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The safety and efficacy of a proteolytic ointment in the treatment of chronic ulcers of the lower extremity
THERAPY The safety and efficacy of a proteolytic ointment in the treatment of chronic ulcers of the lower extremity Anna F. Falabella, MD, Polly Carson, William H. Eaglstein, MD, and Vincent Falanga, MD Miami, Florida Background: Elase is a widely used ointment consisting of a combination of 2 proteolytic enzymes, fibrinolysin and desoxyribonuclease (DNAse). It is said to promote debridement of necrotic and purulent debris from skin ulcers. Objective: Our purpose was to assess the efficacy and safety of this ointment and its components in the treatment of chronic ulcers of the lower extremity. Methods: This was a double-blind, randomized, prospective study of 84 patients with leg ulcers exhibiting necrotic and purulent debris, who were treated for 21 days with twicedaily applications of the ointment, fibrinolysin, DNAse, or who received the ointment vehicle (placebo). We assessed 6 efficacy features: ulcer size, purulent exudate, necrotic tissue, erythema, pain, and overall condition of the lesion at days 8, 15, and 21 after initiation of treatment. We also assessed the frequency of adverse effects. Results: All treatments produced some improvement in the efficacy parameters and overall condition of the ulcers by week 3, but no statistically significant difference was found when compared with placebo. No serious adverse effects were noted. A later retrospective reanalysis of the data found a statistically significant reduction of purulent exudate only at days 3 and 7 of treatment in the group treated with the complete ointment, but not in the other features. Conclusion: The proteolytic ointment provides no long-term clinical benefit in reducing purulent exudate, pain, erythema, necrotic tissue, or overall condition of chronic leg ulcers when compared with either of its two components or placebo. (J Am Acad Dermatol 1998;39:737-40.)
Elase ointment contains 2 active ingredients, fibrinolysin and desoxyribonuclease (DNAse), which are proteolytic enzymes of bovine origin.1 Fibrinolysin lyses and dissolves fibrinous exudates. DNAse produces polynucleotides by depolymerizing deoxyribonucleoproteins and desoxyribonucleic acids present in the necrotic tissue and exudate of skin ulcers.1 Presumably, these enzymatic activities produce a thinned, less tenacious purulent exudate. Both fibrinolysin and DNAse are said to act on extracellular tissue and From the Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine. Supported by the Warner-Lambert/Parke-Davis Corp. Reprint requests: Vincent Falanga, MD, Professor of Dermatology, Boston University, Chairman of Dermatology, Roger Williams Medical Center, Elmhurst Bldg, 50 Maude St, Providence, RI 02908. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/92725
disintegrating cells, but not on living tissue. Enzyme debridement may reduce the need for painful and more costly surgical debridement. On the basis of the enzymatic activity of its 2 components, the proteolytic ointment might be expected to aid in the debridement of necrotic or purulent debris and to produce a clean wound surface. Because it does not act on living tissue, it would not be expected to delay healing. However, proof of efficacy is not available. Previous studies of the efficacy of fibrinolysin and DNAse include those of Roman-Calderon et al,2 who treated 30 patients with second- and third-degree burns, and of Schwartz et al,3 who treated 42 patients with secondary healing wounds. These reports indicated that the proteolytic ointment was an effective debriding agent, but the number of ulcers evaluated was small. The present larger study was undertaken to assess the clinical efficacy and safety of 737
738 Falabella et al
Journal of the American Academy of Dermatology November 1998
Fig 1. Proteolytic ointment or its components have no effect on removal of purulent exudate. Results represent mean scores for each treatment group. Scores for presence of exudate: 0 = none; 1 = < 25%; 2 = 26%50%; 3 = 51%-75%; 4 = > 75%.
Fig 2. Proteolytic ointment or its components failed to remove necrotic tissue. Results represent mean scores for each treatment group. Scores for presence of necrotic tissue: 0 = none; 1 = < 25%; 2 = 26%-50%; 3 = 51%-75%; 4 = > 75%.
the proteolytic ointment and its components in patients with chronic exudative ulcers of the lower extremities.
size increased; systemic antibiotic therapy was required; surgical debridement became necessary; or serious intercurrent illness developed that interfered with skin healing. The materials for the study were supplied by the manufacturer and packaged so as to maintain the blind. The 4 treatment groups were as follows: complete proteolytic ointment (1.28 U fibrinolysin/g, with 1006 U of desoxyribonuclease/g); fibrinolysin in ointment vehicle (1.15 U of fibrinolysin/g); desoxyribonuclease in ointment vehicle (1027 U of desoxyribonuclease/g); and the vehicle ointment alone. Treatment was applied twice daily following a standard regimen. First, the ulcer was cleansed with sterile normal saline. Then, a thin layer of the study drug was applied over the ulcer bed, followed by the application of a nonadherent dressing (Telfa). Before enrollment, a history was obtained and a physical examination was performed on each patient. Efficacy was determined by evaluating the ulcers immediately before treatment, twice a week during treatment, and on the day treatment was terminated (day 21). Observations included ulcer area measurement (in square centimeters); presence of purulent exudate, necrotic tissue, and erythema/redness around the edges, all graded on a scale of 0 to 4; presence of pain graded on a scale of 0 to 3; overall final condition of the ulcer, graded as worse, no change, minimal, moderate, or excellent improvement with respect to baseline. Criteria for overall efficacy were based on primary and secondary features. The primary features were decrease in purulent exudate and necrotic debris. Secondary features were reduction in erythema at ulcer edges, decreased pain, and improvement in overall condition. Evaluation of safety was based on occurrence of adverse reactions.
METHODS This double-blind, randomized, parallel-group, placebo-controlled study was performed during a 3year period in patients with leg ulcers. Inclusion criteria included age of 18 years or older and the presence of a chronic leg ulcer with a purulent and/or necrotic wound bed. Exclusion criteria included patients with a history of hypersensitivity to the ointment; pregnant women and nursing mothers; patients with a systemic illness that could interfere with normal skin healing, such as uncontrolled diabetes, uncontrolled congestive heart failure, or an active malignancy; patients receiving medications that could interfere with clinical results of the study, such as systemic antibiotics, corticosteroids, or immunosuppressive agents; and patients who could not reasonably be expected to complete the study. A signed informed consent was obtained from all the patients. One ulcer per patient was chosen for treatment. Treatment was blinded to investigators and patients. Patients were stratified according to the area of the ulcer at baseline (1-4 cm2, 5-16 cm2, 17-36 cm2, and > 36 cm2), and then randomly assigned to receive 1 of 4 study treatments by a computer-generated randomization code. Ulcers were treated twice daily for 21 days; patients returned twice weekly for evaluation. No other topical medications for the ulcer were allowed during the study period. Treatment was discontinued at any time if any of the following occurred: the patient requested to be withdrawn; the investigator believed the patient to be noncompliant with treatment guidelines; a serious adverse reaction occurred; ulcer
Journal of the American Academy of Dermatology Volume 39, Number 5, Part 1
Falabella et al 739
RESULTS
A total of 84 patients with leg ulcers who satisfied the entry criteria were enrolled in the study. Of this total number, 3 patients were deemed not able to be evaluated for efficacy for the following reasons: inability to confirm their use of the study drug, use of other topical agents, and concurrent systemic inflammatory disease that was not recognized initially. Therefore, although all 84 patients were included in the safety evaluation, efficacy was evaluated in only 81. The mean age of the subjects in treatment groups varied between 56 and 63 years, with a range of 28 to 85 years. The sex ratio was approximately equal, and the ethnic background was similar in all groups. The mean baseline ulcer size (in square centimeters) showed no statistically significant difference (P = .97, Kruskal-Wallis test) among the 4 treatment groups. The results of the clinical assessments are summarized in Figs 1 through 3. As can be seen from Figs 1 and 2, we found no significant difference in purulent exudate and necrotic tissue, respectively, in the complete proteolytic enzyme ointment group compared with placebo vehicle or with treatment with the 2 individual components (P > .3 at week 3). Similarly, as in Fig 3, global assessment of the ulceration showed that none of the 3 proteolytic enzyme ointments had a beneficial effect when compared with placebo control (P = .47). Of all the patients enrolled, only 1 had increased pain and inflammation at the ulcer site, which was thought to be unrelated to the study drug. No other adverse effects were noted in any of the treatment groups. The data from the study were reanalyzed twice after the initial evaluation for any evidence of effectiveness. This reanalysis showed a statistically significant reduction of purulent exudate only at days 3 and 7 in the complete ointment-treated group compared with either component or vehicle. The clinical significance of this is uncertain. DISCUSSION
Debridement has long been considered an essential component of wound care.4 Removal of necrotic tissue and elimination of purulent exudate, decreases the bacterial burden present within ulcers, and, presumably, leads to an acceleration of healing.4 It is also likely that wound debridement has a beneficial effect on the healing process by
Fig 3. Proteolytic ointment or its components failed to improve overall condition of ulcer. Results represent mean scores for each treatment group when compared with baseline appearance of ulcer. Scores for improvement: 0 = worsening; 1 = no change; 2 = minimal; 3 = moderate; 4 = excellent.
facilitating the recruitment of macrophages, endothelial cells, and fibroblasts into the wound and, at least when performed by surgical means, by releasing growth factors and cytokines at the wound site. Wound odor, which can be offensive, is also reduced by debridement. Several nonsurgical means of wound debridement have become available. Some are enzymatic.5-9 Others, such as biosynthetic occlusive dressings, work through yet unexplained mechanisms.10 However, despite the favorable clinical experience, little objective data are available to prove that nonsurgical debriding agents are actually effective. We have described the effect of Elase and its presumably active components, DNAse and fibrinolysin. When compared with the vehicle control, neither the full formulation of the proteolytic ointment nor its enzymatic components were better than placebo in removing pus or necrotic material in chronic leg ulcers treated for 3 weeks. The results argue against the use of this agent in the treatment of chronic leg ulcers, at least as it was used in this study, which corresponds to its recommended treatment regimen. A previously smaller study found the ointment to be effective only in simple, uncomplicated venous ulcers.11 Consistent with our results, that study also failed to demonstrate any effectiveness in complex wounds (venous/ arterial ulcers). REFERENCES 1. Vanscheidt W, Weiss JM. Types of enzymes on the mar-
Journal of the American Academy of Dermatology November 1998
740 Falabella et al
2.
3. 4.
5. 6.
ket. In: Westerhof W, Vanscheidt W, editors. Proteolytic enzymes and wound healing. Berlin: Springer-Verlag; 1994. p. 59-73. Roman-Calderon J. Treatment of second and third degree burns: comparison of effects of proteolytic enzyme combination and silver nitrate. Curr Ther Res 1982;32:30511. Schwarz N. Erfahrungen bei der Wundreinigung mit der Enzymkombination Fibrinolysin/Desoxyribonuklease. Fortschr Med 1981;25:978-80. Donati L, Magliano E, Colonna M, et al. Surgical versus enzymatic debridement. In: Westerhof W, Vanscheidt W, editors. Proteolytic enzymes and wound healing. Berlin: Springer-Verlag; 1994. p. 31-48. Nathan P, Law EJ, Ogle JD, MacMillan BG. Proteolytic enzyme activity in the granulation tissue of the human burn wound. J Trauma 1976;16:912-8. Suomalainen O. Evaluation of two enzyme preparations: trypure and veridase in traumatic ulcers. Ann Chir Gynaecol 1983;72:62-5.
O
7. Anheller JE, Hellgren L, Karlstam B, et al. Biochemical and biological profile of a new enzyme preparation from Antarctic krill (E. superba) suitable for debridement of ulcerative lesions. Arch Dermatol Res 1989;281:105-10. 8. Rowan AD, Christopher CW, Kelley SF, et al. Debridement of experimental full-thickness skin burns of rats with enzyme fractions derived from pineapple stem. Burns 1990;16:243-6. 9. Durham DR, Fortney DZ, Nanney LB. Preliminary evaluation of vibriolysin, a novel proteolytic enzyme composition suitable for the debridement of burn wound eschar. J Burn Care Rehabil 1993;14:544-51. 10. Falanga V. Occlusive wound dressings: Why, when, which? Arch Dermatol 1988;124:872-7. 11. Westerhof W, Jansen FC, Wit FS, et al. Controlled double-blind trial of fibrinolysin-desoxyribonuclease (Elase) solution in patients with chronic leg ulcers who are treated before autologous skin grafting. J Am Acad Dermatol 1987;17:32-9.
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OR PHONE: 1-800-453-4351 Outside the U.S., call 314-453-4351
Elase ointment contains 2 active ingredients, fibrinolysin and desoxyribonuclease (DNAse), which are proteolytic enzymes of bovine origin.1 Fibrinolysin lyses and dissolves fibrinous exudates. DNAse produces polynucleotides by depolymerizing deoxyribonucleoproteins and desoxyribonucleic acids present in the necrotic tissue and exudate of skin ulcers.1 Presumably, these enzymatic activities produce a thinned, less tenacious purulent exudate. Both fibrinolysin and DNAse are said to act on extracellular tissue and From the Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine. Supported by the Warner-Lambert/Parke-Davis Corp. Reprint requests: Vincent Falanga, MD, Professor of Dermatology, Boston University, Chairman of Dermatology, Roger Williams Medical Center, Elmhurst Bldg, 50 Maude St, Providence, RI 02908. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/92725
disintegrating cells, but not on living tissue. Enzyme debridement may reduce the need for painful and more costly surgical debridement. On the basis of the enzymatic activity of its 2 components, the proteolytic ointment might be expected to aid in the debridement of necrotic or purulent debris and to produce a clean wound surface. Because it does not act on living tissue, it would not be expected to delay healing. However, proof of efficacy is not available. Previous studies of the efficacy of fibrinolysin and DNAse include those of Roman-Calderon et al,2 who treated 30 patients with second- and third-degree burns, and of Schwartz et al,3 who treated 42 patients with secondary healing wounds. These reports indicated that the proteolytic ointment was an effective debriding agent, but the number of ulcers evaluated was small. The present larger study was undertaken to assess the clinical efficacy and safety of 737
738 Falabella et al
Journal of the American Academy of Dermatology November 1998
Fig 1. Proteolytic ointment or its components have no effect on removal of purulent exudate. Results represent mean scores for each treatment group. Scores for presence of exudate: 0 = none; 1 = < 25%; 2 = 26%50%; 3 = 51%-75%; 4 = > 75%.
Fig 2. Proteolytic ointment or its components failed to remove necrotic tissue. Results represent mean scores for each treatment group. Scores for presence of necrotic tissue: 0 = none; 1 = < 25%; 2 = 26%-50%; 3 = 51%-75%; 4 = > 75%.
the proteolytic ointment and its components in patients with chronic exudative ulcers of the lower extremities.
size increased; systemic antibiotic therapy was required; surgical debridement became necessary; or serious intercurrent illness developed that interfered with skin healing. The materials for the study were supplied by the manufacturer and packaged so as to maintain the blind. The 4 treatment groups were as follows: complete proteolytic ointment (1.28 U fibrinolysin/g, with 1006 U of desoxyribonuclease/g); fibrinolysin in ointment vehicle (1.15 U of fibrinolysin/g); desoxyribonuclease in ointment vehicle (1027 U of desoxyribonuclease/g); and the vehicle ointment alone. Treatment was applied twice daily following a standard regimen. First, the ulcer was cleansed with sterile normal saline. Then, a thin layer of the study drug was applied over the ulcer bed, followed by the application of a nonadherent dressing (Telfa). Before enrollment, a history was obtained and a physical examination was performed on each patient. Efficacy was determined by evaluating the ulcers immediately before treatment, twice a week during treatment, and on the day treatment was terminated (day 21). Observations included ulcer area measurement (in square centimeters); presence of purulent exudate, necrotic tissue, and erythema/redness around the edges, all graded on a scale of 0 to 4; presence of pain graded on a scale of 0 to 3; overall final condition of the ulcer, graded as worse, no change, minimal, moderate, or excellent improvement with respect to baseline. Criteria for overall efficacy were based on primary and secondary features. The primary features were decrease in purulent exudate and necrotic debris. Secondary features were reduction in erythema at ulcer edges, decreased pain, and improvement in overall condition. Evaluation of safety was based on occurrence of adverse reactions.
METHODS This double-blind, randomized, parallel-group, placebo-controlled study was performed during a 3year period in patients with leg ulcers. Inclusion criteria included age of 18 years or older and the presence of a chronic leg ulcer with a purulent and/or necrotic wound bed. Exclusion criteria included patients with a history of hypersensitivity to the ointment; pregnant women and nursing mothers; patients with a systemic illness that could interfere with normal skin healing, such as uncontrolled diabetes, uncontrolled congestive heart failure, or an active malignancy; patients receiving medications that could interfere with clinical results of the study, such as systemic antibiotics, corticosteroids, or immunosuppressive agents; and patients who could not reasonably be expected to complete the study. A signed informed consent was obtained from all the patients. One ulcer per patient was chosen for treatment. Treatment was blinded to investigators and patients. Patients were stratified according to the area of the ulcer at baseline (1-4 cm2, 5-16 cm2, 17-36 cm2, and > 36 cm2), and then randomly assigned to receive 1 of 4 study treatments by a computer-generated randomization code. Ulcers were treated twice daily for 21 days; patients returned twice weekly for evaluation. No other topical medications for the ulcer were allowed during the study period. Treatment was discontinued at any time if any of the following occurred: the patient requested to be withdrawn; the investigator believed the patient to be noncompliant with treatment guidelines; a serious adverse reaction occurred; ulcer
Journal of the American Academy of Dermatology Volume 39, Number 5, Part 1
Falabella et al 739
RESULTS
A total of 84 patients with leg ulcers who satisfied the entry criteria were enrolled in the study. Of this total number, 3 patients were deemed not able to be evaluated for efficacy for the following reasons: inability to confirm their use of the study drug, use of other topical agents, and concurrent systemic inflammatory disease that was not recognized initially. Therefore, although all 84 patients were included in the safety evaluation, efficacy was evaluated in only 81. The mean age of the subjects in treatment groups varied between 56 and 63 years, with a range of 28 to 85 years. The sex ratio was approximately equal, and the ethnic background was similar in all groups. The mean baseline ulcer size (in square centimeters) showed no statistically significant difference (P = .97, Kruskal-Wallis test) among the 4 treatment groups. The results of the clinical assessments are summarized in Figs 1 through 3. As can be seen from Figs 1 and 2, we found no significant difference in purulent exudate and necrotic tissue, respectively, in the complete proteolytic enzyme ointment group compared with placebo vehicle or with treatment with the 2 individual components (P > .3 at week 3). Similarly, as in Fig 3, global assessment of the ulceration showed that none of the 3 proteolytic enzyme ointments had a beneficial effect when compared with placebo control (P = .47). Of all the patients enrolled, only 1 had increased pain and inflammation at the ulcer site, which was thought to be unrelated to the study drug. No other adverse effects were noted in any of the treatment groups. The data from the study were reanalyzed twice after the initial evaluation for any evidence of effectiveness. This reanalysis showed a statistically significant reduction of purulent exudate only at days 3 and 7 in the complete ointment-treated group compared with either component or vehicle. The clinical significance of this is uncertain. DISCUSSION
Debridement has long been considered an essential component of wound care.4 Removal of necrotic tissue and elimination of purulent exudate, decreases the bacterial burden present within ulcers, and, presumably, leads to an acceleration of healing.4 It is also likely that wound debridement has a beneficial effect on the healing process by
Fig 3. Proteolytic ointment or its components failed to improve overall condition of ulcer. Results represent mean scores for each treatment group when compared with baseline appearance of ulcer. Scores for improvement: 0 = worsening; 1 = no change; 2 = minimal; 3 = moderate; 4 = excellent.
facilitating the recruitment of macrophages, endothelial cells, and fibroblasts into the wound and, at least when performed by surgical means, by releasing growth factors and cytokines at the wound site. Wound odor, which can be offensive, is also reduced by debridement. Several nonsurgical means of wound debridement have become available. Some are enzymatic.5-9 Others, such as biosynthetic occlusive dressings, work through yet unexplained mechanisms.10 However, despite the favorable clinical experience, little objective data are available to prove that nonsurgical debriding agents are actually effective. We have described the effect of Elase and its presumably active components, DNAse and fibrinolysin. When compared with the vehicle control, neither the full formulation of the proteolytic ointment nor its enzymatic components were better than placebo in removing pus or necrotic material in chronic leg ulcers treated for 3 weeks. The results argue against the use of this agent in the treatment of chronic leg ulcers, at least as it was used in this study, which corresponds to its recommended treatment regimen. A previously smaller study found the ointment to be effective only in simple, uncomplicated venous ulcers.11 Consistent with our results, that study also failed to demonstrate any effectiveness in complex wounds (venous/ arterial ulcers). REFERENCES 1. Vanscheidt W, Weiss JM. Types of enzymes on the mar-
Journal of the American Academy of Dermatology November 1998
740 Falabella et al
2.
3. 4.
5. 6.
ket. In: Westerhof W, Vanscheidt W, editors. Proteolytic enzymes and wound healing. Berlin: Springer-Verlag; 1994. p. 59-73. Roman-Calderon J. Treatment of second and third degree burns: comparison of effects of proteolytic enzyme combination and silver nitrate. Curr Ther Res 1982;32:30511. Schwarz N. Erfahrungen bei der Wundreinigung mit der Enzymkombination Fibrinolysin/Desoxyribonuklease. Fortschr Med 1981;25:978-80. Donati L, Magliano E, Colonna M, et al. Surgical versus enzymatic debridement. In: Westerhof W, Vanscheidt W, editors. Proteolytic enzymes and wound healing. Berlin: Springer-Verlag; 1994. p. 31-48. Nathan P, Law EJ, Ogle JD, MacMillan BG. Proteolytic enzyme activity in the granulation tissue of the human burn wound. J Trauma 1976;16:912-8. Suomalainen O. Evaluation of two enzyme preparations: trypure and veridase in traumatic ulcers. Ann Chir Gynaecol 1983;72:62-5.
O
7. Anheller JE, Hellgren L, Karlstam B, et al. Biochemical and biological profile of a new enzyme preparation from Antarctic krill (E. superba) suitable for debridement of ulcerative lesions. Arch Dermatol Res 1989;281:105-10. 8. Rowan AD, Christopher CW, Kelley SF, et al. Debridement of experimental full-thickness skin burns of rats with enzyme fractions derived from pineapple stem. Burns 1990;16:243-6. 9. Durham DR, Fortney DZ, Nanney LB. Preliminary evaluation of vibriolysin, a novel proteolytic enzyme composition suitable for the debridement of burn wound eschar. J Burn Care Rehabil 1993;14:544-51. 10. Falanga V. Occlusive wound dressings: Why, when, which? Arch Dermatol 1988;124:872-7. 11. Westerhof W, Jansen FC, Wit FS, et al. Controlled double-blind trial of fibrinolysin-desoxyribonuclease (Elase) solution in patients with chronic leg ulcers who are treated before autologous skin grafting. J Am Acad Dermatol 1987;17:32-9.
N THE MOVE? Send us your new address at least six weeks ahead
Don’t miss a single issue of the journal! To ensure prompt service when you change your address, please photocopy and complete the form below. Please send your change of address notification at least six weeks before your move to ensure continued service. We regret we cannot guarantee replacement of issues missed due to late notification. JOURNAL TITLE: Fill in the title of the journal here.
OLD ADDRESS:
NEW ADDRESS:
Affix the address label from a recent issue of the journal here.
Clearly print your new address here. Name Address City/State/ZIP
COPY AND MAIL THIS FORM TO: Periodical Subscription Services Mosby, Inc. 11830 Westline Industrial Dr. St. Louis, MO 63146-3318
OR FAX TO: 314-432-1158
OR PHONE: 1-800-453-4351 Outside the U.S., call 314-453-4351