Proprietary Bilberry Fruit Extract (Mirtoselect®) May Aid in Dry Eye Syndrome

Dry eye is a chronic disease that can damage the eye’s surface and diminish the quality of life and work productivity. Dry eye complications include discomfort, vision changes, compromised tear film, and inflammation of the eye’s surface. Bilberry (Vaccinium myrtillus, Ericaceae) extract may be beneficial in promoting eye health. In a previous study, Mirtoselect® (Indena S.p.A.; Milan, Italy), a natural bilberry extract with standardized anthocyanins derived from bilberry fresh frozen fruit, outperformed a generic bilberry extract in improving “retinal circulatory parameters.”1 The purpose of this study was to investigate Mirtoselect’s bioavailability, its ability to relieve dry eye symptoms, and its potential as an antioxidant.

First, an in vivo pharmacokinetic study was performed. The authors did not state where this study occurred. Five male rats were given “bilberry dried extract derived from Vaccinium myrtillus L. fresh frozen fruits (Mirtoselect®, Indena, Milan, Italy), containing 36% anthocyanins and matching the full phytochemical profile of the whole fruit,” while 5 other male rats were given “a highly purified anthocyanin-rich extract, containing 89% anthocyanins and devoid of the non-anthocyanin fraction … .” The dosage was 400 mg/kg body weight, dissolved in water, and administered by mouth. The rats’ blood was then drawn at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes after treatment, processed and evaluated by an ultraviolet (UV) spectrophotometric method at 530 nm. The area under the curve (AUC) was higher for the Mirtoselect group than for the group receiving the highly purified anthocyanin-rich fraction (202.34 ± 24.23 µg·min/ml versus 130.93 ± 4.93 µg·min/ml). Calculation of the dosage-adjusted AUC value ratios revealed that anthocyanosides were 4 times more bioavailable in the Mirtoselect group than in the anthocyanin-rich group.

Next, Mirtoselect was compared to placebo in a 4-week, randomized, double-blinded, parallel-group, comparison study conducted at Ario Nishi-Arai Eye Clinic; Tokyo, Japan. Healthy subjects (n=22; ages 30-60) had visual fatigue or eye strain; at least 4 hours daily of video game, PC, or video display terminal (VDT) use; corrected visual acuity of at least 1.0 decimal (20/20 feet) for both eyes; and no regular ingestion of pharmaceuticals or health foods known to alleviate eye strain. Exclusion criteria included a history of cardiac failure or infarction, treatment for chronic disease, allergies to a component of the investigated products, using contact lenses, eye diseases, entropion palpebrae (introverted eyelids), smoking, poor diet, insufficient sleep, pregnancy, breastfeeding, and childbearing potential. Subjects took 2 tablets of Mirtoselect or placebo daily for 4 weeks. Each dietary supplement tablet contained 80 mg of Mirtoselect and 170 mg of excipients. The placebo tablets contained only excipients.

To recreate VDT visual load, subjects were instructed to play for 45 minutes on a video game console before an examination. Clinical and ophthalmological tests were completed at inclusion and 4 weeks later. Tear flow was quantified with Schirmer’s test (which determines whether the eye produces enough tears to keep it moist); pupil constriction was measured with TriIRIS® C9000 (Hamamatsu Photonics K.K.; Hamamatsu City, Japan; a machine that can monitor the accommodation and convergence function simultaneously) before and after visual load (pupil constriction was used as a surrogate marker for eye strain); diacron-reactive oxygen metabolites (d-ROMs) test was used to evaluate oxidative stress; and biological antioxidant potential (BAP) was used to evaluate antioxidant potential. Modified BAP/d-ROMs ratio was used to comprehensively assess antioxidant potential.

Eleven subjects were randomly assigned to the Mirtoselect dietary supplement group and 11 to the placebo group. One dropped out of the placebo group for personal reasons. It was not reported if the demographic data were balanced.

Schirmer’s test revealed that, after 4 weeks, subjects receiving Mirtoselect had significantly more tear secretion from the right eye (19.5 ± 7.3 mm; P<0.01) and from both eyes (19.7 ± 8.6 mm; P<0.05), but not from the left eye (P=0.062), as compared to baseline. [Note: Data are expressed as the mean ± standard deviation.] The placebo group did not have statistically significant findings for Schirmer’s test values after 4 weeks compared to baseline (right eye, P=0.361; left eye, P=0.118; both eyes, P=0.177). Mean improvement rates from baseline to 4 weeks were higher in the Mirtoselect group compared to the placebo group for the right eye, left eye, and both eyes, with a statistically significant difference for the right eye (P=0.049). When the groups were further divided into severe versus mild symptoms (the authors did not define these terms), the severe Mirtoselect group had a statistically significantly higher improvement rate than the mild Mirtoselect group for the right eye and for the left eye (right eye, P=0.028; left eye, P=0.023), and among all subjects with severe symptoms, the rate of improvement was greater in the Mirtoselect group than in the placebo group for the right eye (P=0.015).

The pupil constriction test revealed no significant findings (data not shown). From baseline to 4 weeks, BAP increased significantly (P=0.003) in the Mirtoselect group only, while d-ROMs increased significantly (P=0.013) in the placebo group only. The modified BAP/d-ROMs ratio results were not statistically significant (P=0.187, Mirtoselect group; P=0.293, placebo group).

In summary, in the Mirtoselect group, anthocyanosides were more bioavailable and tear secretion increased significantly. In addition, Mirtoselect may be an effective antioxidant. The authors hypothesize Mirtoselect’s non-anthocyanin bilberry components may have aided absorption, and Mirtoselect could be an effective dry eye treatment for some people. To be elucidated are Mirtoselect’s complete pharmacokinetic profile, mechanism of action, and patient-reported outcomes. Five of the authors (Riva, Togni, Franceschi, Kawada, and Inaba) are employees of, and 1 author (Giacomelli) is a consultant for, Indena S.p.A., the manufacturer of Mirtoselect.


1Gizzi C, Belcaro G, Gizzi G, et al. Bilberry extracts are not created equal: the role of non-anthocyanin fraction. Discovering the “dark side of the force” in a preliminary study. Eur Rev Med Pharmacol Sci. 2016;20(11):2418-2424.

Riva A, Togni S, Franceschi F, et al. The effect of a natural, standardized bilberry extract (Mirtoselect®) in dry eye: a randomized, double-blinded, placebo-controlled trial. Eur Rev Med Pharmacol Sci. May 2017;21(10):2518-2525.


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