The enzyme of enzymes - Nattokinase

Townsend Letter for Doctors and Patients, Nov, 2002 by Nicholas Dr. Calvino

* Heparin is a drug given IV that acts as an anticoagulant by inhibiting thrombin. Heparin is often associated with side effects, such as increased bleeding and hemorrhage.

* Coumarin/Warfarin is a drug that works by competing with vitamin K for reactive sites in the enzymatic process for the formation of prothrombin and clotting factors, thereby blocking the clotting action of vitamin K.

* t-PA (Tissue Plasminogen Activator) is a "clot buster" that is effective in activating plasminogen to plasmin. Although given as an IV drug, this is also a naturally occurring substance produced endogenously, albeit in much smaller amounts.

* Streptokinase is another enzyme, derived from beta-hemolytic streptococci, which is used as a "clot buster." Its limitation is that its effect is rather short lived and eventually its therapeutic efficiency declines.

In addition to serious side effects and limitations, the "clot busters" lack true broad utility in that to be therapeutic, they must be injected. Therefore, there has been a renewed interest in discovering and using oral anti-clotting enzymes.

Fibrinolytic therapy by oral administration of enzymes was investigated by Sumi and coworkers over 10 years ago in an animal model where enteric-coated urokinase (UK) capsules were given to normal and experimental dogs with saphenous vein thrombosis. Previous findings indicated that intravenous (IV) administration did not show any clear thrombolytic effect, but that oral administration enhanced the fibrinolytic activity, serving as a treatment to lyse the thrombi in a mild but maintained way. The underlying mechanism of such fibrinolytic therapy by oral administration was then confirmed by basic research to involve absorption of the administered UK across the intestinal tract, and release into the blood of endogenous plasminogen activator which originated from the liver and/or endothelial cells. The enteric-coated UK capsules (60,000 U/day for 7 days) also exhibited a clinical efficacy against cerebral thrombi. Moreover, more effective results were obtained in double-blind tests at multicenter trials employin g a dose of 120,000 U/day for 7 days. This supported the idea that oral enzyme agents can and do have systemic fibrinolytic properties, however, an oral fibrinolytic agent that had sustained activity and minimal side-effects was further pursued.

Nattokinase was later discovered by Dr. Sumi and research has found it to be a most promising agent as an ideal oral fibrinolytic agent -- not only reversing clots but in preventing them and modulating the clotting process in ways that help re-establish coagulation homeostasis. Nattokinase is a serine endopeptidase with a molecular weight of 20,000 Daltons and a point of ionization (pI) of 8.6. This isolated fibrinolytic enzyme, derived from a traditional Japanese food, Natto, was discovered by Dr. Hiroyuki Sumi and resembles plasmin. Nattokinase is derived from the vegetable cheese, Natto, a typical and popular fermented soybean food in Japan. It shows potent fibrinolytic activity and was named Nattokinase (NK) -- literally meaning, an enzyme derived from Natto. Dr. Hiroyuki Sumi, while doing research work at the University of Chicago's Medical School, conducted research on about 200 kinds of food, including several types of liquors, from all over the world in search of natural substance that could dissolve and even prevent blood clots. He found that Natto had the highest fibrinolytic activity among all those foods tested. In 1986, Dr. Sumi presented the results of his research in Japan for the first time.