Amisulpride Research Articles

Formulation, Development, Characterization and Solubility Enhancement of Amisulpride

Background: Amisulpride (AMP) is a drug that is poorly water-soluble and is typically characterized by high molecular weights, significant log P values, and low bioavailability. Poor water solubility of a drug is caused by strong intermolecular interaction and a drug's affinity for a lipid environment (lipophilicity). Objective: The current study aims to improve Amisulpride's (AMP) oral bioavailability and solubility by developing a complex with 2-hydroxypropyl β-cyclodextrin (HP-β-CDT). Method: This study describes solubility of AMP with β-CDT and HP-β-CDT. Prepared inclusion complex of AMP and HP-β-CDT by different techniques like physical mixture, kneading and lyophilization. Result: A notable improvement in AMP's solubility was obtained with an optimized inclusion complex. The result of FT-IR, DSC and XRD confirms the complex between AMP and HP-β-CDT. The physical mixture, kneading and lyophilization technique, the kneading method is most successful in producing an inclusion complex. Conclusion: The 1.3 ratio gives the best drug content and dissolution profile.

Detection of Amisulpride Using a Chromium-Salophen Optical Probe

Patients with psychosis around the world are routinely prescribed anti-psychotic medications. Amisulpride (AMI) is one such medication. In order to detect cases like drug overdose, drug abuse, or intentional poisoning, simple, selective and sensitive probes are required. In the present work, we have synthesized a fluorescent probe (CRSA) for detecting Amisulpride (AMI) and characterized it by FT-IR, NMR and mass spectroscopy. The probe emits green light in ethanol and acts as a “turn-off” luminescent sensor for the anti-psychotic drug Amisulpride (AMI) with a quenching percentage of 94% and an excellent limit of detection of 1.6 μM. The sensor responded effectively to only AMI even in the presence of other drugs like sertraline, fluoxetine, escitalopram, paroxetine, olanzapine and clozapine ensuring good selectivity and specificity of the method. The effect of pH on the sensing abilities CRSA and the applicability of the method to real-life samples were also studied using spiked alcohol samples.

Formulation, optimization and evaluation of amisulpride-loaded niosomal intranasal gel for brain targeting.

Aim: To develop stable non-ionic surfactant vesicles containing amisulpride (AMS) to improve brain uptake via nose to brain mechanism. Methods: Niosomes were developed using a modified ethanol injection technique, optimized using 32 factorial design and evaluated for the vesicle size (VS), percent encapsulation efficiency (EE), zeta potential (ZP) and % cumulative drug release (%CDR). Results: Optimized niosomes (Span-60: cholesterol ratio 0:1) showed 191.4nm VS, 84.25% EE, -38.2ZP and 81.31% CDR. In situ gel with these niosomes displayed 78% CDR. TEM analysis revealed spherical niosomes. Pharmacokinetic and brain tissue distribution studies in rats showed enhanced plasma and brain concentrations, indicating successful brain targeting. Conclusion: This strategy demonstrates improved AMS permeation via the nasal cavity, enhancing bioavailability for treating schizophrenia.

A 5-year retrospective study of amisulpride steady-state plasma concentration in patients with schizophrenia in real-life settings based on therapeutic drug monitoring data.

Here, we present a retrospective analysis of the last 5 years' data collected in real-life settings as direct evidence to evaluate the optimal therapeutic window of amisulpride (AMI) for psychiatric patients. Retrospective analysis of the therapeutic drug monitoring (TDM) results of AMI in outpatients and inpatients were obtained from the Xi'an Mental Health Center from 2017 to 2021. The interquartile (P25-P75) AMI concentrations ranged 212.20-574.25ng/mL. The results showed that the proportion of outpatients who received TDM once was significantly higher than that of inpatients who received TDM once (P<0.001), whereas the reverse was true for those who experienced TDM more than twice (P<0.001). Higher estimated plasma concentrations were identified in inpatients, female patients, and patients over 59 years of age. Nearly 57.21% of the samples had high concentrations (>320ng/mL). The optimal therapeutic reference range for AMI may require reconstruction to guide the use of AMI for the treatment of schizophrenia.

Amplified Electrochemiluminescence of the Luminol‐Amisulpride System and its Application for the Ultrasensitive Detection of Amisulpride

AbstractElectrochemiluminescence (ECL) has emerged as a powerful tool in bioassays due to its unique versatility and controllability, but it is still a challenge to amplify ECL signals without utilizing complex synthetic processes, sophisticated nanomaterials, and catalysts. Herein, a new ECL system with high sensitivity and selectivity is reported for the detection of amisulpride (AMS). The AMS was beneficial for enhancing the weak ECL emission of luminol, wherein co‐reaction effect of AMS promoted the generation of superoxide anion radicals (O2⋅−), which significantly improved the ECL efficiency of luminol (emitter). Under the optimized experimental conditions, this anodic ECL system achieved AMS detection (a biphasic curve) with linear concentration ranges of 0.2–5.0 μm and 5.0–100.0 μm. Impressively, the developed system exhibited a low limit of detection (LOD) and quantification (LOQ) of 10.2 nm and 50.5 nm for AMS, respectively. This luminol‐based ECL system is further applied for sensitive AMS detection in real (bulk) drug and pharmaceutical tablet form. Moreover, statistical comparison between the developed and comparison method showed good precision and accuracy of the developed method.

Amisulpride Augmentation in Schizophrenia Patients with Poor Response to Olanzapine: A 4-week, Randomized, Rater-Blind, Controlled, Pilot Study

IntroductionOlanzapine (OLA) is a common first-prescribed antipsychotic and has shown favorable efficacy in acutely exacerbated patients with schizophrenia. The mixed receptor activity of OLA and its greater affinity for serotonin 5-HT2A rather than dopamine D2 receptors are similar to those of clozapine. Pharmacokinetically, OLA is metabolized mainly by hepatic cytochrome enzyme P450 1A2 (CYP1A2). Because risks of antipsychotic polypharmacy include increased drug-drug interactions, pharmacokinetic considerations are important for selection of antipsychotics to be combined. Due to its pharmacological characteristics, amisulpride (AMI), another atypical antipsychotic with proven efficacy, is a promising adjuvant agent of special interest. AMI is unlikely to interact with other drugs due to the low plasma protein binding and metabolism and does not affect the activity of the CYP system. Furthermore, AMI is highly selective for dopamine D2/D3 receptors; has minimal or no affinity for D1, D4, or D5 receptors. Despite the potential benefits of the combination of OLA and AMI, only a few open-label studies have been conducted, and no randomized clinical trial has been performed to date to examine the efficacy and tolerability of the combination. Hence, the goals of this study were to test the hypothesis that AMI augmentation would improve psychotic symptoms and be well tolerated in schizophrenic patients who showed poor response to OLA monotherapy.ObjectivesThe purpose of this study was to compare the efficacy and tolerability of continued olanzapine (OLA) versus amisulpride (AMI) augmentation in schizophrenic patients with poor response to OLA monotherapy.MethodsThe present 4-week, randomized, rater-blinded study included 25 patients with schizophrenia who were partially or completely unresponsive to treatment with OLA monotherapy. Eligible subjects were randomly assigned at a 1:1 ratio to continuation of OLA monotherapy (OLA group) or OLA with AMI augmentation (AMI group). Efficacy was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS) at baseline and at 1, 2, and 4 weeks.ResultsThe changes in PANSS total score and PANSS-positive subscale score were significantly different (p &lt; 0.05) between the OLA and AMI groups. The differences between the two groups in PANSS-negative subscale, PANSS-general subscale, Brief Psychiatric Rating Scale, and Clinical Global Impression-Severity (CGI-S) scale scores were not statistically significant.ConclusionsAMI augmentation could be an effective strategy for patients with schizophrenia who show inadequate early response to OLA monotherapy.Disclosure of InterestW.-M. Bahk Grant / Research support from: Handok Pharmaceuticals, Seoul, Korea, Y. S. Woo: None Declared, S.-Y. Park: None Declared, B.-H. Yoon: None Declared, S.-M. Wang: None Declared, M.-D. Kim: None Declared

NiFe-based Prussian blue analogue nanopolygons hybridized with functionalized glyoxal polymer as a voltammetric platform for the determination of amisulpride in biological samples

A novel voltammetric platform based on pencil graphite electrode (PGE) modification has been proposed, containing bimetallic (NiFe) Prussian blue analogue nanopolygons decorated with electro-polymerized glyoxal polymer nanocomposites (p-DPG NCs@NiFe PBA Ns/PGE). Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and square wave voltammetry (SWV) were utilized to investigate the electrochemical performance of the proposed sensor. The analytical response of p-DPG NCs@NiFe PBA Ns/PGE was evaluated through the quantity of amisulpride (AMS), one of the most common antipsychotic drugs. Under the optimized experimental and instrumental conditions, the method showed linearity over the range from 0.5 to 15 × 10−8 mol L−1 with a good correlation coefficient (R = 0.9995) and a low detection limit (LOD) reached, 1.5 nmol L−1, with excellent relative standard deviation for human plasma and urine samples. The interference effect of some potentially interfering substances was negligible, and the sensing platform demonstrated an outstanding reproducibility, stability, and reusability. As a first trial, the proposed electrode aimed to shed light on the AMS oxidation mechanism, where the oxidation mechanism was monitored and elucidated using the FTIR technique. It was also found that the prepared p-DPG NCs@NiFe PBA Ns/PGE platform had promising applications for the simultaneous determination of AMS in the presence of some co-administered COVID-19 drugs, which could be attributed to the large active surface area, and high conductivity of bimetallic nanopolygons.Graphical

Amisulpride Augmentation in Schizophrenia Patients with Poor Response to Olanzapine: A 4-week, Randomized, Rater-Blind, Controlled, Pilot Study.

ObjectiveThe purpose of this study was to compare the efficacy and tolerability of continued olanzapine (OLA) versus amisulpride (AMI) augmentation in schizophrenic patients with poor response to OLA monotherapy.MethodsThe present 4-week, randomized, rater-blinded study included 25 patients with schizophrenia who were partially or completely unresponsive to treatment with OLA monotherapy. Eligible subjects were randomly assigned at a 11 ratio to continuation of OLA monotherapy (OLA group) or OLA with AMI augmentation (AMI group). Efficacy was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS) at baseline and at 1, 2, and 4 weeks.ResultsThe changes in PANSS total score and PANSS-positive subscale score were significantly different (p < 0.05) between the OLA and AMI groups. The differences between the two groups in PANSS-negative subscale, PANSS-general subscale, Brief Psychiatric Rating Scale, and Clinical Global Impression-Severity (CGI-S) scale scores were not statistically significant.ConclusionAMI augmentation could be an effective strategy for patients with schizophrenia who show inadequate early response to OLA monotherapy.

Effects of dopamine modulation on chronic stress-induced deficits in reward learning.

Anhedonia is characteristically preceded by chronic stress, likely involving downstream effects of glucocorticoid alterations on dopamine (DA) function. To elucidate the neural underpinnings of this interaction, we examined whether acute pharmacological modulation of DA alters reward learning after chronic mild stress (CMS). Forty-eight male Wistar rats were exposed to a 21-day CMS regime (n = 48 nostress controls) before completing the probabilistic reward task (PRT), a well-validated cross-species test of reward learning. We first examined whether stress-induced reward dysfunction could be restored by systemic injections of low-dose amisulpride (AMI), which increases DA transmission via D2-like autoreceptor blockade. Then, we investigated region-specific effects through bilateral infusions of quinpirole (QUIN), a D2-like receptor agonist, into either the nucleus accumbens core (NAcc) or medial prefrontal cortex (mPFC). Blunted reward learning in CMS animals was reversed by acute AMI administration, but this treatment did not alter reward learning in the no stress group. Elevated adrenal gland weight, a proxy for stress reactivity, predicted lower reward learning in the untreated CMS group. This effect was extinguished following AMI treatment. These findings might be attributed to significantly higher D2 receptor density in the NAcc of high stress reactive animals. To this end, NAcc QUIN infusions potentiated reward learning relative to mPFC QUIN infusions in CMS rats, but there was no effect in no stress control rats. Collectively, these findings suggest that DA modulation reverses stress-induced reward dysfunction, even among the most stress-reactive animals. The effect might depend on D2-like receptor activation in the mesolimbic system.

Nose-to-brain delivery of amisulpride-loaded lipid-based poloxamer-gellan gum nanoemulgel: In vitro and in vivo pharmacological studies

Unfavorable side effects of available antipsychotics limit the use of conventional delivery systems, where limited exposure of the drugs to the systemic circulation could reduce the associated risks. The potential of intranasal delivery is gaining interest to treat brain disorders by delivering the drugs directly to the brain circumventing the tight junctions of the blood–brain barrier with limited systemic exposure of the entrapped therapeutic. Therefore, the present research was aimed to fabricate, optimize and investigate the therapeutic efficacy of amisulpride (AMS)-loaded intranasal in situ nanoemulgel (AMS-NG) in the treatment of schizophrenia. In this context, AMS nanoemulsion (AMS-NE) was prepared by employing aqueous-titration method and optimized using Box-Behnken statistical design. The optimized nanoemulsion was subjected to evaluation of globule size, transmittance, zeta potential, and mucoadhesive strength, which were found to be 92.15 nm, 99.57%, −18.22 mV, and 8.90 g, respectively. The AMS-NE was converted to AMS-NG using poloxamer 407 and gellan gum. Following pharmacokinetic evaluation in Wistar rats, the brain Cmax for intranasal AMS-NG was found to be 1.48-folds and 3.39-folds higher when compared to intranasal AMS-NE and intravenous AMS-NE, respectively. Moreover, behavioral investigations of developed formulations were devoid of any extrapyramidal side effects in the experimental model. Finally, outcomes of the in vivo hematological study confirmed that intranasal administration of formulation for 28 days did not alter leukocytes and agranulocytes count. In conclusion, the promising results of the developed and optimized intranasal AMS-NG could provide a novel platform for the effective and safe delivery of AMS in schizophrenic patients.

The effect of amisulpride, olanzapine, quetiapine, and aripiprazole single administration on c-Fos expression in vasopressinergic and oxytocinergic neurons of the rat hypothalamic paraventricular nucleus

Antipsychotics, including amisulpride (AMI), quetiapine (QUE), aripiprazole (ARI), and olanzapine (OLA), are used to treat mental illnesses associated with psychotic symptoms. The effect of these drugs on c-Fos expression in vasopressinergic (AVP) and oxytocinergic (OXY) neurons was studied in the hypothalamic paraventricular nucleus (PVN) of rats. The presence of c-Fos in AVP and OXY perikarya was investigated in seven PVN cells segregations: the anterior (Ant), dorsal cup (Dc), wing-shaped (Wi), periventricular zone (Pe), circle-shaped core (Co) and shell of core (Sh), and the posterior (pPVN) after an acute treatment with AMI-20 mg/kg, QUE-15 mg/kg, ARI-10 mg/kg, and OLA-5 mg/kg/bw in rats. Ninety min after treatments, the animals were sacrificed by transcardial perfusion with fixative and the PVN area sliced into 35 μm thick coronal sections for immunohistochemistry. The c-Fos was processed by avidin-biotin-peroxidase complex intensified with nickel-enhanced 3,3′-diaminobenzidine tetrahydrochloride. Visualization of AVP- and OXY-synthesizing neurons was achieved by a fluorescent marker Alexa Flour 568. The c-Fos-AVP and c-Fos-OXY colocalizations were evaluated from c-Fos stained sections merged with AVP or OXY ones. AMI, QUE, ARI, and OLA, single administration distinctly increased the c-Fos expression in each of the PVN cells segregations. QUE induced the highest magnitude of activation of AVP and OXY neurons, while OLA and AMI had only moderate effects. Incontestable variabilities detected in c-Fos expression in PVN AVP and OXY neurons extend the knowledge of selected antipsychotics extra-striatal actions and may also be helpful in a presumption of their possible functional impact.

Self-assembled ruthenium decorated electrochemical platform for sensitive and selective determination of amisulpride in presence of co-administered drugs using safranin as a mediator

A wholly new electroanalytical protocol for the sensitive determination of Amisulpride (AMS) has been developed. AMS is an antipsychotic and antiemetic medicine that is prescribed at lower dosages intravenously to stop and cure vomiting and postoperative nausea; and at higher orally dosages and intramuscularly for treatment of schizophrenia and serious psychotic seizures. AMS detection is proposed here for the first-time using Ruthenium nanoparticles (Ru) and Safranin (Saf) as a modifier through carbon paste electrochemical sensor platform. The Ruthenium - Safranin sensor was found to possess good electrocatalytic activity and selectivity for simultaneous determination of AMS in the presence of co-administered drug citalopram (CIT). The Ru-Saf/CPE modified sensor exhibited a wide linear response range for electrochemical sensing of AMS (9.8 × 10−8–7.0 × 10−5 M) with LOD of 8.80 × 10−9 M.

Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry for Simultaneous Determination of Antipsychotic Drugs in Human Plasma and Its Application in Therapeutic Drug Monitoring.

PurposeWe developed and validated an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous therapeutic drug monitoring (TDM) and clinical pharmacokinetic antipsychotic drugs: clozapine (CLP), chlorpromazine (CPZ), risperidone (RPD), paliperidone (PLD), quetiapine (QTP;), aripiprazole (APZ), dehydroaripiprazole (DAP), olanzapine (OZP), ziprasidone (ZRD), and amisulpride (ASP).MethodsAnalytes and internal standards (ISs) were separated using a Phenomenex phenyl-hexyl column (50.0 × 2.1 mm, 1.7 μm) with water containing 0.1% formic acid and 2 mM ammonium acetate, and methanol containing 0.1% formic acid and 2 mM ammonium acetate as the mobile phase. The antipsychotic drugs and ISs were extracted from 50 μL of plasma using acetonitrile.ResultsThe calibration ranges were 25.0–1500.0 ng/mL for CLP, CPZ, DAP, and QTP, 10.0–600.0 ng/mL for CPZ and ZRD, 2.5–150.0 ng/mL for RPD, 5.0–300.0 ng/mL for PLD and OZP, and 20.0–1200.0 ng/mL for ASP. Validation was carried out according to the guidelines for bioanalytical validation, including assessment of calibration curves, specificity, accuracy, precision, recovery, stability, dilution integrity, and matrix effect. All the results satisfied the requirements.ConclusionThe results provided significant information to support future clinical TDM and rational drug use research. The proposed method also provided a simple, reliable, specific, and suitable technique for TDM and pharmacokinetic studies.

Highly sensitive Thin-Layer Chromatographic–Densitometric assay for quantitation of Amisulpride & Zolmitriptan in synthetic mixture: Application to pharmaceutical formulation & biological fluids

A new and sensitive (TLC) assay has been estimated for quantitation of synthetic binary mixtures of antipsychotic drug Amisulpride (AMS) with antimigarine drug Zolmitriptan (ZOL). These medications co-administered with each other for treatment of chronic migraine headache associated with psychosis. The synthetic mixture has been separated on precoated silica TLC plates G60 F254 by using mobile phase which consist of mixture of Chloroform: Ethyl acetate: Methanol: Ammonia in ratio (30:30:73:3 v/v/v/v). The mixture has been determined at λmax 231 nm. Retardation factor (RF) values for AMS and ZOL have been 0.6 and 0.43 respectively. Calibration graphs have been linear in range 50–500 ng/spot for all studied drugs. The detection limits have been 6.04 & 10.5 ng/spot and the quantitation limits have been 18.3 & 31.834 ng/spot for AMS and ZOL respectively. The described assay has been utilized for quantitation of synthetic mixture in pharmaceutical tablet &biological fluids.

Highly Sensitive Thin-Layer Chromatographic–Densitometric Assay for Quantitation of Amisulpride &amp; Zolmitriptan in Synthetic Mixture: Application to Pharmaceutical Formulation &amp; Biological Fluids

A new and sensitive (TLC) assay has been estimated for quantitation of synthetic binary mixtures of antipsychotic drug Amisulpride (AMS) with antimigarine drug Zolmitriptan (ZOL). These medications co-administered with each other for treatment of chronic migraine headache associated with psychosis. The synthetic mixture has been separated on precoated silica TLC plates G 60 F 254 by using mobile phase which consist of mixture of Chloroform: Ethyl acetate: Methanol: Ammonia in ratio ( 30:30:73:3 v/v/v/v ). The mixture has been determined at λ max 231 nm. Retardation factor (RF) values for AMS and ZOL have been 0.6 and 0.43 respectively. Calibration graphs have been linear in range 50-500 ng/spot for all studied drugs. The detection limits have been 6.04 & 10.5 ng/spot and the quantitation limits have been 18.3 & 31.834 ng/spot for AMS and ZOL respectively. The described assay has been utilized for quantitation of synthetic mixture in pharmaceutical tablet &biological fluids.

Leki przeciwpsychotyczne II generacji w terapii objawów negatywnych schizofrenii

Farmakoterapia schizofrenii jest trudnym i złożonym procesem, szczególnie w kontekście objawów negatywnych. Konieczne jest właściwe rozpoznanie grup pacjentów, a w szczególności indywidualnych pacjentów ― w zależności czy objawy negatywne są pierwotne, czy wtórne, przeważające czy znaczące, czy też przeważające i przetrwałe. Piśmiennictwo dotyczące oceny skuteczności różnych leków przeciwpsychotycznych II generacji w leczeniu objawów negatywnych jest niejednorodne, a ocena objawów negatywnych, oparta na różnych metodologiach, dotyczy przede wszystkim różnorodnych grup pacjentów, którzy najprawdopodobniej w zróżnicowany sposób reagują na badane leki, w zależności od tego, czy wykazują znaczące, przeważające lub też przeważające i przetrwałe objawy negatywne. Dodatkowo zdecydowana większość badań dotyczy ogólnej populacji chorych na schizofrenię, wśród których oceniano między innymi nasilenie objawów negatywnych. W związku z tym ocena tych badań i ich porównanie między sobą jest praktycznie niemożliwe. Wybór leku przeciwpsychotycznego II generacji, który wykazywałby zdecydowaną przewagę nad innymi, jest również trudny. W ramach niniejszego opracowania wykonano przegląd literatury dotyczącej badań randomizowanych bezpośrednio porównujących kluczowe leki przeciwpsychotyczne II generacji stosowane w terapii objawów negatywnych. W większości analizowanych badań nie wykazano istotnych statystycznie różnic pomiędzy analizowanymi lekami (porównanie risperidonu, amisulprydu, arypiprazolu, olanzapiny pomiędzy sobą). Tylko w pojedynczych badaniach wykazano przewagę olanzapiny nad risperidonem w ocenie wpływu obu tych leków na objawy negatywne. Należy jednak podkreślić, że wyniki cechowały się ograniczoną wiarygodnością w zakresie możliwości wnioskowania o bezpośrednim wpływie leków na objawy negatywne. Przyczynę takiego stanu rzeczy należy upatrywać między innymi w tym, że w badaniach tych nie korygowano uzyskiwanych efektów o czynniki zakłócające, których wpływ na objawy negatywne został potwierdzony. Natomiast w grupie chorych z przeważającymi i przetrwałymi objawami negatywnymi stwierdza się przewagę kariprazyny nad risperidonem. Uzupełniająca analiza opracowań wtórnych dla analizowanych leków wykazała wyższą skuteczność leków II generacji nad lekami I generacji i placebo w różnych grupach pacjentów z objawami negatywnymi. Należy jednak podkreślić, że badania ze względu na swoją niejednorodność są trudne do porównania. Dodatkowym problemem, który pojawia się w kontekście badań klinicznych, a także codziennej praktyki, jest właściwa diagnoza i odróżnienie pierwotnych objawów negatywnych od wtórnych objawów negatywnych.

Risk of Prolonged Corrected QT Interval With Amisulpride Therapy for Renal Function Management in Patients With Schizophrenia.

Amisulpride (AMI) is a popular antipsychotic drug prescribed for the management of schizophrenia. However, patients may experience prolonged corrected QT (QTc) interval. We therefore aimed to assess the risk factors for QTc prolongation during AMI therapy in patients with schizophrenia. This study retrospectively enrolled 271 patients with schizophrenia. Continuous variables were analyzed with a t test or analysis of variance, and categorical variables were analyzed with a χ test. Patients with and without QTc prolongation were compared using a backward stepwise logistic regression analysis to identify the important variables. Comedication of AMI with clozapine (odds ratio, 3.5 [95% confidence interval, 1.3-9.7]) and decreased renal function (mildly decrease, 3.4 [1.2-10.1]; mild to moderately decreased, 4.8 [1.3-17.3]; moderately decreased, 13.6 [2.0-90.6]) were identified as the independent risk factors of QTc prolongation. The dose-normalized plasma concentration of AMI (plasma concentration per dose) was significantly higher in the QTc prolongation group (z = -1.735, P = 0.015) and renal dysfunction group (F = 16.002, P < 0.001). Renal function should be monitored in patients prescribed with AMI, particularly in those taking clozapine. Plasma concentration per dose values can be considered as a risk factor of QTc interval prolongation. The founding help clinicians to analyze the risk of QTc prolongation before prescribing AMI and to monitor QTc prolongation during AMI therapy.

Effect of amisulpride, olanzapine, quetiapine, and aripiprazole single administration on c-Fos expression in vasopressinergic and oxytocinergic neurons of the rat hypothalamic supraoptic nucleus.

The goal of this study was to reveal the impact of four types of atypical antipsychotics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI), with different receptor-affinity profile and dissociation constant, on the activity of hypothalamic supraoptic nucleus (SON) vasopressinergic and oxytocinergic neurons. Male Sprague Dawley rats received a single injection of vehicle (VEH) (0.1 ml/100g), AMI (20 mg/kg), OLA (5 mg/kg), QUE (15 mg/kg/) or ARI (10 mg/kg). Ninety min after treatment, the animals were fixed by transcardial perfusion, the brains removed, and cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black end product. Afterwards, the sections were exposed to vasopressin (AVP) and oxytocin (OXY) antibodies and the reaction product visualized by biotin-labeled fluorescent Alexa Fluor 568 dye. The data were evaluated from c-Fos and AVP or OXY merged sections. The present study shows that all four antipsychotics applied induced c-Fos expression in the SON. With respect to the stimulation efficacy of the individual antipsychotics, estimated based on the quantity of c-Fos-labeled AVP and OXY neurons, could be a preferential action assigned to QUE over moderate effect of ARI and lower effect to OLA and reduced effect of AMI (VEH < AMI < OLA < ARI < QUE). The present data for the first time provide an insight into the quantitative pattern of brain activity within the clusters of SON AVP and OXY cells in response to different atypical antipsychotics single treatment.

Development of Ru(bpy)32+-amisulpride electrogenerated chemiluminescence system for ultrasensitive and selective detection of amisulpride in pharmaceuticals and real plasma

In this study, a new electrogenerated chemiluminescence (ECL) reaction is presented through an oxidative-reductive pathway for amisulpride (AMS) as a new coreactant and Ru(bpy)32+ luminophore for the first time. The unique chemical structure of AMS through the presence of electroactive tertiary amino group in combination with the presence bulky electron donating group attached to α‑carbon of its amino group demonstrates the dramatic increase in ECL intensity of luminophore. Upon electrochemical oxidation of both the AMS and Ru(bpy)32+, the electrogenerated AMS+ undergoes spontaneous deprotonation to produce strong reductant that is reacted with electrogenerated Ru(bpy)33+ for excited state production. The developed method presented highly sensitive, selective, rapid, simple and cost-effective ECL approach for AMS detection. Under optimized parameters, the ECL-concentration plot showed a good linear relationship between ECL intensity and AMS concentrations in presence of 1.0 mM Ru(bpy)32+ over the concentration range of (5.0 × 10−10–2.0 × 10−7 M) with a lower detection limit of 7.6 × 10−9 M and a lower quantification limit of 2.51 × 10−8 M. The developed ECL method is successfully utilized for the determination of AMS in Amipride tablets and real human plasma.

Oral Bioavailability Enhancement of Amisulpride: Complexation and its Pharmacokinetics and Pharmacodynamics Evaluations.

Many CNS drugs have low bioavailability due to their poor water solubility of extensive first-pass metabolism and hence have less effectiveness. The present study aims to enhance the solubility and oral bioavailability of poorly watersoluble antipsychotic drug Amisulpride (AMS) through complexation with 2-hydroxypropyl β- cyclodextrin (HPβCD). It has slow and erratic absorption after oral administration. This report describes the study of the phase solubility diagram, preparation of the inclusion complex and tablet of prepared inclusion complex, characterization of the physico-chemical properties of the inclusion complex and tablet. In-vitro study (100 % drug release in 15 minutes), and in-vivo study of an AL-type (linear type) phase solubility diagram indicated a complex of AMS-HP-β-CD with the constant complex formation of 13245 M-1 at 37°C. The complex formation was confirmed by DSC, IR, and X-ray diffraction. The extent of absorption of the complex was determined in rats and was compared with that of pure drug and the market product. The peak plasma concentration of pure drug was 30.05 ± 1.3 ng/ml (Cmax) at 60 ± 3 min, whereas with the market product the value was 54.85 ± 1.2 ng/ml at 40 ± 1 min and with AMS-HPβCD inclusion complex the value was 79.01 ± 1.5 ng/ml. The AUCtot of the pure drug was 2980.34±3.6, the market product was 7238.73±2.9 and of the inclusion complex was 11871.1±2.8. Pharmacodynamic studies in mice showed improved effectiveness of drug compared to pure drug. The oral bioavailability of AMS was improved from 48% to 78%.