DRUGS EXPTL. CLIN. RES. 200K(5/6) 183-190 (2004) TOPICAL TREATMENT OF PARTIAL THICKNESS BURNS BY SILVER SULFADIAZINE. PLUS HYALURONIC ACID COMPARED TO SILVER SULFADIAZINE ALONE: A DOUBLE-BLIND, CLINICAL STUDY KOLLER, J. Center for Burns anc Reconstructive Surgery, Ruzinov Hospital, Bratislava, Slovakia. ‘Summary: Since its introduction into cinical practice in 1967 by Charles Fox Jr, siner suladiazine has been the gold standard for topical bum therapy. The addition toi of hyaluronic acid, which forms a substantial part of the human tissue intercellular matrix, is med at overcoming one offs very few disadvantages, ie. proion- ‘gation of the wound re-epitheliazation process. Since both hyaluronic acid and silver suladiazine have been used! in therapy for decades and their efficacy is wel! documented, a topical teatment combining these two agents was formulated. The aim of the study was lo investigate the efficacy and tolerabily of @ cream contain. ing a hyaluronic acialsiver sufalazine fixed combination, compared with silver sulladiazine cream alone, for the treatment of superficial and deep second. degree burns in a prospective, double-blind, controlled cfnical study. The findings ofthe study confimed that the association of the two campounds in a new topical treatment significantly reduced the healing time and significant accelerated the reduction of local edema occuring short after injury. Furthermore, this new hyaluronic acid and siver suifaolazine formulation has proven to have favorable antibacterial antiedematous and local analgesic effects, together with a clear stimulatory activity on the re-epithetiaization process. This product may, therefore, significantly enrich the assortment of topical med- ‘cations avaiable forthe treatment of bums and skin defects of other origin, Introduction topical treatment modaities for burn injuries. To date, the most frequently used topical agent remains silver ‘sulfadiazine, although it can compromise the rapidity of epitheliaization of treated wounds. —_ Sider sulfacazine is a metalic compound endowed /aidess for comesondence: Jin Koller, M.D., CS, Head with remarkable antibacterial properties against various Since Sultamylon and silver sulfadiazine were in- troduced on the market, very litle has. changed in (of Teaching Deparment for Buns an Reconsructve Suge, Central Tissue Benk, Universty Hospital Batslava Pubinow Fudinovska 6 - 821 0? Bratislava, Slovak Repubic Tolan: +421 2.4333 6741 E-mail koler@nsprsk, jankller@hatmallcam 0378-6501 /2004/5/6 00183~7 $02.50/0 fungi and dermatophytes and, in particular, against thase micro-organisms often found in infected skin lesions (1-3). Sulfadiazine exerts its bacteriostatic ef {ect by acting on the cell membranes of micro-organ- (© 2004 Bioscience Exipxint Inc 183184 Kotter J sms, while siver nitrate exerts its effect on the endo cellular stuctures. Applied on exudative wounds, siver sulfadiazine releases its silver ions, which increase the bacterio- static effect ofthe sulfonamide radical (4-6). Among local antiseptics,siver sulfadiazine is especially ind cated for therapeutic use: it combines high efficacy ‘and good local tolerance, itis absorbed by the skin nly in negligible quantities, and as a consequence, ithas practically no systemic toxicity Hyaluronic acid (HA) is a high molecular weight polyanionic polysaccharide present in all connective tissues; itbetongs to the class of alycosaminoglycans, better known as mucopolysacchares HA is of great biological importance for the skin, cartilage, synovial fuids, eyes and mucosa, In the skin of a noimal aduit subject, more than half ofthe polysaccharides ofthe ground substance filing up the interstitial space between collagen fibers and cells is made of HA (7), sodium hyaluronate being the pre- dominant form at physiological pH HA\has important mechanical and structural fune- tions end also plays a key role in wound-healing processes (8-10), Brietly, HA tiggers macrophagic response and induces neoangiogenesis in injured tissues, Macrophages are attracted to the damaged site, where they exert their phagocytic activity, remov- ing all necrotic residues. During this process, macro- phages release specilc trophic factors aimed at the fibroblast population whose migrations and biosyn- thetic acinvity is stimulated, leading to the deposition ‘of new collagen. Thus, HA stimulates fibrin develop- ment and the phagocytic mobily and activity of neu- trophil granulocytes and macrophages, and it ele vates the release of chemotactic factors fr fisroblast altraction. ts use for topical treatment of slow-recov- ‘ery ulcerative lesions, such as burns and bedsores, 's well documented (11-14) Since both HA and siver suifadiazine have been sed in therapy for decades and their efficacy is well known, a topical treatment combining these two agents has been formulated, ‘The aim of this study was to investigate the eff- cacy and tolerabilly of @ cream containing an HA-si- ver sulfadiazine fixed combination compared with a ‘eam containing siver sulfadiazine alone, forthe treat ‘ment of superficial and deep second-degree burns in ‘a prospective, double-blind, controled experimental design Materials and methods Patients Thirty-three male and female patients took part in this randomized, double-blind, controlled, par- aletgoup cinical sticy, The patents, aged 18 to 80 years, had la-degree (superficial and ib-degree (Geep dermal) bums exceeding 5% of the body sur- ace area, which corresponds to about 200 cm? in an average adult patient Patients were selected accord- ing tothe inclusion and exclusion erteria set down in tne study protocol. Physical examination and medical history were expected to be normal, as was the labo- ratory screening with the exception of burn-elated findings. The folowing exclusion ofteria were used presence of cardiovascular, hematologic, endocrino- logic, gastrointestinal, hepatic, or renal disease; cis- ease of the central nervous system; long-term drug tweatment due {0 other pathological findings; preg nancy; oa history of drug and alcohol abuse. The clinical study was caried out in accordance with the directive issued by the 1964 Declaration of Helsink a3 amended in Tokyo in 1975 and in Venice in 1969, Unconditional epproval from the local ethics committee was obtained, and prior to entry to the study, each patient was duly informed by the invest- gator about the full nature and purpose ofthe study, including possibie risks and side effects, and full wrt ten informed consent was obtained,Treatment, The recruited patients were randomly allocated to one ofthe two treatment groups set down inthe study protocol according to a comauter-gener- ated randomization list. To full the blind design set down in the study protocol, the two cream formula- tions tested, HA-siver sulfadiazine cream containing 0.2% HA and 1% silver sulfadiazine (lalugen Plus®, IBSA insttut Biochimique SA, Lugano, Switzerland) ‘and siver sulfadiazine cream containing 1% silver sulfadiazine only (IBSA institut Biochimique SA), were provided in unmarked white tubes containing 25 g of ‘cream each, The two products had the same appear ‘ance, color and consistency. After having cleansed the ‘bum wounds with sterle saline solution, approximate- y 5 g/100 cm?of cream was applied topically direct- ly from the tube and spread evenly using a sterile wooden spatula. Then the wounds were covered with several layers of stele ine gauze which wes fixed with bandages. The treatment was applied once a day nti the wounds healed, but forno longer than 4 weeks, Prior to each new application, the residue of the pre- vious application was carefully removed from the wounds using sterile saline solution Clinical parameters, Clinical evaluations were per- formed by suitably trained and qualified staff su geons of the Burns Center. Atte an inital evaluation prior to the start of treatment, clinical parameters were evaluated weekly for the entire duration of the treatment period. The primary efficacy endpoint was residual bur (wound) area, expressed as a percent- age of the pretreatment value, Other parameters in- Cluded "time to nealing’ expressed as total time in days required for the complete healing of the wound; focal edema assessed by the investigator on a four point severity scale (0 = absent; 1 = mikd, 2 = moder: ate; 9 = severe edema); pain assessed by the inves- tigator on a four-point severty scale (0 = absent; 3 severe pain); local infection evaluated as present or absent; palien’s and investigator's assessment on Silver sulfadiazine addled with hyaluronic acid forthe treatment of patel thickness bums the global response to therapy using a four-point scale (none, air, good, excellent); and local tolerability assessed by both the investigator and the patient using a four-point scale (bad, far, good, excellent), ‘The healing process was monitored by recording the percentage of the residual wound area on days 1, 7, 14,21 and 28, and comparing it with pretreatment values. According to the study protocol, treatment was stopped when complete healing of the wound had occurred, je. with 100% epitheliaization and 0% residual wound area, and the day upon which this ‘occurred was recorded as ‘time to healing,” Any adverse event occurring during or immed ately atter the treatment period was recorded and duly reported in the patient's case record form, All concomitant medications were also recorded, both betore study start and during the study, Laboratory testing. On day 1 and on the final day of the study, samples of blood and urine were taken for laboratory ‘esting. Hematological testing mea- sured valves for ted blood cells (RBC), hemoglobin, hhematoci, white b'ood cells, and platelets. Bochern- ical testing measured values for glucose, uric acid, Urea, creatinine, ota proteins, tola bilirubin, AST, ALD. GGT and alkane phosphatase, Analysis of urine was also carried out. Biochemical and hematological lab- ‘ratory testing were performed at the Department of Biochemistry and at the Department of Hematology Of the Rukinov General Hospital in Bratislava. Sero- logical screening and bacteriological investigations were performed by the State Health Institute in Bra- tislava ‘Statistical methods. The completed case recard forms were transferred to an independent organiza- tion (BIS Informatica & Idee S.r, Milan, aly) for the data management operations and the final statistical analysis, The continuous variables were analyzed by ‘analysis of variance (ANOVA) with repeated measures, 185