Metaproterenol Research Articles

437 Bronchodilator effects of inhaled metaproterenol sulfate solution (MSS) in preschool asthmatic children

437 Bronchodilator effects of inhaled metaproterenol sulfate solution (MSS) in preschool asthmatic children

A comparison of atropine sulfate and metaproterenol sulfate in the emergency treatment of asthma: Karpel JP, Appel D, Breidbart D, et al. Am Rev Respir Dis 133:727, 1986

A comparison of atropine sulfate and metaproterenol sulfate in the emergency treatment of asthma: Karpel JP, Appel D, Breidbart D, et al. Am Rev Respir Dis 133:727, 1986

Evaluation of a metered-dose aerosol delivery system using partial flow-volume curves.

In 12 normal subjects, FEV1, FVC, peak expiratory flow rate, and flow at 25% of FVC on maximal (MEFV) and partial (PEFV) expiratory flow volume maneuvers were measured before and after inhalation of 2.6 mg of metaproterenol from a metered-dose inhaler (MDI) or from an MDI-holding chamber (MDI-HC) delivery system. The 2 delivery systems were studied on separate days using a randomized crossover design. Premetaproterenol pulmonary function results were very similar on both days. However, on the MDI-HC day, significantly greater bronchodilatation was observed; this was only detectable on PEFV maneuvers. Compared with those on the MDI day, postmetaproterenol PEFV rates on the MDI-HC day were approximately 11% higher (p less than 0.02); premetaproterenol to postmetaproterenol increments in PEFV rates were also larger on the MDI-HC day (p less than 0.05). These results can be explained by the phenomenon of airway hysteresis. The deep breath taken prior to performance of the FVC maneuver reduced bronchomotor tone in almost all subjects, thereby limiting the magnitude of possible change from inhaled bronchodilator. Partial flow-volume curves were not preceded by deep inspiration and were more sensitive in detecting bronchodilatation.

Bronchodilator effects of oral metaproterenol sulfate in preschool children with asthma

Chez les enfants d'âge prescolaire asthmatiques, le sulfate de metaproterenol provoque une augmentation de 20 a 25% de la conductance respiratoire totale moyenne a tous les dosages. Cette action vasodilatatrice dure au moins 3 heures

Relative Bioavailability of Metaproterenol in Humans Utilizing a Single Dose, Stable Isotope Approach

The relative bioavailability of metaproterenol (3, 5-dihy-droxy-α-[(isopropylamino)methyl]benzyl alcohol) following a single dose (10-mg metaproterenol sulfate tablet) was studied in six normal male volunteers using coadministration of a solution of a deuterated analogue (metaproterenol-d7 sulfate). The bioavailability of the tablet formulation relative to that of the oral solution was 92 ± 9%, with excellent power at the 5% significance level. Comparison of the coadministration of the labeled and unlabeled metaproterenol sulfate solutions in two subjects after a one-week washout demonstrated the absence of an isotope effect on either absorption or elimination. A GC-MS assay for metaproterenol was developed to measure plasma concentrations resulting from oral administration. The assay was linear over the range of 0.5–8ng/mL, corresponding to typical plasma metaproterenol concentrations obtained after a single 10-mg oral dose. Accuracy and precision data were obtained at metaproterenol concentrations of 1.0 and 2.0ng/mL plasma to demonstrate the applicability of the assay for bioavailability studies. Following oral administration, metaproterenol showed peak plasma concentrations of 2.2 to 13ng/mL at 0.75 to 3.0 h, with a terminal harmonic mean half-life of 2.1h over the plasma concentration range studied. The renal clearance of 133–158mL/min for metaproterenol slightly exceeds the glomerular filtration rate in humans.

Albuterol Protects Against Exercise-Induced Asthma Longer Than Metaproterenol Sulfate

Both metaproterenol sulfate and albuterol are inhaled medications commonly used to prevent exercise-induced bronchospasm. Their efficacy and duration of action in controlling exercise-induced bronchospasm were compared with placebo in 18 asthmatic children (age range: 12 to 17 years) in a single-blind randomized crossover study. Standardized treadmill exercise challenges were repeated every two hours for up to six hours following the initial exercise test. With the initial exercise challenge, both active medications blocked exercise-induced bronchospasm with equal efficacy. On the other hand, when the duration of action of the medications was compared: albuterol blocked exercise-induced bronchospasm longer than metaproterenol sulfate in eight subjects, the reverse was true in only one patient, and the medications blocked for equal duration in nine subjects. Thus, although both active agents were equally efficacious in blocking exercise-induced bronchospasm initially, the duration of action of albuterol was significantly (P less than .05) longer on serial testing than that of metaproterenol sulfate. Both medications were significantly better than placebo in efficacy and duration of action.

Comparison of the Acute Cardiopulmonary Effects of Oral Albuterol, Metaproterenol, and Terbutaline in Asthmatics

The acute cardiopulmonary effects of oral albuterol, 4 mg, metaproterenol sulfate, 20 mg, and terbutaline sulfate, 5 mg, were compared over eight hours in 20 moderate to severe asthmatics. The magnitude and time course of bronchodilation following albuterol and terbutaline were comparable. Albuterol and terbutaline had a duration of action of at least eight hours and produced significantly greater bronchodilation than metaproterenol from six to eight hours. Metaproterenol produced a greater degree of bronchodilation than albuterol and terbutaline 30 minutes after drug dosing. Significantly fewer patients receiving albuterol experienced one or more central nervous system or musculoskeletal side effects than patients receiving terbutaline. These findings imply possible therapeutic advantages of oral albuterol and terbutaline with respect to dosing frequency, while the more rapid onset of oral metaproterenol suggests that it may have an advantage when used on an as-needed basis.

1773 EVALUATION OF A HIGH FREQUENCY JET NEBULIZER

A new “jet nebulizer” (JN) system adapted from high frequency jet ventilation was evaluated as a delivery system for bronchodilators. Pulmonary function tests were compared in 15 patients with stable chronic asthma at zero, 15, 30, 60, 120 and 180 minutes after receiving 0.2 ml of metaproterenol sulfate in 2.8 ml of saline by JN and conventional nebulization (CN). One patient developed severe bronchospasm following JN and could not complete the study. In the remaining 14 patients there was no significant difference between CN and JN for the percentage improvement in FVC, FEV1, Peak Flow Rates, and FEF25-75 at any of the time points. Significantly more metaproterenol was delivered by CN (Mean 2.1 ± 0.3 (SD) gm of solution versus 1.9 ± 0.5 (SD) gm by JN). This may have been due to greater loss of aerosolized medication with CN. Several patients reported that the JN treatment led to increased sputum clearance, although this finding was not objectively quantified. Thus, JN does not appear to offer an advantage over CN in the treatment of patients with asthma, although the similar improvement with less medication delivery may reflect improved aerosol deposition. Further research with JN is indicated; first to clarify whether there is improved aerosol particle deposition and secondly, in light of the subjective findings, to investigate whether use of JN in patients with chronic sputum production is advantageous.

Response to Inhaled ß-Agonist in a Patient Receiving ß-Adrenergic Blockers

A 52-year-old man receiving long-term hemodialysis and a beta-adrenergic blocker for hypertension had symptoms of acute bronchospasm when exposed to a new hemodialyzer. Resistant to two doses of subcutaneous epinephrine (1 mL of 1:1000 dilution) and one intravenous dose of aminophylline (250 mg), the bronchospasm was rapidly relieved by metaproterenol sulfate given by inhalation one hour later.

Intravenous aminophylline in the treatment of acute bronchospastic exacerbations of chronic obstructive pulmonary disease

Often chronic obstructive pulmonary disease (COPD) patients treated for acute exacerbations receive intravenous (IV) aminophylline in addition to inhaled bronchodilators that may raise serum levels of theophylline into the toxic range. A double-blind, randomized study of 52 men with COPD who came to the emergency department for treatment of exacerbations was initiated to establish the efficacy and safety of this common practice. After history and physical examination, patients were treated with 28% oxygen by Venturi mask and 0.3 cc metaproterenol sulfate in 2.5 cc saline by nebulizer; an IV line was started and patients received either aminophylline or D5W. Measurements included baseline and two-hour serum theophylline levels, pulmonary function tests, and symptom questionnaires. Mean values from the entire group showed decreases in respiratory rate, cardiac rate, and pulsus paradoxus, and increases in forced expiratory volume in one second (FEV1) and vital capacity (VC) over a two-hour treatment period (P less than .01). Despite the increase in serum theophylline in the treatment group, the demographic, clinical, pulmonary function, and outcome data were found to have no statistically significant differences when compared to control patients. The data were then analyzed according to serum theophylline levels. Theophylline level greater than 20 micrograms/mL occurred in 15 patients with no untoward effects; premature ventricular contractions (PVCs) were no more frequent in this group than in those with lower serum theophylline levels. A theophylline level greater than 10 micrograms/mL after two hours of treatment resulted in the following differences, which were not statistically significant: mean FEV1 response less than or equal to 10 micrograms/mL vs greater than 10 micrograms/mL, 20% vs 28%; mean VC change, 17% vs 30%; or mean emergency department returns in one week, 0.1 vs 0.26. In our experience, oxygen and inhaled metaproterenol are effective treatment for exacerbations of COPD.

Effect of bronchodilator therapy administered by canister versus jet nebulizer

Bronchodilator efficacy of metaproterenol sulfate aerosol therapy delivered either by canister or jet nebulizer was compared in 25 patients, 13 with severe asthma and 12 with COPD. Treatment was carried out in double-blind crossover fashion on 2 days and consisted of either metaproterenol sulfate solution 15 mg in 2.3 ml administered from a jet nebulizer or three puffs of metered-dose metaproterenol sulfate (total 1.95 mg) inhaled sequentially. FVC and FEV 1 were monitored before and after therapy for 2 hr. In 13 asthmatic patients. FEV 1 increased from a baseline mean of 0.83 L to 1.57 L at 2 hr after jet nebulizer therapy and increased from 0.84 L to 1.52 L after canister therapy. In 12 patients with COPD, FEV 1 increased from 0.58 L to 0.78 L after jet nebulizer therapy and from 0.57 L to 0.76 L after canister therapy. FVC also increased similarly after each form of therapy. The two types of aerosol therapy were equally effective and were without side effects. Canister therapy has the advantage over jet nebulizer therapy by being convenient and cheaper.

Effect of aminophylline when added to metaproterenol sulfate and beclomethasone dipropionate aerosol

Twenty-one patients with frequently recurrent severe asthma were treated for 2 wk with placebo capsules and metaproterenol sulfate aerosol therapy followed by beclomethasone dipropionate aerosol therapy sequentially inhaled every 4 to 6 hr and for 2 wk with the same aerosols and aminophylline therapy added. Treatment was double-blind, and the therapy regimens were administered in a random sequence. Patients measured their PEFR at home before and after aerosol inhalation three times a day. The mean PEFRs before inhalation of aerosol were significantly higher when patients were receiving aminophylline therapy. In 86% of the patients, the mean PEFR that was measured after inhalation of metaproterenol sulfate was 11% greater when they were also receiving aminophylline therapy, but this difference was not significant. In 14% of the patients, however, postaerosol inhalation PEFRs were significantly higher (50% to 80%) after aminophylline therapy was added to aerosol therapy. PEFRs were always lowest in the early morning, regardless of the therapy administered. Therapy regimens that contained aminophylline were associated with less dyspnea but produced more adverse side effects and were more costly. Thus in most patients the favorable effect that aminophylline therapy produced by raising baseline PEFRs and attenuating dyspnea should be balanced against the adverse effects this medication also produced, since in most patients aminophylline therapy did not significantly enhance postinhalation PEFRs.

Quantitative gastroesophageal reflux and pulmonary function in asthmatic children and normal adults receiving placebo, theophylline, and metaproterenol sulfate therapy

There is evidence that theophylline therapy inhibits lower esophageal sphincter pressure and enhances gastroesophageal reflux in normal adults and adult asthmatics. No studies have used intraesophageal pH monitoring to assess the effect of bronchodilators over prolonged periods. With the use of the latter procedure, we studied 10 randomly selected chronic asthmatic children (mean age 10.6 yr) and 10 normal adult subjects; all subjects were without clinical symptoms of GER. In this single-blind study, all subjects were evaluated for GER during three separate 24-hr periods while they were receiving oral doses of placebo, theophylline, and metaproterenol sulfate therapy. No significant increase of GER was found in asthmatic subjects or normal subjects on either drug. No adverse correlation of GER and pulmonary function was noted in either group. Asthmatic subjects and normal subjects had asymptomatic or "silent" physiologic GER during sleep and in the 2-hr postprandial period. This study confirms that in chronic asthmatic children standard oral bronchodilator therapy does not adversely affect "silent" GER or pulmonary functions.

Simple Colorimetric Method for Determination of Metaproterenol Sulfate in Pharmaceuticals

A simple colorimetric method is described for the determination of metaproterenol sulfate (orciprenaline sulfate). The method is based on measurement of a colored species formed when metaproterenol sulfate is treated with diazotized dapsone, p-nitroaniline, or benzocaine at room temperature, followed by treatment with an aqueous solution of trimethylamine in the case of benzocaine. Compounds such as starch, talc, and common excipients do not interfere in the reaction. Statistical validation showed that the method was precise and accurate. The results agree well with those obtained by other methods reported in the literature.

Response to bronchodilator drug administration by a new reservoir aerosol delivery system and a review of other auxiliary delivery systems.

Response to bronchodilator aerosols delivered by metered dose inhalers (MDI) depends in part upon the amount of drug depositing on the airways. Ideally, the MDI should be actuated during a slow deep inhalation followed by a breathholding pause, an impossible maneuver for many patients. We developed a new reservoir aerosol delivery system (RADS) consisting of a 700-ml collapsible bag in which aerosol could be injected. The mouthpiece-canister was filtered with a reed that vibrated at inspiratory flows greater than 0.3 L/s to produce a noise. Patients were instructed to keep inhalation silent while breathing from RADS. One puff of metaproterenol (650 microgram) administered via RADS (with one breath rebreathed) was compared with one puff of metaproterenol (650 micrograms) from usual MDI using serial measurements of body plethysmography and spirometry. Respiratory inductive plethysmography measured the point of MDI actuation, volume of inhalation, inspiratory flow, and breathholding pause. Ten patients with chronic airflow limitation caused by asthma or chronic bronchitis were given typed instructions on MDI usage and trained shortly before the study. Metaproterenol via RADS produced significantly greater maximal increase in SGaw (195 +/- 52% SE) compared with metaproterenol via conventional MDI (101 +/- 24%, p less than 0.003). Bronchodilator response in 4 patients unable to coordinate actuation of the MDI with inspiration was significantly less than in 6 patients with good MDI technique (p less than 0.005). The mean flow rates were 0.54 +/- 0.16 L/s during inhalation of metaproterenol compared with 0.19 +/- 0.02 L/s and 0.24 +/- 0.03 L/s during the first and second inhalations, respectively, using RADS. This reservoir aerosol delivery system, which was well accepted by the patients, promotes more effective bronchodilation than the conventional metered dose inhaler.

Relationship between sites of airflow limitation and severity of chronic airflow obstruction.

We studied the relationship between sites of airflow limitation and severity of chronic obstructive pulmonary disease. Pre- and postbronchodilator physiologic testing was performed in 30 subjects with chronic airflow obstruction (CAO). Pulmonary function, including the increase in maximal expiratory flow at 50% of vital capacity after helium-oxygen breathing (delta VEmax50), was reduced before and after inhalation of 1.3 mu mg of metaproterenol. Significant correlations were present between values for delta VEmax50 and measurements of expiratory flow (p < 0.001). In subjects with severe CAO (one-second forced expiratory volume less than or equal to 1.2 L; percentage ratio of one-second forced expiratory volume to forced vital capacity < 50%), delta VEmax50 was always abnormally decreased. An inverse relationship was present between initial delta VEmax50 and changes in delta VEmax50 after inhalation of metaproterenol (p < 0.001). These results suggest that the site of airflow limitation becomes progressively more peripheral as CAO worsens, and that severe CAO is usually associated with peripheral sites of airflow limitation.

Double-Blind Comparison of Metaproterenol and Isoetharine-Phenylephrine Solutions in Intermittent Positive Pressure Breathing in Bronchospastic Conditions

A 5 percent solution of metaproterenol sulfate (Alupent) and a fixed-combination solution of isoetharine and phenylephrine were compared in a single-dose double-blind study in a total of 27 patients with reversible bronchospastic disease. The patients were assigned to parallel groups for treatment and received the usual dose of 0.3 ml of metaproterenol and 0.5 ml of the isoetharine-phenylephrine solution via equipment for intermittent positive-pressure breathing. Tests of pulmonary function, blood pressure, and pulse rate were performed before the treatment and at intervals of 30 minutes to six hours after administration. The duration of effect (defined as an increase over baseline in the forced expiratory volume in one second [FEV1] of at least 15 percent) of metaproterenol averaged four hours, as compared with one hour for the reference solution. The overall response of FEV1 to metaproterenol was significantly (P = 0.01) superior to the response to the isoetharine-phenylephrine solution. Metaproterenol also surpassed the reference drug in terms of increases in the mean forced expiratory flow during the middle half of the forced vital capacity (FEF-25-75%) to a degree approaching statistical significance. Changes in blood pressure and pulse rate were clinically insignificant with both drugs, and the total number of adverse experiences was substantially the same with both solutions.

Relationship between the site of airflow limitation and localization of the bronchodilator response in asthma.

In an effort to determine the relationship between the major sites of airflow limitation and bronchodilator action, physiologic studies were performed in 65 asthmatics before and after the administration of isoproterenol, metaproterenol, or terbutaline. Before the administration of a bronchodilator, the results of routine pulmonary function tests were abnormal; the mean increment in maximal expiratory flow at 50% of forced vital capacity (delta VEmax50) after breathing 80% helium-20% oxygen (He-O2) was reduced (p < 0.001). Prebronchodilator values of delta VEmax50 correlated linearly with VEmax50 breathing air (r = + 0.68, p < 0.001). These data suggested that airflow limitation becomes more peripheral as asthma becomes more severe. After the bronchodilator administration, the results of routine pulmonary function studies improved; delta VEmax50 either increased or decreased, depending upon the prebronchodilator values. Density-dependence tended to (1) increase in subjects with low prebronchodilator values of delta VEmax50, and (2) decrease in subjects with high prebronchodilator values of delta VEmax50. Hence, these results suggested that predominant sites of bronchodilatation in asthmatics are related to the prebronchodilator sites of airflow limitation.

Response to Inhaled Metaproterenol and Isoproterenol in Asthmatic and Normal Subjects

Pulmonary function tests were performed before and after inhalation of 1.3 mg of metaproterenol sulfate or 150 microgram of isoproterenol hydrochloride by 40 asthmatic and 40 normal subjects. PHysiologic measurements included spirometric testing, plethysmographic studies, and maximal expiratory flow-volume curves obtained after inhalation of air and a mixture of 80 percent helium and 20 percent oxygen. In the normal subjects, pulmonary function improved significantly after inhalation of both metaproterenol and isoproterenol. There was no significant difference in responsiveness to either bronchodilator drug. In the asthmatic subjects, pulmonary function also improved significantly after both bronchodilator agents. The sites of predominant bronchodilatation were similar in the asthmatic subjects after both metaproterenol and isoproterenol; however, bronchodilatation was better overall (P less than 0.005) and for most individual tests with metaproterenol. The greater efficacy of metaproterenol in asthmatic subjects but not in normal subjects can be explained by (1) different doses of the bronchodilator drug and (2) differing bronchodilator dose-response relationships in asthmatic and normal subjects.

Synergism of metaproterenol and theophylline

Synergism of metaproterenol and theophylline