Chiral nitrogen-containing compounds are crucial for the chemical, pharmaceutical, and agrochemical industries. Nevertheless, the synthesis of certain valuable scaffolds remains underdeveloped due to the vast chemical space available. In this work, we present a diastereoselective methodology for synthesizing 3,3-diarylallyl phthalimides, which, following iridium-catalyzed asymmetric hydrogenation using Ir-UbaPHOX, yield 3,3-diarylpropyl amines with high enantioselectivity (98-99% ee). The importance of alkene purity to achieve high enantioselectivity is discussed. The synthetic utility of the chiral propylamines obtained is demonstrated through the preparation of medicinally useful bioactive compounds like the drugs tolterodine and tolpropamine and 4-aryl tetrahydroquinolines. This strategy enables the synthesis of these compounds with the highest enantioselectivity reported to date.

The analysis of the results of a multicenter, open, randomized comparative phase III clinical trial on the use of imidafenacin for treating patients with OAB was carried out. A clinical study was conducted according to GCP standards in 12 urological centers of the Russian Federation with the support of company AO "R-Pharm". A total of 296 patients (men and women) aged from 18 to 65 years with OAB and urgent urinary incontinence were included in the study. All patients were randomized into two groups. In Group 1 (n=148) patients received -cholinoblocker imidafenacin 1 tablet (0,1 mg) twice a day. Group 2 patients (n=148) were prescribed a comparison drug tolterodine 1 tablet (2 mg) twice a day, as well. The duration of treatment was 12 weeks. The analysis of results showed a significant decrease in the OAB symptoms in both groups. In Group 1 a decrease of episodes of urge urinary incontinence was more pronounce compared to Group 2, as well as amount of day-time and night-time of episodes of urge urinary incontinence by the 2nd, 4th, 8th and 12th weeks of treatment in comparison with baseline scores. There were no differences between two groups in the severity of reducing average urinary frequency per day. Reducing the severity of urinary disturbances in patients of both groups was accompanied by an improvement in the quality of life. There was a significant and similar decrease in the average total score of both OAB Awareness Tool and EQ-5D questionnaires. Tolerability of treatment was satisfactory in both groups and there were no differences in the adverse events in Group 1 and 2. Imidafenacin showed high clinical efficacy for treating patients with OAB, which is not inferior, and in some values, is superior in comparison to tolterodine. Both drugs had a similar safety and tolerability profile.

To carry out a network meta-analysis of randomised controlled trials (RCTs) of anticholinergic drug treatment for people with overactive bladders. Comprehensive searches for relevant RCTs were carried out starting with RCTs included in previous systematic reviews with the last search in February 2017. Searches included terms for the anticholinergic drugs tolterodine, oxybutynin, trospium, propiverine, solifenacin, darifenacin, imidafenacin, and fesoterodine. Data was extracted from the systematic reviews or reports of studies for cure or improvement, voids per 24 hr, leakage episodes per 24 hr and dry mouth. Data was analysed using frequentist network meta-analysis. 128 studies were found. There was no clearly best treatment for cure or improvement. The differences between treatments for voids and leakages were small and unlikely to be of clinical importance. Transdermally delivered oxybutynin was clearly the best treatment for dry mouth but was still worse than placebo. All the anticholinergic drugs were better than placebo but apart from dry mouth were similar in effect. Transdermal oxybutynin caused less dry mouth than the other treatments, so may be worth considering as the first treatment.

QT interval prolongation typically assessed with dedicated clinical trials called thorough QT/QTc (TQT) studies is used as surrogate to identify the proarrhythmic risk of drugs albeit with criticism in terms of cost-effectiveness in establishing the actual risk of torsade de pointes (TdP). Quantitative systems toxicology and safety (QSTS) models have potential to quantitatively translate the in vitro cardiac safety data to clinical level including simulation of TQT trials. Virtual TQT simulations have been exemplified with use of two related drugs tolterodine and fesoterodine. The impact of bio-relevant concentration in plasma versus estimated heart tissue exposure on predictions was also assessed. Tolterodine and its therapeutically equipotent metabolite formed via CYP2D6 pathway, 5-HMT, inhibit multiple cardiac ion currents (IKr, INa, ICaL). The QSTS model was able to accurately simulate the QT prolongation at therapeutic and supra-therapeutic dose levels of tolterodine well within 95% confidence interval limits of observed data. The model was able to predict the QT prolongation difference between CYP2D6 extensive and poor metaboliser subject groups at both dose levels thus confirming the ability of the model to account for electrophysiologically active metabolite. The QSTS model was able to simulate the negligible QT prolongation observed with fesoterodine establishing that the 5-HMT does not prolong QT interval even though it is a blocker of hERG channel. With examples of TOL and FESO, we demonstrated the utility of the QSTS approaches to simulate virtual TQT trials, which in turn could complement and reduce the clinical studies or help optimise clinical trial designs.

To evaluate the effects of tolterodine on anterior segment and choroidal thickness by using the Pentacam system and optical coherence tomography (OCT) (Pentacam). A total of 122 eyes of 61 patients (34 female; 27 male) were included in the study. All patients underwent a regular ocular examination and intraocular pressure measurements before and after 3 months of antimuscarinic drug tolterodine treatment, in addition, pupil diameter, anterior chamber depth, anterior chamber volume, anterior chamber angle, and lens thickness were measured through Pentacam (Oculus Inc., Wetzlar, Germany) system. Measurements of choroidal thickness were performed by OCT (Spectralis®, Heidelberg Engineering, Heidelberg, Germany). The mean age was 58.4 ± 7.3 years and 56.5 ± 11.1 years for female and male patients. The mean intraocular pressure was 15.10 ± 2.75 mmHg before treatment and 15.18 ± 2.65 mmHg after treatment. Pupil diameters were 3.09 ± 0.48 mm before treatment and 3.12 ± 0.43 mm after treatment. Anterior chamber depth, before and after treatment were 2.68 ± 0.65 mm and 2.70 ± 0.61 mm. The mean value for subfoveal choroidal thickness was 267.92 ± 81.35 μm before the administration of tolterodine, whereas the mean choroidal thickness was 271.83 ± 75.42 μm after the administration of tolterodine. The alterations in the subfoveal choroidal thickness were not statistically significant (p = 0.862). After 3 months of therapy with tolterodine, there were no significant changes in anterior segment parameters and choroidal thickness.

Effect of 22 CYP2D6 variants found in the Chinese population on tolterodine metabolism in vitro

Electrochemical oxidation of 5-hydroxymethyl tolterodine and identification of its oxidation products using liquid chromatography and mass spectrometry

A highly enantioselective copper/N-heterocyclic carbene catalyzed allylic arylation with organolithium compounds is presented. The use of commercial or readily prepared aryllithium reagents in the reaction with allyl bromides affords a variety of chiral diarylvinylmethanes, comprising a privileged structural motif in pharmaceuticals, in high yields with good to excellent regio- and enantioselectivities. The versatility of this new transformation is illustrated in the formal synthesis of the marketed drug tolterodine (Detrol).

Experimental urethral obstruction in rats alters micturition patterns with non-voiding activity (NVA) during filling cystometry, showing similarity to that observed in human detrusor overactivity. Several drug classes with therapeutic potential in overactive bladder in humans have been tested in this model in rats, rabbits or guinea pigs, but no detailed analysis of drug effects on cystometric patterns has been published. The present study uses a rat model of overactivity with partial bladder outflow obstruction (BOO) in combination with the procedures to analyse NVA to study the effects of the anticholinergic drug tolterodine and the novel β(3)-adrenoceptor agonist mirabegron. The current data for the first time show that NVA in rats with BOO is sensitive to both the muscarinergic antagonist tolterodine and the β(3)-adrenoceptor agonist mirabegron, but with clear differences between the two drugs: during progression of bladder filling, tolterodine affected both the amplitude and frequency of NVA whereas mirabegron affected primarily the frequency. In addition, tolterodine dose-dependently reduced voiding contractions, while mirabegron did not. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism which is sensitive to cholinergic excitatory and beta-adrenergic inhibitory inputs. Such concepts could provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs. To investigate the hypothesis that tolterodine and the β(3)-adrenoceptor agonist mirabegron exert their actions on the motor component of the motor/sensory system in the bladder wall: non-voiding activity (NVA). The present study used standard cystometric techniques and a conscious rat model of partial bladder outflow obstruction (BOO). A single dose of either tolterodine (0.01, 0.1 0.3 or 1.0 mg/kg) or mirabegron (0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg) was given i.v. to each animal. In the dose ranges used, tolterodine reduced the voiding contraction amplitude, whereas mirabegron did not. Non-voiding activity consisted of small (<0.6 mmHg) and large (>0.6 mmHg) transients. As a fill progressed, both tolterodine and mirabegron reduced the cumulative activity of the large non-voiding contractions, but had little effect on the small transients. Tolterodine affected both the amplitude and frequency of NVA, whereas mirabegron affected primarily the frequency. Non-voiding activity is sensitive to muscarinergic antagonists and β(3)-adrenoceptor agonists, but there are clear differences between the two drugs. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism with cholinergic excitatory and adrenergic inhibitory inputs. Such concepts may provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs.

To investigate the effects of the selective phosphodiesterase (PDE) type 4 inhibitor IC485 and the widely used antimuscarinic drug tolterodine tartrate on bladder activity in rats with bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle. BOO was induced in female Sprague-Dawley rats by tying a silk ligature around the urethra. Six weeks after inducing BOO, conscious rats were assessed by cystometry with the urethral ligature intact. The effects of IC485 (5, 10 and 50 mg/kg intravenous, i.v.) were examined and compared with those of tolterodine (0.01, 0.1 and 1 mg/kg i.v.). IC485 (5-50 mg/kg i.v.) decreased the number and amplitude of non-voiding contractions during the storage phase by 63-88% and 49-83%, respectively; IC485 also increased bladder capacity by 28-37%. There was no change in blood pressure after applying IC485. Tolterodine tartrate (0.1 and 1.0 mg/kg) significantly decreased the number and amplitude of non-voiding contractions by 38-74% and 29-44%, respectively, and increased bladder capacity by 19-51%. Whereas voiding efficiency and maximum voiding pressure were not altered by IC485 at any dose, tolterodine significantly reduced both, by 35-67% and 19-34%, respectively. Both IC485 and tolterodine tartrate reduced detrusor overactivity in rats with BOO. In addition, doses of IC485 that suppressed non-voiding contractions had no effect on voiding function. Therefore, selective PDE4 inhibitors deserve further study as potential agents for treating detrusor overactivity in patients with BOO.

The anticholinergic drug tolterodine has been suggested to be useful in therapy-resistant enuresis. Imipramine has a proven efficiency in unselected enuretic patients, but due to its side-effect profile it is only indicated, if at all, in therapy-resistant cases. We therefore compared these two drugs to placebo. Twenty-seven children with enuresis resistant to the alarm and to desmopressin in monotherapy were given placebo, tolterodine 1-2 mg, and imipramine 25-50 mg at bedtime for 5 weeks each in a randomised, double-blind, crossover fashion. The number of wet nights during the last 2 weeks of each treatment period was compared. One patient became spontaneously dry at the start of the study, and one dropped out due to side effects. Among the remaining 25 children, the number of wet nights during placebo, tolterodine and imipramine treatment were 11.0 +/- 3.9, 10.4 +/- 3.9 and 7.8 +/- 5.1, respectively (p < 0.001). Imipramine was significantly better than both placebo (p = 0.001) and tolterodine (p = 0.006). Nine children experienced side effects on imipramine and one on tolterodine (p = 0.001). This is the first study on anticholinergics or imipramine in children with therapy-resistant enuresis. Tolterodine, in monotherapy, had no proven effect. Imipramine was better than placebo, but side effects were common.

Anticholinergic agents are used for treatment of overactive bladder syndrome (OAB) by competitive blockade of acetylcholine at the muscarinic receptor. At present five different subtypes of M-receptors can be differentiated. Primary detrusor effects are mediated by M3-receptors as are side effects like dry mouth and constipation. Cardiac and central nervous system side effects appear to be M2 or M1 related. OAB symptom relief by the unselective drugs tolterodine, oxybutynin or trospium chloride and by M3-selective agents like darifenacin or solifenacin seems to be rather similar. Central side effects are different depending on gastrointestinal reabsorption, serum metabolism and penetration of the blood-brain barrier. Slow release formulations may be better tolerated. Anticholinergics that penetrate the blood-brain barrier may cause cognitive imbalance in older patients, as recent studies have shown for oxybutynin. Here M3-selective agents may offer an advantage.

The Importance of Residues in Substrate Recognition Site 3 for the Catalytic Function of CYP2D25 (Vitamin D 25-Hydroxylase)

Implementation of a Nursing Home Urinary Incontinence Management Program With and Without Tolterodine

Implementation of a Nursing Home Urinary Incontinence Management Program With and Without Tolterodine

Efficacy and tolerability of tolterodine in children with detrusor hyperreflexia

Column switching in capillary liquid chromatography–tandem mass spectrometry for the quantitation of pg/ml concentrations of the free basic drug tolterodine and its active 5-hydroxymethyl metabolite in microliter volumes of plasma