- Email: [email protected]
Neural regulation of the gastrointestinal tract
260
Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 259–262
S–7 Introduction to chronobiology Björn Lemmer Institute of Pharmacology and Toxicology, Ruprecht-Karls University, Heidelberg, Germany Circadian rhythms have been documented throughout the plant and animal kingdom at every level of eukariotic organization. Circadian rhythms by definition are endogenous in nature, driven by oscillators or clocks, and persist under free-running conditions. In various species (Drosophila melongaster, Neurospora, Mouse, Golden hamster) the genes controlling circadian rhythms have been identified (genes: per, frq, clock, tau). Recently, clock genes were identified even in human tissues such as the skin and the mucosa. In general, the endogenous clock in man does not exactly run at a frequency of 24 h but somewhat slower. Environmental time cues or Zeitgebers entrain the circadian rhythm to a precise 24-hour period. Most important to note that endogenous biological rhythms are anticipatory in nature! Thus, rhythmicity inherent to all living systems, allows them to adapt more easily and to better survive under changing environmental conditions during the 24 h of a day as well as during varying conditions of the changing seasons. doi:10.1016/j.vascn.2009.04.006
S–8 Chronopharmacokinetics
S–14 Enabling targeted siRNA delivery in vivo using dynamic polyconjugate technology David B. Rozema, David L. Lewis, Darren H. Wakefield, So Wong, Jason J. Klein, Holly L. Hamilton, Jessica Vera, Stephanie L. Bertin, Tom W. Reppen, Qili Chu, Vladimir Trubetskoy, Andrei V. Blokhin, James E. Hagstrom, Jon A. Wolff Mirus Bio Corporation, Madison, WI, United States Achieving efficient, targeted, in vivo delivery of siRNA to the appropriate tissue and cell type would be a major advance in the use of RNAi in gene function studies and as a therapeutic modality. We have developed a new platform named Dynamic PolyConjugate that enables targeted delivery of siRNA after simple intravenous injection. Key features of the Dynamic PolyConjugate technology include: a new class of membrane-active polymers, reversible chemical masking of the polymers so that membrane-lytic activity is revealed only in the acidic environment of endosomes, and the ability to attach ligands to guide the polymer and the siRNA cargo to specific cell types in vivo. We demonstrate the utility of this technology by ligand-mediated delivery of siRNA to liver hepatocytes with high-level knockdown of the targeted gene. Importantly, Dynamic PolyConjugates display a low toxicity profile enabling siRNA redosing and long-term target gene knockdown. The ability to selectively target specific cell types is an important characteristic of the Dynamic PolyConjugate technology and we anticipate that attachment of other ligands will enable siRNA-mediated knockdown of genes in a variety of tissues and cell types. doi:10.1016/j.vascn.2009.04.009
Björn Lemmer Institute of Pharmacology and Toxicology, Ruprecht-Karls University, Heidelberg, Germany It is still a common paradigm in clinical pharmacology that pharmacokinetic parameters as well as drug effects are considered not to be influenced by the time of day of drug administration. However, it is now well established that nearly all functions of the body, including those influencing pharmacokinetic parameters, display significant daily variations. In man the organization in time can also be seen in certain states of disease in which the onset and symptoms do not occur at random within 24 h of a day, e.g. asthma attacks, coronary infarction, angina pectoris, rheumatic symptoms and pain in osteoarthritis, post operation and tooth pain. There are data in experimental animals and in man demonstrating that drugs of different classes used in bronchial asthma (theophylline, antileukotries, steroids), hypertension/angina (beta-blockers, nitrates, digoxin, etc) or for pain treatment (local anesthetics, NSAIDs, opioids, and placebo) cannot only display significant variations in their pharmacokinetics but also in their effects/side effects.
S–16 Neural regulation of the gastrointestinal tract Gary M. Mawe University of Vermont, Burlington, VT, United States
Drug development is a long and expensive process. Identifying potential safety issues early in the process allows resources to be directed to the most promising candidates while providing an opportunity for problems in other candidates to mitigated or managed. The use of genetically modified (GeM) animal models, particularly mouse models, to establish gene function has been well documented in the literature. More recently, GeM models have been applied to evaluating potential safety risks. This presentation will provide examples of how GeM animals, predominantly mice, are currently being used in the drug discovery process to understand safety risks associated with specific targets and compounds.
Nearly a century ago, Langley defined the autonomic nervous system in terms of three divisions: sympathetic, parasympathetic, and enteric. During the intervening decades, most lectures and textbooks on the ANS have incorporated the enteric nervous system (ENS) into the parasympathetic division for the sake of simplicity. However, recent advances in our understanding of the basic elements of the ENS, as well as an increased appreciation for its relevance in gastrointestinal pathophysiology, have led to a resurgence of interest in, and appreciation for, the ENS. This talk will be divided into three sections. The first section will provide an overview of the organization of the ENS, and describe how reflex circuits intrinsic to the ENS can independently regulate gastrointestinal functions such as motility, secretion and vasodilation. The ENS comprises over thirty neuroactive compounds, a plethora of receptors, and more neurons than the entire spinal cord. Subpopulations of neurons serve as primary afferent neurons, interneurons, and excitatory or inhibitory motor neurons. The activity of redundant circuitry along the intestines is crucial for the digestive and absorptive functions of the gastrointestinal tract. The second section of the talk will cover the topic of pharmacological targets in the ENS. In particular, I will discuss how opioid receptor agonists act via a presynaptic inhibitory mechanism to decrease propulsive motility in the gut, and how opioid receptor antagonists can be used to attenuate the constipation side effects experienced by individuals receiving opiate therapy to alleviate pain. I will also discuss the use of compounds that target serotonin receptors for the treatment of diarrhea or constipation. The third section of the talk will concentrate on changes that occur in the neural circuitry of the inflamed colon, and the ways in which these changes contribute to altered colonic function. In summary, the ENS is a complicated neural system, but recent advances in our understanding of the intricacies of enteric circuitry are leading to improved treatment options.
doi:10.1016/j.vascn.2009.04.008
doi:10.1016/j.vascn.2009.04.010
doi:10.1016/j.vascn.2009.04.007
S–13 Genetically modified animals models and safety testing Sandra Engle Pfizer Inc., Groton, CT, United States
Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 259–262
S–7 Introduction to chronobiology Björn Lemmer Institute of Pharmacology and Toxicology, Ruprecht-Karls University, Heidelberg, Germany Circadian rhythms have been documented throughout the plant and animal kingdom at every level of eukariotic organization. Circadian rhythms by definition are endogenous in nature, driven by oscillators or clocks, and persist under free-running conditions. In various species (Drosophila melongaster, Neurospora, Mouse, Golden hamster) the genes controlling circadian rhythms have been identified (genes: per, frq, clock, tau). Recently, clock genes were identified even in human tissues such as the skin and the mucosa. In general, the endogenous clock in man does not exactly run at a frequency of 24 h but somewhat slower. Environmental time cues or Zeitgebers entrain the circadian rhythm to a precise 24-hour period. Most important to note that endogenous biological rhythms are anticipatory in nature! Thus, rhythmicity inherent to all living systems, allows them to adapt more easily and to better survive under changing environmental conditions during the 24 h of a day as well as during varying conditions of the changing seasons. doi:10.1016/j.vascn.2009.04.006
S–8 Chronopharmacokinetics
S–14 Enabling targeted siRNA delivery in vivo using dynamic polyconjugate technology David B. Rozema, David L. Lewis, Darren H. Wakefield, So Wong, Jason J. Klein, Holly L. Hamilton, Jessica Vera, Stephanie L. Bertin, Tom W. Reppen, Qili Chu, Vladimir Trubetskoy, Andrei V. Blokhin, James E. Hagstrom, Jon A. Wolff Mirus Bio Corporation, Madison, WI, United States Achieving efficient, targeted, in vivo delivery of siRNA to the appropriate tissue and cell type would be a major advance in the use of RNAi in gene function studies and as a therapeutic modality. We have developed a new platform named Dynamic PolyConjugate that enables targeted delivery of siRNA after simple intravenous injection. Key features of the Dynamic PolyConjugate technology include: a new class of membrane-active polymers, reversible chemical masking of the polymers so that membrane-lytic activity is revealed only in the acidic environment of endosomes, and the ability to attach ligands to guide the polymer and the siRNA cargo to specific cell types in vivo. We demonstrate the utility of this technology by ligand-mediated delivery of siRNA to liver hepatocytes with high-level knockdown of the targeted gene. Importantly, Dynamic PolyConjugates display a low toxicity profile enabling siRNA redosing and long-term target gene knockdown. The ability to selectively target specific cell types is an important characteristic of the Dynamic PolyConjugate technology and we anticipate that attachment of other ligands will enable siRNA-mediated knockdown of genes in a variety of tissues and cell types. doi:10.1016/j.vascn.2009.04.009
Björn Lemmer Institute of Pharmacology and Toxicology, Ruprecht-Karls University, Heidelberg, Germany It is still a common paradigm in clinical pharmacology that pharmacokinetic parameters as well as drug effects are considered not to be influenced by the time of day of drug administration. However, it is now well established that nearly all functions of the body, including those influencing pharmacokinetic parameters, display significant daily variations. In man the organization in time can also be seen in certain states of disease in which the onset and symptoms do not occur at random within 24 h of a day, e.g. asthma attacks, coronary infarction, angina pectoris, rheumatic symptoms and pain in osteoarthritis, post operation and tooth pain. There are data in experimental animals and in man demonstrating that drugs of different classes used in bronchial asthma (theophylline, antileukotries, steroids), hypertension/angina (beta-blockers, nitrates, digoxin, etc) or for pain treatment (local anesthetics, NSAIDs, opioids, and placebo) cannot only display significant variations in their pharmacokinetics but also in their effects/side effects.
S–16 Neural regulation of the gastrointestinal tract Gary M. Mawe University of Vermont, Burlington, VT, United States
Drug development is a long and expensive process. Identifying potential safety issues early in the process allows resources to be directed to the most promising candidates while providing an opportunity for problems in other candidates to mitigated or managed. The use of genetically modified (GeM) animal models, particularly mouse models, to establish gene function has been well documented in the literature. More recently, GeM models have been applied to evaluating potential safety risks. This presentation will provide examples of how GeM animals, predominantly mice, are currently being used in the drug discovery process to understand safety risks associated with specific targets and compounds.
Nearly a century ago, Langley defined the autonomic nervous system in terms of three divisions: sympathetic, parasympathetic, and enteric. During the intervening decades, most lectures and textbooks on the ANS have incorporated the enteric nervous system (ENS) into the parasympathetic division for the sake of simplicity. However, recent advances in our understanding of the basic elements of the ENS, as well as an increased appreciation for its relevance in gastrointestinal pathophysiology, have led to a resurgence of interest in, and appreciation for, the ENS. This talk will be divided into three sections. The first section will provide an overview of the organization of the ENS, and describe how reflex circuits intrinsic to the ENS can independently regulate gastrointestinal functions such as motility, secretion and vasodilation. The ENS comprises over thirty neuroactive compounds, a plethora of receptors, and more neurons than the entire spinal cord. Subpopulations of neurons serve as primary afferent neurons, interneurons, and excitatory or inhibitory motor neurons. The activity of redundant circuitry along the intestines is crucial for the digestive and absorptive functions of the gastrointestinal tract. The second section of the talk will cover the topic of pharmacological targets in the ENS. In particular, I will discuss how opioid receptor agonists act via a presynaptic inhibitory mechanism to decrease propulsive motility in the gut, and how opioid receptor antagonists can be used to attenuate the constipation side effects experienced by individuals receiving opiate therapy to alleviate pain. I will also discuss the use of compounds that target serotonin receptors for the treatment of diarrhea or constipation. The third section of the talk will concentrate on changes that occur in the neural circuitry of the inflamed colon, and the ways in which these changes contribute to altered colonic function. In summary, the ENS is a complicated neural system, but recent advances in our understanding of the intricacies of enteric circuitry are leading to improved treatment options.
doi:10.1016/j.vascn.2009.04.008
doi:10.1016/j.vascn.2009.04.010
doi:10.1016/j.vascn.2009.04.007
S–13 Genetically modified animals models and safety testing Sandra Engle Pfizer Inc., Groton, CT, United States