Supplementary Material Lipid-based therapy for ocular surface inflammation and disease



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Supplementary Material


Lipid-based therapy for ocular surface inflammation and disease
Agnes Lim1, Markus R. Wenk2,3,4 and Louis Tong1,5,6,7
1 Duke-NUS Graduate Medical School, Singapore

2 Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore

3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

4 Department of Biological Sciences, National University of Singapore, Singapore

5 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

6 Ocular Surface Research Group, Singapore Eye Research Institute, Singapore

7 Department of Cornea and External Eye Disease, Singapore National Eye Center, Singapore
Corresponding author: Louis Tong (Louis.tong.h.t@snec.com.sg)
Table S1. Details of studies on omega-3 and omega-6 fatty acid supplementation


Study type

Lipid pathway

Study subject

Sample size

Intervention

Duration

Effect of treatment compared to control

Ref.

Randomised controlled trial

Omega-3

Dry eye patients

Omega-3:

n = 264
Placebo:

n = 254


Oral omega-3 vs corn oil placebo

3 months

Improved subjective dry eye symptom score, TBUT*, Schirmer’s score

[S1]

Randomised controlled trial

Omega-3

Dry eye patients

Omega-3:

n = 240
Placebo:

n = 256


Oral omega-3 vs corn oil placebo

6 months

Improved subjective dry eye symptom score, TBUT, Schirmer’s score

[S2]

Randomised controlled trial

Omega-3

Dry eye patients

Omega-3:

n = 220
Placebo:

n = 236


Oral omega-3 vs olive oil placebo

3 months

Improved subjective dry eye symptom score, TBUT, Schirmer’s score

[S3]

Randomised controlled trial

Omega-3

Dry eye patients

Total:

n = 30


Oral omega-3 with anti-oxidants vs no oral supplements

3 months

Improved subjective dry eye symptom score, reduced tear pro-inflammatory cytokines

[S4]

Mouse model

Omega-3

Dry eye induced by scopolamine and desiccating stress

Not stated

Eye drops containing 0.2% omega-3 with 0.1% HA vs 0.1% HA

10 days

Reduced corneal surface irregularities, fluorescein staining and tear pro-inflammatory cytokines

[S5]

Randomised controlled trial

Omega-6

Sjogren’s syndrome patients with dry eye

Omega-6:

n = 20
Placebo:

n = 20


Oral omega-6 vs excipient placebo

1 month

Improved subjective dry eye symptom score, reduced fluorescein staining, increased tear prostaglandin E1

[S6]

Randomised controlled trial

Omega-6

Dry eye patients

Omega-6:

n = 13
Placebo:

n = 13


Oral omega-6 vs sugar placebo

45 days

Improved subjective dry eye symptom score, reduced lissamine green staining

[S7]

*TBUT: Tear film break-up time, which measures tear film stability. Large TBUT values indicate increased stability. Schirmer’s score measures tear production. Large Schirmer’s scores indicate increased tear production. Both fluorescein and lissamine green staining of the cornea indicate corneal damage, and increased staining indicates increased damage.
Table S2. Details of clinical trials involving lipid pathways.


Study type

Lipid pathway

Study subject

Sample size

Intervention

Duration

Effect of treatment compared to control

Ref.

Randomised controlled trial



Cyclo-oxygenase (COX)

Dry eye patients

Pranoprofen:

n = 30
Control:

n = 30


Eye drops containing 0.1% pranoprofen with 0.1% HA vs 0.1% HA

30 days

Improved OSDI§ and TBUT*

[S8]

Randomised controlled trial

COX

Sjogren’s syndrome patients with filamentous keratitis

Diclofenac:

n = 14
Control:

n = 16


Eye drops containing 0.1% diclofenac vs 5% NaCl

28 days

More rapid improvement in subjective dry eye symptoms

[S9]

Rabbit model

COX

Dry eye induced by atropine

n = 3 rabbits per group

Eye drops containing 0.1% nimesulide or 0.5% ketorolac vs untreated

17 days

Improved Schirmer’s score, TBUT and reduced fluorescein staining with nimesulide or ketorolac treatment

[S10]

Rabbit model

Lipoxygenase (LOX)

Inflammatory keratitis model

LOX inhibitor:

n = 8


Control:
n = 16

Eye drops containing LOX inhibitor vs vehicle control

27 days

Reduced leukocyte infiltration, neovascularisation and edema formation

[S11]

Mouse model

Resolvin E1 (RvE1)

Dry eye induced by scopolamine and desiccating stress

n = 3 mice per condition

Eye drops containing RvE1 vs vehicle control

5 days

Preservation of conjunctival goblet cells and reduced fluorescent dye staining

[S12]

Mouse model

Resolvin E1

Dry eye induced by atropine

RvE1:

n = 13


Vehicle:

n = 7


Eye drops containing RvE1 vs vehicle control

11 – 21 days

Improvements in Schirmer’s score, and corneal epithelial density

[S13]

Phase II clinical trial

Resolvin E1

Dry eye patients

n = 232 patients

Eye drops containing RvE1 vs placebo

28 days

Improvements in subjective dry eye symptoms

[S14]

Randomised controlled trial

Tear film lipid augmentation

Dry eye patients

Cationorm®:

n = 44
Control:


n = 35

Cationorm® (cationic lipid) eye drop vs non-lipid -containing control

28 days

Greater improvements in TBUT and lissamine green staining

[S15]

Randomised controlled trial

Tear film lipid augmentation

Dry eye patients

Systane® Balance:

n = 25
Control:



n = 24

Systane® Balance (anionic lipid) eye drop vs saline control

28 days

Greater improvements in TBUT scores, corneal staining and goblet cell density

[S16]

Randomised controlled trial

Meibomian gland lipid composition

Meibomian gland dysfunction patients

n = 30 patients

Eyelid warming vs baseline

12 weeks

Decreased lysophospholipids, increased OAHFAs††, decreased ocular evaporation compared to baseline

[S17]

Rabbit model

α-lipoic acid

UVA-induced corneal oxidative damage

n = 5 rabbits per group

Intraperitoneal α-lipoic acid vs untreated

90 days

Reduced oxidative damage

[S18]

Mouse model

α-lipoic acid

UVB-induced corneal oxidative damage

n = 10 mice per group

Oral α-lipoic acid vs untreated

10 days

Reduced oxidative damage, reversed tear reduction

[S19]

























*TBUT: Tear film break-up time, which measures tear film stability. Large TBUT values indicate increased stability. Schirmer’s score measures tear production. Large Schirmer’s scores indicate increased tear production. Both fluorescein and lissamine green staining of the cornea indicate corneal damage, and increased staining indicates increased damage. §OSDI: Ocular surface disease index, which measures the severity of dry eye disease. Increased OSDI score indicates increased severity. ††OAHFAs: O-acyl-ω-hydroxy-fatty acids.
Table S3. Lipid composition and formulation of selected commercially available lipid-based eye drops/sprays.


Product

Company

Formulation

Lipid

Refresh Endura®

Allergan

Emulsion

Castor oil

Refresh Optive® Advanced

Allergan

Emulsion

Castor oil

Artelac®

Bausch & Lomb

Emulsion

Mineral oil

Lipimix®

Tubilux

Emulsion

Phospholipid

Cationorm® (Retaine MGD)

Novagali

Cationic emulsion

Medium chain triglyceride

Systane® Balance

Alcon

Anionic emulsion

Dimyristoyl phosphatidylglycerol
Mineral oil

Tears Again®

OcuSoft

Liposomal spray

Phospholipid


Table S4. The ratio of specific tear lipid to total lipids before and after lid warming therapy for 12 weeks in meibomian gland dysfunction patients (n=32).

Lipid*

p value

baseline ratio(X10-4)

post treatment(X10-4)

% change

 

 

mean

SD

mean

SD

mean

OAHFA18:1/30:1

0.000197

12.01

3.40

15.27

5.31

27.18

OAHFA18:2/34:1

0.000271

1.83

0.73

2.68

1.28

46.41

OAHFA16:1/34:1

0.000351

1.52

0.68

2.10

0.99

38.80

OAHFA18:1/31:0

0.000488

1.71

1.12

2.45

1.55

43.91

LPI18:0

4.08x10-6

9.17

5.44

2.52

3.37

-72.49

LPI20:4

6.32x10-6

0.49

0.31

0.16

0.16

-67.74

LPI16:0

0.000383

0.80

0.52

0.27

0.48

-66.52

LPC20:4

6.18x10-6

0.88

0.57

0.34

0.30

-61.66

LPC16:0e

1.54x10-5

1.37

0.87

0.44

0.49

-67.65

LPC18:0

2.55x10-5

12.62

8.24

8.50

7.13

-32.62

LPC16:1

3.56x10-5

1.92

1.27

0.68

0.87

-64.55

LPC18:2

3.81x10-5

8.44

7.02

3.32

4.32

-60.62

LPC18:0e

5.17x10-5

3.41

1.95

1.37

1.51

-59.77

LPC18:1

0.000135

24.90

15.57

10.95

12.33

-56.02

LPC16:0

0.000181

94.82

59.90

37.94

46.75

-59.99

LPE16:0

6.8x10-6

6.28

4.33

4.04

3.77

-35.64

LPE18:0p

5.58x10-5

88.44

53.25

40.69

33.17

-54.00

LPE20:1p

6.61x10-5

6.87

4.30

3.35

2.24

-51.22

TAG56:8(18:2)

0.000123

0.06

0.04

0.03

0.02

-58.19

PE36:2

0.000144

7.08

10.76

13.70

12.82

93.61

PS38:3

0.00034

1.14

1.29

2.11

2.14

85.40

*only the 21 most significantly changed lipids (by paired t-test) are shown.



e: ether linkage; p: plasmalogen species 

OAHFA: O-acyl-ω-hydroxy-fatty acid; LPI: lysophosphatidylinositol; LPC: lysophosphatidylcholine; LPE: lysophosphatidylethanolamine; TAG: triacylglyceride; PE: phosphatidylethanolamine; PS: phosphatidylserine. Based on [S17].



Supplementary references
S1 Bhargava, R. et al. (2013) A randomized controlled trial of omega-3 fatty acids in dry eye syndrome. Int J Ophthalmol 6, 811–816

S2 Bhargava, R. and Kumar, P. (2015) Oral Omega-3 Fatty Acid Treatment for Dry Eye in Contact Lens Wearers. Cornea 34, 413–420

S3 Bhargava, R. et al. (2015) Oral omega-3 fatty acids treatment in computer vision syndrome related dry eye. Cont Lens Anterior Eye 38, 206–210

S4 Pinazo-Durán, M.D. et al. (2013) Effects of a nutraceutical formulation based on the combination of antioxidants and ω-3 essential fatty acids in the expression of inflammation and immune response mediators in tears from patients with dry eye disorders. CIA 8, 139–148

S5 Li, Z. et al. (2014) Effects of Eye Drops Containing a Mixture of Omega-3 Essential Fatty Acids and Hyaluronic Acid on the Ocular Surface in Desiccating Stress-induced Murine Dry Eye. Curr Eye Res 39, 871–878

S6 Aragona, P. et al. (2005) Systemic omega-6 essential fatty acid treatment and pge1 tear content in Sjögren's syndrome patients. IOVS 46, 4474–4479

S7 Barabino, S. et al. (2003) Systemic linoleic and gamma-linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea 22, 97–101

S8 Liu, X. et al. (2012) The effect of topical pranoprofen 0.1% on the clinical evaluation and conjunctival HLA-DR expression in dry eyes. Cornea 31, 1235–1239

S9 Avisar, R. et al. (2000) Diclofenac sodium, 0.1% (Voltaren Ophtha), versus sodium chloride, 5%, in the treatment of filamentary keratitis. Cornea 19, 145–147

S10 EL-Shazly, A. et al. (2008) Comparison between two cyclooxygenase inhibitors in an experimental dry eye model in albino rabbits. Acta Pharmaceutica 58, 163–173

S11 Verbey, N.L. et al. (1988) Modulation of immunogenic keratitis in rabbits by topical administration of inhibitors of lipoxygenase and cyclooxygenase. Curr Eye Res 7, 361–368

S12 de Paiva, C.S. et al. (2012) Resolvin E1 (RX-10001) reduces corneal epithelial barrier disruption and protects against goblet cell loss in a murine model of dry eye. Cornea 31, 1299–1303

S13 Li, N. et al. (2010) Resolvin E1 improves tear production and decreases inflammation in a dry eye mouse model. J Ocul Pharmacol Ther 26, 431–439

S14 Resolvyx Pharmaceuticals : News & Publications - Press Releases. resolvyx.com. [Online]. Available: http://www.resolvyx.com/news-pubs/releases/082409.asp. [Accessed: 05-Mar-2015]

S15 Amrane, M. et al. (2014) Ocular tolerability and efficacy of a cationic emulsion in patients with mild to moderate dry eye disease - a randomised comparative study. Journal Français d'Ophtalmologie 37, 589–598

S16 Aguilar, A.J. et al. (2014) Effects of Systane(®) Balance on noninvasive tear film break-up time in patients with lipid-deficient dry eye. Clin Ophthalmol 8, 2365–2372

S17 Lam, S.M. et al. (2014) Longitudinal changes in tear fluid lipidome brought about by eyelid-warming treatment in a cohort of meibomian gland dysfunction. J. Lipid Res. 55, 1959–1969

S18 Demir, U. et al. (2005) The Protective Effect of Alpha-Lipoic Acid against Oxidative Damage in Rabbit Conjunctiva and Cornea Exposed to Ultraviolet Radiation. Ophthalmologica 219, 49–53



S19 Chen, B.-Y. et al. (2013) Dietary α-lipoic acid prevents UVB-induced corneal and conjunctival degeneration through multiple effects. IOVS 54, 6757–6766
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