临床抗青光眼药物的新进展
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摘要
青光眼是致盲的主要原因之一,构成视神经的神经节细胞轴突受到多种因素的损伤,其机制尚未完全明了。青光眼最重要的危险因素是眼压升高。由于青光眼的视神经损伤尚不能直接治疗,根据目前提供的唯一已知可治疗的危险因素,可以降低升高的眼压,而眼压与房水流出通道的功能息息相关。这些方面的药物均可以影响青光眼的进展。随着医疗技术的发展以及对青光眼发病机制认识的加深,新型抗青光眼药物也应运而生,为眼科医师提供新的选择。本文将对国内外新型抗青光眼药物从机制、药理特点及临床疗效等方面进行综述。
In glaucoma,the ganglion-cell axons that make up the optic nerve are damaged by a variety of factors, only some of which are understood. The most important risk factor for glaucoma is elevated intraocular pressure. Because the optic-nerve damage in glaucoma is not yet amenable to direct treatment, we provide treatment for the only known risk factors that can be modified the elevated intraocular pressure.However, the function of eye pressure is closely related to the function of the flow passage of the aqueous humor. As more is understood about the molecular biology of the trabecular meshwork and optic nerve in health and disease, the ability to treat glaucoma will likely improve. The new glaucoma drugs are also allowed to come into being.This review will focus on the mechanism, pharmacological characteristics and clinical efficacy of new anti-glaucoma drugs at home and abroad.
In glaucoma,the ganglion-cell axons that make up the optic nerve are damaged by a variety of factors, only some of which are understood. The most important risk factor for glaucoma is elevated intraocular pressure. Because the optic-nerve damage in glaucoma is not yet amenable to direct treatment, we provide treatment for the only known risk factors that can be modified the elevated intraocular pressure.However, the function of eye pressure is closely related to the function of the flow passage of the aqueous humor. As more is understood about the molecular biology of the trabecular meshwork and optic nerve in health and disease, the ability to treat glaucoma will likely improve. The new glaucoma drugs are also allowed to come into being.This review will focus on the mechanism, pharmacological characteristics and clinical efficacy of new anti-glaucoma drugs at home and abroad.
引文
[1]KWON Y H,FINGERT J H,KUEHN M H,ALWARD W L.Primary open-angle glaucoma[J].N Engl J Med,2009,360(11):1113-1124.
[2]HONJO M,INATANI M,KIDO N,SAWAMURA T,YUE B Y,HONDA Y,et al.Effects of protein kinase inhibitor,HA1077,on intraocular pressure and outflow facility in rabbit eyes[J].Arch Ophthalmol,2001,119(8):1171-1178.
[3]TORIS C B,MCLAUGHLIN M A,DWORAK D P,FAN S,HA-VENS S,ZHAN G L,et al.Effects of Rho kinase inhibitors on intraocular pressure and aqueous humor dynamics in nonhuman primates and rabbits[J].J Ocul Pharmacol Ther,2016,32(6):355-364.
[4]SERLE J B,KATZ L J,MCLAURIN E,HEAH T,RAMIREZ-DA-VIS N,USNER D W,et al.Two Phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure[J].Am J Ophthalmol,2018,186:116-127.
[5]MAATTA M,TERVAHARTIALA T,HARJU M,AIRAKSINEN J,AUTIO-HARMAINEN H,SORSA T.Matrix metalloproteinases and their tissue inhibitors in aqueous humor of patients with primary open-angle glaucoma,exfoliation syndrome,and exfoliation glaucoma[J].J Glaucoma,2005,14(1):64-69.
[6]LERNER S F,PARK K H,HUBATSCH D A,ERICHEV V,PACZ-KA J A,ROBERTS T V.Efficacy and tolerability of travoprost 0.004%/Timolol 0.5%fixed-dose combination for the treatment of primary open-angle glaucoma or ocular hypertension inadequately controlled with beta-blocker monotherapy[J].J Ophthalmol,2017,2017:1917570.
[7]WORDINGER R J,SHARMA T,CLARK A F.The role of TGF-beta2 and bone morphogenetic proteins in the trabecular meshwork and glaucoma[J].J Ocul Pharmacol Ther,2014,30(2-3):154-162.
[8]NOLAN M J,GIOVINGO M C,MILLER A M,WERTZ R D,RITCHR,LIEBMANN J M,et al.Aqueous humor s CD44 concentration and visual field loss in primary open-angle glaucoma[J].J Glaucoma,2007,16(5):419-429.
[9]SHPAK A A,GUEKHT A B,DRUZHKOVA T A,KOZLOVA K I,GULYAEVA N V.Brain-derived neurotrophic factor in patients with primary open-angle glaucoma and age-related cataract[J].Curr Eye Res,2018,43(2):224-231.
[10]ODDONE F,ROBERTI G,MICERA A,BUSANELLO A,BONINI S,QUARANTA L,et al.Exploring serum levels of brain derived neurotrophic factor and nerve growth factor across glaucoma stages[J].PLoS One,2017,12(1):e168565.
[11]NAMIKI M,TAGAMI Y,YAMAMOTO M,YAMANAKA A,ITOH M,KANOH M.Presence of human epidermal growth factor(hEGF),basic fibroblast growth factor(bFGF)in human aqueous[J].Nippon Ganka Gakkai Zasshi,1992,96(5):652-656.
[12]GARTAGANIS S P,GEORGAKOPOULOS C D,EXARCHOUA M,MELA E K,LAMARI F,KARAMANOS N K.Increased aqueous humor basic fibroblast growth factor and hyaluronan levels in relation to the exfoliation syndrome and exfoliative glaucoma[J].Acta Ophthalmol Scand,2001,79(6):572-575.
[13]PARRILLA-REVERTER G,AGUDO M,SOBRADO-CALVO P,SALINAS-NAVARRO M,VILLEGAS-PEREZ M P,Vidal-Sanz M.Effects of different neurotrophic factors on the survival of retinal ganglion cells after a complete intraorbital nerve crush injury:a quantitative in vivo study[J].Exp Eye Res,2009,89(1):32-41.
[14]LEBRUN-JULIEN F,DI POLO A.Molecular and cell-based approaches for neuroprotection in glaucoma[J].Optom Vis Sci,2008,85(6):417-424.
[15]LEVKOVITCH-VERBIN H,VANDER S,MAKAROVSKY D,LAVINSKY F.Increase in retinal ganglion cells’susceptibility to elevated intraocular pressure and impairment of their endogenous neuroprotective mechanism by age[J].Mol Vis,2013,19:2011-2022.
[16]CHI W,LI F,CHEN H,WANG Y,ZHU Y,YANG X,et al.Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1beta production in acute glaucoma[J].Proc Natl Acad Sci U SA,2014,111(30):11181-11186.
[17]WAN P,SU W,ZHANG Y,LI Z,DENG C,ZHUO Y.Trimetazidine protects retinal ganglion cells from acute glaucoma via the Nrf2/Ho-1 pathway[J].Clin Sci(Lond),2017,131(18):2363-2375.
[18]GOMES E,PAPA L,HAO T,ROCKWELL P.The VEGFR2 and PKA pathways converge at MEK/ERK1/2 to promote survival in serum deprived neuronal cells[J].Mol Cell Biochem,2007,305(1-2):179-190.
[19]KILIC U,KILIC E,JARVE A,GUO Z,SPUDICH A,BIEBER K,et al.Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1/2 and Akt pathways[J].J Neurosci,2006,26(48):12439-12446.
[20]FOXTON R H,FINKELSTEIN A,VIJAY S,DAHLMANN-NOORA,KHAW P T,MORGAN J E,et al.VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma[J].Am J Pathol,2013,182(4):1379-1390.
[21]PROKAI-TATRAI K,XIN H,NGUYEN V,SZARKA S,BLAZICSB,PROKAI L,et al.17beta-estradiol eye drops protect the retinal ganglion cell layer and preserve visual function in an in vivo model of glaucoma[J].Mol Pharm,2013,10(8):3253-3261.
[22]DANESH-MEYER H V.Neuroprotection in glaucoma:recent and future directions[J].Curr Opin Ophthalmol,2011,22(2):78-86.
[23]YANG F,WANG D,WU L,LI Y.Protective effects of triptolide on retinal ganglion cells in a rat model of chronic glaucoma[J].Drug Des Devel Ther,2015,9:6095-6107.
[24]STOILOV I,AKARSU A N,SARFARAZI M.Identification of three different truncating mutations in cytochrome P4501B1(CYP1B1)as the principal cause of primary congenital glaucoma(Buphthalmos)in families linked to the GLC3A locus on chromosome 2p21[J].Hum Mol Genet,1997,6(4):641-647.
[25]MOROI S E,RAOOF D A,REED D M,ZOLLNER S,QIN Z,RICHARDS J E.Progress toward personalized medicine for glaucoma[J].Expert Rev Ophthalmol,2009,4(2):145-161.
[26]MCLAREN N C,MOROI S E.Clinical implications of pharmacogenetics for glaucoma therapeutics[J].Pharmacogenomics J,2003,3(4):197-201.
[27]ROCHA-SOUSA A,RODRIGUES-ARAUJO J,GOUVEIA P,BARBO-SA-BREDA J,AZEVEDO-PINTO S,PEREIRA-SILVA P,et al.New therapeutic targets for intraocular pressure lowering[J].ISRNOphthalmol,2013,2013:261386.
[28]WANG W H,MCNATT L G,PANG I H,MILLAR J C,HELL-BERG P E,HELLBERG M H,et al.Increased expression of the WNT antagonist s FRP-1 in glaucoma elevates intraocular pressure[J].J Clin Invest,2008,118(3):1056-1064.
[29]LEWIS R A,CHRISTIE W C,DAY D G,CRAVEN E R,WALTERS T,BEJANIAN M,et al.Bimatoprost sustained-release implants for glaucoma therapy:6-month results from a phaseⅠ/Ⅱclinical trial[J].Am J Ophthalmol,2017,175:137-147.
[30]ANDERS F,TEISTER J,LIU A,FUNKE S,GRUS F H,THANOSS,et al.Intravitreal injection of beta-crystallin B2 improves retinal ganglion cell survival in an experimental animal model of glaucoma[J].PLoS One,2017,12(4):e175451.
[31]HERMANN M M,PAPACONSTANTINOU D,MUETHER P S,GEORGOPOULOS G,DIESTELHORST M.Adherence with brimonidine in patients with glaucoma aware and not aware of electronic monitoring[J].Acta Ophthalmol,2011,89(4):e300-e305.
[32]NATU M V,GASPAR M N,FONTES R C,CABRITA A M,DESOUSA H C,GIL M H.In vitro and in vivo evaluation of an intraocular implant for glaucoma treatment[J].Int J Pharm,2011,415(1-2):73-82.
[33]HACKER M C,HAESSLEIN A,UEDA H,FOSTER W J,GARCIAC A,AMMON D M,et al.Biodegradable fumarate-based drug-delivery systems for ophthalmic applications[J].J Biomed Mater Res A,2009,88(4):976-989.
[34]FU J,SUN F,LIU W,LIU Y,GEDAM M,HU Q,et al.Subconjunctival delivery of dorzolamide-loaded poly(ether-anhydride)microparticles produces sustained lowering of intraocular pressure in rabbits[J].Mol Pharm,2016,13(9):2987-2995.
[35]LORENZ K,WASIELICA-POSLEDNIK J,BELL K,RENIERI G,KEICHER A,RUCKES C,et al.Efficacy and safety of preoperative IOP reduction using a preservative-free fixed combination of dorzolamide/timolol eye drops versus oral acetazolamide and dexamethasone eye drops and assessment of the clinical outcome of trabeculectomy in glaucoma[J].PLoS One,2017,12(2):e171636.
[36]NEWMAN-CASEY P A,ROBIN A L,BLACHLEY T,FARRIS K,HEISLER M,RESNICOW K,et al.The most common barriers to glaucoma medication adherence:a cross-sectional survey[J].Ophthalmology,2015,122(7):1308-1316.
[37]NEWMAN-CASEY P A,BLACHLEY T,LEE P P,HEISLER M,FARRIS K B,STEIN J D.Patterns of glaucoma medication adherence over four years of follow-up[J].Ophthalmology,2015,122(10):2010-2021.
[38]KIM M,KIM D M,PARK K H,KIM T W,JEOUNG J W,KIM SH.Intraocular pressure reduction with topical medications and progression of normal-tension glaucoma:a 12-year mean follow-up study[J].Acta Ophthalmol,2013,91(4):E270-E275.
[2]HONJO M,INATANI M,KIDO N,SAWAMURA T,YUE B Y,HONDA Y,et al.Effects of protein kinase inhibitor,HA1077,on intraocular pressure and outflow facility in rabbit eyes[J].Arch Ophthalmol,2001,119(8):1171-1178.
[3]TORIS C B,MCLAUGHLIN M A,DWORAK D P,FAN S,HA-VENS S,ZHAN G L,et al.Effects of Rho kinase inhibitors on intraocular pressure and aqueous humor dynamics in nonhuman primates and rabbits[J].J Ocul Pharmacol Ther,2016,32(6):355-364.
[4]SERLE J B,KATZ L J,MCLAURIN E,HEAH T,RAMIREZ-DA-VIS N,USNER D W,et al.Two Phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure[J].Am J Ophthalmol,2018,186:116-127.
[5]MAATTA M,TERVAHARTIALA T,HARJU M,AIRAKSINEN J,AUTIO-HARMAINEN H,SORSA T.Matrix metalloproteinases and their tissue inhibitors in aqueous humor of patients with primary open-angle glaucoma,exfoliation syndrome,and exfoliation glaucoma[J].J Glaucoma,2005,14(1):64-69.
[6]LERNER S F,PARK K H,HUBATSCH D A,ERICHEV V,PACZ-KA J A,ROBERTS T V.Efficacy and tolerability of travoprost 0.004%/Timolol 0.5%fixed-dose combination for the treatment of primary open-angle glaucoma or ocular hypertension inadequately controlled with beta-blocker monotherapy[J].J Ophthalmol,2017,2017:1917570.
[7]WORDINGER R J,SHARMA T,CLARK A F.The role of TGF-beta2 and bone morphogenetic proteins in the trabecular meshwork and glaucoma[J].J Ocul Pharmacol Ther,2014,30(2-3):154-162.
[8]NOLAN M J,GIOVINGO M C,MILLER A M,WERTZ R D,RITCHR,LIEBMANN J M,et al.Aqueous humor s CD44 concentration and visual field loss in primary open-angle glaucoma[J].J Glaucoma,2007,16(5):419-429.
[9]SHPAK A A,GUEKHT A B,DRUZHKOVA T A,KOZLOVA K I,GULYAEVA N V.Brain-derived neurotrophic factor in patients with primary open-angle glaucoma and age-related cataract[J].Curr Eye Res,2018,43(2):224-231.
[10]ODDONE F,ROBERTI G,MICERA A,BUSANELLO A,BONINI S,QUARANTA L,et al.Exploring serum levels of brain derived neurotrophic factor and nerve growth factor across glaucoma stages[J].PLoS One,2017,12(1):e168565.
[11]NAMIKI M,TAGAMI Y,YAMAMOTO M,YAMANAKA A,ITOH M,KANOH M.Presence of human epidermal growth factor(hEGF),basic fibroblast growth factor(bFGF)in human aqueous[J].Nippon Ganka Gakkai Zasshi,1992,96(5):652-656.
[12]GARTAGANIS S P,GEORGAKOPOULOS C D,EXARCHOUA M,MELA E K,LAMARI F,KARAMANOS N K.Increased aqueous humor basic fibroblast growth factor and hyaluronan levels in relation to the exfoliation syndrome and exfoliative glaucoma[J].Acta Ophthalmol Scand,2001,79(6):572-575.
[13]PARRILLA-REVERTER G,AGUDO M,SOBRADO-CALVO P,SALINAS-NAVARRO M,VILLEGAS-PEREZ M P,Vidal-Sanz M.Effects of different neurotrophic factors on the survival of retinal ganglion cells after a complete intraorbital nerve crush injury:a quantitative in vivo study[J].Exp Eye Res,2009,89(1):32-41.
[14]LEBRUN-JULIEN F,DI POLO A.Molecular and cell-based approaches for neuroprotection in glaucoma[J].Optom Vis Sci,2008,85(6):417-424.
[15]LEVKOVITCH-VERBIN H,VANDER S,MAKAROVSKY D,LAVINSKY F.Increase in retinal ganglion cells’susceptibility to elevated intraocular pressure and impairment of their endogenous neuroprotective mechanism by age[J].Mol Vis,2013,19:2011-2022.
[16]CHI W,LI F,CHEN H,WANG Y,ZHU Y,YANG X,et al.Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1beta production in acute glaucoma[J].Proc Natl Acad Sci U SA,2014,111(30):11181-11186.
[17]WAN P,SU W,ZHANG Y,LI Z,DENG C,ZHUO Y.Trimetazidine protects retinal ganglion cells from acute glaucoma via the Nrf2/Ho-1 pathway[J].Clin Sci(Lond),2017,131(18):2363-2375.
[18]GOMES E,PAPA L,HAO T,ROCKWELL P.The VEGFR2 and PKA pathways converge at MEK/ERK1/2 to promote survival in serum deprived neuronal cells[J].Mol Cell Biochem,2007,305(1-2):179-190.
[19]KILIC U,KILIC E,JARVE A,GUO Z,SPUDICH A,BIEBER K,et al.Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1/2 and Akt pathways[J].J Neurosci,2006,26(48):12439-12446.
[20]FOXTON R H,FINKELSTEIN A,VIJAY S,DAHLMANN-NOORA,KHAW P T,MORGAN J E,et al.VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma[J].Am J Pathol,2013,182(4):1379-1390.
[21]PROKAI-TATRAI K,XIN H,NGUYEN V,SZARKA S,BLAZICSB,PROKAI L,et al.17beta-estradiol eye drops protect the retinal ganglion cell layer and preserve visual function in an in vivo model of glaucoma[J].Mol Pharm,2013,10(8):3253-3261.
[22]DANESH-MEYER H V.Neuroprotection in glaucoma:recent and future directions[J].Curr Opin Ophthalmol,2011,22(2):78-86.
[23]YANG F,WANG D,WU L,LI Y.Protective effects of triptolide on retinal ganglion cells in a rat model of chronic glaucoma[J].Drug Des Devel Ther,2015,9:6095-6107.
[24]STOILOV I,AKARSU A N,SARFARAZI M.Identification of three different truncating mutations in cytochrome P4501B1(CYP1B1)as the principal cause of primary congenital glaucoma(Buphthalmos)in families linked to the GLC3A locus on chromosome 2p21[J].Hum Mol Genet,1997,6(4):641-647.
[25]MOROI S E,RAOOF D A,REED D M,ZOLLNER S,QIN Z,RICHARDS J E.Progress toward personalized medicine for glaucoma[J].Expert Rev Ophthalmol,2009,4(2):145-161.
[26]MCLAREN N C,MOROI S E.Clinical implications of pharmacogenetics for glaucoma therapeutics[J].Pharmacogenomics J,2003,3(4):197-201.
[27]ROCHA-SOUSA A,RODRIGUES-ARAUJO J,GOUVEIA P,BARBO-SA-BREDA J,AZEVEDO-PINTO S,PEREIRA-SILVA P,et al.New therapeutic targets for intraocular pressure lowering[J].ISRNOphthalmol,2013,2013:261386.
[28]WANG W H,MCNATT L G,PANG I H,MILLAR J C,HELL-BERG P E,HELLBERG M H,et al.Increased expression of the WNT antagonist s FRP-1 in glaucoma elevates intraocular pressure[J].J Clin Invest,2008,118(3):1056-1064.
[29]LEWIS R A,CHRISTIE W C,DAY D G,CRAVEN E R,WALTERS T,BEJANIAN M,et al.Bimatoprost sustained-release implants for glaucoma therapy:6-month results from a phaseⅠ/Ⅱclinical trial[J].Am J Ophthalmol,2017,175:137-147.
[30]ANDERS F,TEISTER J,LIU A,FUNKE S,GRUS F H,THANOSS,et al.Intravitreal injection of beta-crystallin B2 improves retinal ganglion cell survival in an experimental animal model of glaucoma[J].PLoS One,2017,12(4):e175451.
[31]HERMANN M M,PAPACONSTANTINOU D,MUETHER P S,GEORGOPOULOS G,DIESTELHORST M.Adherence with brimonidine in patients with glaucoma aware and not aware of electronic monitoring[J].Acta Ophthalmol,2011,89(4):e300-e305.
[32]NATU M V,GASPAR M N,FONTES R C,CABRITA A M,DESOUSA H C,GIL M H.In vitro and in vivo evaluation of an intraocular implant for glaucoma treatment[J].Int J Pharm,2011,415(1-2):73-82.
[33]HACKER M C,HAESSLEIN A,UEDA H,FOSTER W J,GARCIAC A,AMMON D M,et al.Biodegradable fumarate-based drug-delivery systems for ophthalmic applications[J].J Biomed Mater Res A,2009,88(4):976-989.
[34]FU J,SUN F,LIU W,LIU Y,GEDAM M,HU Q,et al.Subconjunctival delivery of dorzolamide-loaded poly(ether-anhydride)microparticles produces sustained lowering of intraocular pressure in rabbits[J].Mol Pharm,2016,13(9):2987-2995.
[35]LORENZ K,WASIELICA-POSLEDNIK J,BELL K,RENIERI G,KEICHER A,RUCKES C,et al.Efficacy and safety of preoperative IOP reduction using a preservative-free fixed combination of dorzolamide/timolol eye drops versus oral acetazolamide and dexamethasone eye drops and assessment of the clinical outcome of trabeculectomy in glaucoma[J].PLoS One,2017,12(2):e171636.
[36]NEWMAN-CASEY P A,ROBIN A L,BLACHLEY T,FARRIS K,HEISLER M,RESNICOW K,et al.The most common barriers to glaucoma medication adherence:a cross-sectional survey[J].Ophthalmology,2015,122(7):1308-1316.
[37]NEWMAN-CASEY P A,BLACHLEY T,LEE P P,HEISLER M,FARRIS K B,STEIN J D.Patterns of glaucoma medication adherence over four years of follow-up[J].Ophthalmology,2015,122(10):2010-2021.
[38]KIM M,KIM D M,PARK K H,KIM T W,JEOUNG J W,KIM SH.Intraocular pressure reduction with topical medications and progression of normal-tension glaucoma:a 12-year mean follow-up study[J].Acta Ophthalmol,2013,91(4):E270-E275.