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   Table of Contents      
ORIGINAL ARTICLE
Year : 1994  |  Volume : 42  |  Issue : 3  |  Page : 149-152

Effect of U74006F (Tirilazad Mesylate) in rabbit eyes after argon laser trabeculoplasty


1 University of Illinois, Chicago, UIC Eye Center 1855 W.Taylor, Chicago, Illionois, USA
2 Wilmer Eye Institute, Johns Hopkins, Baltimore, USA

Correspondence Address:
Richard G Fiscella
UIC Eye Center, 1855 W.Taylor, Chicago, IL 60612
USA
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Source of Support: None, Conflict of Interest: None


PMID: 7829179

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  Abstract 

A new free radical scavenger, U74006F (Upjohn Company, Kalamazoo, MI, USA) was studied to determine if it would have a beneficial effect on preventing intraocular pressure (IOP) spikes and reducing blood-aqueous barrier (BAB) breakdown in rabbits after argon laser trabeculoplasty (ALT). The post-ALT IOP averaged 24.7 mm Hg (+/- 3.8 mm Hg; N = 6) and 30.3 mm Hg (+/- 6.9 mm Hg; N = 7) at 1 hour (p = 0.097) and 22.7 mm Hg (+/- 1.9) and 27.3 mm Hg (+/- 7.0 mm Hg) at 3 hours in the U74006F and vehicle groups (p = 0.137), respectively. By 48 hours, the IOP averaged 12.8 +/- 2.2 mm Hg in the U74006F group and 12.4 +/- 2.4 mm Hg in the vehicle group (P = 0.757). The aqueous fluorescein permeability (AFP) between lasered and unlasered eyes was determined for the U74006F and vehicle-treated groups by aqueous fluorophotometry. Prelaser or baseline AFP was determined for the U74006F (-0.236 +/- 0.236) and vehicle (-0.145 +/- 0.237) groups (p = 0.505). At day 2 posttreatment, the U74006F group and the placebo group both reported similar AFP of 5.109 +/- 4.831 and 5.680 +/- 4.280 (p = 0.827), respectively. At one week post-ALT, AFP for the U74006F group (0.109 +/- 0.367) had returned close to baseline, while that of the vehicle group (0.426 +/- 0.511) was still quite elevated (p = 0.220). U74006F appears to be beneficial in the prevention of acute elevation of IOP following ALT but not in the prevention of Blood-Aqueous Barrier (BAB) breakdown.

Keywords: Intraocular pressure- Free radical scavengers - Blood-aqueous barrier--Argon laser trabeculoplasty - U74006F


How to cite this article:
Fiscella RG, Asrani S G, Hillman D S, Rusin M M, Le H. Effect of U74006F (Tirilazad Mesylate) in rabbit eyes after argon laser trabeculoplasty. Indian J Ophthalmol 1994;42:149-52

How to cite this URL:
Fiscella RG, Asrani S G, Hillman D S, Rusin M M, Le H. Effect of U74006F (Tirilazad Mesylate) in rabbit eyes after argon laser trabeculoplasty. Indian J Ophthalmol [serial online] 1994 [cited 2020 Oct 31];42:149-52. Available from: https://www.ijo.in/text.asp?1994/42/3/149/25570



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The use of ophthalmic lasers has been associated with various ocular side effects, especially increased intraocular pressure and a significant intraocular inflammatory response. [1],[2],[3] Although the mechanisms of action are not fully understood, it is believed that at least three key factors are responsible for these side effects. The release of prostaglandins' with resulting blood-ocular barrier breakdown is believed to be one of the main factors. The release of other inflammatory mediators, such as macrophages, lymphocytes [2] etc., is also believed to contribute. The final factor is the production of free radicals [4][5][6] from laser irradiation of tissues.

The 21-aminosteriods, a series of new compounds with unique free radical scavenging properties, [7][8][9] may be able to prevent or significantly reduce intraocular pressure spikes and postlaser inflammation through a few different mechanisms of action. They are known to inhibit inflammatory cells, such as macrophages, from producing free radicals. Finally, by scavenging free radicals released from the destruction of tissue and by inhibiting lipid peroxidation, they help to preserve endogenous vitamin E levels.

Our study evaluated the effectiveness of the 21­aminosteroid, U74006F on: 1. the prevention of postlaser intraocular inflammation; 2. inhibition of the breakdown of the blood-aqueous barrier; and 3. the prevention of postlaser intraocular pressure increase.

Investigators have utilized a single session of argon laser to the area in the rabbit eye corresponding to the trabecular meshwork of humans to produce elevated intraocular pressure responses. [10][11] They concluded that this model may prove to be beneficial for evaluating antiglaucoma medications.

We evaluated the effect of U74006F, a new free radical scavenger, in reducing intraocular pressure spikes and inflammation after ALT in rabbits.


  Materials and methods Top


Fourteen Dutch belted pigmented rabbits of either sex weighing 1.5 to 2.5 kg each were utilized for this experiment. The rabbit experimentation was conducted as noted in the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Each rabbit was anaesthetized with a mixture of ketamine (25 mg/kg), acepromazine (0.5 mg/kg), and atropine sulfate (0.2 mg/kg). Each rabbit received ALT in the right eye only, while the left eye served as control. The lasered eye received 240 spots of 50 micron size in the anterior chamber angle with the argon laser (Coherent) at a setting of 1.6 watts of power at a 0.1 second pulse.

The rabbits randomly received either placebo vehicle or U74006F 15 to 30 minutes prior to ALT (loading dose of 3 mg/kg) and a repeat dose (1.5 mg/kg) 3 hours post-ALT.

The rabbits were given baseline fluorophotometry measurements using the Fluorotron Master [TM ] (Coherent Medical), a minimum of 5 days prior to argon laser trabeculoplasty. A baseline scan was performed on each animal prior to the sodium fluorescein injection. Fluorescein (33 mg/kg) was then injected through the rabbit marginal ear vein. Blood samples were obtained (in heparinized capillary tubes) from the fellow ear at 5, 40, and 60 minutes after the fluorescein injection, centrifuged with the plasma diluted 400, 200 and 100 times, respectively, and the samples read. Fluorophotometry scans were performed at 15, 40, and 60 minutes after fluorescein injection. Repeat fluorophotometry measurements were obtained on days 2 and 7 after ALT. The penetration ratio (fluorescein in the eye versus the plasma) was analyzed as the change in permeability of fluorescein in both the lasered and control eyes at day 2 and I week post-ALT compared to baseline. The fluorescein plasma integral (FPI) was calculated using the Coherent "log-log" plasma programme and plasma fluorescein sample measurements. [12]

Intraocular pressure was measured in both eyes by pneumotonometry (Alcon Pneumotonometer R) prior to ALT (baseline) and at 0.5, 1, 3, 24 hours and I week post-ALT in both eyes.

Assessment of the anterior chamber flare and cell by slit-lamp examination was done prior to ALT and after ALT at 1, 3, and 24 hours, and 1 week.


  Results Top


One rabbit died (U74006F) related to anaesthesia administration, and was deleted from the evaluation.

Cell and Flare

Anterior chamber flare and cell appeared minimal in both groups. The flare and cell assessment by slit­lamp examination was not beneficial in determining the amount of anterior chamber inflammation.

Aqueous Fluorescein Permeability

The aqueous fluorescein permeability (AFP) between lasered and unlasered eyes was determined for U74006F and vehicle-treated groups by aqueous fluorophotometry [Table - 1].

Prelaser AFP varied little between the U74006F (-0.236 ± 0.236) and vehicle (-0.145 ± 0.237) groups (p=0.505). The AFP at 48 hours was 5.109 ± 4.831 and 5.680 ± 4.280 for the U74006F and vehicle groups, respectively (p=0.827). At one week post-ALT, the AFP for the U74006F group (0.109 ± 0.367) had returned close to baseline, while that for the vehicle group (0.426 ± 0.511) was still elevated (p=0.22).

Intraocular Pressure

Baseline IOPs in both groups of rabbits were 17.6 ± 1.0 mm Hg and 17.5 ± 0.6 mm Hg for the U74006F and the vehicle groups, respectively.

The post-ALT LOP averaged 24.7 ± 3.7 min Hg; N=6 and 30.3 ± 7.0 nun Hg; N=7 at 1 hour (p=0.097) and 22.7 ± 2.0 mm Hg and 27.3 ± 7.0 nun Hg at 3 hours in the right (lasered) eyes of the U74006F and vehicle groups (p=0.137), respectively [Table - 2]. At 48 hours IOPs in both groups of lasered eyes (U74006F and placebo) averaged 12.8 ± 2.2 mm Hg and 12.4 ± 2.4 mm Hg, respectively. By one week, however, the IOPs in the lasered (right) eyes in both groups returned close to baseline readings. The 101 [3] in the control (unlasered) eyes varied little at all time points in both groups. The initial hypertensive reaction, followed by a hypotensive reaction, 24 to 48 hours later in the laser-treated groups, with a slowly developing sustained rise in lOP has been reported in other models of ALT in rabbits.'' At one hour, only one eye (17%) in the U74006F group had an IOP > 27 mm Hg, while five eyes (71%) in the placebo group had an IOP > 27 nom Hg post-ALT.

At 3 hours no eye (0%) in the U7006F group had an IOP > 26 mm Hg, while five eyes (71%) in the placebo group still exhibited IOPs > 26 mm Hg post­ALT.


  Discussion Top


Transient anterior chamber inflammatory responses or uveitis has been reported after most argon laser trabeculoplasty (ALT) procedures. [13] In fact, many clinicians use frequent topical steroids in the immediate postoperative period to help reduce intraocular inflammation. Whether these intraocular inflammatory responses may be responsible for peripheral anterior synechiae (PAS) formation, IOP spikes, and the possible resulting loss of central islands of vision in some high-risk patients has yet to be determined.

Fluorophotometry was performed to evaluate the breakdown of the blood-aqueous barrier after argon laser trabeculoplasty. Feller and Weinreb [14] studied the breakdown and reestablishment of the blood-aqueous barrier with ALT in 17 patients with primary open­angle glaucoma. They found that measurement of fluorescein leakage into the anterior chamber showed significant differences between treated and not surgically treated (control) eyes at both one day postoperatively (p<0.07) and one week postoperatively (p<0.01).

Increases in intraocular pressure after ALT are thought to be in part, related to prostaglandin release.

However, studies investigating the use of corticosteroids, indomethacin, and flurbiprofen have found these agents to be ineffective in controlling postoperative IOP spikes. [1],[13]

Antiglaucoma agents, such as apraclonikine, have also been used after ALT to prevent IOP spikes. Previous investigators have shown that an IOP elevations of more than 10 mm Hg are common in 20 to 40% of patients after argon laser trabeculoplasty. [15],[17] Brown et al evaluated 83 patients for LOP spikes after receiving either topical placebo or apraclonidine. [13] They found a significant number of patients (p<0.062) that had experienced more than a 10 mm Hg increase in lOP in the placebo group (8/42) versus the apraclonidine group (2/41). When evaluating IOP spikes of more than 5 mm Hg, a significant difference was also demonstrated (p<0.095) in the placebo group (10/42) versus the apraclonidine group (4/41).

In our study, the intraocular pressures were still elevated in the placebo group at one (30.3 mm Hg) and three (27.3 mm Hg) hours, while those of the U74006F group at one (24.7 mm Hg) and three (22.7 mm Hg) hours, were closer to baseline IOP.

The AFP was not significantly different at 48 hours (p=0.827) between the treatment and control groups. However, the 48-hour AFP was found elevated in both groups probably secondary to the large laser power utilized in this rabbit model of ALT glaucoma. We expected to produce an exaggerated intraocular inflammatory response and IOP spike because of the high power (1.6 watts) utilized and the number of spots (240 spots) created. Also, the iris tissue may have been lasered during the ALT, which may account for some of the more pronounced initial increases in the BAB permeability. However, the average AFPs for both groups was not significantly different on day 2 (p=0.827), and this possibility appeared to be of little consequence. By week one, the U74006F group appeared to exhibit a more favourable trend (p=0.22) toward restoration of the BAB with AFPs of (0.109 ± 0.367) versus (0.424 ± 0.511) for the vehicle-treated group. However, the optimal dose, schedule, etc., still have to be determined.

From the results of our study, we conclude that U74006F, a new free radical scavenger, may have a beneficial effect in controlling lOP spikes in rabbit eyes after argon laser trabeculoplasty.

 
  References Top

1.
Hotchkiss ML, Robin AL, Pollack IP, et al. Nonsteroidal anti-inflammatory agents after argon laser trabeculoplasty: a trial with flurbiprofen and indomethacin. Ophthalmology. 91:969-974, 1984.  Back to cited text no. 1
    
2.
Lynch MG, Quingley HA, Green WR, et al. The effect of neodymium:YAG laser capsulotomy on aqueous humordynamics in the monkey eye. Ophthalmology. 93:1270-1275, 1986.  Back to cited text no. 2
    
3.
Brown RH, Stewart RH, Lynch MG, et al. ALO 2145 reduces the intraocular pressure elevation after anterior segment laser surgery. Ophthalmology. 95:378-384, 1988.  Back to cited text no. 3
    
4.
Jain S, Shi X, Jain AC, et al. Electron spin resonance investigation of laser and heated metal-tip-induced free radical formation in various tissues. Lasers in Surgery and Medicine. 9:616-622, 1989.  Back to cited text no. 4
    
5.
Clarke RH, Nakagawa K, Isner JM. The production of short-lived free radicals accompanying laser photoablation of cardiovascular tissue. Free Radical Biology & Medicine. 4:209-213, 1988.  Back to cited text no. 5
    
6.
Clarke RH, Nakagawa K, Isner JM. Comparison of free radicals produced by laser and ultrasound ablation of cardiovascular tissue. Photochemistry and Photobiology. 2:205-208, 1988.  Back to cited text no. 6
    
7.
Hall ED, Braughler JM. Central nervous system trauma and stroke (II). Free Radical Biology & Medicine. 6:303­313. 1989.  Back to cited text no. 7
    
8.
Braughler JM, Pregenzer JF. The 21-aminosteroid inhibitors of lipid peroxidation:reactions with lipid peroxyl and phenoxy radicals. Free Radical Biology & Medicine. 7:129-130, 1989.  Back to cited text no. 8
    
9.
Hall ED, Braughler JM, McCall JM. Role of oxygen radicals in stroke: effects of the 21-aminosteroids (Lazaroids). A novel class of antioxidants. Current and Future Trends in Anticonvulsant, Anxiety and Stroke Therapy. 351-362, 1990.  Back to cited text no. 9
    
10.
Ticho U. Laser application to the angle structures in rabbits, cats and in human glaucomatous eyes. Documenta Ophthalmologica. 43:115-125, 1977.  Back to cited text no. 10
    
11.
Gherezghiher T, et al. Laser-induced glaucoma in rabbits. Exp Eye Res. 43:885-894, 1986.  Back to cited text no. 11
    
12.
Rusin M, Fishman C, Larson J, et al. Vitreous fluorophotometry in carriers of choroideremia and x­linked retinitis pigmentosa. Arch Ophthalmol. 107:209­212, 1989.  Back to cited text no. 12
    
13.
Reiss CR, Wilensky JT, Higginbotham EJ. Laser trabeculoplasty. Surv Ophthalmol. 35:407-428, 1991.  Back to cited text no. 13
    
14.
Feller DB, Weinreb RN. Breakdown and reestablishment of blood-aqueous barrier with laser trabeculoplasty. Arch Ophthalmol. 102:537-538, 1984.  Back to cited text no. 14
    
15.
Weinreb RN, Ruderman J, Duster R, et al. Immediate intraocular pressure response to argon laser trabeculoplasty. Am J Ophthalmol. 95:279-86, 1983.  Back to cited text no. 15
    
16.
Hoskins HD, Hetherington J Jr, Minckler DS, et al. Complications of laser trabeculoplasty. Ophthalmology. 90:796-799, 1983.  Back to cited text no. 16
    
17.
Brown RH, Stewart RH, Lynch MG, et al. ALO 2145 reduces the intraocular pressure elevation after anterior segment laser surgery. Ophthalmology. 95:378-384, 1988.  Back to cited text no. 17
    



 
 
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