Total Solution Of Laboratory Animal Science

2003/8/25 更新

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Total Solution of Laboratory Animal Science
「実験動物総合支援システム・特別研究会」

S-1.

　Navigator: 荻原亮介（プライムテック株式会社）

Total Solution of Laboratory Animal Science
「実験動物総合支援システム・特別研究会」

Medcare Scientific Solutions
Bodvar Thorisson, V.P. Sales and Marketing
Medcare Flaga, Reykjavik Iceland
　

Optical Methods for Cellular Ion and Contractility Recording: Emerging Technologies
Tom Udale, Senier Software Engineer,
IonOptix Corp., MA., U.S.A.

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Thursday, September 4

S-1.      Monitoring the Electrocardiogram in Safety Pharmacology: "Pitfalls" to Detect a Potentially Toxic Effect of a Compound, Techniques in the Future.

 Robert Hamlin Ph.D.

 Professor of Department of Veterinary Biosciences, The Ohio State University. Columbus, OH, U.S.A.

 What are the characteristics of a method to improve the ability to detect a potential liability of a pharmacological entity?  Which species/age/sex, when should data be obtained, which leads, what frequency characteristics of the system,  how are deflections, measured and/or quantified, what are "signals" of potential liability in man? We will also discuss the potential for use of animals with pathological substrates (e.g. hypertrophy, heart failure, electrolyte abnormalities).

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Thursday, September 4

S-2      The Application of an Automated Blood Sampling System in Cardiovascular Studies.

 Joseph R. Haywood Ph.D.

Department of Pharmacology & Toxicology, Michigan State University, Michigan U.S.A.

 The understanding of cardiovascular regulation during normal physiological function and in pathophysiological states has been limited by our ability to measure arterial pressure and obtain blood samples during unstressed conditions throughout the day. Development and ease of use of radiotelemetry methodology has made measurement of blood pressure during light and dark periods in rodents common. This methodology has unveiled new insights into blood pressure regulation in resting animals such as exacerbation of day/night differences in blood pressure during high salt intake and the time-course of blood pressure changes in experimental hypertension. Now, development of an automated blood sampling system will permit the assessment of circulating hormones and electrolytes in similarly unstressed conditions. This system will permit new approaches to studying cardiovascular function such as the remote acute administration of drugs and associated blood sampling, timed measurements of hormones to assess diurnal rhythms, and assessment of plasma electrolytes and hormones during the transition of dietary interventions or the onset and maintenance of pathophysiological states. Combined with telemetric measurements of blood pressure, new insights into cardiovascular regulation will be rapid.

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Thursday, September 4

S-3      Electroencephalographic Markers of Pharmacological Compounds

 Michael J. Decker Ph.D, RN, RRT,

Assistant Professor, Department of Neurology, Emory University School of Medicine, Atlanta, GA, U.S.A.

 Transgenic rodent models have helped to advance our understanding of the genetic determinants of many human diseases.  Building upon these models, pharmacogenomic studies seek to determine how genetic inheritance affects the body's response to drugs. Of the many potential physiological parameters than can be assessed, monitoring the electroencephalographic (EEG) activity in transgenic or experimentally-induced rodent models of disease has provided insight into both the neuropathological substrates of neurological disease ad well as potential mechanisms through which pharmacological agents exert their therapeutic effects.  We have developed a rat model of Parkinson’s Disease (PD) by injecting the monoaminergic neurotoxin 6-hydroxydopamine (6-OHDA) into the striatum. Rats with bilateral 6-OHDA lesions of the striatum manifest changes in sleep-wake architecture similar to those seen in human PD (i.e. sleep is disrupted by frequent sleep-state transitions, bouts of wakefulness, as well as a decrease of REM). Rats with 6-OHDA induced lesions of the striatum do not readily sustain the state of wakefulness during the dark phase of the circadian cycle.  The causative mechanism does not appear to be an insufficient amount of sleep as NSW and SWS did not differ between 6-OHDA and control rats during the lights-on phase of the circadian cycle.  The neuropharmacological substrates of these phenomena are under active investigation and may include:  a) indirect effects of dopamine on the pedunculopontine nucleus. b) direct effects of basal ganglia connections on thalamic activity (e.g., reticular thalamic nucleus). or c) heretofore underappreciated direct actions of dopamine upon thalamocortical circuits. In addition, we have assessed electroencephalographic properties in a rat model of chronic renal failure (CRF). Following induction of CRF, blood urea nitrogen (BUN) values increased approximately 400% over baseline levels. During the major sleep period, uremic animals spent an increased percentage of time awake. Of the total sleep time, there was an increased percentage of non-slow wave sleep and a decreased percentage of slow wave sleep. Rapid eye movement sleep did not change but the number of sleep stage transitions decreased significantly. These preliminary data suggest that uremic-induced sleep/wake changes can be expressed in this model and that these alterations are comparable to those obtained in uremic humans, including increased wake and decreased SWS during the major sleep period. In both the rodent model of PD and Uremia, when Bupropion, a dopamine transporter uptake blocker was administered at the beginning of the darkness period, the duration of time spent awake increased followed by increased sleep the following morning. Together, these advances in experimentally and genetically induced rodent models of human disease have necessitated the need for efficient and accurate methodologies to facilitate high throughput phenotyping and to assess therapeutic efficacy of genomic-targeted pharmacological compounds. 

 Keating G.L.,Bailey J.L.,Parker K.P. Rye, D.B.  Sleep Disturbances in a Rat Model of Chronic Renal Failure.  Sleep, Volume 26, Abstract supplement, p. A68, 2003

 Decker M.J., Keating G.L., Hue G.E., Freeman A.A., Rye D.B.  Mesolimbic Dopamines’s Modulation of REM Sleep.  J Sleep Res Suppl; 51, 2002.

 Decker M.J., Keating G.L., Freeman A., Rye D.B.  Focal depletion of dopamine in the sensiromotor striatum of the rat recapitulates Parkinsonian-like sleep-wake disturbances. Sleep 23:A132, Suppl 2000.

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Friday, September 5

S-4      What Constitutes a Complete Cardiovascular Risk Profile?

 Robert Hamlin Ph.D.

Professor of Department of Veterinary Biosciences, The Ohio State University. Columbus, OH, U.S.A.

 A pharmacological agent may constitute a cardiovascular risk to more than the ventricular repolarization. The cardiovascular system possess many physiological properties upon which a drug may exert toxicity. Furthermore these risks may not be acute or even subacute, but may become manifest only after months or years of exposure to the compound. We will discuss how pharmacological agents may affect non-electrophysiological properties (e.g. inotropy, lusitropy, myocardial oxygen consumption, vascular reactivity, baroreceptor sensitivity), as well as conductivity through the atria, AV transmission system and ventricles.

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Friday, September 5

S-5    Safety Pharmacology and Telemetry: Present and Future. 

 Lewis B. Kinter Ph.D.

 AstraZeneca Pharmaceuticals LP, Wilmington, DE. U.S.A

 Telemetry is currently recommended as the most relevant technology for monitoring physiological functions in animals for purposed of human risk assessment (ICH S7A&B).  What will follow the safety pharmacology/telemetry core battery (CV, respiratory & CNS) evaluations in support of first administrations of new drugs in humans?  This lecture will discuss the futures of safety pharmacology and telemetry in terms of a) recent and emerging international guidances and initiatives for pharmaceutical development and risk management, b) lessons learned from the hERG/QT prolongation/ventricular arrhythmia debate, and c) the leveraging the (terrestrial) mammalian pharmaceutical databases in support of new risk assessments in aquatic species.

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Friday, September 5

S-6      Neurochemical and Behavioral Correlates of Neonatal Intermittent Hypoxia

 Michael J. Decker Ph.D, RN, RRT,

Assistant Professor, Department of Neurology, Emory University School of Medicine, Atlanta, GA, U.S.A.

 Disruption of brain perfusion and oxygenation remains the leading cause of perinatal brain damage .  Approximately 2.9 - 9.0 of 1,000 infants experience some degree of perinatal ischemic-anoxic or prolonged anoxic insult.  Neurologic sequellae follow a continuum from permanent and severe cognitive and motor impairments, such as those observed in cerebral palsy, to death.  Ischemic-anoxic insults most often occur in the setting of unambiguous clinical compromise such as placental dysfunction, prolonged labor, premature birth, and cardio respiratory resuscitation.  More insidious mechanisms of perinatal insult exist, such as intermittent apnea with concomitant hypoxia, and occur in 59% to 84% of infants born prior to 36 weeks gestation.  Despite an incidence significantly greater than that of ischemic-anoxic or prolonged anoxic insult, behavioral and neurochemical sequellae of neonatal intermittent hypoxia are not well established. 

 Therefore, we have characterized neurochemical and behavioral traits of adolescent and adult rats exposed to intermittent hypoxic insults as neonates.  Between postnatal days (PN) 7-11, rat pups were exposed to either 20-second bursts of isocapnic hypoxic gas, compressed air, or were left undisturbed with the dam.  On PN 23 pups were instrumented with EEG/EMG electrodes and sleep-wake architecture was characterized.  Locomotor activity was assessed between PN 35-38, learning, and working memory evaluated between PN 53-64.  Rats were sacrificed on PN 80 and tyrosine hydroxylase, vesicular monoamine transporter, dopamine transporter, and dopamine D1 receptors were quantified in the prefrontal cortex, primary sensorimotor cortex, and precommissural striatum by Western blot analyses.  Post-hypoxic pups spent less time awake and more time in REM sleep during the lights-on phase of the circadian cycle, were hyperlocomotive, and expressed impaired working memory.  Striatal expression of vesicular monoamine transporter and D1 receptor proteins were increased in post-hypoxic rats, consistent with depressed dopaminergic signaling.  These observations lead to the intriguing hypothesis that intermittent hypoxia occurring during a period of critical brain development evokes behavioral and neurochemical alterations that are long lasting, and consistent with disorders of minimal brain dysfunction.   Future studies will require the use of long-term monitoring techniques to establish the time point at which these changes first occur as well as their duration.

 1.  Decker M.J., Rye D.B.  Emerging Research: Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning.  Sleep Breath. 2002 Dec;6(4):205-10

2.  Decker M.J.,  Hue G.E., Caudle W.M.,  Miller G.W.,  Keating G.L., Rye D.B.  Episodic neonatal hypoxia evokes executive dysfunction and regionally specific alterations in markers of dopamine signaling (Neurosci, 2003 117:417-4252).

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Thursday, September 4

PS-1  テレメトリー法による無麻酔・無拘束マウス血圧測定法の導入

 柴崎　義明、藤島　和幸、斎藤　恵、平塚　一幸

明治製菓株式会社　薬品総合研究所

 ｻﾝﾌﾟﾙ量が制限される創薬の初期段階の安全性ｽｸﾘｰﾆﾝｸﾞ系としてﾏｳｽを用いた評価は有用である。今回無麻酔・無拘束下ﾏｳｽ血圧測定法の安全性ｽｸﾘｰﾆﾝｸﾞ系導入を検討したので報告する。ﾏｳｽに模擬血圧測定用送信器を腹部大動脈に埋め込み,一般状態観察,体重測定,摂餌量測定を行い,術後3週目 に血液・生化学検査及び剖検・病理検査を実施した(実験1)。更に,血圧測定用送信器を腹部大動脈に埋め込み,血圧,心拍数及び活動量を測定し方法の確認を行った(実験2)。実験1.の結果から,体重は術後2日目まで減少し,術後3日目より回復傾向がみられたが,血液及び血液生化学検査では送信器埋め込みに関連した変化がみられ,一般毒性学的ﾊﾟﾗﾒｰﾀへの影響が示唆された。実験2.では術後1週目より血圧,心拍数および活動量は正常な変動ﾊﾟﾀｰﾝに復し,各薬剤に対する反応も他の動物種での報告とほぼ同様であることから測定法の妥当性が確認された。以上の結果,ﾃﾚﾒﾄﾘｰ法によるﾏｳｽ無麻酔・無拘束下での血圧,心拍数の測定は評価ｻﾝﾌﾟﾙの少量化あるいは遺伝子改変ﾏｳｽｽ等を用いた評価を可能にし,循環器に関する安全性評価の上で有効であることが確認できた。

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Thursday, September 4

PS-2  Investigating the roles of prostaglandins and nitric oxide in cardiorespiratory control of conscious mice.

 James T. Pearson, Mikiyasu Shirai, Hirotsugu Tsuchimochi and Daryl O.Schwenke

 National Institute of Cardiovascular Center, Osaka, Japan

 It is well known that nitric oxide (NO) derived from the neuronal (nNOS), endothelial (eNOS) and inducible NO synthase (iNOS) isoforms play important roles in cardiorespiratory control, including such roles as a neuromodulator and as a powerful vasodilator in the peripheral circulation. Prostaglandins (PG) are important regulators of pulmonary and systemic vasotone, but are also synthesized in the medulla, sympathetic ganglia and peripheral carotid bodies. Prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂) are thought to be produced in these neural tissues as well as the myocardium, especially during ischemia in the latter. As PGI₂ is an important modulator of pulmonary vasotone we first investigated whether NO and PGI₂ both play significant roles in the acute cardiorespiratory responses to hypoxia, and if the absence of both vasodilators leads to exacerbation of hypoxic pulmonary vasoconstriction and therefore diminished ventilatory function. Wild type (WT) and PGI₂ synthase deficient (PGID) mice were implanted with blood pressure telemeters and allowed to recover. Simultaneous measurements of arterial pressure, heart rate (HR), ventilation, O₂ consumption and CO₂ production were made in the same mice in plethysmograph chambers (unrestrained). The cardiorespiratory and metabolic responses of matched pairs of conscious WT and PGID mice to acute hypoxia (10% O₂) were determined under control conditions (saline or DMSO) and after nNOS-specific blockade (7-Nitroindazole) or non-selective NOS blockade (L-NAME) by intraperitoneal bolus injections. We found that neuronal NO is important for potentiating ventilation and HR during hypoxia, and essential for preventing hypometabolism. However, the ventilatory response to hypoxia is not diminished in PGID mice, nor exacerbated in the absence of NO. Endogeneous NO release from multiple isoforms and PGI₂ appear to be important for preventing systemic hypertension during hypoxia in mice.

 Our second aim was to test if a ₂-adrenergic receptor (a ₂-AR) mediated inhibition of sympathetic tone is responsible for attenuation of acute HR and ventilatory responses to hypoxia, and further, if endogeneous PGI₂ enhances this inhibition in conscious mice. The cardiorespiratory and metabolic responses of WT and PGID mice were determined under control conditions (saline) and after a ₂-AR blockade (idazoxan). We found that a ₂-AR do not modify the ventilatory responses to hypoxia. However, the tachycardia induced by acute hypoxia is only inhibited by a ₂-AR in the presence of PGI₂. We conclude that our approach is useful for investigating the roles of neuromodulators and hormones in both central and peripheral control of cardiorespiratory systems under physiologically relevant conditions.

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Thursday, September 4

PS-3　 遺伝子改変マウスの血圧と呼吸、脳波と呼吸の同時・無麻酔無拘束計測

 桑木 共之

 千葉大学大学院医学研究員 先端応用医学研究部門 先端応用医学講座 分子統合生理学

 循環と呼吸の調節に関与する遺伝子を明らかにするために、遺伝子改変マウスの表現形を解析するシステムを構築した。安静時ならびに日常生活で起こりうる各種の揺動を与えた時の血圧と呼吸を記録した。血圧の測定にはテレメトリーシステム、呼吸にはwhole body plethysmograph装置、脳波にはスリップリングを介した有線記録を用いた。これを用いてオレキシン欠損マウスの表現形を解析したところ、情動ストレスによる防衛反応の減弱、睡眠時無呼吸の増加、覚醒時における高二酸化炭素?呼吸促進反応の減弱、が観察された。一方で、痛み刺激による血圧上昇、睡眠時における高二酸化炭素反応等は正常であった。オレキシンは個体の覚醒レベルや情動状態に関連した循環呼吸調節に重要であると結論された。本実験系は、安静時のホメオスタシスだけでなく、ホメオダイナミクスをも遺伝子レベルで研究するのに適していると考えられた。

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Thursday, September 4

PS-4　 Fundamental evaluation of drug-induced QT prolongation in HERG trancefected CHO-K1 cells.

 Shin-ichi Nagayama, Gong Qi, Junko Matsuo, Kiyokazu Yunomae, Mihori Haruyama, Ryoichi Nagata, Go Kito,

Shin Nippon Biomedical Laboratories, Ltd., Kagoshima 891-1394, Japan.

It is well-known that many nonantiarrhythmic drugs produce QT interval prolongation, resulting in torsade de points. In the early phases of new drug developments, standard methods to evaluate the proarrhythmic effect of new drug is important. There are some methods for measuring ion currents in several expression system of HERG such as CHO-K1 cell, HEK293 cell and oocyte cell. We selected HERG-transfected CHO-K1 cell as a model to evaluate cardiac toxicity and studied the effect of several drugs.

[Methods] We used the whole-cell patch-clamp technique to measure the potassium currents on CHO-K1 and HEK293 cell transfected HERG. We compared with these expression system, using non-trancefected cells. We analyzed the tail currents of HERG channels.

[Results] Tail peak currents and steady-state currents in CHO-K1 cells were markedly lower than HEK293 cell. Tail peak currents in HERG-transfected CHO-K1 cells were concentration-dependently inhibited by E-4031, astemizole and terfenadine (0.1nM to 10μM). Tail peak currents in HERG-transfected CHO-K1 cells were use-dependently inhibited by E-4031. The inhibition of the drugs in HERG-transfected CHO-K1 cells was same as to HERG-transfected HEK293 cells. (±)-Sotalol (10nM to 100μM), known to cause torsades de pointes (TdP), did not inhibited tail peak currents in HERG-transfected CHO-K1 cells. Verapamil (10nM to 10μM), which does not cause QT interval prolongation in clinical trials, concentration-dependently inhibited tail peak currents in HERG-transfected CHO-K1 cells. We investigated the effect of solvent on HERG currents. 0.1% and 0.5% DMSO decreased the currents to 94.2% and 61.3% of the control in CHO-K1 cells. We investigate the effect of different external pH on HERG currents in CHO-K1 cells. The amplitude of current was decreased and kinetic of deactivation was faster when external pH was lowered from 7.4 to 6.0. The inhibition by E-4031 and Astemizole (inhibition rate:41.2% and 74.0%) was lower in pH6.0 than pH7.4.

[Conclusion] We recommend that HERG-transfected CHO-K1 cells become standard method to evaluate the cardiac toxicity of new developing drugs.

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Thursday, September 4

SPG-1    Safety Pharmacology and Telemetry: Discipline and Technology Intertwined? 

 Lewis B. Kinter Ph.D.

 AstraZeneca Pharmaceuticals LP, Wilmington, DE. U.S.A

 Physiological functions have transformed to be included as both efficacy and safety endpoints in modern pharmaceutical development.  Telemetry also has transformed from an ‘exotic technique’ to the ‘state-of-the-art’ for monitoring physiological efficacy and safety endpoints in animals (and humans).  Are the resurgence of ‘systems physiology’ and the emergence of telemetry independent or interdependent events?  This lecture will trace co-development of safety pharmacology as an internationally recognized discipline in pharmaceutical development (ICH S7A/B) and of laboratory animal telemetry as an important research technique for obtaining functional physiological endpoints (e.g. biomarkers) in a manner most directly applicable for human risk assessment.  The challenges facing continued growth of telemetry systems in modern drug development will be discussed.

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Thursday, September 4

SPG-2  Good Science Practices: indispensable Safety Pharmacology principles to correctly evaluate the non-clinical propensity of pharmaceuticals to trigger lethal arrhythmia.

Icilio Cavero

Safety Pharmacology Advisor

 The general non-clinical testing strategy proposed by the ICH S7B draft guideline for determining experimentally the potential of pharmaceuticals to prolong QT interval consists of an ion channel assay that measures IKr (IhERG) and an in vivo assay that measures indices of ventricular repolarization such as QT interval. If these tests yield negative results, a repolarization assay that studies the effects on action potential should generally be performed.
 The reliability of results generated by applying this, or in general any research strategy is intrinsically affected by the observance of Good Science Practices (GSP). GSP can be defined as principles to be applied in order to obtain the best experimental answer possible to scientific questions. Hence, GSP require 1) the choice of the most sensitive and specific technology; 2) the preparation of clear and detailed protocols that can be replicated without difficulty by independent investigators; 3) the use of experimental conditions that allow studying as best as feasible the propensity of a test article to produce adverse effects sought-after; 4) the execution of the protocol by experienced technical people; 5) the application of appropriately validated systems for sampling, recording and analyzing results; 6) faithful reporting and objective interpretation of experimental data; and finally 7) working, whenever possible, under GLP conditions (Fig. 1).

(Fig.1)

 For instance, the general non-clinical testing strategy presently propounded by the S7B does not appear to entirely satisfy GSP since it does not recommend a specific study (which is now possible) of the effects of novel pharmaceuticals on major human heart ion transport systems (e.g. INa, ICa, Ito, IKs, IK1) that shape the ventricular action potential. Indeed, test articles producing meaningful changes in any of these currents can jeopardize the electrical stability of the heart.
The main GSP issues to deal with in programming and executing a hERG channel assay are detailed in Fig. 2. Firstly, this channel should preferentially be expressed in a stable manner in a mammalian cell line (e.g. HEK-293). Additionally, temperature, K+ concentration of the cell perfusion medium, channel activation and current reading protocols should replicate as closely as practicable those of the human heart environment within which the channel physiologically operates. Acceptance criteria (e.g. level of current conveyed by the channel under control conditions, stability of responses during control period) to enter a cell into the experimental protocol should be detailed in the protocol and faithfully respected. The use of a matched (or historical) vehicle-treated group has to be decided on the ground of the degree of confidence the investigator wishes to attribute to a threshold effect produced by the highest concentration of a test article studied. Each concentration should be left in contact with the cell for a time sufficiently long to reach a steady-state response before the superfusion of the following concentration is initiated. Experimental-time related decline in the current conveyed by the activated channel (run-down phenomenon) should be quantified and taken into account in the analysis of concentration?response curves if baseline current declines spontaneously by more than 15% over the experimental time. The determination of the nature and the reversibility of the blockade should be considered if this information is deemed of importance in the decision-making process. Validation of the assay with established references should be carried out routinely (blind inclusion of a reference or study of a reference in the matched vehicle?treated group, or on the test item group if the latter does not notably inhibit the current conducted by the channel). The results obtained during the validation procedure of the hERG assay should be compared to those generated for ILSI/HESI sponsored study. The number of cells/concentration tested (> 3) and the number of concentrations (> 3) necessary to build a full concentration-response curve should be selected to allow meaningful conclusions. In order to compute an IC50 variability parameter, the IC50 should be determined by fitting all individual cell data rather than mean values. Statistical tests to analyze the data should be the most robust applicable for the experimental design adopted.

(Fig.2)

 For the ECG assay, important issues (Fig. 3) are the animal species (generally the dog) selected for the study. Anesthesia may be preferable when the test agent has properties (e.g., strong emetic activity) not allowing its correct evaluation in the conscious state. The range of doses investigated should produce plasma levels close to and several fold over those necessary for clinical efficacy whereas the duration of the treatment should be decided on the basis of pharmacokinetic properties of the test item. PR, QRS, RR and QT interval should be routinely measured and any arrhythmic event faithfully reported either when occurring under control or under treatment conditions. The formula for QT correction (Bazett, Fridericia, van der Water, Sarma, individually or group determined, etc.) is of capital importance particularly if the compound produces heart rate changes. A possible better approach to avoid the use of correction formulae is to run experiments under pacing conditions but one should consider that elevated heart rate may obscure or reduce the QT prolonging effects of a test article. The selection of ECG sampling time to determine the effects of a test article may be critical. However, the ideal approach to overcome this problem would be to develop methods allowing the analysis of all heart beats recorded during the entire experimental time (generally 24 h) by using experimentally validated computer technology. The range of baseline values for the parameters measured to enter an animal into the experimental procedure should be detailed in the protocol. Blood samples to determine plasma concentrations of the test article should be taken either during the study of the ECG effects of the compound or in a complementary assay run, if possible, in the same group of animals. The experimental design selected (e.g. crossover or sequential administrations) should be the simplest as possible for revealing the searched effects. Interaction studies may be essential to clearly profile ECG effects of a test article undergoing biotransformation by CYP enzymes. The issue of multiple uses of an instrumented dog should be considered since this has the advantage of having well trained animals known to respond positively to reference drugs delaying cardiac repolarization. The statistical analysis of the large quantity of data generated by ECG experiments requires special attention.

(Fig.3)

 The adoption of GSP studies should become a central preoccupation of Safety Pharmacology investigators to ameliorate quality and to improve the inter-laboratory reproducibility of experimental data. If expertise in a technology used for a Safety Pharmacology study is not available in-house, the help of external independent (not belonging to the CRO staff in charge of the study) consultants are strongly advised to reduce the negligible risk to generate data that do not satisfy GSP requirements and thus failing to correctly assess cardiac safety.

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Thursday, September 4

TL-1  DSI Telemetry in a Safety Pharmacology Setting

 Robert Brockway,

 Senior Marketing Manager - Research Products, Data Science INternational, Arden HIlls, MN U.S.A

 Recent progress by the International Conference on Harmonization (ICH) have provide some guidance and consistency in the conduct of safety pharmacology studies throughout the world.  Implantable telemetry plays a significant role in many of these studies.  GLP studies are playing an increasing role in drug development, particularly in safety pharmacology and toxicology studies.  DSI provides several products as well as value-added tools and services that facilitate conduct of safety pharmacology studies in accordance with ICH guidelines.  Discussion will include telemetry applications, system validation, and other GLP compliance offerings from DSI.

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Thursday, September 4

TL-2   Interest of beat by beat ECG analysis on awaking dogs during 20 hours periods.
Comparison of effects and fast validated reporting system using Excel spreadsheet.

 Philippe Zitoun

 NOTOCORD Systems, Sept 2003

 Many laboratories perform ECG analysis using periodic sampling.  Data is sampled at as 1 minute intervals every 20 minutes during a 24 hour period.  1minute interval sampling is conducted in order to reduce the size of the data file. Sampling is a very common mathematical function. However, limits must be well understood to prevent non desired results or to add unnecessary animals into an assay.

 The basic theorem of sampling was defined in 1948 by Claude Elwood Shannon. This theorem demonstrates that the sampling rate should be at least twice the frequency content of any waveform in order to prevent analysis errors.

 NOTOCORD-hem is able to extract the QT interval on a beat by beat basis as well as 1 minute sampling.  Both signals are available for comparison. On conscious dogs  using telemetry, we demonstrate that QT variations can occur within 1  minute interval sampling (except from drug response). QT interval data sampled every 20 minutes will add a statistic error to the QT measurement. To overcome this error laboratories are add more animals into a study. Analysing data on a beat by beat basis allows for quick validation and reduces the number of animals needed in the study.

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Thursday, September 4

TL-3   Chronic Vascular Access in Rodents: Catheters, Ports, Tethers and Infusion

 Thomas E. Nolan DVM,

  INSTECH-Solomon, Plymouth Meeting, PA, U.S.A.

 Considering the predominant use of rodents in biomedical research and especially the increasing use of transgenic mice, it is essential that investigators and laboratory animal specialist gain current knowledge in the area of vascular infusion in these species. In order to experience success with infusion technology, carefully engineered devices and skillful operative techniques are required. This presentation will focus on the technical aspects of the devices available for vascular infusion. Topics including catheter tip geometry, biocompatibility, and thrombo-resistance will be presented in detail. The design and use of vascular access ports for rodents will be discussed. Discussion of tethering systems will include button tethers, jackets and harnesses, head block systems, swivel design and function, and overall tethering system design.

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Friday, September 5

TL-4   DSI Product Innovations

 Robert Brockway

 Senior Marketing Manager - Research Products, Data Science INternational, Arden HIlls, MN U.S.A

 Several exciting products and collaborations are advancing the applications of implantable telemetry.  An overview will be given on recent and forthcoming product releases including the D70-PCTP, F20-EET, LVP1000, Dataquest A.R.T. 2.3, Physiostat ECG Analysis 4.0 as well as others.  In addition, ongoing collaborations are enabling new advanced applications in telemetry.  Existing collaborations with animal vendors, equipment providers, and data acquisition/analysis companies will be covered.

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Friday, September 5

TL-5   IR-Telemetry controlled & Monitoring of LAB Infusion Pumps

Gudrun M. de Barbera, Harm Kolln

 Sales & Marketing Manager, PEGASUS GMBH, Kiel, Germany

 LogoMed^R GmbH was founded in 1989 and is an expanding medium-sized enterprise. Since 2001 the Manufacturing Department of the LogoMed^R group forms the part company named PEGASUS^R GMBH.

 PEGASUS^R GMBH is developing and  manufacturing the ambulatory infusion pumps PEGASUS^a. They are designed for the treatment of specific diseases, which require the administration of small drug doses. PEGASUS^a pumps are used as well in hospitals as in home care and in research laboratories. Areas of application are e.g., treatment of pain, cancer, hormonal troubles, thromboses­ prophyla­xis, antibiotic therapies etc. PEGASUS^a is recognised by its extreme precision and accuracy.

 The LAB-version of PEGASUS^a has been developed for Laboratory Animal Research. PEGASUS^a LAB permits the transmission of data by telemetry and is a combination of sophisticated hardware and customized software.

 PEGASUS^a LAB is designed to provide the ultimate in "hands-off" tethered or tetherless infusion. All control of the pump can be done from a PC via infra-red signal - no tether or wire are required. This pump for telemetry allows the researcher freedom and flexibility of altering infusion rates as often as desired without disturbing the animal.

 PEGASUS^a LAB can be programmed by the user either for continuous, intermittent or chrono-modulated flow. The programme can be changed, started and stopped as often as desired from a PC. A single PC monitors performance of the pumps, alerts are signalled and may be sent off-site on the PC. A complete record of the continuous monitoring is stored.

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Friday, September 5

TL-6 Respiratory measurement techniques, focussing on Conscious Whole Body Plethysmography and Pulmonary Forced Manoeuvres.

 Peter Connor,

 EMMS, Bordon, Hants, UK

 An introduction to EMMS' range of complete respiratory measurement systems, for use in research, safety pharmacology, toxicology and veterinary studies; illustrated with data sets from asthma and COPD studies.

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Friday, September 5

TL-7 Introduction to the flexiVent - a novel platform for pre-clinical pulmonary research

 Thomas F. Schuessler, Ph.D, President

SCIREQ Montreal, Quebec, Canada

 The flexiVent is a novel, highly integrated platform for pulmonary research that combines a precise small animal ventilator with a computerized data acquisition system and powerful analysis software. The flexiVent allows scientists to efficiently obtain accurate, specific information about the dynamic and quasi-static mechanical properties of different parts of the respiratory system. Using the Forced Oscillation Technique, the flexiVent offers the unique ability to distinguish between airway and tissue mechanics.

 This presentation introduces the flexiVent and provides an overview of its technical and practical advantages for pre-clinical pulmonary research.

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Friday, September 5

TL-8   BION(r): A Self-Contained Injectable Neuromuscular Electrical Stimulation Device

 Yitzhak Zilberman,

 Vice President Business Development, Alfred Mann Foundation, Santa Clarita, CA, U.S.A.

 Injectable BION microstimulators may be used for a variety of animal studies where device size, level of invasiveness and animal freedom to move are a concern.  RF BION devices may satisfy this need.  They are powered by an external magnetic field and are programmable through user-friendly software, allowing the researcher to efficiently modify frequency and pulse shape and other stimulation parameters as necessary. Depending on the implant site, BION microstimulators may be injected or implanted in a cut-down surgery.  Animal studies and biocompatibility tests have shown that the implants are biocompatible, functionally reliable and can remain in situ, without migration and with no adverse effects.

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Friday, September 5

TL-9   Medcare Scientific Solutions

 Bodvar Thorisson,

V.P. Sales and Marketing, Medcare Flaga, Reykjavik Iceland, bodvar@medcare.is

Introduction
Medcare is dedicated to providing progressive technology solutions for the multidisciplinary needs of sleep research. The Medcare Science product line offers an extensive array of hardware and software products for both animal and human applications. Medcare Science products can be configured for complete, integrated solutions or for component solutions designed to work within existing research frameworks. This abstract introduces some of the hardware and software modules offered by Medcare.

Acquisition Solutions
Medcare products can collect and analyze real-time data from Medcare's Embla digital amplifier systems or from other analog amplifiers. The Embla digital acquisition systems are available in configurations designed to meet the requirements of both clinical and animal research applications. Data can also be collected and analyzed from other existing analog amplifiers, by using Analog/Digital conversion boards. By using these options, data can be recorded from a single subject or from multiple animals.
Alternatively, data can be imported from third party systems. Once imported, the data can be reviewed and analyzed with the entire array of powerful Medcare's Somnologica Science software tools. The importing modules support the DSI systems, allowing users to record with the DSI telemetry systems and analyze the data using the Somnologica Science software.

Animal Research Software Solutions
The Somnologica Science offers flexibility and ease-of-use in the research environment.
Somnologica Science comes with a rich portfolio of unique research modules using a modular platform. Flexible software modules provide analysis capabilities for rodent sleep and heart rate analysis as well as custom event scoring for use with any species.

Animal Spectral Tools
The spectral tools can be used to calculate the power and frequency information from any physiological data. The spectral tools include Fast-Fourier Transform (FFT), Power Spectrum, Auto-Regressive (AR) Spectrum, Sleep Power Bands and Spectrogram.
The Fast Fourier Transform (FFT) displays the average frequency components of a selected trace. The average power of each frequency is plotted against the frequency.
The Power Spectrum displays the average of several FFT's. It calculates the power of the given frequency components by overlapped FFT'S. This averaging of the FFT's gives a smoother representation of the frequency components and is useful for longer trace sections.
The Auto Regressive (AR) Spectrum display is an estimation method of signal frequency power where it is assumed that there are several dominant frequencies in the signal.
The number of frequencies to look for is adjustable.
The Spectrogram is a two-dimensional view showing frequency as a function of time.
The energy of each frequency component is shown as a heat map.
The Sleep Power Bands view shows the division of the signal into different frequency bands by estimating the relative power in each band. The bands are user-configurable.

Tools Development Package
This package is for developers, and provides the framework for writing tools for Somnologica Science. This package is named Tools Programmers Interface (TPI) and includes a C++ framework and examples. A number of laboratories have used this option to create their own signal analysis methods.

Rodent Heart Rate Variability Analysis
The Rodent HRV Analysis Module extracts quantified data from a rodent EKG waveform trace and calculates heart rate, heart rate variability and R-R tops.

Rodent Sleep/Wake Analysis
The Rodent Scoring Module analyzes rodent sleep based on user-defined settings and preferences. This automated sleep-scoring module can be used with rats and mice. The Rodent Scoring Export can also be used to export extensive statistical data from a scored rodent file to other software applications.

Event Scoring
A highly flexible manual-scoring interface can be used for creating customized events for sleep staging, respiratory event scoring (apnea, hypopnea, etc), and for many other applications in any animal species.
Detailed event information (including raw data attributes) and statistics are available for custom events.

Generic Exporting
The Generic Export Utility allows creating and saving templates that contain the parameters selected for export. Generic Export Templates can be used with other recordings containing the same signal types.

Animal Reports for Sleep Analysis
In addition to extensive export utilities for creating detailed reports in applications such as Excel., Somnologica Science provides several pre-configured reports for fast and easy report generation. These reports can be used with manual sleep scoring in any species and for automated sleep analysis in rodent data.

Custom Solutions
In addition to the modules offered, Medcare offers to customize solutions as well as assisting in running/analyzing studies.

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Friday, September 5

TL-10 Optical Methods for Cellular Ion and Contractility Recording: Emerging Technologies

 Tom Udale, Doug Tillotson, President,

IonOptix Corp. Milton, MA U.S.A.

 Combined acquisition of intracellular indicator fluorescence and transmitted light data has proven useful for characterizing a wide range of cellular and vascular dynamics.  Simultaneous measurement of intracellular calcium and sarcomere spacing in cardiac myocytes or smooth muscle calcium and diameter in blood vessels permits investigators to test sophisticated hypotheses concerning disease states and pharmacological action.  However, limitations with current sensors and light sources prevent expansion of this technique in obvious and interesting directions for all but the most technically advanced and well-endowed institutions.
 New developments underway at IonOptix aim to remove some of these limitations.  Recent work with ultra high intensity, pulsed LEDs, ultra-low noise avalanche photodiodes, and high-speed digital cameras promise to increase data rates and signal to noise ratios significantly while not greatly increasing cost over current solutions.  These technologies will bring into the mainstream the use of voltage sensitive dyes to investigate the electrical activity of cells; low affinity dyes that promise greatly improved characterization of calcium dynamics; and characterization of the contractility of skeletal muscle just to name a few examples.

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参加予定 海外招待講師

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Professor

Address            Department of Veterinary Biosciences
The Ohio State University
1920 Coffey Road

Columbus, Ohio 43210
Phone (614) 292-8122　Fax (614) 292-6473　e-mail: hamlin.1@osu.edu

Professional　Training and Experience
PhD., The Ohio State University , Columbus
DVM, The Ohio State University, Columbus
Diplomate, American College of Veterinary Internal Medicine

 Research　Interests

• Baroreceptor function in models of heart failure and quantitative lusitropic and inotropic responses to vasoactive drugs, interaortic balloon counterpulsation, positive inotropes, and mineral excesses and deficiencies

• Comparative electrocardiology: pathways of cardiac activation and allometry

• Heart rate variability as affected by heart failure and chronic pulmonary disease Teaching of pulmonary mechanics using physical models Drug safety evaluation

Professional　Activities　/Professional Experience

• Research Fellow, Central Ohio Heart Association
• Research Fellow, (Post-Doctoral) National Institute of Health
• Career Development Awardee, Natioanl Institute of Health
• Stanton Youngberg Professor of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, The Ohio State University
• Senior Attending Clinician, OSU Veterinary Hospital
• Membership (Professional and Honorary Societies)
• American Association for Advancement of Science
• American College of Veterinary Internal Medicine
• American College of Veterinary Cardiology
• American Heart Association, Council on Basic Sciences
• Central Ohio Heart Chapter
• American Physiological Society
• American Academy of Veterinary Cardiology
• Graduate School Faculty
• American Veterinary Medical Association
• Ohio Veterinary Medical Association
• Ohio Academy of Science
• Ohio Thoracic Society
• American Society of Veterinary Physiologists and Pharmacologists
• Visiting Scientists for Minority Institutions /Licensure and Certification
• Ohio and Illinois State Boards of Veterinary Medicine

Diplomate, American College of Veterinary Internal Medicine
- Internal Medicine ? 1973
- Cardiology - 1974

Publications

Partial listing
70. Rath D.P., Zhu H., Tong X., Jiang Z., Hamlin R.L., Robitaille P.M.: Dynamic 13C NMR analysis of pyruvate and lactate oxidation in the in vivo canine myocardium: evidence of reduced utilization with increased work. Magnetic Resonance In Medicine, 38(6):896-906, 1997

71. Hamlin R.L., Nakayama T.: Comparison of some pharmacokinetic parameters of 5 angiotensin-converting enzyme inhibitors in normal beagles. J Vet Int Med, 12(2):93-95, 1998

72. Parameswaran N., Hamlin R.L., Nakayama T.: Increased splenic capacity in response to transdermal application of nitroglycerine in the dog. J Vet Int Med, 13(1):44-46, 1999

73. Parameswaran N., Hamlin R.L., Nakayama T.: Increased splenic capacity in response to transdermal application of nitroglycerine in the dog. J Vet Int Med, 13(1):44-46, 1999

74. Seidler R.W., Mueller K., Nakayama T., Hamlin R.L.: Influence of sotalol on the time constant of isovolumic left ventricular relaxation in anesthetized dogs. Am J Vet Res, 60(6):717-721, 1999.

75. Sawangkoon S., Miyamoto M., Nakayama T., Hamlin R.L.: Acute cardiovascular effects and pharmacokinetics of carvedilol in healthy dogs. AJVR, 61(1):57-60, 2000

76. O'Malley P., Smith B., Hamlin R.L., Nickel J., Nakayama T., MacVicar M., Mann B.: A comparison of bolus versus continuous cardiac output in an experimental model of heart failure. Crit Care Med, 28(6):1985-1990, 2000

▲海外招待講師

Professor
1971, B.S., University of Kentucky
1972, M.S., University of Kentucky
1976, Ph.D., University of Florida
1974, Research Assistant, Sterling-Winthrop Research Institute
1977-78, Research Fellow, University of Iowa
1981-present, Adjunct Scientist, Southwest Foundation for Biomedical Research
1979-1985, Assistant Professor, Pharmacology & Toxicology
1985-1993, Associate Professor, Pharmacology & Toxicology
1993-present, Professor, Pharmacology & Toxicology

Research Synopsis
 My research program is focused on sex differences in the neural and endocrine mechanisms controlling blood pressure in normal and sodium-dependent hypertensive animals. In rat models, central nervous system mechanisms are studied using microinjection and microdialysis techniques to understand the neurochemical basis for changes in sympathoadrenal neural function. Peripheral hemodynamic and neuroendocrine parameters are measured to determine the mechanisms maintaining elevated blood pressure. In related studies, the genetic phenotypes contributing to sodium-dependent hypertension are investigated in a pedigree colony of baboons at Southwest Foundation for Biomedical Research in San Antonio, Texas in which markers for hypertension have been demonstrated. Genetically determined alterations in cell sodium regulation in animals that are hypertensive is being investigated as a triggering factor in the hypertensive process. By understanding the mechanisms contributing to the long-term control of blood pressure, a greater understanding of new, effective ways of treating chronic cardiovascular disease will be gained.

Samples of Recent Publications
VanNess, J.M., C. Hinojosa-Laborde, T. Craig and J.R. Haywood. The effect of sinoaortic deafferentation on
renal wrap hypertension. Hypertension. 33(Pt 2): 476-481, 1999.

Lange, D.L., J.R. Haywood, C. Hinojosa-Laborde. Endothelin enhances and inhibits adrenal catecholamine
release in DOCA-Salt hypertensive rats. Hypertension 35(Pt 2): 385-390, 2000.

Hinojosa-Laborde, C., D.L. Lange, J.R. Haywood. Role of female sex hormones in the reversal of
Dahl salt-sensitive hypertension. Hypertension 35(Pt 2): 484-489, 2000.

Haywood, J.R., S.W. Mifflin, T. Craig, A. Calderon, J.G. Hensler, C. Hinojosa-Laborde. GABA-A function and
binding in the PVN in chronic renal wrap hypertension. Hypertension 37(Pt 2): 614-618, 2001.

▲海外招待講師

Assistant Professor

Address            Department of Neurology

Emory University School of Medicine

Woodruff Memorial Research Building - Suite 6329

1639 Pierce Drive

Atlanta, GA 30322

U.S.A.

Phone: 404-727-5813　Fax :404-727-3157    Email : mdecker@emory.edu

Titles                 2002  Assistant Professor of Neurology
& Affiliations:  2002  Assistant Professor of Nursing

Previous           2000-2002 Instructor of Neurology
Appointment:  1999-2000 Instructor of Anatomy, Case Western Reserve                                                                                University, School of Medicine: Department of Anatomy

Licensure:     Respiratory Care Professional, R.C.P. (1990)
                          Registered Nurse, R.N. (1994)

Education        California College of Health Sciences Respiratory Therapy Program 1984
                          Case Western Reserve University, Bolton School of Nursing, BSN 1994
                          Case Western Reserve University, School of Medicine: Department  of Anatomy,
                          Ph.D 1999

Honors/            Bolton Scholarship: Case Western Reserve University, (1991-93)
Awards:            National Science Foundation: Undergraduate Research Stipend (1993-94)
                         Stearns Foundation Award: Excellence in Anatomy (1999)
                         American Professional Sleep Societies: Research Excellence Award(1999)

Select Publications in Refereed Journals

 Beall C.M., Brittenham G.M., Strohl K.P., Blangero J., Williams-Blangero S., Goldstein M.C., Decker  M.J., Vargas E., Villena M., Soria R., Alarcon A.M., Gonzales C.  Hemoglobin concentration of high altitude Tibetans and Bolivian Aymara.  Am J Phys Anthro 106:385-400, 1998.

 Berkeley JL, Decker MJ, and Levey AI.  The Role of Muscarinic Acetylcholine Receptor-Mediated Activation of Extracellular Signal-Regulated Kinase 1/2 in Pilocarpine-Induced Seizures.  J Neurochem, 82; 192-201, 2002.

 Decker M.J., Rye D.B.  Emerging Research: Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning.  Sleep Breath. 2002 Dec;6(4):205-10

 Beall C.M, Decker M.J, Brittenham G.M., Kushner I., Gebremedhin A., Strohl K.P. An Ethiopian pattern of adaptation to high altitude hypoxia.  Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17215-8.

 Decker M.J.,  Hue G.E., Caudle W.M.,  Miller G.W.,  Keating G.L., Rye D.B.  Episodic neonatal hypoxia evokes executive dysfunction and regionally specific alterations in markers of dopamine signaling (Neurosci, 2003 117:417-4252).

▲海外招待講師

Professor

Address        AstraZeneca, L.P.
                               Safety Assessment US - Development
                              1800 Concord Pike, P.O. Box 15437 (Rollins 8)
                               Wilmington, DE 19850-5437
                               302-885-8193/302-885-7542 (fax)

 Dr. Kinter received his Ph.D (1978) in Medical Physiology from Harvard University where he initiated his professional interests in cardiovascular/renal physiology and pharmacology. Since 1981 he has held positions of increasing responsibility in pharmaceutical R&D, serving with SmithKline Beecham, Sterling Winthrop, Nycomed Amersham, and Astra Merck; he is currently Senior Director, Safety Assessment for AstraZeneca Pharmaceuticals. Dr. Kinter is a Diplomat of the American Board of Toxicology, Fellow of the Academy of Toxicological Sciences, Adjunct Associate Professor of Physiology, University of Pennsylvania School of Medicine, and an author of over 100 research manuscripts and book chapters in basic and applied physiology, pharmacology, and toxicology.

Education

1969-73         B.S.      Union College (Biology)
1973-78         Ph.D.    Harvard University (Physiology)

Postgraduate Training and Fellowship Appointments

2003 -           Senior Director & Head, Safety Assessment US-Development
                     AstraZeneca Pharmaceuticals Inc., Wilmington, DE

2000 - 2002   Senior Director, Preclinical Sciences Skill Group
                      Experimental Medicine, AstraZeneca Pharmaceuticals LP, Wilmington, DE

2000             Director, Preclinical Sciences Skill Group
                      Scientific Skills, AstraZeneca Pharmaceuticals LP, Wayne, PA

 Editorials, Reviews, Chapters, including participation in committee reports (print or other media)

Kinter, L.B. and Tarloff, J.  In Vivo Methodologies Used to Assess Renal Function. 
In: Comprehensive Toxicology    Eds I.G. Sipes, C.A. McQueen, and A.J. Gandolfi, Vol. 7
Renal Toxicology Ed. By R.S. Goldstein Elsevier Science, New York, pp. 99-120, 1997.

Kinter, L.B., Murphy, D.J..  (Major Organ Systems Tox)In: Comprehensive Toxicology
Eds I.G. Sipes, C.A. McQueen, and A.J. Gandolfi, Vol. 7 Renal Toxicology Ed. By R.S.
Goldstein Elsevier Science, New York, pp. 99-120, 1997.

Kinter, L.B., and Johnson, D.K. Remote monitoring of experimental endpoints in animals using
radiotelemetry and bioimpedance technologies. In:  Proc. Intl. Conference on Humane Endpoints in
Animal Experiments for Biomedical Research. Edited by C.F.M. Hendriksen and D.B. Morton,
The Royal Society of Medicine Press Ltd., London, pp. 58-65, 1999.

Kramer, K., Kinter, L.B., Brockway, B.P., Voss, H-P., Remie, R., and van Zutphen, B.L.M.
The use of radio-telemetry in small animals: recent advances. Contemporary Topics in Laboratory
Animal Science (in press), 2001.

Kinter, L.B. and Valentin, J-P.  Safety Pharmacology and Risk Assessment. Fund.
Clin. Pharmacol. 16:175-182, 2002.

Kramer, K. and Kinter, L.B.  Evaluation and application of radio-telemetry in
small laboratory animals. Physiological Genomics (accepted for publication Feb. 2003)

Research Publications, peer reviewed (print or other media)

Sullivan, A.T. and L.B. Kinter.  Status of safety pharmacology
in the pharmaceutical industry - 1995.  Drug Dev. Res. 35:166-172, 1995.

Kinter, L.B. and L.W. Dixon.  Safety pharmacology program for pharmaceuticals.
Drug Dev. Res. 35:179-182, 1995.
 Kinter, L.B.  General pharmacology/safety pharmacology: customers, biologics,
and GLPs.  Drug Dev. Res. 35:142-144, 1995.

Kramer, K., Mills, P.A. Kinter, L.B., and Brockway, B.P.  History of laboratory telemetry and the state of the art of fully implanted radio-telemetry for monitoring laboratory animals.  Proc. 47th AALAS Meeting.  Lab Animal 27(8): 40-46, 1998.

Ladd, D.L., Hollister, R., Peng, X., Wei, D., Wu, G., Delecki, D., Snow, R.A., Toner, J.L., Kellar, K., Eck, J., Desai, V.C., Raymond, G., Kinter, L.B., Desser, T.S., and Rubin, D.L.  Polymeric gadolinium chelate magnetic resonance imaging contrast agents:  design, synthesis and properties.  Bioconjugate Chemistry 10(3): 361-370, 1999.

Liu, Y., Bacon, E., Ballinger, K., Black, C.D.V., Illig, K., McIntire, G., MacNamara, J., Wang, P.P., O’Neill, N., Kinter, L.B. and Desai, V.C.  Pharmacokinetics and hepatic disposition of bis[1-(ethoxycarbonyl)propyl]5-acetylamino-2,4,6-triiodoisophthalate in rats and isolated perfused rat livers. Drug Metabolism and Disposition 28:731-736, 2000.

▲海外招待講師

Professor

Address　　　34, rue Victor Hugo 
                         F-94380 BONNEUIL-SUR-MARNE      France
                         Tel/Fax: 33 1 43 77 51 77      Email: iciliocavero@aol.fr

Education

Degree　　Year        Place
Laurea         1967       University of Pisa,(B.S. Pharmacy) School of Pharmacy, Pisa, Italy.
Ph. D.          1972       University of Pittsburgh,(Cardiovascular Pharmacology)
                                     School of Pharmacy,Department of Pharmacology,Pittsburgh, PA, U.S.A.

 Research　Interests

• Central and peripheral regulation of the cardiovascular system.

• Pharmacology of cardiovascular a1, a2, b1 and b2-adrenoceptors and DA-1 and DA-2 dopamine receptors, PAF receptors.

• Role of calcium and potassium ions and their cell pathways (channels) on the function of vascular and cardiac muscle tissue function.

• Hemodynamic evaluation of drugs.

• Automation of pharmacology laboratories.

• Preclinical and clinical development of cardiovascular drugs [Antihypertensive agents with various mechanisms of action, (a₂-agonists,? a1-adrenoceptor blockers, b-adrenoceptor antagonists, K+ channel openers), antithrombotic and fibrinolytic agents, hypocholesterolemic agents (HMGCo inhibitors), antiarrhythmic agents (class III K+ channel  blockers)] ; agents for the treatment coronary heart diseases (calcium antagonists, K+ channel openers).

• Role of PAF on human pathophysiology. Pharmacology and preclinical development of PAF antagonists.

• Determination of adverse effects of compounds candidate for clinical trials on major organ functions (cardiovascular, renal, gastrointestinal, respiratory, hepatic, etc.)

• Establishment of good laboratory practices (GLP) for functional (general) pharmacological studies on compounds candidate to clinical investigation.

• Identification of novel antidiabetic substances and study of their mechanism of action.

Publications

I. Cavero  and R. Towart (2000)
Avoiding adverse modification of cardiac repolarization. Pharmaceut. Sci. Technol. Today 3: 5-6.

W. Crumb and I Cavero (2000)
Perspectives on the potential of non-cardiovascular drugs to adversely alter cardiac
repolarization  Europ. Pharmaceut.Contractor May 2000 : 63-72.

M. Mestre, Y. Djellas, T. Carriot and I. Cavero (2000)
Frequency-independant blockade of cardiac Na⁺ channels by riluzole: comparison with
established anticonvulsants and class I antiarrhythmics. Fundam. & Clin. Pharmacol. 14:107-117.

I. Cavero, J-M Guillon; M; Mestre and W. Crumb (2000)
Drugs that prolong QT interval as an unwanted effect: assessment of their likelihood of inducing hazardous cardiac
dysrhythmias. Exp.Opin. Pharmacotherap. 1: 947-973.

I. Cavero, and W. Crumb (2001)
Mechanism-oriented assessment of cardiac electrophysiological safety using human heart ion channels.
Business Briefing: Pharma Tech, (CD-Rom edition), July 2001.

I. Cavero, and W. Crumb (2001)
Native and cloned channels from human heart; laboratory models for evaluating the cardiac safety of new drugs.
Eur. Heart J 3 (Suppl K): 53K-63K.

V. Calderone and I Cavero (2002)
Aritmie ventricolari letali: possibile rischio associato all’uso dei farmaci che prolungano l’intervallo QT.
Minerva Cardiologica Minerva  Medica  3:181-197,

W. Crumb and I Cavero (2002)
Patch-clamp studies of human cardiac ion channels in the evaluation of cardiac electrophysiological effects of drugs.
Protocol in Pharmacol. (in press)

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参加予定 国内招待講師

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参加予定 海外メーカー

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Exhibition 機器展示 及び デモンストレーション

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