Institute of Ophthalmology, University College London (UCL), London, UK; Imperial College of Science and Technology, St. Mary's Campus, London, UK; Eye-ACP Duke-National University of Singapore Medical School, Singapore; Singapore Eye Research Institute (SERI), Singapore; Department of Pharmacy Sciences, Creighton University, Omaha, NE, USA; Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, Texas, USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA; Ophthalmology Innovation Center, Santen Inc USA, Emeryville, CA, USA.
Exp Eye Res. 2023 Jul;232:109444. doi: 10.1016/j.exer.2023.109444. Epub 2023 Mar 21.
A multitude of pharmacological compounds have been shown to lower and control intraocular pressure (IOP) in numerous species of animals and human subjects after topical ocular dosing or via other routes of administration. Most researchers have been interested in finding drug candidates that exhibit a relatively long duration of action from a chronic therapeutic use perspective, for example to treat ocular hypertension (OHT), primary open-angle glaucoma and even normotensive glaucoma. However, it is equally important to seek and characterize treatment modalities which offer a rapid onset of action to help provide fast relief from quickly rising IOP that occurs in certain eye diseases. These include acute angle-closure glaucoma, primary angle-closure glaucoma, uveitic and inflammatory glaucoma, medication-induced OHT, and other secondary glaucomas induced by eye injury or infection which can cause partial or complete loss of eyesight. Such fast-acting agents can delay or prevent the need for ocular surgery which is often used to lower the dangerously raised IOP. This research survey was therefore directed at identifying agents from the literature that demonstrated ocular hypotensive activity, normalizing and unifying the data, determining their onset of action and rank ordering them on the basis of rapidity of action starting within 30-60 min and lasting up to at least 3-4 h post topical ocular dosing in different animal species. This research revealed a few health authority-approved drugs and some investigational compounds that appear to meet the necessary criteria of fast onset of action coupled with significant efficacy to reduce elevated IOP (by ≥ 20%, preferably by >30%). However, translation of the novel animal-based findings to the human conditions remains to be demonstrated but represent viable targets, especially EP-receptor agonists (e.g. omidenepag isopropyl; AL-6598; butaprost), mixed activity serotonin/dopamine receptor agonists (e.g. cabergoline), rho kinase inhibitors (e.g. AMA0076, Y39983), CACNA2D1-gene product inhibitors (e.g. pregabalin), melatonin receptor agonists, and certain K-channel openers (e.g. nicorandil, pinacidil). Other drug candidates and targets were also identified and will be discussed.
大量的药理学化合物已被证明可以降低和控制动物和人类受试者的眼内压（IOP），方法是局部眼部给药或通过其他给药途径。大多数研究人员都对寻找具有慢性治疗作用的相对长效药物候选物感兴趣，例如治疗眼压升高（OHT）、原发性开角型青光眼甚至正常眼压性青光眼。然而，从快速起效的角度寻找和表征治疗方式同样重要，以帮助快速缓解某些眼部疾病中快速升高的 IOP。这些疾病包括急性闭角型青光眼、原发性闭角型青光眼、葡萄膜炎和炎症性青光眼、药物引起的 OHT 以及由眼部损伤或感染引起的其他继发性青光眼，这些疾病可导致部分或完全失明。这种快速作用的药物可以延迟或预防需要进行眼部手术，而眼部手术通常用于降低危险的升高的 IOP。因此，这项研究调查旨在从文献中确定具有降低眼内压活性的药物，使数据标准化和统一，确定它们的作用开始时间，并根据在不同动物物种中开始作用的时间（30-60 分钟内）和持续时间（至少 3-4 小时）对它们进行排序。这项研究揭示了一些已获得卫生当局批准的药物和一些研究性化合物，这些药物似乎符合起效迅速与显著降低升高的 IOP（≥20%，最好是>30%）相结合的必要标准。然而，将新的基于动物的发现转化为人类疾病状态仍然有待证明，但代表了可行的目标，特别是 EP 受体激动剂（例如 omidenepag 异丙酯；AL-6598；butaprost）、混合活性 5-羟色胺/多巴胺受体激动剂（例如 cabergoline）、rho 激酶抑制剂（例如 AMA0076、Y39983）、CACNA2D1 基因产物抑制剂（例如 pregabalin）、褪黑素受体激动剂和某些 K 通道开放剂（例如 nicorandil、pinacidil）。还确定了其他药物候选物和目标，并将进行讨论。
