Winter 2009 [pdf] - University of Kentucky - College of Pharmacy

Novel Anti-Overdose Drug Studied
Devastating bodily
harm caused by cocaine
overdose may soon be
avoided because of a
new drug discovery
made by University of
Kentucky College or
Zhan
Pharmacy researchers.
By tweaking a naturally occurring
enzyme, Chang-Guo Zhan, PhD, professor
in the Department of pharmaceutical
sciences at UK’s College of Pharmacy,
and his colleagues created a molecule
that could flush a cocaine overdose
out of the body before it can cause
irreparable damage to the body.
Currently, doctors can only try to
relieve the symptoms of a cocaine
overdose. If the enzyme undergoing
research works in humans, it could
remove the drug from a user’s body.
Enzymes in the body combine cocaine
with water and then, over a sequence of
reaction steps, break it down into two
harmless products. However, this process
is very slow – it takes up to 90 minutes
to dispose half of even a tiny dose, and
much longer for a large overdose. Zhan
says that the molecule his team created
can break down cocaine much faster.
Courtney Swadley, a graduate student
in the lab of Dr. Audra Stinchcomb, has
been awarded a National Research Service
Award Fellowship from the National
Institute on Drug Abuse. Prior to joining
the Pharmaceutical Sciences graduate
program in 2005, Courtney received a BS
degree in chemistry from the University of
Pittsburgh.
Courtney’s project focuses on studying
and optimizing the skin permeation of
cannabinoid 1 (CB1) receptor agonists and
their analogs. CB1 receptor agonists show
therapeutic potential in the treatment
of numerous medical ailments including
pain (e.g. chronic and neuropathic),
nausea and vomiting, and substance
abuse (e.g. alcoholism and smoking)
“Our drug discovery was based
on rational design using a novel
computational approach,” said Zhan.
Zhan and his colleagues, including
scientists at the University of Michigan
Medical School, calculated the energy
required to perform each reaction step,
which enabled them to determine how
much energy a molecule should have
to successfully react. Using computer
simulations that systematically tweak
the structure of the enzyme and predict
the effect of these tweaks on the energy
barrier, Zhan and his colleagues arrived
at a candidate molecule that promised
to speed up the degradation of cocaine
by 2,000 times faster than the naturally
occurring enzyme. The molecule
was then synthesized and tested on
animal models to determine whether
it might work in the human body.
Zhan says the overdose therapy should
have few side effects in humans.
“We expect that this candidate
molecule can be tolerated very well in
the human body because it is a variant
of the primary cocaine-metabolizing
enzyme in the human body and
we have not made any change on
the enzyme surface,” Zhan said.
Swadley Receives NRSA Fellowship from NIDA
making them very interesting for drug
delivery research.
These compounds are being investigated
for transdermal delivery because of this
delivery system’s advantages of providing
a patient-controlled method of use,
potential for controlled release and
long term delivery application, and the
ability to bypass first-pass and gastric
metabolism. CB agonists are generally
of large molecular weight and very
lipophilic, making them good models for
understanding the skin permeation of
compounds with similar physicochemical
properties for which little information
about skin permeation is available. This
project is funded by grants from the NIH
(F31) and the American Cancer Society.
New Research Accounts
July 1, 2008 to Dec. 15, 2008
Dr. Bradley D. Anderson
$60,001 from Boehringer Ingelheim
for “Optimizing Oral Absorption of
Poorly Water Soluble Drug Candidates:
Mechanisms and Predictive Models
for the Selection of Excipients to
Maintain Supersaturation by Inhibiting
Nucleation and Crystallization.”
Dr. Karen M. Blumenschein
$5,000 from American Foundation
for Pharmaceutical Education for
“Do Patients and Pharmacists
Agree on the Interpretation of
Verbal Probability Statements.”
Dr. Peter A. Crooks
$72,550 from University of Rochester
for “A Novel Thiadiazolidine-Dione
Targets Human Leukemia Stem Cells.”
Dr. Charles D. Loftin
$20,000 from PhRMA Foundation for
“Fellowship for Julie Oestreich: The Effects
of P2Y12 Polymorphisms on Platelet
Receptor Expression and Activation.”
Dr. Audra L. Stinchcomb
$7,325 from AllTranz for “Evaluation
of a Drug for Dermal Delivery.”
Dr. Audra L. Stinchcomb
$30,524 from National Institute on
Drug Abuse for “NRSA Fellowship
for Swadley: Transdermal Delivery of
Hydroxyphenylarachidonylamides.”
Dr. Jurgen Rohr
$251,484 from National Cancer
Institute for “Novel Aureolic Acid-
Type Antitumor Agents.”
Dr. Jeffery C. Talbert
$905,686 from Department for Mental
Health Mental Retardation Service
for “Research Information Systems
Management for KY Department for
Mental Health/Mental Retardation.”
Dr. Jeffery C. Talbert
$1,722,468 from KY Cabinet for
Health and Family Services for
“Money Follows the Person (MFP).”
Dr. Steven Van Lanen
$10,000 from Daiichi Pharmaceutical Corp.
for “Biosynthesis of Nucleoside Antibiotics.”
Dr. Chang-Guo Zhan
$498,945 from National Institute
on Drug Abuse for “High-Activity
Mutants of Cocaine Esterase for
Treatment of Drug Addiction.”
Pharmacy Totals: $3,583,983
16 Focus on Pharmacy