Ocular hypotensive action of labetalol in rabbit and human eyes

The ocular hypotensive action of labetalol, a drug endowed with alpha- and beta-adrenergic receptor-blocking properties, was studied in both rabbit and human eyes. In the rabbit, using two different models of experimentally induced ocular hypertension, an impressive decrease of IOP was seen after topical administration of the drug. In this species labetalol was found to be at least as effective as timolol and more active than pilocarpine or propranolol. In human eyes suffering from glaucoma, however, its effectiveness was much less evident and clearly inferior to that of timolol.     

Ocular side effects of checkpoint inhibitors

The incidence and impact of ocular side effects in patients treated with checkpoint inhibitors are not clearly defined.We reviewed prospective phase III clinical trials of checkpoint inhibitors applied in lung cancer, renal cell cancer, and melanoma. Case reports of the occurrence of ocular toxicities in patients receiving immune checkpoint inhibitors were also included. Of the 35 articles corresponding to phase III clinical trials with checkpoint inhibitors, ocular toxicity was described in four. Forty-six clinical cases of ocular toxicity after therapy with checkpoint inhibitors have been reported. The most frequently described ocular toxicities are uveitis, inflammatory orbital disease, and alterations of the ocular surface. Ocular toxicity is underestimated in checkpoint inhibitors clinical trials. Early ophthalmic examination and treatment with corticosteroids may improve the visual prognosis in these patients.     

Ocular hypotensive effect of alpha-adrenoceptor agonist and antagonist in the conscious pigmented rabbit]

It has been reported that some of the topically-used antiglaucomatics have a central ocular hypotensive effect. In this study, the influence of topical and intracerebroventricular (i.c.v.) administration of phenylephrine, clonidine, guanfacine, prazosin, yohimbine on the intraocular pressure (IOP) was investigated in the rabbit. Male pigmented rabbits were used throughout the experiments. For measurement of IOP, an applanation pneumatonograph was used. By unilateral topical administration of phenylephrine, an increase in IOP in the eye in which instillation was performed was observed. On the other hand, a slight decrease in IOP was observed by similar treatment of prazosin and yohimbine. No significant change of IOP in the contralateral eye was observed with these drugs. On the contrary, unilateral topical administration of clonidine or guanfacine decreased the IOP of both eyes. Furthermore, the decrease of IOP was more remarkable in the contralateral eye compared to the eye which received instillation. The IOP of both eyes was decreased in a dose-related fashion by i.c.v. administration of clonidine or guanfacine. The ocular hypotensive effects of clonidine were diminished by the pretreatment by i.c.v. administration with yohimbine. These results suggest that the ocular hypotensive effect of clonidine and guanfacine is due to their alpha 2-adrenoceptor stimulation in the central nervous system.     

Ocular hypotensive effects of cholinergic and adrenergic drugs may be influenced by prostaglandins E2 in the human and rabbit eye

PURPOSE: Increased PGE2 production by the iris and ciliary body regulate intraocular pressure (IOP) in vivo. Various cholinergic and adrenergic compounds are traditionally used as antiglaucoma drugs, and their effect on IOP reduction is antagonised by cyclooxygenase inhibitors, indicating a role for eicosanoids in their hypotensive activity. One of the most potent antiglaucoma drugs, PG2 alpha (Latanoprost), reduces IOP by increasing uveoscleral outflow and also increases PGE2 production by the iris and ciliary body in vivo. We investigated whether cholinergic and adrenergic antiglaucoma drugs induce the production of prostaglandin E2 (PGE2) in vitro by: 1) the iris-ciliary body (ICB) of rabbits and, 2) irises of glaucoma patients. METHODS: Pilocarpine 2%, epinephrine 1% and echothiophate iodide 0.125% were applied topically to both eyes of Albino rabbits. Control groups were treated with the corresponding vehicles, or untreated completely. Human iris specimens were obtained from nine untreated cataract eyes, and five eyes under antiglaucoma medication undergoing surgery. PGE2 were determined by a radioimmunoassay. RESULTS: PGE2 production by the ICB of treated rabbits in vitro was twice that of vehicle-treated or untreated rabbit eyes (p<0.001, for either group). In vitro PGE2 production by treated glaucoma patients' irises was three times higher (p<0.001) than in cataract control patients. CONCLUSIONS: The study found an increase in in vitro production of PGE2 by the irises of eyes treated with cholinergic and adrenergic antiglaucoma medications. This suggests a role for endogenous PG production in the hypotensive effect of both classes of drug.     

Ocular hypotensive effects of topically administered agmatine in a chronic ocular hypertensive rat model

Agmatine, a primary polyamine and potential neuromodulator, exhibits a high affinity to the α₂-adrenergic receptor as well as imidazoline receptors. As α₂-adrenergic receptor agonists display positive ocular hypotensive effects, we assessed whether agmatine effectively lowers intraocular pressure (IOP) using a chronic ocular hypertensive rat model. We raised IOP in unilateral eyes of Sprague-Dawley rats by cauterizing three episcleral veins per eye. Four weeks later, we topically administered 10⁻³ M agmatine solution 4 times a day for 6 consecutive weeks. After confirming the recovery of IOP to pretreatment level at 13 weeks after cauterization, the retinal ganglion cells (RGCs) were retrogradely labeled and counted. Eyes subjected to episcleral vein cauterization (EVC) demonstrated significant increases in IOP (48.39% increase over baseline IOP), and the elevated IOP was well maintained until 12 weeks. Topically administered agmatine powerfully lowered IOP to 30.29% of its pretreatment level, and the associated washout period was about two weeks. EVC was associated with a 55.44% loss of RGCs in the control group, but agmatine appeared to attenuate this RGC loss to 18.65%. Overall, topically administered agmatine appeared to effectively lower IOP and rescue RGCs in a chronic ocular hypertensive rat model. Although the mechanism underlying these effects is not yet established, it is possible that agmatine offers a powerful new ocular hypotensive agent for eyes with chronic ocular hypertension and/or glaucoma.     

Ocular hypotensive action of ergoline derivatives in rabbits: effects of sympathectomy and domperidone pretreatment

Ergot derivatives, such as bromocriptine, lergotrile and pergolide, are potent dopaminergic agonists in various biological systems. In topical doses ranging from 0.001 to 1% applied unilaterally, each agent produced dose-related ocular hypotension in normal rabbits. Utilizing an intraocular pressure (IOP) recovery rate method (aqueous formation index), each agent was observed to suppress the recovery rate of IOP in normal rabbits. Pretreatment with a prejunctional dopamine receptor antagonist (domperidone) inhibited the ocular hypotensive effect of bromocriptine and pergolide more than that of lergotrile. In rabbits with unilateral superior cervical ganglionectomies, IOP was lowered appreciably less by these compounds in the denervated eyes. These studies indicate that: a) lowering of IOP by these ergot derivatives is dependent, in part, on suppression of sympathetic neuronal activity; b) the most probable sites of action are DA2 receptors on sympathetic nerve endings or in sympathetic ganglia; c) ocular hypotension is produced, in part, by suppressing aqueous humor formation.     

Ocular hypotensive effects of an intratracheally delivered liposomal delta9-tetrahydrocannabinol preparation in rats.

This study investigated the effect of an intratracheal (i.t.) administration of a liposome-entrapped Delta9-tetrahydrocannabinol (LTHC) preparation on intraocular pressure (IOP) in nonanaesthetized Brown Norway rats. The ocular hypotensive effects of i.t. LTHC were compared to that of intraperitoneal (i.p.) LTHC administration. All i.t. LTHC doses >0.05 mg/kg significantly decreased IOP (P < 0.05) within 30 min of administration, and doses of i.t. LTHC >0.1 mg/kg decreased IOP within 15 min of administration. A maximal reduction in IOP of 2.32 +/- 0.27 mmHg (n = 4) was seen with 1.0 mg/kg of i.t. LTHC. In comparison, no significant IOP drop was apparent prior to 30 min with all doses (0.01-1.0 mg/kg) of i.p. LTHC tested, although a similar maximum drop in IOP (2.15 +/- 0.12 mmHg; n = 8) was obtained with 1.0 mg/kg of LTHC. The ED(50) for i.t. and i.p. LTHC was 0.08 mg/kg and 0.12 mg/kg, respectively. The IOP-lowering effects of i.p. LTHC (0.2 mg/kg) were reduced by 14% and 80% by 0.25 mg/kg (n = 6) and 2.5 mg/kg (n = 6), respectively, of the CB1R antagonist, SR141716A. In conclusion, i.t. LTHC was superior to i.p. LTHC in producing a more rapid and potent decrease in IOP. The IOP-lowering effect of LTHC was blocked by the CB1R-selective antagonist, SR141716A, suggesting that CB1Rs contribute to the ocular hypotensive effect of Delta9-tetrahydrocannabinol.     

乙酰唑胺滴眼液降低兔眼压的作用

目的:考察加穿透促进剂氮酮的乙酰唑胺滴眼液对正常眼压兔眼的降眼压作用。方法:实验采用白色家兔,用Schitz眼压计进行眼压测定。分别给实验兔局部滴用1g/L氮酮、33g/L乙酰唑胺和1g/L氮酮 33g/L乙酰唑胺滴眼液50μL。在滴药前及滴药后0.5,1,2,3,4,5,6h测量眼压,在同样时间不滴药眼压作为基线眼压。结果:1g/L氮酮滴眼液对兔眼内压无影响。乙酰唑胺滴眼液在滴眼后1,2h均可降低眼压(P<0.05)。1g/L氮酮 33g/L乙酰唑胺滴眼液在滴眼后0.5,1,2,3,4h分别降低兔眼内压0.37,0.54,0.52,0.46,0.26kPa(P<0.01)。最大降眼压值是0.54kPa,下降率是24.3%。结论:加氮酮的乙酰唑胺滴眼液可有效地降低正常眼压白兔的眼内压。     

Ocular hypotensive effect of topical ketanserin in timolol users

Background: Ketanserin is a specific antagonist of 5-HT2 and 5-HT1c receptors. These receptors are linked to the stimulation of phosphoinositide metabolism and are involved in IOP controls. Orally and topically administered ketanserin reduces IOP in normotensive and glaucomatous eyes. Methods: Ketanserin 0.5% eye drops were administered to 20 patients with primary open-angle glaucoma in a randomised, crossover, double-masked fashion to evaluate the effect of ketanserin in glaucomatous patients already receiving timolol who did not have controlled IOP (>21 mmHg). Mean and range of IOP curve (8.00 a.m.–8.00 p.m.), pupil diameter, Schirmer 1, basal secretion test and BUT values were recorded at baseline and after 2 weeks of topical administration of ketanserin or placebo twice daily. The alternative treatment was given 2 weeks later and the same protocol was repeated. Results: When patients received placebo no significant variations were found in the analysed parameters. Ketanserin significantly reduced mean IOP (19.5%) and was effective for up to 12 h without inducing variations of tear secretion or pupil diameter. No systemic side effects were observed, and no significant variations in ocular symptoms and signs were reported. Conclusion: These results indicate that topical administration of ketanserin may be useful to reduce IOP in patients not controlled with beta-blockers.     

Ocular hypotensive effect of sublingual administration of timolol

Purpose: A randomized clinical trial to assess ocular hypotensive effect of sublingual administration of timolol was performed. Patients and methods: Seventeen (9 male, 8 female; age range 45 to 68 years) with bilateral ocular hypertension were selected for the study. Each patient was evaluated with regard to IOP, arterial blood pressure and heart rate before and after each of the following experimental treatment: unilateral ocular administration of 20 l of 0.5% timolol solution; sublingual administration of 20 l of 0.5% timolol solution; unilateral ocular administration of 20 l of saline solution (placebo); sublingual administration of 20 l of saline solution (placebo). The sequence of the treatments and the eye topically treated were randomly chosen. At least four weeks wash-out elapsed between each experimental treatment. Results: Our results showed that sublingual administration of timolol was able to induce a bilateral significant reduction of the IOP. This reduction was not statistically different from that obtained in the eye treated with timolol. A significantly greater reduction of the IOP was obtained by sublingual timolol than in the contralateral eye after unilateral topical administration of timolol solution. No significant modification of arterial blood pressure and heart rate were evidenced after the treatment. Conclusions: Sublingual administration seems to be a new interesting way for reducing the IOP. Long term studies are required in order to test efficacy and safety of this new treatment.     

Ocular hypotensive medications for the treatment of glaucoma

The past 10 years have seen dramatic changes in the pharmacologic treatment of glaucoma. The treatment of glaucoma has changed from surgical to primarily medical. These treatments have improved the effectiveness and safety of lowering the intraocular pressure to prevent progressive vision loss and blindness, but no cure for glaucoma or reversal of blindness is available yet. Research is progressing and can hopefully achieve these final goals sometime in the future.     

Differential effects of inhibitors of monoamine oxidase Types A and B on the adrenergic system of the rabbit iris.

Topical instillation of inhibitors of monoamine oxidase Types A and B into the rabbit eye, followed by the administration of a releaser of monoamines (Ro 4-1284), induces strong and sustained dilation of the iris. The mydriatic pattern differs markedly with A- and B-inhibitors and with the duration of the inhibitor treatment. The Type B inhibitor, deprenyl, prevents the degradation of exogenous 2-phenylethylamine and possibly of the endogenous amine X capable of releasing monoamines from a compartment less accessible to Ro-1284.     

Ocular hypotensive and aqueous outflow-enhancing effects of AL-3037A (sodium ferri ethylenediaminetetraacetate)

AL-3037A (Sodium ferri ethylenediaminetetraacetate), a novel compound shown to stimulate the degradation of glycosaminoglycans, was evaluated for its effects on aqueous humor outflow and intraocular pressure (IOP) in four experimental models. Its effect on outflow facility was assessed in bovine and human ocular perfusion organ cultures. Its IOP effect was tested in normotensive and dexamethasone-induced ocular hypertensive rabbits. In bovine eyes, perfusion with AL-3037A (0.1% w/v, 2.3 m M) significantly increased the outflow facility well above the normal 'wash-out' effect. At 30 min after perfusion, the outflow facility of drug-treated eyes increased by 26.0+/-2.8% (mean +/- S.E.(M.), n = 8), significantly higher than the 12.1 +/- 2.8% increase in vehicle-treated eyes. This difference sustained throughout the study period (2 hr). The compound also enhanced aqueous outflow in perfused human anterior segments. In non-glaucomatous eyes, it produced a small decrease in IOP (15.4 +/- 4.6%, n = 17), but in tissues derived from glaucoma patients, bolus administration of 3 mg (7 micromol) of AL-3037A lowered the IOP by 52-68% (n = 2) lasting for at least 3 hr. This outflow-enhancing effect of AL-3037A in ex vivo studies was confirmed by in vivo results. In normotensive rabbits, oral (50 mg kg(-1)), intravenous (10 mg kg(-1)), or topical (2 mg; 50 microl of 4% w/v solution) administration of AL-3037A produced maximum reduction of IOP, when compared to vehicle-treated animals, by 34.7+/-3.5% (n = 10), 22.0 +/- 4.6% (n = 10), and 21.6 +/-4.5% (n = 10), respectively. In dexamethasone induced ocular hypertensive rabbits, topical application of the compound (0.5 mg; 25 microl of 2% w/v solution) reduced IOP significantly by 19.2+/- 0.4% (n = 7) at 3 hr after dosing. Importantly, the IOP lowering effect of AL-3037A did not diminish even after repeated treatments in consecutive days. Thus, in the four study models across three animal species, AL-3037A was demonstrated to be an efficacious ocular hypotensive compound whose effect is most likely mediated by augmentation of the aqueous outflow. Its proposed action on the metabolism of glycosaminoglycans may provide a new and unique mechanism for the treatment of glaucoma.