Gary Milavetz

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.

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.

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.

Cannabis effects on driving lateral control with and without alcohol

BACKGROUND Effects of cannabis, the most commonly encountered non-alcohol drug in driving under the influence cases, are heavily debated. We aim to determine how blood Δ(9)-tetrahydrocannabinol (THC) concentrations relate to driving impairment, with and without alcohol. METHODS Current occasional (≥1×/last 3 months, ≤3days/week) cannabis smokers drank placebo or low-dose alcohol, and inhaled 500mg placebo, low (2.9%)-THC, or high (6.7%)-THC vaporized cannabis over 10min ad libitum in separate sessions (within-subject design, 6 conditions). Participants drove (National Advanced Driving Simulator, University of Iowa) simulated drives (∼0.8h duration). Blood, oral fluid (OF), and breath alcohol samples were collected before (0.17h, 0.42h) and after (1.4h, 2.3h) driving that occurred 0.5-1.3h after inhalation. We evaluated standard deviations of lateral position (lane weave, SDLP) and steering angle, lane departures/min, and maximum lateral acceleration. RESULTS In N=18 completers (13 men, ages 21-37years), cannabis and alcohol increased SDLP. Blood THC concentrations of 8.2 and 13.1μg/L during driving increased SDLP similar to 0.05 and 0.08g/210L breath alcohol concentrations, the most common legal alcohol limits. Cannabis-alcohol SDLP effects were additive rather than synergistic, with 5μg/L THC+0.05g/210L alcohol showing similar SDLP to 0.08g/210L alcohol alone. Only alcohol increased lateral acceleration and the less-sensitive lane departures/min parameters. OF effectively documented cannabis exposure, although with greater THC concentration variability than paired blood samples. CONCLUSIONS SDLP was a sensitive cannabis-related lateral control impairment measure. During drive blood THC ≥8.2μg/L increased SDLP similar to notably-impairing alcohol concentrations. Despite OFs screening value, OF variability poses challenges in concentration-based effects interpretation.

A bioassay for topical and systemic effect of three inhaled corticosteroids

Comparisons of relative potency for the three inhaled corticosteroids in the United States are limited to assessment of skin blanching.

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 patients side without instruments, is sufficiently accurate to replace laboratory analysis for routine therapeutic drug monitoring.

Controlled Cannabis Vaporizer Administration: Blood and Plasma Cannabinoids with and without Alcohol

BACKGROUND Increased medical and legal cannabis intake is accompanied by greater use of cannabis vaporization and more cases of driving under the influence of cannabis. Although simultaneous Δ(9)-tetrahydrocannabinol (THC) and alcohol use is frequent, potential pharmacokinetic interactions are poorly understood. Here we studied blood and plasma vaporized cannabinoid disposition, with and without simultaneous oral low-dose alcohol. METHODS Thirty-two adult cannabis smokers (≥1 time/3 months, ≤3 days/week) drank placebo or low-dose alcohol (target approximately 0.065% peak breath-alcohol concentration) 10 min before inhaling 500 mg placebo, low-dose (2.9%) THC, or high-dose (6.7%) THC vaporized cannabis (6 within-individual alcohol-cannabis combinations). Blood and plasma were obtained before and up to 8.3 h after ingestion. RESULTS Nineteen participants completed all sessions. Median (range) maximum blood concentrations (Cmax) for low and high THC doses (no alcohol) were 32.7 (11.4-66.2) and 42.2 (15.2-137) μg/L THC, respectively, and 2.8 (0-9.1) and 5.0 (0-14.2) μg/L 11-OH-THC. With alcohol, low and high dose Cmax values were 35.3 (13.0-71.4) and 67.5 (18.1-210) μg/L THC and 3.7 (1.4-6.0) and 6.0 (0-23.3) μg/L 11-OH-THC, significantly higher than without alcohol. With a THC detection cutoff of ≥1 μg/L, ≥16.7% of participants remained positive 8.3 h postdose, whereas ≤21.1% were positive by 2.3 h with a cutoff of ≥5 μg/L. CONCLUSIONS Vaporization is an effective THC delivery route. The significantly higher blood THC and 11-OH-THC Cmax values with alcohol possibly explain increased performance impairment observed from cannabis-alcohol combinations. Chosen driving-related THC cutoffs should be considered carefully to best reflect performance impairment windows. Our results will help facilitate forensic interpretation and inform the debate on drugged driving legislation.

Physician–Pharmacist Collaborative Management of Asthma in Primary Care

To determine if asthma control improves in patients who receive physician–pharmacist collaborative management (PPCM) during visits to primary care medical offices.

β‐Blocker Therapy in Veterans with Asthma or Chronic Obstructive Pulmonary Disease

Study Objectives. To determine whether an association exists between health care resource use and β‐blocker therapy in patients with asthma or chronic obstructive pulmonary disease (COPD), and to determine whether any significant differences exist between type of β‐blocker agent administered and resource use.

Effect of Blood Collection Time on Measured Δ9-Tetrahydrocannabinol Concentrations: Implications for Driving Interpretation and Drug Policy

BACKGROUND In driving-under-the-influence cases, blood typically is collected approximately 1.5-4 h after an incident, with unknown last intake time. This complicates blood Δ(9)-tetrahydrocannabinol (THC) interpretation, owing to rapidly decreasing concentrations immediately after inhalation. We evaluated how decreases in blood THC concentration before collection may affect interpretation of toxicological results. METHODS Adult cannabis smokers (≥1×/3 months, ≤3 days/week) drank placebo or low-dose alcohol (approximately 0.065% peak breath alcohol concentration) 10 min before inhaling 500 mg placebo, 2.9%, or 6.7% vaporized THC (within-individuals), then took simulated drives 0.5-1.3 h postdose. Blood THC concentrations were determined before and up to 8.3 h postdose (limit of quantification 1 μg/L). RESULTS In 18 participants, observed Cmax (at 0.17 h) for active (2.9 or 6.7% THC) cannabis were [median (range)] 38.2 μg/L (11.4-137) without alcohol and 47.9 μg/L (13.0-210) with alcohol. THC Cmax concentration decreased 73.5% (3.3%-89.5%) without alcohol and 75.1% (11.5%-85.4%) with alcohol in the first half-hour after active cannabis and 90.3% (76.1%-100%) and 91.3% (53.8%-97.0%), respectively, by 1.4 h postdose. When residual THC (from previous self-administration) was present, concentrations rapidly decreased to preinhalation baselines and fluctuated around them. During-drive THC concentrations previously associated with impairment (≥8.2 μg/L) decreased to median <5 μg/L by 3.3 h postdose and <2 μg/L by 4.8 h postdose; only 1 participant had THC ≥5 μg/L after 3.3 h. CONCLUSIONS Forensic blood THC concentrations may be lower than common per se cutoffs despite greatly exceeding them while driving. Concentrations during driving cannot be back-extrapolated because of unknown time after intake and interindividual variability in rates of decrease.