CREATING AN AMD · Tolentino Eye Research ... Courtesy: David Callanan, MD - Texas Retina Associates 2017 2000 Main Factors in Pathogenesis of AMD

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www.tolentinoeye.org

CREATING AN AMD CENTER OF EXCELLENCE

Florida Optometric Association

By

Michael J Tolentino, MDPartner Macula Center

Tolentino Eye Research Foundation

Associate Professor University of Central

FloridaDept of Ophthalmology

April 13, 2017


Dr. Michael Tolentino MD

• Began Retinal Research in 7th Grade

• Education: Undergraduate: Brown University, BAMedical School: University of Massachusetts, M.D.Retina Research Fellowship: Harvard Medical SchoolInternship: Harvard Medical SchoolOphthalmology Residency: Harvard Medical SchoolSurgical Retina Fellowship: University of Pennsylvania

• Faculty: Harvard/Upenn/UCF

• At Harvard: Invented anti-VEGF intravitreal injections (Avastin, Lucentis, Eylea) with J.Miller, A.Adamis, E.Gragoudas, N.Ferrara, J.Folkman

• At UPENN: Developed intraocular Gene Therapy, Invented siRNA Bevasiranib

• Principal Investigator in over 120 Retinal Clinical Trials: AREDS2, Eyelea, Lucentis, Macugen, Iluvien, PDT, Darpin, ESBA, Anti-PDGF, Anti-TIE2, Anti-C3, Anti-C5 , Eyedrops

• Founded: OPKO Health, Tolentino Eye Research Foundation

• Recently Joined the The Macula Center

• Consultant/Advisor: To many companies.

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www.tolentinoeye.orgFinancial Disclosure

• Paid Consultant/ Speakers Bureau– Regeneron, Allergan, Novartis/Alcon, Promedior, Notal Vision, Ophthotech, Gerson Lehrman, Bausch and Lomb/Valeant, Bayer, Genentech/Roche, Alimera, Thrombogenics, Allegro, Panoptica, Essilor‐Luxottica,Maculogix, Palleon Therapeutics

* Unpaid Consultant Speaker –– True Blue Vision, Macuhealth, Autogenomics, Leo Lens

• Paid Research Grants– Bayer, Ophthotech, Allergan, GlaxoSmithKline, Novartis/Alcon, Allegro, Tyrogenix, Genentech/Roche, Lpath, Pfizer, Regeneron, Thrombogenics,NEI, Notal Vision, Santen, Xoma, I‐Cos, Alimera, Astellas, Opthea.

• Stocks/Patents– OPKO Health, Esight Eyewear, Palleon

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How to create a Macular Degeneration Center in an optometric practice:

• Understand Macular Degeneration (Wet/Dry) and learn how current treatments were developed technologies that will help to diagnose AMD early.

• Understand Pathogenesis of AMD and the Central Role of Oxidation and Inflammation.

• Understand the role of high energy visible light in the pathogenesis of AMD and the need for correct protection.

• Learn about Macular pigment and how to effectively restore with triple carotenoid therapy.

• Learn to use high dose triple carotenoid therapy to prevent, enhance and eliminate the need for anti-VEGF therapy

Objective

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www.tolentinoeye.orgWhat is Macular Degeneration?

•A spectrum of disease– Early – Dry (Drusen)– Later – Wet (CNV) or Advanced Dry (Atrophy)

www.tolentinoeye.orgDry Macular Degeneration = Rust (Oxidation) ->Corrosion

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www.tolentinoeye.org Wet Macular Degeneration=New Blood Vessels


AMD Risk Factors

Family History, GeneticsDNA

Macular Pigment

Low Macular Pigment Density (MPOD)

Gender – more common in women than in men

Smoking – 3x greater risk

Outdoor Light Exposure Blue Light – 6 X Greater Risk

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www.tolentinoeye.orgDetecting AMD Early

• Eye Exam / OCT/ Photo – Sometimes difficult to detect.

• Impaired Dark Adaptation

www.tolentinoeye.org Current Treatment Standard for Wet AMD

Year 2002‐2012

Stabilizing and

even Gaining vision

Anti-VEGF changed the treatment

of CNV Paradigm

Year 1993‐2000

Purified Avastin for Intraocular use

VEGF sufficient and neccessary

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VEGF in The Eye

Invest Ophthalmol Vis Sci. 1996 Jun;37(7):1334-40

www.tolentinoeye.orgShot Seen Around The World

Avastin

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www.tolentinoeye.orgAnti‐VEGF Injections

Courtesy: David Callanan, MD - Texas Retina Associates

20002017

www.tolentinoeye.orgMain Factors in Pathogenesis of AMD

Oxidation and Inflammation are the main stimulus for VEGF upregulation in AMD.

MTNFCRP

IL-1Il-6

Macrophage

Blue Light

Free Radical

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www.tolentinoeye.orgAMD Pathogenesis

Genes

Impaired Anti-Oxidation

Impaired Complement

System

Visual Cycle+

LightLipofuscin A2E + Blue Light

Free Radical

DrusenInflammatory

DebrisAlternative Complement

Activation

ARMS

CFHC3CFBC2

Low Mac Pigment

VEGFM

TNFCRPIL-1Il-6

Macrophage

ATROPHY


Blue Light Properties that Accelerate AMD

• Photo-oxidizer

• Retina Toxic

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www.tolentinoeye.org Blue light causes photoxidation.

Algevere P, et al. Acta Ophthalmol. Scand. 2006: 84: 4–15


Blue Light Damages the Retina Chronically

LipidPeroxidation

DNA Damage

MitochondrialDamage

DecreasesCFH Production Induces Apoptosis

of Photoreceptors and RPE cells.

Algevere P, et al. Acta Ophthalmol.Scand. 2006: 84: 4–15

Razonowska et al. J Biol Chem. 1995 Aug 11;270(32):18825-30.

A2EepoxideA2E

IncreasesInflammation MCP-1.

TNF-a, Il-9

Narimatsu T et al. Experimental Eye Research, Volume 132, March 2015, Pages 48–51Increase Free

Radical Produces AutoFluorescence

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www.tolentinoeye.orgWavelength Dependent Retinal Damage

Threshold = detectable retinal damage.

Exposure time


Blue Light can damageRetina Acutely

Transient smartphone blindness

Vitrectomy Light Causes Retinal PhototoxicityBlock 475 nm or shorter Wavelength. Risk of Phototoxicity to RPE and Photoreceptors

Sakaguchi H, et al. Retinal Physician, Volume: 9, Issue: March 2012, page(s): 26 - 31

XenonPhototoxic Hazard

Mercury Vapor

Photopicspectral

sensitivity

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Blue Light Can Produce Geographic Atrophy in a Mouse

Tanito et al. IOVS,April 2007, Vol. 48, No. 4

www.tolentinoeye.orgBlue Light in AMD

Outdoor light exposure

6.5 RR >8 hrs

5.5 RR < 8 Hrs

Low Macular Pigment

Smoking -2.4 RR

Modifiable risk factors for Age Related Macular Degeneration

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Blue Light Pollution

Man has not evolved enoughto adapt to this problem.

We Have Brought Day Light Into Our Night

INDOOR LIGHTING

SMART DEVICES

SUN

www.tolentinoeye.orgLumens and Lux

Light Source Lux cd/m2

Iphone 7 705

Iphone 6 558

Samsung Galaxy 8 1020

Surface Pro 371

Very Overcast Day 100

Sunset/Sunrise 400

Overcast Day 1000

Indirect Sun 10000‐25000

Direct Sun 32000‐100000

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www.tolentinoeye.org Blue Light War

• Blue Light IS NOT Harmful– Computer Companies

• Apple, Google, Amazon, Facebook, NetFlix

– Screen Manufacturers• Samsung, Sony, Toshiba, LG

– Government• LED lights should replace all Incandescent Lights

– Environmental Groups• Lowering Carbon footprint with LED lights.

– Academics• Do not have long term data

• Blue Light IS Harmful– Eye Glass Manufacturers

– Circadian Scientists

– Sleep Scientists

– Macular Degeneration Scientists

– Macular Patients

– Post Cataract Patients

– Parents

– Sleep Deprived Patients

– Obese Patients.


What is the best way to protect against Blue Light.

1) Abstinence

2) Glasses Impregnated with Melanin Ocular Lens Pigment (External Protection)

3) Enhancing Macular Pigment ( Internal Protection)

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Melanin Protects Proportionally

Threshold =

detectable retinal damage.

Exposure time

“the wavelengths of the visible light should be

filtered in proportion to their ability to cause damage.”

Dr. Jim Gallas

Nature/Evolution has developed the pigments

OLP and Melanin to serve this purpose

“the wavelengths of the visible light should be

filtered in proportion to their ability to cause damage.”

Dr. Jim Gallas

Nature/Evolution has developed the pigments

OLP and Melanin to serve this purpose


Dr. Gallas Invented the method to Impregnate natures native protection into plastic.

20/20

Melanin OLP= Natures Anti-Blue Light

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Nothing beats nature.

Artigas et al IOVS 2012

Ocular Lens Pigment

Normal Glasses

Yellow Glasses

OrangeGlasses

www.tolentinoeye.orgAbsorption of Different Lenses and Tech

‐

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

360 370 380 390 400 410 420 430 440 450 460 470 480 490 500

1 Lens

Blue FilteringLensBlue FilteringCoatingPolycarbonate

2 Lens

3 Lens

MOLP 1

4 Lens

True BlueMelanin OLP 2

Melanin OLP 1

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As Eye Doctors it is our duty to educate our patients on the potential harmful effects of blue light overexposure and recommend EXTERNAL PROTECTION in the form of

melanin ocular lens pigment impregnated lenses the most effective way to protect against this threat

We also need to recommend Macular Pigment enhancement which represents INTERNAL PROTECTION against blue light

and as we will see an effective way of preventing and enhancing therapies against exudative macular degeneration.

.

Summary


Macular Pigment

The Maculas natural

anti‐oxidant and blue light filter.

Macular Pigment (Macula Lutea)

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www.tolentinoeye.orgMacular Pigment= Carotenoids=Meso Zeaxanthin, Lutein and

Zeaxanthin

Enantiomer

Structural isomer

MZL


Li, Ahmed, and Bernstein: 2010Department of Ophthalmology and Visual SciencesMoran Eye Center, University of Utah School of Medicine

Meso/Lutein/Zeaxanthin Most Potent Anti-Oxidant in The Macula.

LZ

M

LZM

M > Z > L

M Z LMZL

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MZL Potent Anti‐Inflammatory

AP Firidous, G Kuttan R Kuttan :Anti-inflammatory potential of carotenoid meso-zeaxanthin and its mode of action Pages

961-967 | 05 Mar 2015

M

TNF-a

CRPIL-1Il-6

LPS

M L

ComplementFactor 5-9

Complement Factor D

Adaptive Immunity Innate Immunity

Yuan Tian :The Effect of Carotenoids on the

inflammatory pathway in AMD. Dissertation Maastricht

University


MZL not just M, L or Z To Enhance MP

• FOVEAL macular pigment is mostly MezoZ

• Enhance macular pigment significantly more with MZL.

Nolan JM, Akkali MC, Loughman J, Howard AN, Beatty S.. Exp Eye Res. 2012 Aug;101:9-15.

MZL

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Oxidative Stress Upregulates VEGF

High energy visible light

Lipid and protein peroxidation

MTNFCRP

IL-1Il-6

Macrophage

www.tolentinoeye.orgLipid Peroxidation & Inflammation

Genes

Impaired Complement

System

DrusenInflammatory


Activation

CFHC3CFBC2

VEGFLipidPeroxidation

MTNFCRP

IL-1Il-6

Macrophage

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Restore Natural Macular

Anti Oxidation & Anti‐Inflammatory

Genes

Impaired Anti-Oxidation

Impaired Complement

System

Visual Cycle+

LightLipofuscin A2E + Blue Light

Free Radical

DrusenInflammatory


Activation

ARMS

CFHC3CFBC2

Low Mac Pigment

VEGFM

TNFCRPIL-1Il-6

Macrophage

Increase Macular Pigment

MZL

www.tolentinoeye.orgClinical Cases

Restoring macular pigment can reduce free radicals and

inflammation in the macula and reduce stimulus for VEGF

upregulation.

Can MZL Enhance anti‐VEGF treatment

Can MZL help with Diabetic Macular Edema

Can MZL Resolve subretinal fluid w/o injection

with normal or increasing dose of MZL

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MZL Enhances Anti‐VEGF Injections in Exudative AMD

Case CO‐ Normal Dose

Case PL‐ Normal Dose

www.tolentinoeye.org Case CO‐ Anti‐VEGF rescue75 YO male presents with metamorphopsia and blurred vision OS. Prior hx of dry AMD and family Hx of Exudative AMD. Started on Avastin.

BaseLine20/30

7/3/2012

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www.tolentinoeye.org Case CO‐ Anti‐VEGF rescue

20/504/14/2015

20/1603/17/2015

Had continuous injections of Eyelea then Avastin for 2-3 Years but worsened. Started MZL 2 x day on 3/17/15 after an injection of Avastin. Next visit patient felt improved vision.


20/406/15/2015

20/505/16/2015

Continued MZL and Avastin injections.

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20/30 7/3/2012 20/40 7/9/2013 20/50 9/23/2014

20/100 12/16/201420/160 3/17/201520/50 4/14/2015

20/505/16/2015

20/406/15/2015

www.tolentinoeye.org Case PL – Anti‐VEGF Rescue

65 YO female complains of metamorphopsia. Hx of dry AMD. 20/30 Vision OS. Gave injection of Avastin and started Macuhealth. 2/14/14

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www.tolentinoeye.org Case PL‐ Anti‐VEGF rescue

16 Mo Macuhealth3 Avastin Injs

Last 6 mo None20/40

6/30/2015

20/253/11/2014

20/302/14/14


MZL prevents need for Injections in Exudative AMD

Case RW‐ Normal Dose

Case GD‐ Normal Dose

Case JC‐ Normal Dose and Increase Dose

Case FT‐ High Dose

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www.tolentinoeye.org Case RW nl Dose no inject72 YO gentleman from UK presents with metamorphopsia and blurred vision OD. Prior hx of dry AMD and family hx of Exudative AMD.

www.tolentinoeye.org Case RW nl Dose no inject72 YO gentleman from UK presents with metamorphopsia and blurred vision OD. Prior hx of dry AMD and family Hx of Exudative AMD. Started on MZL because refused to pay for injections.

0 Mo20/30

3 Mo20/25

6 Mo20/25

MZL x 1

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www.tolentinoeye.org Case RW Summary6/26/2013

20/30

9/18/2013 20/25

12/18/2013 20/25 MZL x 1

www.tolentinoeye.org Case GD BID dose no inject69 YO female complains of metamorphopsia. Hx of dry AMD. 20/30 Vision OD. Started on MZL BID.

MZL x 2

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www.tolentinoeye.org Case GD BID dose no inject

20/30 3/2015 Base Line

20/25 4/2015 Base Line

20/25 5/2015 Base Line

www.tolentinoeye.org Case SM‐ BID Dose No inject

20/50 7/17/2015 Base Line

74 YO female complains of metamorphopsia. Presents with . 20/50 Vision OD. Started on MZL BID.

MZL x 2

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www.tolentinoeye.org Case SM‐ BID Dose No inject

20/50 7/17/2015 Base Line

20/40 8/6/2015 3 Weeks Macuhealth

20/25 6/9/2016 11 Months Macuhealth

www.tolentinoeye.org Case JC QD to TID Dose No Inject77 YO Male with wavy

vision.Refused Injections

Refused Angiogram

20/6010/22/14

20/5012/3/2014

20/608/27/14

20/609/2/2015

MZL x 1

MZL x 1

MZL x Stopped X 3 Mo

Felt better so stopped in 6/2015

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20/3011/4/15

20/3012/30/15

20/502/10/2016

20/308/17/2016

20/6012/30/2015

20/609/2/2015

MZL x 1

MZL x 2 MZL x 2

Restarted on MZL QD

Increased MZL BID

Case JC QD to TID Dose No Inject

www.tolentinoeye.org Case FT QID to BID Dose No Inj84 YO Male complains of metamorphopsia and vision Loss. Hx of dry AMD and cataracts 20/80 Vision OD. Stopped MZL 6 mo ago. Restarted on MZL QID.

4/19/2012 Prior OCT 20/20 6/20/2016 Presenting OCT 20/80

6/20/2016 Presenting Color and FA 20/80

Stopped MZL x 6

mo

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www.tolentinoeye.org Case FT QID to BID Dose No Inj

6/20/2016 Base Line 20/80

7/15/2016 20/50

9/20/2016 20/30

MZL x 4-3

MZL x 2

Stopped MZL x 6 mo

www.tolentinoeye.org Case FT BID‐QID No Injection

9/20/16 20/306/20/2016 Base Line 20/80

MZL x 2-4

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MZ is Safe

No Observed Adverse Effect Level (NOAEL) = 344 mg/kg/day344mg x 70 kg = 24080 mg or 24.08 kg per day

Dec Mutagenicity and carcinogenic potential of environmentalcarcinogens in animals. Reduced Liver Damage and Cancer


Conclusion

• MZL demonstrates biologic effect in terms of reducing intra and subretinal fluid with or without anti‐VEGF injections in Exudative AMD.

• Prescribing MZL and Melanin OLP Lenses are integral in an AMD center of Excellence.

• Detecting AMD at its earliest stage can motivate patients to start protecting their eyes with MOLP lenses and MZL supplementation.

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www.tolentinoeye.orgAMD Center of Excellence

Early Detection

Preventative Strategy

Melanin OLP

MZL


I Invite all of you in this room to see how much we can reduce

treatment burden and visual loss from AMD the natural way

www.TolentinoEye.org

www.MaculaStore.com

www.MaculaCenter.com

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Questions


Thank you

Documents

CREATING AN AMD · Tolentino Eye Research ... Courtesy: David Callanan, MD - Texas Retina Associates 2017 2000 Main Factors in Pathogenesis of AMD