Current and emerging medical therapies for glaucoma

Review

10.1517/14728214.10.1.109 © 2005 Ashley Publications Ltd ISSN 1472-8214 109

Ashley Publicationswww.ashley-pub.com

Central & Peripheral Nervous Systems

Current and emerging medical therapies for glaucomaJames C Tsai† & Elliott M Kanner†Columbia University, Edward S. Harkness Eye Institute, Department of Ophthalmology, 635 West 165th Street, New York, NY 10032, USA

Glaucoma is a multifactorial optic neuropathy in which there is a characteristicacquired loss of retinal ganglion cells, at levels beyond normal age-relatedbaseline loss, and corresponding atrophy of the optic nerve. Although asymp-tomatic in its earlier stages, the disease is nevertheless one of the leading glo-bal causes of irreversible blindness. Although elevated intraocular pressure(IOP) is one of the most important risk factors and lowering of IOP is the onlyproven treatment so far, the definition of glaucoma has evolved from a diseasecaused by increased IOP to one characterised by an IOP-sensitive, progressiveoptic neuropathy. In recent years, safer and better tolerated topical medica-tions have been developed to control IOP more effectively, thereby limiting theneed for surgery. New research has also noted the importance of diurnal IOPvariation as a critical risk factor for progression of glaucomatous optic neurop-athy (GON) and subsequent visual field loss. Moreover, new discoveries havefurther elucidated the basic pathophysiological and genetic mechanismsunderlying the elevated levels of IOP, as well as the cellular mechanisms ofGON. As our understanding of these complex pathways continues to improve,development opportunities for new therapeutic modalities will be enhanced.

Keywords: glaucoma, intraocular pressure, medical therapy, neuroprotection, ocular hypertension, optic neuropathy

Expert Opin. Emerging Drugs (2005) 10(1):109–118

1. Background

Glaucoma has been described since the middle ages, although for the vast majority ofthe time since then, the basic pathophysiology of the disease has been poorly under-stood. The disease’s association with elevated intraocular pressure (IOP) was first rec-ognised in 1745 by Johann Zacharias Platner, with his observation that theglaucomatous eye was firm to palpation. The first treatments for glaucoma were sur-gical in nature, and of limited effectiveness. In 1856 Albrecht von Graefe showed thatsurgical iridectomy was an effective treatment for some types of glaucoma [1]. Thisobservation was not only an advance in the effectiveness of glaucoma treatment, butalso a breakthrough in its understanding given the realisation that different types ofglaucoma may require different types of treatment. With the introduction ofpilocarpine in the late 1800s, the disease could be treated medically [2].

Although secondary forms of glaucoma do exist that can be directly traced toother specific causes (e.g., pseudoexfoliation, pigmentary dispersion), the most com-mon form of glaucoma is primary open-angle glaucoma (POAG), wherein no iden-tifiable cause has been elucidated. Patients with POAG demonstrate greatheterogeneity in their response to therapy, possibly indicating variability in theunderlying pathophysiological mechanisms. Primary open-angle glaucoma is amongthe leading causes of irreversible blindness worldwide [3]. Based on a review of epide-miological data from populations in Africa, Asia and Europe, Quigley estimated thenumber of people worldwide with POAG by the year 2000 to be near 66.8 million,

1. Background

2. Medical need

3. Existing treatment

4. Therapeutic class review

5. Current research goals

6. Scientific rationale

7. Competitive environment

8. Potential development issues

9. Expert opinion

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Current and emerging medical therapies for glaucoma

110 Expert Opin. Emerging Drugs (2005) 10(1)

with 6.7 million experiencing bilateral blindness [4]. The prev-alence of glaucoma in the US has been estimated to be therange of 1.3 – 4.5%, increasing in the older age groups (similarto neurodegenerative diseases of the CNS).

In addition to those diagnosed with open-angle glaucoma(OAG), there are a significant number of patients withincreased IOP levels who have not yet developed glaucoma-tous optic neuropathy (GON). These patients are classified ashaving ocular hypertension (OHT). In the recently com-pleted Ocular Hypertension Treatment Study (OHTS), thecumulative risk of conversion of untreated OHT to OAG wasnearly 2%/year, a figure that was reduced by ∼ 60% with theuse of topical medications to achieve a moderate (20%)reduction in IOP [5]. In addition, central corneal thickness(CCT) was an important risk factor for progression to OAG,with patients with CCT ≤ 555 µm having a threefold greaterrisk than those with CCT > 588 µm [6].

Normal-pressure glaucoma (NPG) or normal-tension glau-coma (NTG) is diagnosed when patients have normal IOPs(confirmed by diurnal IOP testing), but nevertheless demon-strate GON progressive in nature. Based on the findings ofpopulation-based epidemiological studies, the incidence ofNPG has been noted to be ∼ 25 – 40% of individuals newlydiagnosed with OAG [7,8]. The exact pathophysiologic mecha-nism for the disease is not currently known. However,patients with NPG also have beneficial reductions in the riskof visual field progression by lowering of IOP by ∼ 30% frombaseline levels [9]. Finally, patients with consistently normalIOPs and suspicious-appearing optic nerves are classified asNPG suspects.

A variety of mechanisms have been proposed for the patho-logical optic neuropathy observed in glaucoma, includingalterations in blood flow to the optic nerve head, direct dam-age to the retinal ganglion cells (RGCs), and the triggering ofapoptosis (i.e., programmed cell death process). Theories havebeen advanced proposing that the structure of the nerve ismore sensitive to high IOP, or that ocular blood flow isaffected/reduced in selected vascular beds. Experiments haveshown that significant elevations in IOP can dramaticallyreduce ocular blood flow, whereas more moderate IOPchanges can also affect blood flow [10]. Similar to the rest ofthe CNS, there appears to be an autoregulatory system forocular blood flow, which has been shown to be somewhatineffective in patients with GON [10]. In addition, the inci-dence and prevalence of OAG increases with age, possiblyreflecting an increased vulnerability to optic nerve damagewith older age, similar to other neurodegenerative diseases(e.g., Alzheimer’s disease).

2. Medical need

Patients with OAG demonstrate great variability in the courseand visual outcome with therapy. This variability is likely to bedue to the multifactorial nature of the GON, although theunderlying pathological process appears to be IOP-sensitive.

Because the underlying pathophysiology of the disease is not yetknown, it is difficult to predict the entire spectrum of medica-tions and treatments that may be possible in the future. Moreo-ver, the potential heterogeneity of the underlyingpathophysiological mechanisms may limit the wide-rangingeffectiveness of drugs specifically acting via one mechanism.

In treating patients with glaucoma, the physician aims tobalance the risks and benefits of the therapy. Glaucomapresents a particular challenge, because the disease progressiontends to be very slow, and medications are required forextended periods of time, with the patient feeling no ill effectsof the disease (at least at first), but potentially experiencingthe side effects.

Current medical therapies for glaucoma fall into one of twoclasses: those that reduce aqueous production, and those thatincrease aqueous outflow. Although both classes of medica-tions decrease IOP, there are some theoretical advantages forincreasing aqueous outflow. First, aqueous flow serves func-tions other than the maintenance of an adequately pressuredglobe, such as providing oxygen and nutrients to the anteriorchamber and corneal tissues. If aqueous flow is reduced, thisin turn leads to reduced availability of nutrients and oxygenfor these tissues (except for the superficial cornea, whichderives oxygen from the ambient air). Biophysical modellinghas shown that an increase in aqueous outflow will have agreater effect on IOP spikes, and thereby reducing diurnalfluctuations.

Recent studies have demonstrated the importance of 24-hdiurnal control of IOP fluctuation. It has been hypothesisedthat transient increases in IOP may be sufficient for glaucoma-tous progression. Diurnal fluctuations have been found to be anindependent risk factor for progression [11]. Visual field progno-sis in OAG has been reported to be better in patients withsmaller IOP variation (range and peak) and poorer in patientswith high mean IOP [12]. Spikes in IOP have also been associ-ated with progression [13]. Other studies have shown that diur-nal fluctuations in IOP are larger in glaucoma patients than inunaffected individuals; however, this is not a consistent patternin all glaucoma patients [14]. Therefore, long-acting, effectiveIOP-lowering medications that also limit the extent of diurnalfluctuations in pressure are highly desirable.

3. Existing treatment

A variety of topical glaucoma medications are used to reduceIOP, each with a unique spectrum of action, efficacy, dosingregimen, and ocular and systemic side effects. Although inclinical studies these medications prove quite efficacious, theiractual efficacy outcomes in ‘real world’ patient populationsoften are not as promising as those reported in ‘ideal’ researchenvironments. Specifically, one of the challenges in the ‘realworld’ is the ability of patients to comply with and adhere totheir treatment regimens [15].

Optimum medication compliance is often achieved withless frequent dosing, and an inverse relationship between

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Expert Opin. Emerging Drugs (2005) 10(1) 111

compliance and complexity of the medical regimen has beendescribed across all therapeutic classes [16]. Recently, the com-mon obstacles to medication adherence (i.e., compliance), asreported by patients with glaucoma, have been identified anddescribed [17]. Seventy-one unique situational obstacles werereported and grouped into four separate categories: situa-tional/environmental (49%), medication regimen (32%),patient factors (16%) and provider factors (3%) (Table 1).Utilisation of this systematic classification will assist hopefullyin optimising patient care by means of improved patient edu-cation and appropriate individualised selection of therapeuticregimens.

In the next section, the commonly used classes of topicalocular hypotensive agents will be summarised. The majorityare single therapeutic class agents. However, there has alsobeen recent interest in fixed combination therapy (single for-mulation of two medications together), as a large percentageof glaucoma patients appear to require more than one IOP-lowering medication for effective treatment. For example, inOHTS, 40% of patients in the treatment group were takingtwo or more medications at 60 months follow-up to achievethe targeted 20% reduction in IOP from baseline levels [5].Currently available fixed-combination therapies include dor-zolamide–timolol (Merck, Whitehouse Station, NJ) andlatanoprost–timolol (Pfizer, New York, NY), which is availa-ble in the European Union and Japan, but has not yet receivedapproval by the Food and Drug Administration (FDA) in theUS. There are also new combination agents that are currentlyawaiting FDA approval (see Section 4.7).

4. Therapeutic class review

4.1 β-BlockersTopically applied β-blocker medications decrease aqueous pro-duction, and are very effective at lowering IOP [18]. Theyinclude both noncardioselective and cardioselective (β1-adren-ergic) receptor blockers (Table 2). Timolol was the first topicalβ-blocker used as an ocular hypotensive agent for glaucoma inthe US and is considered the gold standard against which allother antiglaucoma medications are compared.

Despite causing few ocular side effects, topical β-blockersmay be associated with adverse systemic side effects, which aresimilar to those associated with systemic β-blocker therapy.The range of contraindications, which apply to most of thetopical β-blockers, include sinus bradycardia, second- orthird-degree heart block, cardiogenic shock, or overt heartfailure. Caution should also be used in patients with asthmaor other bronchopulmonary disorders.

4.2 Carbonic anhydrase inhibitorsCarbonic anhydrase inhibitors (CAIs) also decrease aqueoushumor production via inhibition of the widely expressedenzyme carbonic anhydrase [18]. Topical CAIs were intro-duced as a better tolerated alternative to oral CAIs, which areassociated with a wide range of systemic side effects,

Table 1. Taxonomy of barriers to adherence.

Factor Sample statement

Regiment factors Refill I only forget to take my drops

when I run out

Cost When my insurance stopped paying for medications, I didn’t take my drops

Complexity It was harder when I was taking four medications; now that I am taking three it is better

Change When I first started taking the drops, I had a harder time remembering

Side effects I decided to quit taking my drops because I had a bad reaction from them

Patient factors

Knowledge/skill Sometimes I miss my eye when taking my drops

Memory Sometimes I just forget to take my drops

Motivation/health benefits I quit taking my drops because I didn’t see benefit from them and didn’t think they were working

Comorbidity It is harder to keep track of my drops because I am taking so many other medications

Provider factors

Dissatisfaction I quit taking my drops because I was dissatisfied with my doctor’s care

Communication I stopped taking my drops because I didn’t understand initially that I need to take them forever

Situational/environmental Accountability/lack of support Living alone, I had problems

taking my drops; now I live with my daughter and have no problems

Major life events Two years ago when my wife died, I had a hard time taking my drops

Travel/away from home When I am on vacation, it is more difficult to take my drops

Competing activities I miss my drops on Sunday morning when I go to church

Change in routine Lifestyle changes that occur on weekends, such as not getting up at a normal hour, cause me to forget to take my drops

Used with permission from [3].



including, but not limited to, electrolyte abnormalities(sodium and potassium), hyperchloremic acidosis, urolithiasis(kidney stones), paresthesias and exacerbation of kidney andliver dysfunction. Currently available topical agents includedorzolamide hydrochloride 2% and brinzolamide 1%.

Topical CAIs are almost as efficacious in terms of IOP-low-ering as timolol [19]. They are used to treat glaucoma on achronic basis, with the oral CAI agents (e.g., acetazolamide,methazolamide) usually reserved for shorter-term treatmentduration or acute severe elevations in IOP. The topical CAIs

also possess good additivity in IOP reduction when usedconcomitantly with other medications, including timolol [20].This IOP additivity effect was instrumental in the develop-ment of the fixed combination timolol–dorzolamidemedication (see below).

4.3 α-AgonistsTopically applied α-agonists reduce IOP by decreasing aque-ous humor production [18]. In addition, this class of medica-tions may primarily lower IOP by increasing unconventional(i.e., uveoscleral) outflow of aqueous humor when used on achronic basis [21]. The newer, more specific α2-agonists (i.e.,brimonidine 0.2%, apraclonidine 0.5%) have fewer systemicside effects (e.g., systemic hypotension) than earlier intro-duced adrenergic agonists, but still have significant ocular sideeffects. Both apraclonidine and brimonidine are effective inpreventing the postsurgical rise in IOP following laser surgery[3]. They are contraindicated for use in patients receivingmonoamine oxidase inhibitors or in patients hypersensitive toeither product or any component of the medications.

Apraclonidine 0.5% is indicated in most cases for short-term adjunctive use, because longer-term use usually results ina high rate of allergic conjunctivitis. Brimonidine 0.2% isused in most cases when an α2-agonist is needed for long-term, sustained therapy. The medication is comparable totimolol 0.5% in terms of its IOP-lowering effect in patientswith OAG or OHT [22,23]. The lower concentration brimoni-dine 0.15% formulation with purite preservative (i.e., Alpha-gan® P/brimonidine tartrate ophthalmic solution, AllerganInc.) is also commercially available and has comparableIOP-lowering efficacy, but with a lower side-effect profile [24].

4.4 Prostaglandin analoguesProstaglandin analogues are among the newest class of topicalantiglaucoma medications and are highly potent at reducingIOP by increasing aqueous humor outflow via the uveoscleraloutflow pathway [3,25-30]. In addition, they are well toleratedand require only once-daily dosing (except for unoprostone0.15%), while maintaining good 24-h diurnal control of IOP.Systemic side effects are mostly rare, although ocular sideeffects, including conjunctival hyperaemia and increased pig-mentation of the iris and periorbital tissue (eyelid), can occur.The prostaglandin analogues should also be used with cautionin eyes prone to develop cystoid macular oedema, includingthose with torn posterior capsule, prior uveitis, aphakia, andstatus post-complicated surgery. In addition, they are usuallyavoided in eyes with active or prior history of severeinflammation.

There have been numerous studies assessing the efficacyand tolerability of the prostaglandin analogues. With theexception of unoprostone, all of the commercially availableanalogues (i.e., bimatoprost 0.03%, latanoprost 0.005%, tra-voprost 0.004%) reduce IOP to a greater degree than timololin patients with OAG and OHT [25-30] (Table 3). Moreover,they offer significant advantages over topical β-blockers

Table 2. β-Adrenergic antagonists used as ocular hypotensives for glaucoma.

Generic/ (trade) name

Concentra-tion (%)

Cardio-selectivity

Dosage

Betaxolol (Betoptic®)

0.5 + 1 drop b.i.d.

Betaxolol (Betoptic® S)

0.25 + 1 drop b.i.d.

Carteolol (Ocupress®)

1.0 - 1 drop b.i.d.

Levobunolol (Betagan®)

0.25, 0.5 - 1 drop b.i.d.

Metipranolol (Optipranolol®)

0.3 - 1 drop b.i.d.

Timolol hemihydrate (Betimol®)

0.25, 0.5 - 1 drop b.i.d.

Timolol maleate (Timoptic®)

0.25, 0.5 - 1 drop b.i.d.

Timolol maleate gel (Timoptic-XE®)

0.25 gel, 0.5 gel

- 1 drop/day


Table 3. Prostaglandin analogues used in the treatment of glaucoma.

Generic/ (trade) name

Concentra-tion (%)

Intraocular pressure reduction (mmHg) (% reduction)

Dosage

Latanoprost (Xalatan®)

0.005 6 – 8 (24 – 32) 1 drop at bedtime

Bimatoprost (Lumigan®)

0.03 7 – 8 (27 – 31) 1 drop at bedtime

Travoprost (Travatan®)

0.004 6 – 8 (23 – 32) 1 drop at bedtime

Unoprostone (Rescula®)

0.15 3 – 4 (13 – 17) 1 drop b.i.d.


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including greater effectiveness in controlling IOP over thediurnal 24-h cycle, safer systemic side-effect profile, and sim-pler dosing regimen. In addition, because the prostaglandinanalogues increase outflow rather than suppress aqueoushumor production, they are theoretically more effective forthe prevention of IOP spikes.

4.5 Cholinergic agonistsCholinergic agonists, such as pilocarpine and carbachol, lowerIOP by increasing conventional trabecular outflow [3]. Giventhe development of more efficacious newer drugs, includingprostaglandin analogues, topical CAIs, and α-agonists, thecholinergic agents are now usually reserved for fourth- orfifth-line use. Nevertheless, in some instances, these medica-tions are quite useful in controlling IOP (especially if theglaucoma responds well to a trabecular outflow enhancer).

Cholinergic agonists do cause pupillary meiosis and areoften used in the treatment of primary angle closure glaucomaassociated with plateau iris configuration, and OAG associ-ated with pigmentary dispersion. They may be used in combi-nation with topical β-blockers, topical and oral CAIs, andα-agonists. There is also a slight additive effect when thesemeiotic agents are taken concomitantly with prostaglandinanalogues (although the potential antagonistic effect ofreduced uveoscleral outflow with cholinergic agonists is ofconcern in choosing this drug combination).

4.6 Nonspecific adrenergic agonistsAdrenaline, a nonspecific adrenergic agonist, has been usedfor > 60 years as a medical treatment for OAG [3]. Because itsIOP-lowering efficacy is less than that of timolol, its utility asa primary or secondary glaucoma therapeutic agent is low.Moreover, the medication has significant ocular and systemicside effects, including profound burning and stinging, con-junctival hyperaemia, follicular conjunctivitis and cardiacarrhythmias. These adverse effects are lessened somewhat ifthe prodrug form, dipivefrin hydrochloride, is substituted.

4.7 Combination agentsA fixed combination of dorzolamide 2% and timolol 0.5%(i.e., Cosopt®, Merck & Co., Inc.) is currently available in theUS and worldwide. It is indicated for the reduction of IOP inpatients with OAG or OHT who are insufficiently controlledwith topical β-blocker therapy alone. In clinical studies, thefixed combination dorzolamide–timolol given twice dailyshowed equivalent efficacy to the concomitant administrationof timolol 0.5% b.i.d. and dorzolamide 2% t.i.d. [32]. Theoverall incidence of adverse side effects experienced bypatients was comparable in both groups.

A fixed combination of latanoprost 0.005% and timolol0.5% (i.e., Xalacom™, Pfizer, Inc.) is currently available inselected countries worldwide including the European Unionand Japan. This agent is currently not yet approved by theFDA in the US. In prospective randomised controlled stud-ies, the fixed combination latanoprost–timolol lowered IOP

by 1.0 – 1.2 mmHg more than latanoprost alone, and by1.9 – 2.9 mmHg more than timolol alone [33,34].

5. Current research goals

The ideal glaucoma medication would be one that requiredinfrequent dosing (for patient convenience and compliance),reduced IOP effectively in all patients, and had negligibleocular and systemic side effect profiles with no or few con-traindications. No current glaucoma drug currently fulfils allthese criteria, but medical science is getting closer. Certainly,the prostaglandin analogues have been a great advance.Although current recommendations are that they be dosedonce daily, recent studies suggest that they may have longer-acting effects. One study indicated that travoprost and latano-prost had significant IOP lowering > 44 h following the lastdose, with the travoprost result statistically superior to latano-prost at 24 h postdose, whereas latanoprost had better efficacy4 h postdose [35].

Although multiple medication regimens are often used forthe effective treatment of glaucoma, their inherent complexitycreates therapeutic problems for medication compliance.Given the current emphasis on consistent control of 24-hdiurnal IOP [11,12], fixed combination therapy, whereby twotopical antiglaucoma medications are combined in a singleformulation, is an attractive option for glaucoma therapy.These combination drugs provide the simplicity of mono-therapy with the presumed increased efficacy from theadditive IOP-lowering effect of two different agents.

It is important to note that not all fixed combination medi-cations necessarily provide the same degree of IOP reduction asthe same medications taken concomitantly. The fixed combina-tion formulation may affect the bioavailability of one or both ofthe selected agents. Nevertheless, these fixed combination med-ications hold great promise in enhancing patient compliancewhen substantial IOP-lowering is needed At least three newfixed combination agents are awaiting approval by the FDA.These include two fixed combination prostaglandin–timololagents, travoprost–timolol (Alcon, Inc., Fort Worth, TX) andbimatoprost-timolol (Allergan, Inc., Irvine, CA), and the fixedcombination brimonidine–timolol medication (Allergan, Inc.,Irvine, CA).

6. Scientific rationale

Various risk factors, such as elevated IOP, ischaemia, andgenetics, are associated with progressive optic nerve and/orRGC damage, thereby leading to neuronal death [36]. Severalpathophysiological mechanisms, including glutamate excito-toxicity, deprivation of neuronal growth factors (neuro-trophins) and other target-derived factors, and ocularischaemia, have been hypothesised to have roles in causingRGC death (Figure 1).

Because the currently defined phenotypic categories ofglaucoma are likely to represent a collection of diseases with



different genetic and other risk factors, it is reasonable to con-clude that many potentially useful agents have not yet beendiscovered. For example, exfoliative glaucoma, a commonform of secondary open angle glaucoma, may involve bothgenetic and environmental factors because marked geographi-cal variations have been demonstrated in its prevalence [37]. Inaddition, patients with exfoliative glaucoma appear to have aworse visual prognosis than those with POAG, given theincreased risk of visual field progression associated with theformer diagnosis [38].

Glaucoma is a chronic and often slowly progressive disease,and the currently used techniques for detecting visual fieldloss appear to require large numbers of RGC loss or dysfunc-tion for clinical detection of reduced retinal sensitivity. Multi-ple new imaging and visual testing techniques are underinvestigation in order to detect ganglion cell damage at earlierstages. For example, frequency doubling technology perimetrymay be a valuable screening test for early-stage glaucoma byselecting activating retinal magnocellular ganglion cells [39]. Inaddition, the multifocal visual evoked potential may detectabnormalities in visual function in patients with early-to-mildglaucomatous damage and normal results on conventionalautomated perimetry [40]. If visual function loss can be

detected prior to the irreversible loss of sufficient RGCs, thenit may be possible to arrest disease progression.

7. Competitive environment

Currently, there is a great deal of debate in the literatureregarding the long-term effectiveness of the various classes ofantiglaucoma medications. This is not surprising as glau-coma is a prevalent ocular disease requiring chronic, long-term use of medications, and, therefore, represents a verylarge market share for the pharmaceutical industry. Clinicalcomparisons have focused disproportionately on a drug’sIOP-lowering efficacy as studies have shown that decreasingIOP is essential for reducing the risk of progression [5,9,41,42],and that diurnal fluctuations in IOP contribute toprogression [11,12].

As the newest and arguably the most effective IOP-lower-ing medications, the prostaglandin analogues have gained anear majority share of the glaucoma market. The three mostcommonly prescribed prostaglandins (latanoprost, bimato-prost and travoprost, in order, respectively) are superior or atleast as effective in IOP efficacy when compared with the goldstandard agent timolol maleate [25-27,29,30,43,44]. Moreover,

Microcirculation

Nutrient delivery andwaste removal

Neurotrophins and othertarget-derived factors

Lamina cribrosa

Bipolar and amacrinecells

Astrocytes

Glutamatehomeostasis

Muller cells

Lateral geniculatenucleus andother targets

IOP

Retinalganglion

cell

Figure 1. Several mechanisms hypothesised to have had a role in causing retinal ganglion cell death in glaucoma.WEINREB RN et al.: Arch. Ophthalmol. (1999) 117:1540-1544. Copyrighted © (1999), American Medical Association. All Rights reserved.IOP: Intraocular pressure.

Tsai & Kanner


these prostaglandin analogues have been demonstrated to besafe and well tolerated.

In addition to proving their effectiveness compared with theolder medications, recent studies comparing the efficacy andside-effect profile of the various prostaglandin analogues havehighlighted slight characteristic differences among them. Sev-eral of the larger prospective studies published so far are high-lighted below. In the XLT study, the efficacy of the threemedications (latanoprost, bimatoprost and travoprost) werestatistically similar, although latanoprost had a lower incidenceof conjunctival hyperaemia [45]. Another study demonstratedthat travoprost was comparable to latanoprost in terms of IOPlowering efficacy in patients with OAG or OHT [27]. A thirdstudy showed that bimatoprost statistically lowered IOP to agreater extent than latanoprost at three time points (08:00,12:00 and 16:00) during the course of the 6-month compari-son study (IOP difference in the range of 1.2 – 2.2 mmHg)[46]. However, conjunctival hyperaemia and eyelash growthwere more common in the bimatoprost-treated patients.

The clinical significance of these disparate results has beenwidely debated both in the literature and many othernonpeer-reviewed settings. Because the study designs andinterpretations of the results of these trials were different,the apparent differences may be statistically significant,whereas the real-world differences between the drugs may beminimal. Thus, variables inherent in the design, conductand interpretation of trial results, may lead to apparent dif-ferences in outcome even though the actual discrepanciesmay be minimal or nonexistent [47]. For example, divergentoutcomes could be due to chance alone or variations inpatient populations (e.g., receptor characteristics, rate ofpenetration in the case of topical prodrugs etc.). If the dif-ferences among the agents were clinically relevant, then theywould be apparent in nearly all studies despite inherentpatient variability.

8. Potential development issues

Neuroprotection and enhancement of ocular blood flow aretwo newly identified targets for development in glaucomatherapy. These strategies have emerged as studies show thatsome patients with glaucoma still have progressive visual lossdespite apparent adequate IOP lowering [9,42,48]. Becauseglaucoma has been identified as a progressive optic neuropa-thy, agents that prevent or slow RGC death have the potentialfor halting its progression [36,49]. As clinicians have postulatedthat compromised ocular blood flow contributes to the patho-genesis of GON, agents that enhance blood flow to the opticnerve and RGC may be of benefit [10].

So far, no medications have been approved for neuropro-tection (independent of IOP reduction) in the treatment ofglaucoma. However, promising preclinical results have beenreported with several classes of medications. Brimonidine, anα2-agonist, has been shown to be neuroprotective in animalmodels with chronic OHT [50]. Memantine, an NMDA-type

glutamate open-channel blocker, has been shown to preservevisually evoked cortical potential and reduce RGC loss in ani-mal models with experimentally induced glaucoma [51]. Basedon these results, the efficacy and safety of memantine is cur-rently being studied in patients with glaucoma. Innovativelaboratory investigations have introduced the concept of ‘pro-tective autoimmunity’, a T-cell based mechanism for neuro-protection [52]. In these experiments, vaccination with Cop-1,an FDA-approved drug for the treatment of multiple sclerosis,has resulted in significant neuroprotection in rat models ofoptic nerve crush and chronic glaucoma.

Promising agents have also been reported for the enhance-ment of ocular blood flow in glaucoma. Dorzolamide, a topi-cal CAI medication, has been shown to increase retinal arteryflow velocities in patients with NTG [53]. The selectiveβ-blocker betaxolol has also been shown to increase bloodflow velocity in the human optic nerve head tissue circulation[54]. More recently, single-dose nimodipine, a centrally actingcalcium channel blocker, was reported to normalise impairedretinal circulation in NTG [55].

Finally, new investigational drugs that lower IOP are beingdeveloped. WIN-55212-2, a cannabinoid agonist at theCB(1) receptor, has been reported to reduce IOP in both nor-mal and glaucomatous monkey eyes [56]. The mechanism ofaction of this cannabinoid agonist appears to be reducedaqueous humor formation (18% reduction from baseline lev-els) with no discernible effect on outflow facility. Nonselectiveand selective serotonin 2 (5-hydroxytryptamine2; 5-HT2)receptor agonists appear to also lower IOP in a primate modelof glaucoma (i.e., cynomolgus monkey with laser-inducedocular hypertension) and are being considered as potentialtherapeutic agents [57]. Another novel treatment for patientswith glaucoma may be the selective inhibitors of 11β-hydroxysteroid dehydrogenase (11β-HSD) isoenzymes (espe-cially for 11β-HSD1, which activates cortisol from cortisone)[58]. Oral carbenoxolone, an inhibitor of 11β-HSD, wasshown to significantly lower IOP by 10% from baseline inpatients with OHT. The patients with the greatest fall in IOPlevels had the largest change in urinary metabolites, indicativeof 11β-HSD1 inhibition.

9. Expert opinion

Of the currently available medications, the prostaglandinanalogues provide the best IOP-lowering efficacy, as well asthe most consistent 24-h circadian control of IOP, in addi-tion to having an attractive dosing schedule. As new therapiesare developed, and new methods to study the progressivedamage of RGCs are validated, clinicians may come to relyon additional medications. Of particular interest is the devel-opment of antiglaucoma therapies that protect against diseaseprogression independent of IOP lowering. The pharmaceuti-cal and biotechnology industry should be encouraged andstimulated to identify and bring to market neuroprotectiveand/or blood-flow enhancing agents that provide an additive



effect to our current IOP reducing drugs. Withadvancements in the sophistication of glaucoma analysisinstruments, clinical comparison of medications will begreatly facilitated, because outcome differences (e.g., extentof diurnal IOP control, extent of progressive optic disc dam-age) may more easily be ascertained and in a shorter timeframe than currently possible.

Financial disclosure

Supported in part by an unrestricted departmental grant fromResearch to Prevent Blindness, Inc., New York, NY.

Over the past several years, Dr Tsai has received research fund-ing and/or been a consultant/speaker for the followingpharmaceutical companies: Alcon, Allergan, Merck and Pfizer.

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AffiliationJames C Tsai MD†1 & Elliott M Kanner MD PhD†Author for correspondence1Columbia University, Edward S. Harkness Eye Institute, Department of Ophthalmology, 635 West 165th Street, New York,NY 10032, USATel: +1 212 305 2725; Fax: +1 212 305 5962;E-mail: [email protected]

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Current and emerging medical therapies for glaucoma