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Aim: Breast cancer is the most recurring cancer among females and is being diagnosed as a major cause of death among women. Materials & methods: Levosulpiride Schiff base derivatives were synthesized and analyzed by physical and spectral (FTIR, 1 H-NMR, 13 C-NMR) analysis. MTT assay against MCF-7 (human breast cancer cell line), scavenging activity and Molecular docking against receptors 1M17, 3PP0, 3IOK and 4KIK along ADME pharmacokinetic studies were performed. Results & conclusion: L1 and L3 synthesized derivatives have revealed better percent cell viability and inhibitory concentration (IC 50 ) with scavenging activity as of the parent compound. L1, L3 and L9 revealed significant docking scores compared with standard drugs. Most of the derivatives showed strong pharmacokinetic profiles while no drug crossed blood-brain barrier. The newly synthesized L1 and L3 levosulpiride-derived compounds have demonstrated promising anticancer properties against breast cancer cells.

Sulpiride (SUL), a benzamide derivative, acts as a multitarget drug with extensive biological properties. However, being a P-glycoprotein efflux substrate with a limited oral bioavailability imposes a challenge to its clinical efficacy. The current research explores the impact of tailored hybrid lipid-polysaccharide nanocomposites in augmenting the biological performance of SUL. Chitosan-graft-tocopherol polyethylene glycol 1000 succinate (TPGS) copolymers were synthesized and integrated as a polysaccharide shell into a SUL-loaded lipid nanocore. The optimized nanohybrids revealed a nanocore-shell structure with 110.1 nm particle size, 23.7 mV zeta potential, 85.42% encapsulation efficiency, a pH-dependent-release profile, and an acceptable mucoadhesive tendency. Employing TPGS into the chitosan backbone alleviated the cellular internalization of nanohybrids into the Caco-2 intestinal cells and hence increased the intestinal permeation and the oral bioavailability of SUL by 3.3, and 8.7-folds, respectively. Reserpine-induced depression rat model confirmed the superior antidepressant activity of nanohybrids, compared with free SUL and a marketed product. The nanohybrids exhibited 1.87- and 1.47-folds enhancement in both serotonin and dopamine levels, respectively. Additionally, nanohybrids were shown to attenuate brain oxidative stress state and SUL irritant effect on different body tissues. Overall, the newly tailored nanohybrids pave the way for an advance in the field of oral drug delivery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Sulpiride (SUL), is a selective antidopaminergic drug that had extensive biological activities. However, its sparingly aqueous solubility and limited gastrointestinal permeability lead to scanty oral bioavailability which hinders its clinical efficacy., Objective: SUL-loaded lipospheres (SUL-LPS) were designed to serve as an oral biocompatible nanovector for improving SUL permeability as well as conquering its low oral absorption and then in turn enhancing its antidepressant action., Methods: SUL-LPS were fabricated via two processing techniques namely, melt emulsification and solvent evaporation. The impact of different lipid cores, phospholipid shells together with various surfactant concentrations and types on the lipospheres properties were screened. Detailed physicochemical elucidations were performed followed by ex vivo permeation appraisal using the non-everted intestine model. The pharmacokinetic parameters of SUL-LPS, free SUL and marketed product were assessed following oral administration to healthy rats. Reserpine-induced depression rat model was used to assess the antidepressant action of SUL-LPS on which full behavioural and biochemical analysis was conducted. Safety attributes of nanoencapsulated SUL on the brain and other internal organs were evaluated., Results: The optimum LPS revealed an excellent nanosize with a narrow PdI, negative zeta potential and acceptable entrapment efficiency of 68.62 nm, 0.242, -30.4 mV and 84.12%, respectively. SUL-LPS showed a sustained release pattern and 2.1-fold enhancement in the intestinal permeation parameters with low mucin interaction. Oral pharmacokinetic appraisal exhibited that LPS provided 3.4-fold improvement in SUL oral bioavailability together with long-circulating properties, relative to the free drug. Pharmacodynamic study confirmed the superior antidepressant action of SUL-LPS as evident by 1.6 and 1.25-fold elevation in the serotonin and dopamine expressions, respectively. Meanwhile, nanotoxicological appraisal proved the biocompatibility of SUL-LPS upon repetitive oral administration., Conclusion: Rationally designed lipospheres hold promising in vitro and in vivo characteristics for efficient delivery of SUL with high oral bioavailability, antidepressant activity together with a good safety profile., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Mohyeldin et al.)

Four common refractory pharmaceuticals, diclofenac (DF), sulpiride (SP), sulfamethoxazole (SMX) and sulfisomidine (SIM) were detected in the Disc Tubular Reverse Osmosis (DTRO) concentrates with higher concentrations ranging from 0.85 to 11.57 μg/L from the local landfill. The effect of complex matrix of DTRO concentrates on the UV-Fenton degradation kinetics of DF, SP, SMX and SIM and their transformation products (TPs) were studied. All the four pharmaceuticals could be degraded more efficiently in the ultrapure water than that in the DTRO-concentrate matrix, which also had a significant negative effect on the kinetic constants of the degradation. Twenty-two out of forty-nine TPs were newly identified by HPLC-QTOF-MS and their peak-area evolution was presented. The main degradation pathways for four pharmaceuticals were identified. When assessing cytotoxicity by using HepG2 cells, there appeared to be an obvious toxicity-increase region for each of SP, SMX and SIM. Eleven TPs were identified as the potential toxicity-increase causing TPs by combination of the QSAR prediction, HepG2 cytotoxicity assessment and peak-area evolution of TPs. Therefore, UV-Fenton process was a promising method for the refractory pharmaceutical degradation even in the complex water matrix and choosing appropriate reaction parameters for the UV-Fenton could eliminate the cytotoxicity of the TPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The aim of this study was to develop levosulpiride-loaded solid lipid nanoparticles (SLNs) with enhanced solubilisation and bioavailability. The levosulpiride loaded-SLNs were composed of levosulpiride, stearic acid, and tween 80 in their respective weight ratios of (1, 5, and 1.5 mg) dissolved in 1 ml distilled water. Physicochemical properties of the SLNs such as particle size, shape, crystallinity, and chemical interaction were evaluated. Further, the in vitro drug dissolution, pharmacokinetic and stability studies of the SLNs were performed. The SLNs were rounded shaped stable nanoparticles with average diameter of 200 nm. They demonstrate 1.5- and 3-fold better drug dissolution when compared with the commercial product and levosulpiride powder, respectively. The SLNs enhanced the bioavailability of levosulpiride 3 times and 7 times, respectively, when compared with the commercial product and levosulpiride powder. It can be concluded that SLNs are capable to improve the dissolution and bioavailability of levosulpiride, even more than the commercial product.

Background: Sulpiride, which has selective dopaminergic blocking activity, is a substituted benzamide antipsychotic drug playing a prominent role in the treatment of schizophrenia, which more selective and primarily blocks dopamine D2 and D3 receptor., Objective: This study has two main objectives, firstly; the molecular modeling studies (MD and Docking, ADME) were conducted to define the molecular profile of sulpiride and sulpiridereceptor interactions, another to synthesize polymeric nanoparticles with chitosan, having the advantage of slow/controlled drug release, to improve drug solubility and stability, to enhance utility and reduce toxicity., Methods: Molecular dynamic simulation was carried out to determine the conformational change and stability (in water) of the drug and the binding profile of D3 dopamine receptor was determined by molecular docking calculations. The pharmacological properties of the drug were revealed by ADME analysis. The ionic gelation method was used to prepare sulpiride loaded chitosan nanoparticles (CS NPs). The Dynamic Light Scattering (DLS), UV-vis absorption (UV), Scanning Electron Microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy techniques were carried out to characterize the nanoparticles. In vitro cell cytotoxicity experiments examined with MTT assay on mouse fibroblast (L929), human neuroblastoma (SH-SY5Y) and glioblastoma cells (U-87). The statistical evaluations were produced by ANOVA., Results: The residues (ASP-119, PHE-417) of D3 receptor provided a stable docking with the drug, and the important pharmacological values (blood brain barrier, Caco-2 permeability and human oral absorption) were also determined. The average particle size, PdI and zeta potential value of sulpiride- loaded chitosan NPs having a spherical morphology were calculated as 96.93 nm, 0.202 and +7.91 mV. The NPs with 92.8% encapsulation and 28% loading efficiency were found as a slow release profile with 38.49% at the end of the 10th day. Due to the formation of encapsulation, the prominent shifted wave numbers for C-O, S-O, S-N stretching, S-N-H bending of Sulpiride were also identified. Mitochondrial activity of U87, SHSY-5Y and L929 cell line were assayed and evaluated using the SPSS program., Conclusion: To provide more efficient use of Sulpiride having a low bioavailability of the gastrointestinal tract, the nanoparticle formulation with high solubility and bioavailability was designed and synthesized for the first time in this study for the treatment of schizophrenia. In addition to all pharmacological properties of drug, the dopamine blocking activity was also revealed. The toxic effect on different cell lines have also been interpreted., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

To test whether sulpiride (SP), an anti-psychotic and prokinetic drug, shows beneficial effects on experimental murine colitis, a colon-targeted prodrug of SP, 5-(aminoethanoylsulfamoyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxybenzamide (glycylsulpiride (GSP)), was synthesized and its colonic delivery and therapeutic activity against 2,4-dinitrobenzenesulfonic acid (DNBS)-induced rat colitis were assessed. Synthesis of GSP was verified by infrared and proton nuclear magnetic resonance spectroscopy. GSP was converted to SP when incubated with the cecal contents but not when incubated with the small intestinal contents. The percent conversion was about 50.5% at 6 h and 67.7% at 10 h. Colonic delivery of GSP was examined by comparison with sulfasalazine (SSZ), a colon-specific prodrug of 5-aminosalicylic acid currently used for the treatment of inflammatory bowel disease. The two prodrugs accumulated similar concentrations of the corresponding parent drugs in the cecum at 2, 4, and 6 h after oral gavage. Although oral gavage of GSP released millimolar level of SP in the large intestine, SP was hardly detected in the blood. GSP improved colonic damage score and reduced myeloperoxidase activity up to 80.5% in the inflamed colon in a dose-dependent manner. Moreover, GSP was able to reduce the levels of inflammatory mediators in the inflamed colon. Overall, the anti-colitic effectiveness of GSP and SSZ was similar. In conclusion, colonic delivery of SP ameliorates DNBS-induced colitis in rats with no significant systemic absorption of SP. Thus, colon-targeted SP may be therapeutically switched to an anti-colitic drug.

Amisulpride (AMS) is an atypical antipsychotic agent used for the treatment of schizophrenia. The effect of different variables, i.e., the type of cyclodextrins (CDs), ratio of drug/CDs, and type of loading on the prepared AMS-CD liposomes (single and double loaded) was studied by applying 2 3 full factorial design. Double-loaded liposomes are loaded with AMS-hydroxyl propyl-β-cyclodextrin (HP-β-CD) in the aqueous phase and free drug in the lipophilic bilayer, while single-loaded liposomes are loaded only with AMS-HP-β-CD in the aqueous phase. Entrapment efficiency, particle size, polydespersibility, and zeta potential were selected as dependent variables. Design Expert® software was used to obtain an optimized formulation with high entrapment efficiency (64.55 ± 1.27%), average particle size of 40.1 ± 2.77 nm, polydespersibility of 0.44 ± 0.37, and zeta potential of - 48.8 ± 0.28. Optimized formula was evaluated for in vitro release, surface morphology and stability study was also conducted. AMS-HP-β-CD in double-loaded liposomes exhibited higher drug release than those in the conventional liposomes and in the single-loaded liposomes. The maximum plasma concentration (C max ) of AMS in optimized AMS-HP-β-CD double-loaded liposomal formulation increased by 1.55- and 1.29-fold, as compared to the commercial tablets and conventional liposomes, respectively. However, the relative bioavailability of AMS double-loaded liposomes was 1.94- and 1.28-folds of commercial tablet and conventional liposomes, respectively.

This study aims to investigate factors affecting weakly basic drugs liposomal systems. Resolution V fractional factorial design (2 V 5-1 ) is used as an example of screening designs that would better be used as a wise step before proceeding with detailed factors effects or optimization studies. Five factors probable to affect liposomal systems of weakly basic drugs were investigated using Amisulpride as a model drug. Factors studied were; A: Preparation technique B: Phosphatidyl choline (PhC) amount (mg) C: Cholesterol: PhC molar ratio, D: Hydration volume (ml) and E: Sonication type. Levels investigated were; Ammonium sulphate-pH gradient technique or Transmembrane zinc chelation-pH gradient technique, 200 or 400 mg, 0 or 0.5, 10 or 20 ml and bath or probe sonication for A, B, C, D and E respectively. Responses measured were Particle size (PS) (nm), Zeta potential (ZP) (mV) and Entrapment efficiency percent (EE%). Ion selective electrode was used as a novel method for measuring unentrapped drug concentration and calculating entrapment efficiency without the need for liposomal separation. Factors mainly affecting the studied responses were Cholesterol: PhC ratio and hydration volume for PS, preparation technique for ZP and preparation technique and hydration volume for EE%. The applied 2 V 5-1 design enabled the use of only 16 trial combinations for screening the influence of five factors on weakly basic drugs liposomal systems. This clarifies the value of the use of screening experiments before extensive investigation of certain factors in detailed optimization studies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rationale: Racemic (RS)-amisulpride (Solian ® ) is an atypical antipsychotic drug used to treat schizophrenia and dysthymia. Blockade of dopamine D 2 /D 3 and/or serotonin 5-HT 7 receptors is implicated in its pharmacological effects. While the (S)-amisulpride isomer possesses a robust discriminative cue, discriminative stimulus properties of (RS)-amisulpride have not been evaluated., Objectives: The present study established (RS)-amisulpride as a discriminative stimulus and assessed amisulpride-like effects of amisulpride stereoisomers, other benzamide derivatives, and antipsychotic, antidepressant, and anxiolytic drugs., Methods: Adult, male C57BL/6 mice were trained to discriminate 10 mg/kg (RS)-amisulpride from vehicle in a two-lever food-reinforced operant conditioning task., Results: (RS)-Amisulpride's discriminative stimulus was dose-related, time-dependent, and stereoselective. (S)-Amisulpride (an effective dose of 50% (ED 50 ) = 0.21 mg/kg) was three times more potent than (RS)-amisulpride (ED 50  = 0.60 mg/kg) or (R)-amisulpride (ED 50  = 0.68 mg/kg). (RS)-Amisulpride generalized fully to the structurally related atypical antipsychotic/antidysthymia drug sulpiride (Sulpor ® ; ED 50  = 7.29 mg/kg) and its (S)-enantiomer (ED 50  = 9.12 mg/kg); moderate to high partial generalization [60-75% drug lever responding (%DLR)] occurred to the benzamide analogs tiapride (Tiapridal ® ) and raclopride, but less than 60% DLR to metoclopramide (Reglan ® ), nemonapride (Emilace ® ), and zacopride. Antipsychotic, antidepressant, and antianxiety drugs from other chemical classes (chlorpromazine, quetiapine, risperidone, and mianserin) produced 35-55% amisulpride lever responding. Lastly, less than 35% DLR occurred for clozapine, olanzapine, aripiprazole imipramine, chlordiazepoxide, and bupropion., Conclusions: (RS)-Amisulpride generalized to some, but not all benzamide derivatives, and it failed to generalize to any other antipsychotic, antidepressant, or antianxiety drugs tested. Interestingly, the (R)-isomer shared very strong stimulus properties with (RS)-amisulpride. This finding was in contrast to findings from Donahue et al. (Eur J Pharmacol 734:15-22, 2014), which found that the (R)-isomer did not share very strong stimulus properties when the (S)-isomer was the training drug.

Objective: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients., Methods: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems., Results: The optimum formulations were composed of different ratios of Capryol™ 90 as an oil phase, Cremophor ® RH40 as a surfactant, and Transcutol ® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19 nm and emulsification time not exceeding 1 min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6-2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies., Conclusions: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.

Objective: The current investigation is focused on the formulation and in vivo evaluation of optimized solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of amisulpride (AMS) for improving its oral dissolution and bioavailability., Methods: Liquid SNEDDS (L-SNEDDS) composed of Capryol™ 90 (oil), Cremophor ® RH40 (surfactant), and Transcutol ® HP (co-surfactant) were transformed to solid systems via physical adsorption onto magnesium aluminometasilicate (Neusilin US2). Micromeretic studies and solid-state characterization of formulated S-SNEDDS were carried out, followed by tableting, tablet evaluation, and pharmacokinetic studies in rabbits., Results: Micromeretic properties and solid-state characterization proved satisfactory flow properties with AMS present in a completely amorphous state. Formulated self-nanoemulsifying tablets revealed significant improvement in AMS dissolution compared with either directly compressed or commercial AMS tablets. In vivo pharmacokinetic study in rabbits emphasized significant improvements in t max , AUC (0-12) , and AUC (0-∞) at p < .05 with 1.26-folds improvement in relative bioavailability from the optimized self-nanoemulsifying tablets compared with the commercial product., Conclusions: S-SNEDDS can be a very useful approach for providing patient acceptable dosage forms with improved oral dissolution and biovailability.

Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg -1 ·d -1 ) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg -1 ·d -1 ) and DEX (8 mg·kg -1 ·d -1 ) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.

Neuroleptic drugs are widely applied in effective treatment of schizophrenia and related disorders. The lipophilic character of neuroleptics means that they tend to accumulate in the lipid membranes, impacting their functioning and processing. In this paper, the effect of four drugs, namely, thioridazine, olanzapine, sulpiride, and amisulpride, on neutral and negatively charged lipid bilayers was examined. The interaction of neuroleptics with lipids and the subsequent changes in the membrane physical properties was assessed using several complementary biophysical approaches (isothermal titration calorimetry, electron paramagnetic resonance spectroscopy, dynamic light scattering, and ζ potential measurements). We have determined the thermodynamic parameters, that is, the enthalpy of interaction and the binding constant, to describe the interactions of the investigated drugs with model membranes. Unlike thioridazine and olanzapine, which bind to both neutral and negatively charged membranes, amisulpride interacts with only the negatively charged one, while sulpiride does not bind to any of them. The mechanism of olanzapine and thioridazine insertion into the bilayer membrane cannot be described merely by a simple molecule partition between two different phases (the aqueous and the lipid phase). We have estimated the number of protons transferred in the course of drug binding to determine which of its forms, ionized or neutral, binds more strongly to the membrane. Finally, electron paramagnetic resonance results indicated that the drugs are localized near the water-membrane interface of the bilayer and presence of a negative charge promotes their burying deeper into the membrane.

The purpose of this work was to investigate the crystal structures and physicochemical properties of amisulpride polymorphs. Except of the previously reported polymorph (named as Form I), a new polymorphic form (named as Form II) was discovered through comprehensive solid-state screening experiments. Both polymorphic forms were characterized by single crystal X-ray structure analysis (SXRD), powder X-ray diffraction (PXRD), dynamic vapor sorption (DVS) and thermal analysis (TGA and DSC) as well. It has been found that the Forms I and II are of conformational polymorph with the main conformational difference around ethylsulfonyl group. Form II possesses lower hygroscopicity and better solubility compared with that of Form I, indicating Form II could be an alternate solid form for formulation development., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this study, an optimized epichlorohydrin-crosslinked semi-interpenetrating polymer network xerogel matrix system (XePoMas) for the controlled delivery of sulpiride was prepared. The ability of XePoMas to sustain drug release was determined by in vitro and in vivo drug release experiments. Swelling of the xerogel over the 24-h experimental period ranged from 346 to 648%; swelling was observed to increase exponentially over the initial 8 h. In vitro drug release depicted a linear zero order drug release profile with an R 2 value of 0.9956. The ability of the fabricated XePoMas to sustain drug release and enhance bioavailability of sulpiride in vivo was investigated by evaluating the plasma drug concentration over 24 h in the large pig model. The optimized XePoMas formulation was shown to increase intestinal absorption of sulpiride to a greater extent than the marketed product in vivo, with a C max of 830.58 ng/mL after 15 h.

Background: There is a poor correlation between total concentrations of proton-accepting compounds (most basic drugs) in unstimulated oral fluid and in plasma. The aim of this study was to compare clozapine, norclozapine, and amisulpride concentrations in plasma and in oral fluid collected using commercially available collection devices [Thermo Fisher Scientific Oral-Eze and Greiner Bio-One (GBO)]., Methods: Oral-Eze and GBO samples and plasma were collected in that order from patients prescribed clozapine. Analyte concentrations were measured by liquid chromatography-tandem mass spectrometry., Results: There were 112 participants [96 men, aged (median, range) 47 (21-65) years and 16 women, aged 44 (21-65) years]: 74 participants provided 2 sets of samples and 7 provided 3 sets (overall 2 GBO samples not collected). Twenty-three patients were co-prescribed amisulpride, of whom 17 provided 2 sets of samples and 1 provided 3 sets. The median (range) oral fluid within the GBO samples was 52 (13%-86%). Nonadherence to clozapine was identified in all 3 samples in one instance. After correction for oral fluid content, analyte concentrations in the GBO and Oral-Eze samples were poorly correlated with plasma clozapine and norclozapine (R = 0.57-0.63) and plasma amisulpride (R = 0.65-0.72). Analyte concentrations in the 2 sets of oral fluid samples were likewise poorly correlated (R = 0.68-0.84). Mean (SD) plasma clozapine and norclozapine were 0.60 (0.46) and 0.25 (0.21) mg/L, respectively. Mean clozapine and norclozapine concentrations in the 2 sets of oral fluid samples were similar to those in plasma (0.9-1.8 times higher), that is, approximately 2- to 3-fold higher than those in unstimulated oral fluid. The mean (±SD) amisulpride concentrations (microgram per liter) in plasma (446 ± 297) and in the Oral-Eze samples (501 ± 461) were comparable and much higher than those in the GBO samples (233 ± 318)., Conclusions: Oral fluid collected using either the GBO system or the Oral-Eze system cannot be used for quantitative clozapine and/or amisulpride therapeutic drug monitoring.

The untargeted chemometric methodology for the impurity profiling of amisulpride pharmaceutical formulations was successfully applied and developed. For this purpose a fast, accurate and specific analytical method was elaborated with the use of ultra high pressure liquid chromatography coupled with high resolution hybrid electrospray ionization quadrupole time of flight mass spectrometer in a fast polarity switching mode. All the obtained chromatographic profiles were aligned and a multivariate chemometric analysis including principal component analysis and partial least square (PLS) was performed. The developed PLS-DA pattern recognition model allowed the identification of all the analyzed pharmaceutical formulations of amisulpride as well as their manufacturers. Additionally, six impurities of amisulpride were identified by the use of MS/MS fragmentation and one of them was found as the main impurity (Imp-1) and can be regarded as the primary impurity "marker" for the analyzed formulations. Furthermore, one new impurity of amisulpride was found and its chemical structure was proposed (4-amino-5-(ethylsulfinyl)-2-methoxy-N-[(1-ethylpyrrolidin-2-yl)methyl]benzamide)., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We previously demonstrated that chotosan (CTS), a traditional herbal formula called Kampo medicine, improves diabetes-induced cognitive deficits. In the present study, we investigated the antidepressant-like effects of CTS in mice. The administration of CTS (1.0 g/kg, for 3 days) decreased the immobility time in the forced-swim test, and this decrease was prevented by the prior administration of sulpiride (an antagonist of D 2/3 receptors) and WAY100635 (an antagonist of 5-HT 1A receptors). None of the treatments tested altered the locomotor activity of mice. These results suggest that CTS exerts antidepressant-like effects through changes in the serotonergic and dopaminergic systems., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

The aim of this study was to assess the effect of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) on the physicochemical characterization and oral bioavailability of a novel l-sulpiride-loaded quaternary microcapsule (QMC). The effect of carriers on drug solubility was investigated. Among the carriers tested, polyvinyl pyrrolidone (PVP), sodium lauryl sulphate (SLS) and TPGS were selected as polymer, surfactant and absorption enhancer, respectively, due to their high drug solubility. Using the solvent evaporation method, numerous QMCs with different ratios of l-sulpiride, PVP, SLS and TPGS were prepared, and their physicochemical properties, solubility and release were evaluated. In addition, the influence of TPGS concentration on the oral bioavailability of various drug doses was evaluated. All QMCs converted the crystalline drug to the amorphous form and remarkably improved the solubility, release and oral bioavailability of the drug. Furthermore, the TPGS concentration in the QMCs hardly affected the crystallinity, particle size and release, but considerably increased the solubility and oral bioavailability of the drug. In particular, as the dose of administered drug was increased, TPGS provided a greater improvement in oral drug bioavailability. Thus, TPGS played an important role in improving the oral bioavailability of l-sulpiride. Moreover, the QMC with a drug/PVP/SLS/TPGS weight ratio of 5:12:1 :20 with approximately 3.3-fold improved oral bioavailability would be recommended as a commercial pharmaceutical product for oral administration of l-sulpiride., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The purpose of this study was to compare the powder properties, solubility, dissolution and oral absorption of solvent-wetted (SWSD) and kneaded (KNSD) l-sulpiride-loaded solid dispersions. The SWSD and KNSD were prepared with silicon dioxide, sodium laurylsulfate and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) using a spray dryer and high shear mixer, respectively. Their powder properties, solubility, dissolution and oral absorption were assessed compared to l-sulpiride powder. The drug in SWSD was in the amorphous state; however, in KNSD, it existed in the crystalline state. The SWSD with a drug/sodium laurylsulphate/TPGS/silicon dioxide ratio of 5/1/2/12 gave the higher drug solubility and dissolution compared to the KNSD with the same composition. The oral absorption of drug in the SWSD was 1.4 fold higher than the KNSD and 3.0 fold higher than the l-sulpiride powder (p<0.05) owing to better solubility and reduced crystallinity. Furthermore, the SWSD at the half dose was bioequivalent of commercial l-sulpiride-loaded product in rats. Thus, the SWSD with more improved oral absorption would be recommended as an alternative for the l-sulpiride-loaded oral administration., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Context: Levosulpiride (LSP) is a hydrophobic benzamide derivative used in the treatment of schizophrenia. SNEDDS were extensively practiced for systemic delivery of poorly aqueous soluble drugs to achieve maximum bioavailability., Objective: The present study was focussed on the formulation, optimisation and evaluation of LSP SNEDDS using castor oil, for enhancement of drug absorption and bioavailability., Materials and Methods: Pseudo-ternary phase diagram was plotted to identify the range of SNEDDS components. Twenty formulations were designed, prepared and characterised by its particle size, zeta potential, viscosity, and stability. In vitro dissolution data modelling was performed. Microscopy, FTIR and in vivo bioavailability studies were conducted for optimum formulation. Results, discussion and conclusion: F18 containing castor oil, 0.9 mL; PEG 600, 1.36 mL and Tween 80, 2.74 mL was found to be optimum. The optimised formulation had shown uniform globule size, no interactions of LSP with SNEDDS components and higher pharmacokinetic parameters than that of commercial preparation.

A novel and efficient sample preconcentration technique based on the Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) coated with silica (SiO2) has been developed for extraction and determination of sulpiride. The functionalized MNPs showed excellent dispersibility in aqueous solution and were applied to magnetic solid-phase extraction of sulpiride from human urine and blood prior to high-performance liquid chromatography analysis. The separation, preconcentration and desorption procedure was completed in 10 min. Optimal experimental conditions, including sample pH, the amount of the MNPs, eluent type and volume, and the ultrasonication time were studied and established. The method showed good linearity for the determination of sulpiride in the concentration range of 10-1000 ng/mL in urine and blood. The recovery of the method was in the range between 91.2 and 97.5%, and the limit of detection was 2 ng/mL for sulpiride in human blood and urine. The results indicated that the present procedure is a suitable pretreatment method for biological samples., (Copyright © 2015 John Wiley & Sons, Ltd.)

Attenuation of pharmaceuticals due to natural sunlight is expected to be an important removal pathway in wastewater treatment plants using treatment lagoon systems. In this work, the photolysis of two antidepressants, amisulpride and desipramine, has been investigated in both ultrapure water and wastewater under simulated solar irradiation. Results showed that for amisulpride short irradiation times (t1/2 approximately 3h in pure water and 4h in wastewater) were adequate to degrade the parent compound while a longer exposure period was required for desipramine (t1/2 of approximately 36 h in pure water), although its degradation is enhanced almost three times by indirect photolysis in wastewaters. A significant number of transformation products (TPs) were identified for both pharmaceuticals by high-resolution mass spectrometry. In general, TPs formed are not persistent although acute toxicity tests for desipramine and its TPs showed an increase of the mixture toxicity after solar irradiation, suggesting that some TPs may be more toxic than the parent compound. In wastewaters collected from treatment lagoons, only amisulpride and one of its major TPs, TP 357, were detected. This indicates that long solar exposure times may be necessary for an effective elimination of these substances in lagoon systems or that photolysis may not be the main removal pathway for these particular compounds., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The enantioselective complexation of sulpiride by a number of cyclodextrins (CDs) was deeply investigated by different techniques with the aim of evaluating the role of the used chiral selectors involved in the enantioseparation of the eutomer levosulpiride (S-SUL) and its dextro-isomer by capillary electrophoresis (CE). A CE method was previously developed with the aim of determining the optical purity of S-SUL and was based on the use of a dual cyclodextrin system, made by sulfated-β-cyclodextrin (SβCD) and methyl-β-cyclodextrin (MβCD). In this paper, a molecular modeling study made it possible to explain the different affinity of sulpiride enantiomers for several CDs, which had been tested during the early phase of CE method development. The potential and the gain energy of the inclusion complexes between the enantiomers and neutral and charged CDs were calculated on the minimized conformations. The calculated docking energies indicated that the most stable complexes were effectively obtained with SβCD and MβCD. A correlation between CE migration time of the last migrating enantiomer S-SUL and the stability of analyte-neutral CDs complexes was postulated. Furthermore, two-dimensional rotating-frame Overhauser effect spectroscopy NMR (2-D ROESY) experiments were carried out, which clearly indicated the formation of complexes and suggested the inclusion of the benzene sulfonamide moiety of S-SUL inside the hydrophobic cavity of the CDs., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Pharmaceutical development was adopted in the current study to propose a pediatric rectal formulation of sulpiride as a substitute to the available oral or parenteral formulations in the management of Tourette syndrome (TS). The goal was to formulate a product that is easy to use, stable, and highly bioavailable and to achieve a rapid clinical efficacy. Towards this aim, sulpiride solid dispersion (SD) with tartaric acid at a weight ratio of 1:0.25 was incorporated into different suppository bases, namely witepsol W25, witepsol H15, witepsol E75, suppocire NA, suppocire A, glycerogelatin, and polyethylene glycols. The formulae were evaluated in vitro using different pharmacotechnical methods such as visual, melting, weight and content uniformities, drug release, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and X-ray diffraction (XRD) analyses. In vivo bioavailability was also assessed in rabbits to compare the bioavailability of either raw sulpiride-incorporated or its SD-incorporated witepsol H15-based suppositories to its oral suspension (reference). Sulpiride SD-incorporated witepsol H15 formulation showed acceptable in vitro characteristics with a bioavailability of 117% relative to oral dosing, which excel that in humans (27% after dosing of oral product). In addition, the proposed formula not only passed the 6-month stability study but also proposed a promising scale-up approach. Hence, it showed a great potential for pediatric product development to manage TS in rural areas.

To understand the structural basis for the Na(+)-sensitivity of ligand binding to dopamine D2-like receptors, using computational analysis in combination with binding assays, we identified interactions critical in propagating the impact of Na(+) on receptor conformations and on the ligand-binding site. Our findings expand the pharmacologically-relevant conformational spectrum of these receptors.

Benign prostatic hyperplasia (BPH) is the most common age-related disease in men. Here we tested the efficacy of Rapatar, a micellar nanoformulation of rapamycin, in two rat models of BPH: testosterone-induced and sulpiride-induced hyperplasia in ventral lobes and lateral/dorsal lobes, respectively. We found that Rapatar prevented hypertrophic and hyperplastic abnormalities and degenerative alterations in both BPH models. Rapatar normalized weight of the lateral lobes in sulpiride-induced BPH, the most relevant animal model of human BPH. Unlike Finasteride, a standard therapy of BPH, Rapatar reduced inflammation caused by sulpiride. No obvious side effects of Rapatar were detected. Our data provide a rationale for clinical trials of Rapatar in patients suffering from BPH.

The study on the conformational and vibrational behaviors of sulpiride molecule which is known as a neuroleptic or antipsychotic drug that is widely used clinically in the treatment of schizophrenic or depressive disorders is an important scientific and practical task. In here, a careful enough study of monomer and dimeric forms of sulpiridine {5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl) ethyl]-2-methoxy-benzamide (C(15)H(23)N(3)O(4)S)} is undertaken by density functional theory (DFTB3LYP) method with the B3LYP/6-31 G(d,p) basis set. The conformations of free molecule were searched by means of torsion potential energy surfaces scan studies through dihedral angles D1 (8 N, 18 C, 20 C, 23 N), D2 (18 C, 20 C, 23 N, 25 C) and D3 (28 C, 30 C, 41 S, 44 N) in electronically ground state, employing 6-31 G basic set. The final geometrical parameters for the obtained stable conformers were determined by means of geometry optimization, carried out at DFT/B3LYP/6-31 G(d,p) theory level. Afterwards, the possible dimer forms of the molecule were formed and their energetically preferred conformations were investigated. Moreover, the effect of basis set superposition error on the structure and energy of the three energetically favourable sulpiride dimers has been determined. The optimized structural parameters of the most stable monomer and three low energy dimer forms were used in the vibrational wavenumber calculations. Raman and IR (4000-400 cm(-1)) spectra of sulpiride have been recorded in the solid state. The assignment of the bands was performed based on the potential energy distribution data. The natural bond orbital analysis has been performed on both monomer and dimer geometries in order to elucidate delocalization of electron density within the molecule. The predicted frontier molecular orbital energies at DFT/B3LYP/6-31 G(d,p) theory level show that charge transfer occurs within the molecule. The first-order hyperpolarizability (β0) and related properties (μ and α) of the title molecule were also calculated.

The current study involved the development of a novel sustained release crosslinked semi-IPN xerogel matrix tablet prepared by chemical crosslinking of poly(ethylene) oxide (PEO) and gellan gum (GG) employing epichlorohydrin (EPI) as crosslinker. A Box-Behnken design was employed for the statistical optimization of the matrix system to ascertain the ideal combination of native polymeric and crosslinking agents. Characterization studies were performed by employing standard polymer characterization techniques such as Fourier transform infrared spectrometry, differential scanning calorimetry, and scanning electron microscopy. Formulated matrix tablets displayed zero-order release kinetics, extending over 24 h. The mechanism of drug release was primarily by swelling and surface erosion. Crosslinked semi-IPN xerogel matrix tablets were compared to non-crosslinked polymer blends; results from the study conducted showed that the physiochemical properties of the PEO and GG were sufficiently modified to allow for sustained release of sulpiride with a 100% drug release at 24 h in a controlled manner as compared to non-crosslinked formulations which displayed further release beyond the test period. Crosslinked formulations displayed water uptake between 450 and 500% indicating a controlled rate of swelling and erosion allowing for sustained release. Surface morphology of the crosslinked system depicted a porous structure formed by interpenetrating networks of polymers, allowing for a greater degree of controlled penetration into the system affording it the ability to sustain drug release. Therefore, conclusively, based on the study performed, crosslinked PEO-GG allows for the sustained release of sulpiride from a hydrophilic semi-IPN xerogel matrix system.

Amisulpride, a substituted benzamide derivative, exerts atypical antipsychotic and antidepressant clinical effects and its (S)-stereoisomer is thought to underlie these actions. In the present study, male C57BL/6 mice were trained to discriminate (S)-amisulpride (10mg/kg, s.c.) from vehicle in a two-lever drug discrimination task for food reward. The (S)-amisulpride stimulus was rapidly acquired and was shown to be dose-related, time dependent (effective between 30 and 120min) and stereoselective: (S)-amisulpride (ED50=1.77mg/kg; 4.2µmol/kg) was about three times more potent than rac-amisulpride (ED50=4.94mg/kg; 13.4µmol/kg) and ten times more potent than (R)-amisulpride (ED50=15.84mg/kg; 42.9µmol/kg). In tests of stimulus generalization, the (S)-amisulpride stimulus generalized completely to sulpiride (ED50=12.67mg/kg; 37.1µmol/kg), a benzamide analog that also is purported to be an atypical antipsychotic, but did not fully generalize to the typical antipsychotic drug haloperidol (maximum of 45% drug-lever responding) nor to the atypical antipsychotic drugs clozapine (partial substitution of 65% drug-lever responding) or aripiprazole (~30% drug-lever responding). These results demonstrated that (S)-amisulpride appears to exert a unique discriminative stimulus effect that is similar to other benzamides, but which differs from other structural classes of antipsychotic drugs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We report an effective and a quantitative analysis method for one of pharmaceuticals, sulpiride, in river water by online solid phase extraction (SPE) connected with liquid chromatography-mass spectrometry (LC-MS) using a molecularly imprinted polymer as a preconcentration medium. The polymer prepared with a pseudo template molecule showed the selective retention ability based on the interval recognition of functional groups in sulpiride. Also, the imprinted polymer provided an effective concentration of a trace level of sulpiride in offline SPE with dual washing processes using water and acetonitrile, although another imprinted polymer prepared by an authentic method using sulpiride and methacrylic acid as a template and a functional monomer, respectively, showed the selective adsorption only in organic solvents. Furthermore, we employed the imprinted polymer as the preconcentration column of online SPE-LC-MS and the results supposed that the proposed system allowed the quantitative analysis of sulpiride with high sensitivity and recovery (10ng/L at 96%). Additionally, the determination of sulpiride in real river water without an additional spiking was effectively achieved by the system., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Solid lipid nanoparticles (SLN), novel drug delivery carriers, can be utilized in enhancing both intestinal permeability and dissolution of poorly absorbed drugs. The aim of this work was to enhance the intestinal permeability of sulpiride by loading into SLN., Methods: A unique ultrasonic melt-emulsification method with minimum stress conditions was used for the preparation of SLN. The mixture of the drug and the melted lipids was simply dispersed in an aqueous solution of a surfactant at a temperature that was 10°C higher than the melting points of the lipids using probe sonication, and was then simultaneously dispersed in cold water. Several formulation parameters were optimized, including the drug-to-lipid ratio, and the types of lipids and surfactants used. The produced SLN were evaluated for their particle size and shape, surface charge, entrapment efficiency, crystallinity of the drug and lipids, and the drug release profile. The rat everted sac intestine model was utilized to evaluate the change in intestinal permeability of sulpiride by loading into SLN., Results: The method adopted allowed successful preparation of SLN with a monodispersed particle size of 147.8-298.8 nm. Both scanning electron microscopic and atomic force microscopic images showed uniform spherical particles and confirmed the sizes determined by the light scattering technique. Combination of triglycerides with stearic acid resulted in a marked increase in zeta potential, entrapment efficiency, and drug loading; however, the particle size was increased. The type of surfactant used was critical for particle size, charge, drug loading, and entrapment efficiency. Generally, the in vitro release profile demonstrated by all formulations showed the common biphasic mode with a varying degree of burst release. The everted sac model showed markedly enhanced sulpiride permeability in the case of the SLN-loaded formulation. The in situ results showed a very good correlation with the in vitro release data., Conclusion: Incorporation of sulpiride into SLN results in enhanced intestinal permeability of sulpiride, that may in turn increase overall oral absorption of the drug. The superior attributes of the prepared SLN, specifically the high particle size uniformity and drug loading capacity, is considered novel, especially given the simplicity and modest nature of the sonication method used.

A simple, precise, rapid, stability-indicating reversed phase high performance liquid chromatographic method with photodiode array detection was developed and validated for the determination of mebeverine hydrochloride in combination with sulpiride or with diloxanide furoate and metronidazole in the presence of their corresponding degradation products. Optimum separation was achieved in less than 10 min using an X-Bridge C18 column (150 mm × 4.6 mm i.d., 3.5 μm particle size); elution was accomplished via the application of a dual-mode solvent and flow rate gradient system. This elution system enables the separation of nine components within a cycle time of 15 min and with a resolution greater than 2.5. Detection was conducted at 230 nm, and purity assessment was performed using a photodiode array detector. The method has been validated with respect to specificity, linearity, accuracy, precision, limit of quantitation, limit of detection, robustness and ruggedness. The validation criteria were met in all cases. The developed HPLC method was successfully applied to commercial tablets. It was shown that this method is very sensitive to the determination of the degradation products, downward to 0.1 w/w% levels, which is far below the limits for testing these degradation products within their corresponding intact drugs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Performance of partial least squares regression (PLSR) is enhanced in the presented work by three multivariate models, including weighted regression PLSR (Weighted-PLSR), genetic algorithm PLSR (GA-PLSR), and wavelet transform PLSR (WT-PLSR). The proposed models were applied for the stability-indicating analysis of mixtures of mebeverine hydrochloride (meb) and sulpiride (sul) in the presence of their reported impurities and degradation products. The work introduced in this paper aims to compare these different chemometric methods, showing the underlying algorithm for each and making a comparison of analysis results. For proper analysis, a 6-factor, 5-level experimental design was established resulting in a training set of 25 mixtures containing different ratios of the interfering species. A test set consisting of 5 mixtures was used to validate the prediction ability of the suggested models. Leave one out (LOO) and bootstrap were applied to predict number of PLS components. The GA-PLSR proposed method was successfully applied for the analysis of raw material (test set 101.03% ± 1.068, 101.47% ± 2.721 for meb and sul, respectively) and pharmaceutical tablets containing meb and sul mixtures (10.10% ± 0.566, 98.16% ± 1.081 for meb and sul)., (Copyright © 2011 John Wiley & Sons, Ltd.)

The purpose of this research was to investigate inclusion complex formation between poorly soluble drug amisulpride (AMI) and γ-cyclodextrin (γ-CD). The solubility of AMI was enhanced by formation of inclusion complex of AMI with nano-hydrophobic cavity of γ-CD. The stoichiometry of inclusion complex was studied by continuous variation Job's plot method and found 1:1. The binding constant was found 1166.65 M(-1) by Benesi-Hildebrand plot. The molecular docking of AMI and γ-CD was done to investigate complexation. The inclusion complex formation was further confirmed by (1)H NMR and FT-IR, DSC and XRD analysis. The solubility of AMI was increased 3.74 times after inclusion complex formation with γ-CD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A new method of the chiral separation of three drugs such as sulpiride, amisulpride and mosapride was developed on the chiral stationary phase of amylose-tris-(5-chloro-2-methylphenylcarbamate) (ACMPC) by high performance liquid chromatography. The chromatographic behaviors of enantiomers of the three drugs were investigated in the mobile phases consisted of ethanol and n-hexane (containing 0.1% (v/v) diethylamine). The chromatographic conditions including the composition of the mobile phase, additives and temperature were further optimized for the chiral separation. The mechanism of racemic resolution for the mentioned drugs is discussed thermodynamically and structurally. The results indicated that these three chiral drugs could be separated on an ACMPC column under the optimum conditions, and their chiral resolutions were improved up to more than 1.5. The chromatographic parameters such as the retention factor kappa, separation factor a are presented, and the thermodynamic functions were calculated for the separation of the enantiomers of the three drugs. The method has been successfully applied to the determination of the enantiomers of the three drugs in tablets and blood serum. It is simple, reliable and accurate.

Metal complexes of the general formula [M(VER)(2)Cl(2)(H(2)O)(2)]·yH(2)O and [Cr(VER)(2)Cl(2)(H(2)O)(2)]Cl·H(2)O (where VER=verlipride, M=Mn(II) (y=2), Co(II) (y=2), Ni(II) (y=2), Cu(II) (y=1) and Zn(II) (y=0)) are prepared and characterized based on elemental analyses, IR, (1)H NMR, magnetic moment, molar conductance, and thermal analyses (TG and DTA) techniques. From the elemental analyses data, the complexes are formed in 1:2 [Metal]:[VER] ratio. The molar conductance data reveal that all the metal chelates are non-electrolytes except Cr(III) complex, it is 1:1 electrolyte. IR spectra show that VER is coordinated to the metal ions in a neutral monodentate manner with O donor site of the carbonyl O atom. On the basis of spectral studies and magnetic moment measurements an octahedral geometry has been assigned for the complexes. The thermal behavior of these chelates is studied using thermogravimetric analysis technique. The results obtained show that the complexes lose hydrated water, HCl and coordinated water molecules followed immediately by decomposition of the ligand molecules in the successive unseparate steps. The VER drug, in comparison to its metal complexes is also screened for its biological activity against Gram positive bacterial (Staphylococcus aureus) and Gram negative bacteria (Escherichia coli) and fungi (Candida albicans and Aspergillus flavus) in vitro. The activity data show that most of the metal complexes have antibacterial activity like or higher than that of the parent VER drug against one or more species., (Published by Elsevier B.V.)

A comparison between support vector regression (SVR) and Artificial Neural Networks (ANNs) multivariate regression methods is established showing the underlying algorithm for each and making a comparison between them to indicate the inherent advantages and limitations. In this paper we compare SVR to ANN with and without variable selection procedure (genetic algorithm (GA)). To project the comparison in a sensible way, the methods are used for the stability indicating quantitative analysis of mixtures of mebeverine hydrochloride and sulpiride in binary mixtures as a case study in presence of their reported impurities and degradation products (summing up to 6 components) in raw materials and pharmaceutical dosage form via handling the UV spectral data. For proper analysis, a 6 factor 5 level experimental design was established resulting in a training set of 25 mixtures containing different ratios of the interfering species. An independent test set consisting of 5 mixtures was used to validate the prediction ability of the suggested models. The proposed methods (linear SVR (without GA) and linear GA-ANN) were successfully applied to the analysis of pharmaceutical tablets containing mebeverine hydrochloride and sulpiride mixtures. The results manifest the problem of nonlinearity and how models like the SVR and ANN can handle it. The methods indicate the ability of the mentioned multivariate calibration models to deconvolute the highly overlapped UV spectra of the 6 components' mixtures, yet using cheap and easy to handle instruments like the UV spectrophotometer., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Photostability of amisulpride under UVA irradiation in methanol solution was investigated and structural elucidation of its photodegradation products was performed. For the purpose of the quantitative and qualitative analysis of amisulpride and the stress degradation products elucidation, the reversed phase UHPLC-DAD system coupled with accurate mass hybrid ESI-Q-TOF mass spectrometer was used. During one run (10 min) with the use of auto MS/MS mode all essential data for the determination of photodegradation kinetics and for the structural formulas elucidation of the products was collected. Four degradation products were found and their masses with high accuracy (0.53-3.05 ppm) and formulas were obtained--258.0666 (C(10)H(14)N(2)O(4)S), 367.1564 (C(17)H(25)N(3)O(4)S), 341.1412 (C(15)H(23)N(3)O(4)S) and 385.1665 (C(17)H(27)N(3)O(5)S). For all the analyzed compounds MS/MS fragmentation spectra were obtained (collision energy 19.8-26.1 V) allowing structural elucidation of unknown degradation products and indicating photodegradation pathways of amisulpride. UHPLC-DAD/ESI-Q-TOF system was found to be a powerful analytical tool for the fast and accurate stability analysis of pharmaceutical substances., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Many proteins with poor transduction efficiency were reported to be delivered to cells by fusion with protein transduction domains (PTDs). In this study, we investigated the effect of levosulpiride on the transduction of PEP-1 ribosomal protein S3 (PEP-1-rpS3), and examined its influence on the stimulation of the therapeutic properties of PEP-1-rpS3. PEP-1-rpS3 transduction into HaCaT human keratinocytes and mouse skin was stimulated by levosulpiride in a manner that did not directly affect the cell viability. Following 12-O-tetradecanoylphorbol- 13-acetate (TPA)-induced inflammation in mice, levosulpiride alone was ineffective in reducing TPA-induced edema and in inhibiting the elevated productions of inflammatory mediators and cytokines, such as cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6 and -1β, and tumor necrosis factor- α. Anti-inflammatory activity by PEP-1-rpS3 + levosulpiride was significantly more potent than by PEP-1-rpS3 alone. These results suggest that levosulpiride may be useful for enhancing the therapeutic effect of PEP-1-rpS3 against various inflammatory diseases. [BMB reports 2011; 44(5): 329-334].

The objective of the present study was to determine the intestinal absorption of sulpiride incorporated into SMEDDS by means of single-pass intestinal perfusion method (SPIP) in rat and to compare the effective permeability coefficient obtained with that of drug solution and micellar solution. The prepared SMEDDS and micelles formulations were investigated for droplets size. SPIP experiment was performed using the three formulations in three of the secluded regions of the small intestine (duodenum, jejunum, and ileum). The amount of the drug in the samples was estimated by HPLC and the effective permeability coefficients in rats were calculated. The human intestinal permeability was predicted based on rat effective permeability coefficient value. The dilution stability of the formulations was also determined. The average droplet size of SMEDDS and micelles was 9.27 nm and 7.20 nm respectively. The effective permeability coefficient of sulpiride was appreciably lower in the ileum weighed against jejunum and duodenum when administered as a solution (P<0.05). The estimated human absorption of sulpiride for the SMEDDS dilutions was superior to that from solution (P<0.05) and similar to micellar solution. The micellar dilutions were unstable whereas the SMEDDS dilutions were stable. Based on the above results, SMEDDS can be a potential candidate for improving the peroral absorption of the sulpiride.

The author describes an original approach to the development of dipeptide drugs based on the concept of the leading role of the beta-bend in the interaction of biologically active endogenous peptides with their receptors. The approach called "peptide-based drug design" includes both developments from the structure of a known psychotropic agent toward its topological peptide analog and developments from the active dipeptide site of a neuropeptide toward its mimetic. This strategy has been worked out at the V.V. Zakusov Research Institute of Pharmacology for 25 years. Results of investigations that discovered endogenous peptide prototypes of the known non-peptidic drugs (piracetam and sulpiride) are presented. They provided a basis for the creation of highly active non-toxic oral dipeptide preparations, such as nootrop Noopept, potential anti psychotic Dilept, and potential selective anxiolytic GB-115.

Levosulpiride is a sulpiride isomer that exerts its prokinetic action through a dual mechanism: 1) as a D(2) dopamine receptor antagonist and 2) as a serotonin 5HT(4) receptor agonist, conferring this drug with a cholinergic effect. At a dosage of 25mg three times daily, levosulpiride accelerates gastric and gallbladder emptying. Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia, while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists. The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D(2) dopamine antagonists. Therefore, this drug is a useful therapeutic option in the management of patients with functional dyspepsia, as well as in those with delayed gastric emptying., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

Sulpiride (SPR; L) is a substituted benzamide antipsychotic which is reported to be a selective antagonist of central dopamine receptors and claimed to have mood-elevating properties. The ligation behaviour of SPR drug is studied in order to give an idea about its potentiality towards some transition metals in vitro systems. Metal complexes of SPR have been synthesized by reaction with different metal chlorides. The metal complexes of SPR with the formula [MCl(2)(L)(2)(H(2)O)(2)].nH(2)O [M=Mn(II), Co(II), Ni(II), Cu(II) and Zn(II); n=0-2] and [FeCl(2)(HL)(H(2)O)(3)]Cl.H(2)O have been synthesized and characterized using elemental analysis (CHN), electronic (infrared, solid reflectance and (1)H NMR spectra) and thermal analyses (TG and DTA). The molar conductance data reveal that the bivalent metal chelates are non-electrolytes while Fe(III) complex is 1:1 electrolyte. IR spectra show that SPR is coordinated to the metal ions in a neutral monodentate manner with the amide O. From the magnetic and solid reflectance spectra, octahedral geometry is suggested. The thermal decomposition processes of these complexes were discussed. The correlation coefficient, the activation energies, E*, the pre-exponential factor, A, and the entropies, DeltaS*, enthalpies, DeltaH*, Gibbs free energies, DeltaG*, of the thermal decomposition reactions have been derived from thermogravimetric (TG) and differential thermogravimetric (DTG) curves. The synthesized ligand and its metal complexes were also screened for their antibacterial and antifungal activity against bacterial species (Escherichia coli and Staphylococcus aureus) and fungi (Aspergillus flavus and Candida albicans). The activity data show that the metal complexes are found to have antibacterial and antifungal activity than the parent drug and less than the standard., (Copyright 2010 Elsevier B.V. All rights reserved.)

A sensitive and selective high-performance liquid chromatography-positive ion electrospray tandem mass spectrometry method was developed and validated for the quantification of amisulpride in 100 microL of human plasma. Following liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a reverse-phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective (M + H)(+) ions, m/z 370-242 for amisulpride and m/z 341-112 for the internal standard. The assay exhibited a linear dynamic range with a lower range of 0.1-100 ng/mL and a higher range of 1-500 ng/mL of amisulpride in human plasma. The lower limit of quantification was 0.1 ng/mL with a relative standard deviation of less than 10%. Acceptable precision and accuracy were obtained for both linearity ranges. A run time of 2.0 min for each sample made it possible to analyze more than 275 human plasma samples per day. The validated method has been successfully used to analyze plasma samples for application in pharmacokinetic studies.

A capillary electrophoretic method has been developed for the enantioselective analysis of amisulpride in pharmaceutical formulations, using beta-cyclodextrin sulfate as the chiral selector. Several parameters, such as cyclodextrin type and concentration, buffer concentration and pH and capillary temperature were investigated for method optimisation. Baseline enantioseparation of the racemic compound was achieved in less than 10 min using a fused silica capillary (50 microm i.d. and 33.0, 8.5 cm, total and effective length, respectively), filled with a background electrolyte consisting of a 10mM citrate buffer at pH 3.5 supplemented with 0.22% (w/v) beta-cyclodextrin sulfate at 20 degrees C and applying a voltage of +15 kV. Formulation analysis was carried out after analyte extraction by methanol. The method was fully validated, with good results in terms of precision, selectivity, accuracy and amount of drug found with respect to the label claim. Thus, the method seems to be suitable for the enantiomeric analysis of amisulpride in pharmaceutical formulations.

Background: This study investigates the effect of the petroleum ether, chloroform, and ethyl acetate fractions of the total ethanolic extract of Convolvulus pluricaulis Choisy (Family: Convolvulaceae) on depression in mice., Material/methods: The petroleum ether (25, 50 mg/kg), chloroform (25, 50, 100 mg/kg), and ethyl acetate (25, 50, 100 mg/kg) fractions were administered orally for 10 successive days to separate groups of Swiss young male albino mice. The effects of the extracts on the mice's immobility periods were assessed in the forced swim test (FST) and tail suspension test (TST). The effects of reserpine (2 mg/kg i.p.), sulpiride (50 mg/kg i.p.), prazosin (62.5 microg/kg i.p.), and p-chlorophenylalanine (100 mg/kg i.p.) on the extracts' antidepressant-like effect in TST was also studied. The extracts' antidepressant-like effect was compared with that of imipramine (15 mg/kg p.o.) and fluoxetine (20 mg/kg p.o.) administered for 10 successive days., Results: Only the chloroform fraction in doses of 50 and 100 mg/kg significantly reduced the immobility time in both FST and TST. This fraction did not significant effect locomotor activity. Its efficacy was found to be comparable to that of imipramine and fluoxetine administered for 10 successive days. The chloroform fraction reversed reserpine-induced extension of immobility period in FST and TST. Prazosin, sulpiride, and p-chlorophenylalanine significantly attenuated the chloroform fraction-induced antidepressant-like effect in TST., Conclusions: The chloroform fraction of the total ethanolic extract of Convolvulus pluricaulis elicited a significant antidepressant-like effect in mice by interaction with the adrenergic, dopaminergic, and serotonergic systems.

Nine accurate methods for determination of amisulpride in tablets: reversed phase high pressure liquid chromatography (RP-HPLC), aqueous capillary electrophoresis (CE), non-aqueous CE, normal phase (NP) and reversed-phase (RP) high performance thin layer chromatography (HPTLC) with densitometry and videodensitometry, and direct and derivative UV spectrophotometry were developed and validated. The HPLC was carried out using Nova-Pak C8 column and mobile phase consisted of acetonitrile-methanol-phosphate buffer pH 4.50 (15:5:80, v/v/v) with flow rate 1 mL min(-1) and UV detection at 225 nm. The moclobemide was used as the internal standard. CE was performed using 75 microm x 82 cm fused silica capillary (65 cm effective), the internal standard was quetiapine. Detection was carried out at 225 nm. For aqueous analysis, the 30 mM phosphate buffer pH 6.00, 30 kV voltage and 30 degrees C temperature were chosen, non-aqueous determination was performed with ammonia acetate 1 mM in acetonitrile-methanol (1:1, v/v), 30 kV voltage and 25 degrees C temperature. NP-HPTLC was carried out using HPTLC silica F254 plates, developed with hexane-ethanol-propylamine (5:5:0.1, v/v/v) through 9 cm distance. RP-HPTLC was developed with HPTLC RP8F254 plates, with mobile phase of tetrahydrofuran-phosphate buffer pH 3.50 (4:6, v/v), distance 4.5 cm. Both analyses were performed in horizontal chambers and scanned with densitometer at 275 nm or videodensitometer at 254 nm. UV spectrophotometry was carried out in methanol, using 224 nm for direct assay and 258 nm (D1) for derivative assay. The precision and accuracy of all the methods were complexively compared. The highest accuracy was observed in RP-HPTLC, the highest precision was achieved in non-aqueous CE method. The differences were not significant, so all the elaborated methods can be used in routine analysis.