Litoxetine: a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties

Angel, Itzchak; Prouteau, M.; Garreau, Mireille; Langer, S.Z.

doi:10.1016/0014-2999(93)90767-c

Cited by 36 publications

(16 citation statements)

References 32 publications

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“…The resulting affinity estimates of fluoxetine (range 0.1-1 JAM, pA2: 6.6), paroxetine (-log KB: 6.1) and litoxetine (pA2: 6.6) are consistent with low to moderate potency of these drugs, as observed at central and peripheral (vagus nerve) 5-HT3 recognition sites (Hoyer et al, 1989;Kilpatrick et al, 1989;Schmidt & Peroutka, 1990;Angel et al, 1993). In contrast, the antagonism exerted by clomipramine on the second phase of 5-HT curve was hardly dependent on concentration, thus preventing the evaluation of affinity estimates of this drug at enteric 5-HT3 receptors.…”

Section: Functional Studiesmentioning

confidence: 65%

“…Conversely, these concentrations shifted to the right, in an apparently concentration-dependent manner, the response caused by 5-MeOT (Figure 7c). 1990; Angel et al, 1993 …”

Section: -Ht4 Receptor Binding In Pig Corpus Striatummentioning

confidence: 99%

“…This study was designed to evaluate whether clomipramine (McTavish & Benfield, 1990), fluoxetine (Benfield et al, 1986), paroxetine (Dechant & Clissold, 1991) and litoxetine (Angel et al, 1993), which block 5-HT reuptake with a noradrenaline/5-HT uptake blocking ratio ranging from 20 to 320 (Benfield et al, 1986;Thomas et al, 1987;Scatton et al, 1988), interact with central and peripheral (enteric) and 5-HT4 receptors. In particular, binding of these drugs to central receptors was assessed by using two different models, the NG 108-15 neuroblastoma-glioma cells and the pig corpus striatum homogenate, which are suitable for studying and 5-HT4 receptors, respectively (Giraldo et al, 1992;Rizzi et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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The interaction of antidepressant drugs with central and peripheral (enteric) 5‐HT₃ and 5‐HT₄ receptors

Lucchelli

Santagostino-Barbone

Barbieri

et al. 1995

British J Pharmacology

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1 A combined study of receptor binding in central neuronal cell membranes and functional responses in isolated segments of guinea-pig small intestine allowed characterization of the interaction of four antidepressant drugs with central and peripheral 5-HT3 and 5-HT4 receptors. 3 In whole ileal segments, concentration-response curves to 5-HT were biphasic, with the high-and low-potency phases involving 5-HT4 and 5-HT3 receptors, respectively. Curves to 2-methyl-5-hydroxytryptamine (2-methyl-5-HT: a 5-HT3 receptor agonist) and 5-methoxytryptamine (5-MeOT: a 5-HT4 receptor agonist) were monophasic. All antidepressants were used at concentrations lacking anticholinoceptor properties, as demonstrated in both electrically stimulated longitudinal musclemyenteric plexus preparations (LMMPs) and in unstimulated LMMPs following addition of acetylcholine (100 nM). 4 Fluoxetine (0.1-1 JM) and litoxetine (0.3-3JM) antagonized both the high-and low-potency phases of the 5-HT curve. Schild analysis for the low-potency phase yielded pA2 estimates of 6.6 ± 0.3 (Schild slope of 1.1) and of 6.6 ± 0.1 (Schild slope of 1.1), respectively. At higher concentrations (3 JM), fluoxetine markedly inhibited the 5-HT response maximum. Clomipramine (10-300 nM) inhibited, by a mechanism independent of concentration, both phases of the 5-HT curve with a reduction of the maximum response. Paroxetine (1 JM) was ineffective on the high-potency phase, but caused a rightward shift of the low-potency phase (pKB: 6.1 ± 0.01).5 Responses to 2-methyl-5-HT were inhibited by 1 JAM fluoxetine (pKB: 5.4 ± 0.02). Like clomipramine (30 and 100 nM), litoxetine (1 and 3 JAM) produced rightward displacements of 2-methyl-5-HT-induced contractions, which were virtually independent of antidepressant concentration (pKB values: 6.0 ± 0.02 and 5.5 + 0.01, respectively). At higher concentrations, fluoxetine (3 JM) and clomipramine (300 nM) markedly reduced the 2-methyl-5-HT response maximum. Paroxetine (1 JAM) was ineffective.6 Responses to 5-MeOT were shifted to the right by fluoxetine (0.1-1 JAM) and litoxetine (1 and 3fJM) in a concentration-dependent manner. At higher concentrations, fluoxetine (3 JlM) markedly reduced the 5-MeOT response maximum, an effect also observed with 100 and 300 nM clomipramine. Paroxetine (1 JM) was ineffective.7 In unstimulated LMMPs, the excitatory effects evoked by 5-HT, 2-methyl-5-HT and 5-MeOT and the antagonism produced by 300 nM clomipramine were comparable to those obtained in whole ileal segments. This suggests that 5-HT contained in the mucosa of whole preparations does not interfere with agonist-induced contractile responses and with the inhibitory effect of antidepressant drugs.

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Section: Functional Studiesmentioning

confidence: 65%

“…Conversely, these concentrations shifted to the right, in an apparently concentration-dependent manner, the response caused by 5-MeOT (Figure 7c). 1990; Angel et al, 1993 …”

Section: -Ht4 Receptor Binding In Pig Corpus Striatummentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The interaction of antidepressant drugs with central and peripheral (enteric) 5‐HT₃ and 5‐HT₄ receptors

Lucchelli

Santagostino-Barbone

Barbieri

et al. 1995

British J Pharmacology

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“…Assessment criteria EEG recording and signalprocessing Four EEG leads (right fronto-temporal F4-T4, left fronto-temporal F3-T3, right temporo-occipital T4-02, left temporo-occipital T1-03 according to the international 10-20 system) were recorded for 5 min on day 1 (single dose) and on day 4 (repeated doses after six administrations) of each treatment period, before then 30 min, 1 h, 2 h, 3 h, 4 h, 6 h and 12 h post-dose.…”

Section: Study Populationmentioning

confidence: 99%

“…These characteristics suggest that litoxetine will exhibit none of the cardiovascular, sedative, anticholinergic and sympathomimetic effects which are often observed in humans with tricyclic antidepressants. The 5HT3-antagonist properties of litoxetine may prove useful to prevent nausea and vomiting, which are common after SSRI intake [4].…”

Section: Introductionmentioning

confidence: 99%

EEG profile of litoxetine after single and repeated administration in healthy volunteers.

Patat¹,

Trocherie²,

Thebault³

et al. 1994

Brit J Clinical Pharma

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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 doserelated 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-'. 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. Mean tmax ranged from 3 to 4 h and mean elimination half-life from 7 to 9 h independently of the dosage. Pharmacokinetic steady-state was achieved on day 4. Litoxetine did not accumulate with a twice daily regimen. 6 In conclusion, the EEG profile of litoxetine resembles those previously described with non-sedative antidepressants. Such EEG changes generally occur at therapeutic dosages.

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The Ferret in Nausea and Vomiting Research: Lessons in Translation of Basic Science to the Clinic

Sert¹,

Andrews²

2014

Biology and Diseases of the Ferret

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Litoxetine: a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties

Cited by 36 publications

References 32 publications

The interaction of antidepressant drugs with central and peripheral (enteric) 5‐HT₃ and 5‐HT₄ receptors

The interaction of antidepressant drugs with central and peripheral (enteric) 5‐HT₃ and 5‐HT₄ receptors

EEG profile of litoxetine after single and repeated administration in healthy volunteers.

The Ferret in Nausea and Vomiting Research: Lessons in Translation of Basic Science to the Clinic

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Litoxetine: a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties

Cited by 36 publications

References 32 publications

The interaction of antidepressant drugs with central and peripheral (enteric) 5‐HT3 and 5‐HT4 receptors

The interaction of antidepressant drugs with central and peripheral (enteric) 5‐HT3 and 5‐HT4 receptors

EEG profile of litoxetine after single and repeated administration in healthy volunteers.

The Ferret in Nausea and Vomiting Research: Lessons in Translation of Basic Science to the Clinic

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Product

Resources

About

The interaction of antidepressant drugs with central and peripheral (enteric) 5‐HT₃ and 5‐HT₄ receptors

The interaction of antidepressant drugs with central and peripheral (enteric) 5‐HT₃ and 5‐HT₄ receptors