A Natural Anti-Inflammatory
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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
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.
(18) 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. (18)
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)
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
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
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)
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)
diseases are characterized by increased production of
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. (25,10)
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.
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. (24)
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. (22)
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)
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.
JB. Gastrointestinal effects of nonsteroidal
anti-inflammatory therapy. Am J Med. 1999; 106
author listed. Regular Use of Pain Relievers Can
Have Dangerous Results. Kaleidoscope Interactive
News, American Medical Association media briefing.
July 24, 1997.
HB, Kirschenbaum, HL. Selective cyclooxygenase-2
inhibitors for the treatment of arthritis. Clin
Ther. 1999; 21(7):1131-57.
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.
DE, Arvanitakis C, Gumpel M, Stead H, Geis GS. An
endoscopic study of gastroduodenal lesions induced
by nonsteroidal anti-inflammatory drugs. Clin Ther.
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.
JT. The effects of NSAID on the matrix of human
articular cartilages. Z Rheumatol. 1999;
PJ, Badia P, Myers BL, Boecker MR, Wright KP Jr.
Nonsteroidal anti-inflammatory drugs affect normal
sleep patterns in humans. Physiol Behav. 1994;
SA, Robertson RP, Fujimoto WY. Inhibition of
prostaglandin E synthesis augments glucose-induced
insulin secretion in cultured pancreas. Diabetes.
C. Modification in the rheological properties of
mucus by drugs. Adv Exp Med Biol. 1982; 144:75-84.
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
HK, Chang DM. Non-steroidal anti-inflammatory
drugs with adverse psychiatric reactions: five
case reports. Clin Rheumatol. 1999;18(4):339-45.
HB, Kirschenbaum, HL. Selective cyclooxygenase-2
inhibitors for the treatment of arthritis. Clin
Ther. 1999; 21(7):1131-57.
MedWatch: The FDA Medical Products Reporting
Program. May 12, 1999. FDA Talk Paper.
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.
K. Intestinal absorption of Serratia Peptidase. J
Appl Biochem. 1980;2:111-16.
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.
A, 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):379-88.
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.
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.
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.
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;
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.
Science Library website. 1999.
K, and Miyatam K. Some information on the
composition of trachael secretions before and
after the administration of Danzen. Exper Ther.
Y, et al. A new method for evaluating mucolytic
expectorant activity and its application to two
proteolytic enzymes, serratiopeptidase and
seaprose. Arznelrnitteltorachung. 1982;
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.
A preliminary trial of
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
This study was planned to assess the response of
serrapeptase in patients with carpal tunnel syndrome
METHODS: Twenty patients with CTS
were evaluated clinically. After baseline
electrophysiological studies, these patients were
given serrapetase10 mg twice daily with initial short
course of nimesulide. Clinical and
electrophysiological reassessment was done after 6
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
CONCLUSIONS: serrapeptase therapy may
proved to be a useful alternative mode of conservative
treatment. Larger study may be further helpful to
establish the role of serrapeptase in CTS.
enzymes: a new treatment strategy for prosthetic
by 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 serrapetase
greatly enhances the activity of ofloxacin on sessile
cultures and can inhibit biofilm formation.
New Method for Evaluating Mucolytic Expectorant
Activity and its Application
II. Application to two proteolytic enzymes,
serrapeptase and seaprose*
By 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)
From the Department of Chemico-Pharmacology. Faculty
of Pharmaceutical Sciences, Kumamoto University,
Summary: Using our new method
described in a preceding paper, in vivo effects of two
proteolytic enzymes such as serrapeptase and seaprose
(SAP) on sputa collected from bronchitis rabbits were
examined. Serrapeptase (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 serrapeptase 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.
Key words: Bromhexine • Bronchitis
• mucolytic expectorants • Proteolytic enzymes •
Seaprose • serrapeptase
In this previous paper , 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.
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
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
1Institute of Clinical Otorhinolaryngology, University
of Naples, Naples, Italy;
2Ear, Nose and Throat Department, 'Gradenigo'
Hospital, Turin, Italy;
3Ear, Nose and Throat Department, 'Villa Sofia'
Hospital, Palermo, Italy;
4Ear Nose and Throat Department, Treviso Regional
Hospital, Treviso, Italy;
5Ear, Nose and Throat Department, 'E. Fornaroli'
Hospital, Magenta, Italy;
6Ear, Nose and Throat Department, Lucca Hospital,
7Ear, Nose and Throat Department, Civil Hospital,
8Ear, Nose and Throat Department, 'Madonna del
Soccorso' Hospital, San Benedetto del Tronto, Italy
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.
for publication 2 January 1990; accepted 16 January
Address for correspondence: A. Mazzone, MD, Institute
of Clinical Otorhinolaryngology, University of Naples,
Via Pansini 5, 80131 Naples, Italy.
The use of enzymes with fibrinolytic, I 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 inflammed tissue.1.7
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
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.
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.
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.
Tolerability of Serralia peptidase was evaluated on
the basis of the presence, absence or severity of side
effects, recorded on the patients' data-collecting
All data were analysed by the most appropriate
statistical tests (^-test and Student's f-test).
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
treatment of breast engorgement with Serrapeptase (Danzen):
a randomised double-blind controlled trial.
Kee WH, Tan SL, Lee V, Salmon YM.
Singapore Med J 1989 Feb;30(1):48-54
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 (Serrapeptase)
was noted to be superior to placebo for improvement of
breast pain, breast swelling and induration and while
85.7% of the patients receiving Danzen (Serrapeptase)
had "Moderate to Marked" improvement, only
60.0% of the patients receiving placebo had a similar
degree of improvement. "Marked" improvement
was found in 22.9% 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
A multi-centre, double-blind study of
serrapeptase versus placebo in post-antrotomy buccal
Tachibana M, Mizukoshi O, Harada Y, Kawamoto K, Nakai
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. Changes 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 0.01 to p 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.