By using opiates with differing lipid solubilities, protein binding, molecular weight and molecular volume (morphine, fentanyl, alfentanyl, sufentanyl) the investigators will use established microdialysis techniques to provide measurements of drug concentrations over time in the spinal cord, CSF and epidural space following either epidural or intrathecal drug delivery. Compartmental and noncompartmental pharmacokinetic parameters determined from those experiments will be correlated with physicochemical properties of the study drugs in order to determine how each property influences drug redistribution to each anatomic site. Having defined characteristics of drugs which are likely to help in the development of new drugs which will minimize onset time, maximize analgesia duration, and minimize redistribution to supraspinal sites, the investigators will proceed to develop the liposome and cyclodextrin drug delivery systems to favorably modify epidural and intrathecal drug redistribution so as to prolong spinal drug action while simultaneously minimizing extraspinal effects. These studies will use in vitro models to identify promising liposome/opioid and cyclodextrin/opioid formulations for in vivo animal testing. In vivo studies will use an intrathecal rat model; the screen for effective liposome formulation will employ a dog model to evaluate the effect of cyclodextrins and liposomes on opioid analgesia and side effects following both intrathecal and epidural drug level.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA007313-04A2
Application #
2119785
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1995-09-30
Project End
1998-08-31
Budget Start
1995-09-30
Budget End
1996-08-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Washington
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Kopacz, D J; Bernards, C M (2001) Effect of clonidine on lidocaine clearance in vivo: a microdialysis study in humans. Anesthesiology 95:1371-6
Ummenhofer, W C; Arends, R H; Shen, D D et al. (2000) Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology 92:739-53
Bernards, C M; Ulma Jr, G A; Kopacz, D J (2000) The meningeal permeability of R- and S-bupivacaine are not different: evidence that pharmacodynamic differences between the enantiomers are not the result of differences in bioavailability. Anesthesiology 93:896-7
Ummenhofer, W C; Stapleton, A E; Bernards, C M (1999) Effect of Staphylococcus aureus bacteria and bacterial toxins on meningeal permeability in vitro. Reg Anesth Pain Med 24:24-9
Bernards, C M; Kopacz, D J (1999) Effect of epinephrine on lidocaine clearance in vivo: a microdialysis study in humans. Anesthesiology 91:962-8
Powers, K M; Schimmel, C; Glenny, R W et al. (1999) Cerebral blood flow determinations using fluorescent microspheres: variations on the sedimentation method validated. J Neurosci Methods 87:159-65
Ummenhofer, W C; Brown, S M; Bernards, C M (1998) Acetylcholinesterase and butyrylcholinesterase are expressed in the spinal meninges of monkeys and pigs. Anesthesiology 88:1259-65
Kern, C; Bernards, C M (1997) Ascorbic acid inhibits spinal meningeal catechol-o-methyl transferase in vitro, markedly increasing epinephrine bioavailability. Anesthesiology 86:405-9
Ummenhofer, W C; Bernards, C M (1997) Acylcarnitine chain length influences carnitine-enhanced drug flux through the spinal meninges in vitro. Anesthesiology 86:642-8
Kern, C; Mautz, D S; Bernards, C M (1995) Epinephrine is metabolized by the spinal meninges of monkeys and pigs. Anesthesiology 83:1078-81

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