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

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.

Comparative QSAR studies of two series of 1,4-dihydropyridines as slow calcium channel blockers.

Quantitative structure activity analysis was applied to two series of dihydropyridine (DHP) calcium channel blocking agents. One series of compounds was composed of DHPs substituted in the 4-position with an ortho or meta nitro substituted phenyl ring. The second group consisted of DHPs substituted at the 4-position with a novel thieno [3,2-c] pyridine ring. Both series consisted of compounds with unsymmetrical ester substitutions on the dihydropyridine ring. The antihypertensive activity of the compounds were determined in a spontaneously hypertensive rat model. Regression analysis indicated the antihypertensive activity of an i.v. dose correlated with the calculated octanol/water coefficent (clogP). Regression analysis did not find correlation with the in vitro potency and the clogP values.

A review of the toxicology of the antibiotic MICOTIL 300.

MICOTIL 300 is a new macrolide antibiotic for the treatment of Bovine Respiratory Disease complex. As with other macrolides used in human and veterinary medicine, overdoses of MICOTIL do not produce pathognomonic lesions. The toxicity dose response varies among laboratory animal and domestic livestock species. However, clinical evidence of MICOTIL toxicity due to large doses is generally a manifestation of the positive chronotropic and negative inotropic cardiovascular effects. No adverse environmental effects are expected from the use of MICOTIL in cattle.

Rat model of arterial thrombosis induced by ferric chloride.

The purposes of these studies were to produce a small animal model of arterial thrombosis for study of novel antithrombotic agents, to validate a simple temperature index of occlusive thrombosis, and to describe the composition of the thrombus. Small thermocouple transducers were fabricated from readily available materials. A thermocouple was inserted under a carotid artery of the anesthetized rat and vessel temperature was recorded continuously. Arterial injury was induced by FeCl3 solution applied topically to the artery above the thermocouple. To validate the relationship between thrombotic occlusion and vessel temperature, blood flow velocity, proximal to the injury, and temperature were recorded simultaneously. Temperature decreased rapidly when velocity averaged 24 +/- 12 percent of control and velocity did not differ from zero within 20 sec. In normal vessels, average flow velocity did not decrease significantly from control until a fixed stenosis decreased diameter by 78 percent. Average time to occlusion (TTO), signaled by the abrupt temperature inflection, ranged from 56 +/- 4 min to 14 +/- 1 min after 10 and 65 percent FeCl3 application respectively. Vessel segments were fixed at various times after FeCl3 exposure and examined by scanning electron microscopy. Endothelial damage was observed and was associated with thrombus composed of activated platelets, fibrin strands and entrapped erythrocytes. The results demonstrate that FeCl3 dose-dependently induced formation of an occlusive mixed thrombus that was indexed by monitoring the time between FeCl3 application and a rapid temperature decrease in the carotid artery of the rat.