Israel United States China Jamaica Brazil...Type 2 Diabetes –Animal Model •Desert Sand Rat...
Transcript of Israel United States China Jamaica Brazil...Type 2 Diabetes –Animal Model •Desert Sand Rat...
Israel BrazilUnited States China Jamaica
Making Cannabinoids Effective Type 2 Diabetes Medicine
Mark J. Rosenfeld, M.S., Ph.D. – President & Chief Science Officer
© ANANDA Scientific 2016 1
The Caribbean Nightmare
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Prevalence Highest in the Americas • 8.5% Worldwide (2014)
• Mortality Rate Among the World’s Highest: 60-80 per 100,000 people(24 in the United States)
• Complications RampantEnd-stage kidney disease (28% of diabetics), retinopathy (37%), amputation (> 936 per 100,000 in Barbados)
• More Frequent in Poorer and Elderly
© ANANDA Scientific 2016 2
Greatest Diabetes Prevalence -- Tokelau
37.5% — 4.4 Times the Global Average (8.5%)
© ANANDA Scientific 2016 3
CHINA
The Most Diabetes -- China
150 Million Type 2 Diabetics (150/431 = 35%)200-300 Million Pre-Diabetics
11.6% of Chinese Adults
© ANANDA Scientific 2016 4
How Insulin Works
IRS1, P13K & GRB2
IRS1 = insulin receptor protein substrate 1P13K = phosphoinositide 3-kinaseGRB2 = growth factor receptor binding protein 2
© ANANDA Scientific 2016 5
Diabetes: Pancreatic β-Cell Failure
Amyloid – Regulates insulin and glucagon, satiation, and gastric emptying;but toxic in excess (an issue in both type 1 and type 2 diabetes)
© ANANDA Scientific 2016 6
Normal Type 1 Diabetes Type 2 Diabetes
β-cells eliminated andreplaced with hyalineconnective tissue
β-cells loss secondary toinsulin resistance; isletamyloid made by β-cellswith insulin B chains
Fine and Rosenfeld, 2013, Rambam Maimonides Med J. 4(4):E002Fine and Rosenfeld, 2014, Curr Pain Headache Rep 18:451
Diabetes and Cannabidiol (CBD)
Aspirin, Ibuprofen, Naproxen
CBD restricts adenosine uptake by inhibiting equilibrative nucleoside transporter 1 – thus enhancing Adenosine A2A's TNF-α suppression.
Prostaglandins -- Regulators of glucose homeostasis, effects on glucose production and insulin secretion
CytokineTNF-α
‒
Adenosine A2A
Type 2 diabetes related to COX-mediated inflammation
Lipoxgenase + ‒Arichodonate
Cyclooxgenase (COX)
LeukotrienesLipoxins
ProstaglandinsThromboxanes
CBD
PhospholipaseA2
EquilibrativeNucleoside Transporter 1a
‒
++
+‒Endocannabinoid
CB1 Receptor
Anandamide
Suppresspostprandial
glycemia
Release arachidonatefrom membranes
Inhibits anandamide breakdown by fatty acid amide hydrolase
Co
rtic
ost
ero
id
© ANANDA Scientific 2016 7
▫ Non-Psychoactive
▫ No Impact on Psychomotor or Psychological Functions
▫ Chronic Use and High Doses (> 1,500 mg/day) Well Tolerated
▫ No Effect on Basic Physiological Parameters (Heart Rate, Blood Pressure, Body Temperature)
▫ No Effect on Food Intake or Gastrointestinal Transit
▫ No Catalepsy (Trance, Seizure, Unconsciousness)
▫ Co-administer CBD and Opioids without Consequence
CBD Very Safe in Humans
© ANANDA Scientific 2016 8
1 cm____
Resolving Unmet Needs:Efficient, Noninvasive (Oral) Drug Delivery
• Entry into the Blood Low when Taken by Mouth▫ 5-6% – Variable and unpredictable therapeutic results
• Oral (Capsules, Pills) Overwhelmingly Preferred▫ Convenience and ease-of-use▫ Greater adherence to treatment regimens
© ANANDA Scientific 2016 9
Smoking: Unacceptable as Medicine
• Harmful to Health▫ Same toxins, irritants and carcinogens as tobacco smoke▫ 50-70% more cancer-causing substances ▫ Precancerous lesions, bronchitis, heart disease▫ Most physicians view smoking unfavorably
• Imprecise Dosing – Unpredictable Effects
• Oral Administration Safer – Preferred by Doctorsand Patients, but with Its Own Challenges
© ANANDA Scientific 2016 10
• Varying Treatment Outcomes▫ Lack of standardization (challenging)▫ Diversity of plant strains and growing conditions▫ THC concentrates
• Unsafe –Adverse Effects (40-47%)▫ Upsurge in emergency room visits (Colorado)▫ Cardiovascular complications ▫ THC-induced paranoia
• Hyperalgesia (Increased Sensitivity to Pain)
Plant Extracts – Problematic and Unscientific
Alcohol-Processed,Whole-Plant Extract
© ANANDA Scientific 2016 11
• Degree to Which a Substance is Present in theBlood after Being Taken by Mouth
• CBD – Low Bioavailability▫ Most wasted – only 5-6% enters the bloodstream
• Predictive of Clinical Outcomes▫ Low
‒ Variable dosing and unpredictable therapeutic results‒ Compensate with larger doses
◦ Drug-induced idiosyncratic liver disease◦ Prohibitive or unaffordable drug costs
▫ High‒ Key to therapeutic success‒ Consistent dosing and predictable treatment outcomes
Oral Bioavailability
© ANANDA Scientific 2016 12
ANANDA Particulate Technology:Increasing CBD Bioavailability & Performance
Nano-Micelle Enhanced CBD
- Nanotechnology- Below 50 nm in Size- GRAS Compounds- FDA Approved- Cost Effective- Unique, Patented
- 100% Water Soluble- High Bioavailability- Enhanced Biological Performance
- Stable for Years, Even at 40 oC
CBD
CBD
- Insoluble in Water- Low Bioavailability- Barely Absorbed after Oral Administration
- Sizable Degradation in Weeks or Months
CBD
© ANANDA Scientific 2016 13
Solubility Is Key
CBD with ANANDA Particulate Technology Phase 1
Unmet NeedSuccessfully Resolved
CBD Only
Intestinal Fluid
CBD’s Poor Solubility Limits Bioavailability PartlyDue to Low Dissolution in Gastrointestinal Fluid
© ANANDA Scientific 2016 14
ANANDA’s UniqueNano-Micelles
SolubilizationTechnologies by Others
•100% Water Soluble•Crystal Clear•Odorless• Tasteless•Bacteriostatic• Stable for 3 years (at 40 oC)
•Poorly Water Soluble• Turbid or Cloudy•Pungent Odor•Bitter, Unpalatable Taste• Supports Bacterial Growth•Refrigeration Needed
95% CBD inNano-Micelles
5% CBD inNano-Micelles
50% CBDSlurry
5% CBDSlurry
ANANDA’s Nano-Micelles1,000 – 10,000 X Smaller
© ANANDA Scientific 2016 15
Enhanced CBD in Capsules and Soft Gels
•Enhanced CBD Capsules•Both Gelatin and Vegetable•Behaves Like an Oil-Based Substance, but Still 100% Water Soluble •Stable Shelf-Life – Over 12 Months
•Enhanced CBD Soft Gels
0.5 cm________
© ANANDA Scientific 2016 16
• Key to the Inflammatory Response▫ Made by activated macrophages, T lymphocytes and other immune cells
• Central to the Pathogenesis of Insulin Resistanceand Type 2 Diabetes
▫ Obesity typified by elevated TNF-α levels▫ Negative impact on insulin signaling and glucose uptake▫ Glucose uptake normal with TNF-α antibodies
• Critical Factor in the Autoimmunity That Leads toType 1 Diabetes
▫ Type 1 disease progression arrested with TNF-α antibodies
Tumor Necrosis Factor Alpha (TNF-α):A Potent Immune System Cytokine
© ANANDA Scientific 2016 17
Tumor Necrosis Factor Alpha (TNF-α):ANANDA-Enhanced CBD & Conventional Extracts
© ANANDA Scientific 2016 18
0
100
200
300
400
Control AE5 AE25 AE50ANA5
ANA25
Single Dose
* *
Whole Plant Extract5, 25 & 50 mg/kg CBD ANANDA Particulate Technology
5 & 25 mg/kg CBD
(No Treatment)
= P < 0.001, Kruskal-Wallis Test*pg = one billionth of a gram
ANANDA-Enhanced CBD & Conventional Extracts
• Significant and Sizeable Reduction in TNF-α withLesser Amounts of ANANDA-Enhanced CBD
• Extracts – Statistically Irrelevant Impact on TNF-α
ANANDA-Enhanced CBD a Prospective Therapy forStabilizing, Reversing and Maybe Even PreventingType 2 and Type 1 Diabetes
© ANANDA Scientific 2016 19
Early Type 1 Diabetes (Honeymoon)Lymphotocytic Infiltration into Islets
Type 2 Diabetes – Animal Model
• Desert Sand Rat (Psammomys obesus)
• Dead Sea Valley, Israel
• Naturally Eat Low-Caloric Vegetation
• Obesity and Type 2 Diabetes with a Laboratory Diet▫ Reach an irreversible hypoinsulinemic state within 4-6 weeks
© ANANDA Scientific 2016 20
423 Meters Below Sea Level
Type 2 Diabetes – Animal Model
• Pancreas in Hyperinsulemic Rodents Protected byEnhanced CBD, Decreased Islet and β-Cell Destruction
• Minimization of Amyloid Deposits, Virtually Disappear
• Increased Insulin Levels
• Blood Glucose Levels Reduced
• Lower Weight with Enhanced CBD – No Obesity
© ANANDA Scientific 2016 21
Damaged Islet in an Untreated Sand Rat
Healthy Islet in a CBD-Treated
Sand Rat
Fine and Rosenfeld, 2013, Rambam Maimonides Med J. 4(4):E002Fine and Rosenfeld, 2014, Curr Pain Headache Rep 18:451
CBD: A Diabetes Therapy
Aspirin, Ibuprofen, Naproxen
CBD restricts adenosine uptake by inhibiting equilibrative nucleoside transporter 1 – thus enhancing Adenosine A2A's TNF-α suppression.
Prostaglandins -- Regulators of glucose homeostasis, effects on glucose production and insulin secretion
CytokineTNF-α
‒
Adenosine A2A
Type 2 diabetes related to COX-mediated inflammation
Lipoxgenase + ‒Arichodonate
Cyclooxgenase (COX)
LeukotrienesLipoxins
ProstaglandinsThromboxanes
CBD
PhospholipaseA2
EquilibrativeNucleoside Transporter 1a
‒
++
+‒Endocannabinoid
CB1 Receptor
Anandamide
Suppresspostprandial
glycemia
Release arachidonatefrom membranes
Inhibits anandamide breakdown by fatty acid amide hydrolase
Co
rtic
ost
ero
id
© ANANDA Scientific 2016 22
© ANANDA Scientific 2016 23
Unmet Need:CBD Purification Very Costly
• Affordable Drugs = Pervasive Health Care
• Unique, Patented Methods
• Set the Stage for Affordability▫ Also, use less with enhancement technology
Pure CBD Patient-ReadySoft Gels
Thank You
MerciGracias
© ANANDA Scientific 2016 24
Contact: Mark J. Rosenfeld, M.S., Ph.D. – [email protected]