Serum Theophylline Concentrations Research Articles

2-Aminopurine-Modified Abasic-Site-Containing Duplex DNA for Highly Selective Detection of Theophylline

2-Aminopurine-modified abasic-site-containing duplex [DNA 5'-TCTGC GTCCT PXT TAACG CACAC-3'/3'-AGACG CAGGA TCA ATTGC GTGTG-5'; P = 2-aminopurine, X = abasic site (Spacer-C3), C = receptor base] is capable of selectively binding to the bronchodilator theophylline with a dissociation constant of 10 microM (5 degrees C, pH 7.0, I = 0.11 M) and is applicable to monitoring serum theophylline concentrations.

Comparison between adverse effects of low and usual doses of intravenous aminophylline

Purpose : Some patients develop side effects from theophylline even at low serum concentrations. We designed a prospective study to evaluate the side effects of theophylline. Methods : A Prospective, controlled trial study was conducted. The low-dose group received an intravenous continuous aminophylline dose of 5 mg/kg/day on the first day and subsequently 10 mg/kg/day on the following two days. The usual-dose group received 10 mg/kg/day for three days and the control group received normal saline for three days. Heart rate, respiratory rate, serum concentration of theophylline, and four adverse events (irritability, sleep disturbance, jitter, and vomiting) were checked at the time of admission and at 2, 12, 24, 48, and 72 h after the start of aminophylline infusions. Results : Nine patients out of 37 in the low-dose group and six of 21 in the usual-dose group dropped out because of uncontrolled irritability. The serum concentrations of theophylline in dropouts (3.681.93 ig/mL) and participants (4.472.45 ig/mL) were not significantly different. Irritability was a more frequent side effect in the usual-dose group at 12 h, but there was no difference between the low-dose and usual-dose groups in terms of vomiting, sleep disturbance, and jitter. Most of the severe adverse effects were observed in children below two years of age. Conclusion : Some patients dropped out regardless of the initiating aminophylline dose, especially patients under the age of two years.

Determination of serum theophylline concentration in ambulatory practice

Serum-theophylline concentration was measured in 486 ambulatory patients from 407 referring practitioners. They had been on maintenance treatment of 350 mg theophylline (Bronchoretard) twice daily. The concentration was within therapeutic range (8 to 20 mg/l) in 53% of patients, while it was below it in 43% and above in 4%. About half the patients receiving this dose would thus need individual adaptation of dosage, guided by clinical findings and serum concentration, in order to achieve optimal use of the drug's prophylactic and therapeutic potential. It is concluded that (1) theophylline dosage based entirely on standard dose will lead to an unacceptably high percentage of under-dosing; (2) schematic consideration of body-weight, sex, age, living habits, and accompanying diseases proved to be unreliable and insufficient for individual dose determination; (3) dose adaptation to individual clinical situations and serum concentration is necessary in theophylline treatment of ambulatory patients and, in the light of present technical facilities, is cost-effective.

An RNA Aptamer-Based Electrochemical Biosensor for Detection of Theophylline in Serum

An electrochemical RNA aptamer-based biosensor for rapid and label-free detection of the bronchodilator theophylline was developed. The 5'-disulfide-functionalized end of the RNA aptamer sequence was immobilized on a gold electrode, and the 3'-amino-functionalized end was conjugated with a ferrocene (Fc) redox probe. Upon binding of theophylline the aptamer switches conformation from an open unfolded state to a closed hairpin-type conformation, resulting in the increased electron-transfer efficiency between Fc and the electrode. The electrochemical response, which was measured by differential pulse voltammetry, reaches saturation within a few minutes after addition of theophylline, and the dynamic range for detecting theophylline is 0.2-10 muM. The electrode displays an inhibited response when applied directly in serum samples treated with RNase inhibitors; however a full response to the theophylline serum concentration was obtained by transferring the electrode to blank serum-free buffer solutions. It was demonstrated that theophylline is detected with high selectivity in the presence of caffeine and theobromine.

Pharmacokinetics of intravenous theophylline in pregnant patients at term.

The pharmacokinetics of theophylline was determined in six pregnant, nonsmoking women in labor at term following a single bolus infusion of 5.6 mg/kg of aminophylline over 20 minutes. Cord blood levels were obtained from three babies at delivery. Compared to values reported in the literature for nonpregnant adult nonsmokers, the volume distribution (mean 573 +/- 53 ml/kg) and clearance rate (mean .88 +/- .24 ml/kg/min) of theophylline is increased in pregnant women, but the half-life (mean 7.95 +/- 2 hrs) remains unaltered. Similar doses of aminophylline can therefore be used in pregnant and nonpregnant adults who do not smoke cigarettes, but the infusion rate required to maintain a mean serum concentration of 10 micrograms/ml (0.5 mg/kg/hr) is almost half that initially reported in the literature. The serum theophylline concentrations in maternal venous and mixed cord blood at delivery were almost identical, which implies that theophylline crosses the placenta rapidly and that the fetus represents a "shallow" drug compartment.

Efficacy of Aminophylline for Treatment of Recurrent Symptomatic Bradycardia After Spinal Cord Injury

Cardiac dysrhythmias and cardiac arrest can occur after acute spinal cord injury (SCI). Disrupted sympathetic innervation after SCI results in unopposed parasympathetic activity leading to baseline bradycardia. Hence, vagal stimulation can result in episodes of exaggerated symptomatic bradycardia. Data supporting pharmacologic intervention for treatment of symptomatic bradycardia after SCI are limited. We describe a patient who sustained a high cervical SCI and subsequently developed episodic symptomatic bradycardia. The addition of aminophylline to the patient's therapeutic regimen was associated with resolution of the bradycardia. Throughout her treatment course, the patient's serum theophylline concentrations were 1.9-3.4 mg/L. These levels were consistent with those identified in other case reports describing treatment with methylxanthines to prevent episodic bradycardia after SCI. Our understanding of drug pharmacokinetics and pharmacodynamics in patients with acute SCI is limited and provides an ideal opportunity for further study in this area.

Serum and Saliva Theophylline Levels in Adult Outpatients with Asthma and Chronic Obstructive Pulmonary Disease (COPD): A Cross-Sectional Study

Due to a narrow therapeutic range, measurment of theophylline serum levels is highly recommended in patients with a long-term theophylline therapy. In this regard, since blood sampling is an invasive method, exploring alternative methods using other biological fluids in particular saliva samples are targeted. This study was designed to determine any relationship between serum and saliva levels of theophylline in patients with asthma and COPD, whom have been under xanthine–therapy for an extended period of time. Also, any relationship between serum or saliva levels of theophylline with possible explanatory factors was investigated. Adult (≥18 years) outpatients with a history of theophylline use (for at least 1 month) entered this study. Serum and stimulated saliva samples obtained 1 h before the morning dose and were measured using a high performance liquid chromatography (HPLC) method. To stimulate saliva production, patients chewed a piece of parafilm for 5 min before sampling. Relevant demographic information, medical and medication histories of the patients were also recorded. Collected data were entered into the SPSS (Statistical Package for Social Scientists, version 11.5) software and analyzed using the appropriate statistical tests (p<0.05). Eighty-six patients (44 males and 42 females) with a mean ± SD age of 58.72 ±14.23 years enrolled in the study. Mean±SD of serum and saliva concentrations of theophylline were 5.4±2.8 mcg/ml and 4.0±2.1 mcg/ml, respectively. Forty five patients (52.3%) had subtherapeutic serum levels of less than 5 mcg/ml. There was a significant direct relationship between serum and saliva levels of theophylline (p=0.0001, r = 0.91). Multivariate analysis led to a model in which only total daily dose of theophylline (mg) could remain as a predictor associated with the serum (p = 0.0002, r = 0.53) and saliva levels (p = 0.0001, r =0.47). A considerable association observed between serum and saliva levels of theophylline, confirms previous reports. The observed high frequency of the patients with subtherapeutic serum levels emphasizes the importance of implementing therapeutic drug monitoring (TDM) of theophylline in patients with a long-term theophylline therapy, using non-invasive alternative sampling methods e.g. saliva sampling.

Reliability of salivary theophylline in monitoring the treatment for apnoea of prematurity

To evaluate the reliability of salivary levels of theophylline in monitoring therapy of apnoea of prematurity. Aminophylline was administered intravenously in 13 infants with apnoea, in a loading dose of 5 mg/kg and maintenance dose of 3 mg/kg, every 8 h. The patients were divided into two groups according to their postconceptional age (PCA): group A, of infants with small PCA (32.8+/-2.0 weeks; n=6 cases), and group B, infants with higher PCA (37.1+/-0.8 weeks; n=7 cases). A total of 57 paired samples of serum and saliva were obtained in all 13 infants. The mean serum level of theophylline was 7.8+/-5.8 microg/ml and the ratio between serum and salivary concentration of theophylline was 1.53+/-0.28. A strong correlation between the serum and salivary concentration of theophylline (r=0.973) was found. Infants with small PCA had significant higher serum concentration of theophylline than those with higher PCA (10.6 vs 5.3 microg/ml; P=0.0002). The difference between the mean ratios of serum/salivary theophylline levels in the two groups was low (1.44 vs 1.62; P=0.0155). The strong correlation of theophylline in serum and in saliva recommends the salivary levels as a reliable method for monitoring the treatment of apnoea of prematurity.

ＣＯＰＤにおける低用量テオフィリンの気道抵抗，呼吸筋力および高感度ＣＲＰへの影響

The purpose of this study was to evaluate the effect of low-dose theophylline on airway resistance(Raw),respiratory muscle strength and high-sensitivity CRP in patients with chronic obstructive pulmonary disease(COPD).The subjects were 11 patients with COPD(8 males ; 3 females).Raw and other pulmonary function parameters were measured by means of body plethysmography.Maximal expiratory pressure(MEP)and the maximal inspiratory pressure(MIP),the parameters of respiratory muscle strength,were measured after 4 weeks of administering low-dose theophylline when serum concentrations of theophylline were 4.7±2.9 micro g/mL.The administration of theophylline decreased Raw,significantly increased FEV 1.0,decreased CRP levels and increased MEP.High-sensitivity CRP levels were negatively correlated with MEP and MIP (R2=0.474,R2=0.657 respectively).The results of the present study suggested that high-sensitivity CRP can be used as an indicator of respiratory muscle strength in patients with COPD.

Therapeutic comparison between low-dose sustained-release theophylline dry syrup and capsule in children with mild persistent asthma

Purpose : Theophylline has recently been reported to have concurrent anti-inflammatory effects at low therapeutic plasma concentrations which are below the doses at which significants, clinically useful bronchodilatation is evident. Sustained-release formulation in capsule and dry syrup forms were developed to reduce its adverse effects and improve its clinical effects. We compared the therapeutic effects of theophylline dry syrup and capsules in children with mild asthma. Methods : Ninety children with mild asthma were randomized to receive either theophylline dry syrup (n=44) or theophylline capsules (n=46); 4 mg per kilogram of body weight, twice a day, for 12 weeks. Baseline and serial measurements of daytime and nighttime asthma symptom score were performed. Compliance scores, drug swallowing scores, and drug usability scores were measured every 4 weeks. Each scoring was rated on a scale of 0-4. Serum theophylline concentration were measured at 4 and at 12 weeks. To examine the anti-inflammatory effect of theophylline on asthma, Serum eosinophilic cationic protein as a marker of airway inflammation caused by eosinophil was measured 12 weeks pre- and post-administration. Results : The daytime and nighttime asthma symptom scores of the two groups after 4 weeks significantly improved over the baseline score. Daytime and nighttime asthma symptom scores in the dry syrup group were statistically lower at all time points except for the nighttime symptom scores at 4 weeks. Compliance scores, drug swallowing scores, and drug usability scores in the dry syrup group were significantly higher at the end time point. Only in the dry syrup group was the serum ECP at the end time point statistically lower than baseline. Conclusion : Low-dose sustained-release theophylline may be safe and effective in bronchial asthma and this effect may be mediated by its anti-inflammatory action mechanisms. Especially, when used in children with asthma, dry syrup formulation is recommended because of its higher compliance than capsule formulation.

Effect of low-dose macrolide antibiotics on theophylline disposition in pediatric patients

Low-dose macrolide antibiotics are administered for the treatment of certain chronic inflammatory sinopulmonary diseases (e.g., sinusitis and panbronchiolitis). Because 14-membered ring macrolide antibiotics administered at antimicrobial doses have been suggested to elicit a significant inhibitory effect on the hepatic metabolism of theophylline, we studied whether low-dose macrolide antibiotic therapy also evokes a clinically relevant alteration in the disposition of theophylline. The steady-state serum theophylline concentration and the urinary concentrations of theophylline and its metabolites [i.e., 1-methyluric acid (1MU), 3-methylxanthine (3MX), 1, 3-dimethyluric acid (DMU), and caffeine] were examined in nine stable asthmatic children who received both theophylline and lowdose erythromycin or clarithromycin (12.3±4.5mg/kg body weight/day) and in ten children who received theophylline alone.An immunoassay and high-performance liquid chromatography with ultraviolet detection (HPLC-UV) were used for serum and urinary drug assay, respectively. Results demonstrated no significant differences in serum theophylline concentration, the metabolic clearance of theophylline to its metabolites, and the renal clearance of theophylline between the two groups. In conclusion, the administration of low-dose macrolide antibiotics for the treatment of sinopulmonary diseases would not stipulate a dosage reduction of concomitantly administered theophylline in pediatric patients

テオフィリン徐放性ドライシロップ剤の先発品と後発品の品質比較評価に関する研究

To evaluate the quality of the original theophylline sustained-release dry-syrup product and 4 generic versions on the market, we conducted a content uniformity test, dissolution test, bioavailability test, and bitter taste test on these products. Serum theophylline concentrations of the original product were investigated in 3 rats according to a test that was divided into 2 different particle sizes with the following results. For the whole preparations, the mean content was about 20% and changing the pH did affect the dissolution rate for any preparation. However, when the preparations were divided into 2 different particle size ranges, there was a large variation in content for the different particle size categories for all preparations. For preparation A, particles of less than 75μm in particle size had the highest content, for preparation B particles from 150 to 300μm had the highest content, preparation C had the highest content in the 75-150μm particle size range and the highest content for preparations D and E was in particles of over 300μm in size. For preparation A, the ratio of the content of particles of less than 75μm in size to that of particles of 150 to 300μm was about 1.7 and the ratio of the area under the concentration time curve for these 2 particle size ranges was about 2.1. In the taste test, all preparations were found to be masked sufficiently against bitterness just after administration, but 2 preparations were not sufficiently masked at 15 seconds after administration. These results suggest that some of the generic products are superior in quality to the original one and some are inferior.

Determination of theophylline concentration in serum by chemiluminescent immunoassay

This study aimed to establish chemiluminescent immunoassay (CLIA) for quantitative determination of theophylline levels in human serum. To measure the concentration of theophylline (n=122) and evaluate the assay. The linear range of the CLIA method was 0.51-40 mg/L (Y=1.02X+0.44, r=0.995). The intra and inter CV (coefficient variance) of CLIA were 3.20% and 3.57%, respectively. The average recovery rate was 102.3%. This method was free from interference by brilirubin (<200 micromol/L), hemoglobin (<10 g/L), and triglycerides (<15 mmol/L). This method is simple, convenient and precise for clinical pharmacokinetics study of theophylline.

Efficacy and safety of intravenous theophylline administration for treatment of mild acute exacerbation of bronchial asthma

The present study was designed to evaluate the efficacy and safety of intravenously administered theophylline (IAT) for the treatment of an acute exacerbation of bronchial asthma. The theophylline was solubilized and not combined with ethylenediamine. The subjects were 22 asthmatic patients with mild acute exacerbation of bronchial asthma. All patients had been taking oral sustained-release theophylline and their serum concentrations of theophylline were measured. The 16 patients whose serum theophylline concentrations were <13 microg/mL were randomly selected and treated with IAT (200 mg theophylline in 200 mL saline) for 2 h. Six patients were randomly selected as controls and received 200 mL of saline. Pulmonary function and asthma severity (Borg scale) before and after treatment were measured. After IAT, both PEF (before IAT, 313+/-79 L/min; after IAT, 335+/-107; P<0.05) and FEV(1) (before IAT, 1.66+/-0.47 L; after IAT, 1.83+/-0.44; P<0.05) increased significantly. Furthermore, their severity of asthma as assessed by the Borg scale (before IAT, 2.5+/-1.2; after IAT, 1.3+/-1.0; P<0.05) improved significantly. In contrast, neither FEV(1), PEF, severity of asthma or Borg scale changed significantly in the group who only received saline. None of the patients treated in this study had any adverse effects. These results suggest that IAT is useful for patients with mild acute exacerbation of bronchial asthma and is safe if serum theophylline concentrations are measured.

Carrageenans can regulate the pulmonary absorption of antiasthmatic drugs and their retention in the rat lung tissues without any membrane damage

Effects of various viscous vehicles on pulmonary absorption of antiasthmatic drugs were examined by an in situ pulmonary absorption experiment. Theophylline and fluticasone propionate were used as antiasthmatic drugs. The serum concentration–time profile of theophylline without viscous vehicles was similar to that following the intravenous injection, indicating that pulmonary absorption of theophylline was rapid and absolute. The serum concentration of theophylline was not controlled in the presence of 5% gelatin or 2% sodium alginate. However, 1% iota-carrageenan could control and regulate the serum concentration of theophylline. In the pharmacokinetic analysis, the C max values of theophylline significantly decreased, and its T max values increased in the presence of 1% and 2% iota-carrageenan, 1% kappa-carrageenan, and 2% sodium alginate compared with the control. The MRT and MAT values of theophylline with 1% iota-carrageenan were significantly higher than those without viscous vehicles. The local concentration of theophylline in the lung at 1 h after intratracheal administration increased five-fold with 1% iota-carrageenan compared with the control. On the other hand, the pulmonary absorption of fluticasone propionate was controlled and regulated in the presence of 0.5% kappa-carrageenan. Additionally, the pulmonary inflammation after the exposure of carrageenans administered to the lung was evaluated in rats. Iota- and kappa-carrageenans did not cause local serious damage and inflammation to the pulmonary tissue. Therefore, these findings indicated that the carrageenans were effective to regulate the absorption rate of antiasthmatic drugs including theophylline and fluticasone propionate.

Pharmacokinetic Behavior of Theophylline following PEEP in Critically Ill Patients with Acute Lung Injury

The effect of Positive End Expiratory Pressure (PEEP) on the hepatic elimination of low to moderate extraction ratio drugs has not been clearly defined. We prospectively investigated the effect of PEEP on the clearance of theophylline in 30 (20 males and 10 females) intubated critically ill adult patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The Mean (±SD) age was 57±17 years, creatinine clearance 86±36 ml/min, serum albumin 3.2±0.57 mg/dl and the median APACHE (acute physiology and chronic health evaluation) II score was 25 (with a range of 16 to 34). Critically ill patients who had met the diagnostic criteria for ALI/ARDS were enrolled on PEEP in low (5-9 cmH2O) and high (10-15 cmH2O) levels. All patients received the ordered dose of aminophylline infusion (3 mg/kg over 30 min and then 15 mg/h) after 2 h of initiating PEEP. Blood samples were collected after the loading dose, 2 and 6 h the aminophylline continuous infusion. Vital signs were recorded before and after 2 h of PEEP and each blood sampling interval. Cirrhotic patients and those who had received any drug which could interact with the metabolism and clearance of theophylline, were not included. The Mean(±SD) value of the pharmacokinetic key parameters of theophylline in high (n=17) and low (n=13) PEEP groups were as follows: Vd=0.42(±0.15) L/kg and 0.54(±0.13) L/kg, clearance = 0.035(±0.024) L/h/kg and 0.056 (±0.025) L/h/kg. Mean measured theophylline concentrations following loading dose were 7.08 mg/L and 5.09 mg/L. The calculated volume of distribution (P<0.03), clearance (P<0.05) and theophylline serum concentration (P<0.05), in high versus low peep group, were found to be significantly different. Positive ventilation tends to reduce Vd and clearance of theophylline in critically ill patients.

Aminophylline therapy during endotoxemia in anesthetized spontaneously breathing rats

Phosphodiesterase inhibitors, such as pentoxifylline and aminophylline, may reduce inflammatory cytokine-induced endothelial permeability. We tested the hypothesis that aminophylline treatment may ameliorate the pulmonary and extrapulmonary effects of endotoxemia in a rat model. In anesthetized rats, a tracheotomy was performed along with catheterization of a femoral vein and artery. Anesthesia, fluid balance, and normothermia were maintained throughout the 6-h experiment. A stable hemodynamic and gas-exchange baseline was established at which time the rats were randomly divided into three groups. Group I received aminophylline (1 mg/kg) over 30 min followed by 0.5 mg/kg/h. Group II received a single dose of endotoxin (4 mg/kg) while Group III received both aminophylline and endotoxin as described for Groups I and II, respectively. Gas-exchange profiles, mean arterial blood pressure, and heart rate were determined every 2 h. At hour 6, the rats were euthanized and lung, kidney, and heart tissue were removed for determination of water content. As our control group, we utilized data from our previously published study involving an identical surgical procedure with normal saline. Endotoxemia produced characteristic respiratory and hemodynamic signs of sepsis including hypotension, hyperventilation, tachycardia, and renal and pulmonary edema. Aminophylline treatment failed to prevent these endotoxemia-induced respiratory and hemodynamic manifestations of sepsis, but significantly improved the acid–base imbalance that developed during surgical procedures in saline-treated control rats. Further studies are warranted to determine potentially beneficial doses of aminophylline and resulting theophylline serum concentrations under such septic conditions.

The new trends in theophylline therapy

Sustained-release theophylline pellets formulation for once-daily evening administration significantly improved patients compliance and adjusted serum levels profile of the drug. The patients conversion from i.v. to p.o. therapy is one of the most critical steps in the treatment of asthma according to its chronopathophysiological character. In our study we have examined safety and efficiency of this conversion in twelve hospitalised asthmatic patients who were given the new sustained-release theophylline pellets formulation for once-daily evening administration. The lung function parameters (FEV1, VC, RV, and Rt) and serum theophylline concentrations were monitored. So, the values obtained for the last day of i.v. therapy and the fifth day of p.o. therapy were compared. We found that 75% of the patients had no change or improved lung function on the conversion. Our results indicate that this conversion from i.v. to p.o. theophylline therapy is safe and could be efficacious. Also, the maximum theophylline serum levels could safely be predicted by measuring only one serum concentration in p.o. therapy with sustained-release theophylline pellets formulation for once-daily evening administration.

Effect of pazufloxacin mesilate on the serum concentration of theophylline

We studied the effect of pazufloxacin mesilate (T-3762), a new fluoroquinolone for intravenous administration, on the serum concentration of theophylline. Evaluation consisted of comparisons of serum levels of theophylline (when it was given alone, as a control), with serum levels of theophylline when T-3762 was given concomitantly. We measured the serum concentrations and the urinary excretion rates of theophylline in healthy adult male volunteers who were given theophylline for 5 days, followed by an i.v. infusion of T-3762. Blood and urine samples were investigated on the third and fifth days after the concomitant dosing with T-3762, to compare the serum levels and urinary concentrations of theophylline with the control values. We found that the serum concentration and the urinary excretion rates of theophylline on the fifth day after concomitant dosing with T-3762 were significantly increased compared with the levels when the volunteers had been given theophylline alone.

Effect of Levofloxacin on Theophylline Clearance During Theophylline and Clarithromycin Combination Therapy

OBJECTIVE:To report a case of decreased theophylline clearance by the addition of levofloxacin in a patient receiving theophylline and clarithromycin.CASE SUMMARY:A 59-year-old Japanese man who was receiving theophylline for emphysema experienced stimulation, insomnia, and tachycardia due to theophylline toxicity after clarithromycin and levofloxacin were added to the regimen. The combination of these agents resulted in a decrease in theophylline clearance to approximately 60% of the initial value obtained while the patient was receiving theophylline alone. The adverse effects disappeared after the dosage was reduced and the theophylline serum concentration decreased; however, there was no change in theophylline clearance. After discontinuation of levofloxacin, the theophylline serum concentration decreased, and theophylline clearance returned to the initial level even though clarithromycin was continued.DISCUSSION:Levofloxacin is believed not to influence the clearance of theophylline, although some new fluoroquinolones have been reported to do so. This case indicates that levofloxacin and clarithromycin inhibited theophylline metabolic pathways catalyzed by both CYP1A2 and CYP3A4 and resulted in the decrease in theophylline clearance. The clearance of theophylline, therefore, is not influenced by clarithromycin alone.CONCLUSIONS:Careful monitoring is required when levofloxacin is prescribed for patients who are taking clarithromycin with theophylline.