Becoming a Cutting Edge Optometric Retina Practice … · 2019-09-25 · 8/21/2019 1 Becoming a Cutting Edge Optometric Retina Practice by Michael J Tolentino, MD Director of Research

8/21/2019

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www.tolentinoeye.org

Becoming a Cutting Edge Optometric Retina Practice

byMichael J Tolentino, MD

Director of ResearchBlue Ocean

Clinical ResearchThe Macula Center A

Vision Integrated PartnersCompany

Associate Professor University of Central Florida

Dept of Ophthalmology10 5 2019

www.tolentinoeye.orgFinancial Disclosure

• Consultant/ Speakers Bureau– Regeneron, Allergan, Novartis/Alcon, Promedior, Notal

Vision, Ophthotech, Bausch and Lomb/Valeant, Bayer, Genentech/Roche, Autogenomics, Alimera, Thrombogenics, Allegro, Panoptica, Personal Dx, True Blue Vision, Essilor-Luxoticca, Macuhealth.

• 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/Founder/Executive– OPKO Health, Panther Pharmaceuticals, Aviceda

Therapeutics, Vision Integrated Partners, Blue Ocean Clinical Research

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www.tolentinoeye.orgFinancial Disclosure

• Consultant/ Speakers Bureau– Regeneron, Merck, Allergan, Novartis/Alcon, Promedior, Notal Vision,

Ophthotech, Bausch and Lomb/Valeant, Bayer, Genentech/Roche, Autogenomics, Alimera, Thrombogenics, Allegro, Panoptica, Personal Dx, True Blue Vision, Essilor-Luxoticca, Macuhealth.

• 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, Appellis, Senju, Ionis, Topcon, Optos, Mallinkrodt, Alkeus.

• Stocks/Patents/Founder/Executive– OPKO Health-Founder/Patent Holder– Panther Pharmaceuticals-Co-Founder/Share Holder – Aviceda Therapeutics-Co Founder/ CSO/Share Holder– Vision Integrated Partners- Co-founder/Partner/Share Holder– Blue Ocean Clinical Research- Co-Founder/Partner/ShareHolder– Tolentino Eye Research Foundation- Co-founder/CEO.

3


How to create a Cutting Edge Optometric Retina Practice:• Understand the importance of macular pigment and triple

carotenoid macular enhnancement therapy in eye and macular health.• Define macular pigment and its properties.

• Understand that to enhance macular pigment requires supplementation with all three carotenoids(Mezozeaxanthin, Lutein and Zeaxanthin.)

• Understand why supplementation with all 3 carotenoids is neccessaryin our patients and why diet or supplementation with 1 or 2 carotenoids is inadequate.

• Understand how dark adaptation can be used to detect early macular degeneration as a measure of RPE 65 function

• Understand how triple carotenoid therapy is an oral anti-VEGF.

• Learn from cases using triple carotenoid therapy.

Objective- Triple Carotenoid/macular pigment enhancement therapy


Clinical understanding of Macular Degeneration, Diabetic Retinopathy.



How to create a Cutting Edge Optometric Retina Practice:• Clinical understanding of Macular Degeneration, Diabetic

Retinopathy.• Understand what macular degeneration and diabetic

retinopathy represents.• Understand the Science Behind the Pathogenesis of

macular degeneration and diabetic retinopathy.• Understand how Factor X was identified to be VEGF• Comprehend the experiments that proved VEGFS role

in DR and AMD and could produce DR and AMD. • Understand the factors that upregulate VEGF in retinal

disease.

Objective- Retinal Disease pathogenesis

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www.tolentinoeye.orgThe Inspiration

“If I had an hour to solve a problem I'd spend 55 minutes thinking about the problem and 5 minutes thinking about solutions.” ― Albert Einstein (role model)

“If people say your experiment will fail or idea is wrong, don’t let that stop you just do it or just prove it correct ” ― Judah Moses Folkman MD (mentor)

Father of AngiogenesisJulie Dykman Andrus Professor of Pediatric Surgery

“There is more fulfillment in curing blindness or cancer than becoming a rock star or actor .” ― Felipe Tolentino MD ( father) Harvard Medical School OphthalmologySurgical Pioneer in Ophthalmology.


Retinal BLINDNESS

AMD* 2010, the World Health Organization estimated 5% of world’s blindness was due to AMD.* Overall, 4.41 million people worldwide are estimated blind or visually impaired from AMD.* Leading cause of blindness over 55 in US developed world* More cases of AMD than Alzheimers, Breast Cancer and Parkinsons combined* Affects 1 in 5 families.

DR*Leading cause of new cases of blindness in US adults ages 20-74 years. *Prevalence.

• ≥40 years of age with diabetes: 28.5%• Type 1 with 20-30 years’ duration: 95%• Type 2 with ≥16 years’ duration: 60%

www.tolentinoeye.orgMacular Degeneration

DRY AMD Geographic Atrophy

OXIDATION

RUSTCORROSION

WET AMD INFLAMMATION

BLISTER

NEOVASCULARIZATION

NEW BLOOD VESSELS

Oxidation+

Retinal Cell Death

+Age

InflammationChronic

InnateResponse

ProgrammedActivated

CNV GA

VEGF APOPTOSIS

www.tolentinoeye.orgDiabetic Retinopathy

Sugar

Glycation

VEGF

PDR

VEGF

Leukostasis NPDR

Inflame/Ischemia

VEGF DME

www.tolentinoeye.orgRisk Factors for DR

Xinzhi Zhang, MD, PhD; Jinan B. Saaddine, MD, MPH; Chiu-Fang Chou, DrPH; Mary Frances Cotch, PhD; Yiling J. Cheng, MD, PhD; Linda S. Geiss, MA; Edward W. Gregg, PhD; Ann L. Albright, PhD, RD; Barbara E. K. Klein, MD, MPH; Ronald Klein, MD, MPH Prevalence of Diabetic Retinopathy in the United States, 2005-2008 . JAMA. 2010;304(6):649-656


1. American Academy of Ophthalmology. Preferred Practice Pattern®: Diabetic retinopathy. Available at: http://www.aao.org/education/library/ppp/upload/Diabetic-Retinopathy.pdf. Accessed August, 2006. 2. Aiello LM, et al. In: Albert DM, Jakobiec FA, eds; Azar DT, Gragoudas ES, assoc eds; Power SM, Robinson NL, managing eds. Principles and Practices of Ophthalmology. 2nd ed. Philadelphia, PA: WB Saunders Co;2000:1900-1914.

Diabetic Retinopathy Is a Progressive Scale1,2

Microaneurysmsonly

Hg A1C - <810-15 years of DM

Mild NPDR

Proliferative DR (PDR)

1 or more of:§ Neovascularization§ Vitreous/preretinal

hemorrhage2

HgA1C > 10 20 years or more

Moderate NPDR

More than just microaneurysms but less than severe nonproliferative diabetic retinopathy

Hg A1C 8 to 1015-20 years of DM

Severe NPDR

Any of the following:§ > 20 intraretinal

hemorrhages in each of 4 quadrants OR

§ Definite venous beading in 2+ quadrants OR

§ Prominent IRMA in 1+ quadrant and no PDR

HgA1C 8 to 1015-20 years of DM

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Path To Blindness in Diabetes 30 years ago

High Sugars

Hemoglobin A1c

Increase Insulin


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Properties of Factor X

• Soluble• Potent vascular permeability

factor• Potent vascular mitogen• Upregulation by Ischemia and

hypoxia

• 1993 – Had over 100 possible candidate molecules for factor X

www.tolentinoeye.orgThe Harvard Factor X Team

Judah Folkman MDFather

ofAngiogenesis

Deceased

Tony Adamis MDYoung Harvard

Faculty Member

Global VP for Roche/

Genentech

Napoleon FerraraMD

Junior Genentech Scientist

Genentech Fellow

Inventor of Bevacizumab and

Ranibizumab

Joan Miller MDYoung Harvard

Faculty Member

First Female Chair

Harvard Ophthalmology

Michael Tolentino MDResearch Fellow

Post DocWorker Bee

Country Eye Doctor

www.tolentinoeye.orgDid VEGF have the correct

factor X properties

• Soluble - Yes

• Permeability Factor - Potent

• Vascular Mitogen – Potent

• Upregulated by hypoxia

Senger, DR; Galli, SJ; Dvorak, AM; Perruzzi, CA; Harvey, VS; Dvorak, HF. Tumor cell secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219 (4587) 983-5.1985

Shweiki D, et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843-5.

Leung D, Cachianes G. et al. Vascular endothelial growth factor is a secreted angiogenic mitogen.Science. 1989 Dec 8;246(4935):1306-9.

www.tolentinoeye.orgKochs/Tolentino Diabetic Retinopathy

Factor X Postulate

1) VEGF Found in DR.2) Can Isolate VEGF.3) Can VEGF cause

diabetic retinopathy. (Sufficient)

4) Inhibiting VEGF resolves or prevent disease progression in DR and models of DR. (Necessary)

www.tolentinoeye.orgVEGF is found correlated to severity of

retinopathy and retinal thicknessArch Ophthal (2002)120:16

Aiello LP, et al. NEJM 1995

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www.tolentinoeye.orgVEGF was cloned and produced

• VEGF-A Four alternatively spliced isoforms that vary in size.

• 2 Receptors • Homodimeric

165

121110 1

1651211101 189

189206

206Plasmin

cleavage site†

HeparinBindingDomain

VEGF ReceptorBinding Region


VEGF Binds Receptors Results in Leakage and Angiogenesis

Receptoractivation

Signaltransduction

Gene expression

ANGIOGENESISVASCULAR LEAKAGE

Nucleus

VEGF-A bindingto VEGFRVEGFR-2


VEGF Produced in Retina

1996


VEGF Causes Retinopathy

1996

www.tolentinoeye.orgVEGF PRODUCES DR

1 November 2001

www.tolentinoeye.orgVEGF PRODUCES PDR

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Intravitreal Anti- VEGF Ab Inhibits Ocular Neovascularization

1996 Intravitreal Bevacizumab

InhibitsOcular Neovascularization

www.tolentinoeye.org VEGF is Factor X

1) VEGF Found in DR.

1) Can Isolate VEGF.2) Can VEGF cause

diabetic retinopathy. (Sufficient)

3) Inhibiting VEGF resolves or prevent disease progression in DR and models of DR. (Necessary)

1) VEGF Found

1) VEGF Purified and Cloned.2) VEGF (sufficient) to produce

diabetic retinopathy when injected into a normal eye

1) VEGF (Neccesary) for DR. When inhibited DR regresses.

www.tolentinoeye.orgRedefined pathophysiology

of diabetic retinopathy

We Can Explain All The Findings in Diabetic Retinopathy with VEGF.


RETINAL ISCHEMIA? VEGF can produce capillary non perfusion

by recruiting inflammatory cells.

Y Reprinted from Miyamoto et al, Am J Pathol, 2000, 156:1733-1739 with permission from the American Society for Investigative Pathology.

ICAM


High HGA1C (AGE) worsens DR?AGE increase VEGF

Journal of Clinical InvestigationVolume 101, Number 6, March 1998, 1219–1224


Initiation of Exogenous Insulin worsens DR?Insulin Like GF increase VEGF

• Increase in insulin given to patients worsens retinopathy in the immediate initiation of Insulin therapy.

• Insulin injected into eyes increases VEGF production by the retina.

Punglia RS1, Lu M, Hsu J, Kuroki M, Tolentino MJ, Keough K, Levy AP, Levy NS, Goldberg MA, D'Amato RJ, Adamis AP. Regulation of vascular endothelial growth factor expression by insulin-like growth factor I. Diabetes. 1997 Oct;46(10):1619-26.

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www.tolentinoeye.orgHow does high sugars lead to NPDR?

High Sugars

Hemoglobin A1cAGE/Oxidation

Increase Insulin

Increase Inflammation

Initiate NPDR

Ischemia

Leukostasis

ICAM 1

Capillary nonperfusion

www.tolentinoeye.orgHow does NPDR lead to DME and PDR

Increase Inflammation

NPDRIschemia

Mac Edema

PDR

Y NVD


Managing diabetic retinopathy the state of the

art.



How to create a Cutting Edge Optometric Retina Practice:• Managing diabetic retinopathy the state of the art.

• Describe how laser reduces VEGF and results in reduction of DME.

• Understand why anti-VEGF is the standard of care for DR and DME.

• Summarize the important trials that demonstrated anti-VEGFs efficacy for DME.

• Comprehend how PDR results in true blindness with traction detachment and Vitreous hemorrhage.

• Recognize the surgeries to restore vision in end stage PDR.

Objective-Diabetic Retinopathy


ETDRS: Macular Laser Photocoagulation in DME% of Eyes With Clinically Significant Macular Edema Losing

≥15 ETDRS Letters of Visual Acuity

Years of Follow-up

0

10

20

30

1 2 3

Control

Focal Laser

24%

12%

*Vision loss: loss of 15 or more letters in the ETDRS visual acuity chartETDRS: Early Treatment Diabetic Retinopathy Study1. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol. 1985;103(12):1796-1806.

0

Vision loss slowed

% E

yes W

ith V

ision

Loss

*

1985 2008 20102005 2014

ETDRS1*

www.tolentinoeye.orgLaser causes DME to slow and PDR to Regress?

Laser reduces VEGF• Laser kills retinal cells which

reduces oxygen consumption by retina and reduces relative hypoxia.

• Reducing relative hypoxia reduces VEGF stimulation.

Pournaras CJ1, Miller JW, Gragoudas ES, Husain D, Munoz JL, Tolentino MJ, Kuroki M, Adamis AP.. Systemic hyperoxia decreases vascular endothelial growth factor gene expression in ischemic primate retina.Arch Ophthalmol. 1997 Dec;115(12):1553-8

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www.tolentinoeye.orgDiabetic Macular Edema:

Anti-VEGF

1996 2008 20102005 2014

RanibizumabRISE/RIDE Studies8*

FDA Approval

EYLEA® (aflibercept) Injection

VISTA/VIVID Studies

FDA Approval9*

VEGF Inhibitors

VEGF Sufficient

Neccessary for DR

2012 2013

Bevacizumab & Ranibizumabin pre clinical eye models

Bevacizumabused off Label for DME and

PDR

Ranibizumab

BevacizumabAflibrecept


18

45

0

10

20

30

40

50

Sham (n=127) Ranibizumab 0.3 mg(n=125)

RISE

12

34

0

10

20

30

40

50

Sham (n=130) Ranibizumab 0.3 mg(n=125)

RIDE

RISE/RIDEIntravitreal Ranibizumab in the Treatment of DME

P≤0.01P≤0.01

% of Patients Gaining ≥15 ETDRS Letters at 24 Months† (Primary End Point)

Mean Change in BCVA over 24 Months‡ (Secondary End Point)

*P<0.001 v s. sham†Compared with baseline in Early Treatment Diabetic Retinopathy Study Best-Corrected Visual Acuity‡BCVA assessed using the ETDRS methodETDRS=Early Treatment Diabetic Retinopathy Study; BCVA=best-corrected visual acuity; Sham=sham injections; rescue laser allowed starting at month 3 (All patients were ev aluated monthly for the need for rescue laser beginning at month 3)Median number of ranibizumab injections: 24 (study design required monthly dosing)Approv ed dose: 0.3 mg monthly (based on an ev aluation of efficacy and safety in RIDE/RISE)Nguy en QD et al. Ophthalmology. 2012;119(4):789-801.Lucentis (ranibizumab injection) [Prescribing Information]. South San Francisco, CA. Genentech. Inc. Feb 2014.

15

10

5

00 4 8 12 16 20 24

Month

*

RISE

Day 7

15

10

5

00 4 8 12 16 20 24

Month

RIDE

Day 7

% o

f Pat

ient

s

Mea

n Ch

ange

in B

CVA,

ET

DRS

Lett

ers

2.3 Sham

10.9* Ranibizumab

0.3 mg

12.5* Ranibizumab

0.3 mg

2.6 Sham


02468

101214

0 4 8 12 16 20 24 28 32 36 40 44 48 52

02468

101214

Week

VIVID

VISTA

Vista/Vivid Treatment for DME: Mean Change in Visual Acuity at Week 52*

P<0.01 Both EYLEA groups vs. control at week 52

P<0.01 Both EYLEA groups vs. control at week 52

VISTA – Control: n=154; 2q4: n=154; 2q8: n=151; VIVID – Control: n=132; 2q4: n=136; 2q8; n=135Control=macular laser photocoagulation at baseline and then as needed; 2q4=EYLEA 2 mg ev ery 4 weeks; 2q8=EYLEA 2 mg ev ery 8 weeks; BCVA= best-corrected v isual acuity; ETDRS=Early Treatment Diabetic Retinopathy Study*BCVA change f rom baseline, as measured by mean ETDRS letters; FAS, LOCF. † Following 5 initial monthly doses (every 4 weeks)Korobelnik JF et al. Ophthalmology. 2014 Jul 8. [ePub ahead of print.]EYLEA® (af libercept) Injection full U.S. Prescribing Information. Regeneron Pharmaceuticals, Inc. July 2014.

EYLEAGroups and Control

BCVA

, Mea

n Ch

ange

From

Bas

elin

e,ET

DRS

Lett

ers

12.5 EYLEA 2q4

10.7 EYLEA 2q8†

0.2 Control

10.5 EYLEA 2q4

10.7 EYLEA 2q8†

1.2 Control

www.tolentinoeye.orgProliferative Diabetic RetinopathyThe truly blinding form of diabetic

Retinopathy!How Do We Treat This?

Proliferative Diabetic RetinopathyThe truly blinding form of diabetic

Retinopathy!How Do We Treat This?

www.tolentinoeye.orgCase PDR Resolution

w/RanibizumabScreening Month 24 High risk PDR ( 71A)Mild NPDR ( 35 E)


Traction Detachment

Traction Detachment 20/20

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Vitreous Hemorrhagewww.tolentinoeye.org

Vitreous Surgery- How we treat VHb and Traction Detachments

Vitreous Surgery XII. New Instrumentation for Vitrectomy Felipe I. Tolentino, MD; Anton Banko, ME; Charles L. Schepens, MD; Hsiao-su Liu, MD; Leslie W. Nesmith, MD; H. MacKenzie Freeman, MDArch Ophthalmol. 1975;93(8):667-672.

www.tolentinoeye.orgCurrent

Microincisional Vitrectomywww.tolentinoeye.org

Diabetes Summary

• Early monitoring By Optometrists can lead to rapid referral to a retina specialist at first sign of diabetic retinopathy.

• Anti-VEGF therapy standard of care for all forms of diabetic retinopathy.

• An optometrist in close realtionship with a retina specialist can prevent blindness in diabetic patients.


Protecting patients vision using Melanin Pigment Impregnated True Blue

Lenses.



How to create a Cutting Edge Optometric Retina Practice:Protecting patients vision using Melanin Pigment Impregnated True Blue Lenses.

• Understand the role of blue light, oxidation, innate inflammation and VEGF on the pathogenesis of macular degeneration.

• Learn why computer, e-device, LED, fluorescent and day light kill retinal cells while initiating and propogating macular degeneration both wet and dry.

• Comprehend why only Melanin/Biologic pigment impregnated lenses (True Blue Lenses) are the only way to effectively protect maculas from degeneration.

Objective-True Blue Light Protection

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Oxidation Upregulates VEGF

1996

www.tolentinoeye.orgBevacizumab reduced leakage

Jan 2000

www.tolentinoeye.orgSiRNA against VEGF inhibits CNV

25 May 2003

www.tolentinoeye.org Current Treatment Standard in Wet AMD

Year 2002-2012

Stabilizing and

even Gaining vision

VascularEndothelial

Growth Factor Anti-VEGF

changed the treatment

of CNV Paradigm

Year 1993-2000

Purified Avastin for Intraocular use

VEGF sufficient and neccessary

Brolucizumab DARPIN

LMZ


Blue Light Main Source of Oxidation and Programmed Cell Death for Macula

O2-

O2-

445 NM Blue LightAll Trans Retinal

IOL Magnifies Blue Light By 1,250,000 XAimed at the Macula

Iphone Blue Light equal to Sunset Overcast Day

1 Cigarette Produces10 15 Free radicals

Photoreceptor Programmed Cell Death


Blue Light Pollution a new threat to the modern world

Man has not evolved enoughto adapt to this problem.

We Have Brought Day Light Into Our Night

INDOOR LIGHTING

SMART DEVICES

SUN445 NMBlue Light

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www.tolentinoeye.orgLumens and Lux

Light Source Lux cd/m2Iphone 7 705

Iphone 6 558

Samsung Galaxy 8 1020

Surface Pro 371Very Overcast Day 100

Sunset/Sunrise 400

Overcast Day 1000

Indirect Sun 10000-25000

Direct Sun 32000-100000


Refraction = Blue Light Magnification on The Fovea

Lenses FocusOxidative BlueLight on the

Fovea. Magnify Energy

I=(rl/0.1mm)2 1kW/M2

250,000 x increase in energy of the blue light


445 nm Blue Light activatesPIP2 mediated cell death.

445 NM Blue Light

Ratnakyake A et al. Scientific Reports | (2018) 8:10207

All Trans Retinal

Phosphotidylinositol 4,5 biphosphateBlue Light Activation

PIP2

www.tolentinoeye.org 445 NM Blue Light+ Retinal is The Suicide Switch

445 NM Blue Light

All Trans Retinal

Photoreceptor/RPE CellHari Kari


Dry AMD

Normal

OXIDATION LEADS TO AMD

59

Geographic Atrophy Wet AMD

Neovascularization

Dry AMD

Drusen

O-2

2-(ω-carboxyethyl)Pyrrole (CEP) DHA

Malondialdehyde(MDA) PUFA

+

COMPLEMENT ACTIVATION

Macrophage ACTIVATION

M1 M1+ M2

VEGF

BLUE

CFH Y402H

Blue Light Cell Death

PHOTOOXIDATIONBlue Light

OXIDATIVEBYPRODUCTS

Cannot Deactivate Complement


How can you Prevent AMDHow does nature protect the macula?

• DRY– Filter Blue Light

• External • Internal

– Anti-oxidant– Anti-Inflammatory

• Wet– Stop VEGF upregulation

Pigment is NATURES NATURAL PROTECTANT

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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


Blue Light Can Produce Geographic Atrophy in a Mouse

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


Dr. Gallas Invented the method to Impregnate natures native protection into plastic. 20/20

Melanin OLP= Natures Anti-Blue Light

Melanin/OLPMelanin/OLP

Uniform distribution

No pigment clumping

Combined with polarization

Cannot be surpassed technologicallyFor filtering the most harmful spectrum of Blue light.


Al l Trans Retinal Activation at 445nm

Melanopsin Peak Spectral Sensitivity

420 Cut off of Al l other blue blocking tech

96% ProtectionTB Vista Sun Polarized

80% ProtectionTB Vista Pro Plus

60 % ProtectionTB Vista Lifestyle

10- 30 % ProtectionBest Blue Blocking Competitor

True Blue Protection Technology

www.tolentinoeye.org Real protection Against Iphone ScreensAll Trans Retinal Activation at 445nm






2-17% ProtectionBest Competitor

www.tolentinoeye.org Real Protection against SunlightAll Trans Retinal Activation at 445nm






10- 30 % ProtectionBest Competitor

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www.tolentinoeye.org True Blue Protection Factor- Developed With Dr. Jim Gallas- Percentage under the curve in terms of blue spectrum protection.- Tested 23 different blue filtering lenses only lenses that have - Blue protection factor > 50 are TRUE BLUE LENSES.- This is the only REAL blue light protection technology

amongst all the FAKE.

https://www.truebluevision.com

External Macular Protection

www.tolentinoeye.orgTrue Blue Lenses

True Sun and Computer Light Protection


Understand the importance of macular pigment and triple

carotenoid macular enhnancement therapy in eye

and macular health.


www.tolentinoeye.org Macular PigmentInternal Macular Protection

Eccentricity, mm-15 -10 -5 0 5 10 15

Lute

in/z

eaxa

nthi

n ra

tio

0.0

0.5

1.0

1.5

2.0

2.5

Mes

o-ze

axan

thin

/zea

xant

hin

ratio

0.2

0.4

0.6

0.8

1.0

L/Z ratio

MZ/Z ratio

Inner Medial Outer

Tota

l L &

Z (p

mol

es)

0

20

40

6062%

p=0.000273%

p=0.01479%

p=0.05

0-5o 5o-19o 19o-38o

L & Z in the retina: AMD vs. Controls

AMDControl

Bone, Landrum et al Invest. Ophthalmol. Vis. Sci., 2001. 42: p. 235-240.

Macular Pigment Lower in AMD Patientswww.tolentinoeye.org

MACULAR PIGMENT FILTERS HARMFUL BLUE LIGHT

lutein zeaxanthin

meso-zeaxanthin

macular pigment

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

Meso/Lutein/Zeaxanthin Macular Pigment

Most Potent Anti-Oxidant in The Macula.

L ZM

LZM

M > Z > LM Z L

www.tolentinoeye.orgMacula Pigment 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-aCRPIL-1Il-6

LPS

ComplementFactor 5-9

Complement Factor D

Innate Immunity

Yuan Tian :The Effect of Lutein on the inflammatory

pathway in AMD. Dissertation Maastricht

University

MezoZea

xanthinLutein

LMZ


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


24 mg / day LMZ IncreasesMacular Pigment

0 3 6 9 12

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

MPOD

(460

nm), 3

0' ret

inal e

ccen

tricity

Time (months)

Macular pigment optical density

LMZ Supplements Increases Macular Pigment

. Exp Eye Res. 2012 Aug;101:9-15.

LMZ

LMZ

www.tolentinoeye.orgWHY WE NEED MZ

Inflammation

Oxidation

Age

MezoZeaxanthin

Macular Pigment

Visual CycleWorsenDark adaptation

Lutein MesoZeaxanthin

RPE 65

www.tolentinoeye.orgRPE65 activity as a measure of AMD

Dark Adaptation vs Removing EyeballPNAS ∣ October 12, 2010 ∣ vol. 107 ∣ no. 41 ∣ 17551–17556

The American Journal of Pathology, Vol. 187, No. 3, March 2017

Lutein Mezo

Zeaxanthin

How do we measure RPE65 activity?

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Measures dark adaptation quickly and effectively in a clinical setting.

Dark Adaptation is the Best Biomarker for Progression of Macular Degeneration

79

High Sensitivity: • Correctly identified 90.6% of

confirmed AMD casesHigh Specificity: • Correctly identified 90.5% of

confirmed normal casesHigh Accuracy:• 90.6% overall accuracy


8 Year Clinical Experience with Triple Carotenoid Therapy

True Blue Lenses

PI in 150 Clinical Trials In Retina Over 1000 patients recruited in 10 years



LMZ


Dry AMD

Normal

MZL and True Blue Protection

81

Geographic Atrophy Wet AMD

Neovascularization

Dry AMD

Drusen

O-2

2-(ω-carboxyethyl)Pyrrole (CEP) DHA

Malondialdehyde(MDA) PUFA

+

COMPLEMENT ACTIVATION

Macrophage ACTIVATION

M1 M1+ M2

VEGF

BLUE

CFH Y402H

Blue Light Cell Death

PHOTOOXIDATIONBlue Light

OXIDATIVEBYPRODUCTS

Cannot Deactivate Complement

MZL

LMZ

LMZ LMZ

LMZ

LMZ


HYPOTHESIS

1) LMZ Supplementation can slow progression of Dry Macular

Degeneration2) LMZ Supplementation can be

used to Reduce Injections.

www.tolentinoeye.orgStops Dry AMD progression

Improves Vision• Compare

– Hi Lutein/Zea vs MZ/L/Z• Contrast Sensitivity improves

more with MZ/L/Z• No Progress with MZ/L/Z

www.tolentinoeye.org85 y.o. Female Dry AMD

June 2010 VA 20/40

Dec 2013 VA 20/30

1 X Day

30 Months

REDUCED CENTRAL DRUSEN

LMZ

8/21/2019

15

www.tolentinoeye.org83 Yo Female Dry AMD

March 2013 VA 20/40

March 2015 VA 20/30

1 X Day

24 Months


LMZ

www.tolentinoeye.org 76 Yo Female Dry AMD

April 2013 VA 20/40

October 2014 VA 20/40

1 X Day

18 Months


LMZ

www.tolentinoeye.org57 Yo Female PED

Nov 2016 VA 20/30-2

March 2017 VA 20/20-2

1 X Day

5 Months

REDUCED SUBRETINAL FLUID

LMZ

www.tolentinoeye.org LP-Drusenoid PED

20/3011/11/2014

20/256/11/2015Drusenoid

PED Resolves

73 YO female with decreasevision started on MZL.

ELIMINATES DRUSENOID PED

7 Months

www.tolentinoeye.org Early Wet AMD72 YO gentleman from UK presents with metamorphopsia and blurred vision OD. Prior hx of dry AMD and family hx of Exudative AMD. No insurance did not want to get injections. Did not qualify for clinical trial vision too good. 20/30

www.tolentinoeye.org Early Wet AMDStarted on MZL QD and followed every 3 months. Patient did not want to pay for to frequent visits and said would return if vision worsened. Claims Vision improved and metamorphopsia resolved.

0 Mo20/30

3 Mo20/25

6 Mo20/25

LMZx1

ELIMINATE SUBRETINAL FLUID NO INJECTIONS

8/21/2019

16

www.tolentinoeye.org 65 YO female Serous PED

February 2014VA 20/50

March 2014VA20/25

1 X Day

1 Months

1 Avastin

ELIMINATE SEROUS PED 1 INJECTION

LMZ

www.tolentinoeye.org Case 65 YO female Serous PED

February 2014VA 20/50

March 2014VA20/25

1 X Day

1 Months

1 Avastin

June 2015 VA20/25

1 X Day

16 Months

3 Avastin

ELIMINATE SEROUS PED Long Term

LMZ

LMZ

www.tolentinoeye.org Serous PED75 YO male presents with metamorphopsia and blurred vision OS. Prior hx of dry AMD and family Hx of Exudative AMD.

BaseLine20/30

July 2012

www.tolentinoeye.org Anti-VEGF rescue

20/40July 2013

10 Avastins

20/50August 2014

9 Eyeleas

12 Months

12 Months


20/50Sept 20141 Avastin

20/100December 2014

3 Avastins

Due to insurance switched back to Avastin.

1 Months

3 Months


20/504/14/20151 Avastin

20/1603/17/20153 Avastins

3 Months

1 Month

Introduce LMZ and combined with Avastin Injection

LMZ

8/21/2019

17


20/406/15/20151 Avastin

20/505/16/20151 avastin

Continued MZL and Avastin injections.

1 Months

LMZ

LMZ


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

Enhances AVASTIN EFFICACY

LMZ


JP Wet AMD No Inject77 YO Male with wavy

vision.Refused InjectionsRefused Angiogram

20/6010/22/14

20/5012/3/2014

20/608/27/14

20/609/2/2015

LMZ x 1

LMZ x 1

LMZ Stopped X 3 Mo

Felt better so stopped in 6/20152 Months

2 Months9 Months


20/3011/4/15

20/3012/30/15

20/502/10/2016

20/308/17/2016

20/6012/30/2015

20/609/2/2015 LMZ x 1

LMZ x 3 LMZ x 3

Restarted on MZL QD

Increased MZL TID

JP Wet AMD No Inject

3 Months

3 Months 6 Months


6 Months6 Months

JP Wet AMD No Inject

20/2011/27/2017

20/203/22/2018

20/309/7/2018

LMZ x 2LMZ x 1

LMZ x 3IF NO INJECTIONS NEED TO CONTINUE ON HIGH

DOSE

14 Months

www.tolentinoeye.org Case 68 Yo Male PED

6 Months4 Months

20/4010/16/2017

20/302/23/2018

20/209/28/2018

LMZ x 2 LMZ x 4No injections Step Father of Retina

Specialist

LMZ x 3

8/21/2019

18

www.tolentinoeye.orgFT-No Injection Hi Dose

84 YO Male complains of metamorphopsia and vision Loss. Hx of dry AMD and cataracts 20/80 Vision OD. Stopped MZL 6 mo ago. Started on MZL BID.

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

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

Stopped LMZ x 6

mo

www.tolentinoeye.orgFT-No Injection Hi Dose

6/20/2016 Base Line 20/80

7/15/2016 20/50

20/25 9/16/16 20/30

LMZ x 4

LMZ x 4

Stopped LMZ x 4 day

I USE THIS TO TREAT MY FATHER


I Invite all of you in this room to become a cutting edge retinal

optometrist

LMZ

Internal Protection External Protection

Early Detection


I was not good enough to be a rock starBut I am pretty good at saving peoples vision

Most Outstanding Filipino Medical ResearcherOphthalmologist


Questions email me at [email protected]

Documents

Becoming a Cutting Edge Optometric Retina Practice … · 2019-09-25 · 8/21/2019 1 Becoming a Cutting Edge Optometric Retina Practice by Michael J Tolentino, MD Director of Research