Search

Résumé La classification traditionnelle des maladies mentales et celle d’Henri Ey y sont discutées et un néo-organodynamisme est présenté. La phase aiguë d’une maladie mentale n’est sans doute qu’une modification temporaire de la maladie de base. La nature de cette dernière peut se décrire par l’importance de la dégénérescence organique. Alors qu’un état psychotique constitue le trouble de base, une phase agrégative aiguë se manifesterait en proportion du degré d’excitations anormales du réseau neuronal. En s’appuyant sur une pluralité d’états mentaux, il est possible de représenter avec précision l’état des patients psychiatriques, qui varie de façon néo-organodynamique avec l’évolution. De la même façon, grâce à la classification proposée, il devient possible de procéder à une recherche clinique comparative des effets des médicaments et des modifications biochimiques. Le concept de « voie accessoire » est introduit. Les contraintes et tensions mentales, ainsi que les actes rituels, promeuvent une construction et une réorganisation du réseau neuronal, qui se fige sous l’effet des répétitions. L’encodage de ce nouveau réseau neuronal dans le subconscient crée une dérivation qui finit par se fixer en tant que « voie accessoire », à l’instar du faisceau de Kent dans le syndrome de Wolff-Parkinson-White. Lorsque la « voie sous-conductrice » est dominante, le patient ne peut plus prendre en considération quoi que ce soit, y compris lui-même. In fine , l’histoire du psychisme est celle d’une hiérarchisation mentale, construite par des voies accessoires et l’encodage dans le subconscient des états mentaux associés. Background Dogmatically conflicting psychological and biological theories make the foundations of psychiatry fragile. Methods Traditional and Henri Ey's classifications of mental illness are discussed and the neo-organodynamism is proposed. The principle of the accessory pathway is also proposed. Results The acute phase of disease may only be a temporary modification of the basic mental illness, the nature of the latter can be expressed in terms of the depth of the organic degeneration. The psychotic state consists of the basic disorder and its acute aggregative phase that is in proportion to the degree of abnormal excitations of neural network. In my classification, mental illness is classified from a normal stage N to X. The degree of acute aggravation is staged from 0 to 7. The twelve stages of organic degeneration multiplied by the eight stages of acute aggravation results in a product of 96 mental stages. By applying this, we can accurately represent the conditions of psychiatric patients that change neo-organodynamically over time. At the same time, clinical comparative research, such as the effects of medicine and of biochemical changes at one time becomes possible. The mental automatism, the mechanism of acute psychosis and treatment concept are discussed with this theory. And this theory may explain what the mental illness is, what the delusion is and what the endogenous psychosis is. Mental pressures or ritual acts promote construction and the reorganization of neural network, and it is fixed by repeating itself. Coding to the subconsciousness of a new neural network namely bypass will be made, and it is immobilized as an accessory pathway like the bundle of Kent of the Wolff–Parkinson–White syndrome. This is the principle of the accessory pathway. When the accessory pathway is dominant, the patient cannot consider anything like himself. This condition shows the low level of his psychic energy (psychasthénie). The history of a mind hierarchy that is constructed with the accessory pathways may be a history of mind. And the history of a mind hierarchy should be what the psychic body is. Treatment concept From the viewpoint of the neo-organodynamism, the conception of organic degeneration is consisted of 1) tissue degeneration literally and 2) generation of accessory pathway by the reorganization of the synapse. The symptoms may be irreversible in the case of the tissue degenerations. But the symptoms that are induced by the accessory pathway may be reversible. If the conductivity of the main pathway becomes dominant as before, the symptom by the accessory pathway has a possibility of the improvement. But the accessory pathway will be remained even if the conductivity of the main pathway becomes dominant as before. One's usual personality is defined as a predominant state of the main pathway. Healing is to return to one's usual personality from the accessory pathway predominant state. In the organic degenerations that are the essence of mental illness, rehabilitation (psychotherapy, cognitive behavioral therapy, mental counseling, etc.) is essential to recuperate lost functions. For the positive symptoms, which are the secondary effects of organic degenerations, medication that focuses on the synaptic neurotransmitters will be effective. Theoretically, the anti-epileptics may be might be designated as the fundamental treatment for the acute aggravation phase because of the abnormal firings of the neuronal network. Conclusions Neo-organodynamism is proposed as a minimum clinical classification of mental illness for psychiatrists. By using this, we can understand that the psychosis is not the special disease, but everyone has the possibility of onset. Neo-organodynamism will eliminate the prejudice against mental illness. [ABSTRACT FROM AUTHOR]

It is of importance to determine whether antipsychotic drugs currently prescribed for schizophrenia exert D-amino acid oxidase (DAO)-inhibitory effects. We first investigated whether human (h)DAO can metabolize D-kynurenine (D-KYN) to produce the fluorescent compound kynurenic acid (KYNA) by using high-performance liquid chromatography with mass spectrometry, and fluorescence spectrometry. After confirmation of KYNA production from D-KYN by hDAO, 8 first- and second-generation antipsychotic drugs, and 6 drugs often prescribed concomitantly, were assayed for hDAO-inhibitory effects by using in vitro fluorometric methods with D-KYN as the substrate. DAO inhibitors 3-methylpyrazole-5- carboxylic acid and 4H-thieno[3,2-b]pyrrole-5-carboxylic acid inhibited KYNA production in a dose-dependent manner. Similarly, the second-generation antipsychotics blonanserin and risperidone were found to possess relatively strong hDAO-inhibitory effects in vitro (5.29 ± 0.47 μM and 4.70 ± 0.17 μM, respectively). With regard to blonanserin and risperidone, DAO-inhibitory effects should be taken into consideration in the context of their in vivo pharmacotherapeutic efficacy. [ABSTRACT FROM AUTHOR]

Highlights: [•] Blonanserin affects DNA methylation profiles of human neuroblastoma cells. [•] About 3,000 CpG sites show changes in methylation levels, regardless of dose. [•] CpG sites related to axonogenesis and neuron differentiation are hypermethylated. [•] With high-dose blonanserin, most CpG sites far from promoters are hypermethylated. [•] Hypermethylation of DRD2 and HTR2A suggests suppressing effects on receptor function. [Copyright &y& Elsevier]

Objective Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol in the switching strategy of schizophrenia. Methods Twenty two Japanese patients with schizophrenia were enrolled into this open study. The antipsychotics of all patients were switched to aripiprazole or blonanserin for the improvement of clinical symptoms or side effects. Plasma monoamine metabolites levels were analyzed with high-performance liquid chromatography. Results There were no significant effects for time ( p = 0.346) or time × group interaction ( p = 0.27) on the changes of positive and negative syndrome scale (PANSS) total score, although blonanserin decreased PANSS scores. We observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = −0.450, p = 0.046). We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. Conclusions There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms. Our results suggest that pHVA may be useful indicator for the switching strategy to aripiprazole or blonanserin in schizophrenia. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Highlights: [•] The method has been developed and validated for the simultaneous determination of blonanserin and its four metabolites in human plasma for the first time. [•] The total run time was much faster and the plasma volume required for sample preparation was much smaller compared to previous literatures. [•] The method was fully validated and applied successfully in a clinical study. [Copyright &y& Elsevier]

Background: It is desirable to establish evidence for the selection of antipsychotics from the viewpoint of recovery of social activity in individual patient with schizophrenia receiving medication. From this perspective, awareness of the importance of studies about drug effectiveness on treatment discontinuation rate, remission rate, and improvement in QOL has grown recently. In Western countries, numerous reports are available in effectiveness studies, which are related to olanzapine and risperidone primarily, whereas evidence for other second-generation antipsychotics (SGAs) is poor. In Japan, no effectiveness study has been reported: thus, it is desirable to collect data that will serve as evidence for selection of the 3 SGAs approved after olanzapine. Methods: The present study was a long-term effectiveness study under healthcare setting in Japan. It was designed as an open-label, multicenter, randomized, comparative study involving 104-week oral treatment with 1 of the 3 drugs (aripiprazole, blonanserin, and paliperidone) in patients with schizophrenia aged 20 years or over who required antipsychotic medication or switching of the current medication to others for reasons such as lack of efficacy and intolerability. The primary endpoint is treatment discontinuation rate for any causes. The secondary endpoints include remission rate, improvement of social activity, alleviation, aggravation or recurrence of psychiatric symptoms, and safety. The target number of subjects was set at 300. Discussion: Because this study is expected to yield evidence regarding the selection of antipsychotics for facilitating the recovery of social activity in patients with schizophrenia, it is considered highly valuable to perform this effectiveness study under ordinary healthcare setting in Japan. [ABSTRACT FROM AUTHOR]

Introduction Blonanserin is a relatively new atypical antipsychotic drug, and has been used in Korea and Japan for 1 and 3 years, respectively. Therefore, the clinical characteristics of blonanserin remain unclear. In this study, to clarify the features of blonanserin, we performed prospective and long-term comparative investigations of patients treated with blonanserin. Methods We followed 10 psychiatric patients who were switched to blonanserin from other antipsychotics for 1 year (schizophrenia: 8; mental retardation: 2). In the light of quality of life, we focused on adverse effects of patients during the follow-up. Results In the long-term follow-up, (i) hyperprolactinemia is more frequently in risperidone than in blonanserin; however, it is more often in blonanserin than in olanzapine; and (ii) weight gain is more common in olanzapine than in blonanserin. Discussion We switched to blonanserin from other antipsychotic drugs within the same case, and then followed the case for 1 year. We consider that long-term observations within the same case lead to obvious comparisons among drugs. On the basis of our findings, we conclude that blonanserin may be useful for the maintenance treatment of schizophrenia without inducing hyperprolactinemia and weight gain. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examined the pharmacological profile of blonanserin, a novel antipsychotic. [•] Blonanserin ameliorates methamphetamine-induced disruption of latent inhibition. [•] Blonanserin increases c-Fos expression in the shell area of the nucleus accumbens. [Copyright &y& Elsevier]

Background: The management of schizophrenia has seen significant strides over the last few decades, due to the increasing availability of a number of antipsychotics. Yet, the diminished efficacy in relation to the negative and cognitive symptoms of schizophrenia, and the disturbing adverse reactions associated with the current antipsychotics, reflect the need for better molecules targeting unexplored pathways. Purpose: To review the salient features of the recently approved antipsychotics; namely, iloperidone, asenapine, lurasidone and blonanserin. Methods: We discuss the advantages, limitations and place in modern pharmacotherapy of each of these drugs. In addition, we briefly highlight the new targets that are being explored. Results: Promising strategies include modulation of the glutamatergic and GABAergic pathways, as well as cholinergic systems. Conclusions: Although regulatory bodies have approved only a handful of antipsychotics in recent years, the wide spectrum of targets that are being explored could eventually bring out antipsychotics with improved efficacy and acceptability, as well as the potential to revolutionize psychiatric practice. [ABSTRACT FROM AUTHOR]

Highlights: [•] Subchronic treatment with PCP induced an enduring deficit in rat NOR. [•] Blonanserin and risperidone are atypical APDs with low 5-HT1A affinity. [•] Blonanserin and risperidone improved the subchronic PCP-induced NOR deficit. [•] The 5-HT1A agonist potentiated the ameliorating effect of blonanserin on NOR. [•] 5-HT1A agonism also contributed to the effect of risperidone to reverse NOR. [ABSTRACT FROM AUTHOR]

Blonanserin was developed as an antipsychotic drug in Japan and approved for the treatment of schizophrenia. It belongs to a series of 4-phenyl-2-(1-piperazinyl)pyridines and acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors. Blonanserin has low affinity for 5-HT2C, adrenergic α1, histamine H1, and muscarinic M1 receptors, but displays relatively high affinity for 5-HT6 receptors. In several short-term double-blind clinical trials, blonanserin had equal efficacy as haloperidol and risperidone for positive symptoms in patients with chronic schizophrenia and was also superior to haloperidol for improving negative symptoms. Blonanserin is generally well tolerated and has a low propensity to cause metabolic side effects and prolactin elevation. We recently reported that blonanserin can improve some types of cognitive function associated with prefrontal cortical function in patients with first-episode and chronic schizophrenia. Taken together, these results suggest that blonanserin may be a promising candidate for a first-line antipsychotic for acute and maintenance therapy for schizophrenia. Further comparative studies are warranted to clarify the benefit/risk profile of blonanserin and its role in the treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

Objective The aim of the study was to better understand blonanserin population pharmacokinetic (PK) characteristics in Chinese healthy subjects. Methods Data from two studies with 50 subjects were analyzed to investigate the population PK characteristics of blonanserin at single dose (4, 8, and 12 mg) under fasting, multidose (4 mg bid or 8 mg qd for 7 days) and under food intake condition (single dose, 8 mg). Blonanserin plasma concentrations were detected using the high performance liquid chromatography tandem mass spectrometry (LC/MS/MS). A nonlinear mixed-effects model was developed to describe the blonanserin concentration-time profiles. Results A two compartment model with first-order absorption was built to describe the time-course of blonanserin. The population-predicted system apparent clearance ( CL/ F), volume of apparent distribution in center ( V1/ F), and the first-order absorption rate constant ( Ka) of blonanserin under fasting was 1230 L/h, 9500 L, and 3.02 h−1, respectively. Food intake decreased Ka of blonanserin to 0.78 h−1. The relative bioavailability between fasting and food intake estimated by the final model was 55%. No clinically significant safety issues were identified. Conclusion This is the first study assessing the PK profile of blonanserin with population PKs method. The results can be used for simulation in further clinical trial and optimize individual dosage regimens using a Bayesian methodology in patients. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Background: There is uncertainty about the efficacy and tolerability of blonanserin in schizophrenia. Method: PubMed, the Cochrane Library databases, PsycINFO, and Google Scholar were searched up to September 2012. A systematic review and meta-analysis of individual patient data from randomized, controlled trials comparing blonanserin with other antipsychotics were conducted. The risk ratio (RR), 95% confidence intervals (CI), numbers-needed-to-harm (NNH), and weighted mean difference (WMD) were calculated. Results: Four studies (total n = 1080) were identified (vs. risperidone studies [n = 508], vs. haloperidol studies [n = 572]). Comparing blonanserin with other pooled antipsychotics, there were no significant differences in the Positive and Negative Syndrome Scale (PANSS) total score (p = 0.75), PANSS positive (p = 0.41), PANSS negative (p = 0.09), and PANSS general psychopathology subscale scores (p = 0.96), and response rate (p = 0.72). However, blonanserin showed greater efficacy in PANSS negative subscale scores compared with haloperidol (WMD = −1.29, CI = −2.29 to −0.30, p = 0.01, I 2 = 0%). No significant differences were found in discontinuation rates between blonanserin and other pooled antipsychotics (due to any cause: p = 0.29, inefficacy: p = 0.32, adverse events: p = 0.56). Blonanserin had a 0.31 lower risk of hyperprolactinemia than the other pooled antipsychotics (CI = 0.20–0.49, NNH = not significant). While dizziness (RR = 0.47, CI = 0.23–0.93, NNH = not significant) and akathisia (RR = 0.54, CI = 0.32–0.90, NNH = 7) occurred significantly less often with blonanserin than with haloperidol, blonanserin had a 1.62 higher risk of akathisia than risperidone (CI = 1.18–2.22, NNH = 3). Conclusion: Our results suggest that although blonanserin has a more beneficial effect on negative symptoms than haloperidol, there was a significant difference in the adverse events profile between blonanserin and other antipsychotics. [Copyright &y& Elsevier]

Schizophrenia is an unexplained, complex and serious mental illness. Blonanserin (BNS) is a new antipsychotic drug widely used in the treatment of schizophrenia. However, large-scale clinical studies have not been conducted in China. A multi-center, prospective, open-label, 12-week surveillance was carried out to evaluate the safety and effectiveness of BNS in patients with schizophrenia in China. Safety assessments included adverse drug reactions (ADRs), extrapyramidal symptoms (EPS), akathisia, concomitant medications for EPS by the end of treatment, and the changes in body weight from baseline by the end of treatment. The effectiveness was evaluated by the Brief Psychiatric Rating Scale (BPRS). From September 2018 to May 2020, of the 1,060 patients enrolled, 1,018 were included in the full analysis set (FAS) and safety set (SS), respectively. ADRs were developed in 205 patients among the included, the incidence being 20.1%. ADRs of EPS occurred in 169 patients, the incidence being 16.6%, ADRs of akathisia occurred in 90 patients, the incidence being 8.8%; concomitant therapeutic and prophylactic agents for EPS accounts for 19.2%; 4.0% of patients had a ≥7% increase in body weight from baseline at 12 weeks after initiating treatment. Using the last-observation-carried-forward (LOCF) method, the changes in total BPRS scores were -11.2 ± 10.17 ( N = 1,018), -16.8 ± 12.69 ( N = 1,018) and -20.6 ± 13.99 ( N = 1,018) after 2/4, 6/8, or 12 weeks, respectively. 53.5% (545/1,018) patients showed response to blonanserin treatment in week 12. The post-marketing surveillance results of BNS demonstrates safety profile and effectiveness of the drug., Competing Interests: The authors declare that this study received funding from Sumitomo Pharma Co., Ltd. and Sumitomo Pharma (Suzhou) Co., Ltd. The funder had the following involvement in the study: the study design and the analysis., (Copyright © 2022 Wu, Wang, Liu, Sang, Bo, Yang, Xun, Li, Zhang, Sun, Cai, Deng, Zhao, Li, Liu, Zhan and Chen.)

Takaki M, Okahisa Y, Kodama M, Mizuki Y, Sakamoto S, Ujike H, Uchitomi Y. Efficacy and tolerability of blonanserin in 48 patients with intractable schizophrenia. Background: Blonanserin is effective for the treatment of schizophrenia in Korea and Japan. Methods: We administered blonanserin to 48 Japanese patients with schizophrenia for whom other atypical antipsychotics were not sufficiently effective or tolerated. Results: Previous antipsychotics were replaced with blonanserin because of its effectiveness (54.2%; 26/48) or tolerability (45.8%; 22/48). Blonanserin was more effective in 65.4% (17/26) of the and better tolerated in 95.5% (21/22) of the patients. Of 48 patients, 33 continued blonanserin for 1 year. The mean Clinical Global Impression of Severity scores improved from 4.60 to 2.48. The mean Global Assessment of Functioning score improved from 29.8 to 51.7. Nineteen patients (39.6%; 19/48) had a social role. The reasons for discontinuation of blonanserin were ineffectiveness against psychosis (27.1%; 13/48) or intolerability (4.2%; 2/48). The ratio of discontinuation for intolerability versus ineffectiveness was 0.15, which was the lowest among atypical psychotics. Conclusions: Blonanserin may be effective and safe for the treatment of intractable schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: Although blonanserin, a novel atypical antipsychotic agent with dopamine D2/serotonin 5-HT2A antagonistic properties, displays good brain distribution, the mechanism of this distribution has not been clarified. P-glycoprotein [(P-gp) or multidrug resistance protein 1 (MDR1)] is an efflux transporter expressed in the brain and plays an important role in limiting drug entry into the central nervous system (CNS). In particular, P-gp can affect the pharmacokinetics and efficacy of antipsychotics, and exacerbate or soothe their adverse effects. In this study, we conducted in vitro and in vivo experiments to determine whether blonanserin is a P-gp substrate. Risperidone and its active metabolite 9-hydroxyrisperidone, both of which are P-gp substrates, were used as reference drugs. Affinity of blonanserin, risperidone, and 9-hydroxyrisperidone for P-gp was evaluated by in vitro transcellular transport across LLC-PK1, human MDR1 cDNA-transfected LLC-PK1 (LLC-MDR1), and mouse Mdr1a cDNA-transfected LLC-PK1 (LLC-Mdr1a). In addition, pharmacokinetic parameters in the brain and plasma (B/P ratio) of test compounds were measured in mdr1a/1b knockout (KO) and wild-type (WT) mice. The results of in vitro experiments revealed that P-gp does not actively transport blonanserin as a substrate in humans or mice. In addition, blonanserin displayed comparable B/P ratios in KO and WT mice, whereas B/P ratios of risperidone and 9-hydroxyrisperidone differed markedly in these animals. Our results indicate that blonanserin is not a P-gp substrate and therefore its brain distribution is unlikely to be affected by this transporter. [Copyright &y& Elsevier]

Abstract: Blonanserin is a novel atypical antipsychotic with highly selective receptor antagonist activity to dopamine D2 and 5-HT2A. N-desethyl blonanserin (blonanserin C) is its major active metabolite in human plasma. Herein we report a new highly sensitive, selective, and rapid liquid chromatography–tandem mass spectrometry method to determine blonanserin and blonanserin C simultaneously in human plasma and urine, with N-desethyl-chlor-blonanserin (blonanserin D) as internal standard (IS). Blonanserin and blonanserin C were extracted from aliquots of plasma and urine with ethyl acetate and dichloromethane (4:1) as the solvent and chromatographic separation was performed using an Agilent Eclipse Plus C18 column. The mobile phase was composed of: acetonitrile and ammonium formate–formic acid buffer containing 5mM ammonium formate and 0.1% formic acid (87:13, v/v). To quantify blonanserin, blonanserin C, and blonanserin D, respectively, multiple reaction monitoring (MRM) transition of m/z 368.2→297.2, m/z 340.2→297.1, and m/z 356.2→313.3 was performed in positive mode. The analysis time was about 5.5min. The calibration curve was linear in the concentration range of 0.01–2ng/ml. The lower limit of quantification reached 0.01ng/ml. The intra and inter-day precision and relative errors were less than 8.0% and 6.6% for three QC levels in plasma and urine. The current LC–MS/MS method was validated as simple, sensitive, and accurate and has been successfully applied to investigate the pharmacokinetics of blonanserin and blonanserin C in humans. [Copyright &y& Elsevier]

Aims: Blonanserin is a second-generation antipsychotic that was developed in Japan. We investigated the relationships between plasma concentration, the plasma anti-5-HT2A activity/anti-D2 activity (S/D) ratio and extrapyramidal symptoms (EPS) in blonanserin dosing. Methods: The subjects were 29 outpatients with schizophrenia. We assessed EPS using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The plasma concentrations were measured by high performance liquid chromatography, and the plasma anti-D2 and anti-5-HT2A activities were measured by [3H]-spiperone and [3H]-ketanserin radioreceptor assays. Results: The results revealed that there were significant correlations between both the plasma concentration and the DIEPSS total score ( P < 0.05). A negative correlative tendency was found between the S/D ratio and the DIEPSS total score. Furthermore, the plasma concentrations were divided into a low plasma concentration group and a high plasma concentration group, and the S/D ratios were divided into a low S/D ratio group and a high S/D ratio group. We then compared each group based on the DIEPSS total scores. The score in the high plasma concentration-low S/D ratio group was significantly higher than in the high plasma concentration-high S/D ratio, low plasma concentration-high S/D ratio and low plasma concentration-low S/D ratio groups ( P < 0.05 for all). Conclusions: These findings indicate that the incidence of EPS during treatment with blonanserin is mainly determined by plasma concentration, but the incidence of EPS may be inhibited when anti-5HT2A activity is predominant over anti-D2 activity. [ABSTRACT FROM AUTHOR]

Abstract: To clarify the mechanisms of action of blonanserin, an atypical antipsychotic drug, we studied the effects of systemic administration of blonanserin and risperidone on extracellular levels of norepinephrine, dopamine, serotonin, GABA and glutamate in the medial prefrontal cortex using microdialysis, and neuronal firing in the ventral tegmental area, locus coeruleus, dorsal raphe nucleus and mediodorsal thalamic nucleus using radiotelemetry. The binding affinities of blonanserin to D2 and 5-HT2A receptors in the rat brain were confirmed and found to be similar. Blonanserin transiently increased neuronal firing in locus coeruleus and ventral tegmental area but not in dorsal raphe nucleus or mediodorsal thalamic nucleus, whereas risperidone increased the firing in locus coeruleus, ventral tegmental area and dorsal raphe nucleus but not in mediodorsal thalamic nucleus. Blonanserin persistently increased frontal extracellular levels of norepinephrine and dopamine but not serotonin, GABA or glutamate, whereas risperidone persistently increased those of norepinephrine, dopamine and serotonin but not GABA or glutamate. These results suggest a pharmacological correlation between the stimulatory effects of these antipsychotics on frontal monoamine release and neuronal activity in monoaminergic nuclei. Inhibition of the α2 adrenoceptor increased extracellular monoamine levels and enhanced blonanserin-induced increase in extracellular serotonin level. These results indicated that the combination of antagonism of D2 and 5-HT2A receptors contribute to the rise in extracellular levels of norepinephrine and dopamine, and that α2 adrenoceptors play important roles in frontal serotonin release. They also suggest that blonanserin-induced activation of monoaminergic transmission could be, at least partially, involved in atypical antipsychotic properties of blonanserin. [ABSTRACT FROM AUTHOR]

Blonanserin is a novel potent dopamine D2 and serotonin 5-HT2 antagonist for treating schizophrenia. The aim of this study was to investigate prandial effects on systemic exposure to blonanserin in healthy volunteers, with particular attention paid to the effect of dose timing relative to meal intake. Volunteers received a single 2-mg oral dose of blonanserin under the following conditions: fasting, 30 min before eating a standard meal; or 30 min or 2 or 4 h after eating the meal. Plasma concentrations of blonanserin were measured using validated high-performance liquid chromatography coupled with tandem mass spectrometry. Ratios and 90% confidence intervals of the geometric means compared with the fasting condition indicated that the maximum concentrations of blonanserin (Cmax) significantly increased with dosing 30 min before meal intake, and 30 min and 2 and 4 h after meal intake, yielding by 330%, 239%, 272%, and 138%, respectively. The truncated area under the concentration-time curve (AUClast) also increased by 386%, 201%, 256%, and 155%, respectively. There was no difference in values of the time to reach maximum concentration between the fasting and the four fed states. Food intake increased the systemic exposure to blonanserin for all time intervals investigated in this study. The marked effect of food on the bioavailability of blonanserin should be taken into account in its dosing schedules. [ABSTRACT FROM AUTHOR]

Abstract: Blonanserin is a novel antipsychotic agent that preferentially interacts with dopamine D2 and 5-HT2A receptors. To assess the atypical properties of blonanserin, we evaluated its propensity to induce extrapyramidal side effects (EPS) and to enhance forebrain Fos expression in mice. The actions of AD-6048, a primary metabolite of blonanserin, in modulating haloperidol-induced EPS were also examined. Blonanserin (0.3–10mg/kg, p.o.) did not significantly alter the pole-descending behavior of mice in the pole test or increase the catalepsy time, while haloperidol (0.3–3mg/kg, p.o.) caused pronounced bradykinesia and catalepsy. Blonanserin and haloperidol at the above doses significantly enhanced Fos expression in the shell (AcS) region of the nucleus accumbens and dorsolateral striatum (dlST). The extent of blonanserin-induced Fos expression in the AcS was comparable to that induced by haloperidol. However, the striatal Fos expression by blonanserin was less prominent as compared to haloperidol. Furthermore, combined treatment of AD-6048 (0.1–3mg/kg, s.c.) with haloperidol (0.5mg/kg, i.p.) significantly attenuated haloperidol-induced bradykinesia and catalepsy. The present results show that blonanserin behaves as an atypical antipsychotic both in inducing EPS and enhancing forebrain Fos expression. In addition, AD-6048 seems to contribute at least partly to the atypical properties of blonanserin. [Copyright &y& Elsevier]

Blonanserin is a novel antipsychotic agent having dopamine D2 and serotonin 5-HT2A receptor antagonist properties. In this communication, a simple method for analysis of blonanserin in human plasma by gas chromatography-mass spectrometry (GC-MS) using hexobarbital as internal standard (IS) is presented. One milliliter of plasma containing blonanserin and 50 ng of IS was mixed well with 0.5 ml of 0.1 M hydrochloric acid and 2.5 ml of distilled water; the mixture was applied to an Oasis HLB cartridge. The cartridge was washed with 5 ml of distilled water, and the target compound and IS were eluted with 2 ml of chloroform. The eluate was evaporated to dryness under a stream of nitrogen. The residue was reconstituted in 50 μl of methanol for use in GC-MS analysis. The calibration curve for blonanserin spiked into human plasma showed good linearity in the range of 0.5–20 ng/ml. The detection limit (signal-to-noise ratio = 3) was about 0.25 ng/ml. The recovery rate was 81.0% at 2.5 ng/ml and 97.5% at 15 ng/ml. The accuracy and precision were also satisfactory. A 60-year-old male volunteer took a 10-mg oral dose of blonanserin; the plasma concentrations of the drug were 0.61 and 1.20 ng/ml at 1.5 and 4 h after ingestion, respectively. [ABSTRACT FROM AUTHOR]

Objective Blonanserin (BNS) possesses anti-serotonin 5-HT2A activity in addition to anti-dopamine D2 activity, which is characteristic of second-generation antipsychotics, little information is available on its pharmacologic profile in vivo. We investigated the BNS daily dose, plasma concentration, plasma anti-D2 activity, and plasma anti-5-HT2A activity in schizophrenia in a total of 14 subjects. Methods Blood samples were taken 14 days after the BNS dose was fixed, and the plasma concentration was measured by means of high-performance liquid chromatographic (HPLC) method. In addition, the plasma anti-D2 activity and anti-5-HT2A activity were measured by means of radioreceptor assays in which [3H]-spiperone and [3H]-ketanserin were used. Results The results revealed a statistically significant correlation between the daily dose and the plasma concentration (p = 0.04). Statistically significant correlations were also observed between the plasma concentration and the anti-D2 activity and between the plasma concentration and the anti-5-HT2A activity (p = 0.003 and 0.04). Conclusions It is therefore believed that both the anti-D2 activity in plasma and the anti-5-HT2A activity in plasma are regulated almost solely by the unchanged principal. Moreover, the mean plasma serotonin/dopamine (S/D) ratio was 0.9 and BNS exhibited both anti-D2 activity and also anti-5-HT2A activity in vivo, as well, so it was clear that the in vitro pharmacological profile was retained in vivo. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Two major metabolites in humans of blonanserin, 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta-[b]pyridine (code name AD-5423), were synthesized. The first, 7-hydroxylated AD-5423, was synthesized through a four-step process starting from 4-fluorobenzoylacetonitrile (1), and the second, 8-hydroxylated AD-5423, a nine-step process also from 1. The optical resolution, structures, and receptor binding properties of the metabolites were documented. [Copyright &y& Elsevier]

1 Several neuroleptics inhibited the 3 μM γ-aminobutyric acid induced-chloride current (GABA-current) on dissociated rat dorsal root ganglion neurons in whole-cell patch-clamp investigations. 2 The IC[sub50] for clozapine, zotepine, olanzapine, risperidone and chlorpromazine were 6.95, 18.26, 20.30, 106.01 and 114.56 μM, respectively. The values for the inhibitory effects of neuroleptics on the GABA (3 μM)-current, which were calculated by the fitting Hill's equations where the concentrations represent the mean therapeutic blood concentrations, were ranked clozapine >zotepine>chlorpro-mazine > olanzapine > risperidone. These inhibitory effects, weighted with the therapeutic concentrations of neuroleptics, were correlated with the clinical incidences of seizure during treatment with neuroleptics. 3 Clozapine reduced the picrotoxin-inhibiton, and may compete with a ligand of the t-butyl-bicyclophosphorothionate (TBPS) binding site. 4 Haloperidol and quetiapine did not affect the peak amplitude of the GABA (3 μM)-current. However, haloperidol reduced the clozapine-inhibition, and may antagonize ligand binding to TBPS binding site. 5 Neuroleptics including haloperidol and quetiapine enhanced the desensitization of the GABA (3 μM)-current. However, haloperidol and quetiapine at 100 μM inhibited the desensitization at the beginning of application. 6 Blonanserin (AD-5423) at 30 and 50 μM potentiated the GABA (3 μM)-current to 170.1 ±6.9 and 192.0±10.6% of the control current, respectively. Blonanserin shifted GABA concentration-response curve leftward. Blonanserin only partly negatively interacted with diazepam. The blonanserin-potentiation was not reversed by flumazenil. Blonanserin is not a benzodiazepine receptor agonist. 7 The various effects of neuroleptics on the GABA-current may be related to the clinical effects including modifying the seizure threshold. [ABSTRACT FROM AUTHOR]