Perforated gastric ulcer in an asthmatic treated with theophylline and steroids. Case report and literature review

We presented a patient with status asthmaticus treated with a combination of theophylline and prednisone who developed a perforated gastric ulcer. The relative etiologic significance of the stress of status asthmaticus, administration of theophylline, or corticosteroids is open to question. The literature, except for anecdotal reports, does not support a significant increase of ulcers in asthmatic patients on either theophylline or steroids. A study following large patient groups on theophylline and a combination of theophylline and steroids might clarify the risk of ulcer formation in patients being treated with these medications for asthma.     

A clinical review of patients with convulsions during theophylline administration II: points to consider in administration and prognosis as determined in patients with theophyline toxicosis]

OBJECTIVES: To discover features of patients with theophylline toxicosis among patients who developed convulsions during theophylline administration. METHODS: Fifteen patients, whose measured or estimated blood theophylline concentration at the time of convulsion development was >/=40 microg/mL, were extracted out of 334 patients who were reported between October 1987 and April 2004 and who developed convulsions during theophylline administration (oral theophylline: 255 patients; intravenous theophylline: 79 patients). Patient background, state of drug administration, blood theophylline concentration, presence or absence of status epilepticus, and outcome were examined. RESULTS: Young children and children with fever were predominant, and eight of 15 patients had both features. Furthermore, the dose exceeded the currently recommended target dose in most of patients whose given dose is known. Patients with misdispensing and patients having problems with administration and ingestion methods were included in them. Outcomes included one case of death, two cases of sequelae, 11 cases of recovery or alleviation, and 1 case of unknown. The patient who died took large doses of theophylline, and both of two patients who had sequelae had fever associated with an infection. CONCLUSIONS: Our study revealed 1) heed should be given to the age of the affected child and to theophylline administration when fever is present in order to avoid theophylline toxicosis and 2) many patients with the toxicosis (11/15) present a relatively favorable prognosis.     

Drug abuse and the asthmatic patient: a case report

The case history of a 17-year-old girl with sudden onset of theophylline toxicity and a serum theophylline concentration of 63 micrograms/ml is presented. A change in theophylline elimination was not sufficient to explain this observation. Subsequently, the patient admitted to recent self-medication with several over-the-counter medications and illicit drugs. Although the etiology of theophylline toxicity in this patient could not be defined, several theories are proposed. Included is a discussion of possible interactions of illicit drugs with asthma medications and a summary of personality characteristics associated with a high potential for drug abuse.     

Theophylline as 'add-on' therapy to cetirizine in patients with chronic idiopathic urticaria. A randomized, double-blind, placebo-controlled pilot study

BACKGROUND: Chronic urticaria is a prevalent condition associated with substantial disability. Its pathogenesis is not clearly understood and is divided into autoimmune and chronic idiopathic urticaria (CIU). We investigated if the non-specific phosphodiesterase inhibitor theophylline could provide additional benefit to the histamine-1 receptor (H-1R) antagonist cetirizine in CIU. METHODS: This was a double-blind, placebo-controlled, parallel study. Patients were randomized to receive either cetirizine and theophylline (200 mg twice daily; group A, 67 subjects) or cetirizine and placebo for 6 months (group B, 67 subjects). Group A patients took theophylline for 6 more months. Response was assessed by visual analog scale (VAS) and treatment effectiveness score (TES). Blood theophylline levels were also determined at visit t=1 and t=7. RESULTS: The study was completed by 54 of the 67 patients (80.6%) in group A and 51 of the 67 patients (76.1%) in group B. The physician VAS values for group A were lower after t=3, while the patient VAS values were decreased after t=2. The physician and patient TES values in group A were statistically higher (p<0.05) at all time points except for t=1. At least 1 month of theophylline addition was necessary to obtain statistically significant benefit over cetirizine, and reducing theophylline by 50% during phase 2 did not alter this benefit. Pruritus values were reduced, but not statistically significant. CONCLUSIONS: Addition of theophylline to conventional H-1R antagonists was well tolerated without any adverse effects and provided considerable additional benefit in the management of CIU.     

Theophylline-associated seizures in children

Four patients are reported who experienced seizures in association with serum theophylline concentrations which were in the mildly toxic range. In three patients, erythromycin administration was a probable factor contributing to the elevated theophylline levels. One patient suffered severe neurologic damage as a result of the seizure.     

High-performance thin-layer chromatographic determination of theophylline in plasma

A high-performance thin-layer chromatographic method for quantification of theophylline from plasma is described. The calibration curves of theophylline in methanol and in plasma were linear in the range 20-100 ng. The correlation coefficients were 0.9971+/-0.0011 and 0.9955+/-0.0003 for standard curves in methanol and in plasma, respectively. The limit of quantitation of theophylline in human plasma (assay sensitivity) was 20 ng and no interference from endogenous compounds was observed. The recovery of theophylline from human plasma using the described assay procedure was 89%. The mean relative standard deviations for intra- and inter-day analyses were 1.67% and 2.34% for 50 ng and 2.25% and 3.14% for 75 ng theophylline concentration, respectively. The method was utilized to monitor plasma concentration of theophylline post-administration of sustained release tablets in human patient volunteers.     

Self-poisoning with theophylline. The effect of repeated doses oral charcoal on drug elimination

A heavy smoking male patient with moderate to severe theophylline poisoning is presented. Repeated doses of oral charcoal were given in addition to usual supportive treatment. During this treatment the elimination half-life of the drug (T1/2) was 2 hours. The toxic symptoms disappeared rapidly when the serum concentration was reduced to the therapeutic concentration range. T1/2 was approximately 24 hours in the same patient in a steady state study without oral charcoal treatment. Repeated doses of oral charcoal seem to increase theophylline elimination and should be administered in moderate to severe theophylline poisoning in addition to the usual supportive treatment and correction of metabolic disturbances.     

Lack of significant arrhythmogenicity from chronic theophylline and beta-2-adrenergic combination therapy in asthmatic subjects

We monitored 14 asthmatic subjects (aged 18 to 60 years), with multiple 24-hour electrocardiogram (Holter) recordings, who were taking continuous sustained-release theophylline and beta-2-adrenergic therapy for control of their symptoms. All of the patients were enrolled in an efficacy study for the antiasthmatic drug lodoxamide. No patient demonstrated intrinsic cardiac disease by history or by a standard 12-lead electrocardiogram recording prior to entry into the study. All of the patients were stable at the beginning of the study while on therapeutic theophylline concentrations and inhaled and oral beta-2-adrenergics. Attempts were made to decrease the theophylline dosage by sequentially reducing the dose each week to one-half, one-quarter, and discontinuation. Holter monitoring was repeated at the end of each week of a new dose level. Five patients were able to reduce dosage and eight were able to discontinue theophylline completely. Theophylline therapy was associated with a higher mean heart rate (85.4 vs 79.9 bpm). The combination of theophylline and beta-2-adrenergics therapy was not associated with quantitative or qualitative changes in atrial or ventricular ectopic activity over beta-2-adrenergic therapy alone.     

Successful treatment with continuous intravenous theophylline therapy at home for a patient with problems of oral theophylline absorption

A 56-year-old male with non-atopic bronchial asthma was admitted to our hospital due to status asthmaticus. His asthma attacks could not be controlled by oral and/or inhalation therapy, but only by intravenous theophylline therapy with corticosteroid. A theophylline absorption test was performed on him after over night fasting. 500 mg of theophylline was administered. The maximum serum theophylline concentration was only 4.0 micrograms/ml at 30 minutes and the urinary one was 13.0 micrograms/ml at 360 minutes after starting the test. The threshold level of absorption from the intestinal tract was higher than the usual level in this patient. We conclude that among patients with intractable bronchial asthma there may be some who have problems with orally administered theophylline. Continuous theophylline therapy at home is recommended for such intractable asthmatics.     

Theophylline Concentrations in Serum and Saliva after Oral Microcrystalline and Sustained-Release Preparations in Asthmatics

Theophylline concentrations in saliva have been compared with those in serum in 13 asthmatic patients after single and multiple oral dosage of a microcrystalline theophylline tablet (Nuelin®) and a sustained-release preparation (Nuelin Retard®).
There was wide individual variation in the ratio of serum to saliva concentrations indicating that, even when individual serum to saliva ratios have been established, the use of saliva theophylline measurements alone is unreliable for the routine monitoring of theophylline therapy.
Both preparations produced mean serum theophylline concentrations within the 10–20 mcg/ml range, the sustained-release tablet giving higher morning trough values and smaller trough to peak variation. The preparations were equally and highly bioavailable.
Side effects were reported by three patients, which were the patients with the highest AUC.
The Nuelin Retard preparation appears to provide smooth, sustained serum theophylline concentrations within the therapeutic range and the simple, twice-daily dosage should result in improved patient compliance.     

Effect of low-dose methotrexate on the disposition of glucocorticoids and theophylline

Low-dose methotrexate (MTX) therapy has been recently proposed as alternative therapy for patients with severe steroid-requiring asthma. Several questions have been raised regarding the mechanism of action, including alteration of pharmacokinetics of two medications used in these patients, specifically, glucocorticoids and theophylline. To address this question, pharmacokinetic studies were performed at baseline and after 6 weeks of treatment with either intramuscular MTX or placebo (folic acid). Plasma concentrations of theophylline were measured by fluorescence polarization immunoassay (TDx, Abbott Diagnostics, Abbott Park, Ill.). Prednisolone, methylprednisolone, and cortisol concentrations were measured by high-performance liquid chromatography. Fifteen adults were enrolled in the double-blind, placebo-controlled trial. No change in prednisolone pharmacokinetic parameters was found. Theophylline clearance decreased an average of 19% in patients randomized to receive MTX, from 48.0 +/- 2.0 ml/hr/kg to 38.9 +/- 3.6 ml/hr/kg (p less than 0.05). This change resembles change observed with theophylline and phenobarbital clearance in which a high degree of interpatient variability is observed. The most likely explanation for the change in theophylline clearance is inhibition of hepatic microsomal enzyme activity. Three patients complained of adverse effects, and dosage was reduced in one patient. The variable effect of MTX on theophylline clearance indicates that theophylline concentration monitoring should be performed in patients receiving both drugs.     

Non-compliance in asthmatic children: a study of theophylline levels in a pediatric emergency room population.

Sub-therapeutic theophylline levels due to patient (parent) non-compliance is a significant cause of outpatient treatment failure in childhood asthma. In a study of 50 known asthmatic children with acute asthmatic episodes, 98% had sub-therapeutic theophylline levels less than 10 mcg/ml with 75.5% due to inadequate patient (parent) compliance.     

Long-term, double-blind comparison of controlled-release albuterol versus sustained-release theophylline in adolescents and adults with asthma

This parallel-group study compared the safety and efficacy of controlled-release albuterol versus sustained-release theophylline, both administered every 12 hours. One hundred twenty-four adolescent and adult patients with asthma and with chronic reversible obstructive airway disease were studied. All patients qualified with an FEV1 less than or equal to 80% of predicted (not receiving treatment) and greater than or equal to 15% reversibility in FEV1 or greater than or equal to 25% reversibility in FEF25-75% after inhaled isoproterenol. All patients were known to be able to take theophylline without unacceptable adverse effects. Theophylline was titrated for patients to receive, unblinded, theophylline serum concentrations of 10 to 20 micrograms/ml. With subsequent randomization, 62 patients continued to receive theophylline and 62 patients started taking albuterol in the 12-week, double-blind, double-dummy portion of the study. Pulmonary function was measured during a pretreatment visit (unmedicated) and serial assessment was made starting just before the morning dose and continuing for 12 hours after the dose at the end of 1, 6, and 12 weeks of treatment. Both treatment groups exhibited statistically significant increases in FEV1 from the pretreatment visit to all times of observation at weeks 1, 6, and 12. The increases in FEV1 were not significantly different between albuterol and theophylline administration. There was no evidence of tolerance to the bronchodilatory effect during 12 weeks in either treatment group. Only one patient in the study stopped treatment because of an adverse effect. This patient had tremor during albuterol administration. All other adverse events were tolerated or resolved during treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Theophylline pharmacokinetics in patients with liver diseases with reference to estimated hepatic blood flow]

Pharmacokinetics of theophylline were determined in patients with liver cirrhosis and idiopathic portal hypertension with reference to estimated hepatic blood flow assessed by indocyanine green (ICG). Decreased plasma clearance of theophylline was noted in patients with liver cirrhosis and the clearance was significantly lower in Child C group than in Child A, B groups (17.5 +/- 3.4 ml/Kg/hr vs 27.6 +/- 8.7, p less than 0.05). Theophylline has been classified as a drug with a low hepatic extraction ratio and it has been believed that changes in hepatic blood flow have little effect on its clearance. The results of present study indicate that theophylline clearance is basically not related to ICG clearance but to theophylline extraction ratio, supporting the common belief. However, it is noteworthy that the clearance was related to decreased hepatic blood flow rather than extraction ratio in a cirrhotic patient with huge extrahepatic shunt, suggesting that hepatic clearance of this drug could be affected by hepatic blood flow under some circumstances.     

Bactericidal capacity of polymorphonuclear leukocytes from patients receiving theophylline therapy

The capacity of polymorphonuclear leukocytes (PMNs) to kill Staphylococcus aureus strain 502 A was studied in 25 patients receiving theophylline therapy and in normal healthy controls. A significant difference in PMN bactericidal capacity was found between controls and patients with serum theophylline levels higher than 8 μg/ml, as determined by high-pressure liquid chromatography. The bactericidal capacity of PMNs from both the patient and control populations was reduced in the presence of theophylline levels above 8 μg/ml. In addition, a transient but significant drug-independent reduction was found in the bactericidal capacity of PMNs from patients receiving theophylline.     

Asthma patients requiring unusually high doses of theophylline

We often see severe asthma attacks occur in patients taking high doses of theophylline and disappear soon after intravenous injection of aminophylline. Theophylline concentration in the serum was investigated in those cases. Twenty five asthmatic patients, 14 males and 11 females, 16-17 years of age, visited our out-patient clinic 41 times in total over a period of 9 months suffering from dyspneic attacks of such severity that they had difficulty in speaking and walking although they had taken at least 200 mg theophylline within 6 hours and 400 mg within 12 hours. All cases were treated with iv infusion of 2.8-14 ml of 2.5% aminophylline for 5-15 minutes until the dyspneic symptoms disappeared. Theophylline levels in the serum (micrograms/ml) before the treatment were 2.0 in 1 case, 6.0-9.8 in 8, 10-20 in 23, and over 20 in 9 cases. Levels after the treatment were 5.8 in 1 case, 10-20 in 15, and over 20 in 25 cases. In one patient, a 27-year-old female, 300-400 mg of theophylline, aminophylline, or choline theophyllinate tablets could increase theophylline concentration in the serum only 4.8 micrograms/ml or less, while her theophylline clearance was normal. The present study revealed that there are asthmatic patients requiring unusually high doses of theophylline, partly because some of them have problems in absorption of theophylline, and partly because many of them need higher levels of blood theophylline than those usually thought of as standard therapeutic concentrations.     

Effect of intravenous isoproterenol on theophylline kinetics

Aminophylline and isoproterenol were simultaneously administered by continuous intravenous infusion to six patients with status asthmaticus and acute respiratory failure. During the isoproterenol administration, an increased theophylline clearance was seen in each patient, with a decrease in clearance after the cessation of the isoproterenol infusion. Arterial pH determinations during this study did not correlate with the changes in theophylline clearance. Two patients treated with mechanical ventilation for acute respiratory failure secondary to status asthmaticus did not demonstrate the changes in theophylline clearance seen in the patients treated with intravenous isoproterenol. Parallel studies done in four mongrel dogs indicated similar results to those noted in patients. In the dogs, urinary theophylline clearances were also measured during the administration of isoproterenol without any detectable change. These observations suggest a significant, previously unreported drug interaction between theophylline and isoproterenol during their simultaneous intravenous administration. Questions regarding the mechanism of the drug interaction and the therapeutic implications of these findings are also raised.     

Increased E-rosette formation by foetal liver and spleen cells incubated with theophylline

Foetal liver and spleen cell preparations pre-incubated with theophylline (which indirectly raises intracellular cyclic AMP levels) had more cells which made rosettes with sheep erythrocytes (E-RFC) than control preparations pre-incubated with medium alone or with levamisole, a drug which reduces cyclic AMP. Increased percentages of E-RFC were found in lymphocytes from cord blood and from one immunodeficient patient following incubation with theophylline; there was no effect on lymphocytes from adenoids or blood from healthy adults. Drugs stimulating cyclic AMP might act like thymus extracts to induce cell maturation and such effects might have therapeutic possibilities.     

Comparison of Enprofylline and Theophylline for Intravenous Treatment of Acute Asthma

Thirty-nine patients with asthma requiring acute treatment were included in a randomized, double-blind, parallel study which compared the effect of enprofylline (1.0 mg/kg) and theophylline (3.0 mg/kg). The drugs were given intravenously over a period of 10 min. Peak flow (PEF), heart rate and plasma concentrations of the drugs were determined before and after the injection. Both enprofylline and theophylline significantly increased the PEF 30 min after the injection, the mean increases over the baseline values being 21% and 23%, respectively. The clinical effects assessed by the patient and the physician and the significant decreases in heart rate were similar for the two drugs. Side effects were rare. Thus, 1.0 mg/kg of enprofylline was comparable to 3.0 mg/kg of theophylline in the treatment of patients with acute asthma.     

Intrasubject variation in sustained-release theophylline absorption

Intrasubject variability in the absorption characteristics of two sustained-release theophylline products was examined. Eight healthy, nonsmoking, adult volunteers received a single 250 mg Slo-Phyllin Gyrocap on two separate study days and a single 304 mg Theo-due tablet on two other study days. Plasma samples were collected over a 24-hr period after each dose and were assayed for theophylline content. Absorption parameters were determined, including peak plasma concentration, peak time, absorption rate; time until 94% absorbed, and area under the plasma concentration time curve. Marked intrasubject variation in these absorption parameters was found by examination of duplicate plasma concentration time curves. These differences are not apparent from examination of mean data only. The implications of this dose-to-dose variation for the individual patient are discussed.