EN3427: A Novel Cationic Aminoindane with Long-Acting Local Anesthetic Properties
EN3427: A Novel Cationic Aminoindane with Long-Acting Local Anesthetic Properties
复制标题
DOI：
10.1213/ane.0000000000000629
复制
发表时间：
2015-04-01
影响因子：
5.7
通讯作者：
Priestley, Tony
中科院分区：
文献类型：
--
作者：
Banerjee, Manish;Baranwal, Atul;Priestley, Tony
背景技术背景：目前批准的局部麻醉药物提供相对短暂的局部麻醉，这在某些情况下是适当的甚至是期望的，但是在其他临床情况下，超过其能力的延长的作用持续时间将是明显的益处。我们实施了一项药物发现计划，旨在确定新型局部麻醉剂分子，这些分子对表达瞬时受体电位（TRP）通道的伤害感受器感觉传入具有特异性的长效优先作用。我们检验的假设是，如果TRP通道激活促进神经元进入，相对膜不渗透的局部麻醉分子是否可以赋予持久的麻醉。目前的工作描述了在体内研究的铅分子，出现了从发现程序，EN 3427，在几个啮齿动物painmodels.METHODS：研究进行了对雄性Sprague-Dawley大鼠使用2种模型的急性机械爪捏诱发和pinpick-evoked伤害性疼痛。在基线时，即在任何药物干预之前，以及在EN 3427单独或与利多卡因联合单次坐骨周或皮下给药后的不同时间点，评估对有害刺激的行为反应。缩爪阈值或皮肤躯干反射进行量化，并在统计学上比较前后药物值的方差分析，然后进行事后Dunnett多范围检验。单次坐骨神经周围注射利多卡因（2%）可缓解夹爪引起的疼痛，这与基线至1小时时间点有显著差异（Dunnett多重性调整P = 0.0081），如使用缩爪或发声终点评估的。EN3427（0.2%），在同一模型中，产生了持久的阻滞，疼痛阈值显著高于基线，直到18小时时间点（Dunnett多重校正P = 0.0002）; EN 3427的组合（0.2%）加利多卡因（2%）产生更持久的镇痛作用，疼痛阈值显著高于基线，直至24小时时间点（Dunnett多重校正P = 0.0073）。使用针刺方法获得了类似的结果。一次皮下注射。注射利多卡因（2%）在0.5小时内使皮肤针刺感觉完全丧失，但在1小时时间点，敏感性阈值与基线无差异，与单独注射EN 3427相似（0.2%）在8小时时间点内产生了与基线显著不同的感觉丧失（Dunnett多重校正P = 0.0045），利多卡因（2%）+EN 3427（0.2%）的组合似乎进一步延长了镇痛持续时间，尽管这仅在10小时时间点与基线有显著差异（Dunnett多重校正P=0.0048）。镇痛效果与剂量相关;使用联合注射方法，我们发现，增加EN 3427剂量与固定的2%利多卡因可显著延长镇痛时间，增加利多卡因剂量与固定剂量的EN 3427联合可显著延长镇痛时间。（0.2%）仅导致作用持续时间的适度增加。目前的研究表明，一个新的分子实体，EN 3427，产生有效的和持久的镇痛作用，在2啮齿动物疼痛模型。EN 3427的镇痛作用比利多卡因明显更持久，并且当EN 3427与利多卡因联合使用时，镇痛作用进一步延长。结果进行了讨论，相对于一个可能的利多卡因介导的TRP通道激活和促进神经元访问的EN 3427，与随后的截留赋予延长的持续时间的疗效。
BACKGROUND: Currently approved local anesthetic drugs provide relatively brief local anesthesia that is appropriate and even desirable in some settings, but an extended duration of action beyond their capabilities would be a distinct benefit in other clinical situations. We implemented a drug discovery program that sought to identify novel local anesthetic molecules that specifically demonstrated a long-acting, preferential action on nociceptor sensory afferents that expressed transient receptor potential (TRP) channels. The hypothesis we tested was whether relatively membrane-impermeant local anesthetic molecules could confer long-lasting anesthesia if neuronal access was facilitated by TRP channel activation. The current work describes in vivo studies on a lead molecule that emerged from the discovery program, EN3427, in several rodent pain models.METHODS: Studies were performed on male Sprague-Dawley rats using 2 models of acute mechanical paw-pinch-evoked and pinprick-evoked nociceptive pain. Behavioral responses to noxious stimuli were assessed at baseline, that is, before any pharmacologic intervention, and at various timepoints after a single perisciatic or subcutaneous administration of either EN3427 alone or in combination with lidocaine. Paw withdrawal thresholds or cutaneous trunci reflexes were quantified, and pre-post drug values were compared statistically with analysis of variance followed by post hoc Dunnett multiple range test.RESULTS: A single perisciatic injection of lidocaine (2%) produced relief of paw-pinch evoked pain that was significantly different from baseline through to the 1-hour timepoint (Dunnett multiplicity-adjusted P = 0.0081), as assessed using paw withdrawal or vocalization end points. EN3427 (0.2%), in the same model, produced a long-lasting block, with pain thresholds being significantly above baseline through to the 18-hour timepoint (Dunnett multiplicity-adjusted P = 0.0002); the combination of EN3427 (0.2%) plus lidocaine (2%) produced even longer lasting analgesia, with pain thresholds being significantly above baseline through to the 24-hour timepoint (Dunnett multiplicity-adjusted P = 0.0073). Similar results were obtained with use of the pinprick approach. A single subcutaneous. injection of lidocaine (2%) produced complete loss of sensation to cutaneous pinprick through 0.5 hours, but sensitivity thresholds were no different to baseline by the 1-hour timepoint, a similar injection of EN3427 alone (0.2%) produced a loss of sensation that was significantly different from baseline through the 8-hour timepoint (Dunnett multiplicity-adjusted P = 0.0045), and the combination of lidocaine (2%) plus EN3427 (0.2%) appeared to further enhance duration of analgesia, although this was significantly different from baseline only through the 10-hour timepoint (Dunnett multiplicity-adjusted P=0.0048). Analgesic efficacy was dose related; using the combined injection approach, we found that increases in the dose of EN3427 with a fixed 2% lidocaine led to substantially extended analgesia and increasing doses of lidocaine combined with a fixed dose of EN3427 (0.2%) led to only modestly increased duration of action.CONCLUSIONS: The present studies demonstrate that a new molecular entity, EN3427, produces effective and long-lasting analgesia in 2 rodent pain models. The analgesic effects of EN3427 are significantly longer-lasting than lidocaine and are further extended when EN3427 is combined with lidocaine. The results are discussed with respect to a possible lidocaine-mediated TRP channel activation and facilitated neuronal access of EN3427, with-subsequent entrapment conferring extended-duration efficacy.