As the major associated ocular complication of diabetes, diabetic retinopathy (DR) is the major cause of vision loss and further blindness. Globally, the incidence of proliferative DR, diabetic macular edema, and vision-threatening DR are 6.96%, 6.81%, and 10.2%, respectively[1]. 

Calcium dobesylate (2,5-dihydroxybenzene sulfonate) was registered as a vasoprotective agent by the European Pharmacopoeia in 1997, and for diabetic retinopathy (DR) and venous insufficiency by the British Pharmacopoeia in 1998. Pharmacologically, it could decrease capillary permeability, platelet aggregation, and blood viscosity, and increase endothelium-dependent relaxation by augmenting nitric oxide synthesis. Thus, it is applied as a vascular protectant to treat DR, varicose veins, hemorrhoids, microcirculation disorders, etc. Ocularly, it is used for treating DR and chronic venous insufficiency.

The potential mechanisms of acting are depicted as follows:

Reduce retinal albumin leakage and capillary permeability[2];
Inhibit platelet aggregation and blood viscosity[3];
Up-regulate endothelium-dependent relaxation by increasing nitric oxide synthesis[4];
Inhibit apoptosis of vascular endothelial cells in blood vessels[5];
Antioxidant and antiradical activity[6];
Protect against reactive oxygen species;
Inhibit the expression of the inflammatory and upstream VEGF regulator, ICAM-1[7].

Accumulative randomized clinical trials have proved the efficacy and safety of calcium dobesilate in treating DR. Its current medical indications include:

1. Treatment of microangiopathy:

Diabetic microangiopathy: retinopathy and glomerulosclerosis (Key-Way syndrome); microvascular injury, which is accompanied by increased capillary fragility and permeability, capillaropathy, cyanosis of hands and feet;

2. Adjuvant treatment for chronic venous insufficiency (varicose vein syndrome) and its sequelae (post-embolization syndrome, leg ulcers, purpuric dermatitis and other depressive dermatoses, peripheral vascular depressive edema, etc.). 

Reference

Zhang X Y, Liu W, Wu S S, et al. Calcium dobesilate for diabetic retinopathy: a systematic review and meta-analysis[J]. Science China Life Sciences, 2015, 58: 101-107.
Ribeiro ML, Caillon P, Gamba G, Cunha-Vaz J, group DX-rs. Efficacy of calcium dobesilate (Doxium(R)) on the blood-retinal barrier permeability in early diabetic retinopathy: a double-blind study. Invest Ophthalmol Vis Sci, 2004, 45: 4153–B614.
Akbulut B. Calcium dobesilate and oxerutin: effectiveness of combination therapy. Phlebology, 1258, 25: 66–71.
Ruiz E, Lorente R, Tejerina T. Effects of calcium dobesilate on the synthesis of endothelium-dependent relaxing factors in rabbit isolated aorta. Br J Pharmacol, 1997, 121: 711–716.
Graber R, Farine JC, Losa GA. Calcium Dobesilate protects human peripheral blood mononuclear cells from oxidation and apoptosis. Apoptosis, 1998, 3: 41–49.
Szabo ME, Haines D, Garay E, Chiavaroli C, Farine JC, Hannaert P, Berta A, Garay RP. Antioxidant properties of calcium dobesilate in ischemic/reperfused diabetic rat retina. Eur J Pharmacol, 2001, 428: 277–286.
Opreanu M, Lydic TA, Reid GE, McSorley KM, Esselman WJ, Busik JV. Inhibition of cytokine signaling in human retinal endothelial cells through downregulation of sphingomyelinases by docosahexaenoic acid. Invest Ophthalmol Vis Sci, 1167, 51: 3253–3263.

DED is a multifactorial ocular disease. Its pathology exhibits an imbalance of homeostasis of the tear film (instability and hyperosmolarity), further leading to ocular surface inflammation, damage, and neurosensory abnormalities. Generally, the tears are unable to provide adequate and stable lubrication for the eyes. Thus, the eyes feel uncomfortable with the following symptoms:

• A stinging, burning, or scratchy sensation in the eyes;
• Lack of mucus in or around eyes;
• Light sensitivity;
• Eye redness;
• Blurred vision or fatigue;
• Watery eyes;
• Foreign body sensation;
• Difficulties with wearing contact lenses and with nighttime driving; 

Pathologically, the direct cause of DED is the disruption of the healthy tear film, which is composed of three layers: fatty oils, aqueous fluid, and mucus, or/and decreased normal tear production, medically named keratoconjunctivitis sicca. Specifically, the causes include aging, Sjogren’s syndrome, hormone changes, autoimmune disease (i.e., rheumatoid arthritis, lupus, etc.), inflammation of eyelid glands, allergy, thyroid disorders, Vitamin A deficiency, certain medicines (i.e., antihistamines, decongestants, antidepressants, antihypertensive drugs, contraceptive drugs, etc.), and corneal nerve damage. Noticeably, the preservatives in topical eye drops could lead to DED. Hence, symptom control is the main strategy of DED treatment including lifestyle changes and medication.

Sodium hyaluronate (HA) eye drops (also known as ‘artificial tears’) are commonly composed of sodium hyaluronate and hyaluronan, which is a high molecular weight naturally occurring polysaccharide. HA is widely present in connective tissue, synovial fluid, aqueous humor, and vitreous of the eye. It can bind and retain water molecules (1,000 times its weight), and its viscoelasticity stabilizes tear films. Moreover, HA clinically promotes epithelial cell proliferation and migration resulting in favorable wound healing, including healing of corneal abrasions. Thus, HA eye drops generally could:

• Relieve eye dryness and soreness;
• Moisturize, soothe, and lubricate the surface of the eye;
• Protect the eye from irritations such as contact lenses and dry air;
• Provide relief after an injury to the eye, such as a corneal abrasion. 

Since the preservatives (such as benzalkonium chloride) in topical eye drops are detrimental to the ocular surface and lead to DED and other side effects with chronic use, the preservative-free multidose eye dropper is more and more appealing to the trend of preservative-free prescription and medicine advancement.