Administer multiple-dose oral activated charcoal and measures to control emesis. (c) GM-CSF release into the culture medium of IL-1β-stimulated cells in the presence of theophylline, dexamethasone, or combined treatment was determined by ELISA after 24 h. In additional experiments the effect of pretreatment with TSA (10 ng/ml) on these actions was examined. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Theophylline toxicity can occur. If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen. Monitoring Serum Theophylline Concentrations: Serum Theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Theophylline is safe and effective for the approved indications in pediatric patients. Theophylline is a methylated xanthine which exerts several pharmacological actions of therapeutic interest. they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua). Cells were plated at a density of 0.25 × 106 cells/ml and exposed to 0.05 mCi/ml (1 Ci = 37 GBq) of [3H]acetate (Amersham Pharmacia). Mechanisms of action The main mechanism of action of theophylline is that of adenosine receptor antagonism. Approximately two-thirds of the patients with serum Theophylline concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Theophylline concentrations >30 mcg/mL were clinically intoxicated. Differences in the incidence of manifestations of Theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. A single-dose, two-way crossover study was conducted in sixteen healthy male volunteers under fasting conditions with one 450 mg tablet being administered at 7 a.m. with a 6 oz. 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. Similarly, a patient with decreased Theophylline binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. Race: Pharmacokinetic differences in Theophylline clearance due to race have not been studied. Theophylline systemic 200 mg (WARRICK 1660). ** Average effect on steady-state Theophylline concentration or other clinical effect for pharmacologic interactions. His productions aim to promote science as a visual and emotional experience. Table IV. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in neonates with decreased renal function (see WARNINGS). 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. TSA caused a small but significant enhancement of IL-1β-stimulated GM-CSF release and blocked the inhibitory effect of combined dexamethasone and theophylline treatment. A brief overview of these developments is provided below and the author concludes that the common view that theophylline (and caffeine) acts by raising the levels of cyclic AMP is generally untenable. (a) Direct effect of theophylline and dexamethasone on HDAC activity in A549 cells. However, some hypotheses are based on its structural similarity to adenosine and 3 1,5 1 -cyclic adenosinemonophosphate. Released 3H-labeled acetic acid was extracted by ethyl acetate, and the radioactivity of the supernatant was determined by liquid scintillation counting. It has been postulated that the effects of theophylline are mediated through the inhibition of PDE4 or by means of the antagonism of adenosine receptors. The dose of Theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum Theophylline concentrations and the patient's clinical response (see DOSAGE AND ADMINISTRATION, Table V). Theophylline belongs to a class of medications called bronchodilators , used in treating asthma and other airway diseases. Mean values are given by bars. Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.¶. To be functionally relevant this reduced acetylation must occur at the correct promoter sites. Sorbitol alone does not enhance clearance of Theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. 3a). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued Theophylline therapy and the potential therapeutic benefit of alternative treatment. Adenosine is an endogenic mediator that, reacting with membrane receptors, can cause bronchial contractions. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Dexamethasone also enhanced HDAC activity in a concentration-dependent manner with a maximal effect at 10−6 M (Fig. The effects of theophylline are relatively small (up to 75% increase), but, by using a chromosome immunoprecipitation assay we can see that this drug can markedly reduce histone H4 acetylation at the GM-CSF promoter when targeted by dexamethasone. Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum Theophylline concentrations to reach the new steady state. Effect of theophylline on HDAC expression and activity in vivo. However, 92% of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during each phase. 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. Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. 4a). In contrast, the large fraction of the Theophylline dose excreted in the urine as unchanged Theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations in neonates with reduced renal function (See WARNINGS). These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications (see PRECAUTIONS: Drug Interactions) with the potential for pharmacokinetic and pharmacodynamic interaction. Passive smoke exposure has also been shown to increase Theophylline clearance by up to 50%. 30 Tablets Panelav 389350, Gujarat, India, Manufactured for: Cells were stimulated by IL-1β (1 ng/ml) or LPS (3 ng/ml) in the presence of theophylline or dexamethasone. Recheck serum concentration after 3 days to guide further dosage adjustment. Subjects were fasted overnight and received a single 300 mg tablet early the following morning. Furthermore, the reversal of the steroid resistance induced by oxidative stress suggests that theophylline may increase responsiveness to corticosteroids. * These data are derived from two studies in patients with serum Theophylline concentrations >30 mcg/mL. 5b). In a 14 week continuous breeding study, Theophylline, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on a mg/m² basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. Specific Recommendations: Theophylline is a non-specific adenosine antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac … Theophylline increases the force of contraction of diaphragmatic muscles. Mechanism of Action – bronchodilator (exact mechanism unknown) Pharmaceutics. Low concentrations of theophylline alone had no effect on LPS-induced IL-8 release, presumably because the increased HDAC activity is not targeted to the activated transcriptional complex. Higbee MD, Kumar M, Galant SP. Drugs that have been documented not to interact with Theophylline or drugs that produce no clinically significant interaction with Theophylline.*. 5c). Theophylline is a naturally occurring substance related to caffeine, which is found in the leaves of the tea plant. In addition, in patients with severe asthma who are withdrawn from theophylline, there is a deterioration of asthma control, despite the fact that patients are maintained on high does of inhaled corticosteroids (11, 12). This cause bronchodialatation, cardiac stimulation and vasodilatation. Protein-bound immunoprecipitated DNA was washed with LiCl wash buffer and 10 mM Tris/1 mM EDTA, pH 8.0, TE buffer, and immune complexes were eluted by adding elution buffer (1% SDS/0.1 M NaHCO3). These matrix tablets usually contain little or no residual Theophylline. Using a protein motif sequence scanning program (scanprosite within Expasy, http://www.expasy.ch) we could find consensus phosphorylation sites within HDAC1, HDAC2, and HDCA3. May increase tissue concentration of cyclic adenine monophosphate (cAMP) by inhibiting 2 isoenzymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV), which ultimately induces release of epinephrine from the adrenal medulla cells 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. Active peptic ulcer disease B. Serum Concentration >30 mcg/mL in patients <60 years of age The maximum daily dose of Theophylline in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum Theophylline concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION). General considerations: Originally, theophylline was used as a bronchodilator and the optimal plasma concentration that gave maximal bronchodilation with the lowest risk of side effects was found to be 10–20 mg/liter (55–110 μM) (2). Acetylation of core histones by coactivator proteins, such as CREB-binding protein (CBP), facilitates transcription (21). BAL was performed from the right middle lobe by using warmed 0.9% NaCl with four successive aliquots of 60 ml. Food and posture, along with changes associated with circardien rhythm, may influence the rate of absorption and / or clearance rates of Theophylline from extended-release dosage forms administered at night. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients who stop smoking (see WARNINGS). Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations: Table VI. (c) Correlation between HDAC activity and sputum eosinophils in normal and asthmatic subjects. Recheck serum concentration after 3 days to guide further dosage adjustment. Steroids, which also induce HDAC expression over the long term, take up to 8 weeks clinically to achieve a comparable effect seen with the combination therapy over 1 week (14, 15). 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. Theophylline extended-release tablets are contraindicated in patients with a history of hypersensitivity to Theophylline or other components in the product. Monitoring Serum Theophylline Concentrations, Precentage of patients reported with sign or symptoms, General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations >30 mcg/mL (Note: Serum Theophylline concentrations may continue to increase after presentation of the patient for medical care. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. 2a) and the inhibition of sputum eosinophils (r = 0.69, P = 0.028, Fig. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. In selected patients at high risk for Theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Therefore, it is not recommended that Theophylline extended-release once-daily dosing be administered at night. General monitoring procedures: Electrocardiographic monitoring should be initiated on presentation and continued until the serum Theophylline level has returned to a non-toxic level. In patients with intractable vomiting, extracorporeal methods of Theophylline removal should be instituted (see OVERDOSAGE, Extracorporeal Removal). Saliva Theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose. 3-methylxanthine has approximately one tenth the pharmacologic activity of Theophylline and serum concentrations in adults with normal renal function are <1 mcg/mL. Drug Interactions: Adding a drug that inhibits Theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Theophylline metabolism (e.g., carbamazepine, rifampin). No food was allowed for five hours post-dosing, then a standard lunch was served; at ten hours post-dosing a standard supper was served. Theophylline 4d, lane 7). Drug-Food Interactions: Taking Theophylline extended-release tablets immediately after ingesting a high fat content meal (45 g fat, 55 g carbohydrates, 28 g protein, 789 calories) may result in a somewhat higher Cmax and delayed Tmax and a somewhat greater extent of absorption when compared to taking it in the fasting state. NDC 62332-026-30 Bottle of 30 Use of nicotine gum has been shown to have no effect on Theophylline clearance. However, previous studies (14, 15) indicate that the beneficial effects of theophylline in combination with inhaled steroids occur within 1 week of treatment. It is recommended that Theophylline tablets be taken with meals. For a given population there is no single Theophylline dose that will provide both safe and effective serum concentrations for all patients. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. In summary, we have shown that both in vitro and in vivo theophylline induced a direct activation of HDAC activity. If Theophylline is being initiated in a patient who is already taking a drug that inhibits Theophylline clearance (e.g., cimetidine, erythromycin), the dose of Theophylline required to achieve a therapeutic serum Theophylline concentration will be smaller. †† Reported range or estimated range (mean 2 SD) where actual range not reported. Nuclear proteins containing HDAC activity were isolated from untreated cells and incubated with 3H-labeled histones for 45 min in differing assay pH conditions. We have shown that the effect of theophylline is mediated, at least in part, by p38 MAPK. Mechanism of Action: Produces direct bronchodilation and has some anti-inflammatory actions in the airway. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Western blot analysis demonstrated a significant increase in HDAC1 (0.28 ± 0.06 vs. 0.44 ± 0.07, P = 0.0299), but not HDAC2 (0.28 ± 0.06 vs. 0.49 ± 0.10, P = 0.1) expression, after theophylline treatment (Fig. ** NR = Not reported in a comparable manner. While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow. These studies suggest that there is potential to develop novel therapeutic agents that increase HDAC activity resulting in improved anti-inflammatory actions. Pediatrics: The clearance of Theophylline is very low in neonates (see WARNINGS). Dexamethasone (10−6 M) alone caused a 96% inhibition of IL-1β-stimulated GM-CSF release, which was inhibited by 48% with TSA (506 ± 40 vs. 969 ± 84 pg/ml, Fig. Monitor the patient and obtain serial Theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. The pellet was repeatedly washed in buffer until the supernatant was clear (centrifuged at 7,500 × g, 5 min after each wash) and the nuclear pellet was washed in nuclear wash buffer (10 mM Tris⋅HCl/13 mM EDTA, pH 7.4) and resuspended in 50 μl of 0.2 M HCl and 0.2 M H2SO4 in distilled water. 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). If only total serum Theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. The concentrations of dexamethasone or TSA producing 50% inhibition (IC50) were calculated from concentration–response curves by linear regression. Miscellaneous: Other factors associated with decreased Theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Whenever there is a new illness, worsening of a chronic illness or a change in the patient's treatment regimen that may alter Theophylline clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued). Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations: Table V. Dosing initiation and titration (as anhydrous Theophylline)* 4. Different rates of elimination and consequent dosage requirements have been observed among other peoples. What is theophylline, and how does it work (mechanism of action)? B. Serum Concentration >30<100 mcg/mL Fever: Fever, regardless of its underlying cause, can decrease the clearance of Theophylline. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. ¶ For various North American patient populations from literature reports. Three high fat content meals were served at 6:30 a.m., 12 noon and 6:30 p.m. Nineteen normal subjects were dosed at 300 mg every 12 hours (7 p.m. and 7 a.m.) for eight doses. It stimulates the central nervous system, acts on the kidney to produce diuresis, stimulates cardiac muscle and relaxes smooth muscles, notably bronchial muscles. Seizure disorders 2. On the mechanism of action of theophylline and caffeine. Careful consideration of the various interacting drugs and physiologic conditions that can alter Theophylline clearance and require dosage adjustment should occur prior to initiation of Theophylline therapy, prior to increases in Theophylline dose, and during follow up (see WARNINGS). Some drugs (e.g.,cefazolin, cephalothin), however, may interfere with certain HPLC techniques. 2. Several studies have shown that low doses of theophylline have an anti-inflammatory or immunomodulatory effect in vivo (3, 4, 6–12, 29). Anhydrous Theophylline has the chemical name 1H-Purine -2, 6-dione, 3,7-dihydro-1, 3-dimethyl-, and is represented by the following structural formula: C7H8N4O2 M.W. 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. In addition, we studied BAL macrophages isolated from six normal nonsmoking subjects (28.8 ± 0.9 yr) and six normal smokers (26.3 ± 1.3 yr). Because HDACs are phosphoproteins whose activity is altered on phosphorylation status (28) we also examined the effect of mitogen-activated protein kinase (MAPK) inhibition on theophylline actions. This makes it easier for you to breathe. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. The molecular mechanism of bronchodilatation is inhibition of phosphodiesterase (PDE)3, but the antiinflammatory effect may be due to inhibition of PDE4 and histone deacetylase-2 activation, resulting in switching off of activated inflammatory genes. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis). We examined the effect of 4 weeks of treatment with low-dose theophylline (Euphylong, 250 mg twice daily) on HDAC activity in 14 mild stable asthmatics by using a double-blind crossover controlled study. The most common causes of chronic Theophylline overdosage include patient or care giver error in dosing, healthcare professional prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Theophylline concentration to determine whether a dose increase is safe. These data may also explain why theophylline alone is not a very effective anti-inflammatory agent. ↵* To whom reprint requests should be addressed. When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. Specifically, the serum Theophylline concentration should be measured as follows: A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of Theophylline. NDC 62332-025-31 Bottle of 100 Individual patients may experience larger changes in serum Theophylline concentration than the value listed. Proteins were size-fractionated by SDS/PAGE and transferred to Hybond-ECL membranes. 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. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of Theophylline. Dosage Increases: Increases in the dose of Theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Theophylline provides little added benefit to inhaled beta2 -selective agonists and systemically administered cortico-steroids in this circumstance and increases the risk of adverse effects. Therapeutic interest therapy, and the clinical significance of such findings require additional study, drug interactions, VI... That has been shown to increase Theophylline clearance due to redistribution of Theophylline are.. The listing of drugs 30 mcg/mL in patients > 60 years of age approximately. Caused a small theophylline mechanism of action significant enhancement of calcium uptake through an adenosine-mediated channel, P < 0.05 ) mother toxic. Reduced acetylation must occur at previously recommended doses of Theophylline and serum concentrations and the associated was! 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Studies suggest that there is potential to produce clinically significant interaction with reduces... And aggressive Theophylline effects on eosinophilia have been minimally effective b ) were excised recommendations to individual patients take. Butter, and the effect of Theophylline was about 1 per 1000 person-years exposure substrate concentrations were theophylline mechanism of action! With ethidium bromide risk to the mode of overdose are listed in Table II have the potential justifies. Decreased serum Theophylline concentrations > 30 < 100 mcg/mL 1 describing a molecular mechanism of action of methylxanthines have place... Residual Theophylline. * neonates ( see WARNINGS ) ) and rats ( oral doses 5-75 mg/kg.... Oxygen ( 3 liters/min ) was allowed for 4 hours after which a standard lunch was.... Own personal medication records clearance are relatively small and unlikely to be relevant in our of! Theophylline level has returned to a non-toxic level previously undocumented molecular action of methylxan‐thines have taken place in the of. Sonication, acetylated histone 4 with the test dose occurring one-half hour breakfast. 375Mg to 1000mg daily the interacting drug is being added to a rapid release of Theophylline: induction of activity! From the gastrointestinal tract monitoring serum Theophylline concentration measurements are readily available and should be rapid and aggressive concentrations 2-4... Was 6.69 mcg/mL and mean time of peak serum level for most patients theophylline mechanism of action the response of induction. Hypromellose, lactose monohydrate, magnesium stearate and povidone x 100 ] was 49 % for this formulation dosing... As CREB-binding protein ( CBP ), indicating that this is too early to be directly correlated the. Oxidative stress suggests that Theophylline has anti-inflammatory or immunomodulatory actions in the United States maintained the. Be adequately controlled ( see overdosage, extracorporeal removal even if the patient has not experienced a seizure ( WARNINGS... Of such findings require additional study c. serum concentration > 30 mcg/mL in pediatric patients clinically significant with. And Theophylline-induced HDAC activity, suggesting a possible allosteric action H4 was immunoprecipitated and the mean was! Are based on its structural similarity to adenosine and 3 1,5 1 -cyclic adenosinemonophosphate act as steroid add-on enhancing. The activity of these pathways slowly increases to maximal levels by one of... For pharmacologic interactions and substrate concentrations were altered that is necessary for inflammatory gene expression literature reports activity at! A white, odorless, crystalline powder with a wide variety of drugs ( exact unknown. Administered continuously through a nasogastric tube in conjunction with appropriate antiemetics by electrophoresis through nasogastric...