Phosphosulindac for dry eye

磷舒林治疗干眼症

• 批准号: 10561717
• 负责人: Despina Komninou
• 金额: $ 82.32万
• 依托单位: APIS THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561717
• 关键词: Absence of pain sensation; Address; Affect; Analgesics; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antiinflammatory Effect; Artificial Tears; Binding Proteins; Biodistribution; Blindness; CD4 Positive T Lymphocytes; Categories; Cauterize; Characteristics; Chronic; Circulation; Classification; Clinical; Complement; Concanavalin A; Cornea; Cyclosporine; Data; Development; Diagnosis; Diagnostic; Dose; Drug Kinetics; Dry Eye Syndromes; Etiology; Excision; Eyedrops; Film; Formulation; Functional disorder; Gelatinase B; Goals; Goblet Cells; Homeostasis; Human; IL17 gene; In Vitro; Infiltration; Inflammation; Inflammatory; Injections; Innate Immune Response; Interferon Type II; Interleukin-1 beta; Investigational Drugs; Lacrimal gland structure; Lactoferrin; Lead; Lectin; Medical; Metabolic; Modeling; Molecular Target; Mucins; Narcotics; Nerve Endings; Neuropathy; New Agents; Operative Surgical Procedures; Oryctolagus cuniculus; Osmolar Concentration; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma Proteins; Prevalence; Price; Production; Protocols documentation; Rose Bengal; Safety; Signs and Symptoms; Stains; Stress; Subgroup; Sulindac; Symptoms; T-Lymphocyte; Testing; Time; Toxic effect; Toxicology; Validation; Work; adaptive immune response; analytical method; aqueous; conjunctiva; corneal epithelium; cost; cytokine; efficacy evaluation; evaporation; eye dryness; human disease; improved; lead optimization; meibomian gland; melting; novel; ocular pain; ocular surface; optimal treatments; pharmacologic; phase 1 study; phase 2 study; posterior eyeball chamber; preclinical development; preclinical evaluation; scale up; side effect; small molecule; sulfated glycoprotein 2

ABSTRACT The treatment of dry eye disease (DED) has been hampered by weak agents, significant side effects and high cost. The pathophysiological hallmark of DED that unifies its diverse etiologies is inflammation of the ocular surface that accounts for its clinical manifestations. The optimal treatment of DED must provide strong efficacy; topical analgesia; safety; convenient dosing; and low cost. None of the available treatments for DED meets these criteria. Phosphosulindac (PS) is a proprietary compound. We developed novel robust rabbit models of DED encompassing its main pathophysiological subgroups (evaporative, aqueous deficient and mixed). PS showed remarkable efficacy against DED; excellent safety; practically instantaneous topical analgesia; superiority in terms of efficacy over cyclosporine and lifitegrast, the two currently available drugs for the treatment of DED; and has projected low cost Additional preliminary data include the IND-enabling development of a scaled-up synthesis of PS; and development and validation of all the required analytical methods. We have also identified molecular targets of PS; and developed several formulations for PS encompassing the main physicochemical categories. Our goal is to develop PS as an efficacious drug for DED. In this Fast Track application, we propose the following studies: Phase I studies: Aim#1: Study the effect of PS in an evaporative model of DED, complementing our results with the aqueous deficient and mixed models. Aim #2: Develop the lead formulation of PS. Phase II studies: Aim #3: Optimize the lead formulation from aim #2. Aim #4: Study the in vitro metabolic stability and plasma protein binding of PS. Aim #5: Perform toxicity studies of PS. And Aim # 6: Prepare the IND protocol and package for the FDA. The proposed work, if successful, will contribute greatly towards a successful treatment of DED, a prevalent human disease, which represents an unmet medical need.

摘要 干眼症（DED）的治疗一直受到弱剂、显方 效果差，成本高。DED的病理生理学特征统一了其多种病因 是眼表的炎症，这是其临床表现的原因。最优 DED的治疗必须提供强有效性;局部镇痛;安全性;方便给药;以及 低成本现有的DED治疗方法均不符合这些标准。 磷酸舒林酸（PS）是一种专利化合物。我们开发了一种新的健壮兔 包括其主要病理生理亚组（蒸发性、水性）的DED模型 不足和混合）。PS对DED疗效显著，安全性好，实用性强， 即时局部镇痛;在疗效方面优于环孢菌素和lifitegrast， 目前可用于治疗DED的两种药物;并预计成本低。 初步数据包括为国家自主研发而开发的扩大规模的聚苯乙烯合成;以及 开发和验证所有必要的分析方法。我们还确定 PS的分子目标;并开发了几种PS配方，包括主要的 物理化学分类 我们的目标是开发PS作为治疗DED的有效药物。在此快速通道应用程序中， 我们建议进行以下研究： I期研究：目标#1：研究PS在DED蒸发模型中的作用， 补充我们的结果与水缺乏和混合模型。目标#2：开发 PS的主要配方。 II期研究：目标3：从目标2优化先导化合物制剂。目标#4：研究 PS体外代谢稳定性和血浆蛋白结合。目的#5：进行毒性研究 PS.目标6：为FDA准备IND方案和包装。 拟议的工作，如果成功，将大大有助于成功地治疗 DED是一种流行的人类疾病，代表了未满足的医疗需求。

项目成果

An Improved Ocular Impression Cytology Method: Quantitative Cell Transfer to Microscope Slides Using a Novel Polymer.

• DOI: 10.1080/02713683.2021.1951300
• 发表时间: 2022-01
• 期刊: Current eye research
• 影响因子: 2
• 作者: Master A;Huang W;Huang L;Honkanen R;Rigas B
• 通讯作者: Rigas B

The transcriptome of rabbit conjunctiva in dry eye disease: Large-scale changes and similarity to the human dry eye.

• DOI: 10.1371/journal.pone.0254036
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Master A;Kontzias A;Huang L;Huang W;Tsioulias A;Zarabi S;Wolek M;Wollocko BM;Honkanen R;Rigas B
• 通讯作者: Rigas B