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Integration of functional endpoints into repeat-dose toxicity studies
Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 259–262
261
S–17 Mechanisms of visceral/cardiac pain perception
S–33 Integration of functional endpoints into repeat-dose toxicity studies
Robert D. Foreman University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
W.S. Redfern, S. Storey, H. Prior, L. Ewart, J.-P. Valentin Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, SK10 4TG, United Kingdom
Visceral/cardiac pain, and its treatment, depends on the neural hierarchy of the brain, spinal cord and the visceral organs to modulate complex mechanisms underlying visceral disease. Recent research from our laboratory has shown that the C1-C2, and T2-T4 segments of the spinal cord are important areas for processing and modulating cardiac afferent information in the neural hierarchy. The spinal cord, especially the upper cervical region, is capable of making important adjustments in sensory processing of cardiac nociceptive information without requiring the direct involvement of supraspinal pathways. The goal of the presentation is to emphasize and highlight processing capabilities of the spinal cord. This information will add to our understanding about the central nervous system integration of noxious visceral information. The study of the neural hierarchy associated with the processing of nociceptive information should help us develop more effective strategies for relieving pain of visceral origin. doi:10.1016/j.vascn.2009.04.011
S–24 Mechanisms of platelet-mediated thrombosis John D. Folts University of Wisconsin, Madison, WI, United States Thrombosis is a critical and necessary response to stop the bleeding from vascular injury to small arteries, capillaries and venules. Platelets collect at the cut in the artery and provide the release of thrombin and fibrin to staunch the bleeding. When platelets become over-active, however, they contribute to the development of atherosclerosis and thrombosis by a variety of mechanisms. There is extensive evidence that antiplatelet therapy reduces cardiovascular disease. Platelet hyperactivity is increased by cigarette smoking, increases in reactive oxygen species, inflammatory mediators, hypertension, hyperlipidemia, and in diabetes. Platelets release growth factors that promote smooth muscle cell proliferation, inflammation, hypertension, release of reactive oxygen species. They also produce vasospasm and narrowing of arteries. This narrowing leads to the development of thrombotic occlusion of the artery, causing strokes and heart attacks. Knowledge of platelet physiology has led to antiplatelet therapy with Aspirin and other agents which have been shown to reduce cardiac events and to prolong life in patients with cardiovascular disease. The Folts In Vivo Cyclic Flow Animal Model as an approach to study platelets/coagulation in the whole body is discussed. doi:10.1016/j.vascn.2009.04.012
S–25 Central mechanisms of baroreflex control of blood pressure Jeanne Seagard Medical College of Wisconsin, Milwaukee, WI, United States This presentation will examine central components of baroreflex control of blood pressure, focusing on the integration of baroreceptor afferent input by neurons in the brainstem. This is a pivotal regulatory moment, because the signal conditioning at these gateway synapses determine the magnitude, pattern and duration of the baroreceptor signals transmitted to distal synapses in the central network to coordinate baroreflex output and ensuing control of blood pressure. Mechanisms involved in the integration and transmission of baroreceptor input, including neurotransmitters and modulators of baroreceptor input, will be discussed. doi:10.1016/j.vascn.2009.04.013
Safety pharmacology studies almost invariably involve a single administration of test compound, followed by functional measurements for up to 24 h. Whereas pharmacological responses tend to be fairly rapid in onset, and are therefore detectable after a single dose, some may diminish on repeated dosing (tolerance), whereas others increase in magnitude. Also, many toxic effects of drugs are either delayed in onset or require multiple exposures before they develop (e.g., neuropathy). Therefore, single-dose safety pharmacology studies may sometimes miss these late-onset effects. To address this, functional measurements can be incorporated into repeat-dose toxicity studies, either routinely (e.g., ECG) or on an ad hoc basis. There are difficulties in doing this: the availability of suitable technical and scientific expertise in the test facility; suboptimal laboratory conditions; simultaneous (as opposed to staggered) dosing; prioritisation of toxicokinetic sampling; manual data processing; unsuitability of certain techniques (e.g., use of anaesthesia; surgical implantation); low portability of certain equipment. Nevertheless, ‘fit-for-purpose’ data can still be acquired, in both rodents and dogs. Examples in our facility include assessment of activity, sensorimotor function, visual function (visual acuity and pupil control), salivation, ambulatory ECG, and respiratory function. This is entirely achievable if measurements are relatively unobtrusive, both with respect to the animals and the toxicology study. doi:10.1016/j.vascn.2009.04.014
S–36 Long-term regulation of arterial blood pressure Kim Hoagland Merck & Co. Inc., West Point, PA, United States In order to develop and maintain adequate tissue perfusion, many complex and redundant mechanisms have evolved to provide a constant dayto-day level of arterial blood pressure. The feedback control mechanisms responsible for moment-to-moment and long-term blood pressure control are fundamentally different. There are two prevailing hypotheses with regards to long-term regulation of arterial blood pressure: (1) the nervous system detects changes in blood pressure and adjusts levels of sympathetic/ parasympathetic tone to stabilize blood pressure and can change the longterm “set point” around which blood pressure is controlled (2) the kidneys can detect and correct arterial blood pressure by adjusting body fluid volumes via the mechanism of pressure-diuresis and natriuresis. Rapid changes in arterial blood pressure related to changes in posture and other daily activities are stabilized by reflex neuro-humoral mechanisms (hypothesis #1), which were addressed in a previous symposium at this meeting. In this presentation, the dominant role of kidney in long-term arterial blood pressure regulation and the pressure-diuresis volume regulation mechanism (hypothesis #2) are addressed. The interaction between arterial blood pressure and renal excretion of water and electrolytes and how this mechanism is modulated by neural, endocrine and autocoid factors will be discussed. doi:10.1016/j.vascn.2009.04.016
S–38 Drug-induced activation of immune function: Mechanisms and potential adverse effects Curtis Maier GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, United States The immune system has developed highly specialized mechanisms to destroy invading pathogens and eliminate errant cells. The immune system is
261
S–17 Mechanisms of visceral/cardiac pain perception
S–33 Integration of functional endpoints into repeat-dose toxicity studies
Robert D. Foreman University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
W.S. Redfern, S. Storey, H. Prior, L. Ewart, J.-P. Valentin Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, SK10 4TG, United Kingdom
Visceral/cardiac pain, and its treatment, depends on the neural hierarchy of the brain, spinal cord and the visceral organs to modulate complex mechanisms underlying visceral disease. Recent research from our laboratory has shown that the C1-C2, and T2-T4 segments of the spinal cord are important areas for processing and modulating cardiac afferent information in the neural hierarchy. The spinal cord, especially the upper cervical region, is capable of making important adjustments in sensory processing of cardiac nociceptive information without requiring the direct involvement of supraspinal pathways. The goal of the presentation is to emphasize and highlight processing capabilities of the spinal cord. This information will add to our understanding about the central nervous system integration of noxious visceral information. The study of the neural hierarchy associated with the processing of nociceptive information should help us develop more effective strategies for relieving pain of visceral origin. doi:10.1016/j.vascn.2009.04.011
S–24 Mechanisms of platelet-mediated thrombosis John D. Folts University of Wisconsin, Madison, WI, United States Thrombosis is a critical and necessary response to stop the bleeding from vascular injury to small arteries, capillaries and venules. Platelets collect at the cut in the artery and provide the release of thrombin and fibrin to staunch the bleeding. When platelets become over-active, however, they contribute to the development of atherosclerosis and thrombosis by a variety of mechanisms. There is extensive evidence that antiplatelet therapy reduces cardiovascular disease. Platelet hyperactivity is increased by cigarette smoking, increases in reactive oxygen species, inflammatory mediators, hypertension, hyperlipidemia, and in diabetes. Platelets release growth factors that promote smooth muscle cell proliferation, inflammation, hypertension, release of reactive oxygen species. They also produce vasospasm and narrowing of arteries. This narrowing leads to the development of thrombotic occlusion of the artery, causing strokes and heart attacks. Knowledge of platelet physiology has led to antiplatelet therapy with Aspirin and other agents which have been shown to reduce cardiac events and to prolong life in patients with cardiovascular disease. The Folts In Vivo Cyclic Flow Animal Model as an approach to study platelets/coagulation in the whole body is discussed. doi:10.1016/j.vascn.2009.04.012
S–25 Central mechanisms of baroreflex control of blood pressure Jeanne Seagard Medical College of Wisconsin, Milwaukee, WI, United States This presentation will examine central components of baroreflex control of blood pressure, focusing on the integration of baroreceptor afferent input by neurons in the brainstem. This is a pivotal regulatory moment, because the signal conditioning at these gateway synapses determine the magnitude, pattern and duration of the baroreceptor signals transmitted to distal synapses in the central network to coordinate baroreflex output and ensuing control of blood pressure. Mechanisms involved in the integration and transmission of baroreceptor input, including neurotransmitters and modulators of baroreceptor input, will be discussed. doi:10.1016/j.vascn.2009.04.013
Safety pharmacology studies almost invariably involve a single administration of test compound, followed by functional measurements for up to 24 h. Whereas pharmacological responses tend to be fairly rapid in onset, and are therefore detectable after a single dose, some may diminish on repeated dosing (tolerance), whereas others increase in magnitude. Also, many toxic effects of drugs are either delayed in onset or require multiple exposures before they develop (e.g., neuropathy). Therefore, single-dose safety pharmacology studies may sometimes miss these late-onset effects. To address this, functional measurements can be incorporated into repeat-dose toxicity studies, either routinely (e.g., ECG) or on an ad hoc basis. There are difficulties in doing this: the availability of suitable technical and scientific expertise in the test facility; suboptimal laboratory conditions; simultaneous (as opposed to staggered) dosing; prioritisation of toxicokinetic sampling; manual data processing; unsuitability of certain techniques (e.g., use of anaesthesia; surgical implantation); low portability of certain equipment. Nevertheless, ‘fit-for-purpose’ data can still be acquired, in both rodents and dogs. Examples in our facility include assessment of activity, sensorimotor function, visual function (visual acuity and pupil control), salivation, ambulatory ECG, and respiratory function. This is entirely achievable if measurements are relatively unobtrusive, both with respect to the animals and the toxicology study. doi:10.1016/j.vascn.2009.04.014
S–36 Long-term regulation of arterial blood pressure Kim Hoagland Merck & Co. Inc., West Point, PA, United States In order to develop and maintain adequate tissue perfusion, many complex and redundant mechanisms have evolved to provide a constant dayto-day level of arterial blood pressure. The feedback control mechanisms responsible for moment-to-moment and long-term blood pressure control are fundamentally different. There are two prevailing hypotheses with regards to long-term regulation of arterial blood pressure: (1) the nervous system detects changes in blood pressure and adjusts levels of sympathetic/ parasympathetic tone to stabilize blood pressure and can change the longterm “set point” around which blood pressure is controlled (2) the kidneys can detect and correct arterial blood pressure by adjusting body fluid volumes via the mechanism of pressure-diuresis and natriuresis. Rapid changes in arterial blood pressure related to changes in posture and other daily activities are stabilized by reflex neuro-humoral mechanisms (hypothesis #1), which were addressed in a previous symposium at this meeting. In this presentation, the dominant role of kidney in long-term arterial blood pressure regulation and the pressure-diuresis volume regulation mechanism (hypothesis #2) are addressed. The interaction between arterial blood pressure and renal excretion of water and electrolytes and how this mechanism is modulated by neural, endocrine and autocoid factors will be discussed. doi:10.1016/j.vascn.2009.04.016
S–38 Drug-induced activation of immune function: Mechanisms and potential adverse effects Curtis Maier GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, United States The immune system has developed highly specialized mechanisms to destroy invading pathogens and eliminate errant cells. The immune system is