Experimental Eye Research 93 (2011) 271e283

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Experimental Eye Research

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Update on the role of alpha-agonists in glaucoma management

Stella Arthur, Louis B. Cantor*

Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA article info abstract

Article history: Glaucoma is the second most common cause of world blindness (following cataract) with estimated Received 30 November 2010 cases reaching 79.6 million by 2020. Although the etiology of glaucoma is multi-factorial, intraocular Accepted in revised form 4 April 2011 pressure (IOP) is the only modifiable factor in glaucoma management proven to alter the natural course Available online 20 April 2011 of the disease. Among various classes of IOP-lowering medications currently available, alpha-adrenergic receptor agonists are used either as monotherapy, as second-line therapy, or in fixed combination with Keywords: beta-blockers. Non-selective adrenergic agonists such as epinephrine and dipivefrin are infrequently glaucoma used today for the treatment of glaucoma or ocular hypertension, and have been replaced by the alpha-2- alpha-agonists monotherapy selective agonists. The use of apraclonidine for IOP reduction in glaucoma or OHT is limited due to a high fixed combinations rate of follicular conjunctivitis. The alpha-2-selective agonist in use today is brimonidine. The brimo- neuroprotection nidineepurite formulations are preferred to brimonidineebenzalkonium chloride (BAC) formulations ocular blood flow due better tolerability while maintaining similar efficacy. Brimonidine is also effective when used in safety and efficacy combination with a beta-blocker. Using brimonidineetimolol fixed combination (BTFC) as first-line compliance and cost of alpha-agonists therapy has an added potential for neuroprotection. This would be a valuable strategy for glaucoma treatment, for patients who are intolerant of prostaglandin analogs, or for patients where prostaglandin analogues are contraindicated as first-line therapy, such as in patients with inflammatory glaucoma. Ó 2011 Elsevier Ltd. All rights reserved.

1. Introduction parasympathomimetics, and alpha-adrenergic receptor agonists (Greenfield et al., 1997; Carroll et al., 2006; Costagliola et al., 2009; Glaucoma is a multi-factorial, neurodegenerative, heterogeneous Crassous et al., 2007; Lee and Higginbotham, 2005; McKinnon group of disorders associated with a characteristic, progressive, optic et al., 2008; Robin, 1997, 1995; Serle et al., 2002). neuropathy and corresponding visual field loss. It is the second most common cause of world blindness (following cataract) with esti- 2. Classification of alpha-adrenergic receptors and mated cases reaching 79.6 million by 2020 (Quigley and Broman, mechanism of action of alpha-agonists used 2006). Annual incidence of primary open angle glaucoma (POAG) for glaucoma treatment in the USA is estimated to be 2.2 million cases (Leske, 2007). Although the etiology of glaucoma is multi-factorial, intraocular pressure (IOP) Adrenergic receptors are cell membrane receptors, which belong is the only modifiable factor in glaucoma management proven to to the G-protein-linked superfamily of receptors. Adrenergic recep- alter the natural course of the disease. Numerous studies have shown tors mediate functions of the sympathetic nervous system, and that IOP reduction prevents glaucoma or delays progression of produce the “fight or flight” reaction. Two classes of adrenergic established glaucoma (Friedman et al., 2004; AGIS Investigators, receptors have been identified: excitatory alpha-receptor and 2002; Lichter et al., 2001; Leske et al., 2003; Collaborative NTG inhibitory beta-receptors (Ahlquist, 1948). Two groups of alpha- study group, 1998; Heijl et al., 2009; Kass et al., 2002, 2010; Hoyng adrenergic receptors, with associated subtypes, have been identi- and Kitazawa, 2002). Several groups of IOP-lowering medications fied: alpha-1 (A, B, D) and alpha-2 (A, B, C) (Gilsbach et al., 2009; are currently available. These include prostaglandin analogs, beta- Docherty, 2010; Piascik et al., 1995; Piascik and Perez, 2001). One adrenergic receptor antagonists, carbonic anhydrase inhibitors, of the primary actions of alpha-1 receptors is induction of smooth þ muscle contraction, which is achieved by activating Ca2 channels or þ by releasing intracellular Ca2 (Docherty, 2010). One of the main * Correspondence to: Louis B. Cantor, Eugene and Marilyn Glick Eye Institute, actions of pre-junctional alpha-2 receptors is inhibition of neuro- Indiana University School of Medicine, Department of Ophthalmology, 702 Rotary Circle, Indianapolis, IN 46202, USA. transmitters (Reitsamer et al., 2006; Starke et al.,1975; Gilsbach et al., E-mail address: [email protected] (L.B. Cantor). 2009). Activation of vascular post-junctional alpha-2 receptors

0014-4835/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.exer.2011.04.002 272 S. Arthur, L.B. Cantor / Experimental Eye Research 93 (2011) 271e283 causes vasoconstriction (Reitsamer et al., 2006) and activation of extracellular matrix (ECM) degradation. ECM within the trabecular post-junctional epithelial alpha-2 receptors inhibits adenylate meshwork plays an important role in increasing outflow resistance, cyclase (Kaufman and Gabelt,1995). The functions of alpha-receptors and within conjunctiva it promotes wound healing. Hence, its and their subtypes are summarized in Table 1. degradation would increase aqueous outflow and promote post- In the eye, alpha-agonists activate alpha-1 receptors that stim- operative survival of a trabeculectomy bleb (Ito et al., 2006). ulate contraction of the iris dilator and Muller muscles, leading to mydriasis and lid retraction. Furthermore, alpha-1 stimulation also 3. Formulations and pharmacokinetics of alpha-agonist leads to vasoconstriction resulting in restricted blood flow to ciliary glaucoma medications muscle and reduced production of aqueous (Docherty, 2010). Similarly, stimulation of vascular post-junctional alpha-2 receptors 3.1. Non-selective alpha-agonists causes ciliary body and episcleral vasoconstriction (Reitsamer et al., 2006). By stimulating post-junctional epithelial alpha-2 receptors, Epinephrine is available in 0.25%, 0.5%, 1.0%, and 2.0% concen- alpha-agonists decrease intracellular cAMP (Mittag and Tormay, trations and is used twice daily. Dipivalyl epinephrine (dipivefrin) is 1985) resulting in decreased production of aqueous and increased available in a 0.1% concentration and is also used twice daily. uveoscleral outflow (Gilsbach et al., 2009; Costagliola et al., 2009; Dipivefrin is a prodrug of epinephrine, and therefore a lower David, 2001; Robin and Burnstein, 1998; Liu and Gallar, 1996; concentration is required topically (Kass et al., 1979). Due to its Mittag and Tormay, 1985, Toris et al., 1995a). Furthermore, by increased lipophilicity, dipivefrin has better corneal penetration stimulating alpha-2 receptors, alpha-agonists oppose the effects of than epinephrine and is cleaved to its active form by corneal beta-receptors on aqueous outflow and mitotic activity of cultured esterases, leading to intraocular concentrations that are similar to human trabecular meshwork endothelial cells (Stamer et al., 1996). topically applied epinephrine. In addition, alpha-agonists have been shown to modulate expres- Numerous studies conducted to elucidate the effect of epineph- sion and enzymatic activity of matrix metalloproteinases (MMPs) rine on aqueous dynamics revealed conflicting results. Some inves- and tissue inhibitors of metalloproteinase (TIMPs), which stimulate tigators found that a single dose of epinephrine (Townsend and Brubaker, 1980; Higgins and Brubaker, 1980), twice daily dose given over 1 week (Schenker et al., 1981), or intravenously administered Table 1 epinephrine (Kacere et al., 1992) may increase aqueous production. Summary of alpha-receptors and their subtypes with mechanism of actions. This effect is thought to be mediated by the beta-adrenergic prop- Receptors Action erties of epinephrine. Other studies found the epinephrine has no effect on aqueous production (Bill, 1969; Schneider and Brubaker, Alpha1A 1. Vasoconstriction of ciliary muscle resulting in reduced production of aqueous and decrease in intraocular 1991). Yet, other studies found that shortly following instillation, pressure (Docherty, 2010) both epinephrine and dipivefrin induce vasoconstriction in the iris 2. Contraction of smooth muscle cells and ciliary body, which leads to decreased aqueous production. This (Docherty, 2010; Piascik and Perez, 2001) 3. Vasoconstriction and regulation of arterial transient effect is initially replaced by an early (within hours) blood pressure (Docherty, 2010; Piascik and Perez, 2001) increase in trabecular outflow facility, and later is sustained by 4. Temperature control (Docherty, 2010; increase in uveoscleral outflow (Garner et al.,1959; Wang et al.,1999; Bexis and Docherty, 2008) Schenker et al., 1981; Townsend and Brubaker, 1980; Bill, 1969; 5. Mediation of hypertrophic growth of myocardial Ballintine and Garner, 1961). cells (Varma and Deng, 2000)

Alpha1B 1. Regulation of arterial blood pressure (Piascik and Perez, 2001). 3.2. Selective alpha-2 agonists 2. Increase of the p38 kinase activity, a mediator of cell growth, proliferation, differentiation, and survival (Waldrop et al., 2002) 3.2.1. Apraclonidine Within the selective adrenergic agonists, the alpha-2 adrenergic Alpha 1. Contraction of smooth muscle cells and regulation 1D agonists are currently the primary therapeutic agents in use. of arterial blood pressure to a lesser degree than alpha1A receptors (Docherty, 2010; Piascik et al., 1995; Apraclonidine, a para-amino derivative of clonidine, was the first Piascik and Perez, 2001) relatively alpha-2-selective agent available. This agent is only 2. Temperature control (Docherty, 2010; mildly selective for the alpha-2 over the alpha-1 receptors. It is Bexis and Docherty, 2008) available in 0.25% and 0.5% concentrations for short-term therapy, 3. Activation of the c-Jun NH2-terminal kinases (JNKs) resulting in inhibition of DNA replication (Waldrop et al., 2002) and a 1% concentration for post-laser use. Apraclonidine reduces aqueous production and flow, does not affect blood-aqueous Alpha2A 1. Decrease in intracellular cAMP (Gilsbach et al., 2009) resulting in decreased aqueous production and increased permeability (Gharagozloo et al., 1988) and reduces episcleral uveoscleral outflow (Liu and Gallar, 1996; venous pressure (Toris et al., 1995a). Apraclonidine may be used Mittag and Tormay, 1985, Toris et al., 1995a) 2e3 times daily. The apraclonidine plasma concentrations range 2. Ciliary vasoconstriction resulting in reduced from nondetectable to 6.2 ng/mL, and are higher for apraclonidine aqueous production (Reitsamer et al., 2006) 0.5% than for apraclonidine 0.25% (Robin and Coleman, 1990). 3. Inhibition of neurotransmitters (Starke et al., 1975; Gilsbach et al., 2009) 4. Bradycardia and hypotension (MacMillan et al., 1996) 3.2.2. Brimonidine 0.2% preserved with benzalkonium 5. Sedation and hypnosis (Gilsbach et al., 2009; chloride and brimonidine 0.2% preservative free Lakhlani et al., 1997) Brimonidine tartrate is the primary alpha-2 agonist used for 6. Consolidation of working memory (Wang et al., 2007) glaucoma therapy today (Cantor, 2006; Cantor et al., 2008a,b). Alpha2B 1. Counteraction of the hypotensive effect of alpha2A Brimonidine-PF (brimonidine 0.2%, preservative free (PF), pH 6.4) is Ò receptors (Link et al., 1996) used in the US, and Alphagan (brimonidine 0.2%/benzalkonium 2. Essential for the placental vascular development (Philipp et al., 2002) chloride (BAC) 0.005%, pH 6.4) is available internationally. Brimo- nidine is up to 30-fold more selective for alpha-2 than for alpha-1 Alpha 1. Involvement with the feedback regulation of adrenal 2C receptors (Burke and Schwartz, 1996). It decreases IOP by catecholamine release (Starke et al., 1975) reducing production of aqueous and increasing its outflow via S. Arthur, L.B. Cantor / Experimental Eye Research 93 (2011) 271e283 273 uveoscleral pathway (Adkins and Balfour, 1998; Wilensky, 1996; 3.3. Brimonidineetimolol fixed combination (BTFC) Toris et al., 1995b). Pre-clinical studies of brimonidine in rabbits, monkeys and mice with plasma brimonidine concentrations of up A fixed combination of brimonidine 0.2% and the non-selective to 118 times higher than therapeutic levels in humans demonstrate beta-blocker timolol 0.5% preserved with BAC (CombiganÔ, Aller- an excellent safety profile (Angelov et al., 1996). In patients, 0.08%, gan Inc, Irvine, CA) has been recently approved by the United States 0.2%, and 0.5% concentrations of brimonidine were found to be Food and Drug Administration, and is now available for glaucoma equally safe and effective in reducing IOP (Derick et al., 1997). treatment. It reduces IOP by increasing uveoscleral outflow and Brimonidine is primarily absorbed through the cornea and decreasing aqueous production. Following rapid absorption into conjunctiva (Cantor, 2000; Acheampong et al., 2002). Animal and ocular tissue, brimonidine achieves terminal half-life in aqueous in human studies demonstrate that brimonidine metabolism in the 1.23 h and timolol achieves terminal half-life in aqueous in 1.12 h. liver is facilitated by aldehyde oxidase (Acheampong et al., 2002, The peak plasma concentration for brimonidine is 32.7 pg/mL and 2003). It has a plasma-life of about 2 h (Cantor, 2000) and is for timolol it is 0.41 ng/mL. In one study, twice daily administration primarily excreted by the kidneys. Due to its rapid metabolism and of BTFC for 7 days to 16 healthy volunteers resulted in area under systemic clearance, it is not associated with significant cardiovas- the plasma concentration time curve (0e12 h) of 128 pg h/mL for cular or pulmonary systemic side effects. In contrast to beta- brimonidine and 2.92 ng h/mL for timolol. Brimonidine plasma blockers, brimonidine is not contraindicated in patients with concentration after 2 weeks ranges between 50.6 pg/mL and cardiovascular or pulmonary pathology (Cantor, 2006; Adkins and 61.0 pg/mL, and after 12 months between 51.5 pg/mL and 56.2 pg/ Balfour, 1998). Upon its rapid absorption, brimonidine is distrib- mL. For timolol the values range from 0.50 ng/mL to 0.74 ng/mL uted throughout the iris, ciliary body, vitreous, choroid, retina, and after 2 weeks, and from 0.54 ng/mL to 0.55 ng/mL after 12 months. optic nerve. The latter is relevant for neuroprotection models The plasma elimination half-life value is 2.43 h for brimonidine and (Acheampong et al., 2002). Brimonidine may be administered 2e3 7.32 h for timolol (Lee and McCluskey, 2008). times daily, but most studies of its usage and efficacy are based on twice daily dosing. Brimonidine reduces IOP within 1 h following 4. Clinical efficacy of selective alpha-2 agonists initial instillation. Mean reductions in peak IOP at 2e3 h after in reducing IOP dosing is approximately 6 mmHg, and at trough IOP 10e14 h after dosing is about 4 mm Hg (Adkins and Balfour, 1998; Cantor, 2006; 4.1. Apraclonidine monotherapy Walters, 1996). Although effective as an ophthalmic solution used twice daily, Numerous studies demonstrate that apraclonidine is very experimental work in rabbits demonstrates that brimonidine- effective in preventing spikes of IOP following various laser loaded nanoparticles may be equally effective by prolonging the procedures (Lewis et al., 1998; Arieta et al., 2002; Chen et al., 2001; drug release over 8 h, hence reducing dosage frequency (Singh and Chevrier et al., 1999; Holmwood et al., 1992). Both apraclonidine Shinde, 2010). 0.5% and 1% are equally effective in preventing pressure spikes following YAG (Nd: YAG) iridotomy (p > 0.7) in patients with 3.2.3. Brimonidine 0.15%-purite, brimonidine 0.1%-purite chronic angle-closure glaucoma (CACG). Apraclonidine 0.5% is more and brimonidine 0.15%-polyquaternium-1 effective than apraclonidine 1% for IOP control following capsu- Two formulations of brimonidineepurite are available: brimo- lotomy (p ¼ 0.04) and less effective for post-trabeculoplasty IOP Ò nidine 0.15%-purite and brimonidine 0.1%-purite (Alphagan control (Rosenberg et al., 1995). Apraclonidine’ control of post-laser Ò P 0.15% and Alphagan P 0.1% respectively, Allergan Inc, Irvine, CA, IOP diminishes in patients with chronic apraclonidine use, Ò USA). Alphagan P 0.15% has a buffered solution of average pH 7.2 presumably due to alpha-2 receptor saturation with apraclonidine Ò and Alphagan P 0.1% has a buffered solution of average pH (Chung et al., 1997). Apraclonidine is effective in preventing post- 7.7. Both are preserved with purite 0.005%, a stabilized oxychloro cycloplegic pressure spikes (Hill et al., 1991). Pre-operative use of complex and oxidative preservative. When exposed to light purite apraclonidine prior to trabeculectomy does not appear to increase is converted to sodium, chloride ions, oxygen, and water, all of incidence of post-operative complications (Azuara-Blanco et al., which are components of natural tears. It has microbicidal prop- 1996). Although clonidine may provide an allergy-free alternative erties and is non-toxic to cells (Cantor, 2006; Cantor et al., 2008a; to apraclonidine (Geyer et al., 2000), its use in glaucoma is limited Acheampong et al., 2002). Despite the differences in the pH, both due to its tendency to penetrate bloodebrain barrier. brimonidine 0.15%-purite and brimonidine 0.1%-purite solutions Clinical evaluations demonstrate that apraclonidine can lower have similar bioavailability and tolerability (Cantor et al., 2008a). IOP up to 29% (Gross et al., 1997; Robin et al., 1995a,b). With When applied topically, brimonidine 0.15%-purite achieves vitreous apraclonidine treatment surgery can be avoided or delayed in up to concentration sufficient to activate the neuroprotective retinal 61% of patients compared to patients managed with placebo alpha-2 receptors in animals (Kent et al., 2006). Brimonidine 0.15%- (p < 0.001) (Robin et al., 1995a,b). A direct comparison of apra- purite has better tolerability than brimonidine 0.2%, yet similar clonidine 0.25%, apraclonidine 0.5% and timolol 0.5% demonstrates efficacy and aqueous concentration (Katz, 2002; Dong et al., 2004). a the mean IOP lowering from baseline at 2 h after drop instillation Brimonidineepurite produces less corneal damage and conjunc- of 5.0 þ 2.9 for apraclonidine 0.5%, 4.3 2.4 for timolol, and tival cell infiltration than glaucoma medications containing BAC 3.2 2.1 for apraclonidine 0.25%. Neither apraclonidine nor timolol (Noecker et al., 2004). produce any significant difference in the mean resting diastolic and Brimonidine 0.15% PQ (Polyquad, Alcon Research Ltd., Fort systolic blood pressures of the volunteers between all treatment Worth, TX) is brimonidine preserved with polyquaternium-1. Pol- arms (Robin and Coleman, 1990). Another study demonstrates that yquaternium-1 is a high molecular weight quaternary ammonium apraclonidine 0.25% and 0.5% reduce IOP to a similar degree as 0.5% that has been used as the preservative in Alcon manufactured timolol 8 h after morning dosing (Stewart et al., 1996). contact lens care products, lens wetting and comfort drops. It is added at a concentration of 0.001% to brimonidine ophthalmic 4.2. Apraclonidine adjunctive therapy solution 0.15% to provide antimicrobial preservation of brimonidine. It has a slightly higher reported incidence of allergic reaction than When added to timolol 0.5%, apraclonidine 0.5% has similar IOP brimonidine 0.15%-P (5.3% vs 4.0%) (Whitson et al., 2006). control in patient with either pseudoexfoliative glaucoma or POAG 274 S. Arthur, L.B. Cantor / Experimental Eye Research 93 (2011) 271e283

(mean SD diurnal IOP 20.5 7.0 vs 20.0 3.4) (Konstas et al., beta-blocker lessens. By year 3 and 4 in long-term studies, brimo- 1999). Both 0.5% and 1% apraclonidine are equally effective as the nidine becomes more effective than timolol at trough. This first adjunctive drug to timolol for at least 90 days. Out of 129 increased efficacy at trough may be in part due to brimonidine’s patients studied, 9 developed sensitivity to apraclonidine 0.5%, and dual mechanism of action. Initially this agent suppresses aqueous 13 to apraclonidine 1% (Stewart et al., 1995). production, but with time also leads to increased uveoscleral outflow (Toris et al., 1995b), which may be long-standing. 4.3. Brimonidine monotherapy When compared to betaxolol, brimonidine decreases IOP by 20% or greater in a significantly higher percentage of patients (Cantor Brimonidine’s IOP reductions average 20%e30% with a nonre- et al., 2001). Up to 74% of patients treated with brimonidine ach- sponder rate of less than 10%. Brimonidine is effective in preventing ieve clinical success as opposed to 57% of patients treated with elevation of IOP following argon laser trabeculoplasty (Barnebey betaxolol (p ¼ 0.027) (Javitt and Goldberg, 2000). A prospective, et al., 1993) and controlling pressure spikes following phacoe- 3-month, multicenter, randomized, double-masked, parallel-group mulsification (Katsimpris et al., 2003). A multicentered, double- study involving 206 patients with POAG or OHT demonstrated that masked, randomized study of 248 patients with argon laser twice daily administration of brimonidine 0.2% solution or betax- trabeculoplasty demonstrates up to 8 mm Hg reduction in mean olol 0.25% was effective in reducing peak and trough IOP at every IOP in groups pre-treated with brimonidine (David et al., 1993). scheduled follow-up visit over the 3-month study. Brimonidine Brimonidine has similar efficacy to apraclonidine in controlling IOP produced a greater decrease at peak (5.8 mm Hg) and trough spikes following ALT (Barnes et al., 1999) or laser peripheral iri- (3.9 mm Hg) than betaxolol (3.8 mm Hg and 3.2 mm Hg respec- dotomy (Chen et al., 2001; Yuen et al., 2005). tively). Brimonidine was ineffective in 2.9% and betaxolol was Brimonidine has been shown to have similar efficacy in reducing ineffective in 4.2% of the cases (Serle, 1996). IOP compared to timolol in short (Katz, 1999) and long-term clinical As monotherapy, brimonidine produces IOP-lowering efficacy trials (Loon et al., 2008). In a large community population study, equivalent to dorzolamide at trough and at one and 3 h after brimonidine was most effective in lowering IOP when used as instillation (Whitson et al., 2004). Both brimonidine and dorzola- monotherapy (20.2%) rather than combination (16.9%) or mide have comparable efficacy and safety (Katz et al., 2007). The replacement therapy (9.8%) (Lee et al., 2000; Lee, 2000). In efficacy and tolerability of twice daily dosages of dorzolamidee patients with normal tension glaucoma (NTG), brimonidine used timolol fixed combination (DTFC) are similar to the efficacy and three times daily produces similar results to twice daily dosage for tolerability of twice daily dosage of the concomitant administration reductions in diurnal IOP (Liu et al., 2004). Another study demon- of 0.2% brimonidine ophthalmic solution and 0.5% timolol strates that brimonidine has lower mean peak reduction in IOP ophthalmic solution. At month 3, the change in adjusted mean than timolol: 6.5 mm Hg vs. 6.1 mm Hg. The effect is especially (standard error) IOP was 5.04 (0.30) mm Hg for DTFC and 5.41 prominent at week 2 and month 3 (P < 0.03). Tachyphylaxis is (0.30) mm Hg for the concomitant therapy per one study (Sall et al., unlikely to occur with either treatment. Dry mouth is more 2003) and 4.30 (0.24) mm Hg versus 5.27 (0.23) mm Hg per other common with the brimonidine treatment (33.0% vs 19.4%) whereas study (Solish et al., 2004). The incidence of drug-related adverse complaints of burning and stinging are more common with timolol experiences and patient-reported assessments of convenience and treatment (41.9%). Headache, fatigue, and drowsiness may occur at satisfaction were similar in the two groups (Solish et al., 2004). similar frequency with either treatment (Schuman et al., 1997). A study comparing monotherapy using brimonidine 0.2% twice Brimonidine 0.2% used three times daily may provide a lower daily vs. latanoprost 0.005% once daily demonstrated higher mean mean diurnal IOP (18.0 2.2) than brimonidine used twice daily IOP reduction in the brimonidine group than in the latanoprost (19.2 2.4) and similar mean diurnal IOP to timolol 0.5% used twice group (DuBiner et al., 2001). However, another study produced daily (17.7 2.7) (Konstas et al., 2001). Its efficacy to sustain low opposite results. In this latter study brimonidine provided a smaller IOP and preserve visual fields is equivalent to timolol 0.5% over a 3 change from baseline in intraocular pressure (mean SD, year period of treatment (Melamed and David, 2000). Brimonidine 23.7 5.6 mm Hg to 21.9 5.7 mm Hg) than latanoprost (mean SD, doesn’t produce any significant chronotropic effects on the heart 21.6 5.1 mm Hg to 17.1 3.3 mm Hg) (p ¼ 0.001). More patients (Katz, 1999), in contrast to timolol, which may decrease heart rate treated with brimonidine (80%) than latanoprost (45%) required (Schuman, 1996). Both brimonidine and timolol have similar effects additional visits to adjust therapy to further lower intraocular on quality of life and mean systolic and diastolic blood pressure pressure or to assess an adverse event (p < 0.001) (Stewart et al., (Javitt and Schiffman, 2000). Furthermore, post hoc evaluation of 2000a). Latanoprost produces lower trough (16.2 2.9 mm Hg) data collected from 926 subjects with ocular hypertension (OHT) or and diurnal IOP (15.4 2.5 mm Hg) than brimonidine (19.6 3.4 mm glaucoma reveals that in contrast to timolol-treated subjects Hg and 17.6 2.2 mm Hg, respectively) (Stewart et al., 2001). concurrently taking systemic beta-blockers, brimonidine-treated In patients with normal tension glaucoma brimonidine is less subjects do not experience significant mean change in heart rate or effective in reducing IOP than latanoprost at 8 am. (11.7 2.2 mm systolic or diastolic blood pressure. Therefore, brimonidine may be Hg vs. 13.7 2.1 mm Hg, p ¼ 0.004) and 4 pm (11.4 2.1 mm Hg vs. a safer first-line therapy for OHT and glaucoma patients concur- 13.2 2.9 mm Hg, p ¼ 0.004) but equally effective in reducing IOP rently taking systemic beta-blockers (Schuman, 2000a). Brimoni- at 12 noon (11.5 2.6 mm Hg vs. 11. 5 2.3 mm Hg, p ¼ 0.967). In dine is also a safer alternative to beta-blockers in geriatric patients contrast to latanoprost, brimonidine produces higher mean diurnal with glaucoma. Brimonidine twice daily produces an additional IOP due to its shorter effect (Liu et al., 2002). mean reduction in IOP of 8.2% (1.4 mm Hg; p < 0.001) when it replaces beta-blockers in geriatric patients (Noecker, 2002). 4.4. Brimonidine adjunctive therapy In Taiwanese patients with glaucoma, short-term brimonidine treatment is equally effective to timolol in reducing IOP (Chen et al., When added to timolol, brimonidine leads to a mean IOP 2003). Other studies demonstrate that at peak response, 2 h reduction from 15.5% (Lee and Gornbein, 2001) to 25% (Arici et al., following dosing, brimonidine is more effective than timolol 2002) and is more effective in reducing IOP than dorzolamide throughout the first year of dosing. At trough, 12 h post-dosing, (Centofanti et al., 2000). brimonidine is slightly less effective than timolol (LeBlanc, 1998). The combination of brimonidine and latanoprost provides more However, in long-term follow-up, the trough effect relative to the significant mean IOP reduction when compared to DTFC at 1 month S. Arthur, L.B. Cantor / Experimental Eye Research 93 (2011) 271e283 275

(39.0% vs.25.1%, p ¼ 0.001) and 3 months (33.4% vs. 26.3%, (Sharpe et al., 2004). No differences in safety and efficacy profiles p ¼ 0.047) (Zabriskie et al., 2003). A large, open-label community were found between brimonidine 0.15%-purite or polyquad (PQ). trial revealed that the addition of brimonidine to latanoprost Peak IOP reductions measured at the 10 am and 5 pm time points monotherapy provides up to 32% (5.89 mm Hg) additional mean ranged from 5.3 to 6.5 mm Hg for brimonidine PQ and from 5.3 to IOP reduction. However, brimonidine is not as effective when 6.6 mm Hg for brimonidine 0.15%-purite (Whitson et al., 2006). added to other combination regimens that included latanoprost. Here the additional mean decreases in IOP range from 15.5% 4.6. Brimonidine 0.15%-purite adjunctive therapy (3.63 mm Hg) to 20.1% (6.62 mm Hg) (Lee and Gornbein, 2001). Brimonidine provides comparable peak IOP reduction to lata- Concomitant use of brimonidine 0.15%-purite with bimatoprost noprost when added as adjunctive therapy for patients with OHT or is more effective in reducing IOP than timolol gel-forming solution glaucoma uncontrolled on beta-blockers. In one study, mean IOP administration with latanoprost (Netland et al., 2003). However, reduction with brimonidine was 4.88 mm Hg at 1 month and concomitant use of brimonidine 0.15%-purite and travoprost 4.55 mm Hg at 3 months. Mean IOP reduction with latanoprost was 0.004% is less effective than concomitant use of travoprost and 5.01 mm Hg at 1 month and 5.49 mm Hg at 3 months. 44 of 54 brinzolamide (Feldman et al., 2007). This three-month, random- patients and 28 of 38 patients in the brimonidine group maintained ized, parallel-group, double-masked, multicenter clinical trial the minimum target 15% IOP reduction at peak drug effect at month studied patients with POAG, exfoliation glaucoma, or OHT with 1 and month 3 respectively. 43 of 53 patients and 30 of 36 patients IOP >18 mm Hg on monotherapy with travoprost (N ¼ 163). in the latanoprost group maintained the minimum target 15% IOP Patients were randomized to receive either twice-daily brimoni- reduction at peak drug effect at month 1 and month 3 respectively. dine 0.15%-purite or twice-daily brinzolamide 1%. Results showed Patients in the brimonidine group were less likely to report watery no difference between the two groups in mean SD IOP at baseline eyes, cold sensation in the hands and feet, or negative quality-of- (21.7 0.33 mm Hg vs. 21.1 0.29 mm Hg, p ¼ 0.16). However, at life variables when compared to patients in the latanoprost group the end of the trial, a significant difference in mean IOP was found (Simmons et al., 2002). between brimonidine 0.15%-purite and brinzolamide (19.3 0.27 Brimonidine was demonstrated to produce an acceptable mm Hg vs. 18.6 0.25 mm Hg, p ¼ 0.035). success rate (58%) compared to latanoprost (70%) or dorzolamide A randomized, controlled, investigator-masked, single-site, (40%) when these drugs are used as additive to a beta-blocker for parallel-group clinical trial demonstrates that brimonidine 0.15%- patients with OHT or POAG. Success was defined as a reduction in purite, as an adjunctive to bimatoprost, at the end of 4 months of intraocular pressure 3 mm Hg without adverse events leading to treatment provides a greater mean IOP-lowering effect than either discontinuation following six months of therapy. Mean SD IOP in dorzolamide or brinzolamide (16.5 mm Hg vs 17.5 mm Hg vs 17.7 mm brimonidine group was 17.4 4.9 mm Hg (4.2 4.5 mm Hg from Hg). Similar trends were observed with latanoprost (16.3 mm Hg vs. the baseline), mean SD IOP in latanoprost group was 17.4 mm Hg vs.17.7 mm Hg) and travoprost (16.8 mm Hg vs 18.0 mm 16.7 3.3 mm Hg (6.3 4.1 mm Hg from the baseline), and mean Hg vs 18.2 mm Hg) (Bournias and Lai, 2009). IOP in dorzolamide group was 20.1 6.1 mm Hg (3.1 5.1 mm Hg from the baseline) at 3 months (Stewart et al., 2000b). 4.7. Brimonidine 0.1%-purite monotherapy A randomized, comparative, investigator-masked study evalu- ated the IOP-lowering efficacy of timolol maleate 0.5%, brinzola- A randomized, double-masked, multicenter, parallel group, non- mide 1%, and brimonidine 0.2% as adjunctive therapy to travoprost inferiority study demonstrates that brimonidine 0.1%-purite twice 0.004% for patients with POAG or OHT. At the end of the 1-month daily has similar efficacy to brimonidine 0.15%-purite twice daily trial, the brinzolamide 1% and timolol maleate 0.5% groups had for lowering IOP in patients with glaucoma or ocular hypertension a greater percentage reduction in mean SD IOP (22.7% 8.6% and previously treated with brimonidine 0.15%-purite (Cantor et al., 20.2% 7.5% respectively) compared with the brimonidine 0.2% 2008b). Furthermore, brimonidine 0.1%-purite has a lower inci- group (13.4% 9.1%) (Reis et al., 2006). dence of treatment-related systemic adverse events (4.7% vs. 14.2%; p < 0.001) and discontinuations due to systemic adverse events 4.5. Brimonidine 0.15%-purite monotherapy (p ¼ 0.025) compared to brimonidine 0.15%-purite (Cantor et al., 2009). Brimonidine 0.1%-purite was found to be effective in A study comparing the efficacy and safety of brimonidine 0.15%- lowering IOP during the diurnal/wake period. However, less IOP- purite to that of brimonidine 0.2% in patients with glaucoma or OHT lowering effect during the nocturnal/sleep period was observed revealed no statistically significant difference between the brimo- (Liu et al., 2010). nidine 0.2% and the brimonidine 0.15%-purite groups with respect to mean IOP at baseline and at the end of 3 months in a multicenter, 4.8. Brimonidine 0.1%-purite adjunctive therapy randomized, double-masked trial (Mundorf et al., 2003). Further- more, many patients, who were previously treated with brimoni- A combination of brimonidine 0.1%-purite and latanoprost dine 0.15%-purite and later switched to generic brimonidine 0.2%, provides greater IOP lowering than brinzolamide/latanoprost at 10 due to a facility formulary change, could be successfully re-treated am (p < 0.001) and 4 pm (p ¼ 0.05). It has and equivalent IOP with brimonidine 0.15%-purite if they developed hypersensitivity lowering to brinzolamide/latanoprost at 8 am (p ¼ 0.716) (Day and to brimonidine 0.2% (Sullivan-Mee et al., 2010). A randomized, Hollander, 2008). multicenter, double-masked, parallel-group study demonstrated no difference in IOP-lowering effect among brimonidineepurite 0.15%, 5. Clinical efficacy of brimonidineetimolol fixed combination brimonidineepurite 0.2% and brimonidine 0.2% for patients with (BTFC) in reducing IOP glaucoma or OHT. However, brimonidineepurite 0.15% had the most favorable safety and tolerability profile and better satisfaction and 5.1. BTFC vs. concomitant therapy with brimonidine comfort rating compared to the other two medications (Katz, 2002). tartrate 0.2% twice daily and timolol 0.5% Brimonidine 0.15%-purite has a lower mean SD diurnal IOP than dorzolamide (19.3 3.1 mm Hg vs. 19.8 2.4 mm Hg, p ¼ 0.46) and A multicenter, double-masked study of 1159 patients with POAG overall similar efficacy to dorzolamide in POAG and OHT patients or OHT randomized to either receiving BTFC twice daily (n ¼ 385) 276 S. Arthur, L.B. Cantor / Experimental Eye Research 93 (2011) 271e283 brimonidine 0.2% three times daily (n ¼ 382) or timolol 0.5% twice Following the water drinking test, mean SD peak IOP was daily (n ¼ 392) demonstrated significantly better IOP control in the 20.94 3.76 mm Hg for the BTFC group vs. 20.98 4.19 mm Hg for BTFC group compared to the other 2 groups throughout the day the DTFC group (p < 0.001). Both groups had similar adverse events (p 0.026). The rate of side effects was lower in the BTFC group (Hatanaka et al., 2008). (Craven et al., 2005). Similarly, a study comparing patients treated prospectively with BTFC to a historical control group of 102 patients 6. Alpha-agonists potential for neuroprotection treated with twice daily brimonidine monotherapy found a 50% reduction in allergy rate in the former (Motolko, 2008). A study Ganglion cell apoptosis in POAG may be caused by the inability involving 371 patients treated either with BTFC or concomitant of mitochondria to maintain normal function due to initial alter- therapy with brimonidine tartrate 0.2% twice daily and timolol 0.5% ations in blood flow, disruption of trophic factors, mechanical twice daily did not demonstrate any significant differences in effects, or other dynamics in the optic nerve head, as well as the baseline and subsequent mean IOP. This study also demonstrated subsequent compromise in the retinal ganglion cell axon energy no difference in rate of side effects (Goñi et al., 2005). Evaluation of requirement. In addition, secondary insult from entering light as the 24-h IOP control with BTFC versus concomitant therapy well as neurotrophic factors (e.g. glutamate, nitric oxide, TNF- demonstrated equal mean SD 24-h IOP reduction from the a released by retinal astrocytes) may play an important role in baseline: 19.2 1.9 mm Hg vs. 19.2 1.6 mm Hg, p ¼ 1.0 (Konstas the pathogenesis of glaucomatous optic neuropathy (Osborne, et al., 2008). 2008; Wheeler et al., 2003). Neuroprotection, therefore, emerges as a potential important aspect in glaucoma management in an 5.2. BTFC monotherapy attempt to limit the cascade of cell death (McKinnon et al., 2008). Clinical studies evaluating the neuroprotective effect of cloni- A study involving 50 patients with POAG or OHT evaluated dine demonstrate that topical clonidine may reduce the mean safety and efficacy of BTFC as monotherapy. The mean SD IOP defect, short-term fluctuation and corrected pattern standard decreased from 23.09 1.98 mm Hg to 17.46 1.47 mm Hg during deviation. In contrast, apraclonidine may cause a significant the first month, and to 17.51 1.43 mm Hg during the second worsening in mean defect (p < 0.05) short-term fluctuation month. During the first month of treatment, 2 patients reported (p < 0.05) and corrected pattern standard deviation (p < 0.01) stinging and 1 patient-reported eye pain. During the second month (Sebastiani et al., 2002). of treatment, 2 patients reported stinging, 2 patients reported Various cell cultures, animal and human studies demonstrate burning and none reported eye pain. One patient developed corneal the neuroprotective effect of brimonidine in laboratory models of epithelial damage and blurry vision and 3 patients did not achieve ocular insult, glaucoma and OHT models. In rats, brimonidine satisfactory IOP control (Papaconstantinou et al., 2009). provides up to 3 months protection against retinal damage and A non-interventional, multicenter, observational, open-label degeneration of retinal projection induced by ligature of the study in Germany evaluated efficacy, tolerability, and safety of ophthalmic vessels (Mayor-Torroglosa et al., 2005). By interacting BTFC in patients with POAG or OHT. Out of 861 patients, 565 directly with alpha-2 adrenergic receptors present in the retinal patients were switched from monotherapy with various medica- ganglion cells (RGCs) brimonidine may prevent retinal ganglion cell tions, 138 patients were switched from other fixed combinations, death independent of the pressure reduction mechanism (Kalapesi and 158 patients were switched from non-fixed combinations of up et al., 2005). Furthermore, brimonidine may interact with alpha-2 to four different active agents. BTFC provided an overall reduction receptors in the retina, which results in reduced accumulation of of mean SD IOP of up to 16.9 2.6 mm Hg after 4e6 weeks and extracellular glutamate and aspartate (Donello et al., 2001) and up to 16.5 2.7 mm Hg after 12 weeks for al switched patients. protection of RGCs from secondary degeneration up to 2 weeks Almost 80% of patients achieved a target pressure of <18 mm Hg. after the initial insult (Yoles et al., 1999). The protective effect of Up to 97% of the physicians and 94% of the patients in the study brimonidine is eliminated by coadministration of an a2-antagonist, rated BTFC tolerability as good or excellent (Thelen et al., 2009). confirming that the effect noted is secondary to alpha-2 receptor activation (Donello et al., 2001; Dong et al., 2008). Similar to lata- 5.3. BTFC vs. dorzolamideetimolol fixed combination (DTFC) noprost brimonidine has been shown to attenuate immunoreac- tivity of glial fibrillary acidic protein, which may cause the loss of A prospective, randomized, double-masked, crossover 6-week RGCs (WoldeMussie et al., 2001; Vidal et al., 2010). By interacting study demonstrated that BTFC had lower mean SD diurnal IOP and with retinal alpha-2 receptors, brimonidine promotes retinal morning IOP than DTFC: 16.28 2.07 mm Hg vs.17.23 2.29 mm Hg metabolism and supports neuronal growth in cultured retinal (difference: 0.95 mm Hg, 95% CI 0.10e1.80, p ¼ 0.03); explants (Prokosch et al., 2010). and 15.85 2.56 mm Hg vs. 17.55 2.67 mm Hg (difference: 1.70, Studies involving in situ RGCs from isolated rat retina point to 95% CI 0.80e2.60, p ¼ 0.001) (García-Feijoó et al., 2010). Pooled data other possible mechanisms of brimonidine neuroprotection. The N- 2þ analysis of two randomized, investigator-masked, 3-month, parallel- methyl-D-aspartate (NMDA) receptors are highly permeable to Ca þ group studies involving 180 patients with POAG or OHT demon- ions. Intracellular Ca2 overload can lead to excitotoxicity and strated a reduction of mean SD IOP from a baseline of 7.7 4.2 mm neuronal cell death. Brimonidine preserves RGCs by blocking Hg (32.3%) with BTFC as monotherapy versus 6.7 5.0 mm Hg NMDA receptors (Dong et al., 2008). Brimonidine has been shown (26.1%) with DTFC as monotherapy. It also demonstrated a reduction to up-regulate endogenous brain-derived neurotrophic factor of 6.9 4.8 mm Hg (29.3%) for BTFC versus 5.2 3.7 mm Hg (23.5%) (BDNF) expression in the RGCs. BDNF is a potent neuroprotective for DTFC as an adjunctive therapy to PGA. Patients on BTFC factor that promotes RGC survival following optic nerve crush experienced less burning, stinging and unusual taste in the month injury (Gao et al., 2002). than patients on DTFC (Nixon et al., 2009). In humans, brimonidine may improve mean sensitivity in visual An 8-week, multicenter, interventional, randomized, open- field tests (Ruiz et al., 2001), contrast sensitivity in POAG patients label, parallel-group study in Brazil demonstrates that BTFC has (Evans et al., 2003) and visual outcome of patients treated efficacy and tolerability equivalent to DTFC. Mean SD diurnal IOP with laser for classic extrafoveal or juxtafoveal choroidal neo- reduction after 8 weeks was 7.02 3.06 mm Hg for the BTFC group vascularization by protecting the neuroretina against collateral (N ¼ 111) and 6.91 3.67 mm Hg for the DTFC group (N ¼ 99). damage caused by the laser treatment (Ferencz et al., 2005). S. Arthur, L.B. Cantor / Experimental Eye Research 93 (2011) 271e283 277

Patients treated with brimonidine appear to have less RNFL loss color Doppler ultrasound were not affected by brimonidine 2% compared to patients treated with timolol over a 12-month period (Lachkar et al., 1998). Topical brimonidine does not appear to alter (Tsai and Chang, 2005). The Low-Pressure Glaucoma Treatment perioptic short posterior ciliary arteries, central retinal artery, or Study (LoGTS) is evaluating neuroprotective effect of twice daily the choroidal vascular system in POAG patients (Schmidt et al., brimonidine 0.2% vs. twice daily timolol 0.5% in190 patients with 2003). On the other hand, brimonidine may induce ciliary body low-pressure glaucoma (Krupin et al., 2005). The results of this vasoconstriction via vascular post-junctional apha-2 receptor acti- large, double-masked randomized clinical trial will be published vation, which may result in decreased ciliary body blood flow and soon aqueous production (Reitsamer et al., 2006). By contrast, there is no evidence to support a neuroprotective action of brimonidine in acute angle-closure glaucoma. In 8. Safety and tolerability in adults and children a prospective study from Singapore (Aung et al., 2004) 31 patients were randomized to the brimonidine group and 28 patients to the Ocular adverse effects of non-selective adrenergic agents timolol group following initial laser peripheral iridotomy. The include irritation, hyperemia, pupillary dilation, follicular analysis of a series of visual field tests over the 16-week period did conjunctivitis, adrenochrome deposits and the potential for cystoid not demonstrate any difference in the prevalence of visual field macular edema in aphakic or pseudophakic eyes. Systemic adverse defects or rate of visual field progression between the brimonidine effects include hypertension, headaches and cardiac arrhythmias and timolol-treated groups. Brimonidine did not cause any signifi- (Schuman, 2000b, 2002). Because dipivefrin is a prodrug, systemic cant modification of the visual field indices (Sebastiani et al., 2002). adverse effects are less likely. Apraclonidine is associated with Although brimonidine meets 3 criteria for neuroprotection a high risk of follicular conjunctivitis and contact dermatitis related (interaction with retinal and optic nerve receptors, adequate to its high oxidative potential, and it is also often associated with pharmacologic levels in the vitreous and retina, and induction of ocular irritation, hyperemia, and ocular discomfort (Feibel, 1995). neuroprotective intracellular changes, in addition to supporting cell The most common systemic adverse effects include hypotension, culture and animal models) it lacks consistent translation into dry mouth and fatigue. Apraclonidine has limited use for chronic effective clinical applications and trials. This discrepancy could be therapy secondary to the high risk of adverse effects and high rate explained by the fact that animal and human alpha-receptors have of tachyphylaxis (Butler et al., 1995). Sensitivity to 0.5% and 1.0% different molecular and structural characteristics, as well as the fact apraclonidine can be observed in 13.8% and 20.3% of patients, that there are no standard outcome measures specific for neuro- respectively (Stewart et al., 1995). protection, thereby rendering human neuroprotection studies very Allergic reaction to brimonidine can occur in up to 25% of challenging. It should also be noted that the timing between initial patients (Blondeau and Rousseau, 2002). Ocular adverse effects of insult and onset of treatment plays a crucial role (Saylor et al., brimonidine include follicular conjunctivitis in 10%e12% of patients 2009), further complicating any prospective clinical trials. during the first year of therapy. This is reduced to 4% of new allergy cases per year by year 3 of follow-up. Brimonidine ocular allergy 7. Alpha-agonists and ocular blood flow generally develops within two weeks of the beginning of treatment (mean time 14.8 17.9 days). History of ocular allergy to eye drops A growing body of literature indicates that ocular blood flow (p ¼ 0.048) and to topical beta-blockers (p ¼ 0.019) and decreased alterations are involved in the pathogenesis of glaucomatous optic tear film production (p ¼ 0.044) are frequently associated with the neuropathy (Harris and Jonescu-Cuypers, 2001; Moore et al., 2008; development of brimonidine tartrate 0.2%-induced ocular allergy Harris et al., 2003, 1997, 1994). The effect of alpha-agonists on (Manni et al., 2004). Patients allergic to brimonidine frequently ocular blood flow has been extensively studied. Topical clonidine develop allergies to subsequently used topical preparations may directly induce a marked reduction in mean blood pressure (Osborne et al., 2005). Rarely, brimonidine can cause anterior (p < 0.01) and indirectly reduce the ocular perfusion pressure uveitis and granulomatous papillary conjunctivitis (Nguyen et al., (p < 0.001). By contrast, apraclonidine does not significantly affect 2008). Newer formulations of brimonidine with reduced concen- ocular perfusion pressure. Brimonidine may increase ocular trations have reduced the incidence and severity of the follicular perfusion pressure values (Sebastiani et al., 2002). toxicity seen with this class of drugs. Contact dermatitis, ocular Animal studies demonstrate that brimonidine may evoke irritation, anterior uveitis and hyperemia may occur in some a consistent nitric oxide-dependent vasodilation in first-order patients (Byles et al., 2000). The most common systemic adverse retinal arterioles, but may evoke a heterogeneous response in effects include fatigue, hypotension, and dizziness. Approximately second-order arterioles by activating alpha-2 receptors in the retina one third of patients may experience dry mouth, but rarely do (Rosa et al., 2006). However, despite the known ocular and systemic patients discontinue because of this adverse effect. In clinical trials, vasoconstrictive effect of alpha-agonists through alpha-1 receptor only approximately 1%e2% of patients who developed these activation there is no evidence that alpha-2 agonists including symptoms required discontinuation of brimonidine. In patients brimonidine and apraclonidine alter optic nerve, retinal, choroidal, with allergic reaction to apraclonidine, the cross-reactive allergic or retrobulbar blood flow (Harris and Jonescu-Cuypers, 2001; response to brimonidine ranges from none (Gordon et al., 1998)to Jonescu-Cuypers et al., 2001). A double-masked, randomized, 10.5% (Shin et al., 1999) to up to 20% (Williams et al., 2000). placebo-controlled study involving 17 patients randomly assigned Clinical studies demonstrate an excellent safety and tolerability to receive brimonidine and 14 to receive placebo demonstrates no profile of BTFC. In fact, it has a lower rate of allergic reaction than effect of brimonidine on retinal capillary blood flow in patients brimonidine 0.2% (Sherwood et al., 2006). The rate of allergic with ocular hypertension (Carlsson et al., 1999). Similarly, Cos- reaction associated with alpha-agonists is due to their ability to tagliola et al. did not find changes in ocular perfusion or visual field reduce cell volume, increase intercellular fluid flow and potentially indices in 16 patients with POAG randomized to brimonidine allow greater access of proinflammatory mediators to the subcon- treatment (Costagliola et al., 2003). Furthermore, no change in junctival tissue. Beta-blockers appear to abort those cell volume retinal blood flow was detected in glaucoma patients following effects, hence BTFC has a reduced rate of allergic reaction (Alvarado instillation of topical brimonidine (Yu et al., 2001). Blood flow et al., 1998; Osborne et al., 2005). However, in patients with velocities (peak systolic and end diastolic velocities) in the central primary Raynaud’s phenomenon, BTFC may cause peripheral skin retinal, ophthalmic, nasal, and temporal ciliary arteries assessed by necrosis. This may be due to vasoconstriction resulting from 278 S. Arthur, L.B. Cantor / Experimental Eye Research 93 (2011) 271e283 unopposed stimulation of alpha-adrenergic receptors secondary to 9. Patient acceptance and compliance with alpha-agonists beta-blockade (Kerr et al., 2010). treatment In children, apraclonidine appears to be better tolerated than brimonidine. Wright and Freedman (2009) retrospectively evalu- Patients’ compliance with medications plays a crucial role in ated safety of apraclonidine 0.5% in 115 eyes of children with glaucoma treatment. Compliance depends on the patient’s glaucoma undergoing angle surgery or examination under anes- commitment to long-term treatment as well as the medication’s thesia. In their study, 2 children developed topical allergy, 3 chil- cost, effectiveness, frequency of its use and side effects, memory dren were noted to have lethargy and 1 child had decreased state (Olthoff et al., 2009) as well as rapport with the physician appetite. Apraclonidine appears to be a safer alternative to brimo- (Weinreb, 1992; Schwartz, 2002). Several categories of factors play nidine for children undergoing angle surgery. a role in adherence to topical medications: situational/environ- Pediatric side effects due to topical brimonidine 0.2% include mental factors (49%); medication regimen (32%); patient factors bradycardia, hypotension, hypothermia, hypotonia, lethargy and (16%); and provider factors (3%) (Tsai et al., 2003; Tsai, 2009). apnea (Carlsen et al., 1999; Daubert, 2006). The review of English Evaluation of 141 Veteran Affairs patients demonstrated that non- literature reports of pediatric glaucoma treatment demonstrates white patients had more difficulties than white patients with eye that brimonidine is contraindicated in children younger than 2 drops compliance due to “drops fall on cheek” (29.1%), “too many years of age due to potentially serious side effects (Coppens et al., drops come out” (20.6%) and “hard to read print” (17.0%) (Sleath 2009). A concomitant topical brimonidine and beta-blockers use et al., 2009). can cause rapid-onset bradycardia and decreased blood pressure in A population-based, retrospective, cohort study evaluated addition to central nervous system depression in infants (Mungan patient compliance with ocular hypotensive medication. In total, et al., 2003). Lai Becker et al. (2009) reviewed the American Asso- 28,741 patients at least 20 years of age were treated with betaxolol, ciation of Poison Control Centers’ Toxic Exposure Surveillance bimatoprost, brimonidine, dorzolamide, latanoprost, timolol or System database and the US Food and Drug Administration’s travoprost as monotherapy between July 1, 1996 and June 30, 2002. Medwatch Adverse Events Reporting System for brimonidine Brimonidine was used by 5057 patients. Half of the patients were exposures in children 0e5 years of age between 1997 and 2005. Out age 65e79 and males. POAG was a presenting diagnosis in 949 of 413 brimonidine repots, no deaths were found. Unintentional cases. The rate ratio for brimonidine discontinuation was 1.45 poisoning, mainly due to ingestion (84.3%) was found in almost half (95% Confidence Intervals: 1.38, 1.52, and p < 0.001) (Reardon et al., of the cases. Drowsiness was presenting symptom in 40.9% of the 2004). The use of fixed medications results in increased patient uses. Less prominent symptoms included ataxia, pallor, irritability, compliance due to use of fewer bottles and dosage, as well as hypotension, bradycardia, miosis and respiratory depression. reduced amount of drops and side effects associated with Eleven patients received naloxone without clear beneficial concomitant therapy (Higginbotham, 2010; Razeghinejad et al., outcome. Al-Shahwan et al. (2005) prospectively investigated 2010). brimonidine-related side effects in 83 children with primary infantile and secondary glaucoma. Excessive sleepiness and leth- 10. Cost of alpha-agonist treatment argy were found in 76%, eye itching and rubbing in 49%, and stinging and burning of the eyes in 39%. Lethargy was associated In 2004 the United States spent more than $2.9 billion in direct with a weight less than 20 kg and an age less than 6 years old. medical costs for treating patients aged 40 years and older with Bowman et al. (2004) evaluated computerized pharmacy visual impairment and blindness (Rein et al., 2006). That cost is records to identify 23 pediatric patients who were prescribed bri- likely to increase with life expectancy and associated incidence of monidine 0.2%. The length of treatment ranged from 1 day to 75 glaucoma (Rein et al., 2009). According to a study conducted by the months. Two patients developed local irritation/allergy, two U.S. Preventive Services Task Force (2005) there is no sufficient developed tiredness and two developed fainting attacks due to evidence of cost benefit from screening for glaucoma. However hypotension. Enyedi and Freedman (2001) retrospectively managing patients with ocular hypertension is cost-effective if reviewed data of brimonidine 0.2% side effects in 32 infants with those patients are between the ages of 55e65 years old and have medically uncontrolled glaucoma. Two children became lethargic a life expectancy of 21e23 remaining years respectively (Kymes and five extremely fatigued after brimonidine administration. The et al., 2006). Furthermore, a computer simulated study of 20 symptoms resolved following discontinuation of the medication. million people followed from age 50 years to death (or age 100 Although most of the reports of serious side effects with brimoni- years) demonstrated that glaucoma management cost is reasonable dine 0.2% are reported in infants under 6 months of age (respiratory when diagnostic assessment costs are included ($46,000 per arrest and the like), most sources urge caution using this medica- quality-adjusted life years [QALYs]) and highly effective when tion in infants under 2 years old. These reports evaluated brimo- diagnostic assessment cost was excluded ($28,000 per QALYs). nidine 0.2%, and one would assume that the 0.15% and 0.1% Annual cost of alpha-2 agonists is $1063 (Rein et al., 2009). formulations may be safer in pediatric population. Currently bri- A UK study compared the use of combined treatment of carbonic monidine should be used with caution in children under 2 years of anhydrase inhibitors (CAI) and prostaglandin analogs with age, and especially in young infants due to reports of cardio- combined treatment of alpha-2 adrenergic agonists and prosta- pulmonary and CNS depression. glandin analogs. Although the annual cost of alpha-2 agonists was In order to prevent deleterious consequences due to side effects, similar to CAI, the former eventually became more expensive than it is imperative for physicians to have a complete knowledge of the latter due to its higher long-term annual rate of failure and need their patients’ medications. A review of general medical records of for a second medication (Denis et al., 2008). In contrast, the cost of 100 patients of one glaucoma specialist demonstrated documen- combined treatment of carbonic anhydrase inhibitors plus beta- tation of eye drops in only 55% of the cases. Alpha-agonists were blockers was similar to the cost of BTFC (£348.04 vs. £356.80 statistically less frequently documented (13%) in the general respectively) (Lafuma and Berdeaux, 2008). When used as a mon- medical record than beta-adrenergic blockers (47%) and prosta- otherapy, the cost of brimonidine was lower than the cost of glandins (44%). Meticulous documentation of glaucoma medica- brinzolamide (£230e£196) (Lafuma et al., 2008). tions by primary care physicians may play an important role in In the US the cost of alpha-agonists is comparable to beta- reducing drug-induced side effects (Jampel et al., 2005). blockers and lower than for prostaglandin analogs. The calculated S. Arthur, L.B. Cantor / Experimental Eye Research 93 (2011) 271e283 279 daily cost of a 5 mL bottle of brimonidine 0.2%, based on average Angelov, O.V., Wiese, A.G., Tang-Liu, D.D., Acheampong, A.A., Ismail, I.M., Brar, B.S., fi e wholesale price (AWP) in the United States twice daily was $0.91 1996. Preclinical safety pro le of brimonidine. Eur. J. Ophthalmol. 6, 21 25. Arici, M.K., Sayici, M., Toker, M., Erdogan, H., Topalkara, A., 2002. A short term study per day in 1999 and $1.29 in 2002. The cost of a 10 mL bottle of of the additive effect of timolol and brimonidine on intraocular pressure. Eye brimonidineepurite twice daily was $0.87 per day in 1999 and 16, 39e43. $1.30 in 2002 (Fiscella et al., 2003). The yearly cost of BTFC is Arieta, C., Amaral, M., Matuda, E., Crosta, C., de Carvalho Moreira Filho, D., José, N., 2002. Dorzolamide X apraclonidine in the prevention of the intraocular pres- $618.62 as opposed to DTFC which costs $789.26 per year (Fiscella sure spike after Nd: YAG laser posterior capsulotomy. Curr. Eye Res. 25, and Jensenb, 2008). In Canada, BTFC has a lower average yearly cost 237e241. ($316.75 5.59) than DTFC ($445.96 5.16) (Ventura et al., 2005). 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Mean IOP decrease achieved with dipivefrin can be up to Barnebey, H.S., Robin, A.L., Zimmerman, T.J., Morrison, J.C., Hersh, S.B., Lewis, R.A., 3.5 mm Hg (Albracht et al., 1993). Generally, non-selective alpha- Coleman, A.L., Cinotti, D.J., Walt, J., Chen, K.S., et al., 1993. The efficacy of bri- agonists can be expected to reduce the IOP approximately 15%e monidine in decreasing elevations in intraocular pressure after laser trabecu- loplasty. Ophthalmology 100, 1083e1088. 20%. The use of apraclonidine for IOP reduction in glaucoma or OHT Barnes, S.D., Campagna, J.A., Dirks, M.S., Doe, E.A., 1999. Control of intraocular is limited due to a high rate of allergic reaction. Although brimo- pressure elevations after argon laser trabeculoplasty: comparison of brimoni- e nidine formulations may be used as first-line therapy in patients dine 0.2% to apraclonidine 1.0%. Ophthalmology 106, 2033 2037. Bexis, S., Docherty, J.R., 2008. 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