A C T A O P H T H A L M O L O G I C A

60 (1982) 252-258

Department oJOphthalmology (Head: N . Ehlers), Arhw Kommunehospital, Vniversiq of Aarhus, h h w , Denmark

PROSTAG LANDlN INHIBITION AND CENTRAL CORNEALTHICKNESS

AFTER CATARACT EXTRACTION

CARSTEN 60 NIELSEN

The effect of systemically given naproxen (a prostaglandininhibitor) on central corneal thickness was studied in vivo, in the normal cornea, and in the cornea made artificially oedematous by cataract surgery. Only after cataract extraction could an effect be demonstrated. The post-surgical oedema was in this case reduced statistically significant corresponding to approximately 50% of control. Further the secondary rise in CCT on the third post-operative day as seen with non-medicated guttata corneas was absent after naproxen.

Key words; corneal thickness - endothelium - prostaglandins - naproxen.

The presence of irin (later found to be a prostaglandin, PG) in the anterior chamber was first demonstrated by Ambache (1957). Inn induced conjunctival hyperaemia, increased intraocular pressure and atropine-resistant miosis. In vitro accumulation of 3H-labelled PGs in antenor uveal tissue and choroid plexuses (Bito 1973), indicated the presence of an active transport mechanism over the ciliary epithelium being able to remove PGs from the aqueous. Elevation of at least one PG (F2a) in the serum of diabetic patients with retinopathy was demonstrated (Waitz- man 1973). Diabetic patients with retinopathy exhibited increased central corneal thickness (Olsen 1980). An increased concentration of PGs in the aqueous was demonstrated during acute anterior uveitis (Whitelocke et al. 1973), a condition with corneal oedema (Olsen 1981). PGs are liberated into aqueous after mechanical stimulation and paracentesis (Ambache et al. 1965; Miller et al. 1973). After intraocular surgery corneal oedema is noticed.

Received on September 28th. 1981.

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Nielsen Prostaglandin and corneal thickness

It was the purpose of the present study to examine the possible influence of PGs on central corneal thickness of the normal as well as the oeckmatous cornea as seen after cataract-extraction. Naproxen, a prostaglandin-inhibitor, was given systemi- cally to students and to patients to be operated on. As previously (Nielsen 1980), the cataract patients were divided into 2 groups, one with normal corneas and one with guttata corneas.

Material and Methods Material Fourteen healthy medical students with no past or present eye disease were studied. Seven students received the drug and 7 served as control. The observer was blinded. No exclusions were done.

The cataract-group to be medicated included 30 consecutive patients with senile cataract as the only past or present eye disease. all had IOP recordings 5 21 mmHg. Three patients were excluded because of surgical complications and one retreated for personal reasons. The medicated group then comprised 26 patients. Of these, 14 (age 72.9 k 2.3, X k SEM) had a normal corneal and 12 (age 72.0 f 2.7, TI k SEM) exhibited guttata endothelium, as classified by specular microscopy. Twenty-seven patients (after exclusions) used earlier (Nielsen 1980) comprised the control group. Fourteen (age 69.1 k 3.6, X k SEM) of these had a normal cornea and 13 (age 73.0 k 1.6, X f SEM) had endothelial guttae. The control patients were operated and examined in exactly the same way as the medicated patients.

Method Examination by non-contact specular microscopy of the endothelium of all eyes to be operated on was performed as described by Olsen (1979). 5-6 exposures were taken of each cornea with respect to the possible presence of centrally located guttae. Dark defects in the endothelial reflex larger than two endothelial cells and changing in size with the focusing were defined as guttae. The presence of more than one gutta on either exposure classified the cornea as guttata.

Further the central corneal thickness and IOP were measured. Only CCT was measured in the student-group. The CCT-measurements (calculated mean of 3 readings) were done with a modified Haag-Streit pachometer (Ehlers & Sperling 1977). using a technique as described by Olsen et al. (1980). IOP was measured by applanation tonometry.

Experiments The 7 students to be medicated were given naproxen (Naprosyn@, Astra-Syntex) 250 mg x 3 for 5 days and CCT was measured daily at the same time of the day.

The patients to be medicated were given naproxen 500 mg on the evening before operation and 250 mg x 3 for the next 6 days.

The CCT was measured daily at the same time of the day, pre-operatively and from the first to the sixth post-operative day. IOP was measured daily, after CCT measurements had been done, pre-operatively and from the second to the sixth post-operative day.

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A 80

I i I I T 7 2 3 . 4 5 6 POSTOP DAY

Fig. 1. CCT (mean f SEM) relative to the pre-operative value. Closed circles: after naproxen. Open

circles: control.

80 I CONTROL

POSTOP DAY Fig. 2.

CCT (mean f SEM) relative to the pre-operative value. Closed circles: after naproxen. Open circles: control.

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Nielsen Prostaglandin and corneal thickness

Results

In the student-group no CCT-difference could be measured between medicated and control (not shown).

Fig. 1 shows the CCT response of the cataract patients with normal corneas. The post-operative corneal oedema after naproxen is significantly less than control (P < 0.00 1, t-test). On any post-operative day approximately half the value of the control.

In Fig. 2 the CCT response of the guttata corneas can be seen. Again the response after naproxen is significantly less than control on any day (P < 0.05, t-test). The oedema is halved, but further it is noticed that a secondary rise in CCT from day 3 to day 4 in the control-group is absent in the medicated group (P < 0.02 1, F-test).

2 3 4 5 6

-6 m d IOP

2 3 4 5 6

d IOP Fig. 3.

IOP (mean f SEM) relative to the pre-operative value. Closed circles: after naproxen. Open circles: control.

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Nielsen Prostaglandin and corneal thickness

The IOP response after naproxen relative to control is shown in Fig. 3. There is no significant difference between the two, but a tendency towards higher IOP- recordings after naproxen can be seen.

Discussion

In the cataract group the post-operative corneal oedema was approximately halved after naproxen compaired to a control-group operated one year earlier. Normal corneas in steady state (students) were not affected by PGinhibition, at least not to a measurable degree. If PGs play a part in regulation of CCT under normal conditions the lack of effect of naproxen might be due to the firm protein-binding of this drug, combined with an intact blood-aqueous barrier, which is partly broken down during post-surgical inflammation. One must however expect the main drug-action to be on the ciliary epithelium where PGsynthesis has been demon- strated.

The actual aqueous concentration of PGs is dependent on synthesis and removal. In the normal condition the capacity for removing the noxious PGs from the anterior chamber may far exceed PG-synthesis. During the inflammation this relation between synthesis and removal may be reversed thus enabling naproxen to have an effect.

Whether the oedema is caused by a direct effect of PGs on the endothelium, or a result of the many metabolic changes during inflammation is not known. Dikstein ( 1 97 1 ) found no direct effect of PGs on the endothelial pumping-rate in vitro.

Along with this decreased oedema the post-operative secondary CCT-rise in the guttata group from day 3 to day 4 was no longer present after medication with naproxen. A similar secondary thickness-increase was also noted by Olsen (1980) and Bramsen & Ehlers (1979). Olsen (1980) demonstrated changes in the endothe- lial reflex during uveitis similar to a guttata drawing, although fully reversible. A possible and interesting connection between guttae and inflammation remains to be further investigated.

Mochizuki et al. (1977) reported decreased corneal oedema after cataract- extraction with topical instillation of 0.5% indomethacin 4 times during the last 3 pre-operative hours. However both medicated and control patients were given dexamethason 0.1 % 3 times a day post-operatively. The same authors could not demonstrate effect on CCT when indomethacin was given systemically under similar conditions probably because the patients received only a single pre-operative dose, shown to be insufficient based on various post-operative inflammatory stigmata (Baikoff et al. 1980). Further the potency of naproxen as inhibitor of

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PG-biosynthesis in the anterior uvea is reported 40% greater than indomethacin (Bhattacherjee 8c Eakins 1974).

Inhibition of PGsynthesis could be beneficial in clinical cases where post- operative endothelial decompensation and excessive corneal oedema is likely to occur, including conditions with pre-operative presence of guttae, low endothelial cell count or earlier attacks of uveitis. This last condition experimentally exhibited a long-lasting abolishment of normal anterior weal PG-accumulative capacity (Bito 1973).

Other anti-inflammatory drugs, like steroids, would appear worth testing to separate the effect on CCT of PG and other inflammatory substances.

Whether the decreased post-operative oedema after naproxen is also reflected in a decreased endothelial cell loss seems interesting.

A long-term study concerning this question is undertaken.

References Ambache N (1957): Properties of kin, a physiological constituent of the rabbit’s iris. J Physiol

Ambache N, Kavanagh L & Whiting J (1965): Effect of mechanical stimulation on rabbits eyes. Release of active substance in anterior chamber perfusates. J Physiol 176: 378-408.

Baikoff G, Drouan P, Bechetoille A & Taglioni M (1980): Indometacine et implant intra-oculaire. Efficacitk d’un traitement prolonge. J Fr Ophthalmol3 : 389-395.

Bhattacherjee P & Eakins K E (1974): A comparison of the inhibitory activity of compounds on ocular prostaglandin biosynthesis. Invest Ophthalmol 13: 967-972.

Bito L (1973): Absorptive transport of prostaglandins from intraocular fluids to blood: A review of recent findings. Exp Eye Res 16: 299-306.

Bramsen T & Ehlers N (1979): Early postoperative changes in graft thickness after penetrating keratoplasty. Acta Ophthalmol (Kbh) 57: 258-268.

Dikstein S (1971): Metabolic requirements for fluid transfer through the corneal endothe- hum. ExpEyeRes 12: 371-372.

Ehlers N & Sperling S (1977): A technical improvement of the Haag-Streit pachometer. Acta Ophthalmol (Kbh) 55: 333-336.

Miller J D, Eakins K E & Atwal M (1973): The release of PGE2-like activity after paracentesis and its prevention by aspirin. Invest Ophthalmol 12: 939-940.

Mochizuki M, Sawa M & Masuda K (1977): Topical indomethacin in intracapsular extraction of senile cataract. Jpn J Ophthalmol2 1 : 2 15-226.

Nielsen C B (1980): The effect of carbonic anhydrase inhibition on central corneal thickness after cataract extraction. Acta Ophthalmol (Kbh) 58: 985-990.

Olsen T ( 1979): Non-contact specular microscopy of human corneal endothelium. Acta Ophthalmol (Kbh) 57: 986-998.

Olsen T ( 1980): Corneal thickness and endothelial damage after intracapsular cataract extraction. Acta Ophthalmol (Kbh) 58: 424-433.

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Olsen T (198 1): Transient changes in specular appearance of the corneal endothelium and in corneal thickness during anterior uveitis. Acta Ophthalmol (Kbh) 59: 100- 109.

Olsen T, Busted N & Schmitz 0 (1980): Corneal thickness in diabetes mellitus. Lancet 19: 883.

Olsen T, Nielsen C B & Ehlers N (1980): On the optical measurement of corneal thickness. 11. T h e measuring conditions and sources of error. Acta Ophthalmol (Kbh) 58: 975-984.

Waitzman M B (1973): Prostaglandins and diabetic retinopathy. Exp Eye Res 16: 307-3 13. Whitelocke R A F, Eakins K E & Bennett A (1973): Prostaglandin and the eye. Proc Roy Soc

Med 66: 429-434.

Author's address:

Carsten Bo Nielsen, M.D., Department of Ophthalmology, Arhus Kommunehospital, DK-8000 Arhus C, Denmark.

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