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Re: Citalopram vs escitalopram ed_uk

Posted by ed_uk on August 15, 2005, at 7:49:03

In reply to Re: Citalopram vs escitalopram, posted by ed_uk on August 15, 2005, at 6:27:53

Hmmm, more info (kindly) provided by the manufacturer......... (independent info would be better!).........

Br J Pharmacol. 2004 May;142(1):172-80. Epub 2004

R-citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter.

Storustovu S, Sanchez C, Porzgen P, Brennum LT, Larsen AK, Pulis M, Ebert B.

Department of Electrophysiology, H. Lundbeck A/S, 9 Ottiliavej, Valby DK-2500, Denmark.

1. Clinical observations with the selective serotonin reuptake inhibitor (SSRI), S-citalopram, indicate that S-citalopram is more efficacious and produces earlier symptom relief than RS-citalopram. Since R-citalopram is at least 20-fold weaker than S-citalopram as inhibitor of the 5-HT transporter (SERT) in preclinical studies, the clinical data suggest an unexpected antagonistic interaction between the two enantiomers. We therefore characterised the interaction of R- and S-citalopram with the SERT in in vivo and in vitro assays. 2. In both behavioural (potentiation of 5-hydroxytryptophan (5-HTP)-induced behaviour) and electrophysiological studies (inhibition of 5-HT-elicited ion currents in Xenopus oocytes expressing the human SERT (hSERT) R-citalopram inhibited the effects of S-citalopram in a dose-dependent manner. With S-citalopram : R-citalopram ratios of 1 : 2 and 1 : 4, 5-HTP potentiation was significantly smaller than with S-citalopram alone. 3. R-citalopram did not antagonise the effects of another SSRI (fluoxetine) in either behavioural or electrophysiological studies. 4. In oocytes, inhibition of hSERT-mediated currents by R-citalopram was almost completely reversible and characterised by fast on- and off-sets of action. In contrast, the off-set for S-citalopram was 35-fold slower than for R-citalopram. 5. Kinetic analysis of the oocyte experiments suggests that S-citalopram binding to SERT induces a long-lasting, inhibited state of the transporter and that coapplication of R-citalopram partially relieves SERT of this persistent inhibition. 6. We propose that the kinetic interaction of R- and S-citalopram with SERT is a critical factor contributing to the antagonistic effects of R-citalopram on S-citalopram in vitro and in vivo.

Pharmacol Biochem Behav. 2004 Feb;77(2):391-8.

R-citalopram inhibits functional and 5-HTP-evoked behavioural responses to the SSRI, escitalopram.

Sanchez C, Kreilgaard M.

Neuropharmacological Research, H. Lundbeck, Ottiliavej 9, DK 2500 -Valby, Copenhagen, Denmark.

Escitalopram mediates the serotonin re-uptake inhibitory and antidepressant effect of citalopram racemate. However, recent studies have shown that R-citalopram inhibits the escitalopram-induced increase of extracellular 5-HT levels in the frontal cortex of rats. Here, we investigated the inhibitory effect of R-citalopram on the escitalopram-induced increase of 5-HT neurotransmission at the behavioural [potentiation of 5-hydroxytryptophan (5-HTP)-induced behavioural changes in mice and rats] and functional (increase in serum corticosterone in rats) levels. The effect of escitalopram was inhibited by R-citalopram in all three models, and R-citalopram, given alone, was inactive. The effects were more pronounced using an escitalopram to R-citalopram ratio of 1:4 than ratios of 1:2 and 1:1, suggesting a dose-dependent effect. The ED(50)-value of escitalopram in mouse 5-HTP potentiation studies corresponded to a serum concentration of approximately 50 ng/ml, which can be considered to be in the range of clinically relevant serum concentrations.In conclusion, R-citalopram inhibited the escitalopram-induced increase of 5-HT activity in functional, as well as behavioural, animal models. The mechanism involved in this interaction is currently unknown, but may be related to an improved clinical effect seen with escitalopram in comparison with citalopram.

Behav Pharmacol. 2003 Sep;14(5-6):465-70.

R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model.

Sanchez C, Gruca P, Papp M.

Neuropharmacological Research, H. Lundbeck A/S, Copenhagen-Valby, Denmark.

The selective serotonin (5-HT) reuptake inhibitor, citalopram, is a racemic mixture of the stereoisomers, S-(+)-citalopram (escitalopram) and R-(-)-citalopram (R-citalopram). R-citalopram has been shown to counteract the 5-HT enhancing properties of escitalopram in acute studies in animals. In the present study we report, for the first time, on an interaction between R-citalopram and escitalopram after repeated dosing in a rat chronic mild stress (CMS) model of depression. The effect of escitalopram (2.0, 3.9 and 7.8 mg/kg per day), R-citalopram (7.8 mg/kg per day) and escitalopram 3.9 mg/kg per day plus R-citalopram 7.8 mg/kg per day were studied and compared to the effect of citalopram (8.0 mg/kg per day), imipramine and R-fluoxetine (8.9 mg/kg per day). Significant effects relative to a vehicle-treated group were achieved from week 1 for escitalopram (3.9 and 7.8 mg/kg per day), from week 2 for citalopram (8.0 mg/kg per day), from week 3 for R-fluoxetine (8.9 mg/kg per day) and from week 4 for escitalopram (2.0 mg/kg per day) and imipramine (8.9 mg/kg per day). R-citalopram (7.8 mg/kg per day) and escitalopram (3.9 mg/kg per day) plus R-citalopram (7.8 mg/kg per day) did not differ significantly from vehicle. There were no drug-induced effects in non-stressed control groups. In conclusion, escitalopram showed a shorter time to response in the rat CMS model of depression than citalopram, which was faster acting than R-fluoxetine and imipramine. R-citalopram counteracted the effect of escitalopram. The mechanism of action of R-citalopram is, at the moment unclear, but may be relevant to the improved clinical antidepressant activity seen with escitalopram in comparison with citalopram, and may also indicate an earlier response to escitalopram compared to other selective serotonin reuptake inhibitors (SSRIs).

Pharmacol Biochem Behav. 2003 Jul;75(4):903-7.

R-citalopram counteracts the effect of escitalopram in a rat conditioned fear stress model of anxiety.

Sanchez C, Gruca P, Bien E, Papp M.

Neuropharmacological Research, H. Lundbeck A/S, Copenhagen-Valby, Denmark.

S-citalopram (escitalopram) mediates the serotonin reuptake inhibitory effect of the racemate, R,S-citalopram. The effect of escitalopram (0.5-3.9 mg/kg) was investigated in a rat conditioned fear stress model of anxiety and compared to the effects of R-citalopram (1.0-7.8 mg/kg), R,S-citalopram (4.0 and 8.0 mg/kg), and escitalopram (2.0 mg/kg)+R-citalopram (7.8 mg/kg). Diazepam (0.95 mg/kg) and buspirone (4.6 mg/kg) were included as positive controls. During an acquisition session, rats were allowed to freely explore a novel cage for 9 min. During that time, they received two inescapable footshocks through an electrifiable grid floor. Groups of nonshocked control rats were run in parallel. During an expression session on the next day, rats were treated with drug or vehicle 30 min before they were reintroduced into the test cage for a 9-min period this time without receiving footshocks and the total distance travelled was recorded. The distance travelled by vehicle-treated rats was markedly suppressed compared to a vehicle-treated group of nonshocked controls. Escitalopram produced a dose-dependent inhibition of the conditioned suppression of exploratory behaviour (minimal effective dose 1.0 mg/kg). Interestingly R,S-citalopram 4.0 and 8.0 mg/kg produced significantly smaller effect than escitalopram 2.0 and 4.0 mg/kg, receptively. R-citalopram, 7.8 mg/kg, produced a significant effect. However, in spite of this, R-citalopram (7.8 mg/kg) significantly inhibited the effect of escitalopram (2.0 mg/kg). The activity in drug-treated nonshocked groups was similar to the vehicle-treated group, except for the buspirone-treated group where a significant reduction was observed. The finding that R-citalopram inhibits the effect of escitalopram may be relevant to the improved clinical efficacy seen with escitalopram compared to R,S-citalopram in the treatment of anxiety and depression.




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