mAChR1/2/3; muscarinic cholinergic receptors

体外活性：Trospium Chloride 是一种竞争性毒蕈碱胆碱能受体拮抗剂。目标：mAChR Trospium氯化物是一种抗毒蕈碱剂，用于治疗伴有急迫性尿失禁、尿急和尿频症状的膀胱过度活动症。

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离体研究： 离体研究评估了曲司氯铵对猪和人类逼尿肌条带活性的影响。研究的参数包括EC50（使卡巴胆碱诱导的张力发生50%逆转的浴槽浓度）、Rmax（在最终浴槽药物浓度下的松弛百分比）、IC50（使电场刺激引发的最大收缩反应发生50%抑制的浴槽浓度）和MI（在最终浴槽药物浓度下收缩振幅的抑制百分比）。
对于猪组织，曲司氯铵的效力显著强于奥昔布宁（EC50值分别为0.006和25 μmol/L，Rmax值分别为100% [在0.1 μmol/L时] 和76.2 ± 8%）。在人类组织中，相应的EC50和Rmax值分别为0.003和10 μmol/L，以及86 ± 13% [在0.1 μmol/L时] 和79 ± 20%（两种组织对比，p < 0.05）(Uckert 等, 1998)。
在人类组织中，曲司氯铵、奥昔布宁和托特罗定的EC50和Rmax值分别为：0.003、10、≤ 1.0 μmol/L 和 86 ± 13%、50 ± 7%、70 ± 8%。相应的IC50和MI值分别为：0.05、10、> 10 μmol/L 和 80 ± 17%、53 ± 7%、40 ± 16%（曲司氯铵与对照药物相比，p < 0.05）。
在卡巴胆碱和电场刺激实验方案中，曲司氯铵在所有测试的浴槽浓度（1, 0.1, 0.01, 0.001, 0.0001, 和 0.00001 μmol/L）下均产生了相较于对照组的显著变化 (Uckert 等, 2000)。在这两项离体研究中，曲司氯铵的效应均呈剂量依赖性 (Uckert 等, 1998, 2000)。[3]

Trospium 具有与其他抗毒蕈碱剂不同的药理学特性。口服后，亲水性曲司氯铵的吸收缓慢且不完全。服用 20 mg 速释制剂后 4-5 小时达到约 4 ng/mL 的血浆峰浓度 (Cmax)。平均生物利用度约为 10%，并随着伴随食物摄入而降低（血浆浓度-时间曲线 [AUC] 下空腹面积的平均值为 26%）。在临床相关剂量范围（20-60 mg）内单剂量给药后，曲司氯铵显示 AUC 和 Cmax 与剂量成比例增加。平均分布容积约为350-800 L。

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体内（动物）研究
研究了单次静脉注射0.1和0.5 mg/kg剂量的曲司氯铵对犬胃肠道动力的影响。在0.5 mg/kg剂量水平，给药后长达0.5小时内，胃和肠道运动活性被完全抑制，胃和空肠动力指数显著降低，给药后2.5小时内结肠收缩和结肠动力指数下降（Hatchet等，1986）。

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体内（人类）研究
在一项针对12名健康人类志愿者进行的安慰剂对照、交叉、双盲试验中，评估了曲司氯铵对24小时空肠动力的影响。口服曲司氯铵15毫克，每日三次，能显著延长餐后不规则收缩活动的持续时间（从平均324分钟延长至368分钟，p < 0.02），并降低其收缩频率（从2.24次/分钟降至1.08次/分钟，p < 0.001）和幅度（从26.5毫米汞柱降至20.3毫米汞柱，p < 0.001）。在空腹状态下，由于第I相（运动静止期）延长（从42分钟延长至78分钟，p < 0.025），移行性运动复合波的周期长度显著延长（从77分钟延长至116分钟，p < 0.01）。第III相显著缩短（从7.3分钟缩短至3.8分钟，p < 0.005），并显示出更慢的口向迁移速度（从8.4厘米/分钟降至4.7厘米/分钟，p < 0.005）。餐后（从24小时内的42次降至14次，p < 0.01）和空腹期间（从24小时内的11次降至4次，p < 0.01）的簇状收缩频率显著降低。该药物消除了连续的簇状收缩。总之，曲司氯铵显著降低了健康志愿者的空肠运动活性（Schmidt等，1994）。
在一项采用双盲、交叉设计的研究中，评估了单次静脉注射0.2、0.5、1和1.5毫克剂量的曲司氯铵对6名女性志愿者胆囊收缩功能的影响。曲司氯铵对脂肪刺激诱导的胆囊收缩产生了剂量依赖性抑制（使用碘泊酸钠测量，p < 0.0001）。两个最高剂量几乎完全消除了收缩功能（Matzkies等，1992）。九名志愿者参与了一项随机、交叉、安慰剂对照试验，评估了单次静脉注射安慰剂、1.2毫克曲司氯铵和5毫克比哌立登对食管动力的影响。曲司氯铵显著降低了原发性蠕动压力波的幅度（从安慰剂组的平均67毫米汞柱降至17毫米汞柱，p < 0.01），但未改变其持续时间。该药物显著增加了原发性蠕动失败的发生频率（从安慰剂组的0%增加至10%，p < 0.05）（单位：120次饮水吞咽中的百分比）。该药物显著减少了空气扩张引发的继发性收缩的百分比（从安慰剂组的95%降至60%，p < 0.01）。曲司氯铵还显著延长了继发性收缩开始的潜伏期（从安慰剂组的7秒增加至11秒，p < 0.05），并降低了其幅度（从安慰剂组的65毫米汞柱降至25毫米汞柱，p < 0.01）。在所有比较中，曲司氯铵的作用与比哌立登的作用在统计学上无法区分。最后，曲司氯铵对食管诱发电位没有影响。总之，曲司氯铵损害食管动力（Pehl等，1998）。
最后，在33名参与双盲、交叉、安慰剂对照试验的健康志愿者中评估了曲司氯铵对胃肠道动力的影响（胆囊N=11，胃排空N=12，胃食管反流和口盲传输时间N=10）。四种处理方案为安慰剂，以及曲司氯铵10、15和20毫克口服，在研究前一天和研究当天早上6点给药。与安慰剂相比，10毫克和20毫克剂量显著降低了胆囊射血分数（分别为p < 0.025和p < 0.01），而10毫克和20毫克剂量的效果无显著差异。与安慰剂相比，15毫克剂量显著延迟了胃排空（p < 0.02，体积无变化提示该药物有抗分泌反应）。与安慰剂相比，15毫克剂量显著增加了24小时研究期间食管pH低于4的时间占比（p < 0.05），也显著延长了口盲传输时间（p < 0.001）（Pfeiffer等，1993）。 [3]

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相较于其他抗毒蕈碱药物，Trospium的主要优势在于，作为一种季胺，它不透过血脑屏障，因此不太可能引起其他几种药物所观察到的中枢神经系统效应。此外，由于其极少的肝脏代谢，且不依赖主要的细胞色素通路，Trospium在服用多种药物的患者中发生药物相互作用的风险较低。Trospium 60 mg 缓释制剂在改善与膀胱过度活动症相关的关键结局参数方面，与Trospium 20 mg 每日两次的给药方案同样有效，但口干（这类药物最常见的副作用）的发生率更低。Trospium在疗效和安全性上与目前市场上其他抗毒蕈碱药物相当。
讨论：据报道，患者对Trospium治疗的持续性良好。目前市场上有大量抗毒蕈碱药物，在临床使用适当剂量的前提下，尚无明确证据能在疗效上区分彼此。
结论：Trospium的新剂型（指60mg缓释片）无疑值得考虑作为膀胱过度活动症患者的药物治疗选择，尤其是对于希望避免潜在认知功能障碍风险的老年患者。[1]

Animal Model Used: Dog model
Dose: 0.1-0.5 mg/kg
Administration route: iv, single dose
Results: Inhibited the gastric and intestinal motility.[3]

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AIMS We examined the relative efficacy and safety of trospium 20 mg bid and 60 mg extended release formulations and position this drug against other antimuscarinic agents.
Methods: Data were identified on the pharmacology and pharmacokinetics of trospium chloride. Key publications on trospium 20-mg and 60-mg clinical studies in patients with overactive bladder (OAB) were identified and efficacy and safety compared between these formulations as well as other antimuscarinic agents.[1]

Trospium chloride is an antimuscarinic agent indicated for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency. Trospium has 3 chemical and pharmacokinetic properties unique among antimuscarinic agents: it is a positively charged quaternary ammonium compound with minimal central nervous system penetration; it is not metabolized by the cytochrome P450 system, resulting in a lower tendency for drug interactions; and it is excreted mainly unchanged in the urine as the active parent compound, providing local activity to achieve early onset of clinical effect and prolonged efficacy. In two 12-week, randomized, placebo-controlled clinical studies in adults with OAB, trospium 20 mg twice daily was more effective than placebo in reducing the number of micturitions per 24 hours, reducing the number of urge incontinence episodes per week, and increasing the volume of urine voided per micturition. Placebo-controlled trials report efficacy with trospium in treatment of OAB; comparative trials with other anticholinergic agents are limited. Current therapy of OAB consists primarily of anticholinergic drugs such as oxybutynin, which are associated with therapy-limiting adverse effects. Because the prevalence of OAB is greatest among the elderly, safety considerations regarding renal function must be noted, with dosage adjustment required in patients with severe renal impairment.[2]

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Trospium chloride is a quaternary ammonium compound, which is a competitive antagonist at muscarinic cholinergic receptors. Preclinical studies using porcine and human detrusor muscle strips demonstrated that trospium chloride was many-fold more potent than oxybutynin and tolterodine in inhibiting contractile responses to carbachol and electrical stimulation. The drug is poorly bioavailable orally (< 10%) and food reduces absorption by 70%- 80%. It is predominantly eliminated renally as unchanged compound. Trospium chloride, dosed 20 mg twice daily, is significantly superior to placebo in improving cystometric parameters, reducing urinary frequency, reducing incontinence episodes, and increasing urine volume per micturition. In active-controlled trials, trospium chloride was at least equivalent to immediate-release formulations of oxybutynin and tolterodine in efficacy and tolerability. The most problematic adverse effects of trospium chloride are the anticholinergic effects of dry mouth and constipation. Comparative efficacy/tolerability data with long-acting formulations of oxybutynin and tolterodine as well as other anticholinergics such as solifenacin and darifenacin are not available. On the basis of available data, trospium chloride does not appear to be a substantial advance upon existing anticholinergics in the management of urge urinary incontinence.[3]

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Healthy volunteers [3]
The pharmacokinetic parameters of trospium chloride have been extensively reviewed recently (Guay 2003). Table 1 illustrates mean data after drug administration by the oral and IV routes. Trospium chloride is absorbed slowly after oral dosing, with mean times to peak plasma concentration of 5–6 h in healthy young volunteers and 3.5 h in healthy elderly volunteers. Using urinary excretion data, the mean ± SD oral bioavailability is 2.91 ± 0.90% (using trospium chloride data only) and 3.25 ± 1.02% (using total compound data). Mean (range) absolute bioavailability of a 20 mg dose based on serum concentration data, is 9.6% (4.0%–16.1%) (Anonymous 2004). Food reduces oral drug bioavailability by 70%–80%. Absorption after single intravesical (into the bladder) doses of 15 and 30 mg is essentially negligible.
Studies have been done using animal models to evaluate the process of absorption of trospium chloride and methods to augment it. Absorption of the drug across the intestinal epithelium is complex, involving P-glycoprotein-mediated secretion and saturable binding to intestinal mucus (Langguth et al 1997). Limited permeability across the epithelial cell layer accounts for the low bioavailability. Use of water/oil microemulsions or cyclodextrin did not enhance, and actually reduced, oral bioavailability (Langguth et al 1997). However, oral bioavailability was enhanced by ion pairing using N-alkylsulfates (6- or 7-carbon chain is optimal) or N-alkylsulfonates (7- or 9-carbon chain is optimal) (Langguth et al 1997). In addition, ion pairing using nonylsulfonate and heptylsulfonate may allow use of a transdermal formulation (transepidermal flux is increased by 7.1 ± 5.7-fold and 13.5 ± 23.0-fold, respectively, over trospium chloride alone) (Langguth et al 1987).
Trospium chloride is 50%–85% plasma protein bound. The mean ± SD apparent volume of distribution is 395 ± 140 L (Anonymous 2004). There are no published data regarding the penetration of the drug into the central nervous system. Renal excretion accounts for approximately 70% of drug clearance. Approximately 80%, 10%, and < 5% of urinary excretion is accounted for by parent compound, spiroalcohol metabolite, and hydrolysis/oxidation products, respectively. Cumulative 48-h urinary excretion after a single 0.5 mg IV dose was 278 ± 59 μg of parent compound and 10 ± 4 μg of the spiroalcohol metabolite (spiroalcohol accounts for a mean of 7.1% of total urinary excretion, range 3.2%–10.9%). Corresponding values after a single oral 10 mg dose were 158 ± 43 μg and 16 ± 12 μg (spiroalcohol accounts for a mean 15.8% of total urinary excretion, range 3.4%–30.4%). Renal clearance is 4-fold higher than creatinine clearance, indicating that filtration and secretion are involved (Anonymous 2004). Terminal disposition half-life (t1/2) is approximately 10–12 h (Anonymous 2004).
Trospium chloride exhibits dose-independence over the single dose range of 20–60 mg (measured by area under the serum concentration-versus-time curve [AUC] data) and dose-dependence when measured by peak concentration [Cmax] data (3-fold increase when doubling from 20 to 40 mg and 4-fold increase when tripling from 20 to 60 mg) (Anonymous 2004). Of interest, there appears to be circadian variability in trospium chloride pharmacokinetics, with a decrease in Cmax of up to 59% and AUC of up to 33% for evening relative to morning dosing (Anonymous 2004). The mean accumulation factor for a 20 mg twice daily oral regimen is 1.1 (90% CI 0.85–1.35).

Special populations[3]
Age does not appear to significantly affect trospium chloride pharmacokinetics although actual data were not presented in the source document (Anonymous 2004). Conflicting results have been noted in studies evaluating the effect of gender on the pharmacokinetics of trospium chloride. After administration of a single oral 40 mg dose in 16 elderly subjects, AUC was 45% lower in females compared with males. In contrast, after 20 mg twice daily administration for 4 days in 12 elderly patients, Cmax and AUC were 68% and 26% higher, respectively, in females versus males (Anonymous 2004).
Trospium chloride Cmax is increased by means of 12% and 63% in subjects with mild (Child-Pugh class A) and moderate hepatic impairment (Child-Pugh class B), respectively, compared with healthy subjects. However, AUC is similar in the three groups. No data are available regarding the effect of severe hepatic impairment (Child-Pugh class C) (Anonymous 2004). Renal impairment significantly alters trospium chloride pharmacokinetics. Patients with severe renal impairment (creatinine clearance < 30 mL/min) demonstrate a 4.5-fold increase in AUC, 2-fold increase in Cmax, and a 2- to 3-fold increase in t1/2 compared with healthy volunteers. In this patient population, a 50% reduction in daily dose is recommended (Anonymous 2004).[3]

Safety[3]
Table 2 illustrates the safety data from the individual placebo- and active-controlled English language clinical trials of trospium chloride (Stohrer et al 1991; Madersbacher et al 1995; Junemann et al 1999; Cardozo et al 2000; Hofner et al 2000; Junemann et al 2000; Frohlich et al 2002; Anonymous 2004; Zinner et al 2004). Table 3 illustrates the product information sheet data, which cite pooled results from two studies (Anonymous 2004; Zinner et al 2004). As would be expected, most adverse events are an extension of the drug’s anticholinergic properties. An interesting finding from these latter data is the increased frequency of anticholinergic adverse events in those subjects 75 years of age and older (15% of trospium chloride recipients were in this age stratum) compared with younger subjects. This is felt to be pharmacodynamic in nature (ie, increased sensitivity) and not pharmacokinetic (Anonymous 2004).

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A double-blind, randomized, placebo-controlled study in 29 healthy volunteers was performed to assess the maximum tolerated single oral dose of trospium chloride. The doses evaluated were 20, 40, 80, 120, 180, 240, and 360 mg. At each dose level, 9 subjects were randomized to active drug and 3 to placebo (exception: at 360 mg, the corresponding numbers were 8 and 2). There were essentially no inter-treatment differences (drug vs placebo) at doses of 120 mg and less. Anticholinergic effects of increasing intensity occurred at a dose of 180 mg and above (pupillary dilatation, decreased salivary flow, increased heart rate). With the 360 mg dose, vital signs were unchanged but subjects found the experience to be “quite unpleasant”. Pupillary effects were not seen until doses were greater than or equal to 180 mg. These three doses produced a long-lasting dilatation significantly different from that of placebo, but dose-dependence was not noted. A similar threshold was found for the hyposalivation effect and, in contrast to the pupillary effect, dose-dependence was noted. A similar threshold was found for the tachycardic effect and, like the pupillary effect, dose-dependence was not noted. Tachycardia appeared at 4 to 8 h post-dosing and disappeared by 12 h post-dosing. No significant effect on blood pressure was noted at any dose. No electrocardiographic effects occurred at any dose except a 10 to 40 ms reduction in the QT interval due to the tachycardia. Of recorded adverse events, only the frequency and intensity of xerostomia was dose-dependent. At lower doses, xerostomia was of mild intensity while after the 240 and 360 mg doses it was of moderate to severe intensity (Breuel et al 1993).
The effect of trospium chloride on QT interval was evaluated in a single-blind, randomized, placebo- and active (moxifloxacin)-controlled trial in 170 healthy volunteers. Subjects were randomized to five days of placebo, moxifloxacin 400 mg once daily, or various doses of trospium chloride (ranging from 20 to 100 mg twice daily). The QT interval was evaluated over a 24 h period at steady state. The QT interval was not affected by any dose of trospium chloride while moxifloxacin had the expected effect (mean Fredericia-corrected prolongation of 6.4 ms). Dose-dependent tachycardia was seen in trospium chloride recipients, with mean increases of 9.1 and 18.0 beats/minute in the 20 and 100 mg dose groups, respectively (Anonymous 2004).
In the gallbladder contractility study reviewed previously, xerostomia did not occur with the single 0.2 and 0.5 mg IV doses of trospium chloride but did occur in 3 of 6 subjects after the single 1.0 and 1.5 mg IV doses. At these latter doses, a transient dose-dependent tachycardia also occurred, reaching a peak at 0.25 h post-dosing (Matzkies et al 1992). Two case reports have also documented the potential for significant tachycardia after IV trospium chloride (Hasselkus 1998; Pfeiffer et al 1999). In one report, IV administration of 2 mg as premedication for endoscopy in 24 patients caused mean heart rate to rise from 81 to 125 beats/min within 1 min after dosing (Hasselkus 1998). In the other report, 31 patients again received the drug as premedication for endoscopy. In these patients, 1.2 mg of IV trospium chloride produced a rise in heart rate of approximately 14 beats/minute at 5, 10, and 15 minutes post-dosing (Pfeiffer et al 1999).
Two electroencephalographic (EEG) studies have been conducted to quantitate the central nervous system effects of trospium chloride, oxybutynin, tolterodine, and placebo in healthy volunteers (Pietzko et al 1994; Todorova et al 2001). The first study was a randomized, crossover design evaluating single doses of trospium chloride (1.2 mg IV, 45 mg oral) and oxybutynin (20 mg oral) in 12 subjects. Ten of these 12 subjects were also evaluated in a no drug state but this was not a placebo phase within the crossover design. No significant EEG effects were associated with trospium chloride by either route of administration. Oxybutynin caused a significant reduction in alpha and beta 1 activity (with eyes open, eyes closed, during reaction time testing). Heart rate significantly rose after IV trospium chloride administration, peaking at 20 min post-dosing with a 60% increase. Heart rate returned to baseline by 4 h post-dosing. No significant heart rate effect was noted with oral trospium chloride while oral oxybutynin caused a significant reduction, which peaked at 3 h post-dosing and did not return to baseline within the 4 h evaluation period. Adverse events included xerostomia (in 1, 2, and 1 trospium chloride oral, trospium chloride IV, and oxybutynin recipients, respectively), tachycardia (in 2 trospium chloride IV recipients), and headache (in 1 trospium chloride IV recipient; moderate to severe, occurring at 7 h post-dosing and lasting 3 h, requiring no treatment) (Pietzko et al 1994). The second study was a randomized, single blind design evaluating trospium chloride (15 mg thrice daily), oxybutynin (5 mg thrice daily), tolterodine (2 mg twice daily), and placebo, with each treatment lasting 1 day. Each of the sixty-four subjects was randomized to 1 of the 4 treatment groups. Trospium chloride and tolterodine did not induce any power change in 5 of 6 EEG frequency bands (delta, alpha 1, alpha 2, beta 1, beta 2) and caused isolated reductions in power of the theta band. In contrast, oxybutynin significantly reduced EEG power in 4 bands: theta, alpha 1, alpha 2, beta 1. Tolerability was rated as “very good” by 81.3, 62.5, 56.3, and 50% of placebo, tolterodine, trospium chloride, and oxybutynin recipients, respectively. Fifty-seven adverse events (36 being possibly drug-related) occurred in 30 subjects: 4 with placebo (maximum of 1/subject), 14 with tolterodine (3 had > 1 event), 15 with trospium chloride (4 had > 1 event), and 24 with oxybutynin (8 had > 1 event). In terms of central nervous system events, 3 events occurred in 3 placebo recipients, 5 events in 4 tolterodine recipients, 11 events in 8 trospium chloride recipients, and 17 events in 8 oxybutynin recipients. The events in trospium chloride recipients included headache in 5 subjects, tiredness in 2 subjects, and impaired concentration, restless sleep, cold sensation, and single myoclonus in 1 subject each (Todorova et al 2001). At the present time, there are no data to support the hypothesis that trospium chloride is less neurotoxic than non-quaternary anticholinergics due to reduced transit across the blood brain barrier (due to its quaternary amine structure).

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Drug–drug interactions[3]
In vitro studies have demonstrated that trospium chloride exerts negligible effects on cytochrome P450 (CYP) isozymes 3A4, 1A2, 2E1, 2C19, 2C9, and 2A6 in human liver microsomes. Although it is a reasonably potent inhibitor of CYP isozyme 2D6, the inhibition constant (ki) is 1000-fold higher than the Cmax achievable with the usual oral regimen. Hence, the likelihood of a clinically-important drug interaction with CYP isozyme 2D6 substrates and trospium chloride is very low (Anonymous 2004). However, no formal studies have been conducted evaluating potential drug–drug interactions with trospium chloride. Whether drugs actively secreted in the renal tubules affect trospium chloride pharmacokinetics (and vice versa) is unknown.

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Drug Induced Liver Injury
Dataset Drug Induced Liver Injury Rank (DILIrank 2.0)
Compound Trospium chloride
vDILI-Concern vNo-DILI-concern
Severity Class 0
Label Section No match
References DOI:10.1016/j.drudis.2016.02.015

5284631 man TDLo oral 2571 ug/kg SENSE ORGANS AND SPECIAL SENSES: MYDRIASIS (PUPILLARY DILATION): EYE; AUTONOMIC NERVOUS SYSTEM: PARASYMPATHOLYTIC; CARDIAC: PULSE RATE INCREASE WITHOUT FALL IN BP Arzneimittel-Forschung. Drug Research., 43(461), 1993 [PMID:8494577]
5284631 rat LD50 intravenous 15500 ug/kg SENSE ORGANS AND SPECIAL SENSES: MYDRIASIS (PUPILLARY DILATION): EYE; BEHAVIORAL: CHANGES IN MOTOR ACTIVITY (SPECIFIC ASSAY); LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Oyo Yakuri. Pharmacometrics., 8(199), 1974
5284631 mouse LD50 subcutaneous 203 mg/kg SENSE ORGANS AND SPECIAL SENSES: MYDRIASIS (PUPILLARY DILATION): EYE; BEHAVIORAL: CHANGES IN MOTOR ACTIVITY (SPECIFIC ASSAY); LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Oyo Yakuri. Pharmacometrics., 8(199), 1974
5284631 rabbit LDLo intravenous 20 mg/kg SENSE ORGANS AND SPECIAL SENSES: MYDRIASIS (PUPILLARY DILATION): EYE; BEHAVIORAL: ALTERED SLEEP TIME (INCLUDING CHANGE IN RIGHTING REFLEX) Oyo Yakuri. Pharmacometrics., 8(199), 1974
5284631 rat LD50 intraperitoneal 97700 ug/kg SENSE ORGANS AND SPECIAL SENSES: MYDRIASIS (PUPILLARY DILATION): EYE; BEHAVIORAL: CHANGES IN MOTOR ACTIVITY (SPECIFIC ASSAY); LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Oyo Yakuri. Pharmacometrics., 8(199), 1974

[1]. Int J Clin Pract.2010 Oct;64(11):1535-40.
[2]. Ann Pharmacother.2009 Feb;43(2):283-95.
[3]. Ther Clin Risk Manag . 2005 Jun;1(2):157-67.

Trospium chloride is an organic chloride salt of trospium. It is an antispasmodic drug used for the treatment of overactive bladder. It has a role as a muscarinic antagonist and an antispasmodic drug. It is an organic chloride salt and a quaternary ammonium salt. It contains a trospium.
See also: Trospium Chloride (annotation moved to).

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Objective: To review the pharmacology, pharmacokinetics, safety, and clinical application of trospium chloride for the management of overactive bladder (OAB).
Data sources: Clinical literature including both primary sources and review articles was accessed through MEDLINE, International Pharmaceutical Abstracts, and Cochrane databases from 1980 through January 8, 2009. Search terms included overactive bladder, urge urinary incontinence, muscarinic receptor antagonists, and urinary frequency. Further data sources were identified from bibliographies of selected articles.
Study selection and data extraction: Basic pharmacology data were extracted from animal studies and pharmacokinetic data were gathered from human studies. Multicenter, parallel, randomized, double-blind, placebo-controlled studies were included to describe the efficacy and adverse effects of trospium.
Data synthesis: Trospium chloride is an antimuscarinic agent indicated for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency. Trospium has 3 chemical and pharmacokinetic properties unique among antimuscarinic agents: it is a positively charged quaternary ammonium compound with minimal central nervous system penetration; it is not metabolized by the cytochrome P450 system, resulting in a lower tendency for drug interactions; and it is excreted mainly unchanged in the urine as the active parent compound, providing local activity to achieve early onset of clinical effect and prolonged efficacy. In two 12-week, randomized, placebo-controlled clinical studies in adults with OAB, trospium 20 mg twice daily was more effective than placebo in reducing the number of micturitions per 24 hours, reducing the number of urge incontinence episodes per week, and increasing the volume of urine voided per micturition. Placebo-controlled trials report efficacy with trospium in treatment of OAB; comparative trials with other anticholinergic agents are limited. Current therapy of OAB consists primarily of anticholinergic drugs such as oxybutynin, which are associated with therapy-limiting adverse effects. Because the prevalence of OAB is greatest among the elderly, safety considerations regarding renal function must be noted, with dosage adjustment required in patients with severe renal impairment.
Conclusions: Whether the pharmacodynamic properties of trospium make it superior to other therapies will require considerable additional experience with the drug. For now, it appears to be a feasible alternative for patients who cannot tolerate oxybutynin. [2]

C25H30NO3.CL

427.96

392.222

C, 70.16; H, 7.07; Cl, 8.28; N, 3.27; O, 11.22

10405-02-4

Trospium-d8 chloride; 10405-02-4 (chloride); 1006028-67-6 (bromide); 1050405-50-9 (iodide); 47608-32-2 (cation); 1006028-56-3 (acetate)

5284631

White to off-white solid powder

266-268ºC

0.7

46.53

1

4

5

30

553

2

C1CC[N+]2(C1)[C@@H]3CC[C@H]2CC(C3)OC(=O)C(C4=CC=CC=C4)(C5=CC=CC=C5)O.[Cl-]

RVCSYOQWLPPAOA-DHWZJIOFSA-M

InChI=1S/C25H30NO3.ClH/c27-24(25(28,19-9-3-1-4-10-19)20-11-5-2-6-12-20)29-23-17-21-13-14-22(18-23)26(21)15-7-8-16-26;/h1-6,9-12,21-23,28H,7-8,13-18H2;1H/q+1;/p-1/t21-,22+,23?;

[(1S,5R)-spiro[8-azoniabicyclo[3.2.1]octane-8,1'-azolidin-1-ium]-3-yl] 2-hydroxy-2,2-diphenylacetate;chloride

IP631; Trospium chloride, IP-631; IP 631; trade name Sanctura; Tropez OD; Trosec; Regurin; Flotros; Spasmex; Spasmoly.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.84 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.84 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.84 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 100 mg/mL (233.67 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。