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Natural Alternative to NSAIDs
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Serrapeptase:
Insect-Derived Enzyme Fights Inflammation
Our bodies have a love-hate
relationship with inflammation. On the one hand, inflammation is a natural
response, necessary to protect the body from invading organisms. On the
other hand, inflammation can limit joint function, and destroy bone,
cartilage and other articular structures.
An elusive goal of scientists
and physicians has been to find a side-effect-free substance to reduce the
pain and inflammation associated with fibrocystic breast disease,
rheumatoid arthritis, idiopathic edema, carpal tunnel syndrome and
post-operative swelling. It appears that the search may be nearing an end,
thanks to an enzyme Serrapeptase produced by the larval form of the silk
moth.
Serrapeptase is an enzyme
that is produced in the intestines of silk worms to break down cocoon
walls. This enzyme is proving to be a superior alternative to the
non-steroidal anti-inflammatory agents (NSAIDs) traditionally used to
treat rheumatoid arthritis and osteoarthritis. Its uses have also been
extended to the treatment of chronic sinusitis and postoperative
inflammation, and some researchers believe the substance can play an
important role in arterial plaque prevention and removal.
Harmful Effects
of NSAIDs
NSAIDs, which include
aspirin, ibuprofen, salicylates, and naproxen, are among the most commonly
prescribed medications for inflammation resulting from rheumatoid
arthritis, joint conditions, osteoarthritis, gouty arthritis, joint and
muscle discomfort associated with systemic lupus erythematosus, and other
musculoskeletal disorders.(1) In some cases, this overeliance on NSAIDs
has proved deadly. Annually, 76,000 people are hospitalized from NSAID-induced
gastrointestinal complications. The American Medical Association estimates
that from 50-80 percent of those hospitalized for gastrointestinal
bleeding are taking some form of NSAIDs. At this stage in the
medication-induced bleeding, there is a ten percent chance of fatality.(2)
NSAIDs lethal effects result
from the inhibition of the biosynthesis of prostaglandins. NSAIDs block
cyclo-oxygenase, the enzyme responsible for catalyzing the reactions of
arachidonic acid to endoperoxide compounds. This process results in the
inhibition of gastric prostaglandin E, a hormone which protects the lining
of the stomach from acid. After prolonged and frequent ingestion of NSAIDs,
the stomach remains defenseless and at increased susceptibility to
ulcers.(3-4) If an ulcer erodes into a blood vessel, bleeding results. An
ulcer can destroy part of the stomach and duodenal walls, leaving a gap
that requires immediate surgery.
In one study, 1,826
osteoarthritis or rheumatoid arthritis patients who had been taking NSAIDs
for six months or more and who had been unable to tolerate continuous
NSAID use because of adverse gastrointestinal symptoms were examined endoscopically for gastroduodenal lesions and ulcers. Clinically
significant gastroduodenal lesions were found in 37.1 percent of the
patients. Of those, 24 percent had ulcers. The prevalence of
gastroduodenal ulcers increased with age, duration of osteoarthritis, and
duration of current NSAID use. The authors of the study wrote: "These
results provide further endoscopic confirmation of the association between
NSAID use and gastroduodenal lesions and ulcers and support the contention
that safer treatment alternatives to conventional NSAIDs are required."(5)
That advice is particularly
wise in light of the other effects NSAIDs have on the gastrointestinal
tract. In one group of 312 NSAID takers, 20 percent had levels of
inflammation comparable to that previously reported in patients with
inflammatory bowel disease.(6) Besides
damaging the gastrointestinal
tract, NSAIDs also interfere with and suppress bone repair and remodeling.
One paper presented data obtained over a 12-year period, and outlined the
effects of NSAIDs on the matrix synthesis and turnover in 650 arthritic
and 180 non-arthritic human cartilages. The study showed that one category
of NSAIDs that includes Naproxen, ibuprofen, indomethacin, and nimezulide
significantly inhibited matrix synthesis and had toxic effects on
cartilage metabolism.(7) Thus, it appears that the drugs many patients
take to relieve their arthritic pains actually contributes to further
destruction of their joints!
Additionally,
NSAIDs have
been shown to interfere with patients' sleep patterns. One study of 37
male and female subjects at the sleep laboratory at Bowling Green State
University in Ohio demonstrated that aspirin and ibuprofen, in comparison
to a placebo, increased the number of awakenings and the percentage of
time spent awake. The drugs also decreased sleep efficiency, and delayed
the onset of the deeper stages of sleep.(8)
Even insulin secretion is affected by NSAIDs. Neonatal rat pancreatic
cells were examined partly to determine the effects of insulin secretion
caused by prostaglandin E (PGE) and drugs that inhibit its synthesis-i.e.
NSAIDs. Two NSAIDs, sodium salicylate (aspirin) and ibuprofen, at drug
concentrations similar to those achieved therapeutically in humans,
inhibited PGE synthesis up to 70-80 percent. Augmented insulin secretion
accompanied the PGE inhibition. Both drugs shifted the glucose-insulin
response curves to the left at low glucose concentrations and augmented
maximal insulin release at high glucose concentrations.(9)
Other NSAID-induced side
effects include kidney damage, blood dyscrasias and cardiovascular
effects, complication of antihypertensive therapies involving diuretics or
beta-adrenoceptor blockade, and adverse effects in patients with heart
failure and cirrhosis.(10) In one instance, a woman treated for rheumatoid
arthritis with the NSAID sulindac developed gallstones composed of
sulindac metabolites.(11)
Interestingly,
NSAIDs have
also induced adverse psychiatric reactions. Five psychiatric
outpatients-two with major depressive disorders, one with a bipolar
disorder, one with a schizophrenic disorder and one with an anxiety
disorder-were treated with NSAIDs due to rheumatoid arthritis,
osteoarthritis, or other painful neuromuscular conditions. All five
patients developed moderate to severe depression. Three patients became
paranoid, and four either attempted or considered suicide. These
psychiatric symptoms disappeared once the patients stopped taking NSAIDs.
When the patients re-started the drugs, the symptoms returned.(12)
NSAID s Roulette
Due to the detrimental
effects of NSAIDs on the body, most physicians resort to a game of "NSAID
musical-chairs," taking a patient off one NSAID as soon as side effects
become evident or the drug stops working, then treating the patient with
another of the 10 most widely prescribed propionic acid-derived NSAIDs.
To provide a more consistent
form of treatment, researchers have long searched for a side-effect free
anti-inflammatory agent. Researchers have recently focused on selective
cyclo-oxygenase (COX-2) inhibitors, more precise versions of NSAIDs.
Whereas previous NSAIDs reduced inflammation by inhibiting all
cyclo-oxygenase activity, these new selective COX-2 inhibitors
differentiate between the two forms of COX: COX-1 appears to regulate many
normal physiologic functions and COX-2 mediates the inflammatory response.
These selective inhibitors are believed to reduce inflammation without
influencing normal physiologic functions by inhibiting only COX-2. By
leaving COX-1 alone, the selective inhibitors result in fewer
gastrointestinal side effects.
At first glance, these COX-2
inhibitors look like the solution to NSAID complications. Upon further
inspection, however, celecoxib, a highly selective COX-2 inhibitor, can
cause headaches, change in bowel habits, abdominal discomfort and
dizziness in osteoarthritis patients. Fewer adverse effects are reported
in rheumatoid arthritis patients, but because the drug is metabolized in
the liver by cytochrome P-450 isozyme CYP2C9, serious drug interactions
are possible. Fung and colleagues pointed out that more clinical studies
are needed before the selective COX-2 inhibitors are put into widespread
use.(13)
Another new drug, Enbrel,
initially showed promise of treating the pain associated with rheumatoid
arthritis. Currently, however, the FDA is advising physicians about safety
concerns of the new drug. Thirty of the 25,000 patients treated with
Enbrel since the drug's approval have developed serious infections,
including sepsis. Several of those patients died as a result of the
infections. Those at greatest risk when taking Enbrel appear to be
patients with a history of chronic or recurrent infections, pre-existing
infections, diabetes, or other conditions making them more susceptible to
infection.(14)
The potentially lethal side
effects associated with NSAIDs and other drugs indicate that a superior
anti-inflammatory substance is needed.
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.(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)
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."(21,19)
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.(25,10)
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.(24)
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.(22)
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. Marriott C.
Modification in the rheological properties of mucus by drugs. Adv Exp Med
Biol. 1982; 144:75-84.
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. 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.
18. Mazzone 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.
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. 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.
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.
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.
A
preliminary trial of serrapeptase
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 serrapeptase in patients with carpal
tunnel syndrome (CTS).
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 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: 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.
Proteolytic enzymes: a new treatment strategy for prosthetic infections?
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.
A 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, Kumamoto (Japan)
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 o
Bronchitis o Mucolytic expectorants o Proteolytic enzymes o Seaprose o
serrapeptase
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
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
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, Lucca, Italy;
7Ear, Nose and Throat Department, Civil Hospital, Lecce, Italy;
8Ear, 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.
Received for
publication 2 January 1990; accepted 16 January 1990.
Address for
correspondence: A. Mazzone, MD, Institute of Clinical Otorhinolaryngology,
University of Naples, Via Pansini 5, 80131 Naples, Italy.
INTRODUCTION
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
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 Serralia
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
The 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
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 (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
engorgement.
A multi-centre,
double-blind study of serrapeptase versus placebo in post-antrotomy buccal
swelling.
Tachibana M,
Mizukoshi O, Harada Y, Kawamoto K, Nakai Y.
Pharmatherapeutica
1984;3(8):526-30
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. 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.
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Therapeutic
Dosage
