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Aminophylline (AMP) is a bronchodilator. The therapeutic and toxic doses are very close. Therefore, therapeutic drug monitoring (TDM) of AMP is essential in clinical practice. Microgels were synthesized by free radical precipitation polymerization. Silver@poly( N -isopropyl acrylamide) (Ag@PNIPAM) hybrid microgels were obtained by loading silver (Ag) nanoparticles into the three-dimensional network of the microgels by in situ reduction. The microgel is a three-dimensional reticular structure with tunable pore size, large specific surface area, and good biocompatibility, which can be used as a sorbent for solid-phase extraction (SPE) of target molecules in complex matrices and as a surface-enhanced Raman spectroscopy (SERS) substrate. We optimized the conditions affecting SERS enhancement, such as silver nitrate (AgNO 3 ) concentration and SPE time, according to the SERS strategy of Ag@PNIPAM hybrid microgels to achieve label-free TDM for trace AMP in human serum. The results showed good linearity between the logarithmic concentration of AMP and its SERS intensity in the range of 1-1.1 × 10 2  µg/mL, with a correlation coefficient ( R 2 ) of 0.9947 and a low detection limit of 0.61 µg/mL. The assay accuracy was demonstrated by spiking experiments, with recoveries ranging from 93.0 to 101.8%. The method is rapid, sensitive, reproducible, requires simple sample pretreatment, and has good potential for use in clinical treatment drug monitoring., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To determine the relationship between theophylline trough levels and urine output in critically ill children administered aminophylline as adjunctive diuretic therapy., Design: Retrospective cohort study., Setting: The PICU of a tertiary care children's hospital., Patients: A mixed population of medical/surgical including postoperative cardiothoracic surgery patients less than 18 years old., Interventions: Electronic medical records of all PICU patients admitted from July 2010 to June 2015 were reviewed, and patients who received aminophylline as diuretic therapy were identified., Measurements and Main Results: Patient cohort data including demographics, daily aminophylline, furosemide and chlorothiazide dosing, theophylline trough levels, fluid intake, urine output and total fluid balance, blood urea nitrogen, and creatinine levels were abstracted. Multivariate analysis based on a generalized estimating equations approach demonstrated that aminophylline administration, when analyzed as a categorical variable, was associated with an increase in urine output and decreased fluid balance. However, aminophylline dosing, when analyzed as a continuous variable, was associated with neither an increase in urine output nor decreased fluid balance. Theophylline trough levels were not correlated with urine output at 24 hours (p = 0.78) and were negatively correlated with urine output at 48 hours (r = 0.078; p < 0.005)., Conclusions: Aminophylline administration provided a measure of increased diuresis, regardless of dosage, and theophylline trough levels. Therefore, achieving a prescribed therapeutic trough level may not be necessary for full diuretic effect. Because, as opposed to the diuretic effect, the side effect profile of aminophylline is dose-dependent, low maintenance dosing may optimize the balance between providing adjunctive diuretic effect while minimizing the risk of toxicity.

Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM) from 71 children (median age 5 months; 90% range 1 week to 10 years) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A 1-compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in noncardiac children, theophylline clearance was markedly reduced across age. In the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50% to 75% lower than those recommended in noncardiac children were needed to achieve target serum concentrations of 5 to 10 mg/L., (© 2016, The American College of Clinical Pharmacology.)

Objective: The suitability of the rabbit as an animal model for the primary screening and selection of the pilot scale batches during the early stages of the formulation development was studied., Materials and Methods: Three modified-release formulations of aminophylline consisted of Carbopol® 971P/HPMC K4M (F-I), and HPMC K100M (F-II) or HPMC K4M (F-III) were used. Commercial products were Aminofilin retard 350 mg tablets, Srbolek, Serbia (R-I) and Phyllocontin(®) 350, tablets Purdue Frederic, Canada (R-II)., Results: Calculated release rate constants and the ƒ2 values between R-I/F-I (84.1) and R-II/F-III (83.4) indicated similar in vitro release while the coefficient n showed presence of different mechanisms of release from Anomalous transport, Fickian diffusion to Case-II transport. Higher Tmax, was found in the rabbits, dosed with F-II (12.00 h), F-III (10.50 h), and R-II (15.00 h) formulation. The highest Cmax (9.22 mg/L) was obtained with F-II, similar lower values was seen for F-I and F-III, while commercial products showed the lowest values R-I (5.58 mg/L) and R-II (4.18 mg/L). Higher AUC values were detected for all three formulations (from 115.90 to 204.06 mgh/L) in relation to commercial products (105.33 and 113.25 mgh/L)., Discussion and Conclusion: The results demonstrated a good correlation of Level A (r(2) = 0.97) for the two formulations (F-I, F-III) and commercial product (R-I) indicates that there is a reasonable assumption that the rabbit might be use as a model for the preliminary comparison of scale up formulations in the early stages of the product development.

Objective: To investigate the pharmacokinetics of aminophylline in very low birth weight infant., Methods: This study investigated 104 very low birth weight infants using aminophylline 5 mg/kg treating apnea who were hospitalized in our department during 2011-2012. The blood concentration of aminophylline was measured in 30 min before, 8 h and 5 d after first time loading dose, and was counterchecked every week before aminophylline withdrawal. The pharmacokinetic parameters of aminophylline were calculated and population pharmacokinetic model was established by MW/Pharm3.6 statistical analysis., Results: The average birth weight of these 104 very low birth weight infants was (1.15 +/- 0.23) kg, average gestational age was (31.19 +/- 2.50) weeks. The results of aminophylline pharmacokinetics showed: the plasma clearance was (17.88 +/- 5.61) mL/(kg x h), the apparent volume of distribution was (0.93 +/- 0.18) L/kg, the half life time was (28.6 +/- 7.59) h. The aminophylline plasma clearance was related to creatinine clearance, gestational age and days of age after birth (related coefficient was 0.68, 0.62, 0.56 respectively, P < 0.05),the apparent volume of distribution was related to birth weight (related coefficient was 0.82, P < 0.05). The population pharmacokinetics model established can predict the concentration-time curve of the patients., Conclusion: The pharmacokinetics of aminophylline in very low birth weight infant was quite different from adult, which suggest blood concentration monitoring and dose adjustment for the clinical use of aminophylline in low birth weight infants.

The CL intensity of luminol-diperiodatoargentate(III) (DPA) system is strongly enhanced by addition of iron nanoparticles (FeNPs) covered with C12E4. On injection of aminophylline into luminol-DPA-FeNPs system, the CL intensity is significantly increased. On this basis, a sensitive CL assay was developed for determination of AmP in human serum. FeNPs could catalyze the oxidation rate of luminol in the present of oxygen. Also, the CL intensity of luminol-DPA-FeNPs system is significantly increased in the presence of aminophylline (AmP). Based on this ruling, a sensitive CL assay was developed for determination of AmP in human serum. The influences of analytical variables on the CL signal were studied and optimized. Under the optimum conditions in the present of FeNPs, the CL intensity is linearly increased with AmP concentration in the range of 1.0×10(-8)-2.0×10(-6) mol L(-1). The detection limit was 9.8×10(-9) mol L(-1) AmP and the relative standard deviation for ten parallel measurements of 8.0×10(-7)mol L(-1) AmP was also 4.8%. The proposed system was successfully applied to determine AmP in human serum samples., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This paper firstly describes a novel method to determine aminophylline (Ami) with boric acid (BA) by spectrophotometry. The study indicates that at pH 12.00 the absorbance of Ami decreases when BA is added. A simple, rapid, sensitive and reliable novel method based on the product of Ami and BA is obtained. Beer's law is obeyed in the range of Ami concentrations of 0.20-200 microg ml(-1). The equation of linear regression is A=-2.57309x10(-4)-0.00355C (microg ml(-1)), with a linear correlation coefficient of 0.9969 and RSD 0.28%. The method is successfully applied to the determination of Ami in pharmaceutical samples and mixed serum samples, and average recoveries were in the range of 97.1-105.9%.

Due to missing information on appropriate dosing of aminophylline in meconium aspiration syndrome (MAS), this study compared effects of high-dose and low-dose aminophylline on lung function of animals with MAS. Meconium-instilled rabbits were treated by low-dose (LD, 1.0 mg/kg), or high-dose (HD, 2.0 mg/kg) aminophylline at 0.5 and 2.5 h after meconium instillation, or were left untreated. Within 5 h of oxygen ventilation, HD-aminophylline improved gas exchange, reduced pulmonary shunts and ventilatory pressures, and decreased edema formation and lung neutrophils. LD-aminophylline enhanced lung function to a lower extent than HD-aminophylline, and failed to reduce lung edema and the number of lung neutrophils. Both treatments decreased lung peroxidation, with a stronger effect of HD-aminophylline on lipid oxidation and of LD-aminophylline on protein oxidation. Tracheal reactivity to histamine decreased after HD-aminophylline, while lung tissue reactivity was more reduced after LD-aminophylline. Although LD-aminophylline showed some anti-inflammatory potential, HD-aminophylline improved most of the parameters more effectively.

Introduction: Venous catheters are sometimes difficult or even impossible to insert and may also be associated with serious complications. This study was carried out to investigate whether intraperitoneal administration of drugs may be an alternative to the intravenous route in patients with limited vascular access., Materials and Methods: Three drugs commonly in use in clinical practise, aminophylline, terbutaline and tobramycin, were administered to pigs intravenously and intraperitoneally in small volumes. Serum concentrations were analysed over a period of 6 h and pharmacokinetic key variables for each drug were calculated., Results: Aminophylline (theophylline), terbutaline and tobramycin were absorbed from the peritoneal space and into systemic circulation. For theophylline, the concentration/time profiles after intraperitoneal and after intravenous administration were almost identical, and the intraperitoneal bioavailability was calculated to 0.94. For terbutaline and tobramycin, the intraperitoneal absorption was delayed without any initial peak. Moreover, the intraperitoneal bioavailability was lower than for theophylline (0.71 and 0.65, respectively)., Conclusion: The pharmacokinetic properties after intraperitoneal administration differed among the three drugs, but the results are encouraging and provide a basis for further investigation in humans.

It is well recognized that the theophylline (TP) concentration in human tears correlates well with the free TP concentration in human plasma. However this correlation was found only in a very narrow range of concentrations of TP, and pharmacokinetic analysis of TP in tears has not been carried out for a wide range of concentrations of TP. The aims of this investigation were to develop a simple kinetic model for TP in guinea pig plasma (total [Cf+b] and free [Cf]), cerebrospinal fluid (CSF) [C](CSF) and tears [C](T), and to examine whether [Cf], [Cf+b] and [C](CSF) can be predicted from [C](T) using the resulting kinetic parameters. [Cf+b], [Cf], [C](CSF) and [C](T) were determined by GC/EI-SIM following bolus i.v. injection of TP in doses of 10, 50 and 100 mg/kg into guinea pigs. The wide range of concentrations of [Cf+b] could be quantitatively described by a two-compartment model with non-linear elimination kinetics and individual volume distribution of TP at each dose. [C](T) and [C](CSF) were analyzed using passive diffusion models with and without the pH-partition theory, respectively. The value of [Cf] could be predicted from the value of [C](T). Thus, the measurement of [C](T) which can be collected non-invasively would be a useful method for the therapeutic drug monitoring of TP.

Objective: This study investigated whether aminophylline has an acute effect on the muscle performance of patients with amyotrophic lateral sclerosis (ALS). The study was a randomized, double-blind, crossover against placebo., Materials and Methods: Twenty-five patients (48.5 +/- 14.1 years) with ALS were evaluated by means of forced vital capacity (FVC), maximal mouth inspiratory and expiratory pressures (P(Imax)/P(Emax)) and endurance, maximum voluntary ventilation (MVV) and handgrip strength (HS); variables were measured before and after the patients received an intravenous infusion of aminophylline or placebo., Results: MVV (P<0.02) and HS of the right and left hands (P=0.05) increased after aminophylline infusion. There was a positive correlation between FVC and P(Imax) (r=0.80; P<0.05); between MVV and P(Imax) post-aminophylline, respectively (r=0.77; P<0.05). Serum aminophylline levels ranged from 5.3 to 10.5 microg/mL (mean 7.30)., Conclusion: The acute administration of aminophylline improves the endurance of respiratory muscles and increases handgrip strength in patients with ALS.

Background: Acute respiratory distress syndrome (ARDS) remains a serious, often fatal, condition, despite progress in modern critical care treatment. Cytokines play important roles in the pathogenesis of the syndrome, although their roles in the evaluation and outcome have not been clearly elucidated yet., Objectives: We tested whether serum concentration of epidermal growth factor (EGF), as one of the important inflammatory mediators, changes with time and administration of mechanical ventilation and aminophylline., Patients and Methods: Thirty patients [mean (SD): age = 56.6 (17.4) years] with ARDS were enrolled. After diagnosis based on inclusion and exclusion criteria, the patients were intubated and mechanically ventilated. Two hours after ventilation with definite positive end-expiratory pressure (PEEP), aminophylline with a specific dose was started. Serum samples were obtained at five time points of 0, 2, 2.5, 4 and 8 h post-starting PEEP., Results: Serum EGF concentration decreased after mechanical ventilation with PEEP (P < 0.05). The serum EGF concentrations 8 h after intervention was statistically lower in the low PEEP group than in the high PEEP group. The Acute Physiology and Chronic Health Evaluation (APACHE) Pi score and PaO2/FiO2 improved significantly after 8 h (P < 0.05)., Conclusion: Beneficial effects of mechanical ventilation and aminophylline on APACHE Pi score and PaO2/FiO2 influence serum EGF levels. These findings may have relevance to the development of multisystem organ failure.

In rats with acute renal failure induced by uranyl nitrate, the hepatic microsomal cytochrome P450 (CYP) 2E1 and CYP3A23 increased 2-4- and 4-times, respectively, CYP2C11 decreased to 80% of control, but the levels of CYP1A2 and CYP2B1/2 were not changed. It has been reported that theophylline was metabolized to 1,3-dimethyluric acid by CYP1A2 and CYP2E1 and 1-methylxanthine via CYP1A2, which was metabolized further to 1-methyluric acid via xanthine oxidase in rats. Hence, it was expected that the formation of 1,3-dimethyluric acid would show an increase in rats with renal failure as a result of induction of CYP2E1. The pharmacokinetics of theophylline were compared in control rats and rats with renal failure after intravenous administration of aminophylline, 5 mg kg(-1) as theophylline. In rats with renal failure, the plasma concentrations of theophylline were considerably lower and the resultant total area under the plasma concentration-time curve from time zero to time infinity (AUC(0- infinity )) of theophylline was significantly smaller (2,200 vs 1,550 microg min mL(-1)) compared with control rats. In rats with renal failure, the plasma concentrations of 1,3-dimethyluric acid were considerably higher and the resultant AUC(0-6 h) of 1,3-dimethyluric acid was significantly greater (44.4 vs 456 microg min mL(-1)) compared with control rats. Moreover, the AUC(0-6 h, 1,3-dimethyluric acid)/AUC(0- infinity, theophylline) ratio increased from 2.02% in control rats to 29.4% in rats with renal failure. The in-vitro intrinsic 1,3-dimethyluric acid formation clearance was significantly faster in rats with renal failure (734 vs 529 10(-6) mL min(-1)) compared with control rats using hepatic microsomal fraction. The results led us to conclude that in rats with uranyl nitrate-induced renal failure after the administration of aminophylline, 5 mg kg(-1) as theophylline, there was an increase in the formation of 1,3-dimethyluric acid as a result of an increase in CYP2E1 expression.

Objective: To compare 8 mg/kg and 6 mg/kg loading doses of aminophylline., Study Design: Sixty-one preterm infants weighing <1500 g were enrolled once a decision to administer intravenous aminophylline was made. A standard maintenance dose was used. Serum levels of theophylline were drawn 8 hours after the loading dose and before the fifth maintenance dose., Results: After the initial loading dose, the 8 mg/kg group achieved recommended serum theophylline levels (7-12 microg/ml) more frequently than the 6 mg/kg group (39% vs 3%, p=0.002). Subsequent levels were similar between the groups. There were no increases in side effects with the higher loading dose., Conclusion: If a clinical decision to start intravenous aminophylline therapy in preterm infants has been made, the use of an 8 mg/kg loading dose appears to be a better and safe way to quickly achieve serum theophylline levels within the recommended range.

The effect and metabolism of theophylline administration after cardiac surgery has never been reported. Two series of 2-hour intravenous aminophylline administrations (3 mg/kg/h) were conducted in 10 adult patients on the operative day (acute phase) and on the 4th or 5th postoperative day (recovery phase). Both blood and urine samples were collected for 24 hours after dosing. Heart rate increased in both phases, but the cardiac index increased with the decrease of diastolic blood pressure only in the acute phase (p < 0.05). Plasma concentration levels of theophylline tended to be slightly higher in the acute phase, and renal clearance increased in the recovery phase (p < 0.05). The urinary ratio of 3-methylxanthine to theophylline was significantly higher in the acute phase (p < 0.05). This suggests that cytochrome P4501A2 is partially activated rather than depressed and that N-demethylation is promoted more than hydroxylation immediately after surgery.

Objective: To determine the degree to which a dual-lumen peripheral catheter prevented precipitation of solutions known to be incompatible due to pH during simultaneous infusion in an in vitro model., Methods: An in vitro model was devised to simulate peripheral venous blood flow from an antecubital source to systemic circulation. Ondansetron was simultaneously infused with fluorouracil, aminophylline, sodium bicarbonate, and ampicillin sodium in concentrations reflective of clinical conditions into the Twin Cath 20/22 (the dual-lumen catheter used in this experiment). Study solutions were primed with the prepared drug solution and administered for 15 minutes. Phase I used Normosol-R as the diluent to gather preliminary data; phase II used human plasma. All samples were obtained immediately before the start of the infusion and at 5, 10, and 15 minutes during the infusion, and 5 minutes after the infusion. Samples were visually inspected at each time point for precipitation and analyzed in duplicate by the appropriate stability-indicating HPLC method (except for sodium bicarbonate). Compatibility was defined as no visual evidence of precipitation and no more than 15% mean change in final versus initial concentration., Results: Phase I experiments showed immediate precipitation in Normosol-R within the venous flow. However, in phase II, because of the buffering capacity that plasma proteins add to plasma, no precipitation occurred. All the drug combinations used in this study have been reported to be incompatible at the concentrations tested; however, we detected no incompatibilities., Conclusions: The results of this study indicate that using a dual-lumen peripheral catheter, such as the Twin Cath, may allow solutions incompatible due to pH to be administered simultaneously.

Effects of felodipine, the calcium channel blocker, on the electroshock, pentetrazole-, aminophylline-, and pilocarpine-induced seizures and on the anticonvulsant activity of different antiepileptic drugs against maximal electroshock were examined in mice. Felodipine increased the threshold for electroconvulsions. The drug exerted also a protective effect against pentetrazole-induced seizures, but not against aminophylline- and pilocarpine-induced seizures. The protective efficacy of diazepam and diphenylhydantoin (but not phenobarbital and valproate) against electroconvulsions was significantly enhanced by felodipine. A pharmacokinetic interaction did not seem to be responsible for the interaction of felodipine with antiepileptic drugs in the maximal electroshock test.

The purpose of the present investigation was to evaluate whether the beta 2-adrenergic agonists affect the pharmacodynamics and pharmacokinetics of aminophylline-induced seizures. Adult male Albino Swiss mice were treated i.p. with salbutamol, fenoterol or terbutaline and 30 min. later they received i.p.aminophylline. During 90 min. observation clonic and tonic seizures and also mortality of mice were registered. Moreover the influence of beta 2-adrenomimetics on electroshock-induced seizure threshold (CS 50) and on plasma aminophylline concentration was estimated. It was found that pretreatment with salbutamol, fenoterol and terbutaline decreased the ED 50 (for clonic and tonic seizures) and LD 50 of aminophylline. Fenoterol decreased but terbutaline increased the CS 50 in mice. Only terbutaline elevated significantly the plasma concentration of aminophylline. The data indicate that concomitant treatment with beta 2-adrenergic agonists together with aminophylline increase the risk of aminophylline-induced seizures. Thus plasma monitoring of aminophylline concentration could be used in all patients treated simultaneously with beta-2-adrenergic agonists and aminophylline.

Background: Diaphragmatic fatigue causes respiratory failure, for which aminophylline has been used as therapy. Because the mechanism of action of aminophylline in reversing diaphragmatic fatigue is unclear, we used in vivo 31P magnetic resonance spectroscopy (MRS) to determine the relation between diaphragmatic activation, force output, and aerobic metabolism., Methods: Bilateral phrenic stimulation was used to pace the diaphragm in pentobarbital-anesthetized piglets (6-10 weeks old; n = 44). Esophageal and abdominal pressures were measured to calculate transdiaphragmatic pressure (Pdi) (Pdi = abdominal pressure-esophageal pressure) as an index of force output. Activation was determined by the amplitude of the compound action potential of the diaphragmatic electromyogram. Aerobic metabolism was assessed with a 31P MRS surface coil on the right hemidiaphragm with the animal in a 4.7-T magnet. The animals were divided into four groups based on aminophylline loading dose: saline, aminophylline 10 mg/kg (A10), aminophylline 20 mg/kg (A20), and aminophylline 40 mg/kg (A40). After aminophylline loading the diaphragm was paced for 25 min followed by a 10-min recovery., Results: Aminophylline concentrations were 12.2 +/- 0.7, 21.9 +/- 2.4, and 44.9 +/- 3.6 mg/l in the A10, A20, and A40 groups, respectively. Compound action potential amplitude decreased in all groups by 30% after 25 min of pacing. Conversely, Pdi remained at 100 +/- 3% of the initial value after 5 min of pacing in the A40 group but decreased to 75 +/- 3% in the saline group. Pdi recovered completely (103 +/- 17%) in the A40 group but remained depressed (72 +/- 6%) in the saline group. Pdi values were intermediate in the A10 and A20 groups. MRS data revealed inadequate energy supply/demand ratio in the saline group such that the ratio of inorganic phosphate to phosphocreatine (Pi/PCr) increased to 1.01 +/- 0.09 after 5 min of pacing. Pi/PCr remained unchanged in the A40 group and was intermediate in the A10 and A20 groups. beta-Adenosine triphosphate and intracellular pH did not differ among groups or as a function of pacing. Diaphragmatic blood flow increased from a resting value of 35-60 to 300-410 ml.min-1 x 100 g-1 during pacing in all groups and was not affected by aminophylline dose., Conclusions: Aminophylline, in a dose-dependent fashion, delays the onset of fatigue and improves recovery from fatigue. Delayed fatigue is associated with improved aerobic metabolism as reflected in a low Pi/PCr ratio.

We studied the design of oral sustained-release theophylline dosing after conversion from constant aminophylline infusion. Twelve children with bronchial asthma (9 boys and 3 girls) were evaluated in this study. Each patient received a constant intravenous administration of aminophylline for 4-10 days. Three hours after conversion from constant aminophylline infusion, they received oral sustained-release theophylline twice daily at 12-hour intervals. Blood samples were obtained at least once during the aminophylline infusion, just before conversion from the aminophylline infusion, and 0, 3 and 6 hours, and 4-5 days after administering oral theophylline. Pharmacokinetic parameters were estimated using the serum theophylline concentrations that were obtained during constant aminophylline infusion. These estimates of pharmacokinetic parameters were used to predict the serum theophylline concentrations during oral theophylline therapy. Predicted serum theophylline concentrations using individual pharmacokinetic parameters were fitted with actual measured values in this study. When switching a patient from intravenous aminophylline to sustained-release oral theophylline, the use of Bayesian analysis of serum theophylline concentration values obtained during intravenous therapy works well in predicting serum theophylline concentrations and in determining oral dosages that maximize the drug's effectiveness.

Aminophylline was used in 64 hospitalized patients with asthma and the change of aminophylline serum concentration and clinical manifestations were observed before and after the addition of diltiazem. The results suggested that mean aminophylline serum concentration increased 0.2 percent (P > 0.05), FEV1 increased 9.2 percent (P < 0.01), PO2 increased 5.3 percent (P < 0.01), PCO2 decreased 7.1 percent (P < 0.01), after the addition of diltiazem. These data indicated that the addition of diltiazem did not change aminophylline serum concentration but ameliorate clinical manifestations. However, after the addition of diltiazem, due attention should be paid to the change of blood pressure.

Twenty two preterm infants were prospectively evaluated to assess the need for dose adjustment when converting enteral and parenteral routes of methylxanthine administration.Serum theophylline concentrations remained unchanged in 18 infants after conversion from intravenous aminophylline to theophylline by mouth without dose reduction, as is currently recommended [corrected]. Intravenous aminophylline and theophylline by mouth may therefore be prescribed at equivalent doses, with a possible reduction in drug errors, and improved stability of serum concentrations.

The adequacy of a loading dose of aminophylline 6 mg/kg i.v. in hospitalized pediatric patients with reactive airway disease was studied. Children six months to 14 years of age were studied to determine their serum theophylline concentrations after they were given an aminophylline loading dose of 5-7 mg/kg i.v. and to see whether they had to receive additional bolus doses. Bolus doses were infused over 20-30 minutes and were followed by a continuous infusion. Additional bolus doses were administered if the patient's serum theophylline concentration and clinical condition indicated they were necessary. Data from two separate phases of the study were combined for analysis. Phase 1 was designed for estimating population pharmacokinetic values. Some 72% of the 64 patients studied had subtherapeutic serum theophylline concentrations (< 10 mg/L) within 5.5 hours of the loading dose, and 78% required at least one additional bolus dose. Males had significantly lower serum theophylline concentrations than females; of the patients with subtherapeutic concentrations, 67% were males. Patients five years of age or younger were more likely than older children to have subtherapeutic theophylline concentrations. A 6-mg/kg loading dose of i.v. aminophylline did not produce adequate serum theophylline concentrations or eliminate the need for a second bolus dose in most pediatric patients with acute exacerbations of asthma.

In humans and cats, the ventilatory response to 30 min of moderate hypoxia is biphasic, an initial increase being followed by a decrease in ventilation to levels that are often less than halfway between the initial response and the air-breathing control level. The decrease, or hypoxic depression, is thought to be of central origin. In humans, intravenous aminophylline, an adenosine blocker, blunts hypoxic depression and may completely block it in anesthetized cats. We studied 11 adult cats while awake, measuring ventilation and end-tidal Po2 (Peto2) and Pco2 (Petco2) during 30 min of isocapnic hypoxia (Petco2 32 Torr (1 Torr = 133.3 Pa), Peto2 60 Torr) after intravenous aminophylline on 1 day and saline on another. On the saline day hypoxia initially produced a 75% increase in ventilation, which declined at 30 min to 110% of control, largely owing to a decrease in tidal volume. With aminophylline, room-air ventilation was slightly increased, and hypoxia initially produced a 50% increase in ventilation, which then declined to 130% of control at 30 min. Late in hypoxia, ventilation was significantly greater with aminophylline than with saline. The degree of hypoxic depression was not related to blood theophylline levels and was similar after aminophylline doses of 10 and 13 mg/kg. We conclude that hypoxic depression is at least partially due to adenosine accumulation, the effect of aminophylline being likely due to central adenosine blockade.

The aim of our study was to evaluate the effect of aminophylline on the contractile function of the human diaphragm during varying muscle fiber length. Ten healthy subjects were studied during maximal sniff maneuvers and bilateral phrenic nerve twitch stimulations, with and without intravenous infusion of aminophylline in a randomized fashion. The transdiaphragmatic pressures generated at various baseline lung volumes, from residual volume to 90% of total lung capacity, were recorded before and after the induction of diaphragm exhaustion. At all levels of lung volume, aminophylline did not have an effect on the contractility of the fresh diaphragm. In the exhausted diaphragm, however, the pressure values, induced by sniffs and twitch stimulations, were significantly improved by aminophylline. This positive effect on diaphragm contractility was also impressive at 60, 75, and 90% of total lung capacity. This indicates that aminophylline significantly improves the contractile function of the exhausted human diaphragm, even if the muscle fibers are shorter than optimal. This effect occurs regardless of the neuronal firing rate, whether it is low (twitch stimulation) or high (sniff maneuver).

During acute hyperinflation, patients with chronic obstructive pulmonary disease are likely to have foreshortened inspiratory muscles. Because the effects of aminophylline on contractile properties of the foreshortened diaphragm have never been studied in vivo, we compared these effects with those obtained at functional residual capacity (FRC). In 12 anesthetized dogs, bilateral phrenic nerve stimulation (1, 10, 20, and 100 Hz) was performed at FRC and near total lung capacity (TLC) before and 1 h after each injection of aminophylline, given in cumulative doses of 20, 40, and 80 mg/kg (serum levels of 18.7 +/- 6.3, 29.9 +/- 5.9, and 60.4 +/- 11.9 mg/l, respectively). Passive diaphragm shortening from FRC to TLC, measured in eight animals, averaged 30 +/- 12% of the resting length and increased to 35 +/- 12 and 34 +/- 13% after 40 and 80 mg/kg, respectively. After aminophylline, the increase in transdiaphragmatic pressure at FRC did not reach statistical significance, whereas near TLC transdiaphragmatic pressure significantly increased with 80 mg/kg at all stimulus frequencies (e.g., at 20 Hz from 4.4 +/- 2.9 to 6.7 +/- 2.9 cmH2O) and with 40 mg/kg at 10 and 20 Hz. Diaphragm length changes during stimulation were unchanged after aminophylline both at FRC and near TLC. We conclude that aminophylline has a pronounced inotropic effect on foreshortened canine diaphragm, even at concentrations close to the therapeutic range in humans.

Objective: To determine the effect of adding intravenous theophylline (administered as aminophylline) to nebulizations of albuterol and intravenous methylprednisolone in adults hospitalized for acute asthma., Design: Randomized, placebo-controlled, double-blind study., Setting: Inpatient service of a tertiary-care, university teaching hospital., Patients: 21 adults (22 to 48 years old)--10 in the aminophylline group and 11 in the placebo group., Interventions: Nebulized albuterol, 2.5 or 5.0 mg every 0.5 to 4 hours; intravenous methylprednisolone, 60 mg every 6 hours; and either individualized doses of aminophylline or placebo for 48 hours., Measurements: Forced expiratory volume in 1 second (FEV1), the number of "as needed" albuterol nebulizations and total dose, asthma symptom scores, and adverse effects., Results: At admission from the emergency department, the mean +/- SD baseline FEV1 was 49% +/- 19% of the predicted value in the aminophylline group and 43% +/- 13% of the predicted value in the placebo group. The improvement in FEV1 at 3 hours was greater in the aminophylline group (29% +/- 23% compared with 10% +/- 10% in the placebo group; mean difference, 19 percentage points; 95% CI, 3 to 35 percentage points; P = 0.023). At 48 hours, FEV1 was 75% +/- 19% of the predicted value in the aminophylline group and 58% +/- 15% of the predicted value in the placebo group (mean difference, 17 percentage points; CI, 0.2 to 34.8 percentage points; P = 0.048). Aminophylline-treated patients required fewer nebulizations of albuterol (10.3 +/- 3.8 compared with 16.4 +/- 5.3; mean difference, -6.1; CI, -10.3 to -1.8) and less total dosage (34 +/- 16 mg compared with 70 +/- 34 mg; mean difference, -36 mg; CI, -60.6 to -11.3 mg P = 0.02). No statistical differences were observed in asthma symptom scores or frequency of adverse effects., Conclusions: Individualized doses of intravenous theophylline added to frequent nebulizations of albuterol and intravenous methylprednisolone appear to benefit adults admitted to the hospital with acute asthma and are well tolerated when serum concentrations are maintained in the therapeutic range.

The effects of aminophylline on pulmonary vascular tone, systemic hemodynamics, and ventricular ejection fractions reported in the literature show some discrepancies. We therefore studied in COPD patients the effects of aminophylline on hemodynamics, on ventricular ejection fractions, and on systolic and diastolic functions of each ventricle, and we measured simultaneously the blood level of the drug. The analysis of the data revealed a relationship between the blood level of aminophylline and the variations of right ventricular ejection fraction (RVEF) (r = 0.83, p = 0.005), left ventricular ejection fraction (LVEF) (r = 0.76, p = 0.017), pulmonary vascular resistance index (PVRI) (r = -0.58, p = 0.096), systemic vascular resistance index (SVRI) (r = -0.60, p = 0.08), and right ventricular peak systolic pressure/end-systolic volume index (RVPSP/ESVI) (r = -0.75, p = 0.02). Modifications of ejection fractions and vascular resistance indices were correlated for both ventricles (RVEF vs PVRI, r = -0.77, p = 0.01; LVEF vs SVRI, r = -0.76, p = 0.02). Finally, RVEF modifications was also correlated to RVPSP/ESVI variation (r = 0.78, p = 0.01). These results suggest that even within the therapeutic range (10 to 20 mg/L), the effects of aminophylline seemed to depend on its blood level. This dose dependency could explain the contradictory data reported in the literature concerning the effects of aminophylline on pulmonary and systemic hemodynamics and on ventricular function.

Objectives: To determine whether maximal inspiratory force predicts successful neonatal extubation, and whether aminophylline affects maximal inspiratory force or the success rate of extubation., Design: Double-blind, prospective, randomized, placebo-controlled trial., Setting: Tertiary level neonatal intensive care unit., Patients: A total of 20 ventilated, preterm, newborn infants: birth weight < 2.5 kg; gestation < 35 wks., Interventions: Intravenous aminophylline 4 mg/kg bolus followed by 2.5 mg/kg every 6 hrs x three doses, then 1.5 mg/kg every 6 hrs; or placebo. Drug administration began when infants were receiving an FIO2 of < 0.4 and were progressively weaning from assisted mechanical ventilation. A standardized weaning protocol was instituted, and patients were extubated when they were able to tolerate a mechanical ventilatory rate of < 5 cycles/min., Measurements and Main Results: Occlusion pressures, including maximal inspiratory force, were measured before aminophylline and daily until endotracheal extubation. Arterial blood gases were measured every 3 hrs, and 24-hr cardiac and respiratory recordings were performed postextubation. Three of ten aminophylline-treated patients failed extubation compared with two of ten placebo infants (p = nonsignificant). Mean apnea frequency postextubation was 0.02/hr in the aminophylline group compared with 0.3/hr in the placebo group (p < .05). Aminophylline had no effect on successful extubation or on maximal inspiratory force. Maximal inspiratory force was not correlated with the success of extubation. Apnea frequency postextubation was significantly reduced by aminophylline., Conclusions: Aminophylline is an effective prophylaxis for postextubation apnea in the preterm infant but does not affect maximal inspiratory force or increase the success rate of extubation in this patient population.

The role of bioelectrical impedance (BI) in estimating the pharmacokinetics and, therefore, individualized doses, of aminophylline in preterm infants (gestational age 26-35 weeks) was assessed in a two-phase study. Multiple regression analysis in the first group of neonates (phase I, n = 19) identified resistance, reactance, weight and length as optimal predictors of distribution volume (adjusted R2 = 0.84, coefficient of variation (CV) = 10.17%), and length2/impedance and postconceptual age as predictors of clearance (adjusted R2 = 0.74, CV = 26.73%). Application of these models to an independent group (phase II, n = 20) generated doses which satisfactorily achieved target theophylline loading and steady-state (SS) 'peaks' of 10 micrograms/mL and SS 'troughs' of 7.7 +/- 0.6 micrograms/mL. A better understanding of specific criteria and limitations of the impedance technique in neonates is necessary in order to refine BI measurements.

The protective efficacy of phenobarbital (PB, 120 min before testing) and valproate (VPA, 30 min before testing) alone or combined with aminophylline (a single dose of 50 mg/kg, 3-day or 14-day administration twice daily 50 mg/kg at 8.00 a.m. and 8.00 p.m.) was evaluated against maximal electroshock-induced seizures (MES) in male mice. All drugs were given intraperitoneally (i.p.), and the protection provided by PB and VPA was evaluated as the respective ED50 value (in mg/kg). Aminophylline in a single dose of 50 mg/kg (30 min before electroconvulsions) distinctly reduced the protective efficacy of both PB and VPA, reflected by the increase in the respective ED50 values from 22 to 31 mg/kg (p < 0.001) for PB and from 247 to 281 mg/kg (p < 0.001) for VPA. After administration of aminophylline for 3 days (electroshock was performed 30 min after the last aminophylline injection), the respective ED50 values for PB and VPA were 29.5 (p < 0.01) and 269 mg/kg (p < 0.01 vs. saline-treated animals). Chronic treatment with aminophylline (14 days) resulted in further impairment of the protective activity of PB and VPA. Specifically, the ED50 value of PB was 39 mg/kg (p < 0.05 vs. PB+single injection of aminophylline) and that of VPA was 318 mg/kg (p < 0.01 vs VPA+single injection of aminophylline). Plasma levels of both PB and VPA were not affected by chronic aminophylline; moreover, the plasma level of theophylline was even lower after chronic aminophylline as compared with single aminophylline administration.(ABSTRACT TRUNCATED AT 250 WORDS)

A single intravenous administration of 2.4%-10.0 euphylline to 35 patients with obstructive affections of the lungs entailed a broncholytic effect in large airways in patients with reversible obstruction under sub-therapeutical theophylline concentrations in the serum. In patients with mixed type of the obstruction and restrictive disturbances ineffective ventilation got worse, ventilation-perfusion relations disagreed, hemoglobin affinity to oxygen grew, pulmonary artery pressure dropped against the signs of pulmonary hypertension, EEG changed according to asynchronism pattern corresponding to brain hyperactivity. There was also elevation of both norepinephrine and epinephrine serum levels due to slow parenchymatous hepatic circulation which inhibited clearance of the substances. There was no relationship between changes in the indices and theophylline concentrations in the range 3.8-8.8 micrograms/ml.

Theophylline pharmacokinetics was investigated upon introduction of euphylline (0.15 g) at four levels of gastrointestinal tract: orally (20 patients), into the jejunum (15 patients) at enterogastroduodenoscopy, in the ileocecal area (8 patients) at colonoscopy and rectally (9 patients). Absorption speed depended on the variant of the gastrointestinal introduction rather than on the variant of chronic nonspecific intestinal disease, and appeared maximal in the drug introduction into the jejunum. Concentration and area under curve became maximal in minor participation of the liver in primary capture and biotransformation of theophylline. Reduced theophylline doses are recommended in lower hepatic metabolism of the drug, in hepatic hypofunction, in rectal route of administration.

To assess if there was any advantage in the prophylactic use of theophylline to prevent apnea in preterms, we treated 56 preterms (Group A) < 34 weeks gestation with theophylline infusion and compared these with 25 age and weight matched preterms (Group B) who received no therapy. Aminophylline (25 mg/ml) was infused from admission in all neonates (group A) at rates ranging 0.2 to 0.38 mg/kg/h and blood levels estimated on an Abbots TDX analyser by Fluorescence Polarization Immunoassay, after 5 days infusion. All neonates (Groups A + B) were monitored on a Corometric 505 neonatal monitor. In Group A, 1/48 developed primary apnea while in Group B, 4-21 had primary apnea (p < 0.05). Serum theophylline ranged from 2.3 to 39.5 micrograms/ml with a mean of 12.7 micrograms/ml. The mean serum level of theophylline in 4 cases who exhibited clinical evidences of toxicity was 30.1 micrograms/ml. A statistically significant difference (p < 0.05) was noted in birth weight and serum level inspite of similar infusion rates of theophylline. A linear correlation r = 0.65 was noted between serum level and infusion rate. Multivariate regression analysis, between birth weight and gestational age to serum level, showed a linear correlationship only between birth weight and serum level (r = 0.45).

The pharmacokinetics of theophylline in acutely ill patients show wide intraindividual variability associated with the severity of clinical status. To investigate the mechanism of this variability, we studied the effects of leukotriene C4 (LTC4)-induced pathophysiologic changes on the disposition of theophylline. The plasma concentration-time profiles were measured after simultaneous intravenous bolus injection of theophylline and antipyrine in guinea pigs. The animals received 5 micrograms/kg of LTC4 intravenously 60 min later. The plasma theophylline concentration 30 min after LTC4 treatment was significantly lower (p less than 0.05) than that of nontreated control animals, whereas the plasma antipyrine concentration at that time was not affected. In addition, the treated animals showed significantly slower declines in plasma concentrations of both drugs (0.0805 +/- 0.0199 and 0.291 +/- 0.020 h-1 for theophylline and antipyrine, respectively, mean +/- SEM) than did controls (0.197 +/- 0.010 and 0.439 +/- 0.028 h-1). Leukotriene C4 treatment also induced moderate bronchoconstriction and metabolic acidosis, increased blood hemoglobin concentration and hematocrit, and decreased concentration of serum proteins. In connection with these changes, the plasma unbound fraction of theophylline increased significantly (p less than 0.001, 94.4 +/- 3.3% in treatment versus 58.2 +/- 4.4% in control), but that of antipyrine was unchanged (94.9 +/- 3.0% in treatment versus 92.1 +/- 0.9% in control). These findings indicated that an increase in the volume of distribution was responsible for the abrupt change in plasma theophylline concentration following LTC4 treatment, and the apparent change in the volume of distribution was estimated as 26.1 +/- 5.6%.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple-dose activated charcoal therapy is used in the management of poisoning emergencies to enhance the elimination of enterohepatically and enteroenterically secreted toxins. This study was conducted to determine if increasing the frequency of activated charcoal administration would enhance the elimination of a toxin. In this crossover study, five healthy adult volunteers were randomly assigned to either a control phase or one of three study phases. Subjects in the control phase and each of the study phases received an intravenous infusion of aminophylline (8 mg/kg). During the study phases each subject additionally received activated charcoal 50 gm and activated charcoal 12.5 gm every hour, 25 gm every 2 hours, or 50 gm every 4 hours over a 8-hour period for a cumulative activated charcoal dose of 150 gm. Ten blood samples were obtained over 12 hours and analyzed for theophylline concentrations. Using area under the curve and half-life calculations it was determined that each of the dosage regimens significantly reduced the reabsorption of theophylline and the plasma half-life when compared with control. There were no significant differences between any of the treatment groups. Decreasing the dose but increasing the frequency of activated charcoal administration is as effective as the traditional every 4 hour-therapy regimen.

The effect of a multiple-dose regimen of oral Enoxacin on Theophylline pharmacokinetics was evaluated in 10 hospitalized patients with COPD. It was found that mean Theophylline concentrations in serum significantly increased 144% (P < 0.01), AUC increased 350.4% (P < 0.01), T1/2K increased 204% (P < 0.01), clearance decreased 76.8% (P < 0.01) during coadministration of enoxacin than before. This results suggested that a multidose regimen of enoxacin significantly slowed the clearance of theophylline and elevated theophylline concentrations in serum. The careful monitoring of serum theophylline level and modification of theophylline dosage in patients receiving enoxacin and theophylline were recommended.

The influence of teicoplanin and aminophylline (theophylline ethylenediamine) on their mutual steady-state pharmacokinetics was studied in two parts, namely experimental and clinical studies. The concentrations of teicoplanin and aminophylline (theophylline) were evaluated at several times after intravenous administration of teicoplanin (3 and 15 mg/kg) and aminophylline (5 mg/kg) in 12 rabbits. Ten COPD patients were treated for 5 consecutive days with a short-term intravenous infusion of 240 mg aminophylline twice daily; ten more patients received for 5 days a short-term intravenous infusion of 200 mg teicoplanin twice daily. On the last day, blood samples were taken for teicoplanin and theophylline determination by means of the HPLC method. Subsequently, while aminophylline and teicoplanin were continued at the same dosage, the first ten patients received in addition a short-term intravenous infusion of 200 mg teicoplanin twice daily, and the second ten patients a short-term intravenous infusion of 240 mg aminophylline twice daily. After 5 days the serial assays of serum teicoplanin and theophylline were repeated. Our results demonstrated, in both experimental and clinical studies, no influence of theophylline on the steady-state pharmacokinetics of teicoplanin. Likewise teicoplanin had no significant effect on the steady-state pharmacokinetics of intravenous administration of theophylline in the form of aminophylline.

The purpose of this study was to evaluate epinephrine-aminophylline-induced arrhythmias during halothane anaesthesia after induction with thiopentone or midazolam. Ten mongrel dogs were studied during 1 MAC halothane and 50% N2O:O2 anaesthesia while maintaining constant acid-base status. The minimal arrhythmogenic infusion rate of epinephrine (MAIRE) and the corresponding plasma concentration of epinephrine (MAPC) required to produce ventricular arrhythmias before and after aminophylline were higher following induction of anaesthesia with midazolam than with thiopentone (P less than 0.05); the MAIREs decreased stepwise with aminophylline (P less than 0.05). The correlation coefficient between individual MAIREs and MAPCs was 0.93 (P less than 0.001). Epinephrine alone and in combination with aminophylline was less arrhythmogenic after induction with midazolam than with thiopentone.

Disposition of diprophylline (DPP) and proxyphylline (PXP) and the effect of enoxacin on their disposition were investigated in rats. Concentrations of the two drugs in plasma and urine were measured by HPLC. The pharmacokinetic parameters of the two drugs were estimated by model-independent methods. Although the chemical structures of the two drugs are very similar, remarkable differences in the disposition of the two drugs were observed. Total body clearance (CLT) of DPP was 1.77 L/h/kg, which was sevenfold greater than that of PXP (0.26 L/h/kg). Diprophylline was excreted in an almost completely unchanged form in the urine, but only 50% of PXP was excreted. However, no binding of either drug to proteins in rat plasma was observed. The DPP renal clearance (CLR) was 1.75 L/h/kg, approximately 13-fold the CLR for PXP (0.13 L/h/kg) and sevenfold the rat glomerular filtration rate. This study indicates that in rats, DPP is mainly excreted by active tubular secretion and that renal tubular reabsorption contributes to renal excretion of PXP with glomerular filtration. No significant changes in any pharmacokinetic parameters of the two drugs were observed when they were coadministered with enoxacin, compared with the drug administered alone, suggesting that enoxacin had no effect on the pharmacokinetics of either drug.

Side effects have been observed when 14-membered macrolides, erythromycin and troleandromycin, have been prescribed concurrently in patients receiving therapeutic doses of theophylline. Rokitamycin is a new 16-membered macrolide antibiotic. We have evaluated its effect on theophylline serum concentrations in 12 adult patients suffering from chronic obstructive pulmonary disease. Initially, six patients were treated for four consecutive days with theophylline as sustained-release formulation in the amount of 600 mg daily; six other patients received for four consecutive days a short term intravenous infusion of 240 mg aminophylline, given over a period of 30 min twice daily. On the last day, blood samples were taken for theophylline determination. Theophylline concentrations were measured serially for 12 hours after oral formulation and 4 hours after aminophylline by enzyme immunoassay technique. Subsequently, while theophylline and aminophylline treatments were continued at the same dosage, each patient received in addition rokitamycin tablets, 400 mg every 12 hours. After seven days of this combined medication, the serial assays of serum theophylline were repeated at the same time intervals as before. Concomitant administration of therapeutic doses of rokitamycin did not affect significantly the steady-state pharmacokinetics of oral theophylline and did not alter the (pseudo-) steady-state pharmacokinetics of intravenous aminophylline, showing that the two drugs may be coadministered without any theophylline dose adjustment.

The effect of the traditional Chinese herbal medicines (Tin Chuan Tang and Hsiao Ching Long Tang) on the serum concentrations and pharmacokinetics of aminophylline was examined in three different ages of SD rats. Each traditional Chinese herbal medicine was orally preadministered to SD rats for one week and then aminophylline was administered intravenously. The serum concentrations and pharmacokinetic parameters of theophylline were estimated by a two-compartment open model. The liver isolated after the last blood sampling was homogenized and the activity of hepatic cytochrome p-450 was determined. Significant difference was found in some pharmacokinetic parameters of theophylline such as K10, t 1/2, Cl and Vd for three different ages of SD rats without pretreatment with Chinese herbal drugs (p less than 0.05). However, pretreatment with Tin Chuan Tang or Hsiao Ching Long Tang did not affect the pharmacokinetic parameters of theophylline in three different ages of SD rats (p greater than 0.05). We also found that there was no correlation between age and activity of cytochrome p-450 of SD rats (p greater than 0.05). The decline in some pharmacokinetic parameters of theophylline in the elderly rats perhaps might be attributed to the decrease in hepatic blood flow and liver volume. It is concluded that there was no drug interaction between theophylline and Tin Chuan Tang or Hsiao Ching Long Tang in the different ages of SD rats.

The drug monitoring of serum concentration of Aminophylline by means of HPLC and FPIA to 72 patients suffering from bronchial asthma and asthmatic bronchitis; the relations among the quantities, serum drug concentrations, effects and side-effects of Aminophylline were reported. The results showed that it is necessary to take Aminophylline individually under the guide of drug monitoring. The monitoring should be combined with clinical observation and comprehensive treatment of the diseases. The major values of effective serum concentration of Aminophylline range from 8 to 20 mg/L, while above the value of 20 mg/L, its side-effects will significantly increase. It is safe and effective for asthmatic adult patients (over 55 Kg weight) if the oral dose of Aminophylline is not more than 200 mg Q8h, or for others with continuous asthmatic attacks to be given with 250 mg of Aminophylline intravenously in drip followed by oral dose of the drug 200 mg Bid.

A double-blind cross-over study was performed on 22 asthmatic patients receiving maintenance treatment with theophylline who, in a previous study, had reported sleep problems. In one of two three-week periods the theophylline medication was replaced by an equipotent dose of slow-release enprofylline. Analysis of sleep questionnaires answered after each treatment period, and sleep diaries filled in throughout the study, showed no significant differences in the quality of sleep between the treatments. Peak expiratory flow (PEF) in the morning did not differ between the treatment periods, but mean PEF in the evening was slightly higher (20 l/min) during theophylline treatment. It was concluded that replacement of theophylline by enprofylline did not improve the quality of sleep subjectively in this group of theophylline treated asthmatics. The results suggest that adenosine receptor antagonism may not be a significant cause of sleep disturbances in asthmatic patients who are receiving theophylline as maintenance treatment.

The dependence of the renal excretion of theophylline on its plasma concentration and urine flow rate has been investigated in asthmatic children of either sex. One group (age 12.25 +/- 0.80, mean +/- s.d. n = 8) was given aminophylline intravenously (i.v.), while another (age 10.00 +/- 3.64 n = 14) was given a sustained release preparation of theophylline orally (single dose and repeated doses). Unchanged drug (11.6% +/- 1.75) was excreted in the urine corresponding to a renal clearance of 10.6 +/- 1.6 mL h-1kg-1. Time dependence of the renal clearance of theophylline was found only after i.v. administration. Dependence of the renal clearance on urine flow rate was found both after i.v. administration and at steady state, but not after a single oral dose of theophylline. After oral administration, renal clearance of theophylline was higher at steady state than after a single dose (0.58 +/- 0.06 L h-1 kg-1 vs 0.23 +/- 0.03 L h-1 kg-1), while urine flow rate was lower (1.1 +/- 0.5 mL min-1 vs 1.8 +/- 0.9 mL min-1). High correlation of theophylline plasma concentration and theophylline excretion rate was obtained in 10 of 14 patients after administration of a single oral dose of the preparation (r = 0.8567 to 0.9830). There was no dose dependence of the renal clearance of the drug either after a single dose, or at steady state.

This clinical investigation was designed to characterize the pharmacologic response to theophylline in elderly individuals. Incremental theophylline plasma concentrations (0, 5, 10, 15, and 20 mcg/mL), achieved through dose escalation of intravenous aminophylline, were correlated with pulmonary airway responses in ten young and ten elderly male asthmatic volunteers. The older group had lower baseline pulmonary function values, suggestive of a greater degree of baseline airways obstruction. Despite wide intersubject variability, the elderly subjects demonstrated a lower absolute change in bronchodilator response to equal concentrations of theophylline than did their younger counterparts (P less than .05). A progressive increase in heart rate was noted with increasing theophylline concentrations, but no significant difference in heart rate change between groups was detected (P greater than .05). Whether the difference in theophylline induced bronchodilator response observed in the young and elderly groups is due to a difference in age or in severity of airway obstruction is yet unknown.

In a randomized, crossover study the influence of enteral feedings (Ensure) on the absorption of theophylline from a sustained-release preparation (Theo-24) was evaluated. Six healthy, male subjects, age 22 to 37 years, participated. In phase 1 the subjects received a single oral dose of Theo-24 6 mg/kg with 100 ml of water at 8:00 A.M. In phase 2, they received 100 ml boluses of Ensure hourly, beginning 3 hours prior to the oral dose and continuing for a total of 1000 ml. In phase 3, subjects received a single 30-minute intravenous infusion of an equivalent dose of aminophylline. After each dose, serial blood samples were collected for 72 hours. No statistically significant differences in area under the curve (AUC infinity 0) (126.0 vs 127.3 micrograms hr/ml), maximum concentration (3.80 vs 4.08 micrograms/ml), or time to peak plasma level (13 vs 11 hrs) were found between phases 1 and 2. Mean AUC infinity 0 for the intravenous phase (161.4 micrograms hr/ml) was significantly higher than the AUC for either oral study (p less than 0.05). The mean bioavailability was 81% for phase 1 and 80% for phase 2. Percent absorbed versus time plots revealed no difference in rate of absorption between treatments. We conclude that short-term administration of the enteral feeding. Ensure does not influence the absorption of theophylline when administered as the sustained-release product Theo-24.