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pharmaceuticals
Article
Medical-Grade Honey Outperforms Conventional Treatments
for Healing Cold Sores—A Clinical Study
Piyu Parth Naik 1, Dimitris Mossialos 2, Bas van Wijk 3, Petra Novakova 4, Frank A. D. T. G. Wagener 3
and Niels A. J. Cremers 5, *
Citation: Naik, P.P.; Mossialos, D.;
Wijk, B.v.; Novakova, P.; Wagener,
F.A.D.T.G.; Cremers, N.A.J.
Medical-Grade Honey Outperforms
Conventional Treatments for Healing
Cold Sores—A Clinical Study.
Pharmaceuticals 2021,14, 1264.
https://doi.org/10.3390/ph14121264
Academic Editor: Zoidis Grigoris
Received: 5 November 2021
Accepted: 2 December 2021
Published: 4 December 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
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iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1Saudi German Hospitals and Clinics, Department of Dermatology, Hessa Street 331 West, Al Barsha 3,
Exit 36 Sheikh Zayed Road, Dubai P.O. Box 391093, United Arab Emirates; drpiyu85@gmail.com
2Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis-Mezurlo, 41500 Larisa,
Greece; mosial@bio.uth.gr
3
Department of Dentistry, Radboud University Medical Center, Philips van Leydenlaan 25, 6525 EX Nijmegen,
The Netherlands; bas.vanwijk@radboudumc.nl (B.v.W.); frank.wagener@radboudumc.nl (F.A.D.T.G.W.)
4LERAM Pharmaceuticals s.r.o., Páteˇrní1216/7, 63500 Brno, Czech Republic;
petra.novakova@leram-pharma.cz
5Triticum Exploitatie BV, Sleperweg 44, 6222 NK Maastricht, The Netherlands
*Correspondence: niels@mesitran.com; Tel.: +31-43-325-1773
Abstract: Cold sores are nasolabial blisters caused by herpes simplex virus (HSV) infections. Novel
therapies demonstrating simultaneously antiviral activity and improved wound healing are war-
ranted. The aim of this study was to investigate the efficacy of medical-grade honey (MGH) for
treating HSV-induced cold sores. A crossover trial was performed in patients with recurrent cold
sores (n= 29). The majority (65.6%) of these patients experience four or more episodes per year,
thus forming a valid self-control group. In this study, patients applied an MGH-based formulation
(L-Mesitran Soft) on their cold sore at the onset of symptoms (62.1%) or appearing of blister (37.9%)
and compared it to their conventional treatments. After complete healing, patients filled in a ques-
tionnaire evaluating healing, pain, and itching. The average absolute healing time was 72.4% slower
with conventional treatment (10.0 days) compared to MGH (5.8 days). After MGH treatment, 86.2%
of all patients experienced faster objective healing (6.9% similar and 6.9% slower) and the subjective
healing score was higher in 79.3% of the patients (20.7% similar). If the patients normally experience
pain and itching during their cold sores, these levels were lower with MGH therapy compared to
conventional treatment in 72.7% and 71.4% of the patients, respectively. Moreover, 100% of the
patients prefer MGH treatment over conventional treatment and will use it again on future cold sores.
MGH is a promising alternative treatment for cold sores, likely by combining both increased antiviral
and wound healing activities while alleviating pain and itching.
Keywords: medical-grade honey; herpes simplex virus; cold sores; wounds; pain; itch
1. Introduction
Cold sores are nasolabial blisters caused by herpes simplex virus (HSV) infections.
Approximately two-thirds of the global population between 0 and 49 years of age have HSV-
1 infection, accounting for an estimated 3.7 billion people [
1
,
2
]. Most of these infections
are oral, while 122 to 192 million people are estimated to have genital HSV-1 infection [
1
].
HSV-2 causes genital infections which are less prevalent (11% globally) [
3
]. However, the
incidence of cold sores is considerably lower than the infection rates, as the infection is
often present in a latent form. The average incidence is 1.6 per 1000 patients per year and
its prevalence is 2.5 per 1000 patients per year [
4
,
5
]. Approximately one-third of all infected
patients suffer relapses [
4
–
7
]. Although most individuals with recurrent cold sores have
up to two episodes in an entire year, 5–10% has at least six recurrences per annum [
7
,
8
].
Triggering elements of recurrent cold sores comprise stress, illness, premenstrual tension,
Pharmaceuticals 2021,14, 1264. https://doi.org/10.3390/ph14121264 https://www.mdpi.com/journal/pharmaceuticals
Pharmaceuticals 2021,14, 1264 2 of 11
ultra-violet light, or surgical procedures. Moreover, having a compromised antiviral
response, such as patients with atopic dermatitis harboring fillagrin mutations may enhance
these triggering events [8,9].
Cold sores develop via several stages characterized by different symptoms (Figure 1).
In the first stage, patients may feel tingling, itching, or a burning sensation, but without the
blister being formed yet. Next, peri-oral and intra-oral lesions will develop, starting with
the vesicular stage (1–2 days after initial symptoms), the opening of the blister(s) (around
day 4), and subsequently drying out (day 5–8), leaving a yellow or brown crust, which
eventually flakes off. The final stage is the healing, and scabs will become smaller in time
until complete healing (normally 7–14 days) [
7
,
10
,
11
]. Effective treatments options are
limited and often restrain on antiviral drugs and topical creams, such as acyclovir (Zovirax),
famciclovir (Famvir), valacyclovir (Valtrex), docosanol (Abreva), and penciclovir (Denavir)
limiting viral DNA replication [
7
,
12
]. These treatments may reduce the duration of a
cold sore by 0.5 to 2.5 days, depending on the type of medication and dosage used [
4
,
12
].
However, these drugs may cause in some cases (1–10%) various side effects, including
discouragement, irritability, tiredness, nausea, vomiting, cramps, diarrhea, body aches
or pain, rash, itching, and sore throats [
13
–
15
]. Clinicians also prescribe nonsteroidal
anti-inflammatory drugs (NSAIDs) to reduce associated pain [
16
–
19
]. Cold sores are
uncomfortable, negatively affect aesthetics, and can be considered embarrassing, creating a
psychosocial impact that affects the quality of life of these patients (Figure 1) [
8
,
19
]. Novel
therapies that have antiviral activity with fewer side effects and decreased wound healing
time are eagerly awaited.
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 12
annum [7,8]. Triggering elements of recurrent cold sores comprise stress, illness, premen-
strual tension, ultra-violet light, or surgical procedures. Moreover, having a compromised
antiviral response, such as patients with atopic dermatitis harboring fillagrin mutations
may enhance these triggering events [8,9].
Cold sores develop via several stages characterized by different symptoms (Figure
1). In the first stage, patients may feel tingling, itching, or a burning sensation, but without
the blister being formed yet. Next, peri-oral and intra-oral lesions will develop, starting
with the vesicular stage (1–2 days after initial symptoms), the opening of the blister(s)
(around day 4), and subsequently drying out (day 5–8), leaving a yellow or brown crust,
which eventually flakes off. The final stage is the healing, and scabs will become smaller
in time until complete healing (normally 7–14 days) [7,10,11]. Effective treatments options
are limited and often restrain on antiviral drugs and topical creams, such as acyclovir
(Zovirax), famciclovir (Famvir), valacyclovir (Valtrex), docosanol (Abreva), and penciclo-
vir (Denavir) limiting viral DNA replication [7,12]. These treatments may reduce the du-
ration of a cold sore by 0.5 to 2.5 days, depending on the type of medication and dosage
used [4,12]. However, these drugs may cause in some cases (1–10%) various side effects,
including discouragement, irritability, tiredness, nausea, vomiting, cramps, diarrhea,
body aches or pain, rash, itching, and sore throats [13–15]. Clinicians also prescribe non-
steroidal anti-inflammatory drugs (NSAIDs) to reduce associated pain [16–19]. Cold sores
are uncomfortable, negatively affect aesthetics, and can be considered embarrassing, cre-
ating a psychosocial impact that affects the quality of life of these patients (Figure 1) [8,19].
Novel therapies that have antiviral activity with fewer side effects and decreased wound
healing time are eagerly awaited.
Figure 1. Example of the development of a cold sore, from the vesicular stage (left) to blister burst and drying out (center)
to scab formation (right).
Natural products may offer such a promising treatment. Medical-grade honey
(MGH) exerts a broad range of antimicrobial activities via multiple mechanisms, includ-
ing low pH, strong osmotic actions, production of hydrogen peroxide, and the presence
of antimicrobial molecules [20].
The antimicrobial activity of honey against bacteria and fungi has been extensively
documented in the literature; however, the antiviral activity of MGH is less described
[21,22]. MGH exerts in vitro antiviral activity against multiple viruses, including HSV-1,
varicella zoster virus, and influenza virus A (H1N1) [23–25]. Interestingly, a recent sys-
tematic review and meta-analysis evaluating 14 randomized controlled trials concluded
that honey was superior to usual care for the improvement of symptoms of upper respir-
atory tract infections and provides a widely available and cheap alternative to antibiotics
[26]. Honey also forms a promising potent treatment for COVID-19 patients and clinical
trials are ongoing [27–29]. A clinical randomized-controlled trial showed that honey in
combination with Nigella sativa consumption by COVID-19 patients led to faster clearance
of the virus and relief of symptoms, earlier hospital discharge, and a four-fold lower mor-
tality rate in severe cases [30].
Synergistic antimicrobial activity of honey and vitamins C and E have previously
been demonstrated. Vitamin C and E supplements in the MGH-based wound care formu-
lation (L-Mesitran Soft) enhance the antimicrobial and wound healing activities when
Figure 1.
Example of the development of a cold sore, from the vesicular stage (
left
) to blister burst and drying out (
center
)
to scab formation (right).
Natural products may offer such a promising treatment. Medical-grade honey (MGH)
exerts a broad range of antimicrobial activities via multiple mechanisms, including low pH,
strong osmotic actions, production of hydrogen peroxide, and the presence of antimicrobial
molecules [20].
The antimicrobial activity of honey against bacteria and fungi has been extensively doc-
umented in the literature; however, the antiviral activity of MGH is less described [
21
,
22
].
MGH exerts
in vitro
antiviral activity against multiple viruses, including HSV-1, varicella
zoster virus, and influenza virus A (H1N1) [
23
–
25
]. Interestingly, a recent systematic
review and meta-analysis evaluating 14 randomized controlled trials concluded that honey
was superior to usual care for the improvement of symptoms of upper respiratory tract
infections and provides a widely available and cheap alternative to antibiotics [
26
]. Honey
also forms a promising potent treatment for COVID-19 patients and clinical trials are
ongoing [
27
–
29
]. A clinical randomized-controlled trial showed that honey in combination
with Nigella sativa consumption by COVID-19 patients led to faster clearance of the virus
and relief of symptoms, earlier hospital discharge, and a four-fold lower mortality rate in
severe cases [30].
Synergistic antimicrobial activity of honey and vitamins C and E have previously been
demonstrated. Vitamin C and E supplements in the MGH-based wound care formulation
(L-Mesitran Soft) enhance the antimicrobial and wound healing activities when compared
to the raw honey component [
31
–
35
]. Since both honey and vitamins C and E have been
Pharmaceuticals 2021,14, 1264 3 of 11
shown to possess antiviral activity [
36
–
40
], they may also help to treat cold sores. The
wound healing activities of MGH are also based on multiple mechanisms, and therefore
may further advance the healing of the cold sores [41,42].
The aim of the present study was to investigate whether topical application of the
MGH-based formulation L-Mesitran Soft would be an effective alternative treatment for
treating recurrent cold sores when compared to conventional treatments. The working
hypothesis was that MGH exerts antiviral activity, promotes wound repair, and improves
the patient’s quality of life.
2. Results
2.1. Healing Time Is Lower with MGH Compared to Conventional Treatment
Patients were asked via a questionnaire how long it normally takes for the cold sores
to completely heal following conventional treatment, and how long it took with MGH
treatment. The average absolute healing time was significantly higher (p< 0.0001) with
conventional treatments (10.0 days) compared to MGH (treatment (5.8 days) (Figure 2a).
On average, this corresponds to slower healing of 72.4% (10.0/5.8) with conventional
treatment compared to MGH treatment.
A sub-analysis could be performed because a large subpopulation of the patients
(11/29 = 37.9%) use antiviral therapy as a conventional treatment. In this sub-analysis,
patients whose conventional treatments consist of acyclovir-based drugs (Zovirax, Her-
pesin, or Vectavir) and patients using other treatments (18/29 = 62.1%) were analyzed
separately. For both subpopulations, it was investigated whether there is a difference in ab-
solute healing time between their conventional treatment and MGH treatment (
Figure 2b,c
).
The average absolute healing time within the subpopulation using antiviral therapy was
5.2 days shorter (p= 0.001) with MGH, 6.2 days versus 11.4 days (Figure 2b). The average
healing time within the other subpopulation that uses other treatments was 3.5 days shorter
(p= 0.0009) with MGH, 5.6 days versus 9.1 days (Figure 2c).
Based on the absolute healing times, the objective healing time was determined for
the complete patient population. The objective healing showed that 86.2% (25/29) of the
patients experienced significantly faster healing (p< 0.005), while 6.9% had similar or
slower healing (2/29 each) (Table 1). Moreover, patients were asked about their subjective
feeling if healing was faster or not with MGH. These results were in line with the objective
healing times and 79.3% (23/29) of the patients achieved faster subjective healing with
MGH compared to their conventional treatments, while healing was experienced similar in
20.7% (6/29), and none of them experienced slower healing (0/29) (Table 1). Representative
examples of the progression of labial and nasal cold sores with L-Mesitran treatment are
shown in Figure 2d,e.
Table 1.
Efficacy MGH treatment on the objective and subjective healing time when compared to conventional treatments.
Number of
Patients
Evaluated
(% of Cohort)
Faster Healing
with MGH
Number (%)
Similar Healing
Number (%)
Slower Healing
with MGH
Number (%)
Significant
Different
Compared to
Conventional
Treatment
Objective healing
time 29 (100) 25 (86.2) 2 (6.9) 2 (6.9) p< 0.005
Subjective healing
experience 29 (100) 23 (79.3) 6 (20.7) 0 (0) p< 0.005
Pharmaceuticals 2021,14, 1264 4 of 11
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 3 of 12
compared to the raw honey component [31–35]. Since both honey and vitamins C and E
have been shown to possess antiviral activity [36–40], they may also help to treat cold
sores. The wound healing activities of MGH are also based on multiple mechanisms, and
therefore may further advance the healing of the cold sores [41,42].
The aim of the present study was to investigate whether topical application of the
MGH-based formulation L-Mesitran Soft would be an effective alternative treatment for
treating recurrent cold sores when compared to conventional treatments. The working
hypothesis was that MGH exerts antiviral activity, promotes wound repair, and improves
the patient’s quality of life.
2. Results
2.1. Healing Time Is Lower with MGH Compared to Conventional Treatment
Patients were asked via a questionnaire how long it normally takes for the cold sores
to completely heal following conventional treatment, and how long it took with MGH
treatment. The average absolute healing time was significantly higher (p < 0.0001) with
conventional treatments (10.0 days) compared to MGH (treatment (5.8 days) (Figure 2a).
On average, this corresponds to slower healing of 72.4% (10.0/5.8) with conventional treat-
ment compared to MGH treatment.
(a)
(b) (c)
Pharmaceuticals 2021, 14, x FOR PEER REVIEW 4 of 12
(d) (e)
Figure 2. L-Mesitran reduces the healing time of cold sores compared to conventional treatment. (a) Dotplot of absolute
healing time in days for both conventional and L-Mesitran treatment, each dot represents one patient (n = 29). (b) Dot plot
of absolute healing time of the subpopulation who use antiviral acyclovir-based therapy (Zovirax, herpesin, or vectavir).
(c) Dot plot of absolute healing time of the subpopulation who use other treatments and do not use antiviral therapy as
conventional treatment. (d) Representative example labial cold sore. Normally, with conventional treatments healing takes
14 days, but healing was achieved within 9 days with L-Mesitran. (e) Representative example nasal cold sore. Normally,
healing takes 14 days, but with L-Mesitran it was healed in 7 days. Significant differences between the groups are indicated
by (** p < 0.01, *** p < 0.001, **** p < 0.0001).
A sub-analysis could be performed because a large subpopulation of the patients
(11/29 = 37.9%) use antiviral therapy as a conventional treatment. In this sub-analysis, pa-
tients whose conventional treatments consist of acyclovir-based drugs (Zovirax, Herpesin,
or Vectavir) and patients using other treatments (18/29 = 62.1%) were analyzed separately.
For both subpopulations, it was investigated whether there is a difference in absolute heal-
ing time between their conventional treatment and MGH treatment (Figure 2b,c). The av-
erage absolute healing time within the subpopulation using antiviral therapy was 5.2 days
shorter (p = 0.001) with MGH, 6.2 days versus 11.4 days (Figure 2b). The average healing
time within the other subpopulation that uses other treatments was 3.5 days shorter (p =
0.0009) with MGH, 5.6 days versus 9.1 days (Figure 2c).
Based on the absolute healing times, the objective healing time was determined for
the complete patient population. The objective healing showed that 86.2% (25/29) of the
patients experienced significantly faster healing (p < 0.005), while 6.9% had similar or
slower healing (2/29 each) (Table 1). Moreover, patients were asked about their subjective
feeling if healing was faster or not with MGH. These results were in line with the objective
healing times and 79.3% (23/29) of the patients achieved faster subjective healing with
MGH compared to their conventional treatments, while healing was experienced similar
in 20.7% (6/29), and none of them experienced slower healing (0/29) (Table 1). Representa-
tive examples of the progression of labial and nasal cold sores with L-Mesitran treatment
are shown in Figure 2d,e.
Table 1. Efficacy MGH treatment on the objective and subjective healing time when compared to conventional treatments.
Number of
123456Patients
123456Evaluated
123456(% of Co-
hort)
Faster Healing
with
MGH123456Num-
ber (%)
Similar Heal-
ing123456
Number
(%)
Slower Healing
with
MGH123456Num-
ber (%)
Significant Different
Compared to
123456Conventional
123456Treatment
Objective
healing time
29 (100) 25 (86.2) 2 (6.9) 2 (6.9) p < 0.005
Subjective
healing
123456experi-
ence
29 (100) 23 (79.3) 6 (20.7) 0 (0) p < 0.005
2.2. Pain Is Lower with MGH Than Conventional Treatment
Figure 2.
L-Mesitran reduces the healing time of cold sores compared to conventional treatment. (
a
) Dotplot of absolute
healing time in days for both conventional and L-Mesitran treatment, each dot represents one patient (n= 29). (
b
) Dot plot
of absolute healing time of the subpopulation who use antiviral acyclovir-based therapy (Zovirax, herpesin, or vectavir).
(
c
) Dot plot of absolute healing time of the subpopulation who use other treatments and do not use antiviral therapy as
conventional treatment. (
d
) Representative example labial cold sore. Normally, with conventional treatments healing takes
14 days, but healing was achieved within 9 days with L-Mesitran. (
e
) Representative example nasal cold sore. Normally,
healing takes 14 days, but with L-Mesitran it was healed in 7 days. Significant differences between the groups are indicated
by (** p < 0.01, *** p < 0.001, **** p < 0.0001).
2.2. Pain Is Lower with MGH Than Conventional Treatment
Not all patients experience pain during their cold sore episodes. In our patient group,
22 out of 29 patients (75.9%) normally experience pain. Within this group, 72.7% of the
patients (16/22) experience less pain with MGH, 27.3% of the patients (6/22) experiences a
similar pain level and none of the patients (0/22) experiences more pain (Table 2).
Pharmaceuticals 2021,14, 1264 5 of 11
Table 2. Effect treatment on the experience of pain.
Number of Patients
Experiencing Pain
(% of Cohort)
Less Pain with MGH
Number (%)
Similar Pain
Number (%)
More Pain with
MGH
Number (%)
Significance
MGH treatment
compared to
conventional
treatment
22 (75.9) 16 (72.7) 6 (27.3) 0 (0) p< 0.005
2.3. Less Itching with MGH Than Conventional Treatment
Not all patients experience an itching sensation during their episode of cold sores.
In our patient group, 21 out of 29 patients (72.4%) normally experience itching. Within
this group, 71.4% of the patients (15/21) experience less itching, 28.6% (6/21) experience a
similar level of itching, and none of the patients (0/21) experiences more itching (Table 3).
Table 3. Relative itching when comparing MGH treatment with conventional treatments.
Number of Patients
Experiencing Itching
(% of Cohort)
Less Itching with
MGH
Number (%)
Similar Itching
Number (%)
More Itching with
MGH
Number (%)
Significance
MGH treatment
compared to
conventional
treatment
21 (72.4) 15 (71.4) 6 (28.6) 0 (0) p< 0.005
2.4. Patients Strongly Prefer MGH over Conventional Therapies
Based on their positive experiences, all included patients (29/29) will use L-Mesitran
for the treatment of future cold sores. Most patients experienced a benefit on multiple
parameters, (faster objective healing, faster subjective healing, less pain, and less itching).
93.1% (27/29) of the patients experienced a beneficial effect on at least one of these param-
eters, 82.8% (24/29) had a beneficial effect on at least two parameters, 62.1% (18/29) on
at least three parameters, and 34.5% (10/29) experienced a benefit on all four parameters.
Notably, many patients do not normally experience pain or itching and therefore this score
is under representative.
The open feedback from the patients was also very positive (Supplementary Table S1).
Most of them refer to the faster healing or reduction of symptoms. However, many patients
also liked the hydrating effect and expressed that “the skin is more elastic, softer, dries out
less, and the blisters are less prone to rupture/crack”. Moreover, multiple patients also
liked the formulation itself; “staying well in place after application, the color of the product
being invisible on the lip, and its taste”. However, some patients also disliked the taste
as they do not like honey. Interestingly, one of the patients who normally developed cold
sores 4–5 times per year started applying L-Mesitran twice daily as a preventive measure,
and she did not develop a new cold sore since then for eight months (still ongoing).
3. Discussion
Cold sores are caused by HSV1 and HSV2 and cause problems such as itching, pain,
and cosmetic appearance. Conventional treatments focus solely on antiviral activity;
however, they do not address the wound that follows the viral infection. The MGH-based
formulation (L-Mesitran Soft) has broad-spectrum antimicrobial and antiviral activity and
promotes wound repair. It was therefore postulated to form an attractive novel therapy
to treat cold sores. In this trial, the average healing time was significantly reduced from
10.0 days with conventional treatments to 5.8 days with MGH. The absolute healing time
of the subpopulations using antiviral therapy and other treatments was in line with the
Pharmaceuticals 2021,14, 1264 6 of 11
results of the total population. Thus, the reduced healing time with MGH was irrespective
of the type of the previously used conventional treatment. Moreover, symptoms as pain
and itching were reduced with MGH in 72.7% and 71.4% of the patients, respectively, when
compared to conventional treatments.
Previous studies investigating the effect of the antiviral acyclovir cream observed
a reduction in healing time in eight out of ten trials, varying from 0.5 (4.3 vs. 4.816) to
2.5 (5.7 vs. 8.315) days [
4
]. None of these studies reported a decrease in the duration
or severity of pain following acyclovir treatment. Two studies investigating penciclovir
showed similar effects, however, one of these studies also reported a reduction in pain
duration by penciclovir (3.5 vs. 4.1 days) [4].
A reduction of 4.2 days with MGH compared to conventional treatments and reduction
in pain and itching is therefore very impressive. However, this may be simply explained
by MGH having both antimicrobial/antiviral and wound healing activities. MGH has
in vitro
antiviral activity against multiple viruses, including HSV-1, varicella zoster virus,
and influenza virus A (H1N1), and showed clinical efficacy against upper respiratory tract
infections and, possibly, COVID-19 [
23
–
29
]. Its wound healing properties are orchestrated
by multiple mechanisms. It creates a moist wound environment, promotes autolytic de-
bridement, angiogenesis, and re-epithelialization, and reduces oxidative and inflammatory
stress [
31
,
41
,
43
–
46
]. Moreover, MGH has previously been shown to have anti-inflammatory
activity, which is in line with the reduced pain and itching in the current study [
41
,
43
].
Drying and cracking make the lesions more susceptible to secondary bacterial infections;
the hydrating properties of honey can inhibit bacterial infections by preventing cracking,
but also via its potent antimicrobial activities [42,47].
Three studies investigated the effect of honey on cold sore treatment before. A recent
randomized controlled trial in 952 human patients with cold sores showed that there was
no difference in efficacy between topical medical-grade kanuka honey (90% honey with
10% glycerine) cream and 5% acyclovir cream [
48
]. The median time to return to normal
skin was between 8 and 9 days for both acyclovir and honey groups (p= 0.56), and there
was no difference in pain level (p= 0.56) and duration (p= 0.90) [
48
]. In another cross-over
trial, the effect of the topical application of honey in 16 patients with recurrent attacks of
labial and genital herpes lesions was investigated and compared to acyclovir cream [
49
].
The used honey had a multifloral origin and was gathered in the United Arab Emirates
and dark yellow in color. The mean duration of pain and mean healing time with honey
treatment were 39% and 43% better for labial herpes and 50% and 59% better for genital
herpes, respectively, when compared to acyclovir [
49
]. Honey reduced healing time by
3.28 days for labial herpes and 2.57 days for genital herpes compared to acyclovir [
49
]. The
third trial, a randomized double-blind placebo-controlled study examined the combined
efficacy of commercially or locally (Egypt) available honey with acyclovir suspension
compared to acyclovir alone in one hundred children aged 2–8 years. The combination of
honey with acyclovir led to faster disappearance of the lesion (3 days vs. 6 days), fewer
eating difficulties, and lower pain scores (all significant) [50].
The latter two studies are well in line with our findings, showing that MGH-based
L-Mesitran Soft was highly effective. The difference in efficacy with the first study may lay
in the different types of honey being used. Methylglyoxal-based honey (such as kanuka)
has previously been demonstrated to be less effective for the treatment of mucositis than
hydrogen peroxide-based honey (such as the honey used in the latter two studies and the
L-Mesitran formulation) [
51
,
52
]. In addition, the vitamin supplements in L-Mesitran have
likely further enhanced the antiviral and healing activity of MGH, making it more effective
than current standard therapies. This synergistic antimicrobial activity of MGH with the
supplements was previously demonstrated against multiple bacteria and fungi [
32
–
35
,
53
].
Instead of a randomized controlled trial in which two groups received different treatments,
our study was performed on patients with recurrent cold sores, and their historic experience
with other conventional treatments was used as a control arm. Patients with recurrent
cold sores have extensive experience with treating their cold sores since their outcome
Pharmaceuticals 2021,14, 1264 7 of 11
is based on multiple episodes and different treatments, this may provide a more reliable
within-patient matched control group.
Interestingly, one of the patients in our study kept using L-Mesitran as a preventive
measure after treatment of her cold sore was successful and she did not develop cold
sores for eight months (still ongoing), even not when getting the flu. More research on
preventive therapies would be interesting to follow up. In a study among 147 skiers with
a history of sun-induced recurrences, oral administration of acyclovir starting 12 days
before sun exposure showed a reduced number of lesions 7% (5 out of 75 acyclovir-treated
patients) compared with 26% (19 out of 72 placebo-treated patients) [
54
]. A setting in which
patients have an increased chance to develop cold sores, such as in skiers, would be perfect
to investigate the prophylactic activity of MGH on cold sore recurrence. Recently, MGH
(L-Mesitran Soft) demonstrated prophylactic activity against infections in two random-
ized controlled studies. A single subcutaneous application in lacerations and after colic
surgeries in horses decreased infection rates a 3-and 4-fold, respectively [
55
,
56
]. Complete
healing of lacerations was also improved, supporting another important asset: promoting
wound healing [
56
]. These activities suggest that L-Mesitran could serve as a putative new
therapy for treating cold sores. However, more research into the exact mechanisms and the
prophylactic activity is needed.
4. Materials and Methods
4.1. Design of the Study
A crossover trial was performed in patients suffering from recurrent cold sores. In
our study, 65.5% of the participants suffer from four or more cold sore episodes per year
(
Table 4
). These patients have thus extensive experience in treating their cold sores and
serve as the best matched-control group. This study design allowed within-patient compar-
isons between treatments because they can serve as their own control subject, removing the
inter-patient variability from the comparison between the treatments and removing bias
between different patients’ experiences. Disease pathogenesis and prognosis are dependent
on a combination of host-and virus-specific factors and may hence differ more between
different patients than within recurrent episodes within the same
patient [11,57].
Moreover,
since patients included in this study have already optimized their personal treatment over
time they can deliver first-hand experiences of their earlier treatments against cold sores.
Since cold sores come in ‘episodes’, there is no carry-over effect and a washout period is
not needed.
Table 4. Distribution of the frequency of the cold sores per patient per year.
Frequency Quite Exceptionally
(about 1 Time per Year)
Occasionally
(2–3 Times per Year)
Often
(4–5 Times per Year)
Very Often
(>5 Times per Year)
Number of patients
(total 29) 3 7 10 9
Percentage 10.3% 24.1% 34.5% 31.0%
4.2. Patient Population
Inclusion took place in two ways; patients with recurrent cold sores were recruited
via a social media campaign or when presenting to the dermatologist. The recruitment via
social media was carried out via Facebook, and patients with recurrent cold sores applied
for participation. There were three calls, in which a total of 56 people responded. All of them
received a free tube of L-Mesitran Soft via regular mail and they subsequently waited for a
cold sore to develop. After one year since the first call, we decided to terminate the inclusion.
All patients who developed a cold sore were asked to fill in a questionnaire to investigate
the experience of the patients (31 patients). Only adult patients who had recurrent cold
sores and who completed the treatment were included (excluding two patients). In total,
29 patients were included in the study, of which four males and 25 females. The age of the
Pharmaceuticals 2021,14, 1264 8 of 11
patients was classified over different ranges (Table 5). Moreover, patients were asked about
the frequency they develop cold sores per year (Table 4), showing that most patients in this
study often experience recurrent cold sores.
Table 5. Age distribution among participating patients.
Age Group 18–26
Years
27–35
Years
36–44
Years
45–53
Years
54–65
Years
>65
Years
Number of
patients
(total 29)
8 5 10 3 2 1
Percentage 27.6% 17.2% 34.5% 10.3% 6.9% 3.5%
4.3. Treatment
The participating patients were asked to apply L-Mesitran Soft (an MGH-based for-
mulation, manufactured by Theo Manufacturing, Maastricht, The Netherlands) on their
cold sores as monotherapy three times daily. L-Mesitran Soft is a medical device class 2B
(FDA approved and CE certified) and used for wound care. L-Mesitran Soft consists of
MGH (40%), lanolin, PEG4000, propylene glycol, and vitamins C and E, and adheres to
strict standards to ensure its quality, safety, and efficacy [20].
Interestingly, all included patients normally use “some kind of treatment” and none
of them leave their cold sores untreated. Conventional treatments were very diverse
and 37.9% of the patients (11 out of 29) commonly used multiple products. Most of the
patients normally treat their cold sores with antiviral therapy, such as Zovirax (acyclovir),
herpesin (acyclovir-based cream) or vectavir (penciclovir) (11/29 = 37.9%), followed by
herbal products (4/29 = 13.8%), tea tree-based products (3/29 = 10.3%), hemagel (wound
care product) (3/29 = 10.3%), zinc-based cream (3/29 = 10.3%), lip balm (2/29 = 6.9%),
vitamin B-based products (2/29 = 6.9%), an “unspecified” product from the pharmacy
(2/29 = 6.9%), or other products (herpes patch, Urgo Film, vaseline, betadine, bepanthen,
Bactroban, L-lysine).
4.4. Outcome Parameters
Patients were asked to fill in an online questionnaire after their cold sores healed
to obtain basic patient information and to assess their experience with L-Mesitran Soft.
The questionnaire (Supplementary Table S2) consisted of 15 questions and all fields in
the questionnaire were mandatory to be filled in. The answers to these questions were
used to determine the following outcomes: absolute healing time (shown as the number
of days needed to heal for each treatment) and objective healing time (as a measure of
absolute healing time of conventional treatment compared to the absolute healing time with
L-Mesitran Soft (Questions 7 and 10), subjective healing time (Question 9), pain experience
(Question 11), itching experience (Question 12), future use (Question 14). Moreover,
patients had the opportunity to submit photos of their cold sores to monitor the healing
progression. This was conducted by 11 patients (37.9%).
4.5. Ethical Statement
Ethical approval to perform the study was granted (reference number DSREC-09/2021_07)
by the Dubai Health Authority. The patients were informed about the study, and they all
gave electronic informed consent to participate in the study and publication of the data and,
when provided, photos. The principles of the World Medical Association’s Declaration of
Helsinki were followed.
4.6. Statistics
The data presented in Figure 2a (dot plot of the absolute healing time) were analyzed
with the Mann–Whitney test using GraphPad Prism software, version 8.01 (San Diego, CA,
Pharmaceuticals 2021,14, 1264 9 of 11
USA). Results were considered significant different when p< 0.05 (* p< 0.05,
** p< 0.01,
*** p< 0.001
) **** p< 0.0001). The other parameters, such as subjective healing time, pain,
and itching were analyzed using the paired-samples sign test with an equal allocation
of ties.
5. Conclusions
Topical application of the MGH-formulation L-Mesitran Soft on cold sores was very
effective. In this patient population with recurrent cold sores, the objective and subjec-
tive healing time was decreased in 86.2% and 79.3% of the patients when compared to
conventional treatments, respectively, and resulted in reducing the healing time from 10.0
to 5.8 days. Moreover, more than 70% of the affected patients experienced less pain and
itching. Together, MGH strongly improves the quality of life of the patients. L-Mesitran
is a potent alternative treatment for treating cold sores, likely due to the combination of
antiviral and wound healing activities.
Supplementary Materials:
The following are available online at https://www.mdpi.com/article/
10.3390/ph14121264/s1, Table S1: Open feedback from the patients, Table S2: Questionnaire for
participating cold sore patients.
Author Contributions:
Conceptualization, P.P.N., D.M., F.A.D.T.G.W. and N.A.J.C.; methodology,
P.P.N., D.M., B.v.W. and F.A.D.T.G.W.; validation, P.P.N., D.M., B.v.W. and F.A.D.T.G.W.; formal
analysis, P.P.N., D.M., B.v.W. and F.A.D.T.G.W.; investigation, P.P.N., P.N., F.A.D.T.G.W. and N.A.J.C.;
resources, P.P.N., D.M., P.N. and N.A.J.C.; writing—original draft preparation, P.P.N., D.M., B.v.W.
and F.A.D.T.G.W.; writing—review and editing, all authors; visualization, P.P.N., D.M., B.v.W. and
F.A.D.T.G.W.; supervision, F.A.D.T.G.W. and N.A.J.C.; project administration, F.A.D.T.G.W. and
N.A.J.C. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement:
The study was conducted according to the guidelines of
the Declaration of Helsinki, and approved by the Ethics Committee of the Dubai Health Authority
(protocol code DSREC-09/2021_07).
Informed Consent Statement:
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: All data relevant to the study are included in the article.
Acknowledgments: The authors would like to thank all the patients involved in the study.
Conflicts of Interest:
P.N. is employed by LERAM pharmaceuticals s.r.o., the distributor of L-
Mesitran products in the Czech Republic. N.A.J.C. is employed by Triticum Exploitatie BV, the
manufacturer of L-Mesitran products. P.N. and N.A.J.C. provided the products free of charge for the
participating patients of this study, and were not involved in the treatment of the patients and did not
have any influence on the outcome of the study, such as the analyses, interpretation, or presentation
of the data. All other authors declare no conflict of interest.
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