Global Market for Oil Palm Phenolics in HealthcareDr. Robert P. Weinberg, D.O., J.D. Research Scientist Biomaterials Science and Engineering Lab M.I.T.

Herbal Medicine7000 plants have medicinal applications 25% of modern prescription drugs have

botanical origins Drug = drogge = to dry

Botanical supplement sales= US$20+

billion/yr Western Herbalists use simples=1 herb Chinese and ayurvedic use many blended together

What is a Dietary Supplement?Definition: (Sec 3.) A product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredientsVitamins Minerals Herbs or other botanicals Amino acids Concentrate, metabolite, constituent, extract or combination of above listed ingredients

3

Dietary SupplementsTraditionally defined as products made of

one or more essential nutrients such as vitamins, minerals, and proteins, but DSHEA broadened definition to include almost any product intended for ingestion as a supplement to the diet Must be identified on label as a D/S

4

Dietary SupplementsDistinguished from Drugs:Drug = article intended to diagnose,

cure, mitigate, treat, or prevent disease Both intended to affect structure and function of body Drug must undergo FDA approval after clinical studies to determine effectiveness and safety D/S = no pre-market testing

5

Dietary SupplementsDistinguished from Foods:Foods not intended to affect structure

and function D/S intended only to supplement dietNot

represented for use as conventional food Not intended as sole item of a meal or the diet

6

H e rb a lPre p a ra ti n s oTe a s, i fu si n s, d e co cti n s m a d e b y n o o ste e p i g a n d so a ki g h e rb i w a te r fo r a n n n fe w m i u te s n Ti ctu re s h e rb i so a ke d i a l h o l n s n co , gl yce ri o r a n a l h o l w a te r n co co m b i a ti n n o E xtra ct a fi te re d o r d i l e d ti ctu re l sti l n Ta b l ts a n d ca p su l s d ryi g th e h e rb , e e n p o w d e ri g i sh a p i g i i to p i l n t n t n ls To p i l h e rb a d d e d to e m o l i n t ca s le I j cti n s ve ry ra re , u su a l y o f a n e o l

St. Johns Wort (Hypericum)Uses: Depression, Anxiety, Antiviral Agent #1 Anti-depressant in Germany Major action is the inhibition of seratonin,

norepinephrine and dopamine uptake and down-regulation of receptors, standardized on hypericin content Likely safe in usual doses, in high doses can cause severe photogenic skin reactions

St. Johns WortDosage: Daily dose of 900 mg of SJW extract

(standardized to 0.3% hypericin) found to be equivalent to 20 mg fluoxetine Doses up to 1800 mg tolerated in severe depression Likely effective in mild to moderate depression Possibly ineffective as antiretroviral agent (and may decrease effectiveness of HIV agents)

Saint Johns WortContraindications: Severe depression with

akinetic mutism, suicidal tendencies, severe agitation, hypersensitivity and pregnancy (estrogen effects) Precautions: photosensitivity Interactions: May precipitate hypertensive crisis with MAO inhibitors (Mueller & Shaefer,1996) May induce serotonin syndrome with SSRIs a with Triptans Interferes with cyclosporine, may cause transpla rejection May cause hypertension with tyramine containin foods Safe with benzodiazapines

Ginkgo bilobaUses: Dilates arteries, capillaries and veins

Used to increase peripheral blood flow and improve intermittent claudication Used to treat varicosoities, cerebral vascular insufficiency, dementia, vertigo, and SSRIinduced sexual dysfunction $1 billion in US sales annually Most frequently prescribed herb in Germany

Ginkgo bilobaLikely safe when used in appropriate doses

for up to a year, unsafe intravenously Possibly effective in dementias (equivalent to a six month delay in disease progression), in improving cognitive function in normal adults and in improving pain free walking distances Ineffective for memory enhancement, ADHD, depression

Ginkgo biloba Precautions and interactions: Ginkolideis a selective

antagonist of platelet aggregation. Case reports of subdural hematoma and spontaneous bleeding with ASA use. Reports of GI disturbances and CNS symptom hematomas

Ginkgo and caffeine may increase risk of subdural

Ginkgo helped SSRI induced sexual dysfunction 91% in

women, 76% in men (Cohen and Bartlik 1998)

Use with extreme caution with stimulants

Top 10 best-selling Herbal productsHerbal Medicinal Conditions Treated Product Glucosamine / arthritis chondroitin Fish oils / animal oils atherosclerosis Coenzyme Q 10 Plant oils Mangosteen Juice Goji Juice Green Tea Echinacea Saw Palmetto Melat Revenue US$ (millions)

Current Global Sales VolumeProduct 1998 2000 2005 2007 2008 2009

What is an Herb?Any part of a plant used for its medicinal , flavoring , or fragrant property

Why People Use Them?Consumer Lab Survey (54% had multiple

reasons)

General Health 67% Colds 53% Osteoarthritis 39% Energy Enhancement 37% Cholesterol Lowering 29% Cancer Prevention 28% Allergies 27% Weight Management 25%

Herbal medicines are rapidly increasing in economic importanceOther Countries

US$ 60 000 million world market sales for herbal medicines (including raw materials )

China

Japan Western Europe USA Canada

Source: Secretariats of the Convention on Biological Diversity (CBD) 2000

Populations Using TM/CAM WorldwidePopulations using traditional medicine for primary careEthiopia Mali Myanmar Rwanda Tanzania Uganda90% 75% 70% 70% 60% 60%

Populations in developed countries who have used complementary and alternative medicine at least once

Germany Canada France Australia USA49% 48% 42%

80% 70%

10/13/10

Sources: Eisenberg DM et al. 1998; Health Canada, 2001;Myanmar and Mali government in 2008, BMJ in 2003.

China + India = >25% Total World Exports Value

2 0 0 6 T o ta l S e le c te d H

Summary of South American Botanical Exports 2008 Volume (kg) and Value (USD)

S o u th A m e ri B R A Z IL A R G E N T IN A

Evaluation of efficacy of herbal medicines

T h e co m b i a ti n n o o f 4 p l n ts a cre a te s a p o w e rfu l syn e rg y fo r m a xi u m m a n ti tu m o u r e ffe ct

R e m o vi g a n y o n e n o f th e 4 p l n ts a w e a ke n s th e e ffe cti n e ss o f ve th e fo rm u l a

Reported by Prof. Yeeng -chi Cheng, Yale Medical School 2001

Worldwide Sales of Leading Therapeutic Classes (in BILLIONS of $USD) and Percent Growth (in local currency)

Class Rank 1 2 3 4 5 6 7 8 9 10

Therapeutic Class Anti-Ulcers Cholesterol & Triglycerol Reducers Antidepressants Calcium Antagonists (plain) NSAIDS ACE-Inhibitors (plain) Cephalosporins & Combinations Non-narcotic Analgesics Antipsychotics Oral Antidiabetics

Sales 1999-2000 15.8 13.4 11.7 9.9 7.7 7.4 7.3 6.2 5.1 4.8

Percent Growth 12 21 17 4 23 5 4 1 26 13

Sales 2000-2001 17.4 15.9 13.4 9.8 9.5 7.3 6.9 6 6 5.9

Percent Growth 13 21 18 2 26 3 -5 3 22 26

29

European Herbals MarketTotal Sale of Herbal Medicines , 2003 = 3 . 7 billion2% 2% 2% 4% 5% 6% 8% 21%Source: IMS 2005

11% 39%

GERMANY FRANCE ITALY POLAND UK SPAIN SWITZERLAND BELGIUM NETHERLANDS OTHERS

Publications on Antioxidants

Increase in Market Sales of Herbal Medicines$US Millions 660 640 620 600 580 560 540 520 Annual Market Sales of Herbal Medicines for Eight Member States

637

649

571

1999

2000

2001

The 8 member states are : the Kingdom of Bhutan, Canada, the Czech Republic, the Islamic Republic of Iran, the Republic of Madagascar, the Islamic Republic of Pakistan, the Republic of Sudan, the Kingdom of Sweden

33

G l b a lM a rke t o f S u p p l m e n ts i o e n 2003( Market Volume : US$ 51 Billion )VMS North America Europe Asia Japan South America 7.9 5.6 1.6 3.5 0.8 Herbs 3.9 6.9 5.1 2.3 0.6 0.8 19.6 Sports / Specialty 4.5 2.5 1.1 1.4 0.3 0.6in retail 10.4 prices

Source: PhytoPharm Consulting, NBJ, EuroConsult, WBP

Total 16.3 15.0 7.8 7.2 1.7 2.6 50.6

Rest of the 1.2 World Total 20.6

34

Asian and Latin American Herbs MarketIn 2005 (China) Sales revenue from traditional Chinese medicines totalled USD 14 billion and increased 23.81% compared to the previous year. TCM market share: 30% of total sales of medicines In 2006 (Japan) Sales revenue of Kampo medicine totalled USD 1.076 billion Kampo market share: 1.67% of total medicine production In 2007 (Brazil) Sales of revenue of herbal medicines reached USD 160 millions.

Annual research report by the Chinese Traditional Medicine Industry , July 2006

Green Facts US$150 billion (As per Current Global Market:WHO) Projection for 2050: US$5000 billion (As per WHO) Chinese Foreign Exchange: Rs 22,000 Crores Indian Share: Rs 500 Crores Chinese Plant Resource: 30% Indian Plant Resource: 30% Indian System: Time tested, trusted and well structured Chinese System: Not so well trusted and structured Some Recent Greens: Ranbaxy, HLL, Colgate

Export of Herbal Products From India

Why do you use them?1.General Health 2.Colds 3.Arthritis 4.Energy Enhancement 5.Cholesterol Lowering 0% 6.Cancer Prevention 7.Allergies 8.Weight ManagementlH ea lth Ge ne ra

0%

0%

0%

0%

0%

0%

0%

ds En e

Ch o

ri t is ha nc le em st en er ol t Lo Ca we nc ri n er g Pr ev en tio n W Al ei le gh rg tM ies an ag em en t En

Co l

rg y

Ar th

Categories of Pharmaceutical Products - 11)

Ethical pharmaceuticals: legend pharmaceuticals, patented, brand name, prescription drugs: Lipitor, Prevacid, Risperdal, etc.

2)

Generic pharmaceuticals: non-patented, prescription drugs, with bioequivalence to the legend pharmaceuticals: Atenolol, Alprazolam, Metoprolol, etc.

3) Biologics & Biological Products: Vaccines, serums, toxoids, etc. 4) Over-the-Counter Medications and

Remedies:

Bayer Aspirin, Lanacaine, Zantac 75, etc.40

Categories of Pharmaceutical Products - 25)

Homeopathic Medicines (minute quantities): Belladonna, Gelsemium, Nux Vomica, etc.

6)

Vitamins & Minerals; 7) Medicinal Botanicals & Herbal Medicines: Black Cohosh, Echinacea, Ginseng, etc.8) Botanical Extracts & Phytochemicals: p-Courmaric Acid, Chlorogenic Acid, Sulforaphane, etc. 9) Dietary Supplements: Chondroitin Sulfate, Creatine, Shark Cartilage, etc. 10) Nutraceuticals.

41

W hy do you use them?

0% G eneral Health C olds Arthritis 0% Energy Enhancem ent 0% Cholesterol Lowering 0% Cancer Prevention 0% Allergies 0% Weight M anagem ent0% 10% 20% 30% 40% 50% 60% 70%

67% 33% 50 % 0%

0%

50 %

Fe m ale M ale

4 Basic Building Blocks of Biosynthesis1. Acetyl coenzyme AMajor role in the synthesis of phenols,

prostaglandins, macrolide antibiotics, and various fatty acids and their derivatives.

2. Deoxyxylulose phosphateTogether with mevalonic acid is responsible for a

vast array of terpenoids and other steroids.

3. Mevalonic acidMajor precursor of cholesterol and other sterols.

4. Shikimic acidMajor precursor of phenylalanine, tyrosine, and

tryptophan and, hence, the majority of plant alkaloids. Also involved in the biosynthesis of lignin, flavonoids, and other aromatics.43

Figure 5

Funding Proposed for HHS Health Programs in Bush Administrations FY HRSA 2006 Budget 11 %CDC 8%

Medicare 58 %

Health Discretionary Programs 9%

IHS 6 % NIH 54 % FDA 3 % SAMHSA 6% CMS - PM 6% OS - DM 6%

SCHIP 1%

Medicaid 33 %

Notes: Totals do not include funding for the Administration on Children and Families, the Administration on Aging and Program Support Center. AHRQ funding is entirely through transfers from other HHS agencies. Totals do not add to 100% due to rounding. SOURCE: HHS, Budget in Brief FY 2006, February 2005.

Total = $592 Billion

Total = $52 . 6 Billion

CAM use in cancer and HIV patients70 60 50 40 30 20 10 0 Cancer patients N=356 HIV patients on HAART N=118 Massage therapy Acupuncture Chiropractic Mind/body therapy Herbal Any CAM use

Patterson (2002) J Alt and Comp Med 8(4):477-485 Risa (2002) Int J STD AIDS 13:706-713

Specific CAM therapies used in HIV/AIDS & palliative careHerbs & supplements Acupuncture Massage therapy Naturopathic medicine Chiropractic Mind-Body therapy

Common uses of herbs & supplements in HIV/AIDS care

Omega 3 oil as an anti-inflammatory-used to treat neuropathy High dose vitamin, mineral and antioxidant therapy to build immune system and slow disease progression Vitamin therapy--treats wasting, lack of appetite, malabsorption of nutrients Chinese herbs to treat diarrhea St. Johns Wort as antidepressant, antiviral, anti-inflammatory agent.

Effect of a vitamin and mineral supplement on infection incidence100 90 80 70 60 50 40 30 20 10 0with infection

n = 130 patients

Percent

P la c e b o T re a tm e n t

N o d ia b e te s

T y p e 2 d ia b e te s m e llitu s

Barringer et al (2003) Ann Int Med 138:365

Jennifer Aniston Pamela Anderson Boris Becker Cherie Blair Tony Blair Dina Carroll Charles, Prince Cher Cindy Crawford Sheryl Crow Queen Elizabeth Jane Fonda Richard Gere Whoopi Goldberg Jerry Hall Geri Halliwell Goldie Hawn

Atkins diet Homeopathy Homeopathy Acupuncture, Homeopathy Reflexology Magnet therapy Homeopathy Homeopathy Eskimo diet Homeopathy Homeopathy Breathing therapy Homeopathy Homeopathy Yoga Ayurveda

Madonna Sir Paul McCartney Demi Moore Kate Moss Martina Navratilova Olivia Newton-John Gwyneth Paltrow Brad Pitt Sir Cliff Richard Sarah, Duchess of York Arnold Schwarzenegger Hugo Speer Margaret Thatcher Uma Thurman Tina Turner Kate Winslet Catherine Zeta-Jones

Yoga, herbalism Alexander Lake algae Acupuncture Homeopathy Homeopathy herbalism Atkins diet Ginseng Bioenergy Breathing Yoga Ayurveda Gem therapy Homeopathy Acupuncture Homeopathy

Ernst MJA 2006; 185 (11/12): 680-681

5 Domains of CAMAlternative Medical Systems Mind-Body Interventions Biological Based Therapies Manipulative And BodyBased Methods Energy Therapies Ayurveda, Chinese, Native American, Aboriginal, African, Middle Eastern, Tibetan, Central and South American cultures, Homeopathy, Naturopathy cognitive-behavioral approaches, meditation, hypnosis, dance, music, art therapy, prayer, mental healing dietary supplements, herbs, orthomolecular (varying concentrations of chemicals, such as, magnesium, melatonin, and mega-doses of vitamins), individual biological therapies (use of laetrile, shark cartilage, bee pollen). chiropractic, osteopathic manipulation, massage

Qi gong, Reiki, therapeutic touch, bioelectromagnetic-based therapies (pulsed fields, magnetic fields, or alternating current or direct current fields)

As Defined by NCCAM

CAM Therapies

http://nccam.nih.gov/news/camsurvey_fs1.htm#domain

CAM Therapies

Pediatric Use of CAMAsthma(Bronx, NY)

80% 64% 64%

Reznik, 2003 Wilson, 2002 (NY) Braun, 2005 (MN) Sanders, 2003 Hagen, 2003

Adolescents

54-69%(Tucson, AZ) (Toronto)

Special Needs ADHD

Rheumatology

(Boston Childrens) Losier, 2005 (Ottawa) Lanski, 2003 (Atlanta)

54%

Chan et al, 2003

Emergency13-45%

Pediatric Use of CAMOncology Cerebral Palsy IBD

47-84%

McCurdy, 2003 (WFU) Neuhouser, 2001 (Seattle) Kelly, 2000 (NYC) Hurvitz, 2003

56% 41%CHOP, PA

Ann Arbor, MI

Heuschkel, 2002London, Boston, Detroit

Autism Spectrum Preoperative Primary Care

30%

Levy, 2003 Lin, 2004

29.5% 12-21%

Boston Childrens

Ottolini, 2001 (Wash D.C.)

Sawni, 2002 (Detroit)

Use of Herbs- Evidence?Alternative Health supplement of the 2002

National Health Interview Survey: data on 10 common herbs Of 30,616 adults, 19% used herbs in past 12 mo, 57% for a specific condition Approximately 2/3 used herbs (except Echinacea) not in accordance with evidence based indications

Mayo Clin Proc, May 2007;82(5): 561-566

Why Should We Care?30,000 herbs on the market currently Estimates of $30-40 billion dollars spent

annually1575

Eisenberg D. et al, JAMA, Nov 11, 1998(18) 1569-

Estimates of 42% of population use CAM

currently1575

Eisenberg D. et al, JAMA, Nov 11, 1998(18) 1569-

Sales of Metabolite 356 approached

$1billion in 1999 Alternative Medicine Alert, January 2000 Relacor $23 Million; 900,000 bottles by July 06

Overall Supplement Use

Why Should We Care? 600 Million Visits a Year to CAM Providers

More Than to Primary Care Providers Why? What is Mainstream Medicine Not

Offering to Our Patients?

E ise n b e rg D . e t a l, JA M A , N o v 1 1 , 1 9 9 8 ( 1 8 ) 1 5 6 9 1575

Nutritional Supplement Recommendations from Sloan-Kettering

20+ billion dollars are spent each year in the USA on vitamins and nutritional supplements Anti-oxidants are highly marketed and are of uncertain benefit Wheat Grass, Gogi, Noni, Acai, Pomegranate, Green Tea, Reveratrol, Vitamins A, C and E have not proven to be of any real benefit

H I H LE V E LS O F G A N TI O X I EN TS D PR O TEC T C A N C ER C E LLS A S W E LL A S H E A LT H Y C E LLS !

Impact of CAMCDC Report (2004) 36% of adults used some form of CAM 55% CAM + conventional treatments 26% used CAM because a medical professional suggested it $36-47 billion on CAM therapies in 1997 $5 billion on herbal remedies JAMA (1998) 12.1% of population use herbal medicine

Impact of CAMAccording to the National Health Statistics Report of the CDC, in 2007: 4 out of 10 adults used a CAM therapy in the last 12 months 1 out of 9 children used CAM therapies in the last 12 months Between 2002 and 2007 increased use was seen among adults for acupuncture, deep breathing, massage therapy, meditation, naturopathy, and yoga

Diseases and Conditions 20021.Back pain or problem 2.Head or chest cold 3.Neck pain or problem 4.Joint pain or stiffness 5.Anxiety/depression 6.Arthritis, gout, lupus or fibromyalgia 7.Stomach or intestinal illness 8.Severe headache or migraine*Barnes PM,et al. Complementary and alternative medicine use among adults: United States 2002; CDC

Diseases and Condition 20071.Back pain 2.Neck pain 3.Joint pain or stiffness 4.Arthritis 5.Other, specify 6.Anxiety 7.Cholesterol 8.Head or Chest Cold

Top 5 CAM Therapies 20021.Natural products, dietary supplements 2.Deep breathing exercises 3.Meditation 4.Chiropractic 5.Yoga

Top 5 CAM Therapies 2007 : Same as 2002

*Barnes PM,et al. Complementary and alternative medicine use among adults: United States 2002; CDC

Top 10 Supplements 20021.Echinacea 2.Ginseng 3.Ginkgo biloba 4.Garlic 5.Glucosamine 6.St. Johns Wort 7.Peppermint 8.Fish oil/Omega 3 9.Ginger 10.Soy

Top supplement for 2007?

*Barnes PM,et al. Complementary and alternative medicine use among adults: United States 2002; CDC

Top 10 Supplements 20071.Fish Oil or Omega 3 or 6. Combination herb pill DHA 7. Ginkgo biloba 2.Glucosamine 8. Chondrotin 3.Echinacea 9.Garlic Supplements 4.Flaxseed oil or pills 10.Coenzyme Q-10 5.Ginseng

National Health Expenditures as a % of GDP

Oil Palm PhenolicsDr. Robert WeinbergResearch Scientist, MIT

September 27, 2010

OPP lowers Blood PressureHypertension is a major cause of morbidity and

mortality globally, affect 250 million people OPP significantly blocks the rise in blood pressure in rats deficient in NO This protection of blood pressure was dosedependent Current global expenditures for antihypertensive treatment are approximately US$

Effect of OPP on Blood Pressure

OPP reduced risk of Ventricular Fibrillation (VF)Ventricular Fibrillation is a leading cause of

death in individuals suffering acute myocardial ischemia

Globally 30 million persons die annually from

Ventricular Fibrillation resulting from ischemia

OPP significantly reduces the risk of VF in rats

subjected to acute myocardial ischemia

Effects of OPP on Cardiac Arrhythmias

Cardioprotective Effects of OPPOPP results in a lower mean duration of VT

in treated rats (control, 120.535.9 vs OPP 85.226.1 s) OPP substantially reduces the incidence of VF (controls, 91% vs. OPP, 52%) OPP shortens duration of VF (control 99.821.2 vs. OPP 47.515.5) OPP substantially reduces overall mortality from myocardial ischemia (control 9/23 [40%] vs OPP 5/25 [20%])

OPP protects against DiabetesGlobally Diabetes mellitus causes substantial

morbidity and mortality affecting 180 million persons

The Nile Grass rat is an animal model of

Diabetes mellitus and metabolic syndrome in man

OPP prevents the development of Diabetes in

the Nile Grass rat

Anti-Diabetic effects of OPP

OPP blocks Cancer Tumor GrowthGlobally cancer is a leading cause of death In 2009, cancer killed over 14 million persons In 2009, over 30 million were diagnosed with

cancer Although the specific organ cancers vary from country to country, it presents a substantial annual healthcare burden costing over US$30 billion OPP substantially reduces cancer tumor growth in mice inoculated with myeloma tumors

Effect of OPP on growth of Myeloma tumors

OPP blocks Atherosclerosis progressionGlobally cardiovascular disease (CVD) resulting

from atherosclerosis is a major cause of morbidity and mortality Annually over 12 million persons die from CVD resulting from atherosclerosis Globally, in 2009, over 45 million persons are impaired or disabled by CVD In a rabbit model of CVD, OPP blocks the progression of atherosclerosis

Effects of OPP on Atherosclerosis