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VeinHealth Pro™

The case for a cost effective and safer alternative for Deep Vein Thrombosis

Approximately 60,000-100,000 Americans die each year of deep vein thrombosis (DVT, also called venous thromboembolism). Blood clots form in the deep veins of the legs, then travel through the bloodstream to the lungs, where they can cause sudden death by pulmonary embolism (PE, i.e. a blockage of the pulmonary artery). About 10-30% of patients with DVT die within one month of diagnosis and sudden death is the first symptom in about 25% of people who have PE. In people who have had DVT, approximately 50% will have long- term complications such as swelling, pain, discoloration, and scaling in the affected limb. One-third of people with DVT will have another recurrence within 10 years35.

Older patients are at the greatest risk for suffering from blood clots; in patients above the age of 80, the incidence of DVT is 1/100. In addition, those who travel on long plane rides in cramped seats, women on birth control drugs, people who have undergone major surgery, obese patients, people that use hormone therapy, and diabetics are all at a higher risk for DVT. For instance, in patients with hip replacement surgery, the historical incidence of DVT in patients not receiving prophylaxis is as high as 69%. This decreases dramatically with various prophylactic measures36,37. Approximately 5-8% of the U.S. population has one or more genetic risk factors, also known as inherited thrombophilias, that increase the risk for thrombosis.

Current treatment for DVT/PE

Anti-coagulants are often used to treat DVT. These medications are commonly called blood thinners or anti-platelets, and they reduce blood clots by inhibiting platelet activity. Patients are typically given a shot or infusion of the blood thinner heparin for a few days. After heparin injections, many possible treatment protocols may be used. Treatments can include injectable blood thinners, such as enoxaparin (Lovenox), dalteparin (Fragmin) or fondaparinux (Arixtra). Some blood thinners are given in pill form, such as warfarin (Coumadin, Jantoven), or rivaroxaban (Xarelto). Anti-platelet medications are often used as well, including clopidogrel (Plavix) and ticagrelor (Brilinta). Unfortunately, most of these medications have side effects, such as excessive bleeding, a burning sensation when injected with heparin, hair loss, and jaundice. They also require regular blood tests and monitoring, adding to healthcare costs.

Research by Bonutti Technologies

Our group compared standard treatments with a less expensive treatment using aspirin and fish oil. In our clinic, we observed results from 200 postoperative patients treated with the blood thinners Xarelto or Lovenox, and compared them to 200 postoperative patients receiving a combination treatment of aspirin (325 mg, two times daily) and fish oil (1000 mg, once a day) for four weeks. Patients on the combination treatment also used pulsatile stockings for 24 hours after surgery, which squeeze the veins of the leg, pushing the blood upwards. Both groups included patients that had 160 knee operations and 40 hip operations. Patients were excluded if they had prior history of DVT or PE. Patients were followed for 90 days postoperatively to assess their risk for DVT.

There was no incidence of DVT in patients treated with a combination of fish oil and aspirin. Only one patient experienced bleeding, which necessitated discontinuation of fish oil. There were no surgical or other medical complications in either group. Groups with patients taking the blood thinners Xarelto or Lovenox had eight hematomas (blood pooling), one of which required reoperation.

Why Our Findings are Important?

Though this is not a randomized study, we found that an over-the-counter combination of aspirin and fish oil, with thelimited use of pulsatile stockings, showed potential as a viable alternative to the costly and potentially risky anti-coagulation protocols. Our research indicated that further evaluation of our product as a DVT prophylaxis in patients is merited.

New Directions for This Research

With the help of AOR, we have formulated a novel nutraceutical product called VeinHealth Pro™. VeinHealth Pro™ is a combination of eicosapentaenoic acid (EPA, an omega-3 fatty acid found in fish oil), white willow bark extract(a precursor to aspirin), billbery extract, and vitamin E.

Research has shown that EPA and willow bark affect both platelets and the internal clotting cascade to effectively protect against adverse venous events38. This could potentially reduce health care costs by offering a cost effective alternative to the expensive drugs that are now used to treat DVT, with the additional benefit of reduced complications due to the diminished risk of bleeding. A rigorous clinical trial would help identify factors related to optimal use of VeinHealth Pro™, so we can improve outcomes for a greater population of people who are at risk for DVT.

“With the help of AOR, we have formulated a novel nutraceutical product called VeinHealth Pro™. VeinHealth Pro™ is a combination of eicosapentaenoic acid (EPA, an omega-3 fatty acid found in fish oil), white willow bark extract (a precursor to aspirin), billbery extract, and vitamin E.” 

Key Terms

Deep Vein Thrombosis (DVT)

DVT, or venous thromboembolism, is a blood clot that forms in a deep vein, usually in the leg. The symptoms of DVT include pain, heavy ache, warm skin, swelling and/or tenderness in the leg (usually in the calf or the back of the leg below the knee). If left untreated, DVT may lead to a pulmonary embolism.

Pulmonary Embolism (PE)

A PE is a blockage (usually a blood clot) in the pulmonary artery—the main vessel that carries blood from the heart to the lungs, and is a potentially life-threatening condition. The main symptoms can include breathlessness, chest pain,and sudden death.

Anti-coagulants

Anti-coagulants, or blood thinners, are medications that help to prevent blood clots. They can be administered in injectable form, such as enoxaparin (Lovenox), dalteparin (Fragmin) or fondaparinux (Arixtra), or in pill form, such as warfarin (Coumadin, Jantoven) or rivaroxaban (Xarelto).

VeinHealth Pro™

Research by Bonutti Technologies has found that the combination of aspirin and fish oil, with the limited use of pulsatile stockings, showed potential as a viable alternative to costly and potentially risky anti-coagulation protocols. Along with research that shows that eicosapentaenoic acid (EPA, an omega-3 fatty acid found in fish oil) and white willow bark extract (a precursor to aspirin) protect against adverse venous events. This work has resulted in the development of a novel nutraceutical called VeinHealth Pro™ which is a combination of EPA, white willow bark extract, billbery extract, and vitamin E.

Dr. Christopher Hillyar

Simply put, early human studies on vitamins produced conflicting results. Although intravenous Vitamin-C was found to produce anti-cancer effects, oral Vitamin-C did not provide anti-cancer benefits. Recent cellular, animal, and human studies have shown that intravenous Vitamin-C may provide anti-cancer benefits or

reduce cancer-related symptoms for certain types of cancer. However, other studies have shown that Vitamin-C may reduce anti-cancer effects, and cause side-effects in combination with certain anti-cancer agents. Vitamin-C (or ascorbic acid) is an essential nutrient, meaning it cannot be made in the human body. In some types of plants and animals, Vitamin-C is synthesized from D-glucose or D-galactose.

Interestingly, humans lack the enzyme L-gulonolactone oxidase, which is required for Vitamin-C synthesis; thus, we require Vitamin-C for the correct synthesis of collagen39, an important structural protein found in skin and connective tissue. Vitamin-C deficiency can cause scurvy, a disease characterized by spontaneous bruising and bleeding due to abnormal collagen structure. Vitamin-C also plays a role in oxidation-reduction (redox) reactions which can generate hydrogen peroxide (H2O2), a substance capable of killing cancer cells. Due to this property, Vitamin-C has been studied as a treatment for cancer since the 1970s. This article highlights the potential uses of Vitamin-C for the treatment of cancer.

Early Human Studies

The first human study of intravenously administered Vitamin-C for the treatment of cancer was conducted by

Ewan Cameron and Allen Campbell in the 1970s40. This led to two early studies of 100 terminal cancer patients, that showed that intravenous Vitamin-C (10 g/day) increased survival by 210-300 days40,41. However, two subsequent human studies conducted in the 1970s and 1980s were unable to show that orally administered Vitamin-C provided the same therapeutic benefit to advanced cancer patients42,43. As a result of these studies, the therapeutic effect of Vitamin-C has largely been abandoned by the field of conventional oncology.

Pharmacokinetic studies (i.e. studies aimed at determining the rate of absorption, distribution, metabolism, and excretion of Vitamin-C in the human body) revealed that the maximum concentration of Vitamin-C in the blood was 100-fold greater when Vitamin-C was administered intravenously (20 mM) compared to orally (0.3 mM)44,45.

Recent Cellular Studies

Despite the setbacks of the early human studies, recent cellular studies of cancer cells grown in a petri dish showed that a wide range of doses (100 µM to 100 mM) of Vitamin-C reduced or inhibited the growth of various types of cancer cells, including:

  • Prostate46
  • Pancreatic47,48
  • Liver49
  • Colon50
  • Mesothelioma51
  • Neuroblastoma51

The mechanism of toxicity of Vitamin-C towards cancer cells (cytotoxicity) may involve the redox (reduction-oxidation) function of Vitamin-C. Vitamin-C participates in redox reactions by transferring electrons between other molecules. It also undergoes auto-oxidation (self-oxidation), a process that produces vast quantities of hydrogen peroxide (H2O2). H2O2 is a highly cytotoxic substance to cancer cells. Thus, the production of H2O2 through the redox function of Vitamin-C may contribute to its anti-cancer effects52.

Cellular studies have also shown that Vitamin-C may improve or enhance the anti-cancer effects of other anti-cancer agents used to treat certain types of cancer, including:

  • Arsenic trioxide on ovarian cancer cells53
  • Gemcitabine (a chemotherapeutic agent) on pancreatic cancer cells48
  • Gemcitabine/epigallocatechin-3-gallate combination therapy on mesothelioma cells54

Radiation therapy on glioblastoma multiforme cells55

Unfortunately, other cellular studies have produced conflicting results. The oxidized form of Vitamin-C (dehydroascorbic acid) was found to reduce the anti-cancer effects of some chemotherapeutic agents for the treatment of leukemia and lymphoma cells56, including:

  • Doxorubicin
    • Methotrexate
    • Cisplatin

Recent Animal Studies

Encouraged by results from cellular studies, scientists transferred human cancer cells into animals to test the effects of Vitamin-C on ‘animal models’ of cancer. Animal studies have shown that Vitamin-C reduced the growth of a variety of types of animal models of solid tumours, including:

  • Pancreatic cancer 47,48,57
    • Liver cancer58
    • Prostate cancer59
    • Sarcoma60
    • Mesothelioma51
    • Ovarian cancer61

Vitamin-C has also been shown to enhance the anti-cancer effects of other anti-cancer agents used to treat certain types of animal models of cancer, including:

  • Gemcitabine for the treatment of a mouse model of pancreatic cancer48
    • Carboplatin and paclitaxel for the treatment of a mouse model of ovarian cancer62

However, an animal study has shown that Vitamin-C reduced the anti-cancer effects of bortezomib (a ‘small molecule’ class of anti-cancer drug) for the treatment of a mouse model of multiple myeloma63. Another animal study has found that the oxidized form of Vitamin-C (dehydroascorbic acid) reduced the anti-cancer effects of doxorubicin for the treatment of mouse models of lymphoma56.

Together, the cellular and animal studies suggest that Vitamin-C may produce anti-cancer effects against some types of cancer cells and animal models of cancer, including prostate, pancreatic, liver, colon, sarcoma, mesotheioloma, ovarian, and neuroblastoma. In combination with certain

types of anti-cancer agents, Vitamin-C may provide additional therapeutic benefit for the treatment of a variety of types of cancer cells and animal models of cancer, including ovarian, pancreatic, mesothelioma, and glioblastoma multiforme. However, Vitamin-C, or the reduced form of Vitamin-C (dehydroascorbic acid), may interfere with or reduce the anti-cancer effects of certain therapies for the treatment of leukemia, lymphoma, and multiple myeloma.

Recent Human Studies

More recently, two human studies have shown that Vitamin-C reduced cancer-related symptoms and improved quality

of life64,65. Out of 125 patients with stage IIa and IIIb breast cancer enrolled in a study by Vollbracht et al. (2011), 53 were treated with intravenous Vitamin-C (Pascorbin® 7.5 g) in addition to standard cancer therapy (Vitamin-C group),

while 72 patients were treated with standard cancer therapy alone (control group). Vollbracht et al. (2011) showed that the cancer-related symptoms were nearly twice as severe in the control group compared to the Vitamin-C group64.

In a study by Yeom et al. (2007), 39 terminal cancer patients were administered oral Vitamin-C (4 g daily for one week) and intravenous Vitamin-C (10 g twice with three day intervals). Quality of life and cancer-related symptoms were

assessed after Vitamin-C treatment and compared with quality of life before Vitamin-C treatment. Yeom et al. (2007) found that quality of life of terminal cancer patients significantly improved after Vitamin-C treatment. In terms of cancer-related symptoms, patients reported reduced fatigue, nausea/ vomiting, pain, and appetite loss after Vitamin-C treatment65.

A number of human studies have assessed the effects of Vitamin-C in combination with other anti-cancer agents. In a phase I human study which assessed treatment safety by Monti et al. (2012), nine stage IV pancreatic cancer patients completed a course of intravenous Vitamin-C

(three infusions per week) in combination with gemcitabine (a chemotherapteuctic) and erlotinib (a ‘small molecule’

anti-cancer drug). Seven of the nine patients had stable disease and two patients had progressive disease and no adverse side effects were reported. In a phase I human study by Welsh et al. (2013), nine stage IV pancreatic cancer patients were treated with a combination of intravenous Vitamin-C (two infusions per week) with gemcitabine. The average (mean) survival of the patients was 13 months and side effects were rare (diarrhea and dry mouth). Both studies suggested that Vitamin-C treatment was well tolerated, i.e. safe66,67.

In a phase I/IIa human study by Ma et al. (2014), twenty-seven stage III/IV ovarian cancer patients were either administered intravenous Vitamin-C in combination with chemotherapy (carboplatin and paclitaxel) or chemotherapy alone

(control group). Intravenous Vitamin-C in combination with chemotherapy was shown to result in fewer chemotherapy related side-effects in comparison to chemotherapy alone68.

Phase II human studies have shown that the combination of intravenous Vitamin-C (1000 mg) with arsenic trioxide for

treatment of multiple myeloma patients is well-tolerated69,71. There have been conflicting studies that have suggested that a similar combination of intravenous Vitamin-C with arsenic trioxide for treatment of metastatic colorectal cancer72and metastatic melanoma73results in severe side-effects, disease progression, and no anti-cancer benefit. However, due to

the fact that these studies did not compare treatment to placebo, the extent to which Vitamin-C may have contributed to the toxic effects of Vitamin-C/arsenic trioxide combination therapy is unclear.

Together, the human studies suggest that Vitamin-C may reduce cancer-related symptoms for breast cancer patients and improve quality of life for terminal cancer patients.

In combination with certain types of chemotherapeutic agents, i.e. carboplatin and paclitaxel, Vitamin-C may reduce chemotherapy-related side-effects. However, conflicting studies have suggested that Vitamin-C in combination with arsenic trioxide may not be well tolerated.

Discussion

Since the controversial early human studies of the 1970s and 1980s, Vitamin-C has been shown to possess anti- cancer properties from cellular and animal studies of certain types of cancer (prostate, pancreatic, liver, colon, sarcoma, mesothelioma, ovarian, and neuroblastoma), or in combination with certain types of anti-cancer agents (i.e. arsenic trioxide, gemcitabine, carboplatin, paclitaxel or radiation therapy). Conflicting cellular and animal studies have also reported that Vitamin-C may reduce the anti-cancer effects of other types of anti-cancer agents (doxorubicin, methotrexate, cisplatin, and bortezomib) for the treatment of leukemia, lymphoma, and multiple myeloma. Translating the potential anti-cancer properties of Vitamin-C into clear clinical effects in human studies has therefore proved difficult.

Human studies suggest that Vitamin-C may reduce cancer- related symptoms for breast cancer patients and improve quality of life for terminal cancer patients. However, conflicting studies have suggested that Vitamin-C in combination with arsenic trioxide may not be well tolerated and may cause cancer progression. A summary of the potential beneficial and detrimental effects of Vitamin-C from cellular, animal, and human studies is shown in Table 1. Due to conflicting reports, further investigation into the anti-cancer effects of Vitamin-C is warranted.

Whether Vitamin-C can protect against the development of cancer is also controversial. In 1991, an epidemiological study suggested that there was ‘strong’ evidence that people with a higher level of Vitamin-C in their diet may be

protected against the development of certain types of cancer, including esophagus, larynx, oral cavity, pancreas, stomach, rectum, breast, and cervix35. However, in 1999 a human

study comparing the effect of Vitamin-C supplementation on the risk of women developing breast cancer (case- control study), dietary intake of Vitamin-C was only found to slightly protect against the development of breast cancer

in post-menopausal women. This result was not significant when the effect of other dietary anti-oxidants was taken into account. There was no difference in Vitamin-C intake between those post-menopausal women who developed cancer and those who did not, or the study was not large enough to detect a difference74. Other human studies of male volunteers who were supplemented with Vitamin-C (500 mg every other day) for 10 years (between 1997 and 2007) showed that Vitamin-C supplementation did not protect against the development of cancer75,76. The lack of protective effect may have been due to insufficient dosage of Vitamin-C.

The role of Vitamin-C in the treatment and prevention of cancer remains up for debate, with some studies reporting beneficial effects of Vitamin-C and others reporting detrimental effects. Further research is needed, since the evidence suggests that Vitamin-C may provide therapeutic benefit for some cancer patients, but not others. For further information on alternative therapies for cancer treatment, please see:https://www.cancer.gov/about-cancer/treatment/cam

Key Terms

Vitamin-C

Vitamin-C (or ascorbic acid) is an essential nutrient, meaning it cannot be made in the human body. Humans require Vitamin-C for the correct synthesis of collagen39, an important structural protein found in skin and connective tissue.

Cytotoxicity

The mechanism of toxicity of Vitamin-C towards cancer cells, i.e. cytotoxicity may involve the redox (reduction-oxidation) function of Vitamin-C. Vitamin-C participates in redox reactions by transferring electrons between other molecules. It also undergoes auto-oxidation (self-oxidation), a process that produces vast quantities of hydrogen peroxide (H2O2). H2O2 is a highly cytotoxic substance to cancer cells.

Cellular Studies

Cellular studies involve exposing cancer cells grown in a lab to Vitamin-C. Cellular studies have shown that a wide range of doses (100 µM to 100 mM)  of Vitamin-C alone or in combination with certain anti-cancer agents reduced or inhibited the growth of various types of cancer cells; however, conflicting studies have shown that Vitamin-C in combination with other anti-cancer agents reduced their anti-cancer effects.

Animal Studies

Animal studies involve the transfer of human cancer cells into mice to test the effects of Vitamin-C on ‘animal models’ of solid tumours. Animal studies have shown that Vitamin-C alone or in combination with certain anti-cancer agents reduced the growth of a variety of types of animal models of solid tumours; however, conflicting studies have shown that Vitamin-C in combination with other anti-cancer agents reduced their anti-cancer effects.

Human Studies

The first human studies conducted in the 1970s showed that intravenous Vitamin-C increased survival of cancer patients by 210-300 days. However, two subsequent human studies were unable to show that orally administered

Vitamin-C provided the same therapeutic benefit to advanced cancer patients. Recent human studies of the anti-cancer effects of Vitamin-C have produced conflicting results (see table 1).

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