A novel propellant-free inhalation drug delivery system for cardiovascular drug safety evaluation in conscious dogs.
BACKGROUND
Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. This paper describes a new strategy for treating conscious labrador dogs with drugs by inhalation using a specially designed mask and a novel inhaler device.


METHODS
Labrador dogs (male or female) were used that had transducers implanted for the measurement of left ventricular and descending aortic blood pressures and an ECG for use together with a telemetry system. Administration by inhalation was achieved using a novel delivery device. The Respimat device is a propellant-free inhaler to deliver aerosols from solutions. The new system was evaluated using Formoterol with four dogs using a 4 x 4 Latin square design. Three doses of Formoterol (0.6, 1.2, and 2.4 microg/kg, dissolved in 60% ethanol) were administered by inhalation together with a vehicle (60% ethanol) treatment by applying three inhalations, each consisting of 10 microl solution.


RESULTS
Formoterol increased HR, QRS-interval, QT-interval, and LVPdP/dtmax and dose-dependently decreased systolic and diastolic BP. This effect lasted up to 14 h.


CONCLUSIONS
Drug administration by inhalation in the conscious labrador dog using the Respimat is a useful new model for safety pharmacology studies of new drug candidates that are intended to be given by inhalation in the clinic.
Markert
Michael
M
Department of Drug Discovery Support, General Pharmacology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Germany. Michael.Markert@bc.boehringer-ingelheim.com
Klumpp
Anja
A
Trautmann
Thomas
T
Guth
Brian
B
D000280:Administration, Inhalation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D004285:Dogs; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004353:Drug Evaluation, Preclinical; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D000068759:Formoterol Fumarate; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009330:Nebulizers and Vaporizers; D013686:Telemetry / Q000295:instrumentation / Q000379:methods
D001993:Bronchodilator Agents; D004983:Ethanolamines; D000068759:Formoterol Fumarate