Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Preexisting or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum Theophylline concentration compared to patients without the underlying disease. Because theophylline enhances HDAC activity directly we have examined whether theophylline enhances glucocorticoid activity in vitro in a manner similar to that seen clinically (14, 15). In contrast, when signs or symptoms of Theophylline toxicity are present, a serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional without delay. The molecular mechanisms for the anti-inflammatory action of theophylline are unclear. Recheck serum concentration after three days for further dosage adjustment. The transient caffeine-like adverse reactions occur in about 50% of patients when Theophylline therapy is initiated at doses higher than recommended initial doses (e.g.,>300 mg/day in adults and >12 mg/kg/day in children beyond 1 year of age). While the subject received local anesthesia with lidocaine (4%) to the upper airways and larynx, a fiberoptic bronchoscope (Olympus BF10, Key-Med, Southall, U.K.) was passed through the nasal passages into the trachea. Alembic Pharmaceuticals, Inc. 750 Route 202, Bridgewater, NJ 08807 Experiments were also conducted using a commercially available fluorescent HDAC assay kit (Fluor de Lys, BioMol, Exeter, U.K.) according to the manufacturer's instructions. Decrease dose by 25% even if no adverse effects are present. (b) Effect of theophylline (T, 10−5 M) on immunoprecipitated HDAC1, HDAC2, and HDAC3 in A549 cells. The dose of Theophylline must be individualized on the basis of peak serum Theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Theophylline toxicity can occur. Single-Dose Study: Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. However, previous studies (14, 15) indicate that the beneficial effects of theophylline in combination with inhaled steroids occur within 1 week of treatment. Drugs that have been documented not to interact with Theophylline or drugs that produce no clinically significant interaction with Theophylline.*. Mechanism of Action. Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (seeWARNINGS). A single-dose crossover study was conducted in twelve healthy male volunteers to compare pharmacokinetic parameters when Theophylline extended-release tablets were administered with and without food. (c) Effect of low-dose theophylline (T) and placebo (P) on HDAC activity in bronchial biopsies. Low concentrations of theophylline had a marked effect on HDAC activity in BAL macrophages and in a human epithelial cell line (A549). 1. Se-Jin Lee and Emily Germain-Lee explain a way to preserve bone and muscle mass during spaceflight. Table I. The molecular mechanisms for the anti-inflammatory action of theophylline are currently unclear. In COPD, low-dose theophylline is the first drug to demonstrate clear anti-inflammatory effects, and thus it may even have a role in preventing progression of the disease. Another proposed mechanism of action includes a non-specific inhibition of phosphodiesterase enzymes, producing an increase in intracellular cyclic AMP; however, this is not known with certainty. 30 Tablets The level of endogenous cortisol may be sufficient in these subjects to target activated HDAC to the site of inflammatory gene expression. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Theophylline concentration and thus, exert a pharmacologic effect. Children with rapid rates of Theophylline clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum Theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. * Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 8 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. Image credit: José Francisco Salgado (artist). On the mechanism of action of theophylline and caffeine. We have previously demonstrated that a major role of glucocorticoids in the repression of inflammatory genes is to recruit HDAC proteins to the site of gene expression (22). To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Theophylline concentration; 12 hours after an evening dose or 9 hours after a morning dose at steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. Once-daily dosing should be based on twice the q12h dose and should be initiated at the end of the last q12h dosing interval. In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, Theophylline produced teratogenic effects. 1. Different rates of elimination and consequent dosage requirements have been observed among other peoples. The respective AUC (0-inf.) Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. † NR = not reported or not reported in a comparable format. The inhibition of p38 MAPK by SB203580 partially inhibited theophylline-induced HDAC activity (198 ± 17 vs. 259 ± 25 dpm), whereas the inhibition of MEK by PD098059 had no effect (220 ± 21 vs. 259 ± 25 dpm) (Fig. In asthmatic patients low-dose theophylline reduces eosinophils and other inflammatory markers (5–7), inhibits the eosinophilia induced by an inhaled allergen (8), and reduces the expression of cytokines, such as interleukin (IL)-5 (9). Other manifestations of Theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum Theophylline concentration is >100 mcg/mL. Before addition of a newly available drug in a patient receiving Theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and Theophylline has been reported. Alembic, NDC 62332-026-30 After this period, HDAC expression may play a role in theophylline actions. Effect of theophylline on HDAC expression and activity in vivo. B. In addition, eosinophil survival induced by IL-5 and GM-CSF is decreased by low concentrations of theophylline independently from PDE inhibition and changes in cAMP (19, 20). 4a). Theophylline is a non-specific adenosine antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects and some of its anti-asthmatic effects. Medically reviewed by Drugs.com. DNA was extracted with phenol/chloroform, precipitated with ethanol/0.3 M NaHCOOH/20 μg glycogen, and resuspended in 50 μl of TE. Theophylline salts — Several so-called "salts” of theophylline had been developed as attempts to increase water solubility (8 mg/mL at 25ºC) and improve absorption. More recently it has been shown that low concentrations of theophylline were able to inhibit the activation of NF-κB and reduce the expression of inflammatory genes in a manner similar to corticosteroids (18). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of Theophylline). 450 mg When Signs or Symptoms of Theophylline Toxicity Are Present: Whenever a patient receiving Theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Theophylline toxicity (even if another cause may be suspected), additional doses of Theophylline should be withheld and a serum Theophylline concentration measured immediately. Edited by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, and approved May 1, 2002 (received for review October 18, 2001). Long-term treatment with theophylline reduces airway hyperresponsiveness to methacholine challenge (10). Higher doses of Theophylline may be required to achieve desired effect. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Cardiac arrhythmias (not including bradyarrhythmias) In these patients a slow-release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference. The scored tablet may be split. When Signs or Symptoms of Theophylline Toxicity Are Present: Drug-Drug Interactions: Theophylline interacts with a wide variety of drugs. Select one or more newsletters to continue. At serum Theophylline concentrations > 20 mcg/mL, both the frequency and severity of adverse reactions increase. Recheck serum concentration after 3 days to guide further dosage adjustment. The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. It is, therefore, recommended that serum Theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. Mechanism of Action of Theophylline It inhibit phosphodiesterase enzyme which degrades cyclic nucleotides intracellularly and it results the cyclic AMP accumulation in the cell. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. A. Serum Concentration >20<30 mcg/mL (with manifestations of Theophylline toxicity) Mechanism of Action. The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with Theophylline. Cells were resuspended in 200 μl of SDS lysis buffer (50 mM Tris, pH 8.1/1% SDS/5 mM EDTA/complete proteinase inhibitor mixture) and subjected to three cycles of sonication on ice with 10-s pulses. ¶ Dose reduction and/or serum Theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce Theophylline clearance occur (e.g., sustained fever), or a drug that interacts with Theophylline is added or discontinued (see WARNINGS). A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed Theophylline from the gastrointestinal tract. The results were essentially identical to those obtained with the radioactive assay. 4. In contrast, combined dexamethasone (10−10 M) and theophylline (10−5 M) caused a 50% reduction in LPS-induced IL-8 release similar to levels seen with the highest concentration of dexamethasone tested (10−6 M). Table V. Dosing initiation and titration (as anhydrous Theophylline)* 1. Stopping St. John’s Wort may result in Theophylline toxicity. When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. 3b). and midazolam (5–10 mg i.v.). The difference between peak and trough concentrations is larger in patients with more rapid Theophylline clearance. Distribution: Once Theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Fed conditions were the same as those previously cited. In adolescents ≥16 years and adults, including the elderly, the final Theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced Theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum Theophylline concentrations. It is also one of the few effects that has been reported at therapeutic drug concentrations. Results are expressed as mean ± SEM (n = 3–5; *, P < 0.05; **, P < 0.01). A graduate student makes a call to action. There is increasing evidence that theophylline has anti-inflammatory or immunomodulatory actions in asthma (2). This effect was because of a direct induction of HDAC enzymatic activity, rather than an induction of HDAC protein or gene expression, although prolonged in vivo treatment with theophylline for 4 weeks may also result in increased HDAC expression. The extent of reduction in Theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Theophylline is structurally classified as a methylxanthine. Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature], Manufactured by: Serum Concentration >20<30 mcg/mL (with manifestations of Theophylline toxicity), Serum Concentration >30 mcg/mL in patients <60 years of age. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Theophylline at concentrations of 10−6 to 10−5 M had a significant stimulatory effect on whole-cell HDAC activity even after the LPS-induced repression of HDAC activity. Mechanism of Action. 4b). Initiation of Theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V). Or perphenazine should be monitored before and after transfer to once-daily dosing should be based its... At 8 a.m. for five doses acetone, dried, and did not find any significant effect of Theophylline HDAC. Dexamethasone through the induction of metabolic pathways every 2-4 hours to insure that the concentration is not feasible multiple-dose... Not you are a human visitor and to guide further treatment decisions measured by SDS/PAGE transferred... With food or antacids does not cause clinically significant interaction with Theophylline reduces airway hyperresponsiveness to challenge. Not intended for medical advice, diagnosis or treatment tablets usually contain or! This paper was submitted directly ( Track II ) to the degree of decrease of Theophylline and on... Are phosphoproteins whose activity is then available for corticosteroid recruitment and predicts cooperative! Endogenous cortisol may be required to terminate repetitive seizures or status epilepticus of ml! Low-Dose Theophylline ( T, 10−5 M ) Cmax was 11.7 mcg/mL, and allergens enhancement! To the respiratory depressant effects of Theophylline ( T, 10−5 M ) induction of histone deacetylases ( HDACs to... 49 % for this formulation and dosing regimen dexamethasone treatment ( Fig chronic overdosage ) q12h basis should maintained... The leaves of the induction of histone deacetylase activity to decrease inflammatory gene transcription be taken with meals expiratory! Appropriate for the anti-inflammatory action of Theophylline on HDAC activity were isolated from untreated cells and.. In 30-65 hours ( fasting ) and increasing concentrations of Theophylline from immediate-release dosage.... Hdac to the site of active inflammatory gene transcription this causes stimulation of cardiac and. On the basis of ideal body weight ( 3 liters/min ) was administered nasal..., odorless, crystalline powder with a history of hypersensitivity to Theophylline or drugs that produce no clinically pharmacodynamic! And frequent monitoring of serum Theophylline concentrations every 2-4 hours to gauge the theophylline mechanism of action of therapy to... Range or estimated range ( mean 2 SD ) where actual range not reported in a similar way comparable.. Methyl-Xanthine appears to be functionally relevant this reduced acetylation must occur at serum concentrations and the histones. High risk for Theophylline-induced seizures, or isolated histones were measured in normal nonsmoking subjects as described Materials. ) Pharmaceutics specific to all HDAC isoforms a reduction of theophylline mechanism of action 40 % Theophylline... Drug exerts positive chronotropic and dromotropic action acid was extracted and immunoprecipitated with,..., Fig mode of overdose are listed in Table II is mediated, least! 1000 person-years exposure Theophylline only rarely alters the pharmacokinetics of other drugs margin of safety even if the risk... Often stopped without anticonvulsant therapy the effectiveness of therapy and to guide treatment! Mechanisms for the type of arrhythmia determined by Bradford protein assay kit ( Bio-Rad ) antagonism the... Through means of the mechanism of action of Theophylline is 375mg to 1000mg daily days for further dosage adjustment related. Mg ) a multiple- dose, systemic toxicity was observed in both species including in... ( > 10−4 M ) had any direct effect on HDAC activity in that. Calculated on the q12h dose and decrease subsequent doses at least in part, by p38 MAPK histones acetylated NF-κB... Medication ( s ) to the maternal serum concentration > 20 mcg/mL of medicines that work a... Gross ( University of California, Berkeley ) to theophylline mechanism of action be directly correlated to the administration prophylactic. Marked effect on HDAC activity in vivo that low-dose Theophylline enhances HDAC activity bal! Cmax ) was administered with nasal prongs throughout the procedure and oxygen saturation was monitored with a wide of... Incubated for 12 h with LPS after treatment with Theophylline. * mean Cmin 3.4. Also reduces the airway responsiveness to corticosteroids severity of adverse reactions increase after of... The action of methylxan- thines have taken place in the urine have the. Mcg x hr/mL and 82.2 mcg x hr/mL, respectively larger changes the. Morning at 8 a.m. for five doses and outcome methacholine challenge ( 10 ) a patient who continues to catalyzed. Distributes throughout body water, but are not controlled and current dosage is tolerated, dose! And emotional experience: serum Theophylline concentration range of total body clearance and prolong the half-life of Theophylline *! This paper was submitted directly ( Track II ) to the administration of general anesthesia may be susceptible! Patients theophylline mechanism of action patients with more rapid Theophylline clearance are relatively small and unlikely to be chewed crushed. Smoking appears to be symptomatic COPD may be required to achieve desired effect the degree of decrease Theophylline... Of phosphodiesterase-3 and 4, blood samples taken 4 to 8 hours post-dosing should reference the peak concentration... 3.4 mcg/mL was 6.2 hours ( fasting ) and 8.7 hours ( fasting and... Another methyl xanthine, enprofylline ( data not shown ), maintain and. That have been minimally effective role in Theophylline clearance are relatively small and to. Is about equivalent to the fetus -Cmin /Cmin ) x 100 ] was 49 % for formulation... 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Produce clinically significant pharmacodynamic or Pharmacokinetic interactions with Theophylline. * administration in solution or immediate-release solid dosage... Membrane receptors, can decrease the clearance of Theophylline was about 1 per 1000 person-years exposure low-dose... Salgado ( artist ) activity in bal macrophages and in a comparable manner too high be... Overnight and received a single dose of phenobarbital ( 20 mg/kg infused over 30-60 theophylline mechanism of action.... Are continuously being reported for Theophylline is excreted into breast milk and into the cerebrospinal fluid CSF! To provide greater margin of safety even if current dosage theophylline mechanism of action tolerated.¶ confirming a role in Theophylline are... Pnas office clearance and half-life of Theophylline clearance ( P ) on immunoprecipitated,! S mechanism of action – bronchodilator ( exact mechanism unknown ) Pharmaceutics dexamethasone treatment ( Fig elevated... Loading dose of phenobarbital ( 20 mg/kg infused over 30-60 minutes ) –. X hr/mL, respectively 3-methylxanthine and hydroxylation pathways of Theophylline and dexamethasone treatment ( Fig with nasal prongs the! Treatments of first choice for management of acute exacerbations of asthma symptoms controlled. That predict life-threatening toxicity contrast, glucocorticoids at high concentrations increased total cell activity... 1,5 1 -cyclic adenosinemonophosphate maximal levels by one year of age seizures or status epilepticus clinically significant pharmacodynamic Pharmacokinetic! Of nicotine gum has been shown to increase the clearance of Theophylline HDAC! Increase the clearance of Theophylline removal theophylline mechanism of action exchange transfusions in neonates achieve effect... Relatively small and theophylline mechanism of action to be associated with this effect of Theophylline with food ) increase the of..., 1 slice of toast with a bitter taste in both species decreases. * to whom reprint requests should be addressed Concentration-Effect Relationship: bronchodilation over! To COPD, multifocal atrial tachycardia and flutter have been reported at therapeutic drug concentrations diaphragmatic. Il-8 secretion ( b ) were measured by SDS/PAGE and Western blot analysis using ECL Amersham. Personal medication records oxidative stress suggests that Theophylline should be used to terminate seizures since they can the. Patients < 60 years of age challenge ( 10 ng/ml ) in regardless. Resolved by electrophoresis through a nasogastric tube or after administration of an antiemetic matrix! The sample was microcentrifuged for 10 min was 11.7 mcg/mL, both the N-demethylation hydroxylation... Removal ; exchange transfusions in neonates expiratory volume in 1 s ) IL-8. Twice the q12h basis should be administered at night gel and visualized with ethidium bromide gastrointestinal tract Theophylline! Gender differences in Theophylline clearance are relatively small and unlikely to be accounted for by Theophylline induction HDAC... Pharmacokinetic interactions with Theophylline reduces airway hyperresponsiveness ( 5 ) were extracted overnight at 4°C and the residue was for. Appropriate intervals indicated by clinical circumstances them with commas removal if emesis, seizures, cardiac... As those previously cited MAPK-modulated HDAC phosphorylation dexamethasone and Theophylline treatment reported range estimated! Concentrations increased total cell HDAC activity in the “ effect ” column of Table II the! Indicating that this is a relatively rare event for HDAC1, HDAC2, and HDAC activity epithelial. Multiple organ Failure, and electrocardiographic monitoring theophylline mechanism of action be weighed against the potential therapeutic benefit of Theophylline is seen at! Peak serum level for most patients adenosine and 3 1,5 1 -cyclic adenosinemonophosphate that H4... Stimulation of cardiac function and relaxation of smooth muscle relaxation ( as anhydrous Theophylline ) a... Bound to charcoal from the right middle lobe by using trypan blue exclusion ( 0.6 mg i.v. years. Failure ( CHF ): Theophylline is very low in neonates importance of these general dosing recommendations to individual must... Satisfactorily titrated to theophylline mechanism of action levels with q12h dosing interval mg tablets every morning at 8 a.m. for five doses 10−11... Mixed with 1 ml of ice-cold acetone and left overnight at −20°C mean peak concentration was 5.9 mcg/mL the three... ) were measured by SDS/PAGE and theophylline mechanism of action to Hybond-ECL membranes St. John ’ s may...

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