piperidines and litoxetine

To investigate the safety and efficacy of litoxetine, a serotonin reuptake inhibitor, in treating urinary incontinence (UI) and mixed urinary incontinence (MUI).. Two randomized, double-blind, placebo-controlled clinical trials (RCT1 and RCT2) were conducted. RCT1, which included 196 women aged 18-75 with MUI randomized 1:1:1:1 to receive 10, 20, or 40 mg litoxetine or placebo orally twice daily (BID) for 12 weeks, investigated the efficacy (including changes in patient reported outcomes) and safety of litoxetine compared to placebo. RCT2, which included 82 men and women aged 18-70 with any UI type randomly assigned 2:1 to receive 30 mg litoxetine or placebo orally BID for 8 weeks including a 2 week dose titration period, investigated the safety (including psychiatric safety) and efficacy of litoxetine compared to placebo. Efficacy was measured as the change in number of incontinence episodes per week and assessed using an analysis of covariance with missing data imputed by Predictive Mean Matching. Safety was assessed by adverse events (AEs) and physical examinations and analyzed using descriptive statistics.. The 30-mg and placebo groups in RCT2 showed no difference in frequency of AEs, and litoxetine reduced the number of incontinence episodes per week compared to placebo. Although RCT1 suffered an unexpectedly high placebo response, and therefore did not meet the primary efficacy endpoint, 71% of participants receiving 40 mg litoxetine reported a clinically meaningful improvement in the King's Health Questionnaire.. Litoxetine may be a safe, effective and well-tolerated treatment for patients with UI.

Topics: Double-Blind Method; Female; Humans; Male; Piperidines; Treatment Outcome; Urinary Incontinence; Urinary Incontinence, Urge

1. The effects of a range of doses of litoxetine (twice daily for 4 days), a novel specific serotonin re-uptake inhibitor, were evaluated in young and middle aged volunteers. 2. Psychometric testing was carried out at various time points on days 1 and 4 of each treatment period. The test battery consisted of critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT), Stroop and Sternberg memory scanning tests. Subjective feelings of sleep and sedation were measured by the Leeds Sleep Evaluation Questionnaire (LSEQ) and line analogue rating scales (LARS). 3. Pharmacokinetic profiles were determined from analyses of blood samples taken after the final dose on day 5. 4. Overall, there were few changes in any of the psychometric tests and although the higher doses of litoxetine improved CFF, these effects were weak in that differences could only be detected when the results were pooled against time. 5. The pharmacokinetic profile of litoxetine was very similar in both the young and middle aged subjects, and there was no difference regarding tolerability. 6. There is little evidence from this study to suggest that litoxetine has any intrinsic sedative activity which is likely to interfere with the performance of activities of everyday life.

Topics: Administration, Oral; Adult; Analysis of Variance; Choice Behavior; Chromatography, High Pressure Liquid; Cognition; Computer Simulation; Cross-Over Studies; Double-Blind Method; Female; Flicker Fusion; Humans; Male; Memory; Middle Aged; Piperidines; Psychomotor Performance; Selective Serotonin Reuptake Inhibitors; Sleep

1. Litoxetine is a selective serotonin reuptake inhibitor with antidepressant activity in animal models and in depressed patients. 2. This double-blind, cross-over, placebo-controlled study was carried out in 12 healthy young male volunteers. The aim was to assess the EEG profile of litoxetine in parallel with its pharmacokinetics after a single dose or multiple administrations for 4 days (6 doses) of two dosages (10 mg and 25 mg). Spectral analysis of four EEG leads (F4-T4, F3-T3, T4-02 and T3-01) was done up to 12 h post-dose. 3. In single or multiple doses, litoxetine induced EEG changes characterised by a dose-related increase in fast beta energies, mainly beta 2, without any changes in slow waves (delta and theta). A slight reduction in alpha activity occurred only after repeated doses. 4. EEG changes occurred after a single oral administration and lasted at least 12 h with litoxetine blood concentrations ranging from 4 to 10 ng ml-1. With repeated administrations, the pharmacodynamic steady-state was achieved as the increase in beta 2 energies was the same before and 12 h post-dose. These effects occurred with litoxetine blood concentrations ranging from 3 to 7 ng ml-1 with the 10 mg dosage and from 8 to 18 ng ml-1 with the 25 mg dosage. The EEG profile did not change after 4 days of repeated administration, indicating that tolerance did not develop. 5. Cmax and AUC showed proportionality between the administered dosages of 10 and 25 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Analysis of Variance; Brain; Dose-Response Relationship, Drug; Double-Blind Method; Electroencephalography; Humans; Male; Piperidines; Selective Serotonin Reuptake Inhibitors

The reported selective serotonin Re-uptake Inhibitor Litoxetine was used as the starting point in the design of a range of potential SSRIs with high ease of synthetic accessibility. Preparation and subsequent optimization yielded a range of potent and highly selective SSRIs.

Topics: Cell Line; Drug Design; Humans; Piperidines; Selective Serotonin Reuptake Inhibitors; Structure-Activity Relationship

The influence of two selective serotonin reuptake inhibitors (SSRIs), litoxetine and fluoxetine, has been studied on 5-HT4 receptor-mediated relaxation in the rat isolated oesophageal muscularis mucosae. In carbachol-precontracted oesophageal tissues, 5-hydroxytryptamine (5-HT) (0.1 nM-1 microM) induced concentration-dependent relaxations. Concentration-response curves were monophasic and reproducible. Litoxetine at concentrations without antimuscarinic properties (10 nM-1 microM) caused concentration-dependent relaxations, which reduced carbachol tone up to 37%. Higher litoxetine concentrations (3 microM-300 microM) were associated with marked relaxation up to the abolition of carbachol tone. The overall curve profile of litoxetine was biphasic in nature with a high (10 nM-1 microM) and a low (3 microM-300 microM) potency phase. Unlike 5-HT, the second curve of litoxetine was not reproducible, with a reduction involving mainly the low potency phase. Compared to litoxetine, fluoxetine caused minimal relaxation (less than 10% at 1 microM). Treatment of rats with parachlorophenylalanine (pCPA: 375 mg kg-1 per day, for two days), to deplete endogenous 5-HT stores, did not modify the relaxant effect of 5-HT, while it significantly reduced the high potency phase of litoxetine. In tissues from untreated rats, this phase was reduced by the 5-HT4 receptor antagonist GR 125487 (10 nM) to an extent similar (P = 0.20: ANOVA for continuous-by-class effects) to that induced by pCPA treatment. However, in tissues from pCPA treated animals GR 125487 (10 nM) exerted a slight but significant antagonism of litoxetine response (P = 0.037: ANOVA for continuous-by-class effects) mainly involving the high potency phase. In tissues from untreated rats, litoxetine (1 microM) increased the relaxant effects of 5-HT, while in tissues from pCPA treated animals it exerted a small but significant depression of the maximal response to 5-HT, without changing its potency value. Fluoxetine (1 microM) slightly, but significantly, antagonized the relaxant effect of 5-HT in an unsurmountable manner. In conclusion, litoxetine up to 1 microM relaxed the rat isolated oesophageal muscularis mucosae through a mechanism involving release of endogenous 5-HT, which in turn activates 5-HT4 receptors. However, based on results with GR 125487 in tissues from pCPA treated rats, a small component of litoxetine-induced relaxation may involve a direct activation of 5-HT4 receptors. It is unlikely that bloc

Topics: Animals; Carbachol; Dose-Response Relationship, Drug; Drug Interactions; Esophagus; Fenclonine; Fluoxetine; In Vitro Techniques; Indoles; Male; Muscle Relaxation; Muscle, Smooth; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Sulfonamides

The selective 5HT uptake inhibitor, litoxetine (SL 81.0385), currently under development as an antidepressant was shown to have antiemetic properties in the ferret. Litoxetine (at 1 and 10 mg/kg i.v.) dose dependently reduced the number of retches and vomiting as well as the number of emetic episodes induced by cisplatin (10 mg/kg i.v.) and delayed the onset of emesis. Fluoxetine (at 1 or 10 mg/kg i.v.) failed to inhibit cisplatin-induced emetic responses and, in contrast, significantly increased the number of retches and vomiting and accelerated the onset of emesis. The possibility that the antiemetic effects of litoxetine may be mediated through an interaction with 5HT3 receptors was studied using [3H]quipazine or [3H]BRL 43694 to label the 5HT3 receptor. Litoxetine has moderate affinity for cerebral 5HT3 receptors (Ki = 85 nM), while fluoxetine, similar to other 5HT uptake inhibitors, has only negligible affinity for this receptor (Ki = 6.5 microM). It is proposed that litoxetine inhibits cisplatin-induced emetic responses due to its moderate 5HT3 antagonist properties. The clinical use of the majority of serotonergic antidepressants (e.g. fluoxetine, fluvoxamine etc.) is associated with gastrointestinal discomfort (particularly nausea and vomiting) as a major side-effect. If nausea and vomiting associated with the use of 5 HT uptake inhibitors are due to stimulation of 5HT3 receptors, the concomitant 5HT3 antagonism of litoxetine may limit the gastrointestinal side-effects of this novel antidepressant and thus offer an important advantage.

Topics: Animals; Antiemetics; Binding, Competitive; Cerebral Cortex; Cisplatin; Dose-Response Relationship, Drug; Ferrets; Fluoxetine; Granisetron; Indazoles; Male; Piperidines; Quipazine; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Vomiting

Compounds known to selectively inhibit the neuronal reuptake of serotonin are clinically effective antidepressants. However, in a number of the behavioral models used for detecting and analysing antidepressant action these drugs are inactive. The forced swimming test is not consistently sensitive to these drugs but it has recently been reported that a variation of this procedure, the tail suspension test in mice, is sensitive. The present study showed that five compounds previously shown to be selective serotonin uptake inhibitors--fluoxetine, zimeldine, paroxetine, indalpine, and litoxetine--produced dose-related decreases in immobility in the tail suspension test typical of the effects shown by other antidepressants. In separate experiments, fluoxetine, zimeldine, and indalpine decreased locomotor activity at doses similar to those that decreased immobility. In contrast, paroxetine and litoxetine had no effect on locomotion at the dose ranges active in the tail suspension test. These results confirm the sensitivity of the tail suspension test and indicate that serotonin uptake inhibitors probably decrease immobility and reduce locomotor activity through different mechanisms.

Topics: Animals; Antidepressive Agents; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred Strains; Motor Activity; Piperidines; Serotonin Antagonists

The mechanism of anorectic action of several serotonin uptake inhibitors was investigated by comparing their anorectic potencies with several biochemical and pharmacological properties and in reference to the novel compound SL 81.0385. The anorectic effect of the potent serotonin uptake inhibitor SL 81.0385 (ED50 = 4 mg/kg, i.p.) was potentiated by pretreatment with 5-hydroxytryptophan and blocked by the serotonin receptor antagonist metergoline. A good correlation (r = 0.98, p less than 0.01) was obtained between the ED50 values of anorectic action and the ED50 values of serotonin uptake inhibition in vivo (but not in vitro) for several specific serotonin uptake inhibitors. Most of the drugs tested displaced [3H]-mazindol from its binding to the anorectic recognition site in the hypothalamus, except the pro-drug zimelidine which was inactive (IC50 greater than 100 microM). Excluding zimelidine, a good correlation (r = 0.835, p less than 0.01) was obtained between the affinities of these drugs for [3H]-mazindol binding and their anorectic action indicating that their anorectic activity may be associated with an effect mediated through this site. Taken together these results suggest that the anorectic action of serotonin uptake inhibitors is directly associated to their ability to inhibit serotonin uptake and thus increasing the synaptic levels of serotonin. The interactions of these drugs with the anorectic recognition site labelled with [3H]-mazindol is discussed in connection with the serotonergic regulation of carbohydrate intake.

Topics: Animals; Appetite Depressants; Eating; Fluoxetine; Indoles; Male; Mazindol; Norepinephrine; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists