A preliminary trial otff 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 serratiopeptidase in patients with carpal tunnel syndrome (CTS).
METHODS: Twenty patients with CTS were
evaluated clinically. After baseline electrophysiological studies, these
patients were given serrapeptase 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: 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.
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,
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
greatly enhances the activity of ofloxacin on sessile cultures and can inhibit
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,
Takahama, T. Hitoshi, Y. Okano,
and T. Miyata
Drug Res. 32 (1), Nr.
Department of Chemico-Pharmacology.,
University, Kumamoto, Japan
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
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.
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.
2. Materials and methods
Animals and drugs
Male rabbits of New Zealand
White-strain, weighing 1.8 to 2.5 kg, were used.
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
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.
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)
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
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.
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 Serratia peptidase was evaluated on the basis of the
presence, absence or severity of side-effects, recorded on the patients'
All data were analysed by the most appropriate statistical tests (^-test and
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
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
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) is a safe and effective method for the treatment of breast engorgement.
Reduction of postoperative swelling objective measurement of swelling of the upper ankle joint in treatment with
Author: Esch PM, Gerngross H, Fabian A
Source: Fortachr Med,107(4):67.8, 71-2 1989 Feb 10
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.
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
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.
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
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.
Serrapeptase: A Natural
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
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
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)
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 serrapeptase (30
mg/day orally for four weeks) on the elasticity and viscosity of the nasal mucus
in adult patients with chronic sinusitis. Serrapeptase reduced the
viscosity of the mucus, improving the elimination of bronchopulmonary
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 serrapeptase 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
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)
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.
1. Raskin JB. Gastrointestinal
effects of nonsteroidal anti-inflammatory therapy. Am J Med. 1999; 106
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.
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;
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;
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.
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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
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.
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Products Reporting Program. May 12, 1999. FDA Talk Paper.
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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;
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
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