In patients with high Theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum Theophylline concentration may be only 30% of peak with a 6-hour dosing interval. Because theophylline affects gene transcription in low concentrations and appears to interact beneficially with corticosteroids, we studied the effect of theophylline alone, and in combination with dexamethasone, on histone acetylation and deacetylation in vitro by using bronchoalveolar lavage (BAL) macrophages and in bronchial biopsies of asthmatic patients treated with low-dose theophylline. At steady-state, the mean peak concentration was 8.8 mcg/mL and the mean trough concentration was 5.9 mcg/mL. loading dose: 6mg/kg over 30min; maintenance dose: 1mg/kg (titrate to level ; lag of 15-60min prior to achievement of the therapeutic serum concentration; low therapeutic index; Indications. Since Theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Patients should be instructed to inform all healthcare professional involved in their care that they are taking Theophylline, especially when a medication is being added or deleted from their treatment. GM-CSF and IL-8 were measured by sandwich ELISA (R&D Systems Europe, Abindon, U.K.) according to the manufacturer's instructions. Stopping St. John’s Wort may result in Theophylline toxicity. Race: Pharmacokinetic differences in Theophylline clearance due to race have not been studied. Category C: What is theophylline, and how does it work (mechanism of action)? The subjects used for this study exhibited a mean half-life of 8.3 hours (range 5.2-12.2) and mean clearance of 3.5 L/hour (range 2.3-5.6) as determined in a separate single-dose clearance study using 500 mg of immediate-release Theophylline, prior to this multiple-dose study. The time of peak concentration (Tmax) was 6.2 hours. In addition, the common side effects of theophylline, nausea and vomiting, are probably because of PDE4 inhibition (13, 17). Cell viability was assessed by using trypan blue exclusion. We examined the direct effect of theophylline and dexamethasone on nuclear extracts containing HDAC activity in vitro, as described (22). Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing Theophylline clearance up to sixfold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Results are representative of three independent experiments. 2. We do not capture any email address. Other factors associated with increased Theophylline clearance include hyperthyroidism and cystic fibrosis. The bronchodilator action of theophylline can be explained by the inhibition of phosphodiesterases (PDEs) in airway smooth muscle, but this occurs at concentrations of >50 μM (16). Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Other adverse reactions that have been reported at serum Theophylline concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. 4. Tablets 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. A peak steady-state serum Theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. If the serum sample is drawn more than 12 hours after the evening dose, or more than 9 hours after a morning dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. Theophylline is safe and effective for the approved indications in pediatric patients. More frequent measurements should be made in the presence of any condition that may significantly alter Theophylline clearance (see PRECAUTIONS, Laboratory Tests). 1. While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow. Concurrent Diseases: Acute pulmonary edema, congestive heart failure, cor-pulmonale, fever (≥102° for 24 hours or more; or lesser temperature elevations for longer periods), reduced renal function in infants <3 months of age, sepsis with multi-organ failure and shock. Theophylline tablets can be taken once a day in the morning or evening. 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. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. Several studies have shown that low doses of theophylline have an anti-inflammatory or immunomodulatory effect in vivo (3, 4, 6–12, 29). Conversely, if Theophylline is being initiated in a patient who is already taking a drug that enhances Theophylline clearance (e.g., rifampin), the dose of Theophylline required to achieve a therapeutic serum Theophylline concentration will be larger. This suggests that theophylline enhances HDAC activity by modulating enzyme function directly, whereas dexamethasone increases HDAC activity indirectly through an increase in HDAC expression. 1 a and b). Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. In such cases, the patient may show signs of toxicity at total (bound + unbound) serum concentrations of Theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. 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). Furthermore, the reversal of the steroid resistance induced by oxidative stress suggests that theophylline may increase responsiveness to corticosteroids. New interactions are continuously being reported for Theophylline, especially with new chemical entities. Recheck serum concentration after three days for further dosage adjustment. However, there was no correlation between the induction of HDAC activity by low-dose theophylline and the change in FEV1 (r = 0.13, P = 0.65, Fig. 1. This product allows a 12-hour dosing interval for a majority of patients and a 24-hour dosing interval for selected patients (see DOSAGE AND ADMINISTRATION section for description of appropriate patient populations). Careful consideration must be given to the benefits and risks of Theophylline use and the need for more intensive monitoring of serum Theophylline concentrations in patients with the following risk factors: 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. NDC 62332-026-31 Bottle of 100 Death from Theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise. While the mechanisms of action of Theophylline are not known with certainty, studies in animals suggest that bronchodilation … The elution was treated successively for 4 h at 65°C in 200 mM NaCl/1% SDS to reverse crosslinks and incubated for 1 h at 45°C with 70 μg/ml proteinase K (Sigma). 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). Mechanism of Action: Produces direct bronchodilation and has some anti-inflammatory actions in the airway. Theophylline doses greater than 400 mg/d should be prescribed with caution in elderly patients. The difference between peak and trough concentrations is larger in patients with more rapid Theophylline clearance. The nuclei were extracted overnight at 4°C and the residue was microcentrifuged for 10 min. Administer a single dose of oral activated charcoal. Monitoring Serum Theophylline Concentrations: The healthcare professional should not assume that a drug does not interact with Theophylline if it is not listed in Table II. Alembic, NDC 62332-026-30 Results are expressed as mean ± SEM (n = 3–5; **, P < 0.01). Effect of theophylline on HDAC expression and activity in vivo. 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. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum Theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI). Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients with reduced hepatic function (see WARNINGS). Once-daily dosing should be based on twice the q12h dose and should be initiated at the end of the last q12h dosing interval. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Theophylline clearance. The effects of combined theophylline and dexamethasone treatment in cells suggest that this direct effect of theophylline on HDAC activity is predominant, at least during the short-term treatment, when rapid increases in lung function are seen. 3a) and theophylline caused a concentration-dependent increase in LPS-suppressed HDAC activity that was maximal at 10−5 M and was returned back to control levels at 10−3 M (data not shown). Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Theophylline Concentrations, and DOSAGE AND ADMINISTRATION). Fed conditions were the same as those previously cited. Dispense in a well-closed container, with child resistant closure [as defined in the USP]. This paper was submitted directly (Track II) to the PNAS office. 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. Theophylline causes an increase in the concentration of cAMP in the cell through inhibition of phosphodiesterase-3 and 4. C. Serum Concentration >100 mcg/mL Mechanism of Action: Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). It also reduces the airway responsiveness to histamine, adenosine, methacholine, and allergens. Careful attention to dosage selection and monitoring of serum Theophylline concentrations are required in pediatric patients (see WARNINGSand DOSAGE AND ADMINISTRATION). Serum Concentration >20<30 mcg/mL (with manifestations of Theophylline toxicity), Serum Concentration >30 mcg/mL in patients <60 years of age. 2. Results are expressed as mean ± SEM (n = 3–5; *, P < 0.05). 450 mg: White to off-white, Capsule shaped, uncoated tablet, with break line and debossing with 'HP63” on one side and plain on other side. and midazolam (5–10 mg i.v.). A single dose of sorbitol may be used to promote stooling to facilitate removal of Theophylline bound to charcoal from the gastrointestinal tract. The extent of reduction in Theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Because of marked individual differences in the rate of Theophylline clearance, the dose required to achieve a peak serum Theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Theophylline clearance (e.g., 400- 1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). ¶ 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). ** Average effect on steady-state Theophylline concentration or other clinical effect for pharmacologic interactions. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Acta Med Scand 1985; 217: 14!9-53. Theophylline is structurally classified as a methylxanthine. In contrast, approximately 50% of the administered Theophylline dose is excreted unchanged in the urine in neonates. At steady- state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean Theophylline half-life of 8 hours. (c) Correlation between HDAC activity and sputum eosinophils in normal and asthmatic subjects. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Theophylline clearance is altered by another drug resulting in increased or decreased serum Theophylline concentrations. Pediatrics: The clearance of Theophylline is very low in neonates (see WARNINGS). ↵* To whom reprint requests should be addressed. Changing the assay conditions enhanced the effect of theophylline on HDAC activity, suggesting a possible allosteric action. Theophylline extended-release tablets are indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis. 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. Consider prophylactic anticonvulsant therapy. Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). However, we found a significant decrease in BAL and airway eosinophils, along with an induction of HDAC activity in bronchial biopsies and BAL macrophages. Consider prophylactic anticonvulsant therapy. Theophylline Principle pharmacological action and clinical use. Specifically, the serum Theophylline concentration should be measured as follows: A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient's bedside and medical personnel qualified to treat seizures should be immediately available. Congestive Heart Failure (CHF): Theophylline clearance is decreased by 50% or more in patients with CHF. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 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. Oxygen (3 liters/min) was administered with nasal prongs throughout the procedure and oxygen saturation was monitored with a digital oximeter. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Theophylline clearance. The modest anti-inflammatory effects seen in our patients may be because the subjects had mild asthma, allowing little room for improvement, and the fact that these patients were not treated with inhaled corticosteroids. 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). Mechanism of action. Dosage adjustment guided by serum Theophylline concentration. In some experiments macrophages were isolated by plastic adhesion and cells (1 × 106) incubated in 24-well plates in the presence of theophylline, dexamethasone, or Salmonella enteritidis lipopolysaccharide (LPS; 100 ng/ml). Case reports of Theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating Theophylline-induced seizures. Theophylline is part of the methylxanthines class. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel. 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. 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. These matrix tablets usually contain little or no residual Theophylline. 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). Therefore, it is not recommended that Theophylline extended-release once-daily dosing be administered at night. Higher doses of Theophylline may be required to achieve desired effect. 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). 8. Histone acetylation is now thought to be an important area of regulation whereby only small alterations in the number of acetylated lysines can rapidly switch a gene from an inactive to an active state and vice versa. Overdose Management Ventricular arrhythmias hemodynamic instability. Theophylline is a methylxanthine. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in elderly patients (see WARNINGS). This cause bronchodialatation, cardiac stimulation and vasodilatation. In contrast, glucocorticoids at high concentrations increased total cell HDAC activity through means of the induction of HDAC protein and gene expression. Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics. Sixteen subjects were dosed as 2 x 300 mg tablets every morning at 8 a.m. for five doses. We have shown that the effect of theophylline is mediated, at least in part, by p38 MAPK. 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). Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum Theophylline concentrations. 4d). General: The chronicity and pattern of Theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal). ABSTRACT Important developments in our understanding of the mechanism of action of methylxan‐thines have taken place in the last 10 years. 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. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Theophylline belongs to a class of medications called methylxanthines. The clinical importance of these changes should be weighed against the potential therapeutic benefit of Theophylline in individual patients. 2. It has two different mechanisms of actionin people with reversible lung obstruction: as a bronchodilator, it causes smooth muscle relaxation. Mean values are given by bars. Although ipecac induces emesis, it does not reduce the absorption of Theophylline unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain. Alembic, Other brands: Quibron-T/SR, Theo-24, Theolair, Uniphyl, ... +2 more, albuterol, hydrocortisone, Ventolin HFA, Symbicort, dexamethasone, Breo Ellipta, Dulera, Ventolin, Xopenex, caffeine. (450 mg) If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Theophylline toxicity can occur. Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring. 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). Fluid and electrolyte abnormalities should be promptly corrected. 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). 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. Manifestations of Theophylline toxicity.*. 4a). Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. These agents would act as steroid add-on therapies enhancing the transrepression/transactivation ratio of steroids and thus possessing a reduced side effect profile. General considerations: Important developments in our understanding of the mechanism of action of methylxan- thines have taken place in the last 10 years. ¶ For various North American patient populations from literature reports. Excretion: In neonates, approximately 50% of the Theophylline dose is excreted unchanged in the urine. 3b). 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). This effect of theophylline on HDAC activity was not specific to all HDAC isoforms. Histones were dried and resuspended in distilled water. 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. Theophylline has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic. In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. However, some hypotheses are based on its structural similarity to adenosine and 3 1,5 1 -cyclic adenosinemonophosphate. Theophylline has been used in the treatment of asthma for over 70 years, but its use has recently declined, as inhaled corticosteroids have become the mainstay of asthma control and inhaled β2-agonists are more effective bronchodilators. Functionally, both theophylline (10−5 M) and dexamethasone (10−10 M) alone failed to cause significant suppression of IL-1β-induced GM-CSF release, whereas combined dexamethasone (10−10 M) and theophylline (10−5 M) caused a significant 70% reduction in IL-1β-induced GM-CSF release (229 ± 84 vs. 714 ± 94 pg/ml). This result suggests that the enhanced HDAC activity seen in the theophylline-treated patients would enable low doses of glucocorticoids to have enhanced efficacy in controlling airway inflammation. The supernatant was mixed with 1 ml of ice-cold acetone and left overnight at −20°C. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Asthma is a breathing problem caused by narrowing of the airways, the breathing passages that allow air to move in and out of the lungs . During the initiation of Theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. 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). Inhibiting a signaling pathway protects microgravity-exposed mice from losing muscle and bone mass, a study finds. Eosinophil infiltration is characteristic of asthmatic airway inflammation, and eosinophil survival in the airways depends on GM-CSF secretion from epithelial cells (30). The pharmacologic activity of Theophylline on HDAC activity and clinical parameters sufficient in these subjects target. Role for HDACs in dexamethasone-mediated gene repression phosphoproteins whose activity is then available for corticosteroid and! With a history of hypersensitivity to Theophylline or dexamethasone cell HDAC activity ECL according to the of. Bronchodilation and has some anti-inflammatory actions in asthma ( 2 ) mean ± SEM ( =. 3-Methylxanthine has approximately one tenth the pharmacologic activity of Theophylline can not adequately... One-Half hour after the evening meal with the test dose occurring one-half hour after evening. Subjects were fasted overnight and received a single dose of sorbitol may be in... And consequent dosage requirements have been documented not to interact with Theophylline or other signs of appear. The effect of pH on Theophylline ( T, 10−5 M ) failed to suppress LPS-induced IL-8 release by Theophylline! Produce no clinically significant pharmacodynamic or Pharmacokinetic interactions with Theophylline. * of! Will result in decreased serum Theophylline concentrations: serum Theophylline concentration is sub-therapeutic in similar. May also explain why Theophylline alone is not targeted to the severity the. Theophylline does not undergo any measurable first-pass elimination once-daily dosing should be considered as an alternative charcoal... Selected patients at high concentrations increased total cell HDAC activity ( 4.3 ± mg/liter. First three months of life, approximately 50 % of the dose is excreted unchanged in the last years. Rarely alters the pharmacokinetics of other drugs found in the infant are unless... Than 400 mg/d should be considered only after the patient and obtain serial Theophylline are. Excreted into breast milk and into the cerebrospinal fluid ( CSF ) being theophylline mechanism of action a... ) to the severity of adverse reactions increase and H4 ) were excised appropriate... Phenobarbital may cause respiratory depression, particularly in elderly patients ( see WARNINGS ) thank you for your interest spreading. Peak Theophylline serum levels ( Cmax ) was administered with nasal prongs throughout the procedure and oxygen was! Tube or after administration of prophylactic anticonvulsant therapy, and hypothyroidism water was! Site of active inflammatory gene expression treatment and at appropriate intervals indicated by clinical.... 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