A call for more integrated cardiovascular safety assessment.

Cardiovascular safety concerns are a significant cause of attrition in the development of new drugs (Lasser et al., 2002). This attrition has significant public health implications and also contributes to the rising cost of developing new drugs. However, a better understanding of the inter-relationship between nonclinical and clinical predictors/measures of cardiovascular risk as well as a more integrated and predictive development strategy could dramatically augment the development of safe and effective medicines for patients in need. In response to this need, a consortium of industrial, academic, and government scientists designed and executed a three day 'think tank' under the auspices of the non-profit ILSI Health and Environmental Sciences Institute (ILSI HESI) in June 2009 in Washington, D.C. This highly interactive scientific forum provided a unique opportunity for experts with diverse cardiovascular-related expertise to collectively discuss issues, challenges, and opportunities to improve the overall pharmaceutical cardiovascular safety assessment paradigm. This article identifies the major points of consensus and recommendations stemming from this workshop.

Cardiovascular effects of detomidine, a new alpha 2-adrenoceptor agonist, in the conscious pony.

The cardiovascular effects of detomidine and xylazine were compared in six chronically instrumented, conscious ponies. Ponies were instrumented with a micromanometer in the left ventricular chamber, a Doppler flow probe on a coronary artery and sonomicrometer crystals in the left ventricular free wall. Heart rate, ventricular systolic pressure, stroke work, dP/dtmax, minute work and coronary blood flow were measured for 4 h following intravenous injection of detomidine at several doses or xylazine at 1.1 mg/kg. Both drugs caused a profound hypertensive response at 15 s post-injection. The magnitude of the pressure change did not increase with detomidine doses greater than 20 micrograms/kg. There was a dose-dependent effect on the duration of the hypertension. Bradycardia and A-V blockade of similar magnitude followed the hypertension at all drug doses. Both drugs caused a negative inotropic effect on the heart at all doses. Minute work, a mechanical index of myocardial O2 demand, and coronary flow decreased to a similar extent following all drug treatments. With the exception of a greater hypertensive response, detomidine at the dosages studied, produced cardiovascular effects that were very similar to those of the recommended dosage of xylazine.

Effects of coronary occlusion duration on reactive hyperemia in conscious dogs and ponies.

Coronary reactive hyperemia duration (RHD) and coronary blood flow debt repayment (BFDR) were compared in conscious dogs and ponies instrumented with coronary artery Doppler flow probes and pneumatic occluders. Additional ponies were instrumented with pacing electrodes. With the use of a Latin square design, eight animals of each species were subjected to a randomized series of nine coronary occlusions ranging from 5 s to 2 min in duration. In both species, postocclusion blood flow velocity rose rapidly and plateaued at similar peak levels relative to control, but in ponies this plateau lasted significantly longer. The interspecies difference in plateau duration increased as a function of coronary occlusion duration (COD). RHD ranged from 19.5 +/- 5.9 to 139.7 +/- 5.9 s in dogs and from 26.6 +/- 9.0 to 395.0 +/- 9.0 s in ponies. The slope of the RHD vs. COD curve was steeper in ponies. BFDR was similar in dogs and ponies at the shortest COD (418.1 +/- 26 vs. 451.4 +/- 58%) but declined in dogs as a function of COD to 232.3 +/- 26%. In ponies, BFDR increased as a function of COD to a maximum of 945.4 +/- 58% with a 60-s occlusion and then declined to 614.3 +/- 58%. RHD was not significantly altered in ponies when heart rate was changed to match that in dogs. Although the underlying basis for these interspecies differences in RHD and BFDR was not determined, the differences were considered to be too large to be explained by animal model differences in coronary conductance, collateral blood flow, or myocardial oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Disuse inhibition of newly functional coronary collateral circulation in ponies.

We evaluated the loss of coronary collateral function in the absence of stimulation (disuse inhibition) by doubling the interval between successive left anterior descending coronary artery (LAD) occlusions in ponies in which collateral function initially had been enhanced by 2-min occlusions at 30-min intervals. Before collateralization, occlusion caused segment systolic shortening, velocity of shortening, and stroke work index in the LAD-dependent left ventricular apex to decrease, whereas heart rate and left ventricular end-diastolic pressure increased. After 476 +/- 102 occlusions, segment function recovered to preocclusion levels and hemodynamics were unchanged during occlusion. Occlusion did not elicit sustained functional deterioration until the occlusion interval was greater than or equal to 32 h. During the occlusion after the 128-h interval, segment systolic shortening, velocity of shortening, and stroke work index were reduced 69 +/- 8, 38 +/- 9, and 46 +/- 13%, respectively. Percent recovery of systolic shortening during successive occlusions declined exponentially (T1/e = 102.0 +/- 17.3 h). Thus, in ponies collateral function progressively declines when the occlusion interval is greater than or equal to 32 h, but complete inhibition does not occur even after 128 h without occlusion. This indicates that collateral function in ponies can be maintained by occlusions that are far less frequent than those needed for initial collateral development. The long time constant of collateral disuse inhibition suggests that equine collaterals are quite resistant to the effects of occlusion cessation and differ from canine collaterals in that respect.

Distribution of coronary collateral blood flow at different levels of collateral growth in conscious ponies.

Coronary collateral growth was stimulated in chronically instrumented conscious ponies by a previously validated intermittent coronary occlusion method. Changes in regional myocardial function (sonomicrometry) and reactive hyperemia (Doppler method) were used to monitor collateral growth and to program measurements of regional myocardial blood flow (microsphere method). A serial analysis of the transmural and lateral distributions of collateral blood flow was performed at the native and three superimposed levels of collateral growth. Results in nine animals undergoing an average of 553 +/- 188 brief coronary occlusions over 68 +/- 18 days demonstrated that as collateral conductance increased, the perfusion field within the ischemic region increased from the epicardium to the endocardium but not from the lateral edges to the center of the ischemic region. The findings are consistent with an analog model consisting of interarterial collaterals whose collective resistance is in series with arteriolar resistance of the recipient artery. No special protection of deeper myocardial layers by a subendocardial plexus or intramural collaterals was noted. Instead, the findings suggest that coronary extravascular compressive forces play a more important role than the transmural location of collaterals in determining the volume and spatial distribution of collateral blood flow during collateral growth in the pony.

Equine coronary hemodynamics during brief coronary occlusions at three levels of collateral function.

Adult-grade ponies were surgically instrumented with a Doppler flow probe and pneumatic cuff occluder on the left anterior descending coronary artery (LAD), sonomicrometry crystals and intraventricular micromanometer in the left ventricle, and catheters in the left atrium, anterior interventricular vein, and, in some animals, the LAD. Conscious-animal studies were begun 2 wk after surgery. Measured variables included regional left ventricular systolic function, end-diastolic wall thickness, oxygen extraction, lactate extraction, and hydrogen ion release. Changes in collateral perfusion were deduced from changes in these variables. Serial data were obtained during a 3-min LAD occlusion before stimulation of collateral function by the intermittent coronary occlusion method and during a 10-min LAD occlusion after 14 +/- 2 and 27 +/- 2 days of stimulation. Hemodynamic interpretation of data was based on a model of the equine coronary circulation consisting of collateral and arteriolar resistances in series. It was concluded that 1) chronic stimulation of collateral function leads to the emergence of a time-dependent reduction in total collateral resistance during acute coronary occlusion; 2) with enhancement of collateral function, the major resistance controlling collateral blood flow shifts from the collateral circulation to the recipient vessel arterioles; and 3) at a certain level of enhanced collateral function, coronary occlusion results in a triphasic blood flow response in collateral-dependent myocardium consisting of early hypoperfusion, transient hyperperfusion, and late autoregulated perfusion. This study demonstrates that chronic stimulation of collateral function is accompanied by specific alterations in coronary hemodynamics during acute coronary occlusion that hasten the recovery of ischemic myocardium.

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.