Efficacy of a Tyrothricin-Containing Wound Gel in an Abrasive Wound Model for Superficial Wounds
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Original Paper Skin Pharmacol Physiol 2013;26:52–56 Received: July 2, 2012 DOI: 10.1159/000343907 Accepted after revision: September 26, 2012 Published online: November 24, 2012 Efficacy of a Tyrothricin-Containing Wound Gel in an Abrasive Wound Model for Superficial Wounds a b a b a W. Wigger-Alberti M. Stauss-Grabo K. Grigo S. Atiye R. Williams c H.C. Korting a b c bioskin GmbH, Hamburg , Engelhard Arzneimittel GmbH & Co. KG, Niederdorfelden , and Department of Dermatology and Allergology, Ludwig Maximilian University, Munich , Germany Key Words corresponding vehicle resulted in statistically significant im- Tyrothricin ؒ Skin ؒ Superficial wound ؒ Wound healing ؒ proved wound healing with an earlier onset of healing in Abrasive wound model particular. Based on these results obtained using an abrasive wound model, it can be concluded that the addition of tyro- thricin 0.1% to the gel vehicle did not interfere with the im- Abstract proved wound healing seen with the vehicle alone. Background: Topical preparations are a common treatment Copyright © 2012 S. Karger AG, Basel for superficial acute wounds, which at the least do not inter- fere with healing and ideally result in enhanced wound heal- ing irrespective of microbial colonization. Objective: To ex- Introduction amine the effects of a topical antimicrobial gel and its vehicle on the wound healing of standardized, superficial abrasions. There is a high incidence of small, superficial, acute Methods: Thirty-three healthy volunteers were enrolled in wounds which are mainly caused by minor cuts, minor a double-blinded, randomized, intraindividual comparison burn injuries (superficial, second degree) or accidental study. Three standardized, superficial abrasions were in- abrasive trauma during sport participation or other daily duced on their forearms. A tyrothricin 0.1% gel (Tyrosur gel; activities. Dirt or bacteria may have been incorporated Engelhard Arzneimittel GmbH & Co. KG, Niederdorfelden, into the fresh wounds. These wounds involve the epider- Germany) and its vehicle were randomly applied to two of mis and sometimes the superficial portion of the dermis. the test areas, and one lesion remained untreated. Results: They are erythematous and mildly painful [1] . People gen- A significant improvement of wound healing was seen with erally treat such minor everyday wounds themselves, usu- both tyrothricin 0.1% gel and its corresponding vehicle in the ally with dressings or wound gels and ointments with or clinical assessment. The mean area under the curve (AUC) of without antibacterial ingredients which do not interfere wound healing scores was the same for both preparations with healing and ideally result in enhanced wound heal- and the mean reepithelization scores were comparable at all ing irrespective of microbial colonization. Topical agents test points over the entire 12 days. A lower mean AUC repre- senting less reepithelization was found for the untreated test fields. Conclusion: The use of tyrothricin 0.1% gel and its H.C.K. has deceased. © 2012 S. Karger AG, Basel Walter Wigger-Alberti, MD 1660–5527/13/0261–0052$38.00/0 bioskin GmbH Fax +41 61 306 12 34 Burchardstrasse 17 E-Mail [email protected] Accessible online at: DE–20095 Hamburg (Germany) www.karger.com www.karger.com/spp E-Mail walter.wigger @ bioskin.de Downloaded by: UB der LMU München 129.187.254.47 - 10/20/2014 2:33:39 PM and a dressing that is minimally restrictive may be of ad- broad antimicrobial effect of tyrothricin has been estab- vantage especially in wounds that are located over joints lished for years and for feasibility/ethical reasons, only the due to the limitation of movement and contracture of the possible direct wound healing effect beyond antimicro- skin [2] . In general, products that promote a moist wound bial activity was investigated here using a recently pub- environment produce better results in wound healing lished wound model based on noninfected wound lesions than those that promote a dry environment [3–12] . More- only [22] . It was important to establish that tyrothricin over, with any open wound skin infection an increased would have no hindering effects on improved wound risk of systemic infection accompanies prolonged healing. healing observed when using the vehicle alone. Infected wounds might also scar more severely. Therefore, the treatment with topical agents in burn and wound care should also take into consideration the risk of additional M e t h o d s skin infection [2] . Common bacterial pathogens relevant Volunteers for skin infections include Gram-positive bacteria (e.g. The study was performed at bioskin GmbH, Hamburg, Ger- Streptococcus pyogenes, Staphylococcus aureus ) and Gram- many, from September 23 to October 8, 2010. The selection of negative bacteria (e.g. Pseudomonas aeruginosa ) [13] , subjects was in accordance with the requirements of the German while Candida is a common source of – rarer – fungal in- drug law as well as the recommendations of the currently valid revision of the Helsinki Declaration and the ICH-GCP guide- fections [14] . Correspondingly, a large variety of topical lines. The study documents were approved by the ethics commit- antimicrobial agents such as bacitracin, polymyxin B sul- tee of the Hamburg Medical Council. The study was registered at fate, neomycin, povidone-iodine, silver sulfadiazine, the competent authorities. Written informed consent was ob- gentamycin, nystatin and others are used in wound care tained from 33 male or female volunteers, aged 18 years or older [2] . Tyrothricin, an antimicrobial peptide (AMP), was with healthy skin in the test area before the start of the study. The 33 volunteers were randomized (20 women and 13 men, mean age identified and found its way into clinical application de- 42.6 years, range 23–58 years). The following were the main exclu- cades before its mode of action was uncovered [15] . AMPs sion criteria: relevant dermatological diseases such as psoriasis or are small, cationic, amphiphilic peptides with broad- lichen ruber planus; suntan, hyperpigmentation or tattoos in the spectrum microbicidal activity against both bacteria and test fields; dark-skinned persons; diabetes; history of wound- fungi [16] . Furthermore, AMPs might help to overcome healing complications, or keloid and hypertrophic scarring; any clinically significant illness 4 weeks before and during the trial; the growing problems of antibiotic resistance in the treat- known allergic reactions to components of the investigational ment of infectious skin diseases due to their special mode products, and treatment with systemic or locally acting medica- of action against microorganisms, namely, directly target- tions (e.g. antihistamines or glucocorticosteroids) within 2 weeks ing and destroying their membranes [17–19] . Tyrothricin before the first treatment. The use of topical products other than is a polypeptide antibiotic produced by Bacillus brevis [20] the investigational products in the test fields was prohibited dur- ing the clinical trial. Bathing, sauna and sunbathing were not al- consisting of the two cyclic decapeptides gramicidin S and lowed. The adhesive bandages used for semiocclusion were not to tyrocidine A [21] . Both peptides have broad bactericidal be soaked through since the wound healing of the test fields might activity against Gram-positive bacteria; tyrothricin has have been influenced. For the same reason exercise causing exces- been shown not to pose a risk with respect to acquired re- sive sweating had to be avoided. sistance of originally susceptible Gram-positive bacteria Test Design [22] and yeasts, not even in the case of S. aureus , both with After enrollment 3 small superficial, abrasive wounds (10 mm MSSA and MRSA strains [Korting et al., unpubl. data]. In in diameter) were induced, 2 on the right forearm and 1 on the left a pilot study, a tyrothricin-containing wound gel (Tyro- forearm of each volunteer. Treatment with tyrothricin 0.1% gel sur gel; Engelhard Arzneimittel GmbH & Co. KG, Nie- (Tyrosur gel; Engelhard Arzneimittel) and its vehicle (excipients: derdorfelden, Germany) showed an improvement in the cetylpyridinium chloride, purified water, propylene glycol, etha- nol 96%, carbomer, Trometamol) was performed topically under healing of noninfected wounds indicated by a higher lev- semiocclusive conditions. Approximately 100 l of the formula- el of reepithelization compared to the untreated test field tions were applied with a gloved finger to the respective test fields [bioskin GmbH, unpubl. data]. The wound gel, its vehicle on the volar forearm once daily over a 12-day study period (11 and a positive control (an ointment containing dexpan- treatments, days 1–11). One test field remained untreated and thenol) were applied once daily over a 12-day treatment served as control. All 3 wounds were covered with semiocclusive patches (Hansaplast Soft Med, hypoallergic without antiseptic sil- period under semiocclusive conditions. The data support- ver). Wound healing was clinically assessed in all 3 test fields on ed the decision to perform the present confirmatory study days 2, 5, 8 and 12. Adverse events were recorded on each day over with the aim of proving significantly better wound heal- the entire study period. ing efficacy compared to untreated wounds. Since the Efficacy of Wound Gel Skin Pharmacol Physiol 2013;26:52–56 53 Downloaded by: UB der LMU München 129.187.254.47 - 10/20/2014 2:33:39 PM 6 Tyrothricin 0.1% Vehicle 5 Untreated test field 4 Color version available online Fig. 1. Course of mean scores (absolute val- 3 ues) in the clinical assessment of reepithe- lization of superficial wounds following 2 treatment with Tyrosur gel and corre- sponding vehicle and untreated test field. 1 Clinical assessment was performed using values) healing (absolute Wound a 6-point scale (0 = 0% healing, 1 = 1–25% reepithelization, 2 = 26–50% reepitheliza- 0 tion, 3 = 51–75% reepithelization, 4 = 1 75% Day 2 Day 5 Day 8 Day 12/end of trial but not complete reepithelization and 5 = Time points 100% complete healing). Values are pre- sented as means 8 SD.