title: Cardiovascular effects of the macrolide antibiotic tilmicosin, administered alone and in combination with propranolol or dobutamine, in conscious unrestrained dogs.
abstract: Tilmicosin(TM), a macrolide antibiotic and active ingredient in formulated Micotil 300 (Eli Lilly and Co., Indianapolis, IN, USA), is the active ingredient in a formulated animal product used for the treatment of respiratory tract infections in cattle. Owing to the concern of governmental regulatory agencies over the possibility of an accidental injection of the antibiotic to a livestock handler, the cardiovascular effects of sub lethal doses of TM were evaluated in conscious mixed-breed dogs. Left ventricular function, systemic arterial blood pressure, and heart rate (HR) responses to TM alone and in combination with propranolol(P) or dobutamine HCl(DOB) were evaluated. Dogs were instrumented with indwelling micromanometers implanted in the left ventricular chamber and in the thoracic aorta. Cardiovascular variables were recorded, and the peak value of the first derivative of left ventricular pressure (dp/dt(max)) was used as an index of left ventricular inotropic state. Six treatments were randomly assigned to each of the six dogs using a Latin square design. The six treatments were vehicle, TM alone (2.5 mg/kg of body weight), TM immediately followed by P, and TM immediately followed by 1 of 3 dosages of DOB infused for approximately 45 min. Additionally, doses of TM alone (0.25, 1.0, 2.5, and 5.0 mg/kg) were administered to complete a dose-response curve. TM caused dose dependent decreases in (dp/dt(max)) and aortic pulse pressure. HR increased dose-dependently. Left ventricular end-diastolic pressure increased at the 2.5 and 5.0 mg/kg dosages. Left ventricular systolic pressure was reduced dose-dependently at the 2.5 and 5.0 mg/kg dosages. Treatment with P exacerbated the negative inotropic effect and the decrease in left ventricular systolic pressure, but did not attenuate the tachycardia associated with TM treatment. DOB attenuated the changes in ventricular inotropic state in a dose-dependent manner. DOB infusion also restored left ventricular systolic pressure at dosages of 3 or 10 micrograms/min/kg. Our data indicate that toxic doses of TM may have a negative inotropic effect in conscious dogs. HR increased in a dose-dependent manner and was not the result of beta 1-receptor stimulation. DOB reversed some, but not all, of the effects caused by TM administration.
authors.affiliation: Lilly-Research Laboratories, Greenfield, IN 46140, USA.
authors.forename: B W
authors.initials: BW
authors.lastname: Main
authors.forename: J R
authors.initials: JR
authors.lastname: Means
authors.forename: L E
authors.initials: LE
authors.lastname: Rinkema
authors.forename: W C
authors.initials: WC
authors.lastname: Smith
authors.forename: R D
authors.initials: RD
authors.lastname: Sarazan
mesh_terms: D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002138:Calibration; D004280:Dobutamine / Q000008:administration & dosage / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation / Q000662:veterinary; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous / Q000662:veterinary; D016014:Linear Models; D018942:Macrolides; D008297:Male; D009200:Myocardial Contraction; D011433:Propranolol / Q000008:administration & dosage / Q000494:pharmacology; D013610:Tachycardia / Q000139:chemically induced; D015645:Tylosin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000900:Anti-Bacterial Agents; D018942:Macrolides; D004280:Dobutamine; D011433:Propranolol; C052319:tilmicosin; D015645:Tylosin