Determination of Aminophylline in Human Serum Using Hydrogel Microspheres for Coupled Surface-Enhanced Raman Spectroscopy (SERS) and Solid-Phase Extraction.

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 (AgNO3) 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 × 102 µg/mL, with a correlation coefficient (R2) 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.

No Requirement for Targeted Theophylline Levels for Diuretic Effect of Aminophylline in Critically Ill Children.

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.

Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass.

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.

[Investigation on pharmacokinetics of aminophylline in very low birth weight infants].

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.

Preliminary evaluation of the in vitro release and in vivo absorption in rabbits of the modified-release dosage forms.

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.

Fast and sensitive chemiluminescence assay of aminophylline in human serum using luminol-diperiodatoargentate(III) system catalyzed by coated iron nanoparticles.

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.

A novel spectrophotometric method for the determination of aminophylline with boric acid in pharmaceutical and mixed serum samples.

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%.

Pharmacokinetics of intraperitoneally instilled aminophylline, terbutaline and tobramycin in pigs.

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.

Comparison of the effects of low-dose vs. high-dose aminophylline on lung function in experimental meconium aspiration syndrome.

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.

Pharmacokinetics of theophylline in Guinea pig tears.

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.

Acute action of aminophylline in patients with amyotrophic lateral sclerosis.

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.

Comparison of the effect of aminophylline and low PEEP vs. high PEEP on EGF concentration in critically ill patients with ALI/ARDS.

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.

A randomized, controlled, double-blind trial comparing two loading doses of aminophylline.

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.

Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of intravenous theophylline in rats: the role of CYP2E1 induction in 1,3-dimethyluric acid formation.

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.

Theophylline metabolism after cardiac surgery.

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.

Effect of a dual-lumen peripheral catheter on the delivery of known incompatible medications.

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.

Influence of felodipine on experimental seizures and activity of different antiepileptic drugs in mice.

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.

[Effect of beta 2-adrenergic agonists on neurotoxic action of aminophyllines]. / Wplyw agonistów beta 2-adrenergicznych na neurotoksyczne dzialanie aminofiliny.

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.

Effect of aminophylline on high-energy phosphate metabolism and fatigue in the diaphragm.

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.

The design of oral sustained-release theophylline dosing after conversion from intravenous to oral therapy.

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.