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Biomedical subjects

R F Brubaker

Publications and source records attributed to R F Brubaker.

At least 73 records · Page 4Linked to original sources

Apraclonidine and timolol. Combined effects in previously untreated normal subjects.

Twenty healthy subjects were tested for the aqueous-suppressing effects of the alpha 2-adrenergic agonist apraclonidine hydrochloride. Apraclonidine caused a 30% reduction of mean (+/- SD) aqueous flow during the daytime from 2.84 +/- 0.61 microL/min, similar to what has been observed for beta-adrenergic antagonists. Apraclonidine, like acetazolamide and unlike timolol maleate, was able to suppress the aqueous flow of sleeping subjects below the spontaneous nocturnal rate of 1.15 +/- 0.40 microL/min to 0.84 +/- 0.28 microL/min, a 27% change. When apraclonidine and timolol were given together in the daytime, no clinically significant or statistically significant additive effect was observed. The range of flows with either drug alone or the combination of the two measured from 2 to 4 PM was 1.41 to 1.78 microL/min. This result contrasts with studies of the effect of apraclonidine on patients who have received long-term beta-blockers where an additive effect is observed. The lack of an additive effect on flow in previously untreated normal subjects suggests that the two drugs act at least in part via a common pathway.

Administration, Topical↗

Topical flurbiprofen pretreatment does not block apraclonidine's effect on aqueous flow in humans.

Flurbiprofen's effect on the ability of apraclonidine hydrochloride (para-aminoclonidine) to reduce aqueous humor flow was studied in 20 healthy human volunteers. Flurbiprofen sodium, in a 0.03% concentration, was administered topically to one eye and a placebo to the contralateral eye of each subject in a random, double-masked fashion. A total of four drops was administered to each eye during a 30-minute period beginning at 7 AM. Thirty minutes later, one drop of 1% apraclonidine was instilled into each eye. Flow rates were measured with fluorophotometry from 7 AM to noon. The mean (+/- SD) rate of flow after administration of flurbiprofen and apraclonidine at the peak of apraclonidine's effect was 1.56 +/- 0.50 microL/min, and after administration of placebo and apraclonidine was 1.53 +/- 0.43 microL/min. With a sample size of 20 and a coefficient of variation of flow measurement of 15%, there is a 95% chance of detecting a difference in flow rate of 15% or greater using the techniques employed in this study. Since there was no statistically significant difference between the rates of flow under the two conditions, we conclude that flurbiprofen has no appreciable effect on apraclonidine's ability to suppress aqueous flow.

Administration, Topical↗

Effect of apraclonidine in long-term timolol users.

A double-blind, randomized study was undertaken to determine if the alpha-agonist apraclonidine has an additive effect in eyes treated with long-term timolol. Seventeen patients (15 with primary open-angle glaucoma, 1 with pigmentary glaucoma, and 1 glaucoma suspect) on long-term timolol treatment in both eyes received a single dose of apraclonidine in one eye and a placebo in the other. Aqueous flow and intraocular pressure were compared in the treated and untreated eyes. There was no statistically significant difference in pretreatment aqueous flow between the two eyes. When flow in the apraclonidine-treated eyes (1.39 +/- 0.41 microliter/min, mean +/- standard deviation) was compared with that of the untreated eyes (1.66 +/- 0.38 microliter/min), a statistically significant difference was found (P less than 0.01). Apraclonidine reduced intraocular pressure by 1.3 mmHg (P = 0.05). The implications of these findings on the understanding of the mechanism of action of adrenergic drugs in the human eye is discussed.

Adrenergic alpha-Agonists↗

The correlation between serum progesterone and aqueous dynamics during the menstrual cycle.

Exogenously-administered progesterone has been shown to lower intraocular pressure. However, attempts to correlate endogenous progesterone levels and aqueous dynamics have produced inconsistent results. In this study, 20 healthy, non-pregnant women were followed over a 28-day menstrual cycle. Serum progesterone level, intraocular pressure, and aqueous flow rate were measured weekly. We were unable to demonstrate any correlation between progesterone levels and either aqueous flow or intraocular pressure.

Adult↗

Flow of aqueous humor in humans [The Friedenwald Lecture].

Based on clinical experiments with fluorophotometry, several observations can be made about aqueous flow through the chambers of the human eye. 1. The rate of flow is 2.75 +/- 0.63 microliters/min in normal subjects, as derived from measurements averaged during normal office hours. The normal range (95%) is 1.8 to 4.3 microliters/min. 2. There is a circadian rhythm of flow, with the highest rates during morning hours, slightly lower rates during afternoon hours, and rates during sleep that are approximately one half of those during the morning. The hormonal basis for this rhythm is unknown, but it is known to be present in both eyes of persons with unilateral Horner's syndrome. 3. A slight decline of the rate occurs after age 10 yr--3.2% per decade. There is no significant difference in aqueous flow between men and women. 4. Of the hundreds of drugs that are used clinically, most are unlikely to have a significant effect on aqueous flow. Exceptions are the beta-adrenergic agonists that, under certain circumstances, are able to increase flow, the corticosteroids that may have a stimulating effect on flow, and three classes of drugs that have therapeutically useful suppressing effects on flow: carbonic-anhydrase inhibitors, beta-adrenergic antagonists, and alpha 2-selective adrenergic agonists. 5. Timolol, which has a remarkably consistent suppressing effect on flow during the day, has no effect on the flow of sleeping subjects. By contrast, acetazolamide and apraclonidine are able to reduce the flow of sleeping subjects. 6. Acute doses of beta-adrenergic antagonists and alpha 2-agonists are not additive, but beta-adrenergic antagonists and carbonic-anhydrase inhibitors are partly additive. 7. The eye adapts partly to the chronic use of timolol and recovers from its effects when it is discontinued. 8. The rate of disappearance of the effect of beta-adrenergic antagonists is longer for the noncardioselective agents, such as timolol and levobunolol, but is relatively short for the cardioselective agent, betaxolol. 9. The rate of aqueous flow is insensitive to moderate changes of intraocular pressure. Clinical studies can provide suggestive leads for more basic investigations or test specific hypotheses. Biochemical, biologic, and pharmacologic approaches in simpler, more controlled experimental conditions are necessary to determine the fundamental processes that bring about aqueous formation in the living eye. The combination of many disciplines (eg, studying molecules, cells, tissues, organs, and the intact living system) has the best chance of furthering our understanding of the aqueous circulation.

Animals↗

The nocturnal suppression of aqueous humor flow in humans is not blocked by bright light.

Normal human subjects were studied hourly by fluorophotometry to measure the normal circadian rhythm of aqueous humor flow. On a separate day, the subjects slept for approximately 1 hr after lunch; this short nap was not found to have any effect on aqueous flow. On a separate night, the subjects slept under a bright light of 2500 lux; the light was not found to have any effect on flow in the sleeping subjects. Because bright light blocks melatonin release in humans, nocturnal suppression of aqueous flow in humans may not be driven by systemic melatonin release.

Aqueous Humor↗

Effect of chronic epinephrine on aqueous humor flow during the day and during sleep in normal healthy subjects.

Epinephrine 2% drops were administered to one eye and a placebo to the fellow eye twice a day for 2 weeks in 18 normal human volunteers. The circadian rhythm of aqueous humor flow was measured by fluorophotometry. Epinephrine (compared with placebo) had no measurable effect on the rate of aqueous flow or the circadian rhythm of aqueous humor flow. These results suggest either that topical application of epinephrine cannot achieve a sustained effect on the mechanism of aqueous formation compared with endogenous epinephrine or that circulating epinephrine is not the sole or principal hormonal messenger that mediates the circadian rhythm of aqueous flow in humans. An experiment in which epinephrine was administered systemically might clarify this ambiguity.

Aqueous Humor↗

Calibration of measurements in vivo of fluorescein in the cornea.

Quenching of fluorescence of fluorescein is not observed with broad field fluorophotometers. Fluorophotometric equipment which measures the fluorescence in a tiny spot has, however, been reported to underestimate the molarity of fluorescein in the rabbit corneal stroma by as much as a factor of two. In this experiment, quenching was measured in the rabbit cornea with two scanning fluorophotometers. The quenching was measured by four different techniques: (1) by elution of fluorescein, (2) by elution of albumin, (3) by polarization of fluorescence, and (4) by spectrofluorophotometry. It was estimated by all four methods that quenching in the living rabbit cornea with these instruments is approximately 20%. Taken together, the four experiments suggest that the quenching of fluorescence of fluorescein can be explained entirely on the basis of the interaction of fluorescein and albumin in the stroma.

Animals↗

The fluorescent indicator pyranine is suitable for measuring stromal and cameral pH in vivo.

Three pH-sensitive fluorescent indicators (fluorescein, bis-carboxyethyl-carboxyfluorescein and pyranine) were studied to determine their usefulness as probes for the living cornea and anterior chamber. Of the three dyes, pyranine had properties which render it almost ideally suited for this purpose. Adequate concentrations are reached in the cornea and anterior chamber after topical administration; measurements can be made by fluorophotometry for many hours. The pH is calculated by measuring the ratio of fluorescent intensity at two excitation wavelengths, I463/I404, a measurement which is dependent on pH but independent of the concentration of the fluorophore and other variables which can alter the intensity. In the rabbit eye, pyranine in the cornea and anterior chamber was observed to undergo easily measurable changes in fluorescent ratios associated with lid closure and contact lens wear, indicating its sensitivity to mild changes in pH.

Albumins↗

Caffeine has no clinically significant effect on aqueous humor flow in the normal human eye.

The effect of orally administered caffeine (400 mg) on aqueous humor flow was studied in 20 normal human subjects. The rate of aqueous flow was measured by fluorophotometry. There was no statistically significant difference in aqueous flow measured hourly from 1 to 4 hours after the administration of caffeine. There also was no statistically significant difference in intraocular pressure (IOP) measured 4 hours after caffeine ingestion. The sample size was large enough to have detected a 15% change in flow, had it occurred.

Administration, Oral↗

Rate of flow of aqueous humor determined from measurements of aqueous flare.

Measurement of light scattered in the anterior chamber can provide important clinical information about the eye. In this study, a scanning ocular spectrofluorophotometer was used to measure scattering in the anterior chamber. Pathologic scattering (flare) was induced by argon laser photocoagulation of the iris in pigmented rabbits. The spectrally corrected intensity of the flare in inflamed eyes decreased as the inverse 2.2 power of the wavelength of the illuminating beam. The strongest signal with this instrument was measured at 470 nm. Diurnal variation of normal and spontaneous scatter from the aqueous humor was measured in nine pigmented rabbits entrained to a 12-hr light/12-hr dark cycle and in eight human subjects. A technique is described for determining the rate of flow of aqueous humor from scattered light when the transfer rate of scattering substance into the anterior chamber is constant. This technique was used to study changes in flow over the diurnal cycle. The rate of flow in human subjects during sleep was 60% of the rate during waking hours. In rabbits, the rate was lowest (44% of maximum) during the 6 hr after the lights were turned on, and were greatest just before the lights were turned on. These findings confirm previous studies of the circadian rhythm of aqueous humor flow in rabbits and humans.

Animals↗

Comparison of a noncardioselective beta-adrenoceptor blocker and a cardioselective blocker in reducing aqueous flow in humans.

In a double-masked crossover study, the dose-response relationship for aqueous flow was determined for four concentrations of betaxolol hydrochloride and levobunolol hydrochloride in 19 normal subjects. One eye of each subject received every concentration of both drugs. Each concentration was administered once daily for 1 week. The fellow eye received a placebo. Aqueous flow was measured for several hours on the last day of administration of each concentration beginning immediately after drug administration. For levobunolol, the mean decrease in aqueous flow compared with baseline was 8% after 1 week's treatment with 0.017% levobunolol, 15% after treatment with 0.05%, 20% after treatment with 0.167%, and 32% after treatment with 0.5%. For betaxolol, the mean decrease in aqueous flow compared with baseline was 3% after 1 week's treatment with 0.017% betaxolol, 12% after treatment with 0.05%, 18% after treatment with 0.167%, and 17% after treatment with 0.5%. Levobunolol-treated eyes but not betaxolol-treated eyes showed a significant drug effect 1 week after discontinuing the drug therapy. The relative potency of the noncardioselective drug was greater than that of the beta 1-cardioselective drug, but the difference in potency was much less than would be expected solely based on their relative affinity for beta 2-receptors in other species and tissues.

Adrenergic beta-Antagonists↗

A study of the relation between intraocular pressure and aqueous humor flow in the pigment dispersion syndrome.

Forty subjects with pigment dispersion syndrome with and without intraocular pressure (IOP) elevation were compared with 40 age-matched controls. Intraocular pressure, resistance to outflow, and the rate of flow of aqueous humor were compared. Eyes with higher IOP and higher resistance to outflow were found to have a normal rate of aqueous flow. The results are interpreted as demonstrating that moderate and chronic elevation of IOP in the adult human eye does not induce a chronic compensatory reduction of aqueous humor flow.

Adult↗

Modification and calibration of the Bigliano-Webb Tonometer for improved accuracy of tonometry in rabbits.

The Bigliano-Webb Tonometer (Pneumatonograph) was calibrated for adult and young rabbit eyes using open stopcock and closed stopcock methods. The performance of an old and new instrument were compared illustrating the importance of recent calibration of the instrument for most accurate use. The fact that this tonometer is a high displacement tonometer which requires specific calibration, not only for species but for age of the animal (or size of the eye) is illustrated. A minor modification of the instrument--reducing the setting of a pressure regulator which supplies gas to the tip from its nominal 9 PSI to 2.5 PSI--is illustrated as a method of reducing the difference between intraocular pressure before tonometry and during tonometry, Pt-Po.

Animals↗

Is the high concentration of ascorbic acid in the eye an adaptation to intense solar irradiation?

Ascorbic acid is known to exist in high concentration in the aqueous humor of the eye in many species. It has been observed that diurnal mammals have a very high concentration in aqueous humor whereas nocturnal mammals do not. It has been hypothesized that ascorbic acid protects the eye from the harmful effects of sunlight. We have discovered that of two closely related species of spiny mice, the diurnal species (Acomys russatus) has a concentration in aqueous humor that is 35 times higher than that of the nocturnal species (Acomys cahirinus). Studies of these two species may be fruitful to extend what is known about adaptation of the eye to protect itself from intense solar radiation.

Adaptation, Physiological↗

Thymoxamine reverses phenylephrine-induced mydriasis.

We performed a randomized double-masked evaluation of the alpha-adrenergic blocking agent thymoxamine (0.1%) as compared to placebo for the reversal of phenylephrine-induced mydriasis. Topically applied thymoxamine reversed the mydriasis from a single drop of 2.5% phenylephrine in 36 of 40 eyes (90%) within one hour. The mydriasis was completely reversed in 25 of 40 eyes (63%). Eyes with blue irides responded more quickly and more completely than did those with brown irides. The 40 contralateral eyes, which had also been dilated with phenylephrine, remained dilated or dilated further after receiving a placebo eyedrop. Twenty subjects (50%) reported mild transient ocular irritation upon instillation of thymoxamine. Thymoxamine was useful in individuals with narrow anterior chamber angles who were at risk of acute closed-angle glaucoma following dilation with an adrenergic agent.

Adult↗