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Effect of continuously nebulized ipratropium bromide plus albuterol on emergency department length of stay and hospital admission rates in patients with acute bronchospasm. A randomized, controlled trial.

OBJECTIVE: To compare the outcome of patients with acute bronchospasm treated with continuously nebulized albuterol plus ipratropium bromide vs albuterol alone. SETTING: The Emergency Department (ED) at the University of California San Francisco Medical Center. PARTICIPANTS: Patients > or = 18 years old presenting to the ED with acute bronchospasm and a peak expiratory flow rate (PEFR) of < 70% predicted. INTERVENTIONS: This was a prospective, randomized, double-blind, placebo-controlled trial. Subjects were treated with either a combination of albuterol (10 mg/h) plus ipratropium bromide (1.0 mg/h) or albuterol alone via continuous nebulization for a maximum of 3 h. Vital signs, Borg dyspnea score, and PEFR were recorded hourly. Primary outcome measures were improvement in PEFR, hospital admission rates, and length of stay in the ED. MEASUREMENTS AND RESULTS: Data was analyzed for 67 subjects. The mean age (-/+ SD) was 47.5+/-18.8, and mean initial PEFR was 44.8+/-12.5% of predicted. The median length of stay for all subjects was 225 min, and 31% of all subjects were admitted. Patients given combination therapy averaged 6.3% greater improvement in PEFR compared with control subjects (95% confidence interval [CI], -15% to 27%. The odds ratio for admission with combination therapy was 0.88 (95% CI, 0.28 to 2.8). The median length of stay in the ED was 35 min shorter for those receiving combination treatment (210 vs 245 min; p = 0.03). However, when adjusted for initial PEFR, there was no statistically significant difference (p = 0.26). CONCLUSION: Although the direction of all three outcome measures favored combination therapy, there was no statistically significant difference between ED patients with acute bronchospasm receiving continuous albuterol plus ipratropium bromide and those receiving albuterol alone.

Acute Disease↗

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↗

The inhaled bronchodilators ipratropium bromide and metaproterenol in adults with CF.

Ten patients with CF who were more than 18 years old, participated in a double-blind, placebo-controlled study evaluating the efficacy of inhaled ipratropium bromide and metaproterenol as bronchodilators. The mean FEV1 of the group improved 17.1 percent after treatment with ipratropium bromide, 12.5 percent after metaproterenol treatment, and 16.6 percent after treatment with both of these medications together. There was no significant difference between these responses and patients who responded to one treatment tended to respond to the others. The side effects with these medications were minimal. When compared with patients in previous studies, our patients, who were much older as a group, demonstrated a greater degree of bronchodilation with ipratropium bromide and metaproterenol, as well as a greater degree of bronchoconstriction with placebo.

Administration, Inhalation↗

Delivery of albuterol and ipratropium bromide from two nebulizer systems in chronic stable asthma. Efficacy and pulmonary deposition.

Bronchodilator responses to both nebulized albuterol (salbutamol) and ipratropium bromide and aerosol delivery to the tracheobronchial tree have been assessed in eight patients with chronic stable asthma (mean baseline FEV1, 50 percent; reversibility greater than 20 percent). Two commercially available nebulizer systems were used, namely, a Turret nebulizer operated at a compressed gas flow rate of 12 L/min (droplet MMD, 3.3 mu) and an Inspiron nebulizer driven at 6 L/min (MMD, 7.7 mu). Albuterol was given as doses of 250 micrograms, 250 micrograms, 500 micrograms, and 1,000 micrograms (cumulative dose, 2 mg) and ipratropium bromide as doses of 50 micrograms, 50 micrograms, 100 micrograms, and 200 micrograms (cumulative dose, 400 micrograms) at intervals of 35 minutes. For albuterol, bronchodilatation was significantly (p less than 0.05) greater at all dosage levels with the Turret. For ipratropium, bronchodilatation was similar for both nebulizers. Measurements of aerosol deposition using 99mTc-labelled pentetic acid (diethylenetriamine pentaacetic acid; DTPA) showed that 9.1 +/- 1.1 percent and 2.7 +/- 0.2 percent of the dose reached the lungs during nebulization to dryness for Turret and Inspiron, respectively (p less than 0.01); distribution within the lungs was similar for the two aerosols. Selection of nebulizer apparatus can influence delivery of aerosol and subsequent bronchodilator response to albuterol in patients with chronic stable asthma but is less important for aerosol delivery of ipratropium bromide in these patients.

Adult↗

Destruction of ethidium bromide in solution by ozonolysis.

Ethidium bromide can be rapidly destroyed in aqueous solutions or in isoamyl alcohol by ozonolysis in the presence of H2O2 to give a mixture of organic acids. In a variety of buffers commonly used in recombinant DNA technology destruction of ethidium bromide was more than 99.9%. The yellow reaction mixture after ozonolysis was shown to be nonmutagenic. This method may be used in laboratories for the disposal of ethidium bromide wastes.

Chemical Phenomena↗

4-Bromophenacyl bromide inhibits prostaglandin D2 synthesis from arachidonic acid rather than phospholipase A2 activity in liver macrophages.

4-Bromophenacyl bromide at a concentration of 50 microM does not inhibit phospholipase A2 activity in liver macrophages. Rather, this compound increases the amount of radioactivity released from [3H]arachidonate-prelabeled Kupffer cells and leads to the formation of small amounts of thromboxane, prostaglandin D2 and prostaglandin E2. Also the zymosan-induced formation of thromboxane and prostaglandin E2 from endogenous sources which is thought to involve phospholipase A2 remains unaffected in the presence of this compound. The generation of superoxide and the formation of prostaglandin D2 from arachidonate and after stimulation of the cells with zymosan, however, are blocked by 4-bromophenacyl bromide. Furthermore, this compound suppresses the incorporation of externally added arachidonate into membrane lipids of the cells. 4-Bromophenacyl bromide seems, therefore, not to be a useful tool to demonstrate the involvement of phospholipase A2 in complex biological systems.

Acetophenones↗

Binding of polylysine and ethidium bromide to nucleosomal DNA: comparison of biochemical and electron microscopical results.

Ethidium bromide and polylysine interact with nucleosomal DNA and lead to change of biochemical properties and to morphological changes as to the distance between the two core particles of a nucleosome dimer. With increasing polylysine concentration, the buoyant density of nucleosomes decrease and the accessibility of the nucleosomal DNA to micrococcal nuclease is lowered. Electron microscopy of polylysine treated nucleosome dimers reveals a shortening of the internucleosomal distance as compared with controls. Treatment of nucleosomes with ethidium bromide leads to an enhanced accessibility of the nucleosomal DNA to micrococcal nuclease. Electron microscopy reveals an increase in length of the DNA connecting the two nucleosome cores in the presence of the dye. Both the binding of polylysine and the treatment with ethidium bromide apparently do not affect the histone arrangement within the nucleosome core as suggested by chemical cross-linking of histones and DNA with formaldehyde, and no obvious morphological change of the nucleosome cores can be observed.

Animals↗

Symptoms among workers with long-term exposure to methyl bromide. An epidemiological study.

Symptoms as an important sign of the effects of methyl bromide were studied in 56 male workers (37 currently exposed and 19 previously exposed) in a methyl bromide factory. The workers were 18 to 62 yr of age (mean age: 41) and were exposed from 1 to 25 yr (mean: 7 yr). They were compared to 56 age-matched referents with a standardized questionnaire. The results of pairwise comparison of the symptoms of the age-matched pairs of exposed and referent subjects showed that the occurrence of dizziness, numbness, paresthesia and weakness of extremities, nightmares, fatigue and dry and scaly skin was statistically significantly higher among the workers than among the referents. When the symptoms during the work shift (acute symptoms) were compared, irritation symptoms such as itching, bullae or reddish swollen hands and runny noses with nasal irritation were reported significantly more often in the exposed groups. The correlation of the symptoms among the exposed workers suggested that chronic symptoms are closely related to acute irritation symptoms and exposure duration. The results suggest that symptom inquiry is useful for detecting the possible effects of exposure to methyl bromide.

Adult↗

[Demyelination and remyelination after multiple intramedullary injections of ethidium bromide in Wistar rats].

The ethidium bromide model of demyelination has been employed to study the central nervous system response to several episodes of demyelination. Twenty-seven Wistar rats received 2 to 4 intraspinal injections of 1 microliter of either 0.1% ethidium bromide in normal saline (19 rats) or saline 0.9% (8 rats) in different anatomical locations. The intervals between the injections ranged from 28 to 42 days. Ten days after the last injection all the rats were perfused with 2.5% glutaraldehyde. The spinal sections were evaluated macroscopically and by light and transmission electron microscopy. The lesions were typical of focal primary demyelination with preserved vascular structures and followed by remyelinization and varied in size and histological aspects. After multiple sequential ethidium bromide injections, the central nervous system seems to modify its response capacity to an inflammatory challenge although there is no change in its pattern of remyelination.

Animals↗

Ethidium bromide-induced demyelination of the sciatic nerve of adult Wistar rats.

Peripheral nerve ultrastructure was assessed after single or multiple local injections of the intercalating dye ethidium bromide. Thirty-four adult Wistar rats of both sexes were divided into five groups and maintained in a controlled environment with rat chow and water ad libitum throughout the experiment. The experimental animals were injected with 1 microl of 0.1% ethidium bromide in 0.9% saline into the central third of the left sciatic nerve 1 (group 1), 2 (group 2), 4 (group 3), 6 (group 4) or 8 (group 5) times. In groups 2 to 5 the injections were made at 28-day intervals. Control animals received the same amount of 0.9% saline. The animals were killed at different times after injection: group 1 at 7 days (2 rats) and 15 days (2 rats); for groups 2, 3, 4 and 5, all rats were killed 10 days after the last injection and the lesions were investigated by light and transmission electron microscopy. In the acute lesions, intoxicated Schwann cells showed a vacuolated cytoplasm and separation of the sheaths from the axon. Myelin sheaths underwent progressive vesiculation and subsequent segmental demyelination. Myelin debris were withdrawn by macrophages and remyelination by Schwann cells was prominent. With the increase in the number of injections collagen fibers also increased in number and progressively enveloped smaller numbers of remyelinated axons composing new fascicles. Wallerian degeneration of fibers apparently not affected by ethidium bromide was more intense in the nerves from groups 4 and 5. The peripheral nerve repairs itself after demyelinating challenges with a profusion of collagen fibers and new fasciculations. This experimental model is valid to mimic recurrent demyelinating neuropathies.

Animals↗

Susceptibility of Maconellicoccus hirsutus (Homoptera: Pseudococcidae) to methyl bromide.

Eggs, crawlers, early nymphs, late nymphs, and adults of the pink hibiscus mealybug, Maconellicoccus hirsutus (Green), were tested for their susceptibility to methyl bromide in 2-h laboratory fumigations at ambient conditions (25 degrees C, 95% RH). Dose-response tests indicated that the egg was the most susceptible life stage with an LC99 of 20.2 mg/liter. Based on probit analysis of dose-response data, no significant differences were observed among susceptibilities of the crawler, early stage or late stage nymphs, or adults at either the LC50 or LC99 level, but late stage nymphs were more tolerant than early stage nymphs in a separate paired comparison test. Confirmatory tests showed that a dose of 48 mg/liter methyl bromide, the USDA-Animal Plant Health Inspection Service treatment dose schedule for mealybugs at 21-26 degrees C, produced 100% mortality of all life stages. On the basis of these results, we conclude that the methyl bromide treatment schedule for mealybugs will provide quarantine security for M. hirsutus infesting commodities for export or import.

Animals↗

Spectroelectrochemistry study on the electrochemical reduction of ethidium bromide.

The electrochemical reduction mechanism of ethidium bromide was first studied by spectroelectrochemistry. This reduction was proved to be a two-step process by cyclic voltammetry, differential pulse voltammetry and spectroelectrochemistry, in which each step was proved to be a one-electron transfer process by a spectropotentiostatic fluorescence technique. Hydroethidine was confirmed to be the final product by comparing the spectrum of the product of the electrochemical reduction to that of the product of the chemical reduction of ethidium bromide, and a carbon-centered radical was concluded to be a reasonable intermediate product during the electrochemical reduction of ethidium bromide.

Benzhydryl Compounds↗

Clinical pharmacokinetics of rocuronium bromide.

A new aminosteroidal neuromuscular blocking agent, rocuronium bromide, has recently been introduced into clinical practice. Its main advantage over other currently used drugs of this kind is its fast onset of action, which could render rocuronium the muscle relaxant of choice for rapid facilitation of tracheal intubation. A further advantage of the new compound over vecuronium bromide is the less extensive formation of breakdown products, reducing the contribution of active metabolites to the neuromuscular blocking effects of the parent compound. Thorough knowledge of the pharmacokinetics of any new drug is highly desirable for the anaesthesiologist because absorption, distribution to the tissue, as well as elimination by biotransformation and excretion, are closely related to its effects. Due to its chemical relationship to other aminosteroidal neuromuscular blocking agents such as pancuronium bromide or vecuronium, rocuronium is expected to display pharmacokinetic behaviour similar to that of its predecessors. Hepatic and renal disease may prolong the effect of rocuronium, but to a lesser extent than seen with pancuronium or vecuronium, because the plasma clearance of rocuronium is not significantly influenced by dysfunction of the liver or kidneys. On the contrary, in elderly or hypothermic patients the reduction in plasma clearance results in a prolonged duration of the action of rocuronium. All information on the pharmacokinetics of this new nondepolarising neuromuscular blocking agent which has been made available to date is presented in this review, with a discussion of the significance of these data for clinical use of the drug.

Adult↗

Fluorescent staining of hair cells with ethidium bromide.

The present study evaluated ethidium bromide, a nucleic acid-specific fluorescing stain for cochlear applications. Tissue exposed to acoustic stimulation did not exhibit the loss of fluorescence in hair cells described in studies on other fluorescing stains. The ethidium bromide fluorescence technique was, however, found to be useful in detecting subtle damage in cell nuclei even before gross structural alterations in cochlear cytoarchitecture appeared. The implications of the use to ethidium bromide staining for histologists are discussed.

Acoustic Stimulation↗

The effect of ipratropium bromide on nasal hypersecretion induced by methacholine in patients with vasomotor rhinitis. A double-blind, cross-over, placebo-controlled and randomized dose-response study.

The effect of various doses of ipratropium bromide aerosol on nasal hypersecretion induced by five concentrations methacholine was studied in 24 patients with vasomotor rhinitis and excessive watery nasal secretion. The volume of nasal secretion was greater with each of the five increasing doses of methacholine from 7.5 to 120 mg/ml. The median volume of nasal secretion was alike in all patients after administration of methacholine only and after treatment by placebo followed by methacholine. When the patients were treated with ipratropium bromide prior to administering methacholine the volume of secretion was reduced significantly. With doses of 40 micrograms and 100 micrograms of ipratropium to each nostril a similar reduction in the volume of secretion occurred but a still greater reduction by the application of 200 micrograms of ipratropium when compared with treatment by the placebo. While the volume of secretion increased with each increasing concentration of methacholine, a similar pattern of reduced secretion for each concentration of methacholine was seen with each greater concentration of ipratropium. In patients with vasomotor rhinitis, treatment with ipratropium bromide was found to reduce significantly the hypersecretion induced by methacholine when compared with treatment by the placebo. This reduction was greater with greater doses of ipratropium.

Administration, Inhalation↗

Manometric evaluation of cimetropium bromide activity in patients with the nutcracker oesophagus.

There are at present few therapeutic alternatives to calcium channel blockers for the medical treatment of patients with nutcracker oesophagus. For this reason, we evaluated by means of a low-compliance manometric system the effect of a new anticholinergic compound, cimetropium bromide (10 mg intravenously), on oesophageal variables of eight patients with nutcracker oesophagus, in a single-blind study. Eight age-matched healthy volunteers served as controls. In both patients and controls, cimetropium bromide significantly decreased lower oesophageal sphincter pressure and the distal and proximal mean contraction amplitude of the oesophageal body. Apart from an increase in pulse rate, no noteworthy side effects were observed. It is concluded that cimetropium bromide may be an effective therapeutic option in patients with nutcracker oesophagus.

Adult↗

Absorption, excretion and metabolism of tiquizium bromide in dogs, and relationship between pharmacological effect and plasma levels of unchanged drug.

The disposition of 14C-tiquizium bromide was investigated in dogs after oral administration and i.v. administration. After oral administration, max. blood concn. of radioactivity were obtained from one to three hours after dosing. The half-lives of terminal phase were 7.1 h (i.v.) and 9.4-12.0 h (p.o.). The relative bioavailability was 26%. The urinary excretion in three days was 24% (i.v.) and 5-9% (p.o.). The most important mechanism of biotransformation was hydroxylation in the 5-position of the thiophene ring, and glucuronides of the isomeric hydroxylated products of tiquizium bromide were found in urine. The time-course of the inhibitory effect of tiquizium bromide on stomach contraction correlated well with the plasma levels of unchanged drug after intraduodenal administration.

Administration, Oral↗

Bioanalytical applications of tandem mass spectrometry in the in vitro metabolism of the anticholinergic drug cimetropium bromide to detect differences in species metabolism.

1. In vitro metabolism of the anticholinergic drug, cimetropium bromide, was investigated using four different animal hepatic microsomal incubates derived from rat, hamster, guinea pig, and mouse livers. 2. Constant neutral loss (CNL) tandem mass spectrometry was used to detect the presence of the N-methylenecyclopropyl-scopine functionality by monitoring loss of 54 daltons (corresponding to loss of methylenecyclopropane) in microsomal incubates. 3. A CNL loss of 46 daltons was used to screen for the presence of ester hydrolysis products. 4. A comparison of the daughter ion spectra obtained on ions detected by CNL scanning, with daughter ion spectra of synthetic standards, determined the presence of ten metabolites of cimetropium bromide. 5. Hydroxylation of the aromatic ring in the ester side-chain was found to be the major metabolic pathway, and ester bond hydrolysis was a minor metabolic pathway. 6. N-Demethylation of the bridgehead nitrogen was observed only in rat and hamster incubates. 7. Using the method of CNL scanning it was possible to screen different animal microsomal incubates without resorting to any major purification procedures such as h.p.l.c. 8. This scanning method revealed differences between species in the metabolic pathways of cimetropium bromide.

Animals↗