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Modified Citrus Pectin & Galectin-3 The Role of Modified Citrus Pectin and Galectin-3 in the Prevention and Treatment of Metastatic Cancer.

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Presentation on theme: "Modified Citrus Pectin & Galectin-3 The Role of Modified Citrus Pectin and Galectin-3 in the Prevention and Treatment of Metastatic Cancer."— Presentation transcript:

1 Modified Citrus Pectin & Galectin-3 The Role of Modified Citrus Pectin and Galectin-3 in the Prevention and Treatment of Metastatic Cancer

2 Elevated Galectin-3 in the body is directly involved in: – Cancer – Cardiovascular Disease – Chronic Hepatitis – Kidney Disease – Diabetes – Inflammation & Fibrosis – Others Galectin-3 & Disease

3 Overall Average 11.9 Galectin-3 Levels & Mortality from All Causes in the General Population: PREVEND

4 In Cancer, Galectin-3 plays a role in: – Cell to Cell Adhesion – Aggregation of Cancer Cells – Tumor Growth – Metastasis – Angiogenesis – Inhibition of Apoptosis Galectin-3 & Cancer

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11 MCP is derived from the pith of citrus fruit peels Complex polysaccharide fiber of repeating galacturonic acid groups with neutral sugar side chains Unmodified citrus pectin molecular weight 50 to 300 kiloDaltons (kDa) with esterification ~70% Optimal biological activity: molecular weight <13 kDa with esterification <10%, and specific structure What is Modified Citrus Pectin (MCP) ?

12 Binds to Galectin-3 molecules Blocks aggregation of cancer cells Blocks docking of cancer cells Blocks interactions with endothelium necessary for angiogenesis Modified Citrus Pectin is a Galectin-3 Blocker

13 Modified Citrus Pectin Cancer Research

14 Anti-Cancer and Anti-Metastasis Blocking of Galectin-3 Effects Synergistic Effect with Chemotherapy Protection Against Post-Radiation Damage Improved Quality of Life Benefits of MCP in Cancer Treatment

15 Method: MCP’s inhibition of prostate cell adhesion to endothelial cells. 0.1% and 1.0% MCP in rats’ drinking water; controls had plain water Results: Significant reduction in lung metastases -- 50% reduction in 0.1% group; 56% reduction in 1.0% group (P<0.03 & P<0.001). Inhibition of Spontaneous Metastasis in a Rat Prostate Model by Oral Administration of Modified Citrus Pectin Pienta KJ, Naik H, Akhtar A, Yamazaki K, Replogle, TS, Lehr J, Donat TL, Tait L, Hogan V, Raz A Wayne State University School of Medicine, Detroit, MI, USA J Natl Cancer Inst (5):

16 Conclusion: MCP acted as potent inhibitor of spontaneous prostate carcinoma metastasis. Inhibition of Spontaneous Metastasis in a Rat Prostate Model by Oral Administration of Modified Citrus Pectin Pienta KJ, Naik H, Akhtar A, Yamazaki K, Replogle, TS, Lehr J, Donat TL, Tait L, Hogan V, Raz A Wayne State University School of Medicine, Detroit, MI, USA J Natl Cancer Inst (5):

17 Method: MCP’s inhibition of breast & colon cancer progression; MCP’s interaction with Galectin-3 Results: 70.2% Reduction in Breast Tumor Growth – Breast Angiogenesis: 66% Reduction – Breast to Lung Metastasis: 0% MCP v. 100% Control – Colon to Liver Metastasis: 0% MCP v. 60% Control – Colon to Lymph Metastasis: 25% MCP v. 100% Control Inhibition of Human Cancer Cell Growth & Metastasis in Nude Mice by Oral Intake of Modified Citrus Pectin Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, Raz A Wayne State University, School of Medicine, Detroit, MI, USA J Natl Cancer Inst (24):

18 Conclusion: MCP inhibits carbohydrate mediated tumor growth, angiogenesis & metastasis via effects on Galectin-3 function Inhibition of Human Cancer Cell Growth & Metastasis in Nude Mice by Oral Intake of Modified Citrus Pectin Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, Raz A Wayne State University, School of Medicine, Detroit, MI, USA J Natl Cancer Inst (24):

19 Method: Human vascular endothelial cell layer & PC-3 prostate cancer cells. Results: Strong tumor cell death response with MCP, compared to controls. Modified Citrus Pectin Induces Cytotoxicity of Prostate Cancer Cells in Co-Culture with Human Endothelial Monolayers Weiss T, McCulloch M, Eliaz I Amitabha Medical Clinic & Healing Center, Sebastopol, CA, USA EcoNugenics, Santa Rosa, CA, USA Intl Conference on Diet & The Prevention of Cancer 1999, Tampere, Finland.

20 Method: MCP 15 g/day to patients with biochemical relapse post local therapy. PSA Doubling Time (PSADT) evaluated at intervals. Results: MCP significantly increased PSADT in prostate cancer patients. Strum S, Scholz M, McDermed J, McCulloch M, Eliaz, I Prostate Oncology Specialist, Marina del Rey, CA, USA Amitabha Medical Clinic & Healing Center, Sebastopol, CA, USA EcoNugenics, Santa Rosa, CA, USA. International Conference on Diet & The Prevention of Cancer 1999, Tampere, Finland. Effect of Modified Citrus Pectin on PSA Doubling Time in Prostate Cancer Patients: A Pilot Clinical Trial

21 Patient MCP Use (Months) PSADT ChangeStatus Patient % Response Patient % Response Patient 3 380% Response Patient 4>1555% Response Patient 5 66% P. Response Patient 6 6-7% Stable Disease Patient % No Response Pilot Clinical Results: MCP’s Effect on PSA Doubling Time

22 Method: 10 men with biochemical prostate cancer relapse used MCP: 15g daily for 1 year. Modified Citrus Pectin Increases the Prostate-Specific Antigen Doubling Time in Men with Prostate Cancer: A Phase II Pilot Study Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jennrich RI Healing Touch Oncology, Marina del Rey, CA, USA Prostate Cancer & Prostatic Disease 2003;6(4):301-4.

23 Results: MCP significantly increased PSADT in 7 out of the 10 participants (p<0.01). Modified Citrus Pectin Increases the Prostate-Specific Antigen Doubling Time in Men with Prostate Cancer: A Phase II Pilot Study Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jennrich RI Healing Touch Oncology, Marina del Rey, CA, USA Prostate Cancer & Prostatic Disease 2003;6(4):301-4.

24 968 % * * Phase II Study: PSADT Results After 1 Year

25 Using Splines to Detect Changes in PSA Doubling Times Guess B, Jennrich R, Johnson H, Redheffer R, Scholz M, Healing Touch Oncology, Marin del Ray, CA, Department of Statistics, UCLA, CA, The Prostate :88-95.

26 MCP Typical Patient Results

27 Method: MCP 15g daily. Results: 49 patients with advanced solid tumors. 29 evaluated after 2 months -- 21% showed stabilization & improvements in quality of life. – One patient w/ metastasized prostate carcinoma showed 50% decrease in PSA, with significant increase in quality of life & decrease in pain. Clinical Benefit in Patients with Advanced Solid Tumors Treated with Modified Citrus Pectin Azémar M, Hildenbrand B, Haering B, Heim ME, Unger C Albert-Ludwigs-University in Freiburg, Germany Sonnenberg-Klinik, Bad Sooden-Allendorf, Germany Clinical Medicine: Oncology :73–80.

28 Conclusion: MCP shows clinical benefits & improvements in quality of life in advanced cancer patients. Clinical Benefit in Patients with Advanced Solid Tumors Treated with Modified Citrus Pectin Azémar M, Hildenbrand B, Haering B, Heim ME, Unger C Albert-Ludwigs-University in Freiburg, Germany Sonnenberg-Klinik, Bad Sooden-Allendorf, Germany Clinical Medicine: Oncology :73–80.

29 Method: 5 groups of 15 mice. MCP: 0.0%, 1.0%, 2.5% and 5.0%; and negative control. – Colon cancer cells injected into spleen except negative control - - liver metastasis observed after 3 wks. ELISA used to detect Galectin-3. Results: MCP groups: Metastasis 80%, 73.3% & 60%. MCP 0.0%: Metastasis100%. Inhibitory Effect of Modified Citrus Pectin on Liver Metastasis in a Mouse Colon Cancer Model Liu HY, Huang ZL, Yang GH, Lu WQ, Yu NR Guangzhou Medical College, Guangzhou, China World J Gastroenterol (48):

30 Conclusion: MCP significantly reduced liver metastasis. Inhibitory Effect of Modified Citrus Pectin on Liver Metastasis in a Mouse Colon Cancer Model Liu HY, Huang ZL, Yang GH, Lu WQ, Yu NR Guangzhou Medical College, Guangzhou, China World J Gastroenterol (48):

31 Method: 1% MCP treatment of human prostate cancer cell lines (LNCaP & PC3) and mouse prostate cancer cell lines (CASP2-1 & CASP1-1) PectaSol-C Modified Citrus Pectin Induces Apoptosis & Inhibition of Proliferation in Human & Mouse Androgen Dependent & Independent Prostate Cancer Cells Yan J, Katz A Columbia University Medical Center, New York, NY, USA Integrative Cancer Therapies :

32 Results: Confirmed apoptosis and inhibition of cancer cell proliferation 4 day MCP treatment showed cytotoxicity: – 52.28% in LNCaP – 48.16% in PC3 – 23.03% in CASP2-1 – 49.01% in CASP1-1 PectaSol-C Modified Citrus Pectin Induces Apoptosis & Inhibition of Proliferation in Human & Mouse Androgen Dependent & Independent Prostate Cancer Cells Yan J, Katz A Columbia University Medical Center, New York, NY, USA Integrative Cancer Therapies :

33 Method: 48 hour effects of PectaSol on Doxorubicin (Dox) cytotoxicity, apoptosis and cell cycle in prostate cancer cell lines. Combination Effect of PectaSol and Doxorubicin on Viability, Cell Cycle Arrest and Apoptosis in DU-145 and LNCaP Prostate Cancer Cell Lines Najmeh T, Houri S, Parvin M, Firouzeh B, Arash HN, Abdolfattah S, Ebrahim H Tehran University, Tehran, Iran Cell Biology International (2012) doi: /CBI IC 50 Decrease: 1.5 foldIC 50 Decrease: 1.3 fold

34 Conclusion: Lower, less toxic doses Dox needed when combined with PectaSol. Combination Effect of PectaSol and Doxorubicin on Viability, Cell Cycle Arrest and Apoptosis in DU-145 and LNCaP Prostate Cancer Cell Lines Najmeh T, Houri S, Parvin M, Firouzeh B, Arash HN, Abdolfattah S, Ebrahim H Tehran University, Tehran, Iran Cell Biology International (2012) doi: /CBI

35 MCP can enhance therapeutic effect of chemotherapy drugs and treatment of chemo resistant cancers – Cisplatin (Platinol), Bortezomib (Velcade), Dexamethasone (Decadron), Doxorubicin MCP use very important in preventing post chemotherapy & radiation damage – Specifically post radiation induced inflammation and fibrosis MCP During Chemotherapy & Radiation

36 MCP Reduces: – Primary Tumor – Angiogenesis – Metastatic Process MCP Provides: – Blocking of Galectin-3 Effects – Synergistic Effect with Chemotherapy – Protection Against Post-Radiation Damage – Improved Quality of Life Summary: MCP in Cancer Treatment

37 Modified Citrus Pectin Immune Research

38 Modified Citrus Pectin: Induces NK Cell Activation Induces NK Cell Activity Activates T Cytotoxic Cells Increases B Cell Activation MCP Immune System Benefits

39 Method (Part I): Healthy human blood samples incubated with increasing doses of MCP and antibodies. At 24 hours samples lyzed and run on a flow cytometer. Analyzed % of activated T-cytotoxic cell, B-cells, and NK-cells; and % increase over untreated control. Activation of Human T-Cytotoxic Cell, B-Cell, and Natural Killer (NK)-Cells and Induction of NK-Cell Activity Against K562 Chronic Myeloid Leukemia Cells with Modified Citrus Pectin Ramachandran C, Wilk, B, Hotchkiss, A, Eliaz, I & Melnick SJ Dharma Biomedical, Miami, FL, USA, EcoNugenics, Santa Rosa, CA, USA Eastern Regional Research Center, ARS, USDA, Wyndmoor, PA, USA Department of Pathology, Miami Children's Hospital, Miami, FL, USA BMC Complementary and Alternative Medicine 2011, 11:59.

40 ** ** *p < 0.05 ** p < 0.01 Results Part I: MCP Activates T-Cytotoxic Cells

41 ** *** Results Part I: MCP Increases B-Cell Activation

42 ** * * Results Part I: MCP Increases NK Cell Activation

43 Method (Part II): NK cell ability to induce leukemia cell death analyzed by co-incubating MCP-treated lymphocytes with K562 T-cell leukemia cells. Healthy human lymphocyte samples treated with increasing doses of MCP. After 24 hours, K562 labeled. Plates returned to incubator (for 4 hrs) to induce leukemia cell death. MCP: Induction of NK-Cell Activity Against K562 Chronic Myeloid Leukemia Cells

44 Results Part II: MCP Induces NK Cell Activity

45 Modified Citrus Pectin: Chelation & Detoxification Research

46 Forms stacked “egg box” structure Each pocket negatively charged Negative charge binds heavy metals Toxic metal trapped in the “egg box” Safely excreted from the body MCP Heavy Metal Elimination

47 Methods: MCP administered for 6 days. Baseline 24 hr urine collection before MCP, and on days 1 and 6. Days 1 - 5: MCP 15 g/day & Day 6: MCP 20 g/day. The Effect of Modified Citrus Pectin on Urinary Excretion of Toxic Elements Eliaz I, Hotchkiss AT, Fishman ML, Rode D; Amitabha Medical Clinic & Healing Center, Sebastopol, CA, USA; Eastern Regional Research Center, ARS, USDA, Wyndmoor, PA, USA; UC, Davis, CA, USA Phytother Res (10):

48 Results: Urinary excretion of lead, mercury, cadmium & arsenic increased. Essential minerals not changed. No side effects reported. The Effect of Modified Citrus Pectin on Urinary Excretion of Toxic Elements Eliaz I, Hotchkiss AT, Fishman ML, Rode D; Amitabha Medical Clinic & Healing Center, Sebastopol, CA, USA; Eastern Regional Research Center, ARS, USDA, Wyndmoor, PA, USA; Univer. of CA, Davis, CA, USA Phytother Res (10):

49 * # # * # # * *p <.05 #p <.10 The Effect of Modified Citrus Pectin on Urinary Excretion of Toxic Elements

50 MCP Chelation: Increased urinary excretion of toxic metals Demonstrated heavy metal chelation due to reduced molecular size & esterification 10% rhamnogalacturonan II -- known for binding affinity and immune enhancement Does not affect essential minerals No side effects reported MCP & Urinary Excretion of Toxins

51 Eliaz I. Amitabha Medical Clinic & Healing Center, Sebastopol, California, USA. EcoNugenics, Santa Rosa, California, USA. 228 th ACS National Meeting, Philadelphia, PA Methods: Oral intake 5 g Modified Citrus Pectin/3x day for 4-10 months. Base line body burden and change measured with DMPS challenge (250mg i.v. followed by 6 hr. urine collection). Results: All subjects showed significant decrease in Mercury levels. Average decrease was 62.17%, ranging between 38.13% & 74.83% (p=0.0313). No significant side effects were noted. Modified Citrus Pectin Decreases the Total Body Burden: A Pilot Human Clinical trial

52 MCP was effective in decreasing the total body burden of Mercury in all subjects. MCP is a promising systemic gentle chelator of heavy metals that can be used on an on going basis. Percent Reduction in Mercury from Baseline 10 months4.5 months6 months 4 months 6.5 months Study Conclusion MCP Intervention Individual Results

53 The Role of Modified Citrus Pectin as an Effective Chelator of Lead in Children Hospitalized with Toxic Lead Levels Zhao ZY, Liang L, Fan X, Yu Z, Hotchkiss AT, Wilk BJ, Eliaz I Children’s Hospital, Zhejiang University, School of Medicine, Hangzhou, Republic of China Centrax International, Inc, San Francisco, CA, USA Eastern Regional Research Center, ARS, USDA, Wyndmoor, PA, USA EcoNugenics, Santa Rosa, CA, USA Altern Ther Health Med (4):34-8.

54 P Value = Lead in Blood Serum

55 P Value = Lead in 24 Hour Urine Excretion

56 Synergistic Benefits of MCP

57 Integrative blend of 33 ingredients: Vitamins, Minerals, Botanically Enhanced Medicinal Mushrooms, and Botanical Extracts Prostate Poly Botanical Formula

58 ProstaCaid Induces G2/M Cell Cycle Arrest & Apoptosis in Human & Mouse Androgen-Dependent & -Independent Prostate Cancer Cells Effects on long-term cell viability by colony formation Effects on cell viability on androgen- dependent, LNCaP (A) & CASP 2.1 (C), & androgen-independent PC3 (B) & CASP 1.1 (D) Yan J & Katz AE; Department of Urology, Columbia University Medical Center, New York, NY, USA. Integr Cancer Ther :

59 Effect of ProstaCaid on Invasive Behavior of Prostate Cancer Cells AB CD uPA ProstaCaid (  g/ml) uPA Density (A) Cell adhesion. PC-3 cells were treated with ProstaCaid for 24 hours and cell adhesion to fibronectin determined. (B) Cell migration. Cell migration was determined after 24 hours of incubation with ProstaCaid in Boyden Chambers. (C) Cell invasion. Cell invasion was determined after 24 hours of incubation with ProstaCaid in Boyden Chambers coated with Matrigel. (D) uPA secretion. PC-3 cells were treated for 24 hours and the expression of uPA detected in conditioned media with anti-uPA antibody by Western blot. * p<0.05

60 ProstaCaid Inhibits Tumor Growth in a Xenograft Model of Human Prostate Cancer Results: No effect on body weight or activity of liver enzymes (ALT, AST). No sign of toxicity in liver, spleen, kidney, lung and heart Inhibition of tumor volumes (1024.6±378.6 vs ±234.3, P<0.001) qRT-PCR analysis showed significant up regulation of expression of CDKN1A (p21) and inhibition of expression of IGF2, NR2F2 and PLAU (uPA) Conclusion: ProstaCaid has significant anticancer activity in vivo with no signs of toxicity.

61 Prostate Polybotanical Formula

62 Contains botanicals, purified biologically active nutritional compounds and botanically enhanced medicinal mushrooms Breast Polybotanical Formula

63 Suppression of Proliferation & Invasive Behavior of Human Metastatic Breast Cancer Cells by Dietary Supplement BreastDefend Jiang J, Wojnowski R, Jedinak A, Sliva D; Cancer Research Laboratory, Methodist Research Institute, Indianapolis, IN, USA Department of Medicine, Indiana University. Cancer Center, School of Med., Indiana University, Indianapolis, IN, USA. Integr Cancer Ther 2011; Jun 10 (2):192 – 200.

64 Method: Highly aggressive triple negative human breast cancer cells (MDA-MB-231) implanted into the mammary gland in mice then given the formula orally (100 mg/kg of body weight) for four weeks. Results: The formula significantly decreased tumor growth and breast to lung metastasis, and did not affect body weight or activity of liver enzymes or show any sign of toxicity in liver spleen, kidney, lung and heart tissues in mice. – The cancer metastasized to the lungs in 67% of controls but only 20 percent of treated mice. The number of metastases per animal was also significantly affected by the formula. – Down-regulation of primary tumor genes PLAU (urokinase plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor- 4). BreastDefend Suppresses MDA-MB-231 Growth and Breast-to-Lung Metastasis in a Orthotopic Tumor Model Jiang J, Thyagarajan-Sahu A, Loganathan J, Eliaz I, Terry C, Sandusky GE, Sliva D. Oncol Rep. 2012; 28:

65 Breast Polybotanical Formula

66 Synergistic and Additive Effects of Modified Citrus Pectin with Two Novel Polybotanical Compounds, in the Suppression of Invasive Behavior of Human Breast and Prostate Cancer Cells Jiang J, Eliaz I, and Sliva D. Cancer Research Laboratory, MRI, Indiana University Health, Indianapolis, IN, USA Amitabha Med. Clinic & Healing Center, Sebastopol, CA, USA Depart. of Med., and Indiana Univer. Cancer Center, Indiana Univer. School of Med., Indianapolis, IN, USA. Integr Cancer Ther March 12 (2):

67 * * * PC3 growth measured using MTT assay. Cells incubated for 24 hrs with ProstaCaid (ug/ml). *P <.05 Prostate Polybotanical Formula Effect on Proliferation of Human Prostate Cancer Cells

68 BA The invasive behavior of PC3 evaluated using migration assay in the presence of (A) MCP (mg/mL) & (B) MCP (mg/mL) plus Prostacaid (10 ug/mL). Prostate Formula & MCP Effect on Migration of Human Prostate Cancer Cells

69 * * * Breast Polybotanical Formula Effect on Proliferation of Human Breast Cancer Cells Growth of MDA-MB-231 measured using MTT assay. MDA-MB-231 cells incubated for 24 hrs with BreastDefend (ug/mL) at the indicated concentrations. *P <.05

70 B A Invasive behavior of MDA-MB-231 evaluated using migration assay in the presence of (A) MCP (mg/mL) & (B) MCP (mg/mL) plus BreastDefend (20 ug/mL). Breast Formula & MCP

71 Modified Citrus Pectin Published Data Summary Preclinical and Clinical Research Highlights on Modified Citrus Pectin

72 Preclinical Studies with MCP (17 Published Articles) *One in vitro study reported on both prostate and breast cancer (Glinskii OV, Huxley VH, Glinsky GV. et al. Neoplasia. 2005;7(5): ). **One article reported two in vivo studies and one in vitro study (Nangia-Makker P, Hogan V, Honjo Y, et al. J Natl Cancer Inst Dec 18;94(24): ). ***One articles reported both an in vivo and an in vitro study (Platt D, Raz A. J Natl Cancer Inst Mar;84(6):438-42) In vitro (Type of Cancer)In vivo (Type of Cancer)Ex vivo (Type of Cancer) 5 (Prostate*)2 (Prostate) including 1 Lung Metastasis Study1 (Immune; Leukemia) 2 (Breast*,**)2 (Breast*,**) including 1 Lung Metastasis Study 1 (Angiosarcoma & Hemangiosarcom) 1 (Melanoma***)1 (Melanoma***) including 1 Lung Metastasis Study 3 (Colon**) including 1 Lymph and 1 Liver Metastasis Study 1 (Non Cancer; Small Intestine Permeability) 2 (Non Cancer; Kidney Injury, Arteriole Fibrosis) 9 Total10 Total2 Total

73 Human Clinical Study (Number of Participants ) Type of TrialResults Zhoa, et al., Altern Ther Health Med (n = 7) Pilot trial: Lead toxicity in hospitalized children ages Very significant decrease in blood serum levels of lead (P =.0016) and very significant increase in 24-hour urine collection (P =.0007). No adverse effects. Azémar, et al., Clinical Medicine: Oncology (n = 49) Pilot trial: To assess the quality of life, clinical benefit and antitumoral efficacy in advanced stage solid tumors (colorectal, prostate, breast, kidney, cervix/uterine, liver, pharynx, pancreatic, melanoma, stomach, bile duct carcinoma and chondrosarcoma) 22.5% patients showed a stable disease (SD) and 12.3% patients had a SD for a period longer than 24 weeks. One patient with metastasized prostate carcinoma showed a 50% decrease in serum PSA level after 16 weeks of treatment associated with a significant increase of clinical benefit, quality of life and decrease in pain. 20.7% patients had an overall clinical benefit response associated with a stabilization or improvement of life quality. All patients tolerated the therapy well without any severe adverse events. Eliaz, et al. Forsch Komplementmed (n = 5) Case studies: Involving lowering of lead and mercury body burden 5 case studies presented show reduction in toxic heavy metals was achieved without side effects. Gradual decrease of total body burden is believed to have played an important role in recovery and health maintenance. Seven Clinical Studies with MCP

74 Human Clinical Study (Number of Participants) Type of TrialResults Eliaz, et al. Phytother Res (n = 8) Pilot trial: Toxic heavy metal removal in healthy population In the first 24 hours the urinary excretion of arsenic increased significantly (p < 0.05). On day 6, urinary excretion was increased significantly for cadmium (p < 0.05). Lead showed a dramatic increase in excretion (p < 0.08), and mercury approached significance on day six. Other elements analyzed including essential elements did not show any significant change in excretion. Eliaz. 228th Annual American Chemistry Meeting. August (n = 5) Pilot trial: Decrease total body burden of mercury A significant decrease in total body mercury burden was seen in all participants. The decrease was found more significant over time. The mercury burden for the group dropped 68.32% (p=0.0313). All individual completed the study, and there were no side effects reported. Guess, et al. Prostate Cancer Prostatic Dis (n = 13) Phase II pilot trial: Lengthening of PSA doubling time in biochemical relapsed prostate cancer patients. There were no serious side effects in any patient, but three patients withdrew from the study due to abdominal cramping or diarrhea. MCP was well tolerated by the remaining 10 evaluable patients. Seven (70%) of these evaluable patients had a significantly increased doubling time of PSA compared with their times before the treatment. Strum, et al. International Conference on Diet and Prevention of Cancer. May (n = 7) Pilot Study: Lengthening of prostate-specific antigen doubling time in biochemical relapsed prostate cancer patients. PSA doubling time was lengthened by more than 30% in 4/7 (57%) of patients. One patient had a partial response, one patient had stable disease, and one patient did not respond. No adverse effects were reported.

75 Galectin-3 Research The role of active biomarker galectin-3 in chronic disease progression

76 The PREVEND Study (Prevention of Renal and Vascular End-stage Disease) de Boer RA, van Veldhuisen DJ, R. T. Gansevoort RT, et al. The fibrosis marker Galectin-3 and outcome in the general population. J Intern Med doi: /j x. University of Groningen, Groningen, The Netherlands

77 Overall Average 11.9 Galectin-3 Levels & Mortality from All Causes in the General Population: PREVEND

78 Galectin-3 in General Population: PREVEND (number of subjects = 7,968) CHARACTERISTIC Median Gal3 TOTAL 11.9 QUINTILE QUINTILE QUINTILE QUINTILE QUINTILE P DM% MI Hypertension Stroke % Systolic BP 129.2± ± ± ± ± ± Diastolic BP74.0± ± ± ± ± ±

79 CHARACTERISTIC Median Gal3 TOTAL 11.9 QUINTILE QUINTILE QUINTILE QUINTILE QUINTILE P CRP 1.29 [ ] 0.89 [ ] 1.04 [ ] 1.33 [ ] 1.53 [ ] 1.98 [ ] Cholesterol5.66± ± ± ± ± ± LDL3.69± ± ± ± ± ± HDL 1.27 [ ] 1.32 [ ] 1.28 [ ] 1.25 [ ] 1.24 [ ] 1.24 [ ] Triglycerides 1.16 [ ] 1.02 [ ] 1.11 [ ] 1.17 [ ] 1.23 [ ] 1.31 [ ] Galectin-3 in General Population: PREVEND (number of subjects = 7,968)

80 The COACH (Coordinating Study on Outcomes of Advising and Counseling in Heart Failure) Multicenter, randomized, controlled trial conducted in The Netherlands. A prospective sub-study was designed to evaluate Galectin-3 in patients with chronic heart failure and define cut-off levels for subsequent validation studies. Galectin-3 levels were measured in 582 banked EDTA-plasma samples.

81 COACH Galectin-3 Sub-Study Mortality from All Causes at 1 Year in Patients with CHF

82 COACH Galectin-3 Sub-Study Cardiovascular Mortality or Heart Failure-Related Hospitalization at 1 Year in Patients with CHF

83 DeFillipi et al, U.S. Cardiology, 7,1, 3–6 (2010) clearly indicate that circulating Galectin-3 is an important factor in fibrosis of many organs and organ systems, and that reducing circulating Galectin-3 may have an important role in remediating cardiac injury and progression to heart failure (HF). Similarly, Psarras et al, Eur. Heart J., April 26 (2011) demonstrate that reduction in Galectin-3 levels in the myocardium may reduce fibrosis in the heart and improve outlook. De Boer et al, Ann. Med., 43,1, 60–68 (2011) identify Galectin-3 as a key indicator in cardiac health. Shash et al, Eur J. Heart Fail., 12,8, 826–32 (2011) identify Galectin-3 levels as a key agent in heart failure through fibrosis. De Boer et al. Eur. J. Heart Fail., 11, 9, (2009) link an increase in Galectin-3 expression and presence to heightened fibrosis, and heart failure. The same article links Galectin-3 to inflammation. Inflammation is the hallmark of arteriosclerosis, therefore Galectin-3 levels also contribute to coronary artery disease, peripheral artery disease, strokes, and vascular dementia. Galectin-3 and Cardiovascular Health

84 Modified Citrus Pectin Reduces Galectin- 3 Expression and Disease Severity in Experimental Acute Kidney Injury Kolatsi-Joannou M, Price KL, Winyard PJ, Long DA. Nephro- Urology Unit, UCL Institute of Child Health, London, UK PLoS ONE 2011 April 6(4): e18683.

85 Background: Folic acid (FA)-induced acute kidney injury model Method: Mice given 1% MCP-supplemented water, or plain water, 1 week before FA injection Results: During initial injury phase, all FA treated mice lost weight while their kidneys enlarged secondary to renal insult – Gross changes significantly lessened in MCP group – MCP clearly reduced renal cell proliferation – Recovery phase: MCP group showed decreased Galectin-3 expression with decreased renal fibrosis, macrophages, pro- inflammatory cytokine expression, and apoptosis MCP & Kidney Injury Study

86 Galectin-3 Mediates Aldosterone- Induced Vascular Fibrosis Calvier L, Miana M, Reboul P, et al. Arterioscler Thromb Vasc Biol Jan;33(1):67-75.

87 Background: Aldosterone is involved in arterial stiffness and heart failure. Galectin-3 plays an important role in inflammation, fibrosis, and heart failure. MCP blocks Galectin-3 Methods and Results: Rats were treated with aldosterone combined with MCP for 3 weeks. Hypertensive aldosterone- treated rats presented vascular hypertrophy, inflammation, fibrosis, and increased aortic Gal-3 expression. Those also treated with MCP treatment abolished all the above effects. Conclusion: Galectin-3 is required for inflammatory and fibrotic responses to aldosterone in vascular smooth muscle cells in vitro and in vivo. By inhibiting Galectin-3, MCP prevents vascular fibrosis. Aldosterone Galectin-3 MCP Vascular Fibrosis Study

88 Test for Galectin-3 levels Address general inflammation & hyperviscosity Use MCP at appropriate dosages by: – Condition – Galectin-3 levels – Therapeutic goal Elevated Galectin-3: What can we do?

89 Serum Galectin-3 Testing Serum Galectin-3 Testing USFDA approved blood test that measures Galectin-3 for Cardiovascular Disease

90 Galectin-3 Levels: Reference Ranges Galectin-3 levels > 17.8 ng/ml are considered to be an extreme risk factor of mortality. Ideal levels are < 14 ng/ml in the general population. For cancer and cardiac patients, ideal levels are < 12 ng/ml. Galectin-3 levels change in 20% of population every 3 months. Repeated testing is important.

91 Desired levels <12.0 ng/ml Follow up on Galectin-3 levels routinely every 3-6 months Galectin-3 Levels: Cancer

92 Levels <17.8, or not tested MCP 15g daily Levels >17.8 MCP g daily Active Cancer

93 Levels < 12.0 ng/ml MCP 5g daily Levels = 12.0 – 14.0 ng/ml MCP 10g daily Levels = 14.0 – 17.8 ng/ml MCP 15g daily Levels >17.8 ng/ml MCP 20 – 25g daily Cancer Long Term Maintenance (3 years post therapy)

94 Galectin-3 Levels: MCP Dosage (grams)

95 Galectin-3 is a novel, active biomarker that is both a cause of multiple diseases and a diagnostic and prognostic biomarker. Modified Citrus Pectin is a proven natural Galectin-3 blocker. In Conclusion: Galectin-3 and Modified Citrus Pectin


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