43rd Orthomolecular Medicine Today Conference

Vancouver

rd

ANNUAL INTERNATIONAL CONFERENCE SYLLABUS

April 25-27 Fairmont Hotel Vancouver

2014 Experience the best education in many areas of orthomolecular medicine at our 43rd Annual International Conference.

Thirteen internationally known physicians and researchers will present five sessions on current advances in orthomolecular psychiatry, endocrinology oncology, gerontology and general medicine.

International Society for Orthomolecular Medicine

International Society for Orthomolecular Medicine April 25, 2014 Dear Delegates, Welcome to our 43rd 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, 16 exhibitors and over 200 delegates and guests from around the world, including Algeria, Canada, England, Japan, Mexico, Norway, Spain, Sweden, Switzerland, and the United States of America.

We are also celebrating the 20th anniversary of the founding of the International Society for Orthomolecular Medicine, which now has 20 country members representing over 30,000 individual members. The ISOM was established in 1994 to unite existing societies and to foster the growth of Orthomolecular Medicine through education, communication and advocacy.

The year 2014 marks the 11th anniversary of the Orthomolecular Medicine Hall of Fame, as we induct three pioneers: John Ely, PhD; Alexander Schauss, PhD; and Patrick Holford.

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 27 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 10 countries in attendance at the Orthomolecular Medicine Today Conference Don’t miss this opportunity to gain an international perspective on Orthomolecular Medicine.

FRIDAY, APRIL 25 8:00 am Registration 8:30 am Exhibits Open Session One • General Orthomolecular 9:00 am Welcome - Introduction

SATURDAY, APRIL 26 12:30 pm Lunch - Visit Exhibits Session Four • Orthomolecular Psychiatry

9:30 am Abram Hoffer Memorial Lecture

Alex Schauss

35 years in the Orthomolecular Medicine Field

2:00 pm

Laurie Mischley The Role of Lithium in Central Nervous System Health

10:00 am Break - Visit Exhibits

3:00 pm

Jonathan Prousky Effective Tapering Strategies to Limit Drug Withdrawal and Destabilization: A Clinician’s Perspective

3:30 pm

Break - Visit Exhibits

4:00 pm

Evan Shute Memorial Lecture Paul Demeda Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

5:30 pm

Exhibit Area Closes

10:30 am Ben Lynch

Optimizing Patient Care by Identifying

and Bypassing Genetic Polymorphisms 11:30 am

Joseph Gabriele Transdermal Delivery of Polyphenols for Pain Management and other Conditions: Technology & Clinical Experience

12:30 pm Lunch - Visit Exhibits Session Two • Orthomolecular Oncology 2:00 pm

Dr Rogers Prize Lecture Balz Frei Vitamin C and Chronic Disease: The Right Molecule at the Right Dose

3:00 pm John Thoreson

Ascorbic Acid: Its Fundamental Importance and

the Glucose Ascorbate Antagonism Theory 4:00

Break - Visit Exhibits

4:30 pm Michael Schachter

The Role of Salvestrols in the Management of

Cancer Patients at the Schachter Center in New York 5:30 pm Exhibit Area Closes

SATURDAY, APRIL 26 8:00 am Registration 8:30 am Exhibits Open Session Three • Orthomolecular Endocrinology 9:00 am Patrick Holford

The Role of Insulin in Weight Gain

and Obesity 10:00 am Break - Visit Exhibits 10:30 am

11:30 am

Ron Brown Bioidentical Hormone Therapy: Fact vs. Fiction Phyllis Bronson The Moods of Aging: Hormones and the Mind-Body Connection

11th Annual Orthomolecular Medicine Hall of Fame Reception, Dinner and Induction Program 7:00 – 9:00 pm

SUNDAY, April 27 8:00 am 8:30 am

Registration Exhibits Open

9:00 am

International Society for Orthomolecular Medicine Annual Meeting

10:00

Break - Visit Exhibits

Session Five • Orthomolecular Gerontology 10:30 am Aileen Burford-Mason

The Aging Brain: Influences of in utero and

Early Childhood Nutrition on Later Neurocognition 11:30 am Patrick Holford

The Etiology of Alzheimer’s Disease

and its Prevention 1:00 pm

Exhibit Area Closes Public Workshop

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

Contents

Conference Schedule...................................................................................................................................2 Exhibitors.........................................................................................................................................................4 Exhibitor Floor Plan......................................................................................................................................5 Speaker’s Biographies..................................................................................................................................6

Session One - General Orthomolecular

Alex Schauss

35 years in the Orthomolecular Medicine Field ................................................................................8

Ben Lynch

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms............... 10

Joseph Gabriele Transdermal Delivery of Polyphenols for Pain Management and other Conditions: Technology & Clinical Experience ............................................................................... 21

Session Two - Orthomolecular Oncology

Balz Frei

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose................................. 29

John Thoreson

Ascorbic Acid: Its Fundamental Importance and the Glucose

Ascorbate Antagonism Theory.............................................................................................................. 39

Michael Schachter The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York............................................................................................................... 43

Session Three - Orthomolecular Endocrinology

Patrick Holford

The Role of Insulin in Weight Gain and Obesity.............................................................................. 52

Ron Brown Bioidentical Hormone Therapy: Fact vs. Fiction..............................................................................64

Phyllis Bronson The Moods of Aging: Hormones and the Mind-Body Connection.......................................... 77

Session Four - Orthomolecular Psychiatry

Laurie Mischley

The Role of Lithium in Central Nervous System Health............................................................... 83

Jonathan Prousky Effective Tapering Strategies to Limit Drug Withdrawal and Destabilization: A Clinician’s Perspective........................................................................................................................... 92

Paul Demeda Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?.................................................................................................................. 95

Session Five - Orthomolecular Gerontology

Aileen Burford-Mason

The Aging Brain: Influences of In Utero and Early Childhood Nutrition on

Later Neurocognition............................................................................................................................. 115

Patrick Holford The Etiology of Alzheimer’s Disease and its Prevention.....................................................125

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

■

■

43rd 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 Boucher Institute of Naturopathic Medicine 200 - 435 Columbia Street New Westminster, BC V3L 5N8 Canada info@binm.org www.binm.org Canadian Society for Orthomolecular Medicine 16 Florence Avenue Toronto, ON M2N 1E9 Canada 416 733 2117 info@csom.ca www.csom.ca College Pharmacy 3505 Austin Bluffs Parkway Colorado Springs, CO 80918 USA 800 888 9358 / 719 262 0022 info@collegepharmacy.com www.collegepharmacy.com Cyto-Matrix Inc. 300 March Road Kanata, ON K2K 2E2 Canada 613 599 1653 info@cyto-matrix.com www.cyto-matrix.com Doctors Data Inc. 3755 Illinois Avenue St. Charles, IL 60174-2420 USA 800 323 2784 / 630 377 8139 inquiries@doctorsdata.com www.doctorsdata.com

Douglas Laboratories of Canada/ Pure Encapsulations 490 Elgin Mills Road East Richmond Hill, ON L4C 0L8 Canada 866 856 9954 info@douglaslabs.ca www.douglaslabs.ca Finlandia Pharmacy & Health Centre 1111 W Broadway Vancouver, BC V6H 3X5 Canada 604 733 5323 / 800 363 4372 www.finlaniapharmacy.com Health Care Prevention Alliance 8194 Birch Bay Drive Blaine, WA, 98230 USA rogerlrajotte@comcast.net www.hcpscanner.com Journal of Orthomolecular Medicine 16 Florence Avenue Toronto, ON M2N 1E9 Canada 416 733 2117 centre@orthomed.org www.csom.ca Metagenics Canada, Inc. 851 Rangeview Road Mississauga, ON L5E 1H1 Canada 800 268 6200 brendaparsons@metagenics.com www.metagenics.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

■

Rocky Mountain Analytical 32 Royal Vista Drive NW Calgary, AB T3R 1R8 Canada 403 241 4500 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 True Balance 203 - 52 Sioux Road Sherwood Park, AB T8A 4X1 Canada 780 464 4506 www.mytruebalance.ca US BioTek Laboratories 13500 Linden Avenue North Seattle, WA 98133 USA 206 365 1256 / 877 318 8728 reporting@usbiotek.com www.usbiotek.com York Downs Pharmacy 3910 Bathurst Street Toronto, ON M3H 5Z3 Canada 800 564 5020 / 416 633 2244 info@yorkdownsrx.com www.yorkdownsrx.com

■

4

■

■

43rd Orthomolecular Medicine Today Conference Exhibitors

5

Nutrition Break

16

4

8

11

15

3

7

10

14

2

6

9

13

1

Nutrition Break

12

Entrance

Entrance Reception

1.

2.

3.

4.

5.

6.

7.

8.

Canadian Society for Orthomolecular Medicine/JOM Cyto-Matrix Inc. Finlandia Pharmacy & Health Centre Doctors Data Inc. Acquired Intelligence Inc. US BioTek Laboratoires True Balance Seroyal International

9. Metagenics Canada 10. Health Care Prevention Alliance 11. Douglas Laboratories/ Pure Encapsulations 12. Boucher Institute of Naturopathic Medicine 13. College Pharmacy 14. Nutritional Fundamentals for Health 15. Rocky Mountain Analytical 16. York Downs Pharmacy

■

■

5

conference speakers Phyllis Bronson Phyllis Bronson, PhD, is a biochemist, researcher and clinician who works in molecular research on the structural differences between synthetic and bioidentical hormones. Her recently published book, Moods Emotions and Aging: Hormones and the Mind-Body Connection, has been highly acclaimed by scientific and medical colleagues, as well as by intelligent women for whom it is mainly intended. Phyllis thinks women need their hormones as they age, more than ever.

Ron Brown Ron Brown, MD, graduated and worked for six years in a solo rural medical practice. He then specialized in OBGYN graduating in 1995.

Dr. Brown has continued to work full-time for the last 18 years in a large group hospital based practice. He is an Associate Clinical Professor in the University of Alberta OBGYN program and is actively involved in resident education. A patient piqued his interest in BHRT eight years ago and he has become a passionate advocate for BHRT since then with over 3,000 patients on treatment. His primary interest is establishing evidence based patterns of BHRT practice.

Aileen Burford-Mason Aileen Burford-Mason, PhD, is an immunologist, cell biologist and orthomolecular nutritionist with a deep interest in the evidence base for nutritional health. She regularly gives seminars for both professional and lay audiences, and has become known for her ability to take complex nutritional research and translate it into concise, evidence-based guidelines for the safe, effective use of supplements.

Dr. Burford-Mason is formerly Assistant Professor in the Department of Pathology in the Faculty of Medicine, University of Toronto, and Director of The Connacher Head and Neck Cancer Research Laboratory at The Toronto General Hospital. In 2004, she co-founded the Holistic Health Research Foundation of Canada.

Paul Demeda Paul Demeda, CNP, is a holistic nutritionist dedicated to investigating, and explaining important nutrition issues and concepts, and is passionate about critical thinking in the context of health, nutrition, and published research. Paul holds clinical practice at the D’Avignon Digestive Health Centre and the Wellness Institute in Toronto, specializing in digestive issues, mental health, and cancer. Paul has created and taught nutrition courses for the Institute of Holistic Nutrition, Centennial College in Toronto, and the Edison Institute of Nutrition, and is author of the upcoming book The Visual Guide to Holistic Health. Paul is a graduate of York University in Toronto and the Institute of Holistic Nutrition.

Balz Frei Balz Frei, PhD, is a distinguished professor of biochemistry and biophysics, and director and Endowed Chair of the Linus Pauling Institute at Oregon State University in Corvallis, Oregon. Dr. Frei’s research interests include the role of vitamins, micronutrients, and other dietary factors in promoting optimum health and preventing disease, in particular atherosclerosis and heart disease; the role of oxidative stress and inflammation in human health and disease; and the health benefits of dietary supplements. He has made important contributions to our understanding of the biological mechanisms and health effects of vitamins C and E, coenzyme Q10, lipoic acid, and flavonoids.

Joseph Gabriele Joseph Gabriele, PhD, is a molecular pharmacologist specializing in signal transduction pathways in numerous disease states. His early experience focused on psychiatry and behavioural neurosciences as a research scientist at McMaster University in Hamilton, Ontario, where he was awarded his MSc and PhD degrees. In 2006 Dr. Gabriele received his postdoctoral training at Queens University on the pharmacological effects of antipsychotic medications in patients with schizophrenia. In 2013, Dr. Gabriele was awarded a grant from the Canadian Government to continue his ground-breaking research developing technologies that provide healthcare practitioners with powerful tools to deliver medications and natural molecules to the body.

Patrick Holford Patrick Holford, BSc, DipION, is a leading spokesman on nutrition in the media, specializing in mental health. He is the author of over 35 books, translated into over 30 languages and selling over a million copies worldwide, including The Optimum Nutrition Bible, The Low GL-Diet Bible, Optimum Nutrition for the Mind and The 10 Secrets of 100% Healthy People. In 1984 he founded the Institute for Optimum Nutrition (ION), an independent educational charity, one of the most respected educational establishments for training nutritional therapists. Patrick is Chief Executive Officer of the Food for the Brain Foundation and director of the Brain Bio Centre, the Foundation’s treatment centre that specialises in helping those with mental issues.

6

conference speakers Ben Lynch Benjamin Lynch, ND, received his BSc in Cell and Molecular Biology from the University of Washington and his ND from Bastyr University. His passion for identifying the cause of disease directed him towards nutrigenomics and methylation dysfunction. Currently, he researches, writes and presents worldwide on the topic of MTHFR and methylation defects. You may learn more about Dr Lynch and his work at www.MTHFR.Net. Dr Lynch is also the President & CEO of Seeking Health, Inc, a company oriented towards disease prevention and health promotion. He lives in Seattle, WA with his wife, Nadia, and three boys, Tasman, Mathew and Theodor.

Laurie Mischley Laurie Mischley, ND, MPH, has been specializing in nutrition and neurological disorders for over a decade. She received a BSc in Nutrition Science in 1997 from Pennsylvania State University, a Doctorate of Naturopathic Medicine (ND) from Bastyr University in 2001, and completed a MPH in Epidemiology from the University of Washington in 2013. In 2010, she was awarded an NIH NCCAM/ Bernard Osher Career Development Award and with the support of this award she is conducting trials on nutritional strategies for neuroprotection. Dr. Mischley maintains a private practice at Seattle Integrative Medicine in Seattle’s University District. She is author of the book, Natural Therapies for Parkinson’s Disease.

Jonathan Prousky 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 and botanical medicine and lifestyle counseling. Dr. Prousky is the current editor of the Journal of Orthomolecular Medicine. His clinician-based research primarily involves the neuro-psychiatric applications of vitamin B3.

Michael Schachter Michael B. Schachter, MD, CNS, is a Board Certified psychiatrist and a Certified Nutrition Specialist and has been involved with nutritional and integrative health care for almost 40 years. A leader in alternative cancer therapies, EDTA chelation and orthomolecular psychiatry, he is a past president of the American College of Advancement in Medicine (ACAM). He has authored numerous articles and was a major contributor to Burton Goldberg’s classic book, Alternative Medicine Definitive Guide to Cancer. Most recently, Dr. Schachter, has been involved in using salvestrols to help cancer patients. Dr. Schachter’s Center is located in Suffern NY. www.schachtercenter.com.

Alex Schauss Alexander Schauss, PhD, FACN, is the Senior Research Director of Natural and Medicinal Products Research, and CEO at AIBMR Life Sciences, in Puyallup, Washington, USA. He has held a number of academic positions, including Clinical Professor of Natural Products Research and Adjunct Research Professor of Botanical Medicine at the National College of Natural Medicine in Portland; Senior Director of the Southwest College Research Institute in Scottsdale and others. He is the author or co-author of over 200 publications in a diverse range of scientific journals, including: Atherosclerosis, Experimental Gerontology, Toxicology and Pharmacology.

Dr. Schauss is also the author/co-author of 23 books in the fields of nutrition and botanical medicine.

John Thoreson John brings a wealth of experience gained from 36 years in the nutritional supplement/natural medicine Industry. Currently John serves as an outside technical consultant with US BioTek Laboratories, Seattle, WA. John has also worked in a similar capacity with other leading companies, including Pharmax and JR Carlson Laboratories. For 20 plus years John has worked with Dr. Nigel Plummer, developer of the HMF and HLC probiotics and owner of Cultech Ltd a UK-based nutraceutical manufacturing company, and has focused on the unique relationship between human commensal microbes and the functional integrity of the mucosal immune system. John has been a featured speaker at medical conferences in the USA, Scandanavia, Mexico, Japan, New Zealand and Australia.

7

Thanks to our generous sponsor

35 years in the Orthomolecular Medicine Field Alex Schauss, PhD

!"#$"%&'

C4B*5MNM<O4*B@7'A237'A97'98P'

!"#$%&'()*#&+*%(#,$-&.*/01#*' ' ()*+,-.*/'01'234,5667'8497':(;<7';:2'

&!/.'=/>4?@?)*35),/'A*.B3B-*'C?.,D';?-E*/*-3*7' F,-3?5G*/7'H/BI64';?)5@JB,7';,-,.,7' (K/B)'#$7'#L%&'

'

(QHAR'2>,S'#LLT'

C/BJ5>*'>?'U,/)D';,/**/'Q-V5*-3*/6'' •!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•! !"#$%&'()*#& (QHAR'NBE*'23B*-3*6'•!

6>,S' •! !#/2,*&3$-(4*#,5(6' •! (/-?).'A*D*/' •!

H,/J,/,':/B*.),-.*/'•!

A*D*/' •!

H,/J,/,'R**.'

•!

H*-':*B-O?).'

•!

7*#5$#8&9,%-$58& •! ;,/?)D-';?6I-' •! :$#-&;<*,)*#' •! :2#,6&9*$8,5=& •! ;BIW*-6':?/'P*,)>4' •! ;)BS?/.'U1'2B@?-6*-'•!

9,-B*)'R1'=XH,-B?-' •! >$?,8&'(##(",5& •!

9*--B6'H5/YBZ' •!

9*/*Y'H/D3*M2@B>4'

9*//B3Y'N?-6.,)*' •!

•!

9B3Y';,/)*>?-' •!

9?/B6'[1'R,KK' @%$51*-&:2*#$64,5' •!

•! @A$5&:$%*#(5& •! :/,-Y'=6YB' B#*8*#,/4&3-*55*#' •!

•!

0*-*'H,Y*/' •!

0*?/O*'\,>6?-' •!

P,//D'\?4)E,/>4' '1%C2#*D&E6%(58' •!

•!

F#A,5&G0(5*& •! [,@*6'[,3Y6?-' [,-B3*']*))*/'84*)K6' •!

•! [?,-'8/B*6>)*D' •!

P,//D'\?4)E,/>4' '1%C2#*D&E6%(58' •!

•! '$#(-8&B(60*#'

•!

F#A,5&G0(5*' [,-B3*']*))*/'84*)K6' •!

•!

H*)#*D&7-$58' •! [?4-'<1'=Z' H(5$02$5&I#,=20& '1=2&+J&G,5/-$,#' •!

•! [?6*K4'UOO*/' •! !"#$"%&'("#))% •! .*58(5&G%,02' N*?-,/.'PBKK34*-' •! .,516&;$1-,5=' •!

A,/GB-'U6)B-O*/' •! +,/2$*-&.*66*#& •!

AB34,*)'[,3?J6?-' ' 8,5)'H?335@B-B' 9,/2$#8&315,5' 9("*#0&:$02/$#0& R?J*/>'[1'8*))*O/B-B'

9(=*#&HJ&I,--,$%6' 2,/,'2)?,-' G0*C2*5&>$?,*6& 2>*K4*-' 234?*->4,)*/' C4*/?-'R,-.?)K4' C4B*5MNM<O4*B@' C45/6>?-'[?4-6?-' ^-BG*/6B>D'?E'<*_' A*+B3?'E,35)>D' \*6>?-'(1'8/B3*' \B))B,@'95`D' \B))B,@'RB-O6.?/E' \B))B,@'P1'84B)K?Z'

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

!&K%*&(<&<$%,5*&LMNOPQJ&& && '*#(,5&A,028#$A$-&6D58#(%*&LMNRNQJ& && !&?,6,K5=&=*5*K/,60&*SC-$,56&$&8*-,5T1*50U6&"*2$?,(#&LMNVWQJ& && !&/2$5/*&8,55*#&,5&'1#(5X&G(102&>$4(0$&LMNVYQJ& && +$-510#,K(5&(5&02*&.$4(0$&G,(1S&#*6*#?$K(5&LMNVYQJ&& && +(8,<D,5=&-,<*#U6&8,*06&$0&+/Z*,-&F6-$58&B*8*#$-&;*5,0*5K$#D&LMNVVQJ& && ;#*6,8*5K$-&!8?,6(#D&:(15/,-&(<&02*&5*A&7$60D#&[5,?*#6,0D\&?(-150**#&0*$/2,5=&LMNVVQJ& && ]2*&8,6/(?*#D&(<&7$4*#^+,--*#&;,54&LMNVPQJ&

•!

•!

•! & •!

G018D,5=&02*&#(-*&(<&8,*0&(5&8*-,5T1*50&"*2$?,(#J&+,-4_&;-*$6*&8(5U0&6$D&,06&%,-4&MNVPQ`& && E#02(%(-*/1-$#&]#*$0%*50&(<&:#,%,5$-&E)*58*#6&LMNVPQJ&

& •! &

8

B,#60&(<&(?*#&MYW&/(1#6*6&(5&Z10#,K(5&$58&7*2$?,(#&"*=,56&,5&:$-,<(#5,$&$58&$#(158&02*&A(#-8& LMNVNQJ& ]2$0U6&F5/#*8,"-*X&]2*&EC#$2&G2(AX&]2*&>(5(21*&G2(AX&](&]*--&02*&]#102X&(?*#A2*-%6&02*& %$,-"(S&LMNVN^MNPaQJ&&

%'

35 years in the Orthomolecular Medicine Field Alex Schauss, PhD

!"#$"%&'

H,Y*/MAB))*/'8B-Y'

C4*'FB6BJ)*'NBO4>'2K*3>/5@'?E'P5@,-6'

•!

•!

•!

•!

•!

•!

&& •!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•!

•! '

>,*0&:#,%*&$58&>*-,5T1*5/D&LMNPWQJ& &&& !#/2,*&3$-(4*#,5(6&6$?*6&02*&8$D&"*<(#*&-*/01#*&$0&02*&[5,?*#6,0D&(<&Z*A&G(102&I$-*6X&GD85*DX&!160#$-,$& LMNPWQJ& && ;-*5$#D&GC*$4*#X&B,#60&Z$K(5$-&:(5<*#*5/*&(5&Z10#,K(5&$58&7*2$?,(#X&!16K5X&]*S$6J&7(#(5&b&A2$0U6& "(#(5&LMNPcQ_&

:2$5=,5=&02*&8,*0&(<&02*&!-$"$%$&d1?*5,-*&/(##*/K(56&6D60*%&LMNPcQ& E?*#&-15/2X&$&5$C4,5&,6&C$66*8&"D&9(8=*#&HJ&I,--,$%6&LMNPcQJ& && :(55*/K5=&6(1#6(C&<#1,0&0(&$0DC,/$-&;$#4,56(5U6&8,6*$6*&,5&e1$%&LMNPcQJ&& G018D,5=&510#,K(5$-&8*f/,*5/,*6&02#(1=2(10&G(102&!<#,/$&LMNPaQJ& && F5?,0*8&.*/01#*#X&+/:$##,6(5&G(/,*0DX&@1#(C*$5&:(5<*#*5/*&(5&Z10#,K(5&$58&7*2$?,(#X&ES<(#8&[5,?*#6,0D& LMNPaQJ& && B,#60&%**K5=&A,02&G,#&'1=2&G,5/-$,#&LMNPaQJ& && G,5/-$,#&$58&02*&+/:$##,6(5&G(/,*0D&"#,5=&%*&"$/4&0(&ES<(#8&$&02,#8&K%*\&.*/01#*&A,02&H(6*C2&@==*#& LMNPYQJ&&& && I'E&G018D&e#(1C&(5&'*$-02&;#(%(K(5&LMNPYQJ& && F5?,0*8&C$5*-,60X&H(,50&;$#-,%*50$#D&:(%%,g**&(5&Z10#,K(5X&7#,K62&;$#-,$%*50&LMNPRQJ& && :,Kh*5U6&B(#&'*$-02&b&02*&-$60&A**4&(<&:(5=#*66&LE/0&MNNOQ&

=G*/','AB))B?-'2BO-,>5/*6'E?/'92PU('

9

#'

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms !"!# $%&'%('# Ben Lynch, ND

Disclaimer & Disclosures

Optimizing Patient Care Identifying and Bypassing Genetic Polymorphisms

The information presented here is for informational and educational purposes only. Seeking Health, LLC and Benjamin Lynch will not be liable for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any materials or information published.

I am President and CEO of SeekingHealth.com and founder of MTHFR.Net # # #

Presenter: Benjamin Lynch, ND Orthomolecular Medicine Today Vancouver BC, Canada April 25 - 27, 2014 “Clinicians will be central to helping consumer-patients use genomic information to make health decisions.” – NEJM

)*+#&,('-#./012340#560*78#9:#

(#

&#

)*+#&,('-#./012340#560*78#9:#

How are these linked?

•!

•!

•!

•!

•!

•!

•!

•!

;<20=/#>?40#20!#@/A2#*2<BA/0/# 5BC#D.E#"BF2A/#6/A#74=7#>/<G3#"BF2A/# H0=/<#"<B3#*7//>/# I63JAB3>#43J<BK/#!G<40=#J</=020*6# L/A76F"BF2A/#20!#MA*740/>>%D2>7# :/J</>>4B0#20!#E7<B04*#:4>/2>/# NF/K2A/!#>/<BAB040#40#2GO>3# P<//*F23J>42#20!#04A<4*#BQ4!/#

$#

)*+#&,('-#./012340#560*78#9:#

)*+#&,('-#./012340#560*78#9:#

'#

Treat the Patient. Not the SNPs

Why?

Key Points about SNPs and Clinical Use •! Most SNPs not clinically relevant •! Optimizing pregnancy •! Increases compliance •! Fantastic for disease prevention •! Ability to optimize patient’s wellness •! Identify possible nutrient deficiencies •! Identify predispositions and risks •! Contributing cause towards patient signs/symptoms •! Ability to create a long-term plan •! Forces a need to understand the normal function and interactions.

•! Identify reasons why patient responds poorly/favorably to treatment.

)*+#&,('-#./012340#560*78#9:#

R#

)*+#&,('-#./012340#560*78#9:#

10

S#

(#

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms !"!# $%&'%('# Ben Lynch, ND

)*+#&,('-#./012340#560*78#9:#

)*+#&,('-#./012340#560*78#9:#

T#

)*+#&,('-#./012340#560*78#9:#

U#

V#

)*+#&,('-#./012340#560*78#9:#

(,#

Testing Levels of Various Folate Forms

!"#$%&'$'()

)*+#&,('-#./012340#560*78#9:#

)*+#&,('-#./012340#560*78#9:#

((#

11

7WJ-%%CCCX7!<4YG>2X*B3%A/>A>%3/A76F2OB0%#

(&#

&#

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms !"!# $%&'%('# Ben Lynch, ND

Genetics: Nuclear DNA 9G*F/2<#:9H#)0:9H+# •! P2A/<02F#20!#L2A/<02F#I/A># •! [4>AB0/>#d#P<BA/*OB0# •! D/J24<#3/*7204>3>#

ZBF2A/# •! :[ZD# •! L\[Z:# •! L\[ZD# •! I[L\# •! Z;5D# •! \]LI# •! I5E(VH(# .(&# •! \E9&#20!#\E9$# •! LLH.#)2?2#*@F.+# L/A74B040/#E6*F/# •! L\D%L\DD# •! LH\(# •! H[E]# •! E.I#

L/A76FA<20>"/<2>/># •! E;L\# •! PNL\# •! .[L\# •! ^HL\# •! [9L\# •! ^9L\# •! P9L\# # ^FGA2A74B0/# •! ^I\L(# •! ^EI# •! ^P_(# •! ^D#

:/ABQ4`*2OB0# •! E6A#P'R,a># •! Ib5\# •! 9H\# H!!4OB02F-# •! HP;N# •! .EL;(# •! Zb\&# •! ^H:# •! LH;H# •! P;9(# •! I;:&# •! :H;# •! ^SP:# •! 9;I(8#&#20!#$#

#

)*+#&,('-#./012340#560*78#9:#

)*+#&,('-#./012340#560*78#9:#

($#

7WJ-%%CCCXB<0FX=BK%>*4%A/*7</>BG<*/>%[G320c^/0B3/%J<B1/*A%40"BX>7A3F#

Genetics: Mitochondria

Genetics: Mitochondria

L4AB*7B0!<42F#:9H#)3A:9H+# •! M07/<4A/!#B0F6#"<B3#L2A/<02F#>4!/#)"234F6#7Q#M3JB<A20A+# •! L21B<4A6#B"#H\P#J<B!G*/!#40#34AB*7B0!<42# •! D/eG4</#43JB<O0=#0:9H#=/0/#J<B!G*A>#AB#"G0*OB0# •! I9PI%3GA2OB0>#40#3A:9H#326#@/#J2A7BFB=4*2F# •! E20*/<# •! :42@/A/># •! E2<!4BK2>*GF2<#:4>/2>/># •! 9/G<B!/=/0/<2OK/#:4>/2>/># •! H=40=# •! :/=/0/<2OK/#:4>/2>/># •! 52*?#B"#[4>AB0/>#d#74=7#<2A/#B"#3A:9H#3GA2=/0/>4>#)(,Q#0:9H+# •! L4AB*7B0!<42F#\<20>*<4JOB0#Z2*AB<#H#)\ZHL+#d#P<BA/*OK/#*B2O0=#20!#</=GF2OB0# •! 3A:9H#*BJ6#0G3@/<#f#*/FF#>G<K4K2F#20!#"G0*OB0#

Mitochondrial DNA (mtDNA)

7WJ-%%*>7J/<>J/*OK/>X*>7FJXB<=%*B0A/0A%R%R%2,(&S'(X"GFFXJ!"#20!# 7WJ-%%CCCX02AG</X*B3%>*4A2@F/%ABJ4*J2=/%3A!02Y20!Y34AB*7B0!<42FY!4>/2>/>YV,$###20!# 7WJ-%%CCCX0*@4X0F3X047X=BK%J3*%2<O*F/>%PLE$TR$&T'%J!"%JB0/X,,T'R($XJ!"#

)*+#&,('-#./012340#560*78#9:#

•! Sperm – 700 molecules of mitochondria •! Oocytes – 200,000 molecules of mitochondria

Cell Division and Mitochondria: •!

•!

•!

L4AB*7B0!<42F# •! I;:# •! EH\# •! 9:bZ# •! H\P# •! E;_#

Mitochondria ‘float’ in cytoplasm Lack of Spindles Randomized

#

H*AB0#.#/A#2FX#LBFX#[G3X#D/J<B!X#&,,'g(,-&$YYY$&#NG<BJ/20#IB*4/A6#B"#[G320#D/J<B!G*OB0#20!#N3@<6BFB=6#

(R#

(S#

)*+#&,('-#./012340#560*78#9:#

Epigenetics

Cell Division and Replication of ‘Sick’ Cells?

Stimulate DNA Bases and ! Cell Proliferation •!

('#

“As an organism grows and develops, carefully orchestrated chemical reactions activate and deactivate parts of the genome at strategic times and in specific locations.

“New” cells created: •! " Glutathione •! Oxidized cell membrane •! " Potassium •! ! ROS •! ! Cell death

Epigenetics is the study of these chemical reactions and the factors that influence them.”

ZF2</#B"#P2O/0A#I63JAB3>#C4A7# 2!!4OB0#B"#ZBF2A/#%#.(&X#

“Epigenetic changes are environmentally responsive mechanisms that can modify gene expression independently of the genetic code.”

!"#"$$%&'&"$()*"'&+",&(-./0(

)*+#&,('-#./012340#560*78#9:#

(T#

)*+#&,('-#./012340#560*78#9:#

12

http://learn.genetics.utah.edu/content/epigenetics/ and Epigenetics and the developmental origins of inflammatory bowel diseases.

(U#

$#

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms Ben Lynch, ND

13

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms !"!# $%&'%('# Ben Lynch, ND

Key ‘Big Picture’ Disturbances •!

•!

•!

•!

•!

•!

•!

•!

•!

•!

12%3","4#$(5$&#

)*+#&,('-#./012340#560*78#9:#

&R#

Environment Lifestyle Diet Pathogens Heavy Metals Xenobiotics Oxidative Stress Nutrient Deficiencies Nutrient Excess SNPs

System-Wide Dysfunction

&S#

)*+#&,('-#./012340#560*78#9:#

Folic Acid ! GMH MTHFR increasing in the population.

•! Folic acid fortification •!

•!

•!

•!

•!

6)7-89(:;<(,/0=#

! Full-Term Pregnancies ! Folate SNPs ! Methylation SNPs ! Inferior SNPs ! Metabolic Issues

! Susceptibility to Environmental Exposures

Natural DeSelection: Survival of the ‘Unfittest’

)*+#&,('-#./012340#560*78#9:#

&T#

)*+#&,('-#./012340#560*78#9:#

7'$(",;',#">(?/.'&"($&'&@$(>@*%,3(2*"3,',#<('.&"*">(,'&@*'.($"."#4/,(',>( 2/$$%A.<(B@4$+(2*"C'.",#"=(B(#./$"*(.//D('&('(2/$$%A."(.%,D(

E$(?/.%#('#%>(3//>(?/*("C"*</,"=(

iMA#4>#76JBA7/>4j/!#7/</#A72A#A7/#/0720*/3/0A#B"#32A/<02F#"BF2A/#>A2AG>#@/"B</#20!#!G<40=# J</=020*6#40#A7/#F2>A#(R#6/2<>#72>#2FA/</!#02AG<2F#>/F/*OB0#@6#40*</2>40=#>G<K4K2F#<2A/>#!G<40=# J</=020*6#B"#40"20A>#JB>>/>>40=#A7/#L\[ZD#ESTT\#JBF63B<J74>38#K42#</!G*OB0#40# 76J/<7B3B*6>A/40/342#2>>B*42A/!#C4A7#A74>#=/0BA6J/#20!#A7/</@6#34>*2<<42=/#<2A/>X## # \74>#2F>B#JB40A>#!4</*AF6#AB#20#40*</2>/!#<2A/#B"#@4<A7>#B"#40"20A>#C4A7#74=7/<#JB>A02A2F# </eG4</3/0A>#"B<#"BF4*#2*4!#0//!/!#"B<#0B<32F#3/A76F2OB0#!G<40=#A74>#*<4O*2F# 0/G<B!/K/FBJ3/0A2F#J/<4B!X## # M"#A7/>/#0G3@/<>#72K/#40*</2>/!#A7/0#>B#72K/#A7/#2@>BFGA/#0G3@/<#B"#40"20A>#A72A#2k/<#@4<A7#"24F# AB#3240A240#A7/#74=7/<#"BF2A/#>A2AG>#/QJ/<4/0*/!#40#GA/<B#A7G>#F/2!40=#AB#20#40*</2>/!#0G3@/<#B"# *2>/>#B"#!/K/FBJ3/0A2F#!4>B<!/<>#>G*7#2>#HGO>3X#:/A/*OB0#B"#A7/#ESTT\#JBF63B<J74>3#2>#C/FF# 2>#BA7/<#3/A74B040/#*6*F/#/0j63/>#</F2A/!#AB#"BF2A/#3/A2@BF4>3#20!#3/A76F2OB0#2A#@4<A7#2>#J2<A# B"#0/C@B<0#>*<//040=#J<B=<23>#*BGF!#!/A/<340/#C74*7#0/C@B<0>#0//!#@/#3B04AB</!#20!# 3240A240/!#B0#!4/A>#B<#>GJJF/3/0A>#A72A#/0>G</#2!/eG2A/#"BF2A/#>A2AG>#!G<40=#A74>#*<4O*2F# JB>A02A2F#0/G<B!/K/FBJ3/0A#J/<4B!Xl

)*+#&,('-#./012340#560*78#9:#

&U#

iM0#IJ2408#A7/#J</K2F/0*/#B"#A7/#L\[ZD#STT\\#=/0BA6J/#72>#</JB<A/!F6#2JJ<BQ432A/F6#!BG@F/!# 40#A7/#JBJGF2OB0#>40*/#A7/#40A<B!G*OB0#40#(VU&#B"#"BF4*#2*4!#>GJJF/3/0A>#"B<#CB3/0#40#/2<F6# J</=020*6lm# # iZBF4*#2*4!#"B<O`*2OB0#20!#>GJJF/3/0A#G>/#34=7A#@/#i2#=/0/O*#O3/#@B3@Xl#\7/#`<>A#J</34>/#B"# A74>#!<232O*#*F2438#A72A#"BF4*#2*4!#G>/#40*</2>/>#A7/#J<BJB<OB0#B"#*74F!</0#@B<0#C4A7#A7/#\#2FF/F/# B"#L\[ZD8#4>#2>#6/A#JBB<F6#!B*G3/0A/!#20!#4>#*F/2<F6#40#G<=/0A#0//!#B"#"G<A7/<#>AG!6X# # IAG!4/>#B"#A7/#L\[ZD#=/0BA6J/#"</eG/0*4/>#40#*74F!</0#@/"B</#20!#2k/<#"B<O`*2OB0#>7BGF!#@/# *2<<4/!#BGA#40#*BG0A<4/>#JF20040=#"B<O`*2OB0#B"#"BB!#C4A7#"BF4*#2*4!X#\7G>8#>2K40=#"/AG>/>#A72A# 72K/#2#=/0/O*#*B0>OAGOB0#A72A#"2KB<>#2@B<OB0#B<#0B0>G<K4K2F#*BGF!#F/2!#AB#*74F!</0#@/40=#@B<0# C4A7#=/0BA6J/>#A72A#"2KB<#40*</2>/!#!4>/2>/#!G<40=#F4"/ln

&V#

)*+#&,('-#./012340#560*78#9:#

14

$,#

R#

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms Ben Lynch, ND

15

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms !"!# $%&'%('# Ben Lynch, ND

Homocysteine Metabolism (Routes)

Homocysteine Metabolism

);*""(F/$$%A."(8/@&"$9( (X! L\D%L\DD#)R,h+# !! ).(&#q#L\[Z+# &X! .[L\## !! )\L^#q#u0+# $X! E.I#)R,h+# !! ).S+# !! ;0F6#/F43402O0=#<BGA/#

)%$$@"(G2"#%H#( ( PF2>32#7B3B*6>A/40/#4>#2#t=<B>>a#2K/<2=/X# 9BA#O>>G/#>J/*4`*X#

NQX#E.I# •! .<240## •! 54K/<# •! P20*</2># •! LG>*F/#

5BC#7B3B*6>A/40/#4># 20#43JB<A20A#`0!40=#

NQX#.[L\# •! 54K/<# •! ;B*6A/# •! v4!0/6#

NQX#L\D# •! .<240# •! ;B*6A/#

G@22/*&(BII(8/@&"$(

$T#

)*+#&,('-#./012340#560*78#9:#

)*+#&,('-#./012340#560*78#9:#

:;'&(>%>(&;"(>/#&/*(>/=(:;'&(;'22",">(;"*"=(

)*+#&,('-#./012340#560*78#9:#

D/=GF2OB0#B"#7B3B*6>A/40/#3/A2@BF4>3#20!#3/A76F2OB0#40#7G320#20!#3BG>/#O>>G/>#20!# 7WJ-%%CCCXJ<B*</F6>X"<%A/F/*72<=/3/0A%JG@F4*2OB0>%7*6c"/<OFc>A/<4FXJ!"# $U#

7"*"(%$(&;"(#/,$"J@",#"K(:;'&(;'22",">=(7/0(&/(*"$&/*"=(

$V#

)*+#&,('-#./012340#560*78#9:#

',#

Homocysteine Kinetics •! Methionine cycle # low Km for sulfur-containing substrate •! ! methionine (sulfur) " methionine cycle

-/.'&"(L<#."#

•! Betaine-Homocysteine Methyltransferase (BHMT) # low Km for Hcy •! Transsulfuration cycle # high Km for sulfur-containing substrate •! ! methionine (sulfur) ! transsulfuration cycle •!

•!

•!

•!

! GSH ! H2S ! Taurine " Hcy

•! ! demand of P5P and serine

)*+#&,('-#./012340#560*78#9:#

'(#

)*+#&,('-#./012340#560*78#9:#

16

'&#

T#

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms !"!# $%&'%('# Ben Lynch, ND

M","(

N'*%', *$EO(P( &( Q/*%",&'4/,R(

8%$D( B.."."(

E$$@"(

I5E(V H(#

U,Hw^# D>(,R(&SS#)Y+#

^#

f#I/<G3#"BF2A/#F/K/F>#)x# D.E#ZBF2A/+#

L\[Z :(#

(VRU^ D>&&$S&&R#)Y+# wH#

E#

x#IA2@4F4A6#20!#H*OK4A6#

L\[Z D#

ESTT\# D>(U,(($$#)Y+#

\#

x#;0/#*2<@B0#3/A2@BF4>3#

L\[Z D#

H(&VU D>(U,(($(#)Y+# E#

E#

x#;0/#*2<@B0#3/A2@BF4>3# )C4A7#STT+#

7WJ-%%CCCX=/0/*2<!>XB<=#

'$#

)*+#&,('-#./012340#560*78#9:#

''#

6"&;%/,%,"(L<#."#

^^# ^H# ^H# ^H#

;<4/0A2OB0#)y+#d#!B#0BA740=#

H@0B<32F#ZBF2A/#L/A2@BF4>3#20!#L2A/<02F#D4>?#"B<#:BC0#I60!<B3/#

)*+#&,('-#./012340#560*78#9:#

;<4/0A2OB0#)Y+#d#ZF4J#A7/#.2>/# #H###\ #^###E# #\###H #E###^#

)*+#&,('-#./012340#560*78#9:#

'R#

'S#

)*+#&,('-#./012340#560*78#9:#

Methionine •! P<BA/40# •! L\[ZD#y#L\D%L\DD# K42#[*6#).(&#y#L\[Z+## •! .[L\#K42#[*6#)u0#y#\L^+# •! P<BK4!/>#IHL#)L=#y#H\P+# K42#LH\#

)*+#&,('-#./012340#560*78#9:# )*+#&,('-#./012340#560*78#9:#

'T#

)*+#&,('-#./012340#560*78#9:#

17

'U#

U#

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms !"!# $%&'%('# Ben Lynch, ND

!%&*%#(ST%>"( !%&*/@$(ST%>"( #

S-Adenosylmethionine (SAM): Functions •! Cofactor for Methyltransferases •!

•!

•!

•!

•!

•!

COMT, PEMT, PNMT, GNMT, GAMT, DNMT

Maintains normal liver function Induces apoptosis in liver cancer cells Modulates iNOS synthesis " NFk-B ! CBS # cysteine and glutathione

:4/A2<6#E7BF40/#20!#./A240/#M0A2?/>#20!#D4>?#B"#E2<!4BK2>*GF2<#:4>/2>/>-#D/K4/C#B"#NJ4!/34BFB=4*2F#NK4!/0*/#20!#7WJ-%% /3/<=/0*6X!B*AB<>B0F6X*BX4F%CJY*B0A/0A%GJFB2!>%&,((%,$%IHL/YA7/<2J6Y40YF4K/<Y!4>/2>/YzY[NPY((X(&XJ!"

#

)*+#&,('-#./012340#560*78#9:#

M","(

G@22/*&(

L\[ZD#

.&#

-@,#4/,(

'V#

E$$@"(

P<BK4!/>#>G@>A<2A/#"B<#L\D%L\DD# x#L\[Z#d#x#L\D% L\DD#

L\D#

.(&#%#u40*# \<20>"/<>#E[$Y#"<B3#L/A76F.(&# )3/A74B0 ##AB#[*6#d#*B@)M+2F2340#y# 40/# 3/A74B040/X#\7/08#</3/A76F2A/># >60A72>/ A7/#*B@)MMM+2F2340#C4A7#L\[ZX#

x#\[Z8#f#[*68#x# IHL8## f#D;I#

+#

L\DD#

)3/A74B0 40/# >60A72>/# </!G*A2> /+#

E.I#

E\[# )E^5+#

M","(

N'*%', *$EO(P( &( Q/*%",&'4/,R(

8%$D( B.."."(

E$$@"(

L\D#

H&TRS D>(U,R,UT#)y+# ^#

^#

f#L\D#"G0*OB0#

L\DD#

HSS^# D>(U,($V'#)y+#

^#

f#;Q4!2OB0#B"#.(&#

E.I#

U$$\w D>RT'&V,R#)Y+# E#

E#

x#[B3B*6>A/40/#

.&#)ZH:+# #D/3/A76F2A/>#A7/#*B@)M+2F2340# f#</!G*/!#E@)M+8#x# C4A7#L\[ZX#&#{3/A74B040/# L\D8#f#[*68#x# >60A72>/|Y*B@)MM+2F2340#y#9H:P[# IHL8#f#D;I# y#&#IHL#d#&#{3/A74B040/# >60A72>/|Y3/A76F*B@)MMM+2F2340#y# &#IH[#y#9H:P)y+#

LH\(H# L2=0/>4G E2A2F6j/>#A7/#"B<32OB0#B"#IHL# 38#EB@2FA8# "<B3#3/A74B040/#20!#H\P# v# H[E]#

R,#

)*+#&,('-#./012340#560*78#9:#

x#IHL8#f#[*6# 7WJ-%%CCCX=/0/*2<!>XB<=#

R(# 9H:# *2A2F6j/>#</K/<>4@F/#76!<BF6>4>#B"# f#IH[8#f#H!/0B>40/# 7WJ-%%CCCX=/0/*2<!>XB<=# IH[#)H!B[*6+#AB#2!/0B>40/#)H!B+# ##f#G<4*#2*4!X#f# L/A76F\#4074@4OB0# 20!#7B3B*6>A/40/#

)*+#&,('-#./012340#560*78#9:#

PYRYP8# [*6###E6>A2A74B040/X#D/=GF2A/># fIHL## [&IX#IA2<A#B"#^FGA2A74B0/# J<B!G*OB0X#.<240X# PYRYP#

)*+#&,('-#./012340#560*78#9:#

N}/*A>#B"#3/A74B040/#>60A72>/#20!#3/A76F/0/A/A<276!<B"BF2A/#</!G*A2>/#=/0/# JBF63B<J74>3>#B0#32<?/<>#B"#B0/Y*2<@B0#3/A2@BF4>3#

R&#

f#B<#x#[*6#20!# [&I#)C7/0#*6>A/40/# G>/!+#

f#B<#x#[*6#20!# E6>A2A74B040/###E6>A/40/X# [&I#)C7/0#*6>A/40/# D/=GF2A/>#[&IX#IA2<A#B"# ^FGA2A74B0/#J<B!G*OB0X##s2>*GF2<X# G>/!+#

SAM Deficiency via MATI/III Inhibitors Oxidative Stress •! NO •! TNF# •! IL-6

L;/.%,"(L<#."#

Causes vicious cycle " SAM # " CBS activity # " Glutathione

6"&;%/,%,"(%,&'D"(+'<(!S)(U(GB6(

7WJ-%%/3/<=/0*6X!B*AB<>B0F6X*BX4F%CJY*B0A/0A%GJFB2!>%&,((%,$%IHL/YA7/<2J6Y40YF4K/<Y!4>/2>/YzY[NPY((X(&XJ!"

)*+#&,('-#./012340#560*78#9:#

# R$#

)*+#&,('-#./012340#560*78#9:#

18

R'#

V#

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms !"!# $%&'%('# Ben Lynch, ND

)*',$$@.?@*'4/,(L<#."#

)*+#&,('-#./012340#560*78#9:# )*+#&,('-#./012340#560*78#9:#

RR#

RS#

)*+#&,('-#./012340#560*78#9:#

CBS and CDO CBS •!

•!

•!

•!

•!

Cofactor: B6 Requires: Serine or Cysteine & Hcy Inhibited by: NO Promoted by: SAM Product: H2S & Cystathionine

CDO •!

•!

•!

•!

•!

Cofactor: Iron & Zinc Requires: Cysteine Inhibited by: #-ketoglutarate, TNF# Promoted by: Sulfur/Cysteine Product: Cysteinesulfinate

LOS(E,;%A%4/,(+'<(."'>(&/(L<$&"%,"(1T#%&/&/T%#%&<( Y! IGJJB<A#E:; Y! IGJJB<A#M:;

#Y#IGJJB<A#E;L\ #Y#IGJJB<A#LH;

#Y#D/3BK/#P2A7B=/0># #Y#D/3BK/#L/A2F>#

G%3,$(Q$",$%4C"(&/(#<$&"%,"(%,&'D"R9(

f#E6>A/40/-IGF"2A/############f#E6>A/40/-\2G<40/###########f#IGF`A/-IGF"2A/#########f#[6!<B=/0#IGF`!/#

)*+#&,('-#./012340#560*78#9:#

RT#

)*+#&,('-#./012340#560*78#9:#

7WJ-%%CCCXC4?4=/0/>XB<=%/%=/0/%/%(,$SX7A3F#20!# 7WJ-%%CCCX0*@4X0F3X047X=BK%JG@3/!%((,RVU(,#20!# 7WJ-%%21J/0!BXJ76>4BFB=6XB<=%*B0A/0A%/2<F6%&,((%,S%(R%21J/0!BX,,(R(X&,((##

RU#

!"@*/&*',$+%$$%/,#

)*+#&,('-#./012340#560*78#9:#

RV#

)*+#&,('-#./012340#560*78#9:#

19

S,#

(,#

Optimizing Patient Care by Identifying and Bypassing Genetic Polymorphisms !"!# $%&'%('# Ben Lynch, ND

M","( Neurotransmission: More than SNPs •!

•!

•!

•!

•!

•!

•!

•!

•!

•!

Diet Lifestyle PAPS (Sulfonation) IDO (Kyurenine – Tryptophan) Th1/Th2 (Cytokines) Methylation (SAM) Cofactors Substrate Infections Heavy Metals

E;L\# SNPs •! COMT •! MAOA •! GAD1 •! GAD2 •!

•!

•!

S(#

)*+#&,('-#./012340#560*78#9:#

E$$@"(

9;I(# 9/G<B 02F#

9/G<BA<20>34W/<X# NQJ</>>/!#40#3206# O>>G/>X#D/=GF2A/># >3BBA7#3G>*F/8# J/<4>A2F>4>8#J/04F/# /</*OB0X#

9/G<BABQ4*4A6#

M002A/#M33G0/# ZG0*OB0# )L2*<BJ72=/>+# •! H0O@2*A/<42F# •! H0OK4<2F# •! H0O"G0=2F# •! \G3B<4*4!2F#

f#:232=/X#f# HGAB433G0/#D4>?X# f#9;I# b0*BGJF40=X##

# # # # # .['8# E2F*4G 9;I&# M0!G*4@ 38#ZH:8# ZL98# F/# 9H:P[#

9;I$#

N0!BA7/ F42F#

:[ZD#

EB<B02<6#>J2>3X## P<B3BA/>#K2>*GF2<# D>&,T,T''X#TUS\# /0!BA7/F42F#=<BCA7# "2*AB<X#H0=4B=/0/>4>X# ##E#)x+# # 7WJ-%%CCCX=/0/*2<!>XB<=# )*+#&,('-#./012340#560*78#9:# E2<!4BK2>*GF2<# 7B3/B>A2>4>X#

9H:P[# D/*6*F/>#.[&###.['8# J</*G<>B<#AB#"BF2A/# J2A7C26#"<B3# !476!<B"BF2A/#

:9H#@2>/# >60A7/>4># </!G*OB08#9;I# G0*BGJF40=#

IHL8# E2A2F6j/>#*2A/*7BF2340/# <>'SU,8# :BC0</=GF2OB0# L=# 20!#*2A/*7BF#7B<3B0/># <>TSV&&'8# f#E2A/*7BF>% E2A/*7BF2340/>#

LH;H#

.&# E2A2F6j/>#!/23402OB0#B"# <>S$&$# :BC0</=GF2OB0# )ZH:+# 2340/>#)!BJ28#>/<BAB0408# 20!# f#2340/># /J4%0B</J4+# <>(,R'U $S$#

^H:(# 20!#&#

L=8#.S# ^FGA232A/###^H.H#

7WJ-%%CCCX=/0/*2<!>XB<=#

)*+#&,('-#./012340#560*78#9:#

3206#

:BC0</=GF2OB0# x#^H.H8#f# ^FGA232A/#

S&#

8"3@.'4/,(

P2A7B=/0>#40!G*/# 49;IX#NF43402A/# J2A7B=/0>X#I//# 0/QA#>F4!/#"B<# 3B</X#

x#H:LH#

S$#

)*+#&,('-#./012340#560*78#9:# )*+#&,('-#./012340#560*78#9:#

S'#

x#ZBF4*#H*4!X# b0*BB?/!#F/2"6# =<//0>#;D#RYL\[Z# C4A7#.(&#

Keep to the Basics

•!

•!

•!

•!

•!

•!

•!

•!

•!

N'*%',&( E$$@"(

<>'S$$#

HNMT PNMT MAOB

M","( L/?'#& -@,#4/,( /*$(

L/?'#& -@,#4/,( /*(

Stay Informed

[4>AB<6# 54"/>A6F/# :4/A# EB3JF420*/# LBOK2OB0# L40!>/A# N0K4<B03/0A# ~2A/<# NQ/<*4>/#

M*"'&(0'<$(&/($&'<(%,?/*+">9( •! 9/C>F/W/<#HK24F2@F/#2A#CCCXL\[ZDX0/A# •! Z2*/@BB?-#7WJ>-%%CCCX"2*/@BB?X*B3%!<@/012340F60*7# •! ;*AB@/<#&,($#9GA<4=/0B34*>#EB0"/</0*/#CCCXI//?40=[/2FA7X0/A# •! L2<*7#&,('#9GA<4=/0B34*>#EB0"/</0*/# #*+!",-)#++,)%.)#''/",-0'%$.01+2-))

Thank You

)*+#&,('-#./012340#560*78#9:#

SR#

)*+#&,('-#./012340#560*78#9:#

20

SS#

((#

Transdermal Delivery of Polyphenols for Pain Management and other Conditions:Technology & Clinical Experience Joseph Gabriele, PhD

!"#$%&'()*$+,-".(/($ Transdermal delivery of polyphenols for pain management and other conditions: technology and clinical experience !

•! 0&/(12/,"$3*,"4,1&/&5.'6#$ •! 7('(,"1*$81.(96.'6:$;,6.&9,/$7('(,"1*$<&291./$ &=$<,9,>,#$ •! ?9.@("'.6A$&=$+2(/)*$B.&4(>.1,/$'1.(91('$,9>$ @(6(".9,"A$4(>.1.9(#$ •! C96,".&$0(96,/$D(,/6*$=&29>,6.&9#$ •! E''.'6,96$)"&=(''&"$F$010,'6("$?9.@("'.6A:$ <,9,>,#$

Orthomolecular Conference April 2014, Vancouver

•! 3&'6>&16&",/$G(//&H:$I2((9 '$?9.@("'.6A:$ !(),"64(96$C=$3'A1*.,6"A#$

Presented by Joseph Gabriele, PhD! !

2

F%$,$/20+(/!".2-&/$!

J(A$K(,"9.95$C-L(16.@('$ "#$!%#&'()(*+!!

•! !"#$%&'$(")*+,-*&%./$0.%&1'".2%+$3%45#%/$*6$7"+8)".8&9$:"'8;%-*&1<!! !"#$%#&$'!()!*%(*$%+$,!()!%$#(-.+(/0%1!2%0/,3$%40-!2$56/(-(7&50-!03#0/5$,!0/3!$#&3$/5$8 90,$3!0-2$%/0+#$,!2(!(%0-!0/3!&/2%0#$/(.,!%(.2$,!()!4$3&50+(/!3$-&#$%1!:!0!-((;!02!5.%%$/2! &//(#0+(/,!0/3!).2.%$!(**(%2./&+$,!)(%!/02.%0-!0/3!*60%405$.+50-!*%(3.52!3$#$-(*4$/2<! !!

•! =)8'"&;">?%1"'$0."%42"&41<$! !=!-((;!&/,&3$!26$!>?@!*%(5$,,!A*%$85-&/&50-!>?@!?!6.40/!5-&/&50-!2%&0-,B!%$C.&%$3!2(!,.**(%2!26$!

3$#$-(*4$/2D!,0)$21D!0/3!$E5051!()!/$'!0/3!,.*$%&(%D!$#&3$/5$890,$3!/02.%0-!*%(3.52,D! 5(49&/$3!'&26!2%0/,3$%40-!3$-&#$%1!%(.2$,<!F%(3.52,!60#$!9$$/!,*$5&G50--1!)(%4.-02$3!2(!

20%7$2!0!#0%&$21!()!5(/3&+(/,!&/!0%$0,!()!5%&+50-!6$0-2650%$!/$$3!&/5-.3&/7H!&/I0440+(/D!J(&/2! *0&/D!0%26%&+,D!5&%5.-0+(/!0/3!#$/(.,!&/,.E5&$/51D!4.,5-$!)0+7.$!0/3!G9%(410-7&0D!0/3!

6$0-&/7!()!'(./3,<!! !

•! @$1,A".8*.$#%/$4*$4."%4$A%-"&41<! !=/!(#$%#&$'!()!7$/$%0-!*0+$/2!0,,$,,4$/2!*%&/5&*-$,!2602!50/!9$!&4*-$4$/2$3!&/!(%3$%!2(! $/,.%$!26$!0**%(*%&02$!.,$!()!2%0/,3$%40-!3$-&#$%1!0/3!/02.%0-!6$0-26!*%(3.52!26$%0*&$,!&/!

'01,!2602!50/!-$03!2(!,.55$,,).-!*0+$/2!(.25(4$,<!

K<!

L!"#$%#&$'!()!2%0/,3$%40-!3%.7!3$-&#$%1!0/3!5.%%$/2!0**-&50+(/,<!

L!=3#0/207$,!()!2%0/,3$%40-!3$-&#$%1<! !

M<!

L! >0+(/0-!3$,&7/!()!0!2%0/,3$%40-!3$-&#$%1!,1,2$4,!0/3!>?@!)(%! %$#(-.+(/0%1!/$'!%(.2$!2(!2%$02!56%(/&5!0/3!05.2$!5(/3&+(/,D! )%(4!*0&/!2(!#0%&5(,$!#$&/,!2(!'(./3!6$0-&/7D!$25<!

N<!

L! O3.50+/7!*61,&5&0/,!0/3!6$0-2650%$!*%05++(/$%,!(/!

26$%0*$.+5!2((-,!0/3!.,$!()!/$'!2%0/,3$%40-!2$56/(-(7&$,!2(!

2%$02!26$&%!*0+$/2,!$E5&$/2-1!0/3!$P$5+#$-1D!,$5.%&/7!,.*$%&(%! %$,.-2,!A&/5-.3&/7!50,$!,2.3&$,!()!*(,&+#$!2%$024$/2!(.25(4$,B<!

3

4

R$$3!)(%!Q%0/,3$%40-!@$-&#$%1!

"#$%#&$'!()!Q%0/,3$%40-! @$-&#$%1!

5

6

21

1

Transdermal Delivery of Polyphenols for Pain Management and other Conditions:Technology & Clinical Experience Joseph Gabriele, PhD Q6$%0*&$,!Q602!S,$!Q%0/,3$%40-!! @$-&#$%1!()!@%.7,!

05".%A/$ T(+(/!U&5;/$,,! =/+80/7&/0!

V1*$%2$/,&(/!

U4(;&/7!W$,,0+(/!

V(%4(/$!>$*-05$4$/2!

Q6$%0*1!

F0&/!T0/07$4$/2!

Q%0/,3$%40-!@%.7!@$-&#$%1!

7.,9$7"+8)"."'$ U5(*(-04&/$!

R&2%(7-15$%&/$!

W-(/&3&/$!

R&5(+/$!

O,2%03&(-!

O,2%03&(-XF%(7$,+/!

Q$,2(,2$%(/$!

Y$/20/1-!

Z&3(50&/$!

•! @&P.,&(/!()!3%.7,!0/3!/02.%0-!4(-$5.-$,!

26%(.76!,;&/!&/2(!26$!3$%4&,D!4.,5-$!(%! ,1,2$4&5!5&%5.-0+(/!)(%!3&,2%&9.+(/!0/3!

26$%0*$.+5!$P$52<!

•! T(,2!2%0/,3$%40-!,1,2$4,!.,$!*0,,&#$!

3$-&#$%1<!

•! R$$3!2(!./3$%,20/3!,2%.52.%$!()!6.40/!,;&/!

9$)(%$!3$,&7/&/7!3$-&#$%1!,1,2$4,!0/3!

3$2$%4&/&/7!*(2$/+0-!0**-&50+(/,<!

8

U2%.52.%$!()!U;&/!

U2%.52.%$!()!U;&/!

Q6$!6.40/!,;&/!&,!5(4*(,$3!()H! !

•!"#$%#!&'()!*+,,(-,./!'01!2##$23#!/4.'5!

16-5/7-82 .! !

•![2!&,!(/$!()!26$!4(,2!%$03&-1!055$,,&9-$! (%70/,!9.2!3&E5.-2!2(!*$/$2%02$<!

•! M!40J(%!-01$%,!()!,;&/!0%$!26$!(.2$%!$*&3$%4&,!

0/3!26$!&//$%!3$%4&,<!!

•! Q6$!$*&3$%4&,H!!

–!,2%0+G$3!,C.04(.,!;$%0+/&]&/7!$*&26$-&0-! +,,.$<!

–!^$%0+/(512$,!A09./30/2B<!

–!/(!50*&--0%&$,!*%$,$/2<!

•! Q6$!@$%4&,H!

•!=**%(\&402$-1!M!4M!,.%)05$!0%$0!&/!

03.-2,!0/3!%$5$&#$,!(/$826&%3!()!26$!9-((3!

5&%5.-0+/7!26%(.76!26$!9(31<!

•!U;&/!0,!0!*(%2!)(%!3%.7!034&/&,2%0+(/! %$5(7/&]$3!)(%!,$#$%0-!3$503$,<!

–! 403$!()!0/!&%%$7.-0%!21*$!()!G9%(.,!5(//$5+#$! +,,.$<!

9

U2%.52.%$!()!U;&/!

10

U;&/!Y./5+(/,!

•! U.95.20/$(.,!+,,.$!

–!4$560/&50-!5.,6&(/!

–!26$%40-!90%%&$%!

–!$/$%71!,2(%07$!

•! F61,&(-(7&50-!)./5+(/!

–!F%(3.5$,!#&204&/!@! !

•! F%(2$5+#$!)./5+(/!

–!T&5%(9&(-(7&50-!90%%&$%!

–!W6$4&50-!90%%&$%!

–!>03&0+(/!90%%&$%!

–!Q$4*$%02.%$!%$7.-0+(/!

–![44./$!%$,*(/,$!

•! =**$/307$,!

–!U'$02!7-0/3,!

–!60&%!)(--&5-$,!

–!U$905$(.,!7-0/3,!

–!R0&-,!

11

12

22

2

Transdermal Delivery of Polyphenols for Pain Management and other Conditions:Technology & Clinical Experience Joseph Gabriele, PhD F%$3&52(%!()!Q%0/,3$%40-!@$-&#$%1!

T$560/&,4,!()!Q%0/,*(%2!!

•! !

•!

Q6%(.76!,;&/!*(%$,D!60&%!)(--&5-$D!7-0/3,!

3=(:=@BCDC0E$FG=HHCFC=!0$ !

0.%&1A*.4$I$H+,J$I$K29L;2ML1";N$I$3$J$@$J$KF'$O$F.N$ $ 3".2"%?8+84/$F*"P;8"&4$I$3$I$7$J$Q$K;2L1";N$$ $ $ $$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$5$ $ R5"."$ $@$I$S,.6%;"$%."%$*6$%AA+8;%-*&$ $ $7$I$78T,18)84/$*6$'.,9$8&$2"2?.%&"$K1U8&N$ $ $Q$I$3%.--*&$;*"P;8"&4$K;."%2L1U8&N$ $ $F$I$F*&;"&4.%-*&$8&$'*&*.$*.$.";"A4*.$ $ $K;."%2$*.$1U8&N$ $ $5$I$058;U&"11$*6$2"2?.%&"$K1U8&N$

Q6%(.76!5$--,!

–! [/2$%5$--.-0%!

–! [/2%05$--.-0%!A2%0/,5$--.-0%B! ! @%.7!2%0/,*(%2!3$*$/3,!(/H!

•!

•!

•!

•!

•!

•!

0C.$(.,!,(-.9&-&21!0/3X(%!(&-X'02$%!*0%++(/!5($E5&$/2!

5(/5$/2%0+(/!&/!26$!)(%4.-0+(/!#$6&5-$D! 26$!,.%)05$!0%$0!()!26$!,;&/!2(!'6&56!&2!&,!$\*(,$3_!

26$!26&5;/$,,!()!26$!,2%02.4!5(%/$.4!A&/#$%,$-1!*%(*(%+(/0-B! Q6$!,2%02.4!5(%/$.4!&,!26&5;$,2!&/!26$!*-0/20%!A,(-$,B!0/3!*0-40%!%$7&(/,!0/3!26&//$,2!&/!

26$!*(,20.%&5.-0%D!0\&--0%1D!0/3!,50-*!%$7&(/,!()!26$!9(31!!

! !

$

$

Q%0/,3$%40-!@%.7!@$-&#$%1!

Q%0/,3$%40-!@%.7!@$-&#$%1!

@&,03#0/207$,H! !

=3#0/207$,H! !

•!

•!

•!

•!

•!

•!

•!

•!

U2$031!*$%4$0+(/!()!3%.7!05%(,,!,;&/!

W(/2%(--$3!3%.7!3$-&#$%1! `((3!)(%!05&3!0/3!$/]14$!%$05+#$!3%.7,!

T&/&4.4!%&,;!()!,&3$!$P$52,!

Z&4&2$3!2(\&5!$P$52,!

W(/#$/&$/5$H!401!%$C.&%$!(/-1!(/5$!'$$;-1<!

O0,1!3%.7!034&/&,2%0+(/! `((3!)(%!-&*(*6&-&5!3%.7!4(-$5.-$,!!

•!

•!

•!

•!

•!

•!

•! !

F(,,&9&-&21!()!0!-(50-!&%%&20+(/! =--$%7&5!%$05+(/,!0%$!*(,,&9-$! >&,;1!)(%!56&-3%$/!

U;&/a,!-('!*$%4$09&-&21!

T(-$5.-0%!,&]$!0/3!*(-0%&21!()!3%.7! [/,.E5&$/2!9&(0#0&-09&-&21! [)!.,&/7!*0256D!26$/!30407$!2(!0!2%0/,3$%40-!*0256!

=b%&9.2$,!()!0!F0,,&#$!Q%0/,3$%40-! @%.7!W0/3&302$!

•!

•!

•!

•!

•!

•!

7%8+/$'*1"$KV$MW$29L'%/N$ X%+6>+86"$KYW$5*,.1$*.$+"11N$ :*+";,+%.$#"8954$KV$ZWW$'%+4*&1N$ :"+-&9$A*8&4$KV$MWW$*FN$ SU8&$A".2"%?8+84/$ D8A8'$1*+,?8+84/$[A%.--*&$;*"P;8"&4$KD*9$3N$$ ?"4#""&$OY\W$%&'$]^$ •! 0*J8;*+*9/$A.*_+"$ $K&*&>8..84%-&9$%&'$&*&>1"&18-`8&9$4*$1U8&N$

Q%0/,3$%40-!@$-&#$%1! >?@!0/3!F(2$/+0-!

$ @1$4";5&*+*98"1$82A.*)"a$45"$A*4"&-%+$*6$'.,91$%&'$%b.8?,4"1$#8++$"JA%&'$ 18

23

3

Transdermal Delivery of Polyphenols for Pain Management and other Conditions:Technology & Clinical Experience Joseph Gabriele, PhD Q%0/3$%40-!@$-&#$%1!()!!

R02.%0-!T$3&5&/$,!! !

Transdermal technologies can now deliver the most stubborn molecules such as: •!

•!

•!

•!

•!

•!

•!

•!

F60%405$.+50-,!@$-&#$%$3!!

Q6%(.76!26$!U;&/!

Transdermal delivery systems are currently being tested with different classes of pharmaceuticals to offer superior delivery, bioavailability, safety with less side-effects, and efficacy (both target specific and systemic):

Curcumin Ubiquinol Melatonin GABA Magnesium Berberine Amino acids Peptides

•!

•!

•!

•!

•!

•!

$ $ $ $ 05"$6,4,."$*6$&*)"+$4.%&1'".2%+$1/14"21$*T".1$"&'+"11$A*118?8+8-"1\$

NSAIDs (melaxicam, ibuprofen) Statins Corticosteroids Anaesthetics (lidocaine, Xylocaine HCl) Bioidentical hormones Sildenafil

The future offers greater possibilities for drug delivery through the skin.

@')%&4%9"1$6*.$3%-"&4$F%."$ 0.%&1'".2%+$'"+8)"./$81$?"&"_;8%+$4*$A%-"&41$ %&'$'*;4*.1$ $ Y\$@)*8'%&;"$*6$,&'"18.%?+"$4%14"$*6$*.%+$ 2"'8;%-*&1a$#58;5$;%&$8&;."%1"$ ;*2A+8%&;"\$ M\$B/A%118&9$45"$9%14.*8&4"1-&%+$KcCN$4.%;4$4*$$ A.")"&4$cC$'"9.%'%-*&$%&'$8..84%-*&\$$ d\$@)*8'%&;"$*6$A%.-%+$_.14$A%11$8&%;-)%-*&$ *6$%;-)"$2*+";,+"1$8&$45"$+8)".\$$

Q(!056&$#$!$P$5+#$!3$-&#$%1!

26%(.76!26$!,;&/!0/3!).--!*(2$/+0-D! 2$56/(-(7&$,!4.,2!9$!&4*%(#$3c!!

0.%&1'".2%+$7.,9$7"+8)"./$!

0.%&1'".2%+$7.,9$7"+8)"./$$ U2%02$7&$,!)(%!&4*%(#&/7!2%0/,*(%2!%02$!

U2%02$7&$,!)(%!&4*%(#&/7!2%0/,*(%2!%02$!

3"&"4.%-*&$"&5%&;".1$ A$7H!d02$%D!Q$%*$/$,D!"-$&5!05&3,D!T$/26(-D!=](/$,!B! •! >$3.5$,!90%%&$%!)./5+(/!()!,;&/<!

•! U(4$!*$/$2%0+(/!$/60/5$%,!%$4(#$!-&*&3,!)%(4!26$!,;&/!!

–! d02$%H!0!/02.%0-!*$/$2%0+(/!$/60/5$%<!

–! =-5(6(-H!0!,(-#$/2!0,!'$--!0,!0!*$/$2%0+(/!$/60/5$%<! $ !%4,.%+$%&'$1,14%8&%?+"$1*+,-*&1$8&$45"$4.%&1'".2%+$A8A"+8&"$ •! Q%0/,3$%40-!90,$,!0%$!/('!9$&/7!5%$02$3!0,!/02.%0-!*60%40890,$3! %$*-05$4$/2,!)(%!2%03&+(/0-!,1/26$+5D!$4(--&$/2890,$3!5%$04,!5.%%$/2-1! .,$3!91!6(,*&20-,D!*60%405$.+50-!0/3!6$0-26!,$52(%!40/.)052.%$%,<!!

•! [/5-.3$!0--8/02.%0-!(&-,!0/3!$\2%052,!0/3!5(/20&/!'02$%!,(-.9-$!4(-$5.-$,<!

•! e%(038,*$52%.4!0/+84&5%(9&0-D!0/+8)./70-D!0/+89052$%&0-!0/3!0-,(!5(/20&/!

0/+8&/I04402(%1!*%(*$%+$,<!

Z&*(,(4$,!AZ&*&3!#$,&5-$,B! •! U*6$%&50-!#$,&5-$,!'&26!0!4$49%0/$!5(4*(,$3!()!0! *6(,6(-&*&3!9&-01$%<!

•! W%$02$3!91!,(/&50+/7!*6(,*6(-&*&3,!&/!'02$%<!

•! O/50*,.-02$,!3%.7!4(-$5.-$<!!

•! Z&*&3!9&-01$%!50/!).,$!'&26!(26$%!9&-01$%,<!

•! [2!/$&26$%!*$/$2%02$,!/(%!).,$,!2(!UW<!!

•! [2!50/!9$!,$/,&+#$!2(!2$4*D!*VD!-&762!$25<!!

24

4

Transdermal Delivery of Polyphenols for Pain Management and other Conditions:Technology & Clinical Experience Joseph Gabriele, PhD 0.%&1'".2%+$7.,9$7"+8)"./$

0.%&1'".2%+$7.,9$7"+8)"./$

F5%++"&9"1$%&'$@."%1$6*.$C2A.*)"2"&4$

F5%++"&9"1$%&'$@."%1$6*.$C2A.*)"2"&4$

@?1*.A-*&$ !

•!

Q%0/,*(%+/7!05+#$!4(-$5.-$,!4.,2!9$!20%7$28,*$5&G5!?!,.,20&/09-$!91! ,(4$!;&/3!()!,-('!%$-$0,$!4$560/&,4<!! !

•!

[3$0-!2%0/,3$%40-!,1,2$4!,6.b-$,!9(26!'02$%!,(-.9-$!0/3!)02!,(-.9-$!

4(-$5.-$,!05%(,,!,;&/!-01$%,<!! !

•! f.&5;!0/3!$P$5+#$!*$/$2%0+(/!&/!,&7/&G50/2!5(/5$/2%0+(/<! !! ! !"#$$%&'%()$W(/J.70+(/!0/3!,2%02$7&5!)(%4.-0+(/!()!-$03!50/3&302$,!0/3!!

05+#$,!2(!5(/2%(-!%02$,!()!09,(%*+(/<!

•! 3*+/A5%.2%;/!&,!26$!5(/,.4*+(/!()!/.4$%(.,!/02.%0-!4(-$5.-$,!0/3X(%! *60%405$.+50-,!20;$/!02!(/$!+4$<!!

•! F%(9-$4!()!4$3&50+(/,!5(./2$%8&/3&50+/7!0/3!5%(,,8%$05+/7!'&26!$056!(26$%D! 0-(/7!'&26!./'0/2$3!,&3$8!$P$52,!()!(#$%-(03&/7!&4*(%20/2!(%70/,!-&;$!26$!

-&#$%!0/3!;&3/$1<! !

•! *%+%$,-.%&/()$Q6$%$!0%$!/02.%0-!90,$,!&/!26$!40%;$2!/('!2602!50/!60/3-$!(#$%!

Ngh!()!0!,&/7-$!4(-$5.-$!0/3X(%!*(-1*60%4051!.,&/7!/.4$%(.,!'02$%!,(-.9-$!

0/3!)0b1!4(-$5.-$,!2(7$26$%<! !

•! !"#$$%&'%()0e%&/7&/7!4.-+*-$!4(-$5.-$,!A'02$%8!0/3!)028,(-.9-$B! ,&4.-20/$(.,-1!2(!033%$,,!0!*0%+5.-0%!26$%0*$.+5!/$$3!(%!3&,$0,$8,202$!0/3!2(!

3$2$%4&/$!26$!40\&4.4!'&/3('!()!/02.%0-!4(-$5.-$,!2602!50/!9$!

5(4*(./3$3!&/!26$,$!90,$,<!

0.%&1'".2%+$7.,9$7"+8)"./$

Q%0/,3$%40-!U1,2$4!@$,&7/H!! d602n,!=6$03o!

F5%++"&9"1$%&'$@."%1$6*.$C2A.*)"2"&4$ 05"$ :*+";,+"$S8`" $F5%++"&9"$ $ •! U;&/!&,!26$!-0%7$,2!(%70/!&/!26$!9(31!A90%%&$%!2(!2(!$/#&%(/4$/20-!&/,.-2,D! *(--.20/2,D!2(\&/,D!$25<D!!0/3!4&5%(9&0-!(%70/&,4,<!!

•! 7"+8)"./$*6$+%.9".$2*+";,+"1$,18&9$"&5%&;"'$A%118)"$%&'$ %;-)"$'"+8)"./$1/14"21$

•! T(-$5.-$,!i!jgg!30-2(/,!*$/$2%02$!,;&/!91!,&4*-$!3&P.,&(/!0/3X(%!'&26! $/60/5$%!50%%&$%!4(-$5.-$,<!

•! :%4".8%+1$%&'$6*.2,+%-*&1$4*$."',;"$1U8&$8..84%-*&a$"&5%&;"$ 45"$%'5"18*&$A.*_+"a$%&'$82A.*)"$;*26*.4$%&'$#"%.$ •! 0.%&1'".2%+$4";5&*+*98"1$K"\9\$A%4;5"1N$#845$1A";8%+8`"'$ '.,9$'"+8)"./$A.*_+"1$

•! *%+%$,-.%&/()$W.%%$/2!2%0/,3$%40-!90,$,!60#$!9%(.762!05%(,,!26$!,;&/!

'02$%8,(-.9-$!4(-$5.-$,!0,!-0%7$!kjl!@0-2(/,!26%(.76!,2%02$7&5!5(/J.70+(/<!

T(-$5.-$,!0%$!0-,(!$/50*,.-02$3!91!.,$!()!)0b1!05&3,!2(!)(%4!-&*(,(40-! ,2%.52.%$,!0%(./3!26$!'02$%!,(-.9-$!4(-$5.-$,!)(%!9$b$%!,;&/!*$/$2%0+(/<!

•! 0."%42"&41$#845$6"%4,."1$45%4$%8'$8&$%AA+8;%-*&$%&'$,1"$ •! e1".$%&'$"&)8.*&2"&4%++/>6.8"&'+/$A%;U%98&9$'"189&1$K"\9\$ 2*&*'*1"$A%;U%98&9N\$$

•! !"#$$%&'%()$W60--$/7$,!&/!26$!G$-3!0%$!2(!2%0/,*(%2!/.4$%(.,!-0%7$%!

4(-$5.-$,!Am!jgg!@0-2(/,B!05%(,,!26$!,;&/D!0/3!&/!05+#$!)(%4!A$<7<!$/]14$,D! -0%7$%!*%(2$&/,D!$25<B<!!

W0,$!U2.31!K!:!Q%0/,3$%40-!@$-&#$%1!

0/3!Q0%7$2$3!F0&/!Q%$024$/2!!

W0,$!U2.3&$,!0/3!Q0;$8V(4$!

-$,,(/,!()!Q%0/,3$%40-!@$-&#$%1!

25

5

Transdermal Delivery of Polyphenols for Pain Management and other Conditions:Technology & Clinical Experience Joseph Gabriele, PhD W0,$!U2.31!K!:!e.%,&+,!0/3! [/I0440+(/!

3,.9$86,6.'6.1'$ !!!!!! ! ! ! ! ! ! ! ! ! ! ! ! !

•! F0&/!&,!0!40J(%!5(/5$%/!)(%!(-3$%!03.-2,!9$50.,$!()!&2,!6&76! *%$#0-$/5$!:!$,+402$3!2(!9$!0,!6&76!0,!pjh!)(%!26(,$!-&#&/7!&/!

26$!5(44./&21!0/3!.*!2(!kgh!()!(-3$%!03.-2,!-&#&/7!&/!-(/78 2$%4!50%$!)05&-&+$,<!

•! W6%(/&5!*0&/!5(,2,!4(%$!260/!50/5$%D!6$0%2!3&,$0,$!0/3!V[q!

5(49&/$3!'&26!3&%$52!6$0-26!50%$!5(,2,!()!rp!9&--&(/<!

•! F%(3.5+#&21!5(,2,!%$-02$3!2(!J(9!-(,,!0/3!,&5;!301,!0%$! $,+402$3!2(!9$!rNl!9&--&(/!*$%!1$0%< !

Need for more sustainable pain treatments – transdermal delivery offers a hope

d61!Q%0/,3$%40-!Q6$%0*1!d(%;$3o!

W0,$!,2.31!As(0/!Z<B! •! jM!1$0%,!(-3D!,.P$%&/7!)%(4!9.%,&+,!&/! ,6(.-3$%!)(%!(#$%!Mg!1$0%,!'&26!/&76t4$!

6$03056$,!0/3!2%(.9-$!,-$$*&/7<!

–! Q%$024$/2!%$7&4$/,!()!(#$%85(./2$%83%.7,! )0&-$3<!

–! =5.*.//52.%$!'(%;$3!9.2!9$504$!2((! $\*$/,&#$<!

–! Q%&$3!2%0/,3$%40-!5%$04!5(/20&/&/7!0/!05+#$! %.+/!2602!60,!,&7/&G50/2-1!%$-&$#$3!*0&/<!

Rutin blocks 5 pain pathways

@')%&;"'$4.%&1'".2%+$'"+8)"./$1/14"21$;%&$&*#$$ A"&"4.%4"$45".%A",-;$#%4".>1*+,?+"$2*+";,+"1$fJ$$ '""A".$45%&$")".$?"6*."\$ $ F5*8;"$*6$%;-)"$2*+";,+"1$81$82A*.4%&4<$ •! >.+/!&,!0!*(2$/2!0/+8&/I04402(%1!0/3!0/0-7$,&5<!

•! pKg!@0-2(/!'02$%8,(-.9-$!I0#(/(&3!)(./3!&/!90%-$1D! '6$02D!0/3!(%0/7$!*$$-<!!

•! d6$/!5(49&/$3!'&26!(26$%!I0#(/(&3,D!502$56&/,D!0/3!

50%(2$/(&3,!0/3!0!1,14%8&%?+"$'"+8)"./$1/14"2D!%.+/!

9%&/7,!09(.2!,&7/&G50/2!0/3!20%7$b$3!%$-&$)!()!*0&/!

0/3!&/I0440+(/!A&/5-.3&/7!9.%,&+,B<! !

34

d61!Q%0/,3$%40-!Q6$%0*1!d(%;$3o! (,-&$?+*;U1$Z$A%8&$A%45#%/1$#5"&$'"+8)"."'$'""A$8&4*$45"$1U8&<$$ $ L!C&58?841$ !84.8;$ GJ8'"$ 3%45#%/$ >$ 26&,! *026'01! 50.,$,! &/I0440+(/! #&0! &/3.5&9-$!

!

/&2%&5!(\&3$!,1/260,$<!

L!C&58?841$ X814%28&"$ 3%45#%/$ >$ 26&,! *026'01! 0/(26$%! 4$3&02(%! ()! &/I0440+(/8! >.+/!;/('/!2(!052!(/!6&,204&/$!(/!26$!7$/$!-$#$-<!

W0,$!U2.31!M!:!Q%0/,3$%40-!@$-&#$%1!0/3!

Q0%7$2$3!q0%&5(,$!q$&/!Q%$024$/2!!

L!C&58?841$ @.%;58'*&8;$ A%45#%/$ >$ Q6&,! *026'01! 26%(.76! 515-((\17$/0,$! 4$3&02$,! &/I0440+(/!26%(.76!*%(,207-0/3&/,!0/3!-$.;(2%&$/$,<! !

L!C&58?841$3.*4"8&$Q8&%1"$F$3%45#%/$>!26&,!*026'01!&/#(-#$3!&/!)(%40+(/!()!

26%(49(\0/$!=MD!&/#(-#$3!&/!*-02$-$2!077%$70+(/<$$ L!C&58?841$;c:3L$3.*4"8&$Q8&%1"$c$A%45#%/$>$Q6&,!*026'01!&/#(-#$3!&/!4$3&0+/7! &/I0440+(/!0/3!&,!26$!,'&256!9$2'$$/!05.2$!0/3!56%(/&5!*0&/<!

26

6

Transdermal Delivery of Polyphenols for Pain Management and other Conditions:Technology & Clinical Experience Joseph Gabriele, PhD g%.8;*1"$g"8&1$$

g%.8;*1"$g"8&1$$ R5%4$%."$g%.8;*1"$ g"8&1h$K;*&-&,"'N$

R5%4$%."$g%.8;*1"$g"8&1h$

$ •! W6%(/&5!#$/(.,!&/,.E5&$/51!(55.%,!'6$/!26$!-$7!#$&/,!3(!/(2!0--('!9-((3!

2(!2%0#$-!905;!2(!26$!6$0%2<!A=%2$%&$,!50%%1!9-((3!0'01!)%(4!26$!6$0%2D!'6&-$! #$&/,!50%%1!9-((3!2(!26$!6$0%2B<!!

$

•! q0%&5(,$!#$&/,!0%$!7/0%-$3D!$/-0%7$3! #$&/,!5-(,$!2(!26$!,;&/a,!,.%)05$<!!

•! Q(!*%$#$/2!905;!I('D!+/1!#0-#$,!&/!

26$!#$&/,!5-(,$!02!%$7.-0%!&/2$%#0-,<![)!

26$,$!#0-#$,!-$0;D!26$!9-((3!50//(2!

4(#$!)(%'0%3!0/3!0!%$#$%,$3!I('!

(55.%,!50--$3!%$I.\<!

•! Q6$!5(/3&+(/!0P$52,!09(.2!jh!()!26$!SU!*(*.-0+(/<!!

•! W0.,$,H!"9$,&21D!7$/$+5,D!6&76!9-((3!*%$,,.%$D!-05;!()!$\$%5&,$D!,4(;&/7D! *6-$9&+,!A,'$--&/7!0/3!&/I0440+(/!()!0!,.*$%G5&0-!#$&/D!9-((3!5-(2!0/3!

4(%$<!

•! 9&.)':(./;!,.%7$%1D!5(4*%$,,&(/!

70%4$/2<!

W0,$!U2.31!M!:!q0%&5(,$!q$&/,! !!!!!! ! ! ! ! ! ! ! ! ! ! ! ! !

R5/$0.%&1'".2%+$05".%A/$R*.U"'h$

W0,$!,2.31!ATZB! •! lp!1$0%!(-3!)$40-$D!,.P$%&/7!)%(4!#0%&5(,$! #$&/,!0/3!%$,.-+/7!*0&/<!

MN(16.@($)(9(6",6.&9$&=$(O1,1.&2'$.95"(>.(96'$'21*$,'P$ Q.61*$*,R(/$

–! Q%&$3!5(4*%$,,&(/!70%4$/2,!9.2!*0&/!'0,!,$#$%$<!

–! F61,&50-!0**$0%0/5$!()!#$&/,!*$%,&,2$3<!!

–! d0,!/(2!5(4)(%209-$!'&26!,.%7$%1D!'6&56!'0,! $\*$/,&#$!0/3!/(!-(/7$%!5(#$%$3!91!26$!

6$0-2650%$!,1,2$4<!

–! Q%&$3!0!2(*&50-!#0%&5(,$!#$&/!5%$04!3$-&#$%$3!3$$*!

26%(.76!26$!,;&/!0/3!$\*$%&$/5$3!,&7/&G50/2! &4*%(#$4$/2!&/!0**$0%0/5$!0/3!%$3.5+(/!()!*0&/! &/!up!'$$;,!()!5(/,&,2$/2!.,$<!

•! K,6.9$9,4(P!"#$#$%&'(!)'*+','#,#$K#$$ •! S*($6,99.9':$@&/,6./($&./':$5,//.1$,1.>:$"('.9:$T,@&9&.>'$ U)"&1A,9.>.9'V:$,9>$&6*("$9,62",/$1&4)&9(96'$.9$.6$5.@($ H.61*$*,R(/$.6'$,'6".95(96:$,96.-,16(".,/:$,96.@.",/:$,96.W .9T,44,6&"A$U),.9W"(/.(@.95V$,9>$,96.'()6.1$X2,/.6.('#$$ $

R5/$0.%&1'".2%+$05".%A/$R*.U"'h$

@"1;8&$'"+8)"."'$4.%&1'".2%++/$

MN(16.@($)(9(6",6.&9$&=$(O1,1.&2'$.95"(>.(96'$'21*$,'P$ D&"'($1*('6926$ •! E9$,96.W.9T,44,6&"A:$,'6".95(96:$,96.'),'4&>.1:$,9>$"(>21('$ 'H(//.95#$$ •! EM8<Y;:$*&"'($1*('6926Z'$4,.9$,16.@($1&9'6.62(96:$"(>21('$ 1,).//,"A$)("4(,-./.6A$,9>$.4)"&@('$@(9&2'$6&9(:$H*.1*$"('2/6'$ .9$'4,//("$@(.9'$,9>$>(1"(,'(>$),.9#$$

Cream 0.5% Aescin Placebo

•! E('1.9$*,'$-((9$'*&H9$6&$)"(@(96$[(A$(9RA4('$="&4$-"(,[.95$ 6*($H,//'$&=$1,).//,".('#$$

27

7

Transdermal Delivery of Polyphenols for Pain Management and other Conditions:Technology & Clinical Experience Joseph Gabriele, PhD 0.%&1'".2%+$7"+8)"./$S/14"2$B"&"_41$ S,22%./$

0.%&1'".2%+$7"+8)"./$S/14"21$ F*&;+,18*&1$

K<! Q$56/(-(7&$,!50/!/('!5-&/&50--1!3$-&#$%!4$3&50+(/,!3$$*$%!260/! $#$%!9$)(%$!*(,,&9-$!'&26!(/7(&/7!&4*%(#$4$/2,!&/!4(-$5.-$!,&]$D! 09,(%*+(/D!0/3!*(-1*60%4051<!!!

K<! Q%0/,3$%40-!3$-&#$%1!2$56/(-(7&$,!0%$!9$5(4&/7!(/$!()!26$!)0,2$,2!

7%('&/7!,$52(%,!&/!26$!*60%405$.+50-!&/3.,2%1<!

\#! E-./.6A$6&$(N(16$"(/.(=$H.6*$9,62",/$4&/(12/('$U,9>$)*,"4,1(26.1,/'V]$ 'A'6(4'$,"($,/.59(>$H.6*$*(,/6*$*(,/6*1,"($)"&=(''.&9,/'$.(#$ ;,62"&),6*':$<*."&)",16&"':$3*A'.&6*(",).'6'$,9>$4,'',5($ 6*(",).'6'#$

M<! =3#0/5$,!60#$!9%(.762!09(.2!9$/$G2,!)(%!9(26!*0+$/2,!'&26!)$'$%! ,&3$8$P$52,!260/!(26$%!%(.2$,!,.56!0,!(%0-!3$-&#$%1!0/3!&/5%$0,$3! $E5051_!*61,&5&0/,!&/!2.%/!9$/$G2!)%(4!&/5%$0,$3!*0+$/2!

5(4*-&0/5$<!!!

N<! F%(#$/!U.,20&/09&-&21H!U1,2$4,!50/!/('!3$-&#$%!&/7%$3&$/2,!'6&56!

0%$!+4$!%$-$0,$3!%$C.&%&/7!-$,,!)%$C.$/2!0**-&50+(/_!3$$*$%! *$/$2%0+(/!v!-('$%!3(,$,<!

^#! S*($4,"[(6$@,/2($=&"$6",9'>("4,/'$.9$?8$.9$\__`$H,'$ab\#cB$,9>$.'$ (d)(16(>$6&$.91"(,'($6&$a^b#`B$.9$\_b`$F$H.6*$'.59.e1,96$5"&H6*$ )&6(96.,/$.9$6*($9(d6$b_$A(,"'#$

w<! T(%$!05+#$,!A*(-1*60%4051B!50/!9$!3$-&#$%$3!&/!0!)./5+(/0-!)(%4<! j<! Q%0/,3$%40-!3$-&#$%1!&,!0!,0)$D!20%7$2$3!'6$/!/$$3$3D!0/3!4(%$! $P$5+#$!0-2$%/0+#$!2(!(%0-!*0&/!4$3&50+(/<!

!

! !

!

Q60/;!x(.!)(%!1(.%! *0%+5&*0+(/<! ! f.$,+(/,o!!

!

28

8

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D.

Ascorbic Acid (Vitamin C)

!"#$%"&'('$&)'(*+,&"-'."/0$/01' 2*0'3"4*#'5,60-760'$#'#*0'3"4*#'.,/0'

OH

!

O

HO

8$69':+0";'<*=.=' ."+0-#,+'$&)'>&),?0)'(*$"+' @"&7/'<$76"&4'A&/B#7#0' C+04,&'D#$#0'E&"F0+/"#G' (,+F$66"/;'C3'HIJJK'

HO

O OH

(AscH2) Ascorbate Chemistry

Oxygen Society Education Program

#?1+-?3!$!.0,'(A4'3!+3@!%(+3,A'(15! '''''' "'@?<-8@2A23@231!#?1+-?3!$!%(+3,A'(12(,!&!+3@!&&!

"#$%!&!'(!&&!

L$M'

L$M'

.,/'(0?/!./?@!

.,/'(0?/!./?@!

30)7-B,&'

CQ")$B,&'

.0*G)+,$/-,+O"-'' P-")'

N@E2'

)*+,-+!.,/'(0+12! $'3/231(+4'3,5!

67897!:;!

.0*G)+,$/-,+O"-' 'P-")' &31(+/2**<*+(!!.,/'(0+12! $'3/231(+4'3,5! =8>!-;!

Vitamin C Deficiency: Scurvy

Enzymatic Functions of Vitamin C

!! Symptoms:

!! Monooxygenases (reducing/co-substrate) !! Dopamine !-Hydroxylase

Defective pro-collagen hydroxylation

!! Peptidylglycine "-Amidating Monooxygenase

!! Dioxygenases !! Prolyl 4-Hydroxylase, Prolyl 3-Hydroxylase, and Lysyl Hydroxylase

Insufficient L-carnitine biosynthesis

!! Lassitude and fatigue (covert) !! Bleeding and bruising, impaired wound healing !! Hair and tooth loss !! Joint pain and swelling !! Death

!! HIF Hydroxylases !! Trimethyllysine Hydroxylase and #-Butyrobetaine Hydroxylase

Swollen and inflamed gums

!! 4-Hydroxyphenylpyruvate Dioxygenase Petechiae (bleeding under the skin)

29

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D.

30-,%%0&)0)'."0#$+G'P66,?$&-0'R3.PS' "&'#*0'E=D='

!"#$%"&'('"&'(*+,&"-'."/0$/0'<+0F0&B,&' '

!T A/'#*0+0'O",6,4"-$6'\6$7/"O"6"#G'R%0-*$&"/%/',Y'$-B,&S'Y,+'$' +,60',Y'F"#$%"&'('"&'-*+,&"-')"/0$/0'\+0F0&B,&'R&,&"&)0Q' )"/0$/0S;'"&'\$+B-76$+'-$+)",F$/-76$+')"/0$/0/'R(!.S1''

!T50&1'HU'%4V)$G' !T8$/0)',&'#*0'F"#$%"&'('"&#$W0'+0X7"+0)'Y,+'ZU[' &07#+,\*"6'/$#7+$B,&'?"#*'6"]60'7+"&$+G'6,//'"&'*0$6#*G' %0&''

!T `G\0+#0&/",&' !T (,+,&$+G'`0$+#'."/0$/0'R(`.S' !T D#+,W0'

!T^,%0&1'I_'%4V)$G' !T>Q#+$\,6$#0)'Y+,%'%0&',&'#*0'O$/"/',Y'O,)G'%$//' !T`"4*0+'3.P'Y,+'\+04&$&#'$&)'6$-#$B&4'?,%0&'

!T ^*$#'"/'#*0'*7%$&V0\")0%",6,4"-$6'0F")0&-0'#*$#'' F"#$%"&'('-,&#+"O7#0/'#,'#*0'\+0F0&B,&',Y'(!.b' ' !T ^*$#'"/'#*0',\B%$6'"&#$W0',Y'F"#$%"&'('"&'*7%$&/b'

!TD%,W0+/1'\67/'J_'%4V)$G' !TP/-,+O$#0'#7+&,F0+'"/'$\\+,Q"%$#06G'J_'%4V)$G'4+0$#0+' "&'/%,W0+/')70'#,'/%,W"&4a"&)7-0)',Q")$BF0'/#+0//'

'

'

'(,+,&$+G'*0$+#')"/0$/0'R(`.S'"/'$&'"&c$%%$#,+G')"/0$/0'

'''3,60',Y'"&c$%%$B,&'$&)',Q")$BF0'/#+0//'"&'$#*0+,/-60+,/"/'

Antioxidants

//

'306$BF0'3"/W',Y'($+)",F$/-76$+'>F0&#/'$%,&4'P\\$+0&#6G'`0$6#*G'<,/#%0&,\$7/$6'^,%0&'P--,+)"&4'#,'8$/0a@"&0'

@0F06/',Y'2,#$6'(*,60/#0+,6'$&)'5$+W0+/',Y'A&c$%%$B,&='>$-*'%$+W0+',Y'"&c$%%$B,&'"%\+,F0)'+"/Wa\+0)"-B,&'%,)06/' O$/0)',&'6"\")'#0/B&4'$6,&0;'$&'0d0-#'#*$#'?$/'/#+,&40/#'Y,+'*/a(3<'$&)'/0+7%'$%G6,")'P=''''''''''''''''''''''''''''''''''''''''''''

."$9;':+0"')+",&-'!)."#$%&-"'-"()*='KHHIiJJI1fUZafKg'

''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''3")W0+'0#'$6='ReUUUS'!"#$%&"'"()*'Jfe1ZJghZfJ' "

Antioxidant Defenses in Human Plasma and LDL

'`,?'0d0-BF06G'),'#*0'0&),40&,7/'

Small Molecule Antioxidants !!

!!

Typical Plasma Concentrations Water-Soluble: µM Uric Acid 300 Ascorbic Acid (Vitamin C) 50 Albumin-Bound Bilirubin 15 Glutathione (GSH) <2 Lipid-Soluble (Lipoprotein-Associated): mol/mol LDL ! Tocopherol (Vitamin E) 25 10 Ubiquinol-10 (Coenzyme Q10) 1.0 0.4 " Carotene (Pro-Vitamin A) 0.5 0.2 Lycopene 0.5 0.2

$&B,Q")$&#/'"&'*7%$&'\6$/%$'RF"#$%"&'(;' 7+"-'$-");'O"6"+7O"&S'$&)'@.@'RF"#$%"&'>S' \+0F0&#'6"\")'\0+,Q")$B,&'$&)',Q")$BF0' R$#*0+,40&"-S'%,)"j-$B,&',Y'@.@b'

30

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D.

!!

Frei B, Stocker R, Ames BN. Proc Natl Acad Sci USA. 1988;85:9748-52

F2-Isoprostanes, a validated marker of in vivo lipid peroxidation: Formation from arachidonic acid

!"#$%"&'('0d0-BF06G'"&*"O"#/'6"\")'\0+,Q")$B,&'"&'*7%$&' \6$/%$'$&)'"/,6$#0)'@.@'"&)7-0)'OG1' !T PX70,7/'\0+,QG6'+$)"-$6/'RPP<`S'':+0"')+",&=;'<LPD'KHZZ;'KHZHi'<,6"),+"')+",&=;' P+-*'8",-*0%'8",\*G/'eUUf''

!T 2*0'4$/a\*$/0',Y'-"4$+0]0'/%,W0'':+0"')+",&=;'8",-*0%'k'KHHK' !T P-BF$#0)'\,6G%,+\*,&7-60$+'607W,-G#0/'':+0"')+",&=;'<LPD'KHZZ;'D#,-W0+')+" ,&=;'<LPD'KHHK'

!T `C(6'$&)'5<CV`eCeV(6a'MVa'LCea!R$\,8'%,)"j-$B,&S'($++')+",&=;' 8",-*0%'k'eUUUi'($++'$&)':+0";'k'8",6'(*0%'eUUK''

!T `7%$&'$,+B-'0&),#*06"$6'-066/''5$+B&'$&)':+0";'P2!8'KHHI' !T D7\0+,Q")0'+$)"-$6/'$&)'*G)+,40&'\0+,Q")0'RlVlC'/G/#0%S'':+0"')+",&=;' P)F'>Q\'50)'8",6'KHHU'

!T (,\\0+''30#/WG')+",&=;'k'8",6'(*0%'KHHJ;'8",-*"%'8",\*G/'P-#$"KHH_;'D7*')+",&-;':385'eUUJ' !T A+,&''80+40+')+",&=;'k'8",6'(*0%'KHHI;'D7*')+",&-;':385'eUUJ' Morrow et al. (1995) New Engl. J. Med. 332, 1198

Supplementation with vitamin C–but not vitamin E–lowers urinary F2-isoprostane levels in smokers

Elevated 8-iso-PGF2! Levels in:

Supplementation with 2 g/d of vitamin C and/or 800 IU/d of vitamin E for 5 days

!! Cigarette smokers Urinary 8-epi-PGF2!, pmol/mmol creatinine

!! Human atherosclerotic lesions !! Diabetics !! Hypercholesterolemics !! Alzheimer s disease patients !! Alcoholics/patients with liver cirrhosis !! Obese subjects !! During vascular reperfusion !! Etc.

n = 4-7 heavy smokers/group

300

200

*

*

Before Treatment After Treatment

100

0 Vitamin E

Vitamin C

Vitamin C+E Reilly et al. Circulation 1996:94:19-25

31

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D.

Vitamin C and E supplementation prevents the increase in plasma F2-isoprostanes following a 50-km ultramarathon

Urinary levels of 4-hydroperoxy-2-nonenal (HPNE) metabolites: Novel markers of in vivo lipid peroxidation

Supplementation with 300 mg RRR-!-tocopheryl acetate and 1000 mg vitamin C daily for 21 days

Kuiper et al. Free Radic Biol Med. 2011;50:848-853

Mastaloudis et al. Free Radic Biol Med. 2004;36:1329-41

Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal (HPNE) metabolites in humans

(,%\,&0&#/',Y'(!.'P-BF"#G1' 5G,-$+)"$6'A&Y$+-B,&'$&)'A/-*0%"-'D#+,W0'

Daily supplementation with 2 x 500 mg vitamin C or placebo for 17 days in 12 non-smokers (6M, 6F) and 10 smokers (6M, 4F) (crossover-design)

m!'L$++,?"&4',Y'P+#0+"$6'@7%0&' ' m!'P#*0+,/-60+,B-'<6$X70'37\#7+0' m!'<6$#060#'P)*0/",&' m!'2*+,%O7/':,+%$B,&'' m!' !$/,-,&/#+"-B,&' D6")0'-,7+#0/G',Y'k=:='n0$&0G;'k+='

Kuiper et al. Free Radic Biol Med. 2011;50:848-853

Superoxide Inactivates Nitric Oxide!

DG&#*0/"/'$&)'P-B,&',Y'>.LC' @aP+4"&"&0' 'LP.<`' ''Ce'''8`f'

@a("#+766"&0'

M' "o($eM"p'

O2 - + NO #$ ONOO-

"-N5<'

!

#o($eM"p'

LCm'

LC'DG&#*$/0'

Pn2'

â&#x20AC;˘! Nitric oxide combines readily with superoxide

<6$#060#'

>&),#*06"$6'(066'

â&#x20AC;˘! Rate Constant = 1.9 x 1010 M-1 s-1 !

N7$&G6G6'(G-6$/0'

2*+,%O"&' P-*'

D*0$+'/#+0//' N2<'

-N5<'

Beckman et al. PNAS 1990

!$/,)"6$B,&'

D6")0'-,7+#0/G',Y'k=:='n0$&0G;'k+='

!

Kissner et al. Chem. Res. Toxicol. 1997

D%,,#*'57/-60'(066'

32

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D.

L,&aA&F$/"F0'50$/7+0%0&#',Y'LCa 50)"$#0)'!$/,)"6$B,&'

Superoxide Inactivates Nitric Oxide!

Vitamin C!

O2 - + NO #//$ ONOO!

!

•! Nitric oxide combines readily with superoxide •! Rate Constant = 1.9 x 1010 M-1 s-1 !

30$6aB%0')"/\6$G',Y'' c,?'F06,-"#G'$&)'' F0//06')"$%0#0+'

Beckman et al. PNAS 1990 Kissner et al. Chem. Res. Toxicol. 1997

E6#+$/,7&)'>F$67$B,&',Y'8+$-*"$6'' P+#0+G'>&),#*06"$6':7&-B,&'

eU['!$/,)"6$B,&'

f=U'%%'

f=Z'%%'

A&-+0$/0)'O6,,)'c,?'

8$/06"&0'

`G\0+0%"$'

Levine, Frei, et al. Circulation 1996;93:1107-1113

!"#$%"&'('2+0$#%0&#'RD*,+#a',+'@,&4a20+%S'A%\+,F0/' 8+$-*"$6'P+#0+G'>.LC'P-B,&'"&'(P.'<$B0&#/'

!"#$%"&'('R_UU'%4hKe'4'OG'A!'"&Y7/",&',+',+$66GS'A%\+,F0/'' !$/-76$+':7&-B,&'R>.LCa.0\0&)0&#'!$/,)"6$B,&S1' !T "&'(P.'\$B0&#/''@0F"&0'0#'$6='RKHHgS'("+-76$B,&'HJ1KKUIaKKKJi'A#,'0#'$6='RKHHZS'P%'k'($+)",6'Ze1IgeaIgIi'N,W-0'0#'$6='

!T fZ'\$B0&#/'?"#*'$&4",4+$\*"-$66G' \+,F0&'(P.' !T 3$&),%"90);'),7O60aO6"&);' \6$-0O,'-,&#+,660)'/#7)G'

RKHHHS'("+-76$B,&'HH1JeJfaJefU''

!T "&'LA..5'$&)'A..5'\$B0&#/''2"&4'0#'$6='RKHHgS'k'(6"&'A&F0/#'HI1eeaeZi'2"%"%"'0#'$6='RKHHZS'k'P%'(,66'($+)",6' JK1__ea__Ii'80-W%$&'0#'$6='ReUUKS'("+-76$B,&'KUJ1KgKZaKgeJi'P&#,&"$)0/'0#'$6='ReUUfS'."$O0#'50)'eK1__ea__Z''

)!B!7C7=!

E+,2*?32!@?*+4'3!B9F!

D!

!T "&'-*+,&"-'/%,W0+/''`0"#90+'0#'$6='RKHHgS'("+-76$B,&'Hf1gaHi'5,#,G$%$'0#'$6='RKHHIS'P%'k'<*G/",6'eIJ1`Kgffa`Kg_Ui'

D!

D-*"&)60+'0#'$6='ReUUUS'($+)",6,4G'Hf1eJHaefg''

!T "&'*G\0+-*,60/#0+,60%"-'/7Or0-#/''2"&4'0#'$6='RKHHIS'("+-76$B,&'H_1egKIaegeei'<0+B-,&0'0#'$6='ReUUUS'

!T !"/"#'K1'O+$-*"$6'76#+$/,7&)'$#' O$/06"&0'$&)'e'*,7+/'$q0+'e' 4+$%/',Y'$/-,+O"-'$-")'

P#*0+,/-60+,/"/'K_e1_KKa_KZ'

!T "&'*G\0+#0&/"F0'\$B0&#/''D,69O$-*'0#'$6='RKHHIS'("+-76$B,&'Hg1K_KJaK_KHi'2$))0"'0#'$6='RKHHZS'("+-76$B,&' HI1eeeeaeeeHi'L$#$6"'0#'$6='ReUUUS'P2!8'eU1efUKaefUg'

!T Y,66,?"&4'$'/"&460'*"4*aY$#'%0$6''<6,#&"-W'0#'$6='RKHHIS'kP5P'egieIZ1'KgZeaKgZg' !T "&'\$B0&#/'?"#*'-*+,&"-'*0$+#'Y$"67+0''`,+&"4'0#'$6='RKHHZS'("+-76$B,&'HI1JgJaJgZi'A#,'0#'$6='RKHHZS'P%'k'($+)",6'

!T !"/"#'e1'O+$-*"$6'76#+$/,7&)'$q0+' JU')$G/',Y'_UU'%4V)$G',Y' $/-,+O"-'$-")'

Ze1IgeaIgI'

!T "&'\$B0&#/'?"#*'$&4"&$'\0-#,+"/'n74"G$%$'0#'$6='RKHHZS'k'P%'(,66'($+)",6'Je1KUJaKUHi'`$%$O0'0#'$6='ReUUKS'P%'k' ($+)",6'ZI1KK_faKK_H'

!T "&'0Q\0+"%0&#$6'*G\0+*,%,-G/#R0S"&0%"$'n$&$&"'0#'$6='RKHHHS'("+-76$B,&'KUU1KKgKaKKgZi'`$&+$]G'0#'$6='

@0F"&0')+",&-'/0123&,45$'KHHgiHJ1KKUIaKKKJ'' N,W-0')+",&-'/0123&,45$'KHHHiHH1JeJfaJefU'

ReUUKS'85('($+)",F$/-'."/,+)'K1K'

33

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D.

Plasma Vitamin C correlates with Unstable Coronary Syndrome (Angina Class) in CAD Patients (n = 149) Plasma Marker

Working Model"

Angina Class (1-4)

R P

O2 - + NO $

!-Tocopherol (Vitamin E) -.06 .68 LDL !-Tocopherol -.18 .27 %-Tocopherol -.08 .56 "-Carotene .07 .66 Lycopene -.01 .95 Retinol -.15 .36 Ascorbic Acid (Vitamin C) -.43 .001 Uric Acid .20 .12 Thiols -.19 .15 Ceruloplasmin .00 .97 Superoxide Dismutase (RBCs) -.08 .64 Lag Phase (LDL Diene Conjugation) -.13 .43 .02 .87 F2-Isoprostanes

Vitamin C $

___

//% ONOO- !

NO (k2 = 1.9 x 1010 M-1 s-1) (~ 0.1 !M) $

$

O2 $

Ascorbic Acid (k2 = 2 x 105 M-1 s-1) (~ 0.1 !M x 105 = 10 mM) $

Vita et al. (1998) J. Am. Coll. Cardiol. 31, 980-986

P/-,+O"-'P-")'0&*$&-0/'8`fa.0\0&)0&#'''''''''''''0LCD' P-BF"#G'$&)'A&#+$-06676$+'8`f'@0F06/' <,+-"&0'P,+B-'>&),#*06"$6'(066/'

t'

e_U'

'P/-,+O$#0'

ZU' gU' fU' '(2@'

eU' U'

8`f' ' 'R['(,&#+,6S'

'@a("#+766"&0'R&%,6V%4V%"&S'

8,F"&0'0LCD'

KUU'

'''''50-*$&"/%',Y'!"#$%"&'('P-B,&'

G!

eUU'

OPN!

KUU'

U=_'

K'

KU'

'8`f'Rs5S'

eU'

U'

N!

%21(+QL@('0?'A12(?3!

REOST! (,&#+,6'

G!

GH?@+4'3I!J3KL-2! %<(3'M2(!

GO!

N!

N!

GO! N!

O!

_U'

U'

N!

ON!

K_U'

O!

!.,/'(0?/!./?@!

OPN!

GO! GO!

N!

N! O!

U<?3'?@!@?QL@('0?'A12(?3!

RUEOPT!

PP'

`7$&4'0#'$6=;'k'8",6'(*0%='eUUU1eI_1KIJHH'

!"#$%"&'('$&)'86,,)'<+0//7+0' <*$/0'AA'3(2'>F")0&-0'' ! !T`G\0+#0&/",&'"/'$'(!')"/0$/0'RA(.'KU'(,)0' KKUaKK_1'`G\0+#0&/"F0')"/0$/0/S' ''

!TD0-,&)'%,/#'-,%%,&'\+0F0&#$O60'-$7/0',Y' )0$#*'"&'#*0'E=D='

V+3+2?!21!+*CI!P77WX!YRST52=7777>9!

34

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D.

mT 3$&),%"90);'),7O60aO6"&);'\6$-0O,' -,&#+,660)'/#7)G' mT !"/"#'C&01'O6,,)'\+0//7+0'%0$/7+0)'$#' O$/06"&0'$&)'e'*,7+/'$q0+'e'4+$%/',Y' $/-,+O"-'$-")' mT !"/"#'2?,1'O6,,)'\+0//7+0'%0$/7+0)' $q0+'JU')$G/',Y'_UU'%4V)$G',Y' $/-,+O"-'$-")''

160 150 140

Diastolic BP

mT JH'\$B0&#/'?"#*'*G\0+#0&/",&;'$40' fHuKJ'G0$+/'

Systolic BP

!"#$%"&'('@,?0+/'86,,)'<+0//7+0'' "&'<$B0&#/'?"#*'>//0&B$6'`G\0+#0&/",&'

P < 0.001 90 80 70

Ascorbic Acid Placebo

0

.7dG')+",&-'6,$2)+'KHHHiJ_f1eUfZaeUfH''

Base

2 hr

1 m on

>d0-#/',Y'!"#$%"&'('D7\\60%0&#$B,&',&'86,,)'<+0//7+01'' 50#$aP&$6G/"/',Y'eH'3(2/'R%0)"$&'_UU'%4V);'Z'?W/S''

>d0-#/',Y'!"#$%"&'('D7\\60%0&#$B,&',&'86,,)'<+0//7+01'' 50#$aP&$6G/"/',Y'eH'3(2/'R%0)"$&'_UU'%4V);'Z'?W/S''

:+7"#'v'!040#$O60'A&#$W0'' $&)'86,,)'<+0//7+0''''''''''''

!"#$%"&'('$&)'(!.'R(`.'$&)'D#+,W0S''

R6!,2(M?3Z,[@T! R9!,2(M?3Z,[@T! RW!,2(M?3Z,[@T!

<+,/\0-BF0'(,*,+#'D#7)"0/' RCO/0+F$B,&$6S'

'Pq0+'Z'?00W/;'#*0'D8<'$&)' .8<',Y'#*,/0',&'#*0'Y+7"#' $&)'F040#$O60')"0#'?0+0' /"4&"j-$&#6G'6,?0+'#*$&' #*,/0',&'#*0'#G\"-$6' P%0+"-$&')"0#='

!T8$/0)',&')"0#$+G'"&#$W0'$//0//%0&#',Y'F"#$%"&'(' '' ' ',+' !T8$/0)',&'\6$/%$'R/0+7%S'60F06/',Y'F"#$%"&'('

'

!T 5,+0'$--7+$#0'%0$/7+0',Y'&7#+"0&#'0Q\,/7+01'&,#'$d0-#0)'OG'+0-$66' O"$/'0#-=;'$&)'#$W"&4'"&#,'$--,7&#'6,//',Y'F"#$%"&'(')7+"&4'Y,,)'/#,+$40' $&)'\+0\$+$B,&'$/'?066'$/'40&0B-'\,6G%,+\*"/%/'"&'F"#$%"&'(' #+$&/\,+#'

'D8<'$&)'.8<',Y'#*,/0',&' #*0'-,%O"&$B,&'R.PD`S' )"0#'?0+0'0F0&'6,?0+='

!!!!!!P\\06'0#'$6='!"#$%&"'"()*"KHHIiJJg1KKKIaKKef'

35

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D.

!;21+8+3+*L,?,!'^!=>!A(',A2/4M2!/'Q'(1!,1<@?2,!'^!M?1+-?3!$!?31+_25!! =YF!*'`2(!$OV!(?,_!

How do genetic factors influence plasma vitamin C levels?

\2!]I!"'3Z!OC!!"#$%$&'#()*+',-$.#/+$0/1'2)3C!P779X=>5PY86SC!

''!"#$%"&'('D7\\60%0&#'E/0'$&)'(`.'3"/W'' "&'#*0'L7+/0/ '`0$6#*'D#7)G' Supplement Use

RR

95% CI

0.72*

(0.61-0.86)

Dose of Vitamin C Supplements 1-400 mg/day

0.82

(0.60-1.12)

401-749 mg/day

0.69*

(0.55-0.87)

750 mg/day or more

0.71*

(0.55-0.92)

Add slide from Table 1 of ascorbate paper: plasma levels in uM associated with largest reduction in risk !

Duration of Vitamin C Supplements <2 years

1.12

(0.45-2.76)

2-4 years

0.77

(0.63-1.12)

5-9 years

0.84

(0.63-1.12)

10 or more years

0.70*

(0.52-0.94) ''''''''''''''''''''''''''''''''''''''''''''C/4$&"$&'0#'$6=;''7//'eUUJ'

Frei, Birlouez-Aragon, and Lykkesfeldt. Crit Rev Food Sci Nutr 2012;52(9):815-29.

5,+#$6"#G'Y+,%'$66'-$7/0/;'-$+)",F$/-76$+')"/0$/0/;'$&)'-$&-0+'"&'' wKH;UUU'%0&'$&)'?,%0&'f_aIH'G0$+/'OG'-$#04,+G',Y'\6$/%$'F"#$%"&'('' '

>7+,\0$&'<+,/\0-BF0'A&F0/B4$B,&'"&#,'($&-0+'R><A(S'L,+Y,6W'KHHJaeUUU'

Mortality rate/100

6 5 4

All cause

3

CVD

2

Cancer

- 60%

1 0 Q1

Q2

Q3

Q4

Q5

Plasma vitamin C category n*$?'0#'$6='6,$2)+'eUUKiJ_I1g_IaggJ'

36

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D. :+7"#'$&)'F040#$O60'"&#$W0'OG'X7"&B60'' ,Y'\6$/%$'F"#$%"&'('"&'%0&''

g/day

R><A('L,+Y,6W'KHHJaKHHIS'

350 300 250 200 150 100 50 0

Vegetable intake Fruit intake

1

2

3

4

5

Vitamin C quintile

aQ+`!21!+*C!4'5-/6!P77=!

:+7"#'v'!040#$O60' A&#$W0'$&)'D#+,W01'' eg['30)7-B,&' '

:+7"#'v'!040#$O60'A&#$W0'' $&)'(,+,&$+G'`0$+#'."/0$/01'' KI['30)7-B,&' ' R!"#$%"&'(V><A(1'gU[S'

R!"#$%"&'(V><A(1'JHa_K[S''

''''''''`0'0#'$6=''"839"8:;)1+)$"eUUIieK1IKIaIeZ'

''''''`0'0#'$6='@$&-0#'eUUgiJgI1JeUaJeg'

Relative Risk for CVD Mortality in 19,496 men and women (EPIC)

1.2 1.0

^*$#'$%,7&#',Y'F"#$%"&'('),' *7%$&/'*$F0'#,'-,&/7%0'#,'$-*"0F0' ,\B%7%'\6$/%$'$&)'B//70'60F06/' $&)'+0$\'#*0'Y766'*0$6#*'O0&0j#/',Y' F"#$%"&'(b !

0.8

- 60%

0.6 0.4 0.2 0

1

<20.8µM

2

38.1µM

3

48.1µM

4

56.8µM

5

72.6µM

Plasma ascorbic acid quintile Khaw et al., Lancet 2001;134:657

37

Vitamin C and Chronic Disease: The Right Molecule at the Right Dose Balz Frei, Ph.D.

Plateau Plasma Ascorbic Acid (µM)

<6$/%$'$/-,+O$#0'-,&-0&#+$B,&/'' $/'$'Y7&-B,&',Y'F"#$%"&'('),/0'

Add slide from Table 1 of ascorbate paper: plasma levels in uM associated with largest reduction in risk !

100

<0$W'<6$/%$'(,&-0&#+$B,&1'fUU'%4V)' 80

60

:"+/#'),/0'O0G,&)'/#00\V6"&0$+'\$+#',Y'' /"4%,")$6'),/0a+0/\,&/0'-7+F01'P77!-Z[@!

40

20

&'x'K_'Y0%$60/' 0 0

500

1000

1500

2000

2500

Dose, mg/day @0F"&0')+",&-'ReUUKS'<!7='HZ1HZfeag'

Frei, Birlouez-Aragon, and Lykkesfeldt. Crit Rev Food Sci Nutr 2012;52(9):815-29.

A&#+$-06676$+'$/-,+O$#0'-,&-0&#+$B,&/'' $/'$'Y7&-B,&',Y'F"#$%"&'('),/0'

''!"#$%"&'('D7\\60%0&#'E/0'$&)'(`.'3"/W'' "&'#*0'L7+/0/ '`0$6#*'D#7)G' Supplement Use

RR

95% CI

0.72*

(0.61-0.86)

Dose of Vitamin C Supplements 1-400 mg/day

0.82

(0.60-1.12)

401-749 mg/day

0.69*

(0.55-0.87)

750 mg/day or more

0.71*

(0.55-0.92)

<0$W'(066'(,&-0&#+$B,&5!eUU'%4V)'

Duration of Vitamin C Supplements

@0F"&0')+",&-'ReUUKS'<!7='HZ1HZfeag'

•! ($&-0+' •! 5AVD#+,W0' •! `G\0+a #0&/",&' •! @$-W',Y' >&0+4G' •! :$B470' •! D-7+FG'

J3KL-2[! c<3/4'3!

(,66$40&' 8",/G&#*0/"/'

(%$Q'''D$#7+$B,&'

'

S77!-Z[@+L!

.,/0'R%4V)$GS'

(0.63-1.12)

5-9 years

0.84

(0.63-1.12)

10 or more years

0.70*

(0.52-0.94)

!T :+0"'6$O;'0/\='(+"/B&$'<,6"),+";'P&"#+$'($++;'$&)'P60Q$&)0+'5"-*06/' !T 8+7-0'L='P%0/'RE&"F0+/"#G',Y'($6"Y,+&"$;'80+W060GS' !T k,*&':='n0$&0G'$&)'k,/0\*'!"#$'R8,/#,&'E&"F0+/"#G'D-*,,6',Y'50)"-"&0S' !T k$/,&'5,++,?'R)0-0$/0)S'R!$&)0+O"6#'E&"F0+/"#GS' !T 5$+W'@0F"&0'RLA..n;'LA`S' ' :7&)"&4'\+,F")0)'OG1' 'ED'L$B,&$6'A&/B#7#0/',Y'`0$6#*'RL`@8A;'L((P5;'LA>`DS'$&)'P%0+"-$&' `0$+#'P//,-"$B,&''

(,&-0&#+$B,&'

bV.!

(0.45-2.76)

0.77

P-W&,?60)40%0&#/'

' '

' ' •! P&B,Q")$&#'''''''' ''''P-BF"#G' •! 0LCDV8`f'' '30-G-6"&4' ' ' ($+&"B&0'$&)' ($#0-*,6$%"&0' 8",/G&#*0/"/'

1.12

2-4 years

''''''''''''''''''''''''''''''''''''''''''''C/4$&"$&'0#'$6=;''7//'eUUJ'

<6$/%$'P/-,+O$#0'(,&-0&#+$B,&1'' !"#$%"&'('.,/0'F/=':7&-B,&' V?,2+,2[!

"L-A1'-!

<2 years

L,'Y7+#*0+'*0$6#*'O0&0j#/'

38

Ascorbic Acid: Its Importance and the Glucose Ascorbate Antagonism 3/28/14!

Theory John Thoreson

The Primary Mantra!

Ascorbic Acid:" Its Fundamental Importance …"

The Glucose Ascorbate Antagonism Theory"

•! “The rate limiting factor of immune system

From work by John T A Ely, PhD, Col US Air Force ret.!

function is intracellular ascorbate.”!

•! If true, this is a most basic underlying principle for maintaining and restoring health … especially in the face of our mutation!!

43rd Annual Orthomolecular Medicine Today!

25 April 2014!

•! Underlying corollary to the mantra is the Glucose Ascorbate Antagonism Theory (GAA)!

Presented by!

John Thoreson, BA!

Key to the corollary GAA!

The Key to the Mantra!

•!

•!

•!

•!

In a normal human leukocyte the intracellular levels of AA are maintained via an insulin mediated active transport system at nearly 50 times the surrounding serum levels!

When needed (i.e. stress, disease, trauma, etc.) the rate of synthesis of converting glucose into AA – in all mammals not mutated (like humans) – increases 10 to 100 times!

•!

This increased amount of AA in circulation now via this uptake pathway results in an elevation in the intracellular levels of AA and a significant increase in immune system function and integrity!

•!

Intracellular ascorbate is monotonically related to driving the HMP shunt – to produce ribose (among other things) needed to make rna when rapid mitosis, high rate of metabolic activity and synthesis are needed!

The GAA is critical as when glucose levels are even modestly elevated over normal, given its ancient sisterhood with AA, glucose will outcompete AA for uptake into the leukocytes!

Leaving the immune system unable to adequately rally to the challenges presented!

A Brief History of Discovery!

It is as simple as …!

Cosmic Rays & Human Health: In the 1970’s Ely proposed a latitudinal relationship between cosmic radiation and human cancers (low latitude low incidence – & vice versa)!

The further from the equator the greater the mutagenic effect of background cosmic radiation!

Nothing is as easy or simple as we would wish it to be,! yet if we had to know it make it work?!

!

1!

39

Ascorbic Acid: Its Importance and the Glucose Ascorbate Antagonism 3/28/14!

Theory John Thoreson

Ely’s work bench in the design phase of his Cosmic Ray Detector For Satellite !

A bit of context and perspective: The Solar System!

High-energy Cosmic Ray Experiment as Part of this Satellite!

Energies Required for Cosmic Ray Secondaries to Reach the Earth s Surface!

Green = 15 GeV

The trouble with Theories!

•!

•!

•!

•!

•!

Red = 0.12 GeV!

For Instance:" Sugar Intake and Breast Cancer Death Rates!

There were anomalies in the cancer data – very disturbing for a physicist (data supported theory pretty much … yet anomalies violated his expectation)!

Mid-latitude countries with higher than predicted cancer rates!

From WHO data - high sugar consumption in these countries!

What does sugar have to do with Cancer? !

Non-mutated mammals able to convert glucose into ascorbate (… then what does ascorbate have to do with cancer?) From this and other papers published on leukocytes in the 1970’s he deduced the GAA … and hence the primary mantra!

!

2!

40

Ascorbic Acid: Its Importance and the Glucose Ascorbate Antagonism 3/28/14!

Theory John Thoreson

How Basic is Basic? … how beautiful is green!

•!

•!

•!

•!

Porphine, Heme and Chlorophyll!

Porphine!

CO2 and H2O – Totally Oxidized!

Nature at its conservative best – the magic of the porphyrin ring!

Reduces, Restores – reload these spent atoms/molecules with sunlight energy!

Oxidized C & Oxidized H become CHO … sugar …

YEAA SUGAR!!!!

Production of Glucose By Photosynthesis in Plants Leads to Ascorbic Acid!

Ascorbic Acid!

Production of Ascorbic Acid in Plants and Mammals!

Galactose!

Adapted from: Nutritional Sciences: From Fundamentals to Food#By Michelle McGuire, Kathy Beerman (2012) !

There will be consequences!

Biosynthesis of Ascorbic Acid in Rat Liver!

•!

•!

•!

Derived from Kustermann, et al., 1998!

•!

To our benefit and loss, alas we are mutated.!

“Solution has its problems” JTA Ely!

•!

Our liver enzyme L-gluonolactone oxidase isn’t so active!

Leukocytes require high AA levels to drive the HMS to supply adequate H2O2 and ribose for effective phagocytosis and mitosis!

In even modest BG elevations (over 130 mg/dL) BG so outnumber AA as to competitively inhibit insulin-mediated active transport of AA into cells – resulting in low intracellular levels, low HMS, cell dysfunction, etc – this is the glucose ‘antagonism’ of AA! The GAA theory gives rise naturally to Aggressive Glycemic Control diet and concurrent supplementation with AA! Ignore this at our own peril … leading to untold morbidity, mortality, great cost, and suffering.!

3!

41

Ascorbic Acid: Its Importance and the Glucose Ascorbate Antagonism 3/28/14!

Theory John Thoreson

Car Story:!

Aging: Predictions of a New Perspective on Old Data" Society for Experimental Biology and Medicine: 2002 pg.939-942 Ely, Krone !

Ely related to Pauling in 1973 this theoretical reason why the clinical trials of vitamin C against colds and cancer may have failed because the high blood sugar in the affluent nations.!

•! Compared our 4,000 mammal relatives ratio of Life Expectancy to Age of First Estrus: R = LE/AFE!

•! Most relatives have an R value of ~25!

•! Humans … 8!

•! Can we live better longer? We shall C!!

My mission in May of 1990: If this is true, and the answer so basic and reasonable – why does it remain so unacted upon?!

Change, although stressful can be good!

John Ely worked relentlessly throughout his life to solve the problems of our shared human dilemma. A fundamental appreciation of the role of Ascorbate in health & immune integrity is just one of his contributions. !

Thank you all for being here.!

4!

42

The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York

!"#"$!%

Michael Schachter, MD 1'O(,*'8+0%

!"#$%&'#$&($)*'+#,-.&',$/0$-"#$ 1*0*2#3#0-$&($4*05#.$6*7#0-,$*-$ -"#$)5"*5"-#.$4#0-#.$/0$8#9$:&.;$

•! S((70;'5T%/7%6+;+0*,%,*E2%/)+%U+;+0*,%U77;%V% 10?T%S;8'5'O/0*@75%'O%0+O975O'W,+%670% ;+/+08'5'5T%(,*'8O%670%*5:%O?WO/*5(+%?O+;%/7% /0+*/2%90+A+5/%70%8'@T*/+%*5:%;'O+*O+%70% (75;'@752%O?()%*O%(*5(+0% •! 47%O?()%(,*'8O%*0+%W+'5T%8*;+%;?0'5T%/)'O% ,+(/?0+% •! X56708*@75%6078%/)'O%,+(/?0+%'O%9?0+,:%670% '56708*@75*,%9?097O+O%*5;%57%(,*'8O%*0+%W+'5T% 8*;+%

&'()*+,%-%.()*()/+0%&12%34.% .()*()/+0%3+5/+0%670%3789,+8+5/*0:% &+;'('5+% <%=>+(?@A+%-7?,+A*0;B%.?'/+%<C<% .?D+052%4+E%F70G%$CHC$% I!JKLMIK!#CCB%EEENO()*()/+0(+5/+0N(78% P0/)787,+(?,*0%&+;'('5+%Q7;*:%3756+0+5(+% R*5(7?A+0%-3%3S%%%S90',%<J2%<C$!% $

]+6+0+5(+O%SA*',*W,+%6078%]+6+0+5(+% ^'O/%*5;%6078%_+WO'/+O%

375Y'(/O%76%X5/+0+O/O% •! S/%7?0%3+5/+02%E+%;7%)*A+%*%;'O9+5O*0:%6078%E)'()% E+%7D+0%9*@+5/O%/)+%79@75%76%W?:'5T%O?99,+8+5/O% /)*/%*0+%0+(788+5;+;N% •! Q)+:%*0+%60++%/7%W?:%87O/%76%%/)+O+%O?99,+8+5/O% +,O+E)+0+2%O?()%*O%*/%*%Z+*,/)%U77;%./70+%70%75%/)+% X5/+05+/% •! S875T%/)+%O?99,+8+5/O2%E+%0+(788+5;%*0+% .*,A+O/07,O2%E)'()%*0+%;'O(?OO+;%'5%/)'O%,+(/?0+% •! [*@+5/O%8*:%*,O7%9?0()*O+%87O/%76%/)+% 0+(788+5;+;%O?99,+8+5/O%75,'5+% •! P5%\:87T+5%-7*0;%76%S;A'O70O%V%8'570%O/7(G%)7,;+02% W?/%\:87T+5%907;?(/O%57/%8+5@75+;%'5%/)'O%,+(/?0+%

•! ]+6+0+5(+O%670%/)'O%,+(/?0+%*0+%*A*',*W,+%6078%/)+% 0+6+0+5(+%,'O/%907A';+;%E'/)%/)'O%,+(/?0+N%4?8W+0O%76% 0+6+0+5(+O%75%O,';+O%0+6+0%/7%/)+%5?8W+0%75%/)+% 0+6+0+5(+%,'O/% •! &*5:%0+6+0+5(+O%*0+%,'5G+;%/7%E+WO'/+O% •! .78+%0+6+0+5(+O%*0+%75%O78+%O,';+O% •! S%870+%(789,+/+%,'O/%76%0+6+0+5(+O%0+,*/+;%/7%3F[$-$% *5;%.*,A+O/07,O%*0+%*A*',*W,+%/7%)+*,/)%(*0+% 90*(@@75+0O%*/%/)+%E+WO'/+`%EEENO*,A+O/07,N(*%%

<&9$6.&(#,,/&0*',$4*0$=#-$>0(&.3*7&0$&0$ 4:6?@?$*0A$)*'+#,-.&',$*-$999B,*'+#,-.&'B5*$

=&*',$&($C#5-D.#$

•! PA+0*,,%*EE.&*5"$-&$-"#$5*05#.$E*7#0-$8F!$ *AA.#,,#A$/0$-"/,$'#5-D.#$ •! U7(?O%E',,%W+%75%*5%/00&+*7+#$-"#&.G$/0+&'+/02$*$ .#'*7+#'G$0&0H-&I/5$*EE.&*5"$-&$E.#+#0702$*0A$ -.#*702$5*05#.$/)*/%O)7?,;%W+%(*00'+;%7?/%9/-"/0$-"#$ 5&0-#I-$&($*$J.&*A#.$*EE.&*5"$-&$'/(#,-G'#$5"*02#,$ *0A$-"#$#'/3/0*7&0$&($-&I/0,$ •! KI5/702L$JD-$+#.G$E.#'/3/0*.G$,D22#,7+#$E&,/7+#$ (,'5'(*,%0+O?,/O%E',,%W+%0+A'+E+;% •! &*/+0'*,%O)7?,;%W+%(75O';+0+;%5&0-.&+#.,/*'$

•! Call 250 483-3640 to get a User Name & Password •! State your credentials and request a User Name and Password •! Once these are obtained, go to the website : www.salvestrol.ca •! Click on Practitioner Login and enter your user name and password. A variety of articles, videos & other information on this subject can then be accessed.

43

$%

The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York

!"#"$!%

Michael Schachter, MD 1G$>0-#.#,-$/0$4:6?@?$*0A$)*'+#,-.&',$

•!

•!

•! X5/+05*@75*,%.7('+/:%670%P0/)787,+(?,*0%&+;'('5+% (756+0+5(+%'5%Q7075/7%!%70%J%:+*0O%*T7% •! Q)+70:%,77G+;%T0+*/%*5;%X%/)7?T)/%*W7?/%'/% •! M/,5&D.*2#A$J#5*D,#$E*7#0-,$-*;/02$)*'+#,-.&',$ 4FNCM$8F!$-*;#$@?OL$$C*#-./'#L$*3G2A*'/0$ •! &7O/%76%8:%(*5(+0%9*@+5/O%E+0+%/*G'5T%-$#%70*,,:%70% XR%*/%/)+%@8+% •! %#5#/+#A$@./*0$)5"*#(#.P,$J&&;$&0$)*'+#,-.&',HQR?Q$ •! ./?;'+;%'/%(*0+6?,,:2%O97G+%/7%-0'*5KW+(*8+%(75A'5(+;% /)'O%'O%*%8*a70%W0+*G/)07?T)%670%?5;+0O/*5;'5T%3S%

•!

•!

•!

•!

•!

•!

^P=%-%*5;%3%

-77G%W:%-0'*5%S%.()*+6+0K<C$<%

[*9+0W*(G%W77GK)'T),:%0+(788+5;+;% M/,5D,,#,$/0$A#E-"$-"#$"/,-&.G$&($-"#$ A/,5&+#.G$&($4:6?@?$S$)*'+#,-.&',$ 3*O+%)'O/70'+O%76%9*@+5/O%?O'5T%O*,A+O/07,O% bO+%76%3F[$-$%/7%)+,9%/7%A#-#5-$5*05#.,$ &*>'8'c'5T%+D+(/O%76%O*,A+O/07,O% &+/%-?0G+2%[7d+0%V%1*5'+,O%'5%/)+%+*0,:% <CCCeO%V%6*O('5*/+;%E'/)%3F[$-$%*5;% .*,A+O/07,O% M/,-./JD-#,$-"#$)*'+#,-.&'$,DEE'#3#0-$/0$ 8&.-"$T3#./5*$ !"*0;,$(&.$E#.3/,,/&0$-&$D,#$,#+#.*'$&($"/,$ ,'/A#,$(&.$-"/,$E.#,#0-*7&0$

^P=%-%*5;%3B%]+6%!%

4:6?@?$=#0#L$1#,,#02#.$%8T$S$ K0UG3#$

=OO+5@*,O%76%/)+%6.&-#/0HK0UG3#% 3F[$-$%

•! 3F[$-$%2#0#%'O%67?5;%'5%+A+0:%(+,,%'5%/)+%W7;:% •! 1#,,#02#.%3F[$-$%'O%67?5;%W7/)%'5%(*5(+0%(+,,O% *5;%,&3#$0&0H5*05#.$5#'',$ •! 3F[$-$%#0UG3#%'O%67?5;%*,87O/%+>(,?O'A+,:%'5% 5*05#.$5#'',$&.$E.#5*05#.&D,$5#'',$ •! 4&0(D,/&0$'5%8+;'(*,%,'/+0*/?0+%*W7?/%E)+0+% 3F[$-$%0+O';+O%'O%,*0T+,:%W*O+;%75%(756?O'75% W+/E++5%/)+%3#,,#02#.$(&.3$&($4:6?@?$*0A$$-"#$ #0UG3#$(&.3%f]+6+0+5(+O%<<K<Mg%

•! Q)+%E.&-#/0H#0UG3#%3F[$-$%'O%90+O+5/%'5%*''$5*05#.$5#'',L$ JD-$/0$0&$0&.3*'$5#'',$&.$/0$70G$VD*077#,$/0$,&3#$ 0&.3*'$5#'',L$E)'()%8*:%W+%'5%/)+%907(+OO%76%W+(78'5T% (*5(+07?O$]+6%MK<<% •! 3F[$-$%'O%(75O';+0+;%*%D0/+#.,*'$5*05#.$3*.;#.%W:%O78+% f+NTN%0+O+*0()+0O%*/%/)+%1*5*%U*0W+0%3*5(+0%3+5/+0%'5% -7O/75g%]+6%H% •! ]+O+*0()%O)7E'5T%/)+%90+O+5(+%'5%W0*'5%(*5(+0%(+,,O%)*O% W++5%;75+%*/%&1%S5;+0O75%3*5(+0%3+5/+0%]+6%%$I% •! 8&$3#07&0$&($-"/,$5&05#E-$*-$8><$9#J,/-#$%#($W$

^+A+,%76%=A';+5(+%f^P=g%-B%]+6+0+5(+O%M%/)07?T)K<M%

^+A+,%76%=A';+5(+%f^P=g%-%%

4&..#5702$.*,A+O/07,%1+h('+5('+O%

=OO+5@*,O%76%)*'+#,-.&',$

•! .*,A+O/07,O%*0+%*%T07?9%76%0+,*@A+,:%'5+0/% O?WO/*5(+O%67?5;%'5%&.2*0/5$9,*5/O% •! .*,A+O/07,O$*0+$5&0+#.-#A$JG$4:6?@?$-&$ 3#-*J&'/-#,$-"*-%/0AD5#$A#*-"$X*E&E-&,/,Y$/0$ 5*05#.$5#'',$ •! &7O/%9+79,+%O?D+0%6078%*%A#Z5/#05G%76%O*,A+O/07,O2%% E)'()%90+;'O97O+O%%/)+8%/7%(*5(+0% •! )*'+#,-.&',$"*+#$0&$#[#5-$&0$0&.3*'$5#'',$E)'()% ;7%57/%)*A+%3F[$-$%

•! -:%+*@5T%&.2*0/5%60?'/O%*5;%A+T+/*W,+O%)'T)%'5% .*,A+O/07,O2%*%9+0O75%E',,%(75A+0/%/)+%.*,A+O/07,O%/7% 8+/*W7,'/+O2%E)'()%*0+%(*9*W,+%76%'5;?('5T%*979/7O'O% '5%*5:%(*5(+0%(+,,O%,?0G'5T%'5%/)+%W7;:% •! U70%/)'O%/7%E70G%9079+0,:2%/0"/J/-&.,$&($4:6?@?$0##A$ -&$J#$*+&/A#A$ •! .*,A+O/07,%;+h('+5(:%(*5%W+%(700+(/+;%E'/)%*%;'+/%0'()% '5%O*,A+O/07,O%70%E'/)%*%,*'+#,-.&'$,DEE'#3#0-$ •! !"#$4:6?@?H)*'+#,-.&'$,G,-#3$3*G$J#$0*-D.#P,$ .#,5D#$3#5"*0/,3$(.&3$5*05#.$ ^P=%-%*5;%3B%]+6+0+5(+O%<2%!2%J2%L<KLJ%

^+A+,%76%=A';+5(+%f^P=g%-%V%3B%]+6+0+5(+O%<2%!2%J2%L<KLJ%

44

<%

The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York

!"#"$!%

Michael Schachter, MD =D+(/O%76%)*'+#,-.&',$&0$4*05#.$$4#'',$ S$8&.3*'$4#'',$

3F[$-$%>0"/J/-&.,$ •! %#,+#.*-.&'$/0$"/2"$A&,#,B%E',,%W+%;'O(?OO+;%]+6%!% •! T3G2A*'/0\]/-*3/0$@?O$\$C*#-./'#$&.$,&D.5#,$,'G+%W'd+0% *90'(7/%G+05+,O%]+6%!% •! 3'/0?O%Y*A*575+%0*./02#0/0$6078%T0*9+60?'/O$]+6%<I% •! 4*.J&0$3&0&I/A#$f90+O+5/%'5%('T*0+d+%O87G+g%]+6%!% •! R*0'7?O%"#.J/5/A#,$*0A$E#,75/A#,L$,D5"$*,$%&D0ADEL$*,$ 9#''$*,$3*0G$"&D,#"&'A$5"#3/5*',$$$$$$]+6%%<H% •! 4++;%/7%*A7';%3F[$-$%'5)'W'/70O%670%/)+8%/7%E70G% 9079+0,:%f*A7';'5T%/7>'5O%'5%/)+%;'+/g% % ^P=%-%*5;%3%

^P=%-B%]+6+0+5(+O%!2%J2%L<KLJ%

)*'+#,-.&'$%/5"$F.2*0/5$^.D/-,L$ ]#2#-*J'#,$S$<#.J,$

<&9$_#.#$)*'+#,-.&',$M/,5&+#.#A`$ •! Q+*8%76%O('+5@O/O%E70G'5T%/7T+/)+02%'5(,?;'5T% 1*5%-?0G+%[)12%i+0*,;%[7d+0%[)1%*5;% S5/)75:%1*5'+,O% •! _+,,%;7(?8+5/+;%7WO+0A*@75%/)*/%3F[$-$% E*O%90+O+5/%'5%(*5(+0%(+,,O2%W?/%57/%5708*,% (+,,O% •! <*D0702$VD#,7&0a$_"G$4:6?@?$/0$5*05#.$ 5#'',$*0A$0&-$/0$0&.3*'$5#'',$

•! ^.D/-,KW,?+W+00'+O2%W,*(GW+00'+O2%O/0*EW+00'+O2% W,*(G%(?00*5/O2%hTO2%/*5T+0'5+O2%,+875O% •! ]#2#-*J'#,K*A7(*;72%*0@()7G+O2%()*0;2%9+*O2% T0++5%W+*5O2%T*0,'(2%7,'A+O2%75'75% •! <#.J,KW*O',2%8',G%/)'O/,+2%8'5/2%9*0O,+:2%07O+8*0:2% O*T+2%/):8+%

^P=%-%*5;%3B%]+6%MK<<%

$$$M*0$@D.;#$S$=#.*'A$6&b#.$_&.;$

1+A+,798+5/%76%.*,A+O/07,O% )DEE'#3#0-,$

!&2#-"#.$

•! -?0G+%*OGO%[7d+0%/7%A#,/20$*0$$*075*05#.$ E.&A.D2$*57+*-*J'#$JG$4:6?@?%'5%(*5(+0% (+,,O%V%)+%;7+O%/)'O2%W?/% •! Q)+:%E75;+0%%/,$4:6?@?$-"#.#$-&$E.&-#5-$ -"#$J&AG$(.&3$5*05#.`$ •! 10N%[7d+0%h5;O%/)*/%8*5:%0*-D.*'% O?WO/*5(+O%E)+5%*;;+;%/7%5*05#.$5#'',$ ,DEE.#,,#A$-"#/.$2.&9-"B%(*,,O%/)+8% ,*'+#,-.&',2%*%;+0'A*@A+%76%/)+%^*@5%E70;% jO*,A'*k%/7%O*A+B%%<C%)*A+%W++5%67?5;B% *W7?/%JC%+>9+(/+;%fA*0'7?O%/:9+O%76% O?WO/*5(+O%;7%/)'Og$ ^P=%-%*5;%3%

•! F.2*0/5$E.&AD5#$*5;%9*0@(?,*0,:% "#./-*2#$X0&0H"GJ./A/U#AY%A*0'+@+O% 907;?(+;%)'T)%l?*5@@+Om%76% .*,A+O/07,ON%% •! .*,A+O/07,OK9*0/%76%/)+%9,*5/O%;+6+5O+% *T*'5O/%6?5T?O%f[):/7*,+>'5Og%% •! Z+,9%0+l?'0+;%/7%8*G+%O?99,+8+5/O%V% /+*8+;%?9%E'/)%S5/)75:%1*5'+,O2%*% 8+()*5'(*,%+5T'5++0%V%)+0W*,'O/% %%%%%S5/)75:%1*5'+,O% •! 3789*5:%4*/?0*,%1+6+5(+%+O/*W,'O)+;% •! 1+(';+;%/7%?O+%60?'/%'5O/+*;%76%)+0WO%

$$M*0$@D.;#$6"M$

$$$=#.*'A$6&b#.$6"M$

45

L%

The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York

!"#"$!%

Michael Schachter, MD .*,A+O/07,OK]+,*@A+%=D+(@A+5+OO`%K[#5-$&0$ 4*05#.$4#'',$+,$8&.3*'$4#'',$

)*'+#,-.&'$6&/0-$)G,-#3$S$M&,*2#,$ •! -*O+;%75%/)+%,#'#57+/-G$&($*57&0$75%3S%AO%4^%(+,,O% •! KI5#''#0-$&.2*0/5$(&&A$A/#-$(75/*'5$WRR$E&/0-,$A*/'G$ •! K*5"$)*'+#,-.&'$6'*70D3$3*9O?,+n%(75/*'5O%$CCC%%70%% <CCC%97'5/O%o!%+>/0*(/O%fW,?+W+00:2%W,*(GW+00:2% O/0*EW+00:2%9++,%76%/*5T+0'5+gpB%%Q*G+5%*q+0%8+*,O% •! S,O7%*%-&E/5*'$5.#*3$/,$*+*/'*J'#$9/-"$?$,*'+#,-.&'$ •! TEE.&I/3*-#$A&,*2#,`%90+A+5@A+%<CCCB%87;+0*/+% ;+h('+5(:%%!2CCC%/7%I2CCCB%.+A+0+%;+h('+5(:%$<2CCC% /7%<C2CCCB%8*'5/+5*5(+%f)'O/70:%76%(*5(+0g%!2CCC% 97'5/O%;*',:%$ ^P=%3%%]+6%!%

^P=%-B%]+6N%!%

_)*/%'O%/)+%=A';+5(+%/)*/%.*,A+O/07,O% _70G%'5%[+79,+r%

c0&90$)DEE&.7+#$8D-./#0-,$-&$/05.#*,#$4:6?@?$&.$ "#'E$4&0+#.-$)*'+#,-.&'$-&$1#-*J&'/-#$

•! 8&$5'/0/5*'$-./*',$&.$5&0-.&''#A$,-DA/#,d$JD-$-"#.#$ *.#$.#E&.-#A$*0A$A&5D3#0-#A$5*,#$"/,-&./#,$$ •! Q)+0+%*0+%(*O+%O/?;'+O2%0+970/+;%'5%L%a7?05*,% *0@(,+O%W:%-0'*5%.()*+6+0%%^P=%-B%]+6+0+5(+O`%%LL2%L!%V%LJ% •! Q)+0+%*0+%'5/0'T?'5T%(*O+%)'O/70'+O%0+970/+;%W:% 9*@+5/O%75%.*,A+O/07,%W,7TO%75%/)+%X5/+05+/%%%^P=%3% •! X56708*,%(*O+%0+970/O%T'A+5%/7%;+A+,79+0O%76% .*,A+O/07,%%^P=%3% •! 4+E%0+970/O%6078%3)'5*%^P=%3% •! &:%'5'@*,%+#.G$E.#'/3/0*.G$(*O+%0+970/O%^P=%3%

•! >.&0K3)+(G%ZTW%*5;%U+00'@5B%/)+%W*(GW75+%76%+A+0:% (:/7()078+%[!JC%=5c:8+%(75/*'5O%'075% •! 1*20#,/D3K!CC%8T%=5)*5(+O%(75A+0O'75%76%O*,A+O/07,%/7% 8+/*W7,'/+% •! 8/*5/0$&.$0/*5/0*3/A#H?RR$8T%/E'(+%;*',:B%%=5)*5(+O% (75A+0O'75%76%O*,A+O/07,%/7%8+/*W7,'/+% •! @/&70%$%8T%/7%J%8T%;*',:KO@8?,*/+O%3F[$-$%907;?(@75% •! )#'#0/D3$*/%,+*O/%<CC%8(T% •! ]/-*3/0$4$$$%/7%L%T0*8O%;*',:%'5%;'A';+;%;7O*T+B%)+,9O% E'/)%;+/7>'h(*@75% ^P=%-%*5;%3B%]+6+0+5(+%!%

-77G`%!"#$%&'()#&*+,)-(.%/+')+0%##.%&&% W:%-0'*5%SN%.()*+6+0%[)1%

3S.=%.Qb1X=.K]+970/+;%'5%e&D.0*'$&($ F.-"&3&'#5D'*.$1#A/5/0#$fL%9*9+0Og% QRRO $

$QR?R $

$$$$$$$$$$QR?Q$

•! [?W,'O)+;%,*/+%<C$L% •! &*'5,:%(&''&9HDE$&0$5*,#,$;+O(0'W+;%'5%L% 9*9+0O%9?W,'O)+;%'5%/)+%s7?05*,%76% P0/)787,+(?,*0%&+;'('5+B%'5(,?;'5T% O+A+0*,%/*W,+O%O)7E'5T%A*0'+/:%76%(*O+O2% ;7O*T+O%?O+;2%'6%(75A+5@75*,%Q>%?O+;2% 875/)O%/7%0+8'OO'752%0*9';%0+O975;+0O2% ,7E%;7O+%0+O975;+0O%*5;%67,,7EK?9% 0+O?,/O% •! 1+O(0'9@75%76%;'*T57O@(%/+O/O%670%(*5(+0% ?@,'c'5T%3F[$-$%*5;%8+/*W7,'/+O%76% .*,A+O/07,O%%

CD02$5*05#.$$$$$$$$$$$@.#*,-$5*05#.$$$$$$$$$$$$$$$$$@.#*,-$5*05#.$ 1#'*0&3* $$C/+#.$5*05#.$$$$$$$$$$$$$$$$$$$$)VD*3&D,$5#''$5*.5/0&3*$&($*0D,$ 6.&,-*-#$4*05#.$$$4&'&0$5*05#.$$$$$$$$$$$$$$$$$$$4".&0/5$CG3E"&5G75$C#D;*#3/*$ @.#*,-$4*05#.$$$$$$$6.&,-*-#$5*05#.$$$$$$$$$$$$$$@#0/20$6.&,-*75$<GE#.E'*,/*$$ @'*AA#.$4*05#.$$$$<&A2;/0P,$'G3E"&3*$$$$6#./-&0#*'$5*05#.$% $$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$6.&,-*-#$5*05#.$ $%

.()*+6+0%-2%Q*5%Z2%-?0G+%12%[7d+0%i2%f<CC#g%4?/0'@75%*5;%3*5(+0`%.*,A+O/07,%3*O+% ./?;'+ONN%!"#$%&'(")(*$+,"-"'./#'&$(0.12/2%.2%<<2%!`%$##K$I<N% % .()*+6+0%-2%1775+0%32%-?0G+%12%[7d+0%i2%f<C$Cg%4?/0'@75%*5;%3*5(+0`%U?0/)+0%3*O+% ./?;'+O%X5A7,A'5T%.*,A+O/07,N%!"#$%&'(")(*$+,"-"'./#'&$(0.12/2%.2%<J2%$`%$#K<LN% % .()*+6+02%-N2%[7d+0%iN2%_77;%]N2%-?0G+%1N%f<C$<g%3*5(+0%*5;%]+,*/+;%3*O+%./?;'+O% X5A7,A'5T%.*,A+O/07,%*5;%3F[$-$N%!"#$%&'(")(*$+,"-"'./#'&$(0.12/2%.3%<#`%$L$K$LIN%

^P=%-%*5;%3%

^P=%-B%]+6+0+5(+O%$L2%$!%*5;%$J%

46

!%

The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York

!"#"$!%

Michael Schachter, MD .?TT+O/+;%6./05/E'#,%6078%U7,,7EK?9O% 670%]+8'OO'75O%

C/3/-*7&0,%/7%-77G%!"#$%&'()#&a$$,)-(.%/+ ')+0%##.%&&$JG$@./*0$)5"*#(#.$

•! .+A+0*,%0+(?00+5(+OB%/)7?T)%O78+%0+8*'5+;%'5%0+8'OO'75% 670%O78+%@8+% •! T''$&($-"#$E*7#0-,$9/-"$.#5D..#05#,$*J*0A&0#A$)*'+#,-.&',$ V%;';%57/%+5T*T+%'5%;'+/*0:%()*5T+O%*q+0%/)+%*,,K(,+*0% O'T5*,%E*O%T'A+5% •! M/#-*.G$5"*02#,L$'/(#,-G'#$5"*02#,$X/05'DA/02$#I#.5/,#Y$S$ ,*'+#,-.&',$,"&D'A$J#$5&070D#A$(&.$'/(#$ •! C&02H-#.3$E&,/7+#$#[#5-,$D05'#*.$W+(*?O+%O+A+0*,%9*@+5/O% O/799+;%/*G'5T%/)+8% •! ^'d,+%70%57%+A';+5(+%75%)7E%E+,,%O*,A+O/07,O%E70G%E)+5% 9*@+5/%)*O%)*;%*$'&-$&($5&0+#07&0*'$-.#*-3#0-$

•! &+;'(*,%0+(70;O%?5*A*',*W,+% •! ]+970/O%W*O+;%75%E)*/%90'8*0',:%9*@+5/O%O*';% •! P/)+0%/0+*/8+5/O%T'A+5%E'/)%O*,A+O/07,OB%O7% )*0;%/7%;+/+08'5+%)7E%8?()%O*,A+O/07,O% )+,9+;% •! [*0@(?,*0,:%/0?+%E'/)%907O/*/+%(*5(+0%9*@+5/O% •! U7,,7EK?9%l?'/+%,'8'/+;%'5%O78+%(*O+O%fW0+*O/% (*5(+0%9*@+5/eO%;+*/)g%

^P=%-B%%]+6%J$

^P=%-%*5;%3`%]+6+0+5(+%J%

3*O+%Z'O/70'+O%6078%@./*0$)5"*#(#.$ *0A$(.&3$-"#$)5"*5"-#.$4#0-#.$

1#-*,-*75$1#'*0&3*a$!.D'G$T3*U/02$ 4*,#$f.()*+6+0%3*O+g%

•! QE7%(*O+O%6078%<CC#%9*9+0%'5%eF1$$$$]+6%LL% •! QE7%(*O+O%6078%/)+%)5"*5"-#.$4#0-#.$ •! 3*5%60+l?+5/,:%,+*05%*%,7/%6078%(*O+%)'O/70'+OB%% _K$)<FNCM$8F!$MK6K8M$)FCKC:$F8$4C>8>4TC$ !%>TC)$(&.$5'/0/5*'$A#5/,/&0,$*0A$*57&0,$9/-"$&D.$ E*7#0-,$$]+6%J% •! )*'+#,-.&',$,##3$-&$0&-$/0-#.(#.#$9/-"$ 5&0+#07&0*'$-.#*-3#0-$*0A$/0$,&3#$5*,#,$ #0"*05#A$/-$

•! HL%:+*0K7,;%E78*5%E)7%(7?,;5e/%E*,G% •! _70G?9%0+A+*,+;%8*,'T5*5/%8+,*578*%'5%75+%,+T% •! 8D3#.&D,$J'*5;$,E&-,$&0$,;/0$/0A/5*702$ 9/A#,E.#*A$3#-*,-*,#,$ •! Q7,;%/7%8*G+%)+0%*O%(78670/*W,+%*O%97OO'W,+B%0&$ 5&0+#07&0*'$-.#*-3#0-$9&D'A$"#'E$ •! U*8',:%T*A+%)+0%.*,A+O/07,OK*W7?/%L2CCC%97'5/O%;*',:% ^P=%-B%]+6%LL%*5;%J%

^P=%-%*5;%3%

&+/*O/*@(%&+,*578*`%Q0?,:%S8*c'5T% 3*O+%f<g%

^?5T%3*5(+0K./*T+%XXX%70%XR%

•! U7,,7E+;%W:%5*/?079*/)%*5;%T'A+5%*%5?8W+0% 76%7/)+0%O?99,+8+5/O% •! _'/)'5%*%6+E%875/)O2%9*@+5/%*W,+%/7%E*,G%*5;% W,*(G%O97/O%6*;'5T% •! K0A$&($G#*.L$9*';/02d$0&$3&.#$J'*5;$,E&-,$ •! 6"G,/5/*0$5&D'A$Z0A$0&$#+/A#05#$&($5*05#.$ •! 1'+;%*%:+*0%70%/E7%,*/+02%O?997O+;,:%*O%*%0+O?,/% 76%(789,'(*@75O%76%8+;'(*,%/0+*/8+5/%670%S1%

•! MH%:+*0K7,;%8*,+%'5%3*5*;*%W+T*5%/7%(7?T)%?9%W,77;%% •! -075()7O(79:%*5;%W'79O:%(75h08+;%Ol?*87?O%(+,,% (*0('578*%76%,?5T% •! Q)+%/?870%E*O%#%(8%*5;%*;)+0+;%/7%/)+%O/+05?8%% *5;%()+O/%E*,,% •! ^:89)%57;+O%*W7?/%L%(8%E+0+%*,O7%;+/+(/+;% •! !D3&.$9*,$A##3#A$/0&E#.*J'#$ •! 8&$5"#3&-"#.*EG$&.$.*A/*7&0$.#5&33#0A#A$ ^P=%-B%]+6%LL%*5;%J%

^P=%-B%]+6%LL%*5;%J%

$

%

47

J%

The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York

!"#"$!%

Michael Schachter, MD ^?5T%3*5(+0K./*T+%XXX%70%XR%f<g%

^?5T%3*5(+0K./*T+%XXX%70%XR%fLg%

•! C/(#$#IE#5-*05G$#,73*-#A$-&$J#$f$-&$?f$ 3&0-",$ •! T-$-"#$D.2/02$&($"/,$,-#E,&02%)+%O/*0/+;%*%;'+/% 76%70T*5'(%60?'/O2%A+T+/*W,+O%*5;%a?'(+OB%8+*/2% 0+h5+;%O?T*0%*5;%;*'0:%E+0+%+,'8'5*/+;% •! )*'+#,-.&',$XgLQRR$6&/0-,Y$,E.#*A$&D-$ -".&D2"&D-$-"#$A*G$,-*.-#A$9*,$2/+#0$ •! >0$&0#$9##;L$"#$,-&EE#A$5&D2"/02$DE$J'&&A$

•! _/-"/0$W$9##;,2%;'*T57O'O%()*5T+;%(.&3$/0&E#.*J'#$-&$ &E#.*J'#$,?5T%(*5(+02%E'/)%/)+%O?TT+O@75%/)*/%/)+% *D+(/+;%,?5T%W+%0+87A+;% •! _'/)'5%*57/)+0%L%E++GO2%*%W'79O:%76%/)+%,*0T+O/%*D+(/+;% ,:89)%57;+%W:%[=Q%O(*5%E*O%W'79O'+;%*5;%5+T*@A+%670% (*5(+0% •! .?0T'(*,%/0+*/8+5/%57E%0+(788+5;+;%E*O%0+87A*,%76% 75+%,7W+%76%*D+(/+;%,?5T% •! .'>%E++GO%*q+0%W+T'55'5T%.*,A+O/07,O2%O?0T+0:%E*O% 9+06708+;%

^P=%-B%]+6%LL%*5;%J%

^P=%-B%]+6%LL%*5;%J%

$ $

%

^?5T%3*5(+0K./*T+%XXX%70%XR%f!g%

^?5T%3*5(+0K./*T+%XXX%70%XR%fJg% •! .?WO+l?+5/,:2%/)+%9*@+5/%0+8*'5+;%'5%.#3/,,/&0$ (&.$*'3&,-$h$G#*.,$Xhi$3&0-",Y$ •! X5%/)+%O90'5T%76%<C$<2%)+%E*O%;'*T57O+;%E'/)% 0+(?00+5/%Ol?*87?O%(+,,%(*5(+0%76%/)+%,?5T% •! ./+9O75%)*;%87A+;%7?/%76%/)+%*0+*% •! Z+%A#5/A#A$-&$ED.,D#$5&0+#07&0*'$-.#*-3#0-$ *5;%;';%57/%0+O/*0/%.*,A+O/07,O%70%()*5T+%)'O% ;'+/*0:%)*W'/O%70%,'6+O/:,+N%% •! 3?00+5/%O/*/?OKb5G57E5%

•! >0,-#*A$&($.#3&+/02$*$'&J#$&($-"#$'D02L$&0'G$ -"#$,".D0;#0$-D3&.$9*,$.#3&+#A$ •! S,,%,:89)%57;+O%0+87A+;%O?0T'(*,,:%E+0+% 5+T*@A+%670%(*5(+0% •! [*@+5/%;++8+;%(*5(+0K60++% •! )*'+#,-.&'$A&,*2#$.#AD5#A$-&$QLRRR$6&/0-,$ A*/'G$T8M$,-&EE#A$9"#0$"#$.*0$&D-d$*',&$ .#-D.0#A$-&$E.#+/&D,$'/(#,-G'#$ ^P=%3%

^P=%3%

8&0H<&A2;/0P,$CG3E"&3*$9/-"$@.*/0$ >0+&'+#3#0-a$$.33&%3*O+$

475KZ7;TG'5eO%^:89)78*%E'/)%-0*'5% X5A7,A+8+5/K<%

•! M<%:+*0K7,;2%8*00'+;%9O:()7/)+0*9'O/%%h0O/%O++5%'5%8&+$ QRRO$9/-"$*$3*.2/0*'$@$4#''$CG3E"&3*$h0O/%;'*T57O+;%'5% 1+(%<CCJ%E'/)%3Q%O(*5%*5;%'5T?'5*,%,:89)%57;+%W'79O:% •! .'>%875/)O%76%]'/?>'5%*5;%3ZP[%()+87/)+0*9:B%3*0G$ *A+#.,#$.#*57&0,L$/05'DA/02$5"#3&$J.*/0$ •! 4*05#.$2#j02$9&.,#$*-$73#$&($?,-$+/,/-$9/-"$D,$*q+0%*% 0+8'OO'75%76%M%875/)O%f'5A7,A+;%)',*0%,:89)*;+579*/):% 76%/)+%,?5TOg% •! U7,,7E+;%W:%10N%t79+,O75%*/%7?0%3+5/+0B%%9*@+5/%E*O% ,77G'5T%670%*5%*,/+05*@A+%/7%870+%()+87/)+0*9:%

•! !.#*-#A$9/-"$A/#-*.G$,D22#,7&0,L$>]$+/-*3/0$4$ *0A$*3G2A*'/0$*5;%8*5:%O?99,+8+5/O$ •! ]+(+'A+;%XR%):;07T+5%9+07>';+%'5%*57/)+0%7u(+% •! ]+(+'A+;%8*5:%O?99,+8+5/O%*5;%,7E%;7O+% 5*,/0+>75+% •! M/A$#I-.#3#'G$9#''$(&.$Z+#$G#*.,$9/-"&D-$ 5&0+#07&0*'$-.#*-3#0-$ •! ]+6?O+;%3Q%*5;%[=Q%O(*5O%

^P=%3%

^P=%3%

48

M%

The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York

!"#"$!%

Michael Schachter, MD 475KZ7;TG'5eO%^:89)78*%E'/)%-0*'5% X5A7,A+8+5/KL%

475KZ7;TG'5eO%^:89)78*%E'/)%-0*'5% X5A7,A+8+5/K!% •! >0$J#-9##0$5"#3&$-.#*-3#0-,L$A/A$2#-$4$A./E,$*0A$ @?Od$3*0G$,DEE'#3#0-,$5&070D#A$ •! Sq+0%J%07?5;O%76%()+87/)+0*9:2%3*,,$,".D0;$JG$ ihk$*0A$5&20/7&0$J#5*3#$0&.3*'d$&05&'&2/,-$ -"./''#A$9/-"$.#,D'-,$ •! P(/%<C$<`%-+T*5%1755'+%F*5(+%907/7(7,%f+>/+5O'A+% )+0W*,%907T0*8g%*,75T%E'/)%7?0%907T0*8% •! F05&'&2/,-$.#5&33#0A,$3&.#$5"#3&-"#.*EG$ O/*0@5T%'5%1+(%<C$<%70%s*5%<C$LB%9*.0#A$&($*$.*E/A$ .#5D..#05#$/($-"/,$/,$0&-$A&0#$

•! PA+0*,,%/)+%9*@+5/%;';%E+,,%?9%/)07?T)%/)+%8';;,+%76% <C$<%fJ%:+*0Og%E'/)%O78+%/E+*G'5T%76%)+0%/):07';2% (75@5?+;%3%;0'9O%E'/)%-$#2%;'+/*0:%()*5T+O% •! s?,:%<C$<K1+A+,79+;%(7T5'@A+%*W5708*,'@+O2%O,?00+;% O9++()%*5;%,7OO%76%W*,*5(+B%*5%&]X%O)7E+;%*%3*,,$/0$ "#.$J.*/0$5&0,/,-#0-$9/-"$*$'G3E"&3*$ •! 375O?,/O%E'/)%4+?07K75(7,7T'O/%*/%8*a70%4F3%(*5(+0% (+5/+0% •! S?T?O/`%<C$<%3)+87/)+0*9:%0+T'8+%O/*0/+;2%W?/%O)+% 5&070D#A$-.#*-3#0-$*-$&D.$4#0-#.$*O%E+,,% ^P=%3%

^P=%3%

475KZ7;TG'5eO%^:89)78*%E'/)%-0*'5% X5A7,A+8+5/KJ%

475KZ7;TG'5eO%^:89)78*%E'/)%-0*'5% X5A7,A+8+5/KM% •! 6*7#0-$,##3,$,*7,Z#A$E'/)%/)'O%9,*5B%W?/2%&05&'&2/,-$ *0A$"D,J*0A$D0"*EEGB%W7/)%E*5/+;%)+0%/7%;7% ()+87/)+0*9:% •! ST*'5O/%/)+%E'O)+O%76%)+0%75(7,7T'O/%*5;%)?OW*5;2% 9*@+5/%W+T'5O%/)+%O*,A+O/07,%907T0*8% •! @?O$9*,$,-&EE#A$*0A$)*'+#,-.&',$9#.#$,-*.-#A$*-$$hRRR$ E&/0-,$A*/'G$S$'*-#.$/05.#*,#A$*,$"/2"$*,$?lLRRR$E&/0-,$ A*/'G$ •! 1755'+%F*5(+%907/7(7,%;0*O@(*,,:%0+;?(+;%*q+0%+5+0T:% /+O@5T%E'/)%.*,A+O/07,O%'5;'(*/+;%/)*/%O78+%76%/)+%)+0WO% 8'T)/%'5/+06+0+%E'/)%/)+%O*,A+O/07,O%

•! M.B$)5"*5"-#.$5&0,D'-#A$9/-"$E*7#0-$S$"D,J*0A$/0$ e*0D*.G$QR?W$ •! 1'O(?OO+;%.*,A+O/07,O%'5%;+9/)%*5;%O?99,'+;%E0'd+5% 8*/+0'*,%'5(,?;'5T%.()*+6+0eO%W77G%*5;%*0@(,+O% •! 10N%.%O?TT+O/O%*%/0'*,%76%)'T)%;7O+%.*,A+O/07,O2%*,75T% E'/)%XR%3%;0'9O%*5;%(75@5?+;%5?/0'@75*,%O?9970/% •! &75'/70%(*0+6?,,:%670%+A';+5(+%76%W0*'5%0+(?00+5(+% •! 3*5%*,E*:O%0+O/*0/%()+87/)+0*9:%'6%(7T5'@A+% 907W,+8O%0+*99+*0%*5;"70%*W5708*,'@+O%75%&]X%

^P=%3%

^P=%3%

%

475KZ7;TG'5eO%^:89)78*%E'/)%-0*'5% X5A7,A+8+5/K#%

475KZ7;TG'5eO%^:89)78*%E'/)%-0*'5% X5A7,A+8+5/KI% •! -:%I%70%H%875/)O%*q+0%()+87/)+0*9:%)*O%W++5% 0+(788+5;+;2%O@,,%57%0+/?05%76%5+?07%O>O% •! S%W.A$1%>$9*,$A&0#$fE'/)7?/%T*;7,'5'?8g%*5;%E*O% *T*'5%5+T*@A+% •! F05&'&2/,-$*3*U#A$,"#$"*,$"*A$0&$.#5D..#05#$*5;%'O% 57%,75T+0%9?O)'5T%()+87/)+0*9:B%O)+%(75@5?+O%/7%T+/% *%W0*'5%&]X%+A+0:%L%875/)O% •! 47E2%$J%875/)O%6078%@8+%()+87%0+(788+5;+;%6++,O% T0+*/%f5?/0'@75*,%907T0*8%/E+*G+;%E'/)% 0+(788+5;*@75O%76%)'T)%;7O+O%76%A'/*8'5%1%*5;%t<% f&t!gB%SO:89/78*@(B%O++8O%h5+%

•! S/%L%875/)O%*q+0%()+87%0+(788+5;+;2% 75(7,7T'O/%O@,,%9?O)'5T%()+87/)+0*9:2%W?/% 9*@+5/%0+O'O/*5/% •! ?,-$1%>$*/%*W7?/%W$3&0-",$*q+0%()+87/)+0*9:% E*O%0+(788+5;+;%'O%0#2*7+#%f75(7,7T'O/% O?090'O+;g% •! T-$l$3&0-",2%9*@+5/%O@,,%)*O%0&$0#D.&'&2/5*'$ ,G3E-&3,$S$Q0A$1%>$0#2*7+#2%/)7?T)%O)+% 0+*(/+;%/7%T*;7,'5'?8$f+>/+5O'A+%)'A+Og%

^P=%3%

^P=%3%

49

#%

The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York

!"#"$!%

Michael Schachter, MD ./*T+%XX%-0+*O/%3*5(+0%f.33&%3*O+g%

./*T+%XX%-0+*O/%3*5(+0%f<g%% •! U7,,7EK?9O`%!D3&.$,'/2"-'G$,"./0;/02L$(##',$3D5"$J#b#.L$ 3&.#$#0#.2GL$,'##E/02$J#b#.L$(&''&9/02$,&3#9"*-$ J#b#.$A/#-$ •! P5,:%(789,*'5/%'O%E*/0$/0$"#.$./2"-$*.3$*,,&5/*-#A$9/-"$ *.&3*-*,#$/0"/J/-&.B%;0*O@(*,,:%'8907A+O%E)+5%O)+% 0+;?(+O%60+l?+5(:%76%/)'O%;0?T% •! )##0$*-$)c>$/0$^#J$QR?gHM&/02$,&$9#''L$1M$,D22#,-,$ *0&-"#.$l$3&0-",$&($^#3*.*$-.#*-3#0-$J#(&.#$*0G$ ,D.2#.GB$bO'5T%S0'8';+>%E)'()%;7+O%57/%(*?O+%*0+%9*'5$ •! &*:%(75O';+0%57/%;7'5T%*5:%O?0T+0:% •! P5%$<2CCC%97'5/O%76%O*,A+O/07,O%

•! #J%:+*0K7,;2%;'A70(+;%T0*5;87/)+0%E'/)%,*0T+% M%(8%0'T)/%W0+*O/%(*5(+0%f=]%V%[]%v%*5;%Z+0<" 4?%5+T*@A+g%h0O/%O++5%s*5%<C$L% •! i+5+0*,,:%6+,/%9770,:2%W*;%+*@5T%)*W'/O% •! _+5/%75%U+8*0*`%[,*5%75%U+8*0*%670%L%875/)O% /7%O)0'5G%3SB%/)+5%,?89+(/78:%*5;%0*;'*@75% 70%8*O/+(/78:% •! )-*.-#A$&0$,*'+#,-.&',$/0$e*0$QR?W$

^P=%%3%

^P=%3%

&-.%S3S&%$$K$L%.*,A+O/07,O%

)*'+#,-.&',$*-$)5"*5"-#.$4#0-#.$(&.$ 4&3E'#3#0-*.G$1#A/5/0#$X)441Y$

!!%

!#.3/0*'$@.*/0$4*05#.,$%#,E&0A/02$/0$ 8#9$m#*'*0A$

•! bO'5T%/)+8%670%75,:%*W7?/%$J%875/)OB%O78+%9*@+5/O%?O'5T% *O%90+A+5@A+%$%70%<%(*9O?,+O%;*',:% •! <CC%70%LCC%9*@+5/O%/*G'5T%O*,A+O/07,O%*/%.33&% •! 8&$*EE*.#0-$,/A#$#[#5-,$0&-#A$#+#0$/0$+#.G$,#0,/7+#$ E#&E'#$ •! 8&-$*$E*0*5#*`%QE7%9*@+5/O%E'/)%+>/0+8+,:%+>/+5O'A+% 8+/*O/*@(%;'O+*O+%O/*0/+;%75%.*,A+O/07,O2%W?/%O?((?8W+;% E'/)'5%<%875/)O% •! &?()%870+%E70G%5++;+;%/7%O++%,'8'/*@75O%76%/0+*/8+5/B% W?/%0+O?,/O%O7%6*0%A+0:%9078'O'5T%

•! 3788?5'(*@75%E'/)%4+E%w+*,*5;%;'O/0'W?/70%76% .*,A+O/07,O% •! .?99,:'5T%.*,A+O/07,O%/7%*;?,/O2%*;7,+O(+5/O%*5;% ()',;0+5%E'/)%/+08'5*,%W0*'5%70%O9'5*,%(70;%(*5(+0B% /7,;%57%6?0/)+0%(75A+5@75*,%/0+*/8+5/%*A*',*W,+% •! T''$E*7#0-,$*EE#*.$-&$J#$.#,E&0A/02$*-$?lLRRR$ E&/0-,$A*/'G$ •! Q)+0+%*0+%*/%,+*O/%I%9*@+5/O%'5%*,,% ^P=%3%%]+6%[+0O75*,%3788?5'(*@75K]+6%LM%

^P=%-%*5;%3% &-.%S3S&%$$K$L%.*,A+O/07,O%

8##A$(&.$@#b#.$!&&',$(&.$M/*20&,/02$ 4*05#.$S$1&0/-&./02$>-$ %

•! 3?00+5/%(75A+5@75*,%/+O/%670%/)+%;'*T57O'5T%76% (*5(+0%*5;%875'/70'5T%'/%*0+%0+,*@A+,:%(0?;+% •! &7O/,:%'5A7,A+O%A*0'7?O%'8*T'5T%/+()5'l?+O%f3Q% .(*5OB%3Q"[=Q%.(*5O2%&]XOg% •! 3Q%O(*5O%*5;%[=Q%O(*5O%0+O?,/%'5%*%,7/%76%0*;'*@75% •! -'79O'+O%*5;%+>*8'5*@75%?5;+0%/)+%8'(07O(79+% •! 3*5(+0%W,77;%8*0G+0O%O78+@8+O%)+,96?,%'5% 875'/70'5T%O78+%(*5(+0O%

)-*.702$E&/0-a$ 4:6?@?$n$D0/+#.,*'$5*05#.$3*.;#.$ )*'+#,-.&',$n$3#-*J&'/U#A$JG$4:6?@?% QE7%;'0+(@75O%/7%/*G+`% •! 1+/+(/%*5;%8+*O?0+%3F[$-$%;'0+(/,:% •! 1+/+(/%*5;%8+*O?0+%/)+%8+/*W7,'(%7?/9?/%76%3F[$-$% *5;%.*,A+O/07,O% S(@A+%0+O+*0()%W+'5T%;75+%57E% %

^P=%-%*5;%3%%

^P=%-%]+6%!2%J2%LH%

50

I%

The Role of Salvestrols in the Management of Cancer Patients at the Schachter Center in New York

!"#"$!%

Michael Schachter, MD )*'+#,-.&'$%#,#*.5"$/0$4"/0*$*-$%#0;*02$<&,EH )&D-"#.0$1#AB$N0/+#.,/-G$X8#*.$<&02$c&02% •! Pu('*,%'5%S?O/0*,'*%;';%E+,,%75% O*,A+O/07,O%V%E*O%*%(75O?,/*5/%/7% /)'O%Z7O9'/*,%'5%3)'5*% •! P5(7,7T'O/O%10N%w)*7%*5;%10N%_*5T% W+T*5%?O'5T%O*,A+O/07,O%V%)*A+% W++5%;7'5T%/)'O%670%/)+%9*O/%:+*0% •! 47E2%/)+:%O*:%/)+:%?O+%'/%*,,%(*5(+0% 9*@+5/O%*,75T%E'/)%(75A+5@75*,% /0+*/8+5/%*5;%O78+%7/)+0% *,/+05*@A+%/0+*/8+5/O%,'G+%.[1Q% f.7579)7/7;:5*8'(%Q)+0*9:%%

)*'+#,-.&'$%#,#*.5"$/0$4"/0*$*-$%#0;*02$<&,EH )&D-"#.0$1#AB$N0/+#.,/-G$X8#*.$<&02$c&02Y$Q% •! j.*,A+O/07,O%)*A+%+5*W,+;%/)+% /+*8%/7%W0'5T%*W7?/%0+A+0O*,%76% /)+%;'O+*O+%'5%A+0:%,*/+%O/*T+% (*5(+0O%E)+0+%90+A'7?O,:%/)+% T0+*/+O/%O?((+OO%E'/)%+*0,'+0% O/*T+%(*5(+0Ok% •! [076N%_*5T%)*O%O*';%/)*/%j*,,%7?0% 9*@+5/O%*0+%'5%W+d+0%O/*W,+% 0+O975O+%/7%7?0%/0+*/8+5/%*q+0% *;;'5T%O*,A+O/07,k%%

%%%%%M.B$m"*&$

^P=%-%*5;%3K[+0O75*,%3788?5'(*@75O%

$$$$M.B$_*02$

4:6?@?$S$)*'+#,-.&',a$6&,,/J'#$1*o&.$ @.#*;-".&D2"$/0$N0A#.,-*0A/02$4T$ •! 3F[$-$%=5c:8+%[07/+'5%'5%*,,%(*5(+0%(+,,O%*5;%A+0:% 8'5'8*,,:%'5%5708*,%(+,,O% •! .*,A+O/07,O%67?5;%'5%70T*5'(%9,*5/O%*0+%(75A+0/+;%/7% 8+/*W7,'/+O%/)*/%'5;?(+%*979/7O'O%f907T0*88+;%(+,,% ;+*/)g%'5%(*5(+0%(+,,O% •! .*,A+O/07,O%*99+*0%/7%W+%*99,'(*W,+%670%*,,%(*5(+0O%*/% *,,%O/*T+O% •! &*:%W+%?O+6?,%670%90+A+5@752%;'*T57O'O%V% 8*5*T+8+5/%76%9*@+5/O%E'/)%(*5(+0% ^P=%-%*5;%&7O/,:%3%%]+6%!KLM2%LI2%LH%

51

H%

The Role of Insulin in Weight Gain and Obesity Patrick Holford, BSc

52

The Role of Insulin in Weight Gain and Obesity

3/26/14!

Patrick Holford, BSc

5**(:;&2(%7<;+%7===( •! Promotes fat storage and stops you breaking down fat, so you gain more and more weight. Increases non-alcoholic fatty liver.

•! Increases cholesterol and triglycerides (blood fats) •! It causes the kidneys to retain both water and salt, which leads to high blood pressure. In time this leads to kidney failure •! Causes rapid deterioration of eyesight •! The combination of too much insulin and to much glucose damages the arteries and raises your blood pressure, both of which make thrombosis, heart attacks and strokes more likely •! Makes cancer cells grow fast mainly due to increased insulinlike growth factor (IGF-1) •! Switches off anti-ageing genes (DAF on, FOXO off)

)*D(#*(+*D1$(%7<;+%7(

)%92(>7<;+%7(?*;+-(@1<;+#(%7(AB1<%#3( ( 2013 !

J. Johnson, Obesity 2012; B.Lemmerz, AmJClinNutr •! Q+)4%+,#8(+,%+#%$4"8)4$%$"%0'%*%6",#'R8',6'%">% ;+*0'$'#%*,;%"0'#+$1%08$%*,+5*(%#$8;+'#%#8))'#$% +$%5+)4$%0'%$4'%"$4'2%:*1%*2"8,;%:+$4%2%92( %7<;+%7(-$%C%79(*B1<%#3=( •! S,+5*(#%:+$4%$4'%#*5'%;+'$%08$%4+)4%"2%(":% +,#8(+,%('='(#%;", $%',;%8&%$4'%#*5'%:'+)4$.% )%92(%7<;+%7("7%:"+<(9"%7(:*$1(D1%92#(:4',% )+=',%*%4+)4%>*$7%6*("2+'%;+'$.% •! )%92(E>F<;9"$G(:1"+<%6*8#'%:*$1(%7<;+%7%2'('*#'7% $4',%0("";%#8)*2%(":#7%:4+64%#$%991$(2;791$%*,;% <;9"$(&$"C%79<.%

•! Q+)4%&2"$'+,M>*$7%(":%6*20%;+'$%T(":%UV%;+'$W% •! V'##%6*20#%*,;%$4'%2+)4$%6*20#7%5"2'%&2"$'+,%T(":%UV%;+'$W% •! Q*=+,)%(":%UX%6*20#%:+$4%&2"$'+,%*,;M"2%:+$4%=+#6"8#% Y02'#%T*64+'='#%(":%UVW% •! Z*A,)%('##%9%(":%6*("2+'%;+'$#7%5";+Y';% *($'2,*$'%;*1 % >*#$#% •! K42"5+85%T+5&2"='#%+,#8(+,%2'6'&A",W% •! V'##%5'*$%*,;%;*+21%T2*+#'#%X,#8(+,9(+<'%U2":$4%G*6$"2%9% XUG9FW%

Q":%$"%(":'2%+,#8(+,%

UV%">%*%;+'$%;'$'25+,'#%+,#8(+,%2'#&",#'% Bao J, Am J Clin Nutr. 2011; Krog-Mikkelsen I, J Nutr. 2011; Grover G, Front Pharm. 2011

•! Q+)4%&2"$'+,M>*$7%(":%6*20%;+'$%T(":%UV%;+'$W% •! V'##%6*20#%*,;%$4'%2+)4$%6*20#7%5"2'%&2"$'+,% T(":%UV%;+'$W% •! Q*=+,)%(":%UX%6*20#%:+$4%&2"$'+,%*,;M"2%:+$4% #8&'2Y02'#%T(":%UVW%

•! UV%+#%*%5"2'%+5&"2$*,$%;'$'25+,*,$#%">%)(16'5+6%*,;% +,#8(+,'5+6%2'#&",#'%$4*,%$4*$%">%6*20"41;2*$'%*(",'.% •! V":%UX90*#';%;+'$#%4*='%0'',%#4":,%$"%&2"5"$'%#*A'$1% *,;%2';86'%&"#$&2*,;+*(%+,#8(+,'5+*.% •! @,(1%$4'%;+'$%#8&&('5',$';%:+$4%$4'%4+)4(1%=+#6"8#%Y0'27% 6"5&*2';%$"%"$4'2%Y02'#7%#80#$*,A*((1%;'62'*#';% &"#$&2*,;+*(%0("";%)(86"#'%*,;%+,#8(+,%#'62'A",.%

53

2!

The Role of Insulin in Weight Gain and Obesity

3/26/14!

Patrick Holford, BSc !+;<1<("7-(:%7;<1<(*,(+*D(&"$B(-%1#<( "! Variations on the Atkins diet, with high protein and fat, and low

•! 34'%U(16'5+6%V"*;%%

carbs, have consistently been shown to be effective for short-term weight loss, but not as good for maintenance/long-term weight loss as low GL diets

">%*%>"";%+#%;'2+=';%>2"5%<,":+,)%0"$4%$4'%% HI84>5J%%

"! Measures of cardiovascular risk improve, as do diabetes

">%$4'%6*20"41;2*$'%T+$#%UX%9%>*#$%"2%#(":.W%%

"! Depending on quantity of protein consumption increased kidney and

*,;%$4'%%

bone mass risks remain

HI8K5>5J%%

"! High meat and especially dairy diets

(1,2) are also associated with raised insulin-like growth factor (IGF-1) and increased risk of both breast, prostate cancer and colorectal cancer

">%$4'%>"";%$4*$%+#%6*20"41;2*$'%

1. Qin, Int J Food Sci Nutr. 2009; 2. Melnick Med Hypotheses. 2009!

E+3&1:%&(4*"-( ( •! 521(E4(*,("(,**-(%<(D*$'1-(*;#("<(,*++*D<L% •! UX%#6"2'%T;+=+;';%01%FJJW%58(A&(+';%01%$4'% *=*+(*0('%6*20"41;2*$'%T6*20"41;2*$'#%5+,8#% Y02'W%+,%)2*5#.% •! !"#$%&"'$()$*+,%"-%",%$.")/*$0% X$#%)(16'5+6%+,;'?%TUXW%+#%&2'[1%4+)47%*0"8$%NH.%% S%#'2=+,)%%">%FHJ%)2*5#%4*#%L%)2*5#%">%*=*+(*0('% 6*20"41;2*$'%&'2%#'2=+,)7%#"%+$#%U(16'5+6%V"*;%+#...%% •! %J.NH%?%L%\%D.-H7%2"8,;';%$"%D7%&'2%#'2=+,).%

M%N1$17#(,$;%#<(2"C1(-%N1$17#(<;9"$<(

Low GL Foods (10GLs)

High GL Foods (10GLs)

2 large punnets of strawberries

2 dates

6 oat cakes

1 slice of white bread

4 bowls of oat flakes or porridge

1 bowl of cornflakes

A large bowl of peanuts

A packet of crisps

1 pint of tomato juice

Half glass of Lucozade

10 handfuls of green beans

10 french fries

6 tablespoons of xylitol

2 teaspoons of honey

]','Y$#%">%*%(":%UV%;+'$%

•! ]'22+'#7%64'22+'#%*,;%&(85#%6",$*+,%5*+,(1% ?1("#'%T(":%UXMUVW% •! S&&('#%*,;%&'*2#%5*+,(1%>286$"#'%T5';+85% UXMUVW% •! ]*,*,*#7%)2*&'#7%2*+#+,#%;*$'#%5*+,(1% )(86"#'%T4+)4%UXMUVWQ+)4%+,%&(85#%T4',6'% $4'+2%(":%UVW% •! ^%$'*#&"",#%?1(+$"(%\%F%$'*#&"",%">%#8)*2%

•! O'+)4$%("##M6",$2"(% •! C2'=',$#%*,;%2'='2#'#%;+*0'$'#% •! C2'=',$#%*,;%2'='2#'#%4'*2$%;+#'*#'7% 41&'2$',#+",7%64"('#$'2"(% •! _';86'#%6*,6'2%2+#<7%'#&'6+*((1%02'*#$%6*,6'2% •! _';86'#%S(`4'+5'2 #%2+#<% •! _';86'#%;'&2'##+",% •! I:+$64'#%",%*,A9*)'+,)%)','#% •! I:+$64'#%"a%)','#%$4*$%&2"5"$'%;+#'*#'%

54

3!

The Role of Insulin in Weight Gain and Obesity

3/26/14!

Patrick Holford, BSc

342''%#+5&('%28('#%$"%(":'2%UV%

•!% Z*$%,"%5"2'%$4*,%DJMLJ%UV#%*%;*1.% •! Z*$%&2"$'+,%:+$4%6*20"41;2*$'.% •! U2*`'%2*$4'2%$4*,%)"2)'.(

(

21 people on my GL diet for 12 weeks weeks...

L%&'"&('%",%$4'%UV%;+'$%>"2%b%:''<#%

Health Marker

Before

After

% change

Greatest % change

Weight

92kg

85kg

7.4% -7kg

11.6%-14kg

HbA1c

6.9

5.9

15%

32%

Cholesterol

5.3

4.6

11%

23%

Triglycerides

1.7

1.2

27%

77%

B.Pressure pressure

137/81

131/73

4/10%

22%/25%

Chol/HDL

4.1

3.7

9%

39%

Trig/HDL

1.5

1.1

27%

78%

Irish RTE television challenged us to transform the weight and diabetes risk of 6 people from the travellers community, who have the worst life expectancy and health statistics in Ireland!

O( #$"C1++1$< (*7(#21(+*D(E4(-%1#(,*$(P( D11'<((

L%&'"&('%",%$4'%UV%;+'$%>"2%b%:''<#% RTE DIET TRIAL STATISTICS NAME

WT (lbs) BEFORE

WT (lbs) AFTER

WEIGHTLOSS

BODYFAT % BEFORE

BODYFAT % AFTER

BODYFAT % REDUCTION

Angela

214

206.5

7.5

46

45.2

0.8

Biddy

181

166

15

44.8

41.5

3.3

Doreen

278

253

25

54.3

50.9

3.4

Marie Elena

138

129

9

37.3

33.6

3.7

Nuala

206

189

17

44.1

41.9

2.2

Silvia

272

250

22

51.9

43.0

8.9

TOTAL

1289

1193.5

95.5lbs

278.4

256.1

18.9%

AVERAGE

215

199

16lbs

46.4

42.6

3.15%

•! ]+;;1 #%0("";%&2'##82'%2';86';%>2"5%FNJMFJF% $"%FDJMb/% •! c"2'', #%0("";%)(86"#'%2';86';%>2"5% N9^55"(M(%$"%D9L55"(M(.%I4'%2';86';%4'2% U(86"&4*)'%>2"5%-%$*0('$#%$"%F.% •! S,)'(* #%0("";%)(86"#'%2';86';%>2"5% F/9Fb55"(M(%$"%N55"(M(.%

55

4!

The Role of Insulin in Weight Gain and Obesity

3/26/14!

Patrick Holford, BSc Blood pressure normalised on GL diet

c+*0'$'#%2'='2#';%:+$4%*%(":%UV%;+'$% Hexeburg S et al. Tidsskr Nor Legeforen 2008; 128:443-5

A low GL diet can actually eliminate the need for diabetic drugs such as insulin and metformin. A case report in Norway of a 61yr old woman who was able to stop injecting with insulin after following a low GL diet, plus supplements and taking regular exercise. She also 176lbs Start 150 iu of Insulin

After 5 months 150 iu of Insulin 4.7

5.4

HbA1c (%) Cholesterol

8.9 5.4

5.6 4.1

5.4 3.8

Weight (lbs)

264

231

176

Medication Glucose

Alison lost 5 stone with the Low GL and alternate day diet, plus zest4Life support!

LJJ<6*(%;+'$%2'='2#'%;+*0'$'#%+,%b%:''<#%

14 months later None

34'%)','A6#%">%6*("2+'%2'#$2+6A",%

Taylor, Diabetologia, 2011!

•! X$%'?$',;#%(+>'#&*,%+,%*,+5*(#%01%H/9/JE%01%<D%#&2%79(*N("( 9171(#2"#(:"'1<(%7<;+%7%*,;%<D%#&2%79(*7("(9171(#2"#( %:S$*C1<(#21("7R*V%-"7#W*V%-"7#(1X;"R*7=% •! M8YZ(F#21(9$%:($1"S1$G(%<(#21(%7<;+%7(9171(3*;(D"7#(#*( <D%#&2(*N%T01%*%(":%UV%;+'$%&(8#%642"5+857%(":'2+,)% +,#8(+,%2'('*#'W% •! YA[A(%<(#21(9171(3*;(D"7#(#*(<D%#&2(*7%T5"2'% *,A"?+;*,$#W% f"82%#8&&(1%">%,*$82*(%*,A"?+;*,$#%)"'#%8&7% ;*5&+,)%;":,%;*5*)+,)%"?+;*,$#. %C2">%g',1",7%:4"% <,":%*;="6*$'#%*%(":%UV%;+'$.% •! X,%*,+5*(#%1"8%",(1%,'';%+*D(&"+*$%1<(1C1$3(*#21$(-"3.% •! M"%$3(S$*-;&#<($"%<1(%7<;+%7%TXUG9FW%

•! Q(*;#(*,(..(-%"B1R&<(<2*D1-($1C1$<"+(*,(#3S1TU(-%"B1#1<(B3( 9%C%79(S1*S+1("(C1$3(+*D(O//(&"+*$%1(-%1#(,*$(1%92#(D11'<.%% •! X$%6*5'%"8$%">%$4'%"0#'2=*A",%$4*$%5*,1%&'"&('%:+$4%;+*0'$'#7% :4"%4*='%$4'+2%#$"5*64#%#$*&(';7%2'&"2$%2'='2#*(%">%;+*0'$'#.% C2">'##"2%_"1%3*1("2%>2"5%d':6*#$('%e,+='2#+$1%:",;'2';%+>%$4'% 0+)%;2"&%+,%6*("2+'#%5+)4$%0'%$4'%2'*#",%*,;%#'$%"8$%$"%Y,;%"8$.% O4+('%$4'%)','2*(%0'(+'>%+#%$4*$%$1&'9H%;+*0'$'#%('*;#%$"% +22'='2#+0('%;*5*)'%$"%0'$*96'((#%+,%$4'%&*,62'*#%$4*$%&2";86'% +,#8(+,7%*,;%$4*$%1"8%6*,%$4'2'>"2'%",(1%6",$2"(%;+*0'$'#7%,"$% 2'='2#'%+$7%$4+#%#$8;1%&2"='#%$4*$%$4+#%0'(+'>%+#%:2",).% !"#$%$&'()% (*+,-$&./&*$%0,.%&"*%1.$&%2+*%&"*%2+*%3,'.$*%,0%/%.*&'.-%,0% -,.+/4%5*&/%3*44%0'-32,-%#-%#-(#6#('/4$%7#&"%&)8*%9%(#/5*&*$: % #*1#%3*1("2%

56

5!

The Role of Insulin in Weight Gain and Obesity

3/26/14!

Patrick Holford, BSc

34'%S($'2,*$'%c*1%]""<#%

Switching on skinny genes Low cals(alt day)&! Low cals(alt day) &!

High antioxidants Low GL diet! (eg resveratrol)!

X

switches on SIRTUIN!

Sugar!

"! 20% less calories than you need

switches on DAF-3!

"! Based on general healthy eating

every other day

(high GL)!

(keeping IGF-1 down)! switches on FOXO!

principles

"! Eat what you like in between "! Studies do confirm ADF diets work, but most use greater calorie restriction

"! 2 days eating 600kcals "! No study on the diet yet "! Based on studies with 3 days on

grim reaper

Burns fat! Slows ageing! Less pain!

three meals, 2 snacks, 1drink/ dessert

•! X%4*='%("#$%:'+)4$%0'>"2'7%08$%4*;, $%,"A6';%4'*($4%0','Y$#%>"2%642",+6%>*A)8'% #1,;2"5'%"2%5+)2*+,'.%@,'%">%$4'%i"1#%">%$4+#%+#%X ='%0'',%*0('7%*,;%5"A=*$';7%$"% '?'26+#'%*)*+,7%'=',%",%$4'%>*#A,)%;*1#.%Z=',%'?'26+#+,)%",%*%>*#A,)%;*1#%;"'#, $% 5*<'%5'%>''(%'?4*8#$';.34'%*($'2,*$'%;*1%>*#$%*(#"%2'*((1%4'(&#%5'%8,;'2#$*,;%:41%X% '*$.%d":%X%<,":%X%:"8(;%"B',%'*$%>"2%>*A)8'.%X%6*,%;+a'2',A*$'%0'$:'',%'*A,)%>"2% &41#+6*(%48,)'2%:4+('%X%:*#%&2'=+"8#(1%'*A,)%:4',%5',$*((1%>*A)8';. % •! d":7%$42''%5",$4#%",%4'2%5+)2*+,'#%*2'%*$%$4'%(":'#$%>2'R8',61%#+,6'%#4'%:*#%*% $'',*)'2j%4'2%(+0+;"%4*#%6"5'%0*6<j%#4'%4*#%5864%5"2'%&41#+6*(%*,;%5',$*(%','2)1% *,;%6*,%'?'26+#'%:+$4"8$%>''(+,)%'?4*8#$';%*B'2:*2;#j%#4'%4*#%5864%('##% ,''; %>"2% #8)*2%"2%6*a'+,'j%4'2%i"+,$%&*+,%4*#%6"5&('$'(1%6('*2';j%4'2% *:>8( %6'((8(+$'%",%4'2% *25#%4*#%6"5&('$'(1%)",'j%#"%$""%4*='%4'2%5',"&*8#*(%#15&$"5#%:+$4%,"%5"2'%4"$% k8#4'#j%*,;%4'2%+558,'%#1#$'5%#''5#%#$2",)'27%:+$4%,"%5"2'%6",#$*,$%6"(;#%*,;% #"2'%$42"*$#.% •! X%4*='%5"2'%','2)1%,":%$4*$%X%4*='%4*;%+,%HJ%1'*2#.%_'6',$(1%",'%">%51%&*A',$#% #*+;%4":%:",;'2>8(%+$%:*#%$"%#''%5'%(""<+,)%#"%:'((.%X%>''(%(+<'%*%,':%:"5*,.%X ;% ;'Y,+$'(1%2'6"55',;%$4+#%(":%UV%;+'$7%*($'2,*$'%;*1%>*#$%*&&2"*64. %X$ #%'*#+'2%$4*,% 1"8%$4+,<%*,;%$4'%4'*($4%0','Y$#%>"2%5'%*2'%6'2$*+,(1%:"2$4%+$. !

Burn Fat Fast! strategy!

:%U V%

26+#

V"

?' %h%'

cG V%S :%U

Holford!

V"

Bhutani!

Obesity, 2013 Feb 14!

'%

1% '2 6+# Sc ' G%h S % %'? cG '2 % 6+# '%

%;* G%-

Eshghinia!

J Diabetes Metab Disorder!

2013 Jan 9!

Z?

Sc

Sc G%/ Sc JJ G%/ <6* JJ (%h <6 %(" *(% :%> h%4 *$ +)4 % %>* $%

%;* XG%F 1M: %;* <%(+R 8 1M :< +;% %#" (+; %

XG%F

H%; * =# 1%;+' %(" :%6 $% *(%

Klempel!

based on three meals, one snack

"! Other days on low GL - 50 Gls -

cardio training (30 mins)

lbs lost! in 8 weeks!

Metabolism, 2012 Aug 10!

"! 3 days on 35 GLs, max 800kcals,

K*#'%9%c2%Z((+'%9%("#$%H%#$",'%TF-<)W% ?!

Harvie!

loss in 8 weeks, versus 3.5lbs on a low calorie diet.

"! Alternate strength (8 mins) and

ADF = alternate day fast!

Int J Obes (Lond), 2011 May!

Mediterranean diet

"! Tested in a trial - achieved 6lb weight

Exercise also switches on fat-burning genes!

ups metabolism! better DNA repair! & inflammation!

Klempel!

protein and fat - meat and dairy - not calorie counted)

"! Other days general advice to eat

lower calories

skinny sweet skinny sweet 16 16

Nutr J, 2012 Nov 21! !

"! 2 day on Atkins-type diet (high

Patrick Holford!

100% health for life!

52$11(<%:S+1($;+1<(

•!% Z*$%,"%5"2'%$4*,%DJMLJ%UV#%*%;*1.%

]e_d%GS3%GSI3%% C_SK3XKSV%

•! Z*$%&2"$'+,%:+$4%6*20"41;2*$'.% •! U2*`'%2*$4'2%$4*,%)"2)'.(

(

57

6!

The Role of Insulin in Weight Gain and Obesity Patrick Holford, BSc

58

The Role of Insulin in Weight Gain and Obesity

3/26/14!

Patrick Holford, BSc

]2'*<>*#$% CEREAL

5 GLs

FRUIT

5GLs

Oat flakes

2 servings

Berries

1 large punnet 1

All Bran

1 serving

Pear

Muesli (no sugar)

1 small serving

Grapefruit

1

Alpen

Half a serving

Apple

1 small

Raisin Bran

Half a serving

Peach

1 small

Weetabix

1 biscuit

Banana

third

Cornflakes

Half a serving

Raisins

10

Q. What does a 5 GL portion of fruit look like?

]2'*<>*#$%

Blueberry pancakes, made with oat ďŹ&#x201A;our and egg, plus berries, yoghurt and a sprinkling of ground seeds, is low GL!

BREADS

10 GLs

Nairns rough oatcakes

5/6 biscuits

Rye Pumpernickel style

2 thin slices

Sourdough rye bread

2 thin slices

Rye wholemeal bread (yeasted)

1 slice

Wheat wholemeal bread (yeasted)

1 slice

White, high fibre bread (yeasted)

<1 slice

ONLY 2 PANCAKES!!

Only 8 GLs per serving with strawberries and soya, cows milk - 10 GLs with oat milk TIPS: Add cinnamon Have a 3 x Carboslow/PGX & glass of water chaser

59

8!

The Role of Insulin in Weight Gain and Obesity Patrick Holford, BSc

60

The Role of Insulin in Weight Gain and Obesity Patrick Holford, BSc

61

The Role of Insulin in Weight Gain and Obesity

3/26/14!

Patrick Holford, BSc

Best sources of soluble fibres

Effect of superfibre on the GL of a meal

CUm%Y02'%2';86'#%*&&'A$'% •! X,%$4+#%#$8;1%:'% :'2'%*0('%$"% #4":%$4*$%$4'% =+#6"8#%Y02'% TCUmW%#8&&('5',$% #+),+Y6*,$(1% 2';86';%48,)'2% >''(+,)#%*,;% &2"5"$';%#*A'$1% ;82+,)%*%&'2+";%">% #+),+Y6*,$%6*("2+6% 2';86A",. %% •!

KQ_@!Xe!% +,#8(+,%&"$',A*$"2%

1"23,3#%$'%"*4%56'(783"9$'$-%:;<<%

K2%+5&2"='#%)(86"#'7%+,#8(+,%*,;%:'+)4$% Balk, Diabetes Care 2007; Chen, Eur.J.Nutr 2014; Drake T, Endo.Pract, 2012; Anton, Diab.Tech.Thera.2008

•! S%#1#$'5*A6%2'=+':%6",6(8;'#n% S5",)%&*2A6+&*,$#%:+$4%$1&'%H% ;+*0'$'#7%642"5+85%#8&&('5',$*A",%+5&2"=';%)(16"#1(*$';% 4'5")("0+,%('='(#%*,;%>*#A,)%)(86"#'.%?2$*:%;:( <;SS+1:17#"R*7(<%97%`&"7#+3(%:S$*C1-(9+3&1:%"(":*79( S"R17#<(D%#2(-%"B1#1<. % •! K42"5+85%$1C1$<1<(%7<;+%7($1<%<#"7&17%+5&2"='#%+,#8(+,%#',#+A=+$1% +,%;+*0'A6#.% •! K42"5+85%4*(='#%+,#8(+,%,'';%",%+,>8#+",%:+$4+,%FH%4"82#.% •! S%#$8;1%)*='%4'*($417%"='2:'+)4$%:"5',%642"5+85%"2%&(*6'0"% >"2%'+)4$%:''<#.%52*<1(*7(&2$*:%;:("#1(+1<<a(,1+#(+1<<(2;79$3a( &$"C1-(,"#(+1<<("7-(+*<#(:*$1(D1%92#=(

62

11!

3/26/14!

The Role of Insulin in Weight Gain and Obesity Patrick Holford, BSc Response and Remission Rates: Cr Picolinate in Atypical Depression

K+,,*5",%#$*0+(+#'#%)(86"#'%l%+,#8(+,% Ziegenfuss J.Int.Soc.Sports.Nutr, 2006; Khan, Diabetes Care, 2003; Hlebowicz, AJCN 2009; Askari, Nutr.Res.2014

Davidson et al., Biol.Psych. 2003; Brownley et al., J.Psychosom.Res. 2013

80

Response >66.6% drop on HAMD 70

Remission HAMD <8

Chromium 600mcg stabilised glucose, reduced bingeing and depression in a recent RCT.!

60

%

40

0

CrPic

PBO

CrPic

•! C2'9;+*0'A6#%)+=',%*%6+,,*5",%'?$2*6$%TK+,,8(+,W%>"2%FH%:''<#7%4*;% +5&2"='5',$#%+,%#'='2*(%>'*$82'#%">%5'$*0"(+6%#1,;2"5'%T2';86';%0("";% #8)*2%('='(#7%0("";%&2'##82'7%0";1%>*$%&'26',$*)'7%"?+;*A",W% •! -^%&*A',$#%)+=',%6+,,*5",%'?$2*6$%>"2%>"82%5",$4#%*,;%#4":';%*% #80#$*,A*(%2';86A",%+,%&"#$95'*(%0("";%#8)*2%('='(#%*,;%*%FJE%2';86A",% +,%>*#A,)%0("";%#8)*2%('='(#.% •! c+*0'A6#%:'2'%)+=',%F)7%-)%"2%L)%">%6+,,*5",%&'2%;*1.%S((%2'#&",;';% :+$4+,%:''<#7%:+$4%0("";%#8)*2%('='(#%HJE%(":'2%",%*='2*)'%$4*,%$4"#'%">% *%6",$2"(%)2"8&.34'%0+))'#$%+5&2"='5',$#%:'2'%:+$4%L).% •! o"(8,$''2#%:'2'%)+=',%2+6'%&8;;+,)7%:+$4%"2%:+$4"8$%6+,,*5",7%>"8,;% $4*$%$4"#'%)+=',%-)%6+,,*5",%&2";86'%('##%+,#8(+,%*B'2%$4'%5'*(.% •! o"(8,$''2#%:+$4%,",9*(6"4"(+6%>*[1%(+='2%;+#'*#'%:'2'%)+=',%F./)% 6+,,*5",%=#%&(*6'0".%X,#8(+,%2'#+#$*,6'%*,;%)(86"#'%2';86';.

PBO

!

O''<(1%;+'$%*,;%'?'26+#'%2"8A,'%

Z?'26+#'%9%*'2"0+6%h%2'#+#$*,6'%+#%<'1%

DIET

•!

•!

•!

•!

•!

•!

•!

I:+$64'#%",%*,A9*)'+,)%)','#%*,;%5*1%(',)$4',%$'("5'2'#% X5&2"='#%+,#8(+,%#',#+A=+$1%*,;%&2"5"$'#%)2":$4%4"25",'% _';86'#%#$2'##7%+5&2"='#%5"";%*,;%5'5"21% _';86'#%2+#<%>"2%#"%5*,1%*)'92'(*$';%;+#'*#'#7%+,6(8;+,)%"0'#+$1% ]8+(;#M&2'#'2='#%('*,%0";1%5*##%T58#6('#W% ]""#$#%4"25",'%('='(#%TcQZS7%$'#$"#$'2",'W% _'#+#$*,6'%$2*+,+,)%>"2%D%5",$4#%\%F<)MH(0#%">%('*,%58#6('%)*+,% H/p-JE%+,62'*#';%#$2',)$4.%X>%1"8%;", $%;"%*,1%'?'26+#'%*B'2%$4'% *)'%">%/J%1"8%("#'%4*(>%*%&"8,;%*%1'*2%">%58#6('.% •! =.$(23-$%3-%'>$%2*+-$-'%'>3,?%'+%",%",@A"?$3,?%/3**7 C2">'##"2% O*1,'%c'25*,7%K*&'%3":,%e,+='2#+$1%

]')+,,'2#%9%O*((%I+$%*,;%]"?%C2'##%

EXERCISE

MONDAY low-GL 35/ 800 calories

30-minute cardio workout

TUESDAY low-GL 55

8-minute strength workout

WEDNESDAY low-GL 35/ 800 calories

30-minute cardio workout

THURSDAY low-GL 55

8-minute strength workout

FRIDAY low-GL 35/ 800 calories

30-minute cardio workout

SATURDAY day off

day off

SUNDAY low-GL 55

8-minute strength workout

]'#$%:*1%$"%("#'%:'+)4$P% •! V'##%6*20#%*,;%$4'%2+)4$%6*20#7%5"2'%&2"$'+,% T(":%UV%;+'$W% •! S(#"%4*=+,)%(":%UV%6*20#%:+$4%&2"$'+,% •! Z*A,)%('##%H%"2%-%;*1#%*%:''<%9%(":%6*("2+'%;+'$#7% 5";+Y';% *($'2,*$'%;*1 %>*#$#% •! I8&'2Y02'#%9%CUm7%)(86"5*,,*,% •! K42"5+85%:+$4%6+,,*5",% •! Z?'26+#'%9%*($'2,*$'%2'#+#$*,6'%*,;%*'2"0+6%

63

12!

Bioidentical Hormone Therapy: Fact vs. Fiction

!"#$"%&'

Ron Brown, MD

>?@8.378A'

5-0.46789' :;92<'#=%&'

•! B2A.6AA'98-A40A'/4'6A8'()*+'?8C401'ACD;/4D' .40/94<' •! E4789'F';8-9<A'4G'()*+'G-./A' •! H44I'-/'A2D;<2J81';-K890'4G'-AA8AAD80/'G49' ()*+';98A.92?20L' •! :0AM89'N68A340A'

E40O2./A'4G'P0/898A/'

P0/9416.340'

()*+' ,-./'-01',2.340'

•! P016A/9C'Q6;;49/'

•! E4<<8L8'4G',-D2<C'S9-.3.8'.893J.-340'%WX$' •! Q4<4'969-<';9-.3.8'AD-<<':<?89/-'/4M0'G49'Y'C8-9A'

–! (6A208AA'98<-340AR2;'M2/R'B46L<-A'H-?A'20' 1878<4;D80/'4G';94;928/-9C'06/9-.863.-<A'

–! #&'R469Z'F'1-C'-'M88I'.-<<'M2/R'>?A/8/92.A'

•! Q;8-I89A'(698-6'

•! >([\T'G8<<4MAR2;']02789A2/C'4G':<?89/-'%WW$'

–! B46L<-A'H-?49-/4928A' –! SEE:' –! (E'T-/694;-/R2.':AA4.U'

–! S4A2378'<2G8A/C<8'.R-0L8'

•! H-9L8'L946;'>([\T';9-.3.8'20'^1D40/40'/4';98A80/' –! :AA4.2-/8'.<202.-<';94G8AA49']'4G':<?89/-'B8;/U'>([\T'

•! P184<4L2.'

•! (4-91'E893J81'20',60.340-<'-01'*8L8089-378' _812.208'M2/R'/R8':D892.-0':.-18DC'4G':03`:L20L''

–! P0J02/8'-01'8789'8V;-0120L'-A'2/'98<-/8A'/4'/R8';98A80/' -;;94-.R'4G'.40780340-<'D812.208'/4'R49D408' 98;<-.8D80/'/R89-;C'

aR898'B21'()*+'Q/-9/'a2/R'_8b'

' •! S-380/'20N629C'-?46/'?24`21803.-<'R49D408A' –! a-A0c/'P'8D?-99-AA81'-?46/'DC'<-.I'4G' I04M<81L8b' •! ()*+'.40G8980.8'20'B80789' •! :D892.-0':.-18DC'4G':03`:L20L' –! (4-91'E893J.-340'20',60.340-<'-01'*8L8089-378' _812.208' –! ']02789A2/C'4G'Q46/R',<4921-'-d<2-340' •! S927-/8';9-.3.8'M2/R'&==='()*+'72A2/A'<-A/' ' ' ' ' ' ' 'C8-9'

64

%'

Bioidentical Hormone Therapy: Fact vs. Fiction

!"#$"%&'

Ron Brown, MD

S-K890A'4G'S9-.3.8'

SRCA2.2-0A'-01'()*+'

•! aR4'/R20IA'18.<2020L'A8V'R49D408A' .40/92?6/8A'/4'/R8'-L20L';94.8AAb' •! aR4'R898'2A'-';98A.92?20L';9-.334089'/R-/' A88A';-380/A'40'-'1-2<C'?-A2Ab' •! aR2.R'4G'C46';98A.92?8A'()*+'40'-'98L6<-9' ?-A2Abb'

•! ^789C408'/R20IA'4G'.R-0L20L'/R8'M49<1Z'?6/'04'408' /R20IA'4G'.R-0L20L'R2DA8<GU'' ' ' ' ' 'H84'+4<A/4C' •! ' ' E469-L8'2A'92LR/<C'8A/88D81'/R8'J9A/'4G'R6D-0' N6-<238AUUU'?8.-6A8'2/'2A'/R8'N6-<2/C'MR2.R'L6-9-0/88A' -<<'4/R89AU'' ' ' ' ' 'a20A/40'ER69.R2<<''

()*+'-01'E469-L8'

aRC'PA'+R898'-'S94?<8Db'

•! P/'/-I8A'.469-L8'/4'A/8;'46/'4G'.40G49D2/C'-01'A8/' -'08M'1298.340' •! _4A/'4G'6A'20'()*+'-98'A6A/-2081'?C'/R8'8V.8<<80/' ;-380/'.<202.-<'98A;40A8A'M8'A88'-01'/R8';-380/' G881?-.I' •! P'?8<2878'()*+'2A'-/'-'.94AA94-1A'-01'G69/R89' 1878<4;D80/'M2<<'98N6298'-;;<2.-340'4G'/R8' A.2803J.'D8/R41'/4'()*+';-K890A'4G';9-.3.8' •! _C'J9A/'98A8-9.R';94@8./'M-A';98A80/81' C8A/891-C'-01'A8.401'2A'20'8/R2.A'-;;947-<' ;94.8AA'

•! T49D-<'R49D408';9416.340';8-IA'-/'-L8'#$'-01'L9-16-<<C' 18.<208A'G94D'-L8'#$'/4'$=' –! B-72A40'e'E<20'^014.9204<'#==$fW=g!X&F`$!'h%i' •! ^-.R'R49D408'18.<208A'2018;80180/<C'4G'8-.R'4/R89'.98-30L' A8V'R49D408'2D?-<-0.8A' •! QCD;/4DA'-..6D6<-/8'-A'R49D408A'18.<208'-01"49'60?-<-0.8' –! jER8.I'^0L208k'1-AR'<2LR/' •! Q6;89J.2-<'ACD;/4D'/98-/D80/'-<<4MA';94L98AA240'/4'.R9402.'

12A8-A8' •! H2G8A/C<8'.R42.8A'.40/92?6/8'/4'2D?-<-0.8A' –! '''''''''''S<-A3.AZ'128/Z'R-?2/AZ'8V;4A698'/4'/4V20A'

:L8'*8<-/81'B8.<208'4G',8D-<8' )49D408A'

_80'+44l'

!"#$%&'() ) ) ) *$%&'"#'$%(') ) ) ) +'"#%"#'$%(') ) ,-./()0$%1#2) ,%$.%(') ) 3,!4)5) *$'&('(6%(') ) ) ) ) 7'6/#%(8() '

65

#'

Bioidentical Hormone Therapy: Fact vs. Fiction

!"#$"%&'

Ron Brown, MD

S8-9<'%f')49D408'B8.<208'-01' *8A6</-0/'B2A8-A8A':98'P0872/-?<8'

()*+':A':')8-</R'S94D4340'Q/9-/8LC'

•! B8.<208'20'A8V'R49D408A'.40/92?6/8'/4'-/'<8-A/'&' D-@49';-/R4;RCA24<4L2.';94.8AA8A'/R-/'-..8<89-/8' <4AA'4G'G60.340-<'.-;-.2/C' •!

•!

•!

•!

'''':0-?4<2.".-/-?4<2.'9-34'18/89249-340' ''''P0.98-A81'ACA/8D2.'20O-DD-340' ''''B8.98-A81'.4L02378'G60.340"D8D49C' '''':..8<89-/81'?408'180A2/C'<4AA'<8-120L'/4' ' '4A/84;802-'-01'4A/84;494A2A'

•! a8'0881'/4'.R-0L8'G94D'-'ACD;/4D'2012.-340'/4' -'m>H'2012.-340'G49'()*+'-01'/R2A'M2<<'40<C' R-;;80'M2/R'98A8-9.R'

+R8':0-?4<2."'E-/-?4<2.'*-34'

+R8':0-?4<2.'"'E-/-?4<2.'*-34' •! a8'A88'/R8'8n8./A'4789'3D8'20'oA-9.4;802-c' MR2.R'2A'@6A/'-0'8V;98AA240'4G'-'18.<2020L' -0-?4<2.`.-/-?4<2.'9-34'' •! ()*+'1298./<C'2D;9478A'-0-?4<2.`.-/-?4<2.'9-34' '''''''''''''''''''''''P0A6<20''''''^#Z'S&Z'B)^:' •! '''''''''''''''''''''E493A4<'''''''''''+8A/4A/89408Z'[)'

•! E923.-<'/4';98A897-340'4G'm>H'-A'M8'-L8' •! E-/-?4<2.'R49D408A'9#'/$)-"):%1(;)-01'20.98-A8'-A' M8'-L8'

–!<("-68()) ) ) )=%$>"%6) •! :0-?4<2.'R49D408A'9?-86:)-")-@;)-01'18.<208'-A'M8' -L8'

–!!"#$%&'() ) )3,!4) –!*$%&'"#'$%(' ) )+'"#%"#'$%(') –!0$%1#2),%$.%('))

•! aR-/'148A'A-9.4;802-'<44I'<2I8b'

S8-9<'#f'\469':0-?4<2."E-/-?4<2.'*-34' 2A'S9812.378'4G',6/698')8-</R' •! :<<'4G'C46'R-78'-0':"E'9-34'-/';98A80/' –! aR-/'14'C46'/R20I'C469A'2A'-/'/R2A'3D8b' •! aR-/'2/'2A'20'C469'&=cA'-01'?8C401'M2<<'18/89D208'N6-<2/C' 4G'<2G8'20'C469'F=cA'-01';89R-;A'4789-<<'<40L872/C' •! P'?8<2878'128/Z'<2G8A/C<8'-01'A6;;<8D80/-340'/6%(''14'04/' 2D;9478'/R8':"E'9-34'20'-'D8-020LG6<'M-C`'C46'0881' R49D408Al' •! \46'D6A/';-C'-K80340'/4'/R2A'-A'2/'2A'08789''''/44'8-9<C'49' <-/8'/4'D412GC'-01'/R8'G6/698' ' ' 'D2LR/'04/'?8'-A' ?92LR/'-A'C46'/R20Il'

66

!'

Bioidentical Hormone Therapy: Fact vs. Fiction

!"#$"%&'

Ron Brown, MD

)8'B21'T4/'[8/')898'a2/R46/' )49D408All' •! Q-9.4;802-'2A'AB+ 20872/-?<8' ' •! Q8V'R49D408AZ'8V89.2A8 -01'128/'.-0' ' ;9416.8 /R8A8'I201'4G'98A6</A' ' ' ' ' ' •! a8'R-78'/4'.R-0L8'/R8' 12-<4L68'G94D' /-<I20L'-?46/'/R8'20872/-?<8` ' '/4'MR-/'148A'/R8' ;-380/'M-0/'-01' ' MR-/ -98'/R8C'L420L'/4';6/' ' ' ' ' ' '''''''''''20l' '

'

'

'

'

'

'

'

S8-9<'!'f')49D408'+98-/D80/'*816.8A' P0O-DD-340' •! :A'M8'-L8'469'R49D408A'18.<208'-01'<878<A'4G' 20O-DD-340'20.98-A8' •! )49D408A'9816.8';9416.340'4G'20O-DD-/49C' .C/4I208A' •! )49D408A'-98'0-/698cA'-03`20O-DD-/4928A' •! B2A8-A8A'4G'20O-DD-340'20.<618' –! )8-9/'12A8-A8'' 'E-0.89' –! :<pR82D89A ' ' ')C;89/80A240' –! B2-?8/8A' •! W=q'4G'.R9402.'12A8-A8A'-98'-'1298./'98A6</'''' ' ' '4G'20O-DD-340'

'

^A/94L80'-01'P0O-DD-340'

)*+'*816.8A'P0O-DD-340''

•! SRCA24<4L2.'98;<-.8D80/'14A8A'4G'8A/94L80'R-78' ?880'AR4M0'/4'9816.8'20O-DD-/49C'.C/4I208' 98A;40A8'/4'8014/4V20' •! ^A/9-124<';-/.R'M2/R'D8-0'^#'<878<'!F&';D4<"<'

•! [C08.4<4L2A/A'R-78'I04M0'/R2A'G49'C8-9A'' –! T,rs'-01'PH`Y'-98'.C/4I208A'/R-/'D812-/8' 20O-DD-340'-01'20.98-A8'M2/R'-L8'h#Z!i' •! )-992A':D'e'_81'%WWWf%=Yg$=Y`%#' •! (941ZQ:''P0O-DD-340'98A'#===f&Wg$Y%`=' –! ^A/94L80'-01'/8A/4A/89408'1298./<C'?201'BT:' ;94D4/89'A2/8A'-01';98780/'/9-0A.92;340'4G';94` 20O-DD-/49C'.C/4I208A'' •! ^9A.R<89':00'*87'_81'#===f$%g#&$`F=h&i'

•!

•!

•!

•!

67

–! )2LR'<878<`'b'B4A8'98A;40A8'.6978'

Q/-01-912p81'14A8'4G'8014/4V20'' PH`Y'''''' '!&%tW&'7A'W!YtY#=' PH`%''' 'X#t%&'7A'%!!t#&' +T,u'''''FFt&Y'7A'#%&tXF'

–! e'E<20'^014'_8/'#==%gXYf#&=!`X''S6189'8/'-<&X'

&'

Bioidentical Hormone Therapy: Fact vs. Fiction Ron Brown, MD

68

Bioidentical Hormone Therapy: Fact vs. Fiction Ron Brown, MD

69

Bioidentical Hormone Therapy: Fact vs. Fiction

!"#$"%&'

Ron Brown, MD

:04/R89'E40O2./'4G'P0/898A/bb'

)4M'+4'_-I8'/R8'_8AA-L8'_812.-<' •! P'140c/'-L988'M2/R'"%.''4G'QQcA' '͘ /98-/D80/ '98.4DD801-340A' •! a92K80'G49'/R8'-789-L8'M4D-0' .40/8D;<-30L' '/R8'()*+'18.2A240' •! +R2A'?44I'2A'DC'-K8D;/ '/4'?920L' A6;;4930L'''D812.-<'872180.8' '20/4'/R8'18.2A240'

+R8'^014.9208'Q4.28/C'

' ' ''

S8-9<'Yf'^A/924<`':'Q;8.2-<'^A/94L80'

S4A2340'Q/-/8D80/'#==Y'

•! E40.89081'-?46/'D2A<8-120L'-01'G-<A8' 20G49D-340'-?46/'?808J/A'-01'92AIA'M2/R'?24` 21803.-<'R49D408'/98-/D80/' •! SRCA2.2-0A'AR46<1'8V89.2A8'.-6340'MR80' ;98A.92?20L' •! _6.R'.40A2189-340'AR46<1'?8'L2780'/4'4AJ)/C;8' 4G)R49D408'/R89-;C' •! E<-2DA'4G'20.98-A81'A-G8/C'60A6;;49/81' •! E4D;460120L';R-9D-.28A'04/'A6?@8./'/4',B:' D402/4920L'G49'14A8Z';692/CZ'A-G8/C'-01'8d.-.C'

•! ^#f^!'9-34'2A'049D-<<C'%f%'20'R8-</RC'M4D80Z'?6/' 92A8A'/4'%f%='20';98L0-0.C' –! S98L0-0.C'1-/-'40'?98-A/'.-0.89'A/92I20L'

•! ^!'R-A'-'%=x'18.98-A81'-d02/C'/4'/R8'-<;R-' 8A/94L80'98.8;/49'/R-0'^#'-01'%=x'18.98-A8'20' /9-0A.92;340'2016.340'-/'/R8'-<;R-'8A/94L80' 98.8;/49h4789-<<'%==x'12n8980.8i' •! Q/6128A'.40.<618'^!'D4A/''M'F>K'6C'-0/-L402p8A' ^#'-/'-'9-34'4G'%='^!f%^#h%=i' •! +R2A'2A'MRC'P'.R44A8'(28A/'X=f#='-/'/R2A'3D8'

–! <)/&$'')F%.@6'#'6C)18#2)4DD)#2')/?%K')"#/#'.'(#"LLL)

^A/924<'-01'(98-A/'E-0.89'

^A/94L80'm64380/'

•! (8A/'872180.8'/4'1-/8'A6LL8A/A'8A/924<'6A81'-/'-0' X=q'9-34'/4'8A/9-124<Z'9816.8A'?98-A/'.-0.89'92AI'

•! ^A/924<"'8A/9408'y'8A/9-124<' •! QR46<1'?8'z'%U='-01'-<M-CA'2A'M2/R'X=f#=' •! Q22/892'8/'-<h%%i'

–! 5-AA2;46<2'8/'-<'%WWW'e'E<20'>0.4<4LC'h%#i'

–! H8D40Z)U'%WF$'E-0.89'!$f%!&%`$!h%!i' –! [94AA'8/'-<'%WFF'e'T-/<'E-0.89'P0A/'$WfF`%%h%&i'

–! %$Z==='M4D80'20'/R8'r-2A89',4601-340')8-</R' S<-0';98L0-0/'G94D'%W$W`%WYF' –! :<<'A8V'R49D408A'-AA-C81'^%"^#"^!"+"S' –! S94A;8.378'.4R49/'<20I81'M2/R'.-0.89'98L2A/9C' –! H208-9'/9801'-AA4.U'M2/R'8A/924<';{U=%' –! $Xq'92AI'9816.340'G94D'%A/'/4'&/R'N6-93<8'

•! ^A/9-124<'2A'-';4/80/'8A/94L80'088181'G49' ACD;/4D'/98-/D80/'?6/'-;;8-9A'/4'R-78'-' .-6A-378'94<8'20'?98-A/'.-0.89'

–! ,4690289'8/'#==$'P0/'e'E-0.89'%%&f&&X`$&h%$i' –! (98-A/'E-0.89'E4<<-?49-378'[946;'#==!'e'T-/<'E-0.89' P0A/fW$f%#%X`#Yh%Yi'

70

F'

Bioidentical Hormone Therapy: Fact vs. Fiction Ron Brown, MD

Menopause

71

Bioidentical Hormone Therapy: Fact vs. Fiction Ron Brown, MD

72

Bioidentical Hormone Therapy: Fact vs. Fiction

!"#$"%&'

Ron Brown, MD

+44'_6.R'>G':'[441'+R20L'E-0'(8' (-1ll'

S94L8A/89408'B8.<208' •! S94L8A/89408'<878<';9416.340'18.<208'-A'M4D80' 98-.R'/R829'<-/8'!=cA' •! >789-<<'$=q'18.<208'G94D'#='/4'&=' –! :01'I88;A'G-<<20L'G94D'/R898l' •! *8<-/81'/4'/R8'N6-<2/C'4G'47-92-0'G4<<2.<8A'/R-/'-98'<8v' -/'/R2A'3D8' •! S449'N6-<2/C'G4<<2.<8A';9416.8'<8AA';94L8A/89408'G94D' /R8'.49;6A'<6/86D' •! E46;<8'/R2A'M2/R'20.98-A81'<878<A'4G'8A/94L80'-01'M8' A88'!"#$%&'()3%.8(/(F')

•! +2')F%(F'@#)%E)2%$.%(')9?/6/(F';)8")F'(#$/6)#%)/() 'NF'66'(#)O,H+)@$%&$/.)

•! P0'/R8';98`D804;-6A-<'C8-9A'8A/94L80'<878<A'.-0'8V.881' -7-2<-?<8';94L8A/89408'168'/4' –! >?8A2/C' –! T-/69-<'S&';9416.340'18.<208' –! )2LR'G-/'128/'' –! ^072940D80/-<'/4V20A'49'V804`8A/94L80A' ^-.R'D40/R'/R2A'.-0'?8'A880'20'/R8'G49D'4G'S_Q''''h'^#"S&' 9-34'i'

^A/94L80'B4D20-0.8'

^A/94L80'B4D20-0.8' •! ^A/94L80'B4D20-0.8'.-0'?8'A880'-/':HH'<878<A' 4G'8A/94L80'

•! ^A/94L80'^V.8AA''''''''S94L8A/89408'B8J.280.C' `! `! `! `! `! `! `!

;449'A<88;"20A4D02-''''''''`;449'A<88;"20A4D02-''''' -L2/-340"-0V28/C''''''''''''''`'-L2/-340"-0V28/C' M82LR/'L-20''''''''''''''''''''''`'M82LR/'L-20' /80189'?98-A/A''''''''''''''''''`'/80189'?98-A/A' R8-1-.R8A''''''''''''''''''''''''`'R8-1-.R8A' D441'AM20LA''''''''''''''''''''`'D441'AM20LA' -.RC'@420/A''''''''''''''''''''''''`'J?94.CA3.'?98-A/A'

–! H4M"D804;-6A-<' –! T49D-<";98`D804;-6A-<' –! )2LR"SE>Q'

•! +R2A'2A'MRC'/98-/D80/'18.2A240A':Ha:\Q'A/-9/' M2/R'8A/94L80'<878<A'-01'ACD;/4DA' •! S-380/'ACD;/4D'N68A3400-298'789C'6A8G6<'/4' 18/89D208'/98-/D80/';9249238A'20'M4D80'

Name: Date:

Your Hormone Balance Inventory 0

PROGESTERONE

ESTROGEN

TESTOSTERONE

None

5

Slightly

10

Moderate

15

Severe

S94L8A/89408'

20

Extreme

Difficulty Concentrating Can’t Sleep (Insomnia) Depressed or Unhappy Anxious Headaches Moodiness / Emotional Swings Painful or Swollen Breasts Weight Gain / Bloating PMS

•! H'6/>K'';94L8A/89408'18J.280.C'2A'8018D2.'

•! QCD;/4D'3;4nA' –! S449'A<88;"20A4D02-' –! :0V28/C"8D4340-<'<-?2<2/C' –! +80189'?98-A/A' •! S94L8A/89408'/98-/D80/'98`8A/-?<2AR8A'?-<-0.8'M2/R' 8A/94L80'/4'2D;9478'ACD;/4DA'

Night Sweats Difficulty Remembering Things Hot Flashes Vaginal Dryness Dry Hair / Skin Incontinence Frequent Urinary Tract Infections Inability to Reach Orgasm Painful Intercourse Loss of Libido Lack of desire to be intimate Loss of motivation Flat mood Diminished well being

GENERAL WELL BEING

Change to Bowel Motions Change of weight Change to Stress Level

How many per day?

Increase Decrease Yes / No (circle) Current Stress Level:

1-10

73

%='

Bioidentical Hormone Therapy: Fact vs. Fiction

!"#$"%&'

Ron Brown, MD

>9-<'S94L8A/89408' ) !!

!!

S94L8A/89408'E98-D'

P/A'D8/-?4<2/8Z'$`-<<4`;98L0804<408Z'2A'A81-30L'-01' 2D;9478A'A<88;' •! *$%.'#$8-.'%==`#=='DL'%$'D20'?8G498'?813D8' 2D;9478A'A<88;'h04M'20'Q-|4M89'42<'i' •! E-0'A;<2/'14A8'7-L20-<<C'G49'+B`<2I8'8n8./' 78F$%(8P':)*$%&'"#'$%('' •! E4D;460181'-/'14A8A'G94D'$=`!==DL'M2/R' -112340'4G'D8<-/4020'2G'98N62981' •! E-0'?8'D498'.4A/'8n8.378'/R-0'S94D8/926D`' .4D;460189'18;801-0/'

+$/(":'$./6)*$%&'"#'$%(')F$'/.)'D-C'?8';98G89981' 2G'20A4D02-'04/'-0'2AA68' !! T4'J9A/';-AA'8n8./'40'/R8'<2789' !! B68'/4'2/A';<-.8'20'/R8'A/89421'AC0/R8A2A'.R-9/Z' /9-0A189D-<';94L8A/89408'.-0'?8'AR60/81'/4'.493A4<' /4';947218'-1980-<'A6;;49/' !! :<<4MA'3/9-340'4G'14A8'/4'ACD;/4DA'20';98` D804;-6A-<'M4D80'-01'98`8A/-?<2AR8A'-'A80A8'4G' .40/94<' !!

S94L8A/89408'E98-D'

+8A/4A/89408'-01'a4D80'

B4A-L8'#=`&='DL'408'/4'/M4'3D8A';89'1-C' )2LR89'14A8A'.-0'?8'6A81'?6/'0881'/4'98.4L02p8'/R-/' /R8A8'-98';R-9D-.4<4L2.'14A8A' !! %=='DL'/M2.8'-'1-C'/R8'D-V2D-<'P'R-78'6A81' !! ^V.8<<80/'G49';98`D804;-6A-<'M4D80'/4'3/9-/8'/4' /R8'S_Q'ACD;/4DA'20'/R829'.C.<8' !! E-0'?8'6A81'40'-'.C.<2.'49'.4030646A'?-A2A'20';98' -01';4A/D804;-6A-<'M4D80'

•! H8-A/'60189A/441'-01'D4A/'.40/94789A2-<' •! [9-16-<'18.<208'20'/8A/4A/89408';9416.340' G94D'-L8'#$'/4'$='

!! !!

–! $=q'18.<208'G94D'-L8'#=`&=' –! %$q'040`98.4789-?<8'194;'G94D'8-.R';98L0-0.C' •! T-/698A'G-D2<C';<-0020Ll'

•! Q/-?<8'-v89'/R8'D804;-6A8' •! ^A/94L80'194;A'A2L02J.-0/<C'-01'98789A8A'2/cA' 9-34'M2/R'/8A/4A/89408' –! _-02G8A/A'-A'-'D46A/-.R8'

' +8A/4A/89408'B8J.280.C' S920.8/40'E40A80A6A'Q/-/8D80/' '

•!

•!

•!

•!

*816.81'A80A8'4G'M8<<`?820L'-01'8089LC' BCA;R492.'D441'h18;98AA240i' S89A2A/80/'608V;<-2081'G-3L68' B8.98-A81'<2?214Z'A8V6-<'98.8;372/C'-01';<8-A698 h02;;<8'-01'.<2/49-<'A80A2372/Ci' •! 5-A4D4/49'20A/-?2<2/C' •! ER-0L8A'20'.4L02340'-01'D8D49C' •! (408'<4AA'-01'9816.81'D6A.<8'A/980L/R' –! (-.RD-00'8/'-<'#==#',893<'Q/892<'FFh&iYY=`$'h!=i'

74

%%'

Bioidentical Hormone Therapy: Fact vs. Fiction

!"#$"%&'

Ron Brown, MD

+8A/4A/89408'

+8A/4A/89408'+98-/D80/'20'a4D80'

•! &'4G'F';92D-9C'ACD;/4DA'6A81'/4'12-L04A8' 18;98AA240'98O8./'+'18J.280.C' –! *816.81'M8<<`?820L'' –! B8;98AA240' –! ,-3L68' –! B8.98-A81'.4L02340'-01'D8D49C' •! PA'2/'D498'D812.-<<C'.4998./'/4'6A8'-03`18;98AA-0/A' /4'/98-/'-0V28/C'-01'18;98AA240'-/'/R2A'3D8b' –! a2<<'M8'A88'-'.R-0L8'M2/R'-';R-9D-.863.-<' /8A/4A/89408b' •! QQ*PcA'-98'T>+';94L8A/89408'-01'/8A/4A/89408' '

! !!!

1+0'2-

34!2- "#$%&!

5&&8';;2-

56'2-

!

-

7+8")+,-9)+):;2-

''''''P/cA':<<'-'_-K89'4G'(-<-0.8'

-

)*+&,-.(/-01($!

)(#2#+3!455$1%%!

<=#('-1:0>'8;2-

!

?----------@-

!

6#&/!

>*=25!/*=!2#?1!&*!$191#81!+1@%21&&1$%A!1&9B!!!!!!!!!!0CD!!!!!!!!!!EF-

-

G="'E-G#0H,+"()2-

7*%&(2!6*51!

?----------@-

6122!

-

/+0",C-<=C;"*"+(2-

7$*8#+91!

?----------@-

:*;1!

A0+",2-

! ! ! ! ! !

'(%&!

-

!

!

1#)'J!721(%1!$1(5!9($1R=22/!(+5!R#22!*=&!(%!9*;H21&12/!(%!

H*%%#S21N!!K,1!#+R*$;(&#*+!H$*8#515!S/!&,#%!T=1%&#*++(#$1! @#22!S19*;1!H($&!*R!/*=$!$19*$5%!(&!*=$!92#+#9!(+5!#%! &$1(&15!(%!9*+R#51+&#(2N!

!"#$%&'()"*+,-%()+.'-/'0+,'-

-

•! QCD;/4D'A.498'D4A/'2D;49/-0/'G-./49'-<40L'M2/R' #'4/R89'N68A340A' •! m6-<2/C'4G'/R8'98<-340AR2;'40'-'A.-<8'4G'%`%=' •! H878<'4G';-380/'<2?214'40'-'A.-<8'4G'%`%=' •! +98-/D80/'2A'?-A81'40';-380/'ACD;/4DA'MR2.R' D6A/'?8';<-.81'20'/R8'.40/8V/'4G'R89'<2G8'-01' 98<-340AR2;' •! +8A/4A/89408'.-0'-1198AA'-'ACD;/4D'o12A.4008./c' •! a4D80'-98'04/'o8-ACc'<2I8'D80l'

<=%#+1%%!

<'8;#(+,-B'+,)=*+8'-1:0>'82B#D-&"&-C#:-='+8-#E-:;F- -

-

!

)15#9(&#*+!

! ! ! ! ! !

D&$1+3&,-.*%(31!

! ! ! ! ! ! !

G#&(;#+%!-!D=HH21;1+&%!

! ! ! ! ! !

! ! ! ! ! !

I=(+&#&/!

I(#D(-5,,'86"';29:86'8CJ7'&"*+,-B";)#8C2! /+0",C-B";)#8C2!

G___/P___ Occupation : Dyspareunia: Alcohol Use: Date of Last:

C-Sec/SVD

B"6=,"6=)'&-9'*)"#(;-+8'-!"#$%"&'"#$()*$"+,-!

Cycle: ____/____

LMP:

Flow :

Marital Status: Yes Yes

No No

Daily Bowel Motion: Am’t per week:

Yes

N o

Pain:

Relationship Quality: Sleep Quality:

Yes Smoker: Mammogram:

Physical:

No

$ $ $ $ $ $ $ :1#3,&J!! .G.!@(&9,15J! ! )=2&#8#&(;#+J! !

M$1/!D1(!D(2&J! !

!

>(#%&!6#$9J! .#%H1+%1$J! !

G#&(;#+!.J! !

45$N!"(&#3=1! !

!

<7J! .#1&!7$*3$(;J! !

F;13(!LJ! !

O7&!6*$&#%*2! !

Contraception: ____________ Libido: 1-10 ____________ ____________

1-10

1-10

!

Am’t per Bone Density: wee k:

>1#3,&J! D211H! ! )(3! !

PG!! !

!

K,1$;*3$(H,/J! ! !

D211HJ! !

K*Q#9#&#1%J! !

!

+8A/4A/89408'-01'a4D80'

+8A/4A/89408'+98-/D80/'20'a4D80'

•! +8A/4A/89408'2A'-1181'/4'(28A/'.98-D'49'6A81' -<408'-01'-;;<281'1-2<C'/4'/R8'76<7-'

•! :2D'G49'$`%$';D4<"<'-A'-'/98-/D80/'/-9L8/' •! (<441'<878<A'40'/98-/D80/'-98'6A81'G49'A-G8/CZ' T>+'8d.-.C' •! +R8'M4D-0'2A'/R8'.80/89';420/'-01'-<<'/98-/D80/' 18.2A240A'G49'/8A/4A/89408'98A/'M2/R'R89ll' •! T4'218-<'<878<'G49'-<<'M4D80'-01'/R898'2A'D6.R'/4' ?-<-0.8'/R-/'C46'140c/'I04M' •! *-0L8'4G'218-<'<878<'08789'.8-A8A'/4'-D-p8'D8`'2/' 2A'98<-340AR2;'18;801-0/''

–! +C;2.-<'A/-9/'14A8'%`#U='DL'20'U#$'..')*+'M2/R'49' M2/R46/'(28A/'

•! (<441'<878<A'8A/-?<2AR)"/E'#C)4G'14A-L8' –! W`%='R469';4A/`-;;<2.-340'

•! a4D-0'18/89D208A'14A-L8'-1@6A/D80/' –! ^V;89280.81'?808J/A' –! ]0M-0/81'A218'8n8./A' –! *8<-340AR2;'.4998<-/8A'

75

%#'

Bioidentical Hormone Therapy: Fact vs. Fiction

!"#$"%&'

Ron Brown, MD

()*+'E40.<6A240A'

()*+'-01'+968'(-<-0.8'

•! ()*+'M49IA'/4'2D;9478'N6-<2/C'4G'<2G8'

•!

•!

•!

•!

–! QCD;/4D-3.'-01';RCA24<4L2.'

•! ()*+'0881A'<2/89-/698'A6;;49/'/4'D478' G49M-91'20'D8-020LG6<'M-C' •! ()*+'-;;8-9A'/4'9816.8'?98-A/'.-0.89'-01' R8-9/'12A8-A8' •! ()*+'148A'04/'20.98-A8'?<441'.<4/'92AI' •! ()*+'R-A'/4'?8';-380/'.80/8981'-01'G4.6A81' 40'/R8'92AI`98M-91'9-344'

B9U'*40'(94M0' FX=`&Y&`&$=Y' A/49I==FU940}LD-2<U.4D' E4D8'72A2/'6A'-/'469'?44/R'G49'/R8'98A/'4G'/41-C'

Q4D83D8A'C46'@6A/'R-78'/4'1278'20l'

76

%!'

91757 Embryon - Symon's Investigator Slides

The Moods of Aging: Hormones and the Mind-Body Connection3/25/14 Phyllis Bronson, PhD

Phyllis J. Bronson, Ph.D. Biochemical Consulting Company Biochemical Research Foundation Aspen, Colorado

Older women need their hormones too

Sad Women •! Hot Flashes, anxiety, and panic attacks are hormone deficiency symptoms, relieved with bioidentical hormones. SSRI anti-depressants do not contain estrogen, and their use for estrogen deficiency is an abuse and victimization of women who suffer from estrogen deficiency.

•! SSRI drugs should not be used to treat estrogen deficiency symptoms.

Dr. Bronson's book could not have been published at a better time.

Brisdelle, a version of Paxil or paroxetine, has just been approved by the FDA as a treatment for hot flashes, despite an advisory committee vote of 10-4 against it.

J.Dach, M.D.

Common Signs of Estrogen Deficiency Insomnia, Difficulty Falling Asleep Hot flashes Night sweats Forgetfulness, Mental Fogginess Depression Mood Disturbance Fatigue, Reduced stamina Decreased sense of sexuality Lessened self-image and attention to appearance Dry eyes, skin, and vagina Sagging breasts and loss of fullness Vaginal Dryness, Pain with sexual activity Weight gain Menopausal Arthritis, back and joint pain Headaches and migraines Gastrointestinal discomfort, bloating -uzzi reiss

Slide

1 77

91757 Embryon - Symon's Investigator Slides

The Moods of Aging: Hormones and the Mind-Body Connection3/25/14 Phyllis Bronson, PhD

What is the Mechanism of Action of Estrogen in Eliminating Anxiety and Depression?

NO on saliva tests because Gender hormones enter portal blood 3 ways

•! Estrogen receptors have been found in the brain, and estrogen increases the expression of an enzyme in the brain called tryptophan hydroxylase-2 (TPH2).

1. Free 2. Loosely bound to Albumin 3. Tightly bound to SHBG

•! This enzyme s job is to convert tryptophan to serotonin, an important neurotransmitter responsible for anti-anxiety and calming effect in the brain.

All are available to dock at receptors if bioidentical

JDach

Estriol is safe

Recent Research !!

The female uses both weakly bound and free forms of these hormones at receptors. Saliva tests only measure the free, unbound portion of the hormone molecule in serum, so they don t give a complete picture of the available potentially active, or bioavailable, hormone.

!!

!!

E3/ Estriol is very safe 80% of naturally occurring estrogen is E3.

Soars 1000X during pregnancy U.S. Department of Defense conducted major study of 15,000 women. Those with highest estriol during first pregnancy had 58% less breast cancer over next 40 years

l. Vliet

Brain Fatigue

Estrogen Receptor Alpha estradiol stimulates both ER alpha and beta

Day-long fatigue -- rising FSH and LH as brain tries in vain to increase falling estradiol. Estrone rises/ estradiol drops and brain fog sets in Flat affect depression Recent data shows diminished E2 levels as being primary issue of estrogen depletion at alpha E receptors (ER!)

Slide

2 78

91757 Embryon - Symon's Investigator Slides

The Moods of Aging: Hormones and the Mind-Body Connection3/25/14 Phyllis Bronson, PhD

Soy Phytoestrogens Very low affiinity for Estrogen receptoralpha High attraction to ER- beta

Estrogen Spectra

•! Carbonyl at 1720, unique to estrone •! Aliphatic OH- diminishes naturally in E2 •! In presence of PAH greatly diminished OH

16 alpha

Calcium,glutamate-induced excitotoxicity /E2/ Neuroprotection

•! 16 alpha metabolite of estrone is precursor to relatively inactive estriol: this does not make estriol toxic

•! Loss of Ca2+ homeostasis in brain disorders such as stroke, seizures is linked to glutamate excitotoxicity

•! Unique spacing of 16 alpha-OH group with proximity to keto group of estrone that lead to negative potent 16 alpha effects

•! Maintenance of intracellular Ca2+ is based on E2 mediated neuroprotection

Slide

3 79

91757 Embryon - Symon's Investigator Slides

The Moods of Aging: Hormones and the Mind-Body Connection3/25/14 Phyllis Bronson, PhD Stability of estrogens The electrode potential of the estrogens do not necessarily reflect their thermodynamic relationship to one another.

The electrode reactions as measured are irreversible, that is kinetically controlled. The current voltage curves which they yield do not necessarily reflect their oxidation/reduction characteristics in physiological systems.

As to the effectiveness of bioidentical hormone therapy, this was established in a recent study by the University of Texas Health Science Center. The researchers followed 296 women who received bioidentical hormone therapy between 2003 and 2010.

Two doctors from the Cleveland Clinic, one of which has represented pharmaceutical companies that manufacture synthetic hormones, recently published a paper that lambasts any perceived benefits of bioidentical hormones.

The study found that the women overall experienced a 25% reduction in emotional mood swings and irritability, 22% less anxiety, and a 14% reduction of night sweats.

The paper, published in December s Cleveland Clinic Journal, states that there is no evidence that bioidentical hormones provide aging benefits, reduce side effects, or present a legitimate option to FDA approved pharmaceutical synthetic hormones.

The researchers concluded that, This study demonstrates that compounded bioidentical hormone replacement therapy improves mood symptoms.

4) Estriol acts differently in the body from esradiol, estrone, and equine hormones. Thus estriol would be expected to carry less risk for breast cancer, stated the paper.

A 2009 review of clinical evidence by Kent Holtorf, MD, found that:

1)! Patients report greater satisfaction with Hormone

5) Progestins from pharmaceutical hormones come with a variety of negative cardiovascular effects, which may be avoided with progesterone.

replacement therapies that contain progesterone compared with those that contain a synthetic progestin.

2)!Bioidentical hormones have different molecular structures and significantly different metabolic effects from synthetic versions.

Dr. Holtorf s paper concluded that bioidentical hormones are linked with reduced risks of breast cancer and heart disease, and are more efficacious than their synthetic and animal-derived counterparts.

3)!Clinical research and physiological data has found

progesterone not to have the risk for breast cancer associated with synthetic progestins.

Slide

4 80

91757 Embryon - Symon's Investigator Slides

The Moods of Aging: Hormones and the Mind-Body Connection3/25/14 Phyllis Bronson, PhD Pharmaceutical Ghostwriting

Shame: a medical person ghostwriting to support opinions of big pharma

The article is entitled, Bioidentical Hormone Therapy: A Review

of the Evidence , by Michael Cirigliano, an Internist at the University of Pennsylvania School of Medicine, published in the Journal of Women s Health. (2007 Jun;16(5):600-31.

His conclusion: Not Big Pharma, then not good, ACKNOWLEDGMENTS: I received editorial assistance from Eugene R.Tombler, Ph.D., Florencia Schapiro, Ph.D., and Monica Ramchandani, Ph.D., of PharmaWrite,LLC.

!!

!!

Distort the evidence: Cirigliano tries to defend Premarin by saying another pharmaceutical Enjuvia, is synthesized to mimic Premarin for relief of vaso-motor symptoms Pharmawrite concludes that this drug is obtained from plant sources and mimics Premarin- this is not the issue with determining bioidentical status

Opposing Effects

News?

Newsweek is an Infomercial

Synthetic progestins may also increase the conversion of weaker endogenous estrogens into more potent estrogens, potentially contributing to their carcinogenic effects, which are not apparent with progesterone.

Masquerading as Medical News

•! Newsweek says: "bioidentical hormones are unregulated". This is an outright falsehood.

Compounded bioidentical hormones are highly regulated at the state levels.

Holtorf

Progesterone inhibits

Huge Distinctions !! Progesterone

has an opposite effect, stimulating the oxidative isoform of 17-beta-hydroxysteroid dehydrogenase, which

Progesterone inhibits estrogen-stimulated breast epithelial cells.

Progesterone also down-regulates estrogen receptor-1 (ER-1) in the breast, induces breast cancer cell apoptosis, diminishes breast cell mitotic activity.

!! increases

the intracellular conversion of potent estrogens to their less potent counterparts.

Holtorf

Slide

5 81

91757 Embryon - Symon's Investigator Slides

The Moods of Aging: Hormones and the Mind-Body Connection3/25/14 Phyllis Bronson, PhD

BRAIN CONNECTION

BRAIN CONNECTION

Estrogen is most important for cognition, but progesterone also serves the brain, decreasing anxiety and mood swings.

Oral Progesterone such as Prometrium or compounded goes through liver first pass, and after being metabolized affects GABA receptors in a more potent BDZ drug like manner.

Progesterone enhances dendritic activity, so that neuroinhibitory molecules are more readily up-regulated.

Natural Progesterone from your ovaries or transdermally applied in sufficient quantity affects GABAA and GABAC receptors.

5-alpha pregnandione is made in upper GI from oral progesterone: this has 12x the potency of Phenobarbital

Allopregnanolone

GABA receptor = FIVE Pentameric subunits

•! Allopregnanolone is potent modulator of GABAA receptor

•! Each subunit has M1-M4 TWO molecules of GABA bond between alpha and beta subunits •! Neurosteroid- THDOC- increases electrical migration

CL-

•! Progesterone breaks down into allopregnanolonein men and women

ionic diffusion or

•! Increase in neuronal excitability dependent on upregulation of alpha-4 subunit of GABAA S.Smith,Ph.D

SIGNS OFSIGNS TESTOSTERONE DEFICIENCY OF TESTOSTERONE DEFICIENCY

"-Aminobutyric acid (GABA) GABA depolarizes neurons by opening GABAA receptor Cl- channel, mimics hydration sphere

Slide

•!

The hormone of self- esteem

•!

Lack of energy & stamina

•!

Loss of sense of security and indecisiveness

•!

Decreased sex drive

6 82

The Role of Lithium in Central Nervous System Health

!"#$"%&'

Laurie Mischley, ND

Geological perspective

LITHIUM IN THE CENTRAL NERVOUS SYSTEM

•! Unevenly distributed throughout crust •! Not unique: Iodine, Selenium •! Medical geography- Harold Foster

Laurie K Mischley, ND, MPH, PhD(c)

•! Largest known deposits are

Bolivia & Chile

Orthomolecular Medicine Today Conference

•! Salar- Spanish salt flats

Photo: Wiki Earth

Vancouver, Canada April 2014

Li Content of Earth’s Crust

Chemical perspective Alkali metal, lightest of all the metals Occurs as a salt

•! Highest where salts have been

concentrated by solar evaporation •! Desert, playa, salar

Swedish chemist Johan August Arfvedison isolated the salt in 1817.

Human Use

Lithium in Industry

Travel to mineral springs dates back ~ 2000 years

•! Lithium is highly anodic in the galvanic series •! Reacts with water something like sodium does •! Not very stable, but excellent energy density •! Joules of energy per kilogram •! Offers electronics that are smaller, lighter, thinner

Gerhard Schrauzer Born in Eastern Europe, grew up interested in the local mineral springs purported by locals to having moodenhancing properties.

German: ‘Natalie Quelle’

•! Widely used battery technology in small electronics

1948- Dr. Schrauzer analyzed this water while employed as a laboratory chemist at a local research institute specializing in mineral waters.

83

%'

The Role of Lithium in Central Nervous System Health Laurie Mischley, ND

!"#$"%&'

Downtown Fountain in Lithia Park, OR

Li is an Essential Nutrient •! Every cell contains lithium.

•! The body does not synthesize it’s own lithium.

•! Must be exogenously supplied: physiologically essential •! Required dose is estimated to be ~ 1 mg/ d.

LITHIUM SCIENCE

Conditional essentiality has yet to be determined: Are there certain populations who may have unique requirements?

Likely, given what we know about biochemical individuality, SNPs, epigenetics, etc.

Is it essential?

What are the symptoms of deficiency?

How is adequacy assessed?

Schrauzer GN. J Am Coll Nutr 2002;21(1):14-21.

Where does it come from ?

Human Intake

•! WATER •! A function of the natural variation in the Earth’s crust •! The higher the rainfall in any region, the lower the lithium level in the water supply.

•! Average US consumption: 650- 3100 µg/d.

Determined by location/ source of water Soil/ mineral content of diet

•! FOOD •! Likely a function of the soil the foods were grown in, and how well they are washed before consumed.

•! Last analyzed 20+ years ago- farming practices have changed substantially.

•! Worldwide variation in intake: Location

Data in humans and rodents suggests the higher the Na content of the diet, the lower the Li. Pickett EE. Biol Trace Elem Res 1992;34(3):299-319.

Schopfer J, Biol Trace Elem Res 1994;40(1):89-101

Lithium Intake

Tijuana, Mexico

1485 + 1009 µg/d

Glaveston, Texas

821 + 684 µg/d

Vienna, Austria

348 + 290 µg/d Schrauzer GN. J Am Coll Nutr 2002

84

#'

The Role of Lithium in Central Nervous System Health Laurie Mischley, ND

85

The Role of Lithium in Central Nervous System Health Laurie Mischley, ND

86

The Role of Lithium in Central Nervous System Health Laurie Mischley, ND

87

The Role of Lithium in Central Nervous System Health Laurie Mischley, ND

88

The Role of Lithium in Central Nervous System Health Laurie Mischley, ND

Drug Addicts: Rx Li for Foul Mood

Pharmacological Doses

24 former drug users Randomized to 400 µg/ d of Li or placebo x 4 weeks

•! Method of Cooper, et al. uses doses of 600-1200 mg/ d,

!"#$"%&'

which targets a serum Li level between 0.65-0.85 mEq/L. •! Just below level of toxicity

Using the Naval Psychological Research Unit measure, there was a statistically significant improvement in mood scores from baseline, particularly in: •! Energy •! Happiness •! Friendliness

•! At pharmacological doses, 1-2 week latency for maximum

effect

•! Clinical efficacy retained for 1-2 weeks following

discontinuation

•! FDA Approval (used this way) for depression, bipolar

disorder

Schrauzer GN et al. Effects of nutritional lithium supplementation on mood. Biol Trace Elem Res 1992

CNS: MECHANISM OF ACTION

Magnesium homeostasis

Decreases neuronal hyperexcitability

•! Diagonal relationship

Low RBC Mg and Li increase neuronal hyperexcitability.

•! Similar ionic radii and potential

Neuronal hyperexcitability involved in: Migraine Seizure Neurodegeneration Multiple Sclerosis

(0.60 A- Li, 0.65 A- Mg) •! Competition at binding sites •! Displacement of Mg by Li

1.5 g Li/ kg body weight x 14 d ! Increase plasma Mg & Decrease RBC Mg Haavaldsen et al. 1973 Li can inhibit Mg-dependent enzymes.

Birch NJ, Lancet 1974; Amari L, Anal Biochem, 1999

Protects cells against glutamate-induced excitotoxicity Bauer M, et al. Pharmacopsychiatry 2003; 36 Supp 3:S250-254.

89

$'

The Role of Lithium in Central Nervous System Health

!"#$"%&'

Laurie Mischley, ND

Regulation of autophagy

Glycogen synthase kinase-3 beta

Autophagy is the process by which cell lysosomes engulf and digest our used and dysfunctional waste, and recycle it into component parts, e.g. amino acids. (Greek, auto “self” and phagein “to eat”)

GSK3b is involved in energy production & neurogenesis.

2 mechanisms by which Li inhibits GSK3b: •! Li dislocates Mg binding to the catalytic core of GSK3b •! Li induces conformational change via phophorylation of the serine-9 residue, rendering it inactive.

Dysregulated autophagy is a major problem in all of the neurodegenerative diseases.

•! In Caenorhabditis elegans, lithium supplementation resulted in

increase in healthspan and mitochondrial energetic function.

Tam ZY, et al. Effects of Li on Age-related Decline in Mitochondrial Turnover and Funciton. 2014 J Gerontol A Biol Sci Med Sci.

Li has been shown to reduce GSK3b at the gene level Mendes CT. Li reduces GSK3b mRNA levels: implications for Alzheimer’s Disease. Eur Arch Psych Clin Neurosci 2009

•! Rodent model of Parkinson’s disease, Li improved clearance of

!synuclein, ubiquitin, & superoxide dismutase 1.

Fornai F, et al. Autophage 2008; Sarkar S, et al. J Cell Biol 2008

Neuroprotection as a Downstream Effect •! Induces secretion of growth factors (e.g. BDNF) Su H, et al. 2009 •! From adult stem cells, Li enhances the differentiation toward

neuronal phenotypes, leading to neurogenesis.

Kim et al., 2004; Fornai et al. 2008a)

INDUSTRY PERSPECTIVE

•! Increases neutropil formation, axonal elongation, and motor

neuron axon collaterals.

Ferrucci et al, 2010, Gilad and Gilad 2007,

Pasquali L, et al. Intracellular pathways underlying the effects of lithium.

Behavioural Pharmacology 2010, 21:473-492.

5 mg …………………………… 300 mg

90

*'

The Role of Lithium in Central Nervous System Health Laurie Mischley, ND

!"#$"%&'

Patents have been filed…

•! Use patent, for an indication •! Parkinson’s Disease •! Neurodegenerative Disease

PUBLIC HEALTH

•! Should one be granted ownership for nutrient repletion?

Mental Health Neuroinflammation Neurodegeneration

PRAGMATIC QUESTIONS:

Recommended Dietary Intake

•! Do our patients have lithium deficiency?

•! None exists

•! If those who are lithium deficient were not, would the symptoms

or course of their disease improve?

•! Not added to multivitamins

•! Physiologic lithium treatment for: •! Psychosis?

•! Depression? Anxiety?

•! Neuroprotection?

•! Levodopa-induced dyskinesia?

•! Dystonia?

•! Infertility?

•! Impulse-control disorders: Tics? Addiction? Seizures?

•! Unfriendliness?

•! Not fortified in water, salt, bread, etc.

Future Research

THANK YOU

•! Distribution of lithium around the world.

•! Water samples to a central lab. Imagine the ROI… •! Analysis of foods for presence of lithium •! As has been done for other required minerals. Thyme?

•! Cross-sectional studies with disease incidence •! Intervention trials •! Prevention •! Lack of progression •! Symptom Improvement

91

+'

3/24/14 Effective Tapering Strategies to Limit Drug Withdrawal and Destabilization: A Clinician’s Perspective

Jonathan Prousky, ND !"#$%&#'()*#+,-.'/0+)0#.,#1'02'3,4,0' 516$7,)0+,$'8+9.':,07;+)<)=')-;' 8#10)>,=,?)%2-@'' A'B=,-,$,)-C1'5#+1*#$%&#' D6'

•! (7#'<#=='+#1*#$0#;'$+,%$'2H'*16$7,)0+6M'8+E' 5#0#+'D+#..,-'N)'*16$7,)0+,10'7,41#=HOM' )9072+#;')-'2*P#;'*,#$#M'Q!"#$%&'()*+$,+',( -+.,$/(0+$/,1(2++#3(4'%516$,*65(7*89( :6,1#*$;$/(4*"9*$<'MR',-'<7,$7'7#'+#4)+G#;' 07)0'<#'<29=;';2'H)+'42+#'.22;',H'<#'7);' *+2.+)41';#&#=2*#;'02')11,10'*)%#-01',-' $24,-.'2"'07#,+'*16$7,)0+,$';+9.1E'

' 8+E'F2-)07)-'5+291G6' B7,#H'I)09+2*)07,$'J#;,$)='KL$#+M'5+2H#112+M'B)-);,)-'B2==#.#'2H'I)09+2*)07,$'J#;,$,-#' !;,02+M'F29+-)='2H'K+07242=#$9=)+'J#;,$,-#' '

S#H#+#-$#@'D+#..,-'5@'(2;)6C1'.+#)0#10'4#-0)='7#)=07'-##;@'*16$7,)0+,$';+9.'<,07;+)<)=' *+2.+)41E'!"#$%"&"'()$*+,(.../01234#*35*6#/7*+8'$95"#"$9:$"44%3856;70%<#$%79'$149 .%#0'$<.<=>:>?@ABACD/0#+=E/'

/24#'+#)12-1'<76'*)%#-01' <,17'02'>#'0)*#+#;'2"' *16$7,)0+,$';+9.1'

T2<';,;')'-2-PJ8'.#0',-02' 7#=*,-.'*)%#-01'0)*#+'2"'07#,+' *16$7,)0+,$';+9.1U'

!!I2'+#$2==#$%2-'2H' H##=,-.1'*+,2+'02' *16$7,)0+,$';+9.1' !!W-19+#',H'*16$7,)0+,$' ;+9.1'7)&#'7#=*#;' !!I#.)%&#'#"#$01'H+24' *16$7,)0+,$';+9.1' !!:,17#1'02'G-2<',H'$)-' =,&#'<,07290'07#4' !!:)-01'02'>#'H+##'2H' 07#4'

!!J6'$=,-,$)='*+)$%$#'V'07#' *)10')-;'07#'*+#1#-0' '

/0#*'XE'*)%#-0' )11#114#-0'

/0#*'ZE'S#1#)+$7'

!! J#-0)='10)>,=,06' !! /!!8/'N/2$,)='19**2+0M' !;9$)%2-M'!Y#+$,1#M'8,#0' )-;'/=##*O' !! J#;,$)='19**2+0' !! 3#&#='2H'+#);,-#11' !! I94>#+'2H'*16$7,)0+,$';+9.

N1O' !! 3#-.07'2H'*16$7,)0+,$';+9.'

7,102+6' !! !10)>=,17,-.')'0+91%-.')-;' *+2;9$%&#'$=,-,$,)-P*)%#-0' +#=)%2-17,*'

!! K>0),-')-',-&#-02+6'2H'07#' *)%#-0C1'$9++#-0'91#'2H' K(B')-;'S[';+9.1M')1'<#==' )1'-)09+)='7#)=07'*+2;9$01'' !! S#1#)+$7'07#' *7)+4)$2G,-#%$1'2H'07#' *16$7,)0+,$';+9.1'07#' *)%#-0',1'0)G,-.' !! D#10'02'0)*#+'07#';+9.'<,07' 07#'=2-.#10'7)=HP=,H#'*+,2+'02' 207#+';+9.1'

92

1

3/24/14 Effective Tapering Strategies to Limit Drug Withdrawal and Destabilization: A Clinician’s Perspective

Jonathan Prousky, ND /0#*'\E'07#'0)*#+,-.' *=)-]10+)0#.6' •! ^2+'#)$7'0)*#+,-.'*#+,2;'N#E.EM'Z' <##G1OM'$2-1,;#+')';21#'+#;9$%2-' 2H'X_`' •! I20')=='*16$7,)0+,$';+9.1'$)-'>#' +#;9$#;',-'X_`';#$+#4#-01' •! (7#'0)*#+,-.'10+)0#.6'-##;1'>#' 1=2<' •! (7#'$2-$9++#-0'91#'2H'-)09+)=' 7#)=07'*+2;9$01'7#=*1'02'#)1#' <,07;+)<)='164*0241'a')11,10'<,07' 2-.2,-.'10)>,=,06'V'124#'91#H9=' 0+#)04#-01',-$=9;#'4#=)02-,-M' -,)$,-)4,;#M'bADAM'3P07#)-,-#M'cP T(5M'+72;,2=)'+21#)'#Y0+)$0M')-;' $24>,-)%2-1'2H'>20)-,$)='#Y0+)$01' '

/0#*'dE'B2449-,$)%2-'

•! B2++#1*2-;',-'<+,%-.'

02'07#'*+#1$+,>,-.' $=,-,$,)-'N-2+4)==6M' 07#'*)%#-0C1'H)4,=6' ;2$02+'2+'*16$7,)0+,10O'

/0#*'cE'e4*=#4#-%-.'07#' *=)-' •! J,%.)%-.'H)$02+1@' –!

–!

–!

–!

–!

–!

–!

–!

–!

–!

S#.9=)+'$29-1#=,-.' /0+2-.'12$,)='-#0<2+G' S#.9=)+'#Y#+$,1#' !)%-.')'7,.7'*+20#,-')-;'=2<' $)+>276;+)0#';,#0' 3,4,%-.'2+')>10),-,-.'H+24' $)"#,-#M')=$272=M')-;'+#$+#)%2-)=' ;+9.1' f9)=,06'1=##*' 5)%#-0',-1,.70' 5+2;9$%&#';),=6'+29%-#' (2=#+)>=#'<,07;+)<)='164*0241' S#.9=)+'*)%#-0P$=,-,$,)-' $2449-,$)%2-'

93

2

3/24/14 Effective Tapering Strategies to Limit Drug Withdrawal and Destabilization: A Clinician’s Perspective

Jonathan Prousky, ND

B24*=#Y'B)1#1' •! I2-#'2H'07#'*)%#-01',-' 07,1')-)=61,1'<#+#'2-' 42+#'07)-'Z'*16$7,)0+,$' ;+9.1')0'07#'%4#'2H'07#,+' ,-,%)='#&)=9)%2-' •! :7#-'*)%#-01')+#'2-' $24*=#Y'*16$7,)0+,$';+9.' $24>,-)%2-1M',0',1'49$7' 42+#';,L$9=0'02'0)*#+' 07#4'2"'

B2-$=91,2-'

5210P0)*#+,-.'H),=9+#1'

•!

•!

•!

•!

94

e0',1'#Y0+#4#=6';,L$9=0'02'*+#;,$0'<7,$7' *)%#-01'<,=='>#'19$$#11H9=',-'0)*#+,-.'2"' *16$7,)0+,$';+9.1'H2==2<,-.'124#'*#+,2;'2H' *+2=2-.#;'#Y*219+#'' 5)%#-01'-##;'02'>#')<)+#'2H'07#'+,1G1' ,-&2=&#;M')1'<#==')1'07#'>#-#g01' 5)%#-01'4910'7)&#')'$#+0),-'=#&#='2H'+#);,-#11M' $2-g;#-$#M')-;')<)+#-#11'12'07)0'07#'*+2$#11' 4,.70'h2<'42+#'2+'=#11'9-#&#-i9==6')1'07#' *16$7,)0+,$';+9.',1'0)*#+#;'' ()*#+,-.'19$$#11H9==6',1')$7,#&)>=#')-;' +#j9,+#1')'$22+;,-)0#;'#"2+0')-;'+#129+$#1' 07)0',-$=9;#'07#'k9;,$,291'91#'2H' 2+07242=#$9=)+'19>10)-$#1M'>20)-,$)=' 4#;,$,-)='#Y0+)$01M')'1=2<'0)*#+,-.'*=)-M' G-2<=#;.#'2H'*7)+4)$2G,-#%$1M'$=21#' $=,-,$,)-P*)%#-0'$2449-,$)%2-M')-;')' H9=124#'9-;#+10)-;,-.'2H'07#'*20#-%)=' +#)12-1'H2+'0)*#+,-.'19$$#11')-;'H),=9+#''

3

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

95

1!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

96

2!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

97

3!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

98

4!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

99

5!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

100

6!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

101

7!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

102

8!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

103

9!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

104

10!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

105

11!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

106

12!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

107

13!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

108

14!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

109

15!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

110

16!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

111

17!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

112

18!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

3/25/14!

Paul Demeda, CNP

113

19!

Controversies in Nutrition - High-Dose EPA and DHA: Are We Missing Something?

Paul Demeda, CNP

114

The Aging Brain: Influences of in Utero and Early Childhood !"#$"%&' Nutrition on Later Neurocognition Aileen Burford-Mason, PhD C5=0->8.'1.:'B*D*.>1# ()*'+,-.,'/01-.2''

•! EFG'H#I%#J'*7>D1=*7'=)1='K80;:K-:*'!$LM'D-;;-8.'

N*8N;*';-O*'K-=)':*D*.>1'

3.45*.6*7'89'!"#$%&'(#1.:'*10;<'6)-;:)88:'' .5=0->8.'8.';1=*0'.*50868,.->8.' ' +-;**.'/50980:?@178.'A)B'

–! +;P)*-D*0Q7':-7*17*'H+BJ'-7'=)*'D87='68DD8.'980D'

•! C5=0->8.'1.:';-9*7=<;*'916=807'D8:-9<'0-7RS'-.6;L'

–! E*-,)='68.=08;')*+,-#,$"#../#01123#441)521678#.4917# –! !'-.=1R*7'89'905-=7'1.:'O*,*=1T;*7S'91U<'V7)SH.8='90-*:J' 1.:'8D*,1?!'0-6)'8-;7'):$''#;&'("%(<#;&'!=%'#>&?-#01.03#01.08#

'

@091A07##

Orthomolecular Medicine Today Vancouver, April 25–27, 2014

–! !'-.=1R*7'89'1.>8W-:1.=7');&"&?#B$%'-#01.63@)0784A0#7'' –! !/?O-=1D-.7'1.:'")8D86<7=*-.*'),#CDE?!(<#CD='F=G(<-#

X-7-.,'(-:*2'()*'3DN16='89'B*D*.>1'8.'

Y1.1:-1.'Z86-*=<''

X-7-.,'(-:*2'()*'3DN16='89'B*D*.>1'8.'

Y1.1:-1.'Z86-*=<#

01.6392).78.2H047#

DIJ8KKL&'!=%'!G'&?&='GD-F&M!G!"&-M=<-G=K'!?!"LNOM&-D%F#

•! ()*'+;P)*-D*0[7'Z86-*=<'89'Y1.1:1'K10.7'89'1' ,08K-.,':*D*.>1'*N-:*D-6'' –! E-;;'8O*0K)*;D')*1;=)610*'1.:':*O17=1=*'=)*' Y1.1:-1.'*68.8D<'-.'8.*',*.*01>8.'

–! Y500*.=;<'.8'*\*6>O*'=0*1=D*.=7'

•! A0*O*.=1>O*'D*1750*7'10*'0*68DD*.:*:'

#

–! $I]'-.60*17*'-.'*W*06-7*' –! A08,01DD*7'=8'N08D8=*')*1;=)<':-*='1.:';-9*7=<;*' 6)8-6*7'

'

()*'/10R*0'F<N8=)*7-7''

X-7-.,'(-:*2'()*'3DN16=' 89'B*D*.>1'-.'Y1.1:1' U<VD&!F&'W?#X(G!&%E#(Q## :="=M=#01.1#

()*'/10R*0'F<N8=)*7-7''

'^'1')-7=80-61;'N*07N*6>O*'^'#

^'N0889'89'N0-.6-N;*'^''#

•! A0889'89'N0-.6-N;*'68D*7'908D'7=5:<-.,'T-0=)' 0*680:7'89'=)87*'!"#$%&'(#:50-.,'91D-.*7' HZK*:*.S'F8;;1.:J'1.:'K10>D*'HEE#J'

•! %_$I72'`*.*01;;<'T*;-*O*:'=)1='=)*'9*=57'K17' N08=*6=*:'908D'.5=0->8.1;')10D' •! ()*'@8=)*0'K85;:'N1<'=)*'.5=0->8.1;'N0-6*'89'=)*' N0*,.1.6<a'010*;<'=)*'6)-;:' •!

#P*E#Q='/#%D&#F(?%## #&R&GOS&#!?#%D&## #J<="#%(#J'(F(%&## #D&=<%DE#M!&%#="M## #<!Q&?%E<&#GD(!G&?## #%(#M&<=E#M&F&"O=# #("?&%-T##

–! Z=5:-*7'1;78'7**R'*O-:*.6*'980'=01.7?,*.*01>8.1;' *\*6=7'

%__I72'B1O-:'/10R*0'@BS'A)B'N08N87*7'=)1=' D1=*0.1;':-*=7'5.T1;1.6*:'-.'D1608.5=0-*.=7'80' :*V6-*.='-.'D-608.5=0-*.=7'

•! /-0=)'K*-,)='57*:'17'1'75008,1=*'980'!"#$%&'(# D1;.5=0->8.'

•! E-;;'91-;'=8'D1=6)'9*=1;'.5=0-*.=':*D1.:7S'1.:'7*=' =)*'7=1,*'980'6)08.-6':-7*17*'-.'1:5;=';-9*'

–! b80'D87='1O1-;1T;*'7=5:-*7S'=)*0*'10*'9*K':-0*6=' D*1750*7'89'16=51;'D1=*0.1;'.5=0-*.='-.=1R*7'

115

%'

The Aging Brain: Influences of in Utero and Early Childhood!"#$"%&' Nutrition on Later Neurocognition Aileen Burford-Mason, PhD ()*'F*0d80:7)-0*'Y8)80='

c=)*;'@10,10*='/50.7-:*'

%_%%?%_&g#

•! 3.'=)*'*10;<'#I=)'Y'=)*0*'K17' K-:*7N0*1:'68.6*0.'1T85='=)*' N)<7-61;':*=*0-801>8.'89'=)*'/0->7)' N*8N;*' •! c=)*;'@10,10*='/50.7-:*'K17' 1NN8-.=*:'F*0d80:7)-0*Q7'V07='Y)-*9' F*1;=)'e-7-=80'1.:'f1:<'3.7N*6=80'89' @-:K-O*7''

•! +'D-:K-9*'1U*.:*:'1;;'K8D*.':50-.,'6)-;:T-0=)'' –! 0*680:*:'=)*'T-0=)'K*-,)='8.'1'610:'

•! +')*1;=)'O-7-=80'K*.='=8'*16)'T1T<Q7')8D*' =)085,)85='-=7'-.91.6<'' –! X*680:*:'-;;.*77*7S':*O*;8ND*.=S'1.:'D*=)8:'89' 9**:-.,L'/1T<'K17'0*?K*-,)*:'1='%'<*10'89'1,*''

•! 3.980D1>8.'K17'=01.760-T*:'-.=8';*:,*07'1='=)*' F*0d80:7)-0*'685.=<'8h6*''

–! 6)10,*:'K-=)'-DN08O-.,'6)-;:0*.7[' )*1;=)'-.'F*0d80:7)-0*'

Extract from the Hertfordshire ledgers kept by midwives from 1911 – 1948

()*'F*0d80:7)-0*'Y8)80='(8:1<'# •! %$SIII''75Ti*6=7'T80.'-.'F*0d80:7)-0*'T*980*'%_&I' 1.:'7>;;'6500*.=;<';-O-.,'=)*0*'' –! X*605-=*:'980'8.?,8-.,'0*7*106)'

•! b-.:-.,7'78'9102'C*KT80.'=*0D'-.91.='j'$;T7S'80'K)8' ,1-.*:'K*-,)='7;8K;<')1:'!'0-7R'89';1=*0';-9*' –! YeBS'3.75;-.'X*7-7=1.6*S'(<N*'33'B-1T*=*7'' –! G7=*8N8087-7'1.:'71068N*.-1'

•! (8':1=*S'=88'9*K'75Ti*6=7')1O*':*O*;8N*:':*D*.>1'=8' :01K'68.6;57-8.7'

3k'-.'Y)-;:)88:'1.:'Y8,.->8.''

-.'G;:'+,*'

C5=0->8.'-.'A0*,.1.6<'1.:'G\7N0-.,'3k'

•! F-,)*0'6)-;:)88:'3k'.8K';-.R*:'=8'N0*7*0O1>8.'89' 680>61;'=)-6R.*77'-.'8;:'1,*')+(<#C?EGD!=%'E-#01.4#,$"#6-##

•! l.71=501=*:'91U<'16-:7'H*7NL'BF+J'17786-1=*:'K-=)'"' 3k'1='g<*107')UF#,#:<!"#B$%'-#01.4#[&G3@A)978.252HA07# •! 38:-.*':*V6-*.6<'0*75;=7'-.'"'O*0T1;'3k'1.:'0*1:-.,' 7680*7'1='g?_'<07')YS!M#*=?&M#B$'?-#01.4/#[&G#.0-#YJ$Z#=D&=M#(Q#

YJ$Z#=D&=M#(Q#J'!"%7#

•! Y8,.->O*''1T-;-=<'1='1,*'%%<*107'61.'N0*:-6=';1=*';-9*' 68,.->O*'1T-;-=<')B&$'(Z!(<#UL!"L-#01.4#[&G346).0780561H57#

J'!"%7#

–! c10;<?;-9*'3k'D8:*01=*7';1=*0';-9*':*O*;8ND*.='89' 680>61;'K)-=*'D1U*0')<N*0-.=*.7->*7'HE@FJ' –! 3.60*17*:'.5DT*07'89''E@F7'10*'1'0-7R'980':*D*.>1#

•! F-,)')8D86<7=*-.*'H"/?O-=1D-.7J';-.R*:'=8' N0*,.1.6<'68DN;-61>8.7'1.:'N880'68,.->8.'-.'

6)-;:)88:'):<!"#:D&F#\=Z#+&M-#0112364).178.120H57#

116

#'

The Aging Brain: Influences of in Utero and Early Childhood !"#$"%&' Nutrition on Later Neurocognition Aileen Burford-Mason, PhD ' ' @-;:'-8:-.*':*V6-*.6<':50-.,'N0*,.1.6<'-7'17786-1=*:'K-=)' 0*:56*:'*:561>8.1;'85=68D*7'-.'=)*'8\7N0-.,2'_?<*10' 98;;8K?5N'89'=)*',*7=1>8.1;'-8:-.*'68)80=L'' ]E"&?#^\#&%#=<-#,#:<!"#Y"M(G'!"(<#+&%=Z-#01.43@A)278.@26H90L''

38:-.*'68.=*.='89'N0*.1=1;'D5;>O-=1D-.7'-.'=)*' l.-=*:'Z=1=*7# \&$"L#U+#&%#=<-#B#Y"L<#,#+&M-#011@3491)@78@4@H61#

•! Z=5:<2'37'D-;:'-8:-.*':*V6-*.6<'-.'N0*,.1.6<'Hl3' m%$I'n,"fJ'17786-1=*:'K-=)';8K*0'3ko'' •! X*75;=72'*O*.'D-;:'-8:-.*':*V6-*.6<':50-.,' N0*,.1.6<'61.')1O*';8.,?=*0D'1:O*07*'-DN16=7' 8.'9*=1;'.*50868,.->8.'

'p_?!"L#%D&#`"%&'"&%/#a&#!M&"Ob&M#.05#"("H J'&?G'!JO("#="M#@9#J'&?G'!JO("#J'&"=%=<# F$<OS!%=F!"?#G$''&"%<E#F='c&%&M#!"#%D&# _"!%&M#X%=%&?-#dQ#%D&?&#F$<OS!%=F!"?/#..6# )A5#"("HJ'&?G'!JO("#="M#05#J'&?G'!JO("7# G("%=!"&M#!(M!"&T#

–! ()*7*'*\*6=7'10*'.8='1D*;-801=*:'T<'-8:-.*' 75h6-*.6<':50-.,'6)-;:)88:'

' '

@1=*0.1;'O-=1D-.'Y':*V6-*.6<':50-.,'N0*,.1.6<' N*07-7=*.=;<'-DN1-07')-NN861DN1;'.*508,*.*7-7'-.'

8\7N0-.,'89',5-.*1'N-,7L'

308.S'T01-.':*O*;8ND*.='1.:';1=*0' .*50868,.->8.'

#gS&M&"HBEZ('L#C#&%#=<-#C\(X#d"&-#01.035).178&6A6AA-#!

•! C*8.1=1;'-08.':*V6-*.6<'1;=*07'*WN0*77-8.'89',*.*7' -DN;-61=*:'-.'+;P)*-D*0[7':-7*17*')*'=!"#>&?&='GD#

# •! `5-.*1'N-,7'10*'1NN08N0-1=*'1.-D1;'D8:*;7'=8' 7=5:<'O-=1D-.'Y'0*r5-0*D*.=7'

011A3.045852eA47#

–! ;-R*')5D1.7'=)*<'61..8='7<.=)*7-P*'O-=1D-.'Y'T5=' :*N*.:'8.':-*=10<'-.=1R*'

•! 308.'-7'60->61;'980'D<*;-.1>8.2'"':-*=10<';*O*;7';*1:' =8')<N8D<*;-.1>8.');<!=#.@@93.5)078A4e@47'

•! Z=5:<2'@10,-.1;'N0*.1=1;'e-='Y':*V6-*.6<';*:'=8' 0*:56*:')-NN861DN1;'D*D80<'95.6>8.'

–! @<*;-.'D1<'-.60*17*'=)*'T01-.[7'0*7-;-*.6*'=8' .*508N1=)8;8,<';1=*0'-.';-9*S'T887>.,'q68,.->O*' 0*7*0O*[')YfJ&'%#>&S!&a#(Q#B&$'(%D&'=J&$OG?#01.03.0)97890@H94.7#

–! '"')-NN861DN1;'O8;5D*'HAmILII%Ja'!I]'9*K*0'.*508.7' –! =)-7'K17'.8='1;;*O-1=*:'T<'N87=.1=1;'e-='Y'0*N;*>8.''

' '

Serum 25-hydroxy D intake as a function of vitamin D intake. ;='<="M#:h#&%#=<-#U"OG="G&'#>&?#01..34.8#915H..#'

()*'*\*6=7'89'O-=1D-.'B'8.'T01-.':*O*;8ND*.=' 1.:'1:5;='T01-.'95.6>8.' ^&?ZE#,C#&%#=<-#+(<#:&<<#Y"M(G'!"(<#01..3465).H078.0.H5#

'

' •! X*O-*K2'O-=1D-.'B'-7'*77*.>1;'980'T01-.' :*O*;8ND*.='1.:'95.6>8.-.,' –! B*V6-*.6-*7'-.'5=*08'1.:'-.'*10;<'6)-;:)88:';-.R*:'=8' 76)-P8N)0*.-1'1.:'15>7D#

•! C**:*:'980'=)*'T-87<.=)*7-7'89'7*08=8.-.S' :8N1D-.*S'.80?1:0*.1;-.*'1.:'1:0*.1;-.*# •! B*V6-*.6-*7'-.'1:5;=)88:';-.R*:'=8'' –! B*N0*77-8.''

–! A10R-.78.[7'B-7*17*' –! +;P)*-D*0Q7':-7*17*' –! Y8,.->O*':*6;-.*'

117

!'

The Aging Brain: Influences of in Utero and Early Childhood !"#$"%&' Nutrition on Later Neurocognition Aileen Burford-Mason, PhD

' ' ' B-*=10<';-N-:7'10*':-\*0*.>1;;<'17786-1=*:'K-=)' )-NN861DN1;?:*N*.:*.='0*;1>8.1;'D*D80<'-.'

N0*N5T*76*.='6)-;:0*.L' *=EF#:\#&%#=<-#UF#,#:<!"#B$%'-#01.6#h&Z#.0-#iYJ$Z#=D&=M#(Q#J'!"%j' '

Omega-3 fatty acid deficiencies in neurodevelopment, aggression and autonomic dysregulation: opportunities for intervention Hibbeln JR et al. Int Rev Psychiatry. 2006;18(2):107-18

•! X*O-*K2'B*V6-*.6<'89'BF+'1.:'cA+'-.'5=*08'D1<' ;8K*0'7*08=8.-.';*O*;7'1='60->61;'N*0-8:7'89'T01-.' :*O*;8ND*.=''

•! Z=5:<2'B8'E*7=*0.':-*=7'-.45*.6*'6)-;:0*.[7' ' )-NN861DN1;?:*N*.:*.='D*D80<o' –! A10>6-N1.=7'H.'s'$#J'1,*:'t?_'<*107' –! `-O*.'b88:?b0*r5*.6<'k5*7>8..1-0*'1.:' 68DN;*=*:'D*D80<'=17R7'

–! D1.-9*7=7'-.'1:5;=)88:'17')*-,)=*.*:'0*7N8.7*'=8' 7=0*77S':*60*17*:')*10='01=*'O10-1T-;-=<'1.:''!/A'

•! Y8.6;57-8.2'GN>D-P-.,'8D*,1?!'cb+'-.=1R*7' :50-.,'*10;<':*O*;8ND*.='1.:'1:5;=)88:'D1<' )*;N'N0*O*.=';1=*0'1,,0*77-8.'1.:')87>;-=<''

•! X*75;=72'uO*'17786-1>8.'T*=K**.'D*D80<'1.:' -.=1R*'89'8D*,1'!'91=7' –! C*,1>O*'17786-1>8.'K-=)'71=501=*:'91=7'1.:'75,10'

Choline: needed for normal development of memory.

Choline

Zeisel SH. J Am Coll Nutr 2000 Oct; 19(5Suppl):528S-531S

•! A0*650780'980'16*=<;6)8;-.*'H1LRL1'=)*'T01-.[7'D*D80<' D1.1,*0'

''''pgD&#F(%D&'W?#M!&%='E#GD(<!"&#M$'!"L#=#G'!OG=<#J&'!(M#!"#

Z'=!"#M&S&<(JF&"%#(Q#D&'#!"Q="%#!"k$&"G&?#%D&#'=%&#(Q# Z!'%D#="M#M&=%D#(Q#"&'S&#G&<<?l---l-#gD&?&#GD="L&?#='&# ?(#!FJ('%="%#%D=%#a&#G="#J!Gc#($%#%D&#L'($J?#(Q# ="!F=<?#aD(?&#F(%D&'?#D=M#&f%'=#GD(<!"&#&S&"#aD&"# %D&?&#="!F=<?#='&#&<M&'<E-#

•! 3.'1.-D1;7S'6)8;-.*'75NN;*D*.=7'-.'N0*,.1.6<'0*75;='-.' ;-9*;8.,'D*D80<'*.)1.6*D*.=''

•! A0*650780'980'N)87N)1>:<;6)8;-.*'.**:*:'980''6*;;' D*DT01.*7' •! @1=*0.1;'6)8;-.*':*V6-*.6<'-.60*17*7'=)*'0-7R'89' .*501;'=5T*':*9*6=7')UF#,#YJ!M&F!(<#01163.918.10H@7#

#

#

#gD$?/#F&F('E#Q$"GO("#!"#%D&#=L&M#'=%#!?/#!"#J='%/# M&%&'F!"&M#ZE#aD=%#%D&#F(%D&'#=%&-T#'

•! @1=*0.1;'0*7*0O*7'10*':*N;*=*:':50-.,'N0*,.1.6<' 1.:';16=1>8.'

'

Diet and Choline ''''“……..when there isn't enough food, the body

•! (K8'91U<'988:7'^'*,,7'1.:';-O*0'^'=01:->8.1;;<' N08O-:*:'D87='89'850':-*=10<'6)8;-.*'-.=1R*'-.' c508N*'1.:'C80=)'+D*0-61''

has to make a decision about how to invest the limited foodstuffs available. Survival comes first. Growth comes second. In this nutritional triage, the body seems obliged to rank learning last. Better to be stupid and alive than smart and dead.”

–! 3.'+7-1.':-*=7'6)8;-.*'-7'1;78'8T=1-.*:'908D'78<'^'*7NL' 95;;'91='=895'

•! X*6*.='7=5:-*7'7)8K'=)1='N0*,.1.6<',0*1=;<' -.60*17*7'9*=1;':*D1.:7'980'6)8;-.*#

' ' Y10;'Z1,1.L!"#$%&'()!*!+,%!-'$,!$.!/!0.&%!-&.12%&.314!"%11!

5'67%&.31!/8%&#('L'' C='=M&#+=L=V!"&/#+='GD#9/#.@@6-# # # #

–! Y500*.=':-*=10<'-.=1R*'D1<'T*'=88';8K'=8'D**='=)*' :*D1.:7'89'=)*':*O*;8N-.,'9*=57')UF#,#:<!"#B$%'-#01.4#[&G3 @A)978.62@H957'

118

&'

The Aging Brain: Influences of in Utero and Early Childhood !"#$"%&' Nutrition on Later Neurocognition Aileen Burford-Mason, PhD ' c;*O1=*:'D1=*0.1;'680>78;';*O*;7':50-.,'N0*,.1.6<'10*' 17786-1=*:'K-=)'0*:56*:'6)-;:)88:'3k''

Vitamin C, Cortisol and Stress' '

\&m!""#^n#&%#=<-#`"%#,#YJ!M&F!(<-#011@34A)978.511H.1-##

•! @87='1.-D1;7'D1R*'O-=1D-.'Y'*.:8,*.857;<' –! Z56)'1.-D1;7'01N-:;<'-.60*17*'=)*-0'O-=1D-.'Y'85=N5=' 5.:*0'7=0*77'^'$?#I'98;:':*N*.:-.,'8.'7N*6-*7')+!<%("#^-#

•! Z=5:<2'f88R*:'980';-.R7'T*=K**.'D1=*0.1;'680>78;''-.' !0:'=0-D*7=*0'1.:'3k'-.'8\7N0-.,'1='1,*'t' •! X*75;=72'@1=*0.1;'680>78;';*O*;7'K*0*'.*,1>O*;<' 0*;1=*:'=8'95;;?761;*'3k'

:(FJ#*!(GD&F#CDE?!(<#U#+(<#`"%&L'#CDE?!(<#0114349).78#65H2@#7'

•! Z=5:<2'F*1;=)<')5D1.7'75Ti*6=*:'=8'165=*'N7<6)8;8,-61;' 7=0*77'T*980*'1.:'1v*0'%&':1<7'89'O-=1D-.'Y'H%,' 757=1-.*:?0*;*17*'>:J'

–! ()-7'*\*6=7'K17':0-O*.'T<')-,)*0'O*0T1;'3k'7680*7'

•! E-=)-.'7-T;-.,'N1-07S'=)*')-,)*7='r5-.>;*'89'680>78;' *WN8750*'K17'17786-1=*:'K-=)'O*0T1;'3k'7680*7'$L$' N8-.=7';8K*0'

–! +v*0'O-=1D-.'Y'=)*<')1:'"'/AS'"'71;-O10<'680>78;')*'(ME#X#&%# =<-#C?EGD(JD='F=G(<(LE#)*&'<7-#01103.2@)4784.@H067#

Rates of vitamin C synthesis in mammals (mg/kg/day)

Recommended Daily Allowances for Vitamin C Man-L S. Yew. PNAS 1973;70(4) 969-972

''

•! Z=5:<2'3DD1=50*'`5-.*1'N-,7'9*:';8KS'-.=*0D*:-1=*' 1.:')-,)';*O*;7'89'O-=1D-.'Y'' •! `-O*.'750,*0<'1.:'=)*.'*O1;51=*:'980'' –! 0*68O*0<'>D*'1v*0'1.*7=)*7-1a'K85.:')*1;-.,'1.:' ,08K=)'01=*7'

•! ()*<'.**:*:'%L$'D,"R,":1<'=8'N0*O*.='7650O<'H&I]' D80*'=)1.'=)*'XB+'980')5D1.7J' –! %M'D,"R,":1<'980'8N>D1;',08K=)'H%I?98;:'-.60*17*J' –! $I'D,"R,":1<'980'0*68O*0<'908D'750,*0<'H!'!!?98;:J'

Species

Low

High (stress)

Goat Rat Mouse Rabbit Dog RDA for Humans

33 39 34 9 5 0.9

190 199 275 226 40 No value given

Levine M. New concepts in the biology and biochemistry of ascorbic acid. N Eng J Med 1986:892-902

c\*6=7'89'T*-.,'T80.'7D1;;'980',*7=1>8.1;'1,*'8.';8.,? =*0D'-.=*;;*6=51;'N*0980D1.6*!

Magnesium and Pregnancy

\$"ML'&"#Y+#&%#=<-#*&?%#C'=G%#>&?#:<!"#Y"M(G'!"(<#+&%=Z-#011A300)478655HAAL'

•! b*=1;':*D1.:7'980'@,':50-.,'N0*,.1.6<' ,*.*01;;<'*W6**:'75NN;<''

•! X*O-*K2'/*-.,'T80.'7D1;;'980',*7=1>8.1;'1,*'HZ`+J' -.60*17*7'0-7R'89'';8K*0'3kS'T*)1O-8501;'N08T;*D7S' 1.:'N880'161:*D-6'N*0980D1.6*'

–! A0*,.1.6<'7)85;:'T*'68.7-:*0*:'1'68.:->8.'89' qN)<7-8;8,-61;')<N8D1,.*7*D-1[)+&M#XG!#+("!%-#011.35)078

–! T0*17='9**:-.,'980'#'MD'91O8501T;<'D8:-V*7'=)*7*' *\*6=7'''

440H617#

•! b5.6>8.1;'D10R*07'89'D1,.*7-5D':*V6-*.6<' 68DD8.'-.'N0*,.1.6<'-.6;5:*'

•! C5=0-*.=?*.0-6)*:'980D5;17')1O*'.8'1:O1.=1,*7' K)*.'-='68D*7'=8'-.=*;;*6=51;':*O*;8ND*.='

–! C86=50.1;';*,'601DN7S'-.60*17*:'T;88:'N0*7750*S' 7)80=.*77'89'T0*1=)"K)**P-.,S'90*r5*.6<'89' 50-.1>8.S'68.7>N1>8.''

–! 3.60*17*7'0-7R'89'01N-:'K*-,)=',1-.'1.:'*O*.=51;' 8T*7-=<'

•! Z*O*0*':*V6-*.6<'61.';*1:'=8'N0*?*6;1DN7-1'

119

$'

The Aging Brain: Influences of in Utero and Early Childhood !"#$"%&' Nutrition on Later Neurocognition Aileen Burford-Mason, PhD Durham Dyspraxia Trial

Durham Educational Authority, Durham, UK# “The response has been very encouraging. In very broad terms, we saw that up to 40 per cent of children on the trial showed dramatic improvements.

•! B<7N01W-12'B-h65;=<':01K-.,S'K0->.,S'T5U8.-.,' 6;8=)*7'80'8=)*0'=17R7'.**:-.,'V.*'D8=80'7R-;;7' –! Gv*.'68?*W-7=7'K-=)'+BFB'1.:':<7;*W-1'

•! %II'6)-;:0*.'1='%#'76)88;7'-.'B50)1D'685.=<',-O*.' *-=)*0'V7)'8-;'80'N;16*T8'61N75;*7'HXY(J''

In some individual cases, we saw reading age gains of between 18 months and four years, and attention gains of as much as 400 percent.”

–! GO*0'%'<0'%#SIII'177*77D*.=7'K*0*'5.:*0=1R*.'

•! (0-1;';88R*:'1='B<7N01W-1'1.:'@8=80'7R-;;7S'T5='=)*0*' K*0*'1;78'95;;'177*77D*.=7'980'B<7;*W-1'1.:'+BFB''

Dr Madeleine Portwood, Senior Educational Psychologist, Durham County'

Supplemental nutrients before and during pregnancy (1)

+BFB'C8KS'B*D*.>1'f1=*0o# •! F<N8=)*7-72'@1.<'.*5086)*D-61;'1.8D1;-*7'7**.'-.' +BFB'8O*0;1N'K-=)'1;=*01>8.7'7**.'-.';1=*?;-9*':*D*.>17'

•! @5;>O-=1D-.2')-,)*0'/?O-=1D-.'68.=*.='H1;;'/' O-=1D-.7S'.8='i57='98;-6'16-:J'

):$''#C?EGD!=%'E#>&J-#01.0#dG%3.6)278220H91#7#

–! 3.6;5:*7'+;P)*-D*0[7S':*D*.>1'K-=)'f*K<'T8:-*7S'1.:' 908.=8=*DN801;':*D*.>1'

–! A0*9*01T;*'=8')1O*'98;-6'16-:'-.'68*.P<D*'980D' –! +::->8.1;'/%#'H75T;-.,51;'D*=)<;68T1;1D-.J'

•! (-D*?0*;*17*:'O-=1D-.'Y'^'%,'T-:'

•! Y8)80='Z=5:<'b-.:-.,72'+:5;=7'K-=)'1')-7=80<'89'+BFB' )1O*'W!'>D*7'=)*'0-7R'89':*O*;8N-.,'f*K<'T8:<':*D*.>1' ;1=*0'-.';-9*')Y$'#,#B&$'(<-#01..3.A).785AHA67'

–! 3.60*17*'T<'%,":1<'N*0'=0-D*7=*0'

•! b-7)'8-;'80'1;,1;'75NN;*D*.='980'O*,*=10-1.7'

–! C8';-.R'7**.'=8'+;P)*-D*0[7'80'D-;:'68,.->O*'-DN1-0D*.=''

Supplemental nutrients before and during pregnancy (2) PgD&#&S!M&"G&#!?#G<&='#%D=%#!"=M&o$=%&# F=L"&?!$F#!"%=c&#!?#G(FF("#M$'!"L# J'&L"="GE#="M#%D=%#%D&#J<=?F=#<&S&<?#(Q# F=L"&?!$F#%&"M#%(#Q=<</#&?J&G!=<<E#M$'!"L#%D&# b'?%#="M#%D!'M#%'!F&?%&'?#(Q#J'&L"="GE-T

•! +::->8.1;'6)8;-.*2'c7N*6-1;;<'-9'.8='*1>.,'*,,7' –! '`-O*.'17'N)87N)1>:<;6)8;-.*' –! #?!',*;'61N7's'%?#'*,,'<8;R7' •! e-=1D-.'B2'Y)*6R'#$?)<:08W<'B'-9'N877-T;*' –! D-.-D5D'#III'3l":1<a'&III'3l'719*'-.'N0*,.1.6<'1.:' N0*O*.=7'N0*=*0D';1T850'1.:'-.9*6>8.7'),#X%&'(!M# *!(GD&F#+(<#*!(<-#01.43.4984.4H017#

•! @1,.*7-5D2'%IID,'D1,.*7-5D',;<6-.1=*'T-:L'A0*9*01T;<S' -.60*17*',01:51;;<'=8'T8K*;'=8;*01.6*'

B0L'@-;:0*:'ZL'Z**;-,'@B'

120

M'

The Aging Brain: Influences of in Utero and Early Childhood !"#$"%&' Nutrition on Later Neurocognition Aileen Burford-Mason, PhD Dementia and Nutritional Deficiencies

Diet in Pregnancy •! F-,)'905-='1.:'O*,*=1T;*''

•! A08=*6>O*'*\*6=7'7**.'K-=)')-,)*0'N;17D1' ;*O*;7'89'/%S'/#S'/MS'98;1=*S'/%#S'YS'BS'cS'1.:' 8D*,1?!'91U<'16-:7')*(aF="#;\#&%#=<-#B&$'(<(LE#

–! @-.-D5D'g'7*0O-.,7a'1-D'980'%I?%#'

•! f8K',;<6*D-6';81:'

–! f8K'80'.8'75,10' –! +;;'7=106)*7'7)85;:'T*'K)8;*,01-.''

01.035A)67806.H@7'

•! +:*r51=*'#$?)<:08W<'B';*O*;7')*$&<<#,X#&%#=<-#,#

•! `88:'91=7'1='*16)'D*1;'

;&'("%(<#U#*!(<#XG!#+&M#XG!-#011@396)A78AAAH@27#

•! @-.*01;72'c7N*6-1;;<'-08.S'P-.6'1.:'D1,.*7-5D'

–! b1U<'V7)S'.5=7S'7**:7S'8;-O*'8-;'' –! 3'^'!'*,,7'1':1<'H80,1.-6S'90**?01.,*'80'8D*,1' !J''

)UF&?#*B#&%#=<-#+(<#U?J&G%?#+&M-#0112309)6H278494H5A7#

•! &?M'8P'N08=*-.'K-=)'*16)'D*1;'

@80*'=)1.'=)*'75D'89'-=7'N10=7o'C5=0->8.'-.' +;P)*-D*0Q7':-7*17*L''

Frontal Lobe Dementia

S("#U'"!F#:U#&%#=<-#B$%'!O("-#01.1#,$<HU$L309)5HA789@6H511#

•! ()*'N1>*.=2'b*D1;*a'Y15617-1.S'Mg'<07L' X*>0*:'=*16)*0''

•! X*O-*K2':-7657*7'-DN80=1.6*'89'D1;.5=0->8.'1.:' D-608.5=0-*.=':*V6-*.6-*7'-.'+;P)*-D*0Q7':-7*17*'1.:' 0*6*.='75NN;*D*.=1>8.'=0-1;7'

–! C8.?7D8R*0'S'.8.':0-.R*0'

•! f-9*?;8.,')-7=80<'89':*N0*77-8.'

•! @100-*:'

–! cO-:*.6*'=)1='D1;.5=0->8.S'8W-:1>O*'7=0*77S'1.:':*V6-=7'89' )8D86<7=*-.*?0*;1=*:'O-=1D-.7'10*'-.O8;O*:'-.'N1=)8,*.*7-7'

–! F1:')1:'=K8'6)-;:0*.'T80.'K-=)'7N-.1'T-V:1a'8.*' 750O-O*:' –! G.*'N)<7-61;;<'.80D1;'6)-;:'K-=)'6)08.-6' :*N0*77-8.'

•! +O1-;1T;*':1=1':8'.8='75NN80='75NN;*D*.=1>8.'89' -.:-O-:51;'D-608.5=0-*.=7'980'N0*O*.>8."=0*1=D*.='' –! F8K*O*0S'1NN0816)*7'K-=)'D5;>N;*'.5=0->8.1;'68DN8.*.=7' D-,)='T*'N08D-7-.,'

Diet and Lifestyle

Frontal Lobe Dementia •! X*=50.*:'=8'6;-.-6'-.'#II_L'Z**-.,'.*508;8,-7=' T*6157*'89'D*D80<'1.:'7N**6)'N08T;*D7' •! 'ZN**6)2'7;8KS')*7-=1.=L'Z=5U*0*:'78D*>D*7''

•! cW*06-7*2''A;1<*:'=*..-7':1-;<'980'N08;8.,*:' N*0-8:7### –! Pd"<E#a=E#%(#'&M$G&#?%'&??T#

–! Y85;:.[='PL&%#%D&#'!LD%#a('M#($%-T##Gv*.#57*:'K08.,' 80'5.0*;1=*:'K80:7S'D-7N08.85.6*:'K80:7# –! F1:'=8'7-DN;-9<'7N**6)L'l7*:'8.;<'P<!I<&#a('M?T#

•! B-*=#8#f-U;*'-.=*0*7='-.'988:'T5='7=1<*:'1K1<' 908D'i5.RL'Gv*.'7R-NN*:'D*1;7' •! Z5NN;*D*.=72'Z=10=*:'68DN0*)*.7-O*'0*,-D*' 89'75NN;*D*.=7'-.'@1<'%___'

•! /*)1O-8501;'6)1.,*72'1N1=)<S'0*7=;*77.*77S' -00-=1T-;-=<S'1,,0*77-8.S'9*;='75-6-:1;' •! Z>;;'N;1<-.,'=*..-7S'T5='685;:.[='98657'

–! /*.*V=*:'1='V07=S'T5='68DN;-1.6*'K17'N880' –! f87='=8'98;;8K?5N'-.'#II#'

–! +665016<'K*.=a'.8'*.*0,<L'Y85;:.[='N;1<'T0-:,*S' T*6157*'7)*'685;:.[='0*D*DT*0'=)*'610:7'

121

t'

The Aging Brain: Influences of in Utero and Early Childhood Nutrition on Later Neurocognition

!"#$"%&'

Aileen Burford-Mason, PhD Frontal Lobe Dementia

Frontal Lobe Dementia

•! B-1,.87-72''b08.=1;';8T*':*D*.>1'

•! A;1.2''/16R'8.'75NN;*D*.=7'17'80-,-.1;;<' 0*68DD*.:*:'H7-D-;10'=8'N0*,.1.6<'0*,-D*J'

–! Y('761.'7)8K*:',*.*01;-P*:'6*0*T01;'1=08N)<'' –! ZAcY('761.'7)8K*:'7*O*0*'908.=1;';8T*')<N8N*0957-8.'

–! '+::->8.1;'/?O-=1D-.7'H-.'68?*.P<D*'980DJ' –! '$D,'/%#'HD*=)<;68T1;1D-.J'

•! Z5NN;*D*.=72'Z>;;'86617-8.1;;<'=1R-.,'=)*D'T5='.8=' 80-,-.1;'0*68DD*.:1>8.7''

•! B-*=2''3.60*17*'O*,*=1T;*7'1.:'905-='Hg?%I'7*0O-.,7' 1':1<J'

–! C8'V7)'8-;S';-U;*'D1,.*7-5DS'#III'3l'O-=1D-.'B' –! /%#'=*7=*:2'%tgND8;"f'8.'%D,":1<'75T;-.,51;' D*=)<;68T1;1D-.'

–! 3.6;5:*')-,)'r51;-=<'N08=*-.'K-=)'*O*0<'D*1;a';8K' 7=106)S'.8'75,10'''

•! +::->8.1;'75NN;*D*.=7'=8'75NN80='D*D80<S' 7N**6)'1.:'K80:'0*61;;''

'

Stress, Speech and Dopamine e-='Y' @,uu'

•! B8N1D-.*'-7'-.O8;O*:'-.'7N**6)'

–! C**:*:'980'O*0T1;'45*.6<'1.:'K80:'0*61;;'

Nor adrenaline

Adrenaline

•! ()*'N0*650780'980':8N1D-.*'-7'=)*'.8.? *77*.>1;'1D-.8'16-:'=<087-.*'

e-='Y' @,uu'

–! 5.:*0'7=0*7795;'68.:->8.7'=<087-.*'T*68D*7' *77*.>1;'

Dopamine

•! B8N1D-.*'-7S'-.'=50.S'=)*'N0*650780'980'.80?

1:0*.1;-.*'

Tyrosine

–! C80?1:0*.1;-.*'-7'950=)*0'D*=1T8;-P*:'=8' 1:0*.1;-.*'

' +::->8.1;'Z5NN;*D*.=7#

e-='Y' @,uu'

'

+::->8.1;'Z5NN;*D*.=7'

•! (<087-.*2'X*r5-0*:'980':8N1D-.*'7<.=)*7-7' •! Y->68;-.*2'A0*650780'980'16*=<;6)8;-.*''0*r5-0*:' 980'D*D80<a'.*508N08=*6>O*a'*.)1.6*7'T01-.' :8N1D-.*')U""#B#p#UG=M#XG!-#01113@018440e4427'' •! f?=)*1.-.*2''1.'1D-.8'16-:'5.-r5*'=8'=*1L''

•! (<087-.*2'&W'MIID,'8.'K1R-.,S'*DN=<' 7=8D16)S'K1-='!I'D-.7'T*980*'*1>.,' –! #?!'*W=01'D-:?;1=*'1v*0.88.'H-9'.**:*:J'1.:' T*980*'1.<'7=0*7795;'*O*.=''

•! Y->68;-.*2'$IID,'T-:' •! f?=)*1.-.*2'#$ID,'-.'=)*'D80.-.,'1.:'T*980*' T*:'

–! +.-D1;7'75,,*7='-DN08O*D*.='-.';*10.-.,'1.:'D*D80<' H,#]&'Z#CD='F=G(%D&'-011939)0780.H417'' –! Y1;D-.,2'-.60*17*7'7*08=8.-.S':8N1D-.*S'`+/+#

–! 3.7=056=*:'=8'=1R*'1.'*W=01'61N75;*'17'.**:*:' :50-.,'=)*':1<'980'1.W-*=<'

122

g'

The Aging Brain: Influences of in Utero and Early Childhood !"#$"%&' Nutrition on Later Neurocognition Aileen Burford-Mason, PhD '

'

G5=68D*'

Y8.6;57-8.'

•! A1>*.='T*,1.'=8'-DN08O*'H.8'D*:-61>8.7J'''

•! C5=0->8.'-.'5=*08'*\*6=7'68,.->O*':*O*;8ND*.='

–! G.*'<*10'1v*0'7=10>.,'75NN;*D*.=7S'K17'=8;:'7)*'K17' p)-,)'95.6>8.-.,w'

•! 3.'=50.S')-,)*0'6)-;:)88:'3k'D1<'N08=*6='1,1-.7=' 68,.->O*':*6;-.*'-.'8;:'1,*'

•! /<'*10;<'#I%!'D*D80<'1.:'7N**6)'.80D1;' •! @1<'#I%!2'=*7=*:'1='/1<60*7='6;-.-6' #P+E#'&?$<%?#='&#Z&I&'#%D="#%D&E#a&'&#0#q#E&='?#=L(#="M#

•! (8'T*'*\*6>O*S':*D*.>1'N0*O*.>8.'N08,01D7' D57='98657'8.'.5=0->8.'=)085,)85='=)*';-9*7N1.'

•! C8='1;;'980D7'89':*D*.>1'0*4*6='-00*O*07-T;*' :*,*.*01>O*':-7*17*'

"(a#i%D&#M(G%('j#?=E?#`#M(#"(%#D=S&#Q'("%=<#<(Z&#M&F&"O=-# XD&#Q&&<?#FE#?J&&GD#J'(Z<&F?#a&'&#%D&#'&?$<%#(Q#E&='?#(Q# ?&S&'&#?%'&??T#

•! Z=1.:10:'80=)8D8;*65;10'1NN0816)*7'D1<'T*' *\*6>O*'-.'0*O*07-.,'78D*'*10;<':*D*.>17''

'

References Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. Whitmer RA1, Gunderson EP, BarrettConnor E, Quesenberry CP Jr, Yaffe K. BMJ. 2005 Jun 11;330(7504):1360 Nutrition and dementia. Coppedè F1, Bosco P, Fuso A, Troen AM. Curr Gerontol Geriatr Res. 2012;2012:926082 Nutritional contributions to dementia prevention: main issues on antioxidant micronutrients. Polidori MC1, Schulz RJ. Genes Nutr.

2014 Mar;9(2):382 Hyperhomocysteinemia as a risk factor for the neuronal system disorders. Petras M1, Tatarkova Z, Kovalska M, Mokra D, Dobrota D, Lehotsky J, Drgova A. J Physiol Pharmacol. 2014 Feb;65(1):15-23.

Rising Tide: The Impact of Dementia on Canadian Society . http://geriatricresearch.medicine.dal.ca/rising_tide.htm Childhood cognitive ability accounts for associations between cognitive ability and brain cortical thickness in old age. Karama S, et al.

Mol Psychiatry. 2013 Jun 4. [Epub ahead of print] Brain white matter damage in aging and cognitive ability in youth and older age. Valdés Hernández Mdel C et al. Neurobiol Aging. 2013 Dec;34(12):2740-7.

Maternal fatty acids in pregnancy, FADS polymorphisms, and child intelligence quotient at 8 y of age. Steer CD1, Lattka E, Koletzko B, Golding J, Hibbeln JR. Am J Clin Nutr. 2013 Dec;98(6):1575-82.

Children of mothers with iodine deficiency during pregnancy are more likely to have lower verbal IQ and reading scores at 8-9 years of age. Leung AM, Brent GA. Evid Based Nurs. 2013 Dec 12. [Epub ahead of print Homocysteine, folic acid and vitamin B12 in relation to pre- and postnatal health aspects. Obeid R1, Herrmann W. Clin Chem Lab Med. 2005;43(10):1052-7.

Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort. Hynes KL et al. J Clin Endocrinol Metab. 2013;98(5):1954-62.

Iodine content of prenatal multivitamins in the United States. Leung AM et al. N Engl J Med. 2009;360(9):939-40 Iron deficiency alters expression of genes implicated in Alzheimer disease pathogenesis. Carlson ES et al. Brain Res. (2008) Relationship of iron to oligodendrocytes and myelination. Connor JR et al. Glia. (1996) Ironing out neurodegeneration: is iron intake important during the teenage years? Thompson PM, Jahanshad N. Expert Rev Neurother.

2012 Jun;12(6):629-31.

Maternal vitamin C deficiency during pregnancy persistently impairs hippocampal neurogenesis in offspring of guinea pigs. TvedenNyborg P et al. PLoS One. 2012;7(10):e48488 The effects of vitamin D on brain development and adult brain function. Kesby JP et al. Mol Cell Endocrinol 2011;347(1-2):121-7 Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Garland CF1, French CB, Baggerly LL, Heaney RP. Anticancer Res. 2011 Feb;31(2):607-11.

Omega-3 fatty acid deficiencies in neurodevelopment, aggression and autonomic dysregulation: opportunities for intervention. Hibbeln JR1, Ferguson TA, Blasbalg TL. Int Rev Psychiatry. 2006 Apr;18(2):107-18.

Dietary lipids are differentially associated with hippocampal-dependent relational memory in prepubescent children. Baym CL et al. Am J Clin Nutr. 2014 Feb 12. [Epub ahead of print] Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Shaw GM1, Carmichael SL, Yang W, Selvin S, 123

_'

The Aging Brain: Influences of in Utero and Early Childhood Nutrition on Later Neurocognition Aileen Burford-Mason, PhD

References Schaffer DM. Am J Epidemiol. 2004;160(2):102-9.

Choline: needed for normal development of memory. Zeisel SH. J Am Coll Nutr 2000 Oct; 19(5Suppl):528S-531S Pregnancy alters choline dynamics: results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women. Yan J et al. Am J Clin Nutr. 2013 Dec;98(6):1459-67.

Literacy – The Path to A More Prosperous, Less Dangerous America. Carl Sagan. Parade Magazine, March 6, 1994 Elevated maternal cortisol levels during pregnancy are associated with reduced childhood IQ LeWinn KZ et al. Int J Epidemiol. 2009;38(6):1700-10.

Micronutrient intakes of wild primates: are humans different? Milton K. Comp Biochem Physiol A Mol Integr Physiol. 2003 Sep;136(1):47-59.

A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress. Brody S et al. Psychopharmacology (Berl). 2002;159(3):319-24 Recommended Daily Allowances for Vitamin C. Man-L S. Yew. PNAS 1973;70(4) 969-972 New concepts in the biology and biochemistry of ascorbic acid. Levine M. N Eng J Med 1986:892-902 New data on toxic metal intoxication (Cd, Pb, and Hg in particular) and Mg status during pregnancy. Semczuk M1, Semczuk-Sikora A. Med Sci Monit. 2001 Mar-Apr;7(2):332-40.

Effects of being born small for gestational age on long-term intellectual performance Lundgren EM et al. Best Pract Res Clin Endocrinol Metab. 2008;22(3):477-88 Durham Dyspraxia Trial. Durham Educational Authority, Durham. UKhttps://www.equazen.co.uk/default.aspx?pid=264 Attention-deficit/hyperactivity disorder in older adults: prevalence and possible connections to mild cognitive impairment. Ivanchak N1, Fletcher K, Jicha GA. Curr Psychiatry Rep. 2012 Oct;14(5):552-60 Previous adult attention-deficit and hyperactivity disorder symptoms and risk of dementia with Lewy bodies: a case-control study.

Golimstok A1, Rojas JI, Romano M, Zurru MC, Doctorovich D, Cristiano EEur J Neurol. 2011 Jan;18(1):78-84.

Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.

Wagner CL et al, J Steroid Biochem Mol Biol. 2013;136:313-20 Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Bowman GL et al. Neurology. 2012 Jan 24;78(4):241-9.

Vitamin D is associated with cognitive function in elders receiving home health services. Buell JS et al. J Gerontol A Biol Sci Med Sci. 2009 Aug;64(8):888-95.

Mineral and vitamin deficiencies can accelerate the mitochondrial decay of aging. Ames BN1, Atamna H, Killilea DW. Mol Aspects Med. 2005 Aug-Oct;26(4-5):363-78.

More than the sum of its parts? Nutrition in Alzheimer’s disease. von Arnim CA et al. Nutrition. 2010 Jul-Aug;26(7-8):694-700 Cytidine (5’)diphosphocholine modulates dopamine K(+)-evoked release in striatum measured by microdialysis. Agut J et al. Ann N Y Acad Sci. (2000) The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. Nathan PJ, Lu K, Gray M, Oliver C. J Herb Pharmacother. 2006;6(2):21-30. Review

124

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD

Dementia & Alzheimer’s The Facts

Patrick Holford Food for the Brain Foundation

•! Three in ten over age 70 have impaired memory, 80% of which will develop dementia within 5 years (2/3rd is Alzheimer’s).

•!

The cause and prevention of Alzheimer’s dementia

550 people (over 6 double decker buses worth) are diagnosed with dementia every day in the UK. (Matthews,PLoSMed,2005)

•! 44 million worldwide have dementia and is expected to double every 20 years to 135 million by 2020.(ADI, 2014)

•!

The current cost is $604 billion a year - 1% of GDP. (ADI, 2014)

Defining Alzheimer’s Smith AD, PNAS,2002; Morris JC, Geriatrics 2005" Winblad B et al.

J Intern Med 2004" Peterson. J Int Med 2004" 4. de Jager CA et al. Psychol Med 2003" 33: 1039–50; Perry RJ, Hodges JR. Brain 1999" Oulhaj A. et al.,Neurology 2009

•! Alzheimer’s Disease (AD) is characterised by a progressive loss of cognitive functions including memory, language, judgment, praxis and orientation and is diagnosed on the basis of shrinking in the thickness of the Medial Temporal Lobe, which is considered to be the primary pathology that generates the associated symptoms.

•! The detectable, preclinical phase of AD presents as Mild Cognitive Impairment (MCI).

Temporal-lobe-oriented CT in confirmed Alzheimer’s disease

Control aged 66: no pathology 16 mm

Demented aged 66: Alzheimer pathology 2 mm

Used with permission of Optima

125

1

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD

Used with permission of AD Smith, adapted from PNAS, 2002 paper!

Subtraction of serial MRI scans at 6 month intervals

The Shrinking Brain Normal ageing ~ 0.5% per year

Mild Cognitive Impairment ~ 1% per year Alzheimer’s Disease ~ 2.5% per year

Control: Hcy 7.8

Alzheimer’s disease Hcy 13.1

Used with permission of Optima

P- Tau and Amyloid-B proteins

All phase 3 drug trials have failed

Sontag E et al., Journal of Neuroscience, 27(11):2751–9 (2007).

#! In AD there are neurofibrillary tangles, and an increasing

deposition of amyloid-B proteins. However, research with drugs aiming to reduce formation of amyloid-B proteins has been singularly unsuccessful, possibly indicating that this hypothesis is wrong.

#! Recently, research has identified P-tau proteins which leads to the build up of these neurofibrillary tangles, which is one of the hallmarks of Alzheimer’s.

#! But is this the cause or the consequence? Homocysteine is high in the sites of decay. It is, itself, capable of damaging neurons.

When there is an increase in P-tau there is a corresponding increase in homocysteine.

Mangialasche et al. Lancet Neurol 2010; 9: 702–16

126

2

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD

The drugs don’t work

Do genes cause Alzheimer’s? #! Bekris L, J.Ger.Psych 2010; Heininger K, Human Psychopharm 2000; Ridge P, PLoS1 2013

•! In a five-year trial of Aricept there was no difference in ‘worthwhile improvements’ in a range of categories: rates of disease progression, the rate at which patients were placed in nursing homes, caregiver time, or how fast behaviour deteriorated, regardless of the dose given. The one benefit is that during the first two years of the study, those on Aricept did slightly better in tests measuring thinking and functional ability. (Lancet 2004) •! In a study of 224 people with Alzheimer’s those who were taking antipsychotic drugs or sedatives had an almost three-fold higher risk of deterioration than those who were taking none. Even worse, for those taking both antipsychotic and sedative drugs together, their risk of deterioration was almost quadrupled. (J Neurol Neurosurg Psychiatry 2007) •! Drugs aimed to reduce amyloid-B synthesis have repeatedly failed.

(Lancet, 2010)

#! Three causative genes (APP, PSEN1, PSEN2) account for less than 1% of cases of AD.

#! Other genes predispose, but don’t cause. For example, having the ApoE4 gene, if expressed, may account for 4% of the inheritability of risk.

#! 11 other genes may account for 7.8% of the inheritability of AD.

#! Gene studies suggest that, in total, genes could account for a third of one’s inherited risk or predisposition. In other words, if you had all the wrong genes you would be 30% more likely to get AD.

Best evidenced non-genetic risk factors

Attribution of risk for Alzheimer’s

Age Low education

Low antioxidant status Low intake of omega-3

Low cognitive activity Low physical activity Diabetes(t2)&^HbA1c

Alzheimer’s Alzheimer’s disease disease

Obesity

Hypertension High cholesterol Smoking

High Homocysteine

112 leading dementia experts signed

#! David Smith et al, Journal of Alzheimer’s Disease 38 (2014) 699–703 We estimate that about half of Alzheimer’s disease cases worldwide might be attributable to known risk factors. Taking immediate action on the known risk factors could perhaps prevent up to one-fifth of predicted new cases by 2025.

P Aisen (university of California, San Diego) M Albert (John Hopkins University, Baltimore, MD) K Anstey (Australian National University, Canberra) J Avila (Centro de Biologia Molecular Severo Ochoa,Madrid) S Banerjee (University of Sussex, Brighton) DE Barnes (University of California, San Francisco) MS Beeri (Mount Sinai School of Medicine, New York) DA Bennett (Rush University Medical Center, Chicago) S Black (University of Toronto) C Brayne (University of Cambridge) J Breitner (McGill University, Montreal) M Breteler (German Center for Neurodegenerative Diseases, Bonn) H Brodaty (University of New South Wales, Sydney) C Chen (National University of Singapore) MJ Chiu (President Taiwan Alzheimer’s Association, National Taiwan University, Taipei) M Combrinck (University of Cape Town) CW Cotman (University of California, Irvine) P Davies (Feinstein Institute, New York) C deCarli (University of California Davis, Sacramento) IV Damulin (I.M. Sechenov First Moscow State Medical University, Moscow) P Dal-Bianco (Medical University of Vienna) J de la Torre (University of Texas, Austin) A de Silva (University of Kelaniya, Colombo, Sri Lanka) B De Strooper (Catholic University of Leuven) B Dubois (University of Paris VI) K Engedal (University of Oslo) S Engelborghs (University of Antwerp) MM Esiri (University of Oxford) RM Faull (University of Auckland) AM Fjell (University of Oslo) L Flicker (University of Western Australia, Perth) A Flöel (Charité-Universitätsmedizin, Berlin) O Forlenza (University of Sao Paulo, Brazil) L Fratiglioni (Karolinska Institute, Stockholm) GB Frisoni (University of Geneva and IRCCS Fatebenefratelli, Brescia) S Gauthier (McGill University, Montreal) S.I. Gavrilova (Mental Health Research Center RAMS, Moscow) H Hampel (Pierre and Marie Curie University, Paris) H Hendrie (Indiana University, Indianapolis) T Iwatsubo (University of Tokyo) R Jacoby (University of Oxford) J Jia (Beijing Capital Medical University) KA Jellinger (Medical University of Vienna) RN Kalaria (University of Newcastle. UK) ZS Khachaturian (The Campaign to Prevent Alzheimer’s Disease by 2020, Potomac. MD) M Kivipelto (Karolinska Institute, Stockholm) D Knopman (Mayo Clinic, Rochester, MN) T Kwok (Chinese University, Hongkong) K Langa (University of Michigan, Ann Arbor) EB Larson (University of Washington, Seattle) L Launer (National Institute on Aging, Bethesda, MD) N Lautenschlager (University of Melbourne) BA Lawlor (Trinity College, Dublin) J Lindesay (University of Leicester, UK) A Lobo (University of Zaragoza, Spain)

There is already sufficient evidence to justify immediate action. Trials in those at risk of developing dementia should be done of the following: exercise; controlling blood sugar, including diabetes treatment; depression treatment; high blood pressure treatment; B vitamins; omega-3 fatty acids; cognitive training; and social activities.

127

J Lökk (Karolinska Institute, Stockholm) O Makeeva (Institute of Medical Genetics, SB RAMS, Tomsk, Russia) J Marksteiner (President, Austrian Alzheimer Society) A McCaddon (Cardiff University Medical School) K Meguro (Tohoku University, Sendai, Japan) LT Middleton (Imperial College, London) MC Morris (Rush University, Chicago) DL Na (Sungkyunkwan University School of Medicine, Seoul) MWS Nasrun (Indonesian Alzheimer Association, Universitas Indonesia, Jakarta) A Ogunniyi (University College Hospital, Ibadan, Nigeria) S Pendelbury (Oxford NIHR Biomedical Research Centre) G Perry (University of Texas, San Antonio) RC Petersen (Mayo Clinic, Rochester, MN) VP Puzyrev (Institute of Medical Genetics, SB RAMS, Tomsk, Russia) G Rebok (Johns Hopkins University, Baltimore, MD) G Rees (CEO, Alzheimer’s Australia) H Refsum (University of Oslo) E Reynolds (King’s College, London) E Richard (University of Amsterdam) J Rinne (University of Turku, Finland) K Ritchie (INSERM, Montpellier) WA Rocca (Mayo Clinic, Rochester, MN) IH Rosenberg (Tufts University, Boston) PS Sachdev (University of New South Wales) N Scarmeas (Columbia University New York and University of Athens) S Scarpa (University of Rome La Sapienza) R Schmidt (Medical University, Graz, Austria) P Scheltens (VU University Medical Center, Amsterdam) S Seshadri (Boston University) A Singh-Manoux (INSERM, Villejuif) I Skoog (University of Gothenburg) AD Smith (University of Oxford) T Sobow (Medical University of Lodz, Poland) R Sperling (Harvard University, Boston) P Srisuwan (Phramongkutklao Hospital and College of Medicine, Bangkok) R Stewart (Institute of Psychiatry, London) DY Suharya (Executive Director, Alzheimer’s Indonesia) M Tripathi (All India Institute of Medical Sciences, New Delhi) AM Troen (Hebrew University of Jerusalem, Israel) J Trojanowski (University of Pennsylvania, Philadelphia) SJ van Rensburg (University of Stellenbosch, South Africa) B Vellas (University of Toulouse) G Waldemar (Director, Danish Dementia Research Centre, University of Copenhagen) H Wang (Peking University Institute of Mental Health) JZ Wang (Tongji Medical College, HUST, Wuhan, P.R. China) M Weiner (University of California, San Francisco) LJ Whalley (University Aberdeen, Scotland) LR White (Honolulu-Asia Aging Study, Chaminade University, Hawaii) PJ Whitehouse (Case Western Reserve University, Cleveland, OH) R Whitmer (Kaiser Permanente, Oakland, California) A Wimo (Karolinska Institute, Stockholm) R Wurtman (MIT, Cambridge, Mass) K Yaffe (University of California, San Francisco) S-Y Yoon (University of Ulsan College of Medicine, Seoul) VV Zakharov (I.M. Sechenov First Moscow State Medical University, Moscow) NG Zhukova (Siberian State Medical University, Tomsk) IA Zhukova (Siberian State Medical University, Tomsk)

3

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD

Good news! Prevalence is declining

#! Brayne C, Lancet, 2014; Christiensen, Lancet 2014; ADI, 2014

#! A UK study comparing dementia incidence in 1994 with 2014 to have declined by 24% in last 20 years (MRC CFAS study)

#! A Danish study compared people in their 90’s, born a decade apart, in 1905 and 1915. Those born later were not physically healthier, but performed better on cognitive tests.

#! However, with a skew towards more older people in many countries

the incidence of Alzheimer’s is still on the rise, currently affecting 44 million people, and expected to affect 75 million people by 2030.

!"

Risk of Alzheimer’s disease

Is raised homocysteine causal?

Zhou J et al, Trends in Pharmacological Science (2010).

Clarke R et al, Archives of Neurology, 1998

5

Odds 4 ratio 3

Those 33% with highest homocysteine levels were compared with those 33% with the lowest levels

#! Oxidative stress

Those 33% with lowest B vitamin levels were compared with those 33% with the highest levels

#! Amyloid protein elevation and tau phosphorylation

#! Demethylation

#! Cerebrovascular damage (lack of oxygen) #! Excitatory damage (NMDA)

2 1 0 Homo- Serum cysteine folate

high!

RBC Vitamin folate B12

#! ER stress (abnormal protein synthesis) #! DNA damage through poor repair

low!

Used with permission of Optima

B6, B12, folate, zinc deficiency

Genetic factors eg MTHFR C677T

Drug induced

eg metformin, caffeine

How high Hcy can raise amyloid and tau

Life style/age eg stress, smoking

•! High Hcy leads to inhibition of methylation reactions because high Hcy leads to high SAH, which is an inhibitor of methyltransferases.

•! DNA methylation controls the expression of presenilin so inhibition of DNA methylation leads to higher production of presenilin and so to more beta-amyloid production.

•! Phosporylated tau is in a dynamic state, constantly being dephosporylated and re-phosphorylated. The enzyme that removes the key phosphate groups is called protein phosphatase 2A (PP2A) and this is activated by methylation. So, if methylation is inhibited, the activity of PP2A is reduced and P-tau builds up, so favouring the formation of neurofibrillary tangles.

High homocysteine Low SAMe

Elevated SAH

Impaired methylation:

DNA, myelin, membrane phospholipids, receptors, neurotransmitter metabolism

NMDA receptor activation

Excitotoxicity

NOS

Oxidative stress

Blood vessel damage

Lack of oxygen

Neurotoxicity / Cell Death

128

4

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD Risk of Alzheimer’s disease

Effect of changes in homocysteine over time on episodic memory test scores

Clarke R et al, Archives of Neurology, 1998

Nurk MD, Annals of Neurology, 2005

Those 33% with highest homocysteine levels were compared with those 33% with the lowest levels

5

Odds 4 ratio 3

Difference in memory score

2 1 0 Homo- Serum cysteine folate

high!

RBC Vitamin folate B12

P = 0.003

Those 33% with lowest B vitamin levels were compared with those 33% with the highest levels

low!

Change in homocysteine over 6 years ($mol/L)

Used with permission of Optima

Two reviews confirm Hcy/AD association

Folic acid improves memory in the elderly

van Dam F, Archives of Gerentology and Geriatrics 2009; Smith AD, Food Nutr Bull, 2008; Oulhaj A et al,Int J Geriatric Psych 2010; Smith AD, Refsum H,Am J Clin Nutr 2009

Durga et al, Lancet. 2007, 369(9557):208-16

#! Both high homocysteine (Hcy) levels, and low folic and B12 levels in blood correlate with increasing risk for AD according to a systematic review.

Another review, in 2008, concludes that of ‘Seventy seven crosssectional studies on more than 34,000 subjects and 33 prospective studies on more than 12,000 subjects have shown associations between cognitive deficit or dementia and homocysteine and/or B vitamins’.

A study conducted by Jane Durga, at Wageningen University in Holland, gave 818 people, aged 50 to 75 with Hcy >13mmol/l, either a vitamin containing 800mcg of folic acid a day, or a dummy pill. That’s almost three times the RDA and the equivalent of 2.5 pounds of strawberries a day – more than you can reasonably eat.

Three years later, different aspects of intelligence were measured.

On memory tests,the supplement users had scores comparable to people 5.5 years younger. On tests of cognitive speed, the folic acid helped users perform as well as people 1.9 years younger.

#! Hcy levels also predict and correlate with rate of cognitive decline, as does B12 status.

#! There is, therefore, ample evidence to propose that lowering homocysteine by giving appropriate supplemental levels of homocysteine lowering nutrients would reduce risk.

B12 lack linked to brain shrinkage

B vitamins stop decline in mild AD

Vogiatzoglou A et al, Neurology 2008;71:826–832

#! Aisen P et al, JAMA, 2008

#! Dr Paul Aisen and colleagues at the University of California, gave

#! More than one third of people over age 61 have

homocysteine-lowering B vitamins to those already diagnosed as suffering from mild to moderate Alzheimer’s. Patients were not selected on the basis of Hcy values (average Hcy was 9.1mmol/l at baseline), and brain scans were not conducted. The patients received folic acid (5mg/d), B12(1mg/d), and B6 (25mg/d over a period of 18 months. No overall difference occurred in rate of cognitive decline in those on the supplements versus placebo.

However, those who had milder Alzheimer’s taking the B vitamins had no decline in memory over 15 months, while those on the placebo showed a steady decline. The average drop in homocysteine over the 18 months was from 9.1 to 6.8$mol/ l.

insufficient B12 to prevent accelarated brain shrinkage and may suffer memory loss as a result. The study from Oxford University found that B12 deficiency was associated with brain shrinkage, a hallmark of dementia risk. B12, which is only found in animal products, becomes increasingly hard to absorb. 40% of people in this study, aged 61 to 87, had insufficient B12.

129

5

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD

Slowing of atrophy depends on baseline Hcy

B12 & folic acid help AD with high Hcy

Smith AD et al, PLoS ONE,, September 2010 | Volume 5 | Issue 9 | e12244

#! Kwok T, Clinical Nutrition, 2011

#! An RCT giving 140 people with mild to moderate AD or vascular

dementia 1mg B12 and 5mg of folic acid versus placebo found no difference overall, but in those with raised Hcy (above 13µM) at baseline, there was no decline in the primary outcome, the Mattis Dementia Rating Scale (MDRS) compared to 2 point decline in the placebo group (construction domain). This was a significant difference (p=0.003).

Rate of atrophy per year (%)

53% lower atrophy rate P = 0.001

Quartiles of baseline homocysteine

Turquoise blue indicates shrinkage: 0.3 to 1mm Placebo group

Atrophy 2.5% per y Placebo Hcy - up from 22 to 30

B vitamin group

Atrophy 0.46% per y Active treatment Hcy - down from 24 to 12

Used with permission of Douaud et al, PNAS 2013

Percentage regional grey matter loss over 2 years in the high homocysteine group (>11µmol/L)

30% reverse dementia rating #! C. de Jager et al, Int. J.Ger. Psychiatry 2012

#! Douaud G et al, PNAS 2013

20

Placebo mean 5.2% B-vitamin mean 0.6%

15 10 5 0 -5

>13µmol/L

There is a 9-fold slower rate of atrophy of these specific brain regions in the B vitamin group

58%

28%

“B vitamin treatment doubles the proportion of people reverting to zero on the Clinical Dementia Rating.”

P=0.02

- 10 - 15

B vitamin treatment in subjects with high tHcy doubles the proportion reverting to zero

130

6

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD

Outcomes of the VITACOG trials #! Smith AD, PLoS ONE 2010; de Jager C, Int. J.Ger. Psychiatry 2012;Douaud, PNAS, 2013

•! B vitamin treatment slows brain atrophy in Mild Cognitive Impairment by up to 53%, with the main area of the brain protected being the ‘Alzheimer’s’ area.

•! B vitamin treatment almost stops further memory loss in those with high homocysteine.

•! The slower the rate of atrophy, the slower the decline in cognitive abilities.

•! The effect is greatest in those with a high baseline level of homocysteine. An effect is seen in those with homocysteine above 9.5µmol/l.

•! High homocysteine levels are found in ~75% of elderly

“It is time we woke up to the fact that Alzheimer’s is a preventable disease, not an inevitable part of ageing.” Professor David Smith, Oxford University

Cognitive Function test Screening

#! Petersen R, J Int Med, 2004 and de Jager CA et al, Psychol Med, 2003

#! Episodic memory impairment is the most common initial symptom of Mild Cognitive Impairment.

#! Poor performance in verbal or visuospatial memory recall,

processing speed, attention and executive function tasks requiring planning or judgement & semantic fluency are common predictors of Alzheimer’s risk.

#! These are included in Food for the Brain’ss

Cognitive

Function Test.

#! If score below par test for homocysteine. www.foodforthebrain.org

“Significant correlations (r = 0.75, p<0.0001) were found between the CFT and paper tests in a pilot study, showing concurrent validity. The online CFT was shown to be suitable for selfadministration in online format for this midlife age group (50-70).”

131

7

The Etiology of Alzheimerâ&#x20AC;&#x2122;s Disease and its Prevention

3/28/14

Patrick Holford, PhD

Accelerated brain shrinkage above this level.

132

8

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD Homocysteine Co-Factor Nutrients

How much B12 to correct deficiency?

Euseen, Arch Intern Med. 2005; Seal, J.Am. Geriatric.Soc, 2002; Smith, J.Intern.Med, 2012

•! Folic acid, folate, methylfolate •! B12 (methylB12, glutathional B12) •! B6 - pyridoxine (pyridoxal-5-phosphate) •! B2 - riboflavin •! B3 - niacin •! Zinc •! Tri-Methyl Glycine (TMG) •! N-Acetyl Cysteine (NAC)

•! A dose-finding RCT to determine the lowest oral dose of B12

required to normalize methylmalonic acid, the biochemical marker of deficiency in older people with mild vitamin B12 deficiency found that only doses of 647 to 1032 µg of B12 were associated with 80% to 90% of the estimated maximum reduction in the plasma methylmalonic acid concentration.

•! A trial with older patients with borderline B12 status (100-150pmol/l) found that 50mcg/d was effective in raising B12 by 51% in a month, but 10mcg was no more effective than placebo.

•! Serum B12 reference range is too low in many countries. Levels below 300pmol/l require treatment.

Common medication inhibits B12

Five a day policy doesn’t work

#! Lam J, JAMA 2013; Singh, A; J.Postgrad.Med 2013; Morrow L, South Med J 1999

#! By age 65 the average person is

#! Both PPI and H2RA antacid use significantly increase B12

on 5 drug prescriptions

deficiency. More than 1.5 PPI pills per day doubles risk.

#! By 75 this can be double.

#! Long-term metformin use increases risk fo B12 deficiency and

#! “Following official medical

neuropathy.

guidelines which results in multiple drug taking is one of the greatest but most invisible threats to health in the ageing population.” Mangin D, Arch.Int Med, 2010

#! Long-term diuretic use for hypertension associated with increased Hcy (18mmol/l vs 10mmol/l).

7 Ways to Lower Your ‘H’ Score

Coffee is Bad News for Hcy Grubben M, AmJClinNutr, 2000; Verhoef P, AmJClinNutr, 2002; Ulvik A, Clin Chem 2008

1.! Eat more greens, seeds, nuts and beans, high in folate 2.! Eat more fish and eggs,high in B12 and methyl nutrients 3.! Cut back on coffee 4.! Limit alcohol 5.! Reduce stress 6.! Stop smoking 7.! Supplement homocysteine lowering nutrients daily

#! A study at the University Hospital Nijmegen assigned volunteers to drink a litre of unfiltered coffee a day – approx. four cups – for two weeks. At the start of the two weeks their average H score was 12.8 µM. At the end of the two weeks their H score was 14.

#! A study by Dr Verhoef and co. at the Wageningen Centre for Food

Sciences in the Netherlands showed that two cups of regular coffee increased homocysteine by 11% after only four hours, while caffeine tablets without coffee increased it by 5%.

#! A study of 10,601 Norwegians found that four cups of coffee a day vs none had 6.8% higher homocysteine and lower B vitamins 11.7% lower folate, 14.1% lower B6, 5.5% lower B2.

133

9

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD Homocysteine Lowering Nutrients H SCORE VERY LOW <7 Dose per day

LOW RISK

AT RISK

HIGH RISK

6-9

9-15

>15

1

2

4

Folate

200µg

400µg

400µg

800µg

MethylB12

10µg

250µg

500µg

1000µg

B6

10mg

20mg

40mg

80mg

B2

5mg

10mg

15mg

25mg

Zinc

5mg

10mg

15mg

20mg

TMG

500mg

1000mg

2000mg

NAC

250mg

500mg

1000mg

Methylfolate, B12, NAC & Glutathione McCaddon A et al., Primary Psychiatry 2010; McCaddon A, Nutr J. 2006;

#! There is a good rationale for using 5-MethylTetraHydroFolate (5MTHF), MethylB12 and/or NAC, glutathione or glutathional B12.

#! This rationale is supported by case reports.

What diet helps prevent memory loss?

•!

•!

•!

•!

•!

•!

•!

•!

Omega 3 and Alzheimer’s disease risk M. Morris et al, Archives of Neurology 2003; Van Gelder et al, Am.J.Clin.Nutr, 2007

#!Eating fish once a week reduces risk of developing AD by 60

Homocysteine lowering nutrients (B vitamins +) Phospholipids (fish, eggs) Omega 3 fats (oily fish, cold climate seeds - flax, chia) Antioxidants (fruit, veg, herbs and spices - NAC, glutathione) Low GL diet (avoid sugar and refined foods) Vitamin D (sunlight, seafood, supplements) LIFESTYLE FACTORS include exercise, education, cognitive and social stimulation, not smoking, weight control MEDICAL FACTORS include controlling blood pressure, cholesterol, diabetes

per cent, according to recent a study by Professor Martha Morris and colleagues from Chicago’s Rush Institute for Healthy Ageing.

They followed 815 people, aged 65 to 94 years, for 7 years and found that the dietary intake of fish was strongly linked to AD risk.

They found that the strongest link was the amount of DHA.The lowest amount of DHA per day that offered some protection was 100mg.

#!Fish consumers have significantly less cognitive decline 5

years later than nonconsumers. An intake of 380mg/d of EPA +DHA was associated with a 1.1 point difference in cognitive decline. Note: fish is also a good source of B12.

Vitamin D - association but no RCTs

DHA good for memory and brain

Annweiler, Front. Pharmacology 2014; Annweiler, Eur.J.Neurol. 2009; Etgen, Dement. Geriatr.

Cogn. Disord 2012; Annweiler, J.Alz.Dis. 2013; Gezen-Ak, J.Alz.Dis. 2014

Yurko-Mauro, Alz. Dement, 2010; Quinn J, JAMA 2010; Witte A, Cerebral Cortex, 2013

#! A 24 week RCT giving 900mg/d of DHA improved learning and

#! Low serum concentrations of vitamin D are associated with global

memory function in those with age-related cognitive decline.

cognitive impairment.

#! An RCT of 402 individuals with mild/moderate Alzheimer’s,

#! People with hypovitaminosis D having more cognitive disorders

were given 2g daily of algal DHA vs placebo for 18 months. No difference between DHA and placebo.

(Etgen) and specifically more executive dysfunctions (Annweiler).

#! Specifically, it has been reported that people with AD have lower

#! 65 healthy 50-75 year olds were given 2.2g a day of omega 3

vitamin D status than controls.

fish oils for 26 weeks. There was a significant increase in executive functions and beneficial structural changes in white matter integrity and grey matter volume. Improvements in executive function correlated with red cell omega 3 status and brain-derived neurotrophic factor (BDNF) and negatively with fasting insulin.

#! Vitamin D deficiency and vitamin D-related gene disruption mimic amyloid pathology. Poor vitamin D status creates vulnerability for neurodegeneration.

134

10

The Etiology of Alzheimer’s Disease and its Prevention

3/28/14

Patrick Holford, PhD Combined nutrient studies

Vitamins E & C and Alzheimer’s

Scheltens, Alzheimer’s & Dementia 2010; J.Alz.Dis.2012; Shah, Alz.Res&Therapy, 2013; Remington R, Am J Alz.Dis, 2009; Chan A, J Nutr Health Ageing, 2010

Zandi, Arch Neurol. 2004; Mangialasche, Exp. Gerontol 2013; Petersen R, NEJM, 2005;Dyksen, JAMA 2014%

#! Use of vitamin E and C (ascorbic acid) supplements in combination was associated with reduced AD prevalence of 78% and incidence 63%. Best results were achieved with 1,000mg of vitamin C and 1,000iu of vitamin E.

#! Two pilot trials of drug-naive AD patients received Souvenaid, a

combination of EPA (300mg), DHA (1200mg) phospholipids (106mg), choline(400mg), uridine monophosphate( 625mg), vitamin E (40mg), vitamin C (80mg), selenium (60mcg), B6 (1mg), B12 (4mcg), folic acid (400mcg) or placebo for 12 and 24 weeks. Small improvement in memory (delayed verbal recall) occurred in the supplemental group. However, a larger trial in AD patients receiving medication found no change.

#! High serum levels of vitamin E are associated with lower risk for cognitive decline.

#! In a double-blind study, subjects with mild cognitive impairment were

randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point.

#! Two small pilot trials of combination of folic acid (400mcg), B12

(6mcg), vitamin E (30iu), NAC (600mg), SAMe(400mg) ALCarnitine (500mg) have shown limited improvements in adults with and without dementia.

#! Supplementing high dose vitamin E (2,000iu a day) was shown to slow down functional decline in those with mild to moderate Alzheimer’s. disease, compared to placebo or the drug memantine.

Cognitive decline linked to disglycemia

Dietary pattern and Alzheimer risk Gu Y et al, Arch Neur 2010

Luchsinger JA et al, Neurology 2004; Abbatecola AM et al, J Am Geriatr Soc, 2004; Xu WL et al, Neurology, 63:1181– 6 (2004); Hassing LB et al, J Int Neuropsychol Soc, 2004; Yaffe K et al, Neurology, 2004; Arvanitakis Z et al, Arch Neurol, 2004; Yaffe K et al, J Nutr Health Aging, 2006; Roberts R et al, Alzheimer Dis Assoc Disord,2010; Garcia-Lara et al, Rev.Invest Clin, 2010; Crane et al, NEJM, 2013

•!

Cumulative survival without Alzheimer’s

Researchers at Columbia University NY finds that twice as many of the participants with high insulin levels developed dementia when compared to those with normal insulin. Also, the people with high insulin levels had the greatest decline in memory.

•!

An Italian study of people free of dementia and diabetes showed that high insulin levels were strongly associated with poorer mental function.

•!

A six-year Swedish study of 1,301 people aged 75 and over showed that those with diabetes were one and a half times more likely to develop dementia.

•!

Researchers at the University of California, San Francisco, studied 1,983 postmenopausal women and found those with glycosylated haemoglobin levels of 7 per cent or higher were four times more likely to develop MCI or dementia.

•!

Having a higher blood glucose (6.4 vs 5.5mmol/l) in preceeding 5 years increases risk for dementia (HR 1.18), as does having higher glucose (10.5 vz 8.9mmol/l) in diabetics (HR 1.40)

Strict adherence Poor adherence Plenty of fish, fruits, vegs, nuts, tomatoes, poultry

2,148 elderly (77y) 251 incident AD cases

Little of high fat dairy, red meat 0

2 4 6 8 10 12 14 Years from baseline

What is the Mediterranean diet that might protect from Alzheimer’s Disease?

Mediterranean diet systematic review Singh B et al, J. Alzheimers Dis., 2014

Scarmeas et al, Ann Neurol, 2006

#!A systematic review of five good quality trials reports

higher adherence to the Mediterranean Diet was associated with reduced risk of MCI and AD. The subjects in the highest tertile had 33% less risk (adjusted HR = 0.67;p < 0.0001) of cognitive impairment (MCI or AD) as compared to the lowest scoring tertile. Among cognitively normal individuals, higher adherence to the Mediterranean Diet was associated with a reduced risk of MCI (HR = 0.73; p = 0.02) and AD (HR = 0.64; p = 0.007).

Intake (g/day) or %

Low Med. diet score Mid High

Dairy Meat Veg Fruit Leg. Cereal Fish U/SFA Alcohol

135

11

The Etiology of Alzheimer’s Disease and its Prevention Patrick Holford, PhD

3/28/14

Flavonoid rich foods and cognition

Fruit and vegetable intake and cognition

Nurk E et al, J Nutr, 2009

Nurk E et al, J. Alzheimers Dis., 2014

Memory test in relation to consumption over previous year in 2,031 elderly

Verbal fluency test in relation to foods consumed over the previous year in 2,031 elderly

Tea

Episodic memory score

Chocolate

Wine

Cognitive test score

0 200 400 600 800 1000

Amount consumed per day (g)

Amount of food consumed per day

Hordaland Health Study: Nurk 2010

125 mL

ACTION •! Eat fish and seeds - supplement omega 3 fish oil •! Up antioxidants •! Minimise sugar and refined foods - eat a low GL diet •! Supplement B vitamins - check your homocysteine •! Limit coffee - green tea is better •! Keep physically, mentally and socially active

www.foodforthebrain.org

136

12