Ipratropium bromide-mediated myocardial injury in in vitro models of myocardial ischaemia/reperfusion.

Ipratropium bromide, a nonselective muscarinic antagonist, is widely prescribed for the treatment of chronic obstructive pulmonary disease (COPD). Analyses of COPD patients, with underlying ischaemic heart disease, receiving anticholinergics, have indicated increased risk of severity and occurrence of cardiovascular events (including myocardial infarction). The present study explored whether ipratropium bromide induces myocardial injury in nonclinical models of simulated myocardial ischaemia/reperfusion injury. Adult Sprague Dawley rat hearts/primary ventricular myocytes were exposed to simulated ischaemia/hypoxia prior to administration of ipratropium at the onset of reperfusion/reoxygenation. Infarct to risk ratio and cell viability was measured via triphenyl tetrazolium chloride staining and thiazolyl blue tetrazolium bromide (MTT) assay. The involvement of apoptosis and necrosis was evaluated by flow cytometry. Mitochondrial-associated responses were detected by tetramethylrhodamine methyl ester fluorescence and myocyte contracture. Ipratropium (1 × 10⁻¹¹ M - 1 × 10⁻4 M) significantly increased infarct/risk ratio and decreased cell viability in a dose-dependent manner. Increased levels of necrosis and apoptosis were observed via flow cytometry, accompanied by increased levels of cleaved caspase-3 following ipratropium treatment. Levels of endogenous myocardial acetylcholine were verified via use of an acetylcholine assay. In these experimental models, exogenous acetylcholine (1 × 10⁻7 M) showed protective properties, when administered alone, as well as abrogating the exacerbation of myocardial injury during ischaemia/reperfusion following ipratropium coadministration. In parallel experiments, under conditions of myocardial ischaemia/reperfusion, a similar injury was observed following atropine (1 × 10⁻7 M) administration. These data demonstrate for the first time in a nonclinical setting that ipratropium exacerbates ischaemia/reperfusion injury via apoptotic- and necrotic-associated pathways.

Effect of an adrenergic agonist and a cholinergic antagonist on the airway epithelium.

The ultrastructure of the rabbit tracheal epithelium was studied 30 minutes after intratracheal administration of two puffs of salbutamol and ipratropium bromide, respectively. The injury to the tracheal epithelium due to the treatment with both bronchospasmolytic drugs was considered moderate to severe. In both experimental groups, the degree of goblet cells' stimulation did not differ significantly, the ciliated cells were less damaged compared with the goblet ones and the morphological signs of the impaired self-cleaning ability were revealed.

The effect of nebulized bronchodilator therapy on intraocular pressures in patients with glaucoma.

A controlled double-blind crossover study of ocular complications associated with nebulized ipratropium bromide and salbutamol therapy for respiratory distress was undertaken in 46 chronic bronchitis patients. There was no significant rise in intraocular pressure or change in anterior chamber angle in patients with open-angle glaucoma, narrow-angle glaucoma or control subjects following treatment with either drug. However, when the two drugs were used in combination, intraocular pressure rose in patients with narrow-angle glaucoma but not in patients with open-angle glaucoma or in control subjects. Transient angle closure was seen in five of these patients. Intraocular pressures did not rise when swimming goggles were used to protect the eyes or when antiglaucoma treatment was continued. Nebulized bronchodilator therapy is safe in nonglaucomatous patients and those with open-angle glaucoma. Ocular complications can follow combined ipratropium bromide and salbutamol nebulization in patients with narrow-angle glaucoma, but can be prevented by using the drugs separately, protecting the eyes and ensuring continued antiglaucoma measures.

Does ipratropium bromide by nebulizer and face-mask have local ocular effects?

No acute ocular atropinic effect of nebulized ipratropium bromide administered by carefully applied or deliberately misplaced face-mask has been demonstrated.

Pharmacology and toxicology of Atrovent.

The anticholinergic drug ipratropium bromide (Atrovent) can be described as having pharmacologically a high degree of activity and a certain bronchoselectivity when administered intravenously. Inhalation studies, however, indicate that this is the most suitable route of administration. Inhalation provides with small doses the most effective concentration locally at the smooth muscle of the airways without producing anticholinergic side effects due to absorption from the airways or from the gastrointestinal tract. In certain experimental models of allergic asthma, ipratropium bromide was shown to be capable of influencing favourably bronchoconstriction and mediator release. Extensive toxicological examinations revealed with high doses all typical symptoms of overdosing an anticholinergic drug, like mydriasis, dryness of the mucosae and meteorism with coprostasis. Acute and long term inhalation studies gave no evidence for a functional and morphological impairment of the lungs and airways.

[General pharmacology and secretion inhibitory action of (8r)-3alpha-hydroxy-8-isopropyl-1alphaH,5alphaH-tropanium bromide-(+/-)-tropate (ipratropiumbromide) (author's transl)]. / Allgemeine Pharmakologie und sekretionshemmende Wirkung von (8r)-3alpha-Hydroxy-8-isopropyl-1alphaH,5alphaH-tropaniumbromid-(+/-)-tropat (Ipratropiumbromid)

(8r)-3alpha-Hydroxy-8-isopropyl-1alphaH,5alphaH-tropaniumbromide-(+/-)-tropate (ipratropiumbromide, Sch 1000) is a quaternary tropic acid tropane ester with pronounced anticholinergic activities (inhibition of secretion and spasmolysis). The effect of the substance of all parasympathetically innervated organs ist 1.4 to 2 times stronger than that of atropine. As an inhibitor of the secretion of free hydrochloric acid in the stomach it proved to be 5 times more effective than atropine. Central activities were not observed. The duration of action of Sch 1000 exceeds that of atropine by far.

[Toxicological studies on ipratropiumbromide (author's transl)]. / Toxikologische Untersuchungen mit Ipratropiumbromid

The acute, subacute and chronic toxicity of (8r)-3alpha-hydroxy-8-isopropyl-1alphaH,5alphaH-tropaniumbromide (ipratropiumbromide, Sch 1000, Atrovent) was studied on mice, rats, dogs and monkeys following oral, s.c., i.v. administration and inhalation. With toxic doses all typical symptoms of atropine or atropine derivatives were present, like mydriasis, dryness of the mucosa and meteorism with coprostasis. It was not possible to determine the LC50 of the substance due to its low toxicity.

New apparatus and method for the toxicological investigation of metered aerosols in rats.

A new apparatus and method for the toxicological investigation of metered aerosols in rats, which is also suitable for tests in other small laboratory animals, is described. It permits: 1. simultaneous treatment of 5 or more animals, 2. administration of metered aerosol doses to individual animals, 3. ventilation of the cages, 4. mechanical tilting of the metered aerosol packs to ensure thorough mixing of the content, and 5. continuous automatic tilting, administration and ventilatied under different ventilation conditions. Blood gases and fluorinated chlorohydrocarbons (abbreviation: fluorocarbons) in the arterial blood were also determined. In tests with spontaneous ventilation of the animal chambers without positive pressure, significant acidosis and hypoxia occurred after 40 puffs of metered aerosol. Where ventilation of the chambers was insufficient, the fluorocarbons led to dose-dependent toxic and lethal effects. The substance and the additives contained in the metered aerosol did not interfere with these effects. After active ventilation with 0.5 atm no symptoms of acidosis or hypoxia were observed. Up to 160 puffs of metered aerosol, no indications of toxic effects were established in the rats. Half-life of the fluorocarbons in the arterial blood after one puff of metered aerosol was 69 to 80 sec for fluorocarbon 11 and 57 to 67 sec for fluorocarbon 12.