This study aims to evaluate the effects of brimonidine eye drops and intravitreal administration in guinea pigs with form-deprivation myopia (FDM) and to analyze the ocular pharmacokinetics and irritation.
Methods:
The experimental guinea pigs were randomized to the normal control, FDM, FDM brimonidine topical eye drops, and FDM intravitreal injection groups. The experiment period was 13 days. Changes in ocular refraction and axial length were monitored regularly. The ocular pharmacokinetics of brimonidine and its metabolite brimonidine-2,3-dione were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. Ocular irritation was assessed by the Draize test, corneal fluorescein staining, and hematoxylin and eosin staining.
Results:
Two administration methods of brimonidine equally inhibited the increase in refraction and axial length in FDM guinea pigs (P < 0.05). Pharmacokinetic analysis revealed significant and sustained accumulation of brimonidine in the iris and choroid. Brimonidine was preferentially distributed to the cornea, conjunctiva, and sclera when administered topically, and preferentially to the retina and vitreous when administered intravitreally. The total area under the curve values for retinal and scleral tissues demonstrated that continuous topical administration was 1.95 times and 1.36 times that of intravitreal administration, respectively. The concentration of brimonidine-2,3-dione was significantly lower than that of brimonidine. Brimonidine topical eyedrops had less ocular irritation.
Conclusions:
At the drug concentrations in this study, both topical and intravitreal brimonidine achieved sufficient ocular exposure to exert similar myopia-suppressing effects. Continuous topical administration can maintain higher drug concentrations in the retinal and scleral tissues with less eye irritation.
DolginE. The myopia boom. Nature, 2015; 519(7543):276–278; doi: 10.1038/519276a
2.
HoldenBA, FrickeTR, WilsonDA, et al.Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050. Ophthalmology, 2016; 123(5):1036–1042; doi: 10.1016/j.ophtha.2016.01.006
3.
Ruiz-MedranoJ, MonteroJA, Flores-MorenoI, et al.Myopic maculopathy: Current status and proposal for a new classification and grading system (ATN). Prog Retin Eye Res, 2019; 69:80–115; doi: 10.1016/j.preteyeres.2018.10.005
4.
VutipongsatornK, YokoiT, Ohno-MatsuiK. Current and emerging pharmaceutical interventions for myopia. Br J Ophthalmol, 2019; 103(11):1539–1548; doi: 10.1136/bjophthalmol-2018-313798
5.
WoldeMussieE, RuizG, WijonoM, et al.Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Invest Ophthalmol Visual Sci, 2001; 42(12):2849–2855.
6.
LiuY, WangY, LvH, et al.α-adrenergic agonist brimonidine control of experimentally induced myopia in guinea pigs: A pilot study. Mol Vision, 2017; 23:785–798.
7.
CarrBJ, NguyenCT, StellWK. Alpha2 -adrenoceptor agonists inhibit form-deprivation myopia in the chick. Clin Exp Optom, 2019; 102(4):418–425; doi: 10.1111/cxo.12871
8.
XiangA, PengZ, HeH, et al.The potential of brimonidine for myopia treatment: Targeting MMP-2 to regulate choroidal thickness and control eye growth. Heliyon, 2024; 10(18):e37416; doi: 10.1016/j.heliyon.2024.e37416
9.
YangY, WuJ, WuD, et al.Intravitreal brimonidine inhibits form-deprivation myopia in guinea pigs. Eye Vis (Lond), 2021; 8(1):27; doi: 10.1186/s40662-021-00248-0
10.
CarrBJ, MiharaK, RamachandranR, et al.Myopia-inhibiting concentrations of muscarinic receptor antagonists block activation of Alpha2A-adrenoceptors in vitro. Invest Ophthalmol Vis Sci, 2018; 59(7):2778–2791; doi: 10.1167/iovs.17-22562
11.
del AmoEM, HammidA, TauschM, et al.Ocular metabolism and distribution of drugs in the rabbit eye: Quantitative assessment after intracameral and intravitreal administrations. Int J Pharm, 2022; 613:121361; doi: 10.1016/j.ijpharm.2021.121361
BronAJ, EvansVE, SmithJA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea, 2003; 22(7):640–650; doi: 10.1097/00003226-200310000-00008
14.
PengZ, XiangA, HeH, et al.Brimonidine as a possible treatment for myopia. BMC Ophthalmol, 2024; 24(1):161; doi: 10.1186/s12886-024-03433-6
15.
KoevarySB. Pharmacokinetics of Topical Ocular Drug Delivery: Potential Uses for the Treatment of Diseases of the Posterior Segment and Beyond. Bentham Science Publishers; 2003; doi: 10.2174/1389200033489488
16.
ChastainJE, SandersME, CurtisMA, et al.Distribution of topical ocular nepafenac and its active metabolite amfenac to the posterior segment of the eye. Exp Eye Res, 2016; 145:58–67; doi: 10.1016/j.exer.2015.10.009
17.
GeroskiDH, EdelhauserHF. Drug delivery for posterior segment eye disease. Invest Ophthalmol Visual Sci, 2000; 41(5):961–964.
18.
SripetchS, LoftssonT. Topical drug delivery to the posterior segment of the eye: Thermodynamic considerations. Int J Pharm, 2021; 597:120332; doi: 10.1016/j.ijpharm.2021.120332
19.
CholkarK, DasariSR, PalD, et al.1—Eye: Anatomy, physiology and barriers to drug delivery. In: Ocular Transporters and Receptors. (MitraAK ed). Woodhead Publishing Series in Biomedicine Woodhead Publishing; 2013; pp. 1–36; doi: 10.1533/9781908818317.1
20.
WangY, WangC. Novel eye drop delivery systems: Advance on formulation design strategies targeting anterior and posterior segments of the eye. Pharmaceutics, 2022; 14(6):1150; doi: 10.3390/pharmaceutics14061150
21.
ThomsonK, KaroutaC, AshbyR. Form-deprivation and lens-induced myopia are similarly affected by pharmacological manipulation of the dopaminergic system in chicks. Invest Ophthalmol Vis Sci, 2020; 61(12):4; doi: 10.1167/iovs.61.12.4
22.
MathisU, FeldkaemperM, WangM, et al.Studies on retinal mechanisms possibly related to myopia inhibition by atropine in the chicken. Graefes Arch Clin Exp Ophthalmol, 2020; 258(2):319–333; doi: 10.1007/s00417-019-04573-y
23.
ThomsonK, KellyT, KaroutaC, et al.Insights into the mechanism by which atropine inhibits myopia: Evidence against cholinergic hyperactivity and modulation of dopamine release. Br J Pharmacol, 2021; 178(22):4501–4517; doi: 10.1111/bph.15629
24.
RosaRH, HeinTW, YuanZ, et al.Brimonidine evokes heterogeneous vasomotor response of retinal arterioles: Diminished nitric oxide-mediated vasodilation when size goes small. Am J Physiol Heart Circ Physiol, 2006; 291(1):H231–H238; doi: 10.1152/ajpheart.01281.2005
25.
RohrerB, StellWK. Basic fibroblast growth factor (bFGF) and transforming growth factor beta (TGF-β) act as stop and go signals to modulate postnatal ocular growth in the chick. Exp Eye Res, 1994; 58(5):553–561; doi: 10.1006/exer.1994.1049
26.
LaiRK, ChunT, HassonD, et al.Alpha-2 adrenoceptor agonist protects retinal function after acute retinal ischemic injury in the rat. Vis Neurosci, 2002; 19(2):175–185; doi: 10.1017/S0952523802191152
27.
SekoY, ShimokawaH, TokoroT. Expression of bFGF and TGF-beta 2 in experimental myopia in chicks. Invest Ophthalmol Visual Sci, 1995; 36(6):1183–1187.
28.
KusakariT, SatoT, TokoroT. Visual deprivation stimulates the exchange of the fibrous sclera into the cartilaginous sclera in chicks. Exp Eye Res, 2001; 73(4):533–546; doi: 10.1006/exer.2001.1064
29.
Anonymous. Pharmacotherapeutic candidates for myopia: A review. Biomed Pharmacother, 2021; 133:111092; doi: 10.1016/j.biopha.2020.111092
30.
HämäläinenKM, KananenK, AuriolaS, et al.Characterization of paracellular and aqueous penetration routes in cornea, conjunctiva, and sclera. Invest Ophthalmol Visual Sci, 1997; 38(3):627–634.
31.
HoribeY, HosoyaK, KimK-J, et al.Polar solute transport across the pigmented rabbit conjunctiva: Size dependence and the influence of 8-bromo cyclic adenosine monophosphate. Pharm Res, 1997; 14(9):1246–1251; doi: 10.1023/A:1012123411343
32.
KhopadeAJ, HalderA, PatelV, et al.Preclinical evaluation of a novel once-a-day brimonidine ophthalmic nanosuspension. J Ocul Pharmacol Ther, 2023; 39(9); doi: 10.1089/jop.2023.0038
33.
AcheampongAA, ShackletonM, JohnB, et al.Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes. Drug Metab Dispos, 2002; 30(4):421–429; doi: 10.1124/dmd.30.4.421
34.
ChienDS, HomsyJJ, GluchowskiC, et al.Corneal and conjunctival/scleral penetration of p-aminoclonidine, AGN 190342, and clonidine in rabbit eyes. Curr Eye Res, 1990; 9(11):1051–1059; doi: 10.3109/02713689008997579
35.
GroveKJ, KansaraV, PrentissM, et al.Application of imaging mass spectrometry to assess ocular drug transit. SLAS Discov, 2017; 22(10):1239–1245; doi: 10.1177/2472555217724780
36.
AhmedI, PattonTF. Importance of the noncorneal absorption route in topical ophthalmic drug delivery. Invest Ophthalmol Visual Sci, 1985; 26(4):584–587.
37.
GukasyanHJ, KimK-J, LeeVHL. The conjunctival barrier in ocular drug delivery. In: Drug Absorption Studies: In Situ, in Vitro and in Silico Models. (EhrhardtC, KimK-J. eds) Springer US: Boston, MA; 2008; pp. 307–320; doi: 10.1007/978-0-387-74901-3_13
38.
Varela-FernándezR, Díaz-ToméV, Luaces-RodríguezA, et al.Drug delivery to the posterior segment of the eye: Biopharmaceutic and pharmacokinetic considerations. Pharmaceutics, 2020; 12(3):269; doi: 10.3390/pharmaceutics12030269
39.
HernándezC, RamosH, LétondorA, et al.Ocular and plasma pharmacokinetics of sitagliptin eye drops: Preclinical data. Pharmaceuticals (Basel), 2024; 17(12):1579; doi: 10.3390/ph17121579
40.
HuangD, ChenY-S, RupenthalID. Overcoming ocular drug delivery barriers through the use of physical forces. Adv Drug Deliv Rev, 2018; 126:96–112; doi: 10.1016/j.addr.2017.09.008
41.
XiangA, HeH, YuH, et al.Ocular posterior segment distribution and pharmacokinetics of brimonidine after intravitreal administration in Guinea Pigs. J Ocul Pharmacol Ther, 2023; 39(7):456–462; doi: 10.1089/jop.2023.0020
42.
ShinnoK, KurokawaK, KozaiS, et al.The relationship of brimonidine concentration in vitreous body to the free concentration in retina/choroid following topical administration in pigmented rabbits. Curr Eye Res, 2017; 42(5):748–753; doi: 10.1080/02713683.2016.1238941
43.
TamhaneM, LuuKT, AttarM. Ocular pharmacokinetics of brimonidine drug delivery system in monkeys and translational modeling for selection of dose and frequency in clinical trials. J Pharmacol Exp Ther, 2021; 378(3):207–214; doi: 10.1124/jpet.120.000483
44.
AcheampongAA, ShackletonM, Tang-LiuDD. Comparative ocular pharmacokinetics of brimonidine after a single dose application to the eyes of albino and pigmented rabbits. Drug Metab Dispos, 1995; 23(7):708–712; doi: 10.1016/S0090-9556(25)06647-4
45.
AwwadS, Mohamed AhmedAHA, SharmaG, et al.Principles of pharmacology in the eye. Br J Pharmacol, 2017; 174(23):4205–4223; doi: 10.1111/bph.14024
46.
BahrpeymaS, JakubiakP, Alvarez-SánchezR, et al.Comprehensive pharmacokinetic evaluation of high melanin binder levofloxacin in rabbits shows potential of topical eye drops for posterior segment treatment. Invest Ophthalmol Vis Sci, 2024; 65(12):14; doi: 10.1167/iovs.65.12.14
47.
ValtariA, KalininS, JänttiJ, et al.Melanin-binding-based discovery of topically instilled carbonic anhydrase inhibitors for targeted delivery and prolonged action in the eye. Mol Pharm, 2025; 22(2):721–732; doi: 10.1021/acs.molpharmaceut.4c00694
48.
HsuehHT, ChouRT, RaiU, et al.Machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery. Nat Commun, 2023; 14(1):2509; doi: 10.1038/s41467-023-38056-w
49.
ShimadaS, MishimaH, KitamuraS, et al.Nicotinamide N-oxide reductase activity in bovine and rabbit eyes. Invest Ophthalmol Visual Sci, 1987; 28(7):1204–1206.
50.
OnoeH, HirookaK, BabaT, et al.The efficacy and safety associated with switching from concomitant brimonidine and ripasudil, or brimonidine or ripasudil monotherapy to a fixed combination of brimonidine and ripasudil in glaucoma patients. J Clin Med, 2024; 13(14):4158; doi: 10.3390/jcm13144158
51.
EnyediLB, FreedmanSF. Safety and efficacy of brimonidine in children with glaucoma. J AAPOS, 2001; 5(5):281–284; doi: 10.1067/mpa.2001.117571
52.
MooreW, NischalKK. Pharmacologic management of glaucoma in childhood. Paediatr Drugs, 2007; 9(2):71–79; doi: 10.2165/00148581-200709020-00001
53.
CimolaiN. A review of neuropsychiatric adverse events from topical ophthalmic brimonidine. Hum Exp Toxicol, 2020; 39(10):1279–1290; doi: 10.1177/0960327120918307
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
