anesthesiology research laboratories university of ... · pdf filemotor function. ... effects...

Anesthesiology Research Laboratories

University of California, San Diego

(Prepared March 2004)

Prepared March 2004

Research in Pain and Analgesia Basic and Translational

OVERVIEW: Laboratory for Anesthesiology Research 7/08

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OVERVIEW: The facility was organized in 1989 to: i) perform investigations into pharmacology and physiology of systems relevant to anesthesia and analgesia; and ii) establish contract research in areas of developed expertise. This group has a long and active history of investigation, both preclinical and clinical, into new technologies and drug development. The strength of the group is its high level of scientific competence and its proven contract organization. Research is funded by three mechanisms: NIH grants, Research Contracts, Service Agreements and Research Recharge agreements. Contracts and recharge agreements are carried out under protocols approved by for-profit sponsors. Preclinical and clinical contract and recharge activity is accomplished by full-time university employees. Service and Recharge activities permit services to be undertaken with protection of sponsor intellectual property Tony L. Yaksh, PhD

Laboratory Director, Professor of Anesthesiology and Pharmacology. Co-director of Symptom Management Res (UCSD Comp Ca Ctr) Kinetics and safety of spinally delivered drugs; spinal transmitter pharmacology

Xiao-Ying Hua, MD, PhD

Senior Research Scientist, Anesthesiology Pharmacology of spinal opioid tolerance, and Modulation of spinal neurotransmitter release

Martin Marsala, MD

Professor, Anesthesiology Spinal cord ischemia; In vivo dialysis; spinal stem cell grafting; neuroregeneration

Steven Rossi, PhD

Director, Analytical Laboratory; Project Scientist Analysis of transmitters and drug kinetics

Camilla Svensson, PhD

Project Scientist, Anesthesiology Director of imaging core, Immunofluorescence, electron microscopy

Linda S. Sorkin, PhD

Professor, Anesthesiology Single unit recording from nerve fascicles in vivo and in vitro; neuroimmune interactions; transmitter pharmacology in spinal sensitization

Mark S. Wallace, MD

Professor, Anesthesiology Director, UCSD Pain Service. Human studies in clinical and experimental pain states


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Senior Technical Support Staff (Grant/Contract Responsibilities) Bethany Fitzsimmons, MS Staff Research Associate Mary Ceccolini, BS Staff Research Associate Shelle Malkmus, BS, RVT Laboratory Manager Marleen Kawahara Staff Research Associate (Analytic Chemistry) Damon Mc Cumber Staff Research Associate Yuri Shtaerman Senior Research Associate (engineer) Joanne Steinauer Imaging core manager Nicole Tozier Staff Research Associate Administrative Support Staff Christina E. Richardson Contracts and Grants Management Patrick Devillier, BS GLP quality assurance officer (contract) Julie Nguyen Administrative Assistant Chris Radewicz Senior Administrative Assistant LABORATORY FACILITIES • The laboratory is a secured and alarmed facility of approximately 5,500 sq. ft.

located at the Clinical Teaching Facility (CTF), Building C, 214 Dickinson St., at the University of California, San Diego (UCSD) Medical Center.

Animal Core Facility • AALAC approved facilities. • 3500 sq. ft. of space for performance of acute physiological experiments. • Rat surgical facility for the preparation of small (rat) animal models with chronic

placements (5 stations, each with isoflurane vaporizers with vacuum exhaust systems, surgical instruments and stereotaxic holder devices).

• Test facility for behavioral measurement and nociceptive testing in small animals; independent stations for conducting acute experimental procedures in small animals (with anesthetic / ventilatory support, instrumentation, and multichannel recording).

• Large animal test facilities delegated exclusively for large animals. Also included in this facility is an approved surgical suite for large animal sterile surgery (positive pressure, one table operating suite with gas anesthetic support and exhaust, temperature regulators and full monitoring capabilities for large animals), with prep and scrub rooms. There are centrifuges, balances, temperature regulators, pulse oximeter/gas analyzers for research procedures and diagnostics.

• Animal housing facilities for all mice, rats are located in AALAC accredited secured CTF facility. Individual runs suitable for 30 dogs. Additional off site facilities for an additional 60 dogs.

• 1.5 and 3 T MRI for dogs and a 10 T rodent magnets • Gamma camera imaging in dog. • BSL-2/BSL-3 approved facility for cell culturing and transfection Human Pain Research Core


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• 300 sq ft facility in the UCSD Medical Center directed by Mark Wallace, M.D. • Equipment and human studies protocols for quantitative somatosensory testing (hot

and cold), tactile thresholds in normal volunteers and clinical pain patients. • Human subject protocols for intradermal capsaicin and repetitive electrical

stimulation to induce facilitated pain states. • Pain protocols for same day surgery and postoperative pain management. • In-hospital studies in GCRC clinical research unit. Analytical Chemistry Laboratory • This is a 600 sq ft facility, under the direction of Steve Rossi, Ph.D. It has been in

continuous operation since 1989. • Equipment includes spin vac/lyophilizer, multiwavelength plate reader with automatic

washer, gamma and scintillation counters, HPLCs, gas chromatographs, liquid sample triple quadrupole mass spectrometer, Applied Biosystems LC-MS/MS, 300 sq ft 4° C coldroom, -70° and -30° C freezers.

• Immunoassay capabilities include developing and validating assays from (commercially) available haptens and antibodies, coupling of iodinated ligand and antibody characterization, including identification of column immunoreactivity. Emphasis is on peptides (enkephalins, NPY, tachykinins, substance P, CGRP), prostanoids (PGE1/2; LTB4/C4/D4), and cytokines (TNF, IL1). catecholamines and amino acids.

• Gas chromatography is employed for a wide variety of drug assays (local anesthetics; anesthetics; tricyclic antidepressants, anticonvulsants).

• HPLC is utilized for numerous drug assays including opiates, local anesthetics, NSAIDs, as well as endogenous modulators, including catecholamines and excitatory amino acids.

• For additional information, see Appendix 1 below and http://yakshlab.ucsd.edu/ Imaging / Molecular Biology Core • Microtomes (Cryotstat, Freezing stage horizontal sliding microtome) • Leica Confocal Microscope (three laser) • Light microscopes • Olympus Fluoresence microscope • Gel Eletrophoretic systems • Centrifuges • Spectrophotometer • Administrative/Computer Core • Administrative offices, including secretarial support, are located on site. • Macintosh computers with graphic, statistical and word processing support are on

line. Engineering Core • 300 sq. ft. shop for electronic, plastic and metal-working, fabrication, and

prototyping. • Development of analgesic testing devices (see Appendix 2). • Directed by Mr. Yuri Shtaerman , electronics and computer engineer.


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Quality Assurance Unit • Quality assurance unit represents an appointment outside of the Department of

Anesthesiology. It is headed by Patrick Devillier. Archives • Archiving is carried out under the direction of Shelle Malkmus. Off site archive

space with appropriate fire protection and security is available. CONTRACT RESEARCH ACTIVITIES The laboratory actively undertakes contract work implementing lines of research using well-defined models. The quality of the research work is reflected by the extensive publication in peer-reviewed literature basic research work. The general areas of investigation and contract work are indicated below.

Analgesic Pharmacology and Activity • Intracranial and intraspinal injections/continuous infusion in acute and chronically-

prepared rats and dogs, for physiological studies. • Nerve injury models for inducing neuropathic states, including: the Bennett model

(thermal hyperalgesia), the Chung model (tactile allodynia); and, intrathecal substance P / NMDA thermal hyperalgesia in mice and rats

• Rat / mouse analgesic test models include: 1) Thermal escape (Hargreaves); 2) Tactile thresholds-Von Frey; 3) Deep pressure (Ugo Basale); 4) Inflamed knee joints and paws (carrageenan)-Tactile allodynia/thermal hyperalgesia; 5) Thermal injury induced Thermal hyperalgesia/Tactile allodynia); 6) Intraplantar Formalin flinching (automated); 7) Chung model –Tactile allodynia; 8) IV vincristine-Tactile allodynia.

• Mouse osteosarcoma pain model • Dog analgesic test model: thermal skin twitch/hindpaw thermal withdrawal /

motor function.

Cerebral, Spinal and Nerve ischemia • Measurement of cerebral blood flow and glucose utilization. • Measurement of indices of ischemic damage in brain and spinal cord. • Spinal cord blood flow and indices of outcome after spinal ischemia • Quantitative cerebral and spinal pathology for drug toxicology and ischemia work. • Cellular replacement in brain and spinal cord

CNS Transmitter Activity and Brain Drug Levels • In vitro transmitter release measured in slices/minces/non neural tissue and in vivo

using intracranial / spinal dialysis and receptor internalization Brain and Spinal Drug Kinetic Studies • Chronic catheterization for sampling cisterna magna-lumbar intrathecal space in

dogs. • In vivo spinal dialysis for measuring - spinal cord CSF drug/transmitter levels in

rats.


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Peripheral nerve delivery • Perineural (sciatic) delivery in rats and dogs. • Perineural drug delivery clearance. Spinal Drug Safety Studies • Chronic rat intrathecal model for bolus or infusion delivery to assess behavior and

spinal histopathology • Validated (GLP) dog models to examine the safety of drugs given as a bolus or by

continuous infusion by the epidural or intrathecal route. • For a listing of PK and safety work see Appendix 3.

INDUSTRIAL ASSOCIATION The following summarizes in alphabetical order industrial/pharma/ biotech entities with which the laboratories have undertaken contract /screening activities since 1994. Abbot Laboratories Adolor Therapeutics, Inc. Advanced Polymer Pharmaceuticals Advanced Targeting Systems, Inc. Algos Pharmaceutical Company Allergan Inc. Alliance Pharmaceutical Corp. Amgen Inc. Amrad Operations Pty Ltd. AnalgesiX Athena Neurosciences Bioassets Biogen Inc. Cambridge NeuroSciences Celgene Cocensys Cognetix Inc. Creative Biomolecules, Inc. Decode Depotech Endo Pharmaceutical Co. Ferring Research Institute Inc. Fujisawa Pharmaceutical Co. GenDerm Co. Glaxo-Welcome Harris FRC Inc. Hydra Biosciences Infusaid Corp. Institute de Recherche Pierre Fabre, Isis Pharmaceutical Irisys

Janssen Research Foundation Knoll Pharmaceuticals Medical Research Devices Medtronic Inc. Merck & Co. Inc. Microbia Neurex Corp. Neuroadjuvants Neurogenetics Inc. Neurology CEDD Neuromed Technologies Inc. NPS Pharmaceuticals Orion Corp. Parke-Davis Research Laboratories Procter & Gamble Pudenz Schulte Medical Corp. RW Johnson Schering Plough Research Institute Scion Pharmaceuticals Scios Inc. Shearwater Polymers Inc. Sibia Skye Pharma Inc. Solace Synaptic Pharmaceutical UCB Pharmaceuticals Vertex Pharmaceuticals Inc. VistaGen Therapeutics Inc. Winston Laboratories Inc. Xenome Ltd. Xenoport Inc.


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LABORATORY PUBLICATIONS The following is a list of selected references published by laboratory staff in several areas of research. They are a selection from over 400 published papers produced by this group since 1994, to reflect methodologies and research approaches employed by the facility. Analgesic Pharmacology Chaplan SR, Bach FW, Shafer SL, Yaksh TL. Prolonged alleviation of tactile allodynia

by intravenous lidocaine in neuropathic rats. Anesthesiology 83: 775-785, 1995. Chaplan SR, Pogrel JW, Yaksh TL. Role of voltage-dependent calcium channel subtypes

in experimental tactile allodynia. J Pharmacol Exper Ther 269: 1117-1123, 1994. Hua XY, Chen P, Polgar E, Nagy I, Marsala M, Phillips E, Wollaston L, Urban L, Yaksh

TL, Webb M. Spinal neurokinin NK1 receptor down-regulation and antinociception: Effects of spinal NK1 receptor antisense oligonucleotides and NK1 receptor occupancy. J Neurochem 70: 688-698, 1998.

Hua XY, Hayes CS, Hofer A, Fitzsimmons B, Kilk K, Langel U, Bartfai T, Yaksh TL. Galanin acts at GalR1 receptors in spinal antinociception: Synergy with morphine and AP-5 J Pharmacol Exp Ther 308:574-582, 2004.

Jun JH, Yaksh TL. The effect of intrathecal gabapentin and 3-isobutyl g-aminobutyric acid on the hyperalgesia observed after thermal injury in the rat. Anesth Analg 86: 348-354, 1998.

Junger, H. and Sorkin, L.S. Nociceptive and inflammatory effects of subcutaneous TNFa. Pain 85: 145-151, 2000.

Khan IM, Stanislaus S, Zhang L, Taylor P, Yaksh TL. A-85380 and epibatidine each interact with disparate spinal nicotinic receptor subtypes to achieve analgesia and nociception. J Pharmacol Exp Ther 297: 230-239, 2001.

Koetzner L, Hua X-Y, Lai J, Porrerca F, Yaksh T. Nonopioid actions of intrathecal dynorphin evoke spinal excitatory amino acid and prostaglandin E2 release mediated by cyclooxygenase-1 and –2. J Neurosci 24, 1451-1458, 2004.

Luo, Z.D., Chaplan, S.R., Higuera, E.S., Stauderman, K.A., Williams, M.E., and Yaksh, T.L. Up-regulation of dorsal root ganglion α2δ calcium channel subunit and its correlation with allodynia in spinal nerve injured rats. J. Neurosci. 21: 1868-1875,2001.

Schafers M, Marziniak M, Sorkin LS, Yaksh TL, Sommer C. Cyclooxygenase inhibition in nerve-injury- and TNF-induced hyperalgesia in rat. Exp Neurol;185:160-168, 2004

Sorkin, L.S., Yu, A.L., Junger, H., and Doom, C.M. Antibody directed against GD2 produces mechanical allodynia, but not thermal hyperalgesia when administered systemically or intrathecally despite its dependence on capsaicin sensitive afferents. Brain Res. 930:67-74, 2002

Svensson CI, Rew Y, Malkmus S, Schiller PW, Taulane JP, Goodman M, Yaksh TL. Systemic and spinal analgesic activity of a ∂-opioid-selective lanthionine enkephalin analog. J Pharmacol Exp Ther 304: 827-832, 2003

Yaksh TL, Dirig DM, Conway CM, Svensson C, Luo ZD, Isakson PC. The acute antihyperalgesic action of nonsteroidal, anti-inflammatory drugs and release of spinal prostaglandin E2 is mediated by the inhibition of constitutive spinal cyclooxygenase-2 (COX-2) but not COX-1. J Neurosci 21: 5847-5853, 2001.


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Preclinical Analgesic Testing Paradigms and Validation Brainin-Mattos J, Smith ND, Malkmus S, Rew Y, Goodman M, Taulane J, Yaksh TL.

Cancer-related bone pain is attenuated by a systemically available delta-opioid receptor agonist.Pain.;122:174-81, 2006

Dirig DM, Salami A, Rathbun ML, Ozaki GT, Yaksh TL. Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli. J Neurosci Meth 76: 183-191, 1997.

Nagakura Y, Malkmus S, Yaksh TL. Determination of current threshold for paw withdrawal with sine-wave electrical stimulation in rats: Effect of drugs and alteration in acute inflammation. Pain. 134:293-301, 2008.

Nozaki-Taguchi N, Chaplan SR, Higuera ES, Ajakwe RC, Yaksh TL. Vincristine-induced allodynia in the rat. Pain 93: 69-76, 2001.

Nozaki-Taguchi N, Yaksh TL. A novel model of primary and secondary hyperalgesia after mild thermal injury in the rat. Neurosci Lett 254: 25-28, 1998.

Wegner K, Horais KA, Tozier NA, Rathbun ML, Shtaerman Y, Yaksh TL. Devlopment og a canine nociceptive thermal escape model. J. Neurosci. Method. 168:88-97, 2008.

Yaksh TL, Ozaki G, McCumber D, Rathbun M, Svensson C, Malkmus S, Yaksh MC. An automated flinch detecting system for use in the formalin bioassay. J Appl Physiol 90:2386-2402, 2001.

Cerebral, Spinal and Nerve Ischemia Carmel, J.B., O. Kakinohana, R. Mestril, W. Young, M. Marsala and R.P. Hart, Mediators

of ischemic preconditioning identified by microarray analysis of rat spinal cord. Exp Neurol,. 185: 81-96. 2004

Cizkova, D., J.B. Carmel, K. Yamamoto, O. Kakinohana, D. Sun, R.P. Hart and M. Marsala, Characterization of spinal HSP72 induction and development of ischemic tolerance after spinal ischemia in rats. Exp Neurol, 185: 97-108, 2004

Kakinohana, O., D. Cizkova, Z. Tomori, E. Hedlund, S. Marsala, O. Isacson and M. Marsala, Region-specific cell grafting into cervical and lumbar spinal cord in rat: a qualitative and quantitative stereological study. Exp Neurol,. 190: 122-32. 2004

Lukacova N; Marsala M; Halat G; Marsala J Neuroprotective effect of graded postischemic reoxygenation in spinal cord ischemia in the rabbit. Brain Research Bulletin, 43:457-65 1997.

Marsala M, and Yaksh TL. Transient spinal ischemia in the rat: Characterization of behavioral and histopathological consequences as a function of the duration of aortic occlusion. J Cereb Blood Flow Metabol 14: 526-535, 1994.

Marsala, M., O. Kakinohana, T.L. Yaksh, Z. Tomori, S. Marsala and D. Cizkova, Spinal implantation of hNT neurons and neuronal precursors: graft survival and functional effects in rats with ischemic spastic paraplegia. Eur J Neurosci,. 20:. 2401-14. 2004

Taira Y; Marsala M. Effect of proximal arterial perfusion pressure on function, spinal cord blood flow, and histopathologic changes after increasing intervals of aortic occlusion in the rat. Stroke, 27:1850-8, 1996


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CNS Transmitter Activity and Brain Drug Levels Dirig DM, Hua X-Y, Yaksh TL. Temperature dependency of basal and evoked release

of amino acids and calcitonin gene-related peptide from rat dorsal spinal cord. J Neurosci 17:4406-4414, 1997.

Hua X-Y, Chen P, Marsala M, Yaksh TL. Intrathecal substance P-induced thermal hyperalgesia and spinal release of prostaglandin E2 and amino acids. Neuroscience 89: 525-534, 1999.

Hua X-Y, Jinno S, Back SM, Tam EK, Yaksh TL. Multiple mechanisms for the effects of capsaicin, bradykinin and nicotine on CGRP release from tracheal afferent nerves: Role of prostaglandins, sympathetic nerves and mast cells. Neuropharmacology 33: 1147-1154, 1994.

Malmberg AB, Yaksh TL. Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: a microdialysis study in anesthetized rats. J Neurosci 15:2768-776, 1995.

Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, Catalano R, Feng Y, Protter AA, Scott B, Yaksh TL. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem 86: 1534-1544, 2003.

Gillardi JR, Svensson CI, Rogers SD, Yaksh TL, Mantyh PW. Constitutive spinal cyclooxygenase-2 participates in the initiation of tissue injury-induced hyperalgesia. J Neurosci 24: 2727-32, 2004.

Human Analgesic Testing Leung A, Wallace MS, Ridgeway B, Yaksh T. Concentration-effect relationship of

intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain. Pain 91: 177-187, 2001.

Wallace MS, Laitin S, Licht D, Yaksh TL. Concentration—effect relations for intravenous lidocaine infusions in human volunteers. Anesthesiology 86:1262-1272, 1997

Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, Rauck RL, Backonja MM, Quessy SN, Meisner PD. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology. 2002 Dec 10;59(11):1694-700.

Wallace MS, Ridgeway BM, Leung AY, Gerayli A, Yaksh TL. Concentration-effect relationship of intravenous lidocaine on the allodynia of complex regional pain syndrome types I and II. Anesthesiology 92: 75-83, 2000.

Yaksh TL, Provencher JC, Rathbun ML, Myers RR, Powell H, Richter P, Kohn FR. Safety assessment of encapsulated morphine delivered epidurally in a sustained-release multivesicular liposome preparation in dogs. Drug Deliv 7: 27-36, 2000.

Ridgeway B, Wallace M, Gerayli A. Ziconotide for the treatment of severe spasticity after spinal cord injury. Pain 85: 287-9, 2000.

Wallace MS, Ridgeway BM, Leung AY, Gerayli A, Yaksh TL. Concentration-effect relationship of intravenous lidocaine on the allodynia of complex regional pain syndrome types I and II. Anesthesiology 92: 75-83, 2000.

Wallace MS, Ridgeway B, 3rd, Leung A, Schulteis G, Yaksh TL. Concentration-effect relationships for intravenous alfentanil and ketamine infusions in human


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volunteers: effects on acute thresholds and capsaicin-evoked hyperpathia. J Clin Pharmacol 42: 70-80, 2002.

Spinal Drug Kinetic / Safety Studies (see Appendix 3) Allen JW, Hofer K, McCumber D, Wagstaff JD, Layer RT, McCabe RT, Yaksh TL. An

assessment of the antinociceptive efficacy of intrathecal and epidural contulakin-G in rats and dogs. Anesth Analg. 104:1505-13, 2007

Allen JW, Horais KA, Tozier NA, Wegner K, Corbeil JA, Mattrey RF, Rossi SS, Yaksh TL. Time Course and Role of Morphine Dose and Concentration in Intrathecal Granuloma Formation in Dogs: A Combined Magnetic Resonance Imaging and Histopathology Investigation. Anesthesiology. 2006;105:581-589, 2006

Allen JW, Horais KA, Tozier NA, Yaksh TL. Opiate Pharmacology Intrathecal Granulomas. Anesthesiology. 105:590-598, 2006.

Allen JW, Mantyh PW, Horais K, Tozier N, Rogers SD, Ghilardi JR, Cizkova D, Grafe MR, Richter P, Lappi DA, Yaksh TL. Safety evaluation of Intrathecal Substance P-Saporin, a targeted neurotoxin, in dogs. Toxicol Sci. ;91:286-98, 2006

Chiari A, Yaksh TL, Myers RR, Provencher J, Moore L, Lee C-S, Eisenach JC. Preclinical toxicity screening of intrathecal adenosine in rats and dogs. Anesthesiology 91: 824-832, 1999.

Horais K, Hruby V, Rossi S, Cizkova D, Meschter C, Dorr R, Yaksh TL. Effects of chronic intrathecal infusion of a partial differential opioid agonist in dogs. Toxicol Sci 71: 263-275, 2003

Kern SE, Allen J, Wagstaff J, Shafer SL, Yaksh T. The pharmacokinetics of the conopeptide contulakin-G (CGX-1160) after intrathecal administration: an analysis of data from studies in beagles. Anesth Analg. 104:1514-20, 2007.

Kohn FR, Malkmus SA, Brownson EA, Rossi SS, Yaksh TL. Fate of the predominant phospholipid component of DepoFoam™ drug delivery matrix after intrathecal administration of sustained-release encapsulated cytarabine in rats. Drug Deliv 5: 143-151, 1998.

Sabbe MB, Grafe MR, Mjanger E, Tiseo PJ, Hill HF, Yaksh TL. Spinal delivery of sufentanil, alfentanil and morphine in dogs. Physiologic and toxicologic investigations. Anesthesiology 81: 899-920, 1994.

Sabbe MB, Penning JP, Ozaki GT, and Yaksh TL. Spinal and systemic action of the alpha2 receptor agonist dexmedetomidine in dogs. Antinociception and carbon dioxide response. Anesthesiology 80: 1057-1072, 1994.

Yaksh TL, Grafe MR, Malkmus S, Rathbun ML, Eisenach JC. Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. Anesthesiology 82:412-27, 1995.

Yaksh TL, Horais KA, Tozier NA, Allen JW, Rathbun M, Rossi SS, Sommer C, Meschter C, Richter P, Hildebrand K. Chronically infused intrathecal morphine in dogs.Anesthesiology 99:174-187, 2003.

Yaksh TL, Rathbun ML, Dragani JC, Malkmus S, Bourdeau AR, Richter P, Powell H, Myers RR, LeBel CP. Kinetic and safety studies on intrathecally infused recombinant-methionyl human brain-derived neurotrophic factor in dogs. Fundam Appl Toxicol 38: 89-100, 1997

Yaksh TL, Rathbun ML, Jage J, Mirzai T, Grafe M.and Hiles RA. Pharmacology and toxicology of chronically infused epidural clonidine HCl in dogs. Fund App Toxicol 23: 319-335, 1994.


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Yaksh TL; Provencher JC; Rathbun ML; Kohn FR. Pharmacokinetics and efficacy of epidurally delivered sustained-release encapsulated morphine in dogs. Anesthesiology 90:1402-12, 1999.

For further information on laboratory activities : Tony L. Yaksh, Ph.D. Mailing Address: Department of Anesthesiology University of California, San Diego 9500 Gilman Drive LaJolla, CA 92093-0818

TEL: 619-543-3597 FAX: 619-543-6070 e-mail: [email protected]


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APPENDIX 1. The UCSD Analytical laboratory has a wide variety of online assays that can be called up and implemented with a recharge arrangement. The following Table provides a listing of representative services and assays. Services include sample extraction, validation of standards and assessment of drug stability. Assay development can also be undertaken. For additional information on sensitivity and sample management please call Steve Rossi, Ph.D. (619-543-3597) Adenylates alfentanil Amitriptiline APA-5 beta-endorphin bile acids (total) bupivacaine bupivacaine metabolites Catecholamines CGRP clonidine codeine cortisol cotinine cromalyn desipramine C.P.M. - gamma dextromethorphan diazepam diphenhydramine DNA-J D.P.M. - 3H D.P.M. - 14C D.P.M. - 3H&14C ECP EFAs EPX Excitatory amino acids extraction - CSF

extraction - plasma extraction - tissue fentanyl fluoxetine 5-HIAA 5-HT GABA Glycine gatifloxacin ghrelin glyburide HGF histamine hydrocodone IL1 IL6 IL8 IL12 insulin ketamine ketorolac ketotifen lidocaine lidocaine metabolites memantine mepivacaine Met-enkephalin methadone methylprednisolone

mexiletine midazolam MK-801 morphine morphine metabolites naloxone NGF NPY PGE2 6ketoPGFalpha protein (total) S-100 Serotonin ST-91 substance P sufentanil testosterone THC plasma - ELISA THC plasma - MS THC - Test Article TNFalpha Abuse tox screen Tryptophan


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APPENDIX 2 Analgesia testing systems available from Department of Anesthesiology engineering group. Paw Thermal escape system. • Under glass radiant stimulus manipulated to individual hind paw. by front of box joystick. • 6-8 animals ((mouse and rat versions) • Multiple stimulus intensities achievable by “plug-and-play” connectors. • Glass surface fixed at designated temperature • Latency to hind paw withdrawal measured by light sensors on stimulus head. • See: J Neurosci Meth 76: 183-191, 1997. Automated formalin testing system. • Automated sensory for counting hind paw paw flinches evoked by intralantar formalin. • Mouse and rat versions • User friendly data collection and analysis soft ware. • See: J Appl Physiol 90:2386-2402, 2001. For information on systems and ordering: Shelle Malkmus, [email protected], 619 543 2589 or 619 543 3597.


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APPENDIX 3 Summary of NIH and Industrial sponsored canine perineural , spinal drug safety/PK studies. DATE Sponsor Study Type Method of Delivery 2008 NIH, GM48085 Efficacy/Tox. Intrathecal Catheter 2007 Johns Hopkins Safety Epidural bolus 2007 Pharmacofore pK/PD Perineural 2007 Medtronics * Safety Intrathecal catheter 2006 Medtronics PK/Toxicology Intrathecal catheter 2005 Advanced Targeting * Toxicology/PK Intrathecal catheter 2004 NIH, DA15353 Efficacy/Tox. Intrathecal Catheter 2003 NIH, GM48085 Efficacy/Tox. Intrathecal Catheter 2002 NIH, GM48085 Efficacy/Tox. Intrathecal Catheter 2001 Organon Labs. PK/PD Intrathecal Catheter 2001 SkyePharma Inc. PK Epidural Catheter 2001 SkyePharma Inc. PK Epidural Catheter 2001 Medtronic Inc. PK Intrathecal Catheter 2000 Medtronic Inc. Characterization Intrathecal Catheter 2000 Medtronic Inc. Safety Intrathecal Catheter 2000 Medtronic Inc. Dose Ranging Intrathecal Catheter 2000 Cognetix Inc. Behavior/PK Intrathecal Catheter 2000 Abbott Labs. Assay Intrathecal Catheter 2000 Allergan DR/Safety Intrathecal Catheter 1999 SkyePharma Inc. PK/PD Epidural Catheter 1999 DepoTech Corp. Characterization Epidural Catheter 1998 Abbott Labs. PD Intrathecal Catheter 1998 Orion Corp. PK/PD IT/Epidural Catheter 1998 Creative Biomolecules. Dose Ranging Intrathecal/Cisternal 1997 Amgen Characterization Intrathecal Catheter 1997 DepoTech Corp. Characterization Epidural Catheter 1996 DepoTech Corp. PK Epidural Catheter 1996 DepoTech Corp.* Toxicology Epidural Catheter 1996 Neurex Corp. PK Intrathecal Catheter 1995 NIH, GM48085 Efficacy/Tox. Intrathecal Catheter 1995 NIH, GM48085 Efficacy/Tox. Intrathecal Catheter 1995 Depotech Corp. Dose Ranging Epidural Catheter 1995 Amgen Inc.* Toxicity Intrathecal Catheter 1995 Glaxo Research* Toxicity Epidural Catheter 1994 Amgen Inc. Dose Ranging Intrathecal Catheter 1994 Amgen Inc. Dose Ranging Intrathecal Catheter 1991 Fujisawa* Tox./PK/PD Epidural Catheter 1989 Infusaid Corp. PK/PD Intrathecal Catheter 1988 Janssen Tox./PK/PD Intrathecal Catheter * GLP.

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