42nd Orthomolecular Medicine Today Conference by Journal of Orthomolecular Medicine

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ANNUAL INTERNATIONAL CONFERENCE

toronto International Society for Orthomolecular Medicine

April 26 â&#x20AC;&#x201C;28, 2013 Fairmont Royal York Hotel

Experience the best education for health care professionals in many areas of Orthomolecular Medicine at our 42nd Annual International Conference. Thirteen internationally known physicians and researchers will present five sessions over three days on current advances in general orthomolecular medicine, cardiology, psychiatry, and oncology.

International Society for Orthomolecular Medicine April 26, 2013 Dear Delegates, Welcome to our 42st Annual International Orthomolecular Medicine Today Conference. We hope these next three days will provide fresh insight and clinical evidence for the advancement of your study and practice in the field of Orthomolecular Medicine. This year we are pleased to bring together 13 speakers, 21 exhibitors and over 200 delegates and guests from 13 countries worldwide, including Algeria, Australia, Brazil, Canada, England, Guatemala, Japan, Mexico, Norway, the Philippines, South Korea, Spain, Sweden, Switzerland, Taiwan, and the United States of America. We extend a special warm welcome to our large delegation of attendees from Japan. In 2013 we celebrate 45 years of Orthomolecular Medicine, since Linus Pauling coined the word, “orthomolecular” in Science April 19, 1968. We also mark the 10th anniverary of the Orthomolecular Medicine Hall of Fame. This year we induct three pioneers: Hiroyoki Abe, MD, founder of the Japanese Society for Orthomolecular Medicine; Ron Hunninghake, MD, Chief Medical Officer of the Riordan Clinic, Wichita, Kansas; and Andrew Saul, PhD, author and co-author of many orthomolecular books and editor of the Orthomolecular Medicine e News Service. We thank you for your continued dedication to Orthomolecular Medicine and wish you a most memorable Conference. With best regards,

Atsuo Yanagisawa, President

Steven Carter, Director

ISOM Meeting Sunday, April 28 9:00 am – 10:00 am Please join us to hear reports on activities in education, communication and advocacy from Canada, Japan, Mexico, Spain, Algeria and others from among the 13 countries in attendance at the Orthomolecular Medicine Today Conference Don’t miss this opportunity to gain an international perspective on Orthomolecular Medicine.

Contents

Conference Schedule...................................................................................................................................3 Exhibitors.........................................................................................................................................................4 Exhibitor Floor Plan......................................................................................................................................5 Conference Schedule...................................................................................................................................6

Presentation Notes

Session One - Orthomolecular Cardiology Jeff Kotulski, DO Orthomolecular Medicine and the Renaissance in Healthcare....................................................7 Ron Hunninghake, MD Endothelial Progenitor Cells and Vascular Health...........................................................................11

Tom Levy, MD Coronary Heart Disease and Cancer: The Common Denominator ......................................... 21

Session Two - Orthomolecular Oncology Hiroyuki Abe, MD Personalized Medicine and Cancer Treatment................................................................................ 32

Michael Gonzalez, DSc, PhD Systemic Saturation in Intravenous Vitamin C Therapy................................................................ 50

Nick Gonzalez, MD The Gonzalez Anti-Cancer Regimen: An Individualized Nutrition, and Enzyme Therapy................................................................................................................................64

Session Three - General Orthomolecular Medicine Kara Fitzgerald, ND An Orthomolecular Approach to Allergic and Atopic Disease.................................................. 69

Robert Lustig, MD Darwin, Diet, Disease, and Dollars....................................................................................................... 87

Efrain Olszewer, MD Controversial Issues in Bioidentical Hormone Therapy..............................................................109

Session Four - Orthomolecular Psychiatry

Bo Jonsson, MD, PhD Orthomolecular Treatment for Depression and Bipolar Disorder.......................................... 118

John Hoffer, MD, PhD Effects of Vitamin C and D Supplementation on Mood and Distress in Acutely Hospitalized Patients.........................................................................................................126

Jonathan Prousky, ND, MSc Orthomolecular Strategies to Prevent Mental Breakdown....................................................... 127

Session Five - General Orthomolecular Medicine Saul Pilar, MD The Deleterious Health Effects of Sodium/Potassium Imbalance: An Orthomolecular Solution................................................................................................................134

John Hoffer, MD, PhD The Abram Hoffer Collection at the University of Saskatchewan The Sickness of Evidence-based Medicine .................................................................................... 141

Badge colour code: Red=Speaker; Blue=Full Delegate; Yellow=Sessional Delegate; Green=Exhibitor

FRIDAY APRIL 26

11:30 am Efrain Olszewer Controversial Issues in Bioidentical Hormone Therapy

8:00 am Registration 8:30 am Exhibits open

12:30 pm Lunch - Visit Exhibits

Session One • Orthomolecular Cardiology

Session Four • Orthomolecular Psychiatry

9:00 am

Welcome - Introduction

9:15 am

Abram Hoffer Memorial Lecture Jeff Kotulski Orthomolecular Medicine and the Renaissance in Healthcare

2:00 pm

John Hoffer Effects of Vitamin C and D Supplementation on Mood and Distress in Acutely Hospitalized Patients

3:00 pm

Bo Jonsson Orthomolecular Treatment for Depression and Bipolar Disorder

4:00 pm

Break - Visit Exhibits

4:30 pm

Jonathan Prousky Orthomolecular Strategies to Prevent Mental Breakdown

5:30 pm

Exhibits Close

10:00 am Break - Visit Exhibits 10:30 am Evan Shute Memorial Lecture Ron Hunninghake Endothelial Progenitor Cells and Vascular Health 11:30 am Tom Levy Coronary Heart Disease and Cancer: The Common Denominator

10th Annual

12:30 pm Lunch - Visit Exhibits

Orthomolecular Medicine Hall of Fame

Session Two • Orthomolecular Oncology 2:00 pm Hiroyuki Abe Personalized Medicine and Cancer Treatment 3:00 pm Michael Gonzalez Systemic Saturation in Intravenous Vitamin C Therapy 4:00 pm Break – Visit Exhibits 4:30 pm

Nick Gonzalez The Gonzalez Anti-Cancer Regimen: An Individualized Nutrition, Detoxification and Enzyme Therapy

5:30 pm Exhibits Close

SATURDAY APRIL 27 Session Three • General Orthomolecular Medicine 9:00 am

Kara Fitzgerald An Orthomolecular Approach to Allergic and Atopic Disease

10:00 am Break - Visit Exhibits 10:30 am Robert Lustig Darwin, Diet, Disease, and Dollars

7:00 pm Reception 7:30 pm Dinner and Induction

SUNDAY APRIL 28 9:00 am

International Society for Orthomolecular Medicine meeting

10:00 am

Break - Visit Exhibits

Session Five • General Orthomolecular Medicine 10:30 am

Saul Pilar The Deleterious Health Effects of Sodium/Potassium Imbalance: An Orthomolecular Solution

11:30 am

Dr Rogers Prize Lecture John Hoffer The Abram Hoffer Collection at the University of Saskatchewan

1:00 pm

Exhibits Close Public Workshop

Mental Health Regained featuring Orthomolecular Practitioners and Recovered Patients 2:00 – 4:00 pm

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42nd Orthomolecular Medicine Today Conference Please Visit Our Exhibitors Acquired Intelligence, Inc. 205 -1095 McKenzie Avenue Victoria, BC V8P 2L5 Canada 250 483 3640 sales@salvestrol.ca www.salvestrol.ca

Doctors Data Inc. 3755 Illinois Avenue St. Charles, IL 60174-2420 USA 800 323 2784 / 630 377 8139 inquiries@doctorsdata.com www.doctorsdata.com

Pascoe Canada 40 Vogell Road Richmond Hill, ON L4B 3N6 Canada 866 535 0099 / 905 737 9837 info@pascoecanada.com www.pascoecanada.com

BDR INT, Inc. 4245 No. 4 Side Road Burlington, ON L7M 0S4 Canada 866 634 8075 bdrint@gmail.com www.nanovitaminc.ca

Douglas Laboratories of Canada/ Pure Encapsulations 552 Newbold Street London, ON N6E 2S5 Canada 866 856 9954 / 519 439 8424 info@douglaslabs.ca www.douglaslabs.ca

Physicians UBI 10555 S Wright Road Eagle, MI 48822 USA 517 202 5959 info@drsubi.com www.drsubi.com

Bioclinic Naturals 1550 United Boulevard Coquitlam, BC V3K 6Y2 Canada 877 433 9860 customersupport@bioclinicnaturals.com www.bioclinicnaturals.com Canadian Association of Naturopathic Doctors (CAND) 20 Holly Street, Suite 200 Toronto, ON M4S 3B1 Canada 800 551 4381 / 416 496 8633 info@cand.ca www.cand.ca

McGuff Pharmaceuticals Ltd. 3524 West Lake Center Dr. Santa Ana, CA 92704 USA 800-854-7220 answers@mcguff.com www.mcguff.com Metagenics Canada, Inc. 851 Rangeview Road Mississauga, ON L5E 1H1 Canada 800 268 6200 brendaparsons@metagenics.com www.metagenics.com

CanPrev Premium Natural Health Products Ltd / Orange Naturals 11 – 60 West Wilmot Street Richmond Hill, ON L4B 1M6 Canada 888 226 7733 / 905 881 6800 info@canprev.ca www.canprev.ca

Nature’s Source 5029 Hurontario Street, Unit 2 Mississauga, ON L4Z 3X7 Canada 905 502 6789 info@natures-source.com www.natures-source.com

College Pharmacy 3505 Austin Bluffs Parkway Colorado Springs, CO 80918 USA 800 888 9358 / 719 262 0022 info@collegepharmacy.com www.collegepharmacy.com

Nutri-Chem Compounding Pharmacy and Clinic 205-1305 Richmond Road Ottawa, ON K2B 7Y4 Canada 613 820 4200 info@nutrichem.com www.nutrichem.com

Cyto-Matrix Inc. 300 March Road Kanata, ON K2K 2E2 Canada 613 599 1653 info@cyto-matrix.com www.cyto-matrix.com

Nutritional Fundamentals for Health (NFH) 3405 F.X. Tessier Vaudreuil-Dorion, QC J7V 5V5 Canada 866 510 3123 info@nfh.ca www.nfh.ca

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Protocol for Life 5-5068 Whitelaw Road Guelph, ON N1H 6J3 Canada 800 265 7245 x 8721 / 519 836 3757 debra.greene@protocolforlife.com www.protocolforlife.com Rocky Mountain Analytical Unit A, 253147 Bearspaw Road NW Calgary, AB T3L 2P5 Canada 866 370 5227 info@rmalab.com www.rmalab.com Seroyal International Inc. 490 Elgin Mills Road East Richmond Hill, ON L4C 0L8 Canada 800 263 5861 / 905 508 2050 sales@seroyal.com www.seroyal.com Smith’s Pharmacy 3463 Yonge Street Toronto, ON M4N 2N3 Canada 416 488 2600 info@smithspharmacy.com www.smithspharmacy.com Square Snacks Inc. 416 461 9379 info@squaresnacks.com www.squaresnacks.com York Downs Pharmacy 3910 Bathurst Street, Room 304 Toronto, ON M3H 5Z3 Canada 800 564 5020 / 416 633 2244 info@yorkdownsrx.com www.yorkdownsrx.com

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42nd Orthomolecular Medicine Today Conference

1. Nature’s Source 2. Physicians UBI 3. College Pharmacy 4. Pascoe Canada 5. McGuff Pharmaceuticals Inc. 6. CAND 7. Bioclinic Naturals 8. BDR INT Inc. 9. Douglas Laboratories/Pure Encapsulations 10. Nutrichem Compounding Pharmacy 11. Metagenics Canada

12. Nutritional Fundamentals for Health 13. York Downs Pharmacy 14. Protocol for Life Balance 15. Smith’s Pharmacy 16. Doctor’s Data 17. Seroyal International Inc. 18. Can Prev/Orange Naturals 19. Rocky Mountain Analytical 20. Cyto-Matrix Inc. 21. Acquired Intelligence ■

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Speaker Biographies president of the Swedish Society for Orthomolecular Medicine. He has (with Andrew Saul) published The Vitamin Cure for Depression: How to Prevent and Treat Depression Using Nutrition and Vitamin Supplementation.

Hiroyuki Abe, MD, is founder and Medical Director of Hakushin Koseikai Medical Foundation and Director of Life Science Research Institute. He is also Chairman of International Society of Personalized Medicine and cofounder of the Japanese Society for Orthomolecular Medicine. He is a medical oncologist with a special interest in immunotherapy, onco-hyperthermia and orthomolecular therapy. Dr. Abe has opened new medical frontiers, especially for cancer patients, using personalized medicine based on molecular diagnostics. He uses a dendritic cell-based cancer vaccine which he developed, along with IV therapy, onco-hyperthermia and other modalities which are acclaimed internationally as having beneficial outcomes. Currently he is appointed as a Visiting Professor at Thomas Jefferson University and Taipei Medical University.

Efrain Olszewer, MD, introduced orthomolecular medicine in Brazil in 1983. He is the clinical director of the Center for Preventive Medicine in Sao Paulo; Scientific Director and Professor of the post graduate courses for FAPESP (Sao Paulo Research Foundation) and Scientific Director of the medical journal Biochemistry. He is author of dozens of scientific papers published in indexed journals; has authored 53 books on medicine, and is a noted lecturer both nationally and internationally. Dr. Olszewer directs post graduate courses in orthomolecular medicine in Bolivia, Argentina, Paraguay, Peru and Brazil.

Kara Fitzgerald, ND, received her doctorate of naturopathic medicine from National College of Natural Medicine in Portland, Oregon. She completed the first CNME-accredited post-doctorate position in nutritional biochemistry and laboratory science at Metametrix Clinical Laboratory. Dr. Fitzgerald is lead author and editor of The Metametrix Institute’s Case Studies in Integrative and Functional Medicine, and a contributing author to the Institute for Functional Medicine’s updated Textbook for Functional Medicine. She is an adjunct faculty member at University of Bridgeport in the school of Human Nutrition and a member of The Institute for Therapeutic Discovery. She is now in private practice in Sandy Hook, Connecticut.

Jeffrey Kotulski, DO, is Board Certified in Family Practice and Neuromusculoskeletal Medicine. He is also a founding Diplomate of the American Board of Holistic Medicine. He graduated from the Chicago College of Osteopathic Medicine in 1991; M.S. in Exercise Physiology, George Williams College in 1986; B.S. in Exercise Science and Elementary Education, Southern Illinois University in 1984. He served 15 years in the United States Army Reserves where he trained as a Preventive Medicine Specialist. He is the medical director and CEO of Between the Bridges Healing Center, LLC. Dr. Kotulski’s wife, Tina is the author of Saving Millie: A Daughter’s Story of Surviving Her Mother’s Schizophrenia. They, along with their four children, reside in Southern Minnesota.

Michael J. Gonzalez, DSc, PhD, is Professor at the Nutrition Program at the University of Puerto Rico and has authored over 150 scientific publications. He is currently Co- Director of RECNAC II project, and Research Director of the InBioMed Project Initiative. Doctor González is a leader in the development of non-toxic chemotherapy treatments for cancer. The findings of their work with intravenous vitamin C as an anti-cancer agent, published in 2002, were confirmed by the NIH in 2005. His group published the first Phase-I clinical study utilizing Intravenous Vitamin C for treatment of terminal cancer patients in 2005, and also published in 2005 the most comprehensive review on Vitamin C and Cancer. Dr. Gonzalez coauthored the book, I Have Cancer What Should I do: The Orthomolecular Guide to Cancer Management in 2009.

Thomas E. Levy, MD, JD, is a board-certified cardiologist and a bar- certified attorney. As an author, he has addressed the critical role of oxidative stress and how best to remedy this condition. He has written books on nutrition, the role of vitamin C in heart disease, and the documented capacity of vitamin C as an antibiotic and universal antidote. His most recent book, Primal Panacea, further examines the many clinical applications of vitamin C and some of the political and legal issues preventing its widespread acceptance. Currently, he is researching and writing, Putting Cancer Into Permanent Remission: Vitamin C as Optimal Chemotherapy. Robert H. Lustig, MD, is Professor of Pediatrics, in the Division of Endocrinology at the University of California, San Francisco. Dr. Lustig is a neuroendocrinologist, with basic and clinical training relative to hypothalamic development, anatomy, and function. Dr. Lustig’s research focuses on the regulation of energy balance by the central nervous system. He is currently investigating the contribution of nutritional, neural, hormonal, and genetic influences in the expression of the current obesity epidemic both in children and adults. Dr. Lustig is the author of many articles, chapters, and reviews on childhood obesity, including the recent Fat Chance: Beating the Odds Against Sugar, Processed Food, Obesity, and Disease.

Nicholas Gonzalez, MD, graduated from Brown University and received his medical degree from Cornell University. During a fellowship under Dr. Robert Good, former President of Sloan-Kettering, Dr. Gonzalez evaluated a nutritional therapy for use against advanced cancer as described in his book One Man Alone. Since 1987, Dr. Gonzalez has been in practice in New York. Results from a pilot study described the most positive data reported for pancreatic cancer. His books include The Trophoblast, which discusses John Beard, who first suggested an anticancer effect for pancreatic enzymes. The book, What Went Wrong, documents Dr. Gonzalez’s battle to have his therapy tested in an NCI clinical study. John Hoffer, MD, PhD, is a professor of medicine at McGill University where he conducts research at the Lady Davis Institute for Medical Research. He earned his medical degree from McGill and his doctorate in Human and Clinical Nutrition from M.I.T. Dr. Hoffer is also a senior physician in the divisions of Internal Medicine and Endocrinology in Montreal’s Jewish General Hospital. His research interests are in protein-energy malnutrition and vitamin therapy for chronic disease. Dr. Hoffer has served for many years on the Nutrition and Metabolism Committee of the Canadian Institutes for Health Research.

Saul Pilar, MD has focused on treating, learning and teaching. He has a background in natural sciences and chemistry with degrees in Chemical Engineering and Medicine from the University of Toronto. For over three decades, he has maintained a large private practice in Vancouver, BC, currently at Connect Health and Kinetic Patterns clinics. His special interests are chronic disease, pain, prolotherapy, anti-aging, mind-body healing, allergy, toxicity, nutritional, orthomolecular and integrative medicine. He is Vice President of Canadian Society of Clinical Hypnosis (BC div.), a member of the Editorial review board of Alternative Medicine Review journal. “Outside of the clinic”, Dr. Pilar says, “I am excited about the world of food, hiking, cycling, music, dancing, arts and spiritual traditions. In the clinic, I enjoy working with a team of multidisciplinary practitioners.”

Ron Hunninghake, MD, is the Chief Medical Officer of the Olive W. Garvey Center for Healing Arts, the clinical division of the Riordan Clinic. A 1976 graduate of the University of Kansas School of Medicine, Dr. Hunninghake has devoted his career to the emerging paradigm of Self Care: the patient as an informed medical partner. In addition to his full-time practice at The Center, Ron is a regular presenter at medical conferences, and The Center’s “Lunch & Lecture” series on timely, health-related topics. Dr. Hunninghake has published three books on health and wellness: The User’s Guide to Inflammation, Arthritis, and Aging (2005); The User’s Guide to Energy-Boosting Supplements (2006); Stop Prediabetes Now (2007).

Jonathan Prousky, ND, MSc, graduated from Bastyr University (Kenmore, WA) with a Doctorate in Naturopathic Medicine. He is the Chief Naturopathic Medical Officer at the Canadian College of Naturopathic Medicine and also supervises at the Robert Schad Naturopathic Clinic. He is a passionate advocate for patients having psychiatric disorders and focuses his clinical practice on optimizing mental and neurological health with orthomolecular nutrition, botanical (plant-based) medicines and lifestyle counseling. He has lectured extensively on various health-related topics, especially mental health. Dr. Prousky is the current editor of the Journal of Orthomolecular Medicine. His clinician-based research primarily involves the neuropsychiatric applications of vitamin B3.

Bo H. Jonsson, MD, PhD, has been a practising psychiatrist for thirty years. He is affiliated with the Department of Clinical Neuroscience, section of Psychiatry, Karolinska Institutet and is medical director of Center for Affective disorders, North Stockholm Psychiatry, St Göran’s Hospital, Stockholm. Dr. Jonsson is on the editorial board of the Journal of Orthomolecular Medicine and is

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Riordan Clinic Research

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2008-2010

•! Two key studies are reviewed in this presentation •! Taken from the “Black Book” •! Commissioned in part by Allan Markin in 2007 •! Contains 18 Peer Reviewed Studies (8 listed – last two slides) •! 20,000 hours of research time by Ph.D. researchers

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3.6

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1.24

11.82

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150

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Tom Levy

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!"#$"#%&' Coronary Artery Disease and Cancer: The Common Denominator

Tom Levy

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!"#$"#%&' Coronary Artery Disease and Cancer: The Common Denominator

Tom Levy

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Tom Levy

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!"#$"#%&' Coronary Artery Disease and Cancer: The Common Denominator

Tom Levy

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Personalized Medicine and Cancer Treatment Hiroyuki Abe

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

!"#$%#&'&

Intravenous Vitamin C: The Systemic Saturation Effect

Discovery is seen what every body else has seen but thinking what nobody else has thought.

Michael J Gonzalez Jorge R Miranda -Massari University of Puerto Rico Medical Sciences Campus RECNAC 2 Project

Albert Szent-Györgyi

RECNAC 2 Cancer Protocol

!"#$%#&'&

Center Improvement Human Functioning (Riordan Clinic) Wichita, Kansas…Original RECNAC

! " RECNAC 2 is a research initiative aimed at the development of effective, non-toxic cancer treatments. ! " Inspired by our personal losses ! " Originated from The Center for the Improvement of Human Functioning International s RECNAC project. (Now Riordan Clinic). ! " RECNAC is cancer written backwards ! " Ultimate Goal: To develop a non-toxic protocol that will achieve the reversion of cancer.

!"Hugh D. Riordan !"Neil H. Riordan

!"#$%#&'&

! " Goals ! " To produce quality research to accelerate the inclusion of these effective/non-toxic interventions in the standard medical guidelines. ! " To enhance quality of life of cancer patients. ! " To provide an alternative for those who refuse or cannot tolerate standard treatment. ! " To educate and support patients, family, and friends on improving quality of life. ! " To develop cost-effective therapies that complement current cancer treatments and reduce their toxicity.

There is a better way… Find it! Thomas A. Edison

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

!"#$%#&'&

!"#$%#&'&*,/H3.9& Original Team

!"#$%&'()*+,-% ./! 0#12%3(-*%#$,'"4*$(5-%4#,"6#$%7%

&()&*+(,-(./01234.5&/6&+17+&8/53&129,(:32/;5&:19(-12&#&12&+3(<9+=& :/<;2933,5&(28&.(2.3,&>(43295)&& &?)&@;(<19=&/6&<163&(28&AB#&12&93,-12(<&.(2.3,&>(43295& &.)&#<121.(<&C9;8=&AB#&3D3.9&/2&,35>/253&(28&5;,:1:(<&/6&.(2.3,& >(43295)&

8/! !#,(+2($3'#"9%+(''*+:($% &()&E53&/6&2/2F9/G1.&2;9,(.3;4.(<5&9/&128;.3&-(<172(29&.3<<&,3F 81D3,324(4/2&/,&.3<<&83(9+&:1(&-19/.+/28,1()&

RECNAC 2 Publications

! " 1995 â&#x20AC;&#x201C;Vitamin C as chemotherapeutic agent (Med Hypotheses. 1995;44:207-13)

! " 2004- IV AA as a chemotherapy agent: a report on clinical cases. P R Health Sci J. 2004;23:115-8.

! " 2001- Cytotoxicity of ascorbate, lipoic acid in hollow fibre in vitro tumours. (Br J Cancer. 2001;84:1544-50)

! " 2005 - Orthomolecular oncology review: AA and cancer 25 years later. Integr Cancer Ther. 2005;4:32-44.

! " 2002- Inhibition of human breast carcinoma cell proliferation by ascorbate and copper. P R Health Sci J. 2002 ;21:21-3.

- Effects of high dose ascorbate administration on L-10 tumor growth in guinea pigs. PRHSJ. 2005;24:145-50.

! " 2003- Intravenous AA: protocol for its application and use.

- A pilot clinical study of continuous iv AA in terminal cancer pts. PRHSJ. 2005;24:269-76.

P R Health Sci J. 2003;22:287-90.

RECNAC 2 Publications

! " 2008 - Pharmacokinetics of Vitamin C: Insights into the Oral and Intravenous Administration of Ascorbate. PRHSJ 2008;27:7-19. ! " Ascorbic Acid, Mitochondria and Cancer: The Energy, Metabolism and Carcinogenesis Relationship. Accepted for Publication. J Orthomolecular med 2009

! " 2006- IV AA as a chemotherapy agent: a report on clinical cases. P R Health Sci J. 2004;23:115-8. ! " Tumor Growth Parameters of an In Vivo Human Breast Carcinoma: A proposed mathematical model for tumor growth kinetics. PR Health Sci J 2006;25:71-73.

! " I have Cancer, What Should I do?: The Orthomolecular Guide to Cancer Treatment. Book (November 2009).

! " 2007 -Schedule-dependence in cancer therapy: What is the true scenario for Vitamin C? J Orthomolec Med; 2007;22:21-6. ! " Vitamin C Pharmacokinetic after Continuous Intravenous Infusion in a Prostate Cancer Patient. Annals of Pharmacotherapy. 2007;41:1082-3

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez RECNAC 2 Publications

RECNAC 2 Publications

•" 2011•" Riordan NH, Rubin DM, González MJ and MirandaMassari JR. Alfaro I, Rodriguez JR, Ricart CM, Cintrón K, Valentín II y Duconge J. El Sistema Inmunologico y el Cancer. ¿Pueden ser las Células Dendríticas la Clave? Medicina y Salud Pública. 2011;18:10-22. •" Ichim TE, Minev B, Braciak T, Luna B, Hunninghake R, Mikirova NA, Jackson JA, Gonzalez MJ, Miranda-Massari JR, Alexandrescu DT, Dasanu CA, Bogin V, Ancans J, Stevens RB, Markosian B, Koropatnick J, Chen CS, Riordan NH. Intravenous ascorbic acid to prevent and treat cancer-associated sepsis? J Transl Med. 2011. 4;9:25.

•" 2010-

•" González MJ, Miranda-Massari JR, Duconge J. Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later: comment on the article by Cabanillas. P R Health Sci J. 2010;29:410-1. •" González MJ, Rosario-Pérez G, Guzmán AM, Miranda-Massari JR, Duconge J, Lavergne J, Fernandez N, Ortiz N, Quintero A, Mikirova N, Riordan NH, Ricart CM. Mitochondria, Energy and Cancer: The Relationship with Ascorbic Acid. J Orthomolec Med. 2010;25:29-38.

RECNAC 2 Publications

•" 2012•" Gonzalez MJ, Miranda Massari JR, Duconge J, Riordan N H, Ichim T. Schedule Dependence in Cancer Therapy: Intravenous Vitamin C and the Systemic Saturation Hypothesis. J Orthomolec Med 2012;27:9-12. •" Gonzalez MJ, Miranda Massari JR, Duconge J, Riordan NH, Ichim T, Quintero-Del-Rio AI, Ortiz N. The Bio-Energetic Theory of Carcinogenesis. Med Hypotheses 2012 79:433-439.

•"Moss, RW. Questioning Chemotherapy. Equinox Press,

Change the Conditions that Encourage Abnormal Growth

New York 1995.

Fungus - heat - moisture - darkness

The paradox of response and survival in cancer therapeutics. Huff CA et al Blood. 2006; 107: 431–4.

Cancer - lack oxygen - sugar feeding - toxin overload - immune suppression - abnormal pH - maldigestion - allergies - parasites

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez Vitamin C (AA)

RECNAC II Cancer Management Therapeutic Strategies

•" Enhances the immune system by increasing lymphocyte production. •" Walls off tumors by increasing collagen formation. •" Prevents metastasis by inhibiting hyaluronidase enzyme. •" Expedites wound healing after surgery. •" Neutralizes carcinogenic substances. •" Enhances mitochondrial function and aerobic metabolism. •" Improves energy in Cancer patients. •" Prevents cellular oxidative damage. •" Induces Apoptosis. •" Ameliorates side effects of Chemotherapy. •" Increases lifespan of Cancer patients nd improves quality of life.

! "Antineoplastic effect:

! "Intravenous high dose Vitamin C ! "H2O2/catalase deficiency

Vitamin C

RECNAC 2

•" Cancer patients are usually tired, listless, bruise easily, don t sleep well, have a low threshold for pain and have poor appetite. •" This presents a very classic picture of scurvy that generally goes unrecognized by physicians. •" AA corrects this universal scurvy present in Cancer patients.

! " Mechanism of Vitamin C Antitumor Activity ! " Generation of Peroxide –" Chen Q et al. PNSA. 2005;102:13604-9.

! " Apoptosis (increase in p53, p21,cellular Ca, and a decrease in mitochondrial membrane potential and activation of caspase 3). –" Lin et al. Melanoma Res. 2006 ;16:509-19

! " Hypoxia Inducible Factor

–" Gao P et al. Cancer Cell 2007;12:230-8.

Vitamin C

RECNAC 2

•" High dose IV AA kills cancer cells by generating Hydrogen Peroxide. •" AA acts as a pro-oxidant in the presence of Oxygen, Cu and Fe. Hydrogen peroxide is then formed that in the normal cells it is rapidly disposed by catalase, which is lacking in Cancer cells. •" High dose IV AA provides the best way to achieve the high concentrations needed to kill the cancer cells.

! " !*+2"$#-6%(;%%<#,"6#$%7%=$:,56('%=+:4#,>% =$:?"$1#(1*$#+%*@*+,%% !" I101,/:(&$)&39&(<)&J&K,(25<&I38)&'LLMNOPQL)& &

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Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez Vitamin C

â&#x20AC;˘" When Cancer patients receive high dose IV AA, their pain level is reduce and they are better able to tolerate chemotherapy. â&#x20AC;˘" The toxicity of Chemotherapy and Radiation is reduce without compromising their cancer killing effects. â&#x20AC;˘" High dose IV AA can be complementary to standard oncologic care since it helps patients withstand the effects of conventional therapies, heal faster, be more resistant to infection, develop an appetite and remain more active overall. All this promotes a better response to their Cancer therapy and a overall improved Quality of Life.

! " Other Possible Mechanisms: 3." Reduction of IGF* 4." Inhibition of COX-2* 5." Intracellular red-ox â&#x20AC;&#x201C; signal transduction â&#x20AC;&#x201C;gene expression. 6." Collagen â&#x20AC;&#x201C; Extra Cellular Matrix â&#x20AC;&#x201C; encapsulation *Lee SK et al. J Cell Physiol 2008;216:180-8. **Catani MV et al. Biochem J 2002;364;441-7. Cameron E. et al. Int J Vitam Nutr Res;1982:115-27.

High dose IV AA

â&#x20AC;˘" Cancer cells are obligate anaerobes, they depend of glucose as their primary source of metabolic fuel. â&#x20AC;˘" Cancer cells employ glucose transporters (Glut s) as a mechanism to facilitate glucose intake. â&#x20AC;˘" AA is synthesized from glucose in only 4 metabolic steps, hence the molecular structure of AA is remarkably similar to glucose.

Selective toxicity of Ascorbate to Cancer Cell â&#x20AC;˘" Dependent on glycolysis â&#x20AC;˘" More glut receptors â&#x20AC;˘" Deficient in catalases â&#x20AC;˘" IV high dose Ascorbate produces very high concentrations â&#x20AC;˘" Ascorbate is structurally similar to glucose â&#x20AC;˘" Lots of ascorbate enters and but the metabolic deficiency of catalases causes H2O2 to accumulate and damage the cell

Ascorbate and Cancer

Ascorbate and Cancer Pharmacokinetics: ! " Is the science that describes what the body does to a substance once it is administered.

Pharmacodynamics: ! "The study of the effects of drugs on the physiology or on infecting microorganisms and their mechanisms of action.

! " What the body does to the substance (drug/ nutrient)

! "What the substance (drug/nutrient) does to the body.

! " Develops mathematical models to explain how a substance moves in the body. !"Absorbed !"Distributed !"Metabolized !"Eliminated

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez USDA Agricultural Research Service

Ascorbate and Cancer

General guideline for interpretation of Plasma AA

Vitamin C deficiency in Cancer Patients ! " 50 pts (28! 22" ) with Advanced cancer ! " Average age 65.2 yrs ! " Estimated dietary intake of 40 mg of AA ! " 30% AA deficient < 11 µM ! " 42% AA low 11.1 -23 µM ! " Low plasma vitamin C significantly associated with low albumin, low PLT, high CRP, shorter survival.

Plasma Adequate

> 23 µM (0.023 mM)

Low

11.1 -23 µM

Deficient

<11.1 µM (0.011 mM)

! " Mayland er al. Palliative Medicine 2005.

Jacob and Sotoudeh. Nutr Clin Care 2002:5:66-74.

Ascorbate and Cancer

Pharmacokinetics of ascorbate Absorption- AA and DHAA ! " Is a saturable, dose dependent process. Occurs by both passive diffusion and active transport. ! " Oxidation to DHAA occurs in Intestine lining and cells (easier to cross the cell membrane). Then back to AA and back to DHAA. ! " Active transport - Na-independent transport systems shuttle (SVCT1) vitamin C across the intestinal wall and tubular renal membrane.* *Mackenzie B. Am J Physiol Cell Physiol. 2008

Benzie IF. Proc Nutr Soc. 1999.

Ascorbate and Cancer

Pharmacokinetics of ascorbate

Absorption- AA and DHAA ! " Saturable Vmax 70 µM (0.070 mM) NIH ! " Now tightly controlled 220 µM (0.220 mM) NIH ! " Intestinal absorption of AA is adaptively regulated in by the level of dietary ascorbate* ! " The mechanism of regulation is an increase or decrease in the number of carriers in the membranes of enterocytes in response to low or high concentrations of ascorbate in the blood.

! ! ! !

"Oral Absorption- AA # DHAA "80-95 % of food AA is absorbed "50% doses 1-1.5 gm "16% doses of 12 gm

Liposome preparation overcomes this limitation Groff JL. The Water Soluble Vitamins. In: Advanced Nutrition and Human Metabolism. Minneapolis: West Publishing Company, 1995.

*Karasov et al. Gastroint and Liver Physiology.1991

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

Ascorbate and Cancer

Pharmacokinetics of ascorbate

! "Dynamic Flow Model (Hickey) ! "System to mimic the physiology of AA synthesizing mammals. ! "This can be achieved by consuming excess ascorbate, over and above the amount normally absorbed. This intake is spread throughout the day, so a consistent supply is achieved. ! "Achieving dynamic flow corresponds to the bowel tolerance technique, described by Cathcart.

! "Bowel tolerance - method of utilizing vitamin C in amounts just short of the doses which produce diarrhea. (RF Cathcart) ! "The amount of oral AA tolerated increases somewhat proportionately to the stress or toxicity of the disease. ! "Bowel tolerance doses of AA ameliorate the acute symptoms of many diseases. Helps RedOx balance.

Ascorbate and Cancer

Pharmacokinetics of Ascorbate

Pharmacokinetics of ascorbate Dynamic Flow – basis ! "Disease states can increase gut permeability ! "Kidney pumps reabsorbs AA but not DHA

Distribution- Plasma AA concentrations/dose

! " 0.02-0.08 mM– nutritional/physiological level 30-180 mg (Kallner 1979) (Blanchard 1997) ! " 0.15-0.2 mM – supplementation level 1-3 gm (Padayatty 2004) ! " 1-15 mM -intravenous 10- 100 gm (Riordan 1995)

Ascorbate and Cancer

Pharmacokinetics of Ascorbate

Distribution ! " AA at 200 mg achieves 0.07-0.85 mM* ! " Doses above 200 mg were beyond the linear portion of the curve. F was complete at this dose. ! " Based on this DRI was recommended to be increased to 200 mg. Saturation leukocytes. ! " At 3000 mg PO q 4 hrs, concentrations were nearly three times greater (0.22 mM)** ! " 50 gm iv (13.4 mM)**

Distribution

! " AA and DHAA in plasma can either be transported freely or be bound to albumin. ! " Penetrates into body cells and tissues. ! " DHAA is the primary form of vitamin C that crosses cellular membranes. (Glucose transporters)* ! " AA in certain tissue concentrations may exceed those found in the plasma. ! " Tissue AA uptake in disease is substantially different and this will affect saturation of tubular reabsorption and Na dependent transporters- !t1/2, "Cl and "Vd

*Proc Natl Acad Sci 1996;93:14344-8 *Proc Natl Acad Sci 2001; 98: 9842-46 **Ann Int Med 2004;140:533-7.

*Fujita I et al Res Commun Mol Pathol Pharmacol. 2000;107:219-31.

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

Ascorbate and Cancer

Pharmacokinetics of Ascorbate

Plasma and tissue concentrations ! " The tissues with greatest percentage of vitamin C — over 100 x plasma conc. (adrenals, pituitary, thymus, and retina).

AA Uptake in cancer cells ! " Anaerobic metabolism ! " Needs more glucose for glycolysis ! " More glut-2 transporters (glucose/DHAA) ! " If Low glucose & high AA (diet & tx) ! " External oxidative environment H202 from H2O and AA # DHAA ! " DHAA enters the cell through glut-2

! " The brain, spleen, lung, testicles, lymph nodes, liver, leukocytes, thyroid, intestinal mucosa, pancreas, kidney, and salivary glands usually have 10 - 50 x plasma conc.

Ascorbate and Cancer

Pharmacokinetics of Ascorbate

AA Doses ! " Nutritional !"Acute deficiency < 5 mg !"Sub clinical deficiency - no excretion of vitamin C (close to RDA) !"Base level – consistent AA in urine !"Dynamic Flow – Excess intake leads to incomplete absorption. ! " Pharmacological !"Oral treatment – Large amounts to BT . !"Intravenous – most effective in tx of ds.

AA Uptake in cancer cells ! " Alpha-Lipoic acid enhances AA cancer killing effect by unknown mechanism. Casciari, J.J., et al. British J of Cancer 2001;84:1544-50 ! " It may facilitate e- flux through membranes or enhance DHAA penetration to the cell. ! " Lipoic acid recycles vitamin C, mediating the reduction of DHAA. Stoyanovsky D. Curr Eye Res. 1995 Mar;14(3):181-9.

Ascorbate and Cancer

Concentration of AA

Chemistry of ascorbate

! "Synergistic AA + lipoic ! "Tumor cell apoptosis 42.9% and necrosis 24.4% at AA of 11.2 mM. ! "Tumor cell apoptosis 57.6% and necrosis 33.1% at AA of 33.7 mM.

! " Can donate two electrons to form DH-ascorbate; this is how it can act as an AO ! " DH-ascorbate breaks down to oxalic & l-threonic acid

Casciari et al. Br. J Cancer; 2001

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

Ascorbate and Cancer

Pharmacokinetics of ascorbate

Metabolism

Excretion

! " The average half-life of AA in blood is around 30 minutes ! " Its half-life is inversely related to intake (low concentration induces tubular reabsorption) ! " DHAA and AA can be reabsorbed by the kidney tubules as long as body pool levels are equal to or less than 1500 mg. ! " As levels increase above 1500 mg, the reabsorption efficiency of the kidneys decreases. ! " Plasma ascorbate levels between 0.8 and 1.4 mg/dl are considered the renal threshold (renal excretion)

Metabolites of vitamin C include: ! " DHAA ! " Oxalic acid ! " 2-O-methyl ascorbate ! " 2-keto-ascorbitol excreted renally.

Ascorbate and Cancer

Intravenous AA Protocols

! ! ! ! !

Intravenous AA Protocols

"Pauling-Cameron "Murata "Riordan "Korean "CTCA

Pauling-Cameron - Protocol ! "100 terminal cancer patients ! "10 g/day AA, iv x 10 days and then orally + standard medical management. ! "1000 historical matched controls, similar patients. Same treatment except for the ascorbate Proc Natl Acad Sci U S A. 1976;73:3685-9.

Ascorbate and Cancer

Intravenous AA Protocols

Murata Protocol ! "2 Sites (Fukuoka and Kamioka) ! " Fukuoka ! "5-30 gm daily ! "99 terminal cancer patients ! "44 controls survived 43 days ! "55 exp AA 246 days ! "Results: Increased survival and Improved quality of life Int J Vitam Nutr Res Suppl 1982;23:103-13.

Pauling-Cameron â&#x20AC;&#x201C; Result ! "The AA group had a mean survival time of about 300 days greater than that of the controls. ! "Survival times greater than 1 yr after the date of un-treatability were: !" 22% of the AA-treated patients !"0.4% of the controls.

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

Ascorbate and Cancer

Intravenous AA Protocols

Murata Protocol ! Kamioka ! "5-30 gm daily ! "31 terminal cancer patients ! "19 controls survived 48 days ! " 6 exp AA 115 days ! "Results: Increased survival and Improved quality of life Int J Vitam Nutr Res Suppl 1982;23:103-13.

Riordan Protocol ! "G-6 PD ! "IVC 15 gm test dose ! "Dose 15-100 gm iv q 2-3 per week ! "Lactated Ringer solution or sterile water ! "5 gm oral AA supplementation off ivc days P R Health Sci J. 2003;22:287-90.

IV C Protocol

Ascorbate and Cancer

•" Although rare, hemolysis can occur in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, due to its oxidative capacity and increased formation of hydrogen peroxide.

Riordan Cases ! "Report of 7 cancer patients ! "Pre-screen G-6 PD ! "IVC 15-100 gm 2-3 times a week ! "Outcomes – All surpassed life expectancy; some had complete remission ! "Safety – not toxic, did not interfere with conventional chemotherapy and decreased toxicity of chemotherapy.

Intravenous AA Protocols

P R Health Sci J. 2004;23:115-8.

Ascorbate and Cancer

RECNAC 2 IV C Protocol

Intravenous AA Protocols

•" Infusion solution adaptation of Riordan Protocol: •" 50-75 g AA •" Ringer's lactate (RL) solution •" 3 x week

Riordan Phase I ! "24 Late stage patients ! "Solid tumors, exhausted other treatments ! "150-710 mg/kg/d (10-50 gm in a 70 kg pt) continuous infusion x 8 weeks ! "Generally well tolerated. One stable disease. ! "Plasma ascorbate 1.1 vs. 1.7 mM

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

Ascorbate and Cancer

Korean ! "10 gm iv x2 q 3 days + ! "4 gm oral qd for a week. ! "Global health/QoL scale p=0.001 ! "Functional scale (physical, emotional, and cognitive) p<0.05 ! "Symptom scale (fatigue, n/v, pain, appetite) p<0.05

CTCA ! "Phase I FDA approved;18 subjects ! "Solid tumors, exhausted other treatments ! "30 g/m2 (50 gm in a 70 kg person) with six dose escalations. ! "Daily for 4 consecutive days for 4 weeks ! "Results: Pending ! " Preliminary results:Not to encouraging!

Intravenous AA Protocols

Yeom CH. J Korean Med Sci 2007; 22: 7-11

Ascorbate and Cancer

Ascorbate and Cancer Safety issues

Intravenous AA Protocols

Adverse effects ! "Mouth dryness ! "Edema ! "Nausea

B19(-12&#P&129,(:32/;5&;53&?=&./-><3-329(,=&(28& (<93,2(4:3&-381.123&>,(.44/23,5&(28&(8:3,53&3D3.95)& ! " I(2;6(.9;,3,5X&=3(,<=&5(<35&Y3,3&ZQL[LLL&\'LLO]&(28& MQQ[LLL&:1(<5&\'LLM]& ! " #/--/2&,3(5/25&6/,&9,3(9-329&12.<;838&1263.4/2[& .(2.3,[&(28&6(47;3)& ! " ^6&W[T'M&>(43295[&ULU&+(8&5183&3D3.95[&-/59<=&-12/,[& 12.<;8127&<39+(,7=_6(47;3& ! " QW&>(43295[&.+(273&12&-329(<&59(9;5&& *(8(=(S=&CJ&39&(<)&*R/C&^23)&'LULNQ\Z]P3UUVUV)&

Systemic Saturation

Ascorbate and Cancer

•" When the concentration of AA in plasma and tissues in the

Safety issues

body is high enough to disturb biochemical parameters. •" AA s conversion to Dehydroascorbate (DHA) is reversed back to AA. Once this takes place, the prooxidant action is decreased, thus AA anticarcinogenic and/or carcinostatic action is reduced or rendered ineffective. •" This physiological phenomenon may occur when high IV doses of AA (100g or more) are given in a continuous schedule. •" Multiple, intermittent, short-term intravenous infusions of vitamin C over a longer time period will correlate with greater antitumor effects than do single continuous IV doses of the same total exposure. •" This may not be an issue with IV Vit C used to treat viral or bacterial infections.

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

Ascorbate and Cancer

Intravenous AA Protocols

What is the most effective dosing regimen? ! "Diverse MOA – not all require same AA plasma/tissue concentrations ! "Higher blood concentrations (milimolar) achieve substantial formation H2O2 ! "H2O2 affects more on rapidly dividing cells ! "Wash out to avoid too much AA (tissue saturation vs. systemic saturation)

What is the most effective dosing regimen? ! "Start at 25 gm and titrate ! "Shorter infusions are more convenient ! "Longer infusions are probably better ! "Synergize (Lipoic and others)

Ascorbate and Cancer

Intravenous AA Protocols

`+(9&15&9+3&-/59&3D3.4:3&8/5127&,371-32a& C.+38;<3&83>32832.3& b/53&(28&%8-12159,(4/2& ! "&QLFU'Q&7-&& ! "K/&(.+13:3&32/;7+&c'^'& d,3e;32.=&\.+,/2/9+3,(>3;4.5]& ! "&'FT&4-35&(&Y330& ! "K/&(:/18&5=593-1.&5(9;,(4/2& ! "K/&>,/8;.3&.=.<1.&>3(05&9/&-(9.+&,323Y127& <(=3,5&/6&-(<172(29&.3<<5&12&9+3&9;-/,)&

AA Saturation ! GI absorption saturation ! Renal reabsorption saturation ! Tissue saturation (interstitial and cellular… not just leukocytes) ! Systemic saturation – When the concentration in plasma and tissues in the body is high enough to disturb biochemical parameters.

Ascorbate and Cancer

Pharmacokinetics of Ascorbate

Intravenous AA Protocols

Distribution- Plasma AA concentrations/dose

A29,(:32/;5&B19(-12&#P& ! " @;(<19=&/6&<163& ! " C;,:1:(<&4-3& ! " K;-/,&-(,03,&,35>/253& ! " K;-/,&7,/Y9+&,35>/253& ! " I39(59(515&12+1?14/2&

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

Ascorbate and Cancer

Intravenous AA Protocols

Duration: 6-12 months; years? Dosing: 50-75gm or higher 100-150 gm? Carcinostatic/Anticarcinogenic? 3 times a week Cancer Protocol: Combined with Oxygen? Other Nutraceuticals? Effect:

Synergistic Nutrients/molecules ! "Oxygen ! "Co-Q10 ! "Lipoic acid ! "ALCAR ! "Others

!"#$%#&'&

RECNAC II ! ! ! ! ! !

If everyone is thinking alike, then no one is thinking

Future Studies

HD iv AA Pkin Studies Hypoxia /hyperoxia /insulin Apoptosis mechanisms Quality of life Liposomal bioavailability studies Full protocol Clinical trials

Benjamin Franklin

People who say it cannot be done should not interrupt those who are doing it.

Systemic Saturation in Intravenous Vitamin C Therapy Michael Gonzalez

This talk is dedicated to the memory of Dr Hugh D. Riordan

!"#$"#%&' The Gonzalez Anti-Cancer Regimen: An Individualized Nutrition, and Enzyme Therapy

Nick Gonzalez

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WILLIAM DONALD KELLEY

1925-2005

JOHN BEARD, D.Sc.

Eccentric Dentist or Cancer Pioneer?

1858-1924

Enzyme Treatment of Cancer

!"#$"#%&' The Gonzalez Anti-Cancer Regimen: An Individualized Nutrition, and Enzyme Therapy

Nick Gonzalez

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NICHOLAS J. GONZALEZ MD Published Works, Books and DVDs

J)/('J*-(' J1,-+' The Truth Behind the Clinical Trial of the Enzyme Treatment of Cancer

!"#$"#%&' The Gonzalez Anti-Cancer Regimen: An Individualized Nutrition, and Enzyme Therapy

Nick Gonzalez

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()*' (1,6),I0/5(' /-:'()*'' ,17+7-5',Z' 4/-4*1'

An Investigation of Nutrition, Cancer, and William Donald Kelley

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Originally Published in 1911, Now Reprinted by New Spring Press

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An Orthomolecular Approach to Allergic and Atopic Disease !"#$"#%&' Kara Fitzgerald

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I see allergic people, they’re everywhere. They don’t know they’re allergic.

IgG IgM Dimeric

IgA IgE

An Orthomolecular Approach to Allergic and Atopic Disease !"#$"#%&' Kara Fitzgerald

670'+)809':;'<110*/=')>2'<9-7?)'

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old infants.

Implication: Immune maturation away from Th2 bias

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J. Nutr. 137: 1031–1036, 2007.

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“…pretreatment with sodium bicarbonate inhibited reappearance of anaphylactic symptoms following wheat and exercise provocation.” Abstract

We present a case of wheat-dependent exercise-induced anaphylaxis, in which pretreatment with sodium bicarbonate inhibited reappearance of anaphylactic symptoms following wheat and exercise provocation. Decrease in blood pH relative to elevation in plasma histamine levels was also inhibited. These results suggest possible efficacy of pretreatment with sodium bicarbonate as a preventive measure in patients with exercise-induced anaphylaxis.

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Mark BJ, Beaty AD, Slavin RG.

Source Section of Allergy and Clinical Immunology, Division of Immunobiology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.

In Abstract one small trial, finned fish allergic patients had negative testslabelto two Fish oil supplements are popular alternative medicines.skin Many manufacturers their products with the warning "avoid this product if you are allergic to fish." The objective of this study was to determine ifsupplements. finned fish (FF)-allergic patients could safely had tolerate fishnegative oil supplements. Six fish oil All FF-sensitive subjects as determined by history and skin testing were selected. They were skin tested challenges with two different fish oil supplements and givenoil an oral challenge of each supplement 1 oral to fish supplements. hour apart. Vital signs were measured at baseline and at 20-minute intervals after each challenge.

Spirometry was measured at baseline and 1 hour after each challenge. Six of six patients with positive skin tests to at least one FF had negative skin tests to both fish oil supplements. All six subjects then had negative oral challenges to both supplements. In this pilot study, FF-sensitive patients tolerated fish oil supplements

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“The basal sIgA levels increased significantly in the experimental subjects but not in controls after 4 weeks of training. An additional practice session immediately after acute stress [also] produced significantly higher sIgA …”

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I am happy to tell you that I am doing quite well . Even my finger nails finally look lady-like. I have not experienced any semblance of polymyalgia. The eczema on my hands which was so horrible for a few years is 95 % better. So wonderful not to have 2-3 band-aids on my hands & fingers at a time…want to thank you for your past support in my " staying the course "

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Darwin, Diet, Disease and Dollars Robert Lustig

•! No disclosures

Darwin, diet, disease, and dollars! Robert H. Lustig, M.D. Division of Endocrinology Department of Pediatrics University of California, San Francisco

OMT, Toronto, Apr. 27, 2013

Past

Present Currently there are 30% more obese than undernourished people worldwide

2001

(World Health Organization)

366 million diabetics in 2011 (5% of the world‘s population)

(International Diabetes Federation)

Future

Venus von Willendorf, Vienna Museum of Natural History Dated to 22,000 BCE, unearthed in 1908

Experts predict 165 million Americans will be obese by 2030

Obesity has been part of the human condition since there were humans

(4 part obesity series in Lancet, August 26, 2011)

100 million Americans will have diabetes by 2050

But something s happened— How did the world get so obese? And how so fast?

(CDC Division of Diabetes Translation, 2011)

Medicare will be broke by 2024

Darwin, Diet, Disease and Dollars Robert Lustig

The explanation? • Obesity continues to worsen, both in prevalence and severity • Obesity is increasing in all developed (and developing) countries

Darwin

• Obesity is increasing in all age groups, and especially in children

The explanation?

• Recidivism is high

• Obesity continues to worsen, both in prevalence and severity

• Obesity is increasing in all developed (and developing) countries

• Obesity is increasing in all age groups, and especially in children

• Recidivism is high

The obvious explanation: Gluttony and sloth

The obvious explanation: Gluttony and sloth The evolutionary explanation: A mismatch between our environment and our biochemistry

What s the selective advantage to obesity?

• Energy storage for a rainy day (month, year, decade)

How is this selective advantage achieved? • Leptin resistance • Insulin resistance

Darwin, Diet, Disease and Dollars Robert Lustig

The neuroendocrinology of energy balance PARADOX:

If you give a 5 year old kid a cookie:

Leptin stimulates the SNS

PARADOX:

If you give a 5 year old kid a cookie:

Mark et al. Acta Physiol Scand 177:345, 2003"

PARADOX:

But if you give a 5 year old obese kid a cookie:

Darwin, Diet, Disease and Dollars Robert Lustig

Dexfenfluramine

The physiology of leptin: The Starvation Response

Weight loss lowers REE/FFM by 20%

Why the negative plateau with weight loss? Because of decreased energy expenditure, to offset the decreased caloric intake •!Decreased non-exercise associated thermogenesis (NEAT) T) • Decreased resting energy expenditure " • Decreased thermic effect of food " • mitochondrial adaptation (UCP's?)

Leibel et al. N Engl J Med 332:621, 1995"

Darwin, Diet, Disease and Dollars Robert Lustig

Energy Expenditure = Quality of Life !

Autonomic Function during the Starvation Response

Decreased energy expenditure:

In response to declining leptin: • Reduced sympathetic activity • decreased lipolysis • decreased gluconeogenesis • decreased energy expenditure

• hypothyroidism • starvation Increased energy expenditure:

• Increased vagal activity • reduced myocardial oxygen consumption • increased adipocyte insulin sensitivity • increased insulin secretion • increased energy storage

• exercise • caffeine • ephedrine (banned)

Aronne et al. Am J Phys 269:R222, 1995"

Lustig, In: Donohoue (ed) Obesity Research and Clinical Applications, Humana, 2008

Lifestyles of the obese (mouse)

Nonogaki et al. Diabetes 52:315, 2003

Darwin, Diet, Disease and Dollars Robert Lustig

Leptin promotes weight loss in a leptin-deﬁcient patient !

Leptin Therapy of Leptin Deficiency

Age 3.5 years

Farooqi et al. N Engl J Med 341:913, 1999"

Age 8 years Farooqi et al, JCI Oct. 2002

Leptin resistance prevents leptin-induced weight loss in obese adults!

Obese subjects are leptin resistant!

Heymsﬁeld et al. JAMA 282:1568, 1999"

Leptin and Leptin Resistance • Leptin levels are a function of adipocyte energy stores • Leptin tells your brain how thin you are, not how fat you are • The brain perceives leptin deficiency as a state of starvation • Leptin deficiency causes energy expenditure to decrease, and thyroid levels to decline, while leptin repletion corrects them • Caloric restriction leads leptin decline before weight loss, and promotes drive to resume caloric intake • Obese subjects are hyperleptinemic and "leptin resistant" • If we could fix leptin resistance, there wouldn't be obesity Rosenbaum et al. JCEM 87:2391, 2002

Darwin, Diet, Disease and Dollars Robert Lustig

The neuroendocrinology of energy balance

What causes leptin resistance?

• Genetic • Anatomic • Functional

Leptin depolarizes, while insulin hyperpolarizes POMC neurons through a PI3K-mediated mechanism

Effects of Insulin on the Adipocyte! !!Stimulates Glut4 mRNA and

protein

!!Stimulates Acetyl-CoA

Carboxylase

!!Stimulates Fatty Acid Synthase !!Stimulates Lipoprotein Lipase !!Hypothalamic actions inhibits

lipolysis by suppressing SNS tone and Hormone-Sensitive Lipase

Hill et al. J Clin Invest 118:1796, 2008

Scherer et al. Cell Metab doi10.1016/j.cmet.2011.01.008

The neuroendocrinology of energy balance

Can hyperinsulinemia block leptin signaling?

Kellerer et al. Diabetologia, 44:1125, 2001

Darwin, Diet, Disease and Dollars Robert Lustig

Anatomic leptin resistance:! Hypothalamic Obesity!

Models/Hypotheses of Hypothalamic Obesity Damaged Ventromedial Nucleus

Damaged Ventromedial Nucleus

Hyperphagia

Vagal Firing Rate

Obesity

Insulin Secretion

Glucose Utilization

IGF-I Receptor

Hyperphagia

Growth

Obesity

Adapted from Sklar. Pediatr Neurosurg. 1994;21:120-123.

Adapted from Bray and Gallagher. Medicine. 1975;54:301-330.

Hypothalamic Obesity Pilot Study— Purpose 1. To assess the insulin secretory dynamics of patients with hypothalamic obesity 2. To assess the efficacy of octreotide in reducing basal and glucose-stimulated insulin release in patients with hypothalamic obesity 3. To assess the efficacy of octreotide in promoting weight loss in patients with hypothalamic obesity

Lustig, Rev Endo Metab Dis 4:23, 2003

Hypothalamic Obesity Pilot Study— Weight and BMI Change

Hypothalamic Obesity Pilot Study— Effects on Glucose and Insulin Responses

Lustig et al. J Pediatr 138:162, 1999"

Darwin, Diet, Disease and Dollars Robert Lustig

Hypothalamic Obesity Pilot Study— Weight Loss Versus:

Octreotide treatment of hypothalamic obesity Demographics • Double-blinded, 6 month placebo-controlled trial of octreotide

• 20 subjects with pediatric hypothalamic obesity ages 8-18; 11M, 9F 2 from St. Jude 18 from other institutions 13 with craniopharyngioma 4 with hypothalamic astrocytoma, optic pathway glioma 1 with suprasellar germinoma 2 with ALL, S/P cranial XRT and chemotherapy • Weight 96.8 ± 5.7 kg, BMI 36.3 ± 1.3 kg/m2, annualized weight gain 15.9 ± 2.9 kg

Lustig et al. J Pediatr 138:162, 1999"

Lustig et al. JCEM 88:2586, 2003"

BMI! P = 0.0005

10! 5!

200!

3! 2! 0!

Octreotide! Placebo! (n = 9)! (n= 9) !

-1!

200! 160!

120!

80!

40!

40! 0! 15! 30! 60! 90! 120!150! 180!

Minutes

Lustig et al. JCEM 88:2586, 2003"

240!

160!

Octreotide! Placebo! (n = 9)! (n = 9)!

Placebo! n = 9!

280!

0 months" 6 months"

240!

Drug! n = 9!

280!

15!

-5!

Octreotide treatment of hypothalamic obesity Insulin dynamics during OGTT (1st Window)"

Insulin (µU/ml)

20!

Weight! P = 0.0008

! BMI

! weight (kg)!

Octreotide treatment of hypothalamic obesity # 1st Window (6 Months)"

0! 15! 30! 60! 90! 120!150! 180!

Minutes

Lustig et al. JCEM 88:2586, 2003"

Octreotide Treatment of Hypothalamic Obesity! PCQL-32 (6 months – 0 months)

Pediatric Cancer Quality of Life! PCQL-32, Version 1!

Functioning

32-item proctored questionnaire " Patient and parent reports on:" "Cognitive functioning" "Physical functioning" "Psychological functioning" "Social functioning" " Validated for ages 8-18 yr"

Placebo Child Parent

Cognitive Physical Psychological Social

0.33 NS 0.33 NS 0.11 NS 0.22 NS

0.33 NS 0.78 NS -0.11 NS -1.22 NS

Octreotide Child

Intergroup

Parent Child Parent

0.22 -1.33 NS NS -1.44 -2.22 NS P=0.05 -1.89 -2.11 P =0.09 P =0.03 -1.89 -1.56 P =0.09 P =0.04

0.11 1.67 NS NS 1.78 3.00 NS P =0.03 2.00 2.00 NS NS 2.11 0.33 NS NS

Lustig et al. JCEM 88:2586, 2003"

Darwin, Diet, Disease and Dollars Robert Lustig

PCQL-32 Parent Report Correlation between !Quality of Life and ! Insulin Response (6 Months â&#x20AC;&#x201C; 0 Months)

!Quality of Life!

30! 15! 0!

P = 0.041

P = 0.77

-15!

"" " " " """""" "

-30! -300!

Lustig et al. JCEM 88:2586, 2003"

Placebo la eb Octreotide O treoti e

-200!

-100!

100!

! Insulin Response!

200!

Octreotide x 1 yr!

Postulated Postulated scheme scheme of of hypothalamic hypothalamic obesity obesity VAGUS OCTREOTIDE

FOOD GLUCOSE INSULIN

YOU

YOUR FAT

Darwin, Diet, Disease and Dollars Robert Lustig

Octreotide-LAR 40 mg IM q 28d Effects on Weight and BMI Stratified By Response

Functional studies of leptin resistance: Octreotide for adult obesity

Patients who completed 24 weeks (n=44)

Hypotheses: Insulin hypersecretion occurs in a subset of obese adults Insulin suppression using octreotide will Slow or reverse adipogenesis Promote weight loss

P< 0.0001

Velasquez-Mieyer et al. Int J Obesity 27:216, 2003"

Octreotide-LAR 40 mg IM q28d " Effects on SpeciďŹ c Nutrient Daily Intake!

ANOVA with repeated measures

Octreotide-LAR 40 mg IM q 28d Insulin Dynamics During OGTT de

(

0.001)"

Velasquez-Mieyer et al. Int J Obesity 27:216, 2003"

Octreotide-LAR 40 mg IM q28d

Octreotide-LAR 40 mg IM q 28d Changes in Plasma Leptin

Changes in Resting Energy Expenditure (REE) d!

! epti"

Lustig et al. Int J Obesity 28:1342, 2004"

Darwin, Diet, Disease and Dollars Robert Lustig

Octreotide-LAR x 6 months

Improvement of functional leptin sensitivity

!! Forced weight loss (Rosenbaum)

!! Drug-induced reduction in insulin (Lustig)

What s the similarity? The drop in insulin

Octreotide-LAR 40 mg IM q28d Changes in the REE:Leptin Ratio

Insulin is an endogenous leptin antagonist (?)

Lustig et al. Int J Obesity 28:1342, 2004"

Darwin, Diet, Disease and Dollars Robert Lustig

Insulin is an endogenous leptin antagonist (?)

Does this make Darwinian sense?

Insulin gives the human the ability to modulate weight gain acutely, by allowing hyperinsulinemia to induce leptin resistance:

1. Puberty 2. Pregnancy

1. Puberty 2. Pregnancy Doesn t it make sense that the same hormone that promotes the energy storage also inhibits leptin, so that energy can be stored?

Where did the hyperinsulinemia come from?!

• Genetics i.e. VNTR of insulin gene

• Epigenetics i.e. SGA, LGA promote insulin resistance

Diet

• Social Environment (cortisol) i.e. economic (food insecurity), acculturation, violence, other societal stressors • Exercise Environment i.e. cars; lack of sidewalks, play areas, school activity • Food Environment i.e. fructose (too much), fiber (not enough) Causes insulin resistance, hyperinsulinemia

Darwin, Diet, Disease and Dollars Robert Lustig

Fructose is not glucose 24 kcal

• Fructose is 7 times more likely than glucose to form Advanced Glycation End-Products (AGE s)

Hepatocyte

• Fructose does not suppress ghrelin • Acute fructose does not stimulate insulin (or leptin)

96 kcal

• Hepatic fructose metabolism is different • Chronic fructose exposure promotes the Metabolic Syndrome Elliot et al. Am J Clin Nutr, 2002 Bray et al. Am J Clin Nutr, 2004 Teff et al. J Clin Endocrinol Metab, 2004 Gaby, Alt Med Rev, 2005

Le and Tappy, Curr Opin Clin Nutr Metab Care, 2006 Wei et al. J Nutr Biochem, 2006 Johnson et al. Am J Clin Nutr 2007 Rutledge and Adeli, Nutr Rev, 2007 Brown et al. Int. J. Obes, 2008

Ethanol is a carbohydrate

CH3-CH2-OH

But ethanol is also a toxin

100

Darwin, Diet, Disease and Dollars Robert Lustig

Acute ethanol exposure

Acute fructose exposure

• CNS depression • Vasodilatation, decreased BP • Hypothermia • Tachycardia • Myocardial depression • Variable pupillary responses • Respiratory depression • Diuresis • Hypoglycemia • Loss of fine motor control

60 kcal (+ 12 kcal glucose)

48 kcal

What s the difference?

Calories 150 Percent CHO 10.5% (sucrose) Calories from fructose 75 (4.1 kcal/gm) other carbs 75 (glucose) alcohol 1st pass GI metabolism 0% Calories reaching liver 90

101

150 3.6% (alcohol) 60 (maltose) 90 (7 kcal/gm) 10% 92

Darwin, Diet, Disease and Dollars Robert Lustig

What s the difference?

Calories 150 Percent CHO 10.5% (sucrose) Calories from fructose 75 (4.1 kcal/gm) other carbs 75 (glucose) alcohol 1st pass GI metabolism 0% Calories reaching liver 90

What s the difference?

150 3.6% (alcohol)

Calories 150 Percent CHO 10.5% (sucrose) Calories from fructose 75 (4.1 kcal/gm) other carbs 75 (glucose) alcohol 1st pass GI metabolism 0% Calories reaching liver 90

60 (maltose) 90 (7 kcal/gm) 10% 92

150 3.6% (alcohol) 60 (maltose) 90 (7 kcal/gm) 10% 92

Fructose induces insulin resistance, which induces leptin resistance

Does this make Darwinian sense? Seasonal insulin resistance: • Fructose was available at harvest, 1-2 months per year • Followed by 4-5 months of winter, with no food available • If leptin worked all the time, you couldn t store energy • Selective advantage by inducing seasonal insulin resistance by gorging on fruit, while it was available

Seasonal fruit binges in orangutans

Fructose induces insulin resistance, which induces leptin resistance

Availability

Calories

Ketones

But fructose is now available globally 24/7/365, and consumed in unlimited amounts And unopposed by fiber (read: orange juice)

Diet Knott, Int J Primatol 19: 1061, 1998

102

Darwin, Diet, Disease and Dollars Robert Lustig

Taste buds

Is sugar addictive? The lay public seems to know….

Tongue Diagram

Sugar hides: • salty (Chex mix, honey roasted peanuts) • sour (German wines, lemonade) • umami (sweet-and-sour pork) • bitter (milk chocolate)

A “Sense”sational Christmas

Taste buds

Tongue Diagram

Rev. 06.02.03

Our sugar craving is also Darwinian

Sugar hides: • salty (Chex mix, honey roasted peanuts) • sour (German wines, lemonade) • umami (sweet-and-sour pork) • bitter (milk chocolate)

Does this make Darwinian sense?

There are no foodstuffs in nature that are both sweet and

Sweet-Ease increases endogenous opioids to reduce pain, Even in neonates

acutely poisonous A “Sense”sational Christmas

Rev. 06.02.03

10 Most Obese States

> 30% obese

Disease

103

Darwin, Diet, Disease and Dollars Robert Lustig 3/2/12

10 Most Obese States

> 30% obese

10 Most Obese States

10 Laziest States

< 63% active

api.imapbuilder.net/1.0/map/15787/

10 Most Unhappy States

10 Laziest States

< 63% active

> 30% obese

Interactive Map by iMapBuilder

api.imapbuilder.net/1.0/map/15787/

3/2/12

10 Most Obese States

> 30% obese

api.imapbuilder.net/1.0/map/15787/

3/2/12

10 Most Unhappy States

10 Laziest States

10 Most Obese States

< 63% active

1/1

api.imapbuilder.net/1.0/map/15787/

10 Most Unhappy States

10 Laziest States

< 63% active

> 30% obese Interactive Map by iMapBuilder

Interactive Map by iMapBuilder

Adult Heart Disease Rate

api.imapbuilder.net/1.0/map/15787/

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11/2/11

3/2/12

10 Most Obese States

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StatPlanet

api.imapbuilder.net/1.0/map/15787/

10 Most Unhappy States

10 Laziest States

Global consumption of sugar/sugarcrops Calories per day, 2007

> 30% obese

< 63% active Interactive Map by iMapBuilder

Adult Heart Disease Rate

api.imapbuilder.net/1.0/map/15787/

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Data from Food and Agriculture Organization, World Health Organization, 2007

104

Darwin, Diet, Disease and Dollars Robert Lustig

An international longitudinal panel analysis of diet and diabetes Food and Agriculture Organization (FAO); FAOSTAT Food Supply data in kcal/capita/day calculation: Food Supply= !Supply Elements - !Utilization Elements = (Production + Import Quantity + Stock Variation â&#x20AC;&#x201C; Export Quantity) - (Feed + Seed + Processing + Waste). Only industrial waste factored in. Extracted Food Supply data for 2000 and 2007: Total Calories Roots & Tubers, Pulses, Nuts, Vegetables Fruits-Excluding Wine Meat Oils Cereals Sugar, Sugarcrops & Sweeteners International Diabetes Federation (IDF) 2000 (1st ed) and 2007 (3rd ed) The World Bank World Development Indicators Database

Prevalence of diabetes, 2010

GDP expressed in purchasing power parity in 2005 US dollars for comparability among countries

Basu et al. PLoS One, Feb 27, 2013

An international longitudinal panel analysis of diet and diabetes

Total 204 countries; complete data for 154 countries (50 not different)

Total 204 countries; complete data for 154 countries (50 not different) Data monitoring and quality Generalized estimating equations Conservative fixed effects approach (Hausman test) Hazard model to control for selection bias (Heckman selection model) Longitudinal data to determine what preceded diabetes (Granger causality) Period effects controlled for secular trends that may have occurred as a result of changes diabetes detection capacity or importation policies.

Basu et al. PLoS One, Feb 27, 2013

An international longitudinal panel analysis of diet and diabetes

An international longitudinal panel analysis of diet and diabetes Total 204 countries; complete data for 154 countries (50 not different)

Diabetes prevalence rose from 5.5% to 7.0% for 204 countries 2000-2007

Data monitoring and quality Generalized estimating equations Conservative fixed effects approach (Hausman test) Hazard model to control for selection bias (Heckman selection model) Longitudinal data to determine what preceded diabetes (Granger causality) Period effects controlled for secular trends that may have occurred as a result of changes diabetes detection capacity or importation policies. Controlled for: GDP per capita

% population living in urban areas

Obesity

% of population over age 65

Basu et al. PLoS One, Feb 27, 2013

105

Darwin, Diet, Disease and Dollars Robert Lustig

106

Darwin, Diet, Disease and Dollars Robert Lustig

How our food dollars have been reallocated

Dollars

Philpott, Mother Jones 2012 (from Bureau of Labor Statistics)

Who s winning the war? • Despite the economic downturn of 2008, McDonald s revenues and stock price continues to rise; and Coke and Pepsi still fared better than the S&P 500 Week of Oct 3, 2011:

^GSPC 1155.46

MCD 87.20

KO 65.90

PEP 61.02

100%

McD

80%

Of the 600,000 items in the American food supply,

60%

Coke

40%

Pepsi

80% have added sugar (sucrose, HFCS)

S&P 500

20% 0

-20% -40%

Jul

Oct

2008

Apr

Jul

Oct

2009

Apr

Jul

Oct

2010

Apr

Jul

Oct

2011

Apr

Jul

Oct

Volume: 4,514,868,224 8B 6B 4B 2B 1D

1950

1960

1970

YTD

Max

1980

FROM: Jan 3 2007

1990

TO: Oct 3 2011

2000

-18.04%

2010

Ng et al. J Acad Nutr Diet 2012

Who s winning the war?

Summary: The Darwinian explanation for the obesity epidemic

Stock prices of various food companies compared to the S&P500 2007-2011 Week of Oct 3, 2011:

^GSPC 1155.46

CAG 25.03

ADM 25.45

PG 63.91

GIS 38.75

KFT 33.76

• Obesity means leptin resistance, or brain starvation

HRL 28.17

• The starvation response causes recidivism 60%

• Energy expenditure and quality of life are the same thing

Hormel 40%

Archer Daniels Midland Kraft General Mills

• Defects in insulin signaling promote leptin resistance

20%

• Insulin appears to be an endogenous leptin antagonist

Kraft

ConAgra

S&P500

-20%

Proctor & Gamble/

• Fructose, through de novo lipogenesis, induces hepatic insulin

-40%

resistance, driving metabolic syndrome, and wasting health care dollars

Jul

Oct

2008

Apr

Jul

Oct

2009

Apr

Jul

Oct

2010

Apr

Jul

Oct

2011

Apr

Jul

Oct

Volume: 4,514,868,224

• Fructose is addictive, and drives excess food consumption

8B 6B 4B 2B 1D

1950

1960

1970

YTD

1980

Max

FROM: Jan 3 2007

1990

TO: Oct 3 2011

2000

• Our food environment is fructosified

-18.04%

• The food industry has no impetus to change its practices

2010

107

Darwin, Diet, Disease and Dollars Robert Lustig

Further reading We have started a non-profit to provide

Is fast food addictive? Andrea K. Garber, Robert H. Lustig

medical, nutritional and legal analysis and consultation

Arterioscler Throm Vasc Biol 25:2451, 2005

Curr Drug Abuse Rev 4:146, 2011

to promote personal and public health vs. Big Food

DOCTORS FOOD PROJECT

Nat Rev Gastroenterol Hepatol 7:251, 2010

Please let me know if you would like more information! rlustigmd@earthlink.net J Am Diet Assoc 110:1305, 2010

Further reading

Current Opinion Gastroenterology, 29:170, 2013

PLoS One 8:e57873, 2013

Hudson Street Press(Viking Penguin)

108

Controversial Issues in Bioidentical Hormone Therapy

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Efrain Olszewer

Controversial aspects on hormone replacement Dr. Efrain Olszewer CMP-Fapes 2013

Safety of bioidentical hormones •! synthetic hormones

•! Bioavailability

•! natural hormones

•! Via hepatic metabolism

•! bioidentical hormones •! Yam, Dioscorea

TRH Lancet (07/02) Breast cancer Cardiovascular risk Endometrial cancer

•! Route of administration

Embolic phenomen alzheimer

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•! Drop in Breast Cancer Rates Due to Less Synthetic HRT UseNew England Journal of Medicine Says Long-Term HRT Probably Caused Breast Cancer in 200,000 Women.

& &

109

Controversial Issues in Bioidentical Hormone Therapy

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Efrain Olszewer

•! The Research: Chlebowski RT, Kuller LH, Prentice RL, Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women, NEJM Vol 360:573-587 February 5, 2009.

245)

•! The Conclusion: In summary, the increased risk of breast cancer associated with estrogen-plus-progestin therapy declined markedly soon after discontinuation of the therapy and was unrelated to a change in the use of mammography. This finding supports the hypothesis that the recent reduction in the incidence of breast cancer among women in certain age groups in the United States is predominantly related to a decrease in the use of combined estrogen plus progestin.

Three cases of endometrial cancer associated with bioidentical hormone replacement therapy John A Eden, Neville F Hacker and Michael Fortune We describe three women who developed endometrial cancer after taking bioidentical hormone replacement therapy (HRT) to relieve menopausal symptoms. Although pharmaceutical HRT is a well established and tested therapy, little is known about the quality control, safety and efficacy of bioidentical HRT. Women should be advised to avoid bioidentical HRT, and those who continue to use it should receive regular endometrial surveillance. (MJA 2007; 187: 244-

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The Medical Journal of Australia ISSN: 0025- 729X 20 August 2007 187 4 244-245 ©The Medical Journal of Australia 2007 www.mja.com.au Notable Cases atient 1 A 71-year-old non-diabetic woman had been on some form of hormone replacement therapy (HRT) since the age of 49 years. She took oral oestrone sulfate 1.25mg daily and medroxyprogesterone acetate 10mg for at least 10 days a month for 8 years. For the next 2 years, she used a 3.2% compounded topical progesterone cream (at a daily dose of one level spoonful ). In December 1997, she had some irregular vaginal bleeding, which was investigated by diagnostic hysteroscopy and curettage. The tissue diagnosis was atrophic endometritis. Between June 1998 and July 2002, she used bioidentical HRT as troches. Each troche contained: oestradiol, 1.75mg; progesterone, 300mg; testosterone, 4.5mg; and dehydroepiandrosterone (DHEA), 5mg. The initial dose was half a troche per day, dissolved in the mouth. Between July 2002 and December 2004, she used one-eighth of a troche in the morning and one-quarter in the evening. Each troche contained: trieste (oestrone, oestradiol, oestriol), 3.0mg; progesterone, 400mg; testosterone, 1.5mg; and DHEA, 5mg. Early in 2004, she presented with several episodes of vaginal bleeding, and an ultrasonic scan revealed a thickened endometrial lining (combined thickness, 18mm; normal for a postmenopausal woman is <5mm). Hysteroscopy confirmed a grossly abnormal endometrium with abnormal vascularisation. Curettage revealed a grade 2 endometrioid carcinoma. She underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The final diagnosis was stage IA, grade 2 endometrial cancer. had been commenced while she was still menstruating. The troches had contained varying doses of DHEA, oestrone, oestradiol, oestriol and progesterone (doses unknown). The troches were posted to her by mail and she was monitored by telephone conversations with a nurse. A pelvic ultrasound revealed a thickened endometrium; hysteroscopy and curettage showed a polypoid lesion at the fundus. Histopathology revealed grade 2 endometrial cancer. She underwent total abdominal hysterectomy and bilateral salpingo- oophorectomy, and the final diagnosis was stage IA, grade 2 endometrial cancer undergo

Competing interests John Eden is a consultant for Wyeth, AstraZeneca, Arkopharma, and Lawley Pharmaceuticals. www.fda.gov/cder/guidance/5412dft.pdf (accessed Jul 2007). 5North American Menopause Society.

110

Controversial Issues in Bioidentical Hormone Therapy

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Efrain Olszewer

Estradiol Activity

Progesterone Activity 40 35

800

Estradiol (pmol/L)

700 600 500 400 300

30 25 20 15 10

200

100 1

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Day of Cycle

Testosterone by Age Distribution

TESTOSTERONE by AGE DISTRIBUTION

Activity in Men

25 20 15 10 5 0 *10-19

20-29

30-39

300

40-49

50-59

60-69

70-80

50-59

60-69

70-80

Age in Decades

DHEA-S 100

Activity in Women

0 10

25 20 15 10 5 20-29

30-39

40-49 Age in Decades

Circadian Rhythym of Cortisol

hGH Decline with Age hGH 2000 1800 1600 1400 1200 1000 800 600 400 200 0

10 20 30 40 50 60 70 80 years

6:00

0 *10-19

Age in Years

DHEA-S (nMol/L)

200

CORTISOL (nmol/L)

Testosterone (pmol/l)

400

30 DHEA-S (nMol/L)

DHEA-S

8:00

10:00

12:00

14:00

16:00

18:00

20:00

22:00

24:00:00

Time of Day

111

Controversial Issues in Bioidentical Hormone Therapy

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Efrain Olszewer

Hormonal aging •! •! •! •!

Somatopause = deficit of growth hormone Adrenopausa = deficit adrenal Andropause = testosterone deficit Menopause = deficit of female sex hormones

Estrogenios Estron

Estradiol oxidation antioxidants

Estriol

Estradiol

estrona

Estradiol

safer 1 - 2 mg daily

2 - OH - estradiol Neutral or benefic

Estradiol

Catecol - o - metil transferasa

16 - OH - estradiol cancerigen

Equilin

4 - OH - estradiol

Stimulate alfa cells

Highly cancerigen

112

Controversial Issues in Bioidentical Hormone Therapy

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Efrain Olszewer

How to treat

phyto •! Vitex agnus cactus

•! When estriol

•! When progesterone

•! Isoflavones

•! When estradiol

•! When testosterone

•! Red clover

•! Angelica sinensis

•! When estron

•! Cimicifuga

Near Adjacent Cancerous Human Breast Tissue Stained for 16!-Hydroxyestrogen (845X)

Normal Human Breast Tissue stained for 16!-Hydroxyestrogen (845X)

Klug TL, US Patent 5,854,009

Breast Cancer Tumor Stained for 2-Hydroxyestrogens (845X)

Normal Human Breast Tissue Stained for 2-Hydroxyestrogens (845X)

Klug TL, US Patent 5,854,009

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Efrain Olszewer

•! ZV •! A study of over 54,000 postmenopausal women in France, the risk of breast cancer among women using HRT and bioidentical hormones for nearly three years. Risk of breast cancer increased by 70 per cent women taking progestins, forms that are not bioidentical progesterone. •! Among those taking bioidentical progesterone, the risk decreased by 10 percent.

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Controversial Issues in Bioidentical Hormone Therapy

13-03-25

Efrain Olszewer

Breast cancer

ANDROPAUSA •! Andropause: "MALE MENOPAUSE"; "VIRINOPAUSA" •! CLINICAL CHANGES ASSOCIATED WITH A DECREASE OF TESTOSTERONE •! HOME VARY BETWEEN 45-60 YEARS •! MOST IMPORTANT DATA: •! FALL OF LIBIDO •! SEXUAL IMPOTENCE •! laboratory: •! DECREASE OF DHEA •! DECREASE OF TESTOSTERONE

•! Receptor •! Tamoxifen •! Melatonin •! Flaxseed powder-lignanas

TESTOSTERONA •! TESTOSTERONA " 5 ! REDUCTASA " DHTA

•! ISOLATED FROM cow TESTICLES IN 1935 •! INTRODUCED IN 1937 AS A TREATMENT •! Steroidogenic enzyme TESTOSTERONE 4 FORM OF CHOLESTEROL: •! 2 ENZYMES ! 5 REDUCTASAS •! 1 ENZYME aromatase •! 2 ENZYMES FOR RECIPIENTS Androgens and estradiol

•! •! •! •! •! •! •! •! •! •!

5 ! REDUCTASA ABUNDANTE EM: PROSTATA PELE TECIDOS DE REPRODUÇÃO DHT E O ANDROGENO MAIS POTENTE TESTOSTERONA VIRA ESTRADIOL PELA ENZIMA: AROMATASA, ABUNDANTE EM: TECIDO ADIPOSO FIGADO SNC

tstosterone

Aging and low testosterone levels •! Decrease muscle tissue

•! Oral

•! DECREASE OF HAIR AND BY

•! transdermal •! intramuscular

•! DECREASE OF SEXUAL FUNCTION AND LIBIDO •! DECREASE hematopoiesis •! Osteopenia and BONE FRACTURED

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Prostatic BPH

Measuring hormones •! urine

•! •! •! •! •!

•! Blood

Finasteride Dutasteride Saw palmetto Nettle root Pygeum africanus

•! saliva

DO YOU KNOW YOUR SEX HORMONE STATUS?

Sexual desire-phirst stage

Will learm of a critical blood marker of hormonal balance called sex hormone-binding globulin or SHBG. SHBG: THE MASTER REGULATOR FOR TESTOSTERONE AND ESTROGEN

" !Initial phase: " !Libid-sexual desire: " !sex-related with satisfaction controlled by dopamine and testosterone

SHBG: is a protein produced primarily in the liver, although the testes, uterus, brain, and placenta also synthesize it. It serves as a transport carrier, shuttling estrogen and testosterone to sex hormone receptors throughout your body. SHBG also safeguards these vital hormones from degrading too rapidly and prevents their clearance from the body.

In females:

Physiological changes

In males:

& & & &

" !Sexual arousal for a man is usually indicated by the swelling and erection of the penis when blood fills the corpus cavernosum. Woman, sexual arousal leads to increased blood flow to the clitoris and vulva, as well as vaginal

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116

Male sexual arousal. On the left of the image the male genitalia are in regular, flaccid state; on the right the male is sexually aroused and his penis has become erect. Penile tumescence and erection The veins in the penis may become more prominent Tightening and/or retraction of the foreskin often exposing the glans penis Emission of pre-ejaculatory fluid Swelling of the testes Ascension of the testes Tensing and thickening of the scrotum Pupil dilation

Controversial Issues in Bioidentical Hormone Therapy

13-03-25

Efrain Olszewer

Second stage

Third stage

" !Erection of genital tissues:

" !orgasm

" !Outcome of penile erection and in women by genital lubrification controlled by acetylcholine and nitric oxide

" !Ejaculation in men defined by serotonin norepinephrine and oxitocine

117

13-03-25! Orthomolecular Treatment for Depression and Bipolar Disorder

Bo Jonsson

Disposition !! !! !! !! !! !! !! !! !!

!"#$%&%'()*'+",-"(+#&(.#,/%",, 0(1"(223%.,+.4,531%'+",032%"4(",, 5%,6,7%.22%.8,9:0:8,;$:0:, <(.#(",/%",=>()?@(,032%"4("28,, A#,BC"+.2,6%213#+'D, 0(1+"#&(.#,%/,<'3.3)+',E(*"%2)3(.)(8, F+"%'3.2G+,H.2?#*#(#8,A#%)G$%'&8,AI(4(., J%:K%.22%.LG3:2(,, !

Presentation Depression inside the box Evolution Depression outside the box Integrative psychiatry Lifestyle factors Orthomolecular treatment for depression Orthomolecular treatment for bipolar disorder Multinutrient treatment

42nd Orthomolecular Medicine Today

Meeting Abram Hoffer in Ottawa 2005

Toronto, 2013, April 27

Toronto, 2013-04-27

Depression inside the box: conventional treatment

!! Patented psychopharmacological drugs !! Psychotherapy

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Depression inside the box: criticism

Evolution

Strong criticism against current medical drug paradigm:

! Nothing in biology makes sense ! except in the light of evolution.! Theodosius Dobzhansky (1900-1975)!

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Orthomolecular Treatment for Depression and Bipolar Disorder13-03-25! Bo Jonsson Evolutionary aspects and! the human condition!

Epigenetics

1. Our place on earth! ! passed time! ! Close to the equator, regular light rhythm.! ! ! !

42nd Orthomolecular Medicine Today

Toronto, 2013, April 27

N:,,E*#"3?%., passed time!

today !

Hunted and gathered food: meat, ďŹ sh, fowl, eggs, vegetables, fruit, roots, nuts!

Cleaner air, water and ground. Contaminated, toxic nature. Hunter/gatherers in interplay Living indoors, separated with nature.! from nature.!

42nd Orthomolecular Medicine Today

O:,,A%)3(#P,

passed time!

Small moving groups.! Crude society. Barter, direct experience, oral tradition.! !

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Toronto, 2013-04-27

Global settlement, big light variations, electricity, shift work, 24hour society.!

42nd Orthomolecular Medicine Today

M:,,!*",1'+)(,3.,.+#*"(, passed time!

today!

Toronto, 2013-04-27

today !

Since 10,000 years: cultivation and cattle breeding: bread, milk. Today: sugar, reďŹ ned food. ! !

42nd Orthomolecular Medicine Today

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Q:,,;2P)$%2%)3+',"('+?%.2, today !

passed time!

Direct mutual contact with few people. Presence in the now (mindfulness). !

Big cities, tight ! living. Complicated society. Money! economy, e-business, unintelligible growth of information.!

Toronto, 2013-04-27

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today!

Unpersonal one-way contact with masses, alienation, hollow social capital. Flight in time and space. !

Toronto, 2013-04-27

13-03-25! Orthomolecular Treatment for Depression and Bipolar Disorder

Bo Jonsson

R:,,<*'#*"(,, passed time! Sensory impressions with few or no aids.!

S:,,T%"G3.U,'3/(,+.4,#()$.%'%UP, passed time! today!

today!

Work framed from needs of a limited group. Simple working tools, intelligible for all.!

Technically sophisticated.!

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42nd Orthomolecular Medicine Today

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Depression outside the box

V:,,;$P23)+',+)?@3#P, passed time!

Vague relation work and need. Increased demands, decreased personal control. Incomprehensible works for the non-! specialist.!

today!

Walking, carrying and Moving and working hunting with own with mechanic power. strength.! Sedentary lifestyle. !

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42nd Orthomolecular Medicine Today

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!! !! !! !! !! !! !! !!

Orthomolecules in food and supplements Physical activity Light therapy Sleep regulation Earthing/grounding, negative ions Nature and culture experience Societal involvement Stress management

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120

available for Taiwan and Puerto Rico. For the primary analysis, sugar consumption rates (cal/cap/day) were correlated with the annual rate of major depression (as described above), using the Pearson correlation coefficient. Cognizant of the fact that other dietary factors may be driving the correlation between sugar and depression, we correlated fish consumption with sugar consumption, based on recent theories of omega-3 fatty acids and depression, as well as the prior work of Hibbeln [Hibbeln, 1998]. FAO fish consumption data were obtained from World Health Organization [1996].

13-03-25! Orthomolecular Treatment for Depression and Bipolar Disorder

Bo Jonsson

Integrative psychiatryFor

RESULTS

the six countries with available data for the primary analysis, there was a highly significant correlation between sugar consumption (cal/cap/day) and the annual rate of depression (Pearson correlation 0.948, P¼0.004). Fish consumption and sugar consumption were not significantly correlated (Spearman correlation �0.210, P¼0.375) for the countries examined, even after of Iceland, which was a statistical outlier outsideremoval the box! (Spearman correlation �0.384, P¼0.105).

Include what’s not excluding what’s inside!

DISCUSSION

42nd Orthomolecular Medicine Today

Lifestyle factors - sugar Westover, Depress Anxiety 2002;16: 118-20

We report a correlation between sugar consumption and the prevalence of major depression. Naturally, a correlation may be due to a variety of factors, such as the action of a third, unobserved variable, and does not necessarily imply etiology. Individual-level correlations cannot be assumed to correlate with aggregate-level correlations. It is also possible that the methodology employed may lead to spurious findings, and caveats must be considered. For example, the limited number of countries with available data for both depression epidemiology and sugar consumption warrants a cautious interpretation of the data. In addition, although the Weissman et al. study is perhaps the most rigorous examination of the cross-national prevalence of major depression, results from other studies have varied widely. A recent study has suggested that the Chinese underreport depressive symptoms, which may help to explain the cross-national differences in the prevalence of depression, especially in the Far East [Parker et al., 2001]. In addition, other factors that vary across cultures may be related to both the incidence of depression and sugar consumption. Hibbeln and other have postulated a relationship between omega-3 fatty acids and depression [Hibbeln, 1998]. Investigation of the relationship between fish intake, as used by Hibbeln and others to assess omega-3 intake in a population, and sugar consumption, did not reveal a significant correlation. Although speculative, there are some mechanistic reasons to consider that sugar consumption may directly impact the prevalence of major depression.

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Orthomolecular treatment for depression – vitamin B2

Yamamoto et al. have found that sucrose taste stimulation significantly increases levels of b-endorphins in rats [Yamamoto et al., 2000]. In addition, the !! The importance of food has for mood increasingly suggested. administration of opioids been is found to increase Arch Gen Psychiatry 2009;66:1090-8 sugarSánchez-Villegas, intake [Zhang and Kelley, 1997], whereas opioid Akbaraly,cause Br J Psychiatry 2009;195:408-13 antagonists marked reduction in sugar intake [Ostrowski et al., 1980]. Hence, it appears that sugar Jacka, Am J Psychiatry 2010;167:305-11 ingestion and opioid production may exist in a Jacka, PLoS One 2011;6:e24805 reinforcing cycle. The possibility that abnormalities in endorphins may contribute to depression has been !! Lifestyle factors are considered as important in mood investigated for many years. Cytokine theories of disorders. depression also ofbeen proposed [Maes et al.,to important Lopresti:have A review lifestyle factors that contribute 1993;pathways Leonard,associated 2001]. A with number studies show that majorofdepression: Diet, sleep and opioids have effects on cytokines [Apte et al., 1989; exercise. J Aff Dis 2013 (in press) Apte et al., 1990; Chao et al., 1994; McCarthy et al., 2001]. Also of interest is a growing body of work that links major depression with oxidative stress in humans [Bilici et al., 2001]. Although the link between increased sugar consumption, increased oxidative stress, and major depression is entirely speculative, one study has reported persistent hyperglycemia in rats fed a sucrose-rich diet long-term [Lombardo et al., 1996]. Hyperglycemia, in turn, has been associated with increased generation of reactive oxygen species [Giugliano et al., 1996] and inhibition of glucose-6phosphate dehydrogenase (G6PD) [Zhang et al., Orthomolecular treatment for reported to 2000]. G6PD from rabbit brain has been be markedly sensitive to inactivation depression – vitamin B1 by oxidants and free radicals [Ninfali et al., 2001]. Also of note, a neuroimaging study in humans has shown pleasant and aversive tastes to activate the orbitofrontal cortex, anterior insula, and amygdala !! Thiamine: mitochondria, CNS, acetylcholine, [O’Doherty et energy, al., 2001]. These same regions demon- antioxidant strate neurophysiologic abnormalities in major depression Brozek, [Drevets, Am2001]. J Clin Nutr 1957;5:109-20 InSmidt, summary, a correlation J Gerontol 1991;M16-22between increasing sugar consumption and increased prevalence of Benton, Neuropsychobiology 1995;32:98-105 major depression may exist. Future research plans Benton, Psychopharmacology (Berl) 1997;129:66-71 include a study of the cross-city relationship between consumer-level sugar consumption and level of 42nd Orthomolecular Medicine Today

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42nd Orthomolecular Medicine Today

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Orthomolecular treatment for depression – vitamin B3

!! Riboflavin: energy, mitochondria, antioxidant, anti-inflammatory

!! Niacin(amide): energy, mitochondria, coenzyme precursor, neuroprotector, anti-inflammatory

Sterner, Am J Clin Nutr 1973;26:150-60 Carney, Br J Psychiat 1982;141:271-2 Benton, Neuropsychobiology 1995;98-105

42nd Orthomolecular Medicine Today

Lifestyle factors

Figure 1. Refixed sugar consumption and prevalence of major depression.

Depression is a symptom of pellagra Babcock, Am J Insanity 1911;67:517-40 Spies, Am J Med Sci 1938;196:461-75 Aring, J Neurol Psychiatry 1939;335-60

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Orthomolecular treatment for depression – vitamin B3

Orthomolecular treatment for depression – NADH

Treatment of depression with niacin or niacinamide Washburne, Ann Intern Med 1950;32;261-9 Tongue, Ann Intern Med 1953;38:551-3 Malcolm, Psychosomatics 1975;16:68-9 Chouinard, Acta Psychiatr Scand 1979;59:395-414 Prousky, J Orthomol Med 2010;25:137-47

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!! NADH: ATP increase, antioxidant, DNA repair Treatment of depression with NADH Birkmayer, New Trends Clin Pharmacol 1991;5:75-86

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42nd Orthomolecular Medicine Today

Orthomolecular treatment for depression – vitamin B6

Toronto, 2013, April 27

Orthomolecular treatment for depression – vitamin B9

!! Pyridoxal phosphate: cofactor in amino acid metabolism

!! Folic acid (synthetic form of folate)

Dietary intake inverse to depressive symptoms in girls and boys Murakami, Psychosom Med 2010;72:763-8

Treatment of depression Coppen, J Affect Disord 2000;60:121-30

Treatment of depression in premenopausal women Williams, Fam Pract 2005;22:532-7

!! L-methylfolate (Deplin) A better alternative in low MTHFR activity (polymorphism) Stahl, J Clin Psychiatry 2008;69:1352-3

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42nd Orthomolecular Medicine Today

Orthomolecular treatment for depression – vitamin B12

Orthomolecular treatment for depression – vitamin C

!! Cobalamin: red blood cells, cell metabolism, nervous system, neurotransmitter synthesis, intracellular antioxidant

!! Ascorbate: antioxidant, mitochondria, cofactor Psychiatric patients need more ascorbate and 1 gram daily decreased depressive, manic and paranoid symptoms Milner, Br J Psychiatry 1963;109:294-9

van Tiggelen, J Orthomol Psychiatry 1983;12:305-11 van Tiggelen, Am J Psychiatry 1984;141:136-7 Froese, Expert Rev Mol Med 2010;12:e37 Hintikka, BMC Psychiatry 2003;3:17 Bar-Shai, Psychosomatics 2011;52:384-6

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Vitamin C improves mood Brody, Biol Psychiatry 2002;52:371-4 Zhang, Nutrition 2011;27:530-3

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RCT: Vitamin D3 1500 IU/d in depression

Orthomolecular treatment for depression – vitamin D

!! Vitamin D: brain receptors and enzymes Correlates with extraversion and openness Ubbenhorst, Psychopharmacology 2011;215:733-7

Vitamin D improves mood Lansdowne, Psychopharmacology (Berl) 1998;135:319-23 Gloth, J Nutr Health Aging 1999;3:5-7 Parker, Acta Psychiatr Scand 2011;124:243-9 Khamba, J Orthomol Med 2011;26:127-35 Angel, Br J Psychiatry 2013;202:100-7

42nd Orthomolecular Medicine Today

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D-vitamin + FXT

20 patients in each group!

Treatment week

Everyone received Fluoxetin 20 mg/d!

* = p < 0.05! Khoraminya, Aust N Z J Psychiatry 2012 ! Oct 23 /Epub ahead of print/! Khoraminya et al. 2012

Orthomolecular treatment for depression – zinc

!! Mg: energy, anti-inflammatory

!! Zn: enzymes, CNS regulatory functions

Magnesium improves mood Weston, Am J Psychiatry 1922;78:637-8 Eby, Med Hypotheses 2006;67:362-70 Barragán-Rodríguez, Magnes Res 2008;21:218-23 Eby, Med Hypotheses 2010;649-60

Zinc is often low in treatment-resistant depression Maes, Biol Psychiatry 1997;42:349-58 Zinc improves mood Nowak, Pol J Pharmacol 2003;55:1143-7 Siwek, J Affect Disord 2009;118:187-95 Sawada, Eur J Clin Nutr 2010;64:331-3 Lai, J Affect Disord 2012;136:e31-9

Toronto, 2013, April 27

42nd Orthomolecular Medicine Today

Orthomolecular treatment for depression – selenium

Toronto, 2013, April 27

Orthomolecular treatment for depression – chromium

!! Se: glutathione peroxidase, other selenoenzymes

!! Cr: ingredient of GTF (glucose tolerance factor)

Selenium improves mood Benton, Nutr Neurosci 2002;5:363-74 Rayman, Biol Psychiatry 2006;59:147-54 Mokhber, J Matern Fetal Neonatal Med 2011;24:104-8

42nd Orthomolecular Medicine Today

Placebo + FXT

Orthomolecular treatment for depression – magnesium

42nd Orthomolecular Medicine Today

Chromium improves mood in atypical depression McLeod, Int J Neuropsychopharmacol 2000;3:311-4 Davidson, Biol Psychiatry 2003;53:261-4 Docherty, J Psychiatr Pract 2005;11:302-14

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13-03-25! Orthomolecular Treatment for Depression and Bipolar Disorder

Bo Jonsson Meta-Analysis of the Effects of EPA in Clinical Trials

Table 2. Model Statistics for the Mixed-Effects Analyses of the Effects of EPA, Dichotomized at 60% of Omega-3 PUFA Dose, on PUFA Supplementation Compared With Placebo

Orthomolecular treatment forCoefficient Model Estimate depressionEffects – ofomega-3 fatty acids EPA 60%

95% CI

Intercept −0.0261 17 −0.2004 to 0.1482 EPA 60% 0.5577 17 0.2772 to 0.8382 Effects of EPA 60% and treatment duration Intercept 0.1882 16 −0.4214 to 0.7979 EPA 60% 0.5528 16 0.2673 to 0.8383 Treatment duration −0.0194 16 −0.0721 to 0.0333 Omega-3 fats: cell membranes Effects of EPA 60% and mean ageand function, anti-inflammatory Intercept −0.0550 16 −0.7058 to 0.5958 EPA 60% 0.5580 16 0.2675 to 0.8485 Mean age 0.0007 16 −0.0139 to 0.0153 Important ina brain health Boldface type indicates statistical significance. Abbreviations: EPA = eicosapentaenoic acid, PUFA = polyunsaturated fatty acid. Sinclair, Lancet 1956;270:381-3

t Value

−0.316 4.195

.7560 .0006

0.655 4.105 −0.779

.5221 .0008 .4474

−0.179 4.072 0.098

.8600 .0009 .9231

quadratic (F2,16 = 3.399, P = .059) function; neither reached significance (Figure 3). However, weighted least-squares regression analyses using weights proportional to the reciprocal of estimated study effectsize SE were significant for both linear (F1,17 = 6.830, P = .018) and quadratic (F2,16 = 3.993, P = .039) approaches.

Orthomolecular treatment for depression – omega-3 fatty acids

Improve mood in case studies

Puri, Int J Clin Pract 2001;55:560-3 DISCUSSION

Chiu, Am J Psychiatry 2003;160:385

In agreement with Ross et al11 and Martins,13 this study identifies EPA as the effective PUFA compoHorrobin, Postgrad Med J 1977;53(Suppl 4):160-5 Improve mood in RCT studies nent in treatment of depression. This Figure 1. Standardized Mean Differences and 95% Confidence Intervals for Studies Sublette, finding is in contrast to the greaterJ Clin Psychiatry 2011;72:1577-84 of Depressive Episodes Comparing Antidepressant Effect Between Omega-3 face validity of DHA, which is the Polyunsaturated Fattyconsumption Acids (PUFAs) and Placebo, Arranged by Percentage of Inverse correlation for fish and depression Eicosapentaenoic Acid (EPA) in the Supplements major brain omega-3 PUFA speHibbeln, Lancet 1998;351:1213 Standardized Mean Difference (95% CI) Study % EPA % Weight cies and has a lower concentration in the brains of depressed subjects Hibbeln, J Affect Disord 2002;69:15-29 29 Peet and Horrobin, 2002 100 9.40 in postmortem studies.2 The lack 37 100 5.60 Nemets et al, 2002 of DHA efficacy could mean that 100 14.20 Frangou et al, 200631 100 9.70 Peet and Horrobin, 200229 acute supplementation does not 100 9.40 Peet and Horrobin, 200229 increase brain DHA concentrations. 100 8.30 Mischoulon et al, 200916 Increases in brain DHA haveMedicine been 42nd Orthomolecular Medicine Today Frangou et al, 200631 Toronto, 2013,100 April 27 37 42nd Orthomolecular Today Toronto, 2013, April 27 13.90 66.67 6.80 Su et al, 200338 reported after supplementation in 66.67 5.60 Nemets et al, 200621 41 42 piglets and rats. The effect of 39 64.71 9.20 Su et al, 2008 dietary DHA supplementation on 60 3.60 da Silva et al, 200818 60 4.40 da Silva et al, 200818 human brain DHA levels has not Overall EPA ≥ 60% been studied; however, intravenously injected radiolabeled DHA43 Freeman et al, 200835 57.89 9.50 55.36 20.70 Carney et al, 200915 resulted in an extremely low rate 42.57 35.50 Rogers et al, 200822 of DHA incorporation into brain 21.43 11.50 Grenyer et al, 200717 in healthy humans: mean ± SD of 20.18 4.00 Rees et al, 200840 20 12.70 Silvers et al, 200519 3.8 ± 1.7 mg/d, or a whole-brain 0 6.10 Marangell et al, 200336 half-life of 2.5 years. If this is an Overall EPA < 60% accurate paradigm for the fate of –1.3 0.0 1.3 dietary DHA, then as noted by Favors Placebo Favors PUFAs Umhau et al,43 effects of supplementation would not be evident in clinical trials lasting a few weeks, and the delay would be from .00046 to .00165. Results from models with the lowimpractical for a therapeutic agent. est Bayes information criterion values are summarized in Table 2. In the primary regression analyses, the best model Possible Explanations of EPA Effects on Depression was the weighted least-squares regression, in which an EPA Thyroid hormones should be considered in treatment-resistant First: Eicosapentaenoic acid could directly or indirectly proportion of at least 60% was a significant determinant depression facilitate an increase in brain DHA levels. Since EPA is a of superiority of PUFA over placebo (t17 = 4.19, P < .001). Altschuler, precursor of DHA, an increase in EPA might increase pro- Am J Psychiatry 2001;158:1617-22 A Welch 2-sample t test confirmed the significance of the 44 duction of DHA, and it has been suggested that decreased effect (t16.83 = 5.10, P < .0001). In secondary covariate Bauer, Neuropsychopharmacology 1998;18:444-55 analyses, neither treatment duration nor age significantly conversion of EPA to DHA could be an etiologic factor in predicted effect size; an EPA proportion of 60% or greater depression.45 However, supplementation with EPA has not was still significant with either variable in the model (see been found to increase plasma or erythrocyte DHA levels Table 2). Interactions were not statistically significant. in humans,46 or brain DHA levels in rats.47 In exploratory analyses, EPA dose in excess of DHA Second: Eicosapentaenoic acid could enter the brain dose (EPA dose − DHA dose) correlated similarly with and act directly as the effector. Given the extremely low effect size using either a linear (F1,17 = 4.054, P = .060) or a EPA level compared with DHA level in the brain (1:274 in

Orthomolecular treatment for depression – omega-3 fatty acids

Orthomolecular treatment for depression – thyroid hormones

1580

Sublette 2011! 42nd Orthomolecular Medicine Today

Toronto, 2013, April 27

42nd Orthomolecular Medicine Today

Orthomolecular treatment for bipolar disorder

Toronto, 2013, April 27

Orthomolecular treatment for bipolar disorder

Folic acid reduces affective morbidity Coppen, J Affect Disord 1986;10:9-13

Magnesium augmented verapamil in mania Giannini, Psychiatry Res 2000;93:83-7

Omega-3 reduces bipolar depression Stoll, Arch Gen Psychiatry 1999;56:407-12 Sarris, J Clin Psychiatry 2012;73:81-6

Mitochondrial dysfunction is common in bipolar disorder Kato, Bipolar Disord 2000;2:180-90 Abram Hoffer on bipolar disorder Hoffer, Townsend Letter 2009;317:44-50

N-acetylcysteine reduces bipolar depression Berk, Biol Psychiatry 2008;64:468-75 Berk, J Affect Disord 2011;135:389-94

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Orthomolecular Treatment for Depression and Bipolar Disorder13-03-25! Bo Jonsson

Multinutrient treatment

!! Max Gerson (1881-1959) for cancer: A B3 C I K !! Frederick Klenner (1907-84) for MS: B1 B2 B3 B6 B12 C E Ca Mg Zn choline lecithin glycine !! William Kaufman (1910-2000) for arthritis: niacinamid B1 B2 C, sometimes A D !! Abram Hoffer (1917-2009) B3 C, followed by broad vitamineral !! Bruce Ames broad vitamineral for metabolic tune-up !! Michael Maes for depression: Zn NAC CoQ10 EPA curcumin resveratrol !! Michael Berk for bipolar: NAC CoQ10 EPA lipoic acid curcumin

If there’s a drug that can alter the brain’s biochemistry, there’s usually a combination of nutrients that can achieve the same thing without side effects. Carl C Pfeiffer (1908-88)

42nd Orthomolecular Medicine Today

Toronto, 2013, April 27

42nd Orthomolecular Medicine Today

Toronto, 2013, April 27

Multinutrient treatment !! True Hope story

!! 1st meeting in Tokyo: International Society of Nutritional Psychiatry Research (ISNPR) !! Date: June 21, 2013 !! Venue: National Institute of Health and Nutrition, Tokyo

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Toronto, 2013, April 27

Effects of Vitamin C and D Supplementation on Mood and Distress in Acutely Hospitalized Patients John Hoffer

1. John Hoffer, MD, PhD Effects of vitamin C and D Supplementation on Mood and Distress in Acutely Hospitalized Patients In this presentation I will describe the results of our studies of the prevalence and medical significance of inhospital hypovitaminosis C and D in a major Montreal teaching hospital, as carried out in my laboratory over 5 years, most of the funding provided by the Hecht Foundation. I will describe the history, motivation, trials, tribulations, and results of these studies. Our most recent findings, presented in abstract form at the Experimental Biology 2013 meeting in the Boston Convention and Exhibition Center on April 22, 2013, will be discussed. Gan R, Eintracht S, Hoffer LJ. Vitamin C deficiency in a university teaching hospital. J Am Coll Nutr 2008;27:428433. Robitaille R, Mamer OA, Miller WH Jr, Levine M, Melnychuk D, Rousseau C, Hoffer LJ. Oxalic acid excretion following intravenous ascorbic acid administration. Metabolism 2009;58:263-269. Rebecca Evans-Olders R, Eintracht S, Hoffer LJ. Metabolic origin of hypovitaminosis C in acutely hospitalized patients. Nutrition 2010; 26:1070-4. Zhang M, Robitaille L, Eintracht S, Hoffer LJ. Vitamin C provision improves mood in acutely hospitalized patients. Nutrition 2011; 27: 530-533. Wang Y, Liu XJ, Robitaille R, Eintracht S, MacNamara E, Hoffer LJ. Effects of vitamin C and vitamin D on mood and distress in acutely hospitalized patients Abstract presentation, Experimental Biology 2013, April 22, 2013, Boston.

126

Orthomolecular Strategies to Prevent Mental Breakdown

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The Abram Hoffer Collection at the University of Saskatchewan John Hoffer

2. John Hoffer, MD, PhD The Abram Hoffer Collection at the University of Saskatchewan This presentation will be an adaptation of an extemporaneous talk given on the occasion of the launch of this scholarly collection in February, 2012. The aim was to provide a historical look back at the scientific career of Abram Hoffer, as well as some thoughts about the current status of the scientific work he did in his life and the potential value of the Abram Hoffer Collection for future scholars. The talk will include much of the material included in an article published in the Journal of Orthomolecular Medicine. Hoffer LJ. The Abram Hoffer Orthomolecular Collection at the University of Saskatchewan. J. Orthomolecular Med 2012;27:53-59.

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