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Alternative Therapies

Alternative Therapies

Nattokinase for prevention gel.12 A useful thrombolytic agent must


cleave the fibrin clot on the thrombus.

of thrombosis One protease known to cleave fibrin is


plasmin.12 Nattokinase is a subtilisin-

N atto, a traditional food made of soy-


beans fermented with Bacillus subtilis,
has been consumed for over 1000 years,
There are limited data from animal and
human studies that have evaluated the
actions of nattokinase.4,5,8,14,15 These stud-
like serine protease that has four times
stronger fibrinolytic activity than plas-
min.4,8,12-14 The fibrinolytic activity of nat-
especially in the Eastern Kanto region of ies focused on investigating the fibrin- tokinase was shown to be equivalent to 40
Japan.1-6 It has a cheese-like appearance, a olytic property of nattokinase. The results casein units (CU) of plasmin or 1600 IU of
strong smell, and a sticky consistency, suggest that nattokinase could be a useful urokinase. 7 The exact mechanism by
which may affect its acceptance as a food fibrinolytic agent to help reduce the which nattokinase accelerates fibrinolysis
choice.6 In the United States, natto is not risk of thrombosis. The purpose of this has not been determined.4,9,11 It has been
as well-known as miso, although both are article is to review the published data eval- shown to hydrolyze thrombi in vitro and
fermented soybean products. uating the pharmacology and efficacy of indirectly convert plasminogen to plas-
Nattokinase is an enzyme commonly nattokinase. min.3 It cleaves and inactivates plasmino-
found in natto that has strong fibrinolytic Mechanism of action. A thrombus gen activator inhibitor (PAI), the primary
properties.1-3,7 Common names for nat- forms when platelets aggregate in a fibrin inhibitor of tissue plasminogen activator
tokinase include natto extract, NK, sub- (tPA).9 This leads to increased activity of
tilisin NAT, and fermented soybeans.1,8 tPA, the enzyme that converts plasmino-
Although people often interchangeably gen to plasmin, and improves clot lysis.
use the term natto and nattokinase, they Fibrinolysis was also observed when PAI
are not the same. Natto refers to the was removed from the fibrin clot, albeit to
whole food, while nattokinase refers to a much lesser extent. This suggests that
one of the enzymes contained in nat- nattokinase can directly dissolve fibrin
to.1,2 Crude extracts of natto contain clots through proteolysis.9 Unlike al-
other proteases besides nattokinase.3 teplase, urokinase, and streptokinase,
Nattokinase, an alkaline protease, is a nattokinase does not function as a plas-
275 amino acid residue with a molecu- minogen activator that directly converts
lar weight of approximately 28 plasminogen to plasmin.9,12,14
kDa.3,4,9,10 Its amino acid sequence is Efficacy. Animal data. Several animal
similar to subtilisin, an extracellular studies have evaluated the thrombolytic
enzyme that catalyzes the breakdown of effects of nattokinase in animals.4,5,8,14
proteins into polypeptides.3,11,12 Subtili- Fujita et al.14 evaluated the effect of nat-
sin proteases are commonly used in tokinase on chemically induced thrombi
laundry detergent and have other com- in rats. A thrombus that resulted in occlu-
mercial applications.11 sion of the carotid artery was chemically
Nattokinase can withstand tempera- induced using acetic acid. After stabiliza-
tures of up to 50 °C and remains active
after five rounds of freezing and thawing.7
The Alternative Therapies column features short reviews of herbals and other “nutraceuticals” for
It is stable between pH 6 and 12 (optimal
which there is some scientific evidence of effectiveness. The contributing editor for Alternative
pH 10.3–10.8) but becomes inactive in an Therapies is Joseph Pepping, Pharm.D., Codirector, Integrative Medicine Service, Kaiser
acidic medium.3,7,10 Nattokinase has been Permanente, Honolulu, HI 96814. Readers are invited to send ideas for the column to AJHP at
shown to be absorbed across the rat intes- 7272 Wisconsin Avenue, Bethesda, MD 20814 (301-657-3000) or ajhp@ashp.org.
tinal tract.13

Am J Health-Syst Pharm—Vol 63 Jun 15, 2006 1121


Alternative Therapies

tion of the thrombus, the thrombolytic (rat chow), rat chow with 50 CU nattoki- ing for about 3 hours). Unfortunately,
effects of injected urokinase, alteplase, nase (low dose), or rat chow with 100 CU results were not reported for all study
plasmin, elastase, and nattokinase were nattokinase (high dose). Both treatment subjects. Nevertheless, the authors con-
examined. Results showed that the res- groups suppressed intimal thickening cluded that nattokinase is a potent natural
toration of blood flow was directly pro- compared with controls. The mural thrombolytic agent that warrants further
portional to the amount of nattokinase thrombi formed in the control and exper- investigation.
injected (17.7% restoration with 0.02 imental groups were morphologically dif- Cesarone et al.15 evaluated the use of
μ mol/kg to 62% with 0.12 μ mol/kg). At ferent. In the control group, the mural Pinokinase on the prevention of venous
an equivalent molar ratio of doses (0.12 thrombi remained attached to the vessel thrombus for long-haul airline flights
μmol/kg), nattokinase was four times walls. Most thrombi in the experimental (seven to eight hours). Pinokinase (Flite
more effective than plasmin at dissolving groups showed dissociation from the ves- Tabs, Aidan Products, Tempe, AZ) is a
a thrombus (62% versus 15.8%, respec- sel walls. No effect on bleeding time was proprietary blend containing nattokinase
tively). The differences were not exam- seen. (amount not disclosed) and pycnogenol
ined for statistical significance. A 45% The fibrinolytic activity of nattokinase (a diuretic). Subjects at high risk for de-
restoration of blood flow was seen with on experimentally induced thrombi was veloping a deep vein thrombosis (DVT)
urokinase (5,000 IU/kg) and alteplase also examined in dogs.5 The thrombi were during a seven- to eight-hour flight were
(13,300 units/kg), comparable to nattoki- evaluated by angiography at time inter- randomized to receive two Flite Tabs each
nase 0.04 μmol/kg. Elastase showed no vals ranging from 2.5 to 24 hours after containing Pinokinase 150 mg (n = 110)
effect on restoring blood flow. The au- thrombosis. There were three dogs in the or placebo (n = 114) two hours before
thors concluded that nattokinase has experimental group (receiving nattoki- their flight and six hours later. Ultrasound
strong fibrinolytic activity in vivo. nase 1 g orally) and six dogs in the control scanning of the venous system was done
Using the rat femoral artery, Suzuki et group (placebo). Angiograms showed within 90 minutes of the plane’s depar-
al.4 investigated the effects of dietary sup- that dogs in the nattokinase group had ture and within 90 minutes of its landing.
plementation with natto on intimal thick- complete dissolution of thrombi within 5 A combined edema score was used to
ening and the time to thrombus dissolu- hours of oral administration of nattoki- assess edema and swelling. Administra-
tion. Rats were assigned to receive either a nase. Dogs in the control group showed tion of Pinokinase resulted in a significant
standard diet of rat chow (control group) no evidence of lysis 18 hours after admin- decrease in thrombotic events (p < 0.025).
or the standard diet plus supplementation istration of placebo. No subjects in the treatment group had a
with crude natto extract (23 g of natto Human data. A small trial of 12 adult thrombotic event compared with seven
extract per kilogram of chow, containing Japanese subjects was conducted to inves- (7.6%) subjects in the control group. The
100,000 CU of nattokinase, 50 times the tigate the effect of nattokinase on plasma treatment group also showed a reduction
concentration found in commercial fibrinolytic activity.5 Initially, all subjects in edema scores compared with an in-
products). After three weeks, intimal received 12 g wet weight of natto. Two crease seen in controls (p < 0.02). Because
thickening was produced using a photo- weeks later, all subjects received an equiv- Pinokinase is a combination product, it is
chemical thrombosis model (radiation alent amount of boiled soybeans. Natto not certain that these positive effects are
and the injection of rose bengal dye). The administration resulted in a shortening of due to nattokinase, pycnogenol, or a
assigned diets were continued for three clot lysis time and an increase in fibri- combination of both. Pinokinase was
weeks after endothelial injury. Euglobu- nolytic activity. Plasma fibrinolytic activ- well tolerated with no major complaints
lin clot lysis time (ECLT) was used to es- ity was enhanced for up to 12 hours after or adverse effects.
timate plasma fibrinolytic activity. natto ingestion compared with soybean Potential uses. Several animal studies
Rats receiving nattokinase had a signifi- administration. After this preliminary ex- have shown that nattokinase has potent
cantly shorter ECLT (p < 0.05) and a sig- amination, subjects were given enteric- fibrinolytic activity and favorable effects
nificant reduction in the cross-sectional coated capsules of nattokinase 1300 mg on intimal thickening. Human trials dem-
area of the intima in the injured femoral three times daily after meals (duration of onstrating the clinical benefits of this ac-
arteries compared with the control group therapy not reported). The euglobulin fi- tion are limited. Based on these data, nat-
(p < 0.05). Natto supplementation did brinolytic activity (EFA), degradation tokinase may improve circulation and
not increase bleeding or affect platelet products from fibrin and fibrinogen, and overall cardiovascular health and de-
aggregation. tPA were used to assess plasma fibrinolyt- crease the risk for thrombosis. It may also
In a similar animal study, Suzuki et al.8 ic activity. Nattokinase administration re- offer some advantage to preventing DVT,
evaluated the effects of natto extract on sulted in a gradual increase in fibrinolytic particularly in at-risk patients who em-
intimal thickening and whether nattoki- activity, as evidenced by a significant in- bark on a long-haul flight. While initial
nase supplementation modulated clot ly- crease in EFA at day 8, a significant surge results are encouraging, there are insuffi-
sis of thrombi on the damaged vessel wall. of fibrin degradation products on day 1, cient data to determine appropriate dos-
Rats received one of three diets: control and an increase in tPA in the plasma (last- ages or patient selection at this time.

1122 Am J Health-Syst Pharm—Vol 63 Jun 15, 2006


Alternative Therapies

Safety. Natto, which contains nattoki- haul flight, two capsules of Flite Tabs taken fied from Bacillus subtilis cleaves and
inactivates plasminogen activator inhibitor
nase, has been consumed in particular two hours before the flight and two cap- type 1. J Biol Chem. 2001; 276:24690-6.
regions of Japan for over 1000 years, sug- sules taken six hours later appear to be 10. Yoshimoto T, Fukumoto J, Tsuru D. Studies
gesting it is generally safe and well tolerat- effective.1,15 on bacterial proteases: some enzymatic and
physicochemical properties of the alkaline
ed.1,5 There are only two published trials Conclusion. Data from animal studies protease from Bacillus natto. Int J Protein
evaluating the effects of nattokinase in suggest that nattokinase has strong fibrin- Res. 1971; 3:285-95.
humans, and the number of subjects en- olytic activity and may be useful for im- 11. Kim W, Choi K, Kim Y et al. Purification and
characterization of a fibrinolytic enzyme
rolled in these studies was small (n = 12 proving circulation and reducing the risk produced from Bacillus sp. strain CK 11-4
and n = 110). While there were no safety of thrombosis. Human data are limited, screened from Chungkook-Jang. Appl
concerns reported in these trials, the the- making the assessment of clinical use dif- Environ Microbiol. 1996; 62:2482-8.
12. Fujita M, Ito Y, Hong K et al. Characteriza-
oretical risk of bleeding exists.2 In addi- ficult. Adverse effects, potential drug in- tion of nattokinase-degraded products from
tion, patients who are receiving antiplate- teractions, and contraindications to nat- human fibrinogen or cross-linked fibrin.
let or anticoagulant therapy should avoid tokinase use in humans are not currently Fibrinolysis. 1995; 9:157-64.
13. Fujita M, Hong K, Ito Y et al. Transport of
nattokinase because of the possible risk of known. Nattokinase should be avoided in nattokinase across the rat intestinal tract.
increased bruising or bleeding.1,15 Because patients with a coagulation disorder and Biol Pharma Bull. 1995; 18:1194-6.
of the lack of safety data, women who are in those receiving antiplatelet or antico- 14. Fujita M, Hong K, Ito Y et al. Thrombolytic
effect of nattokinase on a chemically induced
pregnant or breastfeeding should not take agulation therapy. thrombosis model in rat. Biol Pharma Bull.
nattokinase. 1995; 18:1387-91.
1. Nattokinase. Natural Medicines Compre-
Source and dosages. Nattokinase can 15. Cesarone MR, Belcaro G, Nicolaides A et
hensive Database monograph. Available at
al. Prevention of venous thrombosis in
be produced easily and economically in www.naturaldatabase.com (accessed 2005
long-haul flights with Flite Tabs: the
large quantities by fermenting soybeans Apr 6).
LONFLIT-FLITE randomized, controlled
2. Lutz B. Natto. In: Klasco RK, ed. AltMedDex
with B. subtilis. B. subtilis are generally trial. Angiology. 2003; 54:531-9.
system. Greenwood Village, CO: Thomson
16. Better Health International. Nattokinase
recognized as safe in the United States and Micromedex. (Edition expired December
complex. www.betterhealthinternational.
marketed as natural biological control 2005.)
com/productDetails.asp_Q_prodID_E_
3. Fujita M, Nomura K, Hong K et al.
products in many countries.15 Nattoki- Purification and characterization of a strong 4990 (accessed 2006 Feb 2).
fibrinolytic enzyme (nattokinase) in the 17. Enzymedica. Natto-K (nattokinase). www.
nase can be extracted from natto, with the iherb.com/nattok.html (accessed 2006 Jan
vegetable cheese natto, a popular soybean
purified extract undergoing lyophiliza- 16).
fermented food in Japan. Biochem Biophys
tion to transform it into powder form.4,5,8 Res Commun. 1993; 197:1340-7. 18. Fern’s Nutrition. Nattokinase. www.
4. Suzuki Y, Kondo K, Ichise J et al. Dietary fernsvitamins.com/Heart/nattokinase.
While natto has a very unpleasant smell html (accessed 2006 Jan 16).
supplementation with fermented soybeans
and texture, nattokinase capsules and tab- suppresses intimal thickening. Nutrition. 19. VitaNet Health Foods. Nattokinase fact sheet.
lets are often odorless.16 2003; 19:261-4. www.vitanetonline.com/forums/1/Thread/
5. Sumi H, Hamada H, Nakanishi K et al. 729 (accessed 2006 Apr 17).
Many nattokinase products are avail-
Enhancement of the fibrinolytic activity in
able over the counter. The most common plasma by oral administration of nat- Ming-Wai Tai, Pharm.D. Degree
strengths of nattokinase are 25, 50, and tokinase. Acta Haematol. 1990; 84:139-43. Candidate
100 mg, each containing 20 fibrinolytic 6. Natto. Wikipedia monograph. http:/en. University of Michigan College of
wikipedia.org/wiki/Natto (accessed 2006 Pharmacy
units (FU) of nattokinase per milligram Jan 16).
(500 FU is equivalent to 1 CU).7,16-19 The 7. Sumi H, Hamada H, Tsushima H et al. A Burgunda V. Sweet, Pharm.D., Clinical
most common dosage is 100 mg (2000 novel fibrinolytic enzyme (nattokinase) in Associate Professor of Pharmacy
the vegetable cheese natto; a typical and Drug Information Service
FU) three times daily. It is important to popular soybean food in the Japanese diet. gsweet@umich.edu
note that there is no information about Experientia. 1987; 43:1110-1.
8. Suzuki Y, Kondo K, Matsumoto Y et al. College of Pharmacy
the efficacy or safety of the recommended University of Michigan Health System
Dietary supplementation of fermented soy-
dose of these products. Additional prod- bean, natto, suppresses intimal thickening UH B2D301/0008
ucts containing nattokinase in combina- and modulates the lysis of mural thrombi 1500 East Medical Center Drive
tion with other enzymes or herbal prod- after endothelial injury in rat femoral artery. Ann Arbor, MI 48109-0008
Life Sci. 2003; 73:1289-98.
ucts are also available. 9. Urano T, Ihara H, Umemura K et al. The DOI 10.2146/ajhp050509
For prevention of DVT during a long- profibrinolytic enzyme subtilisin NAT puri-

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