Nedocromil in the outpatient management of asthma.

OBJECTIVE: To more closely approximate the use of a nonsteroidal inhaled anti-inflammatory medication for asthma, nedocromil sodium, under actual ambulatory practice conditions. DESIGN: Large, open-label trial. PATIENTS: One thousand two hundred one patients from 286 primary care and specialty centers. INTERVENTION: Four weeks of treatment with nedocromil sodium (4 mg delivered from the valve and 3.5 mg delivered from the mouthpiece of a metered inhalor [2 puffs, four times daily]). MAIN OUTCOME MEASURES: Asthma symptom scores, peak expiratory flow rate, a lifestyle assessment measures questionnaire, and mean number of days missed per month from work or school. RESULTS: Statistically significant improvements were seen after 1 and 4 weeks of treatment for cough, daytime and nighttime asthma, morning tightness, peak expiratory flow rate, and all four measured lifestyle assessment factors (P < .001). An additional clinically relevant outcome measure, mean number of days missed per month from work or school, was reduced by 75% (P < .001). No serious adverse reactions were reported. CONCLUSION: This study reproduces the high level of efficacy and safety of nedocromil that was previously reported in placebo-controlled clinical studies.

Oral clonidine in patients with asthma: no significant effect on airway reactivity.

Fifteen patients with asthma were randomized into a double-blind, placebo controlled, crossover trial evaluating whether clonidine increased airway resistance. After meeting entry criteria [demonstration of 20% improvement in any two of the following pulmonary function tests after bronchodilator therapy: FVC, FEV1, or forced expiratory flow over the mid-50% of the vital capacity(FEF(25-75)], patients were evaluated on two subsequent visits, receiving sequential doses of clonidine 0.1 mg (maximum cumulative dose 0.3 mg) or placebo in a random fashion. They returned to clinic after a 36-48 hour washout period at which time they received the opposite treatment. The end points were three doses of clonidine or placebo, decrease in blood pressure to < or = 90 mm mercury systolic, and/or < 70 mm mercury diastolic, or a 20% fall in FEV1. Airway reactivity was proved utilizing methacholine on each clinic visit, and blood pressures were monitored continuously during the study period. There were no significant differences in the provocative concentrations of methacholine inducing a 20% fall in FEV1 (PD20) between baseline (1.92), clonidine (1.10), and placebo (1.69). (Numbers in parentheses indicate PD20 values in cumulative dose units).

Description of a delivery method for continuously aerosolized albuterol in status asthmaticus.

The use of continuously nebulized beta agonists may be considered in the treatment of status asthmaticus, particularly when conventional therapy is failing. Methods of administration of continuously nebulized beta agonists may be cumbersome. We describe a delivery method which allowed simplification of this process, yielded accurate delivery of a specified dose of albuterol, and was beneficial in a reported case of status asthmaticus.

Pharmacokinetic comparison of 5 g of azlocillin every 8 h and 4 g every 6 h in healthy volunteers.

To compare the multiple-dose pharmacokinetics of two dosage regimens of azlocillin, we studied 12 healthy volunteers via a randomized, crossover design with a 2-week washout phase between regimens. Serum and urine samples were collected for 8 h following the fifth dose of a regimen of 4 g every 6 h and the fourth dose of a regimen of 5 g every 8 h. Data for concentrations in serum were fitted to a two-compartment open model by nonlinear regression. Statistically significant differences (P less than 0.05) were observed in the following parameters (mean +/- standard deviation) for the 4- and 5-g regimens, respectively: area under the serum concentration-time curve during the dosing interval, 592 +/- 140 versus 772 +/- 151 micrograms.h/ml; terminal elimination rate constant, 0.5364 +/- 0.0912 versus 0.4758 +/- 0.0486 h-1; renal clearance, 87.6 +/- 16.1 versus 76.1 +/- 13.5 ml/min; maximum drug concentration in serum, 381 +/- 89 versus 473 +/- 90 micrograms/ml; and minimum drug concentration in serum, 19 +/- 10 versus 8 +/- 4 micrograms/ml. No significant differences were seen in the following parameters: V1, V beta, k10, k12, k21, total systemic clearance, and nonrenal clearance. These data support the presence of saturable renal elimination of azlocillin, as well as the feasibility of an 8-h dosing interval.

Aerosolized metaproterenol in the treatment of asthmatics with severe airflow obstruction. Comparison of two delivery methods.

The bronchodilator response to metaproterenol delivered by metered-dose inhaler (MDI) with a spacer device (Aerochamber [A]) and by jet nebulizer was studied in 44 asthmatic patients who presented to the emergency department with acute severe (FEV1 less than 50 percent predicted) airflow obstruction. The delivery method was randomized, double-blinded and placebo controlled. The A group received one puff of metaproterenol every five minutes for a total of three puffs (1.95 mg). The jet nebulizer group received 15 mg of metaproterenol by continuous nebulization over ten minutes. Only about 2.75 mg of the original 15 mg delivered by jet nebulizer was calculated to be available for inhalation due to the inefficiencies of the delivery system. The mean percentage of improvement in FVC and FEV1 in the A group was 33.5 and 49.0 percent, respectively. The mean percentage of improvement in FVC and FEV1 in the jet nebulizer group was 22.8 and 33.0 percent, respectively. There was no significant difference in the mean percentage of improvement values between the two groups. We were unable to demonstrate a difference in bronchodilator response to metaproterenol delivered by MDI-A and jet nebulizer in emergency department asthmatics with acute severe airflow obstruction.

Theophylline and diaphragmatic contractility. Investigation of a dose-response relationship.

Our study evaluated whether a dose-response relationship exists for theophylline and diaphragmatic contractility within the usual therapeutic range for theophylline. The study, involving 16 patients with mild to moderate chronic obstructive pulmonary disease, was done in a randomized, placebo-controlled, double-blind, crossover fashion. We found no statistically significant effect of theophylline on diaphragmatic contractility at mean theophylline concentrations of 5.13, 12.07, and 18.6 micrograms/ml.

Oropharyngeal candidiasis in patients treated with beclomethasone dipropionate delivered by metered-dose inhaler alone and with Aerochamber.

We compared the incidence of Candida infection, Candida colonization, and reduction in oral prednisone dose in patients with asthma treated with beclomethasone dipropionate delivered by metered-dose inhaler (MDI) alone and MDI plus Aerochamber. Group M contained 18 patients treated with beclomethasone, four actuations four times a day (672 micrograms/day), delivered by MDI alone. Group A contained 18 patients treated with the same dose of beclomethasone delivered by MDI plus Aerochamber. In group M, four of 18 patients had Candida infection, 12 of 18 patients had Candida colonization, and six of 18 patients were completely removed from oral prednisone. In group A, 0 of 18 patients had Candida infection (p = 0.05), six of 18 patients had Candida colonization (p less than 0.05), and 12 of 18 patients were completely removed from oral prednisone (p less than 0.05). We conclude that beclomethasone delivered by MDI plus Aerochamber is more efficacious in reducing oral prednisone dependency and produces less Candida infection and colonization than beclomethasone delivered by MDI alone.

A comparison of two delivery methods for aerosolized metaproterenol sulfate.

The bronchodilator response to metaproterenol sulfate delivered by metered-dose inhaler (MDI) with a spacer device (Aerochamber) and by jet nebulizer was studied in 15 asthmatic patients. The mean percent increase in absolute forced expiratory volume in 1 second (FEV1) with an MDI plus Aerochamber was 28.6%, and 28.8% with jet nebulization. There were no significant differences in the mean percent increases in FEV1, forced vital capacity (FVC), maximum midflow rate (MMFR), and peak expiratory flow rate (PEFR) with the two delivery methods. It is concluded that there is no difference in the bronchodilator responses to metaproterenol sulfate delivered by MDI plus Aerochamber or by jet nebulizer. The MDI plus Aerochamber has the advantage of being less expensive and more convenient to use.

Dose-dependent disposition of oral propranolol in normal subjects.

The pharmacokinetics and relative systemic availability or oral propranolol were studied in three healthy volunteers following administration of 10, 40, and 80 mg of propranolol hydrochloride. Plasma concentrations of propranolol were determined using a sensitive and specific fluorometric high pressure liquid chromatographic technique. In the dosage range studied, the amount of propranolol reaching the systemic circulation increased with dose, while half-lives remained unchanged. The apparent 'threshold dose' for propranolol was much smaller than previously reported, and its contribution to the observed dose-dependent availability is doubtful. Apparent intrinsic clearance values were shown to decrease with increase in dose, with a true maximal intrinsic clearance of 5.4 l kg-1 h-1. These data suggest the saturation of a low capacity enzyme system in the liver and are consistent with theoretical characteristics of a drug that is extensively metabolized during its first pass through the liver.

Analysis and disposition of low dose oral propranolol.

A sensitive and specific fluorometric high pressure liquid chromatography technique was used to measure propranolol concentrations in the plasma of three healthy volunteers following an oral 10 mg dose of propranolol hydrochloride. Peak propranolol concentrations were 6 to 8 ng/ml and half-lives ranged fro 2.5 to 5.6 hours. The threshold concept for hepatic uptake or oral propranolol is less marked than previously reported.

System for clinical pharmacokinetic monitoring of theophylline therapy.

A system was developed for guiding theophylline therapy in acutely ill patients with respiratory disease and for recovery of pharmacokinetic information. A dosage regimen nomogram was designed based on literature data and preliminary pharmacokinetic studies in patients. Using the nomogram, physicians select the loading and infusion dosages based on previous therapy, body weight, age, and cardiac and hepatic status of the patient. Specifications are provided for loading (up to 5.6 mg/kg) and maintenance doses (0.9, 0.68, or 0.45 mg/kg/hr) of aminophylline, handling of i.v. dosage forms, and collection of three initial blood samples. Serum samples were assayed for theophylline by high-performance liquid chromatography for rapid feedback of data to the physician and computer estimation of body clearance values. The usefulness of the nomogram guidelines was examined prospectively in 72 patients. Near-steady-state serum concentrations in the therapeutic range of 8-20 mg/liter were found in 72% of the patients. Only two patients were outside of the range of 5-25 mg/liter. The relationship between the physician's estimate of the patient's clinical status (three classes) and measured body clearance was highly significant (p less than 0.025). A comprehensive data collection format allows further analysis of the factors responsible for the variability in theophylline disposition in patients undergoing therapy.