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[Ipratropium Bromide, an Anticholinergic Bronchodilator/Behavior of airways resistance in patients with reversible respiratory obstruction following inhalation of various doses of ipratropium bromide].

A dose- and time-response study using different doses of an inhaled derivative of atropine, (8r)-3alpha-hydroxy-8-isopropyl-1 aH, 5aH-tropaniumbromide-(+/-)-tropate (Sch 1000, ipratropium bromide, Atrovent) was performed in 12 patients with reversible chronic obstructuve airways disease. The drug was shown to be an effective bronchodilator with the typical action of reducing airways resistance with 2 puffs (0.02 mg per puff). Increasing the dose to 4 and 8 puffs did not produce any relevant difference in time response. The onset of action was rapid and reached a maximum between 30 and 60 min after inhalation. The duration of bronchodilation was maintained during the observation period of 3 h. 30 min after inhalation the results corresponded to those following the inhalation of 2 puffs of orciprenaline (0.75 mg per puff). Isolated side-effects were independent of the dosage.

Adult

[Ipratropium bromide in controlled clinical trials. Short communication (II): Time-response measurements of pulmonary function after ipratropium bromide and isoprenaline].

(8R)-3alpha-Hydroxy-8-isopropyl-1alphaH, 5alphaH, 5alphaH-tropaniumbromide (+/-)-tropate (ipratropiumbromide, Sch 1000, Atrovent) was compared with isoprenaline in a cross-over study with randomized selection in 12 stable asthmatics, using total airways resistance (Rt) measured by whole-body plethysmography, peak expiratory flow (PEF) and pulse rate as parameters. 2 puffs ipratropiumbromide (0.02 mg per puff) or isoprenaline (0.1 mg per puff) were administered by metered dose inhaler and measurements taken at 5, 20, 35, 50, 90 min, 2, 3, 4, and 6 h later. Drugs were given on alternate days. Rt decreased significantly (p less than 0.001) for 4 h to 53% of the initial value after ipratropiumbromide and to 70% of the initial value after isoprenaline, but only for about 2 h after the latter. The maximum 20-min effect on Rt was almost the same for both drugs. The difference in the time course of the bronchodilation was also significant. The rise in PEF after 4 h following ipratropiumbromide was similarly highly significant (p less than 0.001); as for Rt the time course for both drugs ran nearly parallel. Neither substance caused a significant rise in pulse rate at the dosages used.

Airway Resistance

Effects of ipratropium bromide nebulizer solution with and without preservatives in the treatment of acute and stable asthma.

In a recent study, it was suggested that the preservatives in ipratropium bromide nebulizer solution may cause a paradoxic bronchoconstrictor response in 20 percent or more of patients with stable asthma. The frequency of this response in patients with acute asthma is unknown. The aim of this study was to examine the acute effects of the usual dose of nebulized ipratropium bromide (0.25 mg) in patients with either stable or acute asthma using formulations with and without added preservatives. Twenty-five patients with stable asthma and 25 patients with acute asthma were studied. Each subject was given preservative-containing ipratropium bromide, preservative-free ipratropium bromide, pH 7 preservative-free ipratropium bromide, and saline solution in random order using a double-blind crossover technique with at least 4 h between drug administrations. Very frequent measurements of FEV1 were made for 30 min after each drug administration and then 5 mg of albuterol was nebulized and the FEV1 was measured again after another 30 min. Changes in FEV1 were expressed as a percentage of the predicted FEV1. Paradoxic bronchoconstriction to ipratropium was detected in only one patient with acute asthma (12 percent fall in FEV1) but in none of the patients with stable asthma. A 6 percent fall in FEV1 change occurred with the saline solution in this subject suggesting that the response may have been a nonspecific one due to increased bronchial responsiveness. The mean response (+/- 1 SD) to albuterol plus either preservative-containing ipratropium, preservative-free ipratropium, or pH7 preservative-free ipratropium was significantly greater (p less than 0.05) than the response to albuterol alone both in the patients with acute asthma (25 +/- 12 percent, 27 +/- 15 percent, 26 +/- 15 percent, and 20 +/- 15 percent, respectively) and stable asthma (26 +/- 7 percent, 25 +/- 8 percent, 24 +/- 6 percent, and 22 +/- 9 percent) supporting the use of ipratropium bromide as an additional bronchodilator in patients with asthma who do not show a satisfactory response to nebulized beta-adrenergic agonist.

Aerosols

Effects of allergy and age on responses to salbutamol and ipratropium bromide in moderate asthma and chronic bronchitis.

The bronchodilating responses to 400 micrograms salbutamol and 80 micrograms ipratropium bromide were studied in 188 patients with chronic bronchitis (n = 113) or asthma (n = 75) and mild to moderate airflow obstruction (forced expiratory volume in one second (FEV1) above 50% but below 2 SD of predicted value) in a crossover study on two days a week apart. Both the patients with asthma and the patients with chronic bronchitis varied considerably in their responses to the salbutamol and the ipratropium bromide. The mean increase in FEV1 in the subjects with asthma was higher after salbutamol (0.371 or 18% of the prebronchodilator value) than after ipratropium bromide (0.26 1 or 13%). In chronic bronchitis there was no difference between the increase in FEV1 after salbutamol (0.161 or 7%) and after ipratropium bromide (0.191 or 8%). When patients were categorised into those with a better response to salbutamol 400 micrograms and those with a better response to ipratropium bromide 80 micrograms, patients with chronic bronchitis responded better in general to ipratropium bromide whereas asthmatic patients responded better to salbutamol. The response pattern was also related to allergy and age, allergic patients and patients under 60 being more likely to respond better to salbutamol 400 micrograms than non-allergic patients and older patients, who benefited more from ipratropium bromide 80 micrograms. The response pattern was not related to sex, smoking habits, lung function, bronchial reactivity, respiratory symptoms, or number of exacerbations during the preceding year.

Age Factors

Effect of inhaled ipratropium bromide on the airway response to methacholine, histamine, and exercise in patients with mild bronchial asthma.

We studied the bronchodilator and protective potency of inhaled ipratropium bromide in 33 patients with mild bronchial asthma. Patients were divided into 3 groups with similar baseline lung function and similar degrees of bronchial hyperresponsiveness to participate in the methacholine (study I, n = 9), histamine (study II, n = 9), or exercise challenge tests (study III, n = 18). At each session, 80 micrograms ipratropium bromide or placebo were inhaled in a double-blind randomized fashion. After ipratropium bromide, the mean specific airway resistance (SRaw) decreased from 10.4 to 4.9 (study I, p less than 0.01), 9.3 to 5.4 (study II, p less than 0.05), or 7.8 to 5.1 cm H2O.s (study III, p less than 0.01), respectively. Mean methacholine provocation concentrations necessary to increase SRaw by 100% were 0.43 after placebo and 8.60 mg/ml after ipratropium bromide (p less than 0.01), the respective values after histamine challenges were 1.32 mg/ml after placebo and 2.25 mg/ml after ipratropium bromide (p less than 0.01). In the exercise challenges, the individual responses varied largely with a mean maximum percent increase in SRaw of 231% after placebo and 173% after ipratropium bromide pretreatment (p less than 0.05). Therefore, ipratropium bromide offers bronchodilation and protection against a variety of stimuli and should more often be considered as an effective and safe drug for asthma treatment.

Adult

Double-blind study of ipratropium bromide, a new anticholinergic bronchodilator.

The efficacy and acceptability of ipratropium given by metered-dose inhaler were evaluated in two double-blind crossover tests against placebo, one preceding and one following a 2-wk period of continual open-label ipratropium treatment. Ten patients with chronic bronchitis and 10 with bronchial asthma participated. Ipratropium produced increase in FEV 1 of more than 15% within 5 min of inhalation, and this effect was maintained for 4 to 5 hr. Statistically significant mean increases over the FEV 1 baseline values were recorded after ipratropium treatment in both the initial and the final crossover tests. There were no adverse reactions to any of the placebo or ipratropium test doses or to the ipratropium treatment. Serial electrocardiograms, laboratory tests, blood pressure, and pulse rate showed no change from lthe baseline. Sputum volume and dry-weight determinations in the patients with bronchitis before and after the 14-day treatment revealed no changes.

Adolescent

Ipratropium bromide aqueous nasal spray for patients with perennial allergic rhinitis: a study of its effect on their symptoms, quality of life, and nasal cytology.

Ipratropium bromide is an anticholinergic agent with topical activity that has been studied as a freon-propelled aerosol spray for therapy of nonallergic rhinitis. This is the first report of its use both as an aqueous nasal spray and in perennial allergic rhinitis. In this study 123 patients who had symptoms of perennial allergic rhinitis were randomized to receive ipratropium bromide 21 micrograms or 42 micrograms or placebo, one spray per nostril three times a day for 4 weeks. Patients maintained daily diaries of duration and severity of nasal symptoms and were evaluated weekly. Mean duration and severity of rhinorrhea was decreased in both ipratropium bromide treatment groups by comparison with placebo, with consistently greatest improvement in the group treated with ipratropium bromide 42 micrograms per nostril three times a day. No statistically significant differences occurred among treatment groups in duration or severity of postnasal drip, congestion, or sneezing. Seventy percent of patients treated with 42 micrograms of ipratropium bromide thought it had good or excellent effect on rhinorrhea (p less than 0.05 vs placebo); significantly more patients thought that it had improved the quality of life (p = 0.02). No changes occurred in nasal cytology, and no significant local or systemic adverse events occurred. These data indicate that ipratropium bromide significantly decreases the rhinorrhea of perennial allergic rhinitis.

Administration, Intranasal

Response to nebulized ipratropium bromide and terbutaline in acute severe asthma.

Outpatient studies on asthmatics have shown that inhaled anti-cholinergic agents decrease in efficacy as FEV1 falls. To determine whether there are changes in response to inhaled anti-cholinergics during acute bronchoconstriction we have examined the effects of nebulized ipratropium and terbutaline in nine hospitalized patients recovering from acute severe asthma. At 6 a.m. each day throughout the admission, baseline PEFR was recorded. Ipratropium bromide, 1 mg, was nebulized and PEFR measured again 1 h later. Following this, terbutaline, 5 mg, was nebulized with further measurement of PEFR 15 min after nebulization. Results were analysed by paired t-tests. Mean baseline PEFR rose from 157 l m-1 on patients worst day to 300 l m-1 on their best day (P less than 0.01). Ipratropium improved mean PEFR by 55 l m-1 and 42 l m-1 on patients worst and best days respectively (P less than 0.01). Subsequent terbutaline improved mean PEFR on patients worst day by 23 l m-1 (P less than 0.01) but only by a non-significant 4 l m-1 on their best day (P = 0.09). Hence, ipratropium produced 96% of total bronchodilatation when baseline was highest, but achieved only 71% of total response when baseline was lowest, a highly significant change in response (P less than 0.01). We conclude that in acute severe asthma as baseline PEFR rises response to inhaled ipratropium improves, compared with total response to combined ipratropium followed by terbutaline.

Acute Disease

The effect of ipratropium bromide on maximal exercise capacity in asthmatic and non-asthmatic men.

The effect of 0.5 mg nebulized ipratropium bromide (IB) on the cardio-respiratory responses to a progressive maximal cycle exercise test was compared with a matched placebo (P) in eight mild asthmatic and eight non-asthmatic men. The forced expiratory volume in l s (FEV1) in the asthmatic group was higher after ipratropium bromide both at rest [IB, mean 4.07 (SD 1.18) l versus P, 3.83 (1.29) l, P less than 0.05] and after exercise [IB, 3.64 (1.31) l versus P, 3.30 (1.40) l, P less than 0.02]. Since the percentage fall in the FEV1 after exercise was not significantly changed by ipratropium bromide [IB, -12 (11)% versus P, -16 (14)%], the improvement in the post-exercise FEV1 in the asthmatic group is attributable to the pre-exercise bronchodilatation. The resting and post-exercise FEV1 in the non-asthmatic group were also significantly higher after ipratropium bromide. However, neither group showed any differences in the cardio-respiratory, haemodynamic or subjective responses to the progressive maximum exercise test when ipratropium bromide was compared with placebo. These results demonstrate the absence of significant cardio-respiratory effects during exercise with this relatively high dose of ipratropium bromide, in patients with mild asthma and in non-asthmatic subjects. No ergogenic effect on maximal exercise performance was shown to question its use by asthmatic athletes engaged in high level competition.

Adult

Sodium cromoglycate and ipratropium bromide in exercise-induced asthma.

In thirteen patients with extrinsic asthma the effects of placebo, sodium cromoglycate, ipratropium bromide, and ipratropium bromide plus sodium cromoglycate were studied in a random double-blind fashion to assess their inhibitory action in exercise-induced asthma (EIA). Exercise testing consisted of steady state running on an inclined treadmill for up to eight minutes. In eight of the 13 patients studied the baseline ratio of expiratory flow at 50% vital capacity (VC) breathing helium-oxygen (V50He) to V50air was over 1.20 and they were called responders; the remaining five patients were called non-responders. There was a significantly lower baseline maximum mid-expiratory flow rate (MMEF) in non-responders (P less than 0.02) as compared to responders but no difference in forced expiratory volume in one second (FEV1) or forced vital capacity (FVC). Sodium cromoglycate (P less than 0.02), ipratropium bromide (P less than 0.01), and ipratropium bromide plus spdium cromoglycate (P less than 0.01) all significantly inhibited the percentage fall in FEV1 after exercise in the responders. Ipratropium bromide had no preventive action on non-responders, unlike sodium cromoglycate (P less than 0.05) and ipratropium bromide plus sodium cromoglycate (P less than 0.02). It is postulated that mediator release is an important factor in development of EIA in most extrinsic asthmatics, whereas cholinergic mechanisms are relevant only in those patients in whom the main site of airflow obstruction is in the large central airways.

Adolescent

Bronchodilator action of the anticholinergic drug, ipratropium bromide (Sch 1000), as an aerosol in chronic bronchitis and asthma.

Ipratropium bromide (also known as Sch 1000) is a new atropine-like bronchodilator drug whose mechanism of action is via an anticholinergic pathway and may decrease cyclic guanosine monophosphate. Although of established efficacy in asthma, there are no studies of the use of ipratropium in patients with chronic bronchitis. The single metered aerosol doses of 10 mug, 20 mug, 40 mug and 80 mug of ipratropium bromide, 75 mug and 150 mug of isoproterenol, and placebo were studied in 20 adult patients, half with asthma and half with chronic bronchitis. To qualify, all patients demonstrated at least 20% improvement in the forced expiratory volume in one second while in the drug-free state when tested with isoproterenol. All subjects were tested for six hours with each agent in a double-blind crossover design. The dose-response aspects of the study indicate that in bronchial asthma the optimal range of dosage is 40 mug to 80 mug of ipratropium bromide. These doses are superior to isoproterenol in duration of action. In chronic bronchitis, all doses of ipratropium showed prolonged efficacy, but 80 mug was superior. Isoproterenol lacked this sustained efficacy. No significant alteration in pulse or blood pressure was observed. Ipratropium appears to be an important addition to the bronchodilator agents used in isoproterenol-responsive obstructive pulmonary disease.

Aerosols

Acute bronchodilating effects of ipratropium bromide and theophylline in chronic obstructive pulmonary disease.

The bronchodilator effects of a single dose of ipratropium bromide aerosol (36 micrograms) and short-acting theophylline tablets (dose titrated to produce serum levels of 10-20 micrograms/mL) were compared in a double-blind, placebo-controlled crossover study in 21 patients with stable, chronic obstructive pulmonary disease. Mean peak forced expiratory volume in 1 second (FEV1) increases over baseline and the proportion of patients attaining at least a 15% increase in the FEV1 (responders) were 31% and 90%, respectively, for ipratropium and 17% and 50%, respectively, for theophylline. The average FEV1 increases during the 6-hour observation period were 18% for ipratropium and 8% for theophylline. The mean duration of action was 3.8 hours with ipratropium and 2.4 hours with theophylline. While side effects were rare, those experienced after theophylline use did involve the cardiovascular and gastrointestinal systems. These results show that ipratropium is a more potent bronchodilator than oral theophylline in patients with chronic airflow obstruction.

Adult

Comparison of ipratropium bromide and albuterol in chronic obstructive pulmonary disease: a three-center study.

Seventy-two subjects who had severe chronic obstructive pulmonary disease and a history of heavy smoking completed a study to compare the effect of single doses of ipratropium bromide (0.036 mg), albuterol (0.18 mg), and placebo on the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), heart rate, and blood pressure during a period of 6 hours. During initial testing for reversibility, 40 subjects did not demonstrate a 15% increase in FEV1 from baseline after metaproterenol. Ipratropium produced a significantly greater response than albuterol in FEV1 at 3, 4, and 5 hours and in FVC at 1, 2, 3, 4, and 5 hours. For the entire 6-hour period, ipratropium produced a 25% greater response than albuterol in FEV1 and a 50% greater response in FVC. The difference between the two drugs was even greater between 3 and 6 hours. There were no significant differences between the three treatments as regards adverse reactions, heart rate, and blood pressure measurements. In patients who have chronic obstructive pulmonary disease, ipratropium bromide has apparent benefits over beta 2 agonist therapy, including a longer duration of action. Ipratropium may also be effective when beta 2 agonists are not effective.

Aerosols

Decreased duration of emergency department treatment of chronic obstructive pulmonary disease exacerbations with the addition of ipratropium bromide to beta-agonist therapy.

STUDY OBJECTIVES: To determine the benefit of the addition of ipratropium bromide to beta-agonist therapy of acute exacerbations of chronic obstructive pulmonary disease. DESIGN: The trial was randomized and double blinded. SETTING: The study was conducted in the emergency department of Parkland Memorial Hospital, a busy, inner-city, county hospital. INTERVENTIONS: Patients were treated in the medicine emergency department with either the standard regimen of nebulized isoetharine, 0.5 mL of a 1% solution (5.0 mg) diluted to 2.0 mL with normal saline every hour (control group) or with the same regimen plus ipratropium bromide, 54 micrograms (three puffs) after the first isoetharine treatment and 36 micrograms (two puffs) after the second and fourth (experimental group). A placebo metered-dose inhaler used in the same manner as the ipratropium blinded the study to both the patients and medical personnel. MEASUREMENTS AND MAIN RESULTS: The group treated with the addition of ipratropium (30) was discharged from the ED an average of 91 minutes (P less than .05) sooner than the control group (25) and required on the average one less isoetharine treatment (P less than .05). The pulmonary functions tested, forced expiratory volume in the first second, and the forced vital capacity were the same in the two groups initially and on discharge, as identical discharge criteria were used in each group. CONCLUSION: The addition of ipratropium to standard beta-agonist treatment of chronic obstructive pulmonary disease exacerbations shortens the duration of treatment required in the ED.

Acute Disease

Dose of nebulized ipratropium bromide in acute severe asthma.

The aim of the study was to determine the maximum effective dose of nebulized ipratropium bromide, 0.5 or 1.0 mg, in the treatment of acute severe attacks of asthma. Thirty-two patients (ten males, 19-53 years) who were admitted with acute severe asthma were, in a double-blind trial, randomized to receive either 0.5 or 1.0 mg of isotonic, preservative-free ipratropium bromide nebulized in saline. Ear oxygen saturation, peak flow and heart rate were measured on admission and regularly following nebulization. Two hours after nebulization of the ipratropium, terbutaline (5 mg) was administered by nebulizer and further measurements taken 30 min later. Twenty-six patients completed the study, 13 in each group. Peak expiratory flow (PEF) increased by 51% [1211 min-1 increasing to 1831 min-1 (mean)] in the 0.5-mg ipratropium group, and by 37% (1551 min-1 to 2071 min-1) in the 1.0-mg group. There were no significant differences in heart rate or ear oxygen saturation changes between the groups. Nebulized terbutaline led to a small further rise in peak flow in both groups (341 min-1 in the 0.5-mg group; 411 min-1 in the 1.0-mg group). No side-effects were noticed in either group. We conclude that 0.5 mg of nebulized ipratropium is as effective as 1.0 mg in the treatment of acute severe asthma.

Acute Disease

Inhibition of inhaled metabisulphite-induced bronchoconstriction by inhaled frusemide and ipratropium bromide.

1. The effect of inhaled frusemide and high dose inhaled ipratropium bromide on bronchoconstriction induced by inhaled metabisulphite was studied in 10 atopic volunteers. 2. Frusemide (40 mg), ipratropium bromide (0.5 mg) or saline placebo were administered by nebuliser in a double-blind fashion, prior to construction of a dose-response curve to metabisulphite (2.5-100 mg ml-1). 3. Geometric mean of the provocative dose of metabisulphite that caused a 35% fall in specific airways resistance (sGaw) after placebo was 13 (95% confidence intervals CI 4-36 mumol) compared with 36 (16-78) mumol after ipratropium bromide and 45 (22-94) mumol after frusemide. 4. Mean maximum fall in sGaw was 49 (40-57)% after placebo, 11 (0-22)% after frusemide and -1 (-25-22)% after ipratropium bromide. 5. Frusemide significantly protected against metabisulphite induced bronchoconstriction (P less than 0.005). The protection from high dose ipratropium bromide was also significant (P less than 0.05), but the response was more variable between subjects.

Administration, Inhalation

The influence of terfenadine and ipratropium bromide alone and in combination on bradykinin-induced nasal symptoms and plasma protein leakage.

Nasal instillation of bradykinin elicits many of the characteristic features of rhinitis. To assess the relevance of histamine release from metachromatic cells and the activation of cholinergic pathways, we investigated the effects of terfenadine, a histamine H1-receptor antagonist, and ipratroprium bromide, a selective antimuscarinic agent, on bradykinin induced rhinorrhoea, nasal airways resistance (NAR), nasal pain and plasma protein leakage. Oral terfenadine (120 mg) or matched placebo and nasal ipratropium bromide (80 micrograms) or matched placebo were administered at 4 hr and 30 min respectively prior to bradykinin nasal challenge in two randomized, double-blind and cross-over studies on eight non-rhinitic subjects. Thus subjects received either double-placebo, oral terfenadine and nasal placebo, oral placebo and nasal ipratopium bromide or oral terfenadine and nasal ipratropium bromide, as pretreatment. Bradykinin challenge induced mean maximal increases of 57%, 59%, 77% and 72% in NAR on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratropium bromide pretreatment days respectively. These increments were not significantly different. Similarly rhinorrhoea and nasal pain induced by bradykinin nasal challenge were not significantly different on the four challenge days. Bradykinin nasal challenge caused a mean maximal increase in albumin levels in recovered nasal lavages of 11.5, 13.0, 12.2 and 12.3 times of baseline levels on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratroprium bromide pretreatment days respectively. Similarly total protein levels achieved a mean maximal increase of 8.0, 8.2, 7.9 and 8.8 times of baseline levels on these challenge days. The increments in both albumin and total protein did not significantly differ on the 4 challenge days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Efficacy of salbutamol and ipratropium bromide in decreasing bronchial hyperreactivity in children with cystic fibrosis.

A proportion of patients with cystic fibrosis (CF) suffer from increased airway hyperreactivity but their response to bronchodilators is variable. Adrenergic agents may produce an increase, no change or a decrease in forced expiratory volume in 1 second (FEV1). We hypothesized that the variable response might be related to poor aerosol distribution caused by the presence of secretions. Therefore, in 11 children with CF and airway hyperreactivity the influence of pretreatment with either 0.9% saline, salbutamol, or ipratropium bromide on the methacholine challenge test was evaluated in a double-blind, randomized, cross-over study. FEV1 (mean +/- S.E.) did not change following pretreatment with saline, salbutamol, or ipratropium (1.64 +/- 0.22, 1.63 +/- 0.16 and 1.67 +/- 0.19, respectively). All patients demonstrated airway hyperreactivity with a PC20 below 8 mg/mL (geometric mean, 0.41 mg/mL) after saline pretreatment. Salbutamol inhalation significantly increased the PC20 to 1.24 mg/mL (P less than 0.01), but ipratropium bromide was found to be even more effective than salbutamol (PC20 = 7.37 mg/mL) (P less than 0.0001). We conclude that the variable response to bronchodilator is not secondary to impaired aerosol distribution since ipratropium bromide effectively blocked the response to methacholine. The improvement in PC20 without a change in baseline FEV1 following salbutamol suggests that the adrenergic agent altered the contractile mechanism of smooth muscle.

Adolescent