Abdel-Karim Aly M, Barthlow Herbert G, Bialecki Russell A, Elhilali Mostafa M
Urology Research Laboratory, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada.
J Urol. 2005 Oct;174(4 Pt 1):1488-92. doi: 10.1097/01.ju.0000173004.61302.75.
Increased afferent nerve activity may have an important role in the pathogenesis of neurogenic detrusor overactivity. We tested the efficacy of the neuokinin-2 receptor antagonist M274773 ((S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydro-pyrimidin-l-yl) piperidino]butyl]-N-methylbenzamide dihydrochloride) on neurogenic detrusor overactivity after spinal cord injury in rats.
Included in this study were 48 adult Sprague-Dawley rats (Charles River, Montreal, Quebec, Canada). Six animals served as normal controls, while 32 underwent spinal cord transection at the 10th thoracic vertebra. Two weeks after spinal cord injury 6 animals underwent filling cystometrography to confirm neurogenic detrusor overactivity, while another 12 served as paraplegic controls. The remaining 24 paraplegic animals were used to test the drug and they were divided into 2 equal groups of 12. Group 1 received the drug at a dose of 0.3 mg/kg daily, while group 2 received a dose of 0.6 mg/kg daily. Each paraplegic control and treatment group was further subdivided into 2 subgroups of 6 rats each. In subgroup 1 filling cystometrography was done 3 weeks after spinal cord injury, while in subgroup 2 it was done 4 weeks after spinal cord injury.
Three weeks after spinal cord injury neurogenic detrusor overactivity developed in all paraplegic control animals with a mean bladder capacity +/- SD of 0.7 +/- 0.2 ml and a mean voiding pressure of 59 +/- 14.2 cm H2O. Neurogenic detrusor overactivity resolved in 50% and 83% of the animals that received M274773 for 1 week at doses of 0.3 and 0.6 mg/kg daily, respectively. Mean cystometric bladder capacity was 1.2 +/- 0.5 vs 1.3 +/- 0.4 ml and mean voiding pressure was 46.1 +/- 10.8 vs 40 +/- 9.9 cm H2O in animals that received 0.3 vs 0.6 mg/kg daily, respectively. The drug produced better urodynamic results when given for 2 weeks rather than 1 week.
M274773 is effective for neurogenic detrusor overactivity after spinal cord injury in the rat. It may provide an alternative clinical treatment option for neurogenic detrusor overactivity and urgency/frequency syndrome. This new neurokinin-2 selective antagonist has time and dose response effects, which further suggests the potential for clinical application.
传入神经活动增加可能在神经源性逼尿肌过度活动的发病机制中起重要作用。我们测试了神经激肽-2受体拮抗剂M274773（（S）-N-[2-（3,4-二氯苯基）-4-[4-（2-氧代全氢嘧啶-1-基）哌啶基]丁基]-N-甲基苯甲酰胺二盐酸盐）对大鼠脊髓损伤后神经源性逼尿肌过度活动的疗效。
本研究纳入48只成年Sprague-Dawley大鼠（加拿大魁北克省蒙特利尔市查尔斯河公司提供）。6只动物作为正常对照，32只在第10胸椎水平进行脊髓横断。脊髓损伤后2周，6只动物接受充盈性膀胱测压以确认神经源性逼尿肌过度活动，另外12只作为截瘫对照。其余24只截瘫动物用于测试药物，分为2个相等的组，每组12只。第1组每天接受0.3mg/kg剂量的药物，第2组每天接受0.6mg/kg剂量的药物。每个截瘫对照和治疗组进一步细分为2个亚组，每组6只大鼠。在亚组1中，脊髓损伤后3周进行充盈性膀胱测压，在亚组2中，脊髓损伤后4周进行充盈性膀胱测压。
脊髓损伤后3周，所有截瘫对照动物均出现神经源性逼尿肌过度活动，平均膀胱容量±标准差为0.7±0.2ml，平均排尿压力为59±14.2cmH2O。分别接受0.3和0.6mg/kg每日剂量M274773治疗1周的动物中，神经源性逼尿肌过度活动在50%和有83%的动物中得到缓解。每日接受0.3mg/kg与0.6mg/kg的动物，平均膀胱测压容量分别为1.2±0.5ml和1.3±0.4ml，平均排尿压力分别为46.1±10.8cmH2O和40±9.9cmH2O。药物治疗2周比治疗1周产生更好的尿动力学结果。
M274773对大鼠脊髓损伤后的神经源性逼尿肌过度活动有效。它可能为神经源性逼尿肌过度活动和尿急/尿频综合征提供一种替代性的临床治疗选择。这种新型神经激肽-2选择性拮抗剂具有时间和剂量反应效应，这进一步提示了其临床应用潜力。
