A preliminary trial of serratiopeptidase
in patients with carpal tunnel syndrome.


Panagariya A, Sharma AK

Dept. of Neurology, 
SMS Medical College and Hospital, Jaipur.
J Assoc Physicians India 1999 Dec;47(12):1170-2


OBJECTIVES: This study was planned to assess the response of serratiopeptidase in patients with carpal tunnel syndrome (CTS). 

METHODS: Twenty patients with CTS were evaluated clinically. After baseline electrophysiological studies, these patients were given serratiopeptidase 10 mg twice daily with initial short course of nimesulide. Clinical and electrophysiological reassessment was done after 6 weeks. 

RESULTS: Mean age was 43.9 years with male to female ratio of 1:2.33. Sixty five percent cases showed significant clinical improvement which was supported by significant improvement in electrophysiological parameters. Recurrence was reported in four cases. No significant side effect was observed. 

CONCLUSIONS: Serratiopeptidase therapy may proved to be a useful alternative mode of conservative treatment. Larger study may be further helpful to establish the role of serratiopeptidase in CTS.

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Proteolytic enzymes:
 a new treatment strategy for prosthetic infections?


Selan L, Berlutti F, Passariello C, Comodi-Ballanti MR, Thaller MC

Istituto di Microbiologia, 
Facolta di Farmacia, 
Universita La Sapienza, Rome, Italy.
Antimicrob Agents Chemother 1993 Dec;37(12):2618-21


Among the different mechanisms of bacterial resistance to antimicrobial agents that have been studied, biofilm formation is one of the most widespread. This mechanism is frequently the cause of failure in the treatment of prosthetic device infections, and several attempts have been made to develop molecules and protocols that are able to inhibit biofilm-embedded bacteria. We present data suggesting the possibility that proteolytic enzymes could significantly enhance the activities of antibiotics against biofilms. Antibiotic susceptibility tests on both planktonic and sessile cultures, studies on the dynamics of colonization of 10 biofilm-forming isolates, and then bioluminescence and scanning electron microscopy under seven different experimental conditions showed that serratiopeptidase greatly enhances the activity of ofloxacin on sessile cultures and can inhibit biofilm formation.

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A New Method for Evaluating 
Mucolytic
Expectorant Activity and its Application

II. Application to two proteolytic enzymes, serrapeptase and seaprose*

Y. Kase, H. Seo, Y. Oyama, M. Sakata, K. Tomoda, K.
Takahama, T. Hitoshi, Y. Okano, and T. Miyata

Arzneim.-Forsch. 
 Drug Res. 32 (1), Nr. 4 (1982)

Department of Chemico-Pharmacology.,
 Faculty of Pharmaceutical Sciences, 
Kumamoto University, Kumamoto, Japan

Summary: Using our new method described in a preceding paper, in vivo effects of two proteolytic enzymes such as serrapeptase (SER) and seaprose (SAP) on sputa collected from bronchitis rabbits were examined. SER (20 mg/kg) and SAP (30 mg/kg) significantly reduced the viscosity of sputum (P < 0.05) at the 1-3-h periods and the 4-6-h periods, respectively, after intraduodenal administration. 50 mg/kg of SER also significantly decreased not only viscosity (P < 0.001) but also amount of freeze-dried substance (P < 0.05) of sputum at the 1-3-h periods, but SAP did not affect the amount of dried substance. Both enzymes significantly increased the volume of sputum, probably as the result of liquefaction. Thus, mucolytic expectorant activity of both enzymes can be demonstrated first by the reduction in viscosity and next by the increase in volume of sputa. However, the decrease in amount of freeze-dried substance is not always in accord with the reduction in viscosity.

1. Introduction

In this previous paper [1], we reported a new method which seems to be applicable to examine the in vivo effect of mucolytic expectorants. By the use of this method, the expectorant effect of a drug can be evaluated from the changes in both quantity and quality of sputa, which were quantitatively collected from the rabbits suffering from subacute bronchitis caused by long-term exposure to SO2 gas. The purpose of the present study is to ascertain whether this method is well applicable to the evaluation of mucolytic expectorant effect of the reference drugs as was expected, whose clinical efficacy was already well established. Two proteolytic enzymes, serrapeptase and seaprose, were chosen for such a purpose. Though their chemical properties differ, both enzymes have so far been used as the effective mucolytics in the treatment of various disorders related to viscous sputum or pus, and their efficacies have been war-ranted to be more potent and reliable than those of a-chymotrypsin and others. Therefore, they have widely been used not only in Japan but also in. some other countries. Nevertheless, the pharmacological evidence which sub-stantiates their clinical efficacies, in particular, mucolytic expectorant effect, is insufficient, though they exhibit potent mucolytic activity in in vitro experiments [2, 3]. Bromhexine, a representative of the expectorants, was used as a control drug, because its mechanism of action is quite different from that of proteolytic enzyme, that is, it does not exhibit in vitro mucolytic activity and its main effect is known only by the increase in the volume of respiratory tract fluid (RTF) when it was examined by Perry and Boyd's method [4-7] using normal healthy rabbits. Further pharmacological study, for instance, the acting mechanism of mucolytic expectorant effect of intraduodenally administered enzymes will be described in the subsequent paper.

2. Materials and methods

2.1. Animals and drugs

Male rabbits of New Zealand White-strain, weighing 1.8 to 2.5 kg, were used. Serrapeptase (Danzen*, hereafter abbreviated as SER), a proteolytic enzyme (endopeptidase) prepared from the culture broth of. genus Serratia sp. E-15 (one of enteric bacilli in silkworm) which comes as grayish powder, was provided

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Evaluation of Serratia Peptidase in Acute or Chronic Inflammation of Otorhinolaryngology Pathology: a Multicentre, Double-blind, Randomized Trial versus Placebo

A. Mazzone1, M. Catalan2, M. Costanzo3, A. Drusian4, 
A. Mandol5, S. Russo6, E. Guarini7 and G. Vesperini8

1 Institute of Clinical Otorhinolaryngology, University of Naples, Naples, Italy; 
2 Ear, Nose and Throat Department, 'Gradenigo' Hospital, Turin, Italy; 
3 Ear, Nose and Throat Department, 'Villa Sofia' Hospital, Palermo, Italy; 
4 Ear Nose and Throat Department, Treviso Regional Hospital, Treviso, Italy; 
5 Ear, Nose and Throat Department, 'E. Fornaroli' Hospital, Magenta, Italy; 
6 Ear, Nose and Throat Department, Lucca Hospital, Lucca, Italy; 
7 Ear, Nose and Throat Department, Civil Hospital, Lecce, Italy; 
8 Ear, Nose and Throat Department, 'Madonna del Soccorso' Hospital, San Benedetto del Tronto, Italy 

The efficacy and tolerability of Serratia peptidase were evaluated in a multi-centre, double-blind, placebo-controlled study of 193 subjects suffering from acute or chronic ear, nose or throat disorders. Treatment lasted 7 - 8 days, with the drug or placebo being administered at a rate of two tablets three times a day. After 3-4 days' treatment, significant symptom regression was observed in peptidase-treated patients. There was also a significant reduction in symptoms after 7 -8 days for patients in both treatment groups but the response was more marked in those patients receiving the active drug.  Statistical comparison between the two groups confirmed the greater efficacy and rapid action of the peptidase against all the symptoms examined at both stages. Tolerance was found to be very good and similar for both groups. It is concluded that Serratia peptidase has anti-inflapimatory, anti-edemic and fibrinolytic activity and acts rapidly on localized inflammation.

INTRODUCTION

     The use of enzymes with fibrinolytic, proteolytic and anti-edemic activities has gained increasing support in recent years for the treatment of inflammatory ear, nose and throat (ENT) conditions1.  Included among these enzymes is the Serratia peptidase (Danzen® ), a protease obtained from non-pathogenic enterobacteria of the genus Serratia.  This proteolytic enzyme, which is available in tablet form to enable it to be absorbed from the intestinal lumen, has been shown lo induce intense fibrinolytic. anti-inflammatory, and anti-edemic activity in a number of tissues and results suggest that its anti-inflammatory activity may be of particular use for the treatment of localized or 'closed' forms of inflammation, such as those frequently found in ENT pathologies.' Another important feature of Serratia peptidase is its effect on pain, the enzyme acting by inhibiting the release of pain-inducing amines, such as bradykinin, from inflamed tissue.1.7

     This peptidase induces fragmentation offibrinose aggregates and reduces the viscosity of exudates,"^ thus facilitating the drainage of these products of the inflammatory response and thereby promoting the tissue repair process, and clinical trials have confirmed that the use of Serratia peptidase resulted in fast resolution of the inflammatory process." ° The aim of the present placebo-controlled multicentre study was to evaluate the efficacy and tolerability of the Serratia peptidase in the treatment of ENT inflammatory conditions.

PATIENTS AND METHODS

Patients

Patients, who were recruited from ENT clinics throughout Italy, were all suffering from inherent acute or chronic inflammatory conditions. Any patients with serious concomitant conditions, such as severe renal and/or hepatic impairments, or who required additional drugs were excluded from the tnal, as this could interfere with evaluation of the parameters under examination, and the use of steroids, non-steroidal anti-inflammatory drugs and/or anti-inflammatory/analgesic agents was prohibited. Antibiotics were permitted when deemed necessary.

Treatment

Indistinguishable tablets containing 5 mg Serratia peptidase or a placebo were provided in blister packs and patients were randomly assigned to receive two tablets of either drug, which they were instructed to take three times daily after meals for 7 -8 days.

Evaluation of treatment 
Clinical signs and symptoms were assessed on days 0, 3-4 and 7-8 of treatment on a scale of O-3 (0, absence of the symptoms: 3, maximum severity). Clinical parameters recorded were as follows: pain; quantity of secretion; difficulty in swallowing; nasal obstruction; anosmia; and body temperature. The appearance of the secretion was also recorded on a scale ofO-3 (0, normal; I, mucoid; 2, mucopurulent: 3, purulent). All evaluations were performed by an ENT specialist unaware of the treatment given.  

Evaluation of tolerability 
Tolerability of Serratia peptidase was evaluated on the basis of the presence, absence or severity of side-effects, recorded on the patients' data-collecting forms.

Statistical analysis
All data were analysed by the most appropriate statistical tests (^-test and Student's f-test).  

RESULTS

A total of 193 subjects (96 males, 97 females), aged between 12 and 77 years (mean ± SD 38 ± 15.7 years), with acute or chronic ENT pathologies were recruited to the trial. Of these 193 cases, 97 (43 males, 54 females; mean ± SD 37.3 ± 15.2 years) were placed in group A and 96 (53  

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The treatment of breast engorgement with Serrapeptase (Danzen): a double-blind controlled trial.

Author: Kee WH, Tan SL; Lee V, Salmon YM 
Source:Singapore Med J, 30( I ):48-5s4 1989 Feb 

Abstract

We evaluated an anti-inflammatory enzyme drug Danzen (Serrapeptase) Takeda Chemical Industries, Ltd.) on 70 patients complaining of breast engorgement These patients were randomly divided into 2 groups, a treatment group and a placebo group. A single observer, unaware of the group the patients were in, assessed the severity of each of the symptoms and signs of breast engorgement before treatment was commenced, and daily for 3 days, during which therapy was administered. Danzen was noted to be superior to placebo for improvement of breast pain, breast swelling and duration and while 85.7% of the patients receiving Danzen had "Moderate to Marked improvement, only 60.0% of the patients receiving placebo had a Similar degree of improvement. "Marked improvement was found in 229% of the treatment group and 2.9% of the placebo group. These differences were statistically significant (P less than 0.05), No adverse reactions were reported with the use of Danzen (Serrapeptase). Danzen (Serrapeptase) is a safe and effective method for the treatment of breast engorgement.

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Reduction of postoperative swelling objective measurement of swelling of the upper ankle joint in treatment with serrapeptase.


Author: Esch PM, Gerngross H, Fabian A
Source: Fortachr Med,107(4):67.8, 71-2 1989 Feb 10
 
Abstract

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 postoperative swelling and pain was carried out in 3 randomized groups of patients. To 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 port-operative reduction of swelling, in comparison with the classical conservative measures for example, the application of ice.

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A multi-centre, double-blind study serrapeptase versus placebo in post-antrotomy buccal swelling


Author:  Tachibana M, Mizukosi 0, Harada Y, Kawamoto K, Nakai Y
Source: Pharmatherapeutica, 3(8):526-30 1984

Abstract

A multi-centre, double-blind, placebo-controlled trial was carried out to investigate the clinical efficacy of the anti-inflammatory enzyme serrapeptase in a total of 174 patients who underwent Caldwell-Luc antrotomy for chronic empyema. Eighty-eight patients received 10 mg serrapeptase 3 times on the day before operation, once on the night of the operation and 3 times daily for 5 days after operation, the other 86 received placebo Chanes in buccal swelling after operation were observed as a parameter of the response to treatment. The degree of swelling in the serrapeptase-treated patients was significantly less than that in the placebo-treated patients at every point of observation after operation up to the 5th day (p less than 001 top less than 0.05). Maximal swelling throughout all the post-operative points of observation was also significantly smaller in size in the serrapeptase-treated group than in the placebo-treated group. No side effects were reported.

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Intestinal absorption of serrapeptase in rats. 

Author: Moriya N, Nakata M, Nakamuma M, Takaoka M, lwasa S; Kato K; Kakinuma 
Address: Biotechnology Research Laboratories, Takeda Chemical Industries Ltd., Osaka, Japan

Abstract

A sensitive sandwich enzyme immunoassay (e.i.a) for serrapeptase (TSP), an orally available anti-inflammatory proteinase, was established using affinity-purified anti-TSP rabbit IgG and its Fab fragment conjugated with horseradish peroxidase as the first and the second antibodies respectively TSP in the plasma was determined by the e.i.a. after its oral administration (100 m/kg) to rats. The peak concentration was observed between 30mm and 2 h after administration. TSP in the plasma samples was trapped in a microtitre plate coated with the affinity-purified anti-TSP rabbit IgG. and the hydrolysis of a synthetic fluorogenic substrate, butoxycarbonyl-Glu(benzyloxy)-Ala-Arg-4-methylcoumaryl-7-amide, by the trapped TSP was fluorometrically measured (proteinase  assay. The values obtained by the e.i.a. and those obtained by the proteinase assay correlated well for various plasma samples. These results indicate that orally administered TSP was absorbed from the intestinal tract and transferred into the circulation in an enzymically active form.

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Serrapeptase: A Natural Anti-Inflammatory

Serrapeptase, also known as Serratia peptidase, is a proteolytic enzyme isolated from the non-pathogenic enterobacteria Serratia E15. When consumed in unprotected tablets or capsules, the enzyme is destroyed by acid in the stomach. However, enterically-coated tablets enable the enzyme to pass through the stomach unchanged, and be absorbed in the intestine. Serrapeptase is found in negligible amounts in the urine, suggesting that it is transported directly from the intestine into the bloodstream.(15,16)

Clinical studies show that serrapeptase induces fibrinolytic, anti-inflammatory and anti-edemic (prevents swelling and fluid retention) activity in a number of tissues, and that its anti-inflammatory effects are superior to other proteolytic enzymes.(17)

Besides reducing inflammation, one of serrapeptase's most profound benefits is reduction of pain, due to its ability to block the release of pain-inducing amines from inflamed tissues.(17)  Physicians throughout Europe and Asia have recognized the anti-inflammatory and pain-blocking benefits of this naturally occurring substance and are using it in treatment as an alternative to salicylates, ibuprofen and other NSAIDs.(19)

In Germany and other European countries, serrapeptase is a common treatment for inflammatory and traumatic swellings, and much of the research that exists on this substance is of European origin. One double-blind study was conducted by German researchers to determine the effect of serrapeptase on post-operative swelling and pain. This study involved sixty-six patients who were treated surgically for fresh rupture of the lateral collateral ligament of the knee. On the third post-operative day, the group receiving serrapeptase exhibited a 50 percent reduction of swelling, compared to the controls. The patients receiving serrapeptase also became more rapidly pain-free than the controls, and by the tenth day, the pain had disappeared completely.(20)

Cystic Breast Disease

Serrapeptase has also been used in the successful treatment of fibrocystic breast disease. In a double-blind study, 70 patients complaining of breast engorgement randomly were divided into a treatment group and a placebo group. Serrapeptase was superior to the placebo for improvement of breast pain, breast swelling and induration (firmness). 85.7 percent of the patients receiving serrapeptase reported moderate to marked improvement. No adverse reactions to serrapeptase were reported and the researchers concluded that "serrapeptase is a safe and effective method for the treatment of breast engorgement."(21,22)

Serrapeptase and Sinusitis

Due to its inflammatory properties, serrapeptase has been shown in clinical studies to benefit chronic sinusitis sufferers. In this condition, the mucus in patients’ nasal cavities is thickened and hypersecreted. This thickening causes mucus to be expelled less frequently. Japanese researchers evaluated the effects of serratiopeptidase (30 mg/day orally for four weeks) on the elasticity and viscosity of the nasal mucus in adult patients with chronic sinusitis. Serratiopeptidase reduced the viscosity of the mucus, improving the elimination of bronchopulmonary secretions.(23)

Other clinical trials support serrapeptase's ability to relieve the problems associated with chronic sinusitis. In one study, 140 patients with acute or chronic ear, nose and throat pathologies were evaluated with either a placebo or the active serratia peptidase. Patients taking the serrapeptase experienced a significant reduction in severity of pain, amount of secretion, purulence of secretions, difficulty in swallowing, nasal dysphonia, nasal obstruction, anosmia, and body temperature after three to four days and at the end of treatment. Patients suffering from laryngitis, catarrhal rhinopharyngitis and sinusitis who were treated with serrapeptase experienced a significant and rapid improvement of symptoms after 3-4 days. Physicians assessed efficacy of treatment as excellent or good for 97.3 percent of patients treated with serrapeptase compared with only 21.9 percent of those treated with a placebo.(24)

Respiratory diseases are characterized by increased production of a more dense mucus modified in viscosity and elasticity. Traditionally, in respiratory diseases, muco-active drugs are prescribed to reestablish the physicochemical characteristics of the mucus in order to restore respiratory function. Some of these drugs, however, cause a functional depletion of mucus, whereas Serrapeptase alters the elasticity of mucus without depleting it.(25,27)

A powerful agent by itself, serrapeptase teamed with antibiotics delivers increased concentrations of the antimicrobial agent to the site of the infection. Bacteria often endure a process called biofilm formation, which results in resistance to antimicrobial agents. In an attempt to prevent this bacterial immunity, researchers have experimented with various means of inhibiting biofilm-embedded bacteria. Their search may have ended with serrapeptase. One study conducted by Italian researchers suggests that proteolytic enzymes could significantly enhance the activities of antibiotics against biofilms. Antibiotic susceptibility tests showed that serratiopeptidase greatly enhances the activity of the antibiotic, ofloxacin, and that it can inhibit biofilm formation.(28)

Another double-blind randomized study evaluated the effects of administering the antibiotic cephalexin in conjunction with serrapeptase or a placebo to 93 patients suffering from either perennial rhinitis, chronic rhinitis with sinusitis or chronic relapsing bronchitis. The serratia peptidase treated group experienced significant improvement in rhinorrhea, nasal stuffiness, coryza and improvement of the para-nasal sinus shadows.(22)

Researchers witnessed equally impressive results in the treatment of infections in lung cancer patients undergoing thoracotomy. Serrapeptase and cefotiam, an antibiotic with a broad spectrum of activity against both Gram-positive and Gram-negative microorganisms, were administered to 35 thoracotomy patients with lung cancer. The patients were divided into two groups. A single dose of cefotiam was administered to the 17 subjects in Group I. The 18 subjects in Group II received a combination of Cefotiam and serrapeptase. The level of the antibiotic in the tissues versus the blood was significantly higher in the serrapeptase group than the single dose group.(18)

Cardiovascular Implications

Hans A. Nieper, M.D., an internist from Hannover, Germany, studied the effects of serrapeptase on plaque accumulations in the arteries. The formation of plaque involves deposits of fatty substances, cholesterol, cellular waste products, calcium and fibrin (a clotting material in the blood) on the inner lining of the arteries. Excessive plaque results in partial or complete blockage of the blood's flow through an artery, resulting in arteriosclerosis, or hardening of the arteries, and an ensuing stroke or heart attack. The evidence to support serrapeptase's role in preventing plaque build-up is anecdotal. Still, further studies are called for in this area as Nieper's research indicated that the protein-dissolving action of serrapeptase will gradually break down atherosclerotic plaques.(24)

Conclusion

Regardless of whether serrapeptase is used for inflammatory diseases or to prevent plaque build up on the arteries, it is well-tolerated. Due to its lack of side effects and anti-inflammatory capabilities, serrapeptase is a logical choice to replace harmful NSAIDs. Thanks to the tiny larvae of the silk moth, researchers have taken a large step toward finding relief for inflammatory disease sufferers.

References

1. Raskin JB. Gastrointestinal effects of nonsteroidal anti-inflammatory therapy. Am J Med. 1999; 106 (5B):3S-12S.

2. No author listed. Regular Use of Pain Relievers Can Have Dangerous Results. Kaleidoscope Interactive News, American Medical Association media briefing. July 24, 1997.

3. Fung HB, Kirschenbaum, HL. Selective cyclooxygenase-2 inhibitors for the treatment of arthritis. Clin Ther. 1999; 21(7):1131-57.

4. Geis GS. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? Scand J Rheumatol Suppl. 1999; 109:31-7.

5. Cheatum DE, Arvanitakis C, Gumpel M, Stead H, Geis GS. An endoscopic study of gastroduodenal lesions induced by nonsteroidal anti-inflammatory drugs. Clin Ther. 1999; 21(6):992-1003.

6. Tibble JA, Sigthorsson G, Foster R, Scott D, Fagerhol MK, Roseth A, Bjarnason I. High prevalence of NSAID enteropathy as shown by a simple faecal test. Gut. 1999; 45(3):362-6.

7. Dingle JT. The effects of NSAID on the matrix of human articular cartilages. Z Rheumatol. 1999; 58(3):125-9.

8. Murphy PJ, Badia P, Myers BL, Boecker MR, Wright KP Jr. Nonsteroidal anti-inflammatory drugs affect normal sleep patterns in humans. Physiol Behav. 1994; 55(6):1063-6.

9. Metz SA, Robertson RP, Fujimoto WY. Inhibition of prostaglandin E synthesis augments glucose-induced insulin secretion in cultured pancreas. Diabetes. 1981; 30(7):551-7.

10. Raskin JB. Gastrointestinal effects of nonsteroidal anti-inflammatory therapy. Am J Med. 1999; 106 (5B):3S-12S.

11. Tokumine F, Sunagawa T, Shiohira Y, Nakamoto T, Miyazato F, Muto Y. Drug-associated cholelithiasis: a case of sulindac stone formation and the incorporation of sulindac metabolites into the gallstones. Am J Gastroenterol. 1999;94(8):2285-8.

12. Jiang HK, Chang DM. Non-steroidal anti-inflammatory drugs with adverse psychiatric reactions: five case reports. Clin Rheumatol. 1999;18(4):339-45.

13. Fung HB, Kirschenbaum, HL. Selective cyclooxygenase-2 inhibitors for the treatment of arthritis. Clin Ther. 1999; 21(7):1131-57.

14. FDA MedWatch: The FDA Medical Products Reporting Program. May 12, 1999. FDA Talk Paper.

15. Moriya N, Nakata M, Nakamura M, Takaoka M, Iwasa S, Kato K, Kakinuma A. Intestinal absorption of serrapeptase (TSP) in rats. Biotechnol Appl Biochem. 1994; 20(Pt1):101-8.

16. Miyata, K. Intestinal absorption of Serratia Peptidase. J Appl Biochem. 1980;2:111-16.

17. 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; 18(5):379-88.

18. 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 (Japanese). Jpn J Antibiot. 1986; 39(3):761-71.

19. Aso T et al. Breast engorgement and its treatment: Clinical effects of Danzen an anti-inflammatory enzyme preparation. The world of Obstetrics and Gynecology (Japanese). 1981; 33:371-9.

20. Esch PM, Gerngross H, Fabian A. Reduction of postoperative swelling. Objective measurement of swelling of the upper ankle joint in treatment with serrapeptase-a prospective study (German). Fortschr Med. 1989;107(4):67-8, 71-2.

21. Kee WH, Tan SL, Lee V, Salmon YM. The treatment of breast engorgement with Serrapeptase (Danzen): a randomized double-blind controlled trial. Singapore Med J. 1989;30(1):48-54.

22. Perna L. Osservazionl Clniche sui traitamento in osppio cleco con Serratio peptidasl nella neifre perenna naila ninite cronica nacutizzata con sinusopattia, nella bronchia cronica nacutizzata. Rlv Pat Clin Tuberc Penumol. 1985; 56:509-516.

23. Majima Y, Inagaki M, Hirata K, Takeuchi K, Morishita A, Sakakura Y. The effect of an orally administered proteolytic enzyme on the elasticity and viscosity of nasal mucus. Arch Otorhinolaryngol. 1988;244(6):355-9.

24
. Brewer Science Library website. 1999. 

25. Tomoda K, and Miyatam K. Some information on the composition of trachael secretions before and after the administration of Danzen. Exper Ther. 1972; 477:9-16.

26. Kase Y, et al. A new method for evaluating mucolytic expectorant activity and its application to two proteolytic enzymes, serratiopeptidase and seaprose. Arznelrnitteltorachung. 1982; 32:374-378.

27. Marriott C. Modification in the rheological properties of mucus by drugs. Adv Exp Med Biol. 1982; 144:75-84.

28. 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):2618-21.

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