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
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
Xiao-Ying Hua, MD, PhD
Martin Marsala, MD
Steven Rossi, 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
Senior Research Scientist, Anesthesiology
Pharmacology of spinal opioid tolerance, and
Modulation of spinal neurotransmitter release
Professor, Anesthesiology
Spinal cord ischemia; In vivo dialysis; spinal stem
cell grafting; neuroregeneration
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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OVERVIEW: Laboratory for Anesthesiology Research
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Senior Technical Support Staff (Grant/Contract Responsibilities)
Bethany Fitzsimmons, MS
Mary Ceccolini, BS
Shelle Malkmus, BS, RVT
Marleen Kawahara
Damon Mc Cumber
Yuri Shtaerman
Joanne Steinauer
Nicole Tozier
Administrative Support Staff
Christina E. Richardson
Patrick Devillier, BS
Julie Nguyen
Chris Radewicz
Staff Research Associate
Staff Research Associate
Laboratory Manager
Staff Research Associate (Analytic Chemistry)
Staff Research Associate
Senior Research Associate (engineer)
Imaging core manager
Staff Research Associate
Contracts and Grants Management
GLP quality assurance officer (contract)
Administrative Assistant
Senior Administrative Assistant
LABORATORY FACILITIES
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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
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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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OVERVIEW: Laboratory for Anesthesiology Research
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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
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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
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Administrative/Computer Core
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Administrative offices, including secretarial support, are located on site.
Macintosh computers with graphic, statistical and word processing support are on
line.
Engineering Core
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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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OVERVIEW: Laboratory for Anesthesiology Research
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Quality Assurance Unit
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Quality assurance unit represents an appointment outside of the Department of
Anesthesiology. It is headed by Patrick Devillier.
Archives
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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
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Intracranial and intraspinal injections/continuous infusion in acute and chronicallyprepared 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
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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
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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
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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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OVERVIEW: Laboratory for Anesthesiology Research
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Peripheral nerve delivery
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Perineural (sciatic) delivery in rats and dogs.
Perineural drug delivery clearance.
Spinal Drug Safety Studies
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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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OVERVIEW: Laboratory for Anesthesiology Research
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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. Vincristineinduced 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 mitogenactivated 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, placebocontrolled 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 sustainedrelease 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 PSaporin, 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: 824832, 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.
TEL:
619-543-3597
FAX: 619-543-6070
Mailing Address:
e-mail: tyaksh@ucsd.edu
Department of Anesthesiology
University of California, San Diego
9500 Gilman Drive
LaJolla, CA 92093-0818
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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
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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.
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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, smalkmus@ucsd.edu, 619
543 2589 or 619 543 3597.
13
OVERVIEW: Laboratory for Anesthesiology Research
7/08
APPENDIX 3
Summary of NIH and Industrial sponsored canine perineural , spinal drug
safety/PK studies.
DATE
2008
2007
2007
2007
2006
2005
2004
2003
2002
2001
2001
2001
2001
2000
2000
2000
2000
2000
2000
1999
1999
1998
1998
1998
1997
1997
1996
1996
1996
1995
1995
1995
1995
1995
1994
1994
1991
1989
1988
* GLP.
Sponsor
NIH, GM48085
Johns Hopkins
Pharmacofore
Medtronics *
Medtronics
Advanced Targeting *
NIH, DA15353
NIH, GM48085
NIH, GM48085
Organon Labs.
SkyePharma Inc.
SkyePharma Inc.
Medtronic Inc.
Medtronic Inc.
Medtronic Inc.
Medtronic Inc.
Cognetix Inc.
Abbott Labs.
Allergan
SkyePharma Inc.
DepoTech Corp.
Abbott Labs.
Orion Corp.
Creative Biomolecules.
Amgen
DepoTech Corp.
DepoTech Corp.
DepoTech Corp.*
Neurex Corp.
NIH, GM48085
NIH, GM48085
Depotech Corp.
Amgen Inc.*
Glaxo Research*
Amgen Inc.
Amgen Inc.
Fujisawa*
Infusaid Corp.
Janssen
Study Type
Efficacy/Tox.
Safety
pK/PD
Safety
PK/Toxicology
Toxicology/PK
Efficacy/Tox.
Efficacy/Tox.
Efficacy/Tox.
PK/PD
PK
PK
PK
Characterization
Safety
Dose Ranging
Behavior/PK
Assay
DR/Safety
PK/PD
Characterization
PD
PK/PD
Dose Ranging
Characterization
Characterization
PK
Toxicology
PK
Efficacy/Tox.
Efficacy/Tox.
Dose Ranging
Toxicity
Toxicity
Dose Ranging
Dose Ranging
Tox./PK/PD
PK/PD
Tox./PK/PD
14
Method of Delivery
Intrathecal Catheter
Epidural bolus
Perineural
Intrathecal catheter
Intrathecal catheter
Intrathecal catheter
Intrathecal Catheter
Intrathecal Catheter
Intrathecal Catheter
Intrathecal Catheter
Epidural Catheter
Epidural Catheter
Intrathecal Catheter
Intrathecal Catheter
Intrathecal Catheter
Intrathecal Catheter
Intrathecal Catheter
Intrathecal Catheter
Intrathecal Catheter
Epidural Catheter
Epidural Catheter
Intrathecal Catheter
IT/Epidural Catheter
Intrathecal/Cisternal
Intrathecal Catheter
Epidural Catheter
Epidural Catheter
Epidural Catheter
Intrathecal Catheter
Intrathecal Catheter
Intrathecal Catheter
Epidural Catheter
Intrathecal Catheter
Epidural Catheter
Intrathecal Catheter
Intrathecal Catheter
Epidural Catheter
Intrathecal Catheter
Intrathecal Catheter