The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Dr. Daniel Kohane
Page 1
HST-151
Drug Development
Daniel S. Kohane MD, PhD
This lecture will discuss the evaluation of new drugs (Ch. 5 of Katzung) - with the
definition of drug writ large - using the field of prolonged duration local anesthesia as an
example. The talk will attempt to highlight the importance of basic pharmacological
concepts in drug development, but also introduce (or perhaps re-introduce) more
advanced biotechnological approaches. We will not focus on the clinical or business
aspects of drug development.
Outline of the Lecture
1. The Need
- Magnitude and severity of the problem
- What medical researchers look for vs. what the corporate world looks for
- Existing technologies and their limitations
2. Characteristics of the hypothetical ideal solution
- The importance of asking the right question (most importantly, perhaps:
assuming we can achieve what we set out to achieve, is it actually good for our
patients?)
- The difficulty of overcoming preconceived notions
3. Ways of achieving (2)
• New drugs and drug combinations, or new ways of using old drugs
• New targets
• Chemical modification of drugs
• Novel carrier fluids
• Microparticles
– liposomes and similar particles
– microspheres
4. Key concepts and how they relate (e.g. in choosing a drug or delivery system)
- Potency, and whether it matters
, Page 2
- Efficacy
- Toxicity
local: cytotoxicity, biocompatibility.
systemic: EC50, LD50, therapeutic index
- Pharmacokinetics, phamacodynamics
- High-throughput vs. low-throughput (or, not everything can be modeled)
5. Specific examples will focus on the development of prolonged duration local
anesthetics, particularly recent research by the lecturer.
Glucocorticoids prolong rat sciatic nerve blockade in vivo from bupivacaine
microspheres.
Anesthesiology. 1996 Nov; 85(5): 1157-66.
BACKGROUND: Previous work showed that incorporation of dexamethasone (0.05
weight/weight percentage) into bupivacaine microspheres prolonged blockade by eight to
13 times compared with that produced by bupivacaine microspheres alone. The
determinants of dexamethasone's block-prolonging effect were examined and reported
here. METHODS: Polylactic-co-glycolic acid polymer microspheres (65/35) with 75
weight/weight percentage bupivacaine were prepared. Microspheres were injected
adjacent to the rat sciatic nerve, and sensory and motor blockade were assessed. A
procedure was developed to test drugs for block-prolonging ability in vivo by placing test
drugs in the injection fluid along with a suspension of bupivacaine microspheres.
RESULTS: Dexamethasone alone in suspension did not produce blockade, nor did it
prolong blockade induced by aqueous bupivacaine. Bupivacaine microspheres (150 mg
drug/kg rat weight) produced blockade for 6 to 10 h. Dexamethasone in the suspending
solution of microspheres prolonged block by up to five times. Glucocorticoids prolonged
block in proportion to glucocorticoid/antiinflammatory potency. The corticosteroid
antagonist cortexolone inhibited dexamethasone's blockade-prolonging action. Durations
of blockade with or without dexamethasone were unaltered by hydroxyurea-induced
neutrophil depletion. Microspheres were extracted from rats at time points ranging from 7
h to 7 days, and residual microsphere dry weight and bupivacaine content were similar in
groups of rats injected with either bupivacaine microspheres or bupivacaine microspheres
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