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8/8/2019 Obesity and New Pharmaceutical Approaches
1/26
AND NEW PHARMACEUTICALAPPROACHES
Obesity
American Council on Science and Health
8/8/2019 Obesity and New Pharmaceutical Approaches
2/26
OBESITY AND NEW
PHARMACEUTICAL APPROACHES
by Steven Marks
for the American Council on Science and Health
Ruth Kava, Ph.D., R.D.Project Coordinator and Editor
February 2009
AMERICAN COUNCIL ON SCIENCE AND HEALTH
1995 Broadway, 2nd Floor, New York, NY 10023-5860
Phone: (212) 362-7044 Fax: (212) 362-4919
acsh.org HealthFactsAndFears.com
E-mail: [email protected]
8/8/2019 Obesity and New Pharmaceutical Approaches
3/26
Nigel Bark, M.D.Albert Einstein College of Medicine
Thomas G. Baumgartner, Pharm.D., M.Ed., FASHP,BCNSPUniversity of Florida, Gainesville
George A. Bray, M.D.Pennington Biomedical Research Center
Joseph F. Borzelleca, Ph.D.
Medical College of Virginia
Jack C. Fisher, M.D.University of California, San Diego
Donald A. Henderson, M.D., M.P.H.University of Pittsburgh Medical Center
Ruth Kava, Ph.D., R.D.American Council on Science and Health
Kathryn Kolasa, Ph.D., R.D., LD/NEast Carolina University
Gilbert L. Ross, M.D.American Council on Science and Health
Thomas P. Stossel, M.D.Harvard Medical School
Elizabeth M. Whelan, Sc.D., M.P.H.American Council on Science and Health
ACSH accepts unrestricted grants on the condition that it is solely respon-sible for the conduct of its research and the dissemination of its work to the
public. The organization does not perform proprietary research, nor does it
accept support from individual corporations for specific research projects.
All contributions to ACSHa publicly funded organization under Section
501(c)(3) of the Internal Revenue Codeare tax deductible.
Copyright 2009 by American Council on Science and Health, Inc.
This book may not be reproduced in whole or in part, by mimeograph or any
other means, without permission.
T H E F O L L O W I N G P E O P L E
R E V I E W E D T H I S P U B L I C A T I O N .
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CHAPTER 1
Executive Summary
CHAPTER 2
Introduction
CHAPTER 3
Whats Under the Hood: How the Body Regulates theBalance Between Food Intake and Energy Expenditure
CHAPTER 4
Current Treatments: How Effective Are They?
CHAPTER 5
New Approaches: Putting the Central and PeripheralMechanisms to Work
CHAPTER 6
Central Targets: The Role of the Hypothalamusa. The Serotonin System: A Safer Redux?
b. Gut Hormones: Ensuring Fuel for the Short Trip
CHAPTER 7
Peripheral Mechanisms: Energy Expenditurea. Metabolismb. Fat Storage
CHAPTER 8
Toward the Future
CHAPTER 9
Conclusion
ACKNOWLEDGMENTS
REFERENCES
1
2
4
8
10
11
13
15
16
17
18
CHAPTER PG
C O N T E N T
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Dietary and behavioral changes offer only limited
help; although some people benefit from anti-
obesity drugs, expectations are often unrealistic.
The effectiveness of current treatments is limited;
for the morbidly obese, surgery is the most effective
option, although it is not risk-free.
Efforts to foster weight loss are countered by the
bodys inherent need to preserve weight.
Considerable progress has been made in
identifying new means of treating obesity,
particularly those that suppress appetite or restrict
fat absorption.
The extremely complexity of the bodys energy
system means that altering one part affects others,
as well as other biological systems.
The development of new drugs should focus on
helping patients eat less and better utilize what
they eat; thus far, drugs that stimulate the use
of existing fat stores are in the early stages of
development.
Pharmaceutical agents will not solve the obesity
problem by themselves; lifestyle adjustments will
likely always be necessary.
For the immediate future, the most effective
treatment is likely to be a combination of drug and
behavioral therapy, along with changes in diet, rest,
and exercise.
Obesity and New Pharmaceutical Approches / Chapter 1 / 1
C H A P T E R
Executive Summary
Obesity is a growing problem worldwide, with serious health and quality-of-life implications.
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One of the parents is overweight and the other is obese,
wrote the Harvard Medical School professor and director
of the Optimal Weight for Life Clinic (Ludwig 2007). All
five of the children are even more severely obese, and
although they are still young, they already face the
prospect of lives limited by chronic medical
problems. One of the youngsters shows the first signs of
fatty liver, while another has high blood pressure. Three
have marked insulin resistance, the first sign of type-2
diabetes; four have abnormal cholesterol profiles, and
two complain of orthopedic problems. The children all
express serious emotional distress, stemming from their
obesity. Were the G family unusual, their health problems
could be written off as medical curiosities. Unfortunately,
families like that of Mr. and Mrs. G and their children are
becoming all too common in industrialized nations around
the world.
Today, about 66% of all Americans are overweight or
obese (Ogden 2006). Researchers from the Centers for
Disease Control and Prevention (CDC) report that since
1970, the number of overweight children and adolescents
between the ages of 6 and 19 years has tripled, meaningthat more than 9 million young Americans (or nearly one-
in-five) are at risk for a wide range of obesity-related
problems, including diabetes, hypertension, high choles-
terol, coronary artery disease, respiratory problems,
sleep apnea, gallbladder disease, osteoarthritis, and sev-
eral forms of cancer (Cooke 2006). These trends suggest
that the current generation of Americans may be the first
in the past 200 yeas to
have a shorter life expectancy than their parents had,
according to physicians at the University of Illinois
Medical Center in Chicago (Olshansky 2005). This is
hardly the definition of progress.
In addition to the health consequences, obesity also
entails substantial economic and social costs. An obese
worker costs his employer an estimated $2,500 per
year in added medical expenses and lost productivity,
according to studies from RTI International and the CDC.
Overall, business and industry pay a hefty price for
obesity:$13 billion a year, estimates the Washington,
DC-based National Business Group on Health, a health
policy group comprising the nations largest corporations
(Harper 2007).
Obese people themselves are often stigmatized.
Documented cases of discrimination extend to
employment, education, and healthcare. There have also
been suggestions of bias in adoption proceedings, juryselection, housing, and other areas of public life,
according to Yale University investigators (Puhl 2001).
Obesity is now the nations second-biggest public health
problem, right after smoking. Although lifestyle changes,
Obesity and New Pharmaceutical Approches / Chapter 2 / 2
C H A P T E R
Introduction
The endocrinologist David Ludwig calls his patients, the seven-member Gfamily, a microcosm of 21st-century America.
2
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most notably dietary adjustments and increased
physical activity, can help people lose weight and stave
off obesity, many find it difficult to comply with such
weight-loss regimens. Shedding surplus pounds is
frequently a struggle, but for many people, it's a battle
they are genetically programmed to lose. (Later on, well
learn just why this is so.) For this reason, a great deal ofinterest and hope rests on the potential effectiveness
of pharmaceutical therapies for obesity.
Americans currently spend more than $33 billion a year
on weight-loss treatments (BW 2008), ranging from
prescription drugs to diet programs and nutritional
supplements. Not all such treatments are credible (see
Buyer Beware sidebar in Chapter 4), and the results can
be disappointing for even those treatments that have
value. Nonetheless, the pharmaceutical industry has
invested enormous capital in the search for effective and
safe weight-loss drugs that target the bodys intricate
energy-regulation mechanisms. The research anddevelopment continues today.
Obesity and New Pharmaceutical Approches / Chapter 2 / 3
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8/8/2019 Obesity and New Pharmaceutical Approaches
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Obesity and New Pharmaceutical Approches / Chapter 3 / 5
BMI
19
20
21
222
3
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
Height
(inches)
BodyWeight(pounds)
58
91
96
100
105
110
115
119
124
129
134
138
143
148
15
3
158
162
167
172
177
181
186
191
196
201
205
210
215
220
224
229
234
239
244
248
253
258
59
94
99
104
109
114
119
124
128
133
138
143
148
153
15
8
163
168
173
178
183
188
193
198
203
208
212
217
222
227
232
237
242
247
252
257
262
267
60
97
102
107
112
118
123
128
133
138
143
148
153
158
16
3
168
174
179
184
189
194
199
204
209
215
220
225
230
235
240
245
250
255
261
266
271
276
61
100
106
111
116
122
127
132
137
143
148
153
158
164
16
9
174
180
185
190
195
201
206
211
217
222
227
232
238
243
248
254
259
264
269
275
280
285
62
104
109
115
120
126
131
136
142
147
153
158
164
169
17
5
180
186
191
196
202
207
213
218
224
229
235
240
246
251
256
262
267
273
278
284
289
295
63
107
113
118
124
130
135
141
146
152
158
163
169
175
18
0
186
191
197
203
208
214
220
225
231
237
242
248
254
259
265
270
278
282
287
293
299
304
64
110
116
122
128
134
140
145
151
157
163
169
174
180
18
6
192
197
204
209
215
221
227
232
238
244
250
256
262
267
273
279
285
291
296
302
308
314
65
114
120
126
132
138
144
150
156
162
168
174
180
186
19
2
198
204
210
216
222
228
234
240
246
252
258
264
270
276
282
288
294
300
306
312
318
324
66
118
124
130
136
142
148
155
161
167
173
179
186
192
19
8
204
210
216
223
229
235
241
247
253
260
266
272
278
284
291
297
303
309
315
322
328
334
67
121
127
134
140
146
153
159
166
172
178
185
191
198
20
4
211
217
223
230
236
242
249
255
261
268
274
280
287
293
299
306
312
319
325
331
338
344
68
125
131
138
144
151
158
164
171
177
184
190
197
203
21
0
216
223
230
236
243
249
256
262
269
276
282
289
295
302
308
315
322
328
335
341
348
354
69
128
135
142
149
155
162
169
176
182
189
196
203
209
21
6
223
230
236
243
250
257
263
270
277
284
291
297
304
311
318
324
331
338
345
351
358
365
70
132
139
146
153
160
167
174
181
188
195
202
209
216
22
2
229
236
243
250
257
264
271
278
285
292
299
306
313
320
327
334
341
348
355
362
369
376
71
136
143
150
157
165
172
179
186
193
200
208
215
222
22
9
236
243
250
257
265
272
279
286
293
301
308
315
322
329
338
343
351
358
365
372
379
386
72
140
147
154
162
169
177
184
191
199
206
213
221
228
23
5
242
250
258
265
272
279
287
294
302
309
316
324
331
338
346
353
361
368
375
383
390
397
73
144
151
159
166
174
182
189
197
204
212
219
227
235
24
2
250
257
265
272
280
288
295
302
310
318
325
333
340
348
355
363
371
378
386
393
401
408
74
148
155
163
171
179
186
194
202
210
218
225
233
241
24
9
256
264
272
280
287
295
303
311
319
326
334
342
350
358
365
373
381
389
396
404
412
420
75
152
160
168
176
184
192
200
208
216
224
232
240
248
25
6
264
272
279
287
295
303
311
319
327
335
343
351
359
367
375
383
391
399
407
415
423
431
76
156
164
172
180
189
197
205
213
221
230
238
246
254
26
3
271
279
287
295
304
312
320
328
336
344
353
361
369
377
385
394
402
410
418
426
435
443
Source:Adaptedfrom
ClinicalGuidelinesontheIdentification
,Evaluation
,andTreatmentofOverweight
andObesityinAdults:TheEvidenceReport.
BodyMassIndexTable
Normal
Overweight
Obese
ExtremeObesity
8/8/2019 Obesity and New Pharmaceutical Approaches
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is confounded by the fact that these patients tend to
under-report their food intake by as much as 30%.
Overeating can be gauged only in relation to that
individuals energy expenditure (Spiegelman 2007). Thisobservation means that people who follow a regular
exercise regime and do not overeat routinely tend to
maintain their weight. However, even small changes in
diet or in the amount of physical activity can affect
body weight when the changes extend over a long period
of time.
Under normal conditions, the bodys energy balance
is strictly regulated and controlled. Consider that most
people consume about 700,000 calories each year; even
so, body weight usually does not vary by more than 1
kilogram up or down about 7,000 calories (3,500
calories = 1 pound). This means the body is able to
maintain its fat stores to an accuracy of 99% (Hofbauer2007). The bad news for those trying to lose weight is that
fewer than 20 excess calories a day over the course of a
year will put on 1 pound of fat.
That the body can regulate such a small amount of
overeating one cannot measure 20 calories accurately
is a sign of how finely balanced is our energy
maintenance system, said Randy G. Seeley, Ph.D.,
associate director of the Obesity Research Center at the
University of Cincinnati, in a telephone interview.
Evolutionary pressures, which required prehistoric man to
maintain his energy reserves in the face of a harsh
environment and limited food supplies, predispose ourbodies to prevent weight loss more strongly than weight
gain. Our energy regulatory system contains many
redundant mechanisms to keep us from starving.Our
bodies were not designed to restrict our intake of food but
to help us survive, Dr. Seeley added. Although cavemen
struggled to find food and constantly teetered on the edge
Obesity and New Pharmaceutical Approches / Chapter 3 / 6
Figure 1. Nerve signals from adipose tissue and gastrointestinal organs such as the stomach and intestines influence appetite and
satiation (feelings of fullness) via central and peripheral mechanisms. All of these signals are integrated in the hypothalamus. Fat-cell
signals are primarily responsible for the long-term regulation of hunger, while messages from the organs such as the stomach and
intestines control immediate energy needs and satiety. Adapted from Hofbauer KG, Nicholson JR, and Boss O.
Although cavemen struggled to find
food and constantly teetered on the edge
of starvation, contemporary Americans
eat and overeat for many reasons
other than hunger. Humans eat for
social purposes and to relieve stress and
sometimes for no other reason than that
they can. People find it hard to pass by the
local convenience store if they feel like
enjoying a burrito and fries, and the energy
regulatory system is happy to oblige.
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of starvation, contemporary Americans eat and overeat
for many reasons other than hunger. Humans eat for
social purposes and to relieve stress and sometimes for
no other reason than that they can. People find it hard
to pass by the local convenience store if they feel
like enjoying a burrito and fries, and the energy
regulatory system is happy to oblige. In other words,
getting fat is easy for most people, but losing weight can
be a major struggle.
The relationship between energy intake (i.e., food
consumption), energy expenditure (i.e., body functions,
such as heart beat and breathing, and physical activity),
and weight is often expressed as calories in versus
calories out. Too many calories consumed and too few
calories burned off can lead to overweight, and in time,
obesity. This simple equation explains why understanding
the connection between energy intake and expenditure is
so important. The balance between the two is regulated
by a host of complex biological processes that involve
two basic types of mechanisms the central and
peripheral. Central mechanisms include neuronal
systems in the brain that monitor caloric intake and useand respond to signals from the body that contain
information about energy stores and availability, much as
a warehouse manager keeps track of inventory.
Peripheral mechanisms include hormonal signals from
the gastrointestinal tract, as well as from fat cells to such
organs as the liver and pancreas, skeletal muscle, and
even disease-fighting immune cells that carry out various
metabolic (biochemical) functions important to energy
regulation (Hofbauer 2007) (see Figure 1). These are the
orders the warehouse must fill, sometimes immediately
and other times later in the day.
Here is how the two mechanisms work. First, feelings of
hunger cause one to fix a sandwich or grab an apple.
Eating triggers the process of digestion, and then signals
emanating from the stomach tell the brain you are
satisfied and have had enough to eat. The brain gathers
this information, along with other neuronal and hormonaldata relating to the bodys overall energy status, to
produce a coordinated response to the change in
the nutritional state. In this respect, the role of the
hypothalamus, the part of the brain that regulates
homeostasis (stability), is critical, says Richard Palmiter,
Ph.D., professor of biochemistry at the University of
Washington and an obesity investigator at the Howard
Hughes Medical Institute (personal communication).
Ongoing obesity drug research has targeted both central
and peripheral mechanisms in the search for safe and
effective treatments (Table 2). This research investigates
strategies to reduce food intake by altering appetite,
feelings of satiety (i.e., fullness or satisfaction), andfat absorption, and to elevate energy expenditure by
boosting metabolism.
Obesity and New Pharmaceutical Approches / Chapter 3 / 7
AREAS OF INVESTIGATIONAREAS OF
CURRENT RESEARCHDRUGS NOW IN USE
Central (appetite, satiation,
metabolism)
LeptinMelanocortin systemSerotonin system
LoracaserinMelanin-concentrating hormoneCannabinoid receptors
Zimulti*Gut hormones
Peptide YYCholecystokininGhrelinSynthetic GLP-1
MeridiaSympatomimetics
PhenterminePhendimetrazieBenzphetamine
Glucophage and Sandostatin
Peripheral (metabolism, energy
use, fatnstorage)
Uncoupling proteinsAdipokines
Adiponectin
XenicalAlli (OTC)
* Currently in final clinical studies prior to FDA review
Used for treatment of adolescent obesity, although not approved for that indication
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Centrally acting Meridia blocks the action of several important
chemicals involved mainly in promoting hunger and, to a lesser
degree, food intake. In the clinical trials of Meridia, patients lost about
3% to 4% of their body weight, most of which occurred during the first
six months of treatment. Continued use of the drug helped maintain
the weight loss. Patients also experienced reductions in triglyceride
levels and increases in good (HDL) cholesterol, which could help
prevent the development of metabolic syndrome, diabetes, and heart
disease. However, this benefit was counterbalanced by a slight
increase in blood pressure and heart rate. As a result, for patients with
hypertension or who have had an excessively rapid heart beat in the
past, the use of Meridia may require regular monitoring. The drug did
not affect bad (LDL) cholesterol.
In contrast, Xenical and Alli work on the gastrointestinal system,
where they prevent the absorption of fat. People using these drugs
lose about the same amount of weight as those taking Meridia.
Ongoing treatment also appears to keep the weight off. Unfortunately,
Xenical and Alli may have some socially disturbing side effects that
stem from their special mechanism of action: the fat that is not
absorbed remains in the gut, where it can contribute to flatulence and
the need for frequent bowel movements, which can be difficult
to control. These gastrointestinal difficulties usually occur at thebeginning of treatment and tend to diminish over time, especially
when fat intake is reduced.
A fourth drug, Zimulti/Accomplia (rimonabant), is in late clinical
development and should also be noted. Researchers were prompted
to study the effects of Zimulti and sister drugs on appetite suppression
because cannabis (the active ingredient in marijuana) has long been
known to promote feelings of hunger, the so-called munchies. This
Obesity and New Pharmaceutical Approches / Chapter 4 / 8
C H A P T E R
Current Treatments:How Effective Are They?
The Food and Drug Administration (FDA) has approved three drugs for thelong-term treatment of obesity, Meridia (sibutramine), Xenical (orlistat), andAlli, an over-the-counter (OTC) version of Xenica. Each primarily addressesone of the two mechanisms described above.
4
The shelves of grocery stores and pharmacies are
stocked floor to ceiling with various and sundry
dietary aids, including vitamins, minerals, herbs
and botanicals, and other substances such
as enzymes, amino acids, glandulars, and
metabolites. Some carry the labels natural and
clinically proven. Others guarantee dramatic
weight-loss results. Dont believe a word of it.
Snake oil is still snake oil, even when wrapped in
fancy packaging.
Alli is the only FDA-approved, over-the-counter
treatment for obesity. This means its prescription
version, Xenical, has met rigorous standards for
safety and effectiveness. The difference between
Alli and Xenical relates to dose Alli is half as
potent (60 mg) as Xenical (120 mg) and therefore
deemed safe for consumer use without a doctors
order. In contrast, other weight-reducing aids have
not undergone human clinical testing. Under
current law, these products are categorized as
dietary supplements (i.e., foods); as such, they
can be sold without proof of efficacy. Dietary
supplements can be also harmful. The active
ingredients may interact with common prescription
medications or analgesics such as Tylenol oraspirin, raising the risk of a serious side effect.
Even sorbitol, the sweetener used in sugarless
gum, can cause severe diarrhea and bowel
problems if over-consumed (Bauditz 2008).
(Before taking any dietary supplement, review the
ingredients with a doctor or pharmacist.) The
bottom-line on miracle weight-loss pills: if the
claim sounds too good to be true, it probably is.
BUYER BEWARE
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drug blocks a class of receptors in the brain that respond
to cannabis (cannabinoid receptors), which, in theory,
should reduce the desire to overeat. In clinical trials,
weight loss achieved with Zimulti had positive effects on
a number of risk factors for heart disease, including
cholesterol and triglyceride levels and insulin resistance.
Blood pressure was not affected, which was surprising inlight of the fact that patients taking Zimulti also lost about
3% to 5% of their weight and therefore should have expe-
rienced a reduction in blood pressure. Nearly 20
countries around the world have approved this
medication for use. However, in 2007, the FDA rejected
Zimulti because of the risk of psychiatric side effects,
including depression, anxiety, and loss of sleep. The
manufacturer plans to conduct additional studies and
then resubmit Zimulti for approval.
In addition to Meridia, Xenical, and Alli, which aredesigned and approved for chronic therapy, the FDA also
has approved several other drugs for short-term use.
Phentermine, phendimetrazine, and benzphetamine all
belong to a drug class known as sympathomimetics.
These medications act as appetite suppressants by
mimicking the hormones adrenaline or noradrenaline.
The sympathomimetics commonly prescribed for the
treatment of obesity can serve as helpful adjuncts to a
regimen of diet and exercise. Because these drugs can
be habit-forming and may cause serious side effects,
including high blood pressure, agitation, depression, and
even psychoses, physicians limit their use to two to three
weeks. (See The Serotonin System: A Safer Redux
section in Chapter 6.) The sympathomimetics are not
recommended for children and adolescents because of
the potential for abuse and adverse events.
Current obesity drugs offer only modest benefits.
Moreover, combining Xenical and Meridia does not have
an additive effect the weight loss remains the same.
The lack of robust results puts patients and physicians in
a quandary. Patients are often disappointed to discover
that the drugs will help them lose only about 3% to 4%
of their body weight. A 1997 study examined patientexpectations for obesity drugs and produced startling
results. Obese patients indicated that they hoped to lose
from 31% to 38% of their weight. Twenty-five percent was
deemed acceptable, and 17% was rated as disappointing
(Foster 1997). These findings suggest that obesity
doctors may have a difficult time managing their patients
expectations for drug therapy.
Its true that it has been difficult to develop scientifically
rational treatments that produce the kind of weight loss
that people want, says Dr. Seeley. As things now stand,
our treatments arent even effective enough to be
disappointing! More important, maintaining even themodest reduction in weight requires life-long treatment.
There is a common misconception that any effective
obesity drug can be used for a limited time until the
desired weight loss is achieved and then stopped, says
Rudolph Leibel, MD, professor of molecular genetics at
Columbia University and co-director of the Naomi Berrie
Diabetes Center, in an interview. In this respect, treating
obesity is no different from treating hypertension or high
cholesterol. Any successful drug or combination of drugs
will probably have to be taken indefinitely. The hope is
that, in the future, doctors will have a wider range of drug
therapies that they will be able to use selectively on the
patients best able to benefit from them. That remainsthe objective of current pharmaceutical research and
development.
Obesity and New Pharmaceutical Approches / Chapter 4 / 9
Current obesity drugs offer only modest
benefits. Moreover, combining Xenical
and Meridia does not have an additive
effect the weight loss remains the same.
The lack of robust results puts patients
and physicians in a quandary. Patients are
often disappointed to discover that the
drugs will help them lose only about 3%
to 4% of their body weight.
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The available therapies only address those mechanisms that
fine-tune the energy balance. As one investigator commented, There
are lots of new targets under evaluation, and we hope that some of
them may turn out to be much more effective than the current drugs.
We may not have found the right targets yet, but were still looking.
Obesity and New Pharmaceutical Approches / Chapter 5 / 10
C H A P T E R
New Approaches:Putting the Central and Peripheral Mechanisms to Use
One possible reason for the marginal utility of current drugs, somepharmaceutical researchers believe, is that the bodys most importantregulators of weight remain to be characterized.
5
At present, the most dramatic obesity treatment
is surgery. Many severely obese patients who
undergo bariatic surgery (gastric bypass), for
instance, maintain a significant weight loss of 45 to
60 pounds or more for periods of at least a
decade. However, surgery is highly invasive and
not without risks; as Dr. Randy Seeley of the
University of Cincinnati pointed out, high rates
of rehospitalizations and post-operative
complications can be associated with these
procedures. For this reason, techniques such as
gastric bypass or banding usually are reserved for
the most serious cases people with a BMI >40 or
with a lower score and other coexisting health
problems such as heart disease or diabetes.
Interestingly, scientists from University College in
London recently identified two proteins P2Y1
and P2Y11 that control relaxation of the gut
(BBC News 2008). By blocking the P2Y11
receptor, which directs slow relaxation, a drug
could theoretically help control stomach volume in
a manner not unlike gastric banding. Much
research will need to be carried out before this
provocative concept can be proven, but ifsuccessful, it could prove to be a way to achieve
to the benefits of these surgical interventions
without incurring the risks.
BARIATRIC SURGERY
A WAY TO BYPASS GASTRIC BYPASS?
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Hormones are signaling agents produced by various
tissues in the body. Scientists discovered that leptin is
released from fat cells to inform the brain about the state
of the bodys energy supply. We now know that leptin
circulates in the blood to the hypothalamus, providing
information about the number and size of adipose (fat)
cells in the body the greater the amount of body fat, the
more leptin a person produces, the greater the amount of
body fat. In theory, administration of leptin to obese
people would signal the brain that fat stores were
abundant, thereby reducing food intake. However, early
studies using a genetically engineered form of the
hormone proved to be disappointing: daily injections of
leptin helped only a small percentage of obese subjects
lose weight. This finding led researchers to hypothesize
that many patients are resistant to leptin. At present, obe-
sity researchers are investigating techniques to
overcome this resistance.
Other hormones that signal the hypothalamus and may
prove useful in the regulation of food intake and energy
expenditure include those in the melanocortin system.
The central melanocortin system is arguably the mostimportant neuronal pathway involved in the regulation of
energy homeostasis; it also is active in a wide array of
other processes, including erectile function, blood
pressure, and steroid production. Although obesity
research on melanocortin pharmaceuticals continues,
progress has been stymied by the fact that the these
drugs also produce undesirable effects on the other
biological activities, altering blood pressure and causing
unwanted erections, for example. In addition, there are
several different kinds of melanocortin receptors, two of
which are abundant in the brain, and it is not entirely clear
what the role of each one is. Thus, it is not yet known
whether it will be possible to target melanocortin
receptors in a way that reduces food intake without
causing cardiovascular or sexual side effects.
Various approaches to solve this problem are now
being explored.
The Serotonin System: A Safer Redux?
Another central mechanism currently under investigation
involves the serotonin system. This neurotransmitter
helps control appetite when serotonin levels are low,
people feel hungry. Preventing the re-uptake of serotonin
in the brain keeping levels high, in other words is the
means by which such antidepressants as Paxil and
Prozac work, and this approach also may help control
weight. The first such serotonin re-uptake blocker,
fenfluramine, was used along with the appetite
suppressant phentermine in the mid-1990s as a popular
anti-obesity regimen. Early in 1996, the FDAapproved anupdated version of fenfluramine known as Redux, and
it, too, was combined with phentermine. Eighteen
months later, both serotonin drugs were suddenly
withdrawn from the market following reports of heart
valve problems. Despite this setback, the concept
of altering serotonin levels to dampen appetite
remains valid. A new product, lorcaserin, which targets
a different receptor in the serotonin system than Redux,
Obesity and New Pharmaceutical Approches / Chapter 6 / 11
C H A P T E R
Central Targets:The Role of the Hypothalamus
As noted above, the hypothalamus serves as the central caretaker of energyhomeostasis. Our understanding of the myriad pathways involved in thisprocess took a giant leap forward in 1994 when a hormone called leptin wasidentified.
6
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is now undergoing clinical trials, as is tesofensine, a
compound that inhibits serotonin, noradrenaline,
and dopamine.
In addition to the serotonin system, another central
mechanism that could help lower appetite involves
melanin-concentrating hormone (MCH). This hormone isproduced by neurons in the hypothalamus and acts on
specific receptors in the brain that control our desire for
food. Several different MCH drugs are also now in the
early stages of development.
Gut Hormones:Ensuring Fuel for the Short Trip
Signals from fat cells (such as leptin) seem to be
responsible for maintaining the bodys long-term energy
supply. In contrast, neural and hormonal messages from
the gastrointestinal system contain information about the
status of immediately available energy stores. Importantgut hormones include appetite suppressants such as
peptide YY and cholecystokinin (CCK), as well as
appetite stimulants such as ghrelin. Another gut
hormone that helps reduce the desire for food in diabetic
patients is synthetic glucagon-like peptide 1 (GLP-1).
The first GLP-1 activator, Byetta, is now available, and
others are in the final stages of clinical development.
These medications, which produce weight loss in many
diabetics, are under consideration as anti-obesity
therapies.
One difficulty facing scientists working on the design of a
practicable peptide YY obesity therapy is the chemical
composition of the hormone itself: its complex structure
makes a pill formulation difficult, if not impossible, to
create. Consequently, a nasal spray is being studied,
although this route may reduce the drugs potential
effectiveness. In addition, some patients in clinicalstudies developed nausea and vomiting, raising concerns
about the potential safety of this approach. Those
working on a ghrelin blocker face a different obstacle.
Although such a drug could help obese people cut their
appetite, the treatment would have to be given any time
a person wanted to eat, a potentially costly and
inconvenient approach. Thus, notwithstanding the
intriguing hypotheses underlying the research on gut
hormones, the viability of these concepts still must be
proven in the lab and clinic.
Obesity and New Pharmaceutical Approches / Chapter 6 / 12
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Obesity and New Pharmaceutical Approches / Chapter 7 / 13
C H A P T E R
Peripheral Mechanisms:Energy Expenditure
Uncoupling proteins (UCPs) are specialized substances contained within theinner layer of mitochondria, the cell powerhouse that helps the body produceenergy. Investigations in animals show that increasing levels of UCPs raisesbody temperature.
7
Figure 2. Adipose tissue is an important hormona l, or endocrine, organ that influences other parts of the body. It releases a variety
of factors, such as leptin; adiponectin; RPB4 and TNF-alpha, which affect insulin resistance; and angiopoietins, which help regulate
blood supply. A mix of hormonal and neural signals to fat cells controls the expression of these factors. More complete discussion of
these processes is contained in the text. Adapted from Hofbauer KG, Nicholson JR, and Boss O.
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Unfortunately, early human studies have not been
successful, as mitochondria-rich brown fat cells, which
express UCP1 and play an important role in temperature
regulation in animals, disappear in humans after birth.
Ongoing studies are attempting to find triggers of brown
fat/UCP1 in adults, as well as other genes involved in
energy use. The promise of this science is so great thatDr. Spiegelman at Harvard has written that he is betting
this line of research will lead to treatments that have a
noticeable effect on obesity (Spiegelman 2007).
Metabolism
Contrary to popular perception, fat is more than lumpy
tissue that makes the wearing of horizontal stripes a dicey
matter. We now know that adipose tissue is metabolically
active, and its cells are key sources of certain cellmessengers, called adipokines, which are essential to
many of the bodys most important functions, including
those in the brain, liver, skeletal muscles, pancreas, and
the immune system (see Figure 2). Research has shown
that obese people have low levels of one of those
messengers, a protein called adiponectin, which is
important to the development of insulin resistance, a
pre-diabetic condition in which body cells fail to respond
to insulin and thus are unable to process or store glucose.
In addition to blocking cannabinoid receptors, Zimulti also
stimulates the production of adiponectin; so do such
diabetes drugs as Avandia and Actos. Scientists are now
working on a range of potential chemical approaches to
reduce insulin resistance, including drugs that may
increase adiponectin or target other adipokines that
affect metabolism.
Fat Storage
Tinkering with the bodys fat storage system could be a
productive way to reduce fat supplies. Two strategies
under consideration involve techniques to reduce
adipose cell growth and promote cell death. One possible
way to induce these favorable changes in fat cells wouldbe to limit their blood supply via adipokines called
angiopoietins. Although theoretically reasonable, this
concept may be impractical: it may be difficult to develop
a drug that could selectively target the appropriate fat
cells and not cause other cells, such as those in the liver,
to compensate by storing the additional calories. In that
case, a patient could run the risk of developing the very
health problems (e.g., metabolic syndrome, diabetes, or
heart disease) the treatment was designed to avoid.
Moreover, too few fat cells themselves can cause serious
diseases, such as liposystrophy, in certain individuals.
The research on fat storage therapies is continuing.
What does all of this drug research mean for those who
are seriously overweight or obese? On one hand, much
recent progress has been made in identifying new
mechanisms involved in energy homeostasis, and
these remain promising avenues of drug research and
development. On the other, the bodys energy system
is extremely complex; altering one part leads to
compensatory changes in another, not to mention the
possible deleterious effects such alterations may have on
other biological processes. Developing new drug
treatments for obesity is a more complicated matter than
it might appear at first glance.
Treating obesity is different from treating cancer, Dr.
Seeley indicates. The body doesnt want a tumor.
However, it has been evolutionarily programmed to hold
onto stored calories. Trying to take a finely designed
system and upend it so that obese people lose weight is
counterintuitive. Our bodies simply were not built that
way. Its hard to fool biology, although we continue to try.
Obesity and New Pharmaceutical Approches / Chapter 7 / 14
Treating obesity is different from
treating cancer, Dr. Seeley indicates.
The body doesnt want a tumor. However,
it has been evolutionarily programmed
to hold onto stored calories. Trying to
take a finely designed system and upend
it so that obese people lose weight is
counterintuitive. Our bodies simply were
not built that way. Its hard to fool
biology, although we continue to try.
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Alteration of such control mechanisms could provide a novel
strategy for drug developers that could work hand in hand
with other techniques to multiply the long-term effect of
treatment. Indeed, such an integrated approach, which is
known as systems biology, has already proven useful in the
treatment of blood pressure and heart function.
Using systems biology for weight loss would require
identifying the most promising mechanisms involved in
energy maintenance and moving drug discovery toward
those compounds that could best affect it. Our growing
understanding of the physiology and molecular biology of
obesity hopefully will identify new pathways and constituent
molecules that will be drugable, generating a group of
agents that can be used in combination to address relevant
aspects of both energy intake and expenditure, says Dr.
Leibel. Having a compendium of potential drug therapies that
address both sides of the energy equation will enable
physicians to address obesity in a more systematic fashion.
Indeed, this approach may have just produced its first
. Analyzing liver and fat tissue samples from mice, scientists
from Merck and Rosetta Inpharmatics have identified acomplex of core gene groups implicated in the onset of
obesity, diabetes, and heart disease (Telegraph 2008). Three
new genes, called Lpl, Pmp1l, and Lactb, appear to play an
important role in the onset of obesity. A second Merck
research team, working together with the Icelandic group
Decode Genetics, and the National University in Reykjavik,
Iceland, found a corresponding gene network in obese
humans. According to one of the lead researchers, Eric
Schadt, the fatty tissue of obese individuals displays a
typical pattern of genetic expression that is not visible by
blood-based diagnostic tools, which may explain why this
gene complex was unknown until now.
These studies strongly support the theory that common
diseases such as obesity result from genetic and
environmental disturbances in entire networks of genes
rather than in a handful of genes, Dr. Schadt says. If
diseases like obesity are the result of complex networks of
genes, the accurate reconstruction of these networks will be
critical to identifying the best therapeutic targets.
Alas, even a fully stocked medicine chest of complementary
anti-obesity drugs may not do the trick for some people. As
noted above, people eat for a variety of behavioral and social
reasons, and the only way to achieve lasting weight loss is to
alter lifestyle, by reducing the amount of food we eat and
drink, and increasing the exercise we get. Addressing a
chronic condition such as obesity will require a battery
of approaches, including behavioral counseling, drug
treatment, and changes in lifestyle, to achieve lasting results.
Short-term starvation, fitness programs, or even drugtherapy alone, simply will not do the trick.
The goal of drug discovery and development is to give
physicians a bevy of different drugs so they can rationally
prescribe the best treatment for each individual patient, Dr.
Seeley says. Obesity is a serious dilemma for the public, but
over time, we hope to be able give patients a fighting
chance.
Obesity and New Pharmaceutical Approches / Chapter 8 / 15
C H A P T E R
Toward the Future
Despite the physiological mechanisms that are activated during periods ofrestrictive dieting to reduce the bodys metabolic rate, there are signs that thedevelopment of drugs to produce a persistent change in metabolic rate maybe possible.
8
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Nevertheless, obesity is a condition rife with therapeutic
possibilities. Our knowledge of the mechanisms involved
in energy homeostasis has grown enormously in the past
decade, providing obesity researchers inside and outside
the pharmaceutical industry with many potential drug
targets to test. Although the future introduction of a magic
pill that will help obese people shed fifty or one hundred
pounds painlessly and safely is highly unlikely, a
combination of multiple drugs, behavioral therapy, and
lifestyle changes should enable patients and their doctors
to address the many health and quality-of-life issues
associated with this intractable condition.
Obesity and New Pharmaceutical Approches / Chapter 9 / 16
C H A P T E R
Conclusion
Obesity is a growing public health problem with serious medical and quality-
of-life implications. Although several drug treatments are available, their use-fulness is limited, at best, and patients are often disappointed in the results.
9
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In preparing the sections on anti-obesity drug
research and development, I benefited immensely
from the excellent reviews written by Karl G.
Hofbauer, Janet R. Nicholson, and Olivier Boss
(Ann Rev Pharmacol Toxicol. 2007;47:565-92) and
Dunstan Cooke and Steve Bloom (Nature Rev.
2006;6:919-31). All of the errors are my own. I also
would like to thank David H. Weinberg, Ph.D., for his
invaluable insights and support.
Obesity and New Pharmaceutical Approches / Acknowledgments / 17
A C K N O W L E D G M E N T S
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Raymond Gambino, M.D.Quest Diagnostics Incorporated
Randy R. Gaugler, Ph.D.Rutgers University
J. Bernard L. Gee, M.D.Yale University School of Medicine
K. H. Ginzel, M.D.University of Arkansas for Medical Science
William Paul Glezen, M.D.Baylor College of Medicine
Jay A. Gold, M.D., J.D., M.P.H.Medical College of Wisconsin
Roger E. Gold, Ph.D.Texas A&M University
Rene M. Goodrich, Ph.D.University of Florida
Frederick K. Goodwin, M.D.The George Washington University Medical
Center
Timothy N. Gorski, M.D., F.A.C.O.G.University of North Texas
Ronald E. Gots, M.D., Ph.D.International Center for Toxicology and
Medicine
Henry G. Grabowski, Ph.D.Duke University
James Ian Gray, Ph.D.Michigan State University
William W. Greaves, M.D., M.S.P.H.Medical College of Wisconsin
Kenneth Green, D.Env.American Interprise Institute
Laura C. Green, Ph.D., D.A.B.T.Cambridge Environmental, Inc.
Richard A. Greenberg, Ph.D.Hinsdale, IL
Sander Greenland, Dr.P.H., M.S., M.A.UCLA School of Public Health
Gordon W. Gribble, Ph.D.Dartmouth College
William Grierson, Ph.D.University of Florida
Lester Grinspoon, M.D.Harvard Medical School
F. Peter Guengerich, Ph.D.Vanderbilt University School of Medicine
Caryl J. Guth, M.D.Advance, NC
Philip S. Guzelian, M.D.
University of ColoradoTerryl J. Hartman, Ph.D., M.P.H., R.D.The Pennsylvania State University
Clare M. Hasler, Ph.D.The Robert Mondavi Institute of Wine and
Food Science, University of California,
Davis
Davis Virgil W. Hays, Ph.D.University of Kentucky
Cheryl G. Healton, Dr.PH.Mailman School of Public Health of
Columbia University
Clark W. Heath, Jr., M.D.American Cancer Society
Dwight B. Heath, Ph.D.Brown University
Robert Heimer, Ph.D.Yale School of Public Health
Robert B. Helms, Ph.D.American Enterprise Institute
Zane R. Helsel, Ph.D.Rutgers University, Cook College
James D. Herbert, Ph.D.Drexel University
Gene M. Heyman, Ph.D.McLean Hospital/Harvard Medical School
Richard M. Hoar, Ph.D.Williamstown, MA
Theodore R. Holford, Ph.D.Yale University School of Medicine
Robert M. Hollingworth, Ph.D.Michigan State University
Edward S. Horton, M.D.Joslin Diabetes Center/Harvard Medical
School
Joseph H. Hotchkiss, Ph.D.Cornell University
Steve E. Hrudey, Ph.D.University of Alberta
Clifford A. Hudis, M.D.Memorial Sloan-Kettering Cancer Center
Peter Barton Hutt, Esq.Covington & Burling, LLP
Susanne L. Huttner, Ph.D.University of California, Berkeley
Lucien R. Jacobs, M.D.University of California, Los Angeles
Alejandro R. Jadad, M.D., D.Phil.,F.R.C.P.C.University of Toronto
Rudolph J. Jaeger, Ph.D.Environmental Medicine, Inc.
William T. Jarvis, Ph.D.Loma Linda University
Elizabeth H. Jeffery, Ph.D.University of Illinois, Urbana
Geoffrey C. Kabat, Ph.D., M.S.Albert Einstein College of Medicine
Michael Kamrin, Ph.D.Michigan State University
John B. Kaneene, D.V.M., M.P.H., Ph.D.Michigan State University
P. Andrew Karam, Ph.D., CHPMJW Corporation
Kathryn E. Kelly, Dr.P.H.Delta Toxicology
George R. Kerr, M.D.University of Texas, Houston
George A. Keyworth II, Ph.D.Progress and Freedom Foundation
F. Scott Kieff, J.D.Washington University School of Law
Michael Kirsch, M.D.Highland Heights, OH
John C. Kirschman, Ph.D.Allentown, PA
William M. P. Klein, Ph.D.University of Pittsburgh
Ronald E. Kleinman, M.D.Massachusetts General Hospital/
Harvard Medical School
Leslie M. Klevay, M.D., S.D. in Hyg.University of North Dakota School of
Medicine and Health Sciences
David M. Klurfeld, Ph.D.U.S. Department of Agriculture
Kathryn M. Kolasa, Ph.D., R.D.East Carolina University
James S. Koopman, M.D, M.P.H.University of Michigan School of Public
Health
Alan R. Kristal, Dr.P.H.Fred Hutchinson Cancer Research Center
Stephen B. Kritchevsky, Ph.D.Wake Forest University Baptist Medical
Center
Mitzi R. Krockover, M.D.SSB Solutions
Manfred Kroger, Ph.D.Pennsylvania State University
Sandford F. Kuvin, M.D.University of Miami School of Medicine/
Hebrew University of Jerusalem
Carolyn J. Lackey, Ph.D., R.D.North Carolina State University
J. Clayburn LaForce, Ph.D.University of California, Los Angeles
Robert G. Lahita, M.D., Ph.D.Mount Sinai School of Medicine
James C. Lamb, IV, Ph.D., J.D., D.A .B.T.The Weinberg Group
Lawrence E. Lamb, M.D.San Antonio, TX
William E. M. Lands, Ph.D.College Park, MD
Lillian Langseth, Dr.P.H.Lyda Associates, Inc.
Brian A. Larkins, Ph.D.University of Arizona
Larry Laudan, Ph.D.National Autonomous University of Mexico
Tom B. Leamon, Ph.D.Liberty Mutual Insurance Company
Jay H. Lehr, PH.D.Environmental Education Enterprises, Inc.
Brian C. Lentle, MD., FRCPC, DMRDUniversity of British Columbia
Scott O. Lilienfeld, Ph.D.Emory University
Floy Lilley, J.D.Fernandina Beach, FL
Paul J. Lioy, Ph.D.UMDNJ-Robert Wood Johnson Medical
School
William M. London, Ed.D., M.P.H.California State University, Los Angeles
Frank C. Lu, M.D., BCFEMiami, FL
William M. Lunch, Ph.D.Oregon State University
Daryl B. Lund, Ph.D.
University of Wisconsin-MadisonJohn R. Lupien, M.Sc.University of Massachusetts
Howard D. Maccabee, Ph.D., M.D.Alamo, CA
Janet E. Macheledt, M.D., M.S., M.P.H.Houston, TX
Henry G. Manne, J.S.D.George Mason University Law School
Karl Maramorosch, Ph.D.Rutgers University, Cook College
Judith A. Marlett, Ph.D., R.D.University of Wisconsin, Madison
Lawrence J. Marnett, Ph.D.Vanderbilt University
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James R. Marshall, Ph.D.Roswell Park Cancer Institute
Roger O. McClellan, D.V.M., M.M.S., DABT,DABVT, FATSToxicology and Risk Analysis
Mary H. McGrath, M.D., M.P.H.University of California, San Francisco
Alan G. McHughen, D.Phil.University of California, Riverside
James D. McKean, D.V.M., J.D.Iowa State University
Joseph P. McMenamin, M.D., J.D.McGuireWoods, LLP
Patrick J. Michaels, Ph.D.University of Virginia
Thomas H. Milby, M.D., M.P.H.Walnut Creek, CA
Joseph M. Miller, M.D., M.P.H.Durham, NH
Richard A. Miller, M.D.Pharmacyclics, Inc.
Richard K. Miller, Ph.D.University of Rochester
William J. Miller, Ph.D.University of Georgia
Grace P. Monaco, J.D.Medical Care Ombudsman Program
Brian E. Mondell, M.D.Baltimore Headache Institute
John W. Morgan, Dr.P.H.California Cancer Registry
Stephen J. Moss, D.D.S., M.S.New York University College of Dentistry/
Health Education Enterprises, Inc.
Brooke T. Mossman, Ph.D.University of Vermont College of Medicine
Allison A. Muller, Pharm.DThe Childrens Hospital of Philadelphia
Ian C. Munro, F.A.T.S., Ph.D., FRCPathCantox Health Sciences International
Harris M. Nagler, M.D.Beth Israel Medical Center/ Albert Einstein
College of Medicine
Daniel J. Ncayiyana, M.D.Benguela Health
Philip E. Nelson, Ph.D.Purdue University
Joyce A. Nettleton, D.Sc., R.D.Denver, CO
John S. Neuberger, Dr.P.H.University of Kansas School of Medicine
Gordon W. Newell, Ph.D., M.S., F.-A.T.S.Cupertino, CA
Thomas J. Nicholson, Ph.D., M.P.H.Western Kentucky University
Robert J. Nicolosi, Ph.D.University of Massachusetts, Lowell
Steven P. Novella, M.D.Yale University School of Medicine
James L. Oblinger, Ph.D.North Carolina State University
Paul A. Offit, M.D.The Childrens Hospital of Philadelphia
John Patrick OGrady, M.D.Tufts University School of Medicine
James E. Oldfield, Ph.D.Oregon State University
Stanley T. Omaye, Ph.D., F.-A.T.S., F.ACN,C.N.S.University of Nevada, Reno
Michael T. Osterholm, Ph.D., M.P.H.University of Minnesota
Michael W. Pariza, Ph.D.University of Wisconsin, Madison
Stuart Patton, Ph.D.Pennsylvania State University
James Marc Perrin, M.D.Mass General Hospital for Children
Jay Phelan, M.D.Wyle Integrated Science and Engineering
Group
Timothy Dukes Phillips, Ph.D.Texas A&M University
Mary Frances Picciano, Ph.D.National Institutes of Health
David R. Pike, Ph.D.University of Illinois, Urbana-Champaign
Steven Pinker, Ph.D.Harvard University
Henry C. Pitot, M.D., Ph.D.University of Wisconsin-Madison
Thomas T. Poleman, Ph.D.Cornell University
Gary P. Posner, M.D.Tampa, FL
John J. Powers, Ph.D.University of Georgia
William D. Powrie, Ph.D.University of British Columbia
C.S. Prakash, Ph.D.Tuskegee University
Marvin P. Pritts, Ph.D.Cornell University
Daniel J. Raiten, Ph.D.National Institute of Health
David W. Ramey, D.V.M.Ramey Equine Group
R.T. Ravenholt, M.D., M.P.H.Population Health Imperatives
Russel J. Reiter, Ph.D.University of Texas, San Antonio
William O. Robertson, M.D.University of Washington School ofMedicine
J. D. Robinson, M.D.Georgetown University School of Medicine
Brad Rodu, D.D.S.University of Louisville
Bill D. Roebuck, Ph.D., D.A.B.T.Dartmouth Medical School
David B. Roll, Ph.D.The United States Pharmacopeia
Dale R. Romsos, Ph.D.Michigan State University
Joseph D. Rosen, Ph.D.Cook College, Rutgers University
Steven T. Rosen, M.D.
Northwestern University Medical SchoolStanley Rothman, Ph.D.Smith College
Stephen H. Safe, D.Phil.Texas A&M University
Wallace I. Sampson, M.D.Stanford University School of Medicine
Harold H. Sandstead, M.D.University of Texas Medical Branch
Charles R. Santerre, Ph.D.Purdue University
Sally L. Satel, M.D.American Enterprise Institute
Lowell D. Satterlee, Ph.D.Vergas, MN
Mark V. Sauer, M.D.Columbia University
Jeffrey W. SavellTexas A&M University
Marvin J. Schissel, D.D.S.Roslyn Heights, NY
Edgar J. Schoen, M.D.Kaiser Permanente Medical Center
David Schottenfeld, M.D., M.Sc.University of Michigan
Joel M. Schwartz, M.S.American Enterprise Institute
David E. Seidemann, Ph.D.Brooklyn College
David A. Shaywitz, M.D., Ph.D.The Boston Consulting Group
Patrick J. Shea, Ph.D.University of Nebraska, Lincoln
Michael B. Shermer, Ph.D.Skeptic Magazine
Sidney Shindell, M.D., LL.B.Medical College of Wisconsin
Sarah Short, Ph.D., Ed.D., R.D.Syracuse University
A. J. Siedler, Ph.D.University of Illinois, Urbana-Champaign
Marc K. Siegel, M.D.New York University School of Medicine
Michael Siegel, M.D., M.P.H.Boston University School of Public Health
Michael S. Simon, M.D., M.P.H.Wayne State University
S. Fred Singer, Ph.D.Science & Environmental Policy Project
Robert B. Sklaroff, M.D.Elkins Park, PA
Anne M. Smith, Ph.D., R.D., L.D.Ohio State University
Gary C. Smith, Ph.D.Colorado State University
John N. Sofos, Ph.D.Colorado State University
Laszlo P. Somogyi, Ph.D.SRI International (ret.)
Roy F. Spalding, Ph.D.University of Nebraska, Lincoln
Leonard T. Sperry, M.D., Ph.D.Florida Atlantic University
Robert A. Squire, D.V.M., Ph.D.Johns Hopkins University
Ronald T. Stanko, M.D.University of Pittsburgh Medical Center
James H. Steele, D.V.M., M.P.H.University of Texas, Houston
Robert D. Steele, Ph.D.Pennsylvania State University
Daniel T. Stein, M.D.Albert Einstein College of Medicine
Judith S. Stern, Sc.D., R.D.University of California, Davis
Ronald D. Stewart, O.C., M.D., FRCPCDalhousie University
Martha Barnes Stone, Ph.D.Colorado State University
Jon A. Story, Ph.D.Purdue University
Sita R. Tatini, Ph.D.University of Minnesota
Dick TaverneHouse of Lords, UK
Steve L. Taylor, Ph.D.University of Nebraska, Lincoln
Andrea D. Tiglio, Ph.D., J.D.Townsend and Townsend and Crew, LLP
James W. Tillotson, Ph.D., M.B.A.Tufts University
Dimitrios Trichopoulos, M.D.Harvard School of Public Health
Murray M. Tuckerman, Ph.D.Winchendon, MA
Robert P. Upchurch, Ph.D.University of Arizona
Mark J. Utell, M.D.University of Rochester Medical Center
Shashi B. Verma, Ph.D.University of Nebraska, Lincoln
Willard J. Visek, M.D., Ph.D.University of Illinois College of Medicine
Lynn Waishwell, Ph.D., C.H.E.S.University of Medicine and Dentistry of
New Jersey, School of Public Health
Brian Wansink, Ph.D.Cornell University
Miles Weinberger, M.D.University of Iowa Hospitals and Clinics
John Weisburger, Ph.D.New York Medical College
Janet S. Weiss, M.D.The ToxDoc
Simon Wessley, M.D., FRCPKings College London and Institute of
Psychiatry
Steven D. Wexner, M.D.Cleveland Clinic Florida
Joel Elliot White, M.D., F.A.C.R.Danville, CA
John S. White, Ph.D.White Technical Research
Kenneth L. White, Ph.D.Utah State University
Carol Whitlock, Ph.D., R.D.Rochester Institute of Technology
Christopher F. Wilkinson, Ph.D.Wilmington, NC
Mark L. Willenbring, M.D., Ph.D.National Institute on Alcohol Abuse and
Alcoholism
Carl K. Winter, Ph.D.University of California, Davis
James J. Worman, Ph.D.Rochester Institute of Technology
Russell S. Worrall, O.D.University of California, Berkeley
S. Stanley Young, Ph.D.National Institute of Statistical Science
Steven H. Zeisel, M.D., Ph.D.University of North Carolina
Michael B. Zemel, Ph.D.Nutrition Institute, University of Tennessee
Ekhard E. Ziegler, M.D.University of Iowa
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