Postgrad Med J: first published as 10.1136/pgmj.46.533.154 on 1 March 1970. Downloaded from Postgraduate Medical Journal (March 1970) 46, 154-155.

CURRENT SURVEYS

Enzymes for trauma

RUSSELL R. MILLER* DIRK V. DE YOUNG Pharm. D. M.D. JAMES PAXINOS B.S. Department ofPharmacy, University of Chicago Hospitals and Clinics, and the Continental Assurance Company, Chicago

Summary for of food. However, this review will We will discuss the mechanism of action, efficacy treat only the proteolytic claimed to reduce and side-effects of the proteolytic enzymes. Their the soft tissue swelling and oedema of trauma. exact mechanism of action remains vague which may Examples of such products marketed in the be partly responsible for the uncertainty about their United States are: (a) a mixture of enzymes extracted therapeutic value. from the pineapple fruit called (Ananase, copyright. Use of (Alpha-Chymar) in lens Rorer); (b) the proteolytic papain, extracted extractions has gained general acceptance and the from the fruit of the papaya tree, Carica papaya topical use of trypsin-chymotrypsin (Biozyme), (Papase, Warner-Chilcott); (c) chymotrypsin (Alpha- -streptodornase (Varidase) and fibri- Chymar, Armour; Avazyme, Wampole); and (d) nolysin-desoxyribonuclease (Elase) will also be shown combinations of chymotrypsin and trypsin (Chymo- to be of some value. lase, Warren Teed; Chymoral, Armour; Orenzyme, The merits of oral, buccal or intramuscular adminis- National). Other enzyme preparations, strepto- tration, however, will not be conclusively demon- kinase-streptodornase (Varidase, Lederle) and fibri- strated. Studies showing favourable results for non- nolysin-desoxyribonuclease (Elase, Parke-Davis), http://pmj.bmj.com/ topically administered enzymes are not completely although not chemically proteolytic also will be acceptable, primarily due to the lack of precise discussed because they are said to have the same techniques of measurement. therapeutic indications. The effectiveness of systemically administered pre- parations of proteolytic enzymes as anti-inflammatory Mechanism of action agents will remain to be established. The mechanism by which all of the previously Introduction mentioned enzymes exert their action is unclear. on October 1, 2021 by guest. Protected Various thories have been postulated but firm Proteolytic enzymes are defined as physical sub- evidence to support them is lacking. Innerfield stances that catalyse the of . In (1960) hypothesized that enzymes act as depoly- the medical literature of the past ten years, these merases which reduce the chain-length of a enzymes have been said to be therapeutically indi- molecule. He proposed that denatured protein cated for reducing the soft tisue oedema and macromolecules in the interstices of an inflamed inflammation secondary to trauma. Some pro- area of soft tissue could be depolymerized by pro- teolytic enzymes have also been used clinically as teolytic enzymes. The permeability of the inflamed digestants and have been said to be efficacious in area is supposedly increased, facilitating drainage aiding or replacing those enteric enzymes necessary and tissue repair. *Postdoctoral Fellow, National Library of Medicine, U.S. The mode of action of streptokinase-strepto- Public Health Service. dornase is thought to differ from that of the pro- Reprint requests to: Dr Miller, University of Chicago teolytic enzymes in the following manner. Strepto- Hospitals and Clinics, Box 96, Chicago, Illinois 60637, U.S.A. kinase activates a normal physiological constituent Postgrad Med J: first published as 10.1136/pgmj.46.533.154 on 1 March 1970. Downloaded from Current surveys 155 of the body, plasminogen, transforming it into the not find such an elevation after oral administration. physiological , . Plasmin actively Such results suggest a lack of absorption of the oral lyses the fibrin that is the chief substance composing form of chymotrypsin from the intestine. thrombi. Streptodornase acts by directly depoly- Oral chymotrypsin (Avazyme) and trypsin-chymo- merizing desoxyribonucleic acid and thus is thought trypsin combinations (Chymolase, Chymoral, Oren- to reduce the viscosity of purulent exudates (Sherry zyme) are marketed as enteric-coated tablets in order & Fletcher, 1960). to prevent hydrolysis by gastric juice and to permit These theories represent current speculation; the absorption from the intestine. exact mechanism by which these products exert The stability of these enzymes in human intes- their action has not been established as yet. tinal juice has been investigated. Wohlman, Kaba- coff & Avakian (1962) found that trypsin retained Efficacy only 8% of its activity, while chymotrypsin retained A factor which seems to influence the therapeutic as much as 63% after i hr of incubation in human efficacy of these agents is the method of administra- intestinal juice. At the end of 2 hr 30% of the pro- tion. Intraocular use of chymotrypsin (Alpha- teolytic activity of chymotrypsin still remained. Chymar) to facilitate dissection of the lens zonule Inasmuch as the trypsin-chymotrypsin preparations in intracapsular lentectomy has been accepted on the for oral use contain 68-84% trypsin and 16-23% basis of considerable experimental and clinical chymotrypsin, possibly a preparation containing evidence (New Drugs, 1967). Topical use of strepto- only chymotrypsin may be more efficacious. kinase-streptodornase (Varidase), -des- Despite the apparently destructive properties of oxyribonuclease (Elase), trypsin-chymotrypsin (Bio- intestinal juice, other investigators have been able zyme, Armour) and trypsin (Tryptar, Armour) as to substantiate the presence of enzymes in the debriding agents for removing clotted blood or circulation following oral administration. Various fibrinous or purulent accumulations present after techniques of measurement were used. Ambrus, trauma or inflammation appears to be effective. The Lassman & DeMarchi (1967) substantiated the above commercial preparations seem to be useful absorption of oral trypsin-chymotrypsin (Chymoral) as adjuncts in treating haemothorax, empyema, by identifying shifts in blood esterase levels. Miller, copyright. infected wounds or ulcers and other common sup- Williard & Polachek (1960) confirmed the absorp- purative lesions if applied properly. tion of trypsin from the intestinal tract after labelling The value of oral,* buccal and intramuscular the enzyme with 131I. Miller & Opher (1964) administration of these products has not been fully demonstrated absorption of oral bromelains (Ana- accepted. Since their introduction into therapy, the nase) by these enzymes' ability to lysecasein in serum. non-topical dosage forms have been the subject of These studies demonstrate only that the enzyme much controversy. Clinical trials substantiating their or some derivative of it was absorbed. They do not efficacy are consistently disputed by numerous demonstrate that the amount or the form of the clinicians, which may be due in part to difficulties in absorbed enzyme was able to exhibit a significant http://pmj.bmj.com/ assessing and quantifying the effectiveness of these proteolytic effect in traumatized areas. enzymes' action. There is no precise method of measuring a given amount of inflammation and Clinical trials oedema. Therefore, most clinical trials have relied Numerous controlled double-blind studies are on investigators' subjective interpretations of results. reported confirming the efficacy of the proteolytic Contributing further to this question of efficacy is enzymes. Boutselis & Sollars (1964) found that the absence of evidence that are showing enzymes papain (Papase) increased the rate of resolution of on October 1, 2021 by guest. Protected delivered intact by the circulation to the inflamed swelling following perineal episiotomy. Zatuchni & area, not having been previously affected by the Columbi (1967) found similar effects in post-partum powerful anti-proteolytic activity of serum (Sherry patients with the use of bromelains (Ananase). & Fletcher, 1960). Soule, Wasserman & Burstein (1966) found trypsin- The anti-proteolytic activity of serum was investi- chymotrypsin (Chymoral) effective in reducing gated by Grob (1943). Subsequently Tauber (1950) oedema and ecchymosis in patients after medio- demonstrated a specific inhibition by serum of lateral episiotomy. Favourable results with the use chymotrypsin. Silverman, Livingston & Lipshitz of proteolytic enzymes were also shown for other (1966) measured an increase in the serum's chymo- conditions such as sinusitis (Taub, 1967; Seltzer, trypsin-inhibiting ability after administration of 1967); certain oral surgery (Metro & Horton, 1965; chymotrypsin intramuscularly but these authors did Magnes, 1966); and surgical and accidental trauma * Oral administration refers to preparations that are ofthe face, head andneck (Lewis & Grossman, 1965); swallowed and does not include those intended for buccal hand (Lie, Larsen & Posch, 1967);foot (Frank, 1965); administration. and abdomen (Thorek & Pandit, 1964). Postgrad Med J: first published as 10.1136/pgmj.46.533.154 on 1 March 1970. Downloaded from 156 Current surveys Controlled double-blind trials showing no signi- GYLLING, V., RINTALA, A., TAIPALE, S. & TAMMISTO, T. ficant difference between and (1966) The effect of a proteolytic enzyme combinate enzymes placebos () on the postoperative oedema by oral applica- have also been reported. Gylling et al. (1966) tion. Acta chirurgica Scandanavica, 131, 193. measured the effect of bromelains (Ananase) on HUNTSINGER, L. A. & LEBHERZ, T.B. (1966) Double-blind post-operative oedema after facial plastic surgery, study of the use of oral chymotrypsin in episiotomy. and could show no difference between the Obstetrics and Gynecology, 27, 268. significant INNERFIELD, I. (1960) Enzymes in Clinical Medicine. McGraw- enzyme preparation and a placebo. Sherman & Hill, New York. Ellison (1961) found that patients could not dif- LEWIS, G.K. & GROSSMAN, A.R. (1965) The use of an oral ferentiate between trypsin-chymotrypsin (Orenzyme) in trauma. Journal of the International and a in the of College of Surgeons, 44, 136. placebo relieving pain episiotomy. LIE, K.K., LARSEN, R.D. & POSCH, J.L. (1967) Evaulation of Huntsinger & Lebherz (1966) found chymotrypsin an oral proteolytic enzyme in operations upon the hand. (Avazyme) no different from a placebo in alleviating Surgery, Gynecology and Obstetrics with International the pain, oedema and inflammation induced by Abstracts of Surgery, 125, 595. MAGNES, G.D. (1966) Proteolytic enzymes in oral surgery. episiotomy. Journal of the American Dental Association, 72, 1420. The conflicting results of these clinical trials are METRO, P.S. & HORTON, R.B. (1969) Plant enzymes in oral not entirely unexpected. Substantiating a clinical surgery. Oral Surgery, 19, 309. effect due to the proteolytic enzymes relies on the MILLER, J.M. & OPHER, A.W. (1964) The increased pro- observers' A reliable means teolytic activity of human blood serum after the oral subjective interpretation. administration of bromelain. Experimental Medicine and of measuring the clinical effects, if any, of the Surgery, 22, 277. enzyme preparations remains to be developed and MILLER, J., WILLIARD, R.F. & POLACHEK, A.A. (1960) An this seems to be the major obstacle to the acceptance investigation of trypsin I131 in patients. Experimental of the efficacy of the & Fletcher's Medicine and Surgery, 18, 352. enzymes. Sherry New Drugs (1967) pp. 445-467. American Medical Associa- 1960 statement concerning the clinical value of the tion, Chicago. enzymes still appears to be true, 'The evidence SELTZER, A.P. (1967) Adjunctive use of bromelains on supporting the existence of an anti-inflammatory sinusitis: a controlled study. Eye, Ear, Nose, Throat effect in man for such enzymes as trypsin, chymo- Monthly, 46, 1281. and is still SHERMAN, E. & ELLISON, R.S. (1961) Subjective evaluation copyright. trypsin streptokinase... unsatisfactory of an enzyme preparation in episiotomy pain. American and ... the burden of responsibility for proving this Journal of Obstetrics and Gynecology, 82, 863. effect remains upon those who advocate their use.' SHERRY, S. & FLETCHER, A.P. (1960) Proteolytic enzymes: a therapeutic evaluation. Clinical Pharmacology and Side-effects Therapeutics, 1, 202. SILVERMAN, I., LIVINGSTON, S.F. & LIPSHITZ, H. (1966) The The incidence of side-effects reported with the oral effect of oral and intramuscular chymotrypsin on the or buccal administration of proteolytic enzymes is serum chymotrypsin inhibitor levels in the blood following remarkably low. They include gastro-intestinal radical mastectomy. Experimental Medicine and Surgery, upset (oral) or local tissue irritation (buccal) and 24, 126. SOULE, S.D., WASSERMAN, H.C. & BURSTEIN, R. (1966) Oral http://pmj.bmj.com/ mild allergic manifestations (rash, urticaria, itching). proteolytic enzyme therapy (Chymoral) in episiotomy Intramuscular injection and direct instillation into patients. American Journal of Obstetrics and Gynecology, closed body cavities may cause febrile reactions; 95, 820. anaphylactic reactions have been reported TAUB, S.J. (1967) The use of bromelains in sinusitis: a following double-blind clinical evaluation. Eye, Ear, Nose, Throat intramuscular use. Monthly, 46, 1281. TAUBER, H. (1950) Chymotrypsin inhibition by human References serum in health and disease. Proceedings ofthe Society for

AMBRUS, J.L., LASSMAN, H.B. & DEMARCHI, J.J. (1967) Experimental Biology and Medicine, 74, 486. on October 1, 2021 by guest. Protected Absorption of exogeneous and endogenous proteolytic THOREK, P. & PANDIT, J.K. (1964) Proteolytic enzymes in enzymes. Clinical Pharmacology and Therapeutics, 8, 362. wound repair; immediate postoperative effects. Applied BOUTSELIS, J.G. & SOLLARS, R.J. (1964) The effect of pro- Therapy, 6, 323. teolytic enzymes on episiotomy pain and swelling. Ohio WOHLMAN, A., KABACOFF, B.L. & AVAKIAN, S. (1962) Com- State Medical Journal, 60, 551. parative stability of trypsin and chymotrypsin in human FRANK, S.C. (1965) Use ofchymoral as an anti-inflammatory intestinal juice. Proceedings of the Societyfor Experimental agent following surgical trauma. Journal of the American Biology and Medicine, 109, 26. Pediatric Association, 55, 706. ZATUCHNI, G.I. & COLOMBI, D.J. (1967) Bromelains therapy GROB, D. (1943) The antiproteolytic activity of serum. for the prevention of episiotomy pain. Obstetrics and Journal of General Physiology, 26, 405. Gynecology, 29, 275.