Rapid liquid chromatography/tandem mass spectrometer (LCMS) method for clozapine and its metabolite N‐desmethyl Clozapine (Norclozapine) in human serum

Rao, Lokinendi V.; Snyder, Marion L.; Vallaro, Guy M.

doi:10.1002/jcla.20345

Cited by 16 publications

(4 citation statements)

References 38 publications

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“…Because, leucocytes are activated in EAE, it is possible that immune cells are responsible for an increase in α-1-acid glycoprotein, which binds and retains clozapine in the blood. Peak serum levels of clozapine are reached 1-6 h after oral dosing and the half-life is about 4 to 16 h in healthy adults 42 , and our findings suggest this half-life may be extended during a neuroinflammatory response. MALDI IMS was used for the first time to analyse the distribution of unlabelled clozapine within the brain tissue from healthy and EAE mice.…”

Section: Discussionmentioning

confidence: 49%

Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

Robichon

Sondhauss

Jordan

et al. 2021

Sci Rep

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Multiple sclerosis is a disease characterised by axonal demyelination in the central nervous system (CNS). The atypical antipsychotic drug clozapine attenuates experimental autoimmune encephalomyelitis (EAE), a mouse model used to study multiple sclerosis, but the precise mechanism is unknown and could include both peripheral and CNS–mediated effects. To better understand where clozapine exerts its protective effects, we investigated the tissue distribution and localisation of clozapine using matrix-assisted laser desorption ionization imaging mass spectrometry and liquid chromatography-mass spectrometry. We found that clozapine was detectable in the brain and enriched in specific brain regions (cortex, thalamus and olfactory bulb), but the distribution was not altered by EAE. Furthermore, although not altered in other organs, clozapine levels were significantly elevated in serum during EAE. Because clozapine antagonises dopamine receptors, we analysed dopamine levels in serum and brain as well as dopamine receptor expression on brain-resident and infiltrating immune cells. While neither clozapine nor EAE significantly affected dopamine levels, we observed a significant downregulation of dopamine receptors 1 and 5 and up-regulation of dopamine receptor 2 on microglia and CD4+-infiltrating T cells during EAE. Together these findings provide insight into how neuroinflammation, as modelled by EAE, alters the distribution and downstream effects of clozapine.

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Section: Discussionmentioning

confidence: 49%

Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

Robichon

Sondhauss

Jordan

et al. 2021

Sci Rep

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“…Rapid detection of clozapine and norclozapine by liquid chromatography/tandem mass spectrometry (LCMS) technology has been previously described. 18 Full details are available in the Supplementary methods.…”

Section: Methodsmentioning

confidence: 99%

Enhanced disease reduction using clozapine, an atypical antipsychotic agent, and glatiramer acetate combination therapy in experimental autoimmune encephalomyelitis

Green

Zareie

Templeton

et al. 2017

Multiple Sclerosis Journal - Experimental, Translational and Cl

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BackgroundAtypical antipsychotic agents (AAP) alleviate the symptoms of severe mental health disorders, such as schizophrenia, by antagonizing dopamine and serotonin receptors. Recently, AAP have also been shown to exhibit immunomodulatory properties in the central nervous system (CNS).ObjectiveBuilding on research which demonstrated the ability of the AAP risperidone and clozapine to modify the disease course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we aimed to more fully investigate the potential of clozapine as a possible treatment for MS.ResultsWe report that orally administered clozapine significantly reduced the disease severity of EAE in a dose-dependent manner and was effective when administered prophylactically and therapeutically. In comparison to risperidone, quetiapine, and olanzapine, clozapine was the best at reducing disease severity. While clozapine-treated mice had only modest changes to peripheral leukocytes and cytokine responses, these animals had significantly fewer CNS-infiltrating CD4 T cells and myeloid cells. Furthermore, the CNS myeloid cells displayed a less activated phenotype in mice treated with clozapine. Finally, we found that co-administration of clozapine with glatiramer acetate enhanced disease protection compared to either treatment alone.ConclusionThese studies indicate that clozapine is an effective immunomodulatory agent with the potential to treat immune-mediated diseases such as MS.

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“…The NQAD is claimed to have superior linearity compared with other aerosol-based detectors, covering several orders of magnitude for most analytes (http://www.quant-nqad.com). Quantification by HPLC/ MSD is also normally known to deliver a good linear detector response [25,26]. With regard to NMR spectroscopy, linearity is given over a rather broad range since the intensity of a signal is directly proportional to the number of nuclei being observed [17,27] under well-defined experimental conditions (e.g.…”

Section: Linearity Of Rangementioning

confidence: 99%

Alternatives to amino acid analysis for the purity control of pharmaceutical grade L‐alanine

Holzgrabe

Nap²,

Beyer

et al. 2010

J of Separation Science

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The quality control of drugs is important for safety of patients and consumers. International pharmacopoeias mostly employed HPLC with UV detection for this purpose. This is always a problem when the drugs, such as most amino acids, are lacking a chromophor. Instead of UV detection, the impurity control of alanine was performed using charged aerosol detector, evaporative light-scattering detector, nano quantity analyte detector, MS detector, and as an orthogonal method, quantitative NMR spectroscopy. The charged aerosol detector, MS detector, and quantitative NMR spectroscopy provided similar and precise results, whereas the evaporative light-scattering detector and nano quantity analyte detector revealed some problems regarding sensitivity, linearity, and robustness.

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Rapid liquid chromatography/tandem mass spectrometer (LCMS) method for clozapine and its metabolite N‐desmethyl Clozapine (Norclozapine) in human serum

Cited by 16 publications

References 38 publications

Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

Enhanced disease reduction using clozapine, an atypical antipsychotic agent, and glatiramer acetate combination therapy in experimental autoimmune encephalomyelitis

Alternatives to amino acid analysis for the purity control of pharmaceutical grade L‐alanine

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