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(Investigative Ophthalmology and Visual Science. 2004;45:2732-2736.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.04-0083
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H-7 Effect on Outflow Facility after Trabecular Obstruction Following Long-Term Echothiophate Treatment in Monkeys

B’Ann T. Gabelt, Elizabeth A. Hennes, Jennifer L. Seeman, Baohe Tian, and Paul L. Kaufman

From the Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin.


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. To determine whether H-7 can enhance outflow facility after trabecular meshwork obstruction by extracellular material that accumulates after long-term treatment of monkeys with the cholinesterase inhibitor echothiophate iodide (ECHO).

METHODS. Cynomolgus monkeys were treated topically with 150 µg ECHO in one (n = 4 eyes) or both (n = 8 eyes) eyes for up to 48 weeks. Accommodation response to topical pilocarpine was monitored periodically. Outflow facility response to H-7 was measured by two-level constant pressure perfusion on three or four different occasions after intraocular pressure was elevated for 12 to 18 weeks.

RESULTS. Long-term treatment with ECHO decreased the accommodative response to pilocarpine and increased intraocular pressure, as has been reported. Baseline outflow facility was decreased by 46% ± 7% (n = 12, P < 0.001). H-7 partially restored baseline outflow facility measured during subsequent perfusions while ECHO treatment was continued. Concurrent H-7 enhanced outflow facility by 73% ± 18% (n = 12, P < 0.005) beyond the same-day baseline in ECHO-treated eyes. Cessation of ECHO treatment further restored baseline outflow facility, and the outflow facility response to H-7.

CONCLUSIONS. H-7 can enhance OF in the presence of trabecular obstruction produced by long-term ECHO treatment. This suggests that H-7 may be useful in treating glaucoma, even in the presence of accumulated plaque material that has been described previously.

Long-acting cholinesterase inhibitors such as echothiophate iodide (ECHO) are no longer used routinely for the treatment of human glaucoma. Initially, these drugs reduce intraocular pressure (IOP) by increasing the facility of aqueous humor outflow, but some eyes eventually become refractory.1 Chronic topical treatment of the nonhuman primate eye with ECHO results in an increase in IOP; collapse and densification of the trabecular meshwork, with accumulation of extracellular material; alterations in the shape and orientation of Schlemm’s canal and the ciliary muscle; and discontinuity between ciliary muscle bundles and trabecular beams.2 The pathophysiology of these effects is mediated, in part, by anterior segment muscarinic receptors and underperfusion of the meshwork.3 4 Outlfow facility (OF) and accommodation and their responsiveness to pilocarpine (PILO) are subsequently decreased.5 6

We wanted to use this model of trabecular obstruction and elevated IOP to determine whether drugs such as H-7, which disrupts the actin cytoskeleton of the trabecular meshwork and increases trabecular outflow facility in normal monkeys,7 8 can induce washout of material to the point that normal OF is restored. This could suggest whether these types of compounds may be useful in treating glaucoma, in which plaque material also accumulates.9


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
All experiments complied with the ARVO Statement on the Use of Animals in Ophthalmic and Vision Research.

Animals and Anesthesia
Two groups of four cynomolgus monkeys each were studied more than 1 year apart. Group 1 consisted of two females and two males, 5, 6, 7, and 10 years old, weighing 2.8–5.6 kg, that had undergone 1–3 prior OF measurements in both eyes. Group 2 consisted of three females and one male, 9, 13, 15, and 19 years old, weighing 3.2–5.4 kg, each having one prior OF measurement in both eyes. Monkeys were anesthetized with intramuscular ketamine (10 mg/kg) for IOP measurements and slit lamp examination (SLE), and with intramuscular ketamine followed by intravenous pentobarbital (15 mg/kg) for refraction and OF measurements. When it became necessary to differentiate the OF effects of H-7 obtained in group 1 from those resulting from discontinuation of ECHO treatment and perfusion exchange washout (see later), group 2 was added. Available monkeys were used at each time, regardless of their ages.

ECHO Treatments
Monkeys were restrained in a squeeze cage and were treated consciously once a day with ECHO (group 1: Ayerst Laboratories, New York, NY; group 2: Tocris, Ellisville, MO) in one eye; saline in the opposite eye (group 1) or ECHO in both eyes (group 2). ECHO for group 2 had to be synthesized by Tocris because of the nationwide discontinuation of the commercial product at this time. The dose was ramped up over a 5-week period from 30 µg in 2 µL to the maximum dose of 150 µg in 5 x 2-µL drops, to avoid systemic toxicity.5 6 Animals were continued on this dose for 42–47 weeks. Human doses range from 9–250 µg once or twice daily.10 11

IOP/SLE/Refraction
Table 1 summarizes the timing of the various procedures.


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  		TABLE 1. Procedure Summary

 
IOP (minified Goldmann applanation tonometer)12 and SLE were performed at approximately 3-week intervals before and during the course of treatment. Refraction (Hartinger coincidence refractometer; Jenoptik, Jena, Germany) response of both eyes to topical pilocarpine HCL (PILO; Sigma-Aldrich, St. Louis, MO) was measured before and at 6-week (group 1) or 3-month (group 2) intervals throughout the treatment period. PILO doses of 20, 200, and 1000 µg in 5 x 2-µL drops in 0.1% citrate buffer were used. These produce threshold, half-maximum, and maximum accommodation responses in normal monkeys.13 The following sequence was used: refraction sequentially at (1) baseline; (2) 15–30 minutes after topical 10% phenylephrine (dilates the pupil and prevents strong miosis in the presence of PILO or ECHO)5 ; (3) 30–45 minutes after 15 mg/kg intramuscular hexamethonium Br (HEX, Sigma; produces ganglionic blockade so that only the PILO response is measured)6 ; (4) after placing a 7.5–D contact lens on the eye that was left in place for all subsequent measurements (used to extend the myopic range of the refractometer and to prevent the cornea from dehydrating under pentobarbital anesthesia); and (5) every 5 minutes to plateau (~45–60 minutes) after each progressively higher dose of PILO (contact lens removed before administering each dose).

OF after H-7
When IOP was elevated for ~12–18 weeks, and refraction responses were subsensitive to PILO, OF was determined by two-level constant pressure perfusion14 on three or four different occasions: after 38–42 and 43–48 weeks from the start of ECHO treatment; and after 5 weeks without ECHO treatment; after 9 months (one monkey from group 2) or 2 years (three monkeys from group 1) after discontinuation of ECHO. Before OF measurements at 38–42 and 43–48 weeks, ECHO was discontinued for 1 week (to minimize differences in acetylcholine levels). On each perfusion day, IOP and refraction were measured, monkeys were pretreated with intramuscular HEX and topically in both eyes with 100 µg atropine sulfate (Sigma-Aldrich) to block OF effects of endogenous acetylcholine.15 After 60 minutes, refraction was confirmed to be equal in the paired eyes, and IOP was measured again. Monkeys were then anesthetized with pentobarbital and baseline OF measured for 35–45 minutes (75–90 minutes post-HEX/atropine) using Bárány’s perfusate.14 IOPs were adjusted to either 14.3 ± 0.2 or 23.6 ± 0.3 mm Hg (n = 48) by external reservoirs every 4 minutes and flow from the reservoirs recorded during each 4-minute period. Contents of anterior chambers were then exchanged with (1) 300 µM H-7 (Sigma-Aldrich) in both eyes (group 1, 1st–4th OF; group 2, 4th OF) or (2) H-7 in one eye and Bárány’s perfusate in the opposite eye (group 2, 1st–3rd OF). This dose of H-7 has been shown to be maximal for increasing OF in cynomolgus monkeys.7 16 Reservoirs were closed for 30 minutes, filled with the corresponding exchange solution, then opened and OF measured for 90 minutes.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Results are expressed as the mean ± SEM.

IOP after Long-Term ECHO
In group 1 (Fig. 1A) , comparing pretreatment to 34 weeks treatment values, IOP (mm Hg) increased from 14.8 ± 0.5 to 21.1 ± 1.0 mm Hg (P < 0.02) in ECHO-treated eyes but remained unchanged in contralateral control eyes (14.5 ± 0.3 vs. 17.4 ± 0.8 mm Hg, P < 0.10). IOP was significantly increased in ECHO eyes compared with contralateral control eyes corrected for pretreatment baseline during the interval from 27 to 34 weeks and again after the first OF measurement. ECHO-induced cataract was visible in two of four treated eyes (one starting at 23 weeks and another at 45 weeks). IOP returned to near baseline levels when ECHO was removed 1 week before the first OF determination, increased again as ECHO was continued between the first and second OF experiments, then returned to baseline levels when ECHO was discontinued before the second OF experiment and thereafter.



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  		FIGURE 1. IOP during long-term topical ECHO. (A) Group 1 (ECHO to one eye, {blacksquare}; vehicle to opposite eye, •). (B) Group 2 (ECHO in both eyes). IOP increased in the ECHO treated eyes. Outflow facility (OF) and its response to 300 µM H7 (A, both eyes; B, one eye) was determined. ECHO treatment was discontinued for 1 week between the first and second OF and for the 5 weeks between the second and third OF determinations. Significantly different from pretreatment baseline (*P < 0.05) or from the opposite eye corrected for pretreatment baseline ({dagger}P < 0.05) by the two-tailed paired t-test for differences.

 
Group 2 monkeys (Fig. 1B) responded similarly, with IOP increasing from 16.7 ± 0.3 mm Hg before the first treatment to 21.9 ± 0.5 mm Hg after 41 weeks of treatment (P < 0.001, n = 8). All eyes exhibited ECHO-induced lens changes by 30 weeks after the start of treatment.

Baseline Refraction after Long-Term ECHO
In group 1, baseline resting refraction comparing pretreatment to 36-week treatment responses decreased from –2.8 ± 0.6 to –21.8 ± 1.4 D (P < 0.005) in ECHO eyes and from –2.8 ± 0.5 to –5.0 ± 0.4 D (P < 0.001) in contralateral control eyes (Fig. 2) . Baseline refraction progressively returned toward pretreatment levels on discontinuation of ECHO for 1 week before the first and second perfusions and for 5 weeks before the third perfusion and thereafter.



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  		FIGURE 2. Baseline refraction during long-term ECHO treatment. Group 1, n = 4 (ECHO in one eye, {blacksquare}; vehicle in opposite eye, •). Group 2, n = 8 (ECHO in both eyes, {blacktriangleup}). Baseline refraction in the ECHO-treated eyes decreased during the course of ECHO treatment but gradually recovered when ECHO was removed before outflow facility (OF) measurements (arrows) and/or as a result of H-7 treatment during OF measurements. Group 2 contained only four eyes after week 42. *Significantly different from baseline before any treatment by the two-tailed paired t-test for differences, P < 0.05.

 
In group 2, baseline resting refraction in all eight eyes before the first treatment was –5.9 ± 2.0 D (one monkey was very myopic in both eyes). After 28 weeks of treatment, the average refraction in all eyes was –10.7 ± 1.7 D (Fig. 2) . The lesser decrease in resting refraction in group 2 may have been due to the age of these monkeys compared with those of group 1 (14 ± 2 years vs. 7 ± 1 years, respectively). The remaining refractions included only four eyes because two of the monkeys died shortly after the first perfusion. Refractions in these monkeys also progressively returned to near pretreatment values with each subsequent perfusion and after ECHO was discontinued before the last perfusion and thereafter.

Accommodation Response after Long-Term ECHO
Accommodation response was calculated as the maximum myopic PILO refraction+lens minus the HEX+lens baseline refraction (Table 2) . In group 1, comparing pretreatment to 36-week treatment values, ECHO nearly abolished the accommodation response to all three doses of PILO in the ECHO-treated eye. Control eye accommodation responses were also diminished but were still strong, especially at the 1000-µg PILO dose. In group 2, similarly, 24 weeks of ECHO treatment in both eyes abolished the accommodation response to all three doses of PILO.


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  		TABLE 2. Accommodation Response to Pilocarpine after Long-Term ECHO

 
Outflow Facility Response to H-7 after Long-Term ECHO
In group 1 (Table 3) , baseline OF before the first ECHO treatment was similar in both eyes. After 38 weeks of ECHO treatment, baseline OF in treated eyes was significantly reduced to 50% ± 11% (P < 0.02, n = 4) of pretreatment baseline values and to 59% ± 12% (P < 0.05, n = 4) of control eye values at the time of the first perfusion. Baseline OF remained significantly less than pretreatment baseline OF in all perfusion experiments. Both ECHO and control eyes responded to 300 µM H-7 with an increase in OF averaged over 90 minutes. The response in the ECHO eye was significantly less that in the control eye when corrected for same day baseline, while ECHO treatment was still being continued (1st and 2nd OF). When ECHO treatment was discontinued for 5 weeks between the second and third perfusions, the ratio of the H-7 OF response between the eyes corrected for same-day baseline was no longer significantly different from 1.0, although the OF in the ECHO eyes was still lower than in control eyes. At the third OF (alt), one monkey had substantially lower baseline OF in the treated eye than at the second OF baseline (0.03 vs. 0.21 µL/min per mm Hg). The ECHO-to-control ratio from the second OF baseline was applied to the control value of the third perfusion baseline for this monkey to obtain the alternate value for the treated eye baseline.


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  		TABLE 3. Outflow Facility Response in Group 1 to 300 µM H-7 in Both Eyes after Long-Term Unilateral ECHO

 
Two years later (4th OF), only three monkeys remained from group 1. Baseline OF had not returned to pretreatment values or contralateral control eye values in previously ECHO-treated eyes. OF response to H-7 remained less than in the control eye and was no greater than at the time of the third OF.

In Group 2 (Table 4) , baseline OF before the first ECHO treatment was similar in both eyes and similar to that of group 1. After 42 weeks of ECHO treatment, baseline OF was decreased to 56% ± 0% (P < 0.005, n = 8 eyes) of pretreatment baseline values and was similar in both eyes. The first H-7 exchange in one eye did not enhance OF compared with the control when all eight eyes were considered. However, two monkeys died after this first experiment (within 2–3 days of the perfusion). When the data from the two surviving monkeys were considered, H-7 seems to have increased OF in the first experiment, although there are too few animals to make any conclusions. In the second experiment, baseline OF and the OF response to H-7 appeared to be greater in the previous H-7–perfused eye than in the control and when compared with the first OF baseline. Discontinuation of ECHO between the second and third OF resulted in further recovery of baseline OF in both eyes. The OF response to H-7 was no greater than that obtained during the second OF. All the OF responses to H-7 in group 2 were less than those of group 1. The third H-7 OF in ECHO eyes approached but did not exceed pretreatment baseline levels (0.20 ± 0.04 µL/min per mm Hg, n = 2).


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  		TABLE 4. Outflow Facility Response in Group 2 to 300 µM H-7 after Long-Term ECHO in Both Eyes

 
Nine months later, 1 monkey remained from group 2. Baseline OF in both eyes was similar but remained less than pretreatment baseline levels. Both eyes responded strongly to H-7, although the eye that received H-7 in the previous OF experiments did not respond as strongly as the opposite eye that had not previously received H-7.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The increase in IOP and subsensitivity of the accommodation response to PILO shown here are similar to those reported previously for this model.2 3 4 5 This suggests that the morphologic alterations of the outflow pathways of the eye previously described in other studies and in the introduction were probably also present in the present study. The reduction in baseline OF (Tables 2 3) in the ECHO-treated eyes in the present study also suggests outflow obstruction.

H-7 increases OF through the trabecular meshwork in live monkey eyes,8 in organ-cultured monkey eyes (Hu Y, et al. IOVS 2004;45:ARVO E-Abstract 5027), and in human eyes (Bahler CK, et al. IOVS 2002;43:ARVO E-Abstract 1031) by inhibiting actomyosin contractility, perhaps by inhibiting myosin light chain kinase or rho kinase, leading to deterioration of the actin microfilament system, perturbation of its membrane anchorage, and loss of stress fibers and focal contacts in the trabecular meshwork cells. The resultant relaxation of the juxtacanalicular region of the trabecular meshwork and inner wall cells of Schlemm’s canal, accompanied by an increase in juxtacanalicular extracellular spaces, loss of juxtacanalicular extracellular matrix, and establishment of new fluid flow pathways, leads to increased OF.7 8 17

In the present study, H-7 was effective in increasing OF in the ECHO-treated eyes relative to baseline but not as strongly as in eyes that received no ECHO treatment (Tables 3 4) . It is possible that ECHO-induced extracellular material accumulation or structural alterations inhibits the expansion of outflow pathways by H-7.

In group 1, the ratios of the H-7 response in the ECHO eyes compared with control eyes corrected for baseline were similar in the first and second perfusions, suggesting that there was no persistent enhancement of the OF response to H-7 in the ECHO eye. Once ECHO treatment was discontinued for several weeks (3rd OF) or 2 years (4th OF), the OF response to H-7 was not significantly different between the eyes, although it remained consistently lower in previously ECHO-treated eyes compared with control eyes. Morphologic alterations of the trabecular meshwork and accumulation of extracellular material may or may not reverse on removal of ECHO.2 This reversal may be more likely when some washout has been initiated by the perfusions. It is therefore difficult to tell whether the gradual restoration of baseline OF (Table 3) is partially due to the effects of H-7 or would result just from discontinuing ECHO or exchanging the anterior chamber and perfusing alone.

We attempted to answer this question by repeating the study but treating both eyes with ECHO and perfusing one eye with H-7 (group 2). Although the numbers are small, it appears that previous H-7 treatment enhanced baseline OF (Table 4 , 2nd vs. 1st OF) while ECHO treatment was still ongoing. OF in response to H-7 was also enhanced beyond the effects of exchange and perfusion alone. However, discontinuation of ECHO itself also produced some restoration of baseline OF. H-7 did not increase facility above pre-ECHO baseline in group 2 until ECHO treatment had been discontinued for a prolonged period (4th OF).

Baseline OF remained 30% to 40% less than pretreatment baseline in all eyes that had previously been treated with ECHO, even after prolonged drug-free periods. This suggests that some permanent change had taken place. Part of this reduction might be attributed to atropine pretreatment before each of the post-ECHO perfusions. However, OF in the control eyes from group 1 two years later were no different from the pretreatment baselines obtained without atropine, whereas the previous ECHO eye baseline OF remained decreased.

Monkeys in group 2 were older than those in group 1 (5, 6, 7, and 10 years vs. 9, 13, 15, and 19 years). Although the pretreatment accommodation response to PILO was similar in the two groups, the decrease in resting refraction and the OF response to H-7 seemed to be less in the ECHO eyes of group 2 which comprised the older monkeys. Accommodative responses decline dramatically with age in monkeys, and this decline could account for the resting refraction differences between the groups with ECHO treatment. Aging effects on baseline outflow facility and responsiveness to pilocarpine are significant but less dramatic.15 18 19 Because all monkeys seemed to be able to respond to H-7 and opposite eyes of the same animal were used for the comparisons, age-related effects should not alter the interpretation of the results.

In conclusion, even though the number of monkeys was small, the results suggest that H-7 can enhance OF in the presence of trabecular obstruction produced by long-term ECHO treatment. The apparent permanent reduction of baseline OF suggests that some ECHO-induced changes may be irreversible.2 H-7 may have some value in treating glaucoma, even in the presence of accumulated plaque material.9


   Footnotes
 
Presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, May 2002.

Supported by National Eye Institute EY02698; unrestricted departmental and Physician-Scientist awards from Research to Prevent Blindness, Inc., New York; and the Ocular Physiology Research and Education Foundation.

Submitted for publication January 27, 2004; revised March 9 and 15, 2004; accepted March 20, 2004.

Disclosure: B.T. Gabelt, None; E.A. Hennes, None; J.L. Seeman, None; B. Tian, None; P.L. Kaufman (P)

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Paul L. Kaufman, Department Ophthalmology and Visual Sciences, 600 Highland Ave, F4/328 CSC, Madison, WI 53792-3220; kaufmanp{at}mhub.ophth.wisc.edu.


   References
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 Abstract
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 References
 

  1. Kolker AE, Hetherington J, Jr. Primary open-angle glaucoma. Klein EA eds. Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas. 1983; 5th ed. 231–257. CV Mosby St. Louis.
  2. Lütjen-Drecoll E, Kaufman P. Biomechanics of echothiophate-induced anatomic changes in monkey aqueous outflow system. Graefes Arch Clin Exp Ophthalmol. 1986;224:564–575.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  3. Erickson-Lamy KA, Polansky JR, Kaufman PL, Zlock DM. Cholinergic drugs alter ciliary muscle response and receptor content. Invest Ophthalmol Vis Sci. 1987;28:375–383.[Abstract/Free Full Text]
  4. Croft MA, Kaufman PL, Erickson-Lamy KA, Polansky JR. Accommodation and ciliary muscle muscarinic receptors after echothiophate. Invest Ophthalmol Vis Sci. 1991;32:3288–3297.[Abstract/Free Full Text]
  5. Kaufman PL. Anticholinesterase-induced cholinergic subsensitivity in primate accommodative mechanism. Am J Ophthalmol. 1978;85:622–631.[Web of Science][Medline][Order article via Infotrieve]
  6. Kaufman PL, Bárány EH. Subsensitivity to pilocarpine of the aqueous outflow system in monkey eyes after topical anticholinesterase treatment. Am J Ophthalmol. 1976;82:883–891.[Web of Science][Medline][Order article via Infotrieve]
  7. Tian B, Kaufman PL, Volber T, Gabelt BT, Geiger B. H-7 disrupts the actin cytoskeleton and increases outflow facility. Arch Ophthalmol. 1998;116:633–643.[Abstract/Free Full Text]
  8. Tian B, Gabelt BT, Peterson JA, Kiland JA, Kaufman PL. H-7 increases trabecular facility and facility after ciliary muscle disinsertion in monkeys. Invest Ophthalmol Vis Sci. 1999;40:239–242.[Abstract/Free Full Text]
  9. Lütjen-Drecoll E, Shimuzu R, Rohrbach M, Rohen JW. Quantitative analysis of "plaque material" in the inner and outer wall of Schlemm’s canal in normal and glaucomatous eyes. Exp Eye Res. 1986;42:443–455.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  10. Lütjen-Drecoll E, Kaufman PL. Echothiophate-induced structural alterations in the anterior chamber angle of the cynomolgus monkey. Invest Ophthalmol Vis Sci. 1979;18:918–929.[Abstract/Free Full Text]
  11. Gabelt BT, Kaufman PL. Cholinergic drugs. Netland PA Allen RC eds. Glaucoma Medical Therapy. Principles and Management. Ophthalmology Monograpahs #13. 1999;77–97. The Foundation of the American Academy of Ophthalmology San Francisco.
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  13. Kaufman PL, Bárány EH. Subsensitivity to pilocarpine in primate ciliary muscle following topical anticholinesterase treatment. Invest Ophthalmol. 1975;14:302–306.[Abstract/Free Full Text]
  14. Bárány EH. Simultaneous measurements of changing intraocular pressure and outflow facility in the vervet monkey by constant pressure infusion. Invest Ophthalmol. 1964;3:135–143.
  15. Kiland JA, Croft MA, Gabelt BT, Kaufman PL. Atropine reduces but does not eliminate the age-related decline in perfusion outflow facility in monkeys. Exp Eye Res. 1997;64:831–835.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  16. Tian B, Peterson JA, Gabelt BT, Geiger B, Kaufman PL. The actin cytoskeleton and aqueous outflow. Gramer E Grehn F eds. Pathogenesis and Risk Factors of Glaucoma. 1999;117–122. Springer-Verlag Berlin.
  17. Sabany I, Gabelt BT, Tian B, Kaufman PL, Geiger B. H-7 effects on structure and fluid conductance of monkey trabecular meshwork. Arch Ophthalmol. 2000;118:955–962.[Abstract/Free Full Text]
  18. Kaufman PL, Gabelt BT. Aging, accommodation and outflow facility. Lütjen-Drecoll E eds. Basic Aspects of Glaucoma Research III. 1993;257–274. Schattauer Stuttgart, Germany.
  19. Gabelt BT, Crawford K, Kaufman PL. Outflow facility and its response to pilocarpine decline in aging rhesus monkeys. Arch Ophthalmol. 1991;109:879–882.[Abstract/Free Full Text]




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