Treatment of cutaneous ulcers with benzoyl peroxide WILLIAM E. PACE, MD, M SC, FRCP[C] Benzoyl peroxide, a powerful organic oxidizing agent, was applied topically according to a carefully developed technique to cutaneous ulcers of different types. The healing time was shortened greatly by the rapid development of healthy granulation tissue and the quick ingrowth of epithelium. Exceptionally large pressure ulcers with deep cavities, undercut edges and sinus tracts were successfully treated, as were stasis ulcers of long duration resistant to all other therapy. There were only 13 treatment failures among the 133 cases. The slow, sustained release of oxygen by benzoyl peroxide was thought to be responsible for the success. The only complications were contact irritant dermatitis in 30/0 and contact allergic dermatitis in 20/0 of patients treated. Le peroxyde de benzoyle, un agent oxydant organique puissant, a ste applique localement selon une technique soigneusement mise au point dans des cas d'ulceres cutanes de diff6rents types. Le temps de cicatrisation a ete grandement r6duit par l'apparition hAtive d'un tissu de granulation sam et Ia croissance rapid de l'6pith6lium. Exceptionellement etendus ulceres de decubitus presentant des cavites profondes, des rebords vifs et Ia formation de sinus ont ste traites avec succes, de mime que des ulceres de stase de longue duree resistant a tout autre traitement. II n.y a eu que 13 echecs sur 133 cas. On croit que Ia liberation lente et prolongee d'oxygene du peroxyde de benzoyle est responsable de ce succes. Les seules complications observees ont 6te Ia dermatite de contact par irritation dana 30/0 des cas et Ia dermatite allergique de contact chez 20/o des patients traites.
From the department of medicine (dermatology), University of Western Ontario and Victoria Hospital, London Read in preliminary form before a conjoint meeting of the Canadian Medical Association and the Ontario Medical Association in Toronto, June 26, 1974, the Atlantic Dermatological Conference in Toronto, Oct. 18, 1975 and a conjoint meeting of the Irish Dermatological Society and the Canadian Dermatological Association in Dublin, May 4, 1976 Reprint requests to: Dr. W.E. Pace, 450 Central Ave., Ste. 205, London, Ont. N6B 2E8
Benzoyl peroxide (BPO), a powerful organic oxidizing agent (Fig. 1), may be used for the local treatment of cutaneous ulcers. It is almost insoluble in water but is more soluble in petroleum solvents and various alcohols. While explosive in pure form, BPO can be handled safely when less than 78.5% pure. It is nontoxic to man1 and has no carcinogenic effect on rats or mice.' It is well tolerated by tissues deep to the epidermis' but may produce irritant dermatitis in fair-skinned persons and causes contact allergic dermatitis in 1 to 2.5% of patients treated.4 In a series of papers from 1935 to 1952 Meleney"0 described the use of zinc peroxide (ZPO) in a 10% suspension for treating infected surgical wounds and large undermining and burrowing ulcers. His work was confirmed and extended by Altemeier and Carter11 and others, but ZPO gradually fell into disuse because it could not be made chemically pure and different batches from the same manufacturer showed widely varying oxygen-releasing capacity and clinical effectiveness.' Leake" suggested in 1942 that BPO, which is chemically pure and has almost the identical oxygen-releasing capacity of ZPO (4 ml of oxygen per gram of BPO in 24 hours)," was preferable for treating infected wounds and burns, but his suggestion was not followed up until 1971, when I began using BPO. In this paper I describe the method of use of BPO in treating cutaneous ulcers and my results in uncontrolled trials with 133 patients over 4 years. Method of treatment
General management Treatment of a patient with a pressure ulcer consisted of thorough general medical management, turning of the patient every 2 hours and use of special beds and mattresses when necessary. Material from all ulcers was cultured but a systemic antibiotic was given only when cellulitis was present deep to the
ulcer surface. Necrotic material was surgically debrided from all ulcer stirfaces. Diuretics were taken orally to control edema by patients with leg ulcers, and Unna boots were applied over the BPO dressing in some ambulatory patients. Local management The medication used in most cases was 20% BPO in an oil-in-water emulsion vehicle (20% Benoxyl lotion, Stiefel Laboratories [Canada] Ltd.). Thirteen pi.tients were treated with 50% BPO paste made up as follows: benzoyl peroxide (technical grade, 70% pure), 75.0%; colloidal aluminum magnesium silicate (Veegum K, Vanderbilt Co., Norwalk, Connecticut), 0.5%; and purified water, 24.5%. A dressing was cut from sterile terry cloth to fit the ulcer exactly, moistened with saline, saturated with 20% BPO emulsion or covered with 50% BPO paste, and applied to the ulcer surface. A protective ointment (Desitin ointment, Pfizer Co. Ltd.) was applied to a wide area bordering the ulcer. Plastic film was then placed over the dressing and allowed to adhere to the ointment. An abdominal pad dressing was then applied over the ulcer dressing and taped firmly in place with hypoallergenic adhesive tape (Dermacel, Johnson & Johnson Ltd.). The dressing was changed at 8- or 12-hour intervals. Exuberant granulation tissue was kept below the epidermal level with cauterization by a silver nitrate stick to facilitate ingrowth of epithelium. If an ulcer formed a large cavity or sinus tract or had an undercut margin these areas were firmly packed with surgical gauze saturated with BPO medication so that the BPO would have good contact with the walls of the cavity. To release oxygen effectively BPO must be moist and as close to 370C as possible; the plastic film retained moisture and the thick pad dressing increased the local temperature through its insulating effect. Results
0
I,
0
II
FIG. 1-Structural formula of beuzoyl peroxide.
General response of ulcers to BPO therapy After 48 hours of BPO therapy, ulcers with an adequate arterial blood supply developed a highly vascular granulation tissue, which quickly filled the ulcer defect. Epithelium then grew in from the periphery. The speed with
CMA JOURNAL/DECEMBER 4, 1976/VOL. 115 1101
FIG. 2-Case 1. Left: ulcer of right greater trochanter, 14 cm in diameter, with undercutting of superior border to 3 cm. Right: full healing after 8 months' therapy with beuzoyl peroxide.
FIG. 3-Case 4. Left: stasis ulcer of left lateral ankle; small opening to extreme right leading to undercut area extending 6 cm superiorly and 4 cm laterally. Right: full healing after 45 days' therapy with bcuzoyl peroxide.
FIG. 4-Case 9. Left: ulcer of left hip. Right: full healing after 21 days' therapy wIth beazoyl peroxide.
1102 CMA JOURNAL/DECEMBER 4, 1976/VOL 115
which granulation tissue filled large ulcer defects was frequently remarkable. Ulcers treated with BPO medication often produced copious seropurulent exudate; this was a normal response to treatment and did not indicate increased bacterial infection. Pressure ulcers of sacrum, hips, legs and arms Of 92 patients in whom ulcers were treated with 20% BPO emulsion, healing occurred in 79 (86%). BPO was discontinued in two patients because of irritant dermatitis and in one because of contact allergic dermatitis. Of the 10 patients in whom treatment failed 7 were in a terminal phase of a fatal illness, 1 had uncontrolled diabetes mellitus with probably small-vessel occlusion and 2 were referred for surgical treatment. Case 1: A paraplegic woman aged 67 had multiple large decubitus ulcers beyond surgical repair. An ulcer of the left ilium, 10 cm in diameter, which penetrated to bone, healed after 42 days of BPO therapy, and an ulcer of the right greater trochanter, 14 cm in diameter, healed completely after 8 months (Fig. 2). Case 2: A 10-year-old girl had an ulcer of the right buttock, 3.5 cm in diameter, from which a sinus tract extended 10 cm toward the midline. Complete healing occurred after 39 days of BPO therapy. Case 3: A 60-year-old man with advanced metastatic carcinoma had an ulcer of the right hip, 9 x 6 cm, which extended 6 cm deep to the ischial tuberosity. In spite of the patient's steadily declining health this huge ulcer healed completely in 101 days. The patient died 2 months later. Ulcers of legs due to venous stasis In all 22 cases there had been resistance to extensive previous treatment or there was an unusual problem. Ulcers varied in size from 1.5 x 1.5 cm to 14.0 x 3.0 cm. Fifteen patients were treated with 20% BPO emulsion and seven were treated with 50% BPO paste. Seven patients were treated entirely or mainly in hospital but the remainder were treated while ambulatory. Treatment was discontinued in two patients because of contact allergic dermatitis; in the remaining 20 the ulcers healed. Case 4: A woman aged 41, receiving prednisone therapy for systemic lupus erythematosus, had an ulcer of the left lower leg secondary to cellulitis, which was 2 cm in diameter with undercutting of the surrounding skin 6 cm superiorly and 4 cm laterally. The lesion healed completely after therapy with 20% BPO emulsion for 12 days, then 50% BPO paste for 33 days (Fig. 3). Case S: An 86-year-old man with gross edema of the legs from congestive heart
failure had had 10 stasis ulcers of the right lower leg for 8 years. All ulcers healed after 36 days of therapy with 20% BPO emulsion. Ulcers of legs due to arterial insufficiency
The ulcers in these 10 cases varied in diameter from 0.8 to 9.0 cm and most were painful. Four patients were treated with 20% BPO emulsion and six were treated initially with 20% BPO emulsion and then, when healing was slow, with 50% BPO paste. Eight ulcers healed. Treatment failure occurred in a severely diabetic patient with an ulcer of the heel, 2 cm in diameter, and in a patient with generalized atherosclerosis with an ulcer of the left medial ankle, 1.8 cm in diameter. Case 6: A woman aged 48 had an inoperable occlusion of the right femoral artery and an ulcer of the right lower leg, 3 cm in diameter, which healed completely after 49 days of therapy with 20% BPO emulsion. Case 7: A woman aged 43 with severe Raynaud's disease had had 10 ulcers, 4 to 10 mm in diameter, on the right foot for 8 years. All the ulcers healed after 28 days of therapy with 20% BPO emulsion. Miscellaneous ulcers Cutaneous ulcers due to trauma, infection and trophic factors constituted this group. Seven patients were treated with 20% BPO emulsion and two with 50% BPO paste. All ulcers healed completely except one, owing to persistent osteomyelitis. Case 8: A partially paraplegic man aged 23 had had for 2 years a trophic ulcer, 1.5 cm in diameter, beneath the fifth metatarsal head. The ulcer healed completely with 5 months of therapy with 20% BPO emulsion applied twice a day; during treatment the patient was attending university and doing much walking. Case 9: A 2-year-old girl had 12 fullthickness ulcers, 1.5 to 7.0 cm in diameter, over both hips and legs, the result of meningococcic vasculitis. All ulcers healed with 21 days of therapy with 20% BPO emulsion (Fig. 4). Case 10: In a severely diabetic man aged 62 who had undergone a femoralpopliteal bypass procedure, the incision wound on the anterior thigh broke down and an ulcer, 4.0 x 1.0 cm, developed. The lesion healed after 20 days of treatment with 50% BPO paste. Complications of treatment Irritant dermatitis of the skin surrounding the ulcer developed in 3% of patients. Use of a protective ointment about the ulcer greatly decreased the incidence of this problem. Contact allergic dermatitis occurred in 2% of patients. Some patients complained of a burn-
ing sensation in ulcers treated with BPO. This usually subsided within 30 minutes of the dressing change and in only two cases was severe enough to require the use of an analgesic.
Discussion Meleney believed that BPO assisted ulcer healing by suppressing surface bacterial growth through release of nascent oxygen.14 While there may have been some justification for this view when oxygen-sensitive anaerobic and microaerophilic streptococci were cultured from burrowing ulcers, serial cultures of material from ulcers in my study have failed to show that BPO exerts bactericidal powet against the aerobic organisms commonly found on ulcer surfaces. Local application of modern antibiotic preparations has not proven of any particular benefit in treating cutaneous ulcers.15 Other possible beneficial effects oxygen release might have in facilitating ulcer healing must then he considered. Oxygen is the terminal electron acceptor in biologic electron transport. A cell deficient in oxygen is unable to create the energy required for cell division, which is essential to wound healing.16 Since the cells of an ulcer base are always hypoxic because of interruption of their capillary blood supply, any treatment that increases their oxygen supply should, theoretically, greatly facilitate ulcer repair. Numerous references on ulcer healing support this concept.17.18 Collagen synthesis, an essential component of the healing process in wounds and ulcers, requires the enzyme protocollagen proline hydroxylase, and one of the cofactors of this enzyme is molecular oxygen.19 Thus, an improved oxygen supply should facilitate ulcer repair. The use of a simple, inexpensive chemical such as BPO to supply oxygen is distinctly advantageous compared with the use of a complicated hyperbaric oxygen device. For BPO to be effective, care must be taken that a layer of exudate does not build up on the ulcer surface and prevent BPO from delivering oxygen directly to the cells. It is essential to cleanse the ulcer surface of all exudate at each dressing change. For this reason large ulcer cavities and sinus tracts must be firmly packed with surgical gauze saturated with BPO so that the medication comes directly in contact with the tissue surface. Conclusion I acknowledge that this report is based on uncontrolled studies. The claim that BPO therapy is unusually
CMA JOURNAL/DECEMBER 4, 1976/VOL. 115 1103
(levodopa and carbidopa combination) INDICATiONS Treatment of ParKinson's syndrome with exception of drug induced parkinsonism. CONTRAINDICATIONS When a sympathomimetic amine is contraindicated; with monoamine oxidase inhibitors, which should be discontinued two weeks prior to .starting SINEMET*; in uncompensated cardIovascular, endocrine, hematologic, hepatic, pulmonary or renal disease; in narrowangle glaucoma; in patients with suspicious, undiagnosed skin lesions or a history of melanoma.
WARNINGS When given to patients receiving levodopa
alone, discontinue levodopa at least 12 hours before initiating SINEMET* at a dosage that provides approximately 20% of previous levodopa. Not recommended in drug-induced extrapyramidal reactions; contraindicated in management of intention tremor and Huntington's chores. Levodopa related central effects such as involuntary movements may occur at lower dosages and sooner, and the 'on and off' phenomenon may appasrearlierwith combination therapy. Monitor carefully all patients for the development of mental changes, depression with suicidal tendencies, or other serious antisocial behaviour. Cardiac function should be monitored continuously during pariod of initial dosage adjustment in patients with arrhythmias. Safety of SINEMET* in patients under 18 years of age not established. Pregnancy and lactation: In women of childbearing potential, weigh benefits against risks. Should not be given to nursing mothers. Effects on human pregnancy and lactation unknown.
PRECAUTiONS
General: Periodic evaluations of hepatic, hematopoletic, cardiovascular and renal function recommended in extended therapy. Treat patients with history of convulsions cautiously. Physical Activity: Advise patients improved on SINEMET* to increase physical activities gradually, with caution consistent with other medical considerations. In Glaucoma: May be given cautiously to patients with wide angle glaucoma, provided intraocular pressure is well controlled and can be carefully monitored during therapy. With Antihypertensive Therapy:Assymptomatic postural hypotension has been reported occasionally, give cautiously to patients on antihypartensive drugs, checking carefully for changes in pulse rate and blood pressure. Dosage adjustment of antihypartensive drug may be required. With Psychoactive Drugs: If concomitant administration is necessary, administer psychoactive drugs with great caution and observe patients for unusual adverse reactions. With Anesthetics: Discontinue SINEMET* the night before general anesthesia and reinstitute as soon as patient can take medication orally. ADVERSE REACTIONS Meat Cemmen: Abnormal Involuntary Movements-usually diminished by dosage reduction-choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be earlysigna of excessive dosage. Othrn Smleus ReaeUens: Oscillations in parformance: diurnal variations, indepandent oscillations in akinesia with stereotyped dyskinesias, sudden akinetic crises related to dyskinesias, akinesia paradoxica (hypotonic freezing) and 'on and off' phenomenon. Psychiatric: paranoid ideation, psychotic episodes, depression with or without development of suicidal tendencies and dementia. Rarely convulsions (causal relationship not established). Cardiac irregularities and/or palpitations, orthostatic hypotensive episodes, anorexia, nausea, vomiting and dizziness
Other adverse reactions that may occur: Psychiatric: increased libido with serious antisocial behavior, euphoria, lethargy, sedation, stimulation, fatigue and malaise, confusion, insomnia, nightmares, hallucinations and delusions, agitation and anxiety. Nourologic: ataxia, faintness, impairment of gait, hoadache, increased hand tremor, akinetic episodes, "akinesia paradoxica", increase in the frequency and duration of the oscillations in performance, torticollis, trismus, tightness of the mouth, lips or tongue, oculogyric crisis, weakness, numbness, bruxism, priapism. Gastrointestinal: constipation, diarrhea, epigastric and abdominal distress and pain, flatulence; eructation, hiccups, sialorrhea; difficulty in swallowing, bitter taste, dry mouth; duodenal ulcer; gastrointestinal bleeding; burning sensation of the tongue. Cardiovascular: arrhythmias, hypotension, nonspecific ECG changes, flushing, phlebitis. Hematologic: hemolytic anemia, leukopenia, agranulocytosis. Dermatologic: sweating, edema, hair loss, pallor, rash, bad odor, dark sweat. Musculoskeletal: low back pain, muscle spasm and twitching, musculoskeletal pain. Respiratory: feeling of pressure in the chest, cough, hoarseness, bizarre breathing pattern, poatnasal drip. Urogenital: urinary frequency, retention, incontinence, hematuria, dark urine, nocturia, and one report of interstitial nephritis. SpecialSenses: blurredvision, dipiopia, dilated pupils, activation of latent Homers syndrome. Miscellaneous: hot flashes, weight gain or loss. Abnormalities in laboratory tests reported with levodopa alone, which may occur with SINEMET*: Elevations of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin, alkaline phosphatase or protein bound iodine. Occasional reduction in WBC, hemoglobin and hematocrit. Elevations of uric acid with colorimetric method. Positive Coombs tests reported both with SINEMET* and with levodopa alone, but hemoiytic anemia extremely rare. DOSAGE SUMMARY In order to reduce the incidence of adverse reactions and achieve maximal benefit. therapy with SINEMETk must be Individualized and drug administration continuously matched to the needs and tolerance of the patient. Combined therapy with SINEMET* hes a narrower therapeutic range then with levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made In small steps and recommended dosage ranges not be exceeded. Appearance of involuntary movements should be regarded as a sign of levodopa toxicity and an Indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinesias. Therapy in Patients not receiving Levedepa: initially 'A tablet once or twice a day, increase by 'A tablet every three days if desirable. An optimum dose of 3 to 5 tablets a day divided into 4 to 6 doses. Therapy in Patients receiving Levodopa: Discontinue levodopa tor at least 12 hours, then give approximately 20% of the previous levodopa dose in 4 to 6 divided doses. FOR COMPLETE PRESCRIBING INFORMATION. PARTICULARLY DETAILS OF DOSAGE AND ADMINISTRATION, PLEASE CONSULT PRODUCT MONOGRAPH WHICH IS AVAILABLE ON REQUEST. HOW SUPPLIED Ca8804.TabIetsSiNEMET* 250, dapple-blue. oval, biconvex, scored, compressed tablets coded MSD 654, each containing 25 mg of carbidopa and 250 mg of levodopa. Available in bottles of 100.
MERCK
O I
Trademark
DOHME CANADA LIMITED
Points Claire, Quebec
1106 CMA JOURNAL/DECEMBER 4, 1976/VOL. 115
effective in healing ulcers must rest for the present on repeated clinical observation that ulcers that failed to respond to many other treatments healed promptly with BPO therapy, and that ulcers considered by competent observers to be totally beyond medical management because of their size and complexity have healed with this therapy. During the 4 years of this study I have become convinced that BPO, while not a panacea, is a valuable addition to the presently available medications for local treatment of cutaneous ulcers. I thank Geoffrey S. Pinto, PhD for valuable suggestions regarding the role of oxygen in the healing of ulcers; Mrs. Margaret Morley, rehabilitation nurse coordinator, Victoria Hospital, London, for valuable assistance by supervising treatment and keeping records of the cases reported in this paper; and Stiefel Laboratories (Canada) Ltd. for kindly providing the 50% BPO paste and funds for printing the coloured illustrations. References 1. HooFT FV: Benzoyl peroxide, in Encyclopedia of Clinical Technology, vol 2, KIRK RE, OTEMER DF (eds), New York, Intersci Pub, 1948, p 479 2. SHARRATT M, FRAZER AC, FORBES OC: Study of the biological effects of benzoyl peroxide. Food Cosmet Toxicol 2: 527, 1964 3. LOEVENHART AS: Benzoylsuperoxyd, em neues therapeutisches Agens. Ther Monat 19: 426, 1905 4. PACE WE: A benzoyl peroxide-sulphur cream for acne vulgaris. Can Med Assoc .1 93: 252, 1965 5. MELENEY FL, JoHNsoN B: The prophylactic and active treatment of surgical snfections with zinc peroxide. Surg Gynecol Obstet 64:
382, 1937 6. MELENEY FL: Zinc peroxide in treatment of micro-aerophilic and anaerobic infections, with special reference to group of chronic, ulcerative, burrowing, non-gangrenous lesions of abdominal wall apparently due to microaerophilic haemolytic streptococcus. Ann Surg
101: 997, 1935 7. MELENEY FL, HARVEY HD: Combined use of zinc peroxide and sulfanilamide in the treatment of chronic, undermining, burrowing ulcers due to the micro-aerophilic hemolytic streptococcus. Ann Surg 110: 1067, 1939 8. MELENEY FL: Treatment of traumatic wounds with zinc peroxide. NY State J Med 39: 2188, 1939 9. Idem: Zinc peroxide in surgical infections. Surg Clin North Am 116: 691, 1936 10. Idem: Present role of zinc peroxide in the treatment of surgical infections. JAMA 149: 1450, 1952 11. ALTEMESER WA, CARTER BN: Infected burns with hemorrhage. Ann Surg 115: 1118, 1942 12. LEAKE CD: Advantages of benzoyl peroxide over zinc peroxide or sulfonamides in treating wounds or burns. JAMA 119: 101, 1942 13. REiD MR, ALTEMEJER WA: Peroxide oint-
ments. Ann Surg 118: 741, 1943
14. JOHNSON BA, MELENEY FL: Antiseptic and detoxifying action of zinc peroxide on certain surgical aerobic, anaerobic and micro-aerophilic bacteria. Ann Surg 109: 881, 1939 15. MORGAN JE: Topical therapy of pressure ul-
cers. Surg Gynecol Obstet 141: 945, 1975
16. LEHNsNGER AL: Biochemistry, 2nd ed, New York, Worth, 1975, p 494 17. FsscHER BH: Topical hyperbaric oxygen treatment of pressure sores and skin ulcers.
Lancet 2: 405, 1969 18. BART P0, ENFORS W, EstsKssON G: Hyperbaric oxygen therapy in dermatology. Br J Dermatol 86: 631, 1972 19. GRANT ME, PRocscOi' DJ: The biosynthesis of collagen. N Engl J Med 286: 245, 1972
From the department of medicine (dermatology), University of Western Ontario and Victoria Hospital, London Read in preliminary form before a conjoint meeting of the Canadian Medical Association and the Ontario Medical Association in Toronto, June 26, 1974, the Atlantic Dermatological Conference in Toronto, Oct. 18, 1975 and a conjoint meeting of the Irish Dermatological Society and the Canadian Dermatological Association in Dublin, May 4, 1976 Reprint requests to: Dr. W.E. Pace, 450 Central Ave., Ste. 205, London, Ont. N6B 2E8
Benzoyl peroxide (BPO), a powerful organic oxidizing agent (Fig. 1), may be used for the local treatment of cutaneous ulcers. It is almost insoluble in water but is more soluble in petroleum solvents and various alcohols. While explosive in pure form, BPO can be handled safely when less than 78.5% pure. It is nontoxic to man1 and has no carcinogenic effect on rats or mice.' It is well tolerated by tissues deep to the epidermis' but may produce irritant dermatitis in fair-skinned persons and causes contact allergic dermatitis in 1 to 2.5% of patients treated.4 In a series of papers from 1935 to 1952 Meleney"0 described the use of zinc peroxide (ZPO) in a 10% suspension for treating infected surgical wounds and large undermining and burrowing ulcers. His work was confirmed and extended by Altemeier and Carter11 and others, but ZPO gradually fell into disuse because it could not be made chemically pure and different batches from the same manufacturer showed widely varying oxygen-releasing capacity and clinical effectiveness.' Leake" suggested in 1942 that BPO, which is chemically pure and has almost the identical oxygen-releasing capacity of ZPO (4 ml of oxygen per gram of BPO in 24 hours)," was preferable for treating infected wounds and burns, but his suggestion was not followed up until 1971, when I began using BPO. In this paper I describe the method of use of BPO in treating cutaneous ulcers and my results in uncontrolled trials with 133 patients over 4 years. Method of treatment
General management Treatment of a patient with a pressure ulcer consisted of thorough general medical management, turning of the patient every 2 hours and use of special beds and mattresses when necessary. Material from all ulcers was cultured but a systemic antibiotic was given only when cellulitis was present deep to the
ulcer surface. Necrotic material was surgically debrided from all ulcer stirfaces. Diuretics were taken orally to control edema by patients with leg ulcers, and Unna boots were applied over the BPO dressing in some ambulatory patients. Local management The medication used in most cases was 20% BPO in an oil-in-water emulsion vehicle (20% Benoxyl lotion, Stiefel Laboratories [Canada] Ltd.). Thirteen pi.tients were treated with 50% BPO paste made up as follows: benzoyl peroxide (technical grade, 70% pure), 75.0%; colloidal aluminum magnesium silicate (Veegum K, Vanderbilt Co., Norwalk, Connecticut), 0.5%; and purified water, 24.5%. A dressing was cut from sterile terry cloth to fit the ulcer exactly, moistened with saline, saturated with 20% BPO emulsion or covered with 50% BPO paste, and applied to the ulcer surface. A protective ointment (Desitin ointment, Pfizer Co. Ltd.) was applied to a wide area bordering the ulcer. Plastic film was then placed over the dressing and allowed to adhere to the ointment. An abdominal pad dressing was then applied over the ulcer dressing and taped firmly in place with hypoallergenic adhesive tape (Dermacel, Johnson & Johnson Ltd.). The dressing was changed at 8- or 12-hour intervals. Exuberant granulation tissue was kept below the epidermal level with cauterization by a silver nitrate stick to facilitate ingrowth of epithelium. If an ulcer formed a large cavity or sinus tract or had an undercut margin these areas were firmly packed with surgical gauze saturated with BPO medication so that the BPO would have good contact with the walls of the cavity. To release oxygen effectively BPO must be moist and as close to 370C as possible; the plastic film retained moisture and the thick pad dressing increased the local temperature through its insulating effect. Results
0
I,
0
II
FIG. 1-Structural formula of beuzoyl peroxide.
General response of ulcers to BPO therapy After 48 hours of BPO therapy, ulcers with an adequate arterial blood supply developed a highly vascular granulation tissue, which quickly filled the ulcer defect. Epithelium then grew in from the periphery. The speed with
CMA JOURNAL/DECEMBER 4, 1976/VOL. 115 1101
FIG. 2-Case 1. Left: ulcer of right greater trochanter, 14 cm in diameter, with undercutting of superior border to 3 cm. Right: full healing after 8 months' therapy with beuzoyl peroxide.
FIG. 3-Case 4. Left: stasis ulcer of left lateral ankle; small opening to extreme right leading to undercut area extending 6 cm superiorly and 4 cm laterally. Right: full healing after 45 days' therapy with bcuzoyl peroxide.
FIG. 4-Case 9. Left: ulcer of left hip. Right: full healing after 21 days' therapy wIth beazoyl peroxide.
1102 CMA JOURNAL/DECEMBER 4, 1976/VOL 115
which granulation tissue filled large ulcer defects was frequently remarkable. Ulcers treated with BPO medication often produced copious seropurulent exudate; this was a normal response to treatment and did not indicate increased bacterial infection. Pressure ulcers of sacrum, hips, legs and arms Of 92 patients in whom ulcers were treated with 20% BPO emulsion, healing occurred in 79 (86%). BPO was discontinued in two patients because of irritant dermatitis and in one because of contact allergic dermatitis. Of the 10 patients in whom treatment failed 7 were in a terminal phase of a fatal illness, 1 had uncontrolled diabetes mellitus with probably small-vessel occlusion and 2 were referred for surgical treatment. Case 1: A paraplegic woman aged 67 had multiple large decubitus ulcers beyond surgical repair. An ulcer of the left ilium, 10 cm in diameter, which penetrated to bone, healed after 42 days of BPO therapy, and an ulcer of the right greater trochanter, 14 cm in diameter, healed completely after 8 months (Fig. 2). Case 2: A 10-year-old girl had an ulcer of the right buttock, 3.5 cm in diameter, from which a sinus tract extended 10 cm toward the midline. Complete healing occurred after 39 days of BPO therapy. Case 3: A 60-year-old man with advanced metastatic carcinoma had an ulcer of the right hip, 9 x 6 cm, which extended 6 cm deep to the ischial tuberosity. In spite of the patient's steadily declining health this huge ulcer healed completely in 101 days. The patient died 2 months later. Ulcers of legs due to venous stasis In all 22 cases there had been resistance to extensive previous treatment or there was an unusual problem. Ulcers varied in size from 1.5 x 1.5 cm to 14.0 x 3.0 cm. Fifteen patients were treated with 20% BPO emulsion and seven were treated with 50% BPO paste. Seven patients were treated entirely or mainly in hospital but the remainder were treated while ambulatory. Treatment was discontinued in two patients because of contact allergic dermatitis; in the remaining 20 the ulcers healed. Case 4: A woman aged 41, receiving prednisone therapy for systemic lupus erythematosus, had an ulcer of the left lower leg secondary to cellulitis, which was 2 cm in diameter with undercutting of the surrounding skin 6 cm superiorly and 4 cm laterally. The lesion healed completely after therapy with 20% BPO emulsion for 12 days, then 50% BPO paste for 33 days (Fig. 3). Case S: An 86-year-old man with gross edema of the legs from congestive heart
failure had had 10 stasis ulcers of the right lower leg for 8 years. All ulcers healed after 36 days of therapy with 20% BPO emulsion. Ulcers of legs due to arterial insufficiency
The ulcers in these 10 cases varied in diameter from 0.8 to 9.0 cm and most were painful. Four patients were treated with 20% BPO emulsion and six were treated initially with 20% BPO emulsion and then, when healing was slow, with 50% BPO paste. Eight ulcers healed. Treatment failure occurred in a severely diabetic patient with an ulcer of the heel, 2 cm in diameter, and in a patient with generalized atherosclerosis with an ulcer of the left medial ankle, 1.8 cm in diameter. Case 6: A woman aged 48 had an inoperable occlusion of the right femoral artery and an ulcer of the right lower leg, 3 cm in diameter, which healed completely after 49 days of therapy with 20% BPO emulsion. Case 7: A woman aged 43 with severe Raynaud's disease had had 10 ulcers, 4 to 10 mm in diameter, on the right foot for 8 years. All the ulcers healed after 28 days of therapy with 20% BPO emulsion. Miscellaneous ulcers Cutaneous ulcers due to trauma, infection and trophic factors constituted this group. Seven patients were treated with 20% BPO emulsion and two with 50% BPO paste. All ulcers healed completely except one, owing to persistent osteomyelitis. Case 8: A partially paraplegic man aged 23 had had for 2 years a trophic ulcer, 1.5 cm in diameter, beneath the fifth metatarsal head. The ulcer healed completely with 5 months of therapy with 20% BPO emulsion applied twice a day; during treatment the patient was attending university and doing much walking. Case 9: A 2-year-old girl had 12 fullthickness ulcers, 1.5 to 7.0 cm in diameter, over both hips and legs, the result of meningococcic vasculitis. All ulcers healed with 21 days of therapy with 20% BPO emulsion (Fig. 4). Case 10: In a severely diabetic man aged 62 who had undergone a femoralpopliteal bypass procedure, the incision wound on the anterior thigh broke down and an ulcer, 4.0 x 1.0 cm, developed. The lesion healed after 20 days of treatment with 50% BPO paste. Complications of treatment Irritant dermatitis of the skin surrounding the ulcer developed in 3% of patients. Use of a protective ointment about the ulcer greatly decreased the incidence of this problem. Contact allergic dermatitis occurred in 2% of patients. Some patients complained of a burn-
ing sensation in ulcers treated with BPO. This usually subsided within 30 minutes of the dressing change and in only two cases was severe enough to require the use of an analgesic.
Discussion Meleney believed that BPO assisted ulcer healing by suppressing surface bacterial growth through release of nascent oxygen.14 While there may have been some justification for this view when oxygen-sensitive anaerobic and microaerophilic streptococci were cultured from burrowing ulcers, serial cultures of material from ulcers in my study have failed to show that BPO exerts bactericidal powet against the aerobic organisms commonly found on ulcer surfaces. Local application of modern antibiotic preparations has not proven of any particular benefit in treating cutaneous ulcers.15 Other possible beneficial effects oxygen release might have in facilitating ulcer healing must then he considered. Oxygen is the terminal electron acceptor in biologic electron transport. A cell deficient in oxygen is unable to create the energy required for cell division, which is essential to wound healing.16 Since the cells of an ulcer base are always hypoxic because of interruption of their capillary blood supply, any treatment that increases their oxygen supply should, theoretically, greatly facilitate ulcer repair. Numerous references on ulcer healing support this concept.17.18 Collagen synthesis, an essential component of the healing process in wounds and ulcers, requires the enzyme protocollagen proline hydroxylase, and one of the cofactors of this enzyme is molecular oxygen.19 Thus, an improved oxygen supply should facilitate ulcer repair. The use of a simple, inexpensive chemical such as BPO to supply oxygen is distinctly advantageous compared with the use of a complicated hyperbaric oxygen device. For BPO to be effective, care must be taken that a layer of exudate does not build up on the ulcer surface and prevent BPO from delivering oxygen directly to the cells. It is essential to cleanse the ulcer surface of all exudate at each dressing change. For this reason large ulcer cavities and sinus tracts must be firmly packed with surgical gauze saturated with BPO so that the medication comes directly in contact with the tissue surface. Conclusion I acknowledge that this report is based on uncontrolled studies. The claim that BPO therapy is unusually
CMA JOURNAL/DECEMBER 4, 1976/VOL. 115 1103
(levodopa and carbidopa combination) INDICATiONS Treatment of ParKinson's syndrome with exception of drug induced parkinsonism. CONTRAINDICATIONS When a sympathomimetic amine is contraindicated; with monoamine oxidase inhibitors, which should be discontinued two weeks prior to .starting SINEMET*; in uncompensated cardIovascular, endocrine, hematologic, hepatic, pulmonary or renal disease; in narrowangle glaucoma; in patients with suspicious, undiagnosed skin lesions or a history of melanoma.
WARNINGS When given to patients receiving levodopa
alone, discontinue levodopa at least 12 hours before initiating SINEMET* at a dosage that provides approximately 20% of previous levodopa. Not recommended in drug-induced extrapyramidal reactions; contraindicated in management of intention tremor and Huntington's chores. Levodopa related central effects such as involuntary movements may occur at lower dosages and sooner, and the 'on and off' phenomenon may appasrearlierwith combination therapy. Monitor carefully all patients for the development of mental changes, depression with suicidal tendencies, or other serious antisocial behaviour. Cardiac function should be monitored continuously during pariod of initial dosage adjustment in patients with arrhythmias. Safety of SINEMET* in patients under 18 years of age not established. Pregnancy and lactation: In women of childbearing potential, weigh benefits against risks. Should not be given to nursing mothers. Effects on human pregnancy and lactation unknown.
PRECAUTiONS
General: Periodic evaluations of hepatic, hematopoletic, cardiovascular and renal function recommended in extended therapy. Treat patients with history of convulsions cautiously. Physical Activity: Advise patients improved on SINEMET* to increase physical activities gradually, with caution consistent with other medical considerations. In Glaucoma: May be given cautiously to patients with wide angle glaucoma, provided intraocular pressure is well controlled and can be carefully monitored during therapy. With Antihypertensive Therapy:Assymptomatic postural hypotension has been reported occasionally, give cautiously to patients on antihypartensive drugs, checking carefully for changes in pulse rate and blood pressure. Dosage adjustment of antihypartensive drug may be required. With Psychoactive Drugs: If concomitant administration is necessary, administer psychoactive drugs with great caution and observe patients for unusual adverse reactions. With Anesthetics: Discontinue SINEMET* the night before general anesthesia and reinstitute as soon as patient can take medication orally. ADVERSE REACTIONS Meat Cemmen: Abnormal Involuntary Movements-usually diminished by dosage reduction-choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be earlysigna of excessive dosage. Othrn Smleus ReaeUens: Oscillations in parformance: diurnal variations, indepandent oscillations in akinesia with stereotyped dyskinesias, sudden akinetic crises related to dyskinesias, akinesia paradoxica (hypotonic freezing) and 'on and off' phenomenon. Psychiatric: paranoid ideation, psychotic episodes, depression with or without development of suicidal tendencies and dementia. Rarely convulsions (causal relationship not established). Cardiac irregularities and/or palpitations, orthostatic hypotensive episodes, anorexia, nausea, vomiting and dizziness
Other adverse reactions that may occur: Psychiatric: increased libido with serious antisocial behavior, euphoria, lethargy, sedation, stimulation, fatigue and malaise, confusion, insomnia, nightmares, hallucinations and delusions, agitation and anxiety. Nourologic: ataxia, faintness, impairment of gait, hoadache, increased hand tremor, akinetic episodes, "akinesia paradoxica", increase in the frequency and duration of the oscillations in performance, torticollis, trismus, tightness of the mouth, lips or tongue, oculogyric crisis, weakness, numbness, bruxism, priapism. Gastrointestinal: constipation, diarrhea, epigastric and abdominal distress and pain, flatulence; eructation, hiccups, sialorrhea; difficulty in swallowing, bitter taste, dry mouth; duodenal ulcer; gastrointestinal bleeding; burning sensation of the tongue. Cardiovascular: arrhythmias, hypotension, nonspecific ECG changes, flushing, phlebitis. Hematologic: hemolytic anemia, leukopenia, agranulocytosis. Dermatologic: sweating, edema, hair loss, pallor, rash, bad odor, dark sweat. Musculoskeletal: low back pain, muscle spasm and twitching, musculoskeletal pain. Respiratory: feeling of pressure in the chest, cough, hoarseness, bizarre breathing pattern, poatnasal drip. Urogenital: urinary frequency, retention, incontinence, hematuria, dark urine, nocturia, and one report of interstitial nephritis. SpecialSenses: blurredvision, dipiopia, dilated pupils, activation of latent Homers syndrome. Miscellaneous: hot flashes, weight gain or loss. Abnormalities in laboratory tests reported with levodopa alone, which may occur with SINEMET*: Elevations of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin, alkaline phosphatase or protein bound iodine. Occasional reduction in WBC, hemoglobin and hematocrit. Elevations of uric acid with colorimetric method. Positive Coombs tests reported both with SINEMET* and with levodopa alone, but hemoiytic anemia extremely rare. DOSAGE SUMMARY In order to reduce the incidence of adverse reactions and achieve maximal benefit. therapy with SINEMETk must be Individualized and drug administration continuously matched to the needs and tolerance of the patient. Combined therapy with SINEMET* hes a narrower therapeutic range then with levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made In small steps and recommended dosage ranges not be exceeded. Appearance of involuntary movements should be regarded as a sign of levodopa toxicity and an Indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinesias. Therapy in Patients not receiving Levedepa: initially 'A tablet once or twice a day, increase by 'A tablet every three days if desirable. An optimum dose of 3 to 5 tablets a day divided into 4 to 6 doses. Therapy in Patients receiving Levodopa: Discontinue levodopa tor at least 12 hours, then give approximately 20% of the previous levodopa dose in 4 to 6 divided doses. FOR COMPLETE PRESCRIBING INFORMATION. PARTICULARLY DETAILS OF DOSAGE AND ADMINISTRATION, PLEASE CONSULT PRODUCT MONOGRAPH WHICH IS AVAILABLE ON REQUEST. HOW SUPPLIED Ca8804.TabIetsSiNEMET* 250, dapple-blue. oval, biconvex, scored, compressed tablets coded MSD 654, each containing 25 mg of carbidopa and 250 mg of levodopa. Available in bottles of 100.
MERCK
O I
Trademark
DOHME CANADA LIMITED
Points Claire, Quebec
1106 CMA JOURNAL/DECEMBER 4, 1976/VOL. 115
effective in healing ulcers must rest for the present on repeated clinical observation that ulcers that failed to respond to many other treatments healed promptly with BPO therapy, and that ulcers considered by competent observers to be totally beyond medical management because of their size and complexity have healed with this therapy. During the 4 years of this study I have become convinced that BPO, while not a panacea, is a valuable addition to the presently available medications for local treatment of cutaneous ulcers. I thank Geoffrey S. Pinto, PhD for valuable suggestions regarding the role of oxygen in the healing of ulcers; Mrs. Margaret Morley, rehabilitation nurse coordinator, Victoria Hospital, London, for valuable assistance by supervising treatment and keeping records of the cases reported in this paper; and Stiefel Laboratories (Canada) Ltd. for kindly providing the 50% BPO paste and funds for printing the coloured illustrations. References 1. HooFT FV: Benzoyl peroxide, in Encyclopedia of Clinical Technology, vol 2, KIRK RE, OTEMER DF (eds), New York, Intersci Pub, 1948, p 479 2. SHARRATT M, FRAZER AC, FORBES OC: Study of the biological effects of benzoyl peroxide. Food Cosmet Toxicol 2: 527, 1964 3. LOEVENHART AS: Benzoylsuperoxyd, em neues therapeutisches Agens. Ther Monat 19: 426, 1905 4. PACE WE: A benzoyl peroxide-sulphur cream for acne vulgaris. Can Med Assoc .1 93: 252, 1965 5. MELENEY FL, JoHNsoN B: The prophylactic and active treatment of surgical snfections with zinc peroxide. Surg Gynecol Obstet 64:
382, 1937 6. MELENEY FL: Zinc peroxide in treatment of micro-aerophilic and anaerobic infections, with special reference to group of chronic, ulcerative, burrowing, non-gangrenous lesions of abdominal wall apparently due to microaerophilic haemolytic streptococcus. Ann Surg
101: 997, 1935 7. MELENEY FL, HARVEY HD: Combined use of zinc peroxide and sulfanilamide in the treatment of chronic, undermining, burrowing ulcers due to the micro-aerophilic hemolytic streptococcus. Ann Surg 110: 1067, 1939 8. MELENEY FL: Treatment of traumatic wounds with zinc peroxide. NY State J Med 39: 2188, 1939 9. Idem: Zinc peroxide in surgical infections. Surg Clin North Am 116: 691, 1936 10. Idem: Present role of zinc peroxide in the treatment of surgical infections. JAMA 149: 1450, 1952 11. ALTEMESER WA, CARTER BN: Infected burns with hemorrhage. Ann Surg 115: 1118, 1942 12. LEAKE CD: Advantages of benzoyl peroxide over zinc peroxide or sulfonamides in treating wounds or burns. JAMA 119: 101, 1942 13. REiD MR, ALTEMEJER WA: Peroxide oint-
ments. Ann Surg 118: 741, 1943
14. JOHNSON BA, MELENEY FL: Antiseptic and detoxifying action of zinc peroxide on certain surgical aerobic, anaerobic and micro-aerophilic bacteria. Ann Surg 109: 881, 1939 15. MORGAN JE: Topical therapy of pressure ul-
cers. Surg Gynecol Obstet 141: 945, 1975
16. LEHNsNGER AL: Biochemistry, 2nd ed, New York, Worth, 1975, p 494 17. FsscHER BH: Topical hyperbaric oxygen treatment of pressure sores and skin ulcers.
Lancet 2: 405, 1969 18. BART P0, ENFORS W, EstsKssON G: Hyperbaric oxygen therapy in dermatology. Br J Dermatol 86: 631, 1972 19. GRANT ME, PRocscOi' DJ: The biosynthesis of collagen. N Engl J Med 286: 245, 1972
