Effects and clinical efficacy of diquafosol tetrasodium_Industrial additives

Background and overview^[1]

The chemical name of Tetrasodium diquafosol (Tetrasodium diquafosol) is P1,P4-bis(uridine 5′-tetraphosphate) sodium, which was jointly developed by Santen Pharmaceutical Company and Inspire Pharmaceutical Company in 2010. Launched in Japan under the trade name Diquas, diquafosol tetrasodium eye drops had sales of approximately US$100 million in 2017. Diquafosol tetrasodium eye drops are the first P2Y2 receptor agonist eye drops approved for marketing in the world. It acts on the P2Y2 receptors on the conjunctival epithelium and goblet cell membranes, by increasing the intracellular calcium ion concentration, promoting The secretion of water and mucin can improve the symptoms of dry eye disease and bring the tear film closer to normal state. In addition, diquafosol tetrasodium eye drops are a compound expected to be developed as an expectorant or pneumonia treatment drug that has the effect of inducing expectoration.

Effect^[2]

Evaluating the effect of 30g·L^-1diquafosol tetrasodium ophthalmic solution on healthy normal eyes is of great significance for the clinical application of diquafosol tetrasodium in the clinical treatment of dry eyes. YOKOI et al. found that 30g·L^-1 diquafosol tetrasodium eye solution can increase the amount of ocular surface tear fluid in healthy human eyes. After using 30 g·L ^-1 diquafosol tetrasodium ophthalmic solution for 5 to 30 minutes, compared with artificial tears, the radius of curvature of the tear river surface was significantly increased (P<0.05). SHIGEYASU et al. analyzed tear samples from healthy subjects and found that sialic acid levels in tears transiently and significantly increased after 5 minutes of instillation of 30 g·L^-1 diquafosol tetrasodium ophthalmic solution (P<0.05 ), which suggests that diquafosol tetrasodium may stimulate the secretion of mucin in human ocular surface tissues. Another study showed that after 30g·L^-1diquafosol tetrasodium eye drops were dropped into the eyes, the forward light scattering of the eyes did not change significantly compared with before; the high-order aberrations of the eyes (coma, spherical aberrations) difference and total higher-order aberrations) increased significantly (P<0.05) compared with before, but the amplitude and duration of the increase were less than 3g·L^-1 sodium hyaluronate eye solution or 20g· L^-1Rebamipide eye drops (P<0.001). Moreover, the effect of 30g·L^-1diquafosol tetrasodium eye solution has nothing to do with its viscosity and suspension rate, so it can be shown that the drug will not reduce the user’s vision, which indicates that patients can have better Good compliance.

Clinical efficacy^[2]

1. Watery tear deficiency dry eye

KOH et al. conducted a series of studies on the efficacy of 30g·L^-1 Diquafosol Tetrasodium Eye Drops for aqueous tear-deficient dry eye. The results showed that the use of this eye drops Dry eye symptom scores, eye staining scores, and tear function tests were significantly improved after 6 months, and 30 g·L^-1 diquafosol tetrasodium eye solution could improve the performance of patients with tear-deficient dry eyes. improve visual quality while enhancing tear film stability and reducing corneal epithelial damage. Since most of the patients in the above studies suffered from Sjögren’s syndrome, it can be inferred that 30 g·L ^-1 diquafosol tetrasodium is effective in patients with mild and moderate Sjögren’s syndrome.

2. Dry eye with shortened tear film break-up time

The clinical manifestations of dry eye with shortened tear film breakup time are short tear film breakup time (BUT) and dry eye symptoms without ocular surface damage and tear deficiency. Some scholars conducted a series of studies on the therapeutic effect of 30g·L^-1diquafosol tetrasodium eye drops on BUT-shortened dry eye. SHIMAZAKI-DEN et al.’s study showed that after 3 months of treatment, the subjective symptom scores and BUT of patients with BUT-shortened dry eye were significantly improved compared with before (both P<0.001), and 30g·L^-1The improvement in the diquafosol tetrasodium eye solution group was more significant than that in the artificial tears group; there was no difference in the Schirmer test scores and fluorescein staining scores between the two groups after treatment. Another study by Japanese scholars found that after continuous eye drops of 30g·L-1 diquafosol tetrasodium eye drops for 1 month, the BUT of the group with negative dry eye symptoms increased significantly compared with before, while the increase in BUT of the group with positive dry eye symptoms was not obvious; in contrast, On the contrary, functional visual acuity, maximum visual acuity, minimum visual acuity and higher-order ocular aberrations were significantly improved in the positive dry eye symptom group, while the improvement in the above indicators was not obvious in the negative dry eye symptom group. KOBASHI et al. found that after 2 and 4 weeks of instillation of 30 g·L ^-1 diquafosol tetrasodium eye solution, the BUT of patients with BUT-shortened dry eye was significantly prolonged (P<0.05), and fluorescein Staining scores, Schirmer test scores, and intraocular scattering were all improved (all P < 0.001).

3. Obstructive meibomian gland dysfunction

Obstructive meibomian gland dysfunction is a major cause of lipid-deficient dry eye and evaporative dry eye and may also lead to reduced tear film stability. Currently, P2Y2 receptors have been confirmed to exist in the meibomian glands. The ocular symptoms, eyelid abnormalities, BUT, TMH and eye staining in patients with obstructive meibomian gland dysfunction treated with 30g·L^-1 diquafosol tetrasodium eye solution for 4 months The scores were significantly improved, and the ratio of the meibomian gland area to the total analyzed area increased from 36.9% to 41.5% (P<0.0001). It can be inferred that diquafosol tetrasodium can be considered an effective treatment when traditional treatment options for obstructive meibomian gland dysfunction, such as hot compresses and eyelid cleansing, are ineffective or poorly tolerated. .

4. Dry eye related to anterior segment surgery

Dry eye is one of the common complications after LASIK surgery. The specific mechanism is still unclear, and patients who already have dry eye before surgery will have further aggravation of symptoms after surgery, thus affecting the efficacy of the surgery. For patients with dry eye after LASIK, there are studies�It was found that the uncorrected distance vision in the combined application group of 30g·L^-1diquafosol tetrasodium eye drops and 3g·L^-1sodium hyaluronate eyedrops Higher than 3g·L^-1Sodium Hyaluronate Eye Drops Group, while naked near vision is higher than 30g·L^-1Diquafosol Tetrasodium Eye Drops Group Dry eye symptoms were improved more significantly in the artificial tear group and artificial tear group than in the other groups (P<0.05). MORI et al. found that after continuous use of 30 g·L ^-1 diquafosol tetrasodium eye drops for 12 weeks in patients with persistent dry eye after LASIK, the eye staining score and BUT were significantly improved (P <0.05), but the best corrected visual acuity and Schirmer test did not change significantly compared with before; in terms of subjective symptoms, 6 of the 13 subjective symptoms were significantly improved compared with before (P <0.05), including eye fatigue, dry eyes, foreign body sensation, Discomfort, dyslexia, dry eye area discomfort; and it was observed that mild to moderate superficial punctate keratitis was less severe after treatment with 30 g·L^-1 diquafosol tetrasodium eye drops. There was some improvement before treatment, but there was no significant improvement in severe superficial punctate keratitis. LASIK and cataract surgery have different principles and operations, and the risks and mechanisms of dry eye are also different. Studies have shown that using 30 g·L^-1 diquafosol tetrasodium eye drops for preventive treatment of dry eye before cataract surgery can reduce or prevent the occurrence of iatrogenic dry eye. After TAKESHITA was administered to patients with dry eyes after cataract surgery and poor efficacy of artificial tears, 30g·L^-1 Diquafosol Tetrasodium Eye Drops were treated for 10 to 78 days (an average of 29 days), and BUT was significantly improved. The corneal/conjunctival staining score was significantly improved, and the dry eye symptoms were significantly alleviated, but epiphora also increased (P<0.001). The above-mentioned studies evaluated the efficacy of diquafosol tetrasodium in the treatment of dry eye associated with anterior segment surgery. The results showed that the use of diquafosol tetrasodium is more effective than conventional treatments such as artificial tears for dry eye associated with anterior segment surgery. .

5. Contact lens wearers

Research has found that wearing contact lenses can significantly reduce TMH, and TMH can be significantly improved temporarily after using 30g·L^-1diquafosol tetrasodium eye drops. There are also studies showing that 30g·L^-1diquafosol tetrasodium eye drops can improve dry eye symptoms in contact lens wearers. WATANABE is administered to patients with dry eyes who wear contact lenses and have insufficient efficacy of 3g·L^-1 sodium hyaluronate eye drops 30g·L^-1 diquafosol After the combination of tetrasodium eye drops and 3g·L^-1 sodium hyaluronate eye drops, the fluorescein staining score, BUT, TMH and some subjective symptoms were significantly improved. Therefore, it can be speculated that diquafosol tetrasodium can be used for contact lens-related dry eye.

6. Video terminal syndrome

UCHINO et al. changed the existing treatment plan to 30g·L^-1 diquafosol for video terminal users with suspected or confirmed dry eyes (positive dry eye symptoms and BUT <5s) Tetrasodium eye drops were applied to the eyes. After 4 weeks of treatment, it was found that the conjunctival staining score improved significantly (from 1.1 to 0.3, imported carbon black P=0.0078), and BUT increased significantly (from 2.4s to 3.9s, P=0.0156). , 7 out of 12 subjective symptoms were improved (P<0.05). However, due to the lack of relevant research at this stage, it is temporarily believed that 30g·L^-1 diquafosol tetrasodium may be effective in patients with video terminal syndrome.

7. Effect of combined application with 1g·L^-1 sodium hyaluronate eye drops

Studies have shown that 30g·L^-1 Diquafosol Tetrasodium Eye Drops and 1g·L^-1 Sodium Hyaluronate Eye Drops improve the The effect of fluorescein staining scores in patients with dry eye is the same, but diquafosol tetrasodium is more effective in improving the tiger red staining scores and subjective symptoms. When sodium hyaluronate monotherapy is not effective, 30g·L^-1diquafosol tetrasodium eye drops and 1g·L^-1hyaluronic acid The combination of sodium eye drops can be used as an effective measure in the treatment of dry eyes. Studies have shown that the eye staining score of the group using 30g·L^-1 Diquafosol Tetrasodium Eye Drops and 1g·L^-1 Sodium Hyaluronate Eye Drops , subjective symptoms were significantly improved (both P < 0.05), but the above indicators did not change after treatment with 1g·L^-1 sodium hyaluronate eye drops alone, while the Schirmer test scores were unchanged in both groups. No significant changes. HWANG et al. found that after 3 months of treatment, the 30g·L^-1diquafosol tetrasodium eye drops group and the 30g·L^-1diquafosol tetrasodium eye drops group The combination of eye drops and 1g·L^-1 sodium hyaluronate eye drops without preservatives was better than that of 1g·L^-1 without preservatives. The average ocular surface disease index score, eye staining score, BUT, and Schirmer test scores in the sodium hyaluronate eye drops group were improved more significantly; while the 30g·L^-1 Diquafosol Tetrasodium Eye Drops The group combined with 1g·L^-1 preservative-free sodium hyaluronate eye drops had a more significant decrease in the ocular surface disease index score and eye staining score than the other two groups. From this, it can be inferred that 30g·L^-1diquafosol tetrasodium is combined with 1g·L^-1preservative-free sodium hyaluronate eye drops for treatment It works better on dry eyes.

Security^[2]

30g·L^-1Diquafosol tetrasodium eye drops are well tolerated by general dry eye patients. In 655 patients who received diquafosol tetrasodium eye drops, Among the subjects, 155 cases (23.7%) reported adverse drug reactions, and no serious treatment-related adverse reactions occurred. Most were mild adverse reactions, mainly including eye irritation (46.7%) and eye secretions (4.7%). , conjunctival congestion (3.7%), eye pain (2.7%), eye itching (2.4%), foreign body sensation (2.1%) and eye discomfort (1.1%); with 30g·L^-1With continued use of Diquafosol Tetrasodium Eye Drops, eye irritation and eye pain disappeared in approximately 50% of patients with adverse reactions after 7 days, and the original adverse reactions disappeared in approximately 80% of patients with adverse reactions within 28 days. According to the results of 6-month and 13-month clinical studies, 30g·L^-1 Diquafosol Tetrasodium Eye Drops are still well tolerated over a longer course of treatment. In a 13-month clinical trial, the majority of users of diquafosol tetrasodium eye drops 30g·L^-1 Some adverse reactions are mild, and the most common adverse reactions include eye discharge (6.6%), conjunctival congestion (5.5%), eye irritation (4.4%), and eye pain (3.3%).

), eye discharge (4.7%), conjunctival congestion (3.7%), eye pain (2.7%), eye itching (2.4%), foreign body sensation (2.1%) and eye discomfort (1.1%); with 30g ·With continuous use of L^-1diquafosol tetrasodium eye drops, about 50% of those with adverse reactions will have their eye irritation and eye pain disappear after 7 days, and about 80% of those with adverse reactions will have adverse reactions within 28 days. The original adverse reactions disappeared. According to the results of 6-month and 13-month clinical studies, 30g·L^-1 Diquafosol Tetrasodium Eye Drops are still well tolerated over a longer course of treatment. In a 13-month clinical trial, the majority of users of diquafosol tetrasodium eye drops 30g·L^-1 Some adverse reactions are mild, and the most common adverse reactions include eye discharge (6.6%), conjunctival congestion (5.5%), eye irritation (4.4%), and eye pain (3.3%).