Topical timolol and epinephrine: biochemical actions and interactions in the rabbit eye in vivo

The effects of topical 0.5% timolol maleate and 1% or 2% levo-epinephrine hydrochloride on aqueous humor cyclic-AMP and intraocular pressure were assessed in 97 normotensive New Zealand white rabbits in vivo. The study was conducted using three experimental protocols: (A) timolol and epinephrine individually, (B) timolol and epinephrine in coadministration, and (C) timolol and epinephrine in crossover, applied either in a single dose, twice a day for two days, and/or twice a day for six days. These studies demonstrated that timolol has complex biochemical actions, one of which is beta-adrenergic antagonism. By itself, timolol had no effect on cyclic-AMP levels. However, when used in both single-dose coadministration and in pretreatment in six-day crossover with epinephrine, it significantly diminished the cyclic-AMP elevation produced by a single dose of epinephrine. In the six-day crossover protocol, pretreatment with timolol also significantly reduced the ocular hypotensive effect of a single dose of epinephrine, thereby correlating biochemical cause with clinical effect. Yet, timolol alone had no ocular hypotensive effect. Therefore, timolol's biochemical actions in this animal model cannot explain its marked clinical efficacy in man, which appears to depend on more complex pharmacologic actions.     

单疱病毒性角膜炎继发青光眼

目的：探讨单纯疱疹病毒性角膜炎（herpes simplex keratitis,HSK）继发青光眼的诊治方法和疗效。方法：继发青光眼诊断标准为HSK患者眼压≥24mmHg。以角膜病变静止及停用降眼压药物1wk后眼压≤21mmHg为临床治愈。30例HSK继发青光眼患者给予综合抗病毒、抗炎及降眼压治疗。结果：单纯疱疹病毒性角膜炎继发青光眼患者30例经过抗病毒、抗炎及降眼压治疗均获临床治愈。结论：通过综合抗病毒与抗炎治疗HSK继发青光眼能迅速控制炎症与眼压。个体化的眼压测量对HSK继发青光眼的诊断是必要的。     

Effects of multiple dosing of epinephrine on aqueous humor dynamics in human eyes.

Numerous studies have provided conflicting evidence to explain the ocular hypotensive mechanism of action of epinephrine. Although epinephrine has been shown consistently to increase outflow facility, its effects on aqueous flow and uveoscleral outflow are not as clear. The purpose of this study was to clarify the effects of multiple doses of topical epinephrine on aqueous humor dynamics in human eyes. This was done by evaluating the four main parameters that determine steady state intraocular pressure. These parameters were assessed at baseline and after a week of twice-daily treatment of epinephrine hydrochloride 2% to one eye. Twenty-six human volunteers were enrolled in the study. Intraocular pressure was measured by pneumatonometry, aqueous flow and trabecular outflow facility by fluorophotometry, episcleral venous pressure by venomanometry and uveoscleral outflow by mathematical calculation. In epinephrine-treated eyes compared to baseline, intraocular pressure and aqueous flow were reduced from 21.2 +/- 0.3 to 17.1 +/- 0.2 mmHg (19%, p = .01) and 3.3 +/- 0.2 to 2.9 +/- 0.2 microl/min (12%, p = .03), respectively. Trabecular outflow facility obtained by fluorophotometry was increased from 0.18 +/- 0.02 to 0.26 +/- 0.03 microl/min/mmHg (44%, p = .02). Topical epinephrine did not significantly affect uveoscleral outflow or episcleral venous pressure. In conclusion, multiple topical doses of epinephrine lowered intraocular pressure in human volunteers by reducing aqueous humor formation and increasing trabecular outflow facility. The increase in uveoscleral outflow suggested by other studies was not observed.     

睫状体光凝治疗挫伤性晶状体脱位玻璃体切除术后青光眼临床观察

目的探讨睫状体光凝治疗挫伤性晶状体脱位玻璃体切除术后青光眼的疗效。方法对13例（13眼）因眼挫伤致晶状体脱位继发青光眼行玻璃体切除术后高眼压,经各种降眼压药物治疗无缓解的情况下,采用810nm激光经巩膜睫状体光凝治疗后缓解。结果经一次睫状体光凝后,眼压控制在21mmHg以下者8例（61．54％）;经一次治疗后,眼压在26—31mmHg,联合降眼压药物后控制正常者5例。结论睫状体光凝治疗挫伤性晶状体脱位玻璃体切除术后青光眼能有效控制眼压。     

Inhibition of the epinephrine-induced reduction of intraocular pressure by systemic indomethacin in humans

In a prospective, randomized, double-masked study, 2% epinephrine applied topically twice each day for two weeks to the eyes of patients with glaucoma or ocular hypertension caused an 8.1 +/- 1.4-mm Hg (mean +/- S.E.M.) reduction of intraocular pressure in placebo-treated patients, but only a 1.9 +/- 0.6-mm Hg decrease in patients treated with 25 mg of orally administered indomethacin four times each day (P less than .0005). Systemic treatment with indomethacin for one week did not significantly increase intraocular pressure by itself (baseline, 19.7 +/- 0.6 mm Hg, vs 20.1 +/- 1.4 mm Hg after indomethacin treatment). When indomethacin treatment was discontinued in those patients receiving topical epinephrine, there was a further significant (P less than .05) reduction in intraocular pressure compared with the placebo-treated group. Since the ocular hypotensive effect of topically applied epinephrine is inhibited by indomethacin, a cyclo-oxygenase inhibitor, these results suggest that this reduction of intraocular pressure is at least partially mediated by the endogenous production of prostaglandins, or other cyclo-oxygenase products, and that the intraocular pressure of glaucoma patients undergoing epinephrine therapy may increase when systemic cyclo-oxygenase inhibitors such as indomethacin or aspirin are taken.     

The intraocular pressure lowering effect of colchicine

The plant alkaloids, colchicine and vinblastine were studied for their effects on rabbit intraocular pressure. Both colchicine and vinblastine administered either topically or by intravitreal injection lowered intraocular pressure in a dose-dependent manner. A single topical application of 2–5 μg of either of these compounds reduced intraocular pressure significantly for more than 24 hr without signs of ocular irritation or pupillary constriction. Intravenous administration of colchicine (1 mg/kg) was not found to lower intraocular pressure. Lumicolchicine, an inactive isomer of colchicine with little or no affinity for microtubular protein, failed to lower intraocular pressure when administered either topically or intravitreally. Pretreatment with topical colchicine failed to increase the sensitivity of the rabbit iris to the mydriatic effects of topically applied epinephrine. The present results suggest that the microtubular system is involved in the ocular hypotensive action of colchicine and vinblastine.     

The effects of forskolin on cyclic AMP, intraocular pressure and aqueous humor formation in rabbits

Forskolin was used to study cyclic AMP-mediated regulation of aqueous humor dynamics in rabbits. Crystalline forskolin was solubilized in oil and its pharmacological effects were studied both in vitro and following topical ocular administration. In vitro, using cultured corneal epithelial cells, forskolin rapidly stimulated cyclic AMP production and in vivo increased cyclic AMP concentration in the aqueous humor 10-fold following topical administration. The effect of topical forskolin on intraocular pressure and aqueous humor formation was determined in vivo using pneumatonometry and fluorophotometry, respectively. Forskolin caused a prolonged reduction of intraocular pressure and decreased aqueous humor formation. The ability of forskolin to potentiate the ocular hypotensive effect of epinephrine was investigated. Forskolin in combination with epinephrine caused a decrease in intraocular pressure of longer duration than either 0.1% epinephrine or 1% forskolin administered separately. Forskolin caused a small but significant increase in the permeability of the blood-aqueous barrier at the time of maximal intraocular pressure reduction. This effect on the blood-aqueous barrier may explain the inhibitory effect of forskolin on aqueous humor formation.     

高眼压青光眼白内障三联手术的临床观察

目的:探讨高眼压状态下白内障青光眼联合术的临床疗效。方法:对18例18眼白内障青光眼患者在高眼压下行小切口非超声乳化白内障囊外摘出人工晶状体植入联合小梁切除术,术后观察视力,眼压及并发症情况。结果:术后眼压均比术前用降眼压药的情况下明显下降,11～22mmHg者17例,其中眼压26mmHg者1例。术后视力均较术前有不同程度的提高,术后并发症发生率及严重程度并不比小梁切除术或白内障囊外摘除人工晶状体植入术高。结论:在高眼压下行小切口非超声乳化白内障囊外摘出人工晶状体植入联合小梁切除术发生并发症的机会增多,但仍是一种安全、有效的治疗白内障合并青光眼的联合手术。     

A clinical trial of MK-507, Trusopt, for raised intraocular pressure - The Australian Experience

Background: Since the introduction of carbonic anhydrase inhibitors, a topical preparation has been sought to avoid the complications of systemic medication while retaining the effect of lowering intraocular pressure. Recently, a topical carbonic anhydrase inhibitor, MK-507, has been found superior to others and introduced for multicentre clinical trial.
Patients and methods: As part of an international rnulticentre trial, we compared MK-507 with beta blockers for one year in 20 patients with raised intraocular pressure, both as monotherapy and in combination.
Results: Twelve patients with a mean peak pressure of 31.9 ± 6.8 mmHg (range, 22 to 49 mmHg) off all medication received MK-507. After two weeks, mean peak pressure was 24.7 ± 6.1 mmHg (range, 14 to 41 mmHg) — a 22.6% fall in pressure. Six of these patients had a mean peak pressure of 27.8 ± 6.4 mmHg (range, 21 to 41 mmHg), a fall of 19.2% from day one and were given timolol as add-on therapy. This resulted in a fall to 19.1 ± 2.8 (range, 15 to 24 mmHg) at year one, a fall of 31.3% after add-on. Four patients on timolol and four on betaxolol gave similar falls in pressure with an additional fall when MK-507 was used as add-on therapy.
Conclusions: MK-507 demonstrated its effectiveness as an ocular hypotensive agent in this trial of patients with an unusually high rise in pressure. It showed a hypotensive effect roughly equivalent to beta blockers. It is likely that either a topical carbonic anhydrase inhibitor or a cardioselective beta blocker will be the medication of first choice in newly diagnosed glaucoma.     

Control of blood pressure by a calcium antagonist during cataract surgery]

The authors evaluated the systemic and ocular hypotensive effects of nicardipine hydrochloride (Perdipine:NH) in 31 cases with acute hypertension (over 160/95 mmHg) during cataract surgery. All cases received an intravenous bolus injection of NH 30 micrograms/kg. Blood pressure and intraocular pressure were compared with level at rest, a preoperatively and 5 minutes after the administration of NH. Blood pressure significantly elevated from 136.9 +/- 10.6/73.4 +/- 10.2 mmHg at rest to 187 +/- 11.5/98 +/- 13.1 mmHg preoperatively (p less than 0.001), but it significantly reduced to 125.6 +/- 13.1/67.1 +/- 8.3 mmHg 5 minutes after the administration of NH (p less than 0.001). On the other hand, in the same way an blood pressure changed, intraocular pressure significantly elevated from 13.3 +/- 2.8 mmHg at rest to 19.8 +/- 2.9 mmHg preoperatively (p less than 0.001), but significantly reduced 17.1 +/- 3.0 mmHg 5 minutes after administration of NH (p less than 0.001). The hypotensive effect of NH continued for over 90 minutes. There were no side effects apart from mild tachycardia in all cases. NH is safe, easy to administer and useful for control of acute hypertension during limited-period surgery such as cataract surgery.     

Adrenergic drugs and intraocular pressure: effects of selective beta-adrenergic agonists.

Changes in intraocular pressure and pupil diameter were studied in rabbits following topical administration of relatively selective and non-selective adrenergic agonists. Drugs having strong α-adrenoceptor stimulating effects (norepinephrine, phenylephrine, epinephrine) initially produced a transient increase in intraocular pressure and pupil diameter before eliciting any ocular hypotensive effects. In contrast, those drugs with predominately β-adrenoceptor stimulating properties (isoproterenol, isoetharine, metaproterenol, terbutaline, salbutamol, carbuterol) produced an immediate decrease in intraocular pressure without causing ocular hypertension or mydriasis. Significantly, the decreases in intraocular pressure were more pronounced with those drugs having strong β₂-adrenoceptor stimulating activity. Thus, stimulation of α- and β-adrenoceptors can produce opposite initial effects on intraocular pressure, but α-adrenergic mechanisms may interact with β₁- and/or β₂-adrenoceptor mechanisms to produce subsequent ocular hypotension. Most importantly these data indicate that more selective β₂-adrenoceptor stimulation is an effective mechanism for lowering intraocular pressure.     

beta-Blockers and the eye: an overview.

Some beta-adrenoceptor blocking drugs are exciting new ocular hypotensive compounds. Unlike pilocarpine, the mainstay of glaucoma treatment for the last 100 years, beta-blocking agents do not contract the pupil nor interfere with vision even in patients with central lens opacities. They also do not cause spasm of the ciliary muscle producing transient myopia and disturbance of accommodation. Paradoxically, one of these agents, timolol, causes a fall in intraocular pressure when administered locally even in patients responding to beta-agonists with a reduction in intraocular pressure. Concomitant administration of timolol with epinephrine seems to enhance its ocular hypotensive effect in many patients. The exact mode of action of beta-blockers in reducing intraocular pressure is unknown but appears to primarily reduce aqueous production. This new class of drugs seems destined to play an important role in the treatment as well as in the understanding of glaucoma.     

The short-term IOP-lowering effect of brimonidine 0.2% and dorzolomide 2% combination in primary open-angle glaucoma

PURPOSE: To evaluate the ocular hypotensive effect of dorzolamide 2% in primary open-angle glaucoma (POAG) patients with intraocular pressure (IOP) of at least 22 mmHg despite ongoing twice daily treatment with brimonidine 0.2%. PATIENTS AND METHODS: Nineteen eyes of 19 patients with POAG and IOP >or= 22 mmHg, on twice daily brimonidine therapy, were included in the study. Intraocular pressure and adverse effects were recorded on days 2, 7, 14 and 30 after adding dorzolamide three times daily to the treatment. RESULTS: Mean pretreatment IOP was 27.6 +/- 2.2 mmHg. This decreased to 24.2 +/- 2.2 mmHg after a mean duration of 23.8 +/- 12.1 days. After dorzolamide was added to the treatment, mean IOP was 20.8 +/- 2.3 mmHg on day 2, 19.3 +/- 2.2 mmHg on day 7, 18.0 +/- 2.5 mmHg on day 14 and 17.2 +/- 2.3 mmHg on day 30. The differences between pre- and post-treatment IOP values were statistically significant (p < 0.0001, anova test). CONCLUSION: Dorzolamide administered three times daily has significant additive ocular hypotensive effect in POAG patients whose IOP is elevated despite ongoing treatment with brimonidine.     

The effects of topically applied epinephrine and timolol on intraocular pressure and aqueous humor cyclic-AMP in the rabbit

Intraocular pressure and aqueous humor cyclic-AMP concentrations were measured in albino rabbits following topical treatment of one eye with a single dose of 2% epinephrine alone, 0·5% timolol alone, or epinephrine after timolol pretreatment. Most animals demonstrated a significant hypotensive response 6 hr after epinephrine treatment, which lasted at least an additional 6 hr. However, aqueous humor c-AMP was significantly elevated 30 min after epinephrine treatment, peaked between 60 and 240 min, and declined to baseline by 6 hr before a significant ocular hypotensive response was noted. Timolol treatment alone had no significant effect on either intraocular pressure or aqueous c-AMP. However, in epinephrine-treated animals which were pre-treated with timolol, the c-AMP response was blocked, with no significant alteration of the hypotensive response. Previous reports in the literature suggested a causal relationship between elevated aqueous humor c-AMP and fall in IOP. On the basis of the present work, this relationship is questionable.     

Efficacy of ophthalmic suspension of Brinzolamide (Azopt) in the primary or combined therapy for patients with hypertensive glaucomas

The primary objective of this prospective study was to evaluate the efficacy of lowering intraocular pressure, safety and tolerability of Brinzolamide 1% ophthalmic suspension as primary or adjunctive therapy in hypertensive glaucomas. MATERIAL AND METHOD: Brinzolamide 1% was administrated in monotherapy or in combination for 26 patients suffering from hypertensive glaucomas. The patients were divided in two groups: group I--included 10 patients (20 eyes) with primary open-angle glaucoma in which suspension Brinzolamide was administrated in monotherapy, and, group II--(16 patients with 30 eyes) with diverse forms of hypertensive glaucomas, that the Brinzolamide was administrated in adjunctive therapy, after the failure of another forms of medication, especially, beta-blockers. Intraocular pressure was assessed at 8, 10 AM, and 6 PM in first day, then daily at 8 AM, 7 days, and finally, weekly, at 8 AM all the period. Dilated fundoscopy, automated perimetry, visual acuity, were performed in addition to hematology, blood chemistry, urinalysis testing and ocular events. RESULTS: The intraocular pressure-lowering observed on treatment was as follows: 3.5 mmHg to 4.8 mmHg (13.5% to 18.2%) in patients which Brinzolamide 1% dosed two times a day, and, 4.2 to 5.2 mmHg (17.8 to 20.9%) after administration Brinzolamide three times a day. The association of Brinzolamide with another therapy induces in an additive ocular hypotensive effect, which was stable in the whole period of the study. The ocular and general tolerance was significantly improved for another hypotensive drugs and another carbonic anhydrase inhibitors topically active. This fact allows a long treatment period.     

DROP ATTACK IN GLAUCOMA: THE MELBOURNE EXPERIENCE WITH TOPICAL MIOTICS, ADRENERGIC AND NEURONAL BLOCKING DROPS

We have considered the effectiveness of miotics (pilocarpine 2% and ecothiopate iodide (Phospholine Iodide) 0.125 or 0.25%), adrenaline (Eppy/N 1 %) or adrenaline precursors (dipivalyl epinephrine or dipivefrin hydrochloride (Propine) 0.1%) and neuronal blockers (timolol maleate (Timoptol) 0.5%) in 165 patients in the clinical situation. All drops were effective in lowering intraocular pressure with an average fall of 6.6 mmHg for timolol (160 eyes), 8.21 mmHg for pilocarpine (79 eyes), 5.77 mmHg for dipivalyl epinephrine (57 eyes), 7.23 mmHg for adrenaline (17 eyes) and 10.5 mmHg for ecothiopate iodide (16 eyes). In chronic simple open-angle glaucoma, ocular hypertension and pseudoexfoliative glaucoma, pilocarpine and timolol were almost equally effective while dipivalyl epinephrine and adrenaline were also effective, but more as additive therapy, though dipivalyl epinephrine may be useful on its own in ocular hypertension. In low-tension glaucoma timolol and dipivalyl epinephrine together seemed best, while in secondary glaucomas all were effective at times, but ecothiopate iodide was best in aphakic glaucoma and fluorometholone (FML Liquifilm) 0.1% was important in inflammatory glaucoma. Side effects were frequent with dipivalyl epinephrine and timolol, with respiratory disease a strong contraindication to timolol.     

Interaction of antiglaucomatous drugs and melanin granule

The author investigated the effects of several antiglaucomatous drugs and prostaglandins (E2 and F2 alpha) on intraocular pressure responses in pigmented and albino rabbits, and spectrophotometrically assessed the binding of these drugs to synthetic melanin. Topical application of 0.5% timolol, 1% epinephrine and 3% pilocarpine had greater ocular hypotensive effects in albino rabbits than in pigmented rabbits. However no such differences were seen with application of prostaglandins. Melanin binding of drugs was higher in the order of befunolol, carteolol, timolol, epinephrine and pilocarpine. At higher concentrations of the drugs, the degree of binding increased. Prostaglandins had no binding ability. Thus drugs with lower hypotensive effects in pigmented rabbits than in albino rabbits had high melanin binding ability, whereas drugs with similar effects in pigmented and albino rabbits had no melanin binding ability. It is speculated that some antiglaucomatous drugs bind to melanin, resulting in decreased pharmacological action.     

A comparison of the ocular hypotensive efficacy of once-daily and twice-daily levobunolol treatment

The authors compared the ocular hypotensive efficacy of two different treatment regimens of levobunolol 0.5% in a double-masked, randomized, controlled clinical trial. Seventy-one patients with open-angle glaucoma or ocular hypertension received levobunolol 0.5% as their sole glaucoma medication either on a once-daily or twice-daily treatment regimen for 3 months. Approximately 81% of the patients in the once-daily treatment group and 88% of subjects in the twice-daily treatment group successfully completed the 3-month study period. The overall mean decrease in intraocular pressure (IOP) was 4.5 mmHg in the once-daily group and 5.6 mmHg in the twice-daily group. These differences were not statistically different. For both treatment groups, effects on mean heart rate and blood pressure were minimal. The authors' data from this population suggest that once-daily treatment with levobunolol is an effective glaucoma regimen.     

Effects of ocular hypotensive agents on the circadian rhythm in intraocular pressure in rabbits as measured by telemetry

PURPOSE: To establish a telemetry system for measuring intraocular pressure (IOP) in rabbits and to evaluate the effects of topical application of ocular hypotensive agents on the circadian rhythm of IOP. SUBJECTS AND METHODS: We developed a telemetry system in rabbits housed under a 12-hour light-dark cycle (light and dark phases: 7:00-19:00, 19:00-7:00, respectively). The IOP resulting from a single topical application of ocular hypotensive agents was measured by telemetry during the light phase and the dark phase. RESULTS: The values measured by the telemetry were positively correlated to the value of the anterior chamber pressure measured by a transducer in range from 5 to 50 mmHg (r = 0.987). A single topical application of timolol maleate (0.5%), dorzolamide hydrochloride (1%), and dipivefrine hydrochloride (0.1%) caused no significant reduction in IOP in the light phase, but they did in the dark phase. A single topical application of bunazosin hydrochloride (0.01% or 0.1%) had significant ocular hypotensive effects in both phases. CONCLUSION: These findings indicate that the different effects of ocular hypotensive agents on circadian rhythms of IOP can be measured by the telemetry. Telemetry may be useful for evaluation of ocular hypotensive agents and the circadian rhythm of IOP.     

Topical carbonic anhydrase inhibitors

Dorzolamide, a topically active carbonic anhydrase inhibitor, is an effective new glaucoma medication that creates a decrease in intraocular pressure similar to that produced by beta-blockers. When beta-blockers are contraindicated, dorzolamide may be used as a first-line therapy. It has excellent additivity with other topical ocular hypotensive medications, including beta-blockers and pilocarpine. Systemic side effects are minimal, particularly compared with those of oral carbonic anhydrase inhibitors. However, local side effects, including corneal edema in patients with borderline endothelial function, may occur. Decreased visual acuity and allergic reactions, which occur frequently, may curtail the use of dorzolamide in some patients.