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International Journal of Obesity (1999) 23, 723±732
ß 1999 Stockton Press All rights reserved 0307±0565/99 $12.00
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Synergistic interactions between Fen¯uramine
and Phentermine
PJ Wellman1* and TJ Maher2
1
Behavioral Neuroscience Program, Texas A&M University, College Station, Texas 77843-4235, USA and 2Division of Pharmaceutical
Sciences, Massachusetts College of Pharmacy and Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115, USA
`Fen-phen' refers to the off-label combination of the appetite suppressants fen¯uramine and phentermine. The
rationale for the fen-phen combination was that the two drugs exerted independent actions on brain satiety
mechanisms so that it was possible to use lower doses of each drug and yet retain a common action on suppressing
appetite while minimizing adverse drug effects. The focus of the present review is to consider whether fen¯uramine
and phentermine exert actions that are additive in nature or whether these two drugs exhibit drug-drug synergism.
The fen-phen combination results in synergism for the suppression of appetite and body weight, the reduction of brain
serotonin levels, pulmonary vasoconstriction and valve disease. Fen-phen synergism may re¯ect changes in the
pharmacokinetics of drug distribution, common actions on membrane ion currents, or interactions between neuronal
release and reuptake mechanisms with MAO-mediated transmitter degradation. The synergism between fen¯uramine
and phentermine highlights the need to more completely understand the pharmacology and neurochemistry of
appetite suppressants prior to use in combination pharmacotherapy for the treatment of obesity.
Keywords: monoamine oxidase inhibitors; serotonin; drug-drug interactions; isobologram
Introduction
Obesity remains a chronic disorder of increasing
prevalence1 that contributes to early death and
health disorders.2 Moreover, obesity is known to
have considerable psychological costs in the form of
ostracism and discrimination.3 These physical and
psychological costs provide ample motivation for
obese and near-obese persons to lose body weight.
Among the obesity treatments developed and
implemented over the last 50 y are behavioral modi®cation, exercise, dietary restriction, surgical
approaches such as gastric stapling and=or banding,
and pharmacotherapy.4 The latter approach involves
the use of centrally acting drugs to suppress appetite
and reduce body weight5 and, more recently, agents
that act peripherally to diminish absorption of dietary
fat from the gastrointestinal tract (for example, Orlistat). Many factors have contributed to resistance to
pharmacotherapy including the beliefs that: obesity is
not a disease but a psychological issue, that the
effects of appetite suppressants are modest at best,
and that all appetite suppressants share common
actions with the dangerous stimulant amphetamine.5
Moreover, a major concern remains that any weight
*Correspondence: Paul J Wellman, Behavioral Neuroscience
Program, Texas A&M University, College Station, Texas 778434235, USA. E-mail: [email protected]
Received 5 November 1998; revised 16 February 1999; accepted
3 March 1999
lost during treatment with an appetite suppressant is
quickly regained when the drug is terminated.
Weintraub et al 6 reported on a novel approach to
the pharmacological treatment of obesity using combinations of appetite suppressants rather than traditional monotherapy. This clinical trial employed a
combination of fen¯uramine (30 mg prior to dinner)
with phentermine (15 mg in the morning) and compared the weight reducing effects of this combination
with that induced by fen¯uramine alone (20 mg ± 3
times per day) or phentermine alone (30 mg in the
morning). Over a 24 week period, the combination of
low doses of these anorexic medications produced a
weight loss (8 kg) greater than that of placebo (4 kg),
but that was equivalent to the monotherapies (fen¯uramine alone or phentermine alone). Moreover,
fewer adverse effects were reported for the combination of fen-phen than for either drug alone. In 1992,
Weintraub et al 7 reported on a 4-y study that examined the impact on body weight of a combination of
phentermine with fen¯uramine. This study similarly
noted that the fen-phen combination produced substantial weight loss in some subjects and that this
combination therapy could be used for as long as
4 y.7
The fen-phen approach to pharmacotherapy was
widely adopted following the Weintraub et al 7 publication. Sales of each appetite suppressant soared and
it is estimated that some 18 million prescriptions were
written for the fen-phen combination between 1992
and 1997.8 However, fen¯uramine and the active
enantiomer dexfen¯uramine (dexfen) were withdrawn
from the market in September 1997 following
Fen¯uramine ± Phentermine synergism
PJ Wellman and TJ Maher
724
mounting concerns that use of the fen¯uramines was
associated with valvular disease9 and that appetite
suppressant use has been associated with the development of primary pulmonary hypertension (PPH:
10 ± 15).
The use of fen¯uramine or dexfen¯uramine in
combination with phentermine was `off-label' in the
sense that although each of these drugs had been
approved for use in the treatment of obesity, the
FDA had not explicitly approved this combination
of drugs. The FDA had subjected each of these drugs
individually to varying degrees of scrutiny for safety
and ef®cacy. There was a presumption on the part of
some that one could rationally predict the safety and
ef®cacy pro®le of the combination therapy from earlier research studies using each monotherapy alone.
As a consequence, there appear to have been no
preclinical studies conducted to determine the safety
of the combination of a fen¯uramine with phentermine. Unfortunately at the time of development of the
fen-phen pharmacotherapy, our understanding of the
pharmacology of fen¯uramine and of phentermine
was incomplete while our understanding of the fenphen combination was essentially nonexistent.
Rationale for the fen-phen combination
There exist two different rationales for the fen-phen
combination therapy. The ®rst is that a combination
of low doses of two drugs that share a common
clinical effect (for example, suppression of appetite)
will summate to produce a desired clinical effect.
Because adverse side effects are usually a function of
dose, combining low doses of different drugs should
ideally maintain the desired clinical effect (that is,
those effects will add together) while reducing the
incidence of unwanted side effects. A secondary
notion behind combining these two drugs is that
fen¯uramine acts as a depressant while phentermine
acts as a stimulant.16 Fen¯uramine is a racemic
mixture of two enantiomers, levofen¯uramine (levofen) and dexfen. Whereas, levofen has been shown to
exert antidopaminergic (for example, sedative) activity, phentermine has dopaminergic properties.
Mixing phentermine with racemic fen¯uramine
would theoretically cancel out these dopaminergic
effects, so as to minimize patient complaints and
improve compliance.
Fen-phen combination therapy, however, rests on
the assumption that the two drugs to be combined
produce their clinical effects (appetite suppression)
and adverse effects via independent mechanisms. The
essence of combination therapy is that the two drugs
show at least additivity: that is, their combined
effects should be predictable knowing the action of
each drug alone. The notion of additivity is crucial
for both the clinical and adverse effects of the
combination drugs. If the two drugs are less than
additive in their clinical effect, then the combination
will be less effective. Of greater interest is the
possibility that the two drugs will mutually amplify
their respective clinical effects resulting in drug-drug
synergism. A synergistic combination produces a
greater effect than that associated with the simple
sum of effects of both drugs alone. It is interesting to
note that synergism between phentermine and fen¯uramine was an issue raised by Weintraub et al 6 in
their original fen-phen study:
`Our data also suggest a synergistic effect of the
two medications used together. The combination
treatment group showed a marked, sustained
increase in total fullness whereas mean results
from participants receiving the other active treatments remained near baseline and similar to the
placebo response. It appears that the combination
of half doses of two treatments that by themselves
have no effect, even in full doses, results in
increased effects ± in this case total fullness.'
(6: pages 1147 ± 1148.)
Synergism may apply not only to the clinical outcomes of the fen-phen combination, but also to the
adverse reactions associated with the combination.
Thus, the primary emphasis of the present review is
to consider the known synergism between the fen¯uramines and phentermine with regard to eating and
body weight, cardiovascular activity (valve disease
and PPH), and central nervous system activity.
Neuropharmacology of Fen¯uramine and Phentermine
The FDA approved Phentermine in 1959 while fen¯uramine was approved in 1973. The assumption of
most investigators was that fen¯uramine acted to
reduce feeding by indirectly enhancing serotonin
activity in brain.17 ± 19 Fen and=or its desethylated
metabolite (norfen) blocks the reuptake of serotonin
into axon terminals, and at higher doses releases 5-HT
from presynaptic terminals.20,21 Thus, the net effect of
these actions is to increase 5-HT activity within the
synapse, leading to suppression of appetite, and eventually to weight loss. Additionally, Curzon and coworkers22 have also suggested that fen¯uramine anorexia may partly re¯ect direct actions of fen at brain 5HT receptors (for example 5 HT2c receptors).
Unlike fen¯uramine, phentermine has been viewed
as a dopaminergic agonist similar in action and
mechanism to amphetamine.23,24 An emerging theme
of the recent research literature is the realization that
phentermine is not only a dopaminergic agonist, but
that this drug, at doses that reduce appetite, exerts
important indirect effects on serotonergic neurotransmission. A secondary emphasis of the present review
is that the conjoint effects of phentermine and of
fen¯uramine on serotonin neurotransmission may
help to explain the clinical ef®cacy of the fen-phen
combination, as well as those synergistic actions of
fen-phen that result in toxicity.
Fen¯uramine ± Phentermine synergism
PJ Wellman and TJ Maher
Synergistic Interactions between
Phentermine and Fen¯uramine
Food intake and body weight
Only recently has the interaction between phentermine and a fen¯uramine been formally examined in
animal studies of eating. Roth and Rowland25 examined the impact of daily IP administration of either
dexfen (2 mg=kg), phentermine (5 mg=kg) or a mixture of dexfen=phentermine (2 mg=kg ‡ 5 mg=kg) on
food intake and body weight in rats (see Figure 1).
Daily administration of 5 mg=kg=d phentermine alone
had minimal effects on food intake in rats, whereas
2 mg=kg=d dexfen produced a signi®cant reduction in
food intake. More importantly, when 2 mg=kg dexfen
was combined with 5 mg=kg phentermine, the combination yielded a larger suppression of food intake than
that produced by 2 mg=kg dexfen alone. A similar
synergy between dexfen and phentermine was evident
with respect to the reduction of body weight in this
study.
The ®ndings of Roth and Rowland25 document a
synergism between dexfen and phentermine on eating
and body weight in the rat. In order to further assess
fen-phen synergism over a wide range of drug doses,
Roth and Rowland conducted a follow-up study using
the isobologram technique to index drug-drug interactions that occur between phentermine and dexfen¯uramine.26 The isobolographic technique considers
the potency of each of two drugs on food intake.27 A
dose-response curve for appetite suppression is generated for each drug alone and these curves are in turn
used to predict the dose-additive function for the two
drugs (that is those doses that in combination would
be expected to produce a 50% reduction in food
intake). To examine whether the drugs are additive
Figure 1 Effects of repeated administration of vehicle (open
circle), DEXFEN (open triangle: 2 mg=kg), PHEN (®lled square:
5 mg=kg) and the combination (®lled diamond) of DEXFEN
(2 mg=kg) and PHEN (5 mg=kg) on mean intake of sweetened
milk on 11 consecutive days. (From Roth JD and Rowland NE.
Ef®cacy of administration of dexfen¯uramine and phentermine,
alone and in combination, on ingestive behaviour and body
weight in rats. #1998, Springer-Verlag).
in nature, the experimenter examines how closely
various combinations of the drugs of interest produce
the expected reductions in food intake.
The results from the Roth and Rowland26 study
con®rm a synergism between dexfen and phentermine
on food intake in free-feeding rats (see Figure 2). The
dose-response curves for dexfen and for phentermine
are represented along the x and y axes, respectively.
The solid line represents the theoretical dose additive
line: that is, combinations of doses tested along this
line should yield a 50% suppression of eating in rats.
The two open circles in the ®gure represent the ED50
value of one drug in combination with various doses
of the other drug. In one instance, the investigators
combined 0.5 mg=kg dexfen with various phentermine
doses. The dose additive curve predicts that about
5 mg=kg of phentermine would be required to elicit a
50% reduction in eating in combination with
0.5 mg=kg dexfen. The actual dose required was
approximately 2.0 mg=kg phentermine. Similarly,
when 2.5 mg=kg of phentermine was combined with
various doses of dexfen, less dexfen was required to
elicit a 50% reduction of eating than that predicted by
the dose-additive line. The line (dotted) that bounds
either side of the dose-additive line represents the
95% con®dence interval. In each instance, the combinations of dexfen and phen required smaller doses to
suppress food intake by 50% than that predicted by
the dose-additive line (note that each point lies outside
the 95% CI). This study con®rms and extends their
earlier observations and supports the notion that the
dexfen-phen combination is synergistic with regard to
the suppression of food intake in rats. It will be
important to further extend these studies using the
fen-phen combination, as this was the combination
most commonly used in people.
Figure 2 Isobologram of the effects of either 0.5 mg=kg dexfen
in combination with various doses of phentermine or 2.5 mg=kg
phentermine in combination with various doses of dex-fen. In
each instance, the drug-drug combinations induced greater
suppressions of eating than that predicted on the basis of
dose-additivity. The dotted lines represent the 95% con®dence
intervals. (Figure reprinted with permission from Roth and Rowland,26 courtesy of Elsevier Science, Amsterdam).
725
Fen¯uramine ± Phentermine synergism
PJ Wellman and TJ Maher
726
An advantage presumably conferred on the fenphen combination is a reduced pro®le of adverse drug
effects because the combination allowed for lower
doses of each drug to be used to reduce appetite and
body weight. This section considers whether the
adverse effects of the fen-phen combination exhibit
synergy as was evident for appetite suppression.
Primary pulmonary hypertension
Primary pulmonary hypertension (PPH) is a rare,
progressive, and generally incurable disorder involving increased pulmonary artery pressure and
increased vascular resistance eventually leading to
heart failure. The incidence rate of PPH is 1 ± 2
cases per million in the general population. Exposure
to speci®c appetite suppressants can increase the
incidence of PPH. In the 1960's, PPH was linked to
the use of the appetite suppressant aminorex.13,28
More recently, PPH has been reported to be linked
to the chronic use of dexfen and fen¯uramine10,11,14,15,29 Moreover, exposure to phentermine
alone has resulted in reported cases of PPH.30 ± 32
Serotonin has long been thought to play a role in the
development of PPH.33,34 In the 1970's, a group of
German investigators explored the concept that
enhancement of systemic serotonin might induce
vasoconstriction and in turn contribute to the development of PPH. Subsequently, Herve et al 35 reported
that PPH patients exhibit a signi®cant increase in
plasma serotonin and exhibit a greater release of
serotonin from aggregated platelets. Moreover, pulmonary arterial tissue taken from PPH patients exhibits greater sensitivity to serotonin relative to tissue
from control patients.36 One proposed animal model
of PPH indicates a link between serotonin and pulmonary hypertension. For example, rats injected with
the toxic alkaloid monocrotaline (MCT) develop elevated pulmonary pressures37 within 21 days after
MCT treatment. Kanai et al 38 noted that plasma
serotonin levels are increased in rats 12 h after MCT
treatment and that chronic pretreatment of MCT rats
with the serotonin antagonist DV-7028 suppressed
medial pulmonary artery hypertrophy, right ventricular hypertrophy, and pulmonary artery pressure.
As noted above, phentermine use is known to
produce PPH in some patients and this drug is
known to interact with and to modulate serotonin
activity within the pulmonary system. Seiler et al 34
reported that phentermine prolongs the vasoconstrictive action of serotonin in the isolated rat lung. More
recently, Reeve et al 39 examined pulmonary artery
(PA) pressure in the isolated rat lung by administering
a series of vasoconstrictive stimuli (angiotensin II or
hypoxia), as well as a series of infusions of vehicle
followed by dexfen, or phentermine followed by
dexfen. This report notes that phentermine pretreatment (10 and 100 uM) enhanced the vasoconstrictive
activity of dexfen (10 and 100 uM). Although phentermine alone had no impact on PA pressure,
preexposure to phentermine signi®cantly enhanced
the vasoconstriction in response to dexfen. These
studies indicate that phentermine increases the vasoconstrictive activity of fen¯uramine, an effect that has
been argued as contributing to the induction of PPH.33
As described below, the ability of phentermine to
attenuate the metabolism of serotonin could be the
underlying mechanism to explain this ®nding.
An issue to be resolved in future epidemiological
studies is whether the combination of fen¯uramine
and phentermine leads to a risk for PPH that re¯ects
the additive PPH risk for each drug or whether the risk
for PPH with the combination re¯ects the type of
synergism evident for appetite suppression.
Valvular heart disease
Connolly et al 9 reported varying degress of valvular
regurgitation in a series of 24 fen-phen users. Subsequent histopathological analyses revealed a thickening of the affected valves resulting in reduced valve
mobility. Subsequent studies have sought to establish
the incidence of valve disease as a function of
anorexigen exposure. Although phentermine alone
rarely produces valve disease, an evolving ®nding
has been that the combination of phentermine with a
fen¯uramine produces a greater incidence of valve
disease than that associated with a fen¯uramine alone.
Since the original report by Connolly et al 9 there
have been a number of studies published and presented at meetings that report on the incidence of
valvulopathies following treatment-with fen, dexfen
and=or phen. These studies report a wide range of
valvulopathy incidence for anorexigen exposure ranging from greater than 35% incidence down to 2 ± 4%
(a value equal to control). These studies utilize a wide
range of protocols. Not all the studies report on the
incidence in control groups or when utilized, some
control groups are not appropriately age=weight=sex
matched, the durations of exposure vary widely, and
the criteria used to de®ne valvulopathy severity are
often inconsistent from study to study. Only a few of
these studies have explicitly compared the incidence
of valve disease for a fen¯uramine alone versus a
group exposed to a fen¯uramine used in combination
with phentermine.
In the ®rst study by Khan et al,40 the odds ratio for
cardiac valve abnormalities that met their case de®nition by echocardiography in patients taking dexfen
alone was 12.7, whereas for those patients taking
dexfen plus phentermine, or fen plus phentermine,
the odds ratio increased to 24.5 and 26.3, respectively.
While these authors acknowledge that the variation in
duration of treatment between the groups makes
interpretation dif®cult, the addition of phentermine
appears to signi®cantly increase the likelihood of
valvulopathy. In the second study by Wee et al 41
patients who for various reasons had undergone echocardiographic analysis prior to being prescribed fenphen or dexfen were reevaluated following cessation
Fen¯uramine ± Phentermine synergism
PJ Wellman and TJ Maher
of therapy. Of the 46 patients included in the study,
only two had worsening or newly developed valvulopathies that met FDA criteria (mild aortic or moderate
mitral regurgitation). Both of these patients had taken
fen-phen. None of the patients who had taken dexfen
developed valvulopathies. However, despite the desirability of this study design, so few patients were
included so as to prevent a de®nitive conclusion
regarding the in¯uence of phentermine addition.
A study by Gross et al 42 reported that aortic
insuf®ciency (AI) in fen-phen patients was signi®cantly altered by duration of exposure (greater than 9
months) and by dose of the combination (greater than
60 mg). Given that phentermine alone probably does
not induce valve disease, the ®nding that dose combinations greater than 60 mg=d increase the likelihood
of valve disease indicates that phentermine is not inert
when given in combination with fen¯uramine. This
latter ®nding supports the notion that mixing phentermine with fen¯uramine increases the impact of fen¯uramine on valve disease.
A study by Gardin et al 43 similarly noted an
increase in the incidence of mild or greater aortic
regurgitation associated with fen-phen. While the
control group incidence was 4.1%, the dexfen and
fen-phen group incidences were 8.9% and 13.7%,
respectively.
In a study by Shively et al 44 the incidence of
valvulopathy meeting FDA criteria was 3% in nontreated controls and 7% in patients treated with
dexfen. However, when the potentially confounding
factor of concomitant use of drugs reported to inhibit
monoamine oxidase (for example, estrogens, thyroid)
was excluded, the incidence of valve disease
decreased to 4%, a value not signi®cantly different
from control. The signi®cance of this ®nding relates to
the observation that phentermine is an inhibitor of
monoamine oxidase, the enzyme that inactivates serotonin.45 This ®nding lends further support to the
notion that valve disease associated with fen-phen
re¯ects enhanced systemic serotonin activity.
Valve disease similar to that noted by Connolly et
al 9 has been noted in carcinoid disease as well as in
ergotamine toxicity.46,47 Carcinoid syndrome involves
hypersecretion of serotonin whereas ergotamine is
thought to exert direct actions at serotonin receptors.
Whereas fen-phen-associated valve disease appears to
involve primarily the left-side of the heart,9 carcinoid
disease involves right side heart valves46 and ergotamine alters valves on either side of the heart.47 Fishman33 argues that the difference in pattern of valve
disease re¯ects the role of the lung in the inactivation
of serotonin. In carcinoid syndrome, the lung retains
the ability to remove circulating serotonin, thus the
valve damage is primarily on the right side whereas
during fen-phen use, the lung is impaired in the ability
to clear serotonin, in part because phentermine inhibits
MAO and this impairs the metabolism of serotonin
within the endothelium.
While none of the above studies possesses the ideal
experimental design, or is large enough to yield a
de®nitive conclusion, each appears to support a role of
phentermine in increasing the likelihood of valvulopathy in patients taking one of the fen¯uramines.
Unfortunately, the appropriate study that would control for all the experimental variables and have the
appropriate statistical power cannot be undertaken
since the fen¯uramines are no longer available for
use in humans.
Brain and peripheral serotonin
Serotonin (5-HT) is an indolamine transmitter found
in the brain as well as the periphery. The raphe nuclei
are among the primary sources of 5-HT neurons in
brain and these neurons project diffusely to frontal
cortex, striatum, hippocampus, hypothalamus, and
brain stem. Acute exposure to very large doses of
fen¯uramine reduces brain levels of serotonin.48
Although most of bodily 5-HT is found in the periphery within gut and blood platelets, few studies have
examined the impact of fen¯uramine alone or in
combination with phentermine on peripheral 5-HT
levels and 5-HT activity. The importance of this
remarkable gap is evident given recent suggestions
that fen-phen alterations of systemic 5-HT may represent a primary mechanism by which to explain the
impact of fen-phen therapy on the incidence of valve
disease and of PPH.33,34
Table 1
Authors
Species
PHEN dose
mg=kg (CUMUL)
Baumann et al 49 Mouse 7 (56)
12 (96)
Halladay et al50 Rat
Lew et al 51*
Rat
5 (20), 20 (80)
McCann et al 52
FEN Dose
mg=kg (CUMUL)
Brain regions
3 (24), 10 (80), 30 (240) Forebrain
16 (128)
Striatum
3.125 (12.5), 12.5 (50) Nuc accumbens
Striatum
Amygdala
Hypothalamus
Fr. Parietal cortex
Hippocampus
Mouse 20 (160), 40 (320), 10 (80)
Striatum
Hypothalamus
Hippocampus
Cortex
Impact of FEN Evidence of
on regional 5-HT synergism?
?
7 68%
7 16%
7 27%
7 38%
7 43%
7 50%
7 53%
7 15%
7 17%
7 27%
7 37%
*Rats treated with fen-phen once per hour for 4 hours (all other treatments are 2=day for 4 days)
None
None
PHEN5: YES PHEN 20: NO
PHEN5: YES PHEN 20: NO
PHEN5: YES PHEN 20: NO
PHEN5: No PHEN 20: NO
FHEN5: YES PHEN20: NO
PHEN5: NO PHEN 20: NO
PHEN 20: NO PHEN 40: YES
PHEN20: YES PHEN40: YES
PHEN 20: NO PHEN 40: NO
PHEN 20: NO PHEN 40: NO
727
Fen¯uramine ± Phentermine synergism
PJ Wellman and TJ Maher
728
Several recent research efforts have examined the
potential interactions between fen¯uramine and phentermine on brain 5-HT activity. These four extant
studies are summarized in Table 1. The table presents
the authors, species used, dose per injection (typically
twice per day for 4 d), the cumulative dose of
phentermine or fen¯uramine, the brain regions examined in the study, the impact of fen alone on 5-HT
brain concentration, and whether the study observed
an outcome consistent with synergism.
The ®rst study was that of Baumann et al 49 who
examined the changes in mouse forebrain 5-HT associated with twice a day exposure for 4 days to either 3,
10 or 30 mg=kg fen¯uramine alone or these fen¯uramine doses in combination with a single dose of
7 mg=kg phentermine. The second study of Table 2
was carried out by Halladay et al 50 who examined the
impact of 16 mg=kg fen¯uramine (twice per day for 4
days) on striatal 5-HT levels as well as the impact of
12 mg=kg phentermine given in combination with the
16 mg=kg fen¯uramine regimen. Neither the Baumann
study nor the Halladay study noted evidence of
synergism with regard to reductions of brain serotonin
content. These two studies use different species and a
common exposure regimen. The studies, however are
limited by the use of only a single dose of phentermine, and only examined changes in serotonin in but a
single brain region. Moreover, because these severe
fen¯uramine exposure regimens produced signi®cant
acute reductions in brain indole content, demonstration of synergistic effects with addition of phentermine is made dif®cult.
The last two entries of Table 1 provide some
evidence of a synergistic interaction between phentermine and fen¯uramine on brain serotonin levels. In the
Lew et al 51 study, rats were injected every hour for 4
hours with various combinations of fen-phen and then
sacri®ced either 7 d or 28 d later. The rats were treated
each time with either 3.125 or 12.5 mg=kg fen¯uramine, with either 5 or 20 mg=kg phentermine, or a
combination of 5 mg=kg phentermine with 3.125
mg=kg fen¯uramine or 20 mg=kg phentermine with
3.125 mg=kg fen¯uramine. These authors examined
changes in 5-HT levels in each of six brain regions.
Four hourly injections of either 3.125 or 12.5 mg=kg
fen induced dose-dependent reductions in brain
serotonin in each of the six brain regions. While the
5.0 mg=kg dose of phentermine alone did not alter
serotonin content in any of the six brain regions, this
phentermine dose (a no effect dose for alteration of
brain serotonin) enhanced the impact of 3.125 mg=kg
fen dosing regimen on reducing serotonin in four of the
six brain regions.
In the last entry of Table 1, McCann et al 52 treated
mice twice per day for 4 days with either 10 mg=kg
fen, 20 or 40 mg=kg phentermine or a combination
of 10 mg=kg fen with either 20 or 40 mg=kg phentermine. Levels of brain serotonin were not altered
by phentermine alone. Fen¯uramine reduced brain
serotonin levels and this effect was enhanced by
coadministration of phentermine in hypothalamus
and striatum but not in hippocampus or cortex.
These studies indicate that phentermine, which by
itself did not alter brain serotonin levels, enhances
the impact of fen¯uramine on reducing brain serotonin levels.
Table 1 also presents the impact of fen¯uramine
alone on changes in regional serotonin levels. One
factor that may partly explain whether fen-phen synergism is observed is the basal level of depletion produced by a test regimen of fen¯uramine. In the Lew et
al 51 study, synergism was most likely observed when
fen¯uramine alone produced a small decrease in
regional serotonin. A similar pattern was evident in
the McCann et al 52 study in which phentermine was
most likely to yield synergism when the impact of
fen¯uramine alone on serotonin within a brain region
was small. These results suggest that the failure to
observe synergism in the Halladay et al 50 study may
re¯ect a ceiling effect on depletion of striatal serotonin, thereby masking any possible synergistic effect of
phentermine in combination with fen¯uramine.
The available studies on the interaction of phentermine with fen¯uramine on central serotonin levels
utilize widely varying dose ranges and exposure regimens. A key aspect is that such studies tend to use
high-dose repeated administration regimens. Further
studies using a wider range of pharmacologically
relevant dosages and longer exposure durations will
further indicate the extent to which phentermine and
fen¯uramine exhibit synergism with regard to alteration of brain serotonin systems. Similar caveats apply
to future studies of the impact of fen-phen on systemic
5-HT activity.
Potential mechanisms underlying
fen-phen synergism
Whereas the prior sections present the current state of
the literature on fen-phen synergism, this section turns
to a discussion of the potential explanations for such
synergism.
Pharmacokinetics
A pharmacokinetic explanation would suggest that
phentermine exposure alters the absorption, distribution, metabolism and=or elimination of fen¯uramine.
The impact of phentermine on fen¯uramine pharmacokinetics is a key issue. There are data available as to
whether exposure to anorexic agents similar in structure to phentermine alters fen¯uramine bioactivity.
Hunsinger et al 53 reported that rats given a series of
daily injections of 4.0 mg=kg=day amphetamine
exhibited a greater sensitivity to the toxic actions of
fen relative to rats given daily injections of vehicle.
Speci®cally, amphetamine preexposure lowered the
Fen¯uramine ± Phentermine synergism
PJ Wellman and TJ Maher
LD50 value for fen from 97 mg=kg to 68 mg=kg (53).
Moreover, amphetamine preexposure increased the
brain levels of fen relative to that evident in rats
given vehicle pretreatment. The Hunsinger et al 53
study indicates that exposure to amphetamine alters
the pharmacokinetics of fen so as to prolong the
duration of action and impact of fen. Given the
similarity between amphetamine and phentermine in
structure, activity and mechanism of action, it is
reasonable to expect that phentermine exposure
would also alter fen levels in brain. As described
below, phentermine, like d-amphetamine, is known
to competitively inhibit the enzyme that metabolizes
fen and 5-HT. Additionally, fen, at these high doses,
may also release dopamine and norepinephrine, thus
enhancing `aggregation toxicity' of amphetamine.
Thus, the increased toxicity and CNS accumulation
of fen observed above might result, in part, from an
interference of metabolism of fen and=or 5-HT produced by phentermine.
Ion channels
Changes in ion channel activity and the resulting
changes in membrane potential are key elements in
cell function. Weir and colleagues54 examined the
impact of anorexic agents on K‡ channel currents in
smooth muscle cells taken from rat pulmonary artery.
Both fen and dexfen inhibited K‡ channel current,
induced membrane depolarization and produced vasoconstriction in smooth muscle cells. More recently,
dexfen has been shown to increase Ca‡‡ levels within
smooth muscle cells.55 These studies of peripheral
cardiac muscle cells have not assessed whether K‡
channel inhibition or elevation of intracellular Ca‡‡ is
enhanced by co-administration of fen or dexfen with
phentermine and whether these effects occur at therapeutically relevant concentrations. Weir and colleagues56 have argued that abnormal ion channel activity
appears to increase the susceptibility to the development of PPH after exposure to fen¯uramine.
Serotonergic actions of
phentermine
Inhibition of MAO by phentermine
In the 1970's, two independent research groups
reported that a variety of anorexic drugs had inhibitory actions on monoamine oxidase (MAO), an intracellular enzyme that inactivates serotonin.57,58 Seiler
et al 34 suggested that the MAO-inhibitory (MAOI)
action of phentermine might account for the ®nding
that phentermine prolonged the action of serotonin
infusion on perfusion pressure in the isolated rat lung
preparation. MAO inhibition by phentermine would
also account for the ®ndings of Morita and Mehendale59 in which phentermine delayed the metabolism
of 5-HT in rabbit lung. The observation that phentermine inhibits MAO was recently con®rmed and
extended by Maher et al 45 who noted that phentermine is as potent in its inhibition of MAO as is
iproniazid, an MAOI drug used to treat depression
in some countries. The importance of these ®ndings is
that MAO represents one of two major mechanisms
by which serotonin is inactivated. The other mechanism, of course, is its reuptake into the nerve terminals
or, in the periphery, into platelets. If phentermine, an
MAO inhibitor, were to be combined with fen¯uramine, a drug that releases serotonin and blocks its
reuptake, the expectation would be a further rise in
serotoninergic activity. Thus, the combination of
phentermine and a fen¯uramine would produce
increases in serotonin activity that would appear as
a synergism between the two drugs.
As noted above, the incidence of valve disease to
the fen¯uramines is reduced to control values when
subjects are excluded who were exposed to the coadministration of MAO inhibitors with a fen¯uramine.44 Further support for the notion that fen-phen
synergism re¯ects MAO inhibition by phentermine is
provided by a study in which pretreatment of rats with
the MAOI clorgyline potentiated the appetite suppressant effects of fen¯uramine.60 Thus, inhibition of
MAO is suf®cient to interact with and to potentiate
the appetite suppressant actions of fen¯uramine. Presumably, such effects would also occur when phentermine (an MAOI drug) were coadministered with a
fen¯uramine (cf.25,26 ).
Release of serotonin by phentermine
The conventional wisdom has been that phentermine
does not interact with central serotonin neurons in any
signi®cant manner. Three recent studies using the
microdialysis technique suggest that while phentermine alone has minimal impact on release of 5-HT,
phentermine may further enhance the extracellular 5HT increase induced by fen¯uramine. A study by
Balcioglu and Wurtman61 examined the impact of
phentermine on striatal dopamine and serotonin levels
in conscious rats using the microdialysis technique.
Their ®ndings demonstrated that 2 and 5 mg=kg
phentermine did not alter serotonin within the striatum but did signi®cantly increase striatal dopamine
over baseline levels. A second study by Shoaib et al 62
noted that phentermine alone, at doses of 1.0 and
2.0 mg=kg, slightly increased the extracellular levels
of 5-HT in rat nucleus accumbens, but that the
serotonergic action of phentermine was much less
marked than its impact on brain dopamine. More
importantly, the Shoaib et al 62 study noted that the
mixture of phentermine with fen¯uramine had an
additive effect on increasing brain serotonin levels,
an observation consistent with the MAOI effect of
phentermine. A third microdialysis study by Balcioglu and Wurtman63 reported that whereas 2 mg=kg
phentermine alone did not alter striatal serotonin
729
Fen¯uramine ± Phentermine synergism
PJ Wellman and TJ Maher
730
levels, a combination of 2 mg=kg phentermine with
1 mg=kg fen¯uramine produced a 330% increase in
striatal serotonin in rat in contrast to the 182%
increase in striatal serotonin induced by 1 mg=kg
fen¯uramine only. These studies document that the
acute effects of fen¯uramine on brain serotonin are
enhanced by the addition of phentermine. Given that
phentermine alone has minimal impact on brain
serotonin level, this enhancement would be viewed
as synergistic.
These studies are limited by the small range of
doses tested, by the use of mostly acute exposure to
phentermine (acute exposure to fen produces
increases in extracellular serotonin levels while
chronic high dose fen exposure can produce declines
in brain serotonin content), and by the sampling of
extracellular serotonin in a limited number of brain
regions. Hypothalamic serotonin, for example, is
likely more important for the understanding of the
impact of fen-phen on eating than is serotonin within
the striatum.
As was noted above, few studies have examined
the action of phentermine on serotonin in the periphery. Fristrom et al 64 noted that phentermine released
serotonin from rabbit blood platelets. Platelets are the
major storage pool for 5-HT in blood. A more recent
study in humans, indicates that phentermine may also
play a role in enhancing the level of serotonin in
blood platelets. Maher et al 45 reported that the
administration of either 15 mg or 30 mg phentermine
to human volunteers increased platelet serotonin
levels by approximately 70% after one hour but did
not alter plasma levels of serotonin, indicating that
this effect on platelet serotonin activity probably
relates to the MAO inhibition effected by phentermine. Moreover, few studies have examined the
impact of the fen-phen combination on platelet 5HT activity. Redmon et al 65 reported that chronic
fen-phen exposure did not alter plasma serotonin
levels. This report, however, used only a single
assessment of plasma serotonin (24 h after last dose)
for subjects taking fen-phen, and this study did not
assess platelet serotonin levels in fen-phen treated
subjects.
Conclusions
The fen-phen combination enjoyed wide acceptance
because this combination was thought to reduce body
weight (and associated risks of obesity) in the absence
of signi®cant risk. A remarkable aspect of fen-phen
use in the treatment of human obesity is the fact that
this use occurred `off-label' without animal studies to
either understand the mechanism(s) of action of the
fen-phen combination or to substantiate the safety of
the fen-phen combination. Animal studies clearly
indicate a synergism between phentermine and dex-
fen¯uramine on the reduction of appetite and body
weight in rats.25,26 Animal studies have also demonstrated synergism between phentermine and fen¯uramine on reduction of brain serotonin levels,51,52 and
between dexfen¯uramine and phentermine on vasoconstriction of pulmonary arterial vessels.39 Recent
studies indicate the coadministration of phentermine
increases the incidence of valve disease associated
with fen¯uramine or dexfen¯uramine. Further animal
studies are required to con®rm the magnitude of
synergism between phentermine and the fen¯uramines. Further epidemiological studies are needed to
assess the extent to which synergism is evident in the
impact of fen¯uramine in the cardiovascular system.
In each instance, investigators will need to consider
the use of appropriate designs that allow for the
determination of synergism between phentermine
and the fen¯uramines.
A secondary issue of the present review is that
synergism between phentermine and fen¯uramine can
be viewed in the context of a drug-drug interaction.
Fen¯uramine increases serotonin release and blocks
reuptake of serotonin whereas phentermine may
increase serotonin levels indirectly via inhibition of
MAO. These interactions would be expected to
enhance serotonin activity leading to a synergism of
clinical effect (for example, suppressed appetite and
body weight) as well as adverse effects associated
with excessive serotoninergic activity. The fen-phen
experience may increase our understanding of the
mechanisms of action of these appetite suppressants,
alone and in combination, and is likely to lead to the
future development of appetite suppressant regimens
with known ef®cacy and safety.
Acknowledgements
Dr Wellman and Dr Maher have acted, or have been
approached to act as consultants and=or expert witnesses for both sides involved in litigation over fenphen in the USA.
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