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。

---

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。

---

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）。

---

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]

---

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]

---

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]

Topiramate is an anticholinergic drug indicated for the treatment of overactive bladder (OAB) with symptoms of urinary urgency, frequency, and urge incontinence. Topiramate possesses three unique chemical and pharmacokinetic properties among anticholinergic drugs: it is a positively charged quaternary ammonium compound with extremely low central nervous system penetration; it is not metabolized by the cytochrome P450 system, thus minimizing the possibility of drug interactions; and it is primarily excreted in the urine as the active parent compound, thereby exerting a local effect, achieving early onset and sustained efficacy. In two 12-week randomized, placebo-controlled clinical trials, topiramate 20 mg twice daily was superior to placebo in reducing 24-hour voiding frequency, reducing the frequency of weekly urge incontinence episodes, and increasing the volume of each voiding episode. Placebo-controlled trials reported the efficacy of topiramate in treating OAB. Comparative trials with other anticholinergic drugs are limited. Currently, the main treatments for OAB include anticholinergic drugs such as oxybutynin, but these drugs can cause treatment-limiting adverse reactions. Since OAB is most common in the elderly, renal safety must be considered, and dose adjustment is necessary for patients with severe renal impairment. [2]

---

Topiramate is a quaternary ammonium compound and a competitive antagonist of muscarinic cholinergic receptors. Preclinical studies using pig and human detrusor strips have shown that topiramate is much more effective than oxybutynin and tolterodine in inhibiting carbacholine and electrical stimulation-induced contractile responses. The drug has low oral bioavailability (<10%), and food can reduce its absorption by 70%-80%. It is mainly excreted unchanged via the kidneys. Topiramate, 20 mg twice daily, is significantly superior to placebo in improving bladder pressure parameters, reducing urinary frequency, reducing urinary incontinence episodes, and increasing the volume of each urination. In active drug controlled trials, the efficacy and tolerability of topiramate are at least comparable to immediate-release oxybutynin and tolterodine. The most significant adverse effects of topiramate are dry mouth and constipation caused by its anticholinergic effects. There are currently no comparative data on the efficacy/tolerance of topiramate compared with long-acting hydroxybutyrine and tolterodine, as well as other anticholinergic drugs such as solifenacin and dafenapyr. Based on the available data, topiramate does not appear to have a significant advantage over existing anticholinergic drugs in the treatment of urge incontinence. [3]

---

Health volunteers[3]
Pharmacokinetic parameters of topiramate have been extensively studied recently (Guay 2003). Table 1 lists the mean data after oral and intravenous administration. After oral administration, topiramate is absorbed slowly, with the mean time to peak plasma concentration in healthy young volunteers being 5-6 hours and in healthy older volunteers being 3.5 hours. Based on urinary excretion data, the mean ± standard deviation of oral bioavailability was 2.91 ± 0.90% (using topiramate data only) and 3.25 ± 1.02% (using all compound data). Based on serum concentration data, the mean (range) absolute bioavailability of a 20 mg dose was 9.6% (4.0%–16.1%) (anonymous, 2004). Food can reduce the bioavailability of orally administered drugs by 70%–80%. After a single intravesical (IV) administration of 15 mg and 30 mg doses, absorption is negligible. Studies have used animal models to evaluate the absorption process of topiramate and methods to enhance it. The absorption of this drug via the intestinal epithelium is complex, involving P-glycoprotein-mediated secretion and saturation binding with intestinal mucus (Langguth et al., 1997). Limited permeability of the epithelial cell layer contributes to its low bioavailability. The use of water/oil microemulsions or cyclodextrins has not improved oral bioavailability but rather decreased it (Langguth et al., 1997). However, ion-pairing with N-alkyl sulfates (6 or 7 carbon chains are optimal) or N-alkyl sulfonates (7 or 9 carbon chains are optimal) can improve oral bioavailability (Langguth et al., 1997). Furthermore, ion-pairing with nonylsulfonates and heptasulfonates may allow for transdermal formulations (transdermal flux increased by 7.1 ± 5.7 times and 13.5 ± 23.0 times, respectively, compared to topiramate alone) (Langguth et al., 1987). Topiramate has a plasma protein binding rate of 50%–85%. The mean apparent volume of distribution is 395 ± 140 L (anonymous, 2004). There are currently no data on the drug's penetration into the central nervous system. Renal excretion accounts for approximately 70% of drug clearance. Of the urinary excretion, approximately 80% is the parent drug, 10% is a spirol metabolite, and <5% is hydrolysis/oxidation products. Following a single intravenous injection of 0.5 mg, the cumulative urinary excretion over 48 hours was: 278 ± 59 μg of the parent drug and 10 ± 4 μg of spirol metabolite (spirol accounted for 7.1% of total urinary excretion on average, ranging from 3.2% to 10.9%). Following a single oral dose of 10 mg, the corresponding values were 158 ± 43 μg and 16 ± 12 μg, respectively (spirol accounted for 15.8% of total urinary excretion on average, ranging from 3.4% to 30.4%). Renal clearance was four times that of creatinine clearance, indicating that both filtration and secretion were involved (anonymous, 2004). The terminal disposal half-life (t1/2) was approximately 10–12 hours (anonymous, 2004).
Topiramate showed dose-independent behavior in the single-dose range of 20–60 mg (as determined by area under the serum concentration-time curve [AUC] data), but showed dose-dependent behavior as determined by peak concentration [Cmax] data (3-fold increase when doubling the dose from 20 mg to 40 mg, and 4-fold increase when doubling the dose from 20 mg to 60 mg) (anonymous, 2004). Notably, the pharmacokinetics of topiramate appeared to exhibit diurnal variability, with Cmax decreasing by up to 59% and AUC decreasing by up to 33% when administered at night compared to morning administration (anonymous, 2004). The mean cumulative factor for the twice-daily oral 20 mg regimen was 1.1 (90% CI 0.85–1.35).
Special populations[3]
Although no actual data were provided in the original literature (anonymous, 2004), age did not appear to have a significant effect on the pharmacokinetics of topiramate. In studies assessing the effect of sex on the pharmacokinetics of topiramate, results were contradictory. In 16 elderly subjects, after a single oral dose of 40 mg, the AUC was 45% lower in women than in men. In contrast, in 12 elderly patients, after twice-daily administration of 20 mg for 4 days, the Cmax and AUC were 68% and 26% higher in women than in men, respectively (anonymous, 2004). Compared to healthy subjects, patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment showed elevated Cmax of topiramate by 12% and 63%, respectively. However, the AUC was similar across the three groups. Data on the effects of severe hepatic impairment (Child-Pugh C) are currently unavailable (anonymous, 2004). Renal impairment significantly alters the pharmacokinetics of topiramate. Compared to healthy volunteers, patients with severe renal impairment (creatinine clearance <30 mL/min) showed a 4.5-fold increase in AUC, a 2-fold increase in Cmax, and a 2- to 3-fold increase in t1/2. For these patients, a 50% reduction in daily dose is recommended (anonymous, 2004). [3]

Safety[3] Table 2 lists the safety data of various placebo-controlled and active-drug-controlled clinical trials of topiramate (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 lists the data in the product information sheet, which cites the summary results of two studies (Anonymous, 2004; Zinner et al., 2004). As expected, most adverse events were an extension of the drug’s anticholinergic properties. An interesting finding in the latter data was that subjects aged 75 years and older (15% of topiramate recipients were in this age group) had a higher incidence of anticholinergic adverse events compared to younger subjects. This is considered pharmacodynamic in nature (i.e., increased sensitivity) rather than pharmacokinetic in nature (anonymous, 2004). A double-blind, randomized, placebo-controlled study in 29 healthy volunteers aimed to evaluate the maximum tolerated single oral dose of topiramate. The doses evaluated were 20, 40, 80, 120, 180, 240, and 360 mg. At each dose level, 9 subjects were randomized to the active drug group and 3 to the placebo group (except for the 360 mg dose group, where the corresponding numbers were 8 and 2). At doses of 120 mg and below, there were essentially no differences between the treatment groups (drug group vs. placebo group). Anticholinergic effects were observed at doses of 180 mg and above (pupil dilation, decreased salivation, increased heart rate). At the 360 mg dose, vital signs were not altered, but subjects reported the experience as “quite uncomfortable.” Pupil effects occurred only at doses greater than or equal to 180 mg. All three doses produced prolonged mydriasis, significantly different from the placebo group, but no dose dependence was observed. The salivation reduction effect also had a similar threshold, and unlike the pupillary effect, it was dose-dependent. The tachycardia effect also had a similar threshold, and like the pupillary effect, no dose dependence was observed. Tachycardia appeared 4 to 8 hours after administration and disappeared 12 hours after administration. No significant effects on blood pressure were observed at any dose. Except for a QT interval shortening of 10 to 40 ms due to tachycardia, no electrocardiographic abnormalities were observed at any dose. Of the recorded adverse events, only dry mouth was dose-dependent in both frequency and severity. Dry mouth was milder in the low-dose group, while moderate to severe dry mouth was observed in the 240 mg and 360 mg dose groups (Breuel et al., 1993). In a single-blind, randomized, placebo- and active drug (moxifloxacin) controlled trial, the effect of topiramate on the QT interval was evaluated in 170 healthy volunteers. Subjects were randomized to a placebo group, a once-daily dose of 400 mg moxifloxacin group, or different doses of topiramate (20 to 100 mg twice daily). The QT interval was assessed over 24 hours at steady state. The QT interval was unaffected by any dose of topiramate, while moxifloxacin produced the expected effect (mean prolongation of 6.4 ms after Frederician correction). Dose-dependent tachycardia occurred in the topiramate group, with mean heart rate increases of 9.1 beats/min and 18.0 beats/min in the 20 mg and 100 mg dose groups, respectively (anonymous, 2004). In a previously reviewed study of gallbladder contractility, single intravenous injections of 0.2 mg and 0.5 mg topiramate did not cause dry mouth, but after single intravenous injections of 1.0 mg and 1.5 mg, 3 out of 6 subjects experienced dry mouth. Transient dose-dependent tachycardia was also observed at the latter two doses, peaking 0.25 hours after administration (Matzkies et al., 1992). Two case reports also documented significant tachycardia following intravenous topiramate administration (Hasselkus 1998; Pfeiffer et al. 1999). One report showed that 24 patients who received 2 mg of topiramate intravenously before endoscopy experienced an increase in mean heart rate from 81 bpm to 125 bpm within 1 minute after administration (Hasselkus 1998). Another report showed that 31 patients also received the drug before endoscopy. In these patients, after intravenous administration of 1.2 mg topiramate, heart rate increased by approximately 14 beats/min at 5, 10, and 15 minutes post-administration (Pfeiffer et al., 1999). Two electroencephalogram (EEG) studies aimed to quantify the effects of topiramate, oxybutynin, tolterodine, and placebo on the central nervous system in healthy volunteers (Pietzko et al., 1994; Todorova et al., 2001). The first study used a randomized crossover design to evaluate the effects of a single dose of topiramate (1.2 mg intravenously, 45 mg orally) and oxybutynin (20 mg orally) in 12 subjects. Ten of these 12 subjects were also evaluated in a drug-free state, but this was not the placebo phase of the crossover design. Topiramate did not induce significant EEG effects regardless of the route of administration. Oxybutynin significantly reduced the activity of α and β1 receptors (eye-open, eye-closed, and reaction time tests). Following intravenous administration of topiramate, heart rate significantly increased, peaking at 20 minutes post-administration with an increase of up to 60%. Heart rate returned to baseline levels 4 hours post-administration. Oral topiramate did not show a significant effect on heart rate, while oral oxybutynin resulted in a significant decrease in heart rate, peaking at 3 hours post-administration and failing to return to baseline levels within a 4-hour evaluation period. Adverse events included dry mouth (in one patient receiving oral topiramate, two receiving intravenous topiramate, and one receiving oxybutynin), tachycardia (in two patients receiving intravenous topiramate), and headache (in one patient receiving intravenous topiramate; moderate to severe, occurring 7 hours post-administration, lasting 3 hours, requiring no treatment) (Pietzko et al., 1994). A second randomized, single-blind study evaluated topiramate (15 mg, three times daily), oxybutynin (5 mg, three times daily), tolterodine (2 mg, twice daily), and placebo, with each treatment lasting one day. Sixty-four participants were randomly assigned to one of four treatment groups. Topiramate and tolterodine did not cause any power changes in five of the six EEG bands (delta, alpha1, alpha2, beta1, and beta2 waves), resulting only in an isolated decrease in theta wave power. In contrast, oxybutynin significantly reduced EEG power in four of the six bands (theta, alpha1, alpha2, and beta1 waves). 81.3%, 62.5%, 56.3%, and 50% of participants in the placebo, tolterodine, topiramate, and oxybutynin groups, respectively, reported “very good” tolerability. A total of 57 adverse events occurred in 30 subjects (36 of which were possibly drug-related): 4 in the placebo group (maximum 1 per subject), 14 in the tolterodine group (3 of whom experienced more than one adverse event), 15 in the topiramate group (4 of whom experienced more than one adverse event), and 24 in the oxybutynin group (8 of whom experienced more than one adverse event). Regarding central nervous system adverse events, 3 occurred in 3 subjects in the placebo group, 5 in 4 in the tolterodine group, 11 in 8 in the topiramate group, and 17 in 8 in the oxybutynin group. Adverse events in the topiramate group included: 5 cases of headache, 2 cases of fatigue, and 1 each of inattention, restless sleep, chills, and single myoclonus (Todorova et al., 2001). Currently, there is no data to support the hypothesis that topiramate has lower neurotoxicity than non-quaternary ammonium anticholinergic drugs due to reduced blood-brain barrier transport (due to its quaternary ammonium structure).

---

Drug Interactions[3]
In vitro studies have shown that topiramate has negligible effects on cytochrome P450 (CYP) isoenzymes 3A4, 1A2, 2E1, 2C19, 2C9, and 2A6 in human liver microsomes. Although it is a strong inhibitor of CYP isoenzyme 2D6, its inhibition constant (ki) is 1000 times higher than the Cmax achievable with conventional oral dosing regimens. Therefore, the likelihood of clinically significant drug interactions between topiramate and CYP isoenzyme 2D6 substrates is extremely low (anonymous, 2004). However, no formal studies have been conducted to assess the potential interactions of topiramate with other drugs. It is unclear whether drugs actively secreted by the renal tubules affect the pharmacokinetics of topiramate (and vice versa).

---

Drug-induced Liver Injury
Dataset Drug-induced Liver Injury Rank (DILIrank 2.0)
Compound Topiramate
vDILI Attention vNo DILI Attention
Severity Rank t0
Label Part tNo Match
References tDOI:10.1016/j.drudis.2016.02.015
5284631tmantTDLotoralt2571 ug/kgtSensory Organs and Special Sensations: Pupil Dilation: Eye; Autonomic Nervous System: Parasympathetic Block; Heart: Increased Pulse but No Decrease in Blood Pressure Arzneimittel-Forschung. Drug Research., 43(461), 1993 [PMID:8494577]
5284631trattLD50tintravenoust15500 ug/kgt Sensory organs and special senses: Pupil dilation: eyes; Behavior: altered motor activity (specific test); Lungs, pleura or respiration: respiratory depression. Oyo Yakuri. Pharmacometrics, 8(199), 1974
5284631t mouse tLD50 t subcutaneous t203 mg/kg t sensory organs and special senses: pupillary dilation (pupil expansion): eye; behavior: changes in motor activity (specific assay); lung, pleural cavity or respiration: respiratory depression tOyo Yakuri. Pharmacometrics, 8(199), 1974
5284631t rabbit tLDLotin intravenous injection t20 mg/kg t sensory organs and special senses: pupillary dilation (pupil expansion): eye; behavior: changes in sleep duration (including changes in righting reflex)
Oyo Yakuri. Pharmacometrics., 8(199), 1974
5284631trattLD50tintraperitonealt97700 ug/kgt Sensory organs and special senses: Pupil dilation: eye; Behavioral: changes in motor activity (specific detection); Lung, pleural cavity, 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 the organochlorine salt of topiramate. It is an antispasmodic agent used to treat overactive bladder (OAB). It has a dual role as both a muscarinic receptor antagonist and an antispasmodic agent. It is an organochlorine and quaternary ammonium salt containing the topiramate group.
See also: Topiramate chloride (note moved here).
Objective: To review the pharmacology, pharmacokinetics, safety, and clinical use of topiramate in the treatment of OAB.
Data sources: Clinical literature published in MEDLINE, International Pharmaceutical Abstracts, and the Cochrane database between 1980 and January 8, 2009, including original literature and review articles, was searched. Search terms included overactive bladder, urge incontinence, muscarinic receptor antagonist, and urinary frequency. We identified additional data sources from the references of selected articles.
Study selection and data extraction: Basic pharmacological data were extracted from animal studies, and pharmacokinetic data were collected from human studies. Multicenter, parallel, randomized, double-blind, placebo-controlled studies were included to describe the efficacy and adverse reactions of topiramate.
Data Synthesis: Topiramate chloride is an anticholinergic drug indicated for the treatment of overactive bladder (OAB) with symptoms of urinary urgency, frequency, and urge incontinence. Topiramate possesses three unique chemical and pharmacokinetic properties among anticholinergic drugs: it is a positively charged quaternary ammonium compound with extremely low central nervous system penetration; it is not metabolized by the cytochrome P450 system, thus minimizing the possibility of drug interactions; and it is primarily excreted in the urine as the active parent compound, thereby exerting a local effect, achieving early onset and sustained efficacy. In two 12-week randomized, placebo-controlled clinical studies, topiramate 20 mg twice daily was superior to placebo in reducing 24-hour voiding frequency, reducing the frequency of weekly urinary urgency episodes, and increasing the volume of each voiding episode. Placebo-controlled trials have reported the efficacy of topiramate in treating OAB; however, comparative trials with other anticholinergic drugs are limited. Currently, the main treatments for OAB include anticholinergic drugs, such as hydroxybutyrine, but these drugs can cause adverse reactions that limit treatment. Since OAB is most common in the elderly, renal safety issues must be considered, and patients with severe renal impairment need to have their dosage adjusted. Conclusion: Whether the pharmacodynamic properties of topiramate are superior to other therapies requires extensive clinical research. At present, topiramate appears to be a viable alternative for patients who cannot tolerate hydroxybutyrine. [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。

---

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。

---

View More

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。

---

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.

---

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。