对犬科猕猴(Macaca fascicularis)进行依曲帕米鼻腔喷雾剂的临床前安全性评价,以评估其对阵发性室上性心动过速患者的安全性。

IF 1.2 4区 医学 Q4 PHARMACOLOGY & PHARMACY
International Journal of Toxicology Pub Date : 2024-09-01 Epub Date: 2024-07-22 DOI:10.1177/10915818241263068
Johanne Pion, Carlos Lopez Mendez, Jean-Pierre Moreau, Veronique Boulanger, Douglas Wight
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引用次数: 0

摘要

依曲帕米是一种钙通道阻滞剂,目前正处于治疗阵发性室上性心动过速(PSVT)的三期临床试验阶段。为了支持临床开发,我们在犬科猕猴身上评估了每周一次鼻内注射依曲帕米后的全身和局部毒性。每组动物(N = 8,4雄4雌)的左鼻孔每周注射一次依曲帕米,剂量水平为0(载药)、1.9、3.8或5.7毫克/千克/剂量,共26次。经过 28 天的恢复期后,对研究结果的持续性、可逆性和进展情况进行了检查。临床症状是短暂的,与鼻内给药(如流鼻涕、打喷嚏等)有关。在任何剂量下都没有宏观或全身显微镜检查结果。剂量≥1.9 mg/kg/d时,可观察到与依曲帕米相关的影响鼻腔、喉部和鼻咽部的适应性和反应性局部变化。观察到轻微到严重的剂量依赖性鼻上皮损伤,主要影响呼吸道上皮和过渡上皮。经过 28 天的恢复期后,显微变化仅限于左侧鼻腔和鼻咽部。这些变化的发生率和严重程度明显降低,适应性和反应性变化明显逆转,表明上皮内膜部分或完全恢复。由于缺乏全身毒性,且鼻腔的变化极小且短暂,因此依曲帕米在猴子体内的全身无明显不良反应水平(NOAEL)为高剂量,即 5.7 毫克/千克/剂量。局部毒性的无观测不良效应水平为 1.9 毫克/千克/剂量。总之,这些数据支持将依曲帕米作为治疗PSVT的潜在药物在人体试验中进行进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Preclinical Safety Evaluation of Etripamil Nasal Spray in Cynomolgus Macaques (Macaca fascicularis) to Assess for Safety in Patients With Paroxysmal Supraventricular Tachycardia.

Etripamil is a calcium channel blocker currently in Phase 3 trials for the treatment of paroxysmal supraventricular tachycardia (PSVT). Systemic and local toxicity following once-weekly intranasal administration of etripamil was evaluated in cynomolgus macaques to support clinical development. Groups of animals (N = 8, 4 males and 4 females) were administered etripamil into the left nostril weekly at dose levels of 0 (vehicle), 1.9, 3.8, or 5.7 mg/kg/dose for 26 doses. Persistence, reversibility, and progression of findings were examined following a 28-day recovery period. Clinical signs were transient and were related to the intranasal administration (e.g., nasal discharge, sneezing, etc.) of etripamil. There were no macroscopic or systemic microscopic findings at any dose. Etripamil-related adaptive and reactive local changes affecting the nasal cavity, larynx, and nasopharynx were observed at ≥1.9 mg/kg/dose. Minimal to severe dose-dependent nasal epithelial damage was observed, mainly affecting respiratory and transitional epithelium. Following the 28-day recovery period, microscopic changes were confined to the left nasal cavity and nasopharynx. These changes were significantly lower in incidence and severity, with noticeable reversal of the adaptive and reactive changes, indicating partial to complete recovery of the epithelial lining. Based on the lack of systemic toxicity and the minimal and transient nasal changes, the systemic, no observable adverse effect level (NOAEL) of etripamil in monkeys was the high dose, 5.7 mg/kg/dose. The NOAEL for local toxicity was 1.9 mg/kg/dose. Collectively, these data support further study of etripamil in human trials as a potential treatment for PSVT.

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来源期刊
CiteScore
3.40
自引率
4.50%
发文量
53
审稿时长
4.5 months
期刊介绍: The International Journal of Toxicology publishes timely, peer-reviewed papers on current topics important to toxicologists. Six bi-monthly issues cover a wide range of topics, including contemporary issues in toxicology, safety assessments, novel approaches to toxicological testing, mechanisms of toxicity, biomarkers, and risk assessment. The Journal also publishes invited reviews on contemporary topics, and features articles based on symposia. In addition, supplemental issues are routinely published on various special topics, including three supplements devoted to contributions from the Cosmetic Review Expert Panel.
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