The Next Frontier of Dry Eye Treatment: Mucin and ways to Stimulate Goblet Cells: Diquafosol ophthalmic solution 3 % and Rebamipide, a mucin secretagogue

There is a race to understand the conjunctiva’s goblet cells, their full function, the role of mucin in dry eye symptoms. The conjunctiva is the partly clear covering over the white part of the eye. There is also a race to find ways to stimulate the goblet cells to produce more mucin on the conjunctiva and in other parts of the body, such as the tracheabronchi, and larger bronchioles in the respiratory tract, small intestines, the large intestine, and conjunctiva 

The conjunctival goblet cells are highly specialized epithelial that produce and secrete mucins, which hydrate and lubricate mucosal surfaces.

The Conjunctiva–Structure and Function | Ento Key

Here are some top medications that seem to stimulate mucin production from Goblet Cells:

1. Diquafosol ophthalmic solution 3 %: 
diquafosol tetrasodium 3% ophthalmic solution (Diquas®, Santen Pharmaceutical Co., Ltd., Osaka, Japan) 
-six times per day Diquafosol ophthalmic solution 3 % (Diquas(®)) 
-is a P2Y2 receptor agonist that promotes tear fluid and mucin secretion and is currently approved in Japan and South Korea for the treatment of dry eye.
-still not FDA approved as of 2020: some patients are getting it from Japan

2. Rebamipide, a mucin secretagogue,
-increases mucin secretion from the conjunctival epithelium
-increases the conjunctival goblet cell density 
-decreases ocular surface epithelial damage scores.1-5 
-Studies have confirmed the safety and efficacy of rebamipide, leading to the approval of 2% rebamipide as a mucin secretagogue in the treatment of DED in Japan in September 2011.6,7

– Notes:  2% rebamipide eye drops were associated with improvements in ocular surface differentiation due to changes in mucosal functions at the cellular level, which they note may explain improvements in DED.8
The study included 15 patients with DED who received treatment with 2% rebamipide eye drops QID for 12 weeks. The team analyzed symptom score, tear film break-up time, fluorescein and lissamine green staining score, lid wiper epitheliopathy score, corneal sensitivity, squamous metaplasia grade and goblet cell density. They also evaluated nucleocytoplasmic ratios and corneal epithelial cells.8
The study authors saw a significant improvement in average symptom scores, tear film break-up times, staining scores, lid wiper scores and squamous metaplasia grades after treatment. They add that there were similar significant improvements in the average corneal epithelial cell densities and nucleocytoplasmic ratios upon cessation of treatment.
-still not FDA approved as of 2020: some patients are getting it from Japan

3. Topical 4% Sulglycotide (SOS) drops:
-a polysulfated glycopeptide derived from porcine duodenal mucin, for the treatment of dry eye disease.
-4%SOS eye drops recovered tear production to the baseline levels at 10 days after treatment, which is similar to DQS.

4% SOS eye drops on inflammation in the lacrimal gland was similar to and/or superior to that of CsA. Consequently, we suggested that administration of topical 4% SOS lead to tear stability by mucin increasing and anti-inflammatory effects 

4. Exosomes:
-are cell-derived vesicles that range in diameter from ~50 to 150 nm and are formed when multi-vesicular endosomes fuse with the plasma membrane and release their intraluminal vesicles by exocytosis as exosomes [23]. Exosomal phospholipid membranes encapsulate proteins, microRNA, and messenger RNA, and provide stability to these contents by protecting them from freeze-thaw cycles, ribonuclease digestion and gastric acidity [4]. These vesicles are involved in immune responses, cell adhesion, waste management, protection against stress, and inflammation, with their primary role being intercellular signaling and communication [2].
– Exosomes are released by the majority of body tissues and are therefore present in most body fluids, particularly breast milk.
-Colostrum, which is the first milk that comes out of the breast, has a richer source of exosomes than mature milk, which contains a lower concentration of these vesicles
-Studies have shown that exosomes derived from rat milk promote intestinal epithelial cell viability, enhance cell proliferation, and stimulate intestinal stem cell activity under normal conditions. 

Could this work for the conjunctival epithelium?

I am not sure but I did have a friend who applied her own breast milk to her eye when she once had conjunctivitis. A case of 1 but it worked. 

Has anyone tried Breast Milk for Dry Eyes as a study?
Not that I can find, but it has been done in rats.

Molecular Vision 2016; 22:1095-1102
Received 22 March 2016 | Accepted 7 September 2016 | Published 9 September 2016
© 2016 Molecular Vision
Effect of human milk as a treatment for dry eye syndrome in a
mouse model
Jose L. Diego, Luke Bidikov, Michelle G. Pedler, Jeffrey B. Kennedy, Hugo Quiroz-Mercado, Darren G.
Gregory, J. Mark Petrash, Emily A. McCourt
(The first two authors contributed equally to this work.)
Department of Ophthalmology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045
Purpose: Dry eye syndrome (DES) affects millions of people worldwide. Homeopathic remedies to treat a wide variety
of ocular diseases have previously been documented in the literature, but little systematic work has been performed to
validate the remedies’ efficacy using accepted laboratory models of disease. The purpose of this study was to evaluate
the efficacy of human milk and nopal cactus (prickly pear), two widely used homeopathic remedies, as agents to reduce
pathological markers of DES.
Methods: The previously described benzalkonium chloride (BAK) dry eye mouse model was used to study the efficacy
of human milk and nopal cactus (prickly pear). BAK (0.2%) was applied to the mouse ocular surface twice daily to
induce dry eye pathology. Fluorescein staining was used to verify that the animals had characteristic signs of DES. After
induction of DES, the animals were treated with human milk (whole and fat-reduced), nopal, nopal extract derivatives,
or cyclosporine four times daily for 7 days. Punctate staining and preservation of corneal epithelial thickness, measured
histologically at the end of treatment, were used as indices of therapeutic efficacy.
Results: Treatment with BAK reduced the mean corneal epithelial thickness from 36.77±0.64 μm in the control mice to
21.29±3.2 μm. Reduction in corneal epithelial thickness was largely prevented by administration of whole milk (33.2±2.5
μm) or fat-reduced milk (36.1±1.58 μm), outcomes that were similar to treatment with cyclosporine (38.52±2.47 μm),
a standard in current dry eye therapy. In contrast, crude or filtered nopal extracts were ineffective at preventing BAKinduced loss of corneal epithelial thickness (24.76±1.78 μm and 27.99±2.75 μm, respectively), as were solvents used in
the extraction of nopal materials (26.53±1.46 μm for ethyl acetate, 21.59±5.87 μm for methanol). Epithelial damage, as
reflected in the punctate scores, decreased over 4 days of treatment with whole and fat-reduced milk but continued to
increase in eyes treated with nopal-derived materials.
Conclusions: Whole and fat-reduced human milk showed promising effects in the prevention of BAK-induced loss of
corneal epithelial thickness and epithelial damage in this mouse


Simsek C, Dogru M, Shinzawa M, et al. The efficacy of 2% topical rebamipide on conjunctival squamous metaplasia and goblet cell density in dry eye disease. J Ocul Pharmacol Ther. June 28, 2019. [Epub ahead of print].

1. Urashima H, Takeji Y, Okamoto T, et al. Rebamipide increases mucin-like substance contents and periodic acid Schiff reagent-positive cells density in normal rabbits. J Ocul Pharmacol Ther. 2012;28(3):264-70.
2. Urashima H, Okamoto T, Takeji Y, et al. Rebamipide increases the amount of mucin-like substances on the conjunctiva and cornea in the N-acetylcysteine-treated in vivo model. Cornea. 2004;23(6):613-9.
3. Itoh S, Itoh K, Shinohara H. Regulation of human corneal epithelial mucins by rebamipide. Curr Eye Res. 2014;39(2):133-41.
4. Ohguchi T, Kojima T, Ibrahim OM, et al. The effects of 2% rebamipide ophthalmic solution on the tear functions and ocular surface of the superoxide dismutase-1 (sod1) knockout mice. Invest Ophthalmol Vis Sci. 2013;54:7793-802.
5. Takeji Y, Urashima H, Aoki A, et al. Rebamipide increases the mucin-like glycoprotein production in corneal epithelial cells. J Ocul Pharmacol Ther. 2012;28(3):259-63.

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