Citalopram enantiomers

FIGURE B.3. The chemical structure of citalopram (Celexa), showing its two enantiomers. The S-citalopram enantiomer is escitalopram (Lexapro) (see text). Illustration copyright 2005 by Keren Albala. Used with permission. 

The resolution between the citalopram enantiomers always exceeded 4.0 and was therefore excluded from further considerations. The resolution between oxalate and (R)-citalopram exceeded 2 except for runs with low concentrations of sulfated P-cyclodextrin. Thus, essentially, only the... 

As peak resolution between the citalopram enantiomers and between oxalate and (i )-citalopram was not really an issue in this assay, only migration time of the last migrating compound and current were minimized by the software used in setting the respective values to maxima of 10 min and 80 pA,... 

Foglia, J.P. Pollock, B.G. Kirshner, M.A. Rosen, J. Sweet, R. Mulsant, B. Plasma levels of citalopram enantiomers and metabolites in elderly patients. Psychopharmacol. Bull. 1997, 33, 109-112. 

Since the introduction of the first approved SSRI, fluoxetine (1) in 1987 [9], a number of SSRIs have been developed for the treatment of depression [2], Currently, the five most commonly prescribed SSRIs are fluoxetine, escitalopram (2, S-enantiomer of citalopram), sertraline (3), paroxetine (4) and fluvoxamine (5). Recent effort in the clinical development of new SSRIs has focused on the treatment of premature ejaculation (PE) by taking advantage of the ejaculation-delaying side effects of SSRIs [10]. Although SSRIs have been prescribed off-label to treat this condition, an SSRI with rapid onset of action and rapid clearance could be preferred for on-demand treatment of PE [11,12]. Dapoxetine (LY210448, 6), an... 

Both enantiomers and the racemate of l-(3,4-dichlorophenyl)-3-azabicyclo [3.1.0]hexane, 27a-c, have been reported to be in development. The racemate, DOV 216,303, inhibits the reuptake of NE, 5-HT and DA with IC50 values of 20, 14 and 78 nM, respectively [85]. DOV 216,303 is active in tests predictive of antidepressant activity, including the mouse FST (minimum effective dose = lOmg/kg), reversal of tetrabenazine-induced ptosis and locomotor depression. DOV 216,303 was also reported to be well tolerated in phase I clinical trials [85,86], In a phase II study designed to explore safety and tolerability in depressed individuals, patients received either DOV 216,303 (50 mg, b.i.d.) or citalopram (20 mg, b.i.d.) for two weeks [85]. It was found that the side effect profile was not remarkably different between the two treatment groups. In addition, time-dependent reductions in Hamilton Depression Scores (HAM-D) were similar for both groups. 

Citalopram (Ceiexa), Esdtalopram (Lexapro). Escitalopram is the enantiomer S-citalopram. Citalopram is a 50 50 mixtnre of s- and r-citalopram of which the former is the active component. Both are very selective SSRIs. The side effects of citalopram and escitalopram appear to be comparable to other SSRIs. 

The relative benefits of the enantiomers of antidepressants vary greatly. For example, when the therapeutic properties of the enantiomers are complementary (for example, mianserin) then use of the racemate is an advantage. However, if there are qualitative, but not quantitative, similarities then it would be beneficial to develop the active isomer. This has recently occurred with the development of citalopram. 

The S-enantiomer of citalopram (escitalopram) is over 100 times more potent in inhibiting the reuptake of 5-HT into brain slices than the R-form and is devoid of any activity at the neurotransmitter of other receptor types (racemic citalopram has an affinity for histamine receptors and causes sedation). In in vivo studies, escitalopram is more potent than the R-form or the racemate in releasing 5-HT in the cortex of conscious rats it has been... 

In addition to the five SSRIs currently available, many more compounds are in development which will no doubt be marketed in the near future. Of the new arrivals, escitalopram, the S-enantiomer of citalopram, has already become available in many European countries. A brief discussion of the properties of this drug has been presented on p. 98. 

One example is the enzymatic resolution of 4-[(4-dimethylamino)-l-(4 -fluoro-phenyl)-l-hydroxy-l-butyl]-3-(hydroxymethyl)benzonitrile-a useful intermediate for the synthesis of optically pure citalopram (an efficient human antidepressant), ft has been demonstrated that almost the entire inhibition activity resides in the (S)-(-i-)-enantiomer [27]. Its synthesis has been investigated using several lipases... 

These drugs increase synaptic serotonin by selectively blocking the serotonin reuptake transporter. In preclinical and human studies acute doses tend to be anxiogenic (Bell and Nutt 1998) but chronic administration has anxiolytic effects, possibly due to downregulation of presynaptic autoreceptors (Blier et al. 1990). There are five SSRIs widely available citalopram, fluoxetine, fluvoxam-ine, paroxetine and sertraline. Escitalopram, the S-enantiomer of citalopram. 

Fluoxetine is a secondary amine, which is demethy-lated to norfluoxetine. Norfluoxetine is clinically active. Both compounds have S- and R- enantiomers (Wong et ah, 1990, 1993). Unlike citalopram, S- and R-fluoxetine and S-norfluoxetine are active forms. R-fluoxetine is much less potent than the other two compounds. In addition, it appears that R-fluoxetine and R-norfluoxetine are metabolized more rapidly than the S-enantiomers (Torok-Both et ah, 1992). 

Rochat, B., Amey, M., and Baumann, P. (1995a) Analysis of enantiomers of citalopram and its demethylated metabolites in plasma of depressive patients using chiral reverse-phase liquid chromatography. Ther Drug Monit 17 273-279. 

Serotonin norepinephrine reuptake inhibitor (SNRI). -Enantiomer of citalopram. 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

Although several SSRIs other than the five listed in Table 6—6 have been synthesized, with the exception of the active enantiomers of currently marketed SSRIs such as fluoxetine and citalopram, it is unlikely any new SSRI will be developed as an antidepressant, as many other novel mechanisms are now available for clinical... 

An example of improved efficacy of an enantiomerically pure version of a drug over the racemic version is provided by citalopram. The racemic version, known as Celexa, is marketed as an antidepressant. Studies on the resolved enantiomers have shown that the S-enantiomer is the active one and that it has a more rapid onset of action and a more favorable benefit-to-risk ratio than the racemate. As a result, (S)-citalo-pram (escitalopram or Lexapro) is now being marketed. Not only is this a better and safer drug, but the pharmaceutical company that developed citalopram was able to extend its markel exclusivity for an additional 3 years. 

Citalopram is a racemic bicyclic phthalane derivative and is a highly selective serotonin re-uptake inhibitor with minimal effects on noradrenaline and dopamine neuronal reuptake. Inhibition of 5-HT re-uptake by citalopram is primarily due to escitalopram, the active S-enantiomer of citalopram (1). One would expect escitalopram to be twice as potent as citalopram but otherwise not to differ significantly from the racemic mixture. However, escitalopram is marketed as being more efficacious than citalopram because, it is argued, the inactive R-isomer present in the racemate actually inhibits binding of the S-enantiomer to its site of action, the serotonin transporter. In some, but not all, clinical trials escitalopram has been statistically superior to citalopram in terms of speed of onset of therapeutic action and improvement on depression rating scales. The clinical significance of these differences is debatable (2). 

Single-enantiomer technology— which earned its developers the Nobel Prize in Chemistry in 2000—enables the production of commercial quantities of medications that contain only the desired enantiomer, the other having been removed in the production process. Such is the case, for example, in the antidepressant escitalopram (trade name Lexapro) (see Figure B.3). This drug is the successor of citalopram (trade... 

Citalopram s inactive R enantiomer may interfere with the therapeutic actions of the active S enantiomer at serotonin reuptake pumps... 

Citalopram is a racemic bicyclic phthalane derivative and is a highly selective serotonin re-nptake inhibitor with minimal effects on noradrenahne and dopamine nenronal renptake. Inhibition of 5-HT re-nptake by citalopram is primarily dne to the S-enantiomer (escitalopram). Its most freqnent adverse events (nansea, somnolence, dry month, increased sweating) are mainly transient and mostly mild to moderate (1). 

Escitalopram oxalate is the 5-enantiomer of citalopram (5). The therapeutic activity of citalopram resides in the 5-isomer and escitalopram binds with high affinity to the human serotonin transporter R-citalopram is about 30-fold less potent. The half-life of escitalopram is 27-32 hours. Citalopram and escitalopram have negligible effects on CYP isozymes. 

Plasma level for fluoxetine represents total fluoxetine plus norfluoxetine given the comparable effect of each on 5-HT uptake pump. Plasma levels are a total of both enantiomers for citalopram and fluoxetine. 

I Recent evidence that escitalopram may be more effective, or have an earlier onset of action, than citalopram and have equal efficacy to venlafaxine. This is attributed to escitalopram binding to both the re-uptake site and an allosteric site causing conformational change in the 5-HT transporter and enhancing re-uptake blockade. R-enantiomer blocks this effect. This is not seen with other SSRIs. These are mostly company data so claims need independent verification. 

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