Potential role of systemic enzyme therapy with trypsin, bromelain and rutoside combination in burns


  • Suhas Vidyadhar Abhyankar Department of Burns and Plastic Surgery, Eric Kharas Memorial Burns Centre, Masina Hospital Burns, Sant Savta Marg, Byculla (East) Mumbai, Maharashtra, India
  • Arvind Madhusudan Vartak Department of Burns and Plastic Surgery, Eric Kharas Memorial Burns Centre, Masina Hospital Burns, Sant Savta Marg, Byculla (East) Mumbai, Maharashtra, India
  • Gautam Vinod Daftary Research and development department, Aksigen Hospital Care, Mumbai, Maharashtra, India




Hydrolytic enzymes, Proteolytic, Cytokines, Anti-inflammatory, Anti-oxidant


Burns is a global public health problem, with a higher prevalence rate in the Southeast Asia region, including India. The therapeutic interventions mainly target the control of complications following burn injury and assisting in physiological recovery. However, the excessive inflammatory changes and loss of immunological integrity, seen in burns patients, interfere with the healing process. An orally applied formulation composed of hydrolytic enzymes (bromelain, trypsin) and the flavonoid rutoside has a long history of use as natural anti-inflammatory agents. This combination has been found to exert anti-inflammatory, anti-thrombotic and antioxidant effects through myriad mechanisms that include favorable modulation of inflammatory mediators, enhancement of plasmin levels, reduced leukocyte migration to injury site and suppression of the formation of reactive oxygen species. These actions have been demonstrated in multiple in vitro and animal models. Further, the beneficial effects of the combination on inflammatory markers have been reported from multiple clinical studies. This review provides a discussion of the current understanding of cellular mechanisms and pathways involved in burn injury and the evidence highlighting the beneficial role of systemic enzyme therapy with trypsin-bromelain-rutoside combination in the management of burn injury patients.  

Author Biographies

Suhas Vidyadhar Abhyankar, Department of Burns and Plastic Surgery, Eric Kharas Memorial Burns Centre, Masina Hospital Burns, Sant Savta Marg, Byculla (East) Mumbai, Maharashtra, India

Consultant Burns and Plastic Surgeon, 

Department of Burns and Plastic Surgery,
Eric Kharas Memorial Burns Centre,
Masina Hospital Burns,
Byculla (East), Mumbai, India.

Arvind Madhusudan Vartak, Department of Burns and Plastic Surgery, Eric Kharas Memorial Burns Centre, Masina Hospital Burns, Sant Savta Marg, Byculla (East) Mumbai, Maharashtra, India

Hon. Burns and Plastic Surgeon 

Department of Burns and Plastic Surgery,
Eric Kharas Memorial Burns Centre,
Masina Hospital Burns,
Byculla (East), Mumbai, India.

Gautam Vinod Daftary, Research and development department, Aksigen Hospital Care, Mumbai, Maharashtra, India

Chairman, Akisgen Hospital Care, Research and Development, Aksigen Hospital Care, Mumbai, India


Burns. WHO, 2018. http://www.who.int/ mediacentre/factsheets/fs365/en/. Accessed on April 1, 2021.

Burns. WHO. http://www.who.int/violence_injury _prevention/other_injury/burns/en/. Accessed on April 1, 2021.

Atiyeh B, Masellis A, Conte C. Optimizing Burn Treatment in Developing Low- and Middle-Income Countries with Limited Health Care Resources (Part 1). Ann Burns Fire Disasters. 2009;22(3):121-5.

Church D, Elsayed S, Reid O, Winston B, Lindsay R. Burn Wound Infections. Clin Microbiol Rev. 2006;19(2):403-34.

Rowan M, Cancio L, Elster E, Burmeister D, Rose L, Natesan S et al. Burn wound healing and treatment: review and advancements. Critical Care. 2015;19(1):1-12.

White R, Lowrie L, Stork J, Iskandar S, Lamm M, Emancipator S. Targeted enzyme therapy of experimental glomerulonephritis in rats. Journal of Clinical Investigation. 1991;87(5):1819-27.

Targoni O, Tary-Lehmann M, Lehmann P. Prevention of Murine EAE by Oral Hydrolytic Enzyme Treatment. J Autoimmun. 1999;12(3):191-8.

Gaciong Z, Paczek L, Bojakowski K, Socha K, Wisniewski M, Heidland A. Beneficial effect of proteases on allograft arteriosclerosis in a rat aortic model. Nephrology Dialysis Transplantation. 1996;11(6):987-89.

Talaieva T, Bratus V. Proteolytic Enzyme Combination Reduces Inflammation and Oxidative Stress and Improves Insulin Sensitivity in a Model of Metabolic Syndrome. Adv Enzyme Res. 2015;03(01):1-8.

Nanda M, Kaur M. Role of Oral Enzymes in Post Operative Septoplasty Cases. Indian Journal of Otolaryngology and Head & Neck Surgery. 2014;71(S3):1663-67.

Forrest W, Goodridge D, MacDonald Watson A, Starkey W. Double-blind clinical trials of proteolytic enzyme therapy in oral surgery. British Journal of Oral Surgery. 1968;6(1):7-10.

Kamenícek V, Holán P, Franĕk P. Systemic enzyme therapy in the treatment and prevention of post-traumatic and postoperative swelling. Acta Chir Orthop Traumatol Cech. 2001;68(1):45-9

Singh T, More V, Fatima U, Karpe T, Aleem M, Prameela J. Effect of proteolytic enzyme bromelain on pain and swelling after removal of third molars. Journal of International Society of Preventive and Community Dentistry. 2016;6(9):197.

Baumueller M, Rau S. Efficacy and tolerance of systemic enzyme therapy in the treatment of acute thrombophlebitis–a randomised double-blind controlled trial. Journal Phlebology and Lymphology. 2018;11(1).

Ueberall M, Mueller-Schwefe G, Wigand R, Essner U. Efficacy, tolerability, and safety of an oral enzyme combination vs diclofenac in osteoarthritis of the knee: results of an individual patient-level pooled reanalysis of data from six randomized controlled trials. J Pain Res. 2016;9:941-61.

Shahid S, Turakhia N, Kundra M, Shanbag P, Daftary G, Schiess W. Efficacy and Safety of Phlogenzym-—-A Protease Formulation, in Sepsis in Children. JAPI. 2002;50:527-31.

Kerkhoffs G, Struijs P, Wit C, Rahlfs V, Zwipp H, Van Dijk C. A double blind, randomised, parallel group study on the efficacy and safety of treating acute lateral ankle sprain with oral hydrolytic enzymes. Br J Sports Med. 2004;38(4):431-35.

Wittenborg A, Bock P, Hanisch J, Saller R, Schneider B. Comparative epidemiological study in patients with rheumatic diseases illustrated in an example of a treatment with non-steroidal anti-inflammatory drugs versus an oral enzyme combination. Arzneimittel Forschung/Drug Research. 2000;50(8):728-38.

Hettiaratchy S, Dziewulski P. ABC of burns Pathophysiology and types of burns. BMJ. 2004;328(7453):1427-29.

Arturson G. Pathophysiology of the burn wound and pharmacological treatment. The Rudi Hermans Lecture, 1995. Burns. 1996;22(4):255-74.

Snell J, Loh N, Mahambrey T, Shokrollahi K. Clinical review: The critical care management of the burn patient. Critical Care. 2013;17(5):241.

Nielson C, Duethman N, Howard J, Moncure M, Wood J. Burns. Journal of Burn Care & Research. 2017;38(1):e469-81.

Glas G, Levi M, Schultz M. Coagulopathy and its management in patients with severe burns. Journal of Thrombosis and Haemostasis. 2016;14(5):865-74.

Lotz-Winter H. On the Pharmacology of Bromelain: An Update with Special Regard to Animal Studies on Dose-Dependent Effects. Planta Med. 1990;56(03):249-53.

Castell J, Friedrich G, Kuhn C, Poppe G. Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake. American Journal of Physiology-Gastrointestinal and Liver Physiology. 1997;273(1):G139-46.

Bromelain Monograph. Alternative Medicine Review. 2010;15(4):361-68.

Metzig C, Grabowska E, Eckert K, Rehse K, Maurer H. Bromelain proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo. In Vivo (Brooklyn). 1999;13(1):7-12.

Oh-ishi S, Uchida Y, Ueno A, Katori M. Bromelain, a thilprotease from pineapple stem, depletes high molecular weight kininogen by activation of Hageman factor (factor XII). Thromb Res. 1979;14(4-5):665-72.

SUDA H, YAMAUCHI H, ISO T. Potentiative effect of angiotensin converting enzyme inhibitor on carrageenan edema in rats and the role of tissue kininogen. J Pharmacobio-dyn 1984;7(6):372-77.

Gaspani L, Limiroli E, Ferrario P, Bianchi M. In vivo and in vitro Effects of Bromelain on PGE and SP Concentrations in the Inflammatory Exudate in Rats. Pharmacology. 2002;65(2):83-86.

Mohamed Tap F, Abd Majid F, Ismail H, Wong T, Shameli K, Miyake M et al. In Silico and In Vitro Study of the Bromelain-Phytochemical Complex Inhibition of Phospholipase A2 (Pla2). Molecules 2018;23(1):73.

Fitzhugh D, Shan S, Dewhirst M, Hale L. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clinical Immunology. 2008;128(1):66-74.

Hale L, Greer P, Sempowski G. Bromelain Treatment Alters Leukocyte Expression of Cell Surface Molecules Involved in Cellular Adhesion and Activation. Clinical Immunology. 2002;104(2):183-90.

Maurer H. Bromelain: biochemistry, pharmacology and medical use. Cellular and Molecular Life Sciences. 2001;58(9):1234-45.

Lehmann P. Immunomodulation by proteolytic enzymes. Nephrology Dialysis Transplantation. 1996;11(6):953-55.

Innerfield I, Schwarz A, Angrist A. intravenous trypsin: its anticoagulant, fibrinolytic and thrombolytic effects. Journal of Clinical Investigation. 1952;31(12):1049-55.

Alexander B, Pechet L, Kliman A. Proteolysis, Fibrinolysis, and Coagulation: Significance in Thrombolytic Therapy. Circulation. 1962;26(4):596-611.

White M, Glenn M, Gomer R. Trypsin Potentiates Human Fibrocyte Differentiation. PLoS One. 2013;8(8):e70795.

White M, Gomer R. Trypsin, Tryptase, and Thrombin Polarize Macrophages towards a Pro-Fibrotic M2a Phenotype. PLoS One. 2015;10(9):e0138748.

Ganeshpurkar A, Saluja A. The Pharmacological Potential of Rutin. Saudi Pharmaceutical Journal. 2017;25(2):149-64.

Afanas'ev I, Dcrozhko A, Brodskii A, Kostyuk V, Potapovitch A. Chelating and free radical scavenging mechanisms of inhibitory action of rutin and quercetin in lipid peroxidation. Biochem Pharmacol. 1989;38(11):1763-69.

Kauss T, Moynet D, Rambert J, Al-Kharrat A, Brajot S, Thiolat D et al. Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis. Arthritis Res Ther. 2008;10(1):R19.

Adefegha S, Leal D, de Oliveira J, Manzoni A, Bremm J. Modulation of reactive oxygen species production, apoptosis and cell cycle in pleural exudate cells of carrageenan-induced acute inflammation in rats by rutin. Food Funct. 2017;8(12):4459-68.

Khajevand-Khazaei M, Mohseni-Moghaddam P, Hosseini M, Gholami L, Baluchnejadmojarad T, Roghani M. Rutin, a quercetin glycoside, alleviates acute endotoxemic kidney injury in C57BL/6 mice via suppression of inflammation and up-regulation of antioxidants and SIRT1. Eur J Pharmacol. 2018;833:307-13.

Gerdin B, Svensjö E. Inhibitory effect of the flavonoid O-(beta-hydroxyethyl)-rutoside on increased microvascular permeability induced by various agents in rat skin. Int J Microcirc Clin Exp. 1983;2(1):39-46.

Blumberg S, Clough G, Michel C. Effects of hydroxyethyl rutosides upon the permeability of single capillaries in the frog mesentery. Br J Pharmacol. 1989;96(4):913-19.

Sheu J, Hsiao G, Chou P, Shen M, Chou D. Mechanisms Involved in the Antiplatelet Activity of Rutin, a Glycoside of the Flavonol Quercetin, in Human Platelets. J Agric Food Chem. 2004;52(14):4414-18.

Chen W, Jin M, Wu W. Experimental study on inhibitory effect of rutin against platelet activation induced by platelet activating factor in rabbits. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2002;22(4):283-85.

Maluegha D, Widodo M, Pardjianto B, Widjajanto E. The effects of bromelain on angiogenesis, nitric oxide, and matrix metalloproteinase-3 and -9 in rats exposed to electrical burn injury. Wound Medicine. 2015;9:5-9.

Hilton J. Effects of β-hydroxyethyl rutosides (H-R) administered post burn after thermal-injury-induced plasma volume loss in the nonresuscitated dog. Burns. 1982;8(6):391-94.

RaviKumar T, Ramakrishnan M, Jayaraman V, Babu M. Effect of trypsin–chymotrypsin (Chymoral Forte D.S.) preparation on the modulation of cytokine levels in burn patients. Burns. 2001;27(7):709-16.

Latha B, Ramakrishnan K, Jayaraman V, Babu M. Action of trypsin : chymotrypsin (Chymoral forte DS) preparation on acute-phase proteins following burn injury in humans. Burns. 1997;23:S3-S7.

Latha B, Ramakrishnan M, Jayaraman V, Babu M. The efficacy of Trypsin: Chymotrypsin preparation in the reduction of oxidative damage during burn injury. Burns. 1998;24(6):532-38.

Latha B, Ramakrishnan M, Jayaraman V, Babu M. Serum enzymatic changes modulated using trypsin: chymotrypsin preparation during burn wounds in humans. Burns. 1997;23(7-8):560-64.






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