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Depressive Phase of Bipolar Disorder
Published in Dr. Ather Muneer, Mood Disorders, 2018
Eslicarbazepine (ESC), the active enantiomer of metabolized OXC, shares the dibenzazepine ring with its parent compound and CBZ. The drug was approved for epilepsy by the European Medicines Agency in 2009, and since then has been investigated in BD. Presently, it has no approved psychiatric indications, and in a recently published RCT in acute mania, the drug failed to differ from placebo. However, ESC showed valid efficacy on certain outcome measures, in particular the Clinical Global Impression Scale-Bipolar Version (CGI-BP) in the long term.15 While there are ongoing trials, the verdict is still out on the efficacy of this agent in BD.
Adrenoceptor Antagonists
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Several other a-adrenoceptor antagonists have been used more widely in the past. These include dibenzazepines, such as azapetine, and benzodioxanes, such as piperoxan, the latter having α2-selectivity. Thymoxamine (OpilonR) is a phenoxyethylamine which remains in use as a peripheral vasodilator for the management of Raynaud’s disease. It is said to be selective for α1-adrenoceptors. Certain drugs with predominant pharmacological activity at other sites also have α-adrenoceptor blocking properties. Examples include the tricyclic antidepressants, such as amitriptyline and imipramine, where hypotensive side-effects are attributed to α-adrenoceptor blockade (U’Pritchard et al. 1978). The antipsychotic or major tranquillizer, phenothiazine, chlorpromazine (LargactilR), has α-adrenoceptor antagonistic properties but also blocks 5-HT, histamine, dopamine and muscarinic receptors. How far each of these properties, or a combination of them, explains the central sedative effects and its use in schizophrenia are still uncertain. However, like other α-blockers, it does lower blood pressure and induce reflex tachycardia, although tolerance to the hypotension develops. Chlorpromazine is also an inhibitor of neuronal uptake and a direct vasodilator and has direct negative inotropic activity.
Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
To resolve the conflicting reports on the permeability and gating properties of TPCs, two groups recently suggest that the ion selectivity and gating properties of TPCs are likely determined by the activating ligands. By performing a Ca2+ imaging-based high-throughput screen, Gerndt et al. (2020) identified two lipophilic and structurally distinct TPC2 agonists TPC2-A1-N and TPC2-A1-P. TPC2-A1-N evokes robust Ca2+-signals and non-selective cation currents, whereas TPC2-A1-P induces Na+-selective currents with weaker Ca2+-signals. These properties are mirrored by the Ca2+-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Interestingly, TPC2-A1-N but not TPC2-A1-P also renders the channel H+-permeable. In the other study, Zhang et al. (2019) reported that five chemically closely related classes of dibenzazepine type tricyclic antidepressants (TCAs, i.e. clomipramine, desipramine, imipramine, amitriptyline, and nortriptyline that are named LyNa-VA1.1 to LyNa-VA1.5) and phenothiazine (i.e. chlorpromazine and triflupromazine that are named LyNa-VA2.1 and LyNa-VA2.2)-based antidepressants induce strong inwardly rectifying TPC currents. However, Riluzole (referred to as Lysosomal Na+ channel Agonist 1 [LyNA1]), an FDA-approved amyotrophic lateral sclerosis drug that is known to modulate voltage-gated Na+ channels, evokes TPC2 currents independent of voltage as in the case for PI(3,5)P2. In contrast to TPC2-A1-N and TPC2-A1-P that alter cation permeability in an agonist-dependent manner, LyNa-VA and LyNA do not change ion selectivity of the channel, that is, low Ca2+ but high Na+permeability. Furthermore, these compounds act on TPC1 and TPC2 differently. TPC2-A1-N and TPC2-A1-P only activate TPC2 but neither inhibits nor activates TPC1 (Gerndt et al., 2020); LyNa-VA1.1 and LyNa-VA1.2 activate both TPC2 and TPC1 in a voltage-dependent manner, while LyNa-VA2.1 and Riluzole inhibit TPC1 (Zhang et al., 2019). Overall, TPCs function as either NAADP-activated Ca2+ release channels (Brailoiu et al., 2010a; Grimm et al., 2014; Pitt et al., 2010; Ruas et al., 2015; Schieder et al., 2010b) or PI(3,5)P2-gated Na+ channels (Cang et al., 2013; Guo et al., 2017; Wang et al., 2012; Zhang et al., 2019). The dual activation mechanism allows TPCs to mediate diverse cellular functions in response to various environmental stimuli.
An evaluation of metabolite profiling of six drugs using dried blood spot
Published in Xenobiotica, 2019
Kishore K. Katyayan, Yu-Hua Hui
Carbamazepine (CBZ), a dibenzoazepine, is a tricyclic compound. CBZ is primarily used for the treatment of epilepsy and neuropathic pain. CBZ is almost completely metabolized in the liver with only around 5% of the drug excreted unchanged and more than 30 metabolites have been isolated and identified (Lertratanangkoon et al., 1982). The major route of metabolism is conversion to CBZ 10, 11-epoxide and the biotransformation is primarily catalyzed by CYP3A4 although involvement of CYP2C8 and CYP3A5 has also been suggested (Pearce et al., 2002, 2005, 2008). Minor metabolic pathways, 2-hydroxy-CBZ and 3-hydroxy CBZ formation presumably proceeds via an epoxide intermediate, whereas multiple CYPs have been indicated to be involved in 2-hydroy-CBZ formation and CYP2B6 and CYP3A4 have been indicated to be involved in formation of 3-hydroxy-CBZ (Bu et al., 2007). In vitro metabolism of carbamazepine in rat and human hepatocytes showed the formation of Car1 (Table 2 and Figure 2). The metabolite structure of Car1 was confirmed as CBZ 10, 11-epoxide using an authentic standard. Rat hepatocytes showed formation of a hydroxy sulfate (Car3). The metabolic profile of rat plasma following 1 mg/kg intravenous and 10 and 500 mg/kg CBZ were qualitatively similar and showed formation of CBZ Car1 (10, 11-epoxide), Car2 (a hydroxy metabolite), and Car3 (a hydroxy sulfate metabolite). The rat DBS metabolite profiles were qualitatively similar to that of rat plasma profile, however the metabolite to CBZ ratios in rat plasma appeared to be higher than that in rat DBS.
Eslicarbazepine in patients with brain tumor-related epilepsy: a single-center experience
Published in International Journal of Neuroscience, 2021
Marco Zoccarato, Anna Maria Basile, Marta Padovan, Mario Caccese, Vittorina Zagonel, Giuseppe Lombardi
ESL belongs to the dibenzazepine family and its main mechanism consists of the reduction in VGSC availability thorough enhancement of slow inactivation [20]. ESL is chemically related to carbamazepine (CBZ) and oxcarbazepine (OXC), which are widely used in focal epilepsy. Some structural differences result in different pharmacodynamic, pharmacokinetic and metabolic features, which can benefit its use in BTRE. First, the long half-life of ESL allows once-daily administration [21, 22]. It is well recognized that lower drug-dose frequency improves therapeutic adherence [23] and could reduce discomfort in patients with brain tumor, which, due to complex and chronic symptoms, can lead to prescription of a high number of medications [24]. Secondly, differently from CBZ, ESL has minimal or no effect on the activity of cytochrome P450 (CYP) isoforms and enzymes of the glucuronidation pathway. As a consequence, ESL should have fewer drug interactions [21, 25], which supports its use in BTRE, where AEDs with a better interaction profile are preferred since the efficacy of other chemotherapeutic drugs is not altered [26]. Side effects of AEDs in BTRE seem to be more frequent than in non-oncological patients [1]. In particular, dermatological complications and bone marrow suppression limit the use of CBZ in these patients, along with its unfavorable interaction profile. Like OXC, ESL is less associated with these side effects due to the lack of a toxic epoxide metabolite [27]. Hyponatremia is another common effect of the dibenzazepine family, especially OXC; but low sodium (defined as <125 μmol/L) has been reported in less than 0.5% of cases in trials with ESL as an add-on therapy [28] and in less than 3.5% in real-life studies [12, 13]. In our series, ESL was well tolerated. No dermatological or hematological events were recorded. Thirty-eight percent patients reported some mild adverse effects that never led to the discontinuation of the drug; only one patient developed mild hyponatremia (>125 μmol/L).
What place do carbamazepine-related antiepileptic drugs have in the modern day treatment of epilepsy?
Published in Expert Opinion on Pharmacotherapy, 2020
Simona Lattanzi, Vincenzo Belcastro
CBZ is featured by a dibenzazepine nucleus with a 5-carboxyamide substituent. OXC is a structurally related derivative with a ketone substitution at the 10-position and ESL is structurally different at the 10, 11-position on the dibenzazepine ring (Table 1) [2].