 |
|
Effects of Topical H-7 on Outflow Facility, Intraocular Pressure, and Corneal Thickness in Monkeys
Baohe Tian, MD;
Rong-Fang Wang, MD;
Steven M. Podos, MD;
Paul L. Kaufman, MD
Arch Ophthalmol. 2004;122:1171-1177.
ABSTRACT
| |
Objectives To determine if low concentrations of H-7 (1-[5-isoquinoline sulfonyl]-2-methyl piperazine) topically applied to the eye increases outflow facility and decreases intraocular pressure (IOP) without affecting the cornea in monkeys, and to evaluate if the effect of H-7 on IOP is pressure dependent.
Methods Single or multiple doses of 5% H-7 or vehicle (20 µL) were administered topically to opposite eyes of normal monkeys. A single dose of 2% H-7 or vehicle (50 µL) was administered to the glaucomatous eye of monkeys with laser-induced unilateral glaucoma, with vehicle on day 1 and H-7 on day 2.
Results In normotensive eyes, 1 dose of 5% H-7 maximally decreased IOP by a mean ± SEM of 2.5 ± 1.0 mm Hg (–16.7% ± 5.5%) at 3 hours. Higher baseline IOP and repeated dosing were associated with greater IOP reduction. Outflow facility was increased, but central corneal thickness was not affected. In glaucomatous eyes, 1 dose of 2% H-7 maximally decreased IOP by a mean ± SEM of 5.8 ± 0.6 mm Hg (–16.9% ± 1.6%) at 2 hours.
Conclusions Five percent H-7 increases outflow facility and decreases IOP, but does not affect corneal thickness. Multiple doses of H-7 induce greater reduction of IOP than a single dose. The effect of H-7 on IOP may be pressure dependent.
Clinical Relevance Multiple topical treatments with low doses of H-7 or analogues may substantially reduce outflow resistance in the hypertensive eye without meaningfully affecting the cornea.
INTRODUCTION
The serine-threonine kinase inhibitor H-7 (1-[5-isoquinoline sulfonyl]-2-methyl piperazine) inhibits actomyosin-driven contractility, probably by inhibiting myosin light chain kinase or rho kinase. This leads to deterioration of the actin microfilament system and perturbation of its membrane anchorage and to loss of stress fibers and focal contacts in many types of cultured cells, including human trabecular cells.1-7 H-7 administered intracamerally or topically to living cynomolgus monkeys increases outflow facility and decreases intraocular pressure (IOP)5 by a mechanism independent of the ciliary muscle, presumably acting directly on the trabecular meshwork (TM).8 A morphological study9 of the TM in the live monkey eye indicates that H-7 reduces TM cell contractility, thereby "relaxing" the trabecular outflow pathway, expanding the draining surface, and facilitating flow through the meshwork. Because the effect of H-7 on outflow resistance is pressure dependent,5 it is assumed that H-7 may be more effective in the glaucomatous eye with elevated IOP. However, 20 µL of 400 mM H-7 (approximately 15%) administered topically, which decreases IOP in living monkeys,5 also produces transient changes in corneal endothelial cells and corneal thickness when applied to the central cornea as 4 drops of 5-µL volume.10 Presumably, multiple treatments with the high concentration of H-7 may induce more apparent adverse effects in the cornea.
We hypothesized that repetitive lower concentrations and total doses in higher volumes, spread out over the entire corneal or conjunctival surface in the larger human eye, might minimize or avoid corneal toxicity induced by high concentrations of H-7 without attenuating its effect on outflow resistance, especially in the hypertensive eye.10 To test this hypothesis, we determined the effects of single or multiple doses of 5% topical H-7 on outflow facility, IOP, and corneal thickness in normotensive monkey eyes, as well as the effect of a single dose of 2% topical H-7 on IOP in laser-induced ocular hypertensive monkey eyes.
METHODS
ANIMALS AND ANESTHESIA
Thirty-two adult cynomolgus monkeys (Macaca fascicularis) of both sexes, weighing 2 to 5 kg, were involved in this study. All experiments were conducted in accord with the University of Wisconsin–Madison Medical School and Mount Sinai School of Medicine institutional animal care and use committees, with the National Institutes of Health guidelines, and with the Association for Research in Vision and Ophthalmology Statement on the Use of Animals in Ophthalmic and Vision Research. Five percent H-7 was used in 24 normotensive monkeys studied at the University of Wisconsin–Madison Medical School as 4 groups (groups 1-4); 3 monkeys were included in both group 1 and group 3, and 2 monkeys were included in both group 1 and group 4. Monkeys in group 3 had undergone prior anterior chamber (AC) perfusions, but not within the preceding 5 to 6 weeks. Monkeys in group 4 had higher baseline IOP (mean IOP, 16 mm Hg) under ketamine hydrochloride (hereafter ketamine) anesthesia in both eyes compared with most of the normal cynomolgus monkeys. Two percent H-7 was used in 8 monkeys with unilateral ocular hypertension (mean IOP, 30-35 mm Hg) induced by repeated argon or diode laser photocoagulation of the TM11 studied at the Mount Sinai School of Medicine as group 5. The glaucomatous monkeys had not received any treatment for at least 2 weeks before the testing. All monkeys were free of aqueous humor cells and flare as assessed by slitlamp biomicroscopy. In normal monkeys, anesthesia for tonometry or pachymetry was induced with intramuscular ketamine (10 mg per kilogram of body weight) and maintained with supplemental intramuscular injections as required (usually 5 mg/kg every 30-45 minutes). Anesthesia for AC perfusion was induced with intramuscular ketamine (10 mg/kg), followed by intravenous pentobarbital sodium (15 mg/kg). In glaucomatous monkeys, anesthesia for tonometry was induced with intramuscular ketamine (2-5 mg/kg), with 1 drop of 0.5% proparacaine hydrochloride applied topically 5 minutes before tonometry.
DRUG PREPARATION AND ADMINISTRATION
H-7 was obtained from Sigma-Aldrich Corporation (St Louis, Mo). Five percent H-7 was freshly dissolved for topical administration in isotonic sodium chloride alone or with 25% dimethyl sulfoxide (1 mg/20 µL); isotonic sodium chloride with (group 3) or without (groups 1, 2, and 4) 25% dimethyl sulfoxide served as a vehicle control. The pH (tested by pH paper) of 5% H-7 in isotonic sodium chloride was approximately 2 to 3 (adjustment of pH with sodium hydroxide reduces solubility of H-7). To increase the pH of 5% H-7, we dissolved the drug in 25% dimethyl sulfoxide with isotonic sodium chloride in group 3. Twenty-five percent dimethyl sulfoxide seemed to improve the solubility of H-7 when the pH was slightly elevated (eg, approximately 3-4). Two percent H-7 was freshly prepared in isotonic sodium chloride (1 mg/50 µL), and isotonic sodium chloride served as a vehicle control. Administrations of H-7 or vehicle in the different groups are shown in Table 1. For normal monkeys, H-7 or vehicle (4 x 5 µL) was administered topically to the central cornea of the supine monkey under ketamine anesthesia for tonometry and pachymetry or was administered topically to the superior cornea of the prone monkey under pentobarbital sodium for perfusion.5 To reduce any potential cumulative effect of repeated ketamine anesthesia on IOP or outflow facility during the multiple treatments, some doses of H-7 or vehicle were administered topically to fully conscious and manually restrained monkeys, with fewer and larger drops (2 x 10 µL) applied because of the limited cooperative period from conscious monkeys. For glaucomatous monkeys, H-7 or vehicle (2 x 25 µL) was administered topically to the central cornea in a manner similar to that in ketamine-anesthetized normal monkeys.
|
|
|
|
Table 1. Protocol Description*
|
|
|
IOP MEASUREMENT
In normal monkeys, IOP was determined with a minified Goldmann applanation tonometer,12 using fluorescein as the tear film indicator, with the monkey lying prone in a head holder. For each eye, 3 IOP readings were averaged as a baseline before administration of H-7 or vehicle, and single IOP readings were taken after the drug or vehicle administration at different time points (Table 1). In glaucomatous monkeys, IOP was determined with a calibrated pneumatonometer (model 30 classic; Mentor Inc, Norwell, Mass).
OUTFLOW FACILITY AND OUTFLOW RATE MEASUREMENT
Total outflow facility was determined in normotensive monkeys of group 3 by 2-level constant pressure (approximately 15 or 25 mm Hg) perfusion of the AC with Bárány mock aqueous humor,13 using a 1-needle technique and correcting for internal apparatus resistance (Table 1 and Table 2).14
|
|
|
|
Table 2. Effect of Multiple Treatments With 5% Topical H-7 on Outflow Facility and Outflow Rate*
|
|
|
CORNEAL THICKNESS MEASUREMENT
Central corneal thickness was determined in normal monkeys (group 1) by ultrasonic pachymetry (DGH-1000 ultrasonic pachymeter; DGH Technology, Inc, Solana Beach, Calif). For each eye, 3 readings taken 3 or 5 days before the first dose of 5% H-7 or vehicle were averaged as a baseline. A single value was taken before the fifth treatment; after the fifth treatment, measurements were taken every 30 minutes for 4 hours and then hourly for 2 hours.
SLITLAMP EXAMINATION
In normal monkeys, slitlamp biomicroscopy was performed before drug administration, during IOP measurement (1, 3, and 6 hours after drug administration), and before pachymetry and AC perfusion. In glaucomatous monkeys, slitlamp examination was performed before and 1, 3, and 5 hours after drug administration. The integrity of the corneal epithelium and endothelium, the presence of flare or cells in the AC, and the clarity of lens were noted. All normal animals were free of preexisting ocular abnormalities when studied. All glaucomatous monkeys were free of aqueous humor flare and cells when studied.
DATA ANALYSIS
Data are given as mean ± SEM for the number of eyes or animals. In normal monkeys (groups 1-4), comparisons were made using the 2-tailed paired t test for differences vs 0.0 or for ratios vs 1.0 (predrug or postdrug treated vs contralateral control, postdrug or postvehicle vs ipsilateral baseline, and baseline-corrected postdrug treated vs control). In glaucomatous monkeys (group 5), IOP difference between day 1 (vehicle) and day 2 (H-7) in the ocular hypertensive eye was tested by the 2-tailed paired t test.
RESULTS
INTRAOCULAR PRESSURE
Intraocular pressure changes from 1 to 6 hours after H-7 or vehicle in the different groups are shown in Figure 1, Figure 2, and Figure 3. Maximal IOP reductions after H-7 in the different groups are shown in Table 3.
|
|
|
|
Table 3. Effect of Topical H-7 on Intraocular Pressure (IOP) in Monkeys*
|
|
|
OUTFLOW FACILITY AND OUTFLOW RATE
In group 3 (normal monkeys), H-7 significantly increased outflow facility by 77% ± 32% (n = 8, P<.05) during the overall 90-minute perfusion beginning 1 hours after the seventh dose, adjusted for outflow facility before the seventh dose (baseline) and contralateral control eye washout (Table 1 2). Outflow rate at 25 mm Hg during baseline or postdrug measurement was higher than that at 15 mm Hg in the H-7–treated eye and the contralateral control eye. The increase of outflow rate in the H-7–treated eye at 25 mm Hg was similar to that at 15 mm Hg, after adjustment for baseline and contralateral control eye washout.
CORNEAL THICKNESS
Central corneal thicknesses at baseline and before the fifth treatment were 456.3 ± 15.6 and 469.8 ± 15.7 µm, respectively, in the H-7–treated eye and 449.7 ± 14.8 and 456.2 ± 15.1 µm, respectively, in the contralateral control eye. The central corneal thickness after the fifth treatment varied between 455.8 ± 17.9 and 471.0 ± 15.6 µm in the H-7–treated eye and between 449.2 ± 13.2 and 461.7 ± 14.4 µm in the contralateral control eye during 6-hour pachymetry. No significant difference in the central corneal thickness between eyes was observed at any indicated time (P>.60), after adjustment for ipsilateral baseline (Figure 4).
|
|
|
|
Figure 4. A, Effect of 5 doses of 5% H-7 on central corneal thickness in normal monkeys (group 1). The fifth dose of H-7 or vehicle was given in opposite eyes at time 0. B, Change in central corneal thickness. Data are given as mean ± SEM micrometers for the number of animals (n = 6 rather than 7 because of the exclusion of 1 monkey in which a central corneal epithelial defect had occurred in the cage between the second and the third treatments, accompanied by corneal cloudiness and edema). BL indicates baseline; dashed line, no difference between the H-7–treated eye and the vehicle-treated eye; and slashes, BL was not measured 1 hour or immediately before the drug administration (it was determined 3-5 days before the drug administration. See the "Methods" section). No significant difference between eyes was observed at any time.
|
|
|
SLITLAMP EXAMINATION
During IOP measurement in normal monkeys, most monkeys in groups 1, 2, and 4 had mild punctate corneal epithelial defects (PCEDs) in both eyes, but the defects in H-7–treated eyes were slightly more apparent than in control eyes (Table 4). Two monkeys (one in group 1 and another in group 2) that had shown continuous nystagmus under ketamine anesthesia during IOP measurement had a small epithelial defect in the central cornea of the H-7–treated eye at the end of tonometry. The monkey in group 2, but not the one in group 1, had corneal cloudiness and edema 2 days later. Another monkey in group 1 that had shown some PCEDs during tonometry on day 1 had a central corneal epithelial defect before the third treatment on day 2 (presumably occurring in the cage) and corneal cloudiness and edema on day 3. However, the cornea was normal for all monkeys approximately 16 hours after the sixth dose of H-7 in group 2 (before tonometry) and group 3 (before AC perfusion). In addition, the PCEDs seen during tonometry earlier had disappeared or significantly decreased in both eyes of most monkeys approximately 16 hours after the fourth dose (before pachymetry) in group 1. No other abnormality was observed in any monkey in any protocol during slitlamp examination in groups 1, 2, and 4. In glaucomatous monkeys (group 5), 1 of 8 ocular hypertensive eyes had mild PCEDs 3 and 5 hours after drug administration.
|
|
|
|
Table 4. Results of Punctate Corneal Epithelial Defects (PCEDs) by Slitlamp Examination*
|
|
|
COMMENT
This study showed that single and multiple doses of 5% H-7 decrease IOP in normotensive monkeys, with multiple doses producing greater IOP reduction. This additive effect of multiple treatments occurs with many antiglaucoma drugs in normotensive15-16 and glaucomatous17-18 monkeys. In the present study, IOP reduction after H-7 in normal monkeys with higher baseline IOP (mean IOP, 17 mm Hg) was greater than that in monkeys with lower baseline IOP (mean IOP, approximately 13 mm Hg), consistent with higher outflow rate at 25 mm Hg than at 15 mm Hg during perfusion. This, in conjunction with previous findings,5, 9, 19 suggests that H-7 decreases IOP by reducing outflow resistance in the TM and that the effect of H-7 on outflow resistance is pressure dependent. The similarity of outflow rates as defined by the double ratios ([H-7/Baseline] / [Vehicle/Baseline]) at 25 and 15 mm Hg indicates that the perfusion-induced resistance washout during bilateral baseline and contralateral postvehicle measurements is also pressure dependent. One can reasonably hypothesize that still lower concentrations of H-7 in the hypertensive eye may show the same or stronger effect as 5% H-7 does in normotensive monkeys. As previously hypothesized,10 lower concentrations and total doses in higher volumes might minimize or avoid corneal toxicity induced by high concentrations of H-7.
To test these hypotheses, a single dose of 50 µL of 2% H-7 was applied in laser-induced hypertensive eyes. Fifty microliters of 2% H-7 in glaucomatous eyes produced a similar IOP reduction compared with 20 µL of 5% H-7 in the normotensive eyes of group 1 (–16.9% vs –16.7%). However, compared with the normotensive eyes of group 4, which had higher baseline IOP, the maximal IOP reduction in the glaucomatous eyes after 50 µL of 2% H-7 was smaller than that in the normal eyes after 20 µL of 5% H-7 (–16.9% vs –24.8%). Although 50 µL of 2% H-7 contains the same amount of H-7 (1 mg) as 20 µL of 5% H-7, the former may be less effective than the latter when administered topically in the monkey eye because the 50-µL volume far exceeds the capacity of the monkey's cul-de-sac, so that some of the drug may overflow during the application. This may reduce the amountof drug penetrating into the eye and, in turn, the concentration of the drug in the AC. This speculation is in agreement with previous studies20-22 in which the bioavailability of topical medications can be increased by decreasing the volume of eyedrops. In addition, laser-induced structural changes in outflow pathway may cause the absence of an expected baseline pressure–dependent IOP reduction in the glaucomatous eye. Based on previous studies,23-26 laser photocoagulation of the TM induces scar tissue formation and decreases normal cells in the outflow pathway, which increases the tissue's stiffness and limits its relaxation after H-7. Therefore, although most clinical and investigational ocular hypotensive agents are more effective in the laser glaucomatous monkey model than in the normotensive monkey eye, it may not be so for cytoskeletal drugs (eg, H-7) that increase outflow facility by inhibiting cellular contractility in the TM and inner wall of Schlemm canal. Given the fact that 5% H-7 produced greater IOP reduction in group 4 than in group 1, H-7 might produce greater ocular hypotension in non–laser-induced glaucoma models in the monkey eye (eg, steroid-induced glaucoma27-29) or in glaucomatous human eyes in which anatomy is relatively undisturbed. Further studies are needed to clarify this issue.
Unlike a single topical dose of approximately 15% H-7 (2.9 mg/20 µL),10 5 doses of 5% H-7 (1 mg/20 µL) given topically did not significantly increase the central corneal thickness. This indicates that the 5% concentration of the drug does not significantly affect the corneal endothelium. As assessed by slitlamp biomicroscopy, 5% H-7 is also less toxic to the corneal epithelium.10 Mild PCEDs in both eyes are a common phenomenon during tonometry in ketamine-anesthetized animals and may be due to reduced blinking under ketamine anesthesia and frequent IOP measurements. However, compared with the contralateral control eyes, the slightly more apparent PCEDs in the H-7–treated eyes indicate that 5% H-7 may still mildly affect the corneal epithelium in living monkey eyes. Two monkeys that had a central corneal epithelial defect during tonometry had had continuous vertical nystagmus after ketamine anesthesia. This suggests that 5% H-7 could render the cornea more susceptible to mechanical damage (eg, frequent contact by the moving eye with the tip of the Goldmann applanation tonometer). Similarly, touching the eye by hand because of an uncomfortable feeling following drug treatment and tonometry may be responsible for one monkey's developing a central corneal epithelial defect in its cage. However, this study shows that multiple doses of 5% H-7 seem to have no effect on the cornea as seen by slitlamp examination when the cornea is untouched. In addition, a single dose of 2% H-7 (1 mg/50 µL) did not apparently affect the corneal epithelium as assessed by slitlamp examination in glaucomatous monkeys, compared with a single dose of 5% H-7 (1 mg/20 µL) in normal monkeys. This seems to support the hypothesis from a previous study10 that repetitive lower concentrations and total doses in higher volumes, spread out over the entire corneal or conjunctival surface, may minimize or avoid corneal toxicity.
AUTHOR INFORMATION
| |
Correspondence: Paul L. Kaufman, Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison Medical School, Room F4/328, Clinical Science Center, Mail Stop 3220, 600 Highland Ave, Madison, WI 53792-3284 (kaufmanp{at}mhub.ophth.wisc.edu).
Submitted for publication May 28, 2003; final revision received November 24, 2003; accepted January 21, 2004.
This study was supported by grant EY02698 from the National Eye Institute, Bethesda, Md (Dr Kaufman); core grant EY01867 from Mount Sinai School of Medicine; Glaucoma Research Foundation, San Francisco, Calif (Dr Kaufman); Research to Prevent Blindness, New York, NY (Drs Kaufman and Podos); University of Wisconsin–Madison Alumni Research Foundation (Dr Kaufman); Ocular Physiology Research and Education Foundation, Madison (Dr Kaufman); and May and Samuel Rudin Family Foundation, New York (Dr Podos).
From the Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison Medical School (Drs Tian and Kaufman); and Department of Ophthalmology, Mount Sinai School of Medicine, New York, NY (Drs Wang and Podos). Dr Kaufman has a proprietary interest in a patent related to H-7, which is held by the University of Wisconsin–Madison Alumni Research Foundation.
REFERENCES
1. Birrell GB, Hedberg KK, Habliston DL, Griffith OH. Protein kinase C inhibitor H-7 alters the actin cytoskeleton of cultured cells. J Cell Physiol. 1989;141:74-84.
FULL TEXT
|
ISI
| PUBMED
2. Bershadsky A, Chausovsky A, Becker E, Lyubimova A, Geiger B. Involvement of microtubules in the control of adhesion-dependent signal transduction. Curr Biol. 1996;6:1279-1289.
FULL TEXT
|
ISI
| PUBMED
3. Yu JC, Gotlieb AI. Disruption of endothelial actin microfilaments by protein kinase C inhibitors. Microvasc Res. 1992;43:100-111.
FULL TEXT
|
ISI
| PUBMED
4. Volberg T, Geiger B, Citi S, Bershadsky AD. Effect of protein kinase inhibitor H-7 on the contractility, integrity, and membrane anchorage of the microfilament system. Cell Motil Cytoskeleton. 1994;29:321-338.
FULL TEXT
|
ISI
| PUBMED
5. Tian B, Kaufman PL, Volberg T, Gabelt BT, Geiger B. H-7 disrupts the actin cytoskeleton and increases outflow facility. Arch Ophthalmol. 1998;116:633-643.
FREE FULL TEXT
6. Gills JP, Roberts BC, Epstein DL. Microtubule disruption leads to cellular contraction in human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 1998;39:653-658.
FREE FULL TEXT
7. Liu X, Cai S, Glasser A, et al. Effects of H-7 on cultured human trabecular meshwork cells. Mol Vision. 2001;7:145-153. Available at: http://www.molvis.org/molvis/v7/a21/. Accessed May 20, 2004.
ISI
| PUBMED
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.
FREE FULL TEXT
9. Sabanay 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.
FREE FULL TEXT
10. Tian B, Sabanay I, Peterson JA, Hubbard WC, Geiger B, Kaufman PL. Acute effects of H-7 on ciliary epithelium and corneal endothelium in monkey eyes. Curr Eye Res. 2001;22:109-120.
FULL TEXT
|
ISI
| PUBMED
11. Wang RF, Schumer RA, Serle JB, Podos SM. A comparison of argon laser and diode laser photocoagulation of the trabecular meshwork to produce the glaucoma monkey model. J Glaucoma. 1998;7:45-49.
ISI
| PUBMED
12. Kaufman PL, Davis GE. Minified Goldmann applanating prism for tonometry in monkeys and humans. Arch Ophthalmol. 1980;98:542-546.
FREE FULL TEXT
13. Bárány EH. Simultaneous measurement of changing intraocular pressure and outflow facility in the vervet monkey by constant pressure infusion. Invest Ophthalmol. 1964;3:135-143.
14. Bárány EH. Relative importance of autonomic nervous tone and structure as determinants of outflow resistance in normal monkey eyes (Cercopithecus ethiops and Macaca irus). In: Rohen JW, ed. The Structure of the Eye: Second Symposium. Stuttgart, Germany: FK Schattauer Verlag; 1965:223-236.
15. Crawford K, Kaufman PL, Gabelt BT. Effects of topical PGF2 alpha on aqueous humor dynamics in cynomolgus monkeys. Curr Eye Res. 1987;6:1035-1044.
ISI
| PUBMED
16. Tian B, Gabelt BT, Crosson CE, Kaufman PL. Effects of adenosine agonists on intraocular pressure and aqueous humor dynamics in cynomolgus monkeys. Exp Eye Res. 1997;64:979-989.
FULL TEXT
|
ISI
| PUBMED
17. Serle JB, Podos SM, Kitazawa Y, Wang RF. A comparative study of latanoprost (Xalatan) and isopropyl unoprostone (Rescula) in normal and glaucomatous monkey eyes. Jpn J Ophthalmol. 1998;42:95-100.
FULL TEXT
| PUBMED
18. Wang RF, Camras CB, Lee PY, Podos SM, Bito LZ. Effects of prostaglandins F2 alpha, A2, and their esters in glaucomatous monkey eyes. Invest Ophthalmol Vis Sci. 1990;31:2466-2470.
ABSTRACT
19. Sabanay I, Tian B, Gabelt BT, Geiger B, Kaufman PL. Functional and structural reversibility of H-7 effects on the conventional aqueous outflow pathway in monkeys. Exp Eye Res. 2004;78:137-150.
FULL TEXT
|
ISI
| PUBMED
20. Chrai SS, Robinson JR. Corneal permeation of topical pilocarpine nitrate in the rabbit. Am J Ophthalmol. 1974;77:735-739.
ISI
| PUBMED
21. Patton TF. Pharmacokinetic evidence for improved ophthalmic drug delivery by reduction of instilled volume. J Pharm Sci. 1977;66:1058-1059.
FULL TEXT
|
ISI
| PUBMED
22. File RR, Patton TF. Topically applied pilocarpine: human pupillary response as a function of drop size. Arch Ophthalmol. 1980;98:112-115.
FREE FULL TEXT
23. March WF, Gherezghiher T, Koss M, Nordquist R. Ultrastructural and pharmacologic studies on laser-induced glaucoma in primates and rabbits. Lasers Surg Med. 1984;4:329-335.
ISI
| PUBMED
24. Melamed S, Pei J, Epstein DL. Delayed response to argon laser trabeculoplasty in monkeys. Arch Ophthalmol. 1986;104:1078-1083.
FREE FULL TEXT
25. Melamed S, Epstein DL. Alterations of aqueous humour outflow following argon laser trabeculoplasty in monkeys. Br J Ophthalmol. 1987;71:776-781.
FREE FULL TEXT
26. Dietlein TS, Jacobi PC, Schroder R, Krieglstein GK. Experimental erbium:YAG laser photoablation of trabecular meshwork in rabbits: an in-vivo study. Exp Eye Res. 1997;64:701-706.
FULL TEXT
|
ISI
| PUBMED
27. Melena J, Santafe J, Segarra J. Betamethasone-induced ocular hypertension in rabbits. Methods Find Exp Clin Pharmacol. 1997;19:553-558.
ISI
| PUBMED
28. Bhattacherjee P, Paterson CA, Spellman JM, Graff G, Yanni JM. Pharmacological validation of a feline model of steroid-induced ocular hypertension. Arch Ophthalmol. 1999;117:361-364.
FREE FULL TEXT
29. Hester DE, Trites PN, Peiffer RL, Petrow V. Steroid-induced ocular hypertension in the rabbit. J Ocul Pharmacol. 1987;3:185-189.
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Effects of Topical Administration of Y-39983, a Selective Rho-Associated Protein Kinase Inhibitor, on Ocular Tissues in Rabbits and Monkeys
Tokushige et al.
IOVS 2007;48:3216-3222.
ABSTRACT
| FULL TEXT
|
, P<.03; 
, P<.02; 
, P<.01; ||, P<.005; and ¶, P<.001.
