Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase

Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH. Inhibitors with a 6-fold increase of FAAH potency while maintaining high sEH potency were developed by optimization. Interestingly, compared to most FAAH inhibitors that inhibit through time-dependent covalent modification, t-TUCB and related compounds appear to inhibit FAAH through a time-independent, competitive mechanism. These inhibitors are selective for FAAH over other serine hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH inhibitors have improved cross-species potency. These dual inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition.     

An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice

The dipeptide amide H-Phe-Phe-NH₂ (1) that previously was identified as a ligand for the substance P 1–7 (SP_1–7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP_1–7 and the tetrapeptide endomorphin-2 that is also binding to the SP_1–7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH₂ peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED₅₀) of 4 was superior as compared to gabapentin and morphine that are used in clinic.     

中药止痛贴与吗啡联合应用于癌症疼痛的镇痛效果及安全性

目的:探讨中药止痛贴与吗啡联合应用于癌症疼痛治疗中的镇痛效果及安全性。方法:选取2016年5月至2017年5月我院收治的100例中重度癌症疼痛患者为研究对象,根据随机数字表方法将入选的患者分为对照组和研究组,每组50例。对照组患者给予吗啡治疗,研究组患者在此基础上联合应用中药止痛贴治疗,连续给药14天。比较两组患者的临床疗效、数字评分法(digital scoring method,NRS)、爆发痛次数、吗啡使用量、中医证候评分。结果:研究组患者治疗总有效率为96.0%,显著高于对照组患者(86.0%,P0.05)。研究组盐酸吗啡缓释片使用剂量[(83.23±23.14)mg/d]低于对照组[(110.13±25.23)mg/d](P0.05)。治疗前,两组患者各中医证候评分比较差异均无统计学意义(P0.05);治疗后,两组患者各中医证候评分均较治疗前明显降低,且研究组显著低于对照组,差异有统计学意义(P0.05)。研究组患者的NRS评分、爆发痛次数显著低于对照组(P0.05),两组患者均未见严重的不良反应。结论:中药止痛贴与吗啡联合应用于癌症疼痛的可有效提高镇痛效果,改善患者的中医证候,减少吗啡使用量,且安全性高。     

经皮穴位电刺激治疗术后疼痛的研究进展

术后疼痛是术后常见的一种伤害性疼痛,随着舒适化医疗的倡导,经皮穴位电刺激因其无创、安全等优点受到关注。经皮穴位电刺激是将经皮神经电刺激与针灸穴位理论相结合的一种方法,虽有研究证实其频率、波形、强度、刺激时间的设定及不同穴位的配伍对镇痛效果均可产生较大的影响,但在规范化方面仍有不足。本文总结其使用方法及镇痛疗效,以期对经皮穴位电刺激应用于临床提供最优参数及穴位配伍,使之规范化,从而发挥出最佳镇痛效果。     

Vatalanib decrease the positive interaction of VEGF receptor-2 and P2X(2/3) receptor in chronic constriction injury rats

Neuropathic pain can arise from a lesion affecting the peripheral nervous system. Selective P2X(3) and P2X(2/3) receptors' antagonists effectively reduce neuropathic pain. VEGF inhibitors are effective for pain relief. The present study investigated the effects of Vatalanib (VEGF receptor-2 (VEGFR-2) inhibitor) on the neuropathic pain to address the interaction of VEGFR-2 and P2X(2/3) receptor in dorsal root ganglia of chronic constriction injury (CCI) rats. Neuropathic pain symptoms following CCI are similar to most peripheral lesions as assessed by the Neuropathic Pain Symptom Inventory. Sprague-Dawley rats were randomly divided into sham group, CCI group and CCI rats treated with Vatalanib group. Mechanical withdrawal threshold and thermal withdrawal latency were measured. Co-expression of VEGFR-2 and P2X(2) or P2X(3) in L4-6 dorsal root ganglia (DRG) was detected by double-label immunofluorescence. The modulation effect of VEGF on P2X(2/3) receptor agonist-activated currents in freshly isolated DRG neurons of rats both of sham and CCI rats was recorded by whole-cell patch-clamp technique. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) in CCI group were lower than those in sham group (p<0.05). MWT and TWL in CCI rats treated with Vatalanib group were increased compared with those in CCI group (p<0.05). VEGFR-2 and P2X(2) or P2X(3) receptors were co-expressed in the cytoplasm and surface membranes of DRG. The co-expression of VEGFR-2 and P2X(2) or P2X(3) receptor in CCI group exhibited more intense staining than those in sham group and CCI rats treated with Vatalanib group, respectively. VEGF enhanced the amplitude of ATP and α,β-meATP -activated currents of both sham and CCI rats. Increment effects of VEGF on ATP and α,β-meATP -activated currents in CCI rats were higher than those in sham rats. Both ATP (100 μM) and α,β-meATP (10 μM)- activated currents enhanced by VEGF ( 1nM) were significantly blocked by Vatalanib (1 μM, an inhibitor of VEGF receptors). The stain values of VEGFR-2, P2X(2) and P2X(3) protein expression in L4/5 DRG of CCI treated with Vatalanib group were significantly decreased compared with those in CCI group (p<0.01). Vatalanib can alleviate chronic neuropathic pain by decreasing the activation of VEGF on VEGFR-2 and the positive interaction between the up-regulated VEGFR-2 and P2X(2/3) receptors in the neuropathic pain signaling.     

大鼠侧脑室及鞘内注射孤啡肽对痛反应及电针镇痛的影响

孤啡肽（ＯＦＱ）是最近发现的一种１７肽,为阿片受体家族中一个新成员－“孤儿受体”的内源性配基。ＯＦＱ在痛觉调制中的作用与内阿片肽明显不同。本实验在大鼠电刺激甩尾测痛模型上,观察了侧脑室（ＩＣＶ）及鞘内注射（ＩＴ）ＯＦＱ对伤害性电刺激引起的痛反应及电针镇痛的影响。结果发现,大量ＩＣＶ及ＩＴ０．１μｇ（０．０５５ｎｍｏｌ）ＯＦＱ对痛觉反应无影响,而１．０μｇ（０．５５ｎｍｏｌ）的ＯＦＱ可明显降低痛阈;     

慢性神经痛对抑郁状态以及中枢多巴胺神经元电生理的影响

目的：探讨大鼠慢性神经痛导致抑郁症状发生后,中脑腹侧被盖区多巴胺能神经元自发放电活动的改变情况。方法：24只健康成年大鼠进行随机分组（n=12）：假手术组（Sham）大鼠仅进行坐骨神经分支暴露,坐骨神经损伤组（SNI）进行坐骨神经分支选择性损伤。在神经损伤后的第3、7、14、28、42、56天进行机械刺激计算缩足反射阈值,并进行糖水偏好、强迫游泳、旷场实验等行为学实验来评价大鼠是否发生抑郁症状;利用在体多通道电生理技术,对SNI组大鼠和假手术组大鼠中脑腹侧被盖区神经元分别进行记录分析。结果：与假手术组比较,SNI组大鼠的机械痛阈值明显降低（P<0.01）;在旷场实验、糖水偏好、强迫游泳较对照组出现显著性差异（P<0.01）;大鼠中脑腹侧被盖区多巴胺能神经元自发放电频率、簇状放电活动中动作电位的数量明显增加（P<0.01）。结论：慢性疼痛可以导致大鼠抑郁相关症状的发生,中脑腹侧被盖区多巴胺能神经元自发放电频率增加与疼痛后抑郁发生相关。     

1．06μm激光致皮肤痛觉效应的研究

目的：研究1．06μm激光所致人手背皮肤的痛觉效应。方法：以输出波长为1．06μm的脉冲Nd：YAG激光照射人手背皮肤,记录每次刺激激光的能量以及受试者的反应。采用加权概率单位算法计算诱发痛觉概率为50％时对应的激光剂量ED50,即为痛觉阈值。改变光斑大小和脉冲宽度,测定三种不同刺激条件下的痛觉阈值,并探索温度对激光所致痛觉效应的影响。结果：当皮肤温度约为30℃,分别使用光斑直径1．20mm、脉冲宽度85μs,光斑直径1．20mm、脉冲宽度20ns和光斑直径2．56mm、脉冲宽度20ns的激光刺激时,痛觉阈值分别为394mJ／mm^2、36．4mJ／mm^2和8．92mJ／mm^2。在第一种刺激条件下,当皮肤温度为25℃时,剂量为383mJ／mm^2的激光诱发痛觉的概率为16．7％;当皮肤温度为39℃时,剂量为361mJ／mm^2的激光诱发痛觉的概率为56．7％。结论：1．06“m激光所致痛觉的阈值随脉冲宽度的减小、光斑面积的增大和皮肤表面温度的增加而减小。     

肌内效贴联合经皮神经电刺激对脑卒中后偏瘫肩痛患者肩关节疼痛、肩关节功能和血液流变学的影响

摘要 目的：探讨肌内效贴联合经皮神经电刺激（TENS）对脑卒中后偏瘫肩痛患者肩关节疼痛、肩关节功能和血液流变学的影响。方法：选取2019年5月~2022年1月期间江苏省人民医院收治的脑卒中后偏瘫肩痛患者100例,根据随机数字表法将其分为对照组（n=50）和研究组（n=50）,在常规康复训练的基础上,对照组接受肌内效贴干预,研究组接受肌内效贴联合TENS干预。对比两组视觉模拟评分法（VAS）评分、上肢Fugl-Meyer运动功能评定量表（FMA）、改良Barthel指数（MBI）、Constant-Murley肩关节功能评分量表（CMS）评分、血液流变学指标、肩关节功能变化情况。结果：研究组干预后VAS评分低于同期对照组（P<0.05）。研究组干预后FMA、MBI、CMS评分高于同期对照组（P<0.05）。研究组干预后血浆黏度、纤维蛋白原、全血黏度、红细胞压积均低于同期对照组（P<0.05）。研究组干预后患侧肩关节的外旋、前屈、外展的主动/被动活动度（AROM/PROM）均大于对照组同期（P<0.05）。结论：肌内效贴联合TENS应用于脑卒中后偏瘫肩痛患者,可有效改善肩关节疼痛、肩关节功能和血液流变学。     

非小细胞肺癌患者术后医院感染病原菌分布特征及慢性疼痛的影响因素探讨

摘要 目的：观察非小细胞肺癌（NSCLC）患者术后医院感染病原菌分布特征,统计其术后慢性疼痛发生情况,分析NSCLC患者术后慢性疼痛的影响因素。方法：选取2018年3月~2020年8月期间我院收治的NSCLC患者200例,统计NSCLC患者术后慢性感染情况、发生术后慢性疼痛情况,观察NSCLC患者术后医院感染病原菌分布特征及耐药性,并分析NSCLC患者术后慢性疼痛的影响因素。结果：NSCLC患者200例,术后医院感染31例,发生率为15.50%（31/200）,以呼吸道感染率最高,占比64.52%（20/31）。31 例术后医院感染患者中,共分离培养病原菌43株 ,其中革兰阳性菌13株占比30.23%（13/43）,革兰阴性菌26株占比60.47%（26/43）,真菌4株占比9.30%（4/43）。主要革兰阴性菌中,肺炎克雷伯菌对阿米卡星、头孢曲松耐药率较高;铜绿假单胞菌对头孢哌酮、头孢他啶耐药率较高。主要革兰阳性菌中,表皮葡萄球菌对红霉素和青霉素耐药率较高;金黄色葡萄球菌对红霉素和青霉素耐药率较高。NSCLC患者术后发生慢性疼痛25例,发生率为12.50%（25/200）。单因素分析结果显示,NSCLC患者术后慢性疼痛与年龄、住院时间、手术时长、文化程度、糖尿病史、心理焦虑有关（P<0.05）。多因素Logistic回归分析结果显示,年龄≥60岁、住院时间≥30d、文化程度小学及其以下、有糖尿病史、有心理焦虑为NSCLC患者术后慢性疼痛的危险因素（P<0.05）。结论：NSCLC患者术后医院感染率较高,病原菌以革兰阴性菌为主。且术后发生慢性疼痛的人数占比较高,应格外重视年龄偏大、住院时间偏长、文化程度低、有糖尿病史、心理焦虑的患者,给予相关防范措施,降低术后慢性疼痛发生率。