Tolterodine in the treatment of overactive bladder: analysis of the pooled phase II efficacy and safety data

Larsson, Gregor; Hallén, B; Nilvebrant, Lisbeth

doi:10.1016/s0090-4295(98)00629-3

Cited by 99 publications

(51 citation statements)

References 14 publications

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“…This measurement has been used in other studies, not only as a measure of safety but also as a measure of drug effect on the bladder. This finding is in contrast to dose-finding studies of tolterodine in adults, where there was a clear dose-response relationship for residual urinary volume [26][27][28]. The reason for the difference is not clear but might be a result of there being few patients and that the patients were children in a stressful situation, which may lead to greater variability.…”

Section: Discussioncontrasting

confidence: 81%

The overactive bladder in children: a potential future indication for tolterodine

et al. 2001

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Objective To determine the safety, efficacy and pharmacokinetics of tolterodine in children with an overactive bladder. Patients and methods Thirty-three children (20 boys and 13 girls, aged 5-10 years) with an overactive bladder and symptoms of urgency, frequency and/or urge incontinence were enrolled in an open, dose-escalation study. Patients were treated with oral tolterodine 0.5 mg (n=11), 1 mg (n=10) or 2 mg (n=12) twice daily for 14 days. The primary safety endpoint was the change in residual urinary volume, as determined by ultrasonography. In addition, voiding diary variables (frequency and incontinence episodes) and pharmacokinetics were evaluated. Other safety endpoints included laboratory variables, electrocardiogram recordings and reported adverse events. Results There were no safety concerns in terms of the change in residual urinary volume for any of the three dosage groups; values were comparable with baseline after 2 weeks of treatment for all three dosages. Adverse events were reported by 20 patients (six on 0.5 mg, five on 1 mg, and nine on 2 mg). Most adverse events were not considered to be drug-related; of the 13 possibly related events, 10 occurred in those taking 2 mg. Headache was the most commonly reported adverse event. No serious adverse events were reported and there were no general safety concerns.There was an improvement in voiding diary variables in all treatment groups after 2 weeks of treatment, although the efficacy was greatest in those taking 1 mg and 2 mg. Pharmacokinetic findings were consistent with dose linearity over the range 0.5-2 mg. Conclusion The results support the use of 1 mg twice daily as the optimal dose of tolterodine for treating children aged 5-10 years with an overactive bladder. Keywords tolterodine, antimuscarinic agents, children, overactive bladder, dose-finding study IntroductionThe symptoms of an overactive bladder are urgency and frequency, with or without urge incontinence, caused by uncontrolled contractions of the detrusor muscle. As uncontrolled detrusor contractions are mediated by muscarinic receptor stimulation, antimuscarinic agents are the most frequently used medications for treating this condition [1]. Historically, antimuscarinic agents like oxybutynin have been effective for treating the overactive bladder but they are poorly tolerated because they are not selective for the bladder [2]. Side-effects on the parotid gland, CNS, gastrointestinal tract and on the eye limit their clinical usefulness [3]. Particularly frequent and troublesome is dry mouth, which has been shown to cause poor compliance and frequent discontinuation of treatment [1,[4][5][6].Tolterodine is a muscarinic receptor antagonist that has been shown to be effective for treating the overactive bladder [7][8][9]. The advantages of tolterodine are numerous and are ascribed to its selectivity for the bladder over other tissues and to its low lipophilicity. Differences between tolterodine and oxybutynin have been reported in several preclinical studies, including pharmacologi...

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Section: Discussioncontrasting

confidence: 81%

The overactive bladder in children: a potential future indication for tolterodine

et al. 2001

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“…All of the aforementioned drugs are well known to produce significant QT interval prolongation and, in some cases, torsades de pointes arrhythmia. However, tolterodine, despite widespread clinical use, has not been reported to produce QT prolongation either in controlled clinical trials or during postmarketing surveillance (Larsson et al, 1999;Millard et al, 1999;Layton et al, 2001;Nilvebrant, 2001). After therapeutic doses, C max levels of tolterodine in normal subjects average about 12 to 16 nM of which 96.3% is bound to serum proteins (Brynne et al, 1998;Olsson and Szamosi, 2001), resulting in free plasma levels of Ͻ1 nM.…”

Section: Discussionmentioning

confidence: 99%

“…QT prolongation or torsades de pointe arrhythmia are not associated with tolterodine treatment despite widespread clinical use (Hills et al, 1998;Larsson et al, 1999;Millard et al, 1999;Layton et al, 2001). Other drugs in this chemical and pharmacological class (e.g., terodiline) are known to prolong action potential duration, block cardiac K ϩ channels, and produce QT prolongation and arrhythmia in clinical use (Thomas et al, 1995;Jones et al, 1998).…”

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confidence: 99%

Cardiac Ion Channel Effects of Tolterodine

Kang¹,

Chen²,

Wang³

et al. 2004

J Pharmacol Exp Ther

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Tolterodine is a muscarinic antagonist widely used in the treatment of urinary incontinence. Although tolterodine has not been reported to alter cardiac repolarization, it is chemically related to other muscarinic antagonists known to prolong cardiac repolarization. For this reason, we studied the effects of tolterodine on cardiac ion channels and action potential recordings. Using patch-clamp electrophysiology, we found that tolterodine was a potent antagonist of the human ether-a-go-go-related gene (HERG) K ϩ channel, displaying an IC 50 value of 17 nM. This potency was similar to that observed for the antiarrhythmic drug dofetilide (IC 50 of 11 nM). Tolterodine block of HERG displayed a positive voltage dependence, suggesting an interaction with an activated state. Tolterodine had little effect on the human cardiac Na ϩ channel at concentrations of up to 1 M. Inhibition of L-type Ca 2ϩ currents by tolterodine was frequency-dependent with IC 50 values measuring 143 and 1084 nM at 1 and 0.1 Hz, respectively. Both tolterodine and dofetilide prolonged action potential duration in single guinea pig myocytes over the concentration range of 3 to 100 nM. However, prolongation was significantly larger for dofetilide compared with tolterodine. Tolterodine seems to be an unusual drug in that it blocks HERG with high affinity, but produces little QT prolongation clinically. Low plasma levels after therapeutic doses combined with mixed ion channel effects, most notably Ca 2ϩ channel blockade, may serve to attenuate the QT prolonging effects of this potent HERG channel antagonist.

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“…Millions of patients have benefited from Tol treatment [40] . Furthermore, little has been reported regarding the fatal proarrhythmic effects of Tol in either early clinical tests or follow-up studies [32,33,38,41] . In recent years, studies have shown that Tol can reduce heart rate variability, while its effect on arrhythmia remains unknown [42,43] .…”

Section: Discussionmentioning

confidence: 99%

Tolterodine reduces veratridine-augmented late INa, reverse-INCX and early afterdepolarizations in isolated rabbit ventricular myocytes

Wang

Zhang

et al. 2016

Acta Pharmacol Sin

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Aim: The augmentation of late sodium current (I Na.L ) not only causes intracellular Na + accumulation, which results in intracellular Ca 2+ overload via the reverse mode of the Na + /Ca 2+ exchange current (reverse-I NCX ), but also prolongs APD and induces early afterdepolarizations (EAD), which can lead to arrhythmia and cardiac dysfunction. Thus, the inhibition of I Na.L is considered to be a potential way for therapeutic intervention in ischemia and heart failure. In this study we investigated the effects of tolterodine (Tol), a competitive muscarinic receptor antagonist, on normal and veratridine (Ver)-augmented I Na.L , reverse-I NCX and APD in isolated rabbit ventricular myocytes, which might contribute to its cardioprotective activity. Methods: Rabbit ventricular myocytes were prepared. The I Na.L and reverse-I NCX were recorded in voltage clamp mode, whereas action potentials and Ver-induced early afterdepolarizations (EADs) were recorded in current clamp mode. Drugs were applied via superfusion. Results: Tol (3-120 nmol/L) concentration-dependently inhibited the normal and Ver-augmented I Na.L with IC 50 values of 32.08 nmol/L and 42.47 nmol/L, respectively. Atropine (100 μmol/L) did not affect the inhibitory effects of Tol (30 nmol/L) on Ver-augmented I Na.L . In contrast, much high concentrations of Tol was needed to inhibit the transient sodium current (I Na.T ) with an IC 50 value of 183.03 μmol/L. In addition, Tol (30 nmol/L) significantly shifted the inactivation curve of I Na.T toward a more depolarizing membrane potential without affecting its activation characteristics. Moreover, Tol (30 nmol/L) significantly decreased Ver-augmented reverse-I NCX . Tol (30 nmol/L) increased the action potential duration (APD) by 16% under the basal conditions. Ver (20 μmol/L) considerably extended the APD and evoked EADs in 18/24 cells (75%). In the presence of Ver, Tol (30 nmol/L) markedly decreased the APD and eliminated EADs (0/24 cells). Conclusion: Tol inhibits normal and Ver-augmented I NaL and decreases Ver-augmented reverse-I NCX . In addition, Tol reverses the prolongation of the APD and eliminates the EADs induced by Ver, thus prevents Ver-induced arrhythmia.

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Tolterodine in the treatment of overactive bladder: analysis of the pooled phase II efficacy and safety data

Cited by 99 publications

References 14 publications

The overactive bladder in children: a potential future indication for tolterodine

The overactive bladder in children: a potential future indication for tolterodine

Cardiac Ion Channel Effects of Tolterodine

Tolterodine reduces veratridine-augmented late INa, reverse-INCX and early afterdepolarizations in isolated rabbit ventricular myocytes

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