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Comparison of cardiac function using echocardiography and standard techniques in the anesthetized dog
254
Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 210–258
of a compound whose development was terminated due to a supposed effect on QTc prolongation detected in clinical studies. A Bayesian model, enabling results from the foregoing studies to be integrated and interpreted in terms of the probability of an unwanted cardiac effect was used to characterise the relationships between concentration and QTc and heart rate. We show the concentration–heart rate relationship in the dog was predictive of the effect seen in the humans when taking into account the difference in achieved concentrations. Furthermore, no relationship between concentration and QTc was seen in dog or human studies, suggesting the original interpretation of an unwanted effect on QTc was a false positive. An integrated concentration–response approach to cardiac safety, such as the one presented, should be routine to enable informed decision making.
Comparison of cardiac function using echocardiography and standard techniques in the anesthetized dog
may translate to orders of magnitude greater M/M but may not be manifested for months or years and may cause significant expense and embarrassment to the producer. For example, a 2 mmHg increase in pulse or systolic pressure may translate to a 7% increase in mortality from heart failure or stroke. There are 6 expressions of SAP exist (systolic, diastolic, mean, pulse, late systolic augmentation, velocity) and each, if altered, may translate to specific M/M (e.g., heart failure, stroke, renal impairment). This presentation will review the physiological origin of the aortic pressure pulse, putative normal values for a number of species used commonly in studies of safety pharmacology, how it should be interrogated, major determinants, and how specific drugs (e.g., isoproterenol, phenylephrine, nitroprusside) may be selected as positive controls to identify a potential test article-induced effect. It will conclude with examples of how SAP measured in peripheral arteries may not reflect, accurately, the SAP in the proximal portion of the aorta, and will emphasize that the left ventricle does not pump blood through the peripheral arteries or arterioles, but rather only into the proximal portion of the aorta. Thus it is important to either measure or to derive the pressure pulse in the proximal portion of the aorta, since that pressure, if changed by a test article, may be more likely to reflect a potential liability of a test article.
Jason A. Segreti Abbott Laboratories, Abbott Park, IL, United States
doi:10.1016/j.vascn.2009.04.180
doi:10.1016/j.vascn.2009.04.178
Safety biomarkers are routinely used in the pre-clinical and clinical development of investigational drugs. One cardiac safety biomarker that increasingly affects decision-making in clinical studies is the assessment of left ventricular function by ejection fraction or fractional shortening using echocardiography. The goal of the present study is to provide correlation data between the preclinical and clinical settings. Specifically, how does data from the comprehensively instrumented anesthetized dog correlate to data obtained using echocardiography in the same dog? Reference positive (PI) and negative inotropes (NI) were used to either increase or decrease cardiac function, respectively. Contractility was measured by 1) a Millar catheter inserted into the left ventricle for determination of dP/dt, and 2) M-Mode echocardiography for ejection fraction and fractional shortening. There were significant correlations 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 echocardiography and thermodilution methods and demonstrated a significant correlation between the two methods (PI, r = 0.88, NI; r = 0.87). These data demonstrate that cardiac measurements determined by echocardiography correlate with data obtained in the comprehensively instrumented canine. Therefore, applying echocardiography pre-clinically may provide important translational information of predicted clinical effects.
doi:10.1016/j.vascn.2009.04.179
Origin and interpretation of the systemic arterial pressure pulse in safety pharmacology Robert L. Hamlin The Ohio State University/QTest Labs, Columbus, OH, United States Effects of a test article on systemic arterial pressure (SAP) must be identified, since even small changes may contribute to morbidity and mortality (M/M). Although acute, profound changes in SAP are identified easily, unlike those acute effects or electrophysiological effects that may produce immediate and obvious M/M, subtle changes in SAP
Assessment of left ventricular pressure in conscious beagle dogs using telemetry Kevin Norton Charles River Laboratories Preclinical Services Montreal, Quebec, Canada Historically measurement of left ventricular pressure (LVP) and contractility has been limited to acute studies due to restriction implied by surgical and monitoring techniques. With advances in telemetry it is now feasible to develop chronic models for assessing LVP in conjunction with systemic pressures and ECG evaluations. The objective of this study was to develop a model for continuous evaluation of LPV in conscious non-restrained dogs and assess potential adverse effects not detected by traditional assessments. Baseline LVP was measured over four weeks, during which period values remained stable. Animals were treated with Atenol and Pemobendan, and LVP, systemic pressure, heart rate and ECG intervals measured for up to 24 h. Atenol, caused a rapid decrease in heart rate, ∼30%, which was also followed by a rapid and sustained decreased in maximum left ventricular contractility of a similar magnitude. No effects were noted on blood pressures. Pemobendan caused a rapid increase in maximum left ventricular contractility (+dP/dt mmHg/s). Contractility increased by ∼100% and remained elevated for up to 4 h. Over the same period no significant changes in heart rate or systemic blood pressure were noted. In conclusion this model demonstrates that LVP can be assessed on long term studies in conscious unrestrained animals using telemetry and administration of known positive controls Atenol and Pemobendan, cause significant adverse cardiovascular effects which would not necessarily be detected by regular telemetry assessments of systemic blood pressures and heart rate. doi:10.1016/j.vascn.2009.04.181
Investigation of orthostatic response during telemetry studies: Example with verapamil Pierre Lainee AstraZeneca R&D, Macclesfield, Cheshire, United Kingdom
Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 210–258
of a compound whose development was terminated due to a supposed effect on QTc prolongation detected in clinical studies. A Bayesian model, enabling results from the foregoing studies to be integrated and interpreted in terms of the probability of an unwanted cardiac effect was used to characterise the relationships between concentration and QTc and heart rate. We show the concentration–heart rate relationship in the dog was predictive of the effect seen in the humans when taking into account the difference in achieved concentrations. Furthermore, no relationship between concentration and QTc was seen in dog or human studies, suggesting the original interpretation of an unwanted effect on QTc was a false positive. An integrated concentration–response approach to cardiac safety, such as the one presented, should be routine to enable informed decision making.
Comparison of cardiac function using echocardiography and standard techniques in the anesthetized dog
may translate to orders of magnitude greater M/M but may not be manifested for months or years and may cause significant expense and embarrassment to the producer. For example, a 2 mmHg increase in pulse or systolic pressure may translate to a 7% increase in mortality from heart failure or stroke. There are 6 expressions of SAP exist (systolic, diastolic, mean, pulse, late systolic augmentation, velocity) and each, if altered, may translate to specific M/M (e.g., heart failure, stroke, renal impairment). This presentation will review the physiological origin of the aortic pressure pulse, putative normal values for a number of species used commonly in studies of safety pharmacology, how it should be interrogated, major determinants, and how specific drugs (e.g., isoproterenol, phenylephrine, nitroprusside) may be selected as positive controls to identify a potential test article-induced effect. It will conclude with examples of how SAP measured in peripheral arteries may not reflect, accurately, the SAP in the proximal portion of the aorta, and will emphasize that the left ventricle does not pump blood through the peripheral arteries or arterioles, but rather only into the proximal portion of the aorta. Thus it is important to either measure or to derive the pressure pulse in the proximal portion of the aorta, since that pressure, if changed by a test article, may be more likely to reflect a potential liability of a test article.
Jason A. Segreti Abbott Laboratories, Abbott Park, IL, United States
doi:10.1016/j.vascn.2009.04.180
doi:10.1016/j.vascn.2009.04.178
Safety biomarkers are routinely used in the pre-clinical and clinical development of investigational drugs. One cardiac safety biomarker that increasingly affects decision-making in clinical studies is the assessment of left ventricular function by ejection fraction or fractional shortening using echocardiography. The goal of the present study is to provide correlation data between the preclinical and clinical settings. Specifically, how does data from the comprehensively instrumented anesthetized dog correlate to data obtained using echocardiography in the same dog? Reference positive (PI) and negative inotropes (NI) were used to either increase or decrease cardiac function, respectively. Contractility was measured by 1) a Millar catheter inserted into the left ventricle for determination of dP/dt, and 2) M-Mode echocardiography for ejection fraction and fractional shortening. There were significant correlations 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 echocardiography and thermodilution methods and demonstrated a significant correlation between the two methods (PI, r = 0.88, NI; r = 0.87). These data demonstrate that cardiac measurements determined by echocardiography correlate with data obtained in the comprehensively instrumented canine. Therefore, applying echocardiography pre-clinically may provide important translational information of predicted clinical effects.
doi:10.1016/j.vascn.2009.04.179
Origin and interpretation of the systemic arterial pressure pulse in safety pharmacology Robert L. Hamlin The Ohio State University/QTest Labs, Columbus, OH, United States Effects of a test article on systemic arterial pressure (SAP) must be identified, since even small changes may contribute to morbidity and mortality (M/M). Although acute, profound changes in SAP are identified easily, unlike those acute effects or electrophysiological effects that may produce immediate and obvious M/M, subtle changes in SAP
Assessment of left ventricular pressure in conscious beagle dogs using telemetry Kevin Norton Charles River Laboratories Preclinical Services Montreal, Quebec, Canada Historically measurement of left ventricular pressure (LVP) and contractility has been limited to acute studies due to restriction implied by surgical and monitoring techniques. With advances in telemetry it is now feasible to develop chronic models for assessing LVP in conjunction with systemic pressures and ECG evaluations. The objective of this study was to develop a model for continuous evaluation of LPV in conscious non-restrained dogs and assess potential adverse effects not detected by traditional assessments. Baseline LVP was measured over four weeks, during which period values remained stable. Animals were treated with Atenol and Pemobendan, and LVP, systemic pressure, heart rate and ECG intervals measured for up to 24 h. Atenol, caused a rapid decrease in heart rate, ∼30%, which was also followed by a rapid and sustained decreased in maximum left ventricular contractility of a similar magnitude. No effects were noted on blood pressures. Pemobendan caused a rapid increase in maximum left ventricular contractility (+dP/dt mmHg/s). Contractility increased by ∼100% and remained elevated for up to 4 h. Over the same period no significant changes in heart rate or systemic blood pressure were noted. In conclusion this model demonstrates that LVP can be assessed on long term studies in conscious unrestrained animals using telemetry and administration of known positive controls Atenol and Pemobendan, cause significant adverse cardiovascular effects which would not necessarily be detected by regular telemetry assessments of systemic blood pressures and heart rate. doi:10.1016/j.vascn.2009.04.181
Investigation of orthostatic response during telemetry studies: Example with verapamil Pierre Lainee AstraZeneca R&D, Macclesfield, Cheshire, United Kingdom