Stereopharmacology Research in Anaesthesiology

124 Pages·2016·4.01 MB·English

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Stereopharmacological research in anaesthesiology

A thesis based on selected published works

submitted in fulfilment of the requirements for the degree of

Doctor of Medical Science

of

Sydney Medical School
The University of Sydney

by

Laurence Edward Mather

PhD, MSc, BSc (NSW), DipApplChem (SydTechColl),
FANZCA, FRCA, FFPMANZCA (Hon)

July 2015

“It will be at once admitted that the medical practitioner ought to be acquainted with the
strength of the various compounds which he applies as remedial agents, and that he ought, if
possible, to be able to regulate their potency.”
(John Snow, On the inhalation of the vapour of ether. Lond Med Gaz IV: 498, 1847)

“Dans les champs de l'observation le hasard ne favorise que les esprits préparés.”
(Louis Pasteur, Lecture, University of Lille, December 7 1854)
ii
Summary
This thesis is based on a theme of 63 selected publications taken from three of the author’s
research programs (on local anaesthetic agents, intravenous anaesthetic agents, and
nonsteroidal anti-inflammatory agents) and three individual drug projects (on halothane,
ketamine and thalidomide). The publications have been selected to highlight the bearing of
the chemistry of the drug, especially the stereochemistry, on some or other aspect of its
pharmacology, of which 42 are designated Study (new experimental observations and
knowledge), 18 are designated Review (syntheses of ideas from existent knowledge), and 3
are designated Patent (aspects of invention).

The thesis is shaped by the narrative relating to the development of anaesthesia as first
established by John Snow (1813-1858), and the contemporaneous stereochemical basis of
pharmacology first described by Louis Pasteur (1822-1895). It presents each topic as a
personal commentary identifying the historical context, rationale and outcome, and
recognizing the work of collaborators and others at the institutions where the research was
performed. The selected publications originate from research performed at the University of
Sydney, the Flinders University of South Australia, and the University of Sheffield (UK),
although prior work performed at the University of Washington (USA) also contributed.

The ‘concepts and tools’ supporting the research are described in an historical context,
corresponding to their evolution. In particular, the dual concepts of pharmacokinetics and
pharmacodynamics underpin much of modern pharmacology and run throughout the theme of
this thesis. Their investigation required reliable practical tools for physiological data
acquisition, numerical data analysis, and drug assay methods, especially for the analytical
resolution of chiral drugs used as racemates; however these tools evolved more slowly than
the demands of the concepts. Eventually, when they were combined in appropriate ‘whole
body’ pharmacological preparations, such as the author’s ‘multicannulated sheep preparation’
that allowed anatomically-correct and physiologically-sound assessment of drug disposition
in association with quantitative measures of systemic drug effects, as well as with the
‘Stanford’ quantitative electroencephalography rodent model used for pharmacokinetics-
pharmacodynamics, then real progress became possible, allowing greater insights into drugs
used as racemates, such as those described in this thesis.

The local anaesthetic program was instrumental in the registration and clinical introduction
of two enantiopure substances, ropivacaine and levobupivacaine. The selections from the
intravenous anaesthetic program focus on thiopentone and provide evidence of a greater
margin of safety of R-thiopentone over the more potent S-thiopentone or the clinically-used
racemate. Although the program led to a provisional patent for enantiopure thiopentone,
clinical anaesthesia has since largely moved to using propofol which has a preferred
pharmacokinetic profile to thiopentone. The selections from the nonsteroidal anti-
inflammatory drug program focus on ketorolac, but produced inconclusive pharmacokinetic
data; given the limited resources available, the program was changed to focus on (achiral)
diclofenac. The ketamine project provided useful pharmacokinetic and pharmacodynamic
data supporting the current clinical investigations of the pharmacologically preferred
esketamine. The halothane project was designed to consider that differential enantiomeric
disposition might influence halothane toxicity, but an enantiomeric difference was not found,
and the project was terminated due to lack of funds. Finally, the thalidomide project
documented that racemization precluded the use of a preferred enantiomer, but also produced
a rationale for its use in future combined cancer chemotherapy developments.
iii
Table of Contents
Stereopharmacological research in anaesthesiology
Summary ii
Table of Contents iii
Foreword v
Acknowledgements vi
Thesis structure vii
Declarations vii
Selected publications viii
1. Concepts and tools 1
1.1 Basic medicinal chemical concepts 1
1.2 A glossary of basic stereochemical concepts 3
1.3 Essentials of experimental concepts and tools 7
1.4 Quantitation in anaesthesia – John Snow 8
1.5 Stereochemistry in pharmacology – Louis Pasteur 10
1.6 Stereopharmacology and anaesthesiology 12
1.7 Pharmacokinetics 15
1.8 Pharmacodynamics 17
1.9 Applied pharmacokinetics and pharmacodynamics 18
1.10 The ‘elephant in the laboratory’ 21
2. Translating chemistry into anaesthesiology – in stages 25
2.1 The University of Sydney (1966-1972) 25
2.2 The University of Washington (1972-1976) 27
2.3 Flinders Medical Centre (1976-1981) 31
2.4 The University of Massachusetts Medical Center (1981-1983) 37
2.5 Flinders Medical Centre (1983-1990) 37
2.6 The University of Sheffield (1988) 40
2.7 The University of Sydney (1991-2007) 41
3. Stereopharmacological research in anaesthesiology: the main theme 45
3.1 Introduction 45
3.11 Growing recognition of stereopharmacological issues 47
3.12 The main theme: stereopharmacological programs and projects 49
3.13 Basic concepts and experimental tools 49
Review 01. The rationale of our experimental techniques [110] 49
Reviews 02, 03 and 04. Early reviews of stereopharmacology [198,214,215] 50
3.2 Local anaesthetic agent program 51
3.21 Introduction 51
Reviews 05 and 06. Achiral aspects of local anaesthetic pharmacology [48,49] 51
3.22 Prilocaine 55
Study 01. Pharmacokinetics of prilocaine enantiomers in humans [197] 55
3.23 Bupivacaine 56
Study 02. Pharmacokinetics of mepivacaine and bupivacaine enantiomers in sheep [170] 57
Study 03. Bupivacaine pharmacokinetics with steady state infusion in sheep [177] 57
Study 04. Post-surgical plasma binding of bupivacaine enantiomers in sheep [188] 58
Study 05. Enantioselectivity of bupivacaine tissue distribution in sheep [190] 58
Study 06. Influence of i.v. infusion on bupivacaine pharmacokinetics in sheep [217] 58
Study 07. Bupivacaine pharmacokinetics with intercostal block in humans [218] 58
Study 08. Bupivacaine pharmacokinetics with epidural block in humans [246] 59
3.24 Levobupivacaine 59
Study 09. A new enantiospecific HPLC assay for the levobupivacaine program [250] 64
Study 10. Cardiovascular effects of i.v. bupivacaine and levobupivacaine [244] 64
Study 11. PK-PD analysis of bupivacaine and levobupivacaine [245] 64
Reviews 07 and 08. Levobupivacaine: critical data [243,273] 65
Patents 01 and 02. Use patents on levobupivacaine 65
Study 12. Analysis of fatal toxicity from levobupivacaine [276] 65
Study 13. Chaos model of the CNS toxicity of local anaesthetics [285] 65
Study 14. Direct cardiovascular toxicity of local anaesthetics [280] 66
Study 15. Direct CNS toxicity of local anaesthetics [299] 66
Review 09. Cardiotoxicity of local anaesthetics – rationale [282] 67
iv
Study 16. Acid-base changes on PD and PK of bupivacaine (and thiopentone) [306] 67
Review 10. PK and PD concepts and the acute toxicity of local anesthetics [314] 68
Study 17. Effects of general anaesthesia on local anaesthetic toxicity [323] 68
Study 18. Effects of general anaesthesia on local anaesthetic pharmacokinetics [324] 68
3.25 Broader aspects of local anaesthetic pharmacology involving chirality 69
Review 11, 12 and 13. Translational pharmacology of local anaesthetics [325,327,328] 69
Postscript 1 69
3.3 Intravenous anaesthetic agent program 71
Patent 03. Synthesis and uses of thiopentone enantiomers 76
Study 19. Thiopentone: a chiral assay for future studies [221] 76
Study 20. Preliminary evaluation of thiopentone PK enantioselectivity in sheep [224] 76
Study 21. Evaluation of thiopentone PK enantioselectivity in humans [232] 76
Study 22. Evaluation of thiopentone PK enantioselectivity in rats [259] 76
Study 23. PK-PD study of thiopentone enantioselectivity in rats [262] 77
Study 24. Enantioselectivity of GABA receptor effects of thiopentone [261] 77
A
Study 25. PK study of thiopentone enantiomers from i.v. infusion in humans [264] 77
Study 26. Tissue distribution and effects from thiopentone enantiomers in rats [265] 77
Study 27. Blood-brain equilibration of thiopentone enantiomers in rats [266] 78
Study 28. Nicotinic ACh receptor effects of thiopentone enantiomers [284] 78
Study 29. PK studies of high dose thiopentone in humans [287] 78
Review 14. Thiopentone – a neurological and a neurosurgical analysis in patients [303] 78
Study 30. Acid-base changes on PD and PK of bupivacaine and thiopentone [306] 79
Study 31. Direct cardiac effects of thiopentone and its enantiomers in sheep [307] 79
Postscript 2 79
3.4 Nonsteroidal anti-inflammatory drug program 80
Review 15. A potential role of NSAIDs for postoperative pain management [200] 81
Study 32. Ketorolac enantiomers: a rapid, robust chiral assay [216] 82
Study 33. Study of the renal effects of ketorolac in rats [242] 83
Study 34. Ketorolac - multimodal analgesia study in sheep [269]. 83
Postscript 3 83
3.5 Halothane project 87
Study 35. Halothane enantioselectivity pharmacokinetics in rats [267] 89
Postscript 4 89
3.6 Ketamine project 90
Study 36. Ketamine pharmacokinetics and metabolism in rats [289] 92
Study 37. Pharmacokinetics of ketamine in rats –interaction with alfentanil [296] 93
Study 38. Potentiation of ketamine anaesthetic potency in rats by alfentanil [300] 93
Study 39. Stereoselective potentiation of potency of ketamine in rats by alfentanil [320] 93
Postscript 5 94
3.7 Thalidomide project 95
Study 40. A robust chiral assay for thalidomide in biological samples [316] 96
Study 41. Enantioselectivity of thalidomide pharmacokinetics in rats [319] 96
Study 42. Interpretation of the interaction between thalidomide and cisplatin [321] 97
Postscript 6 97
3.8 Some additional reviews involving stereopharmacology 98
Reviews 16, 17 and 18. Stereopharmacological impact in anaesthesiology [248,305,313] 98
Postscript 7 99
4. Discussion – and some conclusions 100
Afterword 107
v
Foreword
In January 2013, reflecting my interest in history, I participated in the 8th International
Symposium on the History of Anaesthesia held in Sydney. My paper titled, somewhat
cryptically and with apologies to Charles Dickens, 1848, and a Pharmacologic Tale of Two
Cities, sought to apply some precepts of chemistry, my primary discipline, to anaesthesia, my
adopted discipline, and I focused on research of that year by John Snow (1813-1858) in
London, and Louis Pasteur (1822-1895) in Paris. I concluded the paper by projecting some of
their insights onto my own research on thiopentone, a general anaesthetic agent introduced
into clinical anaesthesia in the 1930s that became one of the most important substances in the
history of anaesthesia. The preparation of that paper became the stimulus for this thesis.

Snow was a “man of medicine”, in the Victorian language of the day, who had trained as an
apothecary on the way to gaining his doctorate in medicine in 1844.1 This, he achieved
mainly by training and study applied to clinical practice. Pasteur was a physical scientist who
had written theses in both physics and chemistry for his doctorate in science in 1847, mainly
from his own experimental observations on the nature of matter.2

Snow introduced the principles and practice of dose regulation of volatile anaesthetic agents
and thereby the basis of controllable anaesthesia, as well as the basis of what would become
pharmacokinetics and pharmacodynamics a century later. Pasteur observed mirror image
morphology in crystals of the ‘same’ pure chemical substance, and that solutions thereof
rotated plane polarized light but oppositely and equally, thereby laying the basis for what we
now refer to as chirality and stereochemistry. In my paper, I elaborated by describing how
different stereoisomeric forms of drugs can produce qualitatively and/or quantitatively
different pharmacological effects, and that this is not unexpected since the body is built of
many different stereochemical molecules with which such substances interact. I have referred
to this as ‘stereopharmacology’. Finally, I related that thiopentone is synthesized and used
clinically as a racemate, i.e., an equal part mixture of two mirror image stereoisomers or
enantiomers. I concluded by describing some relevant aspects of my research on the racemate
and separate enantiomers of thiopentone, speculating on how its history might have been
different had thiopentone been developed as an enantiopure substance rather than a racemate.

Pasteur’s biographer Patrice Debré wrote an interesting comment – that he was “a chemist
among the doctors”. This set me thinking. I trained as a chemist and I also worked among
the doctors, attempting to apply the quantitative skills of chemistry to the pharmacology of
anaesthesia and acute pain management which, in this thesis, I term ‘anaesthesiology’. This
thesis comes from a selection of previously published contributions of stereopharmacology
applied mainly to anaesthesiology based on work that I initiated, supervised, and/or at least
strongly influenced. Thus it is an account of one particular aspect of the history of
pharmacology in anaesthesiology, and my very small contributions to it. Looking back, I
think that some of the contributions have remained quite leading edge, others less-so;
nonetheless, all are fixed by time in the notions, issues and techniques of the day. I have also
included a personal narrative of these events, in acknowledgement of the improbability that
anyone will ever be interested enough to ask me to write about such things.

1 Richardson BW. John Snow, M.D., a representative of medical science and art of the Victorian era.
In, Richardson BW, ed, The Asclepiad Vol IV, 1887, pp 274-300: Longmans, Green, and Co:
London.
2 Debré P. (1998). Louis Pasteur. (Translated by E. Forster). Johns Hopkins University Press:
Baltimore Maryland,. ISBN 0-8018-5808-9.
vi
Acknowledgements
My research was always multidisciplinary, with many colleagues, fellows, postgraduate
students, nursing and technical staff of various backgrounds, contributing their abundant skills
to an egalitarian research environment. They are named in the publications of our
multidisciplinary research groups in various places, and I am pleased to again acknowledge
the contributions of each to our research. I learned much from all, and even more from some.

In particular, I acknowledge the Australian and New Zealand College of Anaesthetists for the
support provided to me by the inaugural award of the Douglas Joseph Professorship of
Anaesthetics in 1993. This encouraged me to further expand my ideas on the
stereopharmacology of anaesthetic agents, which eventually led to the theme for this thesis.

Our ‘human lab’ research studies in consenting patients and/or healthy volunteers were
performed collaboratively between medical, nursing and scientist colleagues. Our animal
research studies required no less expertise, and many of the same colleagues participated in
both human and animal studies. Our ‘sheep lab’ studies were particularly ‘high tech’ and
labour intensive, involving exacting surgical preparation of the subjects, each with their
ongoing care and maintenance for periods of up to several months. Experimental studies
typically required many pairs of hands concurrently treating and/or monitoring the subject,
handling the instrumentation, performing serial blood sampling, usually from multiple
catheters, etc. Our ‘rat lab’ studies were less labour intensive, but they were no less exacting,
and also involved surgical preparation and maintenance, along with the pharmacological
studies. All of our studies generated many blood samples for subsequent laboratory analysis,
and this, too, required the highest expertise in analytical chemistry.

I especially acknowledge my principal co-authors in regard to the theme of this thesis. In
alphabetical order, and noting the graduation of my postgraduate candidates who were
involved: anaesthetist Stephen Barratt (PhD Syd, 2000); oncologist Fran Boyle;
pharmacologist Dennis Chang; pharmacologist Mary Collins/Chebib; veterinary anaesthetist
Sue Copeland (PhD Syd, 2008); neurologist Dennis Cordato (PhD Syd, 2001); indefatigable
Head of Department Michael Cousins; molecular biologist Ross Davey; organic chemist
Colin Duke; neurochemist Steven Edwards (PhD Syd, 2007); analytical chemist Bronwyn
Fryirs/Dawson; analytical chemist Xiao-Qing (Sonia) Gu; pharmaceutical chemist Li Huang;
cardiac surgeon YiFei Huang (PhD Adel, 1991); animal house manager the Late Ray Kearns;
veterinary anaesthetist and surgeon Leigh Ladd (PhD Syd, 2007); anaesthetist Peter McCall;
analytical chemist Colin McLean; anaesthetist Larry McNichol; anaesthetist Charles Minto
(PhD Syd, 2002); biologist Susan Murphy (PhD Syd, 2007); anaesthetist Craig Nancarrow
(PhD Flind, 1987); toxicologist and biostatistician John Plummer; biologist Marie Pryor;
anaesthetist and intensivist Bill Runciman (PhD Flind, 1983); biochemist Al Rutten (PhD
Flind, 1996); anaesthetist Nigel Sharrock; my wise postgraduate supervisor and medicinal
chemist Jack Thomas; my longest-time collaborator and pharmacokineticist Geoff Tucker;
pharmacometrician Richard Upton (PhD Flind, 1990); and anaesthetist Bernadette Veering.

I also acknowledge the crucial support of my family in the genesis of this thesis. Sylvia, my
partner of more than a half century supported me through the elations and disappointments of
research for most of that time, as did our kids, Cary, Neryl and Fiona. At various stages and
places, they tolerated yet another late night in the lab finishing a long experiment, or yet
another weekend in the office finishing a grant application because, like me, they believed
that it all was ‘worth it in the end’. My eternal love and respect to each and all.
vii
Thesis structure
The thesis is structured as a Foreword, a narrative of four Sections outlining and discussing,
rather than re-reviewing, the context and content of the publications, an Afterword, an
Appendix, as well as various figures and photographs added to personalise the account.
Explanatory notes and references to the work of others are reported in footnotes, as well as the
selected publications.

The Foreword presents a brief account of how this thesis was conceived. Section 1 is titled
Concepts and tools and here I have attempted to draw together various notions that underpin
the theme. Section 2 is titled Translating chemistry into anaesthesiology – in stages and sets
out the context of the research chronologically, and acknowledges the institutions and
colleagues supporting the research. Section 3 is titled Stereopharmacological research in
anaesthesiology and presents the main theme based upon knowledge relevant at the time of
the original publications. Section 4 presents a discussion and some conclusions arising from
the research. Each subsection is therefore intended to present a ‘stand-alone’ document in its
historical context with an accompanying commentary, rather than to present an up-to-date
review of each topic. The Afterword presents some additional reflections, largely from an
historical perspective. The Appendix gives a full numbered list of publications (cited in
square brackets in the narrative), followed by reprints of the selected publications (cited in
boldface in square brackets in the narrative). Some repetition within and between sections is
hard to avoid, so as to present coherent accounts and to give recognition to those to whom it is
due, but hopefully it is not excessive.
Declarations
This thesis is submitted in accordance with the University of Sydney (Higher Degree by
Research) Rules 2011 (as amended), Part 5 Higher Doctorates.

Rule 5.02 in part, states:
(1) The Academic Board may, on the recommendation of the relevant Faculty, award a
higher doctorate for published work that, in the opinion of the examiners:
(a) constitutes a distinguished contribution to knowledge or creative achievement; and
(b) is recognized by scholars in the relevant field as constituting a distinguished
contribution to knowledge or creative achievement in that field.
Accordingly, I state that the work presented in this thesis comprises a record of published
research and scholarship in a relevant field, and is submitted for consideration for the degree
of Doctor of Medical Science.

Rule 5.03 in part, states:
(1) Subject to this clause 5.03, to be eligible for admission to candidature for a higher
doctorate, an applicant must:
(a) hold a degree from the University that was conferred five or more years prior to the
application date.
Accordingly, I state that I hold the degrees of Master of Science (conferred 1968) and Doctor
of Philosophy (conferred 1972) of the Faculty of Science of the University of Sydney.

Rule 5.04 in part, states:
(2) The application must be accompanied by:
(a) a list of the published works that the candidate proposes to submit for examination;
(b) a description of the themes of the published works; and
viii
(c) where there are a large number of publications whose dates range over a period of
time and cover a range of subjects, a statement of how these publications are related to
one another and to the theme.
Accordingly, I state that this thesis is based on a selection of my publications on a theme in a relevant field – in
this case, that of the bearing of drug stereochemistry to some or other aspect of pharmacology, mainly in the
field of anaesthesiology.
Selected publications
I am conscious that, over time, my principal research role evolved into being the director of
various concurrent research programs and projects. This brought the responsibilities of the
initiation and preparation of research grant applications, supervision of postgraduate students,
maintenance of day-to-day progress in each project, and responsibility for submission of
reports, reviews, and other publications arising from the studies performed. My main
functions thereby became those of mentoring and providing proper welfare and resources;
accordingly, I participated less and less in ‘hands-on’ involvement in day-to-day experiments.
The selected publications present a cohesive theme from my work performed at several
institutions, with numerous colleagues including many postgraduate candidates. Whenever
practicable, any co-authoring postgraduate candidates were placed first in authorship.

I declare that I have been the author or co-author of each of the selected publications,
numbered according to the list below. None has been previously submitted by me for a
degree of The University of Sydney or any other university.

(a) Publications for which I was solely responsible: Nos. 200, 214, 243, 313, 327, 328

(b) Publications for which I initiated the work, provided significant input to the experimental
work performed with my co-author student(s), fellow(s), and/or collaborator(s), and was
solely or substantially responsible for the writing: Nos. 110, 170, 198, 244, 245, 248, 267,
282, 325

(c) Publications for which I initiated the work, contributed to the experimental work
performed by my co-author student(s), fellow(s), and/or collaborator(s), and was substantially
responsible for the writing: Nos. 48, 49, 185, 190, 197, 215, 216, 221, 242, 259, 262, 265,
266, 307

(d) Publications for which I initiated the work, contributed to the experimental work
performed by my co-author student(s), fellow(s), and/or collaborator(s), and was partly
responsible for the writing: Nos. 177, 188, 216, 217, 218, 250

(e) Publications that are mainly collaborative, for which I contributed to the concept,
experimental design and/or data analysis of work performed by my co-author student(s),
fellow(s), and/or collaborator(s), and was partly responsible for the writing: Nos. 197, 224,
246, 273, 284, 287, 303, 305

(f) Publications that have contributed to theses submitted for the degree of Doctor of
Philosophy of The University of Sydney by a candidate under my supervision who is the first
named author: Nos. 232, 261, 264, 273, 285, 287, 289, 296, 299, 300, 316, 319, 320, 321,
323, 324
ix
(g) Publications that have contributed to theses submitted for the degree of Doctor of
Philosophy of The University of Sydney by a candidate under my supervision who is another
of the named authors: Nos. 269, 276, 280, 306, 314

(h) Publications that were additionally included within a thesis submitted for the degree of
Doctor of Science of The University of Sydney by my colleague Michael Cousins: Nos. 48,
259, 266, 267

The publications listed below are grouped under somewhat sketchy subheadings and the
supporting institution, essentially in chronological order. Each publication is designated as a
“Study” (experimental observations and new knowledge), a “Review” (synthesis of ideas
based on relevant knowledge), or a “Patent”, and assigned the identifying number (in square
brackets) according to the Appendix. Each is finally designated (in parenthesis) by authorship
according to the above Declaration.

Basic concepts and experimental tools (Flinders University)
Review 01. [110]. Mather LE, Runciman WB. The physiological basis of pharmacokinetics:
concepts and tools. In, Quantitation, Modelling and Control in Anaesthesia, Stoeckel
HO, ed. Georg Thieme: Stuttgart, pp 12-40, 1985 (b)
Introductory reviews of stereochemistry-pharmacolology (The University of Sydney)
Review 02. [198]. Mather LE, Rutten AJ. Stereochemistry and its relevance in
anaesthesiology. Current Opinions in Anaesthesiology 4: 473-479, 1991 (b)
Review 03. [214]. Mather LE. "Chirality is in your hands" - the Australasian Visitor’s Lecture
for 1994. ANZCA Bulletin 3: 26-32, 1994 (a)
Review 04. [215]. Mather LE, Björkman S. Pitfalls in pharmacokinetics. Anaesthesia
Pharmacology Reviews 2: 260-270, 1994 (c)
Local anaesthetics - basic concepts and tools (Flinders University)
Review 05. [48]. Mather LE, Cousins MJ. Local anaesthetics and their current clinical use.
Drugs 18: 185-205, 1979 (c,h)
Review 06. [49]. Tucker GT, Mather LE. Clinical pharmacokinetics of local anaesthetic
agents. Clinical Pharmacokinetics 4: 241-278, 1979 (c)
The start of the stereopharmacology research - prilocaine (The University of Sheffield)
Study 01. [197]. Tucker GT, Mather LE, Lennard MS, Gregory A. Plasma concentrations of
the stereoisomers of prilocaine after administration of the racemate - implications for
toxicity? British Journal of Anaesthesia 65: 333-336, 1990 (c)
Local anaesthetics program – focus on chiral agents (Flinders University
and The University of Sydney)
Study 02. [170]. Mather LE. Disposition of mepivacaine and bupivacaine enantiomers in the
sheep. British Journal of Anaesthesia 67: 239-246, 1991 (b)
Study 03. [177]. Rutten AJ, Mather LE, McLean CF. Cardiovascular effects and regional
clearances of IV bupivacaine in sheep: enantiomeric analysis. British Journal of
Anaesthesia 67: 247-256, 1991 (d)