Fibrinolytic and Proteolytic Enzymes, Medical Use

by Jeffrey Dach MD

Sam is a 24 year old with a swollen painful ankle after an injury playing basketball.  Xrays are negative for fracture, but Sam cannot walk and stays at home applying ice packs.  Jim is a 62 year old who sees a Cardiologist for episodes of chest pain, and was diagnosed with “stable angina” and given nitro pills.  Ralph sees a urologist for an enlarged prostate, and was given the diagnosis of BPH (Benign Prostatic Hyperplasia).  Sue has chronic sinusitis and bronchitis with thick mucus.   Neal had two episodes of a “mild” stroke with transient slurred speech.  Left Image sprained ankle courtesy of wikimedia commons.

What do all these patients have in common?

They could all benefit from proteolytic enzymes available at the health food store without a prescription.  Since these are supplements, it is unlikely their doctor would mention it.

The three major enzymes are
1) Serrapeptidase,
2) Nattokinase and
3) Lumbrokinase.

Serrapeptidase is made by the silk worm, and used to digest the cocoon.  Serrapeptidase has anti-inflammatory activity, and has been suggested as a replacement for NSAID anti-inflammatory drugs like Ibuprofen and Indomethacin.   Serrapeptidase is just as effective without the adverse side effects of NSAIDS.

“Serratiopeptidase or serrapeptase is a protein (proteolytic) enzyme isolated from the non-pathogenic enterobacteria Serratia E15 found in silkworms. Serratiopeptidase often prescribed in various specialties like surgery, orthopedics, otorhinolaryngology, gynecology and dentistry for its anti-inflammatory, anti-endemic and analgesic effects . In the research in recent years, exploration illustrated enzyme also plays a vital role in the management of atherosclerosis as it does possess fibrinolytic and caseinolytic properties. ” quote (1)

Blood clots, cysts and arterial plaque are all gradually dissolved. Over 50 clinical trials from Europe and Asia attest to the ability of Serrapeptase to successfully treat conditions ranging from sprains, torn ligaments, post-operative swelling (edema), fibrocystic breast disease, deep vein thrombosis (DVT), carpal tunnel syndrome, ear, nose and throat infections and atherosclerosis. Serrapeptase literally digests inflammatory tissue.”Quote(8)

Serrapeptidase useful for Ankle Sprains

Dr Esch studied ankle sprains in 66 patients finding the use of Serrapeptidase significantly reduced pain and swelling after the injury.(2)

Nattokinase

Nattokinase comes from fermented soy products and a staple of the Japanese diet.  Nattokinase has fibrinolytic effects and thought to be useful in prevention of cardiovascular disease, and is currently undergoing a clinical trial at University of Southern California, Dr Howard Hodis. (70):

“Various animal and human trials have demonstrated that NK improves blood circulation and helps decrease the risk of a variety of cardiovascular diseases without producing any adverse side effects.”quote (22)

Lumbrokinase

Lumbrokinase comes from earthworms and is the most potent fibrinolytic enzyme of the three.  It was found effective in improving myocardial perfusion and reducing angina symptoms in patients with coronary artery disease.(1)

Left Image: Improvement in Myocardial Perfusion Scan in Angina Patient after Lumbrokinase. Courtesy of  Kasim 2009. Left column before treatment. Right column alter treatment.  Note perfusion defect between white arrows resolves after treatment.(26)

Lumbrokinase was useful in treatment of  Ischemic Stroke, angina, myocardial ischemia,  deep venous thrombosis, hypertension,  vascular dementia  and hypercoagulation-associated complications.(27)

“serrapeptase is not considered a strong fibrinolytic enzyme and should primarily be used for inflammation and pain association with oral/facial surgeries, sinus infection, arthritis, or chronic airway diseases. Respectively, nattokinase and lumbrokinase would be more suited for patients with mild and severe hypercoagulation or for patients with low and high cardiovascular risks.” Quote from (27)

Proteolytic Enzymes Dissolve Biofilms – Assist Antibiotics

A number of studies show that proteolytic enzymes enhance antibiotic effects by breaking up biofilms.  The enzymes are useful add-ons for antibiotic treatment of infectious micro-organisms known to produce bio-films.  Left image Scanning Electron Microscope of BioFilm fibrin strands courtesy of CNN.

Find Lumbrokinase, Nattokinase and Serrapeptidase on Amazon

Jeffrey Dach MD
7450 Griffin Road, Suite 180/190
Davie, Fl 33314
954-792-4663

Links and References

https://www.sciencedirect.com/science/article/pii/S181808761630160X
1) Tiwari, Manju. “The role of serratiopeptidase in the resolution of inflammation.” Asian journal of pharmaceutical sciences 12.3 (2017): 209-215.

Serratiopeptidase or serrapeptase is a protein (proteolytic) enzyme isolated from the non-pathogenic enterobacteria Serratia E15 found in silkworms. Serratiopeptidase often prescribed in various specialties like surgery, orthopedics, otorhinolaryngology, gynecology and dentistry for its anti-inflammatory, anti-endemic and analgesic effects [42]. In the research in recent years, exploration illustrated enzyme also plays a vital role in the management of atherosclerosis as it does possess fibrinolytic and caseinolytic properties [43]. Like most enzymes, serratiopeptidase also possesses broad substrate affinity and has been to be reported therapeutically useful in the management of pain and inflammation.

Sprained Ankle
2) https://www.ncbi.nlm.nih.gov/pubmed/2647603
Esch, P. M., H. Gerngross, and A. Fabian. “Reduction of postoperative swelling. Objective measurement of swelling of the upper ankle joint in treatment with serrapeptase–a prospective study.” Fortschritte der Medizin 107.4 (1989): 67.

Using a quantitative standardized procedure, the swelling of the ankle produced by supination trauma was measured. In the 66 patients with fresh rupture of the lateral ligament treated surgically at our Department between December 1986 and April 1987, a prospective study of the effect of serrapeptase (Aniflazym) on post-operative swelling and pain was carried out in 3 randomized groups of patients. In the group receiving the test substance, the swelling had decreased by 50% on the third post-operative day, while in the other two control groups (elevation of the leg, bed rest, with and without the application of ice) no reduction in swelling had occurred at that time. The difference is statistically significant (p = 0.013). Decreasing pain correlated for the most part with the reduction in swelling. Thus, the patients receiving the test substance more rapidly became pain-free than did the control groups. On the basis of these results, serrapeptase would appear to be an effective preparation for the post-operative reduction of swelling, in comparison with the classical conservative measures, for example, the application of ice.

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https://www.globalhealingcenter.com/natural-health/health-benefits-of-serrapeptase/
3) The Health Benefits of Serrapeptase Dr. Edward Group DC, NP, DACBN, DCBCN, DABFM Last Updated on June 5, 2017

Discovered in the early 1970’s, this proteolytic enzyme was isolated from the Serratia species of bacteria located in the intestines of silkworms.

references

4)  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 Feb;30(1):48-54.

5) Mazzone A, Catalani M, Costanzo M, Drusian A, Mandoli A, Russo S, Guarini E, Vesperini G. 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 Sep-Oct;18(5):379-88.

6) Kakinuma A, Moriya N, Kawahara K, Sugino H. Repression of fibrinolysis in scalded rats by administration of Serratia protease. Biochem Pharmacol. 1982 Sep 15;31(18):2861-6.

http://www.notjustnotes.ws/Serrapeptase.pdf
7) SERRAPEPTASE Studies and Technical Information Serrapeptase – Scientific Background of the Most Potent Proteolytic Enzyme
Dr. Michelle Kmiec

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https://highlevelwellness.ca/blogs/news/80706436-conquer-inflammation-with-serrapeptase
8) Conquer Inflammation with Serrapeptase By Zoltan P. Rona, M.D., M.Sc.

Blood clots, cysts and arterial plaque are all gradually dissolved. Over 50 clinical trials from Europe and Asia attest to the ability of Serrapeptase to successfully treat conditions ranging from sprains, torn ligaments, post-operative swelling (edema), fibrocystic breast disease, deep vein thrombosis (DVT), carpal tunnel syndrome, ear, nose and throat infections and atherosclerosis. Serrapeptase literally digests inflammatory tissue.

9) 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;18:379-88.

9) Nakamura S, Hashimoto Y, Mikami M, et al. Effect of the proteolytic enzyme serrapeptase in patients with chronic airway disease. Respirology 2003;8:316-20.

10) Tachibana M, Mizukoshi O, Harada Y, et al. A multi-centre, double-blind study of serrapeptase versus placebo in post-antrotomy buccal swelling. Pharmatherapeutica 1984;3:526-30.

11) Harris Interactive Over-The-Counter Pain Medication Study Sponsored by the National Consumers League. January 30, 2003. Chairman of Harris Poll, New York, NY: Humphrey Taylor. Contact: www.harrisinteractive.com and www.nclnet.org.

12) Tachibana M, et al. A muti-centre, double-blind study of serrapeptase versus placebo in post-antrotomy buccal swelling. Pharmatherapeutica; 1984; 3(8); 526-30.

13) Panagariya A, Sharma AK. A preliminary trial of serratiopeptidase in patients with carpal tunnel syndrome. J Assoc Physicians India; 1999; 47 (12); 1170-1172.

14) Kee WH, et al. The treatment of breast engorgement with Serrapeptase (Danzen): a randomized double-blind controlled trial. Singapore Med J.; 1989 30 (1); 48-54.

15) Sasaki S, et al. Serrapeptase-induced lung injury manifesting as acute eosiniphilic pneumonia. Nihon Kokyuki Gakkai Zasshi. 2000; 38 (7); 540-4.

16) Desser L, Rehberger A. Oncology. Induction of tumor necrosis factor in human peripheral-blood mononuclear cells by proteolytic enzymes. 1990;47(6):475-7.

17) Koyama A, Mori J, Tokuda H, Waku M, Anno H, Katayama T, Murakami K, Komatsu H, Hirata M, Arai T, et al. Augmentation by serrapeptase of tissue permeation by cefotiam]. Jpn J Antibiot. 1986 Mar;39(3):761-71.

18) Sivaramakrishnan G, Sridharan K. Role of Serratiopeptidase After Surgical Removal of Impacted Molar: A Systematic Review and Meta-analysis. J Maxillofac Oral Surg. 2018 Jun;17(2):122-128.

https://www.sciencedirect.com/science/article/pii/S2095177917300242
19) Gupte, Vandana, and Umesh Luthra. “Analytical techniques for serratiopeptidase: A review.” Journal of Pharmaceutical Analysis 7.4 (2017): 203-207.

free pdf
https://www.journal-surgery.net/article/S1743-9191(13)00026-5/fulltext
20) Bhagat, Shivani, Monika Agarwal, and Vandana Roy. “Serratiopeptidase: a systematic review of the existing evidence.” International Journal of Surgery 11.3 (2013): 209-217.

CONCLUSION: Serratiopeptidase is being used in many clinical specialities for its anti-inflammatory, anti-edemic and analgesic effects. It is even being promoted as a health supplement to prevent cardiovascular morbidity.

21) https://www.ncbi.nlm.nih.gov/pubmed/12911824
Respirology. 2003 Sep;8(3):316-20. Effect of the proteolytic enzyme serrapeptase in patients with chronic airway disease. Nakamura S1, Hashimoto Y, Mikami M, Yamanaka E, Soma T, Hino M, Azuma A, Kudoh S.
The proteolytic enzyme serrapeptase (SER) is widely used in clinical practice in Japan. We investigated the effect of SER on sputum properties and symptoms in patients with chronic airway diseases.
METHODS:  This study was an open-labelled trial with a non-treatment control group. Patients were randomly assigned to oral treatment with (n = 15) and without (n = 14) SER 30 mg/day for 4 weeks. Patients collected sputum samples for about 4 h in the morning on the day the trial began and 4 weeks later. We measured the amount of sputum by weighing. Part of each sputum sample was weighed and then completely dried and reweighed. The percentage solid component, viscosity and elasticity of the sputum were measured. Mucociliary transportability index was measured using ciliated bovine trachea ex vivo. Sputum smears were also prepared to count sputum neutrophils. Patients’ symptoms were assessed by a questionnaire that used a visual analogue scale.
RESULTS: After 4 weeks of SER treatment, sputum weight in the morning, percentage solid component, viscosity and elasticity of sputum, sputum neutrophil count, frequency of coughing and frequency of expectoration significantly decreased. The mean mucociliary transportability index increased from 13.3 +/- 1.8 to 24.4 +/- 2.5 (P = 0.0103).
CONCLUSIONS: SER may exert a beneficial effect on mucus clearance by reducing neutrophil numbers and altering the viscoelasticity of sputum in patients with chronic airway diseases.

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Nattokinase

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372539/
22) Weng, Yunqi, et al. “Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease.” International Journal of Molecular Sciences 18.3 (2017).

NK can break down blood clots by directly hydrolyzing fibrin and plasmin substrate, converts endogenous prourokinase to urokinase (uPA), degrades PAI-1 (plasminogen activator inhibitor-1), and increases tissue plasminogen activator (t-PA) which supports fibrinolytic activity (Figure 3: Mechanism of action) [2]. Unlike common fibrinolytic proteases, such as t-PA and uPA, which can produce various side effects such as bleeding, NK exhibits little to no side effects. Studies also indicate that an oral administration of NK can be absorbed by the intestinal tract [3,4]. NK exhibits strong fibrinolytic activity after intraduodenal absorption. These characteristics make NK a versatile and potent fibrinolytic enzyme that can be used to combat blood clots.

Nattokinase exhibits exceptionally potent fibrinolytic activity. Natto, a soybean product fermented by B. subtilis (natto) and rich in NK, has been served as a traditional food in Asia for hundreds of years and has recently garnered increased interest in Western medicine. Various animal and human trials have demonstrated that NK improves blood circulation and helps decrease the risk of a variety of cardiovascular diseases without producing any adverse side effects. The unpleasant odor and texture of natto limits its utilization as a dietary nutriment. Costly and complicated extraction and purification processes have inhibited the general use of NK as a nutraceutical. Currently, NK is sold as a dietary supplement in the United States, Canada, and Europe. It is available as a powder contained within a vegetable-based capsule.

https://www.sciencedirect.com/science/article/pii/S0271531709000220
23) Hsia, Chien-Hsun, et al. “Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects.” Nutrition research 29.3 (2009): 190-196.

pdf
24) Xu, Jianping, et al. “Thrombolytic effects in vivo of nattokinase in a carrageenan-induced rat model of thrombosis.” Acta haematologica 132.2 (2014): 247-253.
Nattokinase is a serine protease produced by Bacillus subtilis during the fermentation of the soybean product natto. The fibrinolytic activity and thrombolytic effects of nattokinase have been observed in vitro, but the effect in vivo has still to be researched. The objective of this study was to demonstrate the activity of nattokinase in vivo. Methods: To establish a rat model of thrombosis, κ-carrageenan was injected subcutaneously into the toes of Sprague-Dawley (SD) rats. Histological examination confirmed thrombosis. The rats were then treated with varying doses of nattokinase and the resulting thrombolysis was histologically assessed. ELISA was used to determine the levels of the fibrin/fibrinogen degradation products (FDPs) and D-dimer, which are sensitive indices of fibrinolytic activity. Vermis kinase, a known thrombolytic agent, was used as a positive control. Results: Biopsy results revealed partial thrombolysis in the tail vessels of the rats treated with nattokinase or vermis kinase. FDP and D-dimer levels were higher in rats treated with high-dose nattokinase than in those treated with saline. No difference in FDP or D-dimer levels was observed between rats treated with high-dose nattokinase and those treated with vermis kinase. Conclusions: Both the histological and physiological evidence from this study indicate that nattokinase exerts thrombolytic effects in vivo.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479826/
25) Kurosawa, Yuko, et al. “A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles.”
Our aim was to determine the quantitative effects of a single-dose of Nattokinase (NK) administration on coagulation/fibrinolysis parameters comprehensively in healthy male subjects. A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously.

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Lumbrokinase Boluoke® (lumbrokinase) Canada RNA Biochemical Inc.

26) Myocardial Perfusion Scan before and after Lumbrokinase
Kasim, Manoefris, et al. “Improved myocardial perfusion in stable angina pectoris by oral lumbrokinase: a pilot study.” The Journal of Alternative and Complementary Medicine 15.5 (2009): 539-544.  Improved myocardial perfusion in stable angina pectoris by oral lumbrokinase. Kasim 2009

Recent clinical trials confirmed its clinical efficacyin the treatment of CAD and thrombotic cerebral infarct,8,9
albeit publication related to the former has been largely con-fined to the Chinese language literature.
Two (2) capsules of TrombolesÒ(The Institute of Biophy-sics, Chinese Academy of Sciences, Beijing), each containing
250 mg lumbrokinase extract equivalent to 300,000 U oflumbrokinase derived from an artificially culturedLumbricusstrain, were administered three times daily for 30 consecu-tive days.

Lumbrokinase effects a reduction in the degree and extent of inducible myocardial ischemia with amelioration of anginal symptoms in patients with CAD with stable angina.

http://www.townsendletter.com/May2018/lumbrokinase0518_2.html
27) MAY 2018 Lumbrokinase – An Enzyme for More Than Just Circulatory Health!  by Martin Kwok, BSc, MSAOM, ND

28) http://townsendletter.com/May2018/LumbrokinaseREFS0518.pdf
REFERENCES

lumbrokinase is primarily a fibrinolytic enzyme and it possesses both direct and indirect fibrinolytic effects.
It can activate the innate plasminogen system and also can achieve direct fibrinolysis independent of the plasminogen system (see Diagram 1). In 2004, Zhang el al discovered that lumbrokinase also inhibits PAI-1 activity and enhances t-PA activity.4 In addition to being a strong fibrinolytic agent, lumbrokinase may indirectly achieve anticoagulation by inhibiting platelet functions.

Potential Clinical Applications
As an oral enzyme supplement, lumbrokinase is not allowed or approved to make any therapeutic claims in North America. However, by looking into available animal and human research, it is not too hard for anyone to see the following potential applications:

Ischemic Stroke. To further explore the traditional medical uses of earthworms in stroke, naturally one of the most intensely researched areas has been in the prevention and treatment of ischemic stroke patients. Lumbrokinase has been shown to be safe and effective for treating acute ischemic stroke by lowering blood viscosity, preventing re-perfusion damage, and reducing neural deficits.7-9 It was also shown to improve the efficacy of aspirin as a secondary prevention of stroke.10,11 In fact, for people who are resistant to aspirin (thus does not benefit from taking aspirin as a prevention), lumbrokinase appears to negate aspirin resistance and potentially help achieve the goal of cardiovascular disease prevention.12

On a milligram to milligram basis, the fibrinolytic strength of lumbrokinase is about 300-fold stronger than serrapeptase
On a milligram to milligram basis, the fibrinolytic strength of lumbrokinase is about 30-fold stronger than nattokinase

Therefore, serrapeptase is not considered a strong fibrinolytic enzyme and should primarily be used for inflammation and pain association with oral/facial surgeries, sinus infection, arthritis, or chronic airway diseases. Respectively, nattokinase and lumbrokinase would be more suited for patients with mild and severe hypercoagulation or for patients with low and high cardiovascular risks.

28)  Mihara H, et al. A novel fibrinolytic enzyme extracted from the earthworm, Lumbricus rubellus.
Japanese Journal of Physiology. 1991;41(3):461–472.
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32) Jiang DS, et al. Inhibition of platelet aggregation in hamsters by lumbrokinase extracted from Eisenia fetida.
Journal of Capital Medical University . 1994;15(4):291-294.

33) Zhao J, et al.Eisenia fetida Protease-III-1 Functions in Both  Fibrinolysis and Fibrogenesis. J Biomed Biotechnol 2007;2007(5):97654.
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35)  Li WY, et al. Observation of treating twenty-seven cases of ischemic stroke patients with lumbrokinase. New Chinese Medicine. 2003;34(4):63-64.
36)  Zhang HY. Observation of treating acute ischemic stroke with lumbrokinase. Capital Medicine . 2000;7(3):45-46.

37)  Zhang DJ, et al. Prevention of ischemic stroke recurrence using lumbrokinase. Capital Medicine . 2003;5(10):47-48.

38)  Cao YJ, et al. Oral fibrinogen-depleting agent lumbrokinase for secondary ischemic stroke prevention: results from a
multicenter, randomized, parallel-group and controlled clinical trial.
Chin Med J  (Engl). 2013 Nov;126(21):4060-5.
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Chinese Journal of Gerontology . 2009; 29: 760-761.

40) Liu HS. Clinical observation of treating 60 angina patients with lumbrokinase. Tianjin Pharmacy . 2002;14(2):45-46.

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42) Zhou HS, et al. Clinical observation of treating unstable angina seniors with lumbrokinase capsules. Central Plains Medical
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43)  Kasim M, et al. Improved myocardial perfusion in stable angina pectoris by oral lumbrokinase: a pilot study. J Altern Complement Med
. 2009 May;15(5):539-44.

44)  Song JS, et al. Clinical analysis of treating 17 cases of deep venous thrombosis with lumbrokinase. Occupation and Health 2001;17(4):111-115.

45)  Ye SZ, et al. Observation of treating 51 cases of essential hypertension with lumbrokinase. Clinical Medicine . 2007;27(9):59.
46) Gao Y, et al. Efficacy of combining lumbrokinase with nimodipine in the treatment of vascular dementia. Journal of Liaoning University of Traditional Chinese Medicine . 2008;10(11):5-7.

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63)  Fu YT, et al. Porous gelatin/tricalcium phosphate/genipin composites containing lumbrokinase for bone repair. Bone . 2015 Sep;78:15-22.

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70) Nattokinase Atherothrombotic Prevention Study Howard N Hodis MD University of Southern California. At the conclusion of this trial, the investigators expect to have sufficient evidence as to whether reducing the propensity for thrombus formation and/or increasing fibrinolytic activity can prevent the progression of atherosclerosis and cognitive decline.

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