Cardiovascular effects of the macrolide antibiotic tilmicosin

J. vet. Pharmacol. Therap. 19, 225-232, 1996.

SYSTEMIC PHARMACOLOGY

Cardiovascular effects of the macrolide antibiotic tilmicosin, administered alone and in combination with propranolol or dobutamine, in conscious unrestrained dogs

B. W. MAIN Main, B.W., Means, J.R., Rinkema, L.E., Smith, W.C., Sarazan, R.D.

Cardiovascular effects of the macrolide antibiotic tilmicosin, administered alone J. R. MEANS

and in combination with propranolol or dobutamine, in conscious unrestrained

dogs. J. vet. Pharmacol. Therap. 19, 225-232. L. E. RINKEMA

W. C. SMITH &

R. D. SARAZAN

Tilmicosin(TM), a macrolide antibiotic and active ingredient in formulated

Micotil 300m (Eli Lilly and Co., Indianapolis, IN. USA), is the active ingredient Lilly Research Laboratories, Greenfield, IN

in a formulated animal product used for the treatment of respiratory tract

46140, USA 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 HCI(D0B) were evaluated. Dogs were instru- mented 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(,,,,) 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 ~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(,,,,) 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 pg/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 (31-receptor stimulation. DOB reversed some, but not all, of the effects caused by TM administration.

(Paper received 31 October 1994; accepted for publication 18 December 1995)

Bradley W. Main, Lilly Research Laboratories, Drop GL45, PO Box 708, Greenfield IN, 46140, USA

INTRODUCTION Tilmicosin is a macrolide antibiotic intended for use in the treatment of bacterial infections in livestock. The antibiotic is intended for subcutaneous (SC) administration in cattle with respiratory tract infections. Initial toxicologic data indicated that lethal doses were accompanied by an increase in HR and an apparant loss of ventricular function. The present study was designed with regard to discussions with European regulatory agencies, who expressed concerns about the accidental injection of formulated antibiotic to a livestock handler. The purpose of the present study was to provide detailed data

01996 Blackwell Science Ltd 225 226 B.W. Main

et al.

on the effects of a sub lethal dose (2.5 mg/kg body weight) of tilmicosin alone or in combination with a positive inotrope (dobutamine HCI). A p-adrenergic antagonist (propranolol) was also used to rule out P-agonist activity, as earlier studies that

monitored only HR indicated that HR increased after tilmicosin administration. Additionally. dosages of 0.25. 1.0, 2.5. and 5.0 mg/kg were used to determine the dose-related effects of the compound. MATERIALS AND METHODS Dogs and surgical preparation Mixed-breed dogs (1 1-18.7-months-old) were obtained from a commercial breeder. Mean body weight was 18.3 kg. Dogs were conditioned to canvas jackets, plastic Elizabethan collars, and flexible metal tethers for a minimum of 2 days before surgery. Injectable antibiotic was administered 1 day before surgery. General anaesthesia was induced with a 2% solution of an ultrashort-acting anesthetic (Brevital@ Eli LiUy and Co. India- napolis, IN, USA), 0.5 mL/kg given i.v. to egect. Anesthesia was maintained with isoflurane in 100% 02. A left-sided thoracotomy was performed with each dog positioned in right lateral recumbency. A micromanometer (Konigsberg Inc, Pasadena, CA. USA) was implanted in the descending thoracic aorta through a stab incision and was tied in place, using purse-string sutures of synthetic, non-absorbable suture material. Next, the pericardium was opened and partially resected. A second micromanometer was implanted in the left ventricular chamber through a stab incision in the ventricular apex and was tied in place, using a purse-string suture. The thorax was closed in several layers, and the instrument wires were routed subcutaneously to their exit point between the scapulae. Silver electrodes were implanted SC in the right shoulder and the left hip to record ECG. A sterile cannula was placed in a femoral vein and exteriorized through an incision on the dorsal surface of the dog, near the instrumentation wires. The cannula and wires were routed to a specially designed pocket on the dog's jacket. Post-operative analgesics were administered during and after recovery from general anaesthe- sia, as required for signs of pain. Antibiotic therapy was continued for 4 days after surgery. Each cannula was flushed with heparinked saline solution (5 U of heparin/mL) at least once daily to maintain cannula patency. All dogs were allowed at least 2 weeks to recover from any surgical procedure prior to dosing and data collection. Treatment groups The study was conducted in 2 segments. In phase 1. six dogs were assigned at random to 6 treatment orders, using a Latin square design. The dose of tilmicosin remained fixed at 2.5 mg/ kg. The 6 treatments were vehicle. tilmicosin alone, tilmicosin immediately followed by propranolol treatment, and tilmicosin followed by 1 of 3 dosages of dobutamine HCI infused for ~45 min. In phase 2 of the study, doses of 0.25, 1.0. and 5.0 mg/kg were administered to obtain dose-response informa- tion. The dosing regimen was as follows: Treatment Compounds Adminiskred Intravenously Treatment. 2.5 mg/kg tilmicosin; 2.5 mg/kg tilmicosin + 1 pg/ min/kg dobutamine HCI: 2.5 mg/kg tilmicosin + 3 pg/min/kg