Accommodation dynamics in aging rhesus monkeys.

Accommodation, the mechanism by which the eye focuses on near objects, is lost with increasing age in humans and monkeys. This pathophysiology, called presbyopia, is poorly understood. We studied aging-related changes in the dynamics of accommodation in rhesus monkeys aged 4-24 yr after total iridectomy and midbrain implantation of an electrode to permit visualization and stimulation, respectively, of the eye's accommodative apparatus. Real-time video techniques were used to capture and quantify images of the ciliary body and lens. During accommodation in youth, ciliary body movement was biphasic, lens movement was monophasic, and both slowed as the structures approached their new steady-state positions. Disaccommodation occurred more rapidly for both ciliary body and lens, but with longer latent period, and slowed near the end point. With increasing age, the amplitude of lens and ciliary body movement during accommodation declined, as did their velocities. The latent period of lens and ciliary body movements increased, and ciliary body movement became monophasic. The latent period of lens and ciliary body movement during disaccommodation was not significantly correlated with age, but their velocity declined significantly. The age-dependent decline in amplitude and velocity of ciliary body movements during accommodation suggests that ciliary body dysfunction plays a role in presbyopia. The age changes in lens movement could be a consequence of increasing inelasticity or hardening of the lens, or of age changes in ciliary body motility.

Prostaglandin-induced iris color darkening. An experimental model.

OBJECTIVES: To determine the role of sympathetic innervation and the effect of topical prostaglandin therapy on iris color in pigmented rabbits. METHODS: Twelve Dutch-belted rabbits underwent unilateral superior cervical ganglionectomy (SCGx) at age 1 to 3 months. A second group of 11 rabbits underwent bilateral SCGx at age 1 month and were treated once or twice daily for 6 to 9 months with 1 drop (about 20 microL) of latanoprost, 0.005%, to one eye and its vehicle to the contralateral eye. Standardized color photographs of the iris of each eye were taken at 1- to 2-month intervals for 6 to 10 months and evaluated by 4 to 6 observers in a masked fashion. RESULTS: At 8 to 10 months after unilateral SCGx, 11 of 12 rabbits showed definite heterochromia, with the lighter-colored iris on the SCGx side. Of the 11 rabbits that underwent bilateral SCGx and unilateral latanoprost treatment, 9 showed heterochromia at 6 to 9 months, with the darker-colored iris on the latanoprost-treated side. CONCLUSIONS: These results demonstrate that sympathetic innervation is required for age-related, physiologic darkening of iris color in rabbits, that prostaglandins may compensate for sympathetic denervation to produce darkening in SCGx eyes, and that this model may be useful to study prostaglandin-induced iris color change.

Eye color changes past early childhood. The Louisville Twin Study.

OBJECTIVE: To determine whether eye color changes after 6 years of age. DESIGN: Longitudinal data on eye color were obtained from the Louisville Twin Study, Louisville, Ky. Twins (n = 1513 [individuals]) were assessed at least once and most twins (n = 1386) were examined on 2 or more occasions. Parents of twins were also examined at the study inception, 128 of whom were assessed again from February 1989 to October 1993. MAIN OUTCOME MEASURE: Eye color was assessed at each examination by matching the iridial coloration of the subject to 1 of 15 painted glass eye anterior segments, similar to those in artificial eyes, mounted on a circular disk. The spectrum ranged from light blue (1) to dark brown (15). RESULTS: Among whites (n = 1359), the eye color of 3.8% to 8.6% of the sample twins became 2 U or more darker or 2 U or more lighter during 3- to 9-year intervals between 6 years of age and adulthood (> 18 years, < 24 years). Among identical (monozygotic) twin pairs, there was a high degree of concordance in eye color (r = 0.98 [P < .001]), while in fraternal (dizygotic) twin pairs, the concordance was less pronounced (r = 0.49) and decreased with age (r = 0.07). Among the sample of the mothers of twins, 9% had irides that lightened by 2 U or more during the follow-up period. CONCLUSION: Most individuals achieve stable eye color by 6 years of age. However, a subpopulation of 10% to 15% of white subjects have changes in eye color throughout adolescence and adulthood in the eye color range that can be expected to reflect changes in iridial melanin content or distribution. These data also suggest that such changes in eye color, or the propensity to such changes, may be genetically determined.

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.

Impact of intraocular pressure on venous outflow from the globe: a hypothesis regarding IOP-dependent vascular damage in normal-tension and hypertensive glaucoma.

Increasing focus on so-called normal-tension glaucoma has raised questions concerning the mechanism by which intraocular pressure (IOP) may play a role in the pathophysiology of glaucomatous optic neuropathy. However, examination of pressure-relationships suggests that an increase of a few mm Hg in IOP within the normal-tension range may double the magnitude of one important physiologic parameter, the magnitude of the intravascular waterfall effect at the exit of the central retinal vein (CRV) from the globe. This, in turn, increases the pulsatility or the velocity and turbulence of blood flow, depending on the extent of the restriction to venous outflow at the passage of the CRV through the lamina cribrosa. In the absence of such restriction, increased CRV pulsatility, especially in combination with brief IOP spikes, can be expected to cause foci of microvascular collapse in the optic nerve head. These foci can be converted to permanent vascular defects depending on additional risk factors, such as abnormal blood rheology ro platelet aggregation. Greater than normal laminal restrictions can, on the other hand, reduce perfusion pressure and can cause turbulence-induced endothelial damage and thickening of the CRV wall, ultimately further reducing perfusion pressure. These considerations suggest the hypothesis that the size and configuration of the venous outflow channel through the lamina cribrosa is a primary determinant of the extent of vascular and ultimately neuronal damage that occurs at a given IOP level in normal-tension and hypertensive primary open-angle glaucoma.

Around-the-clock intraocular pressure reduction with once-daily application of latanoprost by itself or in combination with timolol.

OBJECTIVE: To determine whether once-daily, in the morning, topical application of the new ocular hypotensive prostaglandin analogue, latanoprost, yields nocturnal intraocular pressure (IOP) reduction similar to its diurnal IOP reducing efficacy. STUDY DESIGN AND PATIENTS: Placebo- controlled, randomized, and double-masked study on hospitalized patients with ocular hypertension or glaucoma. Patients in group 1 (n=9) were maintained on twice-daily applications of 0.5% timolol maleate. Patients in group 2 (n=10) terminated their timolol treatment 3 weeks before the beginning of the study. In both groups the test drug (0.005% latanoprost) and its vehicle (placebo) was applied by hospital staff every morning for 9 days. MEASUREMENTS: After 4 days of ambulatory treatment, patients were hospitalized, and IOP values were obtained in the supine and sitting positions with a handheld electronic tonometer (Tono-Pen XL, Bio-Rad, Glendale, Calif) and a Goldmann's applanation tonometer, covering every 2-hour interval, around the clock, but not more than at four time points per day during a 5-day period. RESULTS: The mean nocturnal IOPs (Goldmann's applanation tonometer) collected for 5 days were mean +/-SEM 17.9+/-0.6 vs 20.2+/-0.6 mm Hg and 16.8+/-0.3 vs 20.6+/-0.5 mm Hg for the study vs the control eyes in group 1 and group 2, respectively. These nocturnal IOP reductions were statistically significant (P<.001, two-tailed paired Student's t test). The differences between diurnal and nocturnal IOP reductions (handheld electronic or Goldmann's applanation tonometer) were minimal (>0.3 mm Hg) and statistically not significant (P>.31, two-tailed paired Student's t test). CONCLUSION: Once-daily latanoprost treatment provides uniform circadian (around-the-clock) IOP reduction by itself, or in combination with timolol.

Maintained intraocular pressure reduction with once-a-day application of a new prostaglandin F2 alpha analogue (PhXA41). An in-hospital, placebo-controlled study.

To eliminate uncertainties about compliance, 15 patients with glaucoma (intraocular pressure [IOP] > 22 mm Hg and < 40 mm Hg) were hospitalized to participate in a clinical trial of the ocular hypotensive effectiveness of the new prostaglandin F2 alpha analogue prodrug, PhXA41 (13,14-dihydro-17-phenyl-18, 19, 20-trinor-PGF2a-isopropyl ester; latanoprost [World Health Organization generic name]). At 9 PM on each of five consecutive days, one of the investigators applied one drop of a 0.006% solution of PhXA41 (representing approximately 2 micrograms of PhXA41 per treatment) to one eye of nine patients and one drop of placebo to one eye of six patients. This was followed by an evaluation of potential local side effects at 9:30 PM. Complete examinations, including tonometry (Goldmann), were also performed at 8 AM and 8 PM on days 1 to 6, as well as at noon and 4 PM on days 1, 2, and 6. Except for mild conjunctival hyperemia in two PhXA41-treated eyes (once each at 8 AM), no side effects were observed or reported by any patient. Starting with the first IOP measurement after the first treatment (8 AM on day 2), IOP was reduced by 20% to 30% in the eyes treated with PhXA41. This reduction was highly significant (P < .01 at 12 time points and P < .05 at the remaining two measurements) throughout the study. The IOP reduction did not become attenuated during the 23 hours after treatments. At 11 hours after the last treatment, the mean (+/- SD) IOP difference between PhXA41-treated and contralateral control eyes was -5.5 +/- 2.8 mm Hg, as compared with -6.1 +/- 1.8 mm Hg 12 hours later. PhXA41 must, therefore, be regarded as an excellent candidate for use as a once-a-day glaucoma medication.

The ocular effects of prostaglandins and the therapeutic potential of a new PGF2 alpha analog, PhXA41 (latanoprost), for glaucoma management.

In the early days of prostaglandin (PG) research, the infusion of large PG doses into rabbit eyes already traumatized by cannulation, led to the conclusion that PGs have a profound ocular hypertensive effect that is associated with a breakdown of the blood-aqueous barrier. In contrast, repeated topical application of PGs to nontraumatized eyes of several species other than rabbits has later been shown to yield a maintained ocular hypotensive effect, without barrier breakdown. Due to its excellent pharmacokinetic properties, the isopropyl ester form of PGF2 alpha (PGF2 alpha-IE) is a much more potent ocular hypotensive agent and appeared to be better suited for the management of glaucoma, than PGF2 alpha itself or any currently used glaucoma drug. However, even this prodrug caused clinically unacceptable foreign-body sensation and conjunctival hyperemia, which could be reduced, or eliminated, only by some modifications of the omega chain of PGF2 alpha-IE. One such analog, PhXA41, maintained highly significant IOP reduction in glaucoma patients even with once-daily application at the remarkably low concentration of 0.006%. Because PhXA41 reaches intraocular tissues and the systemic circulation in its de-esterified free-acid form, which is a good substrate for the PG transport system, it retains the most important pharmacokinetic advantages of topically applied PGF2 alpha-IE. However, its greatly reduced side effects give PhXA41 a clear therapeutic advantage over PGF2 alpha-IE, making it an effective new drug candidate for the long-term medical management of glaucoma.

Phenyl-substituted prostaglandins: potent and selective antiglaucoma agents.

A series of phenyl-substituted analogues of prostaglandin F2 alpha (PGF2 alpha) were prepared and evaluated for ocular hypotensive effect and side effects in different animal models. In addition, the activity of the analogues on FP receptors was studied in vitro. The results were compared with those of PGF2 alpha and its isopropyl ester. The phenyl-substituted PGF2 alpha analogues exhibited good intraocular pressure reducing effect, were more selective, and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its isopropyl ester. The analogues exhibited high activity on FP receptors in a stereoselective manner for the 15 alpha-hydroxyl group.

Intraocular pressure reduction with PhXA34, a new prostaglandin analogue, in patients with ocular hypertension.

In a randomized, double-masked, parallel study, one drop of 0.003% (1 microgram; n = 9) or 0.01% (3 micrograms; n = 10) PhXA34, a new phenyl-substituted prostaglandin F2 alpha analogue (13,14-dihydro-15[R,S]-17-phenyl-18,19,20-trinor-prostaglandin F2 alpha-1-isopropyl ester), or its vehicle (n = 10) was applied topically twice daily for 6 days to one eye in each of 29 patients with ocular hypertension. Compared with either baseline, contralateral, or vehicle control values, PhXA34 caused a significant (P < .001) dose-dependent reduction of intraocular pressure. The reduction lasted at least 12 hours after each drop and 24 to 48 hours after the last drop, with a significant (P < .0001) mean +/- SEM reduction of as much as 10 +/- 1 mm Hg (40%). Conjunctival hyperemia was not produced by 0.003% PhXA34, but was noted in some eyes treated with 0.01% PhXA34, and after repeated tonometry with either concentration. The prostaglandin analogue did not produce clinically obvious miosis, anterior chamber flare or cellular response, or any subjective adverse effects. PhXA34 is a potent, effective, and well-tolerated ocular hypotensive agent based on our results in this small, short-term study. Its potential as a new drug for glaucoma therapy warrants further investigation in long-term, larger studies.

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.

Effects of prostaglandins F2 alpha, A2, and their esters in glaucomatous monkey eyes.

The effect of prostaglandin (PG) F2 alpha-isopropyl ester (IE), PGA2, or PGA2-IE on intraocular pressure (IOP) was tested in eight cynomolgus monkey eyes with argon laser-induced glaucoma. Dose-response testing and baseline IOP measurements were done. For multiple dose testing, 5 micrograms in 25 microliters (0.02%) of each PG was topically applied twice daily for 5 days. The IOP was measured at 30- or 60-minute intervals for 6 hours after the morning dose each day. A significant (P less than 0.05) reduction of IOP peaked at 5-9 mm Hg below baseline values on the 5th day of treatment for each PG. The ocular hypotensive effect of these PGs progressively became more pronounced during the course of twice-daily dosing, with a significant reduction maintained at least 17 hours after some doses. No more than trace aqueous flare and no cells were observed in any eye during the course of treatment. These findings demonstrate that PGs other than F2 alpha are potent ocular hypotensive agents in primates.

The role of the iris in accommodation of rhesus monkeys.

After unilateral total iridectomy, maximum accommodation inducible by corneal iontophoresis of carbachol in rhesus monkeys was approximately 40% less in the iridectomized than in the contralateral untouched eyes, irrespective of age. Ultrasonographically measured anterior chamber shallowing and lens thickening were also less in the iridectomized eyes. Neither submaximal accommodation induced by intramuscular pilocarpine infusion nor maximum accommodation inducible by midbrain stimulation differed in iridectomized and intact eyes. The authors hypothesize that at maximum cholinomimetic drug-induced contraction, the iris sphincter muscle pulls the ciliary body farther forward and inward than does maximum ciliary muscle contraction alone, allowing additional rounding of the lens and, consequently, additional accommodative power.

Effects of various anesthetic and autonomic drugs on refraction in monkeys.

Resting refractive correction in ketamine-, pentobarbital-, or halothane-anesthetized rhesus and cynomolgus monkeys was approximately 1-3 diopters myopic, with little difference under the various anesthetic regimens. Topical cyclopentolate or atropine, or systemic hexamethonium eliminated much of the myopia, while epinephrine, phenylephrine and thymoxamine had little effect. Anesthesia-induced myopia in monkeys thus seems comparable to tonic accommodation ("night myopia") in the human. Accommodation induced by electrical stimulation of the Edinger-Westphal nucleus averaged approximately 50% less under halothane than under pentobarbital, possibly due to halothane-induced systemic arterial hypotension.

Eicosanoids as a new class of ocular hypotensive agents. 3. Prostaglandin A2-1-isopropyl ester is the most potent reported hypotensive agent on feline eyes.

It has been shown that prostaglandin A2 (PGA2) is a more potent ocular hypotensive agent in cats than other PG free acids. We report here that significant IOP reduction can be achieved in normotensive cat eyes with the use of even lower doses of PGA2-1-isopropyl ester (PGA2-IE) than with PGA2, PGF2 alpha-1-isopropyl ester (PGF2 alpha-IE), or any other known ocular hypotensive agent. Furthermore, single applications of 0.5 microgram of PGA2-IE maintain significant IOP reductions for at least 24 hr. This hypotensive effect is enhanced during the first 3-5 days of daily treatment. Significant IOP reductions were maintained for several months as long as PGA2-IE was applied daily or at least once every 48 hr. None of the cats manifested signs of discomfort in response to treatment with doses ranging from 0.10 to 1.25 micrograms of PGA2-IE. Moreover, the extent of anterior chamber flare was less than that typically observed after the topical application of hypotensive doses of PGE2, PGD2, PGF2 alpha, or the esters or tromethamine salt of PGF2 alpha. Although it is possible that the human eye would respond differently to PGs of the A type, the results of these studies suggests that PGA2-IE or other esters of derived PGs of the A type, and probably the B type, may offer significant therapeutic advantages over the PGF2 alpha tromethamine salt and PGF2 alpha-IE, which have been shown to exert significant hypotensive effects on normal and glaucomatous human eyes.

In vivo videography of the rhesus monkey accommodative apparatus. Age-related loss of ciliary muscle response to central stimulation.

Fourteen rhesus monkeys, aged 1 to 24 years, underwent permanent implantation of a bipolar stimulating electrode into the Edinger-Westphal nucleus and complete unilateral or bilateral iridectomy. Slit-lamp Scheimpflug videography of the lens and slit-lamp goniovideography of the lens equator, zonule, and ciliary body allowed direct real-time observation and video recording of the movements of these structures during centrally stimulated accommodation and during disaccommodation. Scalloping of the lens capsule at the zonular insertion sites was clearly visible during disaccommodation and even during accommodation when the zonules were folded. During accommodation, the lens became axially thicker, the ciliary ring narrowed, and, at high levels of accommodation, the zonular fibers slackened and even folded and the lens moved downward. With increasing age and concomitantly decreasing accommodative amplitude, these excursions all diminished, so that in the oldest animals, they were very minimal or absent. Maximum centrally stimulated accommodative amplitude declined with age on a time scale similar to that for cholinomimetic drug-induced accommodation in the rhesus monkey and voluntary accommodation in the human.

Maintained reduction of intraocular pressure by prostaglandin F2 alpha-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, Schirmer's 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.