Vol. 87 No.

5 May 1999

ORAL SURGERY
ORAL MEDICINE
ORAL PATHOLOGY

ORAL MEDICINE Editors: Jed Jacobson and Margot Van Dis

Oxypentifylline in the management of recurrent aphthous oral

ulcers
An open clinical trial

J. Chandrasekhar, MDS, FFDRCS,a A. A. Liem, MBBS,a N. H. Cox, BSc, FRCP,b and A. W.

Paterson, FRCS, FDSRCS,a Carlisle, United Kingdom
CITY GENERAL HOSPITAL

Objective. The purpose of this study was to determine the efficacy of oxypentifylline in the treatment of recurrent oral aph-
thous ulcers and to compare the results with those of previous studies.
Study design. A 6-week open trial and a patient survey regarding pain were conducted at the Oral and Maxillofacial Surgery
Unit, City General Hospital, Carlisle. Twenty-four patients (11 male and 13 female) were selected from sequential referrals
involving complaints of recurrent oral ulcers. A 2-week pretrial period was used to record data pertaining to the occurrence,
duration, and pain associated with ulcers. A 4-week period of treatment with oxypentifylline (400 mg administered orally 3
times daily) was followed by an assessment of improvement at the end of 6 weeks.
Results. The results were comparable to those of previous studies, with positive responses seen in 63.6% of male patients and
61.5% of female patients. However, recurrence of ulcers was noted in all patients once the drug was discontinued. This was
attributed to the small size of the patient sample studied and to the relatively short duration of treatment. No significant side
effects were noted.
Conclusions. Double-blind, controlled studies are indicated for a definitive assessment of the efficacy of oxypentifylline in the
management of recurrent oral aphthous ulcers. The encouraging results of this study support the suggestion that the use of
oxypentifylline be considered in refractory cases of recurrent oral aphthous ulcers.
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:564-7)

Recurrent aphthous stomatitis (RAS), first described in
1888, is now the most prevalent oral mucosal
disease,1,2 affecting perhaps 20% of the population.
However, its causation remains poorly understood and
its treatment is often unsatisfactory. Suggested causes
include local trauma, microbes, systemic diseases,
nutritional disorders, and genetic and immunologic
factors. Some authorities have suggested deficiencies
in vitamin B12, folic acid, and serum iron as a cause,
but this hypothesis has been rejected by others.3,4
Many treatment methods have been adopted for the
management of RAS; some are based on the clinician’s
perception of the cause, and others are based purely on
symptoms and call for the use of nonspecific anti-
aOraland Maxillofacial Surgery.
bConsultant Dermatologist, Cumberland Infirmary.
Received for publication June 1, 1998; returned for revision July 9,
1998; accepted for publication Dec 12, 1998.
Copyright © 1999 by Mosby, Inc.
1079-2104/99/$8.00 + 0 7/13/97064
inflammatory agents. The immunopathologic nature of
the disease has drawn a considerable amount of atten-
tion. It has been stated that patients with RAS may
have inherent imbalances in immune regulatory mech-
anisms.3-6 In the management of RAS, both immuno-
suppressive and immunopotentiating drugs have been
tried, with varying degrees of success. Drugs used
include dapsone, colchicine, thalidomide, low-dose
interferon-α, levamisole, and Azelastine.1,5,7,8 Results
have varied, and in some cases significant side effects
have been noted.
Oxypentifylline, also known as Trental or pentoxi-
fylline, is an orally active methylxanthine derivative. It is
popularly used in the management of peripheral vascular
disease and is known to influence regional microcircula-
tion as well as the chemical and cellular mediators of
inflammation.9 Pizarro et al10 and Wahba-Yahav11 have
used this drug in open clinical trials for the management
of RAS and reported moderate success. The present clin-
ical trial is based on the positive outcome of previous

564
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Volume 87, Number 5
Table I. Results during the trial
No. of patients (%)
Great improvement Slight improvement
Male (11) 7 (63.6) 0 (0)
Female (13) 7 (53.8) 1 (7.69)
Totals (24) 14 (58.33) 1 (4.17)
reports and on the belief that RAS, as a disease, has an
underlying immunologic basis.
MATERIAL AND METHODS
Twenty-four patients, 11 male and 13 female,
ranging in age from 18 to 67 years, were selected from
sequential referrals for this study, which had the
approval of the Local Regional Ethics Committee.
Criteria for the inclusion of patients in the trial were as
follows:
1. History of RAS: (a) duration, > 1 year; (b) minor,
major, or herpetiform variety; (c) previous treatment
with antiseptic, astringent, steroid, and antibiotic
mouthwashes or sprays, topical gels, and paste
without relief; (d) ulcer-free intervals of < 4 weeks
2. Normal levels of B12, folate, and ferritin: (a)
vitamin B12, 205-876 pg/mL; (b) serum ferritin,
> 20 ng/mL; (c) serum folate, > 3.3 ng/mL
3. Postpuberty, with no upper age limit.
Excluded were all of the following:
1. Patients on regular systemic steroid therapy—eg, use
of prednisolone, dexamethasone, hydrocortisone, or
any anabolic steroids within the previous month.
2. Patients on immunosuppressants such as cyclosporin
3. Patients known to have RAS because of under-
lying specific disorders such as Behçet’s disease,
cyclic neutropenia, Sweet’s syndrome, nutritional
deficiencies, gluten-sensitive enteropathy, and
Crohn’s disease
4. Patients who were pregnant.
Each patient was provided with an information sheet
giving details about the medication and its possible
side effects. A complete clinical history was recorded,
and informed consent was obtained. Clinical examina-
tion included the recording of the site, size, and
number of ulcers. A self-explanatory record sheet was
given to the patient for recording the number and dura-
tion of ulcers in the mouth and indicating the severity
of pain on a visual analog scale. A systematic method
of examining the mouth was explained to the patient
so that errors could be avoided; whenever possible, a
relative or friend was advised to perform the examina-
tion under adequate conditions. Emphasis was placed
on recording the number and duration of new ulcers
that occurred each week. This was done for a pretrial
Chandrasekhar et al 565
No change Worse
4 (36.4) 0 (0)
4 (30.82) 1 (7.69)
8 (33.33) 1 (4.17)
period of 2 weeks, each week’s findings being
recorded separately.
At the next visit, oxypentifylline was prescribed at a
dosage of 400 mg 3 times daily for 1 month; the patient
was advised to continue recording the ulcers as before.
Arrangements were made for a review after 6 weeks, at
which time a clinical examination was completed so
that the site, size, and number of ulcers present could
be recorded. Each patient was questioned about the
occurrence, recurrence, and duration of any ulcers, as
well as about any side effects that had been experi-
enced during the use of the drug or thereafter.
RESULTS
Results were graded as shown in Tables I and II. The
following 4 categories of patients were identified on
the basis of the results:
1. Great improvement: patients who had no ulcers
during the 6-week period, even though there was
some reported recurrence on discontinuation of the
drug
2. Slight improvement: patients who had a decrease in
the number and/or duration of the ulcers during the
6-week period, even though the ulcers recurred on
discontinuation of the drug
3. No change: patients who experienced no benefit
whatsoever with regard to the occurrence and dura-
tion of the ulcers during the 6-week period
4. Worse: patients who had an increased number of
ulcers during the 6-week period.
Of the 24 patients, 11 were male and 13 were female.
Of the males, 63.6% showed great improvement,
whereas 36.4% showed no change. Of the females,
53.8% showed great improvement, whereas 30.82%
showed no change; however, 7.69% of the female
patients showed slight improvement. With respect to
side effects, 2 patients had minor gastrointestinal
symptoms, one complaining of minor cramps that
lasted for 2 days and the other complaining of nausea
that lasted for 2 days. Neither of these patients required
any specific treatment for the side effect experienced;
both side effects resolved spontaneously, and both
patients completed the course of oxypentifylline
without any further problems. No patient had to be
removed from the trial for any reason.
566 Chandrasekhar et al
Table II. Results 2 weeks after completion of trial
No ulcers Recurrence of ulcers
Male (11) 3 4
Female (13) 2 5
Totals (24) 5 9
DISCUSSION
Management of RAS has always posed a challenge
to the clinician. Many treatment modalities are used—
topical and systemic—but current medical therapy
does not provide us with the means by which to cure
the disease.3 Symptomatic treatment has been more
successful than attempts at preventing recurrence.
Topical applications used include steroids, antiseptics,
antibiotics, astringent mouthwashes, and antiallergic
pastes.2 Other treatment methods used include low-
intensity ultrasound,12 CO2 laser,1 and training in
relaxation/imagery.13
Because RAS is a noninfective inflammatory
mucosal disease, control of the inflammation or the
factor influencing the inflammatory process should
form the basis of definitive management. Landesberg
et al6 suggested that patients with RAS may have
primary immunologic abnormalities. Such abnormali-
ties include increases in serum immunoglobulins and
circulatory immune complexes, decrease in the
CD4/CD8 ratio, depression of natural killer cell
activity, and increases in antimucosal antibodies.7
Porter and Scully4 report that these immune abnormal-
ities probably mediate local tissue destruction and that
they appear to be the final common pathway in the
pathogenesis of RAS. Hayrinnen-Immonen et al,14
having subjected tissue lesions from patients with RAS
to immunohistopathologic study, emphasized the
multifaceted nature of RAS and the participation of
multiple effector systems in the local tissue pathogen-
esis of the condition.
There is no unifying explanation for this immuno-
logic basis of RAS, and the precise trigger mechanism
remains a mystery. When the changes that occur in
RAS are considered, it is not surprising that increased
attention is being given to drugs known to act primarily
on the cellular and chemical mediators of inflammation
and that numerous clinical trials have been conducted.
Sun et al7 have reported the immunomodulatory effects
of levamisole in patients with RAS; they found a
significant improvement in clinical symptoms and
normalization of the decreased CD4/CD8 ratio after
treatment. In another double-blind, placebo-controlled
study, Hutchinson et al8 gave recombinant human
interferon α-2a orally once daily in a low concentration
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
May 1999
No. of patients
Decreased ulcers No change Worse
0 4 0
1 4 1
1 8 1
to patients with RAS; 11 of the 19 patients in the trial
experienced complete remission of aphthae, with no
recurrence for a subsequent 6-month period. Ueta et al5
have used Azelastine in a trial involving 43 patients
with RAS; they believe that Azelastine, while
inhibiting the production of tumor necrosis factor, also
stabilizes the cell membrane and suppresses reactive
oxygen generation. The results of Ueta et al5 were
encouraging in that the frequency of recurrence of
ulcers was reduced in all but 4 of the patients.5 AM3,
an oral biologic response modifier, has been used by
Camacho et al15 in an open, controlled clinical trial in
patients with RAS; significant decreases in the number
of ulcers and their mean duration was noted.
In 1987, oxypentifylline, a potent hemorrheologic
drug commonly used in the treatment of intermittent
claudication, was exhaustively reviewed by Ward and
Clissold.9 In 1994, the established and potential clin-
ical applications of the medication were described by
Samlaska and Winfield16; these applications include
the management of vaso-occlusive disorders, infec-
tious diseases, immune deficiency states, hypercoagu-
lable diseases, skin disorders, and some oncologic
diseases. The drug is said to have the property of
suppressing leucocyte function while altering fibro-
blast physiology and stimulating fibrinolysis. Its
immunomodulating actions include increasing leuko-
cyte adhesion. It also causes neutrophil degranulation
and the release of peroxides, promotes natural killer
cell activity and the production of tumor necrosis
factor, and inhibits T and B cell activation.16 These
properties of oxypentifylline have encouraged clini-
cians to use it in trials for the management of RAS.10,11
Pizarro et al10 used oxypentifylline for 6 months in 5
patients known to have RAS and reported an absence
of ulcers in 4 of the patients. Only 1 patient had
gastrointestinal side effects, which were minor. The
patients were assessed immediately after treatment.10
Wahba-Yahav11 conducted a 3-month trial in 6
patients with severe RAS. The first month served as a
run-in period, during which the patients recorded their
ulcers; the second month was the treatment period,
during which oxypentifylline was administered at a
dose of 400 mg 3 times daily; final assessment was
done at the end of the third month. Three of the 6
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Volume 87, Number 5
patients were followed for 9 months to 2 years.
Encouraging results were obtained, all of the patients
being ulcer-free at the end of 3 months. One patient
followed for 2 years had no recurrence. Patients in
Wahba-Yahav’s11 study were selected on the basis of
criteria similar to those used for inclusion and exclu-
sion in the present investigation. The number of
patients included in our study is the largest for any trial
involving the use of oxypentifylline.
A positive response rate of 62.5% was recorded in
this study, though some of our patients did report recur-
rence of ulcers on discontinuing the drug. The response
rate appears to be less than the rates seen in the Israeli
and Spanish trials,10,11 but this could be due to the
comparatively larger number of patients included and
to the well-known multifactorial nature of the disease.
The primary objective of our study was to examine the
efficacy of oxypentifylline in reducing the actual recur-
rence of RAS and to note any effect on its duration.
The medication’s influence on pain was assessed only
as a secondary issue in our trial because we were
looking at oxypentifylline as a drug that would target
the cause of RAS. Of the 14 patients (7 male and 7
female) who reported no ulcers during treatment, 9 (4
male and 5 female) had recurrences when use of the
drug was stopped. The one female patient who was
categorized as having slight improvement reported a
50% decrease in the number of ulcers associated with
lesser pain while she was taking the drug. Minimal side
effects occurred, and none of our patients had to be
taken off the trial for any reason. Although it must be
borne in mind that this was a preliminary trial, the
results are favorable in that there were indications of a
reduction or improvement in RAS ulcers when
oxypentifylline was being used.
CONCLUSIONS
Many questions remain to be answered with regard
to the use of oxypentifylline in the management of
RAS. Double-blind, controlled studies are indicated for
a definitive assessment of the efficacy of the drug in the
management of RAS. The increase in the incidence of
RAS that has resulted from the increase in immune
deficiency diseases, both primary and secondary,
presents a good opportunity for using this drug, which
targets the abnormal immune status as a mode of action
in the control of RAS. These results suggest that
oxypentifylline could be considered in cases of refrac-
tory RAS because it may obviate the need for immune
suppressive therapy with potentially toxic drugs.11
Chandrasekhar et al 567
We acknowledge the approval for this trial that was given
by the Local Regional Ethics Committee. We thank all of the
patients who consented to participate, and we thank Mr. G.
D. Putnam, Consultant Maxillofacial Surgeon, and all staff
members of the Oral and Maxillofacial Unit, City General
Hospital, who helped us conduct the trial successfully.
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Reprint requests:
Mr. A. W. Paterson
Consultant Oral and Maxillofacial Surgeon
Oral and Maxillofacial Surgery
City General Hospital
Carlisle CA1 2HG
United Kingdom