Stability of theophylline elimination rate.

The elimination rate for theophylline varies greatly among patients, but recommendations for maintenance dosing schedules have assumed relatively little intrapatient variability even over extended time periods. Reports of large intrapatient variability of theophylline elimination rate and consequent clearance raise concerns regarding this assumption and also challenge the practice of assuming relative constancy of elimination rate in the performance of bioavailability studies of slow-release formulations. We therefore systematically studied under controlled conditions the elimination rate of theophylline in 10 patients over an extended time interval. The initial elimination rate constants ranged from 0.062 to 0.136 hours-1. The changes ranged from -5.9% to 9.4% of the initial value during intervals of 2 to 11 months. Correlation of the first and second values was 0.96. Thus the elimination rate of theophylline generally appears to vary little within individuals over time when studied under controlled conditions.

A bioassay for topical and systemic effect of three inhaled corticosteroids.

BACKGROUND: Comparisons of relative potency for the three inhaled corticosteroids in the United States are limited to assessment of skin blanching. OBJECTIVE: Development of a method for comparing relative potencies of inhaled corticosteroids for topical effect on human airway and systemic effect. METHODS: With use of partial suppression of immediate response to inhaled allergen and 24-hour urinary free cortisol output, three-point dose-response curves were constructed for beclomethasone dipropionate (50 micrograms/puff), triamcinolone acetonide (100 micrograms/puff), and flunisolide (250 micrograms/puff). A randomized, parallel, single-blind study design was used. Dosing began with one puff four times a day for flunisolide and two puffs four times a day for the others. Doses were doubled after 1 week and again after a second week. RESULTS: Twenty-five patients completed the study. Dose-response relationships were shown for each inhaled corticosteroid for both topical and systemic effect. Dose-response curves for the three preparations were similar when response was plotted against delivered dose in micrograms. CONCLUSION: Within the limits of the assays, relative potencies of the three preparations appeared to be approximately equivalent for both topical and systemic effect when dose was expressed in micrograms. Relative potency per puff is therefore approximately proportional to the dose delivered. This method has potential for evaluation of relative potency of newer inhaled corticosteroids and the relative advantage of alternative delivery systems.

Apparent decrease in population clearance of theophylline: implications for dosage.

BACKGROUND: Having observed in recent years that the theophylline dose requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml infrequently reached previously described mean values, we hypothesized that a downward shift in the range of dose requirements had occurred among patients with asthma. STUDY DESIGN: We examined dosage requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml in all patients with chronic asthma treated with theophylline by the Pediatric Allergy and Pulmonary Clinic at the University of Iowa from 1990 to 1994 (n = 300) and at the Pediatric Pulmonary Clinic at the University of Florida from 1992 to 1995 (n = 93). We then compared these doses to previous dose requirements from 1978 to 1983 determined in the same manner. RESULTS: Despite similar mean peak serum concentrations during both time periods (14 micrograms/ml), mean theophylline dosage requirements during the period of this study were approximately 25% lower among all age groups than those previously observed (p < 0.001). There were no significant differences in mean dosage requirements between the Iowa and Florida patients in any age group examined. CONCLUSIONS: Theophylline dose requirements needed to attain serum concentrations of 10 to 20 micrograms/ml have decreased significantly from those on which current dosing recommendations are based. This suggests a decrease in mean clearance of the population.

The effect of theophylline and beta 2 agonists on airway reactivity.

Increased airway responsiveness occurs in asthma, chronic bronchitis, cystic fibrosis, and other diseases. Theophylline and beta 2 agonists commonly are used as maintenance therapy for symptoms associated with the increased responsiveness. Both drugs can reduce airway responsiveness to a variety of provocational stimuli. With currently used dosing regimens, theophylline appears to produce relatively constant levels of effect on airway responsiveness and clinical efficacy around the clock, while inhaled beta 2 agonists appear to have insufficient effects at the end of longer dosing intervals. Improved dosing strategies for beta 2 agonists may improve the efficacy of these agents in the future.

Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity.

Three slow-release preparations of theophylline have received approval from the U.S. Food and Drug Administration (FDA) for "once-daily" dosing indications, amid controversy regarding the appropriateness of this decision. Because of specific concerns regarding data submitted to the FDA in support of the first of these products to be approved, Theo-24, we examined the absorption characteristics of this newly marketed formulation. Eight healthy volunteers received, in a crossover manner, single doses of a theophylline reference solution and Theo-24, taken both fasting and after a breakfast of bacon and eggs. The concentrations of theophylline were measured up to 60 hours after the dose. Absorption of Theo-24 after an overnight fast was very slow, with only 71 +/- 6 percent (mean +/- SE) of the dose ultimately absorbed. In contrast, food caused precipitous "dose-dumping," resulting in dose-normalized peak levels in the serum that averaged 2.3 times higher than after a fasting dose. About half of the dose was absorbed in a four-hour period, generally beginning six to eight hours after the postprandial dose, and complete absorption was then attained within 24 hours (p less than 0.001). Toxic effects of theophylline occurred in four subjects when they took the dose with food whereas no toxic effects occurred during the fasting regimen. Consequently, doses of Theo-24 that would have attained a predicted peak concentration of 15 micrograms/ml after multiple dosing taken without food would, if taken with food, have resulted in larger fluctuations and in peak concentrations in the potentially toxic range for six of the eight subjects.

Demonstration of in vivo bioequivalence of a generic albuterol metered-dose inhaler to Ventolin.

STUDY OBJECTIVE: To use histamine bronchoprovocation and bioassay statistical procedures to evaluate the in vivo bioequivalence of a generic albuterol metered-dose inhaler (MDI). DESIGN: A randomized, double-blind, balanced, crossover design was used to determine the potency of each generic albuterol MDI actuation relative to Ventolin (Glaxo Wellcome; Research Triangle Park, NC) administration. One treatment was administered on each of 4 study days. A histamine bronchoprovocation procedure was initiated 1.25 h before and 15 min after administration of the study treatment. PATIENTS: Twenty-four nonsmoking subjects with mild-to-moderate asthma were studied (18 to 65 years of age; FEV(1), > 60% of predicted; and provocative concentration of histamine causing a 20% fall in FEV(1) [PC(20)], < or = 8 mg/mL at screening). INTERVENTIONS: One and four actuations (90 and 360 microg, respectively) of the generic MDI and of Ventolin MDI. Placebo inhalers were used to maintain blinding of inhaler and doses. MEASUREMENTS AND RESULTS: The primary outcome variable was histamine PC(20) measured after study treatment administration. A significant dose-effect relationship was present (p < 0.0001). Deviation from parallelism of the generic and Ventolin dose-response curves (p = 0.95) and differences in overall mean response between the two formulations (p = 0.68) were not significant. Using Finney 2 x 2 bioassay statistical procedures, we estimated that one actuation of the generic albuterol MDI was equivalent to 1.01 puffs of Ventolin (90% confidence interval, 0.69 to 1.50). CONCLUSION: The generic albuterol MDI delivers a quantity of albuterol to the beta(2)-receptor site in the lung that is the bioequivalent to Ventolin. Further, this study reinforces the validity of this statistical methodology for determining in vivo bioequivalence.

Dose dependency for absorption and elimination rates of theophylline. Implications for studies of bioavailability.

Dose dependency for absorption and elimination rates of theophylline were examined by administering 2-mg/kg and 6-mg/kg doses of a theophylline solution to 8 adult volunteers. The area under the concentration-time curve extrapolated to infinity after the lower dose was 84% of that calculated after the higher dose. This is associated with a decrease in the slope of the terminal portion of the elimination curve to varying degrees after the higher dose in all 8 patients (p less than 0.001). A significantly smaller fraction of the higher dose was absorbed at 15 minutes (0.46 vs. 0.77, p less than 0.002), but the differences were trivial by 30 to 45 minutes. Dose dependency for elimination may cause changes in a steady-state serum concentration during multiple dosing that is disproportionately larger than changes in dosage. In addition, the slower elimination at higher serum concentrations may confound the assessment of bioavailability of slow-release formulations when the doses used result in a substantial disparity in the range of serum concentrations attained for the slow-release formulation and the reference. The use of unequal doses adjusted to provide similar peak serum concentrations appears to minimize this potential error.

Evaluation of a noninstrumented disposable method for quantifying serum theophylline concentrations.

STUDY OBJECTIVE: To compare the performance of a new point-of-care theophylline assay (AccuMeter) with that of a standard laboratory assay (TDx), and another point-of-care method (AccuLevel). DESIGN: Prospective evaluation of consecutive patients receiving theophylline. SETTING: University-based, ambulatory, allergy-pulmonary clinic. PATIENTS: Forty subjects receiving maintenance theophylline therapy for asthma. INTERVENTIONS: Theophylline concentrations obtained from AccuMeter, TDx, and AccuLevel were compared. MEASUREMENTS AND MAIN RESULTS: The error, or difference, between TDx and AccuMeter results in 40 subjects on maintenance theophylline described accuracy. Mean error, an estimate of bias, was 1.1 (95% CI 0.72-1.5), 0.67 (0.34-1.0), and 0.98 (0.79-1.2) microg/ml for AccuMeter capillary, serum, and heparinized blood samples. Square root of the mean squared error, an estimate of precision, was 1.6 (1.2-2.0), 1.22 (0.90-1.5), and 1.14 (0.96-1.3) microg/ml for AccuMeter capillary, serum, and heparinized samples. Difference between AccuMeter and AccuLevel ME, an estimate of relative bias, was 0.59 (0.04-1.1) microg/ml. The difference in mean squared errors, an estimate of relative precision, was 0.86 (-0.54-2.3) microg/ml. CONCLUSIONS: AccuMeter demonstrated good precision and minimal bias compared with TDx and AccuLevel . Method of sample collection had no effect on its accuracy.

In vitro characteristics of tobramycin aerosol from ultrasonic and jet nebulizers.

STUDY OBJECTIVE: To compare the in vitro performance of an ultrasonic nebulizer and a jet nebulizer in producing a respirable aerosol of tobramycin solution for injection. DESIGN: In vitro observational study DEVICES: Ultrasonic and jet nebulizers. INTERVENTION: Output was determined by measuring the difference in nebulizer weight before and after nebulizing 3 ml of tobramycin injection solution. Mass median aerodynamic diameter (MMAD) and respirable mass were determined by sampling tobramycin aerosol into a cascade impactor. MEASUREMENTS AND MAIN RESULTS: Mean (SD) output was 1.14 (0.09) ml/minute for the ultrasonic nebulizer and 0.64 (0.08) ml/minute (p<0.001) for the jet nebulizer. Mean MMAD for the jet nebulizer (2.31 [0.10] microm) was less than that of the ultrasonic nebulizer (2.81 [0.17] microm, p<0.001). The majority of tobramycin aerosol produced was in the respirable range for both the ultrasonic (65.1% [4.10%]) and jet (60.6% [0.73%], p=0.008) nebulizers. CONCLUSION: Despite small, clinically unimportant differences in aerosol size and respirable fraction, either device would be acceptable to administer tobramycin injection solution.

The long-term outcome of nonsuppurative otitis media with effusion.

Seventy-four children were enrolled in a double-blind placebo-controlled study to define the outcome of nonsuppurative otitis media with effusion (OME) over a 12-week period. Participants were randomly assigned to one of three treatment groups: pseudoephedrine (4 mg/kg/day), chlorpheniramine (0.35 mg/kg/day), or placebo. The children were reexamined at 2, 4, 8, and 12 weeks after enrollment unless earlier dismissed from the study because OME resolved or acute suppurative otitis media developed. Of the 66 children completing the study protocol, 44 percent had resolved OME, 38 percent developed acute suppurative otitis media, 14 percent had unresolved OME, and 4 percent developed severe hearing loss or medication side effects by the end of 12 weeks. The greatest incidence of both suppurative otitis media and resolution of OME occurred by 2 weeks of follow-up. There was no significant difference in resolution of effusion between treatment groups. Children who were 18 months of age or older with unilateral effusion had the best likelihood of resolution.

Pharmacotherapy of asthma and allergic rhinitis.

It has become easier to treat and control the symptoms of asthma, while the treatment of allergies remains directed toward the prevention and blockade of histamine-induced symptoms. This article details treatment options, including beta-2 selective sympathomimetic agonists, methods of delivery, theophylline, cromolyn, corticosteroids, antihistamines, decongestants, and intranasal steroids.

Comparative efficiency of a laboratory and examining room assay for therapeutic drug monitoring of theophylline in ambulatory patients.

The total clinical personnel time for therapeutic drug monitoring of theophylline with a non-instrumented disposable examining room assay was 446 seconds. For a traditional assay, 1115 seconds of clinical personnel time was required to obtain the sample, send it to the laboratory, and subsequently act on the results. The corresponding costs for time, materials, and laboratory charges were +18.02 and +37.25, respectively.

How much antibiotic suspension is enough?

OBJECTIVES: Pilot data suggest that inadequate antibiotic volumes are often dispensed. Study goals were to determine the frequency of inadequate antibiotic volumes dispensed by local pharmacies, develop prescription-writing guidelines to ensure that adequate antibiotic suspension volumes are dispensed, and document the adequacy of verbal/written counseling pharmacists provide. METHODS: Sixty-one local pharmacies filled prescriptions for penicillin potassium (PCN; 250 mg/5 mL [5 mL orally 3 times daily for 10 days]) and Bactrim (trimethoprim-sulfamethoxazole [TMP-SMX] 5 mL orally twice daily for 10 days). The prescriptions noted only to "dispense a 10-day supply. " Volumes were measured first as total amount dispensed and then into total doses dispensed. Written/verbal instructions were documented. RESULTS: The volume of PCN dispensed was 195 +/- 25 mL (range: 105-222 mL) for an average of 29.4 doses, where 30 doses were needed. TMP-SMX dispensed had a volume of 107 +/- 5 mL (range: 98-120 mL) resulting in an average of 16.5 doses, where 20 doses were needed. Twenty pharmacies (33%) did not dispense a measuring device. Verbal counseling by the pharmacist and written instructions were not uniformly given. CONCLUSIONS: We suggest calculating the actual volume needed plus an additional 10% to 30% of volume (depending on the viscosity). The prescription should also request a medication-measuring/administering device. Patient counseling and instruction should be expanded.

Evaluation of the Ames Seralyzer for therapeutic drug monitoring of theophylline.

Dry reagent technology and reflectance photometry are combined in the Ames Seralyzer to offer a solid-phase plastic strip assay methodology. Light reflected from serum placed on the antibody-impregnated strip is quantitated with a two-point standard curve to display a theophylline result in 90 seconds. The accuracy and precision of the Seralyzer for serum theophylline are compared to the enzyme-multiplied immunoassay technique (Emit) which is commonly used to determine drug concentrations. Liquid calibrators (5 and 25 micrograms/ml) and liquid-spiked sera (10, 15, and 20 micrograms/ml) were measured six times daily simultaneously by both methods for twenty days. Eighty patient samples (theophylline range: 0-33 micrograms/ml) were measured twice each during the twenty days. Acceptable assay limits were established and maintained by measuring 15 micrograms/ml spiked sera prior to and during the evaluation period. All within-run and between-run means for the Seralyzer and Emit were within +/- 1 microgram/ml of the spiked value. All ranges of within-run and between-run means were within +/- 2 micrograms/ml of the spiked value. Mean between-run coefficients of variation for the Seralyzer at the 5, 10, 15, 20, and 25 micrograms/ml values were 11.5, 6.7, 4.9, 4.6, and 4.9 percent, respectively. Linear regression on the 80 patient samples gave a slope of 1.02, intercept of -0.28, and correlation of 0.984. The Seralyzer's accuracy and precision compare favorably with Emit for theophylline determinations greater than 7.5 micrograms/ml.

Oral bioavailability of slow-release theophylline from unencapsulated beads in preschool children with chronic asthma.

The relative bioavailability of two slow-release theophylline formulations using bead-filled capsules. Slo-bid and Theo-Dur Sprinkle, was examined in randomized crossover multiple-dose trials using collected saliva. Two groups of seven preschool-age asthmatic children received one of these and Slo-Phyllin Gyrocaps as a reference. Dose-normalized areas under the saliva concentration-time curves were significantly less than the reference for Theo-Dur Sprinkle (p = .02) but not for Slo-bid with the relative bioavailability determinations of 66 +/- 8% (mean +/- SEM) and 109 +/- 5% for Theo-Dur Sprinkle and Slo-bid, respectively. The less complete absorption of Theo-Dur Sprinkle during clinical use in preschool-age children is consistent with the malabsorptive effects of food previously reported for the former but not the latter formulation.

Relationship between rate and extent of absorption of oral theophylline from Uniphyl brand of slow-release theophylline and resulting serum concentrations during multiple dosing.

The relationship between a standardized assessment of rate and extent of absorption of slow-release theophylline and serum concentrations during multiple dosing was examined in eight healthy adult volunteers. Each subject received single doses of a reference theophylline solution in addition to single and multiple doses of Uniphyl, a "once-a-day" theophylline formulation, administered after an overnight fast and after a large breakfast. Extent of absorption was similar during single and multiple dosing but was significantly greater when dose was taken after breakfast; 68 +/- 7% (mean +/- SEM) and 61 +/- 4% of administered doses were absorbed during single and multiple dosing, respectively, when breakfast was withheld, whereas 83 +/- 4% and 86 +/- 4% of administered doses were absorbed when single and multiple doses, respectively, followed breakfast. Observed mean serum concentrations during multiple dosing approximated values predicted from the single-dose study; mean peak serum concentrations averaged more than twice the tough for both predicted and observed values after both fasting and postprandial administration. These data demonstrate incomplete absorption of theophylline from Uniphyl with greater extent of absorption when Uniphyl is taken after food. The study also provides further documentation that characterization of rate and extent of absorption from single doses permit prediction of the mean serum concentration-time profile during multiple dosing at defined rates of theophylline elimination. This provides the potential to anticipate fluctuations in serum concentrations at clinically relevant elimination rates that deviate from the mean of samples typically used for study.

Use of bronchial provocation with histamine to compare the pharmacodynamics of inhaled albuterol and metaproterenol in patients with asthma.

Because measurement of effects on airway responsiveness may have advantages over the study of bronchodilatation for the evaluation of the effects of inhaled beta 2-agents, we developed a method using airway responsiveness for the independent quantitation of the relative potencies and rates of decline in effect of these drugs. This methodology was applied to the evaluation and comparison of inhaled metaproterenol and albuterol. The effects of two different doses of each drug (one and two inhalations of albuterol and two and four inhalations of metaproterenol from commercially available metered-dose inhalers) were compared with a double-blind, randomized, placebo-controlled, crossover study of 13 subjects. The effects of metaproterenol and albuterol declined at rates that were not significantly different. However, based on the effects on activity ratio at 30 minutes, each puff of metaproterenol was an estimated 0.37 times as potent as each puff of albuterol (95% confidence limits, 0.22 to 0.52). In recommended two puff doses, measurable effects of albuterol persisted longer than effects of metaproterenol. However, this appears to be because of a greater initial effectiveness of two puffs of albuterol rather than differences in the rates at which the effects of the two drugs declined with time. Airway responsiveness thus appears to be a useful tool for evaluating inhaled beta 2-agonists and designing beta 2-agonist dosing regimens.

Comparison of the intensity and duration of effects of inhaled bitolterol and albuterol on airway caliber and airway responsiveness to histamine.

Inhaled beta-agonists can produce bronchodilatation and reduce airway hyperreactivity in patients with asthma. Using these two measures, we compared inhaled bitolterol (three puffs, 1110 micrograms), albuterol (two puffs, 180 micrograms), and placebo administered by metered-dose inhaler in a blinded, crossover study of 40 subjects with chronic asthma. On each study day, subjects underwent histamine challenges at 1 1/2 hours before, and 1/2, 2, 4, 6, and 8 hours after inhaling one of the three test-drug treatments. Both drugs produced significant bronchodilatation at 30 minutes through 4 hours and significant effects on airway reactivity at 30 minutes through 2 hours (p less than 0.05). Bitolterol also produced small but significant bronchodilator effects at 6 hours and effects on airway reactivity at 4 hours (p less than 0.05). Effects of bitolterol on airway reactivity diminished significantly more slowly than effects of albuterol in subjects with baseline provocative concentration causing a 20% fall in FEV1 greater than or equal to 1.0 mg/ml of histamine (half-life of biologic effect 1.37 versus 0.92 hours; p less than 0.05) but not in subjects with baseline provocative concentration causing a 20% fall in FEV1 less than or equal to 1.0 mg/ml (half-life of biologic effect of 1.01 versus 1.00 hours; p greater than 0.05).

Evaluation of passively absorbed saliva for determination of oral slow-release theophylline bioavailability in children.

Assessment in young children of the bioavailability of slow-release theophylline formulations is hampered by the requirement for frequent blood sampling. Calculations of bioavailability from serial serum and passively absorbed saliva samples were therefore compared in six 9- to 12-year-old asthmatic children receiving multiple doses of Theo-Dur Sprinkle every 12 hours, using Theo-Dur tablets, a previously characterized formulation, as a reference. Results indicated 85 +/- 5 percent and 82 +/- 8 percent (mean +/- SEM) relative bioavailability based on serum and salivary measurements, respectively. Correlation coefficient for serum and passively absorbed saliva bioavailabilities was 0.90. Passively absorbed saliva provides an acceptably accurate, noninvasive method for theophylline bioavailability assessment and may be a useful alternative for bioavailability studies in young children.

Early intervention with short courses of prednisone to prevent progression of asthma in ambulatory patients incompletely responsive to bronchodilators.

The effect of high orally administered doses of prednisone for 1 week early in the course of an acute exacerbation of asthma incompletely responsive to bronchodilators was examined in 41 patients randomly assigned to receive either prednisone or an identical appearing placebo. All 22 of the patients who received prednisone improved during the week of treatment, although one had a subsequent exacerbation 5 days after discontinuing the study medication. Of the 19 who received placebo, eight required rescue intervention (P = less than 0.004) in association with continued symptoms, increased frequency of metered-dose inhaler use, and decreased pulmonary function; the other 11 improved at about the same rate as those who received prednisone. Although the mean initial FEV1 was suggestively lower among those who did not improve and required intervention, there was considerable overlap with those who improved spontaneously, and no reliable distinguishing characteristics were found at entry into the study that could serve as predictors of those who would or would not improve spontaneously. There were no clinically important adverse effects from the prednisone. Because continued symptoms of asthma often result in emergency care or hospitalization, these data support early intervention with orally administered prednisone for acute exacerbations that do not respond fully to bronchodilators, at least in those patients with a prior history of a protracted course or emergency care.