The bromelain and rutoside advantage in systemic enzyme therapy: pharmacological basis of combination with trypsin


  • James John Medical Services, Siro Clinpharm Limited, Thane, Maharashtra, India
  • Bhushan M. Khemnar Medical Services, Siro Clinpharm Limited, Thane, Maharashtra, India
  • Ganesh H. Divekar Medical Services, Siro Clinpharm Limited, Thane, Maharashtra, India
  • Nikita Patil Medical Services, Siro Clinpharm Limited, Thane, Maharashtra, India



Inflammation, Proteases, Flavonoids, Pain, Swelling


Inflammation involves various interlinked pathways and processes. In its uncontrolled form, inflammation results in variety of diseased sates. Current therapy for inflammatory diseases is limited to steroidal and non-steroidal anti-inflammatory drugs (NSAIDs). But these are associated with safety concerns and have a deleterious effect on wound healing. Proteolytic enzymes, also called proteases, which are naturally occurring substances derived from animal or plant sources, are believed to be effective and safer alternatives to the conventional medications. Combined with the bioflavonoid rutoside, the proteases trypsin and bromelain have been extensively investigated as alternatives to conventional therapies for pain and swelling associated with diverse conditions. Their individual mechanisms of action and the advantages of combining bromelain and rutoside with trypsin has been discussed. The combination not only covers a wider range of processes involved in inflammation, but they also complement each other’s actions and provide a more well-rounded control of the inflammatory processes.


Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017;9(6):7204-18.

Stone WL, Basit H, Burns B. Pathology, inflammation. InStatPearls. StatPearls Publishing. 2021.

Daftary G, Shah A, Divekar G, John J, Patil N, Khemnar B. Systemic therapy with bromelain- trypsin-rutoside combination in inflammation: A narrative review of the pharmacodynamics. Natl J Physiol Pharm Pharmacol. 2022;12(11):1-8.

Beitz JM. Pharmacologic Impact (aka" Breaking Bad") of Medications on Wound Healing and Wound Development: A Literature-based Overview. Ostomy Wound Manag. 2017;63(3):18-35.

Enoch S, Grey JE, Harding KG. Non-surgical and drug treatments. BMJ. 2006;332(7546):900-3.

Hess CT. Checklist for factors affecting wound healing. Adv Skin Wound Care. 2011;24(4):192.

Su WH, Cheng MH, Lee WL, Tsou TS, Chang WH, Chen CS et al. Nonsteroidal anti-inflammatory drugs for wounds: pain relief or excessive scar formation? Mediators inflam. 2010;2010.

Innerfield I, Schwarz A, Angrist A. Intravenous trypsin: Its anticoagulant, fibrinolytic and thrombolytic effects. J Clin Invest. 1952;31:1049-55.

Alexander B, Pechet L, Kliman A. Proteolysis, fibrinolysis, and coagulation: Significance in thrombolytic therapy. Circulation. 1962;26:596-611.

White MJ, Glenn M, Gomer RH. Trypsin potentiates human fibrocyte differentiation. PLoS One. 2013;8:e70795.

White MJ, Gomer RH. Trypsin, tryptase, and thrombin polarize macrophages towards a pro-fibrotic M2a phenotype. PLoS One. 2015;10:e0138748.

Targoni O, Lehmann PV. Modulation of the activation threshold for autoreactive T cells via systemic enzyme therapy with phlogenzym®. J Neuroimmunol. 1995;56:66.

Lehmann PV. Immunomodulation by proteolytic enzymes. Nephrol Dial Transplant. 1996;11:952-5.

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.

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;14:665-72.

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 Pharmacobiodyn. 1984;7:372-7.

Hale LP, Greer PK, Sempowski GD. Bromelain treatment alters leukocyte expression of cell surface molecules involved in cellular adhesion and activation. Clin Immunol. 2002;104:183-90.

Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol. 2008;128:66-74.

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 SA, Leal DB, de Oliveira JS, Manzoni AG, Bremm JM. 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 MR, 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.

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 li, pid peroxidation. Biochem Pharmacol. 1989;38(11):1763-69.

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.

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.

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.

Lorkowski G. Gastrointestinal absorption and biological activities of serine and cysteine proteases of animal and plant origin: review on absorption of serine and cysteine proteases. Int J Physiol Pathophysiol Pharmacol. 2012;4(1):10-27.

Barsom S, Sasse-Rollenhagen K, Betrmann A. Erfolgreiche Prostatitisbehandlung mit hydrolytischen Enzymen. (Effects of simultaneously administered Hydrolytic enzymes on Antibiotic serum levels). Erfahrungsheilkunde. 1982;31:2.

Renzini G, Varengo M. Die Resorption von Tetrazyklin in Gegenwart von Bromelain bei oraler Applikation. Arzneimittel-Forsch (Drug Res). 1972;2:410-2.

Tinozzi S, Venegoni A. Effect of bromelain on serum and tissue levels of amoxycillin. Drug Exp Clin Res. 1978;1:39-44.

Friesen A, Schilling A, Hofstetter A, Adam D. Tetracyclin-Konzentration im Prostata-Sekret. Z. antimikrob. antineoplast. Chirurgie. 1987;2:61-5.




How to Cite

John, J., Khemnar, B. M., Divekar, G. H., & Patil, N. (2022). The bromelain and rutoside advantage in systemic enzyme therapy: pharmacological basis of combination with trypsin. International Journal of Basic & Clinical Pharmacology, 11(6), 658–663.