Topical Aminophylline: Is It Safe and

Effective in Causing Regional Fat Loss?

LISA M TONG AND KRISTIN R GERICKE

Objective: To provide a better understanding of the efficacy and possible adverse effects of topical
aminophylline in causing regional fat loss.
Data Source: Pertinent English-language literature (1958-1995).
Study Selection: Representative articles documenting mechanisms of action and types of drug-induced
reactions, as well as treatment options.
Data Extraction: Data were extracted only from articles that documented relevant and substantive
information backed by clinical studies.
Data Synthesis: Topical aminophylline 2% thigh cream has been introduced as a method of treating cellulite,
or dimpled thighs and buttocks. The proposed method of action is by increasing local concentration, thereby
stimulating lipolysis. Data from two small clinical trials showed that the cream reduced thigh girth and had
no known adverse effects. However, adverse dermatologie effects caused by aminophylline have been
reported in the past.
Conclusions: Topical aminophylline cream appears to be a reasonable option for regional reduction of thigh
girth for some people and has not shown any adverse effects. Nevertheless, larger, long-term studies need to
be done.
/ Pharm Technol 1997;13:80-3.

In the human body, fat is stored whenever the amount of
calories ingested is greater than the amount used. This
stored fat is mobilized and serves as energy when one
does not take in food for several hours. Triacylglycerols,
the highly concentrated energy stores, are accumulated
1
in the cytoplasm of adipose cells.
Dimpled thighs and buttocks are characterized as cel­
lulite. Cellulite, which occurs primarily in women, ap­
pears when fat is found in the loculi between fibrous sep­
ta, the attachment of the dermis of the skin to the deep
2
fascia. This causes a bumpy look on the surface of the
skin. The change in the skin tautness may be caused by
genetics, drastic weight fluctuations, exercise or activity
level, and nutrition. In addition, these sites are the first
sites of deposition of fat. However, when one diets, these
2
sites are often the last sites for fat removal. Adipocytes in
the abdominal subcutaneous region are more metaboli-
cally active than smaller adipocytes of the femoral region
and are generally more responsive to fat-reducing efforts
such as calorie-restàcting diets and exercise. This is at­
tributed to a lower amount of beta-receptors and a high­
er amount of alpha -receptors on thigh fat cells compared
2 nophylline 2% cream directly to the thighs, local concen­
with abdominal fat cells, which leads to increased diffi­
3 4
culty in producing weight loss in the thighs. '
Thigh cellulite reduction methods range from surgery
to diet and exercise to the recently developed topical
cream. Diet and exercise programs are difficult ways to
treat cellulite because they require strict compliance and
a great deal of motivation. Liposuction, a surgical treat­
ment, thins and loosens thick fat deposits and is per­
5
formed by plastic surgeons. Although this treatment
plan does not require rigorous work by the person, it is
an invasive approach to decreasing thigh fat. There are
risks of wound infections and the cost of this surgical
procedure is high.
A topical remedy is a highly attractive approach to re­
ducing cellulite; it does not require effort from the sub­
ject, and it does not involve invasive therapy. Researchers
have introduced a topical cream containing aminoph­
ylline and claim that it can decrease thigh fat. After an
6
abstract was presented at the annual meeting of the
North American Association for the Study of Obesity in
October 1993, interest was generated in the subject of us­
ing topical aminophylline to decrease fat in the thighs.
The authors hypothesized that by applying topical ami­
trations within the fat cells would increase. This would
stimulate lipolysis by increasing regional cyclic adeno-

LISA M TONG PharmD Student, School of Pharmacy, University of California, San Francisco, CA; and KRISTIN R GERICKE PharmD,
Assistant Clinical Professor, Division of Clinical Pharmacy, University of California, 521 Parnassus Ave., Rm. C-152, San Fran­
cisco, CA 94143, FAX 415/476-6632. Reprints: Kristin R Gericke PharmD.

80 JOURNAL OF PHARMACY TECHNOLOGY VOLUME 1 3 MARCH/APRIL 1 9 9 7

sine monophosphate (cAMP) concentrations. In addition,
the authors theorized that because of the increased local
concentration, topically adrninistered airimophylline
would lower the lipolytic threshold of thigh fat cells in
comparison with abdominal fat cells.
A
A topical remedy is a highly
attractive approach to reducing
cellulite; it does not require effort
from the subject, and it does not
involve invasive therapy.
•
Aminophylline is the emylenediamine salt of theoph­
ylline and is composed of 85% anhydrous meophyltine
7
and 15% emylenediamine by weight. Emylenediamine,
a stabilizing and sensitizing agent, is used in the prepara­
tion of dyes, rubber accelerators, fungicides, synthetic
waxes, resins, insecticides, and asphalt wetting agents. 8,9
Dosage forms of ammophylline include tablets, delayed-
release tablets, oral liquid, suppositories, rectal solutions,
10
injections, and now topical creams.
Currently, topical thigh creams that contain amino-
phylline are classified by the FDA as cosmetics rather
than drugs, and are thus marketed as cosmetics. Accord­
ing to Stanley R Milstein, from the FDA Office of Cos­
metics and Colors, as long as the cream is not claimed to
remove cellulite or intended to affect the structure or
function of the body of a human or animal, it is not con­
4
sidered a drug. One such preparation, SmoothContours,
is claimed to bring about "smoother-appearing thighs"
11
and thus is not a thigh reducer. According to the FDA,
no premarket approvals for cosmetics are needed if the
manufacturers do not claim that the product works as a
12
drug. These creams are available on the market at local
drug stores, beauty products stores, and even may be or­
dered on the World Wide Web. Because these thigh creams
contain ammophylline, a prescription drug, consumers
should be aware of the proposed mechanism of action,
efficacy, and adverse effects.
Mechanism of Action
Lipolysis, or fat breakdown, occurs when the enzyme
lipase causes triacylglycerols in the cytoplasm of adipose
cells to split into glycerol and fatty acid constituents.
Through a cascade of events, lipase is activated when the
levels of cAMP are increased. cAMP is converted to
JOURNAL OF PHARMACY TECHNOLOGY
AMP by the enzyme phosphodiesterase, thereby de­
creasing cAMP concentrations and reducing lipase acti­
vation and subsequent fat breakdown. Armnophylline, a
phosphodiesterase inhibitor, blocks the conversion of
cAMP to AMP. This results in higher cAMP concentra­
1
tions, increased lipase activation, and increased lipolysis.
Clinical Trials
Although manufacturers of thigh creams claim that
many clinical trials were conducted, there are few pub­
lished reports of double-blind, randomized, controlled
trials on topical ammophylline creams in peer-reviewed
11
journals. In general, the published trials do not include
large numbers of patients and include only women. Never­
13
theless, these researchers conclude the cream is effective.
A
...there are few published reports
of double-blind, randomized,
controlled trials on topical
aminophylline creams...
•
13
In 1987, Greenway and Bray reported on 28 patients
with obesity treated with one of five treatment regimens.
Three to five times a week for 4 weeks, these subjects (1)
injected isoproterenol, a beta-adrenergic agonist; (2) ap­
plied a cream containing colforsin, another beta-adrener­
gic agonist, armnophylline, a phosphodiesterase inhibi­
tor, and yohimbine, an alpha -antagonist; (3) applied
2
yohimbine cream; (4) applied colforsin cream; or (5) ap­
plied ammophylline cream. The authors hypothesized
that the lipolysis rate of thigh fat cells would increase
with the increased local concentrations of beta-agonists,
phosphodiesterase inhibitors, or alpha -adrenergic recep­
2
tor inhibitors. Treatment efficacy was measured by thigh
circumference, using the xipamide-treated thigh as the
control. AU 28 of the women were more than 20% above
their desirable weight. Five of the 28 subjects applied
2
aminophylline cream 1.3 x 10~ m o l / L on one thigh, and
xipamide base, the control, on the other thigh. The sub­
jects lost an average of 1.5 ± 0.77 cm more girth in the
ammophylline-treated thigh than in the control thigh.
There was no evidence of changes in blood pressure or
heart rate, and no rash was noted. Greenway and Bray
concluded that of all five treatment regimens, topical
ammophylline appeared to be most effective.
6
In their 1993 abstract, Hamilton et al. summarized a
5-week study of regional fat loss. Eleven women applied
ammophylline 2.0% in a cream base once a day for 5
VOLUME 1 3 MARCH/APRIL 1 9 9 7 81
weeks to one thigh and the same base without aminoph-
ylline to the other thigh. The control versus the experi­
mental thigh was assigned randomly, and the study was
double-blind. Weight and thigh girth were measured
weekly, and results were analyzed by a paired f-test. The
net weight loss of the subjects was rninimal. However,
there was a relatively wide individual weight loss varia­
tion of 0.1 ± 2.1 kg (mean ± SD). Nevertheless, there was
an average reduction of 1.51 ± 0.8 cm (p < 0.01) in circum­
ference on the ammophylline-treated thighs. Laboratory
concentrations of systemic theophylline, complete blood
counts, and results of blood chemistry tests were normal,
and there were no reports of sensitivity on skin patch tests.
Adverse Effects
In trials published to date, no cases of adverse reac­
tions from application of topical ammophylline were due
to the aminophylline itself. Normal laboratory results
were reported for theophylline concentration, complete
blood count, and blood chemistry tests. However, there
have been some reported cases of allergy to aminoph­
ylline or ethylenediamine, a component of aminophyl­
line, in the past. In most cases the emylenediamine moiety
of aminophylline rather than the anhydrous theophylline
is reported to be the causal agent of a hypersensitivity re­
action.14
• 17
... no cases of adverse reactions
from application of
topical aminophylline were due
to the aminophylline itself.
Τ study, and only one subject had a mild reaction to a patch
In 1958, a 52-year-old pharmacist developed allergic
contact dermatitis after preparing ammophylline suppos­
15
itories. He developed red, swollen hands, arms, and
face with papules and vesicles. Skin patch tests were per­
formed with suspected remedies, various antibiotics, sul-
fones, and antihistaminics. Ammophylline was not test­
ed because it was not suspected as a cause. Results of all
of these tests were negative. The patient was treated for
his dermatologie problems, but his condition did not im­
prove. He then changed to a job that did not require con­
tact with arnmophylline, and the symptoms resolved.
However, when he returned to the initial job and started
to make aminophylline suppositories again, the condi­
tion reappeared with the additional symptoms of sneez­
ing and wheezing. He then realized that the problems he
82 JOURNAL OF PHARMACY TECHNOLOGY
was having may have been due to aminophylline. The
result of a skin patch test using aminophylline 1% was
strongly positive with the formation of bulla; the result
obtained with mœphylline 1% was negative. It was con-
cluded that this patient was strongly sensitive to the
emylenediamine fraction of aminophylline.
9
Baer et al. reported an additional case of sensitivity to
aminophylline. In 1953, a 58-year-old pharmacist pre-
sented with severe eczematous, erythematous, edema-
tous, scaling eruption all over his body, from the scalp to
the lower extremities. The patient's history showed four
prior hospital visits for similar symptoms and a positive
result on a patch test using dust from the patient's phar-
macy. The patient stated that he would tend to have ex-
acerbations of his condition after filling capsules contain-
ing papaverine, amobarbital, and arnmophylline. Patch
tests with the three drugs were performed, and the only
strongly positive result was obtained with aminoph-
ylline. Additional patch tests were conducted to determine
which component of ammophylline caused this reaction.
Positive findings on four patch tests resulted from the
emylenediamine fraction of ammophylline.
16
Provost and Jillson reported cases of sensitivity to
emylenediamine. Eleven of 13 patients had patchy eczem-
atous eruptions due to a patch test with Mycolog, which
contained ethylenediarnine, neomycin, and merthiolate.
After discontinuation of the cream, the eruptions cleared.
Because of the potential for adverse effects from use of
the highly publicized topical ammophylline, in 1995 Si-
mon and Terzian expressed their concern about the
cream. Emphasis on prior topical dermatitis due to a type
IV hypersensitivity reaction to the ethylenecüamine com-
plexée! in the aimnophylline molecule was made. One of
the developers of a topical ammophylline cream licensed
by Heico, Inc., and marketed as SmoothContours, re-
18
sponded to the letter. He stated that there have been
controlled trials studying the effects of topical amino-
phylline on approximately 100 women. Only a few had
minor reactions. Fifty-one subjects participated in one
test. In a second study, all 34 women who were treated
with arnmophylline ointment for 6 weeks had negative
results on patch tests and did not have any adverse reac-
tion to the ointment. In other studies, two reports of con-
tact dermatitis were noted with aminophylline 2%, and
these cases resolved when the cosmetic was withdrawn.
Frame further discussed the possibility that hypersensi-
tivity to arnmophylline topical creams was due to the ox-
idation of ethylenediamine (oxidation causes the cream
to turn yellow and crystallize, causing increased inci-
dence of skin rashes because of irritation).
Summary
To date, topical arnmophylline 2% has been found to
reduce thigh circumference by approximately 1.5 cm
VOLUME 1 3 MARCH/APRIL 1 9 9 7
 TOPICAL AMINOPHYLLINE

over a period of 4 - 5 weeks. Only miriimal adverse ef­
fects, such as skin irritation, have been reported recently,
but more serious cases of ammophylline-induced contact
dermatitis have been published in the past. Because these
small studies have potential for type Π error, larger clini­
cal trials would be useful to provide information regard­
ing long-term efficacy and safety. Overall, for people who
are opposed to diet and exercise programs and liposuc­
tion to treat cellulite, the use of topical arrimophylline ap­
pears to be a reasonable option for regional reduction of
thigh girth. However, the amount of reduction is mini­
mal and must be weighed against the cost of the product
and the potential for dermatologie adverse effects. —
References
1. Stryler L. Biochemistry. 3rd ed. New York: WH Freeman and Co.,
1988:464,472.
2. Corlett RJ. The elusive 'cellulite' (letter) Aust Fam Physician 1989;18:
168.
3. Smith U, Hammersten J, Bjorntorp P, Kral JG. Regional differences
and effect of weight reduction on human fat cell metabolism. Eur
J Clin Invest 1979;9:327-32.
4. Raeburn P. About that thigh cream. Allure 1994:62-3.
5. Lockwood T. Lower body lift with superficial fascial system sus­
pension. Plast Reconstr Surg 1993;92:1112-22.
6. Hamilton EC, Greenway FL, Bray GA. Regional fat loss from the
thigh in women using topical 2% anünophylline cream (abstract).
Obesity Res 1993;l(suppl 2):95S.
7. Ellis EF. Theophylline and derivatives. In: Middleton E, Reed CE,
Ellis EF, eds. Allergy: principles and practice. St. Louis: CV Mos-
by, 1978:434-54.
8. White MI, Douglas WS, Main RA. Contact dermatitis attributed
to ethylenediamine. Br Med J 1978;1:415-6.
9. Baer RL, Cohen HJ, Neidorff AH. Allergic eczematous sensitivi­
ty to aminophylline. Arch Dermatol 1958;79:647-8.
10. BeDell LS. Physicians genRx, vol. 2. St. Louis: Mosby-Year Book,
Inc., 1996:83-6.
11. Thigh cream marketers smear it on thick. Tufts Univ Diet Nutr Lett
1994;ll(12):3-6.
12. Griffin Κ A thigh-sUrnming cream that works? Health 1994;8(2):36-
8.
13. Greenway FL, Bray GA. Regional fat loss from the thigh in obese
women after adrenergic modulation. Clin Ther 1987;9:663-9.
14. Allergy to aminophylline (editorial). Lancet 1984;2:1192-3.
15. Tas J, Weissbeig D. Allergy to aminophylline. Acta Allerg 1958;12:
39-42.
16. Provost TT, Jillson OF. Ethylenediamine contact dermatitis. Arch
Dermatol 1967;96:231-4.
17. Simon PA, Terzian CG. Skin reactions to topical aminophylline
(letter). JAMA 1995;273:1737-8.
18. Frome BM. Skin reactions to topical aminophylline (letter). JAMA
1995;273:1738.

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