Loading Dose Of Aminophylline Research Articles

Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.

Background:Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies.Methods:A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt-form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg IV load then 1.8 mg/kg IV q6h). The ability of different dosing regimens to achieve target concentrations (4–10 mg/L) associated with clinical response was examined.Results:Birth weight was a significant predictor of theophylline clearance and volume of distribution (p<0.05). The median half-life was 39.5 h (range 27.2 to 50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates.Conclusions:In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population.

Comparative Efficacy and Safety of Caffeine and Aminophylline for Apnea of Prematurity in Preterm (≤34 weeks) Neonates: A Randomized Controlled Trial.

To compare the efficacy and safety of standard doses of Caffeine and Aminophylline for Apnea of prematurity. Randomized controlled trial. Tertiary-care referral centre and a teaching institution in Southern India. Trial was conducted from February 2012 to January 2015. 240 preterm (≤34 wk) neonates with apnea of prematurity. Neonates randomized into two groups: Caffeine group received loading dose of caffeine citrate (20 mg/kg) followed by 5 mg/kg/day maintenance dose every 24 hour. Aminophylline group received loading dose of Aminophylline - 5 mg/kg and maintenance dose of 1.5 mg/kg 8-hourly. Difference in apneic spells, associated respiratory morbidity, and acute adverse events were assessed. Association of efficacy with therapeutic drug levels was also evaluated. Infants on aminophylline experienced less apnea spells in 4-7 days of therapy (P=0.03). Mean apnea rate and isolated desaturations were similar in 1-3, 4-7 and 8-14 days of therapy. No difference was noted in duration of Neonatal Intensive Care Unit stay and hospital stay. Mean heart rate was significantly high in Aminophylline group (P<0.001). Risk of developing tachycardia was less (RR 0.30; 95% CI range 0.15 to 0.60; P<0.001) in Caffeine- over Aminophylline-treated infants. Aminophylline is as effective as caffeine for prevention of apneic spells in preterm neonates; however, dosage optimization needs to be done to reduce toxicity.

THEOPHYLLAMINE AND THE ANTIPARKINSONIAN RESPONSE TO LEVODOPA TREATMENT

In an open preliminary study theophyllamine (theophylline-ethylenediamine) was administered to eight patients with idiopathic parkinsonism showing residual signs of parkinsonism though already in treatment with levodopa. Although theophyllamine in preclinical studies was found effective in potentiating the response to central dopamine stimulation, the drug in the present clinical study was without effect on idiopathic parkinsonism. After a loading dose of aminophylline, 5.6 mg per kilogram given intravenously, a maintenance dose of 0.9 mg per kilogram per hour infused during 2 h resulted in serum levels of theophylline of 23.5 +/- 3.9 mg per liter. 3-methyl-xanthine, a pharmacodynamic active metabolite of theophylline was analyzed in the serum samples. Less than 0.5 mg per liter was found.

Effects of theophylline on renal function in premature infants.

Xanthines are frequently being used in the management of premature babies. Studies in adult subjects have demonstrated a diuretic effect of aminophylline due to the inhibition of solute reabsorption in various segments of the nephron. We evaluated the effects of aminophylline on the developing kidney. Nineteen premature infants, with a mean +/- SD gestational age of 31.1 +/- 2.8 weeks and mean birth weight of 1481 +/- 454 g were studied at mean age of 4.5 +/- 4.0 days before and after a 20-minute loading infusion of 6 mg/kg aminophylline, followed by maintenance therapy at a dose of 2 mg/kg every 12 hours. A marked diuresis occurred immediately after the loading dose, the ratio of urinary output to water intake increased from 0.58 +/- 0.36 to 1.19 +/- 0.65. Concomitantly, the fractional excretion of sodium increased from 2.7 +/- 2.6% to 5.7 +/- 4.4% and that of potassium rose from 21 +/- 19% to 31 +/- 21%. Urinary calcium and uric acid excretion were also enhanced: calcium to creatinine ratio rose from 0.31 +/- 0.29 to 0.60 +/- 0.54 and uric acid to creatinine ratio increased from 2.5 +/- 1.5 to 3.8 +/- 2.0. Tubular reabsorption of phosphorus (TRP) was not affected. Most of the effects were no longer evident after 24 hours, despite continuing aminophylline maintenance therapy. In premature infants the aminophylline loading dose, but not maintenance therapy, affected renal functions. Because heart rate, blood pressure, and creatinine clearance did not change, it appears that aminophylline acts directly on tubular reabsorptive functions.

Aminophylline and Doppler time-averaged mean velocity in the middle cerebral artery in preterm neonates.

The purpose of this study was to assess the effect of an intravenous loading dose of aminophylline (6 mg/kg) on Doppler time-averaged mean velocity in the middle cerebral artery in ventilated preterm neonates. Twenty infants were studied by colour/duplex Doppler technique prior to and at 5, 10, 30 and 60 min after the administration of aminophylline. Aminophylline treatment was associated with a statistically significant reduction in time-averaged mean velocity from baseline (P < 0.001) and an increase in heart rate (P < 0.001) at all timepoints. The largest reduction in time-averaged mean velocity of 19% (95% confidence interval -10 to -28%) occurred at 10 min post-dose. There were no statistically significant changes in transcutaneous PCO2 or mean arterial blood pressure. The observed reduction of 19% from baseline in time-averaged mean velocity following treatment with aminophylline alone is unlikely to be of clinical importance. Whether aminophylline in combination with other drugs that decrease central blood flow velocity such as indomethacin and/or dexamethasone could result in a clinically significant reduction deserves further study.

Effect of Aminophylline on High-energy Phosphate Metabolism and Fatigue in the Diaphragm

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. 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. 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. 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.

Adequacy of recommended aminophylline loading doses in children

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.

Enhancement of Theophylline Clearance by Oral Albuterol

The possible effect of albuterol on theophylline clearance was studied in ten adult volunteers. Subjects received intravenous aminophylline loading dose (5.6 mg/kg), with oral albuterol (4 mg every 6 h), or inhaled albuterol (200 micrograms every 6 h), or alone (control). Theophylline levels were determined for 12-h periods. Theophylline clearance and elimination t 1/2 were calculated. Theophylline clearance was significantly higher when given with oral albuterol, in comparison with control (0.83 +/- 0.05 vs 0.73 +/- 0.06 ml/kg/min, p less than 0.02). Theophylline elimination t 1/2 was shorter with the coadministration of oral albuterol, compared with control (7.1 +/- 0.3 vs. 8.1 +/- 0.6 h, p less than 0.02). These alterations in theophylline clearance and elimination were greater in subjects who had lower control theophylline clearance. Theophylline clearance and elimination t 1/2 recorded with inhaled albuterol were not significantly different from control values. Coadministration of oral albuterol and theophylline resulted in enhancement of theophylline clearance, particularly in subjects with initially slow theophylline elimination. Such patients may require theophylline dosage adjustment as a result of this interaction.

The efficacy of an aminophylline loading dose in acute asthma

The efficacy of an aminophylline loading dose in acute asthma

Aminophylline Therapy for Acute Bronchospastic Disease in the Emergency Room

To assess the role of aminophylline in the treatment of acute exacerbations of bronchospastic disease when used in addition to inhaled beta-agonists and intravenous corticosteroids. Randomized, double-blind, placebo-controlled intervention study. One hundred thirty-three adult patients with either asthma or chronic obstructive pulmonary disease who presented to the emergency department with asthma or wheezing. All patients received therapy with both aerosolized metaproterenol and intravenous methyl-prednisolone. Patients were randomly assigned to receive either a loading dose of aminophylline followed by a routine infusion (n = 65) or an equal volume of placebo as a loading dose and infusion (n = 68). At discharge from the emergency department, the median serum theophylline concentration for the aminophylline group was 54 mumol/L (9.7 mg/L). The two groups showed no differences (P greater than 0.2) in measurements of forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC), or peak expiratory flow rate (PEFR) at baseline or at 60 or 120 minutes after aminophylline administration. Neither patient satisfaction nor physician assessment of response to therapy differed between the two groups. There was no difference (P greater than 0.2) in the frequency of side effects, except for a trend toward a higher frequency of nausea (P = 0.13) in the aminophylline group. There was, however, a threefold decrease in the hospital admission rate for patients treated with aminophylline (6%) compared with placebo recipients (21%) (P = 0.016). Aminophylline, in doses producing levels just below the commonly accepted therapeutic range, appears to decrease hospital admissions in patients with acute exacerbation of asthma or chronic obstructive pulmonary disease. This finding, if confirmed in larger studies, may represent a substantial cost savings.

Evaluation of Three Theophylline Dosing Methods in Pediatric Patients

Three methods used for individualizing theophylline dosing were prospectively evaluated in 34 pediatric patients to compare the methods' ability to accurately predict steady-state serum theophylline concentrations (STCs) from non-steady-state data. Methods evaluated included a Bayesian weighted sum of squares regression program, an algebraic method developed by Chiou, and a commonly used population-based pediatric dosing algorithm. An expanded retrospective evaluation was also done to further compare the Bayesian and Chiou methods. Patients (aged 1-11 y) admitted to the hospital for acute bronchospasm refractory to inhaled beta agonists and with physician's orders to receive intravenous aminophylline were eligible for participation. Study patients received a 6-mg/kg loading dose aminophylline, followed by a 0.8-1.0 mg/kg/h constant aminophylline infusion. STCs were obtained 0.5 and 5.5 hours postinfusion. Subjects were randomized to one of three dosing method groups (Bayesian, Chiou, or pediatric algorithm). Doses were calculated using the assigned method to attain a target steady-state STC. Predictions from each dosing method were compared with actual serum concentrations for bias and precision. Additionally, analysis of fit-to-the-line-of-identity for predicted versus observed STCs was evaluated for each method. Precision of methods was also compared with regard to their ability to predict within 20 percent of their observed steady-state STC. Results from the prospective evaluation showed no significant difference between the three methods tested. Predicted STCs fell within 20 percent of their observed steady-state concentrations for 18 percent (2/11) of patients in the algorithm group, and 45 percent (5/11) of patients in the Chiou group and 17 percent (2/12) of the patients in the Bayesian group met this criterion. Retrospective analysis of all 34 patients demonstrated that the Bayesian and Chiou methods had similar bias and precision and no statistical difference was found between them. The results from this evaluation suggest that the pediatric dosing algorithm is equivalent in predictive bias and precision to the Bayesian and Chiou methods as well as in its ability to identify doses that result in steady-state STCs within 20 percent of their target values. Given the relative inaccuracy of these methods, cautious use of these techniques is recommended when evaluating non-steady-state STCs obtained from children during the acute stages of reactive airway disease.

Effect of body weight on the volume of distribution of theophylline

The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW 0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.

The rationale for an aminophylline loading dose regimen in the markedly obese asthmatic patient: An emergency department study

The rationale for an aminophylline loading dose regimen in the markedly obese asthmatic patient: An emergency department study

The Effect of Aminophylline on Cerebral Blood Flow in Patients with Chronic Obstructive Pulmonary Disease

Aminophylline has been shown to produce a reduction in cerebral blood flow (CBF) in animal models and patients with neurologic symptoms or signs. The effect of aminophylline on regional CBF (rCBF) in patients with chronic obstructive pulmonary disease (COPD) has not previously been reported to our knowledge. We studied the effect of loading and maintenance infusions of aminophylline on CBF in five subjects with moderate to severe COPD. rCBF was determined in eight homologous regions of each cerebral hemisphere at three intervals: (1) baseline; (2) following the IV loading dose of aminophylline (6.0 mg/kg body weight); and (3) early and late in the maintenance infusion (0.5 mg/kg/hr) period. Aminophylline loading caused a 26 percent reduction (p = 0.005) in mean rCBF from 40.6 +/- 5.2 (SD) ml/100 g/min to 30.1 +/- 6.0 ml/100 g/min. A 23 percent reduction (31.5 +/- 6.9 ml/100 g/min) persisted throughout the maintenance phase. Thus, aminophylline, as customarily used in subjects with COPD, is associated with a significant reduction in rCBF.

Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation

Methylxanthines are primary agents used in treatment of hypersensitivity disease. Because polymorphonuclear leukocyte (PMN) activation is associated with generation of potent inflammatory mediators, xanthine effects on the PMN respiratory burst were studied. Enprofylline, a xanthine with important therapeutic potential, does not antagonize adenosine and was contrasted with theophylline. Although enprofylline was more potent at low concentrations, both drugs exhibited dose-dependent inhibition of PMN activation at concentrations >10 μmol/L (1.8 μg/ml). Oxygen metabolite generation was decreased by 30% to 40% at therapeutic drug concentrations and by 85% at 1 mmol/L of theophylline. Inhibition by isoproterenol or prostaglandin E 2 but not dibutyryl cAMP was potentiated by either xanthine. Isoproterenol effects were also increased when isoproterenol was evaluated in whole blood specimens obtained from subjects after a loading dose of aminophylline. Although these results were most compatible with cAMP phosphodiesterase inhibition, other commonly proposed mechanisms of methlxanthine activity were also studied. Theophylline but not enprofylline blocked adenosine inhibition of PMN activation. Neither xanthine shifted the calcium dose-response when PMNs were activated with calcium ionophore. Because oxygen metabolites generated by the PMN are mediators of inflammation and hypersensitivity, direct inhibition of PMN activation as well as potentiation of catecholamine activity may be important therapeutic effects of theophylline and enprofylline.

Comparison of intravenous and oral routes of theophylline loading in acute asthma

In a prospective, randomized clinical trial, 19 patients with an acute exacerbation of asthma were given a loading dose of aminophylline by the IV (n = 10) or oral route (n = 9) of administration following treatment with epinephrine. Plasma concentrations of theophylline were measured prior to giving the loading dose, and one, two, three, and 24 to 48 hours later. Therapeutic effectiveness was evaluated by analyzing spirometric measurements prior to giving the loading dose, and one, three, and 24 to 48 hours later. Side effects also were recorded. In the IV group, the mean peak plasma theophylline concentration was 15.1 micrograms/mL one hour after loading, and in the oral group the mean peak serum theophylline concentration was 14.2 micrograms/mL three hours after loading. There was no correlation between theophylline concentrations and normalized change in spirometric values. There was no significant difference in spirometric values between the IV and oral groups. Nausea was slightly more common in the IV group. We conclude that there is no therapeutic advantage to giving a loading dose of aminophylline by the IV route rather than orally in patients with mild-to-moderate exacerbation of asthma initially treated with epinephrine.

Theophylline kinetics in chronic obstructive airway disease in the elderly

Theophylline kinetic studies, serial spirometric function tests, and arterial blood gas determinations were performed in 39 adult men with stable chronic obstructive airway disease (COPD). Subjects were given an intravenous aminophylline loading dose of 5.6 mg/kg and a maintenance dose of 0.9 mg/kg/hr for 6 hours. Elderly (greater than 60 years old) nonsmoking subjects had 36% lower theophylline clearance (Cl) and a 40% longer serum theophylline elimination t1/2 than did middle-aged (less than 60 years old) nonsmoking subjects (mean +/- SE; clearances of 32.6 +/- 3.2 [n = 13] and 50.7 +/- 8.5 ml/kg/hr [n = 8] and t1/2s of 11.0 +/- 0.8 and 7.4 +/- 0.8 hours, respectively). There were also differences in Cl and t1/2 between elderly and middle-aged subjects in both the smoking and nonsmoking groups: elderly group, Cl = 43.6 +/- 3.7 mg/kg/hr and t1/2 = 9.0 +/- 0.7 hours; middle-aged group, Cl = 57.6 +/- 6.0 mg/kg/hr and t1/2 = 6.7 +/- 0.6 hours). There was consistent improvement in spirometric functions in both nonsmoking and smoking elderly subjects: percent changes in forced expiratory volume in 1 second of 19% to 25%; in forced vital capacity of 25% to 31%; in forced expiratory flow at 25% to 75% of vital capacity of 59% to 67%; and in maximum mid-flow time of -25% to -30%, at serum theophylline concentrations of 10 to 13 mg/L (group mean). We conclude that elderly nonsmoking subjects with COPD cleared theophylline more slowly than did middle-aged, nonsmoking subjects with COPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Some Recent Advances in the Management of Asthma

serum theophylline levels has resulted in a better understanding of the pharmacokinetics of the methylxanthines, resulting in more physiologic use of these drugs. With oral aminophylline, optimum serum levels occur with the administration of 6 mg/kg every six hours or about 300 to 400 mg four times daily in the average adult.1 Liver disease and congestive heart failure decrease the rate of metabolism of theophylline and, therefore, result in higher blood levels.2 A recent therapeutic advance in oral theophylline has been the sustained-release oral preparations. A dozen or so acceptable sustained-release theophyllines are commercially available, and these seem to give more stable blood levels with less peak-and-trough effect. Furthermore, the drugs can be administered twice daily, and this should increase patient compliance. During acute attacks of asthma, an initial intravenous (IV) loading dose of aminophylline (6 mg/kg) is given during 20 minutes to patients who were not taking an oral theophylline. For those on an oral maintenance theophyl¬ line regimen, this loading dose is eliminated. Recommend¬ ed IV maintenance doses are given in Table 1. The initial maintenance dose is 0.5 mg/kg/hr by constant IV infusion in healthy nonsmoking adults. In older patients and in those with cardiac or hepatic disease, a lower initial maintenance dose is recommended because of longer serum half-life.3

Metabolic responses to plasma concentrations of theophylline

We investigated the effect of intravenous infusions of aminophylline on plasma glucose, insulin (IRI), glucagon (IRG), growth hormone (HGH), cortisol, and free fatty acid (FFA) levels in healthy young subjects. Six received an intravenous loading dose of aminophylline (6.0 mg/kg over 20 min) followed by a maintenance dose (0.9 mg/kg/hr) for 100 min. Another 7 subjects initially received smaller loading (3.0 mg/kg) and maintenance (0.45 mg/kg/hr) doses, and after 60 min they received a second loading dose (3.0 mg/kg) followed by a larger maintenance dose (0.9 mg/kg/hr) over 120 min. In these fasting volunteers, infusion of aminophylline, which produced theophylline levels in the usual therapeutic range (10 to 20 microgram/ml) caused small increases in plasma glucose levels without changing IRI, IRG, HGH, or cortisol. There were rapid, pronounced, and prolonged rises in FFA associated with the aminophylline infusion. Increases in FFA paralleled the rise in theophylline levels. It is concluded that routine therapeutic doses of theophylline, i.e., doses that achieve serum levels normally encountered in treatment for bronchial asthma, cause a marked rise in FFA and a slight rise in glucose (8 +/- 3 mg/dl) without changing levels of IRI, IRG, HGH, or cortisol.