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Review
Abstract
Introduction: C
igarette smoking is largely driven by the reinforcing properties of nicotine.
Intravenous (IV) self-administration procedures are the gold standard for investigating the reinforcing effects of psychoactive drugs. The goal of this review was to examine the results of published investigations of the reinforcing effects of nicotine measured using IV self-administration
procedures in humans and nonhuman primates.
Results: The body of literature using nonhuman primate subjects indicates nicotine functions as a
positive reinforcer when available for self-administration via IV catheters. However, it can also be
difficult to establish IV nicotine self-administration in nonhuman primates and sometimes supplemental strategies have been required (e.g., priming injections or food deprivation) before subjects
acquire the behavior. Although the body of literature using human subjects is limited, the evidence
indicates nicotine functions as a reinforcer via the IV route of administration in adult cigarette
smokers. Rates of nicotine self-injection can be variable across subjects and responding is sometimes inconsistent across sessions in both humans and nonhuman primates.
Conclusions: The Family Smoking Prevention and Tobacco Control Act, enacted in 2009, gave the
Food and Drug Administration regulatory authority over the manufacture, marketing, and distribution of tobacco products. Research examining the threshold reinforcing doses for initiation and
maintenance of nicotine self-administration, comparisons of the reinforcing effects of nicotine in
adolescent versus adult subjects, investigations of gender differences in the reinforcing effects of
nicotine, and studies of the abuse liability of non-nicotine tobacco product constituents and their
ability to alter the reinforcing effects of nicotine will inform potential tobacco regulatory actions.
Introduction
The Centers for Disease Control and Prevention (CDC) reported
that 18% of adults in the United States were cigarette smokers in
2012.1 Among adult smokers, the CDC estimates nearly 90% began
smoking before the age of 18.2 Compared to people who have
never smoked, life expectancy for cigarette smokers is decreased by
at least one decade3 and more than 480,000 Americans die from
smoking related illnesses every year, making tobacco use the largest
preventable cause of death and disease in the United States.4 From
20092012, at least $133 billion was spent on direct medical care
related to cigarette smoking, and lost productivity costing $156 billion was attributed to cigarette smoking.1 With the passage of the
Family Smoking Prevention and Tobacco Control Act in 2009, the
U.S. Food and Drug Administration (FDA) was given authorization
Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2015.
This work is written by (a) US Government employee(s) and is in the public domain in theUS.
Results
IV Self-Administration of Nicotine in Nonhuman
Primates
Table 1 summarizes the methods and results from studies of the
reinforcing effects of IV nicotine in nonhuman primates. One of the
first attempts to establish nicotine self-administration in a nonhuman primate species was carried out by Deneau and Inoki in 1967.31
Initially, nicotine was available for self-injection in seven nave
rhesus monkeys (unspecified gender and age). When spontaneous
nicotine self-administration did not occur, a response-independent
injection (i.e., priming injection) was delivered every hour. When
nicotine self-administration was still not established following two
months of hourly priming injections, the automatic injections ceased
and the nicotine dose was increased and spontaneous nicotine selfadministration occurred in two subjects. Following additional automatic nicotine injections over 210days, nicotine self-administration
was initiated in the remaining five subjects (i.e., priming injections
were required). The average daily total intake of nicotine self-administered was variable and ranged from 0.7 to 1.7mg/kg. The dose
of nicotine per injection was then increased each month until selfadministration ceased. Of the six monkeys tested in this fashion, one
stopped at 0.05mg/kg/injection, two stopped at 0.1mg/kg/injection,
one stopped at 0.5mg/kg/injection, one stopped at 1.0mg/kg/injection, and one continued to self-administer at the highest dose tested
(2.0mg/kg/injection). At the 2.0mg/kg/injection dose, the subject
self-administered an average daily dose of 9.6mg/kg. Unfortunately,
details about the number of injections, and pattern and rate of
responding across sessions and subjects were not provided. Thus,
we cannot determine if the results from these studies satisfy any currently acceptable criteria for determining if a drug functions as a
reinforcer (i.e., dose-dependent changes in responding, comparison
to responding for vehicle injections). In addition, many methodological details were not reported (e.g., injection volume, duration of
injection, time-out periods). Nonetheless, the authors concluded
that under the conditions employed in their study, nicotine was selfadministered intravenously in rhesus monkeys without a prior history of operant conditioning using drug or food reinforcement.31
The importance of a subjects experimental history and the duration of access to the test compound (e.g., session duration) was evident in another early nicotine self-administration study by Yanagita32
(see also Yanagita etal.33). Given 24-hr access to nicotine injections,
six out of six rhesus monkeys (unspecified gender and age) described
as self-administration experienced by the authors, self-injected at
least one dose of nicotine relative to saline injections. Only four out
of seven experimentally nave subjects did so when nicotine was substituted for saline. The average total daily intake of nicotine ranged
from 0.22.0mg/kg.33 Importantly, nicotine injections consistently
maintained responding above vehicle levels. When access was limited to 4hr, however, nicotine was not self-administered in experienced monkeys when it was substituted for a psychostimulant
(lefetamine) that was already maintaining self-administration. It has
been well-established that experimental history and session duration
can influence self-administration behavior.19,34 Yanagita32 was the
first to report nicotine maintained responding above vehicle levels in
an old world nonhuman primate species.
Another key factor related to pattern of drug self-administration is the timeout period following a self-injection. In adult male
baboons (Papio anubis and Papio hamadryas) previously trained to
lever press for food or other drugs as reinforcers, Griffiths et al.35
reported that nicotine failed to maintain responding above vehicle
levels during 24-hr sessions of nicotine availability with concurrent
Griffiths etal.35
Goldberg etal.37
Dougherty etal.40
Slifer41
Sannerud etal.60
Wakasa etal.
1979
1981
1981
1982
1982
1983
1983
1985
1987
1994
1995
47
rhesus
Yanagita32,33
1977e
rhesus
squirrel
rhesus
drug SA (n=4)
drug SA (n=6)
nave (n=7)
not described (n=4)
nave (n=7)
Subject history
rhesus
baboon
squirrel
squirrel
rhesus
baboon
squirrel
rhesus
Species
1967
Authors
FR 160
second order
FRf
FR 1
FR 1
PR
FR 1
Schedule
0.03
0.010.1c
FR 10
24 hr
FR 5
1hr or 12 injections FR 30
3 hr
FR 10
1 hr
0.010.3c
0.0080.25c
FR 1
1 hr
0.00010.1c
0.00010.1c
FR 1
0.010.56c
1 hr
2hr or 1012
second orderl
injectionsl
2hr or 50 injections FR 2
0.0030.1c
0.010.32c
subject
dependentj
2hr or 10 injections FI (5min)
24 hr
1.5hr or 12
injections
3 hr
4 hr
24 hr
24 hr
24 hr
24 hr
Session duration
0.0030.56c
0.0030.56c
0.0150.27a
0.0013.2c
0.03c
0.00250.64b
0.020.2b
0.020.2b
0.050.2b
0.012.0a
Dose range
(mg/kg/
injection)
15 min
5 min
unspecified
unspecified
unspecified
unspecified
60 s
15 s
13minl
1 min
1 min
unspecified
3 hr
3 min
unspecified
unspecified
unspecified
unspecified
unspecified
Methodological strategies
Time out
Year
0.03
0.030.056
0.0080.06h
0.010.1
0.010.1
0.030.1
0.010.1h
0.010.1h,m
0.0030.056h
0.010.56h
0.030.56h
0.0150.09h,k
none
0.03h
none
0.020.2h
0.020.2h
0.050.2
0.0252.0
Doses selfadministered
(mg/kg/injection)d
Gould etal.48
Mello etal.57
Justinova etal.54
Mascia etal.55
Panlilio etal.56
2009
2011
2011
2011
2011
2012
squirrel
squirrel
squirrel
rhesus
rhesus
rhesus
squirrel
Species
nicotine experienced
(n=4)
nicotine SA (n=3)
nicotine SA (n=4)
nave (n=5)
Subject history
0.03
0.03
0.03
1 hr
1 hr
1 hr
0.000320.1a 1hr or 20
injections
0.010.1a
1.513hrn
FR 10
FR 10
FR 10
second order
PR
PR
PR
0.0030.06a
0.0120.05a
FR 10
Schedule
1 hr
Session duration
0.0030.03a
Dose range
(mg/kg/
injection)
1 min
1 min
1 min
10 s
10 min
30 min
unspecified
1 min
Time out
Methodological strategies
0.03
0.03
0.03
0.00320.01
none
0.0120.05o
0.0030.06
0.0030.03
Doses selfadministered
(mg/kg/injection)d
Le Foll etal.50
Authors
2007
Year
Table1. Continued
4
Nicotine & Tobacco Research, 2015, Vol. 00, No. 00
6
Table2. Infusion Rates in Nicotine IV Self-Administration (SA) Studies
Year
1977d
Authors
Yanagita32,33
Species
rhesus
Griffiths etal.35
Goldberg and Spealman38
Spealman and Goldberg39
baboon
squirrel
squirrel
1983
baboon
1983
1983
1983
1985
Henningfield etal.62
Henningfiled and Goldberg63,64
Slifer41
Slifer and Balster42
human
human
rhesus
rhesus
1987
1994
1995
rhesus
squirrel
rhesus
2003
Rose etal.65
human
2004
2007
2008
2009
2010
Harvey etal.66
Le Foll etal.50
Sofuoglu etal.67
Freeman and Woolverton49
Rose etal.68
human
squirrel
human
rhesus
human
10
0.2i
30
10
180510j
2011
2011
2011
2011
2012
Gould etal.48
Mello etal.57
Justinova etal.54
Mascia etal.55
Panlilio etal.56
rhesus
rhesus
squirrel
squirrel
squirrel
10
1
0.2
0.2
0.2
1/23
0.000430.11e
Injection
volume
Dose range
SA?
0.25ml/kg
0.0250.64b mg/kg/injection
no
0.020.2b mg/kg/injection
0.0013.2c mg/kg/injection
0.0030.56c mg/kg/injection
0.0030.56c mg/kg/injection
0.0030.1c mg/kg/injection
0.010.32c mg/kg/injection
0.010.56c mg/kg/injection
0.753.0a mg/injection
0.753.0b mg/injection
0.00010.1c mg/kg/injection
0.00010.1c mg/kg/injection
0.010.3c mg/kg/injection
0.0080.25c mg/kg/injection
0.010.1c mg/kg/injection
0.03b mg/kg/injection
0.03b mg/kg/injection
0.03b mg/kg/injection
individualizeda,h
(0.040.15mg/injection)
0.753.0a mg/injection
0.0030.06a mg/kg/injection
0.10.7a mg/injection
0.0120.05a mg/kg/injection
individualizeda,h
(0.050.21mg)
0.010.1a mg/kg/injection
0.000320.1a mg/kg/injection
0.03mg/kg/injection
0.03mg/kg/injection
0.03mg/kg/injection
yes
no
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
1/23
10/120
0.2/0.2
0.2/0.2
0.2/0.2
1/5
1/5
1/10
1/9.2
1/10
1/10
1/10
1/10
0.2/0.2
1/23
1/23
1/23
not described
0.00300.030 0.25ml/kg
0.000170.53e
10mlg
e
0.0122.20
0.2 ml
0.0122.20e
0.2 ml
0.0120.40e
0.2 ml
0.0501.60e
1 ml
0.0502.80e
1 ml
0.0750.30e
1 ml
0.0820.33e
1 ml
0.00080.08e
1 ml
0.00080.08e
1 ml
0.0080.24e
1 ml
0.00640.20e
1mle
0.0400.40e
0.2 ml
0.0052
0.25ml/kg
0.0013
1ml/kg
0.0003
4ml/kg
0.020.075 not described
1/10
0.2/0.2
5/30
not described
not described
0.0750.30
1 ml
0.040e
0.2mli
0.00330.023
5 ml
0.0120.050e not described
0.601.90j not described
1.5/10
0.1/1
0.2/0.2
0.2/0.2
0.2/0.2
0.00800.08e
0.00260.80e
0.12e
0.12e
0.12e
1.5 ml
0.1 ml
0.2 ml
0.2 ml
0.2 ml
yes
yes
yes
yes
yes
no
yes
yes
yes
yes
1979
1982
1982
46
120f
0.2
0.2
0.2
5
5
10
9.2
10
10
10
10
0.2e
33e
130e
567e
2
e
Infusion rate
(mg/s)
in Table2 does not provide clear evidence that the rate of infusion
predicts the likelihood of IV nicotine self-administration in nonhuman primates.
In 2007, adult nave male squirrel monkeys with no prior
operant behavioral training, no food deprivation or concurrent
food self-administration, with no automatic (i.e., priming) injections of nicotine, but with the use of associated auditory and
visual stimuli, engaged in high rates of nicotine self-administration.50 Since rodent studies had suggested that the reinforcing effects of nicotine were, in part, due to its enhancing the
reinforcing effectiveness of environmental stimuli, 5153 a colored
stimulus light was paired with nicotine injections and a different colored light was paired with completion of the FR requirement on a second inactive lever. Responding on each lever
was compared to ascertain if nicotine injections were affected
by the presentation of the different stimuli. Subjects responded
significantly more on the lever associated with the nicotinepaired visual stimulus than on the lever paired with only a
visual stimulus. Thus, in the absence of behavioral and drug
histories and without employing facilitatory conditions (e.g.,
priming injections, food deprivation), nicotine was an effective
positive reinforcer in adult male squirrel monkeys. The ability
of IV nicotine injections to reinforce behavior in experimentally
nave subjects was shown to be similar to that of cocaine. 46 The
highest nicotine intake appears to have been approximately
0.35mg/kg during 1hr sessions. Later studies conducted by the
same research group reported an approximate average nicotine
intake of 1.5mg/kg during 1-hr sessions in adult male squirrel
monkeys. 5456 At this point, however, it is unknown whether IV
nicotine injections are reinforcing in the absence of changes in
associated visual and auditory stimuli in experimentally nave
nonhuman primate subjects.
Additional studies in nonhuman primates have focused on
assessing the preclinical efficacy of various pharmacological interventions to decrease or stop nicotine self-administration (e.g.,
medications development). For example, after demonstrating
that nicotine, cocaine, and combinations of nicotine and cocaine
maintained responding above vehicle levels in rhesus monkeys,57
the effects of chronic treatment with buspirone58 and varenicline59
on self-administration were examined. The effects of clofibrate,56
WY14643 and methOEA,55 and sertraline60 on nicotine self-administration have also been examined. As discussed below (Future
Directions), the reinforcing effects of non-nicotine tobacco product constituents (e.g., anatabine) are also being investigated in
squirrel monkeys.61
Thus, the body of literature in nonhuman primates confirms
that nicotine functions as a positive reinforcer when available
for self-administration via IV catheters (Table 1). Nicotine is
self-administered in multiple nonhuman primate species, in both
experienced and nave subjects, and across multiple experimental conditions (e.g., various schedules of reinforcement, timeout
periods, and duration of infusions). Nicotine self-administration,
however, can also be difficult to establish in nonhuman primates,
sometimes requiring supplemental strategies (e.g., priming injections or food deprivation) before subjects acquire the behavior.
Rates of nicotine self-injection can also be variable across subjects and inconsistent across sessions within a study. It has been
suggested that non-nicotine tobacco product constituents may
enhance the reinforcing effects of nicotine, or have reinforcing
effects on their own that contribute to maintaining nicotine
Future Directions
Threshold Reinforcing Doses of IV Nicotine
Reducing nicotine levels in tobacco products has been suggested as
a strategy for lowering the abuse liability and harm associated with
tobacco products.6974 The effects of both gradual and immediate
methods of nicotine dose reduction on nicotine self-administration
have been studied in rodents. For example, two schedules of nicotine dose reduction and their effects on maintenance of established
self-administration have been compared in rats.75 A gradual
reduction approach (nicotine doses were systematically lowered by
half approximately every 10 sessions after self-administration was
established) was compared with an immediate reduction approach
(nicotine doses were immediately lowered across sessions after selfadministration was established) and the results suggested similar
behavioral changes occurred with both methods. Both schedules
of nicotine dose reduction produced significant decreases in selfadministration behavior, accompanied by some temporary compensatory behavior.75 Thus, it is possible that lowering nicotine levels in
tobacco products may result in decreased exposure to nicotine and
other tobacco product constituents, and/or elimination of exposure
altogether via an extinction of smoking behavior, in a significant proportion of tobacco users. Indeed, the introduction of denicotinized
cigarettes to cigarette smokers in controlled laboratory conditions
resulted in decreased smoking behavior.76
There are two distinct phases of nicotine self-administration
(acquisition and maintenance) that may be used to investigate the
role of a threshold reinforcing nicotine dose. Reports in rodents generally indicate that higher unit doses of nicotine are required for
levels. Under a concurrent FR schedule of reinforcement, responding on one lever resulted in a nicotine injection and responding on
a different lever resulted in a saline injection.66 The number of injections was significantly greater for nicotine than for saline, though
there was a dose-dependent decrease in the number of nicotine injections at the highest dose tested. In addition, the effect of different FR
values (101600) and timeout length (120min) on lever responding were evaluated in some subjects. At the four upper FR values
(200, 400, 800, and 1600), nicotine maintained responding above
saline levels. No significant changes in response rate were associated
with the changes in timeout length. Harvey etal.66 were the first to
demonstrate a clear inverted-U dose-response curve for IV nicotine
self-administration and responding under a high FR requirement in
cigarette smokers.
IV nicotine self-administration was also compared to a vehicle
control condition in smokers in a study conducted by Sofuoglu and
colleagues.67 They were interested in doses of nicotine that resembled those expected to be delivered in a typical cigarette puff. During
experimental sessions, sample injections from each of two syringes
(saline and nicotine) were given, and subjects were then allowed to
choose between the two syringes (six choice opportunities/session).
The two highest doses of nicotine tested (0.4 and 0.7mg/injection)
were chosen more than saline.67
Preference for IV nicotine was compared to IV saline and to puffs
of denicotinized cigarette smoke and sham puffs by Rose and colleagues68 in smokers. Abaseline smoking session was used to identify the average nicotine dose smoked for each participant, followed
by two training sessions in which participants were trained to discriminate between IV nicotine or saline, and then between puffs of
denicotinized smoke and sham puffs. Lastly, four experimental sessions occurred in which choice behavior was characterized during
choice components of the sessions that followed satiation components. The four possible satiation conditions (one per session) were:
denicotinized cigarette puffs + IV nicotine injections; denicotinized
cigarette puffs + IV saline injections; sham puffs + IV nicotine injections; and sham puffs + IV saline injections. Satiation components
consisted of programmed administration of puffs and injections
based on each subjects unlimited smoking during baseline sessions.
During experimental sessions, the first component was a satiation
component, followed by a choice component, then a second satiation
component, a second choice component, a third satiation component, and then finally a third choice component. The first two choice
components provided a choice between only two alternatives: IV
nicotine versus IV saline or cigarette puffs versus sham puffs. The
third choice component provided all four alternatives. During choice
components, subjects controlled the number of puffs and injections.
Satiation components were 60min in duration and choice periods
were 10min in duration. When IV nicotine and IV saline injections
were available during either of the first two choice periods, participants demonstrated a significant preference for IV nicotine injections.
Denicotinized puffs were selected significantly more than sham puffs
during the first two choice conditions. When all four alternatives were
available, participants had a significant preference for denicotinized
cigarette puffs when compared to sham puffs, nicotine injections, and
saline injections. Thus, Rose etal.68 was the first study to compare the
reinforcing effects of non-nicotine tobacco components to those of
nicotine in humans. While denicotinized cigarette puffs were chosen
most often, this may be due to sensory cues associated with smoking
behavior (e.g., smell) or other pharmacologically active non-nicotine
tobacco product constituents (e.g., acetaldehyde).
Schedule
Time out
Doses selfadministered
(mg/injection)
0.753.0a
3 hr
FR 10
1 min
unspecifiedd
0.753.0b
3 hr
FR 10
1 min
unspecifiede
individualizeda,f
(0.040.15)
4 hr
FR 1
unspecified
unspecifiedg
0.753.0a
3 hr
FR 101600
120 min
0.753.0
0.10.7a
1.5 hr
choiceh
15 min
0.4, 0.7
individualizeda,f
(0.050.21)
3.5 hr
FR 1
nonei
Year
Authors
Subjects
Subject history
unspecified
Dose range
(mg/injection)
10
11
Are there gender differences in the threshold dose of nicotine
required to maintain IV self-administration in adult humans and
nonhuman primates?
Are there gender differences during the initiation and or maintenance of IV nicotine self-administration in adolescent nonhuman
primates?
Are there gender differences in the correlation of other outcome
measures (e.g., pharmacokinetic outcomes) with IV nicotine selfadministration in adolescent and adult nonhuman primates and
humans?
Are there gender differences in the abuse potential of non-nicotine tobacco product constituents in adult and adolescent nonhuman primates?
Do individual non-nicotine tobacco product constituents alter
the reinforcing effects of nicotine differentially in adolescent and
adult male and female nonhuman primates?
Gender Differences
There is some evidence of gender differences in the reinforcing effects
of nicotine in laboratory animals and human smokers (for reviews
see Perkins etal.108 and Fattore etal.109). Female rats more quickly
acquired nicotine self-administration at lower doses and earned more
injections of nicotine on a progressive-ratio schedule compared to
male rats.110 In addition, increased nicotine self-administration was
more pronounced in male adolescent rats than in adolescent female
rats (compared to adult males and females), though the effect was
more persistent over time in females.27,79,85,111 In other studies, female
rats had higher rates of responding for presentations of a visual discriminative-stimulus without nicotine injections compared to male
rats.112,113 While a few nonhuman primate studies have used females
as subjects,33,47,59 no study has systematically compared females and
males on measures of the reinforcing effects of IV nicotine. Similarly,
human studies have sometimes included female subjects,67,68,114 but
a systematic comparison of the reinforcing effects of IV nicotine in
male and female subjects has not beendone.
Some gender comparisons of smoking behavior have been
reported. In female cigarette smokers, changes in the nicotine dose
contained in cigarettes had less of an effect on the reinforcing
properties of smoking when compared to male smokers,115 indicating female smokers may be less sensitive to the reinforcing effects
of nicotine in cigarettes. Conversely, female rodents110 and female
smokers116,117 may be more sensitive to non-pharmacological stimuli
associated with nicotine administration.
Thus, addressing all of the experimental questions posed
throughout the Future Directions section in male and female nonhuman primate and human subjects would provide useful information
for understanding the role of gender in the initiation and continued
use of tobacco products. More specifically:
Are there gender differences in the threshold dose of nicotine
required for the initiation of IV nicotine self-administration in
adult nonhuman primates?
In addition to the specific areas identified above using IV self-administration procedures in humans (i.e., threshold reinforcing dose
required to maintain IV nicotine self-administration, gender differences in the maintenance of IV nicotine self-administration, gender
differences in the correlation of other outcomes measures with IV
nicotine self-administration), there are other potentially useful areas
that may be applicable to human subjects including:
What is the threshold reinforcing dose of IV nicotine that maintains smoking behavior in humans under controlled laboratory
settings versus naturalistic conditions?
Are immediate or gradual IV nicotine dose reduction schedules
more effective at decreasing smoking behavior in humans?
As noted above, the effects of behaviorally active doses of the vast
majority of non-nicotine tobacco product constituents are not known
and these compounds, at behaviorally active doses, should not be
examined in humans in the absence of data from animal studies. Also
described previously, however, one study compared denicotinized cigarettes to IV nicotine in humans,68 allowing the reinforcing effects of a
combination of non-nicotine tobacco product components to be examined in humans. Recently, the reinforcing effects of cigarette smoke
extract have been examined in rodents102 and future studies in humans
(and nonhuman primates) may find this approach useful for comparing the reinforcing effects of IV nicotine with cigarette smoke extract.
Summary
In summary, studies of IV nicotine self-administration procedures in
nonhuman primates and humans are particularly useful for addressing several relevant research questions aimed at providing an empirical basis for informing tobacco product regulation. The body of
literature indicates that nicotine functions as a positive reinforcer
when available for self-injection in nonhuman primates and human
cigarette smokers. Further research using nonhuman primates examining the threshold reinforcing doses of IV nicotine that are required
to initiate and maintain self-administration, comparing the reinforcing effects of nicotine in adolescent versus adult subjects and male
versus female subjects, investigating the abuse potential of non-nicotine tobacco product constituents, and evaluating the effects that
non-nicotine tobacco product constituents may have on the reinforcing effects of nicotine will inform the FDA in its mission to promote
public health through the regulation of tobacco products.
12
Funding
U.S. Food and Drug Administration/Center for Tobacco Products (NCTR
Protocol E07537-01).
Declaration of Interests
None declared.
Acknowledgments
The information in these materials is not a formal dissemination of information by the FDA and does not represent agency position or policy.
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