Pratap Challa, MD, MS and David L. Epstein, MD, MMM
Topical beta-blockers decrease aqueous humor formation (AHF)1,2 and are used long term in the therapy of the chronic open-angle glaucomas and short term for various acute glaucomas. The introduction of the topical beta-blocker timolol in 1978 was greeted with overwhelming enthusiasm not only because of the remarkable efficacy of beta-blockers but also because of the relative low frequency of ocular side effects. Before the beta-blockers, the only topical antiglaucoma medications available were the miotics and epinephrine-like compounds, the potential side effects of which will be discussed shortly. In practice, the potential ocular side effects from these latter agents resulted in an appropriate hesitancy for clinicians to treat elevated intraocular pressure (IOP), even if substantial, unless there was obvious end-organ damage (optic nerve) or abnormalities in (preautomated perimetry) visual fields. The occurrence of these side effects also adversely affected patient compliance when aggressive therapy was required for advanced glaucomatous damage.
In the ensuing years, we have continued to observe that ocular side effects from topical beta-blockers are not common, and in fact, potential long-term adverse effects of reduced aqueous humor flow on intraocular structural integrity, which some had predicted, have not occurred. However, we have become increasingly aware of the possibility of significant systemic side effects3 from topical beta-blockers, even in patients with no known systemic predisposition. In fact, systemic side effects are the major limitation to the use of topical beta-blocker therapy.
Although there likely is some absorption through conjunctival blood vessels, a major site for systemic absorption of topical drugs seems to be the nasal mucosa. Therefore, we frequently instruct patients to perform punctal occlusion4 for a few minutes after eye drop administration: the eye is closed and the index finger exerts firm pressure over the (lower) punctum, conceptually thus preventing egress of excess medication from the tear film into the nasal mucosa via the occluded punctum (Figure 12-1). Alternatively, gentle eyelid closure for several minutes by itself without punctal occlusion (and without blinking) has been reported by Zimmerman et al5 to be just as effective as punctal occlusion and likely more patient friendly.
Punctal occlusion or gentle eyelid closure is effective in some but not all patients, especially those with mild or moderate symptoms. However, it is not a panacea, and we have been disappointed in its efficacy in patients with advanced systemic symptoms, which most often requires discontinuation of the medication.
Systemic symptoms from topical ocular beta-blockers can be serious and even life threatening. The most common of these symptoms is systemic beta-blockage involving respiratory and cardiac function. The ophthalmologist needs to be alert for symptoms of bronchospasm and bradycardia. Frequently, the patient is either unaware of or misinterprets the cause of these symptoms, attributing it to primary systemic disease. The diagnosis of a presumed systemic condition is often made by the general physician for the first time only after the patient has been placed on topical beta-blockers. We have not made an effective-enough effort of informing our family medicine and internal medicine colleagues about the occurrence of these systemic symptoms resulting from topical ocular medication.
It is very important to listen to patient breathing at the time of slit-lamp examination; patients will commonly not call symptoms of dyspnea to the attention of their ophthalmologist (because they do not associate eye drops with systemic problems) and often may not themselves be fully cognizant that their breathing has “been a little worse lately” since the topical beta-blocker therapy was initiated. Routinely check the pulse rate and blood pressure of patients receiving ocular beta- blocker therapy. Patients are often unaware of bradycardia, which may not be fully symptomatic until a threshold level (that occurs subsequently) is passed. Any patient with a cardiac conduction defect or bradycardia should avoid beta-blockers.
Figure 12-1. Technique of punctal occlusion. The index finger is placed over the lower punctum, and gentle pressure is applied with the eyelid closed. Pressure is then removed, and the eye is opened after 5 minutes.
Topical beta-blockers should be used with caution in heart failure patients because the beta-1 blocking activity could depress myocardial contractility and theoretically worsen heart failure. However, systemic beta-blockers have been shown to decrease morbidity in heart failure patients and are essentially standard therapy in this disorder. One should realize that systemic beta-blocker therapy is typically started at low dosages and titrated to the highest dose that does not worsen the heart failure. Therefore, patients are likely in a narrow therapeutic range with their current systemic therapy, and the addition of a topical beta-blocker may tip the patient over into worsening heart failure. Therefore, topical beta-blockers should be used in consultation with the patient’s cardiologist. Very uncommonly, patients with no apparent heart failure symptoms (but likely preexisting maximally compensated heart function) can develop heart failure for the first time as a result of topical beta-blocker therapy.
Some patients receiving topical ocular beta-blockers report fatigue, which may not be due to bradycardia or heart failure but rather might have a central nervous system origin. Symptoms of fatigue can occur with systemic beta-blocker therapy6 and seem to represent a real potential side effect from topical beta-blockers. Such symptoms seem to respond better to punctal occlusion or gentle eyelid closure than those of bradycardia or bronchospasm, the latter two of which, it again is stressed, can be life threatening and require discontinuation of the drug. Depression has also been associated with systemic beta-blocker therapy.6 However, studies have not supported the concept of increased depression among patients receiving topical7 or systemic8 beta-blockers.
The true majority of glaucoma patients treated with topical beta-blockers does not develop any systemic side effects, and this class of therapy has been a remarkable advance in our armamentarium. But, the ophthalmologist needs to be vigilant for the possible occurrence of such systemic symptoms, even in patients with no known predisposition. It is this latter group that has sensitized us all to the potential systemic hazard of this form of glaucoma therapy, because the occurrence of these serious systemic symptoms has been so unexpected but also so frequently undetected or misdiagnosed. There is no “free lunch” for either the patient with glaucoma or for us as glaucoma clinicians, and unfortunately, all of our therapies have benefit/risk considerations. We have not yet developed the “magic bullet” for either the trabecular meshwork or optic nerve in glaucoma, but when we do, such therapy will likely also entail benefit/risk considerations.
Other uncommon systemic side effects, such as sexual dysfunction9 and rarely Raynaud’s disease–type symptoms, have occasionally been attributed to topical ocular beta-blocker therapy (as well as to systemic beta-blocker therapy). In our experience, occasional patients do report sexual side effects, and punctal occlusion or gentle eyelid closure can be effective in preventing these side effects. Regarding Raynaud’s disease–type symptoms (presumably vasoconstriction of peripheral vessels from unopposed adrenergic input), we have yet to see a patient with this. Moreover, the literature has anecdotal case reports of this phenomenon,10 and studies11,12 have not shown adverse effects of beta-blockers in patients with Raynaud’s disease. Other rarely reported side effects include masking hypoglycemic symptoms13 in patients with diabetes, masking of symptoms of thyrotoxicosis, enhanced muscle weakness in certain myasthenic syndromes, and interactions in patients on systemic catecholamine-depleting drugs, such as reserpine.
Topical beta-blockers, like almost all topical ocular drugs, have not been proven safe in pregnancy or in breastfeeding mothers and should also be used with caution in pediatric patients. Fetal bradycardia and cardiac arrhythmias have been reported from topical timolol use during pregnancy.14
Topical nonselective beta-blockers may cause a small but meaningful adverse effect on blood lipoproteins presumably due to systemic absorption.15 Topical carteolol, in addition to its nonselective beta-blocking ability and intrinsic sympathomimetic action, has been reported to have less of this effect.16 The true implications of this observation need further elucidation, and this phenomenon does not, in itself, direct our choice of a beta-blocker for initial therapy.17 On the other hand, this observation involving systemic lipoproteins might indicate the need to have all patients taking topical beta- blocker therapy perform punctal occlusion or gentle eyelid closure.
Pratap Challa, MD, MS and David L. Epstein, MD, MMM
When evaluating clinical trials involving glaucoma patients, it should be noted whether the population being studied consists of patients who have never been treated with the specific medication or whether glaucoma veterans are studied. The latter type is what one commonly observes in pharmacological studies in the literature, and there is then an important preselection factor that the reader should understand. Not only are the latter veteran glaucoma patients already using the antiglaucoma therapy that is being evaluated in the study and, therefore, more likely to respond with a therapeutic IOP response to the given agent (otherwise, why were they being treated chronically before the study with the given agent?), but they are also preselected to not have developed untoward side effects (yet) to the given medication.
Thus, the use of glaucoma veterans in these clinical trials usually underestimates the frequency of side effects and overestimates the IOP efficacy. Yet, studies using such patients are the “bread and butter” of clinical pharmacological glaucoma research. These patients frequently receive a given therapy for a long time period and then have this therapy discontinued for several weeks (termed a washout period). They are then randomized to 1 of 2 agents, which usually includes the previous therapy. Meaningful clinical information can be obtained by such studies, which are often the only way to obtain the large numbers of patients required. However, it should be understood that the clinical relevance to one’s practice from such studies is usually framed more appropriately as the question, “If I have a patient on agent X, what is the relative benefit of switching the patient to agent Y?” There may be residual effects lasting even more than a few weeks1,2 in washing out patients from existing therapy that can complicate the interpretation (eg, when one is dealing with adrenergic agonists and antagonists in the same study).
It follows that for the clinical question, “What antiglaucoma agent should I use in the newly diagnosed patient with glaucoma?” one would prefer a study of ocular virgins. But, as mentioned, it is harder to find patients for such a protocol. Yet, this real life–type of study is important and can offer important clinical information. The following 2 examples may be appropriate.
When we performed a randomized prospective clinical trial of timolol therapy vs no treatment in ocular virgins with elevated IOP,3 a surprising and unanticipated substantial incidence of side effects occurred in the timolol group that resulted in cessation of therapy and complicated the statistical analysis (once randomized, always analyzed). Yet, the occurrence of these side effects in patients never treated with timolol before was a clinically relevant important observation in itself. Also, although some have criticized this particular study because the sample size was too small (n = 107) and meaningful conclusions could only thereby be achieved in a larger multicenter study (which creates other problems of standardization and true comparison), it was often forgotten that our sample consisted only of ocular virgins, which is an important clinical group. In truth, there are weaknesses in most clinical studies in glaucoma, if for no other reason than individual glaucoma classifications likely represent more than one disease, the subclassification of which we have been unable to discriminate. It is one of the challenges but also one of the charms of the field that glaucoma clinicians can thus constantly refine our understanding by performing more than a single study with the same apparent protocol. We seem to spend too much time criticizing studies, especially when they do not conform to our previous dogma, and spend insufficient time trying to gain potentially important clinical insights within the context of the limitations of the data, which are our constant companion.
The second example is another study4 in which we randomized primary open-angle glaucoma virgins in a different proposed long-term protocol to either treatment with timolol or epinephrine. Although nowadays epinephrine is rarely used to treat glaucoma, this example is still conceptually valid. At the time, our rationale was that epinephrine was the only glaucoma agent that seemingly had been documented to alter the natural history of the disease.5,6 Hence, we wanted to compare the efficacy of timolol to this standard. We were surprised (and it actually ruined the study) to find out that about one-third of such unselected glaucoma patients did not get a clinically meaningful reduction in IOP from epinephrine.6 That is, about one-third of new glaucoma patients are nonresponders to epinephrine. “In a newly diagnosed glaucoma patient, should I utilize timolol or epinephrine as initial therapy?” is different from “In glaucoma patients who are both ‘epinephrine responders’ and ‘timolol responded,’ which is the better therapy?” If one, as has been common in the literature, chooses patients already receiving chronic epinephrine-like antiglaucoma therapy, and thus are likely epinephrine responders, washes them out, and then randomizes them to timolol or epinephrine, this potentially offers information to this second question but not the first. The reader should keep this example in mind when reading published drug therapy trials.
REFERENCES
1. Thomas JV, Epstein DL. Timolol and epinephrine in primary open angle glaucoma: transient additive effect. Arch Ophthalmol. 1981;99:91-95.
2. Cyrlin MN, Thomas JV, Epstein DL. Additive effect of epinephrine to timolol therapy in primary open angle glaucoma. Arch Ophthalmol. 1982;100:414-418.
3. Epstein DL, Krug Jr JH, Hertzmark E, et al. A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. Ophthalmology. 1989;96:1460-1467.
4. Alexander DW, Berson FG, Epstein DL. A clinical trial of timolol and epinephrine in the treatment of primary open angle glaucoma. Ophthalmology. 1988;95:247-251.
5. Becker B, Morton WR. Topical epinephrine in glaucoma suspects. Am J Ophthalmol. 1966;62:272-277.
6. Shin DH, Kolker AE, Kass MA, Kaback MB, Becker B. Long-term epinephrine therapy of ocular hypertension. Arch Ophthalmol. 1976;94:2059-2060.
Respiratory side effects with beta-blockers are attributed to beta-2 receptor actions. Thus, one might expect that beta-1 selective blockers might be free from such beta-2 blocking side effects. But the key word is selective, which is a relative rather than an absolute term. For example, Betoptic (betaxolol), a selective beta-1 blocker, was observed in one human study18 to produce aqueous humor levels sufficient to produce substantial beta-2 blockade. Thus, betaxolol can demonstrate some beta-2 blockade properties, and such terminology, regardless, ignores other important biochemical issues, such as turnover time on the beta-receptor and other important pharmacodynamic issues. Also, because a drug systemically absorbed from ocular administration would pass first to the lung from the right side of the heart (first-pass phenomenon), the lung tissue might experience higher drug levels than those commonly measured in the peripheral venous system. From a practical clinical point of view, a beta-1 selective blocker such as betaxolol is not absolutely safe for glaucoma patients with respiratory disease. In fact, in patients with respiratory disease, a beta-blocker should not be the initial therapy. In patients with respiratory disease that is not severe, a beta-1 blocker can sometimes be used with great caution and close observation, but it is best to do this with the consultation of a pulmonologist. Regardless, the selective advantage of beta-1 blockers, such as betaxolol, is relative.
Pratap Challa, MD, MS and David L. Epstein, MD, MMM
Timolol produces minimal if any IOP reduction in albino rabbits.1 This is the usual, although questionable, model for glaucoma drug testing and has led many to predict the unsuitability of timolol and other beta-blockers for human glaucoma therapy. The differences between normal, young, healthy rabbits and aged humans with disease are extraordinary, yet the rabbit model for glaucoma drug screening persists. How many other potentially useful antiglaucoma therapies may have been similarly missed due to the lack of a suitable animal model for drug testing?
REFERENCE
1. Bartels SP, Roth HO, Jumblatt MM, et al. Pharmacological effects of topical timolol in the rabbit eye. Invest Ophthalmol Vis Sci. 1980;19:1189-1197.
SYSTEMIC BETA-BLOCKERS AND PSEUDO–LOW-TENSION GLAUCOMA
Systemic beta-blocker therapy can lower IOPs and hence explain certain patients who appear to have low-tension glaucoma. The IOP was higher in the past when nerve damage apparently occurred before the patient was placed on systemic beta-blocker therapy for other systemic disease.
Because both betaxolol, a beta-1 selective blocker, and timolol, a nonselective (beta-1 and beta-2) blocker, both block beta-1 receptors, one would think that both drugs should produce similar degrees of bradycardia (a beta-1 action). But, again, the selectivity of the agent should not be equated with beta-blocker potency. The latter involves issues including drug turnover and bioavailability. In fact, betaxolol seems to produce less bradycardia than timolol,19 and sometimes, if one has exhausted other therapeutic options, with internal medicine consultation, one can try betaxolol in glaucoma patients in whom bradycardia has developed while receiving timolol. We have used this several times with success. However, this should never be attempted in patients who develop severe bradycardia or who have preexisting bradycardia. For such patients, the risks are too great in the long term, even if it were effective in the short term.
INTERACTIONS OF TOPICAL BETA-BLOCKER THERAPY WITH SYSTEMIC BETA-BLOCKER THERAPY
Some have reported that topical beta-blockers added to systemic beta-blockers can produce, for the first time, symptoms of systemic beta-blocker side effects. This is very rare and unexpected in our experience, considering the usual fluctuation in blood levels of drugs given systemically compared with those given topically.
A more common question is whether topical beta-blockers are as effective in decreasing IOP in patients already taking systemic beta-blocker therapy. Systemic beta-blockers can produce IOP lowering20,21 (this observation is what originally initiated the interest in topical beta-blocker therapy for glaucoma), but the effect is usually small and somewhat variable. In practical terms, if a topical beta-blocker would seem to be the logical first choice of drug, it should still be initiated in glaucoma patients who are receiving oral beta-blocker therapy for systemic disease. In fact, in keeping with the above systemic blood drug level considerations, there likely is a lesser chance for systemic side effects from topical beta-blockers in glaucoma patients who are already taking systemic beta-blocker therapy for other medical purposes.
Why systemic beta-blockers do not produce greater IOP lowering than they do has not been fully clarified, but this is most likely due to insufficient ocular levels of the drug, or possibly bioavailability factors. Beta-blocker receptors in the eye are responsible for decreasing AHF and reside on vascular or ciliary epithelial cell membrane sites. The observed weak IOP-lowering effect of systemic beta-blocker therapy might provide important insight into physiological mechanisms (and perhaps favor the theory of a cellular site of drug action).
OCULAR SIDE EFFECTS
Despite great initial concern about the potential for ocular side effects when the topical beta-blockers were introduced (because of the observation of an idiosyncratic reaction of a pemphigoid-like syndrome with one systemic beta-blocker,22,23 and also the potential of beta-blockers to induce corneal anesthesia24), such ocular side effects have been uncommon. Topical beta-blockers are very well-tolerated topical medications for glaucoma patients. As with any drop, symptoms of stinging, burning, redness, itching, and tearing may occur and be troublesome.
Corneal hypesthesia can definitely occur25 and can be of concern, but it is uncertain whether a small measured decrease in corneal sensitivity without any clinical symptoms or signs is clinically important. In patients with punctate keratitis, the topical beta-blocker therapy should be suspected. Switching to another topical beta-blocker (if the symptoms and signs are not severe), especially, at least theoretically, one without significant membrane-stabilizing activity (which seems at least theoretically to relate to the hypesthetic potential) should perhaps be tried first and can be surprisingly effective. Furthermore, the benzalkonium preservatives used in many eye drops can produce punctate keratitis as well. If the surface disease is refractory to switching topical drops, then one can consider prescribing preservative-free timolol. Available as Timoptic Ocudose in 0.25% and 0.5% concentrations, these are single-dose vials of timolol prescribed twice daily.
Medications can produce a great variety of side effects, and this needs to be kept in mind with topical beta-blocker therapy. But from a practical point of view, the systemic26 rather than the ocular side effects have been the major limitation to the use of topical beta-blocker therapy for glaucoma.
ESCAPE AND DRIFT IN INTRAOCULAR PRESSURE ON BETA-BLOCKER THERAPY
The first drop of a beta-blocker such as timolol applied to a glaucoma patient’s eye produces a greater IOP-lowering effect than the subsequent drops over the next couple days. Some have called this phenomenon beta-blocker escape.27,28 This effect quickly plateaus in a steady state of sustained, clinically meaningful IOP reduction for more than 90% of glaucoma patients.29 This phenomenon was extensively studied by Boger and colleagues,27,28 who along with Irving Katz, MD, at Merck, deserve a great deal of credit for persisting and advocating continued clinical evaluation of timolol when some thought that the escape phenomenon was equivalent to a tachyphylaxis-type mechanism. (Zimmerman30 and others were also important advocates and deserve our praise, but Boger and Katz deserve special credit for their elucidation of chronic dosing phenomena.)
Beyond these short-term events of escape, which at a cellular level might possibly relate to changes in the actual receptors themselves, in glaucoma patients who were receiving long-term beta-blocker therapy, there was a slow but real upward drift in IOP.27,28 In our studies of timolol vs no treatment in patients with elevated IOP,31 we observed this apparent drift in the timolol group. We also observed a similar, comparable phenomenon in the no-treatment group, suggesting to us that timolol (and likely other beta-blockers) does not diminish in ability to decrease the rate of AHF in glaucoma eyes once the patient is beyond the short-term escape phenomenon. Rather, the disease process in the trabecular meshwork in such early glaucoma patients continues to worsen (in both control and timolol-treated patients), which results in the apparent drift upward of IOP. That is, at the level of the ciliary body, timolol with chronic therapy does not progressively lose its ability to decrease aqueous humor production, but rather there is a slow decrease of trabecular meshwork function due to the underlying disease process.
Figure 12-2. Conceptual scheme for explaining IOP effects of epinephrine, timolol, and their combination. (Left) By stimulating beta receptors in the trabecular meshwork, epinephrine improves outflow facility. Timolol blocks this effect of epinephrine, but because no innervative “tone” in the primate meshwork exists, when timolol is used alone, it does not impair outflow facility. (Right) Epinephrine effect on inflow is mixed due to a combined beta effect stimulating inflow and a nonbeta effect (alpha) decreasing inflow. Because there is “tone” to the ciliary body, timolol blocks beta-receptors, and it causes a decrease in inflow.
MECHANISM OF ACTION OF BETA-BLOCKERS: INTERACTIONS WITH ADRENERGIC AGONISTS
Initially, the fact that both beta-blockers and beta-agonists could each lower IOP was confusing (and, in fact, unanticipated from laboratory rabbit data). Combination studies of agonists and antagonists have been fairly consistent in their results and led us to the following concept that has achieved general, although perhaps not universal, acceptance.
The fact that both beta-agonists and antagonists can lower IOP is explainable in part because each is believed to exert its beneficial action at a different site within the eye—the beta-blocker at the ciliary body and the beta-agonist in the outflow pathway (Figure 12-2). As mentioned previously, although beta-agonists are not commonly used for glaucoma management due to their high frequency of side effects, one still needs to understand their mechanism of action and side effects because there is ongoing research into developing new variants of these medications.
Pratap Challa, MD, MS and David L. Epstein, MD, MMM
We commonly encounter confusing data from certain laboratory glaucoma studies as far as applicability to humans, because we still do not really have adequate animal or in vitro models for what we want to study. The fact has been mentioned that albino rabbits do not show much if any reduction of IOP in response to topical beta-blockers, and in truth, there are very substantial differences between rabbits and humans both in terms of ocular anatomy and tissue reactivity. It is sad, therefore, that rabbits continue to be the predominant model for glaucoma drug development. More recently, rodents have been used to study glaucoma medications and outflow physiology. Rodents have a more similar outflow pathway to humans with a visible trabecular meshwork. However, no spontaneous models of primary open-angle glaucoma exist. The rodent models of glaucoma that have been employed consist of damaging the outflow pathway in unnatural ways (sclerosing episcleral vessels/Morrison model) or appear to mimic pigmentary forms of glaucoma (DBA2J mice). However, recent developments in generating transgenic rodent models may hold more promise. These transgenic models can be used to test the effects of altering specific glaucoma genes or even splicing human disease variant genes into the mouse genome. Combined with instruments that measure rodent IOPs, optical coherence tomography of the ganglion cell layers, and facility of outflow measurements, rodent models are becoming very powerful to test new glaucoma hypotheses.
Nonhuman primates offer more similarity to humans, but there are issues of cost, availability, and ethics. Certainly, before drugs are used on humans, it would be more appropriate to use these in nonhuman primates. But for earlier development, we are still lacking appropriate, readily available testing models. One consideration is to use in vitro models1,2 or certain cell culture assays3 for high-throughput drug screening. In fact, assays of cell shape and attachment4 and cell monolayer permeability5 may be the most efficient and effective means to screen for aqueous humor outflow glaucoma drugs. These models are currently being used to screen for drugs that affect the cytoskeleton of trabecular meshwork cells. By altering their shape—essentially shrinking these cells—a decrease in aqueous outflow resistance can be achieved. Rho and rho-associated kinase (ROCK) inhibitors are drugs that fall into this category (see Chapter 17).
There are notable differences between nonhuman and human primates; there seems to be a substantially higher outflow through the nontrabecular unconventional outflow pathway in the nonhuman primate. Further, in anterior chamber perfusion studies, the conventional trabecular outflow pathway in the nonhuman primate is believed to behave physiologically differently than in humans, by demonstrating a progressive decline in outflow resistance (washout effect) with continued perfusion.6 Further, there are, unfortunately, no animal models for human glaucoma, and diseased, aged human outflow pathway tissues7 might respond differently from young, normal animal tissue with an anatomically and physiologically different outflow pathway. In one study,8 the threshold dosage for a drug outflow effect was seemingly 10-fold lower in the human eye than the animal eye. Therefore, in vitro models will likely become even more important in the future of glaucoma drug development.
We need to keep this in mind in our research efforts in glaucoma. There likely is also much more that can be done in direct evaluation of humans with glaucoma. Tonography studies9 allowed the dissection of beta-1 and beta-2 effects directly in human glaucoma patients and helped clarify what was a confusing clinical situation at the time. Such a study was a source of much satisfaction for the clinicians involved. One thinks also of the work of Richard Brubaker,10 who, by measuring AHF in human participants, is adding further clarity not only to antiglaucoma drug effects but also to normal physiological influences.10
For clinician scientists, patients with disease are a clinical laboratory from which it is possible to make meaningful observations from “nature’s own experiments.”
REFERENCES
1. Erickson-Lamy K, Rohen JW, Grant WM. Outflow facility studies in the perfused human ocular anterior segment. Exp Eye Res. 199l;52:723-731.
2. Johnson DH, Tschumper RC. Ethacrynic acid: outflow effects and toxicity in human trabecular meshwork in perfusion organ culture. Curr Eye Res. 1993;12:385-396.
3. Erickson-Lamy K, Schroeder A, Epstein DL. Ethacrynic acid induces reversible shape and cytoskeletal changes in cultured cells. Invest Ophthalmol Vis Sci. 1992;33:2631-2640.
4. Grewal A, O’Brien ET, Epstein DL. Control of cell shape in the trabecular meshwork. Invest Ophthalmol Vis Sci. 1994;35(suppl):2725.
5. Underwood J, Alvarado JA, Murphy CG, et al. Steroid-induced decreases in hydraulic conductivity (HC) were blocked in human trabecular meshwork (TM) cells by an antisense oligonucleotide to ZO-I. Invest Ophthalmol Vis Sci. 1994;35(suppl):1847.
6. Erickson-Lamy K, Epstein DL, Schroeder AM, et al. Absence of time-dependent facility increase (“washout”) in the perfused enucleated human eye. Invest Ophthalmol Vis Sci. 1990;31:2384-2388.
7. de Kater AW, Melamed S, Epstein DL. Patterns of aqueous humor outflow in glaucomatous and nonglaucomatous human eyes. A tracer study using cationized ferritin. Arch Ophthalmol. 1989;107:572-576.
8. Liang LL, Epstein DL, de Kater AW, Shahsafaei A, Erickson-Lamy KA. Ethacrynic acid increases facility of outflow in the human eye in vitro. Arch Ophthalmol. 1992;10:106-109.
9. Allen RC, Epstein DL. Additive effect of betaxolol and epinephrine in primary open angle glaucoma. Arch Ophthalmol. 1986;104:1178-1184.
10. Brubaker RF. Flow of aqueous humor in humans [The Friedenwald Lecture]. Invest Ophthalmol Vis Sci. 1991;32:3145-3166.
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