马来酸阿塞那平舌下膜剂的HPLC法测定

建立了高效液相色谱法测定马来酸阿塞那平舌下膜.采用C18色谱柱,以1.0％三乙胺溶液(用磷酸调至pH 6.8)∶乙腈(46∶54)为流动相,检测波长274 nm.阿塞那平在20～80 μg/ml浓度范围内线性关系良好,平均回收率为99.8％,RSD为0.5％.     

Asenapine for the treatment of bipolar disorder

Introduction: Bipolar I disorder (BDI) is amongst the most debilitating psychiatric conditions with a great impact on both patients and their families. A class of drugs commonly used in this condition is second-generation antipsychotics (SGAs) including asenapine, one of the latest to be introduced into the clinical practice worldwide to treat manic episodes in BDI.

Areas covered: The aim of this paper is to critically review the literature on the pharmacological characteristics, tolerability, and safety data of asenapine, as well as on its short- and long-term clinical trials in manic episodes as both a monotherapy and as an add-on treatment.

Expert opinion: The available data indicate that asenapine is an effective antimanic agent in both adult and pediatric patients and that it might also improve depressive symptoms and recurrences in BDI patients. Its tolerability profile is good, and its most common side effects are somnolence, light extrapyramidal symptoms, dizziness, weight gain, and oral (but reversible) hypoesthesia. Taken together, the published studies indicate that asenapine might be an effective therapeutic agent in BDI with a broad spectrum of clinical activities. Further double-blind, short- and long-term studies are, however, necessary to clarify its precise role in the treatment of BD.     

Asenapine versus olanzapine in acute mania: a double‐blind extension study

Objective: To assess the efficacy and tolerability of asenapine versus olanzapine in the extended treatment of bipolar mania. Methods: Patients with bipolar I disorder experiencing acute manic or mixed episodes who completed either of two 3‐week, double‐blind trials with asenapine 5 or 10 mg twice daily, olanzapine 5 to 20 mg once daily, or placebo were eligible for this 9‐week, double‐blind extension study. Patients receiving active medication in the 3‐week trials continued the same regimen; those who had received placebo were blindly switched to asenapine but were assessed for safety outcomes only. The primary efficacy measure was the change from baseline to day 84 on the Young Mania Rating Scale (YMRS) total score in the per‐protocol population. Results on the primary efficacy outcome were used to determine the noninferiority of asenapine versus olanzapine. Results: A total of 504 patients (placebo/asenapine, n = 94; asenapine, n = 181; olanzapine, n = 229) were enrolled in the extension study. At day 84, the mean (SD) change from baseline in YMRS total score was ?24.4 (8.7) for asenapine and ?23.9 (7.9) for olanzapine. Prespecified statistical analysis for noninferiority indicated no significant difference between asenapine and olanzapine. The overall incidence of treatment‐emergent adverse events was similar across treatment groups (77% placebo/asenapine, 77% asenapine, 78% olanzapine). Clinically significant weight gain occurred in 10%, 19%, and 31% of the placebo/asenapine, asenapine, and olanzapine groups, respectively. Conclusions: Asenapine was efficacious, showed noninferiority to olanzapine, and was well tolerated in the extended treatment of patients experiencing manic symptoms associated with bipolar I disorder.     

Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis

ABSTRACT

Introduction: Antipsychotic-induced weight-gain (AIWG) is a very important, yet often neglected side-effect in the treatment with first and second generation antipsychotics. AIWG can increase the risk of developing metabolic syndrome, diabetes and cardiovascular disease. Meta-analyzes mostly concentrate on AIWG in schizophrenic and bipolar patients, even though antipsychotics are prescribed off-label across many other diagnostic groups (e.g. anxiety disorders, depression, autistic disorder).

Areas covered: Pub Med and Web of Science were systematically searched for RCTs reporting on AIWG with a sample size of ≥ 100 published between 2014 and 2019. All diagnoses and ages were included.

Expert opinion: Inclusion criteria were fulfilled by 27 RCTs. All antipsychotics led to significantly more weight-gain (p < .001) and most antipsychotics led to a significantly higher risk for a clinically relevant weight-gain of ≥7% compared to placebo (RR = 2.04). The results support previous findings that weight-gain occurs quickly. To efficaciously and efficiently tackle the problem of AIWG in clinical practice and trials, people at high risk need to be identified by predictive tools enabling the clinician to offer tailored adjunctive therapies (medication and/or lifestyle interventions). Most importantly, weight and metabolic monitoring ought to be consequently implemented in clinical routine in the treatment of any patient with any diagnosis when antipsychotics are prescribed.     

The preclinical profile of asenapine: clinical relevance for the treatment of schizophrenia and bipolar mania

Introduction: Asenapine is a novel antipsychotic drug approved for the treatment of acute schizophrenia, manic, or mixed episodes associated with bipolar I disorder, as a maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Areas covered: This review focuses on the preclinical profile of asenapine. It analyzes the pharmacological, neurochemical, behavioral, and molecular mechanisms of asenapine and their contribution to the beneficial therapeutic advantages of the drug as reported in published preclinical and clinical studies, product labels, and poster presentations.

Expert opinion: Asenapine exhibits a broad pharmacological profile that targets a wide range of neurotransmitter receptors with variable affinities. The drug preferentially increases dopamine, norepinephrine, and acetylcholine levels in cortical and limbic brain areas. It also potentiates cortical glutamatergic neurotransmission, and is active in behavioral animal models predictive of antipsychotic, antidepressant, and pro-cognitive activities. Chronic administration of asenapine alters the abundance of dopamine, serotonin, glutamate, adrenergic, and cholinergic receptor subtypes in different brain regions. These action mechanisms of asenapine might contribute to its unique psychopharmacological properties in the improved treatment of schizophrenia and other psychotic disorders.     

Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain

Asenapine, a new pyschopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has a unique human receptor binding signature with strong affinity for dopaminergic, α‐adrenergic, and, in particular, serotonergic receptors raising the possibility of interactions with glutamatergic receptors. Changes in ionotropic glutamate (Glu) N‐methyl‐D ‐aspartic acid (NMDA) receptors and 2‐amino‐3‐(3‐hydroxy‐5‐methyl‐isoxazol‐4‐yl)propionic acid (AMPA) receptors in rat forebrain regions were quantified after repeated administration of multiple doses of asenapine (0.03, 0.1, or 0.3 mg/kg, subcutaneous, twice/day) or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex, caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP), and processed for in vitro receptor autoradiography. Four weeks of treatment with 0.03, 0.1, or 0.3 mg/kg of asenapine significantly (P < 0.01) decreased binding of [³H]MK‐801 to NMDA/MK‐801 modulatory sites in NAc (by 27%, 29%, and 26%, respectively), medial CPu (by 25%, 28%, and 24%), and lateral CPu (by 24%, 31%, and 26%). In contrast, the same doses of asenapine did not alter binding of [³H]glycine to NMDA/glycine modulatory sites in any of the brain regions examined. [³H]AMPA binding to AMPA receptors was selectively and significantly (P < 0.001) elevated in hippocampal CA₁ (41%) and CA₃ (40%) regions but only at the highest dose tested. These results indicate that chronic treatment with asenapine has region‐specific and dose‐dependent effects on ionotropic Glu‐receptor subtypes in rat forebrain, which might contribute to the unique psychopharmacologic properties of asenapine. Synapse 63:413–420, 2009. © 2009 Wiley‐Liss, Inc.     

Effects of asenapine on prefrontal N‐methyl‐D‐aspartate receptor‐mediated transmission: Involvement of dopamine D1 receptors

Asenapine is a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder. Like clozapine, asenapine facilitates cortical dopaminergic and N‐methyl‐D ‐aspartate (NMDA) receptor‐mediated transmission in rats. The facilitation of NMDA‐induced currents in cortical pyramidal cells by clozapine is dependent on dopamine and D₁ receptor activation. Moreover, previous results show that clozapine prevents and reverses the blockade of NMDA‐induced currents and firing activity in the pyramidal cells by the noncompetitive NMDA receptor antagonist phencyclidine (PCP). Here, we investigated the effects of asenapine in these regards using intracellular electrophysiological recording in vitro. Asenapine (5 nM) significantly facilitated NMDA‐induced currents (162 ± 15% of control) in pyramidal cells of the medial prefrontal cortex (mPFC). The asenapine‐induced facilitation was blocked by the D₁ receptor antagonist SCH23390 (1 μM). Furthermore, the PCP‐induced blockade of cortical NMDA‐induced currents was effectively reversed by 5 nM asenapine. Our results demonstrate a clozapine‐like facilitation of cortical NMDA‐induced currents by asenapine that involves prefrontal dopamine and activation of D₁ receptors. Asenapine and clozapine also share the ability to reverse functional PCP‐induced hypoactivity of cortical NMDA receptors. The ability of asenapine to increase both cortical dopaminergic and NMDA receptor‐mediated glutamatergic transmission suggests that this drug may have an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms. Synapse 64:870–874, 2010. © 2010 Wiley‐Liss, Inc.     

Synthesis of stable isotope‐labeled metabolites of asenapine

The stable isotope‐labeled synthesis of four of the major metabolites of asenapine is described. The synthesis of [¹³CD₃]‐asenapine N‐oxide proceeded in two synthetic steps. Preparation of [¹³CD₃]‐asenapine 11‐hydroxysulfate and [¹³C₆]‐N‐desmethylasenapine paralleled established synthetic protocols with effective utilization of labeled precursors. The synthesis of [¹³CD₃]‐asenapine N⁺‐glucuronide was achieved in three chemical steps followed by purification.