Neurochemical and pharmacological studies on a new 5HT-uptake inhibitor, FG4963, with potential antidepressant properties

Lassen, J. Buus; Squires, Richard F.; Christensen, J. A.; Molander, Lars

doi:10.1007/bf00428820

Cited by 87 publications

(14 citation statements)

References 32 publications

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“…Both drugs caused a decrease in salivation, amitryptyline being more powerful (26% reduction) than femoxetine (8% reduction). Although the greater effect of amitriptyline than femoxetine in reducing salivation is consistent with the greater anticholinergic potency of amitryptyline, it may also reflect the greater potency of amitriptyline in blocking aadrenoceptors (Buus Lassen et al, 1975;U'Prichard et al, 1978). The results of the salivation test are in agreement with those obtained previously in volunteers (Clemmensen et al, 1984) and patients (Ghose et al, 1977).…”

Section: Autonomic Activitysupporting

confidence: 89%

“…In addition, hydroxytryptamine. In contrast to the tricyclic Correspondence: Dr B. K. Skrumsager, Ferrosan Research Division, DK-2860 Soeborg, Denmark antidepressants, femoxetine has only a weak inhibitory effect on noradrenaline uptake into peripheral organs, and has little or no central and peripheral anticholinergic action (Buus Lassen et al, 1975). The clinical efficacy of femoxetine is comparable with that of amitriptyline and desipramine (Dahl et al, 1982;Tamminen et al, 1982;Ahlberg et al, 1982) and it is believed to have little effect on the cardiovascular system (Nielsen, 1982).…”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular (ECG and systolic time intervals) and anticholinergic effects of repeated doses of femoxetine‐a comparison with amitriptyline and placebo in healthy men.

Warrington¹,

Turner²,

Skrumsager³

1989

Brit J Clinical Pharma

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Research Division, DK-2860 Soeborg, Copenhagen, Denmark 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.

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Section: Autonomic Activitysupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Cardiovascular (ECG and systolic time intervals) and anticholinergic effects of repeated doses of femoxetine‐a comparison with amitriptyline and placebo in healthy men.

Warrington¹,

Turner²,

Skrumsager³

1989

Brit J Clinical Pharma

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“…1), citalopram (Hyttel 1977), fluvoxamine (Claassen Offprint requests to : D.R. Thomas et al 1977), fluoxetine (Wong et al 1974), femoxetine (Buus Lassen et al 1975) and zimeldine (Ross et al 1976). …”

mentioning

confidence: 99%

Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytryptamine uptake inhibitor

1987

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Paroxetine was shown to be a potent (Ki = 1.1 nM) and specific inhibitor of [3H]-5-hydroxytryptamine (5-HT) uptake into rat cortical and hypothalamic synaptosomes in vitro. Lineweaver-Burk kinetic analysis determined that this inhibition was competitive in nature, implying a direct interaction with the 5-HT uptake transporter complex. Oral administration of paroxetine produced a dose-related inhibition of [3H]-5-HT uptake (ED50 = 1.9 mg/kg) into rat hypothalamic synaptosomes ex vivo with little effect on [3H]-l-noradrenaline (NA) uptake (ED50 greater than 30 mg/kg). This selectivity for 5-HT uptake was maintained after oral dosing for 14 days. Paroxetine (ED50 1-3 mg/kg PO) prevented the 5-HT depleting effect of p-chloroamphetamine (PCA) in rat brain, demonstrating 5-HT uptake blockade in vivo. Radioligand binding techniques in rat brain in vitro showed that paroxetine has little affinity for alpha 1, alpha 2 or beta adrenoceptors, dopamine (D2), 5-HT1, 5-HT2 or histamine (H1) receptors at concentrations below 1000 nM. Paroxetine demonstrated weak affinity for muscarinic receptors (Ki = 89 nM) but was at least 15 fold weaker than amitriptyline (Ki = 5.1 nM). Paroxetine, therefore, provides a useful pharmacological tool for investigating 5-HT systems and furthermore should be an antidepressant with reduced tricyclic-like side-effects.

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“…1304 luoxetine, a selective blocking agent inhibitory action of chlorpromazine on erotonin reuptake (20), and FG-4963, GABA reuptake (24). )tent but less selective blocking agent Lysergic acid diethylamide is a weak zrotonin reuptake (21), were adminis-serotonin agonist at postsynaptic sites in d for the same 14-day period. Unex-the forebrain (16,25).…”

mentioning

confidence: 99%

Tricyclic Antidepressants: Long-Term Treatment Increases Responsivity of Rat Forebrain Neurons to Serotonin

Montigny¹,

Aghajanian²

1978

Science

467

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Long-term treatment of rats with clinically effective tricyclic antidepressant drugs induced a selective increase in the inhibitory response of forebrain neurons to serotonin applied by microiontophoresis. Long-term administration of some related drugs which lack antidepressant efficacy failed to induce such a change. The enhanced response to serotonin induced by the clinically active tricyclic drugs took 1 to 2 weeks to develop, a time course which correlates with the delayed onset of therapeutic effects in humans.

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Neurochemical and pharmacological studies on a new 5HT-uptake inhibitor, FG4963, with potential antidepressant properties

Cited by 87 publications

References 32 publications

Cardiovascular (ECG and systolic time intervals) and anticholinergic effects of repeated doses of femoxetine‐a comparison with amitriptyline and placebo in healthy men.

Cardiovascular (ECG and systolic time intervals) and anticholinergic effects of repeated doses of femoxetine‐a comparison with amitriptyline and placebo in healthy men.

Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytryptamine uptake inhibitor

Tricyclic Antidepressants: Long-Term Treatment Increases Responsivity of Rat Forebrain Neurons to Serotonin

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