Escitalopram oxalate:Pharmacodynamics,Mechanism and clinical research

Introduction

Escitalopram oxalate (Figure 1) is the S-enantiomer of the selective serotonin (5-HT) re-uptake inhibitor (SSRI) citalopram, aracemic compound that has been used worldwide to treat ~40 million patients, and is known to be a safe, effective and well-tolerated antidepressant. Citalopram is a mixture of R- and S-enantiomers in equalproportions. Hyttel et al. observed that the desired pharmacological effect of citalopram to inhibit 5-HT re-uptake resides in the S-enantiomer. Escitalopram oxalate is more than twice as potent an inhibitor of 5-HT uptake in rat brain synaptosomes than citalopram. By comparison, in these experiments, the R-enantiomer of citalopram was 167 times less potent than escitalopram. Known chemically as (S)-(+)-1-[(3-dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate, escitalopram oxalate was developed jointly by the Danish pharmaceutical company H. Lundbeck A/S and Forest Laboratories, Inc., (US) for the treatment of depression and other psychiatric disorders.[1]

Pharmacodynamics

Escitalopram oxalate belongs to a class of medications called selective serotonin re-uptake inhibitors (SSRIs). These agents cause an increase in serotonin levels in neuronal synapses by preventing the re-uptake of serotonin (5-HT) into the presynaptic terminals of serotonergic neurons. As compared to other SSRIs, it appears to have a relatively quick onset of effect due to its potency. SSRIs as a class have been associated with abnormal bleeding, particularly in patients receiving concomitant therapy with other medications affecting hemostasis, and with the development of serotonin syndrome. Use escitalopram oxalate with caution in patients with a higher-than-baseline risk of bleeding and in patients receiving concomitant therapy with other serotonergic drugs. Escitalopram oxalate may also cause a discontinuation syndrome with abrupt removal of the drug, and should be slowly tapered if discontinuation of therapy is warranted.[2]

Mechanism of action

Escitalopram oxalate, like other selective serotonin re-uptake inhibitors, enhances serotonergic activity by binding to the orthosteric (i.e. primary) binding site on the serotonin transporter (SERT), the same site to which endogenous 5-HT binds, and thus prevents the re-uptake of serotonin into the presynaptic neuron. Escitalopram oxalate, along with paroxetine, is also considered an allosteric serotonin re-uptake inhibitor - it binds to a secondary allosteric site on the SERT molecule to more strongly inhibit 5-HT re-uptake. Its combination of orthosteric and allosteric activity on SERT allows for greater extracellular 5-HT levels, a faster onset of action, and greater efficacy as compared to other SSRIs. The sustained elevation of synaptic 5-HT eventually causes desensitization of 5-HT1A auto-receptors, which normally shut down endogenous 5-HT release in the presence of excess 5-HT - this desensitization may be necessary for the full clinical effect of SSRIs and may be responsible for their typically prolonged onset of action.17,13 Escitalopram  oxalate has shown little-to-no binding affinity at a number of other receptors, such as histamine and muscarinic receptors, and minor activity at these off-targets may explain some of its adverse effects.[3]

Escitalopram oxalate induces apoptosis in U-87MG cells and autophagy in GBM8401 cells

Glioblastoma multiforme (GBM) is recognized as a most aggressive brain cancer with the worst prognosis and survival time. Owing to the anatomic location of gliomas, surgically removing the tumour is very difficult and avoiding damage to vital brain regions during radiotherapy is impossible. Therefore, therapeutic strategies for malignant glioma must urgently be improved. Recent studies have demonstrated that selective serotonin reuptake inhibitors (SSRIs) have cytotoxic effect on certain cancers. Considering as a more superior SSRI, escitalopram oxalate exhibits favourable tolerability and causes generally mild and temporary adverse events. However, limited information is revealed about the influence of escitalopram oxalate on GBM. Therefore, an attempt was made herein to explore the effects of escitalopram oxalate on GBM. The experimental results revealed that escitalopram oxalate significantly inhibits the proliferation and invasive ability of U-87MG cells and significantly reduced the expressions of cell cycle inhibitors such as Skp2, P57, P21 and P27. Notably, escitalopram oxalate also induced significant apoptotic cascades in U-87MG cells and autophagy in GBM8401 cells. An animal study indicated that escitalopram oxalate inhibits the proliferation of xenografted glioblastoma in BALB/c nude mice. These findings implied that escitalopram oxalate may have potential in treatment of glioblastomas.[4]

The repurposing of escitalopram oxalate and clonazepam drugs individually

Bacterial resistance has become one of the most serious public health problems, globally, and drug repurposing is being investigated to speed up the identification of effective drugs. The aim of this study was to investigate the repurposing of escitalopram oxalate and clonazepam drugs individually, and in combination with the antibiotics ciprofloxacin and sulfamethoxazole-trimethoprim, to treat multidrug-resistant (MDR) microorganisms and to evaluate the potential chemical nuclease activity. The minimum inhibitory concentration, minimum bactericidal concentration, fractional inhibitory concentration index, and tolerance level were determined for each microorganism tested. In vitro antibacterial activity was evaluated against 47 multidrug-resistant clinical isolates and 11 standard bacterial strains from the American Type Culture Collection. Escitalopram oxalate was mainly active against Gram-positive bacteria, and clonazepam was active against both Gram-positive and Gram-negative bacteria. When associated with the two antibiotics mentioned, they had a significant synergistic effect. Clonazepam cleaved plasmid DNA, and the mechanisms involved were oxidative and hydrolytic. These results indicate the potential for repurposing these non-antibiotic drugs to treat bacterial infections. However, further studies on the mechanism of action of these drugs should be performed to ensure their safe use.[5]

Summary

Preclinical studies demonstrate that the therapeutic activity of citalopram resides in the S-isomer and that escitalopram binds with high affinity to the human serotonin transporter. Conversely, R-citalopram is approximately 30-fold less potent than escitalopram at this transporter. Escitalopram oxalate has linear pharmacokinetics, so that plasma levels increase proportionately and predictably with increased doses and its half-life of 27-32h is consistent with once-daily dosing. In addition, escitalopram oxalate has negligible effects on cytochrome P450 drug-metabolising enzymes in vitro, suggesting a low potential for drug-drug interactions. The efficacy of escitalopram in patients with major depressive disorder has been demonstrated in multiple short-term, placebo-controlled clinical trials, three of which included citalopram as an active control, as well as in a 36-week study evaluating efficacy in the prevention of depression relapse. In these studies, escitalopram was shown to have robust efficacy in the treatment of depression and associated symptoms of anxiety relative to placebo. Efficacy has also been shown in treating generalised anxiety disorder, panic disorder and social anxiety disorder. Results also suggest that, at comparable doses, escitalopram oxalate demonstrates clinically relevant and statistically significant superiority to placebo treatment earlier than citalopram. Analysis of the safety database shows a low rate of discontinuation due to adverse events, and there was no statistically significant difference between escitalopram 10 mg/day and placebo in the proportion of patients who discontinued treatment early because of adverse events. The most common adverse events associated with escitalopram oxalate which occurred at a rate greater than placebo include nausea, insomnia, ejaculation disorder, diarrhoea, dry mouth and somnolence. Only nausea occurred in >10% of escitalopram-treated patients.[1]

References

[1] Burke WJ. Escitalopram. Expert Opin Investig Drugs. 2002;11(10):1477-1486. doi:10.1517/13543784.11.10.1477

[2] Sanchez C: The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of S-citalopram. Basic Clin Pharmacol Toxicol. 2006 Aug;99(2):91-5. doi: 10.1111/j.1742-7843.2006.pto_295.x.

[3] Sanchez C, Reines EH, Montgomery SA: A comparative review of escitalopram, paroxetine, and sertraline: Are they all alike? Int Clin Psychopharmacol. 2014 Jul;29(4):185-96. doi: 10.1097/YIC.0000000000000023.

[4] Chen VC, Hsieh YH, Chen LJ, Hsu TC, Tzang BS. Escitalopram oxalate induces apoptosis in U-87MG cells and autophagy in GBM8401 cells. J Cell Mol Med. 2018;22(2):1167-1178. doi:10.1111/jcmm.13372

[5] Rosa TFD, Machado CS, Serafin MB, et al. Repurposing of escitalopram oxalate and clonazepam in combination with ciprofloxacin and sulfamethoxazole-trimethoprim for treatment of multidrug-resistant microorganisms and evaluation of the cleavage capacity of plasmid DNA. Can J Microbiol. 2021;67(8):599-612. doi:10.1139/cjm-2020-0546

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