntroductionDespite effective in vitro preclinical strategies to identify cardiovascular (CV) liabilities, there remains a need for early functional assessment prior to complex in vivo mammalian models. The larval zebrafish (Danio rerio, Zf) has been suggested for this role: previous data suggest that cardiac electrophysiology and vascular ultrastructure are comparable with mammals, and also indicate responsiveness of individual Zf CV system endpoints to some functional modulators. Little information is, however, available regarding integrated functional CV responses to drug treatment. Consequently, we developed a novel larval Zf model capable of simultaneous quantification of chronotropic, inotropic and arrhythmic effects, alongside measures of blood flow and vessel diameter. MethodsNon-invasive video analysis of the heart and dorsal aorta of anaesthetized and agarose-embedded larval ZF was used to measure multiple cardiovascular endpoints, simultaneously, following treatment with a range of functional modulators of CV physiology. ResultsChanges in atrial and ventricular beat frequencies were detected in response to acute treatment with cardio-stimulants (adrenaline and theophylline), and negative chrono/inotropes (cisapride, haloperidol, terfenadine and verapamil). Arrhythmias were also observed including terfenadine-induced 2:1 atrial–ventricular (A–V) block, a previously proposed hERG surrogate measure. Significant increases in blood flow were detected in response to adrenaline and theophylline exposure; and decreases after cisapride, haloperidol, terfenadine, and verapamil treatment. Using dorsal aorta (DA) blood flow and ventricular beat rate, surrogate stoke volumes were also calculated for all compounds. DiscussionThese data support the use of this approach for CV function studies. Moreover the throughput and compound requirements (approximately 3 compounds/person effort/week and <10mg) make our approach potentially suitable for higher throughput drug safety and efficacy applications, pending further assessment of ZF-mammalian pharmacological comparability.

Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer

To assess the effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan HBr (CYP2D6 substrate) and theophylline (CYP1A2 substrate) in patients with metastatic castration-resistant prostate cancer (mCRPC). Men with progressive metastatic mCRPC who failed gonadotropin-releasing hormone therapy and ≥1 lines of chemotherapy were enrolled. Patients received two doses of dextromethorphan HBr-30 mg (n = 18; group A) or theophylline-100 mg (n = 16; group B) under fasting conditions; one dose on cycle 1, day -8, and the other dose on cycle 1, day 8. Only patients with extensive CYP2D6 metabolizing status were assigned to group A. All patients received continuous daily oral abiraterone acetate (1,000 mg) plus prednisone (10 mg) starting on cycle 1, day 1. Coadministration of abiraterone acetate plus prednisone increased the systemic exposure of dextromethorphan by approximately 100%. Ratios of geometric means for maximum plasma concentration (C(max)) (275.36%) and area under plasma concentration-time curves from time 0 to 24 h (AUC(24h)) (268.14%) of dextromethorphan were outside the bioequivalence limit. The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone. Ratios of geometric means [C(max); 102.36% and AUC(24h); 108.03%] of theophylline exposure parameters were within the bioequivalence limit. The safety profile of abiraterone acetate was consistent with reported toxicities. Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone.

Changes in Submaxillary Gland Gene Expression in F344 Rats by Multiple Dosing of Theophylline

Multiple exposure to theophylline, a phosphodiesterase (PDE) inhibitor, induces acinar hypertrophy in the salivary gland. This study examined the effect of theophylline on the gene expression of secretory proteins and phosphodiesterases in the submaxillary gland. Male F344 rats received saline or theophylline (50 mg/kg) intraperitoneally for 4 days. The gene expressions for the secretory protein, cystatin S (CysS), and PDE subfamilies 3A and 4D in the submaxillary gland were quantified using RT-PCR. Theophylline exposure resulted in a sustained increase in mRNA expression for CysS and PDE3A, but PDE4D gene expression was unchanged. Our results suggest that submaxillary hypertrophy is primarily caused by the enhanced transcription of CysS, and that the transcription of each PDE subfamily gene is regulated differently.

Changes in Salivary Gene Expression in F344 Rats Exposed to Theophylline

Exposure to theophylline, a phosphodiesterase (PDE) inhibitor, increases the basophilic basal part and conspicuous nucleoli in salivary acini. These histological findings imply increased gene expression. The purpose of this study was to examine the effect of theophylline on the expression of representative genes in the salivary glands which are regulated by cyclic AMP. Male F344 rats received saline or theophylline (50 mg/kg) intraperitoneally. Parotid and submaxillary glands were isolated from rats at 4, 8, and 24 h post-administration, and gene expression for the principal secretory proteins, amylase 1 (AMY1) and cystatin S (CysS), dominant PDE subfamilies 3A and 4D, and a water channel, aquaporin 5 (AQP5) were quantified by RT-PCR. The cyclic AMP concentration was determined by enzyme-immunoassay. Theophylline exposure resulted in a transient increase in mRNA expression for AMY1 in the parotid gland, CysS in the submaxillary gland, and PDE3A in both salivary glands. The cyclic AMP concentration was elevated in both glands. PDE4D and AQP5 gene expressions were not altered in either gland. Our results suggest that theophylline induces cyclic AMP signals through PDE inhibition, leading to enhanced gene transcription and subsequent histological changes.

Effects of long-term theophylline exposure on recovery of respiratory function and expression of adenosine A1 mRNA in cervical spinal cord hemisected adult rats

Our lab has previously shown that when administered acutely, the methylxanthine theophylline can activate a latent respiratory motor pathway to restore function to the hemidiaphragm paralyzed by an ipsilateral C2 spinal cord hemisection. The recovery is mediated by the antagonism of CNS adenosine A1 receptors. The objective of the present study was to assess quantitatively recovery after chronic theophylline administration, the effects of weaning from the drug, and the effects of the drug on adenosine A1 receptor mRNA expression in adult rats subjected to a C2 hemisection. Rats subjected to a left C2 hemisection received theophylline orally for 3, 7, 12, or 30 days and were classified as 3D, 7D, 12D, or 30D respectively. Separate groups of 3D animals were weaned from drug administration for 7, 12, and 30 days before assessment of respiratory recovery. Additional groups of 7D and 12D animals were also weaned from drug administration for 7 and 12 days prior to assessment. Sham-operated controls received theophylline vehicle for similar periods. Quantitative assessment of recovered respiratory activity was conducted under standardized electrophysiologic recording conditions approximately 18 h after each drug application period. Serum theophylline analysis was conducted at the end of electrophysiologic recordings. Adenosine A1 receptor mRNA expression in the phrenic nucleus was assessed with in situ hybridization and immunohistochemistry. Chronic theophylline induced a dose-dependent effect on respiratory recovery over a serum theophylline range of 1.2–1.9 μg/ml. Recovery was characterized as respiratory-related activity in the left phrenic nerve and expressed as a percentage of activity in the homolateral nerve in noninjured animals under similar recording conditions. Recovered activity was 34.13 ± 2.07, 55.89 ± 2.96, 74.78 ± 1.93, and 79.12 ± 1.75% respectively in the 3D, 7D, 12D, and 30D groups. Theophylline-induced recovered activity persisted for as long as 30 days when drug administration was stopped and serum levels of the drug were virtually undetected. Furthermore, recovered activity in 3D and 7D animals increased significantly as a function of duration of weaning. Adenosine A1 receptor mRNA expression was not significantly changed by theophylline administration. It is concluded that recovery of respiratory function in C2-hemisected rats induced by chronic theophylline is unrelated to adenosine A1 receptor mRNA expression. Recovered activity persists even when drug administration has been stopped. The significance of our results is that in the clinical application of theophylline to improve respiratory impairment, intermittent drug administration may be sufficient to engender and maintain the therapeutic benefits of the drug.

THE IMMUNOMODULATORY IMPACT OF THEOPHYLLINE ON CARDIAC ALLOGRAFT REJECTION

77 Theophylline has been demonstrated to enhance suppressor T cell function and inhibit cytokines that modulate T cell activation and proliferation. To elucidate the possible effect of theophylline on patterns of cardiac allograft rejection, we investigated 96 consecutive adult heart transplant recipients between 1995-1997 with at least 3 month survival, by analyzing 2 groups. Group I: received theophylline within 72 hours of transplantation for post transplant bradycardia (n=39); Group II: no theophylline (n=57). Detailed donor and recipient related risk factors for rejection were collected, and the independent impact of theophylline on subclinical and clinical indices of rejection episodes within 3 months after transplantation was analyzed. Results: (Table)TableMean theophylline exposure was 420± 123 mg/d for a duration of 132 ± 28 days. Theophylline use was not found to influence rejections with hemodynamic compromise or humoral rejection. The groups did not differ with respect to donor and recipient sex and race, crossmatch results, immunosuppression regimens and statin therapy (p=ns). Conclusions: Theophylline decreases episodes of clinical (treated episodes) and subclinical (average biopsy score) indices of cellular cardiac allograft rejection. This immunomodulatory and anti-inflammatory property may be an important "bystander benefit" in heart transplantation, and likely plays a clinically relevant role in ameliorating allograft rejection.

Temporal relationship between A 1 adenosine receptor upregulation and alterations in bicuculline seizure susceptibility in rats

The temporal requirements for theophylline-induced upregulation of A 1 adenosine receptors and elevation of seizure threshold were examined. Chronic theophylline exposure (75 mg/kg twice daily) elicited a significant upregulation of [ 3H]cyclohexyladenosine ([ 3H]CHA) binding sites following 7 and 14 days of treatment. Alterations in seizure threshold followed a similar temporal pattern of development. The reversibility of theophylline-induced upregulation of high affinity [ 3H]CHA binding sites was complete at 10 days following cessation of theophylline administration, while the alteration of seizure threshold required 21 days to return to control values.

Chronic theophylline exposure increases agonist and antagonist binding to A 1 adenosine receptors in rat brain

Chronic treatment of rats with theophylline (75 mg/kg twice-daily for 21 consecutive days) significantly increased the specific binding of [ 3HCHA and [ 3H]DPCPX in cerebral cortical membranes. The absolute increase in the number of binding sites following theophylline treatment was approximately the same for each ligand, although this number represents a larger percentage of the total sites available to [ 3H]CHA. Saturation analysis of [ 3H]DPCPX binding indicated that theophylline treatment increased the maximum number of binding sites from 799 ± 13 to 920 ± 22 fmol/mg protein, while the affinity of [ 3H]DPCPX for A 1 receptors was unaltered.These results suggest that chronic theophylline exposure produces both an increase in the number of A 1 adenosine receptors and an enhancement of coupling of these receptors to G proteins.

Complex interactions of caffeine and its structural analogs with ultraviolet light in cell killing.

We measured the clonogenic survival response of cultured mouse 10T1/2 cells exposed to UV light and caffeine post-treatment. When 0.5 and 1 mM caffeine were present for 24 h immediately following UV, the D0 values of the biphasic survival curves suggest that one subpopulation was sensitized and one subpopulation was protected from killing by UV light. A cloned survivor from the radioprotected subpopulation responded to UV plus caffeine in identical manner as the parent cells. When the caffeine exposure was prolonged to 48 h, only the radiosensitizing effect was observed. Two demethylated analogs of caffeine were also tested. The response of 10T1/2 cells to 1 mM theophylline present for 24 h after UV irradiation was approximately the same as that for the same treatment with 1 mM caffeine. However, prolonging the theophylline exposure to 48 h failed to produce the same kind of potentiation of cell killing as that observed for caffeine. Xanthine by itself was as toxic to 10T1/2 cells as caffeine, but had no synergistic effect as caffeine when given to UV-irradiated cells for 24 or 48 h. It is therefore unlikely that all the effects of caffeine on UV-irradiated cells are mediated by its demethylated metabolites.

Effect of Cholera Toxin on Rabbit Jejunal Carbohydrate-Metabolizing Enzymes

Cholera enterotoxin is a well studied, remarkable polypeptide which causes intestinal secretion by increasing the mucosal concentration of cAMP. Little is known about the effect of cholera toxin on intestinal metabolism other than alterations of intracellular cyclic nucleotide levels. This study was designed to investigate the effect of cholera toxin on key enzymes mediating carbohydrate metabolism in rabbit jejunum. Biopsies of proximal jejunum were maintained for up to 12 hr in organ culture, and the effect of purified cholera toxin on mucosal cAMP, fructose diphosphatase, pyruvate kinase, and fructose diphosphate aldolase was examined. After exposure to 10 μg per ml of cholera toxin, mucosal cAMP increased significantly by 4 hr of incubation. Fructose diphosphatase activity, an enzyme unique to gluconeogenesis, also increased significantly after incubation with toxin. Pyruvate kinase, an enzyme unique to glycolysis, was reciprocally decreased after exposure to cholera toxin, whereas activity of fructose diphosphate aldolase, an enzyme which catalyzes a reversible reaction common to both glycolysis and gluconeogenesis, remained unchanged. To further characterize the mechanism of these changes, the phosphodiesterase inhibitor, theophylline, was used instead of cholera toxin to increase cAMP. After incubation with 10-3 m theophylline, mucosal cAMP levels were noted to be increased within 15 min of exposure. Similar but more rapid alterations were noted in carbohydrate-metabolizing enzymes after theophylline exposure when compared with cholera toxin. Fructose diphosphatase activity increased and pyruvate kinase activity was reciprocally decreased, whereas fructose diphosphate aldolase remained unchanged. We conclude that cholera enterotoxin has a profound effect on the activities of key carbohydrate-metabolizing enzymes in intestinal mucosa characterized by enhancement of gluconeogenesis and reciprocal depression of glycolysis. Moreover, the mechanism of these changes appears to be mediated by toxin- stimulated increase in mucosal cAMP concentration. Lastly, the organ culture system is a useful method to study the effect of bacterial enterotoxins on intestinal mucosa.