Natto LP by Allegany Nutrition

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Celiac disease. Although there has been interest in using oral lipase for celiac disease, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Dyspepsia. It is unclear if oral lipase is beneficial for improving symptoms of postprandial distress syndrome. Details: A small clinical trial shows that taking a specific acid-resistant lipase (Amano Enzyme USA) 280 mg immediately before a high-fat meal does not reduce postprandial bloating and nausea when compared with placebo in individuals with postprandial distress syndrome (101900).
• Inflammatory bowel disease (IBD). Although there has been interest in using oral lipase for IBD, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Prematurity. It is unclear if adding a specific form of lipase, recombinant human bile salt-stimulated lipase (rhBSSL), to infant formula improves outcomes in premature infants. Some research suggests a potential increased risk for adverse effects. Details: Human breast milk contains rhBSSL, but it is inactivated when breast milk is pasteurized for donation. Clinical research in infants born before 32 weeks' gestation shows that adding rhBSSL as 8700 units per 100 mL formula or pasteurized breast milk, for 4 weeks does not increase growth velocity, body length, or head circumference over the next 12 months when compared with formula or pasteurized breast milk devoid of lipase. However, the infants who were small for gestational age (SGA), which made up approximately 15% of the study population, grew by an additional 1.9 grams/kg daily on average when compared with placebo (101940). More evidence is needed to rate lipase for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. Although there has been interest in using oral nattokinase for angina, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Atherosclerosis. It is unclear if nattokinase is beneficial in patients with atherosclerosis. Details: Clinical research in patients at low risk for cardiovascular disease shows that taking nattokinase 2000 fibrinolytic units orally daily for a median of 3 years is not associated with any change in subclinical atherosclerosis, as measured by carotid artery intima-media thickness and carotid arterial stiffness, when compared with placebo (106406). However, a retrospective observational study of Chinese patients with hyperlipidemia and/or mild atherosclerosis has found that taking nattokinase 10,800 fibrinolytic units daily for 12 months may modulate the progression of atherosclerosis. Nattokinase use was associated with a 22% reduction in carotid artery intima-media thickness and a 36% reduction in the size of the carotid artery plaque when compared to baseline. These effects appear to be enhanced by regular exercise, avoidance of smoking and alcohol, and co-administration with aspirin (111252). The validity of these findings is limited by a lack of control group and the retrospective nature of the study.
• Cancer. Although there has been interest in using oral nattokinase for cancer, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral nattokinase for CVD, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral nattokinase for CFS, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Endometriosis. Although there has been interest in using oral nattokinase for endometriosis, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Fibromyalgia. Although there has been interest in using oral nattokinase for fibromyalgia, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Hemorrhoids. Although there has been interest in using oral nattokinase for hemorrhoids, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Hyperlipidemia. It is unclear if oral nattokinase is beneficial in patients with hyperlipidemia. Details: A retrospective observational study in Chinese patients with hyperlipidemia and/or mild atherosclerosis shows that taking nattokinase 10,800 fibrinolytic units daily for 12 months is associated with a 15% to 17% improvement in total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides when compared to baseline. This effect seems to be amplified in subjects who have a higher body mass index, smoke, drink alcohol, and exercise regularly. Furthermore, the anti-hyperlipidemic effect of nattokinase appears to be enhanced by co-administration of vitamin K2 and aspirin (111252). However, the validity of these findings is limited by a lack of control group and the retrospective nature of the study. In contrast, some preliminary clinical research in patients with hyperlipidemia shows that taking nattokinase 200 mg (7000 fibrinolytic units) daily in combination with red yeast rice 1200 mg daily in divided doses for 6 months reduces LDL cholesterol and total cholesterol when compared with placebo. However, taking nattokinase alone did not improve lipid levels when compared with placebo (92312). It is likely that the lipid lowering effects of the combination are due to red yeast rice, which contains monacolin K, a chemical similar to lovastatin.
• Hypertension. It is unclear if oral nattokinase is beneficial in patients with hypertension. Details: Some clinical research suggests that nattokinase can reduce systolic blood pressure (SBP) and diastolic blood pressure (DBP). One study in patients with hypertension shows that taking nattokinase (NSK II, Japan Bio Sciences Laboratories Company Ltd.) 2000 fibrinolytic units daily for 8 weeks reduces SBP by 6 mmHg and DBP by 3 mmHg when compared with placebo (64835). In another study, taking a natto extract 30 grams daily (unknown nattokinase content) for 4 days reduces SBP and DBP by 11% and 10%, respectively, when compared with baseline (64837). However, in patients with normal blood pressure or controlled hypertension, taking nattokinase 2000 fibrinolytic units daily for a median of 3 years has no effect on blood pressure (106406).
• Impaired glucose tolerance (prediabetes). Oral nattokinase has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with prediabetes shows that taking a combination product containing nattokinase 34 fibrinolytic units, chokeberry 1.64 grams, Panax ginseng 1.36 grams, and shiitake mushroom 960 mg twice daily for 12 weeks improves measures of insulin resistance, but does not reduce fasting blood glucose, postprandial glucose, or glycated hemoglobin (HbA1c), when compared with placebo (108301).
• Infertility. Although there has been interest in using oral nattokinase for infertility, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Peripheral arterial disease (PAD). Although there has been interest in using oral nattokinase for PAD, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Stroke. Although there has been interest in using oral nattokinase for stroke, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Venous insufficiency. It is unclear if oral nattokinase is beneficial in patients with venous insufficiency. Details: A small, uncontrolled clinical study in patients with venous insufficiency who underwent vascular surgery suggests that taking nattokinase 2000 fibrinolytic units daily for 30 days after surgery may induce remission of clinical symptoms (109553). The validity of these findings is limited by a lack of control group.
• Venous thromboembolism (VTE). It is unclear if oral nattokinase is beneficial in patients with VTE. Details: A small, uncontrolled clinical study in patients with deep vein thrombosis (DVT) or phlebitis suggests that taking nattokinase 2000 fibrinolytic units daily for 30 days after a 30-day regimen of fondaparinux or enoxaparin may induce remission of clinical symptoms (109553). The validity of these findings is limited by a lack of control group and the use of anticoagulants before nattokinase therapy. Nattokinase has also been evaluated in combination with other ingredients for prophylaxis of DVT during long-haul flights. A small clinical trial shows that taking two capsules of a specific combination product (Flite Tabs, Aidan), containing 150 mg of a proprietary blend of nattokinase and maritime pine bark (Pycnogenol, Horphag Research), 2 hours before a flight and 6 hours later, might decrease the risk of DVT during long plane flights (12075). The effect of nattokinase alone on DVT risk during long-haul flights is unclear. More evidence is needed to rate nattokinase for these uses.

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Proteolytic enzymes represent a wide group of enzymes that are used alone or in combination. See specific monographs for effectiveness information.

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There is insufficient reliable information available about the safety of lipase.

CHILDREN: POSSIBLY UNSAFE
when recombinant human bile salt-stimulated lipase (rhBSSL) is used orally by premature infants. Adding rhBSSL to infant formula or pasteurized breast milk increases the risk for serious gastrointestinal adverse effects in premature infants (101940).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Nattokinase is a natural component of the soy food natto. It has been routinely consumed in Japan for hundreds of years (12072,12073).

POSSIBLY SAFE ...when used orally for medicinal purposes. Nattokinase has been used with apparent safety in doses of 2000 fibrinolytic units daily for up to 3 years or 10,800 fibrinolytic units daily for up to 12 months (64835,92312,106406,111252).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately. Various proteolytic enzymes have been safely used orally in clinical research (716,964,965,968,969,6252,6253,10622,11457,18281,18284) (91104,91105,91106,91111,96449). Side effects are typically mild to moderate and most often include gastrointestinal effects. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes. ...when used topically and appropriately. Various proteolytic enzymes have been safely used topically in clinical research (67835,67843,67845,91113). Some proteolytic enzymes might cause allergic reactions when used topically. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Nattokinase might increase the risk of bleeding when used with anticoagulant/antiplatelet drugs.  Details Nattokinase has thrombolytic and anticoagulant effects (12070,12073,92311). There is a case report of intracranial hemorrhage in a patient who added nattokinase to aspirin therapy (64834).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, nattokinase might increase the risk of hypotension when used with antihypertensive drugs.  Details Some clinical research suggests that nattokinase may reduce systolic and diastolic blood pressure (64835,64837).

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General ...No adverse effects have been reported in adults. However, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Gastrointestinal adverse effects, such as necrotizing enterocolitis, when recombinant human bile salt-stimulated lipase is used in premature infants.

Gastrointestinal ...Orally, when added to the formula or pasteurized breast milk consumed by premature infants, recombinant human bile salt-stimulated lipase (rhBSSL) can cause gastrointestinal adverse effects, including abdominal distension, flatulence, constipation, colic, abdominal pain, gastroenteritis, vomiting, regurgitation, and rectal bleeding (101940). Premature infants receiving rhBSSL also had a slightly higher rate of necrotizing enterocolitis (NEC) when compared with those receiving placebo. After review by a panel of experts, it was determined that the rate of confirmed or suspected NEC in infants consuming rhBSSL was 3.3%, compared with 0.5% in those receiving placebo. Although this rate of NEC is lower than the historical rate of occurrence in premature infants (11%), a possible increased risk for NEC cannot be ruled out (101940).

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General ...Orally, nattokinase is generally well tolerated. Preliminary clinical trials suggest that the incidence of adverse effects with nattokinase is similar to that with placebo.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis, hemorrhage.

Hematologic ...Orally, nattokinase has been associated with rare reports of hemorrhage (64834,109551). A case of intracranial hemorrhage (ICH) has been reported in a 52-year-old female who took nattokinase while taking low-dose aspirin for secondary prevention of ischemic stroke. Seven days after initiating nattokinase 400 mg daily, the patient reported vertigo and unsteady gait and was diagnosed with an acute cerebellar hemorrhage. It was suggested that the thrombolytic and anticoagulant effects of nattokinase combined with aspirin's antiplatelet effects contributed to the ICH (64834). In another case, a 92-year-old female taking nattokinase daily (dose unknown) for atrial fibrillation presented to the hospital after a fall. The patient was on no other anticoagulant or antiplatelet drugs. Abdominal CT showed a ruptured hepatic cystic lesion and intraperitoneal hemorrhage, which was difficult to stop despite several transfusions of red blood cells and fresh frozen plasma. The authors attributed the bleeding complications, in part, to nattokinase use (109551).

Immunologic ...Orally, nattokinase can cause hypersensitivity reactions, including anaphylaxis, in individuals sensitive to natto (109552,111253). A case series examining hypersensitivity reactions to natto shows that the causative allergen can be either nattokinase or polygamma glutamic acid (PGA), both of which are found in the sticky substance surrounding natto soybeans. In patients with hypersensitivity to nattokinase, specifically, symptoms occurred within 2 hours after ingestion, were limited to the pharynx and larynx, and included swelling, tightness, and itching in the throat and lips and dyspnea. All patients with nattokinase sensitivity shared a history of atopic dermatitis (111253).

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General ...Orally, proteolytic enzymes are generally well tolerated. See specific monographs for detailed safety information related to individual proteolytic enzymes.
Most Common Adverse Effects:
Orally: Gastrointestinal upset.
Serious Adverse Effects (Rare):
Topically: Allergic reactions.

Gastrointestinal ...Orally, some patients taking proteolytic enzymes may have gastrointestinal complaints (101517).

Immunologic ...Proteolytic enzymes are commonly found in laundry detergents and pre-spotter products. Rarely, protease specific IgE positive tests possibly related to these products have occurred. Exposure may be airborne or topical (102705). In addition, in case reports, occupational exposure to the airborne proteolytic enzyme pepsin has resulted in allergic rhinoconjunctivitis or asthma (102706,102707).

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