Vol.3, No.1, 49-55 (2011) Health
Copyright © 2011 SciRes. Openly acc es sible at http://www.scirp.org/journal/HEALTH/
Effi cacy and to lerabi lity of propolis speci al extract
GH 2002 as a lip balm against h erpes labialis: a
randomized, double-blind three-arm dose finding study
Simona Holcová1*, Marie Hladiková2
1Outpatient Department of Dermatovenerology, Brno, Czech Republic; *Corresp ondi ng A ut hor: simona.holcova@e mail. cz
2Departmen t for Medical Informatics, 2nd Medical Faculty of the Charles Universit y, Prague, Czech Republic;
statist i ka.hladi ko va@seznam.cz
Received 11 October 2010; revised 17 November 2010; accepted 19 November 2010.
A dose-finding study was performed with re-
spect to the clinical applicability and tolerability
of three different concentrations of propolis
special extract GH 2002 in a lip balm (0.1%, 0.5%
and 1%). The trial was designed as a dou-
ble-blind, randomized dermatological study in
150 outpatients with Herpes labialis. The pri-
mary parameter was the duration in days until
painless incrustation in 50% or 90% of the pa-
tients (observable in 121 patients). Secondary
parameters were local pain (assessed on a vis-
ual analogue scale), itching, burning and ten-
sion/ swelling on a verbal rating scale, and tol-
erability. Visits were performed on days 2/3, 5/6
and 8/9. Best efficacy results with shortest
healing ti me (3.4 and 5.4 days i n the 50th and 90th
percentile, respectively; p = 0.008 vs. 1% and
0.09 vs. 0.1%) and good tolerability were ob-
served with the 0.5% concentration. All three
concentrations achieved highly significant
therapeutic results in comparison with baseline
values (p < 0.000 5) f or all seco nd a r y parameters
as early as day 2/3. Analgesia was the most
prominent effect for the patients. Conclusion:
The 0.5 % concentration of propolis special ex-
tract GH 2002 in a lip balm was found to have
the best risk-benefit ratio for the treatment of
Herpes labialis.
Keywords: Herpes labialis; propolis; lip balm;
dose-finding study
Herpes labialis, generally caused by infection with
Herpes simplex type 1 (HSV-1) virus, is characterized by
various consecutive stages. An episode begins with a
prodromal phase with local pain, tingling and burning,
followed by erythematous and papular phases with in-
flamed and reddened papules, and vesicular phase with
fluid-filled blisters. Via the ulceration phase or the
bursting of the vesicle with wound formation it finally
leads to the incrustation and healing phase [1].
The typical duration of the natural course of an un-
treated episode of Herpes labialis is seven to fifteen days
[1,2]. This duration can be significan tly reduced to 4.5-6
days by the topical application of antiviral nucleoside
analogues such as aciclovir or penciclovir [2-9]. Both
are antimetabolites which inhibit viral replication and
thus multiplica tion in the cel l. Ho wever, the wid e-spread
use of nucleoside analogues is associated with the de-
velopment of resistance [10].
Ultimately, the antiviral effect is only one aspect of
treatment. It combats the cause, but the symptoms sec-
ondary to the virus infection such as injured and in-
flamed skin and secondary bacterial infections must not
be forgotten. The clinical benefits of nucleoside analo-
gues aciclovir and penciclovir have been critically as-
sessed for the lack of such additional effects [4,6,9].
Treatment options with additional antimicrobial and an-
ti-inflammatory effects are clearly welcome.
Propolis, the “bee-glue” from hives, is a natur al pro d-
uct with an interesting combination of pharmacological
prop erties, which led to var ious applicatio ns in tradition-
al medicine and naturopathy with documented use over
at least two Millennia [11-15]. The broad spectrum of
propolis effects is expla ined by the fact t hat propolis has
the function of protecting the bee-hive against many
harmful organisms, such as bacteria, fungi and insects.
Modern research with propolis resulted in the descrip-
tion of antimicrobial [15-17], fungicidal [13,18], and
anti-inflammatory [19] effects.
Antiviral effects have likewise been described in vitro
S. Holcová et al. / Health 3 (2011) 49-55
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[20-25], and the clinical applicability has been demon-
strated with regard to Herpes genitalis (HSV-2) [26].
Among others, flavonoids, caffeic acid ester and cin-
namic acid have been described as constituents contri-
buting to the antiviral effect of propolis [22,24,25,27].
Reproducibility of antiviral efficacy requires a stan-
dardized product quality due to the regional variability
of the chemical co mposition of prop olis. For our clinical
research we therefore selected the special extract GH
2002 for which the propolis is exclusively collected in
one defined area, and where the composition of the ex-
tract is standardized to reproducible contents of flavo-
noids, polyphenols and phenyl carboxylic acids. In addi-
tion, manufacturing involves purification by removal of
potentially allergenic waxes and resins, adding to the
safety of application.
This same extract GH 2002 has been shown to possess
potent time- and concentration-dependent antiviral ef-
fects against Herpes simplex virus in vitro [28,29], with
a remarkably low IC50 of 2 × 10-5% against HSV-1, and
an IC50 of 4 × 10-4% against HSV-2. The mechanism of
action is not based on antimetabolite effects as with
aciclovir and penciclovir, but on a denaturation of the
viru s memb r ane .
In an earlier, as yet unpublished study we found a
significant therapeutic effect in 150 patients suffering
from Herpes labialis after treatment with a lip balm
containing 2 % of GH 2002. However, we were not ful-
ly convinced of the therapeutic applicability due to the
observation of reversible skin irritation with itching and
burning in a proportion of the patients exceeding the
typical incidence rate of local adverse skin reactions of
2.0-3.8 % with the application of creams containing
aciclov ir or pencic lovir [2,4,8].
The ai m of the present dose-finding study was there-
fore to identify the optimal dose range with respect to
efficacy and tolerability. The conclusions shall be ap-
plied in a controlled clinical trial which is currently in
preparation. We also wanted to examine to what extent
the broad biological spectrum of propolis effects, espe-
cially the anti-inflammatory and antimicrobial proper-
ties, may lead to additional therapeutic benefits in the
treatment of Herp e s lab ia li s.
2.1. Study Participants
The study objective was to determine the concentra-
tion of pr opolis extrac t in a lip balm where the treat ment
effect against Herpes labialis is still satisfactory and to-
lerability is acceptable. We also intended to assess the
effect of the propolis preparations against symptoms of
local irritation, pain, inflammation and wound healing.
The study was performed as a mono-centre, randomized,
dose-controlled, three-arm double-blind dose-finding
We selec ted outpatients prese nting to our der matolog-
ical practice with an unequivocal diagnosis of Herpes
labialis. The number of study participants was chosen to
match the number of patients in our earlier study with
the application of 2% propolis special extract GH 2002
in a lip balm (n = 150).
Patients were eligib le when the y presented themselves
within 24 hours after noticing the first prodromal symp-
toms of Herpes labialis. The exact time when prodromal
symptoms were first noted by the patient was docu-
mented. Patients could not be included when they had a
known allergy against propolis or an excipient of the lip
balm, or if they required systemic antiviral treatment.
Any local concomitant treatment was excluded, as was
systemic medication potentially influencing the immune
system, such as corticosteroids, immunosuppressants,
methotrexate o r cytostatic s.
The study was planned and carried out in accordance
with the criteria of Good Clinical Practice (GCP) and the
ethical standards defined in the declaration of Helsinki.
All patie nts signed an informed consent sheet.
2.2. Interventions
The study medicat ion consisted of a lip b alm with the
active constituent propolis special extract GH 2002. Ex-
tract and lip balm were manufactured by Gehrlicher
Pharmazeutische Extrakte (Eurasburg, Germany). The
propolis extract was embedded in a soft water-in-oil
emulsion, without the use of preservatives or dyes. The
three study preparations differed only in the concentra-
tion of the active constituent (0.1, 0.5 and 1%). They
were indistingui sha b le wi th r e ga r d t o co lo ur, consi ste nc y
and external presentation, and were delivered to the
study centre in externally identical tubes numbered ac-
cording to the random list for allocation concealment.
Patients were told to apply the lip balm every 2-3 hour s,
five times daily, to the entire upper and lower lip. No
other local preparations including cosmetics were per-
mitted during the study.
2.3. Randomization and Blinding
The study participants were allocated to one of three
treatment groups according to a pre-prepared random
plan. Treatments were blinded for study personnel and
monitoring, the patients, the statistician and the sponsor
until conclusion o f the st ati stical evaluation.
2.4. Study Parameters
The symptoms of Herpes labialis were documented at
S. Holcová et al. / Health 3 (2011) 49-55
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every visit, using the usual classification in prodromal,
erythe mal, papular, vesicular, ero sive and incrusted/healed
stages. For each stage the exact time of the occurrence
was documen t ed.
Following the first visit, examinations of the patients
took place on day 2 or 3 and on day 5 or 6. A follow-up
examination was made on day 8 or 9 for any patients
who were not yet healed on day 5/6. The primary as-
sessment parameter was the time between erythem-
al/papular phase and painless incrustation. The corres-
ponding data was taken from the individual case report
for ms (CRFs).
The development of pain, itching, tension/swelling
and burning were assessed on day 2/3 as secondary pa-
rameters. Pain intensity was determined using the inter-
nationally accepted visual analogue scale (VAS), in
which the patient defines his/her sensation of pain on a
scale of 100 mm between 0 and 100 (0 = no pain; 100 =
highest possible pain). The evaluation of the parameters
itching, swelling/tension and burning was made on a
4-step verbal rating scale (VRS) (0 = nonexistent, 1 =
slight, 2 = moderate, 3 = severe). Finally, local tolerabil-
ity and any signs of adverse reactions were assessed over
the whole treat ment period.
2.5. Statistical Methods
SPSS v.16.0 was used as the statistical software. Mis si ng
values were to be replaced by carrying over the respec-
tive last measurement. Statistical methods are indicated
with the results for every single evaluation. For testing
of the primary parameter in the three treatment groups
(1% vs. 0.5%, 1% vs. 0.1%, and 0.5% vs. 0.1%) the sig-
nificance level was established with p = 0.05, using the
Holm-Bonferroni method. Secondary analyses were
performed descriptively in all patients with complete
data sets (per protocol population).
3. Results
150 patients were included into the study. 102 were
female (68%), 48 were male (32%). The age of the pa-
tients was 9 to 81 years (mean 41.6 ± 16.4 years, range
9-81). The majority of patients (n = 125; 83.3%) had a
history of recurrent Herpes labialis infection with an
average of 3.5 ± 1.7 episodes per year (range 1-10) for
several years. The average duration of an episode was
9.1 ± 2.0 days. 25 (16.7%) of the patients were expe-
riencing Herpe s labialis for th e first time.
Through the randomization procedure patients were
allocated to treatment with 0.1% propolis extract (n =
48), 0.5 % (n = 50), and 1% extract (n = 52). All 150
patients were a vailab le for t he visit on tre at ment day 2 /3.
Five drop-outs occurred following the examination on
study day 2/3: Four patients were excluded due to the
observation of local skin reactions (1 patie nt each of the
0.1% and 0.5% groups, and 2 patients from the 1.0%
group). One patient from the 0.1% group did not come
back for the follow-up examinations for unknown rea-
sons. 1 45 patients continued treatment after day 2/3 (n =
46 i n the 0.1% group, n = 49 in the 0.5% group, and n =
50 in the 1 % group).
3.1 Primary Parameter: Time to Painless
121/145 patients were assessable for healing time with
painless incrustation, whereas in 24 patients healing oc-
curred with an exfoliative epithelialisation with no in-
crustation phase. Results correlated well with the obser-
vation of secondary parameters (see below). Within this
subset of 121/145 patients we calculated the number of
days starting from the erythemal/papular phase to com-
plete incrustation of the lesions. The shortest average
healing time was found in the 0.5 %-group (3.8 ± 1.5
days), followed by the 0.1 %-group (3.9 ± 1.8 days) and
the 1 % group (4.9 ± 1.7 days).
For the statistical assessment the pre-planned calcula-
tion of the time when 50% and 90% of patients have
reached the incrustation phase (50th and 90th percentile)
gives more reliable results. The distribution of patients
per group and the corr espond ing result s for he aling t ime
are displayed in Figure 1. Shortest healing times were
again found in the treatment arm with 0.5% propolis
extract in the lip b a lm.
The difference between treatment groups was statisti-
cally significant (Kruskal-Wallis test: p = 0.017). The
difference between groups was also assessed by pair-wise
comparison in the Mann-Whitney test. Whereas for the
comparisons between the 0.1% and the 0.5% concentra-
tion with the 1% concentration the difference was in both
cases statistically significant (p = 0.026 and 0.008, re-
spec tively), s ignifica nce was not rea ched for the compar-
ison between 0.1 and 0.5 % (p = 0.09).
In addition to the primary para meter the time fro m the
prodromal phase to complete painless incrustation (n =
121) and the time from prodromal symptoms to com-
plete heali ng in all p atient s with a nd without i ncrustation
(n = 145) was calculated. For the mean healing time the
same sequence was confirmed: With the 0.5% concen-
tration the healing time was 4.8 ± 1.5 days (n = 1 21) and
4.8 ± 1.8 days (all patie nts), re spectively. With 0.1% t he
respective results were 5.1 ± 1.8 and 4.9 ± 2.0 days. Fi-
nall y, t he result s for the 1 .0 %-group were 6.1 ± 1.8 and
5.8 ± 2.1 day s , respectively.
Healing was also calculated in the 50th and 90th per-
centile of each group in all 121 (data not shown) and 145
patients (Figure 2), with very similar findings in both
analyses. Again, the difference between treatment groups
S. Holcová et al. / Health 3 (2011) 49-55
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Figure 1 . Time from erythemal/papular phase to complete painless incrustation of lesions (n = 1 21).
Figure 2. Time from prodromal phase to complete healing (n = 145).
was statistically significant (Kruskal-Wallis test: p =
0.006 and 0.05). The pair-wise analysis of treatment
groups by the Mann-Whi tney-test resulted in significant
differences for the comparisons of the 0.1% and the
0.5% concentrations with the 1% concentration (p =
0.025 and 0.034, respectively, for the comparison of
0.1% and 1.0%; p = 0.002 and 0.036, respectively, for
the comparison of 0.5 % and 1.0%), whereas signific-
ance was in both cases not reached for the comparison
betwee n trea tments with 0 .1 and 0.5 % propolis extract.
3.2 Secondary Parameters: Pain
The secondary parameters pain, itching, swel-
ling/tension and burning were assessed in all 145 pa-
tients. For all parameters a highly significant improve-
ment was found on day 2/3 when values were compared
with baseline (McNemar Test, in all cases p < 5 × 10-5).
Due to the distinct improvement of symptoms on day 2/3
these parameters were not further statistically investi-
gated on study days 5/6 and 8/9. In no case a deteriora-
tion of the symptoms was observed after study day 2/3.
Pain reduction was fast, with distinct alleviation ob-
served already few hours after the first application of the
lip ba lm (dat a not sho wn). A highly si gnifica nt red uction
of pain was recorded with all three concentrations of
active constituent. There was no statistically significant
difference in the outcome of the various concentrations
(covariance analysis; dependent variable VAS on day 2/3,
p = 0.4). Already on day 2/3 the decrease of local pain
had reached high statistical significance when compared
with baseline values (paired t-test, p < 10-8 in a ll groups) .
A reduction of VAS scores from baseline values of 65-70
to 15 units was observed on day 5/6 (Figu re 3).
3.3. Itching, Swelling/Tension and Burning
The decrease of itching, swelling/tension and local
burning was likewise highly significant in all three con-
centrations when compared with baseline values (n=145;
McNemar ’s tests: p < 5 × 10-4 in all groups, Table 1 and
Figure 4). The difference between groups was not sig-
nificant with all three parameters (Chi2-test by linear
association, p = 0.34 for itching, p = 0.4 for ten-
sion/swelling and p = 0.077 for burning), but in each
case an increasing percentage of patients with absent or
mild complaints was associated with increasing dose.
3.4. Assessment of Global Efficacy and
Local Tolerability
The assessment of global efficacy by the physician on
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Fi gure 3. Effect of different concentrations of propolis extract on pain redu ction in
mm VAS (n = 145, all results p < 10-8).
Figure 4. Effect of different concentrations of propolis extract on ten-
sion/swelling on study day 2/3 (Assessment by VRS): Percent of patients with
moderate to severe symp toms (n = 145, all results p < 5 × 10-4).
study day 5/6 resulted in good and very good treatment
effects in 80-89% of patients with all three concentrations.
This finding is in line with the results from the evaluations
Tab le 1. Effect of different concentrations of propolis extract in
the lip balm on itching, burning, and tension/swelling on study
day 2/3 (Assessment by VRS). Percent of patients with moderate
to severe sympto ms (n = 145, all results p < 5 × 10 -4).
Day 0
Day 0
Day 0
Day 2/3
0.1% 87.0 26.1 74.5 17.4 78.7 10.9
0.5% 87.8 22.4 59.2 10.2 77.6 8.2
1.0% 83.3 18.0 66.0 6.0 78.0 6.0
of the pri mary an d secondary paramet ers.
On day 2/3 reversible local irritation was observed in
one patient each of the 0.1% (n = 48) and the 0.5%-group
(n = 50), and in 2 patients of the 1% group (n = 52). No
local allergi c r eactions t o pro p o li s were encountered.
The aim of this study was to provide data justifying
the choice of a defined dose scheme. Correspondingly,
the primary statistical parameter used for the assess-
ment was not the effect on the symptoms of Herpes
labialis, but the statistically more reliable and repro-
ducible calculation of the time to reaching the 50th and
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90th percentile of healing until painless incrustation.
Thi s parameter allows an exact comparison of different
treatments, a nd thus p rovid es an answer to the q uestion
which concentration of propolis should be used in fu-
ture research.
Despite the lack of a control group (placebo or refer-
ence) the study still provides information which allows
concluding on a clinically important efficacy. The as-
sessment of symptoms was addressed as secondary out-
come parameters. These secondary parameters confirm
the positive impact of propolis on the healing of Herpes
labialis, and will be formally re-confirmed in a con-
trolled clinica l efficacy study.
The impact on healing time is clearly clinically impor-
tant: The natural healing time of Herpes labialis to pain-
less incrustation of usually >8 days can be reduced to
approximately 6.5 days with the application of Aciclovir
cream [30]. The application of a lip balm with propolis
extract leads to a similar shortening of the Herpes epi-
sode (5. 4 days in the 90th percentile with 0.5% of e xtract
in the preparation). Propolis is therefore confirmed to be
a potent antiviral agent under clinical conditions.
Propolis special extract GH 2002 as an active consti-
tuent of a lip balm was effective against Herpes labialis
in all three tested concentrations, 0.1%, 0.5% and 1%.
The size of the effect was comparable to the effect size
observed in an earlier study, where we used an identical
galenical preparation with 2% propolis extract (unpub-
lished). The strong effect of the relatively low concen-
tration of 0.1% active ingredient was surprising and re-
trospectively confirms the clinical importance of the
potent antiviral effect observed in vitro [28,29]. In pa-
tients with Herpes labialis the application of lip balm
with propolis extract leads to shortened healing times as
compared with the natural untreated course of the
Herpes episode [1,2].
Already after 2-3 days the secondary parameters pain,
itching, tension/swelling and burning showed distinct
improvements with all three extract concentrations. P ain
reduction on study day 2-3 was especially remarkable,
with a surprisingly rapid onset of effects reported only
hours after the first application. The results from the
assessment of the secondary parameters underline the
beneficial contribution of additional pharmacological
effects of propolis such as anti-inflammatory, wound-
healing and antimicrobial properties, beyond the antivir-
al activity. For the patients such benefits clearly are
clinically important.
The overall results of this study point to a concentra-
tion of 0.5% of propolis extract in the lip balm as the
preparation with the best risk-benefit ratio. Healing
times were shorter than with the 0.1 %-preparation –
which was expected , but also signi fica ntl y sho rter tha n
wit h 1 % pr opolis extract, which was not expected, and is
as yet unexplained. As a hypothesis, the better effect of
the 0.5% concentration might be related to subclinical
tolerability. As we had already observed an increased
rate of skin irritation with the 2% concentration, it is
possible that the 1% concentration still results in an in-
creased r ate of local irr itation which is u ndisting uishable
from the s ympto ms o f Herpes lab ialis. T his phenomenon
would obviously no longer occur with the 0.5% dose,
with no reduction of efficacy despite the lower dose.
With regard to safety of application, there was other-
wise no difference between the two lower tested concen-
trations, with one observed case of local irrita tion both in
the 0. 1% (1/48, 2.1%) and 0.5% groups (1/50, 2.0%). In
the 1% group there were two cases (2/52, 3.9%). These
findings are well comparable with those from treatment
with aciclovir and pencilovir (2.0-3.8% of patients)
[2,4,8]. Furthermore, the results retrospectively confirm
that the observation of an increased rate of local irrita-
tion with a prepa ration co ntaini ng 2 % of propolis extract
were in fact dose-related. As the dose can be reduced
without loss of antiviral efficacy, but with a remarkable
gain in safety of application, future research will focus
on the 0.5% co ncentr ation.
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