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Biomedical subjects

G Milavetz

Publications and source records attributed to G Milavetz.

At least 19 recordsLinked to original sources
PubMed2000

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.

Adolescent↗
PubMed1997

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.

Adolescent↗
PubMed1995

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.

Administration, Inhalation↗
PubMed1990

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).

Administration, Inhalation↗
PubMed1990

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.

Asthma↗
PubMed1989

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.

Costs and Cost Analysis↗
PubMed1988

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.

Administration, Oral↗
PubMed1988

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.

Biological Availability↗
PubMed1987

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.

Adolescent↗
PubMed1987

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.

Administration, Oral↗
PubMed1987

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.

Adolescent↗
PubMed1987

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.

Adult↗
PubMed1987

Gastrointestinal side effects with erythromycin preparations.

This study was designed to determine the incidence and severity of gastrointestinal (GI) side effects in patients taking erythromycin. More patients complained of GI side effects with the enteric-coated tablet (70.8 percent) than with the stearate (51.4 percent) or the ethylsuccinate (48.9 percent) salts. The enteric-coated tablet was associated with a higher incidence of individual adverse reactions; more patients discontinued it because of adverse GI effects. These data demonstrate a high incidence of GI side effects to erythromycin. Additionally, GI side-effect incidence appears to be higher with the enteric-coated tablet.

Adolescent↗
PubMed1987

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.

Administration, Oral↗
PubMed1986

Multicentre evaluation of disposable visual measuring device to assay theophylline from capillary blood sample.

A device using enzyme immunochromatography to indicate visually theophylline concentration in a small capillary blood sample was evaluated for precision and accuracy at four hospitals. Preliminary studies indicated sensitivity as low as 2.5 micrograms/ml, and accuracy and precision matched those in test samples ranging from 5 to 30 micrograms/ml. Absence of theophylline was also reliably detected. Paired samples of capillary and venous blood from 214 patients were used to compare this method with four standard laboratory assays. Correlations with the standard assays were 0.93-0.97, slopes 1.00-1.27, and y intercepts -1.91-0.46. The within-run coefficients of variation on twenty replicate patient sample analyses at the four hospitals were 5.1-9.7% and between-run coefficients of variation on a 15.9 microgram/ml control 5.7-9.4%. This disposable device for theophylline monitoring, which can be done within 15 min at the patient's side without instruments, is sufficiently accurate to replace laboratory analysis for routine therapeutic drug monitoring.

Analysis of Variance↗
PubMed1986

Evaluation of a scheme for establishing and maintaining dosage of theophylline in ambulatory patients with chronic asthma.

To assess the utility of a dose-titration scheme for determining maintenance theophylline requirements, dose requirements and stability of serum concentrations were examined using 3537 serum determinations from 1073 patients with chronic asthma during a 5-year period. When the dosing scheme was followed, 78% of initial serum concentrations were within the target range of 10 to 20 micrograms/ml; the mean number of measurements to attain this range was 1.3. Among 404 of these patients prospectively questioned, adverse effects were not present in all 41 whose initial serum concentration was less than 10 micrograms/ml, occurred in eight of 296 patients when serum concentrations were between 10 and 20 micrograms/ml, and were present in 21 of 67 when concentrations were greater than 20 micrograms/ml. After final dose adjustment, mean dose requirements among those who attained serum concentrations of 10 to 20 micrograms/ml averaged 22 mg/kg/day in 1- to 9-year-old children, 20 mg/kg/day in 9- to 12-year-old children, 18 mg/kg/day in 12- to 16 year-old children, and 13 mg/kg/day in the 94 patients older than 16 years of age. Repeat serum concentrations after 3 months to 2 years showed 66% remaining within the 10 to 20 micrograms/ml range and another 15% between 7.5 and 10 micrograms/ml; 9% were greater than 20 micrograms/ml, and none greater than 30 micrograms/ml. Thus the dosing scheme produces serum concentrations in the usual therapeutic range with a minimum of samples and few side effects; most patients maintained acceptably stable blood levels.

Adolescent↗
PubMed1986

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.

Humans↗