{"title":"一种新型的n -丙基溴化季铵胺碘酮对角膜疼痛具有长效镇痛作用。","authors":"Yumi Kotoda, Sohei Hishiyama, Jaehoon Shim, Hiroki Kobayashi, Ayasa Takamino, Masako Abe, Kenji Kashiwagi, Takashi Matsukawa, Masakazu Kotoda","doi":"10.2147/DDDT.S486031","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Corneal pain is one of the most common eye symptoms caused by various types of epithelial injuries, including traumatic abrasion, chemical injury, ulcers, ultraviolet exposure, and infection. However, current therapeutic options for corneal pain are limited. In this study, we synthesized a novel quaternary ammonium compound, N-propylamiodarone bromide (NPA), and employed a rodent model of corneal injury to investigate whether NPA offers prolonged corneal analgesia through transient receptor potential vanilloid 1 (TRPV1) channel-mediated selective cellular entry, without hindering corneal epithelial recovery.</p><p><strong>Methods: </strong>In the corneal injury model, 24 adult Wistar rats received a topical application of normal saline, oxybuprocaine, or NPA (n = 8 each), and corneal pain sensitivity was assessed using the von Frey technique. Another set of 32 rats with intact corneas received oxybuprocaine, capsaicin (a TRPV1 agonist), or NPA with or without capsaicin (n = 8 each), followed by a mechanical sensitivity evaluation. Potential adverse effects on normal epithelial recovery were evaluated using fluorescence and hematoxylin-eosin staining in an additional 8 rats with corneal injury.</p><p><strong>Results: </strong>In the corneal injury model, NPA produced significantly longer-lasting analgesia than oxybuprocaine (duration of the maximum effect: 215 ± 11 vs 25 ± 2 min, P < 0.001). None of the animals presented any signs of eye irritability. In contrast to injured eyes, NPA alone did not significantly increase mechanical sensitivity in naïve eyes. However, the co-administration of NPA and capsaicin produced significantly longer-lasting corneal anesthesia than oxybuprocaine (duration of the maximum effect: 165 ± 15 vs 31 ± 2 min, P < 0.001). NPA did not hamper wound healing.</p><p><strong>Conclusion: </strong>The novel quaternary ammonium NPA produced long-lasting analgesia against corneal injury without hampering corneal recovery, suggesting that it is a potential candidate for analgesic medicine targeting corneal pain.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"6199-6208"},"PeriodicalIF":4.7000,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669046/pdf/","citationCount":"0","resultStr":"{\"title\":\"A Novel Quaternary Ammonium N-Propylamiodarone Bromide Provides Long-Lasting Analgesia Against Corneal Pain.\",\"authors\":\"Yumi Kotoda, Sohei Hishiyama, Jaehoon Shim, Hiroki Kobayashi, Ayasa Takamino, Masako Abe, Kenji Kashiwagi, Takashi Matsukawa, Masakazu Kotoda\",\"doi\":\"10.2147/DDDT.S486031\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Corneal pain is one of the most common eye symptoms caused by various types of epithelial injuries, including traumatic abrasion, chemical injury, ulcers, ultraviolet exposure, and infection. However, current therapeutic options for corneal pain are limited. In this study, we synthesized a novel quaternary ammonium compound, N-propylamiodarone bromide (NPA), and employed a rodent model of corneal injury to investigate whether NPA offers prolonged corneal analgesia through transient receptor potential vanilloid 1 (TRPV1) channel-mediated selective cellular entry, without hindering corneal epithelial recovery.</p><p><strong>Methods: </strong>In the corneal injury model, 24 adult Wistar rats received a topical application of normal saline, oxybuprocaine, or NPA (n = 8 each), and corneal pain sensitivity was assessed using the von Frey technique. Another set of 32 rats with intact corneas received oxybuprocaine, capsaicin (a TRPV1 agonist), or NPA with or without capsaicin (n = 8 each), followed by a mechanical sensitivity evaluation. Potential adverse effects on normal epithelial recovery were evaluated using fluorescence and hematoxylin-eosin staining in an additional 8 rats with corneal injury.</p><p><strong>Results: </strong>In the corneal injury model, NPA produced significantly longer-lasting analgesia than oxybuprocaine (duration of the maximum effect: 215 ± 11 vs 25 ± 2 min, P < 0.001). None of the animals presented any signs of eye irritability. In contrast to injured eyes, NPA alone did not significantly increase mechanical sensitivity in naïve eyes. However, the co-administration of NPA and capsaicin produced significantly longer-lasting corneal anesthesia than oxybuprocaine (duration of the maximum effect: 165 ± 15 vs 31 ± 2 min, P < 0.001). NPA did not hamper wound healing.</p><p><strong>Conclusion: </strong>The novel quaternary ammonium NPA produced long-lasting analgesia against corneal injury without hampering corneal recovery, suggesting that it is a potential candidate for analgesic medicine targeting corneal pain.</p>\",\"PeriodicalId\":11290,\"journal\":{\"name\":\"Drug Design, Development and Therapy\",\"volume\":\"18 \",\"pages\":\"6199-6208\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2024-12-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669046/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Design, Development and Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2147/DDDT.S486031\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S486031","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
目的：角膜疼痛是由各种类型的上皮损伤引起的最常见的眼部症状之一，包括创伤性擦伤、化学损伤、溃疡、紫外线照射和感染。然而，目前治疗角膜疼痛的方法是有限的。在本研究中，我们合成了一种新型季铵化合物n -丙基胺碘酮溴化（NPA），并采用啮齿动物角膜损伤模型来研究NPA是否通过瞬时受体电位香素样蛋白1 （TRPV1）通道介导的选择性细胞进入来延长角膜镇痛，而不阻碍角膜上皮的恢复。方法：在角膜损伤模型中，24只成年Wistar大鼠分别外用生理盐水、羟布鲁卡因和NPA（各8只），采用von Frey技术评估角膜疼痛敏感性。另一组32只角膜完好的大鼠分别给予羟布鲁卡因、辣椒素（一种TRPV1激动剂）或含或不含辣椒素的NPA (n = 8)，然后进行机械敏感性评估。对另外8只角膜损伤大鼠进行荧光和苏木精-伊红染色，评估其对正常上皮恢复的潜在不良影响。结果：在角膜损伤模型中，NPA的镇痛持续时间明显长于奥布鲁卡因（最大作用持续时间：215±11 min vs 25±2 min， P < 0.001）。没有一只动物表现出眼睛易怒的迹象。与受伤眼相比，NPA单独没有显著增加naïve眼的机械敏感性。然而，NPA和辣椒素联合使用的角膜麻醉持续时间明显比奥布鲁卡因长（最大作用持续时间：165±15分钟vs 31±2分钟，P < 0.001）。NPA不妨碍伤口愈合。结论：新型季铵盐NPA对角膜损伤具有持久的镇痛作用，且不影响角膜的恢复，是一种潜在的角膜疼痛镇痛药物。
A Novel Quaternary Ammonium N-Propylamiodarone Bromide Provides Long-Lasting Analgesia Against Corneal Pain.
Purpose: Corneal pain is one of the most common eye symptoms caused by various types of epithelial injuries, including traumatic abrasion, chemical injury, ulcers, ultraviolet exposure, and infection. However, current therapeutic options for corneal pain are limited. In this study, we synthesized a novel quaternary ammonium compound, N-propylamiodarone bromide (NPA), and employed a rodent model of corneal injury to investigate whether NPA offers prolonged corneal analgesia through transient receptor potential vanilloid 1 (TRPV1) channel-mediated selective cellular entry, without hindering corneal epithelial recovery.
Methods: In the corneal injury model, 24 adult Wistar rats received a topical application of normal saline, oxybuprocaine, or NPA (n = 8 each), and corneal pain sensitivity was assessed using the von Frey technique. Another set of 32 rats with intact corneas received oxybuprocaine, capsaicin (a TRPV1 agonist), or NPA with or without capsaicin (n = 8 each), followed by a mechanical sensitivity evaluation. Potential adverse effects on normal epithelial recovery were evaluated using fluorescence and hematoxylin-eosin staining in an additional 8 rats with corneal injury.
Results: In the corneal injury model, NPA produced significantly longer-lasting analgesia than oxybuprocaine (duration of the maximum effect: 215 ± 11 vs 25 ± 2 min, P < 0.001). None of the animals presented any signs of eye irritability. In contrast to injured eyes, NPA alone did not significantly increase mechanical sensitivity in naïve eyes. However, the co-administration of NPA and capsaicin produced significantly longer-lasting corneal anesthesia than oxybuprocaine (duration of the maximum effect: 165 ± 15 vs 31 ± 2 min, P < 0.001). NPA did not hamper wound healing.
Conclusion: The novel quaternary ammonium NPA produced long-lasting analgesia against corneal injury without hampering corneal recovery, suggesting that it is a potential candidate for analgesic medicine targeting corneal pain.
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
Specific topics covered by the journal include:
Drug target identification and validation
Phenotypic screening and target deconvolution
Biochemical analyses of drug targets and their pathways
New methods or relevant applications in molecular/drug design and computer-aided drug discovery*
Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes)
Structural or molecular biological studies elucidating molecular recognition processes
Fragment-based drug discovery
Pharmaceutical/red biotechnology
Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products**
Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development
Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing)
Preclinical development studies
Translational animal models
Mechanisms of action and signalling pathways
Toxicology
Gene therapy, cell therapy and immunotherapy
Personalized medicine and pharmacogenomics
Clinical drug evaluation
Patient safety and sustained use of medicines.
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