Erratum to: Zotepine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of schizophrenia

Prakash, Amitabh; Lamb, Harriet M.

doi:10.1007/bf03257358

Cited by 13 publications

(15 citation statements)

References 57 publications

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“…Although ZTP is structurally similar to tricyclic antidepressants and has been reported to show norepinephrine transporter binding affinity (Leysen et al, 1993;Prakash and Lamb, 1998;Tatsumi et al, 1999), we demonstrated for the first time in the present study the more potent norepinephrine reuptake inhibitory activity of norZTP by using cell-based functional assay, closely comparable with that of conventional antidepressants. These results suggest that NET inhibitory activity of norZTP may contribute to the clinical effects of ZTP, at least in part.…”

Section: Discussionsupporting

confidence: 51%

“…Although the term "atypical antipsychotics" did not exist at its development, ZTP was later proposed to be classified as such (Meltzer et al, 1989b;Stockmeier et al, 1993), along with other drugs exerting antipsychotic activity with low EPS liability, such as clozapine [8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo [b,e][1,4]diazepine] (Meltzer et al, 1989a). Indeed, ZTP is a dopamine D 2 receptor antagonist and serotonin 5-HT 2A receptor antagonist like olanzapine [2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno [2,3-b] [1,5]benzodiazepine] and risperidone [3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one] (Schotte et al, 1996;Prakash and Lamb, 1998).…”

mentioning

confidence: 99%

“…Furthermore, ZTP is also known to exert a rapid antimanic effect without inducing depression in severe mania patients (Amann et al, 2005). In addition to its antagonistic activity on D 2 and 5-HT 2 receptors, ZTP displays bind-ing affinity for the norepinephrine transporter (NET) with potency comparable with that of conventional antidepressants (Leysen et al, 1993;Prakash and Lamb, 1998;Tatsumi et al, 1999). Shiraga et al (1999) reported that incubation of ZTP with human liver microsomes produced four metabolites: Ndesmethylzotepine, 3-hydroxyzotepine, zotepine S-oxide, and 2-hydroxyzotepine.…”

mentioning

confidence: 99%

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Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Shobo

Yamada²,

Mihara³

et al. 2010

J Pharmacol Exp Ther

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The antipsychotic drug zotepine [ZTP;f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine] is known to have not only atypical antipsychotic effects but also antidepressive effects in schizophrenia patients. Norzotepine [norZTP;f]thiepin-10-yl)oxy]-N-methylethan-1-amine] has been postulated to be a major metabolite of ZTP in humans. Here, we characterized norZTP through several in vitro studies and in animal models of psychosis, depression, and extrapyramidal symptoms (EPS) and compared the pharmacological profiles with those of ZTP. Although both compounds showed similar overall neurotransmitter receptor binding profiles, norZTP showed 7-to 16-fold more potent norepinephrine reuptake inhibition than ZTP. In a pharmacokinetic study, both ZTP and norZTP showed good brain permeability when administered individually in mice, although norZTP was not detected in either plasma or brain after intraperitoneal injection of ZTP. In the methamphetamineinduced hyperlocomotion test in mice, norZTP and ZTP showed similar antipsychotic-like effects at doses above 1 mg/kg i.p. In contrast, unlike ZTP, norZTP did not induce catalepsy up to 10 mg/kg i.p. norZTP significantly antagonized the hypothermia induced by reserpine [(3␤,16␤,17␣,18␤,20␣)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester], suggesting in vivo inhibition of the norepinephrine transporter. In the forced-swim test, norZTP exerted an antidepressant-like effect at the effective doses for its antipsychotic action, whereas ZTP neither antagonized reserpine-induced hypothermia nor showed antidepressant-like effect. These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. Given that norZTP is the major metabolite observed in humans, norZTP may contribute to the unique clinical profiles of its mother compound, ZTP.

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Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Shobo

Yamada²,

Mihara³

et al. 2010

J Pharmacol Exp Ther

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“…However, in this tissue the compound achieved mean C max (6.6p3.7 nmol g − 1 ) and AUC (352 nmol min g − 1 ) approximately 20-times those in plasma (0.4p0.3 nmol mL − 1 and 16.8 nmol min mL − 1 , respectively). This brain-to-plasma ratio lies between those of the structurally-related clozapine ( 10 to 24, depending on experimental protocol) (Baldessarini et al 1993 ;Weigmann et al 1999) and zotepine in the rat (20-30) (Prakash & Lamb 1998). It remains to be clarified whether this ratio reflects the true extent of brain partition, since the plasma protein binding of JL13 was not evaluated in this study.…”

Section: Brain Distribution Studiesmentioning

confidence: 93%

Distribution of the methylpiperazinopyridobenzoxazepine derivative JL13, a potential antipsychotic, in rat brain

Guiso

Caccia

2001

Journal of Pharmacy and Pharmacology

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The brain uptake and distribution of the potential antipsychotic 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3][1,5]benzoxazepine fumarate (JL13) was examined in rats after neuropharmacologically active doses. Plasma and brain concentrations of the compound were measured by reversed-phase HPLC with UV detection (210 nm). Clozapine was used as an internal standard. After an intraperitoneal dose of 10 mg kg(-1), the compound attained mean maximum plasma concentrations within 5 min of dosing, then declined with a mean elimination half-life of approximately 1 h. It rapidly crossed the blood-brain barrier and equilibrated with plasma, achieving mean maximum concentrations and area under the curve approximately 20-times those in plasma, with slight regional differences. Disappearance from whole brain almost paralleled its disappearance from plasma. There was a linear relationship between JL13 concentrations in plasma and brain regions, and in all tissues the concentrations of the compound increased almost linearly with the dose over the range of 5-20 mg kg(-1). It thus appears that JL13 brain pharmacokinetics parallels that in plasma, and that plasma concentrations accurately predict brain concentrations in rats.

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“…After clozapine, other atypical antipsychotics, e.g., risperidone (30), olanzapine (31), sertindole (66), zotepine (49) have been introduced. All of them are clinically efficacious in the treatment of positive symptoms and most of them reduce negative symptoms, although many have still a variety of side effects.…”

Section: Introductionmentioning

confidence: 99%

Neuropharmacological Profile of an Atypical Antipsychotic, NRA0562

et al. 2003

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Schizophrenia is a serious and disabling psychiatric disorder affecting approximately 1% of the world's population. A new generation of atypical antipsychotics has been introduced over the past decade. These atypical antipsychotics have comparable or greater efficacy than traditional antipsychotics in the treatment of the psychotic symptoms of schizophrenia and a much improved neurologic side effect profile. This paper reviews the pharmacological efficacy and safety of a potential atypical antipsychotic, NRA0562.NRA0562 has a high affinity for dopamine D 1 , D 2L , D 4.2 , 5-HT 2A receptors as well as á 1 -adrenoceptors, and has a moderate affinity for H 1 receptors. NRA0562 strongly binds to 5-HT 2A receptors and á 1 -adrenoceptors in the frontal cortex, its binding to striatal D 2 receptors is weaker, similar to that of clozapine.NRA562 displayed potent antipsychotic activities in animal models of schizophrenia, such as methamphetamine (MAP)-induced hyperactivity, apomorphine-induced disruption of pre-pulse inhibition and conditioned avoidance test. NRA0562 is more potent in reversing the inhibitory effects of MAP at A10 than at A9 dopamine neurons. It increased Fos-like immunoreactivity in the nucleus accumbens more effectively than in the dorsolateral striatum, indicating that NRA0562 has the profile of an atypical antipsychotic. In vivo assays for extrapyramidal side effect liability showed that NRA0562 has a low rate of neurological side effects. Thus, NRA0562 may have unique antipsychotic activity with a lower propensity for extrapyramidal side effects.

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Erratum to: Zotepine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of schizophrenia

Cited by 13 publications

References 57 publications

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Distribution of the methylpiperazinopyridobenzoxazepine derivative JL13, a potential antipsychotic, in rat brain

Neuropharmacological Profile of an Atypical Antipsychotic, NRA0562

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