Evaluation of Role of Oxitard Capsules in the Treatment of OSMF

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Evaluation of Role of Oxitard Capsules
in the Treatment of Oral Submucous
Fibrosis
SINGH B.P., NEELAM MITTAL, VISHAL SHARMA, PALANI
ABSTRACT

Oral submucous fibrosis is a chronic debilitating disease of the oral cavity. It is characterized by
inflammation and progressive fibrosis of the oral submucosal tissues.
Present study evaluates the role of Oxitard capsules in the treatment of oral sub mucous fibrosis.
This study comprised of 48 cases who attended the Out Patient Department of Sir Sunderlal
Hospital of Banaras Hindu University, Varanasi for chronic oral mucosal fibrosis lesions. Oxitard
was given to all the patients a dose of 2 capsules, twice daily for a period of 3 months. All the
patients were evaluated at monthly intervals for a period of 3 months, for the parameters like
difficulty in opening mouth, hyperkeratosis, pain and lesion size. All the parameters were
evaluated by a random score as 0 – nil, 1 – mild, 2 – moderate, 3 – severe.
The parameters of difficulty in opening the mouth, pain over the lesion, and hyperkeratosis
reduced significantly. There was mild decrease in the size of the lesion. This study indicates that
Oxitard capsules used in cases of oral submucous fibrosis showed statistically significant improvement
in the symptoms like difficulty in opening the mouth, pain in the mouth and hyperkeratosis. Oxitard
capsules was safe in the dose administered and well tolerated by the patients.
Key Words: oral submucosal fibrosis, Oxitard, hyperkeratosis
INTRODUCTION

Oral submucous fibrosis is a
chronic debilitating disease of the
oral cavity. It is characterized by
inflammation and progressive fibrosis
of the submucosal tissues. In this
condition, the patient usually
complains of burning sensations in
the mouth, particularly while taking
hot and spicy foods. This is often
followed by the formation of multiple
ulcerations or inflammatory reactions
in the oral mucosa. There can be
Dr. B.P. Singh, M.D.S.,
Head of the Department
Dr. Neelam Mittal, M.D.S.,
Reader,
Dr. Vishal Sharma, B.D.S.,
Resident, Post Graduate
Department of Dentistry,
Institute of Medical Sciences,
Banaras Hindu University, Varanasi, India
Dr. Palani*, M.D.,
Medical Advisor
R&D Center
The Himalaya Drug Company
Makali, Bangalore, India
*Corresponding Author
Specially Contributed to "The Antiseptic"
Vol. 106 No. 10 & P : 503 - 507

October 2009

excessive salivations or decreased
salivations and defective gustatory
sensations. It is observed that males
are more frequently affected with this
disease than the females.
In the initial phase of the disease,
palpation of the mucosa causes a
wet leathery feeling. In the advanced
stage the oral mucosa loses its
resiliency and becomes blanched and
stiff. Usually it is believed that the
disease initiates from the posterior
part of the oral cavity and it gradually
spreads to the anterior locations.
Other features of the disease include
pain in the ear or deafness, nasal
phonation of voice, restriction of the
movement of the soft palate, bud-like
shrunken uvula, thinning and
stiffening of the lips, pigmentation of
the oral mucosa, dryness of the
mouth
and
impaired
mouth
movements.
The common causes of oral sub
mucous fibrosis are products, which
cause irritation such as pan masala
and gutkha, excessive consumption
THE ANTISEPTIC

of red chillies, immunological
diseases, extreme climatic conditions,
prolonged deficiency to iron and
vitamins in the diet.
The pathogenesis of the disease
is not well established, but the cause
of oral submucous fibrosis is believed
to be multifactorial. A number of
factors trigger the disease process
by
causing
a
juxtaepithelial
inflammatory reaction in the oral
mucosa. Factors include Areca
catechu chewing, ingestion of
chillies, genetic and immunologic
processes, nutritional deficiencies,
and other factors.
Management of oral submucosal
fibrosis include advising the patient
to avoid chewing betel nut and
tobacco,
spicy
foods
and
consumption of chillies should be
minimal, to maintain proper oral
hygiene. Specific treatment include
steroids, placental extracts, IFN
gamma, lycopene, pentoxyfylline,
surgical excision, laser removal of
the lesion etc.

503

This study was planned to
evaluate the role of Oxitard capsule,
a herbal antioxidant formulation, in
the management of oral submucosal
fibrosis.
This formulation contains the
extracts of Mangifera indica,
Withania somnifera, Daucus carota,
Glycyrrhiza glabra, Vitis vinifera;
powders of Emblica officinalis and
Yashada bhasma; and oils of Triticum
sativum.
Aim: To evaluate the role of
Oxitard capsules in the treatment of
oral sub mucous fibrosis.
MATERIALS AND AMETHODS:
Study design

An open clinical evaluation was
conducted on 48 cases who attended
the Outpatient Department of Sir
Sunderlal Hospital of Banaras Hindu
University, Varanasi, India, for chronic
oral mucosal fibrosis lesions.
Inclusion criteria

Inclusion criteria included adult
patients of either sex with oral
submucous
fibrosis
with
hyperkoratosis, difficulty in opening
the mouth and pain.
Exclusion criteria

Patients with evidence of
pregnancy, lactation, any patients
with severe psychiatric / cardiac,
gastrointestinal
disorders
or
metabolic disorders were excluded
from the study.
Study procedure

The present study comprised of
48 cases who attended the Out
Patient Department of Sir Sunderlal
Hospital of Banaras Hindu University,
Varanasi for chronic oral mucosal
fibrosis lesions. Detailed history of
tobacco or betel nut chewing and the
course of the fibrosis were elicited. A
thorough examination was conducted
and signs and symptoms were
recorded. Patients entered into the
study after signing the voluntary
consent form. Oxitard was given to
all the patients at a dose of 2
capsules twice daily for a period of 3
months.

504

Follow up and assessment

All the patients were evaluated at
monthly intervals at the end of 1st
month 2nd month and 3rd month for a
period of 3 months, for the parameters
like difficulty in opening mouth,
hyperkeratosis, pain and lesion size.
All the parameters were evaluated by
a random score as 0 – nil, 1 – mild,
2 – moderate, 3 – severe,
Primary and secondary outcome
measure

The primary outcome measures
were clinical recovery from oral
submucosal
fibrosis
for
the
parameters like difficulty in opening
mouth, hyperkeratosis, pain and
lesion size. Secondary end points
were clinical safety and toxicity profile
of Oxitard.
Adverse events

All adverse events reported or
observed by patients were recorded
with information about severity, date
of onset, duration and action taken
regarding the study drug. Relation of
adverse events to study medication
was predefined as “Unrelated” (a
reaction that does not follow a
reasonable temporal sequence from
the administration of the drug),
“Possible” (follows a known
response pattern to the suspected
drug, but could have been produced
by the patient’s clinical state or other
modes of therapy administered to the
patient),”Probable” (follows a known
response pattern to the suspected
drug that could not be reasonably
explained
by
the
known
characteristics of the patient’s clinical
state) and “Certain” (the adverse

events
must
have
definitive
relationship to the study drug, which
cannot be explained by concurrent
disease or any other agent).
Patients
were
allowed
to
voluntarily withdraw from the study
if they had experienced serious
discomfort during the study or
sustained serious clinical events
requiring specific treatment. For
patients withdrawing from the study,
efforts were made to ascertain the
reason for dropout. Non-compliance
(defined as failure to take less than
80% of the medication) was not
regarded as treatment failure, and
reasons for non-compliance were
noted.
Statistical analysis

Results were analysed statistically
by students ‘t’ test. The minimum
level of significance was fixed at a
99% confidence limit and p value of
<0.05 was considered significant. All
values are expressed as mean ± SEM.
RESULTS:

The present study comprised of
48 cases who attended the outpatient
department of Sir Sunderlal Hospital
of Banaras Hindu University, Varanasi
for chronic oral mucosal fibrosis
lesions. Detailed history of tobacco
or betel nut chewing and the course
of the fibrosis were elicited (Table 1).
All the patients received Oxitard 2
capules, twice daily for a period of 3
months and underwent clinical
examination and evaluation of the
parameters on entry and at monthly
intervals for 3 months. Adverse
effects if any were noted down. The
protocol of the study was as per the
ICH-GCP guidelines and the patients

Table 1: Demographic Data

Total number of patients

48

Mean age in years (Mean ± SD)

40.50 ± 4.50

Mean weight in kgs (Mean ± SD)

58.50 ± 4.30

Sex ratio (M:F)

29:19

No. of tobacco chewing patients

14

No. of betel nut chewing patients

31

THE ANTISEPTIC

October 2009

were free to withdraw from the study
if they so desired. No other
medication was allowed for these
patients.
The parameters of difficulty in
opening the mouth and pain over the
lesion reduced significantly showing
statistical significance (p<0.05)
(Tables 2 and 3). Hyperkeratosis
reduced and statistical significant
reduction was seen at 3 rd month
(Table 4). There was mild decrease in
the size of the lesion and it was not
significant (Table 5).
Two patients experienced mild
abdominal discomfort effects. All the
patients tolerated the drug well. None
of the patients had withdrawn due to
adverse effects.

Table 2: Effect of Oxitard capsules in difficulty
in opening mouth

Number of patients (n=48)

Degree of difficulty
At entry

1st month

2nd month

Nil-0

09

21

34*

44*

Mild-1

12

10

05*

01*

Moderate-2

27

17

09*

03*

Severe- 3

-

-

-

-

3rd month

*p<0.05 compared to “At entry” values

DISCUSSION:

Oral submucous fibrosis is a
chronic debilitating disease of the
oral
cavity
characterized
by
inflammation and progressive fibrosis
of the submucosal tissues (lamina
propria and deeper connective
tissues). Oral submucous fibrosis
results in marked rigidity and an
eventual inability to open the
mouth.1,2 The buccal mucosa is the
most commonly involved site, but any
part of the oral cavity can be
involved, even the pharynx.3
The condition is well recognized
for its malignant potential and is
particularly associated with areca nut
chewing, the main component of betel
quid. Betel quid chewing is a habit
practiced predominately in Southeast
Asia and India that dates back for
thousands of years. It is similar to
tobacco chewing in westernized
societies. The mixture of this quid, or
chew, is a combination of the areca
nut (fruit of the Areca catechu palm
tree, erroneously termed betel nut)
and betel leaf (from the Piper betel,
a pepper shrub), tobacco, slaked lime
(calcium hydroxide), and catechu
(extract of the Acacia catechu tree).1
Lime acts to keep the active ingredient
in its freebase or alkaline form,
enabling it to enter the bloodstream
via sublingual absorption. Arecoline,
an alkaloid found in the areca nut,
promotes salivation, stains saliva red,
and is a stimulant.
The pathogenesis of the disease
is not well established, but the cause
October 2009

Table 3 : Effect of Oxitard capsules on hyperkeratosis

Degree of hyperkeratosis

Number of patients(n=40)
At entry

1st month

Nil-0

6

18

25

34*

Mild-1

18

12

9

4*

Moderate-2

16

10

6

2*

Severe- 3

-

-

-

-

2nd month 3rd month

*p<0.05 compared to “At entry” values

Table 4 : Effect of Oxitard capsules in pain in patients of oral
submucosal fibrosis

Degree of pain

Number of patients (n=42)
At entry

1st month

2nd month 3rd month

Nil-0

03

18

30*

40*

Mild-1

14

8

5*

0*

Moderate-2

12

6

4*

2*

Severe- 3

13

10

3*

0*

*p<0.05 compared to “At entry” values
THE ANTISEPTIC

505

Palani
of oral submucous fibrosis is believed
to be multifactorial. A number of
factors trigger the disease process
by
causing
a
juxtaepithelial
inflammatory reaction in the oral
mucosa. Factors include areca nut
chewing, ingestion of chillies, genetic
and
immunologic
processes,
nutritional deficiencies, and other
factors.
Arecoline, an active alkaloid found
in betel nuts, stimulates fibroblasts
to increase production of collagen
by 150%.4 In one study, arecoline
was found to elevate the mRNA and
protein expression of cystatin C, a
nonglycosylated
basic
protein
consistently up-regulated in a variety
of fibrotic diseases, in a dosedependent manner in persons with
oral submucous fibrosis.5
In 3 separate but similar studies,
keratinocyte growth factor-1, insulin
like growth factor-1, and interleukin 6
expressions, which have all been
implicated in tissue fibrogenesis, were
also significantly up-regulated in
persons with oral submucous fibrosis
due to areca quid chewing, and
arecoline may be responsible for their
enhanced expression. 6 8 Further
studies have shown that arecoline is
an inhibitor of metalloproteinases
(particularly metalloproteinase-2) and
a stimulator of tissue inhibitor of
metalloproteinases, thus decreasing
the overall breakdown of tissue
collagen.9
Flavanoid, catechin, and tannin in
betel nuts cause collagen fibers to
cross-link, making them less
susceptible
to
collagenase
degradation. 10 This
results
in
increased fibrosis by causing both
increased collagen production and
decreased collagen breakdown.2 Oral
submucous fibrosis remains active
even after cessation of the chewing
habit, suggesting that components
of the areca nut initiate oral
submucous fibrosis and then affect
gene expression in the fibroblasts,
which then produce greater amounts
of normal collagen.11 Chewing areca
quid may also activate NF-kappaB
expression, thereby stimulating
collagen fibroblasts and leading to
further fibrosis in persons with oral
submucous fibrosis.12

506

Table 5: Effect of Oxitard capsules on lesion size in patients of
oral submucosal fibrosis

Degree of change
in the lesion

Number of patients (n=48)
0 month 1st month 2nd month 3rd month

Nil-0

-

05

13

29

Mild-1(0-1 cm)

25

23

20

16

Moderate- 2(>1 cm and 2 cm)

18

16

12

00

Severe -3(>2 cm)

05

04

03

03

No Significant change
Areca nuts have also been shown
to have a high copper content, and
chewing areca nuts for 5-30 minutes
significantly increases soluble copper
levels in oral fluids. This increased
level of soluble copper supports the
hypothesis that copper acts as an
initiating factor in persons with oral
submucous fibrosis by stimulating
fibrogenesis through up-regulation of
copper-dependent lysyl oxidase
activity. 13 Further, a significant
gradual increase in serum copper
levels from precancer to cancer
patients has been documented, 14
which may have a role in oral fibrosis
to cancer pathogenesis.
Iron deficiency anemia, vitamin B
complex deficiency, and malnutrition
are promoting factors that derange
the repair of the inflamed oral mucosa,
leading to defective healing and
resultant scarring.2
Management of oral submucosal
fibrosis include advising the patient
to avoid chewing betel nut and
tobacco,
spicy
foods
and
consumption of chillies should be
minimal, to maintain proper oral
hygiene. Specific treatment include
steroids, placental extracts, IFN
gamma, lycopene, pentoxyfylline,
surgical exicision, laser removal of
the lesion etc. 2
Glycyrrhiza
glabra
has
immunomodulatory effect. It is known
to have anti-inflammatory,15 has a role
in normalising hoarsness of voice.16
THE ANTISEPTIC

The fruits of Vitis vinifera have
anti-inflammatory and astringent
activities. It is used to alleviate the
thirst, relieve flatulence and as a mild
laxative. As it alleviates pitta, it is
salutary to curb burning sensation,
agitation and thirst in fevers. The
raisins are recommended as tonic in
tuberculosis
to
regain
the
bodyweight.
The
raisins
are
commonly used as a tonic in
convalescence.17
In Ayurveda, Withania somnifera
is considered a rasayana herb, having
anti-stress,
anti-anxiety,
antiinflammatory, anti-arthritic and anticonvulsive medicinal properties.
Hence, it provides overall health and
wellness. It also performs as
rejuvenator, revitalizer, restorative and
tissue builder. This herb is also
considered an adaptogen which is an
herb that works to normalize
physiological function, working on
the HPA axis and the neuroendocrine
system.18
Yashada
bhasma
contains
processed zinc that plays a significant
role in protein synthesis, in cell
division and in wound healing. It has
shown beneficial effects in acne and
is known to have antiseptic and
astringent properties.19
Syzygium aromaticum has shown
to have antigastric, prevents
intractable hiccups, thirst, gastric
distension.20,21
Different parts of Mangifera
indica have various properties like
October 2009

Evaluation of Role of Oxitard Capsules in the Treatment of Oral Submucous Fibrosis
Singh B.P., Neelam Mittal, Vishal Sharma, Palani ....................................................................... 503
anti-asthmatic, antiseptic, antiviral,
cardiotonic, emetic, expectorant,
hypotensive, laxative. Extracts of
unripe fruits and of bark, stems and
leaves have shown antibiotic activity.
In some of the islands of the
caribbean, the leaf decoction is taken
as a remedy for diarrhea, fever, chest
complaints, diabetes, hypertension
and other ills.22
Triticum sativum or wheat is a
good source of mineral nutrients.
Wheat is a rich source of tocopherols
with high vitamin-E potency that
nourishes and prevents loss of
moisture from the skin. The oil is
used to tone and soften the lips and
has a potent antioxidant activity. This
protects the skin from scavenging
free-radicals, prevents premature
aging and reduces ultra violet rays
induced damage. It helps in proper
drainage of secretions from the
sebaceous and other glands of the
skin.23
Daucus carota is a rich source of
vitamin A, which acts as an antiseptic
and prevents putrescent changes
within the body.24
Emblica officinalis is a rich source
of vitamin C, which has anabolic,
antibacterial and resistance building
properties. Pre-treatment with Emblica
officinalis selectively increases the
increased the proliferation of splenic
leukocyte to B cell mitogen, LPS and
cytotoxic activity against K 562 cells
indicating
immunomodulating
property.25 Preliminary antibacterial
screening of aqueous, hexane and
alcoholic extracts of Emblica
officinalis against several pathogenic
and opportunistic microorganisms
shows encouraging antibacterial
activity against test bacteria. 26
SUMMARY AND CONCLUSION:

This study shows that Oxitard
capsules used in cases of oral
submucous
fibrosis
showed
significant improvement in the
symptoms like difficulty in opening
the mouth, pain in the mouth and
hyperkeratosis. There was a mild
decrease in the size of the lesion
through not significant. Oxitard was
safe in the dose of two capsules
twice daily for 3 months and well
tolerated by the patients.
October 2009

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