piperidines and femoxetine

Narcolepsy is a disorder of the central nervous system, the main symptoms of which are excessive daytime sleepiness (EDS) and cataplexy (an abrupt and reversible decrease in or loss of muscle tone, affecting the limbs and/or trunk, elicited by emotional stimuli). Narcolepsy has an adverse impact on people's quality of life. Together with stimulant drugs (used to control EDS), antidepressants are usually recommended to counteract cataplexy. In addition, some antidepressants are also reported to improve EDS.. To evaluate the effects of antidepressant drugs on EDS, cataplexy, quality of life, and their side effects in people with narcolepsy.. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to 2003), EMBASE (1980 to 2003), PsycINFO (1872 to 2003), and CINAHL (1981 to 2003). Bibliographies of identified articles were reviewed to find additional references. Unpublished randomised trials were searched for by consulting governmental and non-governmental clinical trial registers, disease-specific websites, investigators and experts in the field, pharmaceutical companies/manufacturers.. Parallel or cross-over randomised or quasi-randomised controlled trials testing the treatment of narcolepsy with any type of antidepressant drug versus no treatment, placebo, or another antidepressant drug.. Two reviewers independently selected trials for inclusion and extracted data. Outcomes were: (a) elimination of EDS; (b) mean reduction of EDS; (c) elimination of cataplexy; (d) 50% or greater reduction in cataplexy frequency; (e) mean reduction of cataplexy; (f) mean improvement in quality of life; (g) adverse events; (h) withdrawal from treatment.. Two cross-over trials were included. The methodological quality of both studies was unclear and so the influence of common biases was impossible to define. As the trials tested two different comparisons (one femoxetine versus placebo, the other fluvoxamine versus clomipramine) meta-analysis was not performed. In the first trial (10 participants) femoxetine had no significant effect in eliminating or reducing EDS; a significant reduction of cataplexy was in favour of femoxetine. Mild and transient side effects were reported in the femoxetine treatment period by two participants. In the second trial the authors inappropriately treated the trial design as a parallel study and no conclusions can be reached in favour of either drug.. There was no good quality evidence that antidepressants are effective for narcolepsy or improve quality of life. Despite the clinical consensus recommending antidepressants for cataplexy there is scarce evidence that antidepressants have a positive effect on this symptom. There is a clear need for well-designed randomised controlled trials to assess the effect of antidepressants on narcolepsy.

Topics: Antidepressive Agents; Cataplexy; Clomipramine; Fluvoxamine; Humans; Narcolepsy; Piperidines; Randomized Controlled Trials as Topic

1. The cardiovascular and anticholinergic effects of femoxetine and amitriptyline were compared with those of placebo in a double-blind cross-over trial in 12 healthy men. The daily doses administered were therapeutic: 600 mg femoxetine and 150 mg amitriptyline. Duration of treatment with each drug was 13 days. 2. The statistically significant effects on systolic time intervals and ECG comprised a larger decrease of QS2 index during femoxetine than during amitriptyline, and an increase of PEP/LVET ratio and QRS duration by amitriptyline. These results suggest that femoxetine and, to a lesser extent, amitriptyline increase contractility compared with placebo, and amitriptyline, but not femoxetine, causes delay in intracardiac conduction. 3. The effects of amitriptyline on the systolic time intervals are difficult to interpret because of the changes in heart rate and intracardiac electrical conduction caused by the drug. These problems of interpretation are discussed. 4. No significant changes in blood pressure were observed. The heart rate during both femoxetine and amitriptyline periods was significantly faster than during the placebo period, amitriptyline causing a significantly greater increase. 5. Salivary secretion was decreased more by amitriptyline (26%) than by femoxetine (8%), the latter being not significantly different from placebo. Femoxetine tended to increase pupil diameter and amitriptyline to increase accommodation near point, but no visual disturbances were reported on any treatment. Symptoms such as dry mouth, constipation and sedation were significantly less frequently reported during femoxetine than during amitriptyline treatment.

Topics: Administration, Oral; Adult; Amitriptyline; Double-Blind Method; Electrocardiography; Heart Rate; Humans; Male; Myocardial Contraction; Parasympathetic Nervous System; Piperidines; Serotonin; Systole

Fifty-two patients with depressive illness characterized by four symptoms (periodical course, psychomotor retardation, diurnal variation, unrealistic self-depreciation) and a score of at least 18 on the Hamilton Depression Scale 1-17 (HDS) were allocated to a double-blind randomized study with femoxetine and imipramine. Patients were diagnosed according to RDC and further classified according to the Newcastle-II index. During the six weeks of treatment, efficacy was evaluated by means of HDS and a global evaluation. Side-effect symptoms were recorded on a check-list by questioning. After six weeks of treatment with femoxetine or imipramine (recommended daily standard dosages are 600 mg femoxetine and 150 mg imipramine (b.i.d.); in the present study, dosages were flexible and could be adjusted according to effect/side-effects) evaluation of efficacy based on HDS, a six-item subscale, groups of HDS items as well as single items showed no statistically significant differences between the treatment groups except with regard to the factor for sleep disturbances in the HDS, where greatest reduction was seen in the femoxetine group. No statistically significant differences regarding side-effect profile were seen. However, in the imipramine group, higher frequencies of such moderate to severe symptoms as dry mouth, constipation and urination difficulties were observed (the greatest difference was seen for dry mouth, p 0.1, while p-values for the remaining two symptoms were greater than 0.1). Moreover, based on the patients' own opinion on side-effects, femoxetine seemed to be better tolerated. One patient took an overdosage of approx. 26 g femoxetine; half of the intake was removed by gastric emptying at the hospital.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Half-Life; Humans; Imipramine; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Random Allocation; Time Factors

A study was carried out in general practice to compare the effectiveness of femoxetine, a selective serotonin reuptake inhibitor, with the effect of placebo in helper patients more than 20 per cent above their ideal weight to lose weight. Patients were allocated at random to receive either 600 mg femoxetine (36 patients) or placebo (37 patients) daily over a period of 16 weeks. They were also asked to restrict their calorie intake to 1200-1600 kcal. (5.0-6.7 MJ)/day. The results showed that there was no statistically significant greater weight loss in patients treated with femoxetine (median = 8.3 kg) than with placebo (median = 6.2 kg) after 16 weeks. In subgroups of patients with obesity problems for more than 20 years and of patients previously in anorectic treatment, femoxetine tended towards causing a larger weight loss. Side-effects were generally minor in nature, and the incidence and nature of them were almost comparable in the two groups except for gastro-intestinal symptoms, which were reported more often in the femoxetine group. As femoxetine in several randomized group comparative studies in depressive illness has been shown to have an antidepressant efficacy which is comparable with the efficacy amitriptyline and imipramine, femoxetine may be particularly useful in the management of obese patients requiring antidepressant treatment.

Topics: Adolescent; Adult; Aged; Appetite; Body Weight; Clinical Trials as Topic; Diet, Reducing; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Obesity; Piperidines; Random Allocation

In a randomized general practice study, the prophylactice effect of femoxetive (a 5HT uptake inhibitor) was compared with placebo in migraine patients. Treatment, with separate randomization schedules in each practice, was allocated to 65 patients. Each patient was treated for 16 weeks with 200 mg increasing during the first nine days to 600 mg daily. No effect of femoxetine could be demonstrated in attack frequency and headache index. Separate analysis of maximum reduction in serotonin concentration during treatment revealed no difference in efficacy when compared with placebo. This supports earlier studies that femoxetine generally exerts no prophylactic effect on migraine, and the hypothesis that platelet 5HT might be of major importance in the pathogenesis of migraine is not supported.

Topics: Adolescent; Adult; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines

A randomized, double-blind cross-over trial was carried out in 10 patients with narcolepsy to evaluate the effect of 600 mg femoxetine versus placebo. In comparison to placebo, femoxetine treatment resulted in a significant decrease in both the number and severity score of cataplectic attacks per day. There were also significantly fewer attacks of sleep paralysis, whilst the effects on nightmare and hypnogenic hallucinations were minor. The frequency of sleep attacks decreased slightly during femoxetine treatment, but the overall estimated sleep time during the day and excessive daytime sleepiness remained un-affected. An ambulatory sleep recording for 48 h one week after the start of the femoxetine and placebo period showed that femoxetine treatment resulted in a significant decrease in the total time spent in REM sleep. The side-effects of femoxetine were restricted to transient nausea in 2 patients. It is concluded that femoxetine or other selective serotonin reuptake inhibitors may be a useful alternative for narcoleptic patients who experience troublesome side-effects with tricyclic antidepressants.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Narcolepsy; Nausea; Piperidines; Sleep Stages

Patients with a depressive illness with 4 major symptoms of depression and a score of at least 17 on the Hamilton Depression Scale (1-17) (HDS) were allocated to a randomized double-blind group comparative study in general practice. After retrospective analysis, all 81 patients except one were characterized as suffering from a 'Definite Major Depressive Disorder', as defined by Spitzer et al. (1978). After 6 weeks of treatment with a daily dosage of 600 mg femoxetine or 150 mg amitriptyline, no statistically significant differences between the 2 treatment groups were observed, either when using the HDS or the clinical global assessment scale. Confidence limits of 95% for differences between therapeutic effect showed a non-significant tendency in favour of amitriptyline. During treatment, there were statistically significant differences in the reduction of HDS score between the 2 treatments in week 2. These differences were the result of amitriptyline's significantly greater effect on the 3 sleep items at week 2, as indicated by the results of single item analysis. Drop out rates due to side effects were between 14-15% in both treatment groups. Of the patients treated with femoxetine, 38% experienced no side effects, compared to 14% of patients treated with amitriptyline. Nausea was the side effect most commonly reported by patients treated with femoxetine, whereas a significantly greater frequency of anticholinergic side effects was recorded during treatment with amitriptyline (P less than 0.05). Unlike amitriptyline, femoxetine did not increase body weight. Treatment with the active drug was continued after the trial period in 14 and 18 patients in the femoxetine and amitriptyline groups respectively.

Topics: Adolescent; Adult; Aged; Amitriptyline; Antidepressive Agents; Body Weight; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Random Allocation; Serotonin

The effects on human psychomotor performance of femoxetine (FEMO), a 5-hydroxytryptamine-selective antidepressant, alone and in combination with alcohol (EtOH) were compared with those of amitriptyline (AMI) and placebo in a controlled double-blind crossover trial in 11 student volunteers. Objective measurements (body sway, choice reaction, flicker fusion, tracking, nystagmus, digit symbol substitution, backwards recall) and subjective self-assessment (visual analogue scales, reporting of side-effects) were done after single doses of FEMO, AMI and placebo, and subacute administration of FEMO and placebo. Single doses of 200 mg FEMO did not impair psychomotor performance, but 50 mg AMI did so in several respects. AMI but not FEMO increased the objective and subjective effects of EtOH. After FEMO 600 mg/d for 10 days almost no objective difference from placebo was noted, although mild sedation at home was reported as a side-effect. FEMO either did not increase or slightly decreased the effect of EtOH on reactive and co-ordination skills. The plasma concentrations of FEMO varied widely from 0 to 156 ng/ml, as in previous clinical trials but reduced a blood 5-hydroxytryptamine concentration in each subject indicating an effect of FEMO on serotoninergic mechanisms.

Topics: Adult; Amitriptyline; Antidepressive Agents; Automobile Driving; Double-Blind Method; Drug Interactions; Ethanol; Female; Humans; Kinetics; Male; Piperidines; Psychomotor Performance; Serotonin

The amplitude of visual evoked potentials (VEPs) for flickering light has been reported to be increased in migraine. In the present study, we have examined whether the VEPs are attenuated when the clinical state of the patient improves during a double-blind experiment with propranolol and femoxetine. VEPs for sinusoidally-modulated light were measured by spectral analysis, and an index depicting the visual reaction type was calculated. The group mean VEP index closely followed the group mean attack frequency, but individual variance was considerable. The changes were most evident in VEPs elicited by stimuli of about 20 Hz. During the treatments, the VEP and headache were also significantly correlated among subjects. The results suggest a close relationship between the enlarged VEPs and the headache mechanisms.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Evoked Potentials, Visual; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Propranolol; Visual Pathways

The antidepressant and biochemical effects of femoxetine, a selective serotonin uptake inhibitor, and desipramine, a selective nor-adrenaline uptake inhibitor, have been compared in a double-blind study in 42 outpatients with depressive illness. The patients were allocated at random to treatment with either 600 mg femoxetine or 150 mg desipramine daily for 6 weeks. The total depression score showed a significant decrease in both groups, indicating an overall improvement in depressive symptoms. The patients treated with femoxetine reported significantly less severe anticholinergic effects during the whole treatment period than the desipramine patients. Both drugs, decreased the level of 5-HIAA in CSF, whereas no consistent changes were found in the MHPG and HVA levels. The pretreatment level of the metabolites had no predictive value for the outcome of the treatment with either drug. No significant correlation was found between therapeutic effect and the plasma concentration of the active compounds.

Topics: Adult; Aged; Antidepressive Agents; Depressive Disorder; Desipramine; Double-Blind Method; Female; Glycols; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Phenylacetates; Piperidines

The new selective serotonin (5-HT)-uptake inhibitor femoxetine was compared with amitriptyline in a double-blind clinical trial comprising 77 depressed patients. The depressive symptoms were evaluated with the Hamilton rating scale, and a global clinical evaluation. Both drugs showed an antidepressive effect and no significant differences were found. Femoxetine induced a significantly lower frequency of dry mouth and blurred vision; this difference is presumably due to the weak anticholinergic effect of this substance. A small but significant weight loss was observed in the femoxetine group but not in the amitriptyline group.

Topics: Amitriptyline; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales

Topics: Adult; Appetite Depressants; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Obesity; Piperidines; Pregnancy; Pregnancy Complications

The prophylactic effect in migraine of femoxetine, a 5-HT-uptake inhibitor, was compared to that of placebo in a double-blind group-comparative study. A total of 59 patients, referred to the department from general practitioners, was stratified according to age, sex, duration, and frequency of attacks and then allocated at random to treatment with either femoxetine or placebo. Each patient was treated for 12 weeks with 200 mg in the first week and 300 in the remaining weeks. Ten patients on femoxetine and four patients on placebo failed to complete the study. Headache index as well as number and severity of attacks showed a significant reduction with time. The patients on femoxetine showed the greatest improvement over time. It was, however, not statistically significant. Direct comparison between femoxetine and placebo revealed no statistically significant difference. Three patients in the femoxetine group withdrew due to side-effects combined with lack of therapeutic effect. Other side-effects were slight and infrequent. They did not interfere with the treatment. These results indicate that femoxetine could be useful in migraine as a prophylactic drug.

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Placebos; Random Allocation; Serotonin; Serotonin Antagonists

The prophylactic effect of the 5-HT uptake inhibitor femoxetine was compared with propranolol (Frekven R) in a double-blind crossover trial of 6 months duration. Forty-nine patients commenced the trial. Twelve patients withdrew because of drug failure or failure to attend checkups (6), side effects (4) or other non-drug related causes (2). In the 37 patients who completed the trial there was no significant difference between propranolol 160 mg and femoxetine 400 mg with respect to the number of headache days or the number of migraine attacks during the last 2 months of each treatment, Propranolol, however, was superior to femoxetine when the headache index was used (P less than 0.05). The study has shown that partial depletion of thrombocyte 5-HT by a 5-HT uptake inhibitor does not lead to a marked improvement in all patients contrary to what might be expected from the 5-HT hypothesis of migraine. Nevertheless, due to the infrequent subjective side effects associated with femoxetine treatment it may be a valuable prophylactic drug to a subgroup of migraine patients.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Propranolol; Serotonin Antagonists

In this study the chemical modification of paroxetine was employed to determine which structural differences between the paroxetine-like and femoxetine-like selective serotonin reuptake inhibitors is responsible for the differential potency of these agents in the inhibition of Staphylococcus aureus multidrug efflux pump systems.

Topics: Bacterial Proteins; Biological Transport, Active; Drug Resistance, Multiple, Bacterial; Paroxetine; Piperidines; Staphylococcus aureus; Structure-Activity Relationship

Structural variants of phenylpiperidine selective serotonin reuptake inhibitors (P-SSRIs) inhibited the function of two unique Staphylococcus aureus multidrug efflux pumps. The most active compound was the paroxetine isomer NNC 20-7052, which had an IC(50) for ethidium, acriflavine, and pyronin Y efflux of 9, 53, and 18% of its MIC, respectively, against the NorA pump. The unbalanced effect of NNC 20-7052 on the efflux of different substrates suggests the possibility that P-SSRIs function by a physical interaction with NorA. Under the conditions employed pump inhibition partially extended to the resistance-nodulation-division (RND) pump AcrAB-TolC, but not to the Pseudomonas aeruginosa RND pumps MexAB-OprM or MexCD-OprJ.

Topics: Biological Transport, Active; Drug Resistance, Multiple, Bacterial; Hydrogen-Ion Concentration; Membrane Potentials; Paroxetine; Piperidines; Selective Serotonin Reuptake Inhibitors; Staphylococcus aureus

The solution structures of (3R,4S)- and (3S,4R)- 4-(4-fluorophenyl)-3-hydroxylmethyl- 1-methylpiperidine, which are intermediates in the synthesis of the two pharmaceuticals paroxetine and femoxetine, were studied by vibrational circular dichroism (VCD) spectroscopy. In addition, six derivatives with different substituents attached to the C3 atom were prepared and their VCD and absorption spectra discussed with the aid of ab initio simulations. The VCD spectra were found to be sensitive to the geometry changes. In addition, a subtle variation caused by intermolecular aggregation was apparent in the spectra. The VCD technique can be applied for structural analysis of chiral pharmaceuticals in solutions.

Topics: Circular Dichroism; Models, Chemical; Paroxetine; Piperidines; Selective Serotonin Reuptake Inhibitors

Two-fold crystallization of trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine enriched in (+)-enantiomer 3b (65.2-79.4% ee) yielded the racemate that crystallized out of solution and the mother liquor highly enriched in 3b (95.4-97.6% ee). Differences in infrared spectra of the racemate and enantiomer proved that the racemate consists of a racemic compound. Furthermore, solution NMR spectra of enriched 3b showed differentiation of some resonances (self-induced non-equivalence), which indicated strong diastereomeric interactions between solutes in apolar solvent. The enantiomeric composition of products was determined by NMR spectroscopy in the presence of R-Mosher acid.

Topics: Crystallization; Humans; Magnetic Resonance Spectroscopy; Paroxetine; Piperidines; Selective Serotonin Reuptake Inhibitors; Stereoisomerism

A series of neuroleptic agents and their structural isomers have been tested as inhibitors of HIV-replication. At non-toxic concentrations, cis (Z)- and trans (E)-flupentixol and several derivatives of the 5HT-uptake-inhibitors paroxetine and femoxetine, inhibit HIV-1 replication. The findings indicated that these compounds could be used in combination with other anti-retroviral therapy in HIV-1 infected patients with AIDS-related dementia.

Topics: Antibodies, Monoclonal; Antidepressive Agents; Antipsychotic Agents; Cell Line; Flupenthixol; gag Gene Products, Human Immunodeficiency Virus; Gene Products, gag; HIV Antigens; HIV Core Protein p24; HIV-1; Humans; Immunohistochemistry; Paroxetine; Piperidines; Viral Proteins; Virus Replication

The inhibitory potencies of selective serotonin (5-hydroxytryptamine, 5-HT) uptake inhibitors on isolation-induced aggressive behaviour in male mice were studied. Furthermore, the role of postsynaptic 5-HT1A receptors in the mediation of aggressive behaviour was studied. The selective 5-HT uptake inhibitors, sertraline, floxetine, femoxetine and fluvoxamine, showed weak antiaggressive effects, and citalopram and paroxetine were ineffective. This rank of potencies corresponded with neither uptake inhibitory potencies in vitro nor potentiation of 1-5-hydroxytryptophan (1,5-HTP)-induced motor effects in vivo, as citalopram and paroxetine were among the most potent compounds in these tests. A subeffective dose of 1,5-HTP (110 mumol/kg = 25 mg/kg, s.c.) potentiated the antiaggressive effect of citalopram and paroxetine more than 110 and 1600 times, respectively. The effects of sertraline, fluvoxamine, fluoxetine and femoxetine were only potentiated 3, 36, 4 and 16 times, respectively. The 5-HT releasing compound fenfluramine inhibited the aggressive behaviour dose dependently, and depletion of 5-HT by treatment with p-chloro-phenylalanine methyl ester attenuated this effect significantly. p-Chloro-phenylalanine methyl ester was ineffective itself, but potentiated the antiaggressive effect of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamin)tetralin (8-OH-DPAT). The beta-adrenoceptor/5-HT1A receptor antagonist, (-)-penbutolol, reversed the antiaggressive effects of 8-OHDPAT. In conclusion, selective 5-HT uptake inhibitors act in different ways on isolation-induced aggressive behaviour, and postsynaptic 5-HT1A receptors are involved in mediating the aggressive behaviour.

Topics: 1-Naphthylamine; 5-Hydroxytryptophan; 8-Hydroxy-2-(di-n-propylamino)tetralin; Aggression; Analysis of Variance; Animals; Behavior, Animal; Brain; Citalopram; Dose-Response Relationship, Drug; Fenclonine; Fluoxetine; Fluvoxamine; Male; Mice; Paroxetine; Penbutolol; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Selective Serotonin Reuptake Inhibitors; Sertraline; Synaptosomes

In rats allowed access to a 35% sucrose solution, following a 4-h period of food and water deprivation, an initial period of sucrose consumption was followed by a short period of grooming and exploratory behaviour, later superseded by resting. This "behavioural satiety sequence" was advanced in time by the 5-HT uptake inhibitors femoxetine and paroxetine and by the 5-HT1A/B agonist eltoprazine at anorectic and subanorectic doses. These effects, which are similar to those previously observed with another 5-HT uptake inhibitor, fluoxetine, are compatible with an increase in postprandial satiety.

Topics: Animals; Behavior, Animal; Male; Paroxetine; Piperazines; Piperidines; Rats; Receptors, Serotonin; Satiety Response; Serotonin Antagonists

Tricyclic antidepressants, when administered acutely, are known to potentiate morphine-induced antinociception. Systemic administration of morphine has been shown to increase the metabolism of serotonin (5-HT) at the level of the nucleus raphe magnus, as measured by in vivo electrochemistry, in freely-moving rats. Using a similar electrochemical detection of 5-hydroxyindole (peak "3") in the nucleus raphe magnus, the present study investigated the effect of the specific 5-HT uptake inhibitor, femoxetine, on peak 3 and on changes in the metabolism of 5-HT, induced by morphine. Acutely administered femoxetine (40 mg/kg i.p.) induced a significant decrease in peak 3 and completely abolished the effect of morphine (10 mg/kg i.p.) on the metabolism of 5-HT. These data do not support the contention that potentiation of morphine-induced analgesia, by tricyclic depressants results from an interaction between the tricyclic antidepressants and the morphine-induced increase in metabolism of 5-HT, at the level of the nucleus raphe magnus.

Topics: Animals; Electrochemistry; Hydroxyindoleacetic Acid; In Vitro Techniques; Male; Morphine; Oxidation-Reduction; Piperidines; Raphe Nuclei; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists

Acute administration of tricyclic antidepressants (TCAs) is known to potentiate morphine antinociception. At the medullary dorsal horn (MDH) level systemic morphine has been shown to increase serotonin (5-HT) metabolism as measured by in vivo electrochemistry in freely moving rats. Using similar electrochemical detection of 5-hydroxyindole (peak '3') within the MDH, the present study investigated the effect of the specific 5-HT uptake inhibitor femoxetine on peak 3 and the effects of this TCA on changes in 5-HT metabolism induced by morphine. Acutely administered femoxetine (40 mg/kg i.p.) (i) induced a small but significant increase in peak 3 and (ii) strongly potentiated the effect of morphine (10 mg/kg i.p.) on 5-HT metabolism, this potentiation being opiate specific since simultaneous injection of naloxone (1 mg/kg i.p.) abolished the effect of morphine. These findings provide an in vivo neurochemical basis for the potentiation of morphine antinociception by TCAs. They further emphasize the importance of 5-HT bulbospinal descending pathways in morphine antinociception.

Topics: Animals; Antidepressive Agents, Tricyclic; Biological Transport; Drug Synergism; Electrochemistry; Electrophysiology; Male; Medulla Oblongata; Morphine; Motor Activity; Naloxone; Piperidines; Rats; Rats, Inbred Strains; Reference Values; Serotonin; Serotonin Antagonists

The substrates were incubated at various concentrations for 30 minutes with rat liver microsomes. FG 4962 was metabolized more rapidly than femoxetine, i.e. approximately 20% more FG 4962 was degraded during 30 min incubation at saturating substrate concentration. Femoxetine was metabolized predominantly by O- and N-demethylation, almost equally, whereas FG 4962 was metabolized mainly by N-demethylation. Chiralphase HPLC studies revealed that incubation of the racemate with rat liver microsomes resulted in the impairment of the N-demethylating metabolic route for femoxetine, while the metabolism of FG 4962 was not impaired. Induction of the rat livers with sodium phenobarbital gave almost the same qualitative results but with increased rates of metabolism.

Topics: Animals; Female; In Vitro Techniques; Microsomes, Liver; Piperidines; Rats; Rats, Inbred Strains; Stereoisomerism

Structure-activity relationships for 25 structural variants around the 5-hydroxytryptamine (5-HT) uptake inhibitors paroxetine and femoxetine have been investigated. Three parameters related to the 5-HT system were investigated: (i) The inhibition of [3H]5-HT uptake into rat brain synaptosomes, (ii) the inhibition of [3H]paroxetine binding to rat neuronal membranes and (iii) the effect of the compounds on the affinity of [3H]imipramine for the human platelet membrane binding site, measured as the dissociation rate of the [3H]imipramine human platelet membrane binding site complex. A highly significant correlation was found for 5-HT uptake inhibition and inhibition of [3H]paroxetine binding for the different substances, indicating that the two parameters are closely connected. However the slope of the regression line was only 0.6 and not 1.0; this may indicate that [3H]paroxetine binding is necessary, but not sufficient for 5-HT uptake inhibition. No correlation was found between the inhibition of [3H]paroxetine binding and the affinity of the compounds for the [3H]imipramine binding site complex. The two binding sites are therefore probably situated on different parts of the 5-HT transport system, the [3H]paroxetine binding site being part of the 5-HT transport mechanism whereas the [3H]imipramine binding site may represent a site modulating the activity of, and affinity for, 5-HT in the 5-HT transport mechanism. Structure-activity relationships among the substances showed that stereochemical changes from (-)- to (+)-trans changed the activity towards both 5-HT uptake inhibition and [3H]paroxetine displacement for most of the (-)-/(+)-pairs. The substitution of -H with -F or -CH3 also affected the activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Platelets; Humans; Imipramine; In Vitro Techniques; Neurons; Paroxetine; Piperidines; Rats; Serotonin; Structure-Activity Relationship; Synaptosomes

The ability of desipramine and maprotiline (NA uptake inhibitors), as well as citalopram and femoxetine (5-HT uptake inhibitors) to protect mice against brain NA depletion induced by H 77/77 (4-alpha-dimethyl-m-tyramine), has been compared with their ability to counteract reserpine (2.5 mg kg-1)- or apomorphine (16 mg kg-1)-induced hypothermia and to potentiate TRH (40 mg kg-1)-induced hyperthermia in mice. While both NA uptake inhibitors antagonized the action of H 77/77, maprotiline being weaker than desipramine, femoxetine and citalopram were inactive. However, in contrast to citalopram, femoxetine was active in the other tests, being about twice as weak as maprotiline, which itself was several times weaker than desipramine in those tests. On the basis of the results obtained it is concluded that functional in-vivo tests for NA uptake inhibitors are more sensitive than the H 77/77 biochemical test; moreover, femoxetine, which in-vitro studies is less selective than citalopram, may inhibit the uptake of NA in-vivo.

Topics: Animals; Apomorphine; Body Temperature; Brain; Citalopram; Desipramine; Male; Maprotiline; Mice; Monoamine Oxidase Inhibitors; Norepinephrine; Piperidines; Propylamines; Reserpine; Serotonin Antagonists; Thyrotropin-Releasing Hormone; Tyramine

A 51-year old woman treated with femoxetine--a new serotonin reuptake inhibitor with antidepressive effect--developed toxic hepatitis during the treatment. In spite of that, the elimination half-life of femoxetine in plasma was within normal limits.

Topics: Antidepressive Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Middle Aged; Piperidines; Serotonin Antagonists

The present investigation has been undertaken to illustrate the antibacterial effect on 20 diarrhoea producing enterobacteriaceae of an anti-depressive drug available as femoxetine and its three analogs. It has been shown that the stereo-isomeric trans forms of femoxetine are more than twice as active as the cis forms and inhibited all the strains below 400 microgram/ml (1.2 mM). The two cis compounds only inhibited 11 and 9 of the 20 strains respectively in the investigated area 100 microgram/ml - 800 microgram/ml (0.3 mM - 2.4 mM). Our investigations point out that the bacterial cell has a target for psychopharmacologically active agents. Thus the known psychopharmaca and their stereo-isomeric analogs may represent a pool of potentially new antimicrobial drugs. Furthermore the bacterial model may be useful as a model system in the study of the interaction of neuropharmacological agents and other membrane active compounds with biological membranes.

Topics: Anti-Bacterial Agents; Diarrhea; Enterobacteriaceae; Humans; Piperidines; Stereoisomerism; Structure-Activity Relationship

The possibility of a pharmacokinetic interaction between femoxetine and cimetidine has been evaluated in 8 healthy volunteers. Two volunteers received single doses of femoxetine, and 6 were given multiple doses of femoxetine for 7 days with and without concurrent cimetidine. No influence of cimetidine was observed on the kinetics of single doses of femoxetine, but after multiple doses the plasma concentration of femoxetine was significantly increased. Similarly, the AUC at steady state tended to be increased, but not to a significant extent. Concurrent cimetidine did not cause a reduction in the AUC of the active desmethyl metabolite. It is recommended that femoxetine is given in reduced doses (e.g. 400 mg) when administered with cimetidine.

Topics: Adult; Antidepressive Agents; Cimetidine; Drug Interactions; Female; Humans; Kinetics; Male; Piperidines

A pilot study of the possible anticholinergic side effects of femoxetine comprised eight depressive patients (age 42-65), followed up for a month, and five healthy volunteers (age 26-39), who received medication for a week. As judged primarily from ophthalmic parameters (accomodation, lacrimation, pupil size, intraocular pressure, exe motility, visual acuity and visual fields, slit lamp examination and ophthalmoscopy), there was no indication of anticholinergic side effects of the drug. According to Schirmer-1-test (tear wetting), the rather dry eyes of depressive patients even improved somewhat during medication.

Topics: Adult; Aged; Antidepressive Agents; Eye Diseases; Female; Glaucoma; Humans; Male; Middle Aged; Piperidines; Tears; Vision Disorders; Xerophthalmia

5-HT uptake inhibitors and pirenperone (a 5-HT2 receptor antagonist), which in previous experiments antagonized fenfluramine (5-HT releaser)-induced hyperthermia in heat adapted rats, were tested against hyperthermia induced by the directly acting 5-HT agonist--m-CPP and quipazine. Pirenperone and --to a lesser degree--amitriptyline and femoxetine antagonized the hyperthermia. Citalopram and clomipramine were inactive. It is concluded that hyperthermia induced by 5-HT-like drugs in rats is due to the stimulation of the 5-HT2 receptor and that the antagonistic effect of citalopram and clomipramine against fenfluramine-induced hyperthermia might be connected with their effect on the uptake of 5-HT.

Topics: Adaptation, Physiological; Amitriptyline; Animals; Body Temperature; Citalopram; Clomipramine; Dose-Response Relationship, Drug; Hot Temperature; Male; Piperazines; Piperidines; Propylamines; Quipazine; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists

The pharmacokinetics of femoxetine (a 5-HT uptake inhibitor with antidepressive effect) was studied in 12 patients with liver cirrhosis and in 6 healthy controls after a single oral dose of femoxetine HC1. The average blood concentration of femoxetine, as assessed by the values of AUC (area under the plasma concentration/time curve), was significantly higher in the patients with liver cirrhosis than in the healthy controls in spite of dose reduction in the patients. The elimination half-life of femoxetine was within the normal limits in most of the patients. The oral clearance of femoxetine was considerably lower in patients, (0.65-4.02 1/hr/kg) than in the controls (8.13- greater than 50 1/hr/kg). It was not directly related to the metabolic function of the liver, measured as the galactose elimination capacity being 0.015-0.024 mmol/min./kg and 0.033-0.041 mmol/min./kg, respectively. When treating patients with reduced liver function, it is recommended to reduce the doses and to monitor closely the plasma levels.

Topics: Adult; Aged; Antidepressive Agents; Female; Galactose; Humans; Kinetics; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged; Piperidines

Twelve healthy volunteers were given oral single doses of a reference drug (nortriptyline), test drugs, and placebo on a randomised single-blind basis at weekly intervals. The doses corresponded to average daily patient medication. Spontaneous whole mouth salivation was measured before (at 10 p.m.) and 10 hours after drug administration (at 8 a.m.). Drug plasma levels were determined after 4 and 10 hours. When analysing the salivations 10 hours after drug administration adjusted for the effects of the pre-treatment salivations, statistically significant inhibition of salivation was found after nortriptyline (56%), femoxetine (34%), and mianserin (29%) when compared with placebo, while for citalopram and cis- and trans-flupenthixol no significant inhibition of salivation was demonstrated (Fig. 1, Table 5). From the estimated log linear regression coefficients, relating adjusted salivation rates and drug plasma levels 10 hours after drug administration (Table 6), and reported average steady-state plasma drug levels (Table 7), semiquantitative predictions of the average level of anticholinergic activity during long-term treatment may be made: For femoxetine and mianserin, moderate anticholinergic activity, less pronounced than with nortriptyline, are predicted, while for citalopram no such activity can be predicted (Table 7).

Topics: Adolescent; Adult; Antidepressive Agents; Citalopram; Dibenzazepines; Female; Flupenthixol; Humans; Male; Mianserin; Nortriptyline; Piperidines; Propylamines; Random Allocation; Salivation; Serotonin Antagonists

The prophylactic effect of a 5-HT uptake inhibitor, femoxetine, was compared with that of propranolol in a double-blind crossover study of 6-months duration. 29 patients commenced the experiment. 3 subjects withdrew because of side effects and 2 because the program was inconvenient for them. In the 24 patients who continued the study to the end, the periods of propranolol (administered 160 mg daily) and of femoxetine (given 400 mg daily) differed significantly from each other with respect to the attack frequency and headache index. A significant reduction in the use of medication relieving attacks was observed during the propranolol treatment as compared with the pre-treatment period. The study showed that partial depletion of thrombocyte 5-HT uptake inhibitor did not lead to a marked improvement in headache, contrary to what might be expected on the grounds of the 5-HT hypothesis of migraine.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Propranolol; Serotonin Antagonists; Time Factors

Topics: Animals; Drug Interactions; Female; Male; Morphine; Pain; Piperidines; Rats; Serotonin

The availability of trans-(+)-3-[(4-methoxy-phenoxy)methyl]-1-methyl-4-phenylpiperidine (femoxetine, HCl; 500 mg) from an enteric coated tablet and from a water solution, respectively, have been compared in a single dose, cross-over study using six healthy volunteers. The tablet gave a longer lag time and a slower absorption rate than the solution. The mean availability of the tablet was 71% (range 12-150%), relative to the availability of the solution in five of the subjects. During a multiple dose study, where the same six volunteers took 400-600 mg (as tablets) per day for a week, no change in the kinetic parameters was observed and no discrepancy between the parameters obtained in the single dose study and the ones from the multiple dose study was seen within each subject. A high first pass effect is presumed to be the main reason for the relatively great inter-individual variations. The formation and elimination rate of an active metabolite, norfemoxetine, were very similar in three of the four subjects for whom the rates could be calculated.

Topics: Adult; Biological Availability; Female; Humans; Intestinal Absorption; Kinetics; Male; Middle Aged; Piperidines; Serotonin; Tablets, Enteric-Coated; Time Factors

Hepatic elimination of femoxetine was studied in seven anaesthetized 40 kg pigs by means of constant rate infusions of 3-41 mg/min. (8.6-118 mumol/min.) into the portal vein. The elimination followed saturation kinetics (Michaëlis-Menten constants: Vmax 12 mg . min.-1 . kg-1 liver; Km 1.3 mg . 1-1 blood) and was characterised by high hepatic extraction, due to metabolism. The hepatic output of the active metabolite, nor-femoxetine, was very low, indicating that other metabolic pathways than demethylation were more important in the pig. The high hepatic elimination in the pig corresponds to the high first pass effect, earlier found in man, and it depends upon the infusion rate as well as the total dose.

Topics: Animals; Bile; Biotransformation; Female; Kinetics; Liver; Male; Piperidines; Swine

Hepatic elimination of femoxetine was studied in six anaesthetized pigs during intravenous administration. Femoxetine was given into a jugular vein as a constant infusion of 0.4-7.2 mg/min. in five pigs and as a bolus injection of 383 mg in one pig. The hepatic extraction was high (92-98%) corresponding to earlier findings of 91-99% when femoxetine was infused into the portal vein in pig or given orally to man. The urinary excretion was low, less than 5% of the dose, and the estimated extrahepatic metabolism was not significantly different from zero.

Topics: Animals; Antidepressive Agents; Female; Infusions, Parenteral; Liver; Piperidines; Swine

Sixteen patients with a headache resembling the so-called "tension headache" and a clear response to doxepin (demonstrated in a previous work) were given femoxetine, 400 mg p.d., and placebo in a cross-over, double-blind fashion. Only single blindness was kept in the last third of the study. Placebo and femoxetine tablets were each given for four weeks. Whereas there was a daily or practically daily occurring headache untreated, placebo was associated with a headache frequency of 92%. The corresponding figures for doxepin and femoxetine were 27% and 41%, respectively. Femoxetine led to transitory nausea and gastrointestinal discomfort, but in contrast to doxepin, no weight gain and only slight, if any, sedation. Most patients preferred femoxetine to doxepin. Femoxetine, an antidepressant phenylpiperidine derivative with predominant serotonin re-uptake inhibition (little effect on noradrenaline), thus seems to counteract so-called "tension headache".

Topics: Adolescent; Adult; Double-Blind Method; Doxepin; Female; Headache; Humans; Male; Middle Aged; Piperidines; Serotonin; Serotonin Antagonists; Stress, Psychological

Topics: Adult; Antidepressive Agents; Asthma; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperidines; Serotonin Antagonists

Reports have indicated that patients with migraine have abnormalities in platelet function and in the metabolism of vasoactive monoamines. On the basis of these findings, a number of compounds with a stabilizing effect on the level of free vasoactive monoamines in plasma or with anti-platelet effects have been evaluated with regard to their prophylactic effect in migraine. Femoxetine, a new phenylpiperidine derivative and a potent selective serotonin uptake inhibitor, has been suggested as a useful prophylactic drug in migraine. The present studies were designed to evaluate platelet function and blood serotonin levels in patients with migraine before and during femoxetine treatment. During the treatment of 11 patients with migraine with 300 mg femoxetine daily, blood serotonin decreased from 0.17 +/- 0.06 microgram/ml (mean +/- SD) to 0.06 +/- 0.02 microgram/ml. In 8 patients treated with 300 mg femoxetine daily for 12 weeks, 14C-serotonin uptake into platelets in vitro was reduced significantly. Unlike most drugs used in migraine prophylaxis, femoxetine did not influence platelet aggregation in vitro. The demonstration of a certain prophylactic effect of femoxetine in some patients lends support to theories of a serotonin involvement in the pathogenesis of migraine. It does not, however, exclude the possibility of a platelet abnormality as the primary cause of migraine. A hypothesis combining the 2 theories is put forward.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Female; Humans; Middle Aged; Migraine Disorders; Piperidines; Platelet Function Tests; Serotonin

1 The behavioural responses of drugs known to act through central 5-hydroxytryptamine (5-HT) mechanisms have been investigated in rats receiving a neuroleptic (trifluoperazine) in their drinking water for 4 to 6 months.2 5-Hydroxytryptophan (5-HTP) induced 5-HT-dependent behaviours including head bobbing and lateral head weaving, reciprocal forepaw treading, tremor, backward walking, body writhing and ;wet-dog' shakes. In doses of 50 to 150 mg/kg, 5-HTP induced more intense behavioural effects in neuroleptic-treated rats than in the control animals.3 Similarly the putative 5-HT agonist, quipazine (1 to 20 mg/kg) and the 5-HT releasing drug, fenfluramine (5 to 20 mg/kg), both induced significantly greater motor responses in the chronically neuroleptic-treated rats.4 A 5-HT uptake inhibitor (femoxetine, 2.5 to 10 mg/kg) had little behavioural effect in either control or trifluoperazine-treated rats.5 Total specific high-affinity binding of radiolabelled 5-HT was significantly increased in crude membrane fractions prepared from the cortex, striatum and substantia nigra of neuroleptic-treated rats compared to control animals.6 High-affinity uptake of radiolabelled 5-HT into striatal slices was similar in experimental and control animals.7 Behavioural and biochemical data would indicate that postsynaptic 5-HT mechanisms are enhanced in rats treated chronically with trifluoperazine. Chronic neuroleptic therapy may thereby induce cerebral 5-HT receptor supersensitivity in addition to the well-documented cerebral dopamine receptor supersensitivity.

Topics: Animals; Anisoles; Antipsychotic Agents; Behavior, Animal; Brain; Female; Fenfluramine; Piperidines; Quipazine; Rats; Receptors, Dopamine; Receptors, Serotonin; Serotonin

Topics: Adult; Humans; Middle Aged; Obesity; Piperidines; Serotonin; Serotonin Antagonists

The metabolism of femoxetine, a serotonin uptake inhibitor, has been investigated in rats, dogs, monkeys, and human subjects using two 14C-femoxetine compounds with labelling in different positions. The metabolic pathways were oxidation (and glucuronidation) and demethylation, both reactions most probably taking place in the liver. Nearly all femoxetine was metabolised, and the same metabolites were found in urine from all four species. Only a small percentage of the radioactivity excreted in the urine was not identified. Rat and dog excreted more N-oxide than monkey and man, while most of the radioactivity (60-100%) in these two species was excreted as two hydroxy metabolites. The metabolic pattern in monkey and man was very similar. About 50% was excreted in these two species as one metabolite, formed by demethylation of a methoxy group. A demethylation of a N-CH3 group formed an active metabolite, norfemoxetine. The excretion of this metabolite in urine from man varied from 0 to 18% of the dose between individuals. Most of the radioactivity was excreted with the faeces in rat and dog, while monkey and man excreted most of the radioactivity in urine. This difference in excretion route might be explained by the difference in the metabolite pattern. No dose dependency was observed in any of the three animal species investigated.

Topics: Animals; Dogs; Female; Humans; Macaca mulatta; Male; Piperidines; Rats; Rats, Inbred Strains; Serotonin Antagonists; Species Specificity

Topics: Animals; Anisoles; Brain; Clomipramine; Diet; Dioxolanes; Female; Male; Motor Activity; p-Chloroamphetamine; Paroxetine; Piperidines; Rats; Serotonin; Serotonin Antagonists

Topics: Animals; Anisoles; Anti-Inflammatory Agents, Non-Steroidal; Drug Evaluation, Preclinical; Phenylbutazone; Piperidines; Rats

Topics: Animals; Anisoles; Blood Pressure; Desipramine; Dioxolanes; Guanethidine; Heart Rate; Hypertension; Piperidines; Rats; Serotonin Antagonists; Time Factors

Femoxetine, a phenylpiperidine derivative with potent serotonin (5-HT)-uptake inhibitory properties, was investigated in 12 depressive patients for its clinical effect as well as its effect on 5-HT concentration in whole blood. The global evaluation after 6 weeks showed a good effect in six patients. The 5-HT concentration was found to be reduced from a mean value of 0.21 to about 0.05 micrograms/ml, indicating a total depletion of 5-HT from the thrombocytes. The steady-state concentrations of femoxetine resulted in reduction of 5-HT to the same level in all patients. No correlation between degree of 5-HT reduction and therapeutic effect was found.

Topics: Anisoles; Depression; Depression, Chemical; Female; Humans; Piperidines; Psychiatric Status Rating Scales; Serotonin; Serotonin Antagonists; Time Factors

A single treatment with 5-HT uptake inhibitors potentiates the hypermotility in mice produced by the MAO-inhibitor nialamide. The effect of nialamide on motility was studied in mice after 4 weeks of feeding with a normal diet and diets containing various concentrations of the 5-HT uptake inhibitors chlorimipramine and femoxetine. Chronic treatment with the two substances enhanced the motor effects of nialamide about equally, which indicates a preservation of the neuronal 5-HT uptake inhibition during such treatment. The effect of chlorimipramine and femoxetine was obtained at plasma levels equivalent to or lower than the steady-state plasma concentrations found in patients treated with two 5-HT uptake inhibitors. Determination of decreased blood 5-HT after the 4 weeks of treatment was used as an in vivo test for inhibition of 5-HT uptake into platelets. Femoxetine was a much weaker depletor of blood 5-HT than chlorimipramine. These results indicate that blockade of neuronal 5-HT uptake is obtained at lower doses of femoxetine than blockade of 5-HT uptake into platelets. In contrast, chlorimipramine presumably inhibits 5-HT uptake into neurons and platelets at about the same dose.

Topics: Animals; Anisoles; Blood Platelets; Clomipramine; Desipramine; Female; Mice; Neurons; Nialamide; Piperidines; Serotonin; Serotonin Antagonists; Time Factors

A procedure has been developed for the gas chromatographic determination of a structurally new 5HT-uptake inhibitor with antidepressant properties (FG 4963) in plasma and urine. The method involves an extraction from alkaline solution with n-pentane, and a quantitative determination by gas chromatography using an internal standard and a nitrogen-sensitive detector. The binding of FG 4963 to glass during storage and evaporation necessitates the addition of a structurally similar compound to the vials used for collection of the blood and urine, in order to compete for the binding sites of the glass. The method is suitable for pharmacokinetic and clinical studies, the sensitivity being ca. 5 ng/ml in plasma and 1 ng/ml in urine and the precision being 10-15% for concentrations greater than 10 ng/ml.

Topics: Adsorption; Anisoles; Antidepressive Agents; Chromatography, Gas; Glass; Methods; Piperidines; Solvents

Topics: Animals; Anisoles; Clomipramine; Dibenzazepines; Dose-Response Relationship, Drug; Drug Synergism; Female; Fenclonine; Lithium; Mice; Mice, Inbred Strains; Motor Activity; Nialamide; Piperidines; Serotonin; Stimulation, Chemical; Time Factors; Tryptophan