Laszlo Z. Bito

Species differences in the responses of the eye to irritation and trauma: a hypothesis of divergence in ocular defense mechanisms, and the choice of experimental animals for eye research ☆

Information published during the past century, especially the last decade, has identified pronounced species differences, not only in the morphological organization of ocular structures, but also in the functional responses of the eyes of different mammals to experimental and surgical procedures, as well as to drugs and autacoids. For the most part, these differences have been regarded as peculiarities or weakness rather than as fundamental evolutionary adaptations optimally suited to the environment and behavior of each species. This paper proposes a working hypothesis of evolutionary divergence in ocular defense mechanisms, based on some of the known morphological and functional differences among mammals, and discusses the implications of these differences with regard to the choice of appropriate animals for use as models in different areas of ophthalmic research.

Reduction of intraocular pressure in normal and glaucomatous primate (Aotus trivirgatus) eyes by topically applied prostaglandin F2α

Topical application of a single dose of 1.0 mg prostaglandin F2 alpha (PGF2 alpha) onto the cornea of five trained owl monkeys (Aotus trivirgatus) caused a prolonged and highly significant ocular hypotony. The intraocular pressure (IOP) of the treated eye was 4.7 +/- 0.9 mm Hg below that of the control eye 18 to 24 hr after PGF2 alpha application and remained significantly reduced for over 72 hr. Miosis, aqueous flare, and accumulation of cells in the anterior chamber were minimal in extent. The hypotensive effect of PGF2 alpha was even more pronounced when applied to a glaucomatous owl monkey eye with angle recession, which had IOPs consistently in the 45 to 55 mm Hg range (mean: 47.2 +/- 0.7) as measured periodically over a one-year period. The application of a single dose of 1.0 mg of PGF2 alpha to this hypertensive eye reduced IOP by over 25 mm Hg within 4 hr, with a relative hypotony lasting for at least 6 days. These results show that topical application of certain PGs to normotensive or hypertensive primate eyes can cause a long lasting and highly significant decrease in IOP, and suggest that prostaglandins or their analogues may aid in the therapeutic control of ocular hypertension and glaucoma.

Prostaglandins: A New Approach to Glaucoma Management with a New, Intriguing Side Effect

This introductory overview considers the advantages of a class of local hormones-the prostaglandins (PGs)-for the management of intraocular pressure (IOP) in glaucoma, over agonists and antagonists of neurotransmitters that dominated this field in the 20th century. PGs and PG analogues, in particular esterified prodrug forms of PGF2 alpha, are effective ocular hypotensive agents, but cause some conjunctival hyperemia and corneal sensory irritation at higher concentrations. Based on structure-activity studies, a 17-phenyl PGF2 alpha prodrug, latanoprost (PhXA41), was found to have a greatly improved therapeutic index, without compromising the ocular hypotensive potency of PGF2 alpha prodrugs. The IOP lowering mechanism of such PGF2 alpha s, increased uveoscleral outflow, can be expected to have great physiologic advantages, especially with respect to normal tension glaucoma, over most currently used ocular hypotensive drugs. The introduction of this new approach has already led to a new insight into the control and clinical significance of this outflow route. Similarly, the newly discovered ocular side effect, PG-induced increase in iridial pigmentation, can be expected to provide insight into the oculo-protective role of iridial melanocytes and into the punative association between a decline in the ocular melanin system and the vulnerability of the eye to some age-related diseases.

Circadian intraocular pressure management with latanoprost: diurnal and nocturnal intraocular pressure reduction and increased uveoscleral outflow.

Based on their mechanism of action, the most frequently used ocular hypertensive agents, the beta-blockers, cannot be assumed to reduce IOP during sleep. The need for drugs that reduce IOP around-the-clock is underscored, however, by the fact that inadequate nocturnal ocular perfusion pressure is considered to be one of the likely causes of glaucomatous optic neuropathy especially in some cases of normal tension glaucoma. The studies reviewed here demonstrate that latanoprost, a new ocular hypotensive prostaglandin F2 alpha analogue, applied once a day at a concentration of 0.005%, maintains a statistically highly significant IOP reduction around-the-clock. The magnitude of this IOP reduction was found to be essentially identical during the day and at night, both in patients maintained on timolol and in those not receiving other glaucoma medication. Latanoprost-induced IOP reduction was also found to be associated with increased uveoscleral outflow in normotensive volunteers, both during the day and at night. These circadian studies suggest that this new ocular hypotensive agent can be expected to be particularly useful for the medical management of some forms of glaucoma, such as normal tension glaucoma, when the cause of the glaucomatous damage cannot be linked specifically to diurnal IOP abnormalities.

Maintained reduction of intraocular pressure by prostaglandin F2α-1-isopropyl ester applied in multiple doses in ocular hypertensive and glaucoma patients

In a randomized, double-masked, placebo-controlled study, 0.25 microgram (n = 11) or 0.5 microgram (n = 13) of prostaglandin F2 alpha-1-isopropyl ester (PGF2 alpha-IE) was applied topically twice daily for 8 days to one eye of ocular hypertensive or chronic open-angle glaucoma patients. Compared with contralateral, vehicle-treated eyes, PGF2 alpha-IE significantly (P less than 0.05) reduced intraocular pressure (IOP), beginning 4 hours after the first 0.5-microgram dose and lasting at least 12 hours after the fourteenth dose, with a significant (P less than 0.005) mean reduction of 4 to 6 mmHg maintained throughout the last day of therapy with either dose. A contralateral effect was not observed. Mean tonographic outflow facility was significantly (P less than 0.05) higher in PG-treated compared with vehicle-treated eyes (0.17 +/- 0.02 versus 0.12 +/- 0.01 microliter/minute/mmHg, respectively; +/- standard error of the mean) for the 0.5 microgram dose. Conjunctival hyperemia reached a maximum at 30 to 60 minutes after PGF2 alpha-IE application. Some patients reported mild irritation lasting several minutes after some doses. Visual acuity, accommodative amplitude, pupillary diameter, aqueous humor flare, anterior chamber cellular response, Schirmers test, pulse rate, and blood pressure were not significantly altered. Our findings show that PGF2 alpha-IE is a potent ocular hypotensive agent and a promising drug for glaucoma therapy.

Intraocular fluid dynamics. III. The site and mechanism of prostaglandin transfer across the blood intraocular fluid barriers

When a mixture of 3H labelled prostaglandin E1(PGE1) and 14C-sucrose is injected into the vitreous body, 3H leaves the vitreous at a substantially higher rate (t12 = 3 hr) than 14C (t12 = 15 hr). High levels of 14C were observed in the aqueous humour 4 to 20 hr following intravitreal injection, indicating that much of the sucrose leaves the eye by the bulk flow. 3H was not detected in the aqueous humour at any time following the intravitreal injection; therefore, PGE1 must be lost from the eye before it can enter the anterior chamber. Less than 3% of the originally injected activity was detected in intraocular tissues, indicating that the high rate of 3H loss is due to rapid transfer of PGE1 across some region of the blood-ocular fluid barriers, and consequent loss into the circulation. Although it was not possible to accurately determine rates of loss of 3H and 14C from the posterior fluid following injection of 3H-PGE1 and 14C-sucrose into the posterior chamber, such attempts showed that 3H leaves the posterior chamber several times faster than sucrose. When the same mixture was injected into the anterior chamber the rates of loss of 3H and 14C from the aqueous humour were essentially identical; thus, in contrast to posterior chamber, there is no specific mechanism to facilitate the removal of PGs from the anterior chamber of the eye. When a mixture of [3H]PGE1 and [14C] sucrose or [14C] thiourea was presented to the blood side of the blood intraocular fluid barrier by short-term close arterial infusion, the 3H/14C ratios in the anterior and posterior aqueous and in the vitreous humour were less than that of the infusion medium. Thus, either the passive permeability of these barriers to PGE1 is less than that of thiourea or sucrose or that, some of the PGE1 molecules which cross these barriers are transported out again by an active process. These and previous results suggest that the ciliary processes (and/or the posterior surface of the iris) and possibly the blood-vitreal barrier possess specific transport mechanisms to facilitate the removal of prostaglandins from the extracellular fluid compartments of the posterior segment of the eye.

Steroid glaucoma: Corticosteroid-induced ocular hypertension in cats

This study was undertaken to develop a feline model of corticosteroid-induced ocular hypertension. In the first experiment, eight cats were selected whose intraocular pressure (17 +/- 0.4 mmHg) was consistently below the mean baseline intraocular pressure of our colony (24 +/- 0.5) during the preceding 2 months. Unilateral twice or thrice daily topical application of 10 microliters 1% dexamethasone sodium phosphate caused a gradual intraocular pressure increase that became significant (P less than 0.05) within 2-3 weeks. There was no significant change in body weight, but several eyes developed cataracts. Similar results were obtained with treatment of normotensive cat eyes with dexamethasone, or with 1.0% prednisolone acetate (PredForte) twice a day. Topical application of PGF2 alpha-1-isopropyl ester (0.1 or 0.25 microgram PG equivalent) to such steroid-treated eyes yielded significant intraocular pressure reduction and pupillary miosis, similar in magnitude to those exhibited by normal eyes. When dexamethasone treatment was reduced to once daily, after prolonged twice daily treatment, intraocular pressure decreased only slightly within 10 days. When dexamethasone treatment was stopped, intraocular pressure declined to normal levels within 6-7 days. These findings show that adult cat eyes develop steroid-induced ocular hypertension that is maintained and reversible. As opposed to previous findings on rabbits, steroid-induced feline ocular hypertension appears to be a good model for this clinical condition and may be suitable for the testing of potential glaucoma drugs.

The ocular pharmacokinetics of eicosanoids and their derivatives. 1. Comparison of ocular eicosanoid penetration and distribution following the topical application of PGF2α, PGF2α-1-methyl ester, and PGF2α-1-isopropyl ester *

These experiments were undertaken to determine whether the increased ocular hypotensive potency of topically applied prostaglandin (PG) PGF2α esters, as compared with that of PGF2α free acid, can be accounted for by increased penetration of the eicosanoid moiety of the esterified PG into the eye. One hour after the topical application of [3H]PGF2α-1-methyl ester (ME) in peanut oil, the 3H activities in the cornea, aqueous humor, and ciliary body of the rabbit eye were 32-, 22-, and 8-fold higher, respectively, than they were following the topical application of [3H]PGF2α free acid. 3H activity during the first 3 hr declined rapidly in the cornea and more slowly in the aqueous humor, but remained essentially constant in the ciliary body for up to 6 hr, declining rapidly only between 6- and 24 hr. 3H activity in eyes that received [3H]PGF2α ME was also several-fold higher in the anterior sclera and iris than in eyes that were treated with [3H]PGF2α free acid, but this difference was much smaller in the conjunctiva. At 1 hr, most of the 3H activity in the aqueous humor was associated with PGF2α, as determined by chromatography, but at 2- and 3 hr other peaks, presumably reflecting metabolites of PGF2α, became apparent. The penetration and intraocular distribution of 3H activity was similar when [3H]PGF2α ME was applied to the eye in normal saline rather than in peanut oil or when the isopropyl rather than the methyl ester of PGF2α was used. These studies indicate that esterification of the carboxyl group of PGF2α greatly enhances the penetration of the PFG2α moiety into the eye and suggests that effective de-esterification of the PGF2α ester occurs in the cornea, resulting in the delivery of PGF2α free acid into the aqueous humor. It is concluded that topically applied PG esters act as pro-drugs and that the increased ocular penetration of these esters may account for the previously reported increase in their ocular hypotensive potency as compared to that of PG free acid or salts.

Slit-lamp studies of the rhesus monkey eye. I. Survey of the anterior segment.

Slit-lamp photographic studies of 144 caged rhesus monkeys, aged 2 months to 35 years, show age-related changes in anterior-chamber depth, lens thickness, anterior and posterior curvatures of the lens, and location of the posterior lens surface relative to the anterior corneal surface. For these parameters, as well as for those measured by other techniques, a difference in slope magnitude and (or) slope sign was found between the growth phase which lasts for 5-6 years, and the adult phase (greater than 5-6 years). Age-related changes in the adult rhesus eye are qualitatively similar in almost all aspects to those observed in the human eye, indicating that the rhesus is a good animal model for the study of human loss of accommodative amplitude.

Comparison of the ocular hypotensive efficacy of eicosanoids and related compounds

It has recently been shown that prostaglandin (PG)E2 or F2 alpha reduces the intraocular pressure (IOP) of cats and primates when applied topically to the eye in very small doses, and that reduced IOP can be maintained in these species as long as the topical application of one of these PGs is repeated daily or twice daily. In the present study the ocular hypotensive efficacy and some of the ocular side-effects of 15 eicosanoids and related compounds, especially derivatives of PGF2 alpha, were compared and were also compared to some clinically used ocular hypotensive agents. Derivatives of PGF2 alpha were found that had short-term and long-term ocular hypotensive potencies some 10- to 50-fold greater than PGF2 alpha itself.