几种药物合成新工艺

曲司氯铵合成新工艺 曲司氯铵为1990年上市的毒覃碱拮抗剂,广泛用于抗尿失禁药,可有效降低膀胱平滑肌的紧张度、解除痉挛状态,显著增加最大膀胱容量,有效减轻尿频,尿急以及尿失禁症状等。     

治疗膀胱过度活动症的β3肾上腺素能受体激动剂vibegron

膀胱过度活动症是排尿功能障碍常见的临床表现之一,治疗目的在于抑制膀胱逼尿肌的过度活动,从而增加膀胱容量。其常伴有尿频和夜尿增多症状,可伴有急迫性尿失禁,严重影响患者的日常生活和社会活动,已成为困扰人们的一大疾病。近年来,一种具有强选择性的β_3肾上腺素能受体激动剂作为膀胱过度活动症的潜在治疗手段有了很大发展。vibegron是一种作用机制新颖的尿失禁治疗药物,改变了30多年来采用传统的抗胆碱药物治疗尿失禁的思路,从而提高膀胱的充盈以及贮尿能力。主要从药物概况、相关背景、合成路线、药理作用、临床研究、安全性等方面进行介绍。     

女性急迫性尿失禁患者的ICIQ-SF问卷与尿动力学检查的相关性研究

目的明确急迫性尿失禁患者的ICIQ-SF评分与尿动力学检查结果之间的相关性并了解抗胆碱能治疗前后这些参数的变化情况。方法我们对2007年8月～2009年7月间北京大学深圳医院泌尿外科就诊的急迫性尿失禁女性患者进行研究。常规采集病史、查体后,每个患者均完成ICIQ-SF问卷,然后接受尿动力学检查,尿动力学检查结果表现为逼尿肌过度活动性尿失禁的患者给予3个月的抗胆碱能药物治疗。治疗后,每个患者再次完成ICIQ-SF问卷并接受尿动力学检查。结果患者年龄介于43～70（58.8±13.6）岁之间。我们发现治疗前后的平均ICIQ-SF评分、初始感觉容量、最大膀胱容量、最大逼尿肌压力、膀胱顺应性均具有显著性差异（P〈0.01）。治疗前平均ICIQ-SF评分和初始感觉容量之间存在负相关（相关系数-0.275,P〈0.05）。治疗前平均ICIQ-SF评分与最大逼尿肌压力呈正相关（相关系数为0.412,P〈0.01）。结论ICIQ-SF问卷是急迫性尿失禁患者治疗前和治疗后可靠且易于使用的评价工具。ICIQ-SF评分和尿动力学检查参数之间存在显著地相关性。ICIQ-SF问卷在临床实践中具有良好的应用前景。     

α,M受体阻滞剂与膀胱功能训练对急迫性尿失禁的疗效评价

目的：研究α,M受体阻滞剂与膀胱功能训练对急迫性尿失禁的疗效。方法：口服α,M受体阻滞荆及膀胱功能训练，应用尿动力学指标(膀胱压、逼尿肌压力、尿道压及膀胱容量)进行评价。结果：治疗58例，各项指标好转30例，有效率为52％。结论：α,M受体阻滞剂与膀胱功能训练，对急迫性尿失禁有较好疗效。     

膀胱下尿路梗阻对大鼠逼尿肌稳定性影响的实验研究

目的 观察膀胱下尿路梗阻对大鼠逼尿肌稳定性的影响。方法 建立Wistar大鼠膀胱下尿路梗阻动物模型,6周后行充盈性膀胱测压,观察逼尿肌不稳定的发生率、最大膀胱容量等膀胱功能指标。根据逼尿肌是否稳定,将动物分为逼尿肌不稳定组和逼尿肌稳定组,用拉力传感器检测离体逼尿肌肌条自发性收缩的频率及收缩幅度,分别进行统计和分析。结果 大鼠膀胱下尿路梗阻6周后,逼尿肌不稳定发生率为62.1％;梗阻后最大膀胱容量及膀胱湿重均较正常对照组明显增加（P<0.01）;体外肌条自发性收缩频率及收缩幅度,逼尿肌不稳定组较逼尿肌稳定组及正常对照组明显增强（P<0.01）,正常对照组与逼尿肌稳定组之间无显著差异（P>0.05）。结论 膀胱下尿路梗阻使逼尿肌自发性收缩的节律发生改变,是引起逼尿肌不稳定的一个重要因素。     

膀胱下尿路梗阻对大鼠逼尿肌稳定性影响的实验研究

目的观察膀胱下尿路梗阻对大鼠逼尿肌稳定性的影响.方法建立Wistar大鼠膀胱下尿路梗阻动物模型,6周后行充盈性膀胱测压,观察逼尿肌不稳定的发生率、最大膀胱容量等膀胱功能指标.根据逼尿肌是否稳定,将动物分为逼尿肌不稳定组和逼尿肌稳定组,用拉力传感器检测离体逼尿肌肌条自发性收缩的频率及收缩幅度,分别进行统计和分析.结果大鼠膀胱下尿路梗阻6周后,逼尿肌不稳定发生率为62.1%;梗阻后最大膀胱容量及膀胱湿重均较正常对照组明显增加(P《0.01);体外肌条自发性收缩频率及收缩幅度,逼尿肌不稳定组较逼尿肌稳定组及正常对照组明显增强(P《0.01),正常对照组与逼尿肌稳定组之间无显著差异(P》0.05).结论膀胱下尿路梗阻使逼尿肌自发性收缩的节律发生改变,是引起逼尿肌不稳定的一个重要因素.     

β_3肾上腺素受体与前列腺增生所致不稳定膀胱的相关性研究

<正>良性前列腺增生是泌尿外科常见病之一,主要引起的下尿路症状为膀胱出口梗阻和逼尿肌不稳定。膀胱出口梗阻引起的逼尿肌不稳定体外试验为不稳定膀胱,临床表现为尿频和急迫性尿失禁。膀胱出口梗阻主要治疗方法为手术解除梗阻,而逼尿肌不稳定主要靠药物治疗。     

雌性大鼠产仔后膀胱功能的改变

目的比较产仔大鼠与未孕大鼠膀胱功能的差异。方法 6个月龄雌性大鼠34只,根据与雄鼠合笼后妊娠分娩与否分为2组:未孕大鼠组(16只)和产仔组大鼠(18只)。各组均做活体膀胱测压和离体膀胱肌条实验。结果产仔大鼠的排尿量、残余尿、膀胱顺应性和膀胱湿质量与未孕大鼠相似。与未孕大鼠相比,产仔大鼠最大膀胱容量、逼尿肌收缩的张力阈值和收缩频率增高,而其逼尿肌最大收缩力和逼尿肌平均收缩力降低。结论妊娠分娩可造成膀胱功能的损害,尤其是影响了膀胱的收缩功能。     

多沙唑嗪光学异构体对小鼠膀胱逼尿肌作用及作用机制研究

目的观察多沙唑嗪[(±)Dox]及其对映体[(-)Dox和(+)Dox]对小鼠离体膀胱逼尿肌的作用并分析其机制。方法采用小鼠离体膀胱条张力实验及电场刺激诱发小鼠离体膀胱条收缩实验。结果卡巴胆碱浓度依赖性诱发小鼠膀胱逼尿肌收缩,苯肾上腺素对小鼠膀胱逼尿肌无收缩作用。1μmol/L的(-)Dox、(+)Dox或(±)Dox对卡巴胆碱诱发的收缩反应均无显著影响(P>0.05),1μmol/L的Atr可完全阻断其收缩反应;(-)Dox、(+)Dox和(±)Dox对电场刺激诱发小鼠膀胱逼尿肌收缩反应无显著影响(P>0.05)。结论药物或电刺激诱发的小鼠膀胱逼尿肌收缩反应无去甲肾上腺素能成分的参与,多沙唑嗪及其对映体对其收缩反应无影响。     

糖尿病大鼠膀胱逼尿肌兴奋性与收缩性实验研究

目的观察糖尿病膀胱病变逼尿肌兴奋性与收缩性变化,并探讨其发病机制。方法建立糖尿病大鼠模型,正常大鼠作对照,测定不同糖尿病病程离体逼尿肌肌条机械性牵张及胆碱能药物刺激后逼尿肌的兴奋性、收缩性变化。结果糖尿病组大鼠膀胱逼尿肌机械性牵张及胆碱能药物刺激后最大收缩力、平均收缩力、收缩频率均较对照组下降。结论糖尿病膀胱病变逼尿肌收缩功能受损,且随病程延长损害程度逐渐加重。逼尿肌对早期胆碱能药物干预反应敏感。     

Influences of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers

Trospium chloride and oxybutynin are two antimuscarinergic agents used in the treatment of unstable bladder, urge incontinence, combined stress urge incontinence and detrusor hyperreflexia. The possibility that these two drugs produce changes in central nervous electrical activity was examined in an open, prospective, phase I study involving 12 volunteers.Quantitative evaluation of the multichannel electroencephalogram obtained from young healthy volunteers showed statistically significant decreases in alpha and beta₁ activity after oxybutynin, but not after intravenous or oral administration of trospium chloride. The biological activity of both drugs was ascertained by continuous simultaneous recording of the heart rate. A decrease in heart rate was detected after oral administration of oxybutynin, and an increase was seen after i.v. administration of trospium chloride.The results suggest that trospium chloride is less likely to produce central nervous adverse effects than to oxybutynin.     

Trospium chloride: an anticholinergic quaternary ammonium compound for the treatment of overactive bladder

The International Continence Society has defined overactive bladder (OAB) as urinary urgency, with or without urge urinary incontinence, usually with urinary frequency and nocturia. Approximately 17% of men and women in the US report OAB symptoms, which can affect quality of life. Trospium chloride, which has recently been introduced in the US as Sanctura^®, has been prescribed for > 10 years in Europe as, for example, Spasmo-lyt, Regurin and Spasmex. Trospium chloride has been shown to be effective in relieving OAB symptoms, and has a favourable safety profile, showing < 1% difference for all adverse events compared with placebo, except for dry mouth, constipation and headache. Metabolic drug–drug interactions are unlikely, given that trospium chloride is not metabolised by cytochrome P450 isozymes. The fast-acting efficacy of trospium chloride, coupled with its good safety profile and tolerability, make it an important new option for treatment of OAB.     

Trospium chloride in the management of overactive bladder

Trospium chloride is an orally active, quaternary ammonium compound with antimuscarinic activity. It binds specifically and with high affinity to muscarinic receptors M(1), M(2) and M(3), but not nicotinic, cholinergic receptors. It is hydrophilic and does not cross the normal blood-brain barrier in significant amounts and, therefore, has minimal central anticholinergic activity. Peak plasma trospium chloride concentrations are attained approximately 5-6 hours after oral administration, which should occur before meals as concurrent food ingestion significantly reduces trospium bioavailability. Trospium chloride undergoes negligible metabolism by the hepatic cytochrome P450 system; few metabolic drug interactions are known. While trospium chloride dosage adjustments based on age or sex appear unwarranted, such adjustments may be needed in patients with severe renal impairment. Direct comparative studies in patients with overactive bladder indicate that trospium chloride is at least as effective as oxybutynin and tolterodine. Placebo-controlled studies have also confirmed the efficacy of trospium chloride in terms of improved urodynamic parameters; small-scale, noncomparative studies have documented significant trospium chloride-induced improvements in patients with reflex neurogenic bladder, postoperative bladder irritation and radiation-induced cystitis; and observational studies including >10,000 patients have also revealed favourable findings for trospium chloride, including a marked decrease in incontinence episodes and substantial improvement in health-related quality of life.Trospium chloride is generally well tolerated, and significantly more so than immediate-release oxybutynin. The most frequent adverse events, occurring in >1% of trospium chloride-treated patients, are dry mouth, dyspepsia, constipation, abdominal pain and nausea.Available for many years in several countries outside North America, trospium chloride is likely to develop an important role in the management of overactive bladder following its approval in the US on 28 May 2004.     

Trospium chloride: an anticholinergic quaternary ammonium compound for the treatment of overactive bladder

The International Continence Society has defined overactive bladder (OAB) as urinary urgency, with or without urge urinary incontinence, usually with urinary frequency and nocturia. Approximately 17% of men and women in the US report OAB symptoms, which can affect quality of life. Trospium chloride, which has recently been introduced in the US as Sanctura, has been prescribed for > 10 years in Europe as, for example, Spasmo-lyt, Regurin and Spasmex. Trospium chloride has been shown to be effective in relieving OAB symptoms, and has a favourable safety profile, showing < 1% difference for all adverse events compared with placebo, except for dry mouth, constipation and headache. Metabolic drug-drug interactions are unlikely, given that trospium chloride is not metabolised by cytochrome P450 isozymes. The fast-acting efficacy of trospium chloride, coupled with its good safety profile and tolerability, make it an important new option for treatment of OAB.     

Responses of isolated normal human detrusor muscle to various spasmolytic drugs commonly used in the treatment of the overactive bladder

The spasmolytic activity of flavoxate (CAS 15301-69-6) and the anticholinergic agents oxybutynin (CAS 5633-20-5), tolterodine (CAS 124937-51-5) and trospium chloride (CAS 10405-02-4), all of which are commonly utilized in the treatment of urinary incontinence, on muscarinic tension and electrically evoked contractions of isolated human detrusor smooth muscle strips was studied using the organ bath technique. Within the concentration ranges tested (trospium chloride 10(-11)-10(-6) mol/l, flavoxate and oxybutynin 10(-9)-10(-5) mol/l, tolterodine 10(-10)-10(-5) mol/l), each drug caused a concentration-dependent relaxation of the tension elicited by muscarinic stimulation and dose-dependently attenuated the contractions induced by electrical field stimulation (EFS). The effects of trospium chloride and tolterodine on carbachol-induced muscarinic tension were more pronounced than those of oxybutynin, while trospium chloride and oxybutynin were most effective in inhibiting the contractions induced by EFS. Flavoxate was significantly less effective than all other drugs tested. Regardless the individual drug concentrations needed for maximal efficacy, the potency of oxybutynin and flavoxate to reverse muscarinic tension and attenuate EFS-evoked contractions was almost comparable while tolterodine and trospium chloride were more effective in relaxing the muscarinic tension of the detrusor strip preparations than causing inhibition of EFS-induced contractions. Our results again underline the ratio for the use of nortropane analogues (trospium chloride) and phenylpropylamine cresols (tolterodine) in the treatment of frequency, urgency and urge incontinence secondary to an overactive bladder.     

Terodiline inhibition of human bladder contraction. Effects in vitro and in women with unstable bladder

Abstract Terodiline, a drug with anticholinergic and calcium antagonistic properties, effectively relaxed carbachol-contracted, isolated human bladder preparations. In the concentrations used, terodiline displaced to the right the concentration-response curve obtained on cumulative addition of carbachol. The maximum response was slightly reduced only at the highest terodiline concentration used (5μM), suggesting a mainly competitive antimuscarinic effect. Nine patients, aged 12–78 years, suffering from urge urinary incontinence were investigated by simultaneous urethro-cystometry before and after treatment with terodiline 12.5 mg twice or three times daily for 10 days. The patients reported subjective improvement with almost no side effects. Objectively, the number of uninhibited bladder contractions and the amplitude of the contractions decreased. The bladder capacity was almost doubled. There were no marked effects on bladder and urethral pressures at rest, and only two of the investigated patients had slight residual urine after treatment. The results suggest that terodiline is a promising alternative to existing drugs for inhibition of undesired detrusor activity.     

New insights into molecular targets for urinary incontinence

Urinary incontinence (UI) is a disease affecting quality of life of 200 million patients worldwide. It is characterized by involuntary loss of urine. The factors involved are cystitis, detrusor hyperreflexia, spinal injury, benign prostatic hyperplasia, etc. The surge in the number of reviews on this subject indicates the amount of research devoted to this field. The prevalence is increasing at an alarming rate but unfortunately, only a few medications are currently available for this condition. There are peripheral as well as central targets including cholinergic, vanilloid, prostaglandin, kinin, calcium channel, cannabinoid, serotonin, and GABA-receptors, which act by different mechanisms to treat different types of incontinence. Drugs acting on the central nervous system (CNS) increase urinary bladder capacity, volume, or pressure threshold for micturition reflex activation while peripherally acting drugs decrease the amplitude of micturition contraction and residual volume. Anticholinergic drugs specifically M3 receptor antagonists are the first choice but have frequent side effects such as dry mouth, CNS disturbances, etc. Therefore, there is a need to understand the biochemical pathways that control urinary dysfunction to determine the potential to which they can be exploited in the treatment of this condition. This article reviews the central and peripheral molecular targets and the potential therapeutic approaches to the treatment of UI.     

Trospium chloride: the European experience

The primary pharmacological therapy for overactive bladder syndrome is muscarinic receptor antagonists. Muscarinic receptor blockade is effective in decreasing the symptoms of urinary urgency and urgency incontinence, but can be associated with troublesome complications, such as dry mouth, blurred vision, constipation and CNS side effects. Trospium chloride, an antimuscarinic medication, has been available in Europe for > 20 years and has recently been approved by the FDA for the treatment of overactive bladder. Trospium chloride is a quaternary amine that is minimally metabolised, not highly protein bound and, importantly, has not been demonstrated to cross the unaltered blood-brain barrier in healthy volunteers. Some characteristics of this unique antimuscarinic agent and the European experience with trospium chloride are reviewed in this article.     

Trospium chloride: the European experience

The primary pharmacological therapy for overactive bladder syndrome is muscarinic receptor antagonists. Muscarinic receptor blockade is effective in decreasing the symptoms of urinary urgency and urgency incontinence, but can be associated with troublesome complications, such as dry mouth, blurred vision, constipation and CNS side effects. Trospium chloride, an antimuscarinic medication, has been available in Europe for > 20 years and has recently been approved by the FDA for the treatment of overactive bladder. Trospium chloride is a quaternary amine that is minimally metabolised, not highly protein bound and, importantly, has not been demonstrated to cross the unaltered blood–brain barrier in healthy volunteers. Some characteristics of this unique antimuscarinic agent and the European experience with trospium chloride are reviewed in this article.     

Inhibitory effects of trospium chloride on cytochrome P450 enzymes in human liver microsomes

Trospium chloride, an atropine derivative used for the treatment of urge incontinence, was tested for inhibitory effects on human cytochrome P450 enzymes. Metabolic activities were determined in liver microsomes from two donors using the following selective substrates: dextromethorphan (CYP2D6), denitronifedipine (CYP3A4), caffeine (CYP1A2), chlorzoxazone (CYP2E1), S-(+)-mephenytoin (CYP2C19), S-(-)-warfarin (CYP2C9) and coumarin (CYP2A6). Incubations with each substrate were carried out without a possible inhibitor and in the presence of trospium chloride at varying concentrations (37-3000 microM) at 37 degrees in 0.1 M KH2PO4 buffer containing up to 3% DMSO. Metabolite concentrations were determined by high-performance liquid chromatography (HPLC) in all cases except CYP2A6 where direct fluorescence spectroscopy was used. First, trospium chloride IC50 values were determined for each substrate at respective K(M) concentrations. Trospium chloride did not show relevant inhibitory effects on the metabolism of most substrates (IC50 values considerably higher than 1 mM). The only clear inhibition was seen for the CYP2D6-dependent high-affinity O-demethylation of dextromethorphan, where IC50 values of 27 microM and 44 microM were observed. Therefore, additional dextromethorphan concentrations (0.4-2000 microM) were tested. Trospium chloride was a competitive inhibitor of the reaction with Ki values of 20 and 51 microM, respectively. Thus, trospium chloride has negligible inhibitory effects on CYP3A4, CYP1A2, CYP2E1, CYP2C19, CYP2C9 and CYP2A6 activity but is a reasonably potent inhibitor of CYP2D6 in vitro. Compared to therapeutic trospium chloride peak plasma concentrations below 50 nM, the 1000-times higher competitive inhibition constant Ki however suggests that inhibition of CYP2D6 by trospium chloride is without any clinical relevance.