mAChR1/2/3; muscarinic cholinergic receptors

In vitro activity: Trospium Chloride is a competitive muscarinic cholinergic receptor antagonist. Target: mAChR Trospium chloride is an antimuscarinic agent indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.

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Ex vivo studies: Ex vivo studies have evaluated the effect of trospium chloride on the activity of porcine and human detrusor muscle strips. Parameters studied included EC50 (bath concentration inducing 50% reversion of carbachol-induced tension), Rmax (% relaxation at final drug concentration in bath), IC50 (bath concentration causing 50% inhibition of maximum contractile response to electrical field stimulation), and MI (% inhibition of contraction amplitude at final drug concentration in bath). For porcine tissue, trospium chloride was significantly more potent than oxybutynin (EC50 values of 0.006 and 25 μmol/L and Rmax values of 100 [at 0.1 μmol/L] and 76.2 ± 8%, respectively). Corresponding values for EC50 and Rmax in human tissue were 0.003 and 10 μmol/L and 86 ± 13 (at 0.1 μmol/L) and 79 ± 20% (both tissues, p < 0.05) (Uckert et al 1998). In human tissue, EC50 and Rmax values for trospium chloride, oxybutynin, and tolterodine were 0.003, 10, and ≤ 1.0 μmol/L, respectively and 86 ± 13, 50 ± 7, and 70 ± 8%, respectively. Corresponding IC50 and MI values were 0.05, 10, and > 10 μmol/L and 80 ± 17, 53 ± 7, and 40 ± 16% (trospium chloride vs comparators, p < 0.05). In the carbachol and electrical field stimulation protocols, trospium chloride produced significant changes from control at all tested bath concentrations (1, 0.1, 0.01, 0.001, 0.0001, and 0.00001 μmol/L) (Uckert et al 2000). The effects of trospium chloride were dose-dependent in both ex vivo studies (Uckert et al 1998, 2000). [3]

Trospium has pharmacologic properties that are distinct from other antimuscarinic agents. After oral administration, absorption of the hydrophilic trospium chloride is slow and incomplete. Peak plasma concentrations (Cmax) of approximately 4 ng/mL are reached 4-5 hours after administration of a 20 mg immediate-release preparation. The mean bioavailability is approximately 10% and decreases by concomitant food intake (to a mean of 26% of the fasting area under the plasma concentration-time curve [AUC]). Trospium chloride displays dose proportional increases in AUC and Cmax after a single dose within the clinically relevant dose range (20-60 mg). The mean volume of distribution is approximately 350-800 L.

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In vivo (animal) studies
The effect of trospium chloride on gastrointestinal (GI) motility in dogs was studied after single 0.1 and 0.5 mg/kg intravenous (IV) doses. At the 0.5 mg/kg dose level, complete inhibition of gastric and intestinal motor activity occurred for up to 0.5 h post-dose, the gastric and jejunal motility indices (MoI) were substantially reduced, and colonic contractions and the colonic MoI fell for 2.5 h post dose (Hatchet et al 1986).

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In vivo (human) studies
In a placebo-controlled, crossover, double-blind trial conducted in 12 healthy human volunteers, the effect of trospium chloride on 24-h jejunal motility was evaluated. Trospium chloride 15 mg orally thrice daily significantly prolonged the duration of irregular contractile activity after meals (from mean 324 to 368 min, p < 0.02) and decreased its contraction frequency (from 2.24 to 1.08/min, p < 0.001) and amplitude (from 26.5 to 20.3 mm Hg, p < 0.001). In the fasting state, the cycle length of the migrating motor complex was significantly prolonged (from 77 to 116 min, p < 0.01), due primarily to an extended phase I (motor quiescence) (from 42 to 78 min, p < 0.025). Phase III was significantly shortened (from 7.3 to 3.8 min, p < 0.005), and showed a slower aboral migration velocity (from 8.4 to 4.7 cm/min, p < 0.005). Clustered contractions were significantly less frequent during postprandial (from 42 to 14 per 24 h, p < 0.01) and fasting periods (from 11 to 4 per 24 h, p < 0.01). Runs of clustered contractions were abolished by the drug. In summary, trospium chloride significantly reduced jejunal motor activity in healthy volunteers (Schmidt et al 1994).
The effects of single 0.2, 0.5, 1, and 1.5 mg IV doses of trospium chloride on gallbladder contractility were evaluated in 6 female volunteers using a double-blind, crossover design. Trospium chloride produced a dose-dependent inhibition of gallbladder contraction induced by a fat stimulus and measured using sodium iopodate (p < 0.0001). The two highest doses virtually abolished contractility (Matzkies et al 1992). Nine volunteers participated in a randomized, crossover, placebo-controlled trial evaluating the effect of single IV doses of placebo, 1.2 mg trospium chloride, and 5 mg biperiden on esophageal motility. Trospium chloride significantly reduced the amplitude of primary peristaltic pressure waves (from mean 67 mm Hg on placebo to 17 mm Hg, p < 0.01) but not their duration. The frequency of failed primary peristalsis was significantly increased by the drug (from 0 on placebo to 10%, p < 0.05) (unit = % of 120 water swallows). The percentage of secondary contractions elicited by air distension was significantly reduced by the drug (from 95% on placebo to 60%, p < 0.01). Trospium chloride also significantly increased the latency to onset of secondary contractions (from 7 s on placebo to 11 s, p < 0.05) and reduced their amplitude (from 65 mm Hg on placebo to 25 mm Hg, p < 0.01). The effects of trospium chloride were statistically indistinguishable from those of biperiden in all comparisons. Lastly, trospium chloride had no effect on esophageal evoked potentials. In summary, trospium chloride impairs esophageal motility (Pehl et al 1998).
Lastly, the effect of trospium chloride on GI motility was evaluated in 33 healthy volunteers participating in a double-blind, crossover, placebo-controlled trial (gallbladder N = 11, gastric emptying N = 12, gastoesophageal reflux and orocecal transit time N = 10). The 4 treatments were placebo and trospium chloride 10, 15, and 20 mg orally at 0600, 1400, and 2200 the day prior to study and at 0600 on the day of the study. Gallbladder ejection fractions were significantly reduced by 10 and 20 mg doses compared with placebo (p < 0.025 and p < 0.01, respectively), while the effects of the 10 and 20 mg doses were not significantly different. Gastric emptying was significantly delayed by the 15 mg dose compared with placebo (p < 0.02, no change in volume suggests an antisecretory response to the drug). The fractional time of esophageal pH below 4 as a percentage of the 24-h study period was significantly increased by the 15-mg dose compared with placebo (p < 0.05), as was the orocecal transit time (p < 0.001) (Pfeiffer et al 1993). [3]

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Trospium offers the principal advantage over other antimuscarinic agents that, as it is a quaternary amine, it does not cross the blood-brain barrier and is therefore less likely to cause central nervous system effects observed with several other agents. Moreover, with its minimal liver metabolisation, independent of the main cytochrome pathways, trospium has a low risk of drug-drug interaction in patients taking multiple pharmacological agents. Trospium 60 mg ER is as effective as trospium 20 mg bid in improving the key outcome parameters associated with OAB, but with a lower rate of dry mouth, the most common side effect of these agents. Trospium has comparable efficacy and safety to the other antimuscarinic agents currently marketed. Discussion: Good patient persistence with treatment has been reported with trospium. There are currently a large number of antimuscarinic drugs on the market without clear evidence to distinguish one agent from another in terms of efficacy, provided that an adequate dose is used in the clinical setting. Conclusion: The new formulation of trospium is certainly worth considering as a pharmacological treatment of patients with OAB, particularly in the elderly, in whom one wants to avoid the potential for cognitive dysfunction.[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]

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]

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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]

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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).

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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).

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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

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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (233.67 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)