of a compound whose development was terminated due to a supposedeffect on QTc prolongation detected in clinical studies. A Bayesian model,enabling results from the foregoing studies to be integrated andinterpreted in terms of the probability of an unwanted cardiac effectwas used to characterise the relationships between concentration andQTcand heart rate. We show the concentration–heart rate relationship in thedog was predictive of the effect seen in the humans when taking intoaccount the difference in achieved concentrations. Furthermore, norelationship between concentration and QTc was seen in dog or humanstudies, suggesting the original interpretation of an unwanted effect onQTc was a false positive. An integrated concentration–response approachto cardiac safety, such as the one presented, should be routine to enableinformed decision making.

doi:10.1016/j.vascn.2009.04.178

Comparison of cardiac function using echocardiography andstandard techniques in the anesthetized dog

Jason A. SegretiAbbott Laboratories, Abbott Park, IL, United States

Safety biomarkers are routinely used in the pre-clinical andclinical development of investigational drugs. One cardiac safetybiomarker that increasingly affects decision-making in clinicalstudies is the assessment of left ventricular function by ejectionfraction or fractional shortening using echocardiography. The goalof the present study is to provide correlation data between the pre-clinical and clinical settings. Specifically, how does data from thecomprehensively instrumented anesthetized dog correlate to dataobtained using echocardiography in the same dog? Referencepositive (PI) and negative inotropes (NI) were used to eitherincrease or decrease cardiac function, respectively. Contractilitywas measured by 1) a Millar catheter inserted into the left ventriclefor determination of dP/dt, and 2) M-Mode echocardiography forejection fraction and fractional shortening. There were significantcorrelations when comparing dP/dt to fractional shortening(PI, r=0.95, NI; r=0.76) and ejection fraction (PI, r=0.87, NI;r=0.74). Additionally, cardiac output was determined by echocar-diography and thermodilution methods and demonstrated asignificant correlation between the two methods (PI, r=0.88, NI;r=0.87). These data demonstrate that cardiac measurementsdetermined by echocardiography correlate with data obtained inthe comprehensively instrumented canine. Therefore, applyingechocardiography pre-clinically may provide important transla-tional information of predicted clinical effects.

doi:10.1016/j.vascn.2009.04.179

Origin and interpretation of the systemic arterial pressure pulsein safety pharmacology

Robert L. HamlinThe Ohio State University/QTest Labs, Columbus, OH, United States

Effects of a test article on systemic arterial pressure (SAP) must beidentified, since even small changes may contribute to morbidity andmortality (M/M). Although acute, profound changes in SAP areidentified easily, unlike those acute effects or electrophysiological effectsthat may produce immediate and obvious M/M, subtle changes in SAP

may translate to orders of magnitude greater M/M but may not bemanifested for months or years and may cause significant expense andembarrassment to the producer. For example, a 2 mmHg increase inpulse or systolic pressure may translate to a 7% increase in mortalityfrom heart failure or stroke. There are 6 expressions of SAP exist(systolic, diastolic,mean, pulse, late systolic augmentation, velocity) andeach, if altered, may translate to specific M/M (e.g., heart failure, stroke,renal impairment). This presentation will review the physiologicalorigin of the aortic pressure pulse, putative normal values for a numberof species used commonly in studies of safety pharmacology, how itshould be interrogated, major determinants, and how specific drugs(e.g., isoproterenol, phenylephrine, nitroprusside) may be selected aspositive controls to identify a potential test article-induced effect. It willconclude with examples of how SAP measured in peripheral arteriesmay not reflect, accurately, the SAP in the proximal portion of the aorta,andwill emphasize that the left ventricle does not pump blood throughthe peripheral arteries or arterioles, but rather only into the proximalportion of the aorta. Thus it is important to either measure or to derivethe pressure pulse in the proximal portion of the aorta, since thatpressure, if changed by a test article, may be more likely to reflect apotential liability of a test article.

doi:10.1016/j.vascn.2009.04.180

Assessment of left ventricular pressure in conscious beagle dogsusing telemetry

Kevin NortonCharles River Laboratories Preclinical Services Montreal, Quebec, Canada

Historically measurement of left ventricular pressure (LVP) andcontractility has been limited to acute studies due to restrictionimplied by surgical and monitoring techniques. With advances intelemetry it is now feasible to develop chronic models for assessingLVP in conjunction with systemic pressures and ECG evaluations. Theobjective of this study was to develop a model for continuousevaluation of LPV in conscious non-restrained dogs and assesspotential adverse effects not detected by traditional assessments.

Baseline LVP was measured over four weeks, during which periodvalues remained stable. Animals were treated with Atenol andPemobendan, and LVP, systemic pressure, heart rate and ECG intervalsmeasured for up to 24 h. Atenol, caused a rapid decrease in heart rate,∼30%, which was also followed by a rapid and sustained decreased inmaximum left ventricular contractilityof a similarmagnitude. No effectswere noted on blood pressures. Pemobendan caused a rapid increase inmaximum left ventricular contractility (+dP/dtmmHg/s). Contractilityincreased by ∼100% and remained elevated for up to 4 h. Over the sameperiod no significant changes in heart rate or systemic blood pressurewere noted. In conclusion this model demonstrates that LVP can beassessed on long term studies in conscious unrestrained animals usingtelemetry and administration of known positive controls Atenol andPemobendan, cause significant adverse cardiovascular effects whichwould not necessarily be detected by regular telemetry assessments ofsystemic blood pressures and heart rate.

doi:10.1016/j.vascn.2009.04.181

Investigation of orthostatic response during telemetry studies:Example with verapamil

Pierre LaineeAstraZeneca R&D, Macclesfield, Cheshire, United Kingdom

Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 210–258254