Pang I H, Moll H, McLaughlin M A, Knepper P A, De Santis L, Epstein D L, Clark A F
Alcon Research, Ltd, 6201 South Freeway, Fort Worth, TX 76134, USA.
Exp Eye Res. 2001 Dec;73(6):815-25. doi: 10.1006/exer.2001.1087.
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.
AL-3037A（乙二胺四乙酸铁钠）是一种新型化合物，已证实其能刺激糖胺聚糖的降解。在四种实验模型中，对其影响房水流出和眼内压（IOP）的作用进行了评估。在牛和人眼灌注器官培养物中评估了其对流出易度的影响。在正常血压和地塞米松诱导的高眼压兔中测试了其对眼内压的影响。在牛眼中，用AL-3037A（0.1% w/v，2.3 mM）灌注可显著提高流出易度，远高于正常的“冲洗”效应。灌注后30分钟，药物处理眼的流出易度增加了26.0±2.8%（平均值±标准误，n = 8），显著高于载体处理眼增加的12.1±2.8%。在整个研究期间（2小时），这种差异一直持续。该化合物还增强了灌注人眼前节的房水流出。在非青光眼眼中，它使眼内压略有降低（15.4±4.6%，n = 17），但在来自青光眼患者的组织中，推注3 mg（7 μmol）的AL-3037A可使眼内压降低52 - 68%（n = 2），持续至少3小时。AL-3037A在体外研究中的这种流出增强作用在体内结果中得到了证实。在正常血压兔中，口服（50 mg kg⁻¹）、静脉注射（10 mg kg⁻¹）或局部应用（2 mg；50 μl的4% w/v溶液）AL-3037A与载体处理动物相比，分别使眼内压最大降低34.7±3.5%（n = 10）、22.0±4.6%（n = 10）和21.6±4.5%（n = 10）。在用地塞米松诱导的高眼压兔中，局部应用该化合物（0.5 mg；25 μl的2% w/v溶液）在给药后3小时可使眼内压显著降低19.2±0.4%（n = 7）。重要的是，即使连续重复治疗，AL-3037A的降眼压作用也不会减弱。因此，在三种动物物种的四个研究模型中，AL-3037A被证明是一种有效的降眼压化合物，其作用最可能是通过增加房水流出介导的。其对糖胺聚糖代谢的推测作用可能为青光眼的治疗提供一种新的独特机制。
