Changes in intraocular pressure and aqueous humor dynamics of normal human eyes after topical application of bunazosin hydrochloride

The effects of topically applied bunazosin hydrochloride, a recently developed highly selective alpha 1-adrenergic antagonist, on intraocular pressure, pupillary diameter, aqueous protein concentration, anterior chamber volume, aqueous flow rate and tonographic outflow facility were investigated in eight normal human volunteers. A single application of 0.1% bunazosin hydrochloride caused a significant unilateral reduction in the intraocular pressure from 30 minutes through 4 hours after the application, with a maximum decrease of 2.0 +/- 0.5mmHg (mean +/- SEM) below the contralateral control eyes at 2 hours post-application. Neither pupillary diameter, anterior chamber volume nor outflow facility was affected by the drug application. Both aqueous protein concentration measured with a flare-cell meter and aqueous flow rate determined by fluorophotometry were unaltered. The mechanism of intraocular pressure reduction appears to be an increase in uveoscleral outflow and/or a decrease in episcleral venous pressure.     

Effect of topical pergolide on aqueous dynamics in normal and glaucomatous monkeys

The effects of pergolide mesylate, an ergoline derivative, were studied on intraocular pressure (IOP), outflow facility, aqueous humor flow, and pupil size in monkeys. Unilateral topical administration of two 20-microliters drops of 0.1% pergolide significantly lowered IOP in the treated- and contralateral eye in both normal- and glaucomatous monkeys. In 12 normal monkeys, the baseline IOP of 18.3 +/- 0.4 mmHg [mean +/- S.E.(M.)] was maximally reduced to 14.4 +/- 0.7 mmHg in the treated eye (P less than 0.001) and 14.6 +/- 0.6 mmHg in the contralateral eye (P less than 0.001) at 2 hr after drug administration. In 10 monkeys made bilaterally glaucomatous by argon laser treatment of the trabecular meshwork, the baseline IOP of 33.9 +/- 3.0 mmHg [mean +/- S.E.(M.)] in the treated eyes and 31.7 +/- 3.3 mmHg in the untreated eyes maximally decreased to 23.9 +/- 2.2 mmHg (P less than 0.05) and 26.2 +/- 3.3 mmHg (P less than 0.005), respectively, at 5 hr. No significant change (P greater than 0.7) in outflow facility occurred in either eye of 11 normal monkeys 2 hr after unilateral 0.1% pergolide treatment. In six normal monkeys, the baseline aqueous humor flow of 1.58 +/- 0.20 microliter min-1 in treated eyes and 1.44 +/- 0.18 microliter min-1 in untreated eyes was reduced to 0.92 +/- 0.08 microliter min-1 (P less than 0.02) and 1.09 +/- 0.11 microliter min-1 (P greater than 0.10), respectively, from 0.5- to 3.5 hr after drug administration. A mydriatic response was observed in both eyes after unilateral treatment from 1- to 2 hr in eight normal monkeys. By the third day of treatment, bilateral twice a day 0.1% pergolide drops in eight glaucomatous monkey eyes no longer significantly (P greater than 0.05) decreased IOP.     

Effects of topically applied bunazosin hydrochloride on choroidal capillary blood flow and intraocular pressure of rabbit eye]

The effects of topically applied bunazosin hydrochloride, a selective alpha 1 blocker under development as a drug to treat glaucoma, were studied in regard to the choroidal capillary blood flow, intraocular pressure (IOP), and blood pressure in albino rabbit eyes in comparison with propranolol hydrochloride, a non-selective beta blocker. The capillary blood flow was measured using a thermal diffusion flowmeter. Single instillations (50 ul) of 0.005% bunazosin hydrochloride, lowered the IOP to almost the same degree as did 1.0% propranolol hydrochloride. The maximum decreases from initial IOP were 3.3 +/- 1.2, 3.6 +/- 1.7 mmHg for bunazosin hydrochloride and propranolol hydrochloride, respectively. No significant effect on mean blood pressure was observed with these instillations. The choroidal capillary blood flow was reduced by propranolol hydrochloride for 3 hours after instillation (maximum rate of decrease was 10.0 +/- 4.6%), while it was increased by bunazosin hydrochloride for 150 min. (maximum rate of increase was 8.3 +/- 3.8%). When phenylephrine hydrochloride (0.5%), an alpha 1 agonist, was instilled with bunazosin hydrochloride (0.005%), the choroidal capillary blood flow showed no significant change. This was felt to imply an action mechanism involving the alpha 1 receptor.     

Prostaglandin F2 alpha isopropyl ester versus iloprost phenacyl ester in rabbit and beagle eyes

One and 2 micrograms of prostaglandin F2 alpha isopropyl ester (PGF2 alpha -IE) applied topically to the rabbit eye caused a biphasic response. The hypotensive phase was dose-dependent with a maximum reduction in intraocular pressure (IOP) of 9.4 +/- 1.7 mmHg at a dose of 2 micrograms. In beagles, 0.4 to 2 micrograms topical PGF2 alpha-IE resulted in a sustained IOP reduction; 2 micrograms produced the maximum reduction of 7-9 mmHg. No initial hypertensive response was observed. Iloprost phenacyl ester (Iloprost-PE) caused a greater decrease in IOP when dissolved in 0.5% hydroxypropyl methylcellulose (AT) than in saline. In rabbits, doses of 0.1 to 1 microgram in AT caused a biphasic response with a sustained IOP decrease fluctuating between 7 and 8 mmHg. In beagles 1 and 2 micrograms Iloprost-PE resulted in a mean IOP reduction of 5.8 +/- 0.4 mmHg and 5.8 +/- 0.5 mmHg (P less than 0.005), respectively; the decrease persisted for 5 hrs. No initial hypertensive response was observed. In beagles PGF2 alpha-IE induced a strong miosis lasting more than 6 hours; Iloprost-PE had no effect on pupil size. Both PG-esters induced a slight hyperemia in rabbit and beagle eyes. In rabbits Iloprost-PE affects the blood-aqueous barrier more than PGF2 alpha-IE, since higher protein concentrations are seen in the aqueous humor after application of Iloprost-PE. Neither PG-ester had a noticeable effect on aqueous protein in beagles. In rabbits, both PG-esters led to slightly increased aqueous humor cyclic-AMP concentrations. In beagles aqueous humor cyclic-AMP was elevated only after Iloprost-PE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of brinzolamide on aqueous humor dynamics in monkeys and rabbits.

This study examines the mechanisms by which brinzolamide reduces intraocular pressure (IOP) in healthy rabbits and in monkeys with unilateral ocular hypertension. Intraocular pressures were measured by pneumatonometry and aqueous flow was determined by fluorophotometry before and after three twice-daily drops of 1% brinzolamide to both eyes per monkey and after similar treatment to one eye per rabbit. In monkeys, outflow facility was determined by fluorophotometry and uveoscleral outflow was calculated. In rabbits, outflow facility was determined by two-level constant pressure infusion and uveoscleral outflow was measured by an intracameral tracer technique. Compared with contralateral vehicle-treated rabbit eyes, IOP was reduced in brinzolamide-treated eyes by 2.5 +/- 1.9 mmHg (mean +/- standard deviation; p =.006) at four hours after the second dose. Aqueous flow was reduced by 0.50 +/- 0.65 microl/min (p =.02). This effect was found in rabbits previously treated with brinzolamide but not in naive rabbits. Treated hypertensive eyes of monkeys had a reduction in IOP of 7.3 +/- 8.8 mmHg (p = 0.01) and aqueous flow of 0.69 +/- 1.10 microL/min (p = 0.05) when compared with baseline. Brinzolamide did not affect outflow facility or uveoscleral outflow in either rabbits or monkeys. It is concluded that, in normotensive eyes of rabbits and hypertensive eyes of monkeys, brinzolamide reduces IOP by reducing aqueous flow and not by affecting aqueous humor drainage.     

Ocular hypotension induced by electroacupuncture.

The purpose of this study was to investigate the effects of electroacupuncture (EA) on aqueous humor dynamics in rabbits. EA stimulation was performed through two acupuncture needles placed in close proximity to the sciatic nerve. The sites of needle entry were anesthetized. After 1 hr of EA stimulation, intraocular pressure (IOP) decreased and was accompanied by reductions of blood pressure and aqueous humor flow rate. The maximum reduction of IOP was 9 mmHg at 3 hr and decreases in norepinephrine and dopamine levels in aqueous humor occurred simultaneously. In addition, EA stimulation induced an 8-fold increase of endorphin levels in aqueous humor. Ocular hypotension induced by EA lasted for more than 9 hrs and was antagonized by naloxone pretreatment. Furthermore, the EA-induced ocular hypotension was reduced markedly in sympathetically denervated eyes compared with the response of intact, normal eyes. Antagonism of EA-induced ocular hypotension by naloxone, suppression of aqueous humor flow and catecholamine levels by EA and elevation of endorphin levels in aqueous humor by EA indicate that opioids/opiate receptors are involved in modulating ocular hydrodynamics in response to EA.     

改良式前房放液在白内障超声乳化术后早期高眼压中的应用

目的:探讨改良式前房放液法在白内障超声乳化吸出术后早期高眼压的应用价值。方法:对我院3170眼白内障超声乳化吸出术患者中14眼出现术后早期高眼压的患者经过一次性注射器针头轻压角膜侧切口放出部分房水,降低眼压,减轻角膜水肿。结果:经过上述处理后14眼眼压下降为(11.4±5.1)mmHg,角膜透明;视力大于或等于0.7者8眼,0.3～0.5者5眼,0.2者1眼;未出现与改良式前房放液相关并发症。结论:改良式前房放液治疗白内障超声乳化术后早期高眼压简单易行、安全有效,值得推广。     

Time dependent effects of sympathetic denervation on aqueous humor dynamics and choroidal blood flow in rabbits

PURPOSE: This study investigates the time-dependent effects of superior cervical ganglionectomy (SCGx) on aqueous humor dynamics and ocular blood flow in rabbits. METHODS: Measurements were made at various times between 24 hours and 12 months after SCGx. Intraocular pressure (IOP) was measured by pneumatonometry, aqueous flow by fluorophotometry and outflow facility by tonography. Uveoscleral outflow was determined by an intracameral tracer infusion technique and blood flow to the choroid was evaluated with fluorescent microspheres. Values in denervated eyes were compared with the contralateral, normally-innervated eyes using a paired Student's two-tailed t-test. RESULTS: At 24 hours after SCGx, IOP in denervated eyes was less than in normally-innervated eyes (14.6 +/- 0.8 vs 20.1 +/- 1.5 mmHg, 27%, p < 0.002). At one month, IOPs were not different between eyes. Compared with normally-innervated eyes at 10-12 months, IOP in denervated eyes was greater (20.4 +/- 0.7 vs 17.2 +/- 0.9 mmHg, 19%, p < 0.001), outflow facility was less (0.15 +/- 0.02 vs 0.21 +/- 0.01 microl/min/mmHg, 29%, p < 0.01) and blood flow to the choroid was less (12.1 +/- 5.0 vs 16.2 +/- 6.0 ml/min/gm tissue, 25%, p < 0.05). Aqueous humor flow was not significantly altered by SCGx at any time. CONCLUSIONS: The reduction in IOP at 24 hours after SCGx was not due to any change in aqueous flow or uveoscleral outflow (current study) but rather to an increase in outflow facility (previous studies). At 10-12 months, IOP was elevated because outflow facility was significantly reduced. The reduction in choroidal blood flow at 10-12 months may have occurred because of the increased IOP.     

Ocular hypotensive effects of topically applied bunazosin, an alpha 1-adrenoceptor blocker, in rabbits and cats]

Effects of topically applied bunazosin, an alpha 1-adrenoceptor blocker, on intraocular pressure (IOP) and pupillary diameter were investigated in normotensive rabbits and cats, in addition to experimentally hypertensive rabbits. Bunazosin (0.005% to 0.1%) applied to both eyes significantly lowered IOP in a concentration-dependent manner in normotensive rabbits and cats. The unilateral application of 0.1% bunazosin significantly lowered the IOP in the treated eye, whereas it caused no significant change in the contralateral eye, suggesting that the effect of bunazosin is due mainly to a direct and local action and is not systemic. Bunazosin was also effective in experimentally hypertensive models induced both by water-loading and by alpha-chymotrypsin in rabbits. There was a significant correlation between the IOP decrease caused by bunazosin and the IOP value before the application, indicating that the IOP-lowering action of bunazosin is dependent on the height of the original IOP level. Bunazosin had no influence on pupillary diameter even when 0.5% was applied to rabbits. Topically applied bunazosin may be useful as a new antiglaucoma agent.     

Effect of flunarizine, a calcium channel blocker, on intraocular pressure and aqueous humor dynamics in monkeys

PURPOSE: To evaluate the effects of flunarizine, a nonselective calcium channel blocker, on intraocular pressure (IOP) in monkeys with laser-induced unilateral glaucoma and on aqueous humor dynamics in normal monkeys. METHODS: The IOP was measured before and hourly for 6 hours after single-dose administration of 0.5%, 1%, or 2% flunarizine to the glaucomatous eye of 8 monkeys with unilateral laser-induced glaucoma. In a separate multiple-dose study, 0.5% flunarizine was applied twice daily for 5 consecutive days to the glaucomatous eye of the same 8 monkeys. IOP was measured at untreated baseline, after treatment with vehicle only, and on treatment days 1, 3, and 5. Tonographic outflow facility and fluorophotometric flow rates of aqueous humor were measured in 7 normal monkeys before and after the fifth dose of twice-daily treatment with 0.5% flunarizine. RESULTS: Unilateral application of 50 microL of 0.5%, 1%, or 2% flunarizine reduced IOP bilaterally. In the treated glaucomatous eyes, flunarizine reduced the IOP for 2, 3, or 5 hours, with a maximum reduction of 2.5+/-0.5 (mean+/-SEM) mm Hg (9%), 3.0+/-0.4 mm Hg (10%), and 5.0+/-0.8 mm Hg (18%) following the 0.5%, 1%, and 2% concentrations, respectively (P<0.01). The maximum reductions in IOP in the contralateral untreated eyes were 1.3+/-0.5 mm Hg, 1.5+/-0.3 mm Hg, and 2.9+/-0.7 mm Hg following the 0.5%, 1%, and 2% concentrations, respectively (P<0.05). Both the magnitude and duration of the ocular hypotensive effect of 0.5% flunarizine were enhanced with twice-daily administration for 5 days. Outflow facility in normal monkey eyes was increased (P<0.05) by 39% in the treated eyes compared with vehicle-treated contralateral eyes and by 41% compared with baseline values, and aqueous humor flow rates were unchanged (P>0.30). CONCLUSIONS: Flunarizine reduces IOP in a dose-dependent manner when administered to glaucomatous monkey eyes, but also has an ocular hypotensive effect on the contralateral untreated eyes. An increase in tonographic outflow facility seems to account for the IOP reduction in normal monkey eyes.     

Aqueous humor messengers in the transient decrease of intraocular pressure after ganglionectomy.

Intraocular pressure (IOP) decreases in rabbits 1 day after superior cervical ganglionectomy. It was hypothesized that this IOP decrease was caused by an accumulation of norepinephrine (NE) released from the iris-ciliary body into the aqueous humor during nerve degeneration. Direct measurement of aqueous humor NE concentration, however, was not successful because of the technical difficulty. In the current study, aqueous humor NE after superior cervical ganglionectomy was extracted and quantified using high-performance liquid chromatography-electrochemical detection. Twelve New Zealand albino rabbits were maintained in a daily 12-hr light-12-hr dark environment. Unilateral ganglionectomy was done on these rabbits during the light phase under halothane anesthesia. Twenty-two hours after the procedure, a significant IOP decrease occurred. The IOP was 16.1 +/- 0.6 mmHg (mean +/- the standard error of the mean) in the operated eye and 20.9 +/- 0.6 mmHg in the contralateral eye (P < 0.01). Aqueous humor NE concentration in the operated eye (475 +/- 81 pg/ml) was not different from that in the contralateral eye (469 +/- 58 pg/ml). However, the concentration of aqueous humor cyclic adenosine monophosphate (cAMP) in the operated eye (29.8 +/- 6.8 pmol/ml) was significantly higher (P < 0.05) than that in the contralateral eye (11.7 +/- 0.8 pmol/ml). These data indicate that aqueous humor NE per se does not cause the transient IOP decrease after superior cervical ganglionectomy and cAMP-mediated ocular activities may be involved in this change in IOP.     

Effects of topical anaesthetics and repeated tonometry on intraocular pressure

Purpose: To investigate the effects of repeated measurements of intraocular pressure (IOP) using Goldmann applanation tonometry (GAT) and applanation resonance tonometry (ART) to identify mechanisms contributing to the expected IOP reduction. Methods: A prospective, single‐centre study with six healthy volunteers. Consecutive repeated series (six measurements/serie/method) were made alternately on both eyes for 1 hr with oxybuprocaine/fluorescein in the right eye and tetracaine in the left. The left eye was Pentacam^® photographed before and repeatedly for 20 min after the IOP measurements. On a separate occasion, the same volunteers received the same amount of anaesthetic drops for 1 hr but without repeated IOP measurements. Results: A significant IOP reduction occurred with both ART and GAT in the oxybuprocaine‐treated eye, ?4.4 mmHg and ?3.8 mmHg, respectively and with ART in the tetracaine eye, ?2.1 mmHg. There was a significant difference in IOP reduction between the oxybuprocaine and tetracaine eyes with ART. There was a significant drop in anterior chamber volume (ACV) immediately after the IOP measurements, ?12.6 μl that returned to pretrial level after 2 min. After 1 hr of receiving anaesthetic eye drops (without IOP measurements), the IOP decreased significantly in the oxybuprocaine eye for both ART and GAT, ?3.1 and ?1.7 mmHg, respectively, but not in the tetracaine eye (p = 0.72). Conclusion: The IOP reduction cannot be explained solely by aqueous humor being pressed out of the anterior chamber. While significant IOP reduction occurred with both tetracaine and oxybuprocaine after repeated mechanical applanation, the IOP reduction was significantly greater with oxybuprocaine.     

前房放液治疗白内障超声乳化吸出术后早期高眼压

目的探讨前房放液治疗白内障超声乳化吸出及人工晶状体植入术后早期高眼压合并角膜上皮水肿的可行性。方法白内障超声乳化吸出及人工晶状体植入术1572眼中31眼术后早期高眼压合并角膜上皮水肿,平均眼压46mmHg(1kPa=7.5mmHg),前房放液在裂隙灯显微镜下进行,镊子轻压上方切口后缘,缓慢放出少量房水,即可见角膜上皮水肿明显减轻或消失。结果29眼1次放液后眼压未再升高,角膜上皮水肿消失,其余2眼为后囊膜破裂患者,1眼术后第1d、2d2次放液后眼压恢复正常,1眼术后第1d、2d2次放液联合降眼压药物治疗,于术后5d眼压恢复正常。结论前房放液是治疗白内障术后早期高眼压合并角膜上皮水肿的理想方法。     

Effects of ibopamine eye drops on intraocular pressure and aqueous humor flow in healthy volunteers and patients with open-angle glaucoma

PURPOSE: On the basis of intraocular pressure measurements and fluorophotometry we assessed the effects of 2% ibopamine eye drops on aqueous humor production in normal and glaucomatous eyes. METHODS: Thirty subjects (15 healthy volunteers and 15 open-angle glaucoma patients with ocular hypertension) were included in a placebo-controlled study with random assignment of treatment from masked containers. All subjects underwent ophthalmologic examinations and intraocular pressure (IOP) measurements. Fluorophotometry was done in both eyes at baseline (without treatment) and during treatment. Each subject was treated with 1 drop of 2% ibopamine in one eye and 1 drop of placebo in the fellow eye 30 minutes before fluorophotometric scans and every hour after the first instillation (for a total of 4 times). Safety was evaluated by recording adverse events and ocular symptoms and signs. Aqueous humor flow data were analyzed using the paired t-test, comparing ibopamine and placebo-treated eyes. RESULTS: No changes in IOP were detected in normal eyes, whereas glaucomatous eyes showed a mean increase of 4 mmHg (95% CI 3.46-4.51) from baseline. The difference in IOP between healthy eyes and those with glaucoma was significant (p < 0.0001). In normal eyes and patients with glaucoma ibopamine led to a significant increase in aqueous humor flow compared with placebo-treated eyes (p < 0.01). The safety profile of ibopamine was very good. CONCLUSIONS: The results seem to confirm that ibopamine increases aqueous humor production in normal and glaucomatous eyes, raising IOP only in eyes with glaucoma.     

The effect of topical PGF2 alpha on uveoscleral outflow and outflow facility in the rabbit eye.

Prostaglandin F2 alpha (PGF2 alpha) is a powerful ocular hypotensive agent in rabbit, cat, dog, monkey and human. In cynomolgus monkeys, the intraocular pressure (IOP) lowering is due to increased uveoscleral outflow (Fu). Because the anatomy of the rabbit outflow apparatus differs significantly from that of the primate, we sought to determine whether the mechanism of the PGF2 alpha-induced IOP fall was the same. PGF2 alpha tromethamine salt (PGF2 alpha-TS) (50 micrograms) applied to one eye of 14 conscious rabbits produced a significant IOP fall of 7.4 +/- 0.9 mmHg (P less than 0.001). In untreated control eyes, Fu determined from the quantity of intracamerally perfused [125I]albumin found in the ocular and periocular tissues accounted for 5-8% of total aqueous outflow. In 15 unilaterally PGF2 alpha-treated rabbits, after 4-6 hr dosing Fu was 49 +/- 14% higher in the treated than in the contralateral control eyes. Total outflow facility of outflow from the anterior chamber to the general circulation were measured concurrently in 11 rabbits using a two-level constant pressure perfusion and isotope accumulation technique. Both facilities tended to be higher in the treated eyes than in the controls, with a strong correlation between drug-induced changes in total facility and changes in facility of flow to blood (r = 0.85, P less than 0.001). In eight rabbits treated unilaterally with 50 micrograms PGF2 alpha-TS, the fluorophotometrically determined aqueous formation rate was probably not decreased relative to control eyes. Protein levels in the aqueous humor were approximately eight-fold higher in PG-treated vs. control eyes, suggesting a drug-induced compromise of the blood-aqueous barrier.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of serotonergic compounds on aqueous humor dynamics in monkeys

PURPOSE: The effects of several serotonergic agonists on aqueous humor formation (AHF), total outflow facility (OF) and intraocular pressure (IOP) were investigated in living cynomolgus monkeys. METHODS: We determined the effect of a single topical unilateral 300 microg or 3 mg dose of the 5-HT agonists serotonin, 5-carboxamidotryptamine (5-CT), sumatripan, gepirone, and 8-hydroxy-2(di-n-propylaminotetralin) (8-OH-DPAT) and a 450 microg dose of flesinoxan on IOP (Goldmann applanation tonometry), AHF (scanning ocular fluorophotometry) and total OF (8-OH-DPAT only, topically and intracamerally). RESULTS: Serotonin, 5-CT, sumatripan or gepirone had no significant effect on IOP or AHF. 8-OH-DPAT caused an AHF increase of approximately 70% over 6 hr in both ipsilateral drug- and contralateral vehicle-treated eyes, but no significant change in IOP compared with baseline measured on a separate occasion in the same animals. 8-OH-DPAT did not increase protein levels or rate of entry of systemically administered fluorescein in the anterior chamber aqueous humor compared to historic controls, and no difference was seen between ipsilateral and contralateral eyes. Flesinoxan had no effect on IOP and produced an insignificant 25% increase in flow in treated eyes compared to baseline. CONCLUSION: The results for 8-OH-DPAT and possibly flexinoxan indicate the presence of a secretion-stimulating 5-HT1A receptor in monkey ciliary epithelium that has little effect on IOP. OF was unchanged following 8-OH-DPAT administered topically or following intracameral exchange.     

Effect of mitomycin C on aqueous humor flow, flare and intraocular pressure in eyes with glaucoma 2 years after trabeculectomy

· Background: The purpose of this study was to determine the intraocular pressure (IOP), aqueous humor flow, flare and ocular side effects in eyes with a history of hypotony after trabeculectomy with adjunctive mitomycin C (MMC). · Methods: Thirty-six eyes with primary or secondary open-angle glaucoma and IOP ≤8 mmHg during the postoperative period were studied 745±315 days after surgery. MMC (0.2 or 0.5 mg/ml) was applied to the episclera with a cellular sponge. Flare was studied with the Kowa Laser Flare Meter 500. Aqueous humor flow was measured in the afternoon (Fluorotron Master II). IOP, visual fields and best corrected visual acuity were also examined. Twenty-two contralateral eyes without surgical intervention served as controls. · Results: The mean age of patients was 44.5±16.8 years. The mean IOP was significantly lower in the MMC group than in the control group: 9.6±6.4 mmHg vs 18.0±13.6 mmHg at 2 years (P<0.001). Aqueous flow was significantly lower in subjects treated with MMC than in controls (P<0.001). The flare values were significantly higher in the MMC-treated group, with a mean of 12.0±7.7 photon counts/ms, than in the control group, mean 7.9±4.6 photon counts/ms (P<0.019). · Conclusion: Our data suggest that MMC is a useful ocular hypotensive agent which seems to participate in a change in aqueous humor dynamics when applied topically as an aqueous solution. Received: 14 October 1997 Revised version received: 20 February 1998 Accepted: 4 March 1998     

Studies on the mechanism of action of timolol and on the effects of suppression and redirection of aqueous flow on outflow facility

Long-term use of drugs that suppress aqueous humor formation, such as timolol and dorzolamide, or that redirect aqueous humor outflow from the trabecular meshwork, such as prostaglandin F2alpha analogues, could cause underperfusion of the trabecular meshwork and a secondary decrease in outflow facility. We investigated the mechanism of suppression of aqueous humor formation by timolol in monkey eyes by measuring aqueous humor ascorbate levels. We also determined whether suppression of aqueous humor formation with and without redirection of aqueous humor away from the trabecular meshwork could lead to a subsequent reduction in outflow facility, and whether this reduction was correlated with increased fibronectin levels in anterior chamber aqueous humor. In cynomolgus monkeys, unilateral dose/aqueous humor formation response curves were generated for timolol, dorzolamide, and a combination of timolol + dorzolamide. Aqueous humor formation and/or outflow facility were measured in both eyes after approximately four days, four weeks and seven weeks of twice daily treatment with 3.5 microg timolol + 1.0 mg dorzolamide to one eye and 30% DMSO to the other. In some monkeys, 5 microg prostaglandin F2alpha-isopropyl ester (PG) was added to timolol + dorzolamide for 4-week treatments. Intraocular pressure and corneal endothelial transfer coefficients (k(a)) were also measured at four weeks. Aqueous humor fibronectin levels were determined in four monkeys after approximately 9.5 weeks of timolol + dorzolamide treatment. Aqueous humor formation, intraocular pressure, and aqueous humor ascorbate levels were also determined in rhesus monkeys at baseline and after a single unilateral topical administration of 25 microg timolol. Compared to baseline for the same eye, aqueous humor formation was significantly decreased in treated eyes at all doses of timolol and at 1.8 and 4 mg dorzolamide. Compared to the opposite control eye, aqueous humor formation was lower in treated eyes after 3.5 and 5 microg timolol and after all doses of dorzolamide. Aqueous humor formation after treatment with 3.5 microg timolol + 1.0 mg dorzolamide was decreased in treated vs. control eyes, after four days and was suppressed in both treated and control eyes after four weeks of treatment, but not when PG was added. There was no difference in k(a) values with or without the addition of PG. Intraocular pressure was significantly lower in both treated and control eyes vs. baseline after approximately 6.5 weeks treatment with timolol + dorzolamide when taken 2 hr after the last dose and after approximately 3.5 weeks treatment with timolol + dorzolamide + PG when measured 6 hr after the last dose. Outflow facility after treatment with timolol + dorzolamide was unchanged after four days, tended to be lower in the treated vs. control eyes after four and seven weeks, and was significantly lower in treated vs. control eyes after four weeks treatment with timolol + dorzolamide + PG (0.352 +/- 0.052 vs. 0.515 +/- 0.096 microl min(-1) mmHg(-1), p < or = 0.02). Both treated vs. control eye aqueous humor fibronectin levels were below the level of detection for our assay (0.01 microg ml(-1)). The 25 microg timolol dose decreased ipsilateral, but not contralateral intraocular pressure (12.6 +/- 1.7 vs. 15.2 +/- 0.9; p < 0.05) and aqueous humor formation (1.40 +/- 0.08 vs. 2.03 +/- 0.09 microg ml(-1), p < or = 0.01). There was no difference in anterior chamber ascorbate levels in treated vs. control eyes or compared to their respective baselines. Our findings indicate that timolol affects neither ciliary epithelial transport of ascorbate nor aqueous fibronectin levels. Our data also indicate that decreasing aqueous humor formation over a period of time can lead to reduction in outflow facility, particularly when combined with therapy that redirects aqueous from the trabecular meshwork. Future intraocular pressure-lowering therapies for glaucoma may better be directed at enhancing flow through the trabecular pathway as opposed to decreasing aqueous humor formation or rerouting aqueous humor away from the trabecular meshwork.     

Effects of atrial natriuretic factor (ANF) on intraocular pressure and aqueous humor flow in the cynomolgus monkey.

Atrial natriuretic factor (ANF: human sequence) was examined for its effects on basal and terbutaline-stimulated aqueous humor flow, intraocular pressure (IOP) and uveoscleral outflow in cynomolgus monkeys under pentobarbital anesthesia. A dilution method with radioactively labeled albumin was used for the determination of aqueous humor flow. ANF was given by i.v. infusion or intracamerally. Intracameral administration of terbutaline increased the aqueous humor flow significantly; 1.10 +/- 0.05 microliter min-1 in the control eye and 1.69 +/- 0.06 microliter min-1 in the treated eye. I.v. infusion of ANF, 97 fmol kg-1 min-1, increased the aqueous humor flow by about 44% from basal values in the control eye. There was a small but not statistically significant increase on the terbutaline-treated side. The IOP was not changed by ANF at this dose. An ANF dose of 97 pmol kg-1 min-1 increased the aqueous humor flow by 51% in the control eye and by 19% in the terbutaline-treated eye. A further rise of about 8% in aqueous humor flow was registered on the control side when the infused ANF-dose was doubled. Doubling the dose also resulted in a decrease of the IOP by 1.3 +/- 0.3 mmHg on the control side and 2.2 +/- 0.4 mmHg on the terbutaline-stimulated side. Intracameral administration of ANF (81-162 pmol ml-1 perfusion fluid) increased the aqueous humor flow transiently by approximately 50% with a maximum after about 2 hr. The uveoscleral outflow tended to increase and IOP tended to decrease in the ANF-treated eye compared with the control. However, these effects were not statistically significant. These results suggest that ANF may be involved in the control of aqueous humor formation.     

Modulation of ocular hydrodynamics and iris function by bremazocine, a kappa opioid receptor agonist

This study was designed to determine the activity of bremazocine (BRE), a relatively selective kappa opioid receptor agonist, on intraocular pressure (IOP), aqueous humor formation and pupil diameter (PD) in conscious, normal, dark-adapted New Zealand white (NZW) rabbits. IOP was measured in normal and unilaterally sympathectomized rabbits using a calibrated pneumatonometer and the aqueous flow rate was determined by the use of a Fluorotron Master. A masked-design study was conducted in which the rabbits' eyes were treated with BRE topically and unilaterally; the fellow eyes received vehicle. IOP and PD measurements were taken at 0.5 hr and 0 time before BRE and 0.5, 1, 2, 3, 4 and 5 hr post-treatment. Fluorophotometry recordings were taken at 1 hr before and 0.5, 1.5, 2.5 and 3.5 hr after topical application of the drug or vehicle. The effect of the relatively selective kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI), on bremazocine-induced changes in IOP, PD and aqueous flow was also determined. BRE (10 and 100 micrograms 25 microliters-1 vehicle) produced dose-related, bilateral reductions in IOP, PD and aqueous humor flow. A large increase in IOP (14 mmHg) was observed when BRE (100 micrograms) was applied to sympathectomized eyes. This ocular hypertensive effect was antagonized when the sympathectomized eyes were pretreated with naloxone (200 micrograms), a non-selective opioid receptor antagonist. BRE (10 and 100 micrograms) decreased the aqueous humor flow rate bilaterally by approximately 48 and 60%, respectively, at 0.5 hr after administration to the ipsilateral eye. Nor-BNI (100 micrograms) antagonized the effect of BRE (10 micrograms) on IOP and aqueous flow rates more effectively than on PD. These data indicate that bremazocine causes reductions in IOP by suppressing aqueous flow, but the ocular hypotensive effects are dependent on the presence of intact sympathetic nerves. Antagonism of BRE's effects on aqueous humor dynamics by nor-BNI suggests that the mechanism of IOP and aqueous flow reduction may involve, in part, an action on kappa receptors. Further experiments are necessary to fully define the opioid receptor populations in the ciliary body.