Therapy
`
`Eur J Dermatol 2008; 18 (4): 433-9
`
`Janusz MARCINKIEWICZ’
`Anna WOJAS-PELC2
`Maria WALCZEWSKAI
`Sylwia LIPKO-GODLEWSKA2
`Renata JACHOWICZ3
`AIdona MACIEJEWSKA3
`Anna BIALECKA4
`Andrzej KASPROWICZ4
`
`’ Department of Immunology Jagiellonian
`University MedicalCollege, 18 Czysta St.,
`31-121 Cracow, Poland
`2 Department of Dermatology Jagiellonian
`University Medical College
`3 Department of PharmaceuticatTechnology
`and Biopharmaceuties Jagielionian
`University Medical College
`4 Center of Microbiological Research and
`
`AutovaccinesLtd. Cracow, Poland
`
`Reprints: J. Marcinkiewicz
`<mmmarcin@cyf-kr.edu.pl>
`
`Article accepted on 1813/2008
`
`Topical taurine bromamine, a new candidate
`in the treatment of moderate inflammatory acne
`vulgaris - A pilot study
`
`Taurine bromamine (TauBr), the product of taurine and hypobromous acid
`(HOBr), exerts anti-inflammatory and antibacterial properties. Recently
`we have shown that Propionibacterium acnes, a potential pathogenic
`agent of acne, is extremely sensitive to TauBr. As topical antibiotics are
`associated with the emergence of resistant bacteria, TauB r seems to be a
`good candidate for topical therapy for acne vulgaris. }n our double blind
`investigation, the efficacy and safety of 3.5 mM TauBr cream was evalu-
`ated. 1% Clindamycin gel (Clindacin T), one of the most common topical
`agents in the treatment of acne vulgaris, was used as a control. Forty
`patients with mild to moderate inflammatory facial acne vulgaris were
`randomly treated with either TauBr or clindamycin for 6 weeks, twice-a-
`day. More than 80% of the patients markedly improved with both treat-
`ments, without any adverse effects observed. Both TauBr and clindamycin
`produced a significant reduction in inflammatory skin lesion counts
`(papules/pustules). After 6 weeks, comparable reductions of ache lesions,
`65% and 68%, were observed in the TauBr and clindamyein groups,
`respectively. In conclusion, these data support our concept that TauBr can
`be used as a topical agent in the treatment of acne vulgaris, especially in
`patients who have already developed antibiotic resistance.
`
`Key words: ache vulgaris, clindamycin, Propionibacterium acnes,
`taurine bromamine (N-bromotaurine), topical treatment
`
`A cne 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. Ache 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 HOCI, are major haloamines
`generated at the site of inflammation [ 16, 17]. Both haloam-
`ines exert anti-inflammatory, anti-oxidant and microbicidal
`,~. properties [ 18-20]. TauBr, similarly to TauC1, decreases the
`production of proinflammatory mediators [20, 21]. The
`_d.. cytoprotective activity of taurine haloaminesrelates to their
`antioxidant properties. In addition, both induce the genera-
`
`tion of heme oxygenase-1 (HO-1), a stress-inducible en-
`zyme, which also has antioxidant and anti-inflammatory
`capacity [22]. TauCl and TauBr reduce generation of reac-
`tive 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 clini-
`cal 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 aches, seems to
`be a promising candidate as a topical agent in ache.
`The aim of this study was to evaluate the clinical effective-
`ness of taurine bromamine as a topical agent in the treat-
`ment of moderate, inflammatory, facial ache 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
`
`EJD, vol. 18, n° 4, July-August 2008
`
`l 433
`
`1 of 7
`
`Almirall EXHIBIT 2034
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`in accordance with the need to develop strategies to mini-
`mize 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 etal. [26], with small modifications (Patent No. EP
`1663195). The presence and concentration of TauBr was
`determined by UV spectra (~. = 200 to 400 nm, molar ex-
`tinction coefficient 430 M-~cm-I at A329). Stock solution of
`TauBr in a phosphate buffer, containing 40-fold excess of
`taurine, was kept at 4 °C before use.
`
`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 inflam-
`matory ache by the presence of 15-50 papules and/or pus-
`tules 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 ache preparations, topical anti-
`microbial 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 anyother type ofacnethan
`vulgaris, patients with any active skin disease other than
`inflammatory ache vulgaris, patients with a history of al-
`lergy to clindamycin. At the initial visit, a medical history
`was obtained and patients were given a dermatological
`Preparation of TauBr in a cream
`examination to determine their eligibility for the study. The
`formulation face lesion count was taken, noting the number of papules,
`pustules, and nodules. Additionally, the investigator deter-
`mined an acne severity grade.
`
`TauBr cream was obtained by emulsifying an aqueous
`solution of TauBr to Cetomacrogol Cream, according to the
`formula of The Extra Pharmacopoeia (Twenty-ninth Edi-
`tion, 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 raM.
`
`Evaluation of bactericidal activity of TauBr in vitro
`
`Propioniacterium acnes (ATCC 11827) strain was grown
`in a Schaedler Agar Base (Difco, USA) at 35 °C for 72
`hours in anaerobic conditions. Staphylococcus epidermidis
`(ATCC 12228) was grown in a Tryptic Soy Broth (Difco,
`USA) at 35 °C for 18 hours in aerobic conditions. Bacteria
`were centrifuged at 1800 x g, washed twice with 0.9%
`NaCI and diluted in saline to a concentration of l x 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 x 105 c.f.u./mL and then incubated with different concen-
`trations of TauBr (1 - 3500 pM). Immediately after the
`incubation (30 rain.), aliquots were removed and the viable
`cell count was determined by the pour-plate method, as
`described previously [24].
`
`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 agree-
`ment to include a placebo group). Each patient was in-
`structed 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 ache lesion count and patients
`were supplied with appropriate amounts of the study medi-
`cation 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 as-
`
`Clinical study design sessed. To optimise the consistency of subjective evalua-
`tions, the same physician saw the patients at each visit.
`
`This was a double-blind, randomized, parallel group evalu-
`ation of topical taurine bromamine (3.5 mM TauBr cream)
`and 1% clindamycin gel (Clindacin T, Polfarma -Tra-
`chomin, Poland). The study was conducted in the Depart-
`ment 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 Hel-
`sinki (South Africa, 1996 amendment) and Good Clinical
`Practice guidelines. Subjects aged 18 years or older pro-
`vided written informed consent to participate.
`
`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 sig-
`nificance 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.
`
`Patient selection
`
`Results
`
`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 ache vulgaris on the face were enrolled in this
`study. Mild to moderate inflammatory ache was defined
`
`Stability oftaurine bromamine (TauBr)
`
`To determine the stability of TauBr in the solution used for
`preparation of TauBr cream, the stock solution of TauBr was
`
`434 ~,
`
`E~o, vol. 18, n°4 July August 2008
`
`2 of 7
`
`

`

`A) A)
`
`4.0
`
`&.
`
`3.5
`I’~ 3.0
`
`~ ~’ 2.0
`
`~--1.5
`C
`1.0
`
`O
`
`0.5
`
`0.0
`
`0
`
`B)
`
`~
`
`¯
`
`--"---~ ¯
`
`-[
`
`1’4
`2’1
`Days B)
`
`4.0 -
`
`3.5|
`
`~< ~ ..,.,
`
`-~ 4 oc
`-II- RT
`
`"~ 2.5-
`
`I.
`
`=
`8
`"’~
`0
`
`1.5-
`1.o-
`0.5-
`0.0
`
`1
`
`2
`
`3 zl 5
`Days
`
`6
`
`-f
`
`8
`
`Figure 1. Stability of TauBr in phosphate buffer (pH.7.4).
`TauBr was monitored by UV absorption spectra and the con-
`centration of TauBr (taurine monobromamine) was estimated
`as described in Methods. The figure shows the results of one of
`3 independent experiments. A) 3 weeks observation at 4 °C; B)
`7 days observation at room temperature (RT) and 4 °C.
`
`stored at different temperatures, for 3 weeks. The decompo-
`sition of TauBr was time and temperature dependent. As
`shown in figure 1, the concentration of TauBr stored at the
`temperature of 4 °C decreased significantly (> 30%)on day
`21, while the same degree of decomposition of TauBr
`stored at room temperature was observed on day 7.
`
`Antimiernbial activity of TauBr to skin bacteria
`
`The stock solution of TauBr was stored for 3 weeks at 4 °C
`and bactericidal activity of TauBr to P. acnes and S. epider-
`midis was tested at different time points, as described in
`Methods. Concentrations of the agent ranged from 1 to
`3500 gM. TauBr shows strong bactericidal activity against
`both strains. However, significant differences between
`P.. aches and S. epidermidis in their susceptibility to TauBr
`have been observed. MBC (minimal bactericidal concen-
`tration) of TauBr to P. aches was - 10 ~tM and to S. epider-
`midis -220 gM (figure 2). The MBC value of TauBr to
`S. epidermidis was similar to IC5o of TauBr for cytokine
`production [21]. To analyse the effect of TauBr storage on
`its bactericidal potential, TauBr was diluted to a concentra-
`tion of 200 pM. 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. aches. On the other
`
`EJD, ,,ol. 18, n° 4, July-Augu.ff 2008
`
`250
`
`200-
`
`~ 100
`
`50
`
`0
`
`150
`
`.t-
`
`..Q 100
`
`-~ 50
`"6
`
`,
`P. acnes
`
`S. epidermidis
`
`-~ P. acnes
`~ S. epidermidis
`
`"~
`
`0
`
`0
`
`1’4 2’1
`Days
`
`2;
`
`Figure 2. Susceptibility of P. acnes (PA) and S. epidermidis
`(SE) to TauBr. A) Minimal bactericidal concentration (MBC)
`of TauBr to P. aches and S. epidermidis. Bacteria (1 x 105/mL)
`were incubated at different concentrations of TauBr in a phos-
`phate buffer (pH 7.4) for 30 minutes. The reduction of bacteria
`growth was determined as described in Methods. Data are
`expressed as MBC values (the concentrations of TauBr that
`cause 100% inhibition of bacteria growth) and represent the
`mean (_+ SE) calculated from 5 separate experiments.
`P = 0.000003 (Mann-Whitney U test) - the differences be-
`tween P aches versus S. epidermidis bacterial strains in their
`susceptibility to TauBr. B) Effect of the preservation of TauBr
`solution on its bactericidal activity. The stock solution of
`TauBr (3.5 raM) was stored for 3 weeks. Bactericidal activity
`of TauBr against P. aches and S. epidermidis was tested on day
`0, 7, 14 and 21. On the indicated day, TauBr was diluted to a
`final concentration of 222 gM (equal to MBC of TauBr to SE)
`and incubated with bacteria as described above. The results are
`expressed as % of killed bacteria and represent one of 3
`independent experiments.
`
`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.
`
`~ 435
`
`3 of 7
`
`

`

`Table 1. Subject disposition and the baseline data
`
`Gender
`Male
`Female
`Age
`Total lesion counts
`Papule counts
`Pustule counts
`Nodule counts
`
`N (%)
`N (%)
`Mean
`Mean -+ SD
`Mean _+ SD
`Mean _+ SD
`Mean -+ SD
`
`Clinical study
`
`Baseline characteristic of subjects
`
`Clindamycin 1% (N= 18)
`
`TauBr (N = 22)
`
`Total (N = 40)
`
`33%
`67%
`22.9
`20.1 +- 13.6
`17.8 +_ 9.4
`3.8 +_. 1.6
`1.2 +- 0.8
`
`36%
`64%
`22.5
`22.8 _+ 16.4
`18.4 + 7.3
`1.0 _+ 0.5
`0.7 -+ 0.5
`
`35%
`65%
`22.7
`20.4 + 13.6
`18.2 _ 11.5
`2.2 _+ 3.6
`0.9 -+ 2.0
`
`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% clindamy-
`cin 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 compa-
`ruble in terms of gender and age distribution (table 1).
`38 subjects completed the study.
`’
`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 sta-
`tistically 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
`
`25-
`
`Lz Baseline
`
`I Week 4
`
`20- I Week 6
`
`¯ £
`_~
`
`15-
`
`,-, 10-
`
`25- ~ Baseline
`
`1 Week4
`
`20 I Week 6
`
`o
`"-
`8 15.
`m
`
`L
`
`I
`
`*
`
`10-
`
`z
`5 54
`
`.
`
`o o
`Nodules Pustules Papules Nodules Pustules Papules
`
`Figure 3. The mean numbers of papules, pustules and nodules
`at the baseline, week 4 and week 6 in TauBr-treated patients,
`The asterisks indicate a significant difference (P < 0.05) in
`lesion counts between the baseline and week 4 *(Pt,4) and
`between the baseline and week 6 **(Pl,6).
`
`Figure 4. C]indamycin-treated patients. The mean numbers of
`papules, pustules and nodules at the baseline, week 4 and week
`6. The asterisks indicate a significant difference (P < 0.05) in
`lesion counts between the baseline and week 4 *(PI,4) and
`between the baseline and wcek 6 **(Pl,6).
`
`436 m
`
`EJo, voL 18, n° 4, July-August 2008
`
`4 of 7
`
`

`

`A)
`
`Week 4
`
`r--i Clindamycin
`ml TauBr
`
`No change
`
`Clear
`
`Moderate/
`marked
`
`Week 6
`
`r-
`O 20-1
`
`"o
`o
`~ 404
`e-
`E
`~. 604
`,~
`.
`~ 8ol
`Baseline
`
`~- TauBr
`-~ Clindamycin
`
`\
`"\
`\
`
`.
`
`\
`I~’-----~-~
`
`_#
`
`Week 4
`
`Week 6
`
`Figure 6. Mean percent reduction of total inflammatory lesion
`counts (pustules plus papules) from the baseline at week 4 and
`week 6. There was no statistical significant difference between the
`TauBr-treated group and the Clindamycin-treated group. Clinda-
`mycin vs TauBr: * at week 4 - p=0.77; # at week 6 - p=0.33.
`
`r-1 Clindamycin
`l TauBr
`
`Discussion
`
`70-
`65-
`60-
`55-
`50-
`’~ 45-
`._~ 40-
`~0. 35"
`’a 30
`25
`20
`15
`10
`5
`0
`
`B)
`
`7O
`65
`60
`55
`50
`co
`E 45
`, ¯ 40
`
`15
`10
`5
`0
`
`A variety of agents are available today to treat acne vulgaris.
`Current clinical strategies in cases of mild to moderate in-
`flammatory acne involve the combination of a topical retin-
`oid, 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 inflam-
`mation 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 re-
`ducing 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 clini-
`cal studies on the topical treatment of patients with mild to
`moderately severe acne vulgaris [12, 34, 35].
`However, P. aches resistance to anti-ache 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 vulgar&? We have previously shown that TauBr is well
`tolerated by mice when applied locally up to a concentra-
`tion 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 proper-
`ties of TauBr may enhance its therapeutic potential in the
`topical treatment of ache vulgaris, as detrimental overpro-
`
`~ 437
`
`No change
`
`Moderate/
`marked
`
`Clear
`
`Figure 5. Total improvement after 4 weeks (A) and after 6
`weeks (B) of the treatment. Results are shown as a percentage
`of patients with the indicated reduction of inflammatory lesion
`counts: (i) "no change" - the reduction < 40% (the effect
`considered as not satisfactory); (ii) "moderate/marked" the
`reduction of 40-90% lesions; (iii) "clear" - patients with no
`more than 1 papule/pustule left.
`
`both TauBr and clindamycin was more pronounced in pa-
`tients 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).
`
`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 dermato-
`logical AEs were classified by investigators as being very
`mild (table 3). None of the subjects discontinued the study
`due to the drug related AEs.
`
`EJD, vol. 18, n° 4, July-August 2008
`
`5 of 7
`
`

`

`Table 2. Mean percent reduction of inflammatory lesion counts (pustules plus papules) from the baseline at week 4 and week 6
`
`Treatment
`
`TauBr
`
`Ctindamycin 1%
`
`*Ache severity
`
`Mild (n = l l)
`
`Moderate (n = 10)
`
`Mild (n = 8)
`
`Moderate (n = 9)
`
`Mean percent reduction of inflammatory lesions (%)
`4 week 6 week
`
`62%
`
`60%
`
`59%
`
`46%
`
`74%
`
`60%
`
`88%
`
`67%
`
`*The imprm,ement in patients with mild (< 15 ir~ammatom lesion counts) versus moderate (15-50 it![tummatory lesion counts) ache. There was no
`sign~f!ean! d~[f~erence between the TauBr-group and CIindumycin-groups.
`
`duction of hydrogen peroxide in acne inflammatory lesions
`has been documented [38, 391.
`In addition, TauBrat rnicromolar, non-cytotoxic concentra-
`tions, exerts bactericidal activity in vitro, which is signifi-
`cantly stronger than that of TauCl [21,24]. Since P. acnes,
`a pathogenic factor of ache, 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 1663t 95).
`To prove this hypothesis, adouble blind, randomised 6-week
`pilot study was perfbrmed to assess the clinical efficacy of
`TauBr cream in a twice-a-day topical therapy. Clindacin T
`(1% clindamycin gel ibrmulation) was used as a reference
`agent commonly used in topical acne therapy [10]. TauBr
`cream formulation contained 3.5 mM of TauBr, the concen-
`tration 350 times higher than the MBC of TauBr for P. ac-
`nes. The addition of taurine in excess to TauBr (taurine
`monobromamine), enables the formation of toxic taurine
`dibromamine (TauBr2) and enhances the antioxidant poten-
`tialoftheformulation[16,26].Taurinealonedoesnotexert
`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 de-
`creased by 65% for both active treatments. The results
`concerning the efficacy of I% clindamycin are in agree-
`ment 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% clinda-
`mycin gel for !2 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 subjezts suffered from mild ache 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 combina-
`tion products confer specific advantages over single-agent
`topical therapy of ache [ 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 atv 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 bro-
`mamine 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 resis-
`taut 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.
`
`Table 3. Overview of adverse events occurred during the study
`
`Clindamycin 1% (N = 18)
`
`Adverse events (AEs)
`
`Dryness or peeling of the skin
`
`Feeling of warmth
`
`Tingling
`
`Burning
`
`Blistering
`
`Itching
`
`Redness
`
`Swelling
`Eczema
`All dermatological AEs
`Non-dermatological AEs
`
`438 .-.
`
`N
`
`1
`
`0
`
`1
`
`0
`
`0
`
`0
`
`0
`
`0
`0
`2
`0
`
`6 of 7
`
`TauBr (N = 22)
`N
`
`1
`
`1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`0
`2
`0
`
`Total (Y = 40)
`
`N
`
`2
`
`1
`
`I
`
`0
`
`0
`
`0
`
`0
`
`0
`0
`4
`0
`
`!
`
`EJD, vr,,L h% r? 4, July-Augu.’,t 2008
`
`

`

`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 die
`treatment of ache vulgaris. ¯
`
`Acknowledgments. Financia! support: This study was
`
`supported by Jagietlonian University Medical College
`(,~;rant number WL/291iPiL) and partly by Center of
`Microbiological Research and Autovaccines Ltd., Krako~;
`PolazM, Conflict of Interest." None.
`
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