Natto / Spermidine

 

Spermidine (Natto)

• Extended mice lifespan by 10%. 

• Dietary spermidine is associated with reduced overall, cardiovascular and cancer-related mortality in humans.

• Autophagy is required for the anti-aging effect of spermidine – inhibition of autophagy abolishes the longevity-extending effects of spermidine on yeast, worms and flies.

• People who ate high amounts of fermented soy (natto and miso) had a 13-14% lower death rate in the 15 year period (~45 grams per day of fermented soy).

Spermidine delays aging in humans (link)

External supply of the natural polyamine spermidine can extend life span in model organisms including yeast, nematodes, flies and mice. Recent epidemiological evidence suggests that increased uptake of spermidine with food also reduces overall, cardiovascular and cancer-related mortality in humans. in mice, the supplementation was able to suppress the age-related decline in cardiovascular function (as measured at 24 months of age) and increased overall longevity by approximately 10% [3]. Until now the literature on the longevity-enhancing effects of spermidine has been limited to model organisms. Now, two prospective population-based studies (summarized in the same paper) report for the first time that nutritional spermidine uptake is also linked to reduced overall, cardiovascular and cancer-related mortality in humans [15]. The inhibition of EP300 by spermidine stimulates autophagy [9] Autophagy is required for the anti-aging effect of spermidine as indicated by the fact that genetic inhibition of autophagy (by knockout or knockdown of essential autophagy-relevant genes) abolishes the longevity-extending effects of spermidine on yeast, worms and flies [11]. 

Spermidine is one of the most powerful anti-aging nutrients.

• It's been shown in numerous studies to extend the lifespan of lab animals.

• Supplement companies are working on coming up with spermidine supplements. But it's also readily available in foods. The richest sources are wheat germ, soy, aged cheese and mushrooms.

• Natto, a ferm of fermented soy, is one of the best sources (rich in spermidine, spermine, putrescine, and other polyamines –– all associated with longevity and health benefits).

Eat Natto, Live Longer? (link)

Key Findings of the BMJ Study People who ate high amounts of fermented soy (natto and miso) had a 13-14% lower death rate in the 15 year period. This group ate about 45 grams per day of fermented soy. The higher mortality group in the comparison ate about 9 grams per day.

Eating fermented soy products may reduce the risk of premature death, researchers report.

Some soy products, like tofu, are not fermented. But others — miso, natto and tempeh, for example — are made using bacteria or mold in a fermentation process. Soy sauce, if made in the traditional way, is also fermented.

The study, in BMJ, followed the diets and health of 92,915 Japanese men and women aged 45 to 74 for an average of 15 years. During this time, 13,303 of the study participants died.

After controlling for other diet components, hypertension, diabetes, smoking, alcohol intake and other factors, the researchers found that compared with those in the lowest one-fifth for fermented soy intake, those in the highest one-fifth had a 10 percent lower risk of death from any cause. Those in the highest one-fifth for natto intake, but not miso, had an 18 percent lower risk of cardiovascular disease death, possibly because of the lower sodium content of natto.

Are You Ready to Eat Your Natto? (link)

As with most probiotics, the science about natto is at an early stage. Dr. Ralph Holsworth, an emergency room supervisor and biomedical researcher in a rural hospital in Colorado who has coauthored several studies on the enzyme nattokinase, a byproduct of natto fermentation, said that the enzyme “breaks down fibrin in the blood, a protein aggregate involved in blood clotting, decreases the ‘stickiness’ of the red blood cells, and assists in the prevention of arterial plaque formation.” These blood-thinning actions, he said, may lessen the severity of heart attacks and strokes.

Natto is the way to go! (link)

First, NK has potent fibrinolytic/antithrombotic activity.3–6 In addition, in both animal and human studies, NK also has an antihypertensive,7,8 anti-atherosclerotic,9,10 lipid-lowering,9,11antiplatelet/anticoagulant,12 and neuroprotective actions.13,14 All these pharmacologic actions of NK have relevance to the prevention and treatment of CVD. Indeed, NK supplementation has shown to enhance markers of fibrinolysis and anticoagulation and to decrease blood pressure (BP) and atherosclerosis in human subjects.8,9,15–17

The carotid plaque size and CCA-IMT reduced from 0.25 ± 0.12 cm2 to 0.16 ± 0.10 cm2 and from 1.13 ± 0.12 mm to 1.01 ± 0.11 mm, respectively. The reduction in the NK group was more significant (P < .01) than that in the group treated with simvastatin (daily dose of 20 mg). Our data suggested that NK was a better alternative to statins, a commonly used drug to reduce atherosclerosis, and furthermore, NK could be a viable alternative therapy for cardiovascular attack and stroke in patients.9

Long-term oral polyamine intake increases blood polyamine concentrations

Although the intracellular de novo synthesis of the polyamines decreases with age, there is no similar trend in blood polyamine levels, but rather there is wide individual variability. We hypothesized that dietary polyamines attenuate a decrease in blood polyamine levels with age and augment the previously observed individual variability. The effect of a polyamine rich diet, in both mice and humans, on blood polyamine concentrations was examined in this study. Jc1:ICR male mice were fed test diets containing 3 different polyamine concentrations. Healthy human male volunteers added 50 to 100 g of the polyamine-rich fermented soybean product, natto, to their daily intake. After 26 wk, the mean blood spermine concentration in mice receiving the test diet with high polyamine concentrations was 10.1+/-2.4 micromol/L, while the mean concentrations found in mice fed with a diet with normal or low polyamine concentrations were 5.2+/-0.9 and 4.7+/-0.5 micromol/L, respectively (p<0.05). A mean daily intake of 66.4+/-3.7 g (range=46.4-89.3 g) of natto for 2 mo by human volunteers increased the mean blood spermine concentration by a factor of 1.39 (n=10) (p<0.01), while in control volunteers (n=7), asked to exclude polyamine-rich foods from their diet, blood spermine concentration remained unchanged. The individual variability of blood polyamine levels was enhanced after polyamine intake in mice and, to a lesser extent, in humans. The long-term oral intake of enhanced polyamine diets increases blood polyamine levels in both mice and humans.

The clinical significance of tissue, blood and urine polyamine in renal cell carcinoma

With the use of a newly developed and convenient enzymatic method, tissue, urine and blood polyamine (diamine, spermidine and spermine) levels were evaluated as a tumor marker of renal cell carcinoma (RCC) in 50 cases with the disease. Furthermore, blood and urine polyamines were periodically determined and evaluated as a follow-up marker. The pretreatment three polyamine levels in tissue, blood and urine of the patients were all significantly higher than those of the controls. However, because of their low sensitivities, they were not always decisive for biochemical diagnosis of RCC. Tissue spermidine levels were increased with the advance of the stages. Tissue diamine level also showed a good correlation with the pathological grade. Tissue diamine was found to predict distant metastasis. Blood spermidine and urine diamine were useful as follow-up markers. In conclusion, combined determination of tissue, blood and urine polyamine levels was thought to be useful as tumor markers of RCC.

The Prognostic Value of Erythrocyte Polyamine in the Post-Nephrectomy Stratification of Renal Cell Carcinoma Specific Mortality, 2010

Purpose:

The polyamines spermine and spermidine are ubiquitous polycationic structures which are essential for cell proliferation and differentiation. Circulating polyamines, spermine and spermidine, represent valuable prognostic markers in prostate cancer, acute leukemia and supratentorial malignant glioma. We tested whether spermine and spermidine could improve the prognostic ability of several established predictors of cancer specific mortality after partial or radical nephrectomy for renal cell carcinoma.

Materials and Methods:

Testing was performed on 399 patients with stages T1–4, N0–2, M0–1 renal cell carcinoma who were treated with radical or partial nephrectomy at a single institution between 1990 and 2007. Univariable and multivariable Cox regression models tested the prognostic ability of spermine and spermidine levels in cancer specific mortality predictions. Covariates consisted of TNM stage, Fuhrman grade, tumor size and symptom classification. Harrell's concordance index (c-index) quantified accuracy and 200 bootstrap resamples were used to correct for overfit bias.

Results:

The 5-year cancer specific mortality-free survival of patients with spermine levels 3 or less, 3.1 to 8, 8.1 to 13 and greater than 13 nmol/8×109 erythrocytes was 88.8%, 75.8%, 40.2% and 21.8%, respectively. Similarly the 5-year cancer specific mortality-free survival of patients with spermidine levels 12 or less, 12.1 to 15, 15.1 to 21 and greater than 21 nmol/8×109 erythrocytes was 79.0%, 56.6%, 53.2% and 27.4%, respectively. On multivariable analyses addressing cancer specific mortality after surgery spermine (p = 0.007) and spermidine (p = 0.04) achieved independent predictor status. Consideration of spermine and spermidine also improved the accuracy of established cancer specific mortality predictors by 2.2% (p <0.001).

Conclusions:

Spermine and spermidine may significantly improve the prognostic value of established cancer specific mortality predictors after partial or radical nephrectomy for all stages of renal cell carcinoma. Independent external validation of our findings is required.

Natto supplementation and decreased platelet count in a case with rheumatoid arthritis

 In this case, natto yeast supplementation was used. After 1 month, the interesting finding is the dramatically reducing of the platelet count to the normal range (150,000/mm 3 ). Of interest, this reducing of platelet count is not concordant with the persistent high ESR value.

• Typically, the nattokinase activity in natto varies from 1,400 FU to 2,000 FU per 50g of commercially available natto. 

• 450mcg Vit K2 in 3 tablespoons, 50g of Natto (R). [Studies supplement 45mg K2 daily, 100x natto serving] 

• 5-15mg Spermidine in 50g serving of natto (R)

Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized controlled trial

The aim of this study was to investigate whether menatetrenone (MNT) suppresses hepatocellular carcinoma (HCC) recurrence in patients undergoing hepatectomy. Between January 2005 and September 2009, 101 patients who underwent curative hepatectomy for primary HCC were enrolled in the study. Patients were divided into two groups: a non-MNT group (n=51), and an MNT group (n=50) that was administered 45 mg of MNT daily. During the observation period, recurrence was observed in 33 patients in the non-MNT group and in 28 patients of the MNT group (p=0.545). In patients with a preoperative Des-γ-carboxy-prothrombin (DCP) level lower than 40 AU/l (n=38), the cumulative disease-free survival rates at 12, 36, and 60 months in the non-MNT group, were 81.3%, 0.0%, and 0.0%, respectively, while those in the MNT group were 78.3%, 58.1%, and 31.0%, respectively (p=0.060). MNT has a moderately suppressive effect on HCC recurrence after hepatectomy, especially in patients with a normal preoperative DCP level.

Nattokinase is a Natural Solution to Reduce Blood Pressure (link)

Nattokinase works by reinforcing the actions of plasmin, your body’s own enzyme that breaks down the clotting agent called fibrin, thereby preventing abnormal thickening of the blood. Because plasmin production slows as you age, this type of support is a real boon for those who want to naturally lower blood pressure. I’ve seen nattokinase reduce high blood pressure by 10–20 systolic points and 5–10 diastolic points.

How to Lower Your Blood Pressure Naturally With Nattokinase

• With nattokinase, you want to start at 50 mg a day and raise the dose to 100 mg a day after a week. Be sure to regularly check your blood pressure as you begin taking the supplement to monitor its effects. You’ll likely be in for a pleasant surprise and find that your doctor may be able to reduce your blood pressure medication.

• Patients who are taking blood thinners such as Coumadin (warfarin) should not take nattokinase because both products thin the blood to reduce blood pressure. However, I don’t see any problem taking nattokinase if you are taking low-dose aspirin (81 mg). Aspirin causes the platelets in your blood to be less sticky, which is a different action than the one caused by Coumadin.

• Everyone taking nattokinase should limit their fish oil intake to no more than 3 g a day because the omega-3 fatty acids in fish oil also make blood less sticky and less likely to form clots.

Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance, 2016

Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.

In Brief

Pietrocola et al. show that short-term fasting or autophagy-inducing caloric restriction mimetics, such as hydroxycitrate and spermidine, improves the antitumor efficacy of chemotherapy in vivo. The effect is specific for autophagy-competent tumors and depends on regulatory T cell depletion from the tumor bed.

[Negative] Spermidine as a target for cancer therapy, 2020

Spermidine, as a natural component from polyamine members, is originally isolated from semen and also existed in many natural plants, and can be responsible for cell growth and development in eukaryotes. The supplementation of spermidine can extend health and lifespan across species. Although the elevated levels of polyamines and the regulation of rate-limiting enzymes for polyamine metabolism have been identified as the biomarkers in many cancers, recent epidemiological data support that an increased uptake of spermidine as a caloric restriction mimic can reduce overall mortality associated with cancers. The possible mechanisms between spermidine and cancer development may be related to the precise regulation of polyamine metabolism, anti-cancer immunosurveillance, autophagy, and apoptosis. Increased intake of polyamine seems to suppress tumorigenesis, but appears to accelerate the growth of established tumors. Based on these observations and the absolute requirement for polyamines in tumor growth, spermidine could be a rational target for chemoprevention and clinical therapeutics of cancers.

The mechanisms by which polyamines accelerate tumor spread, 2011

Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased activity of enzymes responsible for polyamine synthesis. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as cancer tissues, food, and intestinal microbiota. Because polyamines are indispensable for cell growth, increased polyamine availability enhances cell growth. However, the malignant potential of cancer is determined by its capability to invade to surrounding tissues and metastasize to distant organs. The mechanisms by which increased polyamine levels enhance the malignant potential of cancer cells and decrease anti-tumor immunity are reviewed. Cancer cells with a greater capability to synthesize polyamines are associated with increased production of proteinases, such as serine proteinase, matrix metalloproteinases, cathepsins, and plasminogen activator, which can degrade surrounding tissues. Although cancer tissues produce vascular growth factors, their deregulated growth induces hypoxia, which in turn enhances polyamine uptake by cancer cells to further augment cell migration and suppress CD44 expression. Increased polyamine uptake by immune cells also results in reduced cytokine production needed for anti-tumor activities and decreases expression of adhesion molecules involved in anti-tumor immunity, such as CD11a and CD56. Immune cells in an environment with increased polyamine levels lose anti-tumor immune functions, such as lymphokine activated killer activities. Recent investigations revealed that increased polyamine availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells' anti-tumor immune functions.

Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy, 2017

Liver fibrosis and hepatocellular carcinoma (HCC) have worldwide impact but continue to lack safe, low cost, and effective treatments. In this study, we show how the simple polyamine spermidine can relieve cancer cell defects in autophagy, which trigger oxidative stress-induced cell death and promote liver fibrosis and HCC. We found that the autophagic marker protein LC3 interacted with the microtubule-associated protein MAP1S, which positively regulated autophagy flux in cells. MAP1S stability was regulated in turn by its interaction with the histone deacetylase HDAC4. Notably, MAP1S-deficient mice exhibited a 20% reduction in median survival and developed severe liver fibrosis and HCC under stress. Wild-type mice or cells treated with spermidine exhibited a relative increase in MAP1S stability and autophagy signaling via depletion of cytosolic HDAC4. Extending recent evidence that orally administered spermidine can extend lifespan in mice, we determined that life extension of up to 25% can be produced by lifelong administration, which also reduced liver fibrosis and HCC foci as induced by chemical insults. Genetic investigations established that these observed impacts of oral spermidine administration relied upon MAP1S-mediated autophagy. Our findings offer a preclinical proof of concept for the administration of oral spermidine to prevent liver fibrosis and HCC and potentially extend lifespan.

Increased polyamine intake inhibits age-associated alteration in global DNA methylation and 1,2-dimethylhydrazine-induced tumorigenesis, 2013

Polyamines (spermine and spermidine) play many important roles in cellular function and are supplied from the intestinal lumen. We have shown that continuous high polyamine intake inhibits age-associated pathologies in mice. The mechanism by which polyamines elicit these effects was examined. Twenty-four week old Jc1:ICR male mice were fed one of three experimental chows containing different polyamine concentrations. Lifetime intake of high polyamine chow, which had a polyamine content approximately three times higher than regular chow, elevated polyamine concentrations in whole blood, suppressed age-associated increases in pro-inflammatory status, decreased age-associated pathological changes, inhibited age-associated global alteration in DNA methylation status and reduced the mortality in aged mice. Exogenous spermine augmented DNA methyltransferase activity in Jurkat and HT-29 cells and inhibited polyamine deficiency-induced global alteration in DNA methylation status in vitro. In addition, increased polyamine intake was associated with a decreased incidence of colon tumors in BALB/c mice after 1,2-demethylhydrazine administration; 12 mice (60%) in the low polyamine group developed tumors, compared with only 5 mice (25%) in the high polyamine group (Fisher's exact probability = 0.027, p = 0.025). However, increased polyamine intake accelerated the growth of established tumors; maximal tumor diameter in the Low and High groups was 3.85±0.90 mm and 5.50±1.93 mm, respectively (Mann-Whitney test, p = 0.039). Spermine seems to play important roles in inhibiting age-associated and polyamine-deficient induced abnormal gene methylation as well as pathological changes including tumorigenesis.

Oil for the cancer engine: The cross-talk between oncogenic signaling and polyamine metabolism, 2018

The study of metabolism has provided remarkable information about the biological basis and therapeutic weaknesses of cancer cells. Classic biochemistry established the importance of metabolic alterations in tumor biology and revealed the importance of various metabolite families to the tumorigenic process. We have evidence of the central role of polyamines, small polycatonic metabolites, in cell proliferation and cancer growth from these studies. However, how cancer cells activate this metabolic pathway and the molecular cues behind the oncogenic action of polyamines has remained largely obscure. In contrast to the view of metabolites as fuel (anabolic intermediates) for cancer cells, polyamines are better defined as the oil that lubricates the cancer engine because they affect the activity of biological processes. Modern research has brought back to the limelight this metabolic pathway, providing a strong link between genetic, metabolic, and signaling events in cancer. In this review, we enumerate and discuss current views of the regulation and activity of polyamine metabolism in tumor cell biology.

Elevated contents of spermidine and spermine in the erythrocytes of cancer patients

Red blood cells (RBC) from 69 patients with advanced cancer and 37 healthy controls were subjected to polyamine determination by using high-performance liquid chromatography. The polyamine contents in normal human RBC were spermidine 15.04 +/- 3.63 nmol and spermine 8.82 +/- 3.12 nmol per 10(10) RBC. Spermidine and spermine levels in RBC were elevated in patients with cancer (p less than 0.005). Serial studies in seven patients with cancer indicated that both polyamines in RBC were reduced after successful surgery. Our data indicate that the determination of polyamine levels in RBC is clinically useful as a marker of disease activity in patients with cancer.

Spermidine/spermine N(1)-acetyltransferase activity associates with white blood cell count in myeloid leukemias, 2014

The metabolism of polyamines, the cationic small molecules essential for cell proliferation and differentiation, is altered in cancer cells and can be exploited in cancer diagnosis and therapy. Spermidine/spermine N(1)-acetyltransferase (SSAT), which regulates intracellular levels of polyamines by catabolizing spermidine and spermine, has a controversial role in the development of cancers. In this study, the polyamine metabolism and function of SSAT were characterized in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoid leukemia patient samples. Also, mice overexpressing SSAT and having a myeloproliferative phenotype were analyzed for their response to decitabine and histone deacetylase inhibitor trichostatin A. The presence of epigenetic factors in the bone marrow cells of SSAT mice was analyzed. Elevated levels of spermidine and spermine, as well as increased activity of SSAT, were detected in AML, CML, and acute lymphoid leukemia patients compared with the controls. However, we found SSAT activity to be associated with white blood cell count only in AML and CML patients. Decitabine treatment brought the peripheral blood and bone marrow cell counts of SSAT mice to the level of wild-type mice. Spermidine/spermine N(1)-acetyltransferase mice had increased histone methylation and an increased level of histone deacetylase 1 in their bone marrow cells. The study suggests that SSAT influences the development of myeloid malignancies, and epigenetic factors partly contribute to the SSAT overexpression-induced myeloproliferative disease in mice.

Reply to Gostner and Fuchs (link)

Dear Editor: We appreciate the comments by Gostner and Fuchs. 

Polyamines are essential for cell proliferation and growth and dysregulation of polyamine metabolism is common to various types of cancers ( 1). Invoking the cyto-protective effects of polyamines and their putative immunosuppressive functions, Gostner and Fuchs express concern over the safety of polyamines in the context of tumorigenesis. Interference with inflammatory and immunoregulatory pathways does indeed exert complex effects on tumor growth and dissemination (1). For example, in the recent CANTOS trial, canakinumab targeting the IL-1 β innate immune pathway unexpectedly reduced lung cancer incidence and mortality ( 2). With regards to spermidine, initial research in knockout and transgenic mice suggested that amplification of polyamine synthesis promotes carcinogenesis ( 3); however, in our own study, high dietary spermidine intake did not increase the frequency of spontaneous tumors in aging wild-type mice ( 4). Restoration of autophagy afforded by spermidine has clear tumor-suppressive effects ( 1) and spermidine supplementation in mice has recently been demonstrated to enhance anticancer immunosurveillance ( 5). Actually, spermidine supplementation reduced the incidence of hepatocellular carcinoma induced by chemicals ( 6), slowed the growth of colorectal tumors transplanted into immunocompetent mice ( 7), and counteracted the growth of transplantable tumors in mice treated with chemotherapeutics ( 5). This latter effect is shared by other caloric restriction mimetics that, like spermidine, cause a depletion of regulatory T lymphocytes (Treg cells) from the tumor bed ( 5). One study suggested that polyamines inhibit colon carcinogenesis in mice, but favor tumor growth once a cancer has developed ( 8). Data in humans are sparse. One largescale prospective study yielded preliminary evidence for an inverse association between high dietary polyamine intake and risk of colorectal cancer in overweight women ( 9). We found an inverse association between diet rich in spermidine and fatal cancers (10); however, these findings refer to naturally occurring spermidine in quantities typical for a Western or Mediterranean diet and allow no conclusions on high-dose spermidine supplements or extreme diets. Overall, there is no convincing signal for tumor-promoting effects of moderate doses of spermidine in experimental and epidemiologic studies (but rather the opposite). However, more research is required to reach definite conclusions and caution is warranted in patients with manifest cancer. 

Spermidine (link)

• Increases lifespan in C57BL/6 mice by 10%, improves cardiac function, increases autophagy.[35]

• Polyamine-rich chow extends lifespan in Jc1:ICR mice by 29% and reduces glomerulosclerosis.[36]

• Prevents retinal degeneration in a mouse model of optic nerve injury.[37]

• Extends life by 25% and rescues liver failure in autophagy-deficient mice.[38]

• Reverses age-related arterial stiffness and endothelial dysfunction in C57BL/6 mice.[39]

Cardioprotection and lifespan extension by the natural polyamine spermidine, Nature, 2016 

The late-in-life supplementation experiment (d) 

Spermidine: An Autophagy Inducer Acting As An Anti-Aging Vitamin In Humans? link

Powerful and safe fibrin inhibitor

This is a purchase for an elderly person in order to help with cardiovascular issues. Natto is a blood thinner and has fibrinolitic action. If you don't understand that, please do some research as the AMA considers any natural treatment or cures as no-nos. Suffice to say I gave this to my ailing mother and we were able to successfully avoid Warfarin/Coumadin which is a refined formulary of a rat poison known as strychnine. That's what your doctor will prescribe most of the time to 'help' thin your blood. Natto does the same thing naturally and the blood will still coagulate outside the body, which is something NOBODY can claim for strychnine-based 'medications.'

Nattokinase

• Has potent fibrinolytic activity, antihypertensive, anti-atherosclerotic, and lipid-lowering, antiplatelet, and neuroprotective effects

• Hypothetically, it can help dissolve the fibrin coating around a tumor, and increase oxygen supply in the blood to inhibit cancer cell growth.

• Generally, anti-clotting agents may work against cancer tumor environment and metastatis (E.g. Warfarin. Dipyridamole, etc). 

• It’s dangerous to combine anti-clotting agents with aspirin. 

• But it can be alternated? Because NK dissolves clots. 

• NK is sold as a supplement and its dose can be adjusted to match with one serving of Natto/day (2000FU or 100mg). In this sense, it can viewed as a food item. 

• Reduced BP in one study at 100mg daily dose. 

Effects of Nattokinase on Blood Pressure: A Randomized, Controlled Trial, 2008

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.

A clinical study on the effect of nattokinase on carotid artery atherosclerosis and hyperlipidaemia, 2017

Methods: 82 patients were randomly assigned to one of two groups, NK and Statin (ST) group. NK Group-patients were given NK at a daily dose of 6 000 FU and ST Group-patients were treated with statin (simvastatin 20 mg) daily. The treatment course was 26 weeks. CCA-IMT, carotid plaque size and blood lipid profile of the patients were measured before and after treatment.

Results: A total of 82 patients were enrolled in the study and 76 patients (NK 39, ST 37) completed the study. Following the treatments for 26 weeks, there was a significant reduction in CCA-IMT and carotid plaque size in both groups compared with the baseline before treatment. The carotid plaque size and CCA-IMT reduced from(0.25±0.12)cm(2) to (0.16±0.10)cm(2) and from (1.13±0.12)mm to (1.01±0.11)mm, respectively. The reduction in the NK group was significantly profound (P<0.01, 36.6% reduction in plaque size in NK group versus 11.5% change in ST group). Both treatments reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG). 

Conclusions: Our findings from this pioneer clinical study suggests that daily NK supplementation is an effective way to manage the progression of atherosclerosis and potentially may be a better alternative to statins. The mechanism underlying the reduction of carotid atherosclerosis by NK may be independent from its lipid-lowering effect, which is different from that of statins.

Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases, 2018 

Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease, 2017

Nattokinase Dr's best

• It's working. Reviewed in the United States on November 13, 2016. Size: 270 Count (Pack of 1)

My husband has a Rare blood cancer (polycythemia vera) that makes his blood too thick. The Dr. was taking a pint of blood every 2 weeks plus he was taking aspirin each day hoping his body would finally get the message that it didn't need to make so much, this wasn't helping. The only other option was blood thinners which we refuse to start. I did my research and found what has helped other people and prayed it would help my husband.

I started him on:

NOW Foods Ginkgo Biloba 120mg, 1 per day

BLUE ICE Fermented Cod Liver Oil, 2 per day

Life Extension Natural Vitamin E, 1 per day

Doctor's Best Nattokinase, 2 in the morning on empty stomach and 2 before supper on empty stomach

It has been been 6 weeks and the Dr. hasn't had to draw off any blood. We will continue with this treatment.

UPDATE: My husband saw the Dr. yesterday and is still doing fine.

• Whiter teeth???

It dissolved most the plaque off my teeth. I'm assuming that's a positive side effect.

• Beware this can kill. Size: 90 Count (Pack of 1)Verified Purchase

Please please be careful taking this. I had stroke two weeks after taking this for fibroids and ended up in the icu. The only thing I have taking is serrapeptase and natokkinase. I am 36 years and no medical history

Nattokinase has been promoted as an alternative anticancer treatment based on the notion that it can help dissolve the fibrin coating around a tumor, and increase oxygen supply in the blood to inhibit cancer cell growth, link

Nattokinase Crude Extract Inhibits Hepatocellular Carcinoma Growth in Mice, link

Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases, link

Consumption of nattokinase is associated with a reduced blood pressure, link

One case study exists in a patient with cerebral microbleeds (stroke survivor) using daily Aspirin who also used 400mg nattokinase daily for a week. The patient experienced cerebellar hemorrhage attributed to the combination of two anti-clotting agents.[39]

In one case study, pairing nattokinase with an anticoagulant was possibly related to the occurrence of a stroke (which is normally the reason why pairing blood thinning agents is widely warned against).

Japan NattoKinase Association What is Nattokinase? link

About intake of Nattokinase

The recommended amount of Nattokinase is more than 2,000FU/ day.

The Nattokinase activity level in natto commercially available varies from 1,400 FU/ pack (50g) to 2,000FU/ pack (100mg) as Figure 7 shows. The enzymatic activity of Nattokinase is indicated by FU which stands for Fibrin Degradation Unit. Fibrin degradation method (using FU) is used to indicate a Nattokinase activity level as it is reproducible and accurate to quantify. (Figure 8) It is considered best to take Nattokinase after dinner or before sleep since thrombus is more likely to be produced around the mid night to the early morning. It is recommended to take Nattokinase on a regular basis for those who are over 40 years old, stressed-out, have relatively high blood pressure, and have high blood viscosity due to hyperlipidemia or diabetes.

High D-dimer levels are associated with poor prognosis in cancer patients, link

Warfarin may prevent cancer, link

Anticoagulation Strategies in Cancer Patients - American College of Cardiology, link

Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial (link)

79 subjects were enrolled upon screening for elevated blood pressure (BP; systolic BP ≥130 or diastolic BP ≥90 mmHg) who consumed placebo or 100 mg nattokinase/d for the 8-week study duration. 

Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases

Cardiovascular disease (CVD) is the leading cause of death in the world and our approach to the control and management of CVD mortality is limited. Nattokinase (NK), the most active ingredient of natto, possesses a variety of favourable cardiovascular effects and the consumption of Natto has been linked to a reduction in CVD mortality. Recent research has demonstrated that NK has potent fibrinolytic activity, antihypertensive, anti-atherosclerotic, and lipid-lowering, antiplatelet, and neuroprotective effects. This review covers the major pharmacologic effects of NK with a focus on its clinical relevance to CVD. It outlines the advantages of NK and the outstanding issues pertaining to NK pharmacokinetics. Available evidence suggests that NK is a unique natural compound that possesses several key cardiovascular beneficial effects for patients with CVD and is therefore an ideal drug candidate for the prevention and treatment of CVD. Nattokinase is a promising alternative in the management of CVD.

Nattokinase: Health Benefits, Safety Information, Dosage, and More, link

Selfhacked NK, link

Oral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation, 2010

Background: A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.

Objectives: To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.

Main results: Of 8187 identified citations, five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The quality of evidence was moderate for all outcomes. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.94; 95% CI 0.8 to 1.03) at two years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (P = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74).

Authors' conclusions: Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while increasing the risk for bleeding.

Anticoagulants and cancer mortality in the Finnish randomized study of screening for prostate cancer, link

Our study does not support reduced cancer mortality among anticoagulant users. Future studies on drug use and cancer mortality should be adjusted for anticoagulants as they are associated with significantly higher risk of cancer death.

Effects of long-term treatment with warfarin on fibrinogen, FPA, TAT, and D-dimer in patients with coronary artery disease, link

Link 1, Link 2, Link 3, Link 4, Link 5

The recommended amount of Nattokinase is more than 2,000FU/ day.

The Nattokinase activity level in natto commercially available varies from 1,400 FU/ pack (50g) to 2,000FU/ pack as Figure 7 shows. The enzymatic activity of Nattokinase is indicated by FU which stands for Fibrin Degradation Unit. (link)

Effects of nattokinase, a pro-fibrinolytic enzyme, on red blood cell aggregation and whole blood viscosity, 2006

The vegetable cheese-like food, natto, is extremely popular in Japan with a history extending back over 1000 years. A fibrinolytic enzyme, termed nattokinase, can be extracted from natto; the enzyme is a subtilisin-like serine protease composed of 275 amino acid residues and has a molecular weight of 27.7 kDa. In vitro and in vivo studies have consistently demonstrated the potent pro-fibrinolytic effect of the enzyme. However, no studies to date have evaluated the effects of nattokinase on various hemorheological parameters and thus we have begun to assess the effects of the enzyme on RBC aggregation and blood viscosity. Blood samples were incubated with nattokinase (final activities of 0, 15.6, 31.3, 62.5 and 125 units/ml) for 30 minutes at 37 degrees C. RBC aggregation was measured using a Myrenne MA-1 aggregometer and blood viscosity assessed over 1-1000 s(-1) with a computer controlled scanning capillary rheometer (Rheolog). Our in vitro results showed a significant, dose-dependent decrease of RBC aggregation and low-shear viscosity, with these beneficial effects evident at concentrations similar to those achieved in previous in vivo animal trials. Our preliminary data thus indicate positive in vitro hemorheological effects of nattokinase, and suggest its potential value as a therapeutic agent and the need for additional studies and clinical trials.

A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles, 2015

A Randomized Study Assessing the Effect of Nattokinase-Meriva Formula on Low Grade Inflammation and Blood Viscosity in Adults with Increased Visceral Adiposity, 2021

Background: Chronic systemic inflammation in obesity spurs from local immune responses generated from visceral adipose body compartment and this entails a wide range of inflammation-mediating cytokines and adipometrics plasticity. On the other hand, while obesity is a leading risk factor for type 2 diabetes, its prevalence is significantly in the elderly. As a matter of fact, it has been shown that the age-associated increase in adipose tissue inflammation represents a different entity from what observed in obesity. In both contexts, a silent low-grade inflammation of adipose tissue (AT), mainly visceral AT (VAT) in which M1 are the main contributors, is a common pathophysiological feature behind insulin resistance and type 2 diabetes (T2D).

Aim of the study: The aim of this study was to characterize the profile of a broad range of pro-inflammatory cytokines, their related gene expression and blood viscosity in individuals with general mild-moderate overweight and in non-obese subjects with increased VAT.

Study design: This was a cross-sectional investigational research including 66 mildly overweight patients (body mass index (BMI) ≤ 29) and also 31 non-overweight subjects (BMI ≤ 22) with impending metabolic syndrome, classified as normal-weight obese (NWO). Subjects were supplemented with 1cp two times a day of J2622/G (Modulase, Named ltd, Italy), a mixture of nattokinase, high-absorption curcumin (Meriva), Bromelin, papain, and mirrha.

Results: As compared to healthy control, overweight status was associated with significantly elevated levels of IL- 6, TNF-α, IL-1β, MCP-1, IL-4, IL13, IL-8 and hsCRP (p<0.05). Treatment with J2622/G enabled a significant decreased of all the above inflammatory markers (p<0.01) whereas it did not affect the values of those markers which were within normal limits at baseline. Cytokines significantly correlated with adipometrics, irrespective of the mildly overweight or NWO subgroups. Gene expressions related to those abnormal cytokines were found to be significantly up regulated (p<0.05) and were reverted to healthy control gene expression levels at the end of the treatment period (p<0.05). There was no correlation between blood viscosity and antrometrics, nor the former were different from healthy control. However, the treatment with J2622/G already after 1 months treatment yielded a statistically significant decrease of blood viscosity (p<0.05). Adiponectin was found to be decreased only in the 25-29 BMI cohort and this was increased at the end of nutraceutical treatment (p<0.05).

Conclusion: We confirmed that either mild over-weight and NWO subjects harbor a relentless low-grade inflammation which may pave the way to silent progression of cardiovascular and metabolic diseases. A nattokinasemeriva formulation proved to yield a therapeutic and likely preventative efficacy for its robust anti-inflammatory and microcirculatory properties.

Nattokinase atherothrombotic prevention study: A randomized controlled trial

Article type: Research Article, 2021

Abstract: BACKGROUND:Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. OBJECTIVE:To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. METHODS:In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers. RESULTS:After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. CONCLUSIONS:Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Proteolytic enzymes (nattokinase, serrapeptase, lumbrokinase, and bromelain) 

The potential role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications, 2022

Clots are normally removed by plasmin, a serine protease, but some clots (such as fibrin amyloid microclots) contain antiplasmin compounds [88]; the plasma of acute COVID patients also contains anti-thrombolytic compounds [913–915], despite raised levels of tissue plasminogen activator (tPA) [915]. However, a variety of other enzymes have thrombolytic activity [916–919]. Considered less potent and safer than post-stroke ‘clotbusters’ such as tPA [920], nattokinase is a fibrinolytic [921–923] (and amyloid-degrading [924]), orally available despite having to pass through the gut wall [925–931], safe [932,933], serine protease enzyme from Bacillus subtilis (an organism which may itself be of value [934]). It is found naturally in the Japanese fermented food nattō [751,928,935–939], (which is also a source of vitamin K, and has antiviral properties directly [940]). Its structure is known [941,942], and it may also be produced recombinantly [943–950]. It also has antiplatelet [951], anti-inflammatory [952], and anti-hypertensive [953] properties, and along with pycnogenol [954] was active in preventing DVT on longhaul flights [955]. Serrapeptase (serratiopeptidase) [934,956–959] has a similar activity (as well as others such as mucolytic behaviour [958]) and comes from a Serratia marcescens strain that originates in the guts of silkworms, where it has a natural role in helping the worms emerge from their cocoons. Lumbrokinases are another orally active [960] set of fibrinolytic enzymes that have been found in earthworms [961–965], and may also be produced recombinantly [966,967]; they may also have some tPA activity [965]. Each has been proposed as of value in acute and/or Long COVID treatment [751,958,968]. With two (positive) exceptions [968,969], and another planned [970], randomised controlled trials are awaited. In the plant kingdom, bromelain (from pineapples) is a cysteine protease found in pineapple tissue [971–974]. Multiple effects imply its utility in preventing or treating SARS-CoV-2 infection and acute COVID-19 [975–978]. Given the significance of fibrin amyloid microclots; however, it would seem of value (i) to stress the importance of quality control in nutraceutical production and (ii) to assess the comparative activities of these enzymes in removing fibrin amyloid microclots in vitro.

Oral therapy with proteolytic enzymes decreases excessive TGF-beta levels in human blood, 2001

Therapy with oral proteolytic enzymes (OET) with combination drug products containing papain, bromelain, trypsin, and chymotrypsin has been shown to be beneficial in clinical settings such as radiotherapy-induced fibrosis, bleomycin pneumotoxicity and immunosuppression in cancer, all of which are nowadays known to be accompanied by excessive transforming growth factor-beta (TGF-beta) production. It has been demonstrated that proteolytic enzymes reduce TGF-beta levels in serum by converting the protease inhibitor alpha2 macroglobulin (alpha2M) from the "slow" form into the "fast" form, whereby the "fast" form binds and inactivates TGF-beta irreversibly. In this study we have investigated the effect of OET on the concentration of TGF-beta1 in serum of patients with rheumatoid arthritis (RA) (n = 38), osteomyelofibrosis (OMF) (n = 7) and herpes zoster (HZ) (n = 7). Seventy-eight healthy volunteers served as controls. TGF-beta1 levels in serum were assessed by enzyme-linked immunosorbent assay (ELISA). We have demonstrated that in healthy volunteers and in patients there exists a correlation between active and latent TGF-beta1 in serum (r=0.8021; P<0.0001). Treatment with OET had no significant effect on TGF-beta1 concentration in healthy volunteers or patients with a normal level of TGF-beta1. In patients with elevated TGF-beta1 concentration (> 50 ng/ml serum), OET reduced TGF-beta1 in RA (P < 0.005), in OMF (P < 0.05) and in HZ (P < 0.05).

Conclusion: These results support the concept that OET is beneficial in diseases characterized in part by TGF-beta1 overproduction.

Oral enzymes as additive cancer therapy, 2001

Oral therapy with proteolytic enzymes (OTPE) (papain, bromelain, trypsin, chymotrypsin amylase and lipase) has been used in additive cancer therapy for several years and has led to a reduction in adverse effects after cancer treatment (radiation and chemotherapy). OTPE has been proven to have a beneficial effect, especially in cancers and other conditions involving elevated transforming growth factor-β (TGF-β) expression. Proteases such as trypsin, chymotrypsin, bromelain and papain have been demonstrated to be capable of converting the slow form of α2-macroglobulin into the fast form. This form of α2-macroglobulin is capable of irreversibly binding TGF-β. Subsequently the TGF-β-α2-macroglobulin complex can be quickly removed via endocytosis. Since the production of TGF-β is regulated by an autocrine loop, removal of TGF-β results in down-regulation of TGF-β overproduction. It has been proposed that OTPE may act through this interruption of the autocrine loop. In vitro reduction in TGF-β overexpression in tumor-associated macrophages leads to enhanced tumor killing capacity as well as to stimulation of natural killer cell and granulocyte cytotoxicity. In clinical trials with patients suffering from polycythemia vera or myelofibrosis, treatment with proteolytic enzymes has been shown to reduce elevated serum concentrations of TGF-β. These findings suggest that through reduction of TGF-β overproduction, OTPE could be beneficial in the inhibition of fibrosis and in additive tumor therapy.

Serrapeptase and nattokinase intervention for relieving Alzheimer's disease pathophysiology in rat model

Serrapeptase (SP) and nattokinase (NK) are proteolytic enzymes belonging to serine proteases. Oral administration of SP or NK in a rat model of AD daily for 45 days resulted in a significant decrease in brain AchE activity, TGF-β, Fas and IL-6 levels. 

Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats, 2002

Donald Poe My naturopath recommended trying proteolytic enzymes based on his experience treating a patient with pretty severe pulmonary fibrosis. He took them every waking hour of the day for 30 days. He went back to the pulmonologist who said he must have been misdiagnosed, breathing was resolved as well. These enzymes have been used to dissolve fibrin and blood clots. Pretty well documented. I also read about it being used for osteomyelofibrosis. I don’t have the link. It reduces TGF beta which is associated with fibrosis and inflammation.

Proteolytic enzymes (link)

Proteolytic enzyme (PE) treatments were first popularized in Germany in the 1960s for inflammation, osteoarthritis, autoimmune diseases, and viral infections. The products usually contain a mixture of pancreatin, papain, bromelain, trypsin, and chymotrypsin. Preclinical studies indicate that PEs have immunomodulatory and tumoricidal properties (1) (2) (3) (4) (5) (6). Such effects are thought to result from degradation of abnormal immune complexes.

In clinical studies, oral administration of PEs to healthy volunteers resulted in immunomodulatory effects (7). Systemic therapy with PE before and after exhaustive exercise increased maximal concentric strength and had favorable effects on inflammatory, metabolic, and immune biomarkers (18). In a randomized trial of subjects with moderate-to-severe knee osteoarthritis, oral PE had effectiveness comparable to diclofenac in relieving pain and increasing function (19).

Although some clinical and epidemiological studies suggest benefit with adjuvant PEs in patients with head and neck cancers (8), multiple myeloma (9), breast cancer (10), and cervical cancer (11), conflicting data do not support the findings (12). A randomized controlled trial also failed to find sufficient evidence to support use of PEs for preventing mucositis (13). Further, results from a study involving patients with inoperable pancreatic cancer showed a decrease in overall survival and poorer quality of life with PEs compared with standard gemcitabine-based chemotherapy (14).

Findings from two meta-analyses suggest that PEs may be useful for preventing acute radiation-induced skin reactions (20), but more studies are needed to confirm such effects.

8. Gujral MS, Patnaik PM, Kaul R, et al. Efficacy of hydrolytic enzymes in preventing radiation therapy-induced side effects in patients with head and neck cancers. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S23-28.

9. Sakalova A, Bock PR, Dedik L, et al. Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S38-44.

10. Beuth J, Ost B, Pakdaman A, et al. Impact of complementary oral enzyme application on the postoperative treatment results of breast cancer patients—results of an epidemiological multicentre retrolective cohort study. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S45-54.

11. Dale PS, Tamhankar CP, George D, et al. Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: evidence of the reduction of acute side effects. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S29-34.

12. Martin T, Uhder K, Kurek R, et al. Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic irradiation? Results of a double-blind randomized trial. Radiother Oncol. Oct 2002;65(1):17-22.

13. Dorr W, Herrmann T, Study G. Efficacy of Wobe-Mugos E for reduction of oral mucositis after radiotherapy : results of a prospective, randomized, placebo-controlled, triple-blind phase III multicenter study. Strahlenther Onkol. Mar 2007;183(3):121-127.

14. Chabot JA, Tsai WY, Fine RL, et al. Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol. Apr 20 2010;28(12):2058-2063.