ARTICLE
Auteur(s) : Janusz
Marcinkiewicz1, Anna Wojas-Pelc2, Maria
Walczewska1, Sylwia Lipko-Godlewska2, Renata
Jachowicz3, Aldona Maciejewska3, Anna
Białecka4, Andrzej Kasprowicz4
1Department of Immunology Jagiellonian University
Medical College, 18 Czysta St., 31-121 Cracow, Poland
2Department of Dermatology Jagiellonian University
Medical College
3Department of Pharmaceutical Technology and
Biopharmaceutics Jagiellonian University Medical College
4Center of Microbiological Research and Autovaccines
Ltd. Cracow, Poland
accepté le 18 Mars 2008
Acne vulgaris is the most common inflammatory skin disorder that
widely affects adolescents and young adults. Pathogenesis of acne
is complex, involving multiple abnormalities of the pilosebaceous
unit, including hyperkeratinisation, sebum production, bacterial
proliferation and inflammation [1-3]. One of the pathogenic factors
of acne is the proliferation of normal flora and, especially, of
Propionibacterium acnes. Acne is not an infectious disease, but the
role of P. acnes is outlined by much data [4-6]. Many oral and
topical agents are available nowadays to treat acne vulgaris. These
include topical antibiotics known for their anti-bacterial and
anti-inflammatory properties, such as clindamycin, the principle
antibiotic used [7-11]. However, an increasing number of isolated
P. acnes strains with unidentified resistance mechanisms indicate
the need to develop new strategies to minimize the use of
antibiotics in acne therapy [12-15].
Taurine bromamine (N-bromotaurine, TauBr) and taurine chloramine
(TauCl), the physiological products of reactions between taurine
and HOBr or HOCl, are major haloamines generated at the site of
inflammation [16, 17]. Both haloamines exert anti-inflammatory,
anti-oxidant and microbicidal properties [18-20]. TauBr, similarly
to TauCl, decreases the production of proinflammatory mediators
[20, 21]. The cytoprotective activity of taurine haloamines relates
to their antioxidant properties. In addition, both induce the
generation of heme oxygenase-1 (HO-1), a stress-inducible enzyme,
which also has antioxidant and anti-inflammatory capacity [22].
TauCl and TauBr reduce generation of reactive oxygen species (ROS)
[19, 23]. However, only TauBr, but not TauCl, neutralizes hydrogen
peroxide, the major oxygen species generated at a site of
inflammation [21]. On the other hand, TauBr shows strong
antibacterial activity at physiological, non-cytotoxic
concentrations. From a clinical point of view, it is interesting
that the susceptibility of P. acnes to TauBr appeared to be
significantly higher than that of Staphylococcus epidermidis, as we
have recently shown [24]. Both species, P. acnes and S.
epidermidis, belong to the bacterial flora of the skin, but only P.
acnes is considered to be involved in the pathogenesis of chronic
skin inflammation in acne vulgaris [1, 4, 6]. Therefore, TauBr, due
to its ability to selectively kill P. acnes, seems to be a
promising candidate as a topical agent in acne.
The aim of this study was to evaluate the clinical effectiveness
of taurine bromamine as a topical agent in the treatment of
moderate, inflammatory, facial acne vulgaris. In this paper we also
discuss the rationale of acne therapy with TauBr, related to its
anti-inflammatory, anti-oxidant and anti-bacterial properties. As
P. acnes resistance has become a worldwide problem, the lack of
evidence of bacteria resistance against TauCl and TauBr [24, 25]
supports the idea of using TauBr for acne therapy. This approach is
also in accordance with the need to develop strategies to minimize
the use of antibiotics in the therapy of acne.
Materials and methods
Synthesis and determination of TauBr
Taurine bromamine (TauBr) was prepared as described by Thomas et
al. [26], with small modifications (Patent No. EP 1663195). The
presence and concentration of TauBr was determined by UV spectra (λ
= 200 to 400 nm, molar extinction coefficient 430
M–1cm–1 at A329). Stock solution
of TauBr in a phosphate buffer, containing 40-fold excess of
taurine, was kept at 4 °C before use.
Preparation of TauBr in a cream formulation
TauBr cream was obtained by emulsifying an aqueous solution of
TauBr to Cetomacrogol Cream, according to the formula of The Extra
Pharmacopoeia (Twenty-ninth Edition, 1989). Formulations were
prepared in aseptic areas according to the standards of Good
Manufacturing Practice for Pharmaceutical Products. The final
concentration of TauBr in a cream formulation was 3.5 mM.
Evaluation of bactericidal activity of TauBr in vitro
Propioniacterium acnes (ATCC 11827) strain was grown in a Schaedler
Agar Base (Difco, USA) at 35 oC for 72 hours in
anaerobic conditions. Staphylococcus epidermidis (ATCC 12228) was
grown in a Tryptic Soy Broth (Difco, USA) at 35 oC
for 18 hours in aerobic conditions. Bacteria were centrifuged at
1800 × g, washed twice with 0.9% NaCl and diluted in saline to a
concentration of 1 × 108 c.f.u./mL. Before use, bacteria
were diluted in a phosphate buffer (PBS) (pH 7.4) to achieve a
final concentration of 1 × 105 c.f.u./mL and then
incubated with different concentrations of TauBr (1 – 3500 μM).
Immediately after the incubation (30 min.), aliquots were
removed and the viable cell count was determined by the pour-plate
method, as described previously [24].
Clinical study design
This was a double-blind, randomized, parallel group evaluation of
topical taurine bromamine (3.5 mM TauBr cream) and 1%
clindamycin gel (Clindacin T, Polfarma –Trachomin, Poland). The
study was conducted in the Department of Dermatology, Jagiellonian
University Medical College in Krakow, Poland. The study was
approved by the appropriate regulatory and ethics committees in
Poland and was performed in accordance with the Declaration of
Helsinki (South Africa, 1996 amendment) and Good Clinical Practice
guidelines. Subjects aged 18 years or older provided written
informed consent to participate.
Patient selection
40 patients (14 men and 26 women), at least 18 years of age, with a
mean age of 22.7 years, with mild to moderate inflammatory acne
vulgaris on the face were enrolled in this study. Mild to moderate
inflammatory acne was defined according to the Leeds Revised Acne
Grading System [27]. Mild inflammatory acne was defined by the
presence of not more than 15 papules and/or pustules and moderate
inflammatory acne by the presence of 15-50 papules and/or pustules
and not more than three nodules on the face. Patients with a
predominantly comedonal acne were excluded. All concomitant
treatments were withdrawn according to the following schedule:
topical acne preparations, topical antimicrobial agents, medicated
cosmetics, soaps, or shampoos at least 2 weeks before entry,
systemic anti-microbials at least 3 months before entry, and oral
isotretinoin at least 2 years before entry. Exclusion criteria
included: pregnant and lactating women, patients with more than
three nodular lesions on the face, patients with any other type of
acne than vulgaris, patients with any active skin disease other
than inflammatory acne vulgaris, patients with a history of allergy
to clindamycin. At the initial visit, a medical history was
obtained and patients were given a dermatological examination to
determine their eligibility for the study. The face lesion count
was taken, noting the number of papules, pustules, and nodules.
Additionally, the investigator determined an acne severity grade.
Treatment regiment
Patients who met all eligibility criteria were assigned to receive
either 1% clindamycin gel or taurine bromamine in a double-blind,
randomized manner (There was no agreement to include a placebo
group). Each patient was instructed to apply the medication to the
face twice a day. Patients were required to return for a control
visit at weeks: 1, 2, 3, 4, 5 and 6 of therapy, to assess clinical
improvement and to exclude the presence of adverse effects. At each
visit, the investigator repeated the acne lesion count and patients
were supplied with appropriate amounts of the study medication for
the next week.
Study assessments
Treatment efficacy was determined by inflammatory lesion counts -
noting the number of papules and pustules on the whole face.
Macules, comedones and deep inflammatory lesions were not included
in the lesion counts. At each visit, the physician assessed the
global change from the baseline. Adverse events were recorded
throughout the study and their severity and relationship to the
treatment was assessed. To optimise the consistency of subjective
evaluations, the same physician saw the patients at each visit.
Statistical analysis
Demographic data were analyzed using Student’s T-test. Percent
changes from the baseline in the acne lesion count were analyzed
using analysis of covariance. Statistical significance was defined
as p ≤ 0.05. Results are expressed as Mean ± SEM. Statistical
differences in the susceptibility to TauBr between P. acnes and S.
epidermidis were analyzed using the Mann – Whitney U test.
Results
Stability of taurine bromamine (TauBr)
To determine the stability of TauBr in the solution used for
preparation of TauBr cream, the stock solution of TauBr was stored
at different temperatures, for 3 weeks. The decomposition of TauBr
was time and temperature dependent. As shown in figure 1, the concentration
of TauBr stored at the temperature of 4 oC
decreased significantly (> 30%) on day 21, while the same
degree of decomposition of TauBr stored at room temperature was
observed on day 7.
Antimicrobial activity of TauBr to skin bacteria
The stock solution of TauBr was stored for 3 weeks at
4 oC and bactericidal activity of TauBr to P. acnes
and S. epidermidis was tested at different time points, as
described in Methods. Concentrations of the agent ranged from 1 to
3500 μM. TauBr shows strong bactericidal activity against both
strains. However, significant differences between P. acnes and S.
epidermidis in their susceptibility to TauBr have been observed.
MBC (minimal bactericidal concentration) of TauBr to P. acnes was
~10 μM and to S. epidermidis ~220 μM (figure 2). The MBC value
of TauBr to S. epidermidis was similar to IC50 of TauBr
for cytokine production [21]. To analyse the effect of TauBr
storage on its bactericidal potential, TauBr was diluted to a
concentration of 200 μM. As shown in figure 2B, the solution of
TauBr stored for 21 days lost 50% of activity against S.
epidermidis, but only 10% against P. acnes. On the other hand,
after 7 days, the agent did not alter its bactericidal activity
against either bacterial strain tested. Therefore, in our clinical
study, to maintain a bactericidal effect of TauBr in vivo, TauBr
cream was prepared weekly and used twice-a-day, for 7 consecutive
days, in the topical therapy of acne vulgaris. In the preliminary
study, 3.5 mM solution of TauBr, applied on the skin of healthy
volunteers for just 30 minutes, decreased the number of skin
bacteria more than 1000 times. On the contrary, the effect of
vehicle (plecebo) on skin bacteria was negligible (data not shown).
No adverse effects were observed.
Clinical study
Baseline characteristic of subjects
A total of 40 subjects (14 male; 26 female) were included in the
study: 22 subjects (8 male: 14 female) in the TauBr group, 18
subjects (6 male: 12 female) in the 1% clindamycin gel group. The
mean age of the whole group of 40 patients was 22.7 years of age,
in the TauBr group – 22.5, and in the clindamycin group – 22.9. All
subjects in both groups were white/Caucasians. Both groups were
comparable in terms of gender and age distribution (table 1). 38 subjects completed the study.
Table 1 Subject disposition and the baseline data
|
|
Clindamycin 1% (N= 18)
|
TauBr (N = 22)
|
Total (N = 40)
|
|
Gender
|
|
|
|
|
|
Male
|
N (%)
|
33%
|
36%
|
35%
|
|
Female
|
N (%)
|
67%
|
64%
|
65%
|
|
Age
|
Mean
|
22.9
|
22.5
|
22.7
|
|
Total lesion counts
|
Mean ± SD
|
20.1 ± 13.6
|
22.8 ± 16.4
|
20.4 ± 13.6
|
|
Papule counts
|
Mean ± SD
|
17.8 ± 9.4
|
18.4 ± 7.3
|
18.2 ± 11.5
|
|
Pustule counts
|
Mean ± SD
|
3.8 ± 1.6
|
1.0 ± 0.5
|
2.2 ± 3.6
|
|
Nodule counts
|
Mean ± SD
|
1.2 ± 0.8
|
0.7 ± 0.5
|
0.9 ± 2.0
|
Efficacy evaluation
Both TauBr and clindamycin treatments were associated with a
progressive reduction in acne lesion count after 4 and 6 weeks of
the therapy. At the baseline, in both groups of patients, the mean
number of papules was 18.2, pustules 2.2 and nodules 0.9 (table 1). The improvement in lesion counts
(absolute values) is shown in figure 3 and figure 4. At the baseline
in the TauBr group, the mean number of papules was 18.4, of
pustules it was 1.0 and of nodules 0.7, in the clindamycin group
the mean number of papules was 17.9, of pustules – 3.8 and of
nodules – 1.2. After 6 weeks treatment in the TauBr group the
mean number of papules was 6.3, of pustules – 0.6 and of
nodules – 0.4 and in the clindamycin group the mean number of
papules was 5.8, of pustules – 1.1 and of nodules – 0.4.
A significant (p < 0.01) reduction in the number of papules was
observed in TauBr-treated patients at week 4 and week 6 (figure 3). Similarly, a
statistically significant reduction of the number of papules (P
< 0.01) was observed in the clindamycin treated patients (figure 4). In both
experimental groups (TauBr- and clindamycin- treated patients) a
progressive reduction of total acne lesion numbers was observed
after 4 and 6 weeks of the therapy (figures 3 and 4).
The percentage of patients with at least 40% improvement after
4-week therapy is shown in figure 5A. The percentage
was notably greater for TauBr at week 4 (81% – TauBr group; 71% –
clindamycin group). On the other hand, at week 6, the percentage of
subjects markedly improved or almost cleared after treatment with
1% clindamycin was higher than that after treatment with TauBr.
However, the difference between the groups was numerical but not
statistically significant (figure 5B).
The results of the percentage reduction from the baseline in
inflammatory lesions (papules and pustules together) at week 4 were
60% in the whole TauBr group and 49% in the clindamycin group (figure 6).
Importantly, the efficacy of both TauBr and clindamycin was more
pronounced in patients with mild than moderate acne (table 2).
After 6 weeks of such treatment the percent reduction in total
inflammatory lesions from the baseline was 65% in the TauBr group
and 68% in the clindamycin group (figure 6). There was no
statistically significant difference between the groups. The above
results demonstrate that the efficacy of topical TauBr is similar
to that of 1% clindamycin (Clindacin T).
Table 2 Mean percent reduction of inflammatory lesion
counts (pustules plus papules) from the baseline at week 4 and week
6
|
Treatment
|
*Acne severity
|
Mean percent reduction of inflammatory lesions (%) 4 week 6
week
|
|
TauBr
|
Mild (n = 11)
|
62%
|
74%
|
|
Moderate (n = 10)
|
60%
|
60%
|
|
Clindamycin 1%
|
Mild (n = 8)
|
59%
|
88%
|
|
Moderate (n = 9)
|
46%
|
67%
|
*The improvement in patients with mild (< 15
inflammatory lesion counts) versus moderate (15-50 inflammatory
lesion counts) acne. There was no significant difference between
the TauBr-group and Clindamycin-groups.
Safety evaluation
40 subjects experienced a total of 4 adverse events (AEs): 2
patients in the clindamycin-treated group and 2 in the TauBr-group.
Both active treatments were well tolerated. No non-dermatological
AEs were reported. All dermatological AEs were classified by
investigators as being very mild (table
3). None of the subjects discontinued the study due to the
drug related AEs.
Table 3 Overview of adverse events occurred during the
study
|
Clindamycin 1% (N = 18)
|
TauBr (N = 22)
|
Total (N = 40)
|
|
Adverse events (AEs)
|
N
|
N
|
N
|
|
Dryness or peeling of the skin
|
1
|
1
|
2
|
|
Feeling of warmth
|
0
|
1
|
1
|
|
Tingling
|
1
|
0
|
1
|
|
Burning
|
0
|
0
|
0
|
|
Blistering
|
0
|
0
|
0
|
|
Itching
|
0
|
0
|
0
|
|
Redness
|
0
|
0
|
0
|
|
Swelling
|
0
|
0
|
0
|
|
Eczema
|
0
|
0
|
0
|
|
All dermatological AEs
|
2
|
2
|
4
|
|
Non-dermatological AEs
|
0
|
0
|
0
|
Discussion
A variety of agents are available today to treat acne vulgaris.
Current clinical strategies in cases of mild to moderate
inflammatory acne involve the combination of a topical retinoid,
topical benzoyl peroxide and topical antibiotics [8, 9, 11, 28,
29]. Topical antibiotics are known for their anti-bacterial,
anti-oxidant properties and their capacity to inhibit inflammation
caused by bacteria. During the last few years benzoyl peroxide and
clindamycin have been the two most widely prescribed topical drugs
in the treatment of acne [4, 30-33]. Benzoyl peroxide shows
antibacterial activity and decreases inflammatory damage by
inhibiting the release of reactive oxygen species (ROS), due to the
killing of neutrophils [10]. Clindamycin, a bactericidal
antibiotic, suppresses the complement-derived chemotaxis of
neutrophils, thereby reducing the potential for inflammation [10].
Several topical formulations of clindamycin are currently marketed.
One of them, 1% clindamycin gel, has demonstrated efficacy and good
overall tolerability in several well designed clinical studies on
the topical treatment of patients with mild to moderately severe
acne vulgaris [12, 34, 35].
However, P. acnes resistance to anti-acne antibiotics is being
increasingly reported, and the emergence of resistant strains, the
primary factor in the pathogenesis of acne vulgaris, can be
associated with the therapeutic failure of topical treatment [13,
36, 37]. Searching for an alternative topical anti-acne drug, we
have chosen taurine bromamine. Is TauBr a good candidate for
topical therapy in treating acne vulgaris? We have previously shown
that TauBr is well tolerated by mice when applied locally up to a
concentration of 5 mM (Koprowski, Ph. D Thesis 2005). In vitro, at
non-cytotoxic concentrations, TauBr exerts anti-inflammatory
properties by induction of heme oxygenase-1 expression and by
inhibition of inflammatory mediator generation by activated
macrophages, with effectiveness similar to a well documented
activity of taurine chloramine (TauCl) [20-22]. Moreover, TauBr
showed antioxidant properties by inhibition of ROS generation,
mainly by degradation of hydrogen peroxide [24]. The latter
properties of TauBr may enhance its therapeutic potential in the
topical treatment of acne vulgaris, as detrimental overproduction
of hydrogen peroxide in acne inflammatory lesions has been
documented [38, 39].
In addition, TauBr at micromolar, non-cytotoxic concentrations,
exerts bactericidal activity in vitro, which is significantly
stronger than that of TauCl [21, 24]. Since P. acnes, a pathogenic
factor of acne, is more susceptible to TauBr than S. epidermidis,
it supports the concept of using TauBr as a selective topical
disinfectant in treatment of acne vulgaris, without affecting non
pathogenic skin flora. ([40], Patent No. EP 1663195).
To prove this hypothesis, a double blind, randomised 6-week
pilot study was performed to assess the clinical efficacy of TauBr
cream in a twice-a-day topical therapy. Clindacin T (1% clindamycin
gel formulation) was used as a reference agent commonly used in
topical acne therapy [10]. TauBr cream formulation contained
3.5 mM of TauBr, the concentration 350 times higher than the
MBC of TauBr for P. acnes. The addition of taurine in excess to
TauBr (taurine monobromamine), enables the formation of toxic
taurine dibromamine (TauBr2) and enhances the
antioxidant potential of the formulation [16, 26]. Taurine alone
does not exert any anti-bacterial properties. In this pilot study a
placebo group was not included, however, in the preliminary in vivo
experiments, we have shown that TauBr, but not vehicle,
significantly reduced the number of skin bacteria.
The results from this study demonstrate an improvement in the
inflammatory lesions of acne over a 6-week treatment period with
the two topical therapies used. Basically, the efficacy evaluation
at the end point shows no difference between TauBr and Clindacin T
treatment. However, after the first 4 weeks of the treatment, a
greater improvement (reduction) in total lesion counts was observed
in the TauBr group than in the Clindacin T group. In our study,
after the 6-week treatment, the inflammatory lesion counts
decreased by 65% for both active treatments. The results concerning
the efficacy of 1% clindamycin are in agreement with other reports.
For example, M. Alirezai et al. [32] demonstrated a 65% reduction
from the baseline in the inflammatory lesion count in patients with
moderate acne (the majority of subjects) treated topically with 1%
clindamycin gel for 12 weeks. In our experimental design, a similar
improvement was already observed after 6 weeks. This may be
explained by the fact that approximately 50% of our subjects
suffered from mild acne and were more susceptible to the
clindamycin treatment than the subjects with moderate acne. Greater
effects (> 70% improvement) have been observed in trials in
which patients were treated with clindamycin + benzoyl peroxide
[30]. These results support the commonly accepted opinion that the
combination products confer specific advantages over single-agent
topical therapy of acne [10, 15, 28, 31]. It also suggests that a
therapeutic effect of TauBr may be improved by using TauBr in
combination with other topical anti-acne agents. Further studies
are necessary to evaluate this problem. Importantly, the TauBr
cream was well tolerated and there were no local adverse effects
reported during the study.
In conclusion, these data demonstrate that the taurine bromamine
cream formulation is of efficacy comparable to that of 1%
clindamycin gel formulation in the topical treatment of acne
vulgaris. However, topical clindamycin, like other antimicrobials,
is associated with the emergence of resistant microorganisms. By
contrast, TauBr provides potent anti-bacterial and
anti-inflammatory activity without the risk of inducing bacterial
resistance. Therefore, TauBr used in monotherapy or in a
combination with other medicine may be a desirable alternative
treatment for acne vulgaris. Further 8 -12 week, active and
placebo-controlled clinical studies, performed on a greater number
of subjects, are necessary to confirm the clinical efficacy of
TauBr in the treatment of acne vulgaris.
Acknowledgments
Financial support: This study was supported by Jagiellonian
University Medical College (grant number WŁ/291/P/L) and partly by
Center of Microbiological Research and Autovaccines Ltd., Krakow,
Poland. Conflict of Interest: None.
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