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Effect of Ibopamine on Aqueous Humor Production in Normotensive Humans

¹From the Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota; and the ²Medical Department, Angelini Pharmaceuticals, Inc., ACRAF SpA, Rome, Italy.

	Abstract

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PURPOSE. Ibopamine is a prodrug of epinine (deoxyepinephrine) that exhibits activity at dopaminergic and adrenergic receptors. Topical ocular application has been shown to cause mydriasis without cycloplegia and to increase the rate of aqueous humor flow in normotensive human eyes. Mydriasis can interfere with the measurement of aqueous flow. In this study ibopamine’s effect on aqueous humor production was measured while making allowance for the potential artifact caused by its mydriatic effect.

METHODS. The effects of topical ibopamine on pupillary diameter, aqueous humor flow measured by fluorophotometry, and intraocular pressure were studied in 24 healthy, blue-eyed humans. Ibopamine was administered with and without the -adrenergic antagonist dapiprazole, and its effects were compared with those of tropicamide, with and without dapiprazole in a double-masked, randomized, crossover design.

RESULTS. Ibopamine dilated the pupil from a diameter of 3.7 ± 0.64 (mean ± SD, n = 24) to 7.7 ± 0.70 mm. Ibopamine, during its peak mydriasis, was associated with a very large increase in the rate of clearance of topically applied fluorescein from the cornea and anterior chamber, an effect that was not associated with tropicamide during its peak mydriasis. The mydriatic effect of ibopamine was completely blocked by dapiprazole, and the increase in fluorescein clearance was partially blocked. When mydriasis was blocked, ibopamine increased fluorescein clearance by 13% (P < 0.0001), which was interpreted as an increased rate of aqueous humor production. Compared with placebo and with the tropicamide control, ibopamine decreased intraocular pressure, despite its stimulation of aqueous humor flow.

CONCLUSIONS. Ibopamine is in a specific class of drug, along with pilocarpine, epinephrine, and bimatoprost that in humans increases the rate of aqueous humor flow as measured by fluorophotometry. This effect is partly responsible for its ability to increase intraocular pressure in persons suspected to have abnormally low aqueous humor outflow facility. The transient apparent doubling of aqueous humor flow, measured by fluorescein clearance after administration of ibopamine is an artifact of increased fluorescein clearance through the dilated pupil while accommodation is active.

Virno et al.¹⁰ studied the aqueous humor dynamics of 12 human subjects, six with healthy eyes and six with glaucoma, and found that ibopamine increased the calculated rate of aqueous humor production remarkably, but increased intraocular pressure only in the glaucomatous eyes. This finding led to the study of ibopamine as an adjunctive treatment of ocular hypotony after vitreoretinal surgery.⁶

The ability of ibopamine to increase aqueous humor production puts it into a nearly unique class. Only three other compounds have been shown to increase aqueous humor production in humans: pilocarpine,¹¹ bimatoprost,¹² and epinephrine.¹³ The effects of pilocarpine (a cholinergic compound)¹¹ and bimatoprost (a prostamide compound)¹² are barely measurable and are of no clinical significance. Epinephrine has the strongest effect, whether administered topically¹³ or intravenously,¹⁴ but the effect is still relatively small compared with the normal rate of aqueous secretion. Dopamine at low infusion rates increased aqueous humor flow by approximately 30% in rabbits, although at high infusion rates it decreased the flow rate.¹⁵ Because epinine stimulates dopamine receptors, it is not surprising that its prodrug ibopamine has been found to increase aqueous humor production. The magnitude of its effect is surprising, however; Virno et al.¹⁰ estimated flow rates more than twice the untreated rates.

Ibopamine, in addition to its other effects, causes mydriasis without cycloplegia.² Under this condition, fluorescein, used to measure aqueous flow, may not be completely contained within the anterior chamber but could leak into the posterior chamber. With this loss, the rate of clearance of fluorescein would no longer be a reliable measure of the rate of aqueous humor formation. Maus and Brubaker¹⁶ demonstrated this artifact by measuring fluorescein clearance after topically administering phenylephrine and tropicamide.

The mechanism of action of ibopamine is the key to its clinical application as a provocative test in glaucoma and to its potential use in the treatment of hypotony. In this study we measured ibopamine’s effect on aqueous humor production while we blocked or controlled for mydriasis.

	Methods

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Twenty-four healthy blue-eyed white subjects aged 22 to 40 years were studied in a randomized, double-masked, paired-comparison, crossover design. Participants were screened for eligibility and had two normal well-matched eyes and no eye disease or current use of topical medications. Subjects were excluded if they had narrow iridocorneal angles based on the ratio of the depth of the temporal anterior chamber to corneal thickness of less than 4 or an anterior chamber volume less than 120 µL. Each subject gave written informed consent to participate. This study was reviewed and approved by the Institutional Review Board of the Mayo Clinic and adhered to the tenets of the Declaration of Helsinki.

Each subject was studied on three separate days (sessions A, B, and C) separated by at least 1 week. During each of these sessions intraocular pressure, diameter of the pupil, fluorescein concentration in the anterior chamber and cornea, and intraocular pressure were measured in the same sequence. Pupil diameter and fluorescence in the anterior chamber and cornea were measured at 07:45 and 08:15, and then hourly until 16:15. Estimates of aqueous humor flow represented the mean flow rate during the interval between fluorescence measurements and were graphed at the midpoint of the interval. Drugs or placebos were instilled at 08:00, 08:45, 09:45, and 10:45. Intraocular pressure was measured at 12:30 and 16:30.

In each session, two drugs or placebos were administered topically, one 5 minutes after the other, to each eye. All eyedrops were administered from code-labeled containers by one technician; another technician measured all variables. In preparing for a session, the subject self-administered 2% fluorescein eye drops 6 hours before the first fluorescence measurement. Drugs used in the study were: ibopamine hydrochloride 2% ophthalmic solution (Tubilux, Pomezia, Italy), tropicamide 1% ophthalmic solution (Bausch & Lomb Pharmaceuticals, Tampa, FL), dapiprazole hydrochloride 0.5% ophthalmic solution (Bausch & Lomb Pharmaceuticals), and a placebo (HypoTears PF Lubricant Eye Drops; Ciba Vision, Duluth, GA). For each subject, the order of the three sessions was randomized as was the left eye–right eye assignment of the drug combination, as shown in Table 1 . We will refer to the eye that received the ibopamine as the "treated eye" and the eye that received the tropicamide as the "control eye."

(1)

where M_f is the loss of mass of fluorescein from the combined cornea and anterior chamber during an interval t, is the average concentration of fluorescein in the anterior chamber during the same interval (estimated from the initial and final concentrations assuming an exponential decay), and 0.25 µL/min is the assumed flow rate equivalent to the diffusional loss of fluorescein from the eye.¹⁹ Aqueous humor flow rate was estimated at 1-hour intervals, except for the first interval, which was 30 minutes.

The diameter of the pupil was measured in ordinary room light (100–300 ft-cd) by comparing the appearance of the pupil with a series of solid black circles, of diameters 2.0 to 9.0 mm in increments of 0.5 mm, on a white background.

The intraocular pressure was measured with a pneumatonometer (Mentor O&O, Inc., Norwell, MA) at 12:30 and 16:30. One drop of anesthetic (proparacaine hydrochloride; Bausch & Lomb Pharmaceuticals) was placed in each eye. Three consecutive measurements of intraocular pressure in the right eye were averaged and three consecutive measurements of intraocular pressure in the left eye were averaged.

Significance of differences between treated and control eyes was tested by using two-sided paired t-tests ( = 0.05). In previous studies of normal subjects, the mean aqueous humor flow rate was 2.80 µL/min and the SD of the difference between aqueous humor flow rate in left and right eyes was 0.45 µL/min. The sample size of 24 was selected to provide a 95% chance of detecting a statistically significant difference of 12% or more in the rate of aqueous humor flow ( = 0.05, two-sided paired t-test).

The relationship between aqueous humor flow rate and pupil diameter was examined by calculating Spearman’s correlation coefficient (data were nonnormally distributed). Flow rates estimated on each 1-hour interval (starting with the interval from 08:15–09:15) were paired with the mean of the pupil diameters at the beginning and end of the interval. The relationship between intraocular pressure and aqueous humor flow rates was examined by calculating the Pearson’s correlation coefficient and its significance in a similar way. Flow rates estimated on the intervals from 12:15 to 13:15 and 15:15 to 16:15 were paired with intraocular pressures measured at 12:30 and 16:30, respectively.

	Results

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Session A—Treated Eye: Placebo, Placebo; Control Eye: Placebo, Placebo
Pupil diameters of the treated eyes (range of means, 3.7–3.8 mm) and the control eyes (range of means, 3.7–3.8 mm) were steady throughout the 8 hours of measurement. The rate of aqueous humor flow was slightly lower in the afternoon than it was in the morning. During the 8 hours of measurement, the flow rate in the treated eyes was 2.82 ± 0.54 µL/min (mean ± SD, n = 24) and in the control eyes was 2.79 ± 0.52 µL/min (Figs. 1 2) .

View larger version (19K): [in this window] [in a new window]   FIGURE 1. Pupil diameter during sessions A (treated eye: placebo, placebo; control eye: placebo, placebo) and B (treated eye: ibopamine, placebo; control eye: tropicamide, placebo). Ibopamine and tropicamide dilated pupils by nearly the same amount. *Time of instillation of test solutions; , placebo-placebo instilled in the treated eye; , placebo-placebo instilled in the control eye.

View larger version (20K): [in this window] [in a new window]   FIGURE 2. Aqueous humor flow rate during sessions A (treated eye: placebo, placebo; control eye: placebo, placebo) and B (treated eye: ibopamine, placebo; control eye: tropicamide, placebo). The mean estimated aqueous humor flow transiently doubled after ibopamine. Tropicamide did not change the flow rate. Symbols are as in Figure 1 .

Session B—Treated Eye: Ibopamine, Placebo; Control Eye: Tropicamide, Placebo
Both ibopamine and tropicamide dilated the pupil as expected. The onset of tropicamide’s effect was somewhat sooner and longer lasting than ibopamine’s effect. Mean pupil diameter increased from 3.7 ± 0.64 mm at 07:45 in both eyes to 7.7 ± 0.70 mm in the ibopamine-placebo–treated eye and 7.5 ± 0.67 mm in the tropicamide-placebo–treated eyes at 10:15. This difference was not statistically significant during the peak response, from 09:15 to 12:00 (Fig. 1) .

Tropicamide had no significant effect on the estimated aqueous humor flow. The mean flow in the tropicamide-placebo control eyes was 2.72 ± 0.51 µL/min, whereas mean flow in the placebo-placebo control eyes was 2.79 ± 0.52 µL/min. In contrast, the aqueous humor flow calculated in the ibopamine-placebo–treated eyes increased to a peak of 7.77 ± 5.0 µL/min at 09:45 and descended to 2.81 ± 0.43 µL/min by 15:45 (Fig. 2) . Average flow rates during the corresponding intervals of session A (placebo-placebo) were 2.92 ± 0.71 µL/min and 2.64 ± 0.44 µL/min (P < 0.0001 and P = 0.11, flow during session B compared with flow during session A at 09:45 and 15:45, respectively).

Tropicamide had no significant effect on intraocular pressure at 12:30 but increased pressure slightly at 16:30, compared with placebo (session A). At 12:30 the intraocular pressure in the tropicamide-placebo control eyes was 17.3 ± 2.1 mm Hg, whereas pressure in the placebo-placebo control eyes was 17.0 ± 2.0 mm Hg. At 16:30 intraocular pressure in the tropicamide-placebo control eyes was 16.8 ± 2.3 mm Hg, slightly higher than the 15.9 ± 2.2 mm Hg in the placebo-placebo control eyes (P = 0.05). In contrast, intraocular pressure in the ibopamine-placebo–treated eyes at 12:30 was 15.9 ± 2.4 mm Hg and at 16:30 was 13.5 ± 2.1 mm Hg. These were lower than intraocular pressures in the same placebo-placebo–treated eyes and in the same contemporaneous tropicamide-placebo–treated eyes at both times (P < 0.0001).

Session C—Treated Eye: Ibopamine, Dapiprazole; Control Eye: Tropicamide, Dapiprazole
Dapiprazole completely blocked the pupillary dilation by ibopamine and partly blocked the dilation by tropicamide (Figs. 3 4) .

View larger version (18K): [in this window] [in a new window]   FIGURE 3. Pupil diameter in treated eye during the three sessions. Dapiprazole blocked pupil dilation by ibopamine. Symbols are as in Figure 1 .

View larger version (19K): [in this window] [in a new window]   FIGURE 4. Pupil diameter in control eye during the three sessions. Dapiprazole partially blocked pupil dilation by tropicamide. Symbols are as in Figure 1 .

View larger version (18K): [in this window] [in a new window]   FIGURE 5. Dapiprazole blocked the transient increase in calculated aqueous humor flow rate induced by ibopamine. Symbols are as in Figure 1 .

View larger version (17K): [in this window] [in a new window]   FIGURE 6. Ibopamine increased the calculated aqueous humor flow rate by 13% compared with tropicamide, in the presence of dapiprazole. Symbols are as in Figure 1 .

View larger version (17K): [in this window] [in a new window]   FIGURE 7. Tropicamide in combination with dapiprazole had no effect on flow compared with placebo-placebo or to tropicamide-placebo. Symbols are as in Figure 1 .

Correlations of Flow with Pupil Diameter and Intraocular Pressure
To help understand the relation between the diameter of the pupil and the calculated rate of aqueous humor flow, flow estimated for each 1-hour interval was graphed as a function of mean pupil diameter. Spearman’s correlation coefficients and the significance of the correlation for each drug combination are given in Table 2 . In eyes treated only with placebo, aqueous humor flow correlated weakly with pupil diameter, although in eyes treated with tropicamide combined with either placebo or dapiprazole aqueous humor flow did not correlate with pupil diameter (Fig. 8) . Only one subject with each of these treatments had estimates of flow rate greater than 5 µL/min, regardless of pupil diameter.

View larger version (22K): [in this window] [in a new window]   FIGURE 8. Aqueous humor flow correlated weakly with pupil diameter in eyes that were treated with placebo-placebo in session A. The least-squares regression lines from the two eyes in session A were not distinguishable (solid line). Aqueous humor flow did not correlate with pupil diameter in eyes treated with tropicamide, combined with either placebo or dapiprazole. Symbols are as in Figure 1 .

View larger version (24K): [in this window] [in a new window]   FIGURE 9. Aqueous humor flow correlated with pupil diameter in eyes treated with ibopamine-placebo (solid line) or ibopamine-dapiprazole (dashed line). Regression lines were determined by the method of least squares. Symbols are as in Figure 1 .

	Discussion

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This study confirms the potent and relatively short mydriatic effect of topical ibopamine.⁴ Like phenylephrine, this effect is mediated by -adrenergic receptors in the dilator of the iris and is antagonized by the -adrenergic antagonist dapiprazole.

The study also confirms the great increase in the clearance rate of fluorescein from the anterior chamber after instilling ibopamine,¹⁰ an effect that was not completely blocked by dapiprazole. The rate of clearance correlated strongly with pupil size in the ibopamine-treated eyes but only weakly or not at all under the other treatments. One interpretation of these results is that ibopamine is an extremely potent stimulator of aqueous humor production and that this effect is inhibited by the -adrenergic antagonist dapiprazole. However, several aspects of this and previous studies of aqueous humor dynamics suggest that this interpretation may not be correct.

The clearance of fluorescein from the combined cornea and aqueous humor is an accurate measure of bulk flow of aqueous humor through the anterior chamber when several important criteria are met. This method provides an accurate estimate of flow rate only if fluorescein is principally cleared through the outflow of aqueous humor rather than by other routes of loss, such as exaggerated diffusion across the blood–aqueous barrier or by transfer to the posterior chamber. Herman et al.²⁰ showed a very high fluorescein clearance in eyes with various kinds of uveitis and previous cataract surgery, a finding they interpreted as a demonstration of fluorescein loss through the pupil and mixing with the vitreous.

Maus and Brubaker¹⁶ demonstrated high rates of fluorescein clearance in eyes treated with phenylephrine or in eyes treated with a combination of phenylephrine and tropicamide but not with tropicamide alone. They found an increased rate of clearance in eyes when pupils were dilated without cycloplegia or in eyes where the pupillary border had pulled away from the surface of the crystalline lens. Marchini et al.²¹ examined the anterior segment by ultrasound biomicroscopy during mydriasis induced by ibopamine and phenylephrine and found a prominent separation between the margin of the iris and lens as well as an increase in the scleral–iridial angle after ibopamine. In this condition, fluorescein-stained aqueous humor in the anterior chamber could easily mix with the posterior chamber aqueous through the large pupil.

Like phenylephrine, ibopamine dilates the pupil without paralyzing the ciliary muscle. If the accommodative motion of the ciliary muscle and lens and the separation between the iris margin and the lens enhance fluorescein loss to the posterior chamber through the dilated pupil, then fluorescein clearance from the anterior chamber would increase. From the posterior chamber, fluorescein could diffuse into the vitreous or be transported out of the eye. Under this condition, particularly with active accommodation, our assumption that flow is directly related to clearance, as expressed in equation 1 , would no longer be valid. Instead, flow rate would be overestimated in proportion to the amount of fluorescein lost through this posterior route. The variability of motion and space between the iris and lens noted by Maus and Brubaker¹⁶ and Marchini et al.²¹ may explain some of the large differences in apparent flow between subjects with widely dilated pupils after ibopamine (Fig. 9) . Although we did not examine the pupil margin, the subjects with flow rates estimated above 10 µL/min perhaps had a greater space between the iris and lens, whereas, in the others with normal flow rates, contact between the lens and iris was maintained. If accommodation were paralyzed, as it is with tropicamide, the lack of motion between the iris and lens would prevent loss to the posterior chamber, even in the presence of a widely dilated pupil. This would explain why apparent flow was not elevated when tropicamide dilated the pupil in this experiment and in the experiment by Maus and Brubaker.¹⁶

Our measurements also demonstrate a fundamental limitation of measuring aqueous humor flow by fluorophotometry: If fluorescein leaves the anterior chamber by a route other than the outflow pathways of aqueous humor, flow rate will be overestimated. Aqueous humor flow rate is likely to be overestimated in eyes with widely dilated pupils, particularly if accommodation is active, and caution must be used in interpreting results of these measurements.

This explanation is supported by other studies that demonstrated no increase in intraocular pressure of normal eyes during maximum pupil dilation by ibopamine.^{4 5 10} If aqueous humor production were increased by the amount that we estimated, a measurable elevation of intraocular pressure would be expected. According to the Goldmann equation

(2)

where P_i is intraocular pressure, flow is pressure-sensitive outflow, C is outflow facility, and P_e is episcleral venous pressure, a fivefold increase in aqueous humor inflow would have to be accompanied by an approximate fivefold increase in outflow facility to avoid an increase in intraocular pressure, if other variables remained unchanged. A rapid increase and recovery of this magnitude in outflow facility is unlikely.

Further interpretation of the results of this experiment is clearly supported by the data. When the pupillary dilation of ibopamine was blocked by dapiprazole (session C), ibopamine increased the rate of aqueous humor production by approximately 13% (Fig. 10) compared with the control eye. This effect is similar to the small stimulation of flow by the closely related catecholamine epinephrine in healthy volunteers. Topically applied 1% epinephrine in 24 healthy subjects increased aqueous humor flow by 19% over a 7-hour measurement.¹³ The relatively small stimulation of aqueous production after ibopamine would be unlikely to cause a measurable increase of intraocular pressure in healthy eyes, especially because ibopamine, like epinephrine, appears to lower intraocular pressure by mildly improving outflow facility or by some other unknown mechanism. In rabbits under diurnal conditions, ibopamine and epinephrine have similar effects on intraocular pressure, first causing an increase followed by a decrease.²²

View larger version (17K): [in this window] [in a new window]   FIGURE 10. Differences in calculated aqueous flow between ibopamine-treated, ibopamine-blocked, and placebo-treated eyes. PP - PP is the difference in estimated flow rate between placebo-placebo and placebo-placebo; IP - TP is the difference in estimated flow rate between ibopamine-placebo and tropicamide-placebo; and ID - TD is the difference in estimated flow rate between ibopamine-dapiprazole- and tropicamide-dapiprazole- treated eyes. Symbols are as in Figure 1 .

	Acknowledgements

 
The authors thank Fabio DeGregorio and Gary Novack for their assistance in designing this study.

	Footnotes

 
Supported by National Eye Institute Grant EY 00634 (RFB), Research to Prevent Blindness, Inc., New York, New York; the Bonner Foundation, Princeton, New Jersey; the Mayo Foundation, Rochester, Minnesota; and Angelini Pharmaceuticals, Inc., Rome, Italy.

Submitted for publication February 28, 2003; revised June 24, 2003; accepted July 15, 2003.

Disclosure: J.W. McLaren, Angelini Pharmaceuticals, Inc. (F); D.C. Herman, Angelini Pharmaceuticals, Inc. (F); R.F. Brubaker, Angelini Pharmaceuticals, Inc. (F); C.B. Nau, Angelini Pharmaceuticals, Inc. (F); L.L. Wayman, None; M.G. Ciarniello, Angelini Pharmaceuticals, Inc. (E); M.T. Rosignoli, Angelini Pharmaceuticals, Inc. (E); P. Dionisio, Angelini Pharmaceuticals, Inc. (E)

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 1734 solely to indicate this fact.

Corresponding author: Jay W. McLaren, Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; mclaren.jay{at}mayo.edu.

	References

Top Abstract Methods Results Discussion References

 

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