Comparison of the early effects of brimonidine and apraclonidine as topical ocular hypotensive agents.

OBJECTIVE: To compare the mechanism of action of short-term administration of brimonidine tartrate and apraclonidine hydrochloride as topical ocular hypotensive agents. SUBJECTS AND METHODS: Two randomized, double-masked, placebo-controlled studies of 19 normal human subjects were carried out. The first study compared brimonidine with apraclonidine in timolol maleate-treated eyes, and the second study compared latanoprost with placebo in timolol-treated eyes. The rate of aqueous flow and intraocular pressure were measured in both studies. The topical drug combinations were instilled the night before and repeated the morning before the measurements. Aqueous humor flow was measured by the rate of disappearance of topically applied fluorescein. Intraocular pressure was measured by pneumatonometry every 2 hours from 8:15 AM to 4:15 PM. RESULTS: Both brimonidine and apraclonidine further reduced aqueous flow in timolol-treated eyes from 1.23 +/- 0.21 microL/min to 0.96 +/- 0.16 microL/min and 0.98 +/- 0.17 microL/min, respectively. Consistent reductions were observed in intraocular pressure, with average reductions of 19% with brimonidine and 17% with apraclonidine. Latanoprost had no effect on aqueous flow in timolol-treated eyes (P = .15), but showed an average reduction in intraocular pressure of 13%. CONCLUSIONS: Brimonidine and apraclonidine are similar in their effects on the aqueous system. Both reduce intraocular pressure in the timolol-treated eye, primarily, if not exclusively, by further suppressing aqueous flow. In contrast, latanoprost reduces intraocular pressure in the timolol-treated eye without affecting aqueous flow.

Pediatric third, fourth, and sixth nerve palsies: a population-based study.

PURPOSE: To determine the population-based incidence and cause of cranial nerve palsies affecting ocular motility in children in the circumscribed population of Olmsted County, Minnesota. METHODS: The Rochester Epidemiology Project medical records linkage system captures virtually all medical care provided to Olmsted County residents. By means of this database, all cases of third, fourth, and sixth cranial nerve palsy were identified among county residents less than 18 years of age from 1978 through 1992. Medical records were reviewed to confirm the diagnosis, determine the cause, and document county residency. Incidence rates were adjusted to the age and sex distribution of the 1990 white population in the United States. RESULTS: Over this 15-year period, 36 incidence cases of cranial nerve palsy were identified in 35 children in this defined population. The age-adjusted and sex-adjusted annual incidence of third, fourth, and sixth nerve palsies combined was 7.6 per 100,000 (95% confidence interval, 5.1 to 10.1). The most commonly affected nerve was the fourth (36%), followed by the sixth (33%), the third (22%), and multiple nerve palsies (9%). The most common cause was congenital for third and fourth nerve palsy, undetermined for sixth, and trauma for multiple nerve palsies. Although three cases were associated with neoplasia, a cranial nerve palsy was not present at the time of diagnosis in any case. CONCLUSIONS: Unlike many institutionally based referral series, our population-based study provides data on the incidence and cause of third, fourth, and sixth nerve palsies in a geographically defined population. In contrast to previous institutionally based series, nearly half the cases were congenital in origin, and in no case did intracranial neoplasia present as an isolated nerve palsy.

Measurement of aqueous humor flow by fluorophotometry in the presence of a dilated pupil.

PURPOSE: To determine by means of fluorophotometry whether pharmacologic dilation of the pupil can interfere with the measurement of aqueous flow. METHODS: Ten normal human volunteers underwent dilation with tropicamide, phenylephrine, and a combination of the two drugs. Before and after dilation, the rate of aqueous flow was measured by the rate of disappearance of fluorescein from the cornea and the anterior chamber. RESULTS: Dilation of the pupil with tropicamide alone had no effect on the rate of clearance of fluorescein. Dilation with phenylephrine increased the rate of clearance of fluorescein by 40% and caused a small increase in the variability among subjects. Dilation with a combination of tropicamide and phenylephrine caused clearance of fluorescein at more than double the normal rate and a marked increase in variability among subjects. CONCLUSIONS: When the pupil is dilated sufficiently to permit mixing of aqueous humor in the posterior and anterior chambers, fluorescein can leave the system by a posterior route, and its rate of clearance may not be an accurate measure of the net rate of aqueous humor flow through the anterior chamber.

Additive effect of dorzolamide on aqueous humor flow in patients receiving long-term treatment with timolol.

OBJECTIVE: To determine the additive effect on aqueous humor flow of short-term dorzolamide treatment in patients with glaucoma receiving long-term treatment with timolol. SUBJECTS AND METHODS: Thirty-nine patients with glaucoma, 19 at Mayo Clinic, Rochester, Minn, and 20 at the University of Uppsala, Uppsala, Sweden, who had been receiving timolol treatment in both eyes for at least 1 year were studied. Aqueous flow was measured with fluorophotometry and intraocular pressure with tonometry. The effect of dorzolamide was compared with placebo when added to the long-term treatment regimen with timolol. RESULTS: Dorzolamide reduced aqueous humor flow by 24% +/- 11% (mean +/- SD). The intraocular pressure as compared with placebo in the US cohort was reduced by 10% +/- 6% and in the Swedish cohort by 18% +/- 9%. CONCLUSIONS: Dorzolamide, a carbonic anhydrase inhibitor, has additive effects as an ocular hypotensive agent with timolol, a beta-adrenergic antagonist, even though both drugs are suppressors of aqueous humor flow. Dorzolamide's effect on flow in these patients is the same as reported previously in normal subjects who are not taking a beta-adrenergic antagonist.

Comparison of the efficacy of apraclonidine and brimonidine as aqueous suppressants in humans.

OBJECTIVE: To measure and compare the effect of apraclonidine hydrochloride and brimonidine tartrate on the rate of aqueous humor flow in human subjects. SUBJECTS AND METHODS: Forty normal human subjects were given apraclonidine or brimonidine by topical instillation. Aqueous humor flow was measured by the rate of disappearance of topically applied fluorescein. Intraocular pressure was measured by applanation tonometry. RESULTS: Apraclonidine suppressed aqueous humor flow between 39% and 44% and lowered intraocular pressure between 20% and 23%. Brimonidine suppressed aqueous humor flow between 44% and 48% and lowered intraocular pressure between 19% and 22%. CONCLUSION: No statistically significant differences were found between the effects of the 2 drugs on aqueous humor dynamics in normal subjects.

The effect of dorzolamide on aqueous humor dynamics in normal human subjects during sleep.

OBJECTIVE: The purpose of the study was to measure the effect of the topical carbonic anhydrase inhibitor, 2% dorzolamide hydrochloride, on the rate of aqueous humor flow in sleeping humans. DESIGN: A randomized, double-masked, placebo-controlled study. PARTICIPANTS: Twenty-five normal human subjects. INTERVENTION: Topical instillation of 2% dorzolamide hydrochloride versus topical placebo. MAIN OUTCOME MEASURES: Rate of aqueous humor flow in sleeping humans and intraocular pressure immediately after awakening from sleep. RESULTS: The rate of flow in sleeping subjects at night (12 AM to 6 AM) was 1.28 +/- 0.30 microliters/min (mean +/- standard deviation; n = 25) in placebo-treated eyes, whereas the nighttime flow in dorzolamide-treated eyes was 1.17 +/- 0.38 microliters/min (P = < 0.001), resulting in a nighttime reduction of 9% (P = 0.032). In contrast, the daytime (8 AM to 4 PM) rate of flow in ambulatory subjects was 2.97 +/- 0.64 microliters/min in placebo-treated eyes and 2.60 +/- 0.63 microliters/min (P = 0.032) in dorzolamide-treated eyes, resulting in a daytime reduction of 13% (P = < 0.001). CONCLUSIONS: Topically administered dorzolamide hydrochloride is effective for reducing the rate of aqueous humor flow in normal human eyes during the day and at night during sleep. The efficacy of dorzolamide at these two times is approximately half that of systematically administered acetazolamide.

Comparison of dorzolamide and acetazolamide as suppressors of aqueous humor flow in humans.

OBJECTIVE: To compare the efficacy of topical 2% dorzolamide hydrochloride (Trusopt) as a suppressor of aqueous humor flow in the human eye with the efficacy of systemically administered acetazolamide (Diamox). DESIGN: A randomized, double-masked, placebo-controlled study of 40 human subjects in 2 academic centers. The effect of dorzolamide on aqueous humor flow was compared with that of acetazolamide as measured by the rate of clearance of topically applied fluorescein. RESULTS: Acetazolamide reduced aqueous flow from 3.18 +/- 0.70 (mean +/- SD) to 2.23 +/- 0.48 microL per minute, a reduction of 30% (P < .001), and dorzolamide reduced the flow to 2.65 +/- 0.64 microL per minute, a reduction of 17% (P < .001). The difference between the effect of acetazolamine and dorzolamide was significant (P < .001). When acetazolamide is added to dorzolamide, the aqueous flow was reduced further to 2.21 +/- 0.47 microL per minute, an additional reduction of 16% (P < .001). When dorzolamide was added to acetazolamide, no additional reduction was observed (P = .73). Similar effects were observed for intraocular pressure. Acetazolamide reduced pressure from 12.5 +/- 2.2 (mean +/- SD) to 10.1 +/- 2.2 mm Hg, a decrease of 19% (P < .001) and dorzolamide reduced it to 10.8 +/- 2.1 mm Hg, or a decrease of 13% (P < .001). The greater effect of acetazolamide than dorzolamide was significant (P = .03). CONCLUSIONS: For reasons that are not known, the topically applied carbonic anhydrase inhibitor 2% dorzolamide hydrochloride is not as effective as systemically administered acetazolamide. Clinicians who prescribe dorzolamide should expect less of an ocular hypotensive effect than that experienced from systemically administered acetazolamide.

The effects of sleep on circulating catecholamines and aqueous flow in human subjects.

We measured the rate of aqueous flow and analysed its relation to the time of day, the state of wakefulness and the urinary excretion of catecholamines. Two groups of subjects were studied. One group comprised 20 normal subjects who were studied over two 22-hr periods. During one period, the subjects were permitted to sleep during their customary hours of sleep; during the other, they were not permitted to sleep, but remained active for all 22 hr. The other group comprised ten subjects with obstructive sleep apnea who were studied over a 22-hr period and slept during their customary hours of sleep but without the aid of any respiratory device. Aqueous flow was measured with fluorophotometry. Motion of the wrist was monitored by a seismograph (wrist Actigraph) and served as a surrogate of activity and wakefulness. Urinary catecholamine excretion was measured during different periods of the wake/sleep cycle. Both groups exhibited the normal nocturnal suppression of flow (59% lower compared to morning in the normal group; 56% lower compared to morning in the apneic group). During sleep deprivation, the rate of flow at night in normal subjects was 30% lower than during the morning (P < 0.001) and 60% higher than during sleep (P < 0.001). Lid closure during sleep deprivation had no effect on the results. Aqueous flow correlated with a 'catecholamine index', derived from the combined excretion of epinephrine and norepinephrine. Flow also correlated with an 'activity index', and 'sleep efficiency', indices derived from motion of the wrist. We conclude that the day-night difference of aqueous humor flow as measured by clearance of fluorescein from the human eye is driven partly by a factor that has a circadian rhythm and partly by a factor that depends on the activity of the subject. We hypothesize that these factors are the catecholamines, epinephrine and norepinephrine.

Topically applied hydralazine: effects on systemic cardiovascular parameters, blood-aqueous barrier, and aqueous humor dynamics in normotensive humans.

Local application of hydralazine has been found to alter intraocular pressure in animal eyes. This study was undertaken to determine, in normotensive humans, the effects of topically-applied hydralazine on systemic cardiovascular parameters, blood-aqueous barrier, and aqueous humor flow. Two different concentrations of hydralazine were used: 0.03%, and 0.1%. Twenty healthy normotensive subjects were studied. Blood pressure, pulse rate, and intraocular pressure were measured every hour for six hours after hydralazine or placebo was instilled into the conjunctival sac in a double-masked, randomized fashion. With either hydralazine dose, there was no significant change in systemic blood pressure or pulse. In addition, spectrophotometrically-measured polarization of fluorescence and flare failed to show any significant breakdown of the blood-aqueous barrier. In most individuals, application of hydralazine was followed by a brief, mild to moderate, conjunctival hyperemic response. Compared to placebo at the same time of day, a small increase in intraocular pressure was observed with 0.03% hydralazine (p < .05). At 0.1%, this increase tended to be less. There was no statistically significant difference in aqueous humor flow between hydralazine-treated and placebo-treated eyes at the lower concentration (3.20 +/- 0.63 vs. 3.05 +/- 0.61 microL/min (mean +/- S.D.) or at the higher concentration (3.37 +/- 0.53 vs. 3.28 +/- 0.60 microL/min) of hydralazine. These results suggest that acute topical application of 0.1% hydralazine to the eyes of normal humans does not cause clinically significant cardiovascular effects or significant ocular toxicity.

Aqueous flow in humans after adrenalectomy.

PURPOSE: This study was performed to determine if the circadian rhythm of aqueous humor formation and the aqueous humor suppressing effect of beta-adrenergic antagonists can occur in the absence of adrenally derived epinephrine. METHODS: Twenty-one human subjects who had undergone bilateral adrenalectomy were studied during a 28-hour period. The study was divided into four time periods as follows: morning 1 (8 AM to noon), afternoon (noon to 4 PM), night (midnight to 6 AM), and morning 2 (8 AM to noon). At 6:45 AM before the morning 2 measurements, one drop of 0.5% timolol was applied to one eye and one drop of placebo (artificial tears) was applied to the other eye. Topical fluorescein and a scanning fluorophotometer were used to measure the rate of aqueous humor flow. Twenty normal controls were studied in a similar fashion but did not undergo the morning 2 measurement. RESULTS: In the subjects lacking adrenals, the daytime rates of aqueous flow were 3.17 +/- 0.78 microliters/min (mean +/- SD) and 3.16 +/- 0.67 microliters/min for the morning 1 and afternoon periods, respectively. The rates in daytime periods were not significantly different from each other (P = 0.699). The rate of aqueous flow for the night period was 1.37 +/- 0.37 microliters/min, a 57% reduction from both morning 1 and afternoon periods (P < 0.001). The morning, afternoon, and night rates of flow in normal controls were not significantly different from the rates in subjects lacking adrenals. For the morning 2 period, the aqueous flow was 2.74 +/- 0.54 microliters/min for the placebo-treated eye and 1.77 +/- 0.38 microliters/min for the timolol-treated eye. The rate of aqueous flow was reduced (35%) in the timolol-treated eye when compared to the fellow placebo-treated eye (P < 0.001). The timolol-treated eye also showed a 26% reduction in intraocular pressure when compared to the fellow placebo-treated eye (P < 0.001). CONCLUSION: The study demonstrates that both the circadian rhythm of aqueous flow and the daytime response to timolol persist in the absence of the adrenal glands.

Ocular effects of scopolamine dermal patch in open-angle glaucoma.

The purpose of this study was to determine the effect of transdermal scopolamine patches on intraocular pressure, pupil size, anterior chamber volume, and accommodation in patients with open-angle glaucoma. Forty patients with chronic open-angle glaucoma participated in a double-masked randomized, placebo-controlled study. Of these 40 glaucoma patients, 20 were on treatment regimens that included pilocarpine (Pilo Group) and 20 were on treatment regimens that excluded pilocarpine or any other cholinergic drug (Non-Pilo Group). For both groups, there was a significant increase in pupil size, anterior chamber volume, and near point on the scopolamine day compared to the placebo day. The pupil size, as measured by pupillography, was increased 17% for the Pilo group and increased 12% for the Non-Pilo group. The volume of the anterior chamber, as measured by photograrmmetry, was increased 8% for the Pilo group and increased 11% for the Non-Pilo group. The near point receded 12% for the Pilo group and receded 19% for the Non-Pilo group. We were unable to detect any statistically significant differences in intraocular pressure for either group. Minimal side effects were reported from both groups. We conclude that it is safe for patients with open-angle glaucoma to use transdermal scopolamine patches.

A comparison of two methods of measuring aqueous flow in humans: fluorophotometry and flare measurement.

The technique of Anjou and Krakau for measuring flare and Krakau's method for estimating aqueous humor flow in humans was compared to the fluorophotometric procedure of Jones and Maurice. The precision of flare was measured in 20 normal human volunteers, and the precision of flow was measured with fluorophotometry in 24 volunteers. In addition, the circadian rhythms of both flow and flare were measured simultaneously in a separate group of 20 subjects. This simultaneous measurement allowed us to calculate the entry rate of scattering substances into the aqueous humor as a function of time of day. This entry rate is critical for measuring flow by the method of Krakau. The mean coefficient of variation (+/- SD) of repeated measurements of flare at the same time of day was 23.2% +/- 10.3%. The mean coefficient of variation of the measurement of aqueous flow by fluorophotometry was 15.9% +/- 8.2%, significantly better than the measurement of flare (p = 0.01). The daytime entry rate of scattering substances into the aqueous humor varied from 1.39 +/- 0.86 microgram/min (calculated as albumin) to 1.05 +/- 0.58 microgram/min. The rates in daytime hours were not significantly different from each other. At night during sleep, the entry rate was 0.67 +/- 0.48 microgram/min, significantly slower (p between 0.002 and < 0.001). These data indicate that the flare technique cannot be used alone to calculate the circadian rhythm of flow and that direct measurement of flow by fluorescein clearance is likely to be the most repeatable and accurate of the two.