Estudos

http://aformulabr.com.br/qrcode/nattokinafv01.pdf
 NATTOKINASE
Enzima no tratamento de doenças cardíacas e Alzheimer

DESCRIÇÃO
Enzima fibrinolítica da família das peptidases, potente extraída e purificada a partir do alimento japonês chamado
“NATTO”, considerado uma protease da serina do tipo subtilisina composta por partes de aminoácidos.

MECANISMO DE AÇÃO
Aumenta a capacidade natural do corpo no combate a formação de coágulos sanguíneos dissolvendo a fibrina
diretamente, apresentando ação fibrinolítica, ocasionando o aumento na produção orgânica de plasmina e outros
agentes de dissolução do coágulo, destacando sua ação antitrombótica, incluindo a uroquinase (endógena), além de
reduzir a pressão sanguínea, atuando como um inibidor da ECA natural, causando bloqueio da ação da enzima
conversora da angiotensina, com menor formação de angiotensina II.
Estudos apontam que o uso de Nattokinase atua na ruptura da fibrina reduzindo a quantidade de depósitos de
amiloide encontrada nos vasos sanguíneos do cérebro de ratos com Alzheimer, causando melhorias na memória.

INDICAÇÕES

 Insuficiência venosa discreta, trombose venosa profunda e varizes; histórico familiar de doenças
cardiovasculares trombo-embólicas;
 Viagens de avião de longo curso (profilaxia a trombose venosa); vida sendentária, tabagismo e obesidade;
 Auxiliar no tratamento de doenças cardiovasculares, tromboembólicas (doentes em diálise), acidente vascular
cerebral, aterosclerose e hipertensão arterial.

DOSE USUAL

Recomendação oral de 50 a 200mg de Nattokinase ao dia.

SUGESTÕES DE FÓRMULAS

Nattokinase......................................................... 30mg Nattokinase......................................................... 50mg

Picnogenol......................................................... 100mg Red yeast rice 0,4%........................................... 300mg
Pomegranate (40% ácido elágico) .......................... 200mg
Modo de Uso: 1 dose, 2 vezes ao dia.
Modo de uso: 2 doses, 2 horas antes e 1 dose a Indicação: hiperlipidemia.
cada 4 a 6 horas (em viagens de avião).
Indicação: prevenção de trombose venosa profunda.

PRINCIPAIS REFERÊNCIAS

FUJITA M.; OHNISHI K.; TAKAOKA S.; OGASAWARA K.; FUKUYAMA R.; NAKAMUTA H. Antihypertensive effects of continuous oral
administration of nattokinase and its fragments in spontaneously hypertensive rats. Biol Pharm Bull. V.34, nº11, p.1696-701. 2011. Disponível
em:< http://www.ncbi.nlm.nih.gov/pubmed/22040882>. Acesso em: 17 de Julho de 2015, às 08:30.

YANG N.C.; CHOU C.W.; CHEN C.Y.; HWANG K.L.; YANG Y.C. Combined nattokinase with red yeast rice but not nattokinase alone has potent
effects on blood lipids in human subjects with hyperlipidemia. Asia Pac J Clin Nutr. V.18, nº3, p.310-7. 2009. Disponível em:<
http://www.ncbi.nlm.nih.gov/pubmed/19786378>. Acesso em: 23 de julho de 2015, às 11:42.
 NATTOKINASE
ESTUDOS CLÍNICOS

Nattokinase improves blood flow by inhibiting platelet aggregation and thrombus formation

The effects of nattokinase on the in vitro platelet aggregation and in vivo thrombosis were investigated in comparison
with aspirin. Rabbit platelet-rich plasma was incubated with nattokinase and aggregation inducers collagen and
thrombin, and the platelet aggregation rate was analyzed. Nattokinase significantly inhibited both the collagen- and
thrombin-induced platelet aggregations. Nattokinase also reduced thromboxane B 2 formation from collagen-activated
platelets in a concentration-dependent manner. Rats were orally administered with nattokinase for 1 week, and their
carotid arteries were exposed. Arterial thrombosis was induced by applying 35% FeCl 3-soaked filter paper for 10 min,
and the blood flow was monitored with a laser Doppler probe. Nattokinase delayed the FeCl 3-induced arterial
occlusion in a dose-dependent manner, doubling the occlusion time at 160 mg/kg. In addition, a high dose (500
mg/kg) of nattokinase fully prevented the occlusion, as achieved with aspirin (30 mg/kg). The results indicate that
nattokinase extracted from fermented soybean inhibit platelet aggregation by blocking thromboxane formation, and
thereby delay thrombosis following oxidative arterial wall injury. Therefore, it is suggested that nattokinase could be a
good candidate without adverse effects for the improvement of blood flow.

Antihypertensive effects of continuous oral administration of nattokinase and its fragments in spontaneously
hypertensive rats

To determine whether the antihypertensive effect of nattokinase is associated with the protease activity of this
enzyme, we compared nattokinase with the fragments derived from nattokinase, which possessed no protease
activity, in terms of the effect on hypertension in spontaneously hypertensive rats (SHR). In the continuous oral
administration test, the groups were given a basic diet alone (control), the basic diet containing nattokinase (0.2, 2.6
mg/g diet) or the basic diet containing the fragments derived from nattokinase (0.2, 0.6 mg/g diet). The group fed the
basic diet containing high-dosage nattokinase (2.6 mg/g diet) showed significant reductions in systolic blood pressure
(SBP), diastolic blood pressure (DBP) and plasma fibrinogen level, compared with control group and no influence on
activities of renin and angiotensin-converting enzyme (ACE, EC 3.4.15.1), and plasma angiotensin II level in the renin-
angiotensin system. The treatment of the basic diet containing high-dosage fragments (0.6 mg/g diet) significantly
decreased SBP, DBP and plasma angiotensin II level in plasma but the treatment did not influence on plasma
fibrinogen level. These results suggest that nattokinase and its fragments are different from each other in the
mechanism to reduce hypertension. Nattokinase, retained its protease activity after absorbance across the intestines,
may decrease blood pressure through cleavage of fibrinogen in plasma. The fragments, which absorbed as
nattokinase-degradation products, prevents the elevation of plasma angiotensin II level to suppress hypertension.

Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in
human subjects with hyperlipidemia

The purpose of this randomized, double-blind, placebo-controlled, parallel comparison study was to evaluate the lipid-
lowering effect of orally administrated nattokinase and nattokinase combined with red yeast rice (RYR) extract on
blood lipids in patients with hyperlipidemia. A total of 47 patients with hyperlipidemia were assigned to one of three
groups: 1. nattokinase-mono formula (50 mg/capsule), 2. combined formula of nattokinase with RYR (300 mg of
extract/capsule) and 3. placebo. Subjects received a twice daily dose of two capsules for six months. The mono
formula showed no effects on blood lipids until month six, while the combined formula ameliorated all of measured
lipids starting from month one. In the combined group significant decreases were found with regard to: triglycerides
(TG) by 15%, total cholesterol (TC) by 25%, low-density lipoprotein cholesterol (LDL-C) by 41%, TC/high-density
lipoprotein cholesterol (HDL-C) ratio by 29.5%, and increases in HDL-C by 7.5%. These changes were sustained until
the end of study. After controlling for baseline levels, only the combined group, but not mono group, showed a
significant difference (p<0.0001) in TC, LDL-C and TC/HDL-C ratio when compared with the placebo group. In
summary, this study provides long-term efficacy of nattokinase supplementation and shows that the combined formula
has relatively more potent effects than the mono formula on lowering of blood lipids, suggesting that combined
nattokinase with RYR will be a better neutraceutical for patients with hyperlipidemia than nattokinase alone.
Effects of nattokinase on blood pressure: a randomized, controlled trial

The objective of this study was to examine the effects of nattokinase supplementation on blood pressure in subjects
with pre-hypertension or stage 1 hypertension. In a randomized, double-blind, placebo-controlled trial, 86 participants
ranging from 20 to 80 years of age with an initial untreated systolic blood pressure (SBP) of 130 to 159 mmHg
received nattokinase (2,000 FU/capsule) or a placebo capsule for 8 weeks. Seventy-three subjects completed the
protocol. Compared with the control group, the net changes in SBP and diastolic blood pressure (DBP) were -5.55
mmHg (95% confidence interval [CI], -10.5 to -0.57 mmHg; p<0.05) and -2.84 mmHg (CI, -5.33 to -0.33 mmHg;
p<0.05), respectively, after the 8-week intervention. The corresponding net change in renin activity was -1.17 ng/mL/h
for the nattokinase group compared with the control group (p<0.05). In conclusion, nattokinase supplementation
resulted in a reduction in SBP and DBP. These findings suggest that increased intake of nattokinase may play an
important role in preventing and treating hypertension.

Thrombolytic effect of nattokinase on a chemically induced thrombosis model in rat

Nattokinase is a new fibrinolytic enzyme which cleaves directly cross-linked fibrin in vitro. In this study, we investigated
the thrombolytic effect of nattokinase on a thrombus in the common carotid artery of rat in which the endothelial cells
of the vessel wall were injured by acetic acid. When a section of occluded vessel was stained for CD61 antigen by
immunofluorescence utilizing a monoclonal antibody, the antigen was localized around the surface of the occluded
blood vessels. This result suggests that the occlusive thrombosis was caused by platelet aggregation. In addition,
thrombolysis with urokinase (UK; 50000 IU/kg, i.v.) or tissue plasminogen activator (tPA; 13300 IU/kg, i.v.) in our
model was observed to restore the blood flow over a 60 min monitoring period. The results indicate that our chemically
induced model is useful for screening and evaluating a thrombolytic agent. We evaluated the thrombolytic activity of
nattokinase using this model and compared it with fibrino(geno)lytic enzyme, plasmin or elastase. On a molar basis,
the recovery of the arterial blood flow with nattokinase, plasmin and elastase were 62.0 +/- 5.3%, 15.8 +/- 0.7% and
0%, respectively. The results indicate that the thrombolytic activity of nattokinase is stronger than that of plasmin or
elastase in vivo.

Transport of nattokinase across the rat intestinal tract

Intraduodenal administration of nattokinase (NK) at a dose of 80 mg/kg, resulted in the degradation of fibrinogen in
plasma suggesting transport of NK across the intestinal tract in normal rats. The action of NK on the cleavage of
fibrinogen in the plasma from blood samples drawn at intervals after intraduodenal administration of the enzyme was
investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis
with an anti-fibrinogen gamma chain antibody. The 270 kDa fragment carrying antigenic sites for the binding of the
anti-fibrinogen gamma chain antibody appeared within 0.5 h and was then degraded gradually to a 105 kDa fragment
via a 200 kDa fragment. This suggests that fibrinogen was degraded to a 105 kDa fragment via several intermediates
(270 and 200 kDa). In parallel with the degradation process, plasma recalcification times were remarkably prolonged
NK was also detected in the plasma from blood samples drawn 3 and 5 h after administration of the enzyme by SDS-
PAGE and Western blotting analysis with an anti-NK antibody. The results indicate that NK is absorbed from the rat
intestinal tract and that NK cleaves fibrinogen in plasma after intraduodenal administration of the enzyme.
REFERÊNCIAS

JANG J.Y.; KIM T.S.; CAI J.; KIM J.; KIM Y.; SHIN K.; SEI KIM K.S.; PARK S.K.; LEE S.P.; CHOI E.K.; MAN HEE RHEE M.H.; KIM Y.B.
Nattokinase improves blood flow by inhibiting platelet aggregation and thrombus formation. Lab Anim Res. V. 29, n°4, p. 221–225. Dec. 2013.
Disponível em:< http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879341/>. Acesso em: 17 de Julho de 2015, às 10:03.

FUJITA M.; OHNISHI K.; TAKAOKA S.; OGASAWARA K.; FUKUYAMA R.; NAKAMUTA H. Antihypertensive effects of continuous oral
administration of nattokinase and its fragments in spontaneously hypertensive rats. Biol Pharm Bull. V.34, nº11, p.1696-701. 2011. Disponível
em:< http://www.ncbi.nlm.nih.gov/pubmed/22040882>. Acesso em: 17 de Julho de 2015, às 08:30.

YANG N.C.; CHOU C.W.; CHEN C.Y.; HWANG K.L.; YANG Y.C. Combined nattokinase with red yeast rice but not nattokinase alone has potent
effects on blood lipids in human subjects with hyperlipidemia. Asia Pac J Clin Nutr. V.18, nº3, p.310-7. 2009. Disponível em:<
http://www.ncbi.nlm.nih.gov/pubmed/19786378>. Acesso em: 23 de julho de 2015, às 11:42.

KIM J.Y.; GUM S.N.; PAIK J.K.; LIM H.H.; KIM K.C.; OGASAWARA K.; INOUE K.; PARK S.; JANG Y.; LEE J.H. Effects of nattokinase on blood
pressure: a randomized, controlled trial. Hypertens Res. V.31, nº8, p.1583-8. Aug; 2008. Disponível em:<
http://www.ncbi.nlm.nih.gov/pubmed/18971533>. Acesso em: 16 de Julho de 2015, às 10:43.

FUJITA M.; HONG K.; ITO Y.; FUJII R.; KARIYA K.; NISHIMURO S. Thrombolytic effect of nattokinase on a chemically induced thrombosis model
in rat. Biol Pharm Bull. V.18, n°10. p.1387-91. Oct; 1995. Disponível em:< http://www.ncbi.nlm.nih.gov/pubmed/8593442>. Acesso em: 16 de
Julho de 2015, às 10:35.
FUJITA M.; HONG K.; ITO Y.; MISAWA S.; TAKEUCHI N.; KARIYA K.; NISHIMURO S. Transport of nattokinase across the rat intestinal tract.
Biological & Pharmaceutical Bulletin. V.18, nº9, p.1194-1196. 1995. Disponível em:< http://europepmc.org/abstract/med/8845803>. Acesso em:
17 de Julho de 2015, às 08:15.