Journal of Ocular Pharmacology and Therapeutics最新文献

{"title":"Neuritin 1 Drives Therapeutic Preservation of Retinal Ganglion Cells in an <i>Ex Vivo</i> Human Glaucoma Model.","authors":"Shahna S Hameed, Nicole E Bodi, Ryan C Miller, Tasneem P Sharma","doi":"10.1089/jop.2024.0041","DOIUrl":"10.1089/jop.2024.0041","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> Glaucoma is a leading cause of irreversible blindness. Glaucomatous intraocular pressure (IOP) triggers deleterious effects, including gliosis, optic nerve (ON) axonal retraction, neurotrophic factor deprivation, inflammation, and other pathological events, leading to retinal ganglion cell (RGC) loss. Trophic factor impairment enhances RGC apoptosis susceptibility. Neuritin 1 (NRN1), a neurotrophic protein downstream of various neurotrophins, exhibited RGC protection and regeneration in axotomy models. We evaluated human recombinant NRN1's impact on human RGCs cultured in pressurized conditions within the <i>ex vivo</i> translaminar autonomous system to simulate glaucoma pathogenesis. <b><i>Methods:</i></b> Human glaucomatous and non-glaucomatous donor eyes were obtained from eye banks according to the Declaration of Helsinki. Initially, we evaluated NRN1and RGC marker expression in glaucoma and non-glaucomatous retina to determine the NRN1 level and its association with RGC loss. Further, we evaluated NRN1's therapeutic potential by treating pressurized human eyes at normal and high IOP for seven days. Retina, ON, and conditioned medium were analyzed for RGC survival (<i>THY1</i>, <i>RBPMS</i>), gliosis (<i>GFAP</i>), apoptosis (<i>CASP3</i>, <i>CASP7</i>), and extracellular matrix deposition (COLIV, FN) by qRT-PCR and western blotting. Paraphenylenediamine staining assessed ON axonal degeneration, whereas ex <i>vivo</i> electroretinogram assessed retinal activity. <b><i>Results:</i></b> Glaucomatous retinas exhibited significant reductions in both NRN1 (<i>*p</i> = 0.007, <i>n</i> = 5) and RGC marker expression (<i>*p</i> = 0.04, <i>n</i> = 5). NRN1 treatment reduced gliosis, extracellular matrix deposition, ON degeneration, and increased retinal activity in pressure-perfused eyes. <b><i>Conclusions:</i></b> Our study confirms that NRN1 enhances human RGC survival and improves retinal function in degenerative conditions, substantiating it as a promising candidate for rescuing human RGCs from degeneration.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"596-607"},"PeriodicalIF":1.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Ocular Pharmacokinetics of Dexamethasone Implants in Rabbits.","authors":"Jihyun Won, Juhyung Kang, Wonku Kang","doi":"10.1089/jop.2024.0052","DOIUrl":"10.1089/jop.2024.0052","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> Dexamethasone eye implant has been used to treat macular edema and non-infectious uveitis. To date, its ocular pharmacokinetics are not fully characterized, and the development of generic preparations is in progress, as the patent of the original brand expires soon. Therefore, this work was designed to 1) determine the time course of vitreous dexamethasone concentrations following intravitreal implantation in rabbits and 2) explore the alternative use of NDF-SI01 from a pharmacokinetic point of view compared to Ozurdex^®, which is currentlyused in the market. <b><i>Methods:</i></b> Ozurdex^® and NDF-SI01 were implanted into the right and left eyes of the rabbit, respectively. A serial vitreous collection was performed to minimize the sacrifice of animals, and dexamethasone concentrations were measured by HP LC-MS/MS. <b><i>Results:</i></b> After implantation, dexamethasone concentration reaches the maximum concentration (3.1 μg/mL) in 19.5 days and decreases with a half-life of 40.3 h. AUC and clearance are 683.9 μg·h/mL and 1.29 mL/h, respectively. There is no significant difference in pharmacokinetic parameters between NDF-SI01 and Ozurdex^®. The overall patterns of the cumulative release of both implants are similar. <b><i>Conclusions:</i></b> NDF-SI01 could alternate Ozurdex^® in clinics based on the in vivo comparative pharmacokinetic study and in vitro dissolution test.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"608-614"},"PeriodicalIF":16.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Basic Fibroblast Growth Factor Supports the Function of Limbal Niche Cells via the Wnt/β-Catenin Pathway.","authors":"Bihui Jin, Guanyu Su, Xiao Zhou, Lingjuan Xu, Wei Wang, Tianyu Zhou, Yongyao Tan, Shusheng Wang, Guigang Li","doi":"10.1089/jop.2024.0042","DOIUrl":"10.1089/jop.2024.0042","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> To test the effects and underlying mechanisms of basic fibroblast growth factor (bFGF) on the limbal niche cell (LNC) function <i>ex vivo</i>. <b><i>Methods:</i></b> By using different concentrations of bFGF (0, 4, 8, 12, and 16 ng/mL) and fibroblast growth factor receptor (FGFR) inhibitors, the effects of bFGF on LNC proliferation, expression of stem cell markers, and transcription levels of the β-catenin were investigated. Single-cell RNA sequencing (scRNA-seq) was used to analyze the action and mechanisms of FGFR subtypes and the Wnt/β-catenin pathway during LNC culture. An mature corneal epithelial cell (MCEC)/LNC three-dimensional model was constructed to verify whether bFGF activates the Wnt/β-catenin pathway in LNC by inhibiting FGFR or β-catenin targets. <b><i>Results:</i></b> scRNA-seq showed that <i>FGFR1</i> is the main receptor in LNC, along with the molecules in the Wnt pathway, including <i>WNT2, FZD7, LRP5, LRP6,</i> and β-catenin. The 12 ng/mL bFGF treatment group showed higher LNC proliferation rate and transcription levels of <i>OCT4, SOX2, NANOG</i>, and β-catenin than any other groups (<i>P</i> < 0.001). In the MCEC/LNC co-culture model, MCEC/LNC treated with 12 ng/mL bFGF promoted the aggregation of the spheres than other groups, associated with increased transcription levels of <i>P63α</i>, <i>WNT2</i>, β-catenin, and a decreased transcription level of <i>CK12</i> (<i>P</i> < 0.001). Wnt/β-catenin inhibitor LF3 treatment reversed the abovementioned effect of bFGF. <b><i>Conclusions:</i></b> bFGF could maintain and promote the stemness of LNC via the <i>FGFR1</i>/<i>Wnt2</i>/<i>FZD7</i>/<i>LRP6</i> axis in a concentration-dependent manner.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"571-580"},"PeriodicalIF":16.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Stability, Sterility, And Cost-Effectiveness of 0.05% Chlorhexidine Gluconate as Antisepsis for Intravitreal Injection.","authors":"Asad F Durrani, Bita Momenaei, Viren Soni, Matthew Tennant, Jason Hsu, James Vander, Marc Spirn, Eugene Yu-Chuan Kang, Yih-Shiou Hwang, Gagan Kaushal, Sunir J Garg","doi":"10.1089/jop.2024.0071","DOIUrl":"10.1089/jop.2024.0071","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> Commercially available chlorhexidine gluconate (CHG) has a beyond-use date of 24 h. This study evaluated the stability and sterility of 0.05% CHG for 30 days after opening and compared its cost to povidone iodine (PI) for intravitreal injection antisepsis. <b><i>Methods:</i></b> 0.05% CHG was aliquoted into 1-mL syringes and stored at room temperature or refrigerated. Turbidity, pH, high-performance liquid chromatography (HPLC), and sterility testing were performed. A cost analysis was conducted. <b><i>Results:</i></b> 0.05% CHG remained stable for at least 30 days. All samples had measured turbidity <0.5 nephelometric turbidity units. The pH of all samples remained between 5.0 and 7.0. HPLC demonstrated CHG concentration at day 30 relative to day 0 of 98.52% ± 4.16% at room temperature and 99.99% ± 3.38% at 2°C -6°C. The cost per week to perform 150 injections using 0.05% CHG was $463.25 when opening a new bottle daily compared with $16.73 for 5% PI. This cost decreased to $23.16 when utilizing a bottle of CHG for 30 days. <b><i>Conclusion:</i></b> 0.05% CHG remains stable and sterile for at least 30 days after opening. The ability to use CHG for at least 30 days after its opening significantly decreases its utilization expense.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"581-587"},"PeriodicalIF":16.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in Human Meibum Lipid Composition Related to the Presence and Severity of Meibomian Gland Dysfunction.","authors":"Ashley Nguyen, Kugen K Naidoo, Layla Ajouz, Xiaoming Xu, Cathy Zhao, Michael R Robinson, Douglas Borchman","doi":"10.1089/jop.2024.0063","DOIUrl":"10.1089/jop.2024.0063","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> Changes in meibum composition and quantity in meibomian gland dysfunction (MGD) result in tear film instability and dry eye. This exploratory study aimed to identify changes in (O-acyl)-ω-hydroxy fatty acid (OAHFA) and hydrocarbon chain (HC) unsaturation levels in meibum related to the presence and severity of MGD. <b><i>Methods:</i></b> Meibum samples were collected from 3 cohorts of adults with no MGD, mild-to-moderate MGD, and severe MGD in a noninterventional clinical trial (NCT01979887). OAHFAs, cholesterol esters (CE), HC unsaturation, and HC length in the meibum samples were quantified with ¹H-nuclear magnetic resonance spectroscopy using 2 methods of normalization. <b><i>Results:</i></b> Meibum samples from 62 subjects were analyzed: 21 non-MGD, 21 mild-to-moderate MGD, and 20 severe MGD. Meibum OAHFA and CE levels and HC unsaturation were reduced with increasing severity of MGD, with most pairwise comparisons significant (<i>P</i> < 0.05, <i>t</i>-tests), following the order non-MGD > mild-to-moderate MGD > severe MGD. Regardless of the resonances used for normalization, each pairwise comparison of OAHFA, CE, and HC unsaturation levels in MGD (combined severities) versus non-MGD samples was significant (<i>P</i> < 0.01, <i>t</i>-test). Analysis using various normalization equations showed reductions of 20%-22% for OAHFAs, 51%-57% for CE, and 36%-66% for HC unsaturation in MGD (combined severities) compared with non-MGD. HC length was not altered in MGD (combined severities) compared with non-MGD samples (<i>t</i>-test). <b><i>Conclusions:</i></b> Meibum OAHFA, CE, and HC unsaturation levels were reduced in MGD and were lowest in the severe MGD cohort. These findings may contribute to the understanding of the pathophysiology of MGD.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"562-570"},"PeriodicalIF":1.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ocular and Systemic Pharmacokinetics of Lotilaner Ophthalmic Solution, 0.25%, Following a Single Dose or Repeated Doses in Dutch-Belted Rabbits.","authors":"Christopher S Crean, Elizabeth Yeu, Sathi Maiti, Sesha Neervannan","doi":"10.1089/jop.2024.0074","DOIUrl":"10.1089/jop.2024.0074","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> To evaluate the ocular and systemic pharmacokinetics of lotilaner ophthalmic solution, 0.25%, following bilateral topical ocular administration of single and repeated doses in rabbits. <b><i>Methods:</i></b> Dutch-belted rabbits (<i>n</i> = 34) were administered lotilaner ophthalmic solution, 0.25%, eye drops, either in a single bilateral dose (Group 1) or twice a day bilaterally for 7 days and once on Day 8 (Group 2). The pharmacokinetics and tissue distribution levels of lotilaner were assessed following the single dose in Group 1 and the last dose in Group 2. The drug levels were examined in various ocular tissues and whole blood. The maximal concentration of the drug (Cmax), time to maximal concentration, the terminal phase elimination half-life, the area under the concentration-time curve (AUC), and total clearance of the drug were determined. <b><i>Results:</i></b> In the eyelid margins, lotilaner exhibited the highest observed concentrations at 0.25 hour (h), presenting a mean Cmax of 14,600 ng/mL in Group 1 and 20,100 ng/mL in Group 2. The highest AUC was in the eyelid margin at 242,000 h×ng/mL in Group 1 and 535,000 h×ng/mL in Group 2. In the eyelid margin, the observed clearance rate (0.634 mL/h in single dose, 0.288 mL/h in repeat dose) was the slowest among all ocular tissues in both groups, with the longest half-life of 152 h (∼6.3 days) observed in the repeat dose group. <b><i>Conclusions:</i></b> Lotilaner ophthalmic solution, 0.25%, demonstrated rapid ocular tissue absorption into the eyelid margin tissue with a long half-life of almost a week. No adverse effects were observed following topical ocular administration in Dutch-belted rabbits.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"588-595"},"PeriodicalIF":16.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two Decades of Research in Drug Delivery Systems for the Treatment of Diseases of the Posterior Segment of the Eye.","authors":"Sílvia L Fialho, Armando Silva-Cunha","doi":"10.1089/jop.2024.0096","DOIUrl":"10.1089/jop.2024.0096","url":null,"abstract":"","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"545-549"},"PeriodicalIF":16.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory Requirements of Biosimilars: Drug Development in Ophthalmology, Part 1.","authors":"Cheryl L Rowe-Rendleman","doi":"10.1089/jop.2024.0151","DOIUrl":"10.1089/jop.2024.0151","url":null,"abstract":"","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"550-552"},"PeriodicalIF":16.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survey of Dopamine Receptor D2 Antagonists as Retinal Antifibrotics.","authors":"Ashley Y Gao, Madison G Whaley, Namita Saraf, Sophie J Bakri, Andrew J Haak","doi":"10.1089/jop.2024.0006","DOIUrl":"10.1089/jop.2024.0006","url":null,"abstract":"<p><p><b><i>Purpose:</i></b> To evaluate the potency and efficacy of a library of dopamine receptor D2 (D2R) antagonists in the mitigation of fibrotic activation in retinal pigment epithelial (RPE) cells. <b><i>Methods:</i></b> ARPE-19 cells were cultured and treated with methotrexate or 27 district D2R antagonists using a fibronectin deposition assay. The most potent compounds were then further assessed in assays measuring cellular proliferation, cellular migration, and profibrotic gene expression. <b><i>Results:</i></b> The previously established antifibrotic D2R antagonist loxapine exerted a robust and dose-dependent inhibition of fibronectin deposition, whereas methotrexate exerted minimal inhibition. The most potent D2R antagonist identified, fluphenazine, effectively blocked <i>in vitro</i> models of fibrosis at 300-1,000 nM concentrations. <b><i>Conclusions:</i></b> Here we found multiple FDA-approved D2R antagonists that potently block RPE cell fibrogenesis. These findings further support the potential of D2R antagonism as a potential therapeutic for retinal fibrotic disease.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"536-542"},"PeriodicalIF":1.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eyes on New Product Development.","authors":"Gary D Novack","doi":"10.1089/jop.2024.0132","DOIUrl":"10.1089/jop.2024.0132","url":null,"abstract":"","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"467-468"},"PeriodicalIF":1.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}