ROLE OF DIOSMIN-HESPERIDIN COMBINATION (DAFLON ...

ROLE OF DIOSMIN-HESPERIDIN COMBINATION
Egypt. J. Otolaryngol., Vol. 25, No. 1 January, 2009
ROLE OF DIOSMIN-HESPERIDIN COMBINATION (DAFLON® SERVIER) IN
TREATMENT OF VASOMOTOR RHINITIS OF PREGNANCY;
A RANDOMIZED CONTROL STUDY
Waleed Ezzat, 1 Samia Fawaz, 1 Ali El Makhzangy, 1 Ahmed Rateb 2
1 OtoRhinolaryngology, 2 Gynecology and Obstetrics departments, Faculty of Medicine, Ain-Shams University, Egypt
Objective: To determine the validity and efficacy of use of micronised purified Diosmin-Hesperidin combination (Daflon®
Servier), a known safe drug in pregnancy, in the improvement of symptoms of females suffering from vasomotor rhinitis of
pregnancy (VMRP).
Design: A prospective non company sponsored randomized control study.
Setting: Antenatal and ENT outpatient clinics of Ain Shams University Hospital, Cairo, Egypt.
Methods Forty-eight pregnant women suffering from symptoms and signs of VMRP attending the antenatal clinic were asked
to fill up a questionnaire and referred to the ENT clinic for objective assessment and counseling. They were subsequently
followed up in both clinics till delivery*
Main outcome measures: Subjective grading of VMRP was done using the 7 most related items from the modified sinonasal
outcome test (SNOT) scale scoring system, and objective grading of it using the rhinoscan acoustic rhinometer (by
Rhinometrics®).
Results: The Diosmin-hesperidin combination only group showed similar response to Fluticasone propionate, while
combination of Diosmin-hesperidin and Fluticasone propionate gave better response than the Fluticasone propionate only
group.
Conclusions: Diosmin-hesperidin combination is an effective treatment line in the control of symptoms of VMRP, either
alone or in combination with Fluticasone propionate.
Keywords: Vasomotor rhinitis, pregnancy, Diosmin-Hesperdin combination.
INTRODUCTION
Vasomotor rhinitis is characterized by prominent
symptoms of nasal obstruction, rhinorrhea, and congestion.
These symptoms are excessive at times and are exacerbated
by certain odors (e.g., perfumes, cigarette smoke); alcohol;
spicy foods; emotions; pregnancy and environmental
factors such as temperature, and barometric pressure
changes. (1)
Pregnancy is a delightful event that most women will
experience at some time of their fertile lives, but like any
other event in which there are drastic physiologic changes
occurring in the body to fulfill its requirements, it does not
pass without some annoyance. One of these annoyances
can be vasomotor rhinitis of pregnancy (VMRP).
The pathophysiology of VMRP has been widely studied by
several researchers, and the various factors that were
alleged or proven to be responsible for this condition
included; 1) raised estrogen levels, acting directly (2)
producing nasal congestion, and indirectly causing
histamine release, cyclicAMP production, (3) and Vasoactive
Intestinal Peptide (VIP) release by nasal nerve terminals, (4)
all causing congestion. 2) Raised serum progesterone levels
leading to nasal vascular wall smooth muscle relaxation,
and subsequently vascular pooling. (5) 3) Increased blood
volume, which also increases vascular pooling (5) and 4) the
continuous secretion of placental growth hormone (PGH)
after the first trimester, also leading to effects similar to
EJO, Vol. 25, No 1 Jan., 2009 61

progesterone, (6) namely increasing extracellular volume
and peripheral vascular dilatation). (7)
Other mechanisms contributing to VMRP are explained as
follows; a) nasal congestion by vascular smooth muscle
relaxation, and increased extracellular volume, all affect the
vascular tone of the capacitance vessels, with the resultant
additional nasal obstruction. (8) Plasma extravasation also
creates fluid which contributes to interstitial swelling and
increased nasal secretions, (9,10). b) vascular distension and
osmolar changes lead to neural depolarization of the
branches of the trigeminal nerve with reflexes ensuing from
the parasympathetic nerves, leading to increased secretions
and sneezing in addition to the depolarization of type C
nociceptive fibers in afferent neurons of the V nerve with
resultant local release of neuropeptides as substance P and
neurokinin A, (9,11,12,13) which in turn produce local
inflammatory effects (neurogenic inflammation) directly
affecting blood flow and glandular secretion (12) by acting
on endothelial junctions opening them and allowing
plasma to escape (10,12,14) c) An additional proposed factor
may be the non-immune degranulation of mast cells with
the release of chemical mediators including histamine and
prostaglandin E215 with the resultant increase in the
sensitivity of nerve endings and increased vascular
permeability and cellular recruitment. (7) To
summarize, there are alterations in blood flow, increased
nasal secretions, and imbalance in neuropeptide function.
Recent work suggested that fibroblasts in nasal mucosa of
pregnant females are influenced by progesterone and these
subsequently affect the extracelluler matrix. They also
proposed that oestrogen and progesterone change
neurotransmitter concentrations such as substance P to
cause the symptoms of nasal stuffiness experienced by
pregnant women. (16)
Diagnosis of VMRP in general is made by default after
excluding other causes of rhinitis. (8) Nasal cytology may be
a simple but necessary option to rule out eosinophilic
rhinitis, or non allergic rhinitis with eosinophilia syndrome
(NARES). VMRP is usually diagnosed in the second
trimester of pregnancy when all the previously mentioned
factors start to appear and become active with peaking of
hormonal levels. Usually congestion is more problematic
than nasal discharge. (8)
Treatment of vasomotor rhinitis (VMR) in general is often
unsatisfactory, and medications that have been tried
include those used for allergic rhinitis, but they are usually
not as effective as they are in allergic rhinitis. In VMRP the
issue of possible fetal harm is another hamper, so most if
not all physicians ask the patient to tolerate the condition,
or just revert to the regular vasoconstrictive nasal agents
with possible suffering of their long term side effects. (17)
Ezzat, W. et al
Local nasal steroids have been used for several indications
starting from the second trimester of pregnancy and with
no apparent teratogenic effect, but its efficacy in VMRP has
been questioned by many. On the other hand, pregnant
females often suffer from varicosities, either pelvic, or in
the lower limbs or both, and for a long time have been
treated by the natural flaviniods as the commercial
diosmin-hesperidin combination (Daflon®, Servier), which
withstood the test of safety, but this drug has never been
tested in the local control of the congestion that occurs in
the nose in cases of VMRP.
The general modes of action of micronized flavinoids are
through increasing vascular tone, protection of vascular
endothelium (both normal and diseased) and decreasing
edema. (18,19) It has also been demonstrated to have antiinflammatory
effects through reduction of histamine,
bradykinin and leukotrienes release, thus preventing
escape of macromolecules from the microcirculation,
decreasing the activation of complement system, and
preventing adherence of leukocytes to endothelial cells
diminishing capillary permeability. (18-23)
OBJECTIVE
To determine the validity and efficacy of use of micronized
purified Diosmin-Hesperidin combination (Daflon®
Servier), a known safe drug in pregnancy, in the
improvement of symptoms of women suffering from
vasomotor rhinitis of pregnancy (VMRP).
PATIENTS AND METHODS
Design: A prospective non company sponsored
randomized case control study.
Material: In this study we selected 48 pregnant women
referred to our E.N.T clinic, as they specifically complained
from symptoms related to VMRP. The patient was selected
by the obstetrician when she complained of annoying nasal
obstruction on routine inquiry during each follow up and
subsequently was referred to the otolaryngologist.
Inclusion criteria:
The studied women were all between the age 20 and 35
years, regardless of parity.
All were healthy, and were not receiving any additional
treatments for any disease, aside from calcium and iron
supplements.
Exclusion criteria:
1) Association with any acute or chronic gestational or
non gestational disease.
2) Presence of any manifestation of complicated
pregnancy.
62 Egypt. J. Otolaryngol.

3) Any prior nasal allergy or chronic nasal disease.
4) Also any nasal surgery, irrespective of its nature
Methodology: After appropriate counseling, the patients
were asked to fill out an initial questionnaire (modified
Sino-nasal-outcome-test, SNOT) 24. A modification of the
SNOT test was used addressing 7 common nasal related
symptoms. The test evaluates the degree of affection in a
numerical value ranging from 0 to 5, where 0 meant that
the symptom did not exist, and 5 means that she is
suffering from that symptom all or most of the time, with
values 2, 3 and 4 in between, the grade of symptoms
included in the SNOT test and their results were collected
to be analyzed
A more detailed history was taken by the otolaryngologist
in order to determine the onset of the complaint and to rule
out possible exclusion criteria that were missed, After
selecting the subjects they were informed and consented in
writing that they are receiving a new untested treatment
modality and a few paragraphs about the drugs used, with
their references and websites for further reading, were
given to the patients on demand for further information
about the medications. An objective rhinometric test using
the rhinoscan acoustic rhinometer (by Rhinometrics®) was
performed for patients who consented. The rhinometric test
was done twice with an interval of 30 minutes in-between,
no vasoconstrictive or topical agent was given and the
subject just had to blow her nose twice before each testing.
An average of the two readings was taken, and then the
readings of both sides were also averaged, and calculated
in cubic centimeters. This value was considered as the
baseline patency value for that specific subject before
commencing treatment.
The patients were divided into three groups. The line of
treatment was chosen according to a random calendar
system, i.e. patients attending the ORL clinic on day 1-15
from the Gregorian month would be group A, those
attending on day 16-22 would be group B, and those
attending on day 23-31 would be group C. Doubling the
duration of patient choice for the main study group A was
intended to widen the database of this specific group.
ROLE OF DIOSMIN-HESPERIDIN COMBINATION
Group A included 24 patients and they were treated using
Diosmin-hesperidin combination only. Group B included
14 females, and were treated by Diosmin-hesperidin
combination and a local nasal steroid, namely fluticasone
propionate (Flixonase®,GSK), and group C included 12
females treated by Fluticasone propionate only.
The dose of administered Diosmin-hesperidin combination
was the therapeutically producer recommended 500
milligram twice daily, the dose of Fluticasone propionate
was also the recommended 2 puffs (100
microgram)/nostril/day.
A follow up visit to the otolaryngologist was scheduled
after 4 weeks and both the SNOT and rhinometric tests
were repeated in exactly the same manner as previously
mentioned. The subject was asked to account on her
symptoms in the last two weeks of treatment and not the
period at the start of therapy.
The study took 7 months to be completed.
Statistical analysis: The results were tabulated and data
were analyzed using the statistical package for the social
science (SPSS, version 15, Inc., Chicago, IL) When applying
statistical analysis for the SNOT test, the total score of all
the symptoms was calculated by simple addition of the
individual scores, the scale was from zero (absolutely no
symptoms) to 35 (maximum complaint from all the
symptoms all the time). The distributional characteristics of
the continuous variables were examined by Kolmogorov-
Smirnov test. Normally distributed continuous variables
were examined using one-way analysis of variance and
Tukey test. Skewed variables were examined using
Kruskall Wallis & Mann-Whitney U tests. X2 analysis used
for frequency data. Fisher exact test was used when cell
size was small. Significance level was established at P

Statistical analysis of the results showed that all three
groups were statistically equivalent when assessed before
treatment (non-significant statistical difference), but in the
post-treatment assessment there was a highly significant
difference in both the subjective and objective findings,
always in favor of post-treatment assessment (P

We compared three groups of women by using three
modalities of treatment. Comparing the results of the three
groups with each other, which revealed that Diosminhesperidin
combination when used alone showed an
improvement both subjectively and objectively from before
to after treatment. While the combination group (group B)
showed a highly significant improvement, which is better
than the other two groups.
These findings implicate that Diosmin-hesperidin
combination, as a micronized flavinoid drug, can and
should be used in VMRP as an effective line of treatment,
whether alone instead of local nasal steroid to give the
same improvement with more range of safety to the
pregnant women or in combination with other lines in
severe cases to give better response.
Also in our study no side effects occurred to the pregnant
women or their offspring after delivery.
CONCLUSION
Our findings demonstrate that the use of Diosminhesperidin
combination, either as a monotherapy, or in
combination with local nasal steroids, in the regular doses
of 1000 mg/day, has proved to be a safe as well as effective
mode of treatment of VMRP.
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