AstaREALAstaREAL®®

Astaxanthin: Astaxanthin: Reducing Eye fatigueReducing Eye fatigue

Clinical SummaryClinical Summary

Summary

• Eye fatigue suffers a global problem.

• Only 50% of sufferers respond to conventional measures e.g. ergonomics

• Astaxanthin alleviates eye fatigue by directly improving the ciliary body function that controls lens refraction.

• Astaxanthin reduces inflammation and improves retinal blood flow.

Eye Fatigue & Accommodation

1.1. Toyama Medical & Toyama Medical & Pharmaceutical UniversityPharmaceutical University

2.2. Fujita Health University Fujita Health University School of MedicineSchool of Medicine

3.3. Hokkaido University Hokkaido University School of Medicine x 2School of Medicine x 2

4.4. Kajita ClinicKajita Clinic

SixSix independent facility (eighteight clinical trials) demonstrated that eye fatigue and accommodation were significantly improved after AstaREAL supplementation.

1-1. 1-1. AccommodationAccommodation

A double masked study

VDT=Visual Display Terminals

5 mg astaxanthin per day or placebo during 4 weeks

0

1

2

3

4

NoSupplementation

After

Astaxanthin 5mg/ day (n=13)

Placebo (n=13)

non-VDT Subjects (n=13)

Acc

om

od

atio

n (

Dio

pte

rs)

Before

p<0.01

1-2. 1-2. Eye FatigueEye Fatigue

0

2

4

6

8

10

12

14

Before After

Astaxanthin5mg/ day Placebo

No.

of

sub

ject

s w

ith

Eye

Fati

gue

p<0.05

A questionnaire

before and after the administration period.

54% 54% reduction reduction

0

1

2

3

4

5

0 mg 2 mg 4 mg 12 mg

Before After

Acc

om

mod

atio

n (

sec.

)

A double blind study

46 eye fatigue subjects

0 mg (placebo, n=10) 2 mg (n=10) 4 mg (n=13)12 mg (n=13)Astaxanthin per day or placebo for 28 days

Dose DependentDose DependentEffect!!Effect!!

2. 2. AccommodationAccommodation

3-1. Dose Finding Study-13-1. Dose Finding Study-1

Sub-objective Accommodation PowerSub-objective Accommodation Power

0

2

4

6

0 mg 6mg 12mg

Start 4w

p<0.05

Obj

ectiv

e A

ccom

mod

atio

n P

ower

(D

)

A double blind study

30 eye fatigue subjects

0 mg (placebo, n=10) 6 mg (n=10)12 mg (n=10)Astaxanthin per day or placebo for 4 weeks

Singificantly increased by 12mg supplementation at week 4 compared to start

0

2

4

6

0 mg 6mg 12mg

Start 4w

*

3-1. Dose Finding Study-23-1. Dose Finding Study-2

Positive Accommodation TimePositive Accommodation Time

- 6mg supplementation; Significantly shortened at week 4 compared to start

- 12mg supplementation;Also significantly shortenedat week 4 comparedto start

* p<0.05

Pos

itive

Acc

omm

odat

ion

Tim

e (D

/s)

*

0

2

4

6

0 mg 6mg 12mg

Start 4wNeg

ativ

e A

ccom

mod

atio

n T

ime

(D/s

)3-1. Dose Finding Study-33-1. Dose Finding Study-3

Negative Accommodation TimeNegative Accommodation Time

- 6mg supplementation; Singificantly shortenend at week 4 compared to start & placbo

P<0.05

Optimal DoseOptimal Dose= 6mg/day= 6mg/day

3-2. Efficacy-Identification 3-2. Efficacy-Identification Study-1Study-1Sub-objective Accommodation PowerSub-objective Accommodation Power

Sub

-obj

ectiv

e A

ccom

mod

atio

n P

ower

R

ate

of C

hang

e (%

)

A double blind study

40 eye fatigue subjects

0 mg (placebo, n=20) 6 mg (n=20)Astaxanthin per day or placebo for 4 weeks

Sigificantly higher at week 2 & 4 compared to start & placebo

0

50

100

150

200

0 mg 6mg

Start 2w 4w

P<0.01

P<0.01

3-2. Efficacy-Identification 3-2. Efficacy-Identification Study-2Study-2

Pos

itive

Acc

omm

odat

ion

Tim

e R

ate

of C

hang

e (%

)

Sigificantly higher at week 2 & 4 compared to start & placebo

0

50

100

150

200

0 mg 6mg

Start 2w 4w

P<0.01

P<0.01

Positive & Negative Accommodation TimePositive & Negative Accommodation Time

Neg

ativ

e A

ccom

mod

atio

n T

ime

Rat

e of

Cha

nge

(%)

0

50

100

150

200

0 mg 6mg

Start 2w 4w

P<0.01

P<0.01

4. Accommodative recovery4. Accommodative recoveryHFC (High Frequency Component in Accommodative Mirco-Fluctuation HFC (High Frequency Component in Accommodative Mirco-Fluctuation of ciliary body)of ciliary body)

10 healthy subjects(Male: 5, Female: 5)

HFC difference was calculated between HFC at VDT (visual display terminal) working for 30min and HFC at 20min rest after VDT. The difference was measured before and after 6 mg astaxanthin/day for 2 weeks.

Increase of HFC after the rest was singificantly restrained by astaxanthin supplementation.

-4

-2

0

2

4

6

8

10

12

HF

C D

iffer

ence

Before After

P<0.05

Visual Acuity for Sports Performance

Sawaki,K. Sawaki,K. et alet al. 2002, Journal of Clinical. 2002, Journal of Clinical Therapeutics & Medicines, 18:(9) 73-88.Therapeutics & Medicines, 18:(9) 73-88.

- Double blind placebo controlled studies on male handball atheletes

- 6 mg (n=9) astaxanthin vs placebo (n=9) for 4 weeks

- Improving of depth perception & critical flicker fusion

- improved ciliary muscle function for visual acuity

Visual Acuity-1-Depth Perception-

Before Before Ex.Ex.After After Ex.Ex.

** * * p<0.05p<0.05

****

**

**

0.00.0

10.010.0

20.020.0

30.030.0

40.040.0

50.050.0

60.060.0(mm)(mm)

Before After

Treated

Before After

Placebo

Visual Acuity-2-Critical Flicker Fusion -

Before After

Treated

Before After

Placebo

30.030.030.030.0

35.035.035.035.0

40.040.040.040.0

45.045.045.045.0

**

**

Before Before Ex.Ex.After After Ex.Ex.

** p<0.05p<0.05

Photoreceptors processed light better in astaxanthin group.

Why Astaxanthin Reduces Eye Fatigue?Why Astaxanthin Reduces Eye Fatigue?

1. Retinal Blood Flow1. Retinal Blood Flow

100

150

200

250

300

Placebo Treated

0W R 4W R 0W L 4W L

p<0.01

p<0.01

Ret

inal

Blo

od F

low

A double blind study

36 healthy subjects

0 mg (placebo, n=18) 6 mg (n=18)Astaxanthin per day or placebo for 4 weeks

Singificantly increased in the astaxanthin supplemented group at week 4 in both eyes

Nagaki,Y. et al. 2005, J. Clinical Therapeutics & Medicines 21(5):537(73)-542(78).

Why Astaxanthin Reduces Eye Fatigue?Why Astaxanthin Reduces Eye Fatigue?2. Anti-Inflammation2. Anti-Inflammation

0

10

20

30

40

cont. 0 1 10 100 pred.

Infi

ltra

tin

g c

ells (

×1

05 /

ml)

p<0.01p<0.01

mg/kg

[Cellular Infiltration]

0

10

20

30

cont. 0 1 10 100 pred.

Pro

tein

Con

c.

(m

g /

ml)

p<0.01

p<0.01

mg/kg

p<0.05

[Protein]

0

50

100

150

cont. 0 1 10 100 pred.

NO

Con

c.

(μM

)

p<0.01p<0.01

mg/kg

p<0.01

p<0.01

[NO]

0

200

400

600

800

1000

cont. 0 1 10 100 pred.

TN

F-α

(

ｐｇ

/m

l)

p<0.01p<0.0

1

p<0.01

p<0.01

mg/kg

[TNF-alpha]

Ohgami,K. et al. 2003, Invest Ophthalmol Vis Sci. 44(6):2694-2701. New publication 2006 also available.

0

3

6

9

12

15

cont. 0 1 10 100 pred.

PG

E2

Con

c.

(n

g /

ml)

p<0.01

p<0.01

p<0.01p<0.01

[PGE2]

mg/kgAstaxanthin suppressed the development of endotoxin-induced uveitis in rats.

The anti-inflammatory effect of 100 mg/kg Ax was as strong as that of 10 mg/kg prednisolone.

Measured in the aqueous humor

The aqueous humor was collected 24hr after LPS treatment.

Pred.=10mg/kg Prednisolone by iv as a positive control

Eye Health -rat model-

0

10

20

30

40

cont. 0 1 10 100 pred.

Infi

ltra

tin

g c

ells (

×1

05 /

ml)

p<0.01p<0.01

mg/kg

[Cellular Infiltration]

0

10

20

30

cont. 0 1 10 100 pred.

Pro

tein

Con

c.

(m

g /

ml)

p<0.01

p<0.01

mg/kg

p<0.05

[Protein]

0

50

100

150

cont. 0 1 10 100 pred.

NO

Con

c.

(μM

)

p<0.01p<0.01

mg/kg

p<0.01

p<0.01

[NO]

0

200

400

600

800

1000

cont. 0 1 10 100 pred.

TN

F-α

(

ｐｇ

/m

l)

p<0.01p<0.0

1

p<0.01

p<0.01

mg/kg

[TNF-alpha]

K. Ohgami et al., Invest Ophthalmol Vis Sci. 44(6), 2694-2701 (2003).

Astaxanthin suppressed the development of endotoxin-induced uveitis in rats

Measured in the aqueous humor

The aqueous humor was collected 24hr after LPS treatment.

Pred.=10mg/kg Prednisolone by iv as a positive control

0

3

6

9

12

15

cont. 0 1 10 100 pred.

PG

E2

Con

c.

(n

g /

ml)

p<0.01

p<0.01

p<0.01p<0.01

[PGE2]

mg/kg

Action Mechanism of Anti-inflammation by Astaxanthin

DNA

m-RNA

COX-2

PGE₂

NO

iNOS

Pro-inflammatory response

Astaxanthin suppresses NF-kB activation

Experimental Eye Reaseach, in press

Normal iris-ciliary body LPS administration LPS + Astaxanthin　　　　　　　　　　　　　　　　　　

　　　　　

↑ NF-kB positive cells** p<0.01

NF-kB p65 were immunostained with antibodies

Green: normal nuclei Red: NF-kB p65

ConclusionAstaxanthin

- reduced ciliary muscle strain during eye fatigue*

- improved ciliary muscle function for visual acuity*

- by increasing the

retinal blood flow

- by inhibiting the

inflammation in

the eyes

*US & JP Patent pending