Disease relevance of Terodiline

• We report five patients (four women, one man; mean age 74 years, range 55-87) taking terodiline who had torsades de pointes ventricular tachycardia associated with prolongation of the QT interval [1].
• CONCLUSIONS: QT prolongation associated with racemic terodiline is caused exclusively by the R(+)-enantiomer, which therefore appears to be responsible for the ventricular arrhythmias caused by the drug [2].
• When administered to adult patients with urge incontinence (generally as a 25mg twice-daily dose) terodiline reduces diurnal and nocturnal micturition frequency and incontinence episodes [3].
• 1. The cardiac electrophysiological effects of S-oxybutynin, a single-enantiomer drug under evaluation for the management of urinary incontinence, have been investigated and compared with those of terodiline, an incontinence agent withdrawn following reports of QT lengthening and ventricular tachyarrhythmia [4].
• Terodiline was widely prescribed for urinary incontinence before reports of adverse cardiac effects that included bradycardia, QT lengthening, and ventricular tachyarrhythmia [5].

Psychiatry related information on Terodiline

• The anticholinergic and calcium antagonistic drug terodiline inhibited all muscle activity, making it suitable for treatment of diurnal enuresis [6].

High impact information on Terodiline

• Torsades de pointes ventricular tachycardia and terodiline [1].
• Elimination of terodiline enantiomers was not significantly delayed in two genotypic poor metabolizers of debrisoquin (CYP2D6) [2].
• METHODS: A double-blind, placebo-controlled, randomized crossover study was performed that involved nine healthy volunteers who were given single oral doses of racemic terodiline hydrochloride (200 mg), R(+)-terodiline hydrochloride (100 mg), S(-)-terodiline tartrate (100 mg), or placebo [2].
• 3. The durations of action potentials in guinea-pig and rabbit papillary muscles driven at 1 Hz were unaffected or moderately shortened by 0.1 - 100 microM S-oxybutynin, but lengthened by terodiline [4].
• 5. The results indicate that S-oxybutynin has relatively weak non-specific effects on cardiac ion channels, and that clinically relevant submicromolar concentrations are unlikely to have terodiline-like proarrhythmic actions on the myocardium [4].

Chemical compound and disease context of Terodiline

• INTRODUCTION: Terodiline hydrochloride, widely prescribed for urinary incontinence, has been reported to cause bradycardia and torsades de pointes [7].
• Meladrazine caused a high incidence of side effects; therefore, treatment with terodiline separately is recommended for geriatric patients who have severe motor urge incontinence [8].
• The elderly form an important target group for the treatment of urinary urge incontinence with drugs such as terodiline (Mictrol, Terolin) [9].

Biological context of Terodiline

• Clinically relevant concentrations (<10 microM) of terodiline lengthened the action potential duration by up to 12%; higher concentrations shortened the duration in a concentration-dependent manner [5].
• Inhibition of IKr by terodiline appeared to be voltage-independent, and the parameters of the Hill equation describing the inhibition were IC50 = 0.7 microM and nH = 1 [10].
• Although there were consistent trends towards greater improvement in the urodynamic measurements, when the terodiline and placebo groups were compared these did not reach statistical significance, partly due to a large improvement in the placebo group [11].
• Bioavailability and disposition of terodiline in man [12].
• CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system [13].

Anatomical context of Terodiline

• In addition, action potential lengthening by E4031 in guinea-pig papillary muscles (29+/-3%) was abolished (3+/-2%) (P<0.001) by terodiline pretreatment [10].
• Blocking action of terodiline on calcium channels in single smooth muscle cells of the guinea pig urinary bladder [14].
• In experiments on rabbit ventricular myocytes, 3 and 30 microM S-oxybutynin inhibited I:(to) by 9+/-2% and 35+/-3%, respectively, whereas 3 and 30 microM terodiline inhibited the current by 31+/-3% and 87+/-3%, respectively [4].
• METHODS AND RESULTS: In this study, we characterized the electrophysiologic effects of terodiline in dog cardiac tissues in vivo and in isolated canine cardiac Purkinje fibers [7].
• In vivo studies demonstrated that high doses of terodiline (3 mg/kg) lengthened AH and HV intervals, slowed spontaneous sinus rate, prolonged ventricular refractoriness, and inhibited vagally induced slowing of the sinus node [7].

Associations of Terodiline with other chemical compounds

• Emepronium bromide, oxybutynin, and terodiline were active only at muscarinic receptors, with IC50 values of 236, 5.4, and 588 nM, respectively [15].
• In a randomised, double-blind study, 20 women with idiopathic detrusor instability and associated symptoms were treated with terodiline 25 mg bd, placebo, and emepronium bromide 200 mg tds--each drug being given for 3 weeks with placebo as wash-out period before cross-over [16].
• Terodiline in both forms was able to rapidly penetrate through the skin, even in the absence of enhancers, with 20.2 and 9.8 times higher fluxes respectively, than the corresponding forms of propiverine [17].
• Serum creatinine and alkaline phosphatase increased slightly on terodiline and the diastolic blood pressure was probably also increased by terodiline [18].
• On the other hand, in the in vitro studies, prifinium and atropine had little or no effect on contractions induced by electrical stimulation, KCl and BaCl2, whereas oxybutynin and terodiline antagonized all of the stimuli to a similar extent [19].

Gene context of Terodiline

• A calcium blocking and anticholinergic agent (terodiline) in the treatment of detrusor hyperreflexia: a placebo-controlled, cross-over trial [20].
• Prolongation of the QT interval and malignant ventricular arrhythmia have been observed in patients administered terodiline for urinary incontinence [10].
• To assess the role of these metabolites in the therapeutic effects of oxybutynin, the antimuscarinic and antispasmodic effects of RS-, R- and S-oxybutynin, RS-, R- and S-desethyloxybutynin and, for comparative purposes, RS-terodiline (CAS 7082-21-5) on isolated strips of guinea pig bladder, were examined [21].

Analytical, diagnostic and therapeutic context of Terodiline

• OBJECTIVE: To study the cardiovascular and electrocardiographic (ECG) effects of the R(+)- and S(-)- enantiomers of terodiline [2].
• Thus, terodiline is effective and well tolerated in patients with urge incontinence or neurogenic bladder dysfunction, and will claim an important place in the treatment of such patients in light of the limitations of alternative therapies [3].
• Terodiline: a dose titrated, multicenter study of the treatment of idiopathic detrusor instability in women [11].
• Urodynamic effects of intravesical instillation of terodiline in healthy volunteers and in patients with detrusor hyperactivity [22].
• Side effects such as dryness of the mouth were reported by four patients receiving terodiline in the double-blind study and by six in the long-term study [23].

References