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Serrapeptase

Scientific Name(s): Serralysin, Serrapeptasa (Spanish), Serrapeptase (INN), Serrapeptasi (Italian), Serrapeptidase, Serratia peptidase, Serratiopeptidase
Common Name(s): Serrapeptase

Medically reviewed by Drugs.com. Last updated on Aug 1, 2019.

Clinical Overview

Use

Serrapeptase is promoted as an anti-inflammatory and mucolytic agent, but efficacy for either use has not been well established. Two randomized controlled trials reported no reduction in swelling caused by sprained ankles, and results of studies evaluating use for pain and swelling after dental surgery are conflicting. Two clinical trials evaluating serrapeptase as a mucolytic agent also reported conflicting results.

Dosing

The usual adult dosage of serrapeptase is 10 mg 3 times daily (range, 15 to 60 mg/day) 2 hours after meals. Serrapeptase has been taken for 1 to 2 weeks as an anti-inflammatory agent and up to 4 weeks as a mucolytic agent.

Contraindications

None known.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Serrapeptase was well tolerated in short-term clinical trials, but long-term safety has not been evaluated. Rare, serious adverse effects reported with serrapeptase include eosinophilic pneumonitis, bullous pemphigoid, hemorrhage in a patient with Behcet disease, and possibly Stevens-Johnson syndrome.

Toxicology

No information is available.

History

Serrapeptase is an extracellular proteolytic enzyme produced by Serratia marcescens ATCC 27117 (formerly Serratia strain E-15).1 In the 1960s, the bacterium was isolated from the intestines of the silkworm Bombyx mori.2 This strain of Serratia performs an important function in the life cycle of the silkworm. The serrapeptase that it secretes dissolves the silkworm's cocoon, enabling it to emerge as a moth. In 1968, serrapeptase was introduced to the Japanese pharmaceutical market with a broad range of indications, including use as an anti-inflammatory agent for swelling due to surgery or trauma and for the treatment of chronic sinusitis and breast engorgement; as a mucolytic agent in patients with bronchitis, asthma, and tuberculosis, and for the clearing of bronchial secretions after surgery.3 In 2011, the manufacturer voluntarily recalled serrapeptase from the Japanese market after postmarketing clinical trials found it ineffective for anti-inflammatory use.3 In India, serrapeptase is marketed alone or in combination with a nonsteroidal anti-inflammatory drug (NSAID), including diclofenac and aceclofenac.4 In 2014, serrapeptase was licensed as a natural health product in Canada.5

Chemistry

Serrapeptase is an extracellular metalloendopeptidase composed of 470 amino acids, with a molecular weight of approximately 50,000 kilodaltons.6 The active site of the enzyme, which contains a zinc atom, hydrolyzes nonterminal peptide linkages of polypeptides. Maximal proteolytic activity occurs at 40°C (104°F) and at a pH of approximately 8 (range, 6 to 10).2, 7 Maintaining the temperature at 55°C (131°F) for 15 minutes inactivates the enzyme.8 Serrapeptase is manufactured by fermentation technology in which the enzyme is purified from bacterial culture. According to the Japanese Pharmacopoeia, 1 unit of serrapeptase produces 5 mcg of tyrosine per minute from 5 mL of substrate solution, with 2,000 to 2,600 units equivalent to 1 mg of serrapeptase.9 A dose of 10,000 to 20,000 units is equivalent to 5 to 10 mg of serrapeptase.

Serrapeptase is a member of the serralysin subfamily of proteases secreted by gram-negative bacteria with similar physiochemical properties.6, 7, 10 Serratia proteases are considered major virulence factors. Pathogenic effects in infected hosts include enhanced vascular permeability via activation of Hageman factor, inflammation via inactivation of human plasma protease inhibitors such as alpha-1-protease inhibitor and alpha-2-macroglobulin (which regulate the kallikrein-kinin cascade), and tissue degradation (via breakdown of fibronectin and collagen).6, 10, 11

Uses and Pharmacology

A systematic review identified 17 published clinical studies evaluating serrapeptase for a broad range of indications.2 Grading by the Scottish Intercollegiate Guidelines Network checklist found that most of these studies had poor methodology. Limitations included small sample size, poorly defined enrollment criteria and outcomes, unclear statistical methods, short duration, and failure of some studies to report the dose and duration of therapy. Two low-quality studies evaluated serrapeptase as an adjunct to increase the penetration of antimicrobial drugs into sites of infection. Other conditions evaluated in low-quality studies included postoperative or traumatic swelling, carpal tunnel syndrome, secretory otitis media, and chronic airway disease, but the resulting evidence was insufficient to evaluate the efficacy of serrapeptase for these indications. Among the 17 clinical studies identified, 5 were randomized controlled trials published in English and with a low risk of bias are summarized in the following sections.12, 13, 14, 15, 16

Anti-inflammatory/postoperative pain and swelling

In vitro studies

Anti-inflammatory activity of serrapeptase has been attributed to hydrolysis of inflammatory mediators such as bradykinin, histamine, and serotonin.2 However, experimental evidence to support this mechanism has not been published.

Animal data

The results of rat studies investigating the anti-inflammatory activity of oral serrapeptase are conflicting. In a scalded rat model of acute inflammation, serrapeptase inhibited activation of fibrinolysis; this activity was related to the enzyme's proteolytic activity.17 In a study evaluating carrageenan-induced paw edema for acute inflammation and cotton pellet–induced granuloma for subacute inflammation, serrapeptase demonstrated dose-dependent anti-inflammatory activity that was synergistic with aspirin.18 In a study evaluating formalin-induced paw edema, serrapeptase demonstrated dose-dependent inhibition of acute and chronic inflammation that was comparable with that of diclofenac.19 A final study evaluating carrageenan-induced paw edema found that a low dose of diclofenac reduced edema formation, but serrapeptase did not reduce edema and did not demonstrate a synergistic effect with diclofenac.5

Clinical data

Takeda Pharmaceuticals (Japan) conducted 2 postmarketing studies that found serrapeptase ineffective for relief of sprained ankle swelling. Synopses provide limited information regarding these unpublished multicenter, double-blind, parallel-group trials in which patients were randomized to receive serrapeptase 10 mg 3 times daily after meals or placebo for 1 week.20, 21 The first study, completed in 2002, enrolled 301 patients. The second study, completed in 2009, enrolled 252 patients. In both studies, there was no difference between serrapeptase and placebo for the primary end point, the change rate in the injured ankle joint sectional area on computed tomography scan.

Three randomized, double-blind clinical trials evaluated serrapeptase for relief of pain and swelling after extraction of impacted third molars.12, 13, 22 Although 1 study suggested that adding serrapeptase to acetaminophen may have some benefit over acetaminophen alone, 2 studies have suggested that serrapeptase is ineffective. In a crossover study, 24 patients with symmetrically impacted mandibular third molars had their molars removed in 2 sessions.12 After each session, patients were randomized to receive either acetaminophen 1,000 mg plus serrapeptase 5 mg or acetaminophen 1,000 mg plus placebo, with both regimens taken 3 times daily for 7 days. The addition of serrapeptase to acetaminophen reduced pain intensity on postoperative days 1 to 3 and reduced cheek swelling on days 2, 3, and 7. A second study randomized 150 patients to receive ibuprofen 600 mg, acetaminophen 1,000 mg, betamethasone 0.5 mg, serrapeptase 20 mg, or placebo 3 times daily for 7 days after third molar extraction.13 While ibuprofen and betamethasone reduced postoperative pain and swelling, results with serrapeptase did not differ from those with placebo for either outcome. A third study randomized 110 patients to receive dexamethasone 1 mg or serrapeptase 10 mg 3 times daily for 3 days after third molar extraction.22 Dexamethasone was more effective than serrapeptase in reducing pain and swelling.

A double-blind, placebo-controlled trial evaluated serrapeptase in 174 patients undergoing Caldwell-Luc antrotomy for chronic sinusitis.16 Patients were randomized to receive placebo or serrapeptase 10 mg 3 times daily from the day before until 5 days after surgery. Swelling was evaluated by measuring the distance from ear to nose and from eye to mouth. Serrapeptase significantly reduced buccal swelling compared with placebo, as measured by the distance from ear to nose (P < 0.05). Maximal swelling measured from ear to nose, which occurred 24 hours after surgery, was approximately 2 mm less with serrapeptase than placebo (P < 0.01). There was no significant difference between serrapeptase and placebo for swelling, as measured by the distance from eye to mouth.

Breast engorgement

Clinical data

A randomized, placebo-controlled clinical trial evaluated serrapeptase 30 mg/day for 3 days in women with postpartum breast engorgement.14 On a composite score that considered swelling, induration, and impaired breast-feeding, the incidence of marked or moderate improvement was 85.7% with serrapeptase and 60% with placebo (P < 0.05).

Mucolytic

Clinical data

Serrapeptase appears to reduce the viscosity of both sputum and nasal mucous. An open-label study in 29 patients with chronic bronchitis and bronchiectasis reported that 4 weeks of treatment with serrapeptase reduced sputum volume, percent solid component, elasticity, viscosity, and neutrophil concentration.23 A similar study in patients with chronic sinusitis found that 4 weeks of treatment with serrapeptase reduced nasal viscosity but not elasticity.24

A double-blind trial randomized 193 patients with acute or chronic ear, nose, and throat (ENT) disorders to receive 7 or 8 days of therapy with placebo or serrapeptase 10 mg 3 times daily after meals.15 Outcomes, evaluated in only 140 patients who completed the study, included pain, quantity of secretions, purulence of secretions, difficulty swallowing, nasal obstruction, nasal dysphonia, anosmia, and temperature. An ENT specialist, blinded to treatment allocation, rated outcomes on a 4-point scale. Scores for pain and quantity of secretions each significantly improved by approximately 1 point (P < 0.001 for both) with serrapeptase. Purulence of secretions and difficulty swallowing each significantly improved by approximately 0.5 points (P < 0.001 for both) with serrapeptase. Additional outcomes that improved significantly with serrapeptase over placebo included nasal dysphonia (P < 0.001), nasal obstruction (P < 0.001), anosmia (P < 0.001), and temperature (P < 0.01).

Takeda Pharmaceuticals conducted a postmarketing study evaluating serrapeptase as a mucolytic agent in chronic bronchitis. A synopsis provides limited information regarding this unpublished multicenter, double-blind, parallel-group trial in which 311 patients with difficulty expectorating were randomized to receive serrapeptase 10 mg 3 times daily after meals or placebo for 2 weeks.25 There was no difference between serrapeptase and placebo for the primary end point (difficulty expectorating). Serrapeptase also did not outperform placebo on secondary end points, including frequency of sputum, frequency of coughing, and global improvement.

Adjunct to antibiotics

In vitro studies

Serrapeptase has the potential to enhance the activity of antibiotics by inhibiting the production of biofilms and adhesion to host cells by pathogenic bacteria. In an in vitro study involving strains of Pseudomonas aeruginosa and Staphylococcus epidermidis obtained from infected prosthetic joints, serrapeptase reduced biofilm formation and enhanced the activity of ofloxacin against these pathogens in sessile culture.8 In another in vitro study, serrapeptase reduced the ability of Listeria monocytogenes to form biofilms, invade host cells, and lyse red blood cells.1 Mass spectrometry analysis found that serrapeptase inhibited the production of proteins necessary for L. monocytogenes to invade host cells. Additional studies reported a similar effect of serrapeptase on Staphylococcus aureus and S. epidermidis, with a reduction in biofilm formation and inhibition of specific cell surface proteins necessary for virulence.26, 27 Inhibition of fibrinolysis by serrapeptase is proposed to enhance the penetration of antibiotics to sites of infection.17, 28

Animal data

In a rat model of prosthetic joint infection with S. epidermidis, 1 group of animals was untreated, another received ofloxacin alone, and the third received ofloxacin and serrapeptase injected into the affected joint.28 Incidences of persistent infection were 63.2%, 37.5%, and 5.6%, respectively.

Clinical data

Two low-quality studies evaluated serrapeptase's ability to increase the absorption of antibiotics in bone and joint infections, and into pulmonary tissue in lung cancer patients undergoing thoracotomy.2, 29, 30 An open-label trial in 8 patients with bone or joint infections found that serrapeptase tended to increase the penetration of sulbenicillin into exudates.30 In the study of thoracotomy patients, the ratio of cefotiam in pulmonary tissue to blood was 29% with cefotiam alone and 44% with cefotiam plus serrapeptase (P < 0.05).29 These preliminary studies suggest that serrapeptase has the potential to enhance the absorption of antibiotics into infected tissues.

Other uses

Preliminary studies describe the development of topical products that pair serrapeptase with either ciprofloxacin or tetracycline for the management of periodontal disease.31, 32 An additional study describes the development of a wound-healing formulation that incorporates metronidazole and serrapeptase into alginate-based microspheres.33 Although serrapeptase has been promoted to prevent atherosclerosis, evidence to support use is only anecdotal.2

Dosing

GI absorption of large proteins such as serrapeptase may be impeded by a number of factors, including hydrophilicity, large molecular weight, chemical instability, nonspecific binding to biologic surfaces, and metabolism by intestinal enzymes.34 Some oral formulations of serrapeptase have an enteric coating intended to protect it from degradation in the stomach and enable dissolution in the more alkaline environment of the small intestines.2 Although a study in rats reported GI absorption of serrapeptase into the systemic circulation in an active form, studies evaluating GI absorption in humans are lacking.35 A Canadian natural health product monograph notes that enteric-coated products are the only acceptable formulation of serrapeptase.5

A serrapeptase dose of 5 to 10 mg is equivalent to 10,000 to 20,000 serrapeptase units.9 For use as a natural health product in Canada, the maximum dose of serrapeptase is 60 mg/day (120,000 serrapeptase units/day).5 To reduce swelling and pain, the dose is 15 to 60 mg/day (30,000 to 120,000 serrapeptase units/day); a health professional should be consulted for use of longer than 1 week. To reduce symptoms of ENT infections and as a mucolytic enzyme, the dose is 30 to 60 mg/day (60,000 to 120,000 serrapeptase units/day); a health professional should be consulted for use of longer than 4 weeks. Serrapeptase should be taken 2 hours after a meal. In 1968, serrapeptase was approved in Japan for use as a mucolytic and anti-inflammatory agent at a dosage of 10 mg 3 times daily after meals and taken for 1 to 2 weeks.20, 21, 25

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None documented. Serrapeptase may increase the risk of bleeding with anticoagulants or antiplatelet drugs.2

Adverse Reactions

Serrapeptase was well tolerated in short-term clinical trials enrolling more than 1,400 patients, with an incidence of adverse effects similar to that with placebo.12, 13, 15, 16, 20, 21, 25 Hypersensitivity reactions and gastric pain have been reported.5, 15 With treatment lasting only 1 to 2 weeks, these studies do not provide long-term safety data for serrapeptase.2 At least 4 cases of eosinophilic pneumonia have been reported with serrapeptase in Japan.36, 37, 38, 39 Single case reports of serious adverse effects associated with serrapeptase include bullous pemphigoid, hemorrhage in a patient with Behcet disease, and Stevens-Johnson syndrome.40, 41, 42 The case of Stevens-Johnson syndrome occurred with a combination product containing serrapeptase and diclofenac, an NSAID reported to cause Stevens-Johnson syndrome.43

Toxicology

No information is available.

References

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2. Bhagat S, Agarwal M, Roy V. Serratiopeptidase: a systematic review of the existing evidence. Int J Surg. 2013;11(3):209-217.23380245
3. Takeda voluntarily recalls its anti-inflammatory enzyme preparation, Dasen in Japan [press release]. Takeda Pharmaceutical Company Ltd website. http://www.takeda.com/news/2011/20110221_3829.html. Published February 21, 2011. Accessed November 16, 2014.
4. Joshi KK, Nerurkar RP. Anti-inflammatory effect of the serratiopeptidase—rationale or fashionable: a study in rat paw oedema model induced by the carrageenan. Indian J Physiol Pharmacol. 2012;56(4):367-374.23781657
5. Health Canada. Drugs and Health Products. Natural Health Products Ingredients Database: Serrapeptase. http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=serrapeptase&lang=eng. Published February 14, 2014. Accessed November 21, 2014.
6. Maeda H, Morihara K. Serralysin and related bacterial proteinases. Methods Enzymol. 1995;248:395-413.7674934
7. Baumann U. Chapter 180: Serralysin and related enzymes. In: Rawlings N, Salvesen G, eds. Handbook of Proteolytic Enzymes. 3rd ed. Waltham, MA: Academic Press; 2013:864-867.
8. Selan L, Berlutti F, Passariello C, Comodi-Ballanti MR, Thaller MC. Proteolytic enzymes: a new treatment strategy for prosthetic infections? Antimicrob Agents Chemother. 1993;37(12):2618-2621.8109925
9. Yamaguchi T. Perspectives on enzyme products in the Japanese Pharmacopoeia. Presented at: USP Enzyme Workshop Meeting; July 8, 2009; Rockville, MD. http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/yamaguchi.pdf. Accessed November 19, 2014.
10. Azzopardi EA, Ferguson EL, Thomas DW. The enhanced permeability retention effect: a new paradigm for drug targeting in infection. J Antimicrob Chemother. 2013;68(2):257-274.23054997
11. Häse CC, Finkelstein RA. Bacterial extracellular zinc-containing metalloproteases. Microbiol Rev. 1993;57(4):823-837.8302217
12. Al-Khateeb TH, Nusair Y. Effect of the proteolytic enzyme serrapeptase on swelling, pain and trismus after surgical extraction of mandibular third molars. Int J Oral Maxillofac Surg. 2008;37(3):264-268.18272344
13. Chopra D, Rehan HS, Mehra P, Kakkar AK. A randomized, double-blind, placebo-controlled study comparing the efficacy and safety of paracetamol, serratiopeptidase, ibuprofen and betamethasone using the dental impaction pain model. Int J Oral Maxillofac Surg. 2009;38(4):350-355.19168326
14. Kee WH, Tan SL, Lee V, Salmon YM. The treatment of breast engorgement with Serrapeptase (Danzen): a randomised double-blind controlled trial. Singapore Med J. 1989;30(1):48-54.2688125
15. Mazzone A, Catalani M, Costanzo M, et al. Evaluation of Serratia peptidase in acute or chronic inflammation of otorhinolaryngology pathology: a multicentre, double-blind, randomized trial versus placebo. J Int Med Res. 1990;18(5):379-388.2257960
16. Tachibana M, Mizukoshi O, Harada Y, Kawamoto K, Nakai Y. A multi-centre, double-blind study of serrapeptase versus placebo in post-antrotomy buccal swelling. Pharmatherapeutica. 1984;3(8):526-530.6366808
17. Kakinuma A, Moriya N, Kawahara K, Sugino H. Repression of fibrinolysis in scalded rats by administration of Serratia protease. Biochem Pharmacol. 1982;31(18):2861-2866.6753849
18. Viswanatha Swamy AH, Patil PA. Effect of some clinically used proteolytic enzymes on inflammation in rats. Indian J Pharm Sci. 2008;70(1):114-117.20390096
19. Jadav SP, Patel NH, Shah TG, Gajera MV, Trivedi HR, Shah BK. Comparison of anti-inflammatory activity of serratiopeptidase and diclofenac in albino rats. J Pharmacol Pharmacother. 2010;1(2):116-117.21350623
20. Synopsis: Post-marketing clinical study on serrapeptase (Dasen tablet) in patients with sprained ankle. Takeda Pharmaceutical Company Ltd website. http://www.takeda.com/research/ct/pdf/report/TSP_CCT-910_results_en.pdf. Published January 5, 2011. Accessed November 16, 2014.
21. Synopsis: Post-marketing clinical study on serrapeptase (Investigation on swelling associated with sprained ankle joint). Takeda Pharmaceutical Company Ltd website. http://www.takeda.com/research/ct/pdf/report/TSP_CCT-902_results_en.pdf. Published January 5, 2011. Accessed November 16, 2014.
22. Murugesan K, Sreekumar K, Sabapathy B. Comparison of the roles of serratiopeptidase and dexamethasone in the control of inflammation and trismus following impacted third molar surgery. Indian J Dent Res. 2012;23(6):709-713.23649050
23. Nakamura S, Hashimoto Y, Mikami M, et al. Effect of the proteolytic enzyme serrapeptase in patients with chronic airway disease. Respirology. 2003;8(3):316-320.12911824
24. Majima Y, Hirata K, Takeuchi K, Hattori M, Sakakura Y. Effects of orally administered drugs on dynamic viscoelasticity of human nasal mucus. Am Rev Respir Dis. 1990;141(1):79-83.2404442
25. Synopsis: Post-marketing clinical study on serrapeptase (Investigation on chronic bronchitis). Takeda Pharmaceutical Company Ltd website. http://www.takeda.com/research/ct/pdf/report/TSP_CCT-901_results_en.pdf. Published January 5, 2011. Accessed November 16, 2014.
26. Artini M, Papa R, Scoarughi GL, et al. Comparison of the action of different proteases on virulence properties related to the staphylococcal surface. J Appl Microbiol. 2013;114(1):266-277.23057709
27. Papa R, Artini M, Cellini A, et al. A new anti-infective strategy to reduce the spreading of antibiotic resistance by the action on adhesion-mediated virulence factors in Staphylococcus aureus. Microb Pathog. 2013;63:44-53.23811076
28. Mecikoglu M, Saygi B, Yildirim Y, Karadag-Saygi E, Ramadan SS, Esemenli T. The effect of proteolytic enzyme serratiopeptidase in the treatment of experimental implant-related infection. J Bone Joint Surg Am. 2006;88(6):1208-1214.16757752
29. Koyama A, Mori J, Tokuda H, et al. Augmentation by serrapeptase of tissue permeation by cefotiam [in Japanese]. Jpn J Antibiot. 1986;39(3):761-771.3525882
30. Okumura H, Watanabe R, Kotoura Y, Nakane Y, Tangiku O. Effects of a proteolytic-enzyme preparation used concomitantly with an antibiotic in osteoarticular infections [author's translation]. Jpn J Antibiot. 1977;30(3):223-227.853579
31. Maheshwari M, Miglani G, Mali A, Paradkar A, Yamamura S, Kadam S. Development of tetracycline-serratiopeptidase-containing periodontal gel: formulation and preliminary clinical study. AAPS PharmSciTech. 2006;7(3):76.17025256
32. Singh KP, Chhabra G, Sharma V, Pathak K. Thermosensitive periodontal sol of ciprofloxacin hydrochloride and serratiopeptidase: Pharmaceutical and mechanical analysis. Int J Pharm Investig. 2014;4(1):5-14.24678456
33. Rath G, Johal ES, Goyal AK. Development of serratiopeptidase and metronidazole based alginate microspheres for wound healing. Artif Cells Blood Substit Immobil Biotechnol. 2011;39(1):44-50.20553201
34. Kv S, Devi GS, Mathew ST. Liposomal formulations of serratiopeptidase: in vitro studies using PAMPA and Caco-2 models. Mol Pharm. 2008;5(1):92-97.18159928
35. Moriya N, Nakata M, Nakamura M, et al. Intestinal absorption of serrapeptase (TSP) in rats. Biotechnol Appl Biochem. 1994;20(pt 1):101-108.7917060
36. Hirahara K, Saitoh T, Terada I, et al. A case of pneumonitis due to serrapeptase [in Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi. 1989;27(10):1231-1236.2693781
37. Kai N, Shirai R, Hirata N, et al. A case of eosinophilic pneumonia due to Nicolase (serrapeptase) after recovery from acute eosinophilic pneumonia [in Japanese]. Nihon Kokyuki Gakkai Zasshi. 2009;47(3):254-258.19348276
38. Sasaki S, Kawanami R, Motizuki Y, et al. Serrapeptase-induced lung injury manifesting as acute eosinophilic pneumonia [in Japanese]. Nihon Kokyuki Gakkai Zasshi. 2000;38(7):540-544.11019569
39. Yokota Y, Kagami A, Nagano A. A case of Pulmonary infiltration with eosinophilia syndrome induced by serrapeptase [in Japanese]. Nihon Naika Gakkai Zasshi. 1992;81(11):1865-1866.1479230
40. Shimizu H, Ueda M, Takai T, et al. A case of serratiopeptidase-induced subepidermal bullous dermatosis. Br J Dermatol. 1999;141(6):1139-1140.10722270
41. Celik MM, Kavvasoglu G, Celik E, Bulgurca M. Serratiopeptidase induced hemorrhage in a patient with Behcet’s disease. Int J Basic Clin Studies. 2013;1(1):190-196.
42. Moitra S, Sen S, Banerjee I, Das P, Tripathi SK. Diclofenac-serratiopeptidase combination induced Stevens-Johnson syndrome—a rare case report with review of literature. J Clin Diagn Res. 2014;8(7):YD08-YD11.25177625
43. Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128(1):35-44.17805350

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