Search

Clozapine and its metabolites require close therapeutic monitoring (TDM) in patients due to poor correlation between the administrated doses and resulting plasma concentrations, the narrow therapeutic interval, high inter-individual variability, and the risk of serious side effects once toxic levels are exceeded. The aim of the study was to develop a simple (relatively cheap) LC-UV method for the quantification of clozapine and its metabolites in plasma and urine samples. For sample preparation, liquid-liquid extraction (LLE) in n -octanol was more efficient and less limiting in injection volumes compared to the in-situ formation of SUPRAS. When analyzing urine, an alkalinization step before extraction was required. The proposed method produced linear concentration responses with/without internal standard (IS) for the target analytes, with LLOQs within the targeted range of 50 ppb and %RSD within the acceptable 15% range. Furthermore, sample stability studies proved that pre-extracted samples were stable for the short term at room temperature and long-term when frozen.

A relevant approach based on the attractive inherited merits of fluorescence spectroscopy has been established for quantitative estimation of a newly approved second-generation atypical antipsychotic lurasidone (LUR) in its raw materials and pharmaceutical dosage forms. This study brings to light the strong native fluorescence of LUR at 400 nm in water after excitation at 316 nm. Different experimental parameters that may compromise the fluorescence of the drug were carefully investigated and optimized. A linear response was established between the relative fluorescence intensity and concentration over the concentration range of 50-650 ng/mL with excellent correlation (r = 0.9998). The validity of the method was evidenced in accordance with International Council for Harmonization guidelines, with minimal detection and quantification limits of 2.88 and 8.73 ng/mL, respectively. The method was effectively applied for the estimation of LUR in spiked human plasma and urine samples with acceptable recoveries. The biopharmaceutical significance of the method was heightened by its successful applications for both content uniformity and in vitro dissolution testing. Three different tools accredited the greenness character of the presented study. Eco-friendliness, effortlessness, and cost effectiveness are crucial hallmarks of our study. The presented study demonstrates potential applicability in quality control laboratories with limited resources., (© 2024 John Wiley & Sons Ltd.)

A liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed for 25 antipsychotic drugs and their metabolite in urine for monitoring medication compliance of mentally disordered criminals on probation. Target compounds were extracted with a solid-phase extraction technique using a newly developed hydrophilic-lipophilic balanced sorbent to remove interferences and minimize the matrix effect (ME). Extracted sample was injected into the LC-MS-MS with an electrospray ionization source in positive mode and multiple-reaction monitoring mode. The analytes were separated and detected within 10 minutes using a reversed-phase column with a gradient elution method using 0.1% formic acid in water and 0.1% formic acid in methanol as mobile phase. The validation parameters were evaluated as follows: selectivity, limit of detection, lower limit of quantification (LLOQ), linearity, accuracy and precision, stability, dilution integrity, recovery (RE), ME and process efficiency (PE). The LLOQs were 0.1 to 2.0 ng/mL, and determination coefficients of the calibration curve were above 0.9943 over the concentration ranges. The intra-and inter-day accuracy ranged from -10.4% to 9.9% and from -9.6% to 9.4%, while the intra-and inter-day precision were within 10.7% and 9.9%. The bench-top and long-term stability ranged from 92.1% to 109.5% and 88.7% to 111.6%, respectively. The reproducibility of auto-sampler stability was <10% for all analytes. The accuracy and precision of dilution integrity ranged from -11.7% to 10.5% and 0.4% to 9.9%, respectively. The relative standard deviation of RE and ME was from 0.6% to 6.6% and 0.5% to 3.9%, respectively, while that of PE was 1.3% to 4.5%. The developed LC-MS-MS method for medication compliance monitoring was successfully applied to urine samples from mentally disordered probationers and determined to be one of effective ways for preventing the recurrence of mentally disordered crimes., (© The Author(s) 2020. Published by Oxford University Press on behalf of Society of Forensic Toxicologists, Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Separation of antipsychotic drugs from whole blood and urine is of great importance for clinic and forensic laboratories. In this work, chlorprothixene, haloperidol and risperidone representing the first and second generations of antipsychotic drugs were studied. Among them, chlorprothixene and risperidone were investigated for the first time by electromembrane extraction (EME). After the screening, 2-nitrophenyl octyl ether (NPOE) was used as the supported liquid membrane (SLM). The EME performance for spiked water (pH 2), whole blood and urine was tested and optimized individually. Using NPOE and 60 V, efficient EME was achieved from urine and whole blood with trifluoroacetic acid as the acceptor solution. The equilibrium time required for EME was dependent on the sample matrices. The steady-state of EME was reached in 30 min and 20 min for whole blood and urine, respectively. At steady-state, the EME recoveries of the targets from different sample matrices were satisfactory, and were in the range of 74%-100%. The proposed EME approach combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was evaluated using whole blood and urine. The obtained linearity was 1-200 ng mL -1 , and the coefficient of determination (R 2 ) was ≥ 0.9853 for haloperidol and ≥ 0.9936 for chlorprothixene and risperidone. The limit of detection (LOD) and accuracy for all the targets ranged from 0.2-0.6 ng mL -1 and 102%-110%, respectively, and the repeatability at low (1 ng mL -1 ), medium (10 ng mL -1 ) and high (200 ng mL -1 ) concentration was ≤ 12% (RSD). Finally, the validated approach was successfully used to determine chlorprothixene, risperidone and haloperidol in whole blood and urine from rats, which were treated with chlorprothixene, risperidone and haloperidol at low therapeutic dose, respectively., 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. Published by Elsevier B.V.)

This work focused on the development and validation of a method based on hollow fiber-based solid-phase microextraction coupled to ultra-performance liquid chromatography tandem mass spectrometry (HF-based-SPME-UPLC-MS/MS) for the determination of five antipsychotics at a pg mL -1 level in human whole blood and urine. Four types of hollow fiber membrane materials, including polyether sulfone, polypropylene, polyvinyl chloride and polyvinylidene fluoride were investigated. Finally, polyether sulfone hollow fiber without any modification was selected as the adsorption medium for solid-phase microextraction (SPME) with the following extraction procedure: the analytes were adsorbed onto the hollow fiber in the sample bottle with application of ultrasonication. Subsequently, the hollow fiber was transferred into a slim glass tube containing an appropriate solvent, and the analytes were desorbed by ultrasound treatment before detection by UPLC-MS/MS. In order to obtain satisfactory extraction efficiency, extraction parameters such as hollow fiber membrane material, pH, hollow fiber length, extraction time, desorption solvent and desorption time were investigated. Under the optimum experimental conditions, this method allowed for determination of five antipsychotics in human whole blood with excellent limits of quantification (LOQs) (25.0, 12.5, 25.0, 25.0 and 12.5 pg mL -1 for perphenazine, chlorpromazine, chlorprothixene, promethazine and trifluoperazine, respectively). The corresponding LOQs in human urine were 25.0, 12.5, 12.5, 12.5 and 12.5 pg mL -1 for the respective antipsychotics. The precision (RSD) was no more than 13.3%. The extraction recoveries for human whole blood and urine were in the range of 46.4-96.6% and 65.2-101.9%, respectively. The proposed method was compared with other methods from the literature and the results demonstrate that it is a simple, sensitive, efficient and green technique. It is suitable for analyzing trace target analytes in complex matrices such as biological samples and can provide a reliable tool for drug monitoring especially in forensic analysis and case of drug abuse., Competing Interests: Declaration of Competing Interest The authors declare that there is no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Adherence to prescribed antipsychotics is an ongoing problem. Traditionally, estimates of adherence have been made from patient interviews, pill counting and blood testing. A number of methods for the analysis of antipsychotics in blood have been reported for both therapeutic drug monitoring and postmortem testing for toxicity. This report details a dilute and shoot method for the analysis of 19 different antipsychotics and metabolites. The method takes advantage of earlier reports demonstrating unique, prevalent urine metabolites for aripiprazole, brexpiprazole, haloperidol and lurasidone to enhance sensitivity for these analytes. With a fast analysis time and minimal sample preparation, this method can be used for quantitation of antipsychotics in urine. Finally, this method has been used to test samples for over a year with the results summarized in this report. While further improvements are certainly possible, this method is selective and sensitive for this group of important compounds., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We report a novel electrochemical sensor for the sensitive and selective determination of the antipsychotic drug chlorpromazine (CPZ) based on the iron (Fe) nanoparticles-loaded graphene oxide (GO-Fe)/three dimensional (3D) honeycomb-like zinc oxide (ZnO) nanohybrid modified screen printed carbon electrode (SPCE). The 3D hierarchical honeycomb-like ZnO was synthesized using a novel aqueous hydrothermal method and the GO-Fe/ZnO nanohybrid was prepared based on an inexpensive and fast sonochemical method using a high-intensity ultrasonic bath (Delta DC200H, 200 W, 40 KHz). Characterizations including scanning electron microscopy, elemental mapping, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and Raman spectroscopy were carried out as part of this work. The electrocatalytic oxidation behavior of CPZ at various electrodes was investigated using the cyclic voltammetry technique, through which the GO-Fe/ZnO modified SPCE was identified as the best performing electrode. The quantitative determination of CPZ was then performed using the differential pulse voltammetry technique. The as-prepared GO-Fe/ZnO/SPCE sensor exhibited a quick and sensitive response towards the oxidation of CPZ with linear concentration ranges from 0.02 to 172.74 μM and 222.48 to 1047.74 μM. The modified SPCE sensor displayed a low detection limit (LOD) of 0.02 µM and a high sensitivity of 7.56 µA µM -1 cm -2 . The proposed sensor also showed remarkable operational and storage stability, reproducibility, and repeatability. Furthermore, the practicability of the GO-Fe/ZnO/SPCE sensor has been verified with real sample analysis using commercial antipsychotic CPZ tablets and human urine samples, and adequate recovery has been achieved., (Copyright © 2019 Elsevier B.V. All rights reserved.)

There has been only a few reports regarding aripiprazole causing false positive urine amphetamine drug screens, exclusively on children accidently ingesting aripiprazole. Herein, we present the first reported case of a 40 year old woman affected by Bipolar I Disorder, treated with aripirazole at therapeutic oral dose ranging from 15 mg/day to 30 mg/day, in the context of a depressive episode with mixed and psychotic features, showing a false positive urine amphetamine drug screen. We document the relationship between aripiprazole-dose, plasma concentration and amphetamines values in toxicologic urine examinations over time. Awareness of potential false positive urine amphetamine drug screens during aripiprazole treatment can condition therapeutic choices and prevent legal implications., (Copyright © 2019. Published by Elsevier Inc.)

Antipsychotics are the drugs most often involved in drug poisoning cases, and therefore, therapeutic drug monitoring (TDM) is necessary for safe and effective medication administration of these drugs. In this study, a coffee ring effect-based surface-enhanced Raman spectroscopy (CRE-SERS) method was developed and successfully used to monitor antipsychotic poisoning by using urine samples for the first time. The established method exhibited excellent SERS performance since more hot spots were obtained in the "coffee ring". Using the optimized CRE-SERS method, the sensitivity was improved one order more than that of the conventional method with reasonable reproducibility. The antipsychotic drug clozapine (CLO) spiked into urine samples at 0.5-50 μg mL -1 was quantitatively detected, at concentrations above the thresholds for toxicity. The CRE-SERS method allowed CLO and its metabolites to be ultimately distinguished from real poisoning urine samples. The coffee-ring effect would provide more opportunities for practical applications of the SERS-based method. The frequent occurrence of drug poisoning may have created a new area for the application of the CRE-SERS method. It is anticipated that the developed method will also have great potential for other drug poisoning monitoring., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: This study developed clinical recommendations for the use of proven urine testing technologies to assess antipsychotic medication adherence among people with serious mental illness., Methods: Guided by the RAND/UCLA Appropriateness Method, researchers conducted a literature review and semistructured interviews and convened an expert panel to develop clinical consensus recommendations for the use of urine monitoring to assess antipsychotic medication adherence., Results: The expert panel identified six circumstances in which urine monitoring was recommended at initial evaluation and five scenarios in which monitoring was recommended after initial evaluation. Conducting monitoring at the site where psychiatric medication is prescribed and providing education prior to testing and feedback after testing were recommended., Conclusions: A consensus was reached on clinical recommendations for use of urine monitoring at intake and during ongoing treatment. There was strong agreement that monitoring can be used to improve assessment and thence clinical care and outcomes.

High-resolution mass spectrometry (HRMS) has gained recognition as a valuable tool for comprehensive drug screening in a variety of biological matrices. HRMS instruments collect untargeted, accurate mass data, which permit identification of known and unknown compounds in a single analytical run. One of the most challenging aspects of implementing an HRMS drug screen is establishing appropriate data analysis parameters for identifying compounds. Unlike other types of mass spectrometry data, guidelines for HRMS data analysis and acceptability criteria have not been established. Although many laboratories have published on the utility of HRMS for drug screening, few have included details on how they determined allowable errors and set positivity criteria. Previously, we developed and validated a comprehensive 169-compound drug screen on a high-resolution quadrupole time of flight mass spectrometer. Here we report the detailed procedure that we used to determine appropriate positivity criteria for our screening procedure. Our approach was empirical; we collected data and analyzed it with commonly available software. We found that a combined scoring approach using a threshold of 70, with 70% weight given to library match and 10% weight given to each of mass error, retention time error and isotope pattern difference provided optimum drug identification efficiency of 99.2%. Our results demonstrate the importance of library matching in accurately identifying compounds, and underscore the utility of robust product ion spectra that contain information on the lineage, mass and relative abundance of fragments. The method we describe is easily adaptable to include alternative parameters that may be available in software associated with a variety of HRMS platforms. With careful selection of error limits and positivity criteria, HRMS instruments are capable of producing high-quality, high-confidence results that may reduce the need for confirmatory testing., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Patients on opioid replacement therapy (ORT) to treat opioid use disorder are frequently monitored for these medications, but it is not known if they are also adhering to their psychotropic medications. This is an analysis of measure of potential adherence to psychotropic medications by patients on ORT., Methods: This is a retrospective cohort study of patients (n=1470) on antidepressants and/or antipsychotics and tested by the Millennium Health laboratory. Potential adherence to psychotropic medications was measured by urine drug test (UDT) results. The consistency of UDT for expected psychotropic medication in patients on ORT was compared to patients not on ORT (control group) during 3-months period. The study used propensity score methods to match individuals from both groups on their demographics and their psychotropic medication., Results: There were 457 participants (31.09%) on ORT and 1013 participants (68.91%) in the control group. Only 55.33% of UDTs (n=1388) were consistent for expected psychotropic medications in the ORT group compared to 73.69% of UDTs (n=4953) consistent for expected psychotropic medications in the control group (χ 2 =172.99, p<0.001). After matching, patients in the ORT group were less likely than the control group to have consistent UDTs for expected psychotropic medications (OR: 0.81, 95% CI: 0.76-0.85, P<0.001)., Conclusion: There is a high rate of inconsistent UDT for prescribed psychotropic medication among patients on ORT. This could reflect potential poor adherence. Monitoring adherence to psychotropic medications should be part of every clinical visit for patients on ORT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Treatment adherence is often an issue with mental health patients. For those prescribed quetiapine (Seroquel ® ), the low levels of parent drug and plasma metabolite(s) (e.g., 7-hydroxyquetiapine) typically used in urine drug monitoring can result in false negatives with concomitant unfavorable impacts on patient care. Literature review coupled with liquid chromatography/time-of-flight mass spectrometry analysis of patient positive urine samples indicated the presence of quetiapine carboxylic acid and quetiapine sulfoxide as significant urinary metabolites of quetiapine. Analysis of these two metabolites determined that they are abundant in the urine of quetiapine patients and can result in apparent adherence rates that are improved relative to those determined using only quetiapine and 7-hydroxyquetiapine. For example, analysis of a random set of 114 patients who were prescribed quetiapine exhibited an apparent adherence rate of 47% using the quetiapine carboxylic acid and quetiapine sulfoxide metabolites. Traditional metabolite testing with quetiapine and 7-hydroxyquetiapine yielded apparent adherence rates of ~31% while all four analytes resulted in apparent adherence of 48%. The prevalence of these metabolites suggests that quetiapine urine drug testing would be more consistent with prescriptions when they are included in the analysis., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Urine drug screens (UDSs) are used to identify the presence of certain medications. One limitation of UDSs is the potential for false-positive results caused by cross-reactivity with other substances. Amphetamines have an extensive list of cross-reacting medications. The literature contains reports of false-positive amphetamine UDSs with multiple antidepressants and antipsychotics. We present 2 cases of presumed false-positive UDSs for amphetamines after ingestion of aripiprazole. Case 1 was a 16-month-old girl who accidently ingested 15 to 45 mg of aripiprazole. She was lethargic and ataxic at home with 1 episode of vomiting containing no identifiable tablets. She remained sluggish with periods of irritability and was admitted for observation. UDS on 2 consecutive days came back positive for amphetamines. Case 2 was of a 20-month-old girl who was brought into the hospital after accidental ingestion of an unknown quantity of her father's medications which included aripiprazole. UDS on the first day of admission came back positive only for amphetamines. Confirmatory testing with gas chromatography-mass spectrometry (GC-MS) on the blood and urine samples were also performed for both patients on presentation to detect amphetamines and were subsequently negative. Both patients returned to baseline and were discharged from the hospital. To our knowledge, these cases represent the first reports of false-positive amphetamine urine drug tests with aripiprazole. In both cases, aripiprazole was the drug with the highest likelihood of causing the positive amphetamine screen. The implications of these false-positives include the possibility of unnecessary treatment and monitoring of patients., (Copyright © 2015 by the American Academy of Pediatrics.)

Objective: The goal of the present study was to demonstrate that the analytical assay of interest can detect antipsychotics in human urine specimens., Method: Forty inpatients treated with haloperidol, quetiapine, risperidone, or olanzapine were recruited to participate in a one visit study. During the study visit, demographic and clinical information was collected as well as one urine sample that was forwarded to the Ameritox Laboratory and assayed for the presence of antipsychotic medications and/or metabolites. Urine samples were analyzed to determine detection sensitivity for four antipsychotic medications and their metabolites (risperidone, quetiapine, olanzapine, and/or haloperidol) using Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry., Results: All urine samples produced positive results for the antipsychotic(s) the participants were known to be taking. Urine concentrations (level of quantification) for parent drugs ranged from <25-417 ng/mL for haloperidol, <25-4017 ng/mL for quetiapine, 0-997 ng/mL for risperidone, and 57-700 ng/mL for olanzapine., Conclusion: The analytical assay produced by Ameritox, Ltd using Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry can qualitatively detect antipsychotics in human urine specimens. The present study highlights the potential utility of the urine assay to help monitor adherence to antipsychotic medications., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Benzodiazepine prescribing for schizophrenia occurs in clinical practice and antipsychotic trials. This review examined the clinical outcomes for benzodiazepines in schizophrenia., Method: A systematic search identified randomised controlled trials that evaluated benzodiazepines in comparison with placebo or antipsychotics, and also as adjuncts to antipsychotics. Relevant clinical outcome data was extracted., Results: Twenty six studies were included with some reporting multiple comparisons. Seven short-term studies compared benzodiazepines with placebo: benzodiazepine superiority was found in two out of five studies for global improvements and two out of four studies for psychiatric/behavioural outcomes. Eleven studies compared benzodiazepines with first-generation antipsychotics (FGAs): four out of nine studies (including two long-term studies) reported greater global improvements for antipsychotics; four out of five studies showed no treatment differences for psychiatric/behavioural outcomes. Fourteen studies compared benzodiazepines (as adjunct to antipsychotics) vs antipsychotics alone (mostly FGAs); benzodiazepine superiority was found for global improvement in one out of eight studies and inferiority in two out of eight short-term studies whereas superiority was found for psychiatric/behavioural outcomes in three out of 12 short-term studies and inferiority in three out of 12 studies., Conclusion: Benzodiazepine superiority over placebo was found for global, psychiatric and behavioural outcomes, but inferiority to antipsychotics on longer-term global outcomes. Conflicting evidence exists regarding the addition of benzodiazepines to antipsychotics; thus the use of benzodiazepines in clinical practice and antipsychotic trials should be limited., (© The Author(s) 2014.)

A field-amplified sample injection (FASI) technique was elaborated for fast and sensitive determination of selected central nervous system drugs in human urine samples. Factors affecting the sensitivity enhancement, such as background electrolyte (BGE) and the analytical matrix composition were optimized and discussed. Pseudo-isotachophoresis (p-ITP) mechanism contribution in preconcentration mechanism was discussed. All separations were performed in uncoated fused silica capillaries 50 μm × 57 cm at 22 kV. The optimized analytical matrix was composed of 0.25 mM HCOOH in 90% (v/v) methanol, while BGE contained 45 mM TRIS/HCl (pH 2.20). The head-column injection was performed in 0.25 mM HCOOH water solution (3s, 3.45 kPa). Sample was introduced into the capillary by electrokinetic injection (70 s, 5 kV) followed by short BGE plug (3s, 3.45 kPa). Seven psychiatric drugs (olanzapine, prochlorperazine dimaleate, trifluoperazine dihydrochloride, perphenazine, promazine hydrochloride, clomipramine hydrochloride, and chlorprothixene hydrochloride) were separated in about 6 min. The elaborated method was additionally supported with dispersive liquid-liquid microextraction (DLLME) technique which in summary with FASI provided about 8000-13,000-fold sensitivity enhancement in comparison to the capillary zone electrophoresis (CZE) method with standard hydrodynamic injection (5s, 3.45 kPa)., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Asenapine (Saphris®) is an atypical antipsychotic approved in the USA in 2009 for the treatment of schizophrenia and bipolar disorder. The Los Angeles County Department of Coroner Toxicology Laboratory developed an analytical method for the detection and quantitation of asenapine by gas chromatography-mass spectroscopy in multiple specimens of postmortem casework. Asenapine was isolated from specimens through a basic, liquid-liquid extraction procedure and quantitated utilizing D5-fentanyl as an internal standard. Method validation for asenapine was conducted utilizing the Scientific Working Group Toxicology (SWGTOX) method validation draft proposal and the tissue distribution of four case studies was determined. The authors believe that these are the first cases to be reported in the literature and are intended to assist other forensic toxicologists with interpreting their casework.

In this study an extraction procedure using molecular imprinted polymer nanoparticles for the determination of haloperidol in biological samples is proposed. The haloperidol imprinted polymer nanoparticles were synthesized successfully by precipitation polymerization in a flask containing haloperidol as a template, ethyleneglycoldimethacrylate as a crosslinking agent, methacrylic acid as a functional monomer, and 2,2'-azobisisobutyronitrile as an initiator. The leached and unleached polymer nanoparticles have been characterized by infrared spectroscopy and scanning electron microscopy. The effect of different variables such as the pH of solution, uptake and elution time, type, and the least amount of eluent for elution of haloperidol from polymer was evaluated. Extraction efficiencies more than 97% were obtained by elution of the polymer with 1.5 mL of methanol-acetic acid-trifluoroacetic acid 79.9:20:0.1. Under optimal conditions maximum adsorption capacity was obtained 153.84 mg g(-1). The detection limit of the proposed procedure was between 0.2 and 0.35 μg L(-1). Finally this method was applied to the determination of haloperidol in plasma and urine samples and satisfactory results were achieved (RSD<6.9%)., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This paper describes the detection and characterization of unusual metabolite/breakdown products of the anti-psychotic drug risperidone in post-mortem blood and urine as part of a toxicological investigation into an unexpected death of a male suffering from paranoid schizophrenia prescribed risperidone and previously paroxetine. Compounds detected in the post-mortem blood and urine specimens were shown to be benzisoxazole ring scission products of risperidone and a hydroxy metabolite. These compounds are never routinely detected in blood and urine but can be present in mammalian faeces indicating that gut bacteria could be responsible for their formation. In this case, evidence for this process was demonstrated by the controlled in vitro stability study of risperidone spiked into the case blood and urine leading to the hypothesis that the post-mortem blood and urine samples analyzed could have contained bacteria with the ability to breakdown risperidone and its metabolite in this way. This finding is very unusual and has not been encountered before in any previous risperidone cases investigated by the authors, or widely reported in the post-mortem toxicological literature. However, a recently published paper has supported these findings in blood. As a result of this work, it was shown that the deceased had taken risperidone prior to death, even in the absence of any risperidone or its hydroxy metabolite(s) in the blood and urine. Given that risperidone has been reported to interact with paroxetine, the ingestion of risperidone could have been a factor that contributed to the death., (Copyright © 2013 John Wiley & Sons, Ltd.)

A rapid and simple quantitative method for preconcentration and determination of haloperidol in biological samples was developed using ultrasound-assisted emulsification microextraction, based on the solidification of floating organic droplet combined with HPLC-DAD. The effects of several factors were investigated. A total of 30 μL of 1-undecanol as an extraction solvent was injected slowly into a glass-centrifuge tube containing 4 mL alkaline sample solution that was located inside the ultrasonic water bath. The formed emulsion was centrifuged and the fine droplets of solvent were floated at the top of the test tube, then it was cooled in an ice bath and the solidified solvent was transferred into a conical vial, after melt, the analysis of the extract was carried out by HPLC. Under the optimal conditions, the extraction efficiencies were more than 90% and the preconcentration factors were obtained between 119-122. The LOQs were obtained between 4-8 μg/L and the calibration curves were linear within the range of 4-1000 μg/L. Finally this method was applied to the determination of haloperidol in plasma and urine samples in the range of μg/L and satisfactory results were achieved (RSDs <7%)., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Sequential injection chromatography (SIC) is a recent, simple, and inexpensive green miniaturized separation technique. In the current study, SIC was exploited for the first time for biochemical analysis. A new SIC method for the separation and quantification of chlorpromazine in human urine, as well as pharmaceutical formulations, was developed and validated. Clozapine was used as an internal standard. Chlorpromazine was successfully separated on a C18 monolithic column (25x4.6 mm id). The UV detection was carried out at 250 nm using miniaturized fiber optic spectrometric devices. The optimum mobile phase composition was 30 mmol/L phosphate-acetonitrile-methanol (55.0 + 31.5 + 13.5, v/v/v) at pH 3.0. The sample volume was 40 microL and flow rate was 40 microL/s. Acceptable chromatographic results were obtained. The resolution was 2.7, peak symmetry was 1.1, and number of theoretical plates was more than 1 x 10(6). Good linearity (r = 0.9997) in the range of 25-100 microg/mL was also obtained. The method offered acceptable recovery for both human urine (89.6-93.1%) and pharmaceutical formulations (96.9-98.5%), which was sensitive enough to detect chlorpromazine. The LOD and LOQ in human urine were 61 and 204 ng/mL, respectively. The method was rapid and reagent-saving, and hence safe for the environment. The sample throughput was 26.3 samples/h and the total volume of consumed reagents was 4.0 mL.

The article presents the data concerning the application of technique of thin-layer chromatography in the conditions of laboratory diagnostics to identify benzamide derivative neuroleptics (amisupride, sulpiride, tiapride) in derivate from human biologic fluids and tissues with the possibility to separate the analyzed tissues from soextractive tissues.

Background: Disposable pipette extraction with reversed-phase sorbent is proposed for the fast and simple GC determination of the antipsychotic drugs chlorpromazine, olanzapine, clozapine and biperiden - an anticholinergic drug - in human urine. The method was validated and successfully applied to postmortem urine samples. The analytical run was 11 min and lidocaine was used as the internal standard., Results: The developed method showed good linearity, over the range of 0.34 to 5 ng/µl, for all compounds. The within-day and between-day precision and accuracy assays revealed values ≤15%, while the recoveries ranged from 85 to 120%. LOD and LOQ ranged from 0.28 to 0.42 ng/µl and from 0.85 to 3.58 ng/µl, respectively., Conclusion: The developed method is a user-friendly technique, which is simple and fast.

To support the evaluation of the pharmacokinetic parameters of asenapine (ASE) in urine, we developed and validated online solid-phase extraction high-performance liquid chromatography methods with tandem mass spectrometry detection (SPE-LC-MS/MS) for the quantification of ASE and two of its major metabolites, N-desmethylasenapine (DMA) and asenapine-N⁺-glucuronide (ASG). The linearity in human urine was found acceptable for quantification in a concentration range of 0.500-100 ng/mL for ASE and DMA and 10.0-3000 ng/mL for ASG, respectively., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Risperidone, quetiapine, amisulpride and aripiprazole are atypical antipsychotics increasingly prescribed in Greece., Results: We have developed and validated a UHPLC-diode array detector method for the determination of these drugs in whole blood, urine and cerebrospinal fluid, following SPE. The separation was achieved within 7 min. Validation was performed in terms of linearity, selectivity, accuracy, precision and stability. Following validation, the method was applied to post-mortem blood, urine and cerebrospinal fluid samples., Conclusion: The method proved fast and simple for the determination of four atypical antipsychotic drugs in whole blood, urine and cerebrospinal fluid. To the best of our knowledge, this is the only available method for the simultaneous determination of these drugs in cerebrospinal fluid.

Antipsychotic drugs are becoming a larger part of the prescription drug market. In combination with -traditional indications for prescribing these drugs, new effective therapies are proving worthwhile as well. Here, a successful method for detecting both first- and second-generation antipsychotics is presented using a solid phase extraction method and LC-MS/MS detection. This method is used for many sample matrices and can also be used for detecting antidepressants, which are often prescribed in conjunction with antipsychotics.

The metabolism of 3,4-dihydro-7-[4-(1-naphthalenyl)-1-piperazinyl]butoxy]-1,8-naphthyridin-2(1H)-one (NPBN) was investigated in rats. Animals were administered 30 mg/kg NPBN that was labeled with both tritium and carbon-14. The mass recovery of drug-related material was 96-98%, with almost all material excreted in feces. Metabolism occurred by oxidation reactions followed by conjugation. The main route of metabolism of NPBN occurred via oxidation of the naphthylene ring, which led to naphthol and dihydrodiol metabolites as well as a relatively novel N-dearylated metabolite in which the naphthylene ring was removed. In vitro investigation in rat liver microsomes also showed a glutathione adduct on the naphthalene and a glutathione adduct of naphthoquinone, which, along with the dihydrodiol metabolite, is consistent with the initial generation of an epoxide. A mechanism is proposed whereby the N-dearylation arises via epoxidation, followed by formation of an exocyclic iminium ion intermediate that is hydrolyzed to yield the N-dearylated metabolite. An additional mechanism involves oxidation of the naphthol metabolite via a radical mechanism, since this metabolite was also shown to undergo N-dearylation.

An LC-MS/MS method for the determination of the atypic neuroleptic clozapine and its two main metabolites norclozapine and clozapine-N-oxide has been developed and validated for serum and urine. After addition of d4-clozapine as deuterated internal standard a fast single-step liquid-liquid extraction under alkaline conditions and with ethyl acetate as organic solvent followed. The analytes were chromatographically separated on a Synergi Polar RP column using gradient elution with 1 mM ammonium formate and methanol. Data acquisition was performed on a QTrap 2000 tandem mass spectrometer in multiple reaction monitoring mode with positive electrospray ionization. Two transitions were monitored for each analyte in order to fulfill the established identification criteria. The validation included the determination of the limits of quantification (1.0 ng/mL for all analytes in serum and 2.0 ng/mL for all analytes in urine), assessment of matrix effects (77% to 92% in serum, 21 to 78% in urine) and the determination of extraction efficiencies (52% to 85% for serum, 59% to 88% for urine) and accuracy data. Imprecision was <10%, only the quantification of norclozapine in urine yielded higher relative standard deviations (11.2% and 15.7%). Bias values were below ±10%. Dilution of samples had no impact on the correctness for clozapine and norclozapine in both matrices and for clozapine-N-oxide in serum. For quantification of clozapine-N-oxide in urine a calibration with diluted calibrators has to be used. Calibration curves were measured from the LOQ up to 2,000 ng/mL and proved to be linear over the whole range with regression coefficients higher than 0.98. The method was finally applied to several clinical serum and urine samples and a cerebro-spinal fluid sample of an intoxicated 13-month-old girl.

The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.

A simple method has been proposed for the determination of clozapine (CLZ) and chlorpromazine (CPZ) in human urine by dispersive liquid-liquid microextraction (DLLME) in combination with high-performance liquid chromatography-ultraviolet detector (HPLC-UV). All important variables influencing the extraction efficiency, such as pH, types of the extraction solvent and the disperser solvent and their volume, ionic strength and centrifugation time were investigated and optimized. Under the optimal conditions, the limit of detection (LODs) and quantification (LOQs) of the method were 13 and 39 ng/mL for CLZ, and 2 and 6 ng/mL for CPZ, respectively. The relative standard deviations (RSDs) of the targets were less than 5.1% (C=0.100 μg/mL, n=9). Good linear behaviors over the tested concentration ranges were obtained with the values of R (2)>0.999 for the targets. The absolute extraction efficiencies of CLZ and CPZ from the spiked blank urine samples were 98.3% and 97.8%, respectively. The applicability of the technique was validated by analyzing urine samples and the mean recoveries for spiked urine samples ranged from 93.3% to 105.0%. The method was successfully applied for the determination of CLZ and CPZ in real human urine.

Two schizophrenic patients who had been taking medication for a long period presented with visual disturbance of 6-month duration. Slit-lamp examination revealed fine, discrete, and brownish deposits on the posterior cornea. In addition, bilateral star-shaped anterior subcapsular lens opacities, which were dense, dust-like granular deposits, were noted. Although we strongly suspected that the patient might have taken one of the drugs of the phenothiazine family, we were unable to obtain a history of medications other than haloperidol and risperidone, which were taken for 3 yr. We performed a drug profiling test using urine samples and detected methotrimeprazine. The patient underwent surgery for anterior subcapsular lens opacities. Visual acuity improved in both eyes, but the corneal deposits remained. We report an unusual case of methotrimeprazine-induced corneal deposits and cataract in a patient with psychosis, identified by using the urine drug profiling test.

Background: The metabolic/biotransformation pathways of atypical antipsychotics (aripiprazole, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) have been characterized and reviewed. However, comparisons of excretory pathways remain unexplored., Objective: To analyze the excretion profile of atypical antipsychotic agents and compare the overall magnitude of metabolism (changed vs. unchanged drug) and route of excretion (feces vs. urine). Secondary objectives include providing: 1) dosing information in hepatic and renal impairment, and 2) context of the specific enzymes and pathways involved in each agents' biotransformation., Methods: Published literature and each manufacturer's radiolabeled drug absorption, distribution, metabolism and excretion data and U.S. prescribing information were reviewed., Results: With the exception of paliperidone, atypical antipsychotics undergo extensive metabolism (i.e.,

The use of a molecularly imprinted polymer (MIP) as a selective surface for ambient mass spectrometry is demonstrated. The MIP is used to sequester target analytes from urine and easy ambient sonic-spray ionization mass spectrometry (EASI-MS) is shown to be able to efficiently desorb the analytes from the MIP surface and then transfer them in protonated forms to the gas phase for MS analysis. A set of five phenothiazines (chlorpromazine, perphenazine, triflupromazine, thioridazine and prochlorperazine) were chosen from a proof-of-principle class of drug samples. A chlorpromazine-imprinted methacrylic polymer was synthesized and used to prepare a MIP probe. The MIP-EASI-MS technique using acidified methanol as solvent has been shown to allow quantification of all five drugs in urine with LOQ of ca. 1 micromol L(-1).

Objective: The effect of trimethoprim, a potent organic cation transport inhibitor, on the pharmacokinetics (PK) of paliperidone extended-release tablets (paliperidone ER), an organic cation mainly eliminated via renal excretion, was assessed., Methods: Open-label, two-period, randomized, crossover study in 30 healthy males. Single dose of paliperidone ER 6 mg was administered either alone on day 1 or day 5 during an 8-day treatment period of trimethoprim 200 mg twice daily. Serial blood and urine samples were collected for PK and plasma protein binding of paliperidone and its enantiomers. The 90% confidence interval (CI) of ratios with/without trimethoprim for PK parameters of paliperidone and its enantiomers calculated., Results: Creatinine clearance decreased from 119 to 102 mL min(-1) with trimethoprim. Addition of trimethoprim increased unbound fraction of paliperidone by 16%, renal clearance by 13%, AUC(infinity) by 9%, and t((1/2)) by 19%. The 90% CIs for ratios with/without trimethoprim were within the 80-125% range for C(max), AUC(last), and renal clearance. For AUC(infinity), 90% CI was 79.37-101.51, marginally below the lower bound of the acceptance range. Paliperidone did not affect steady-state plasma concentrations of trimethoprim., Conclusions: No clinically important drug interactions are expected when paliperidone ER is administered with organic cation transport inhibitors.

On-site drug screening devices are widely used today for their simple test procedures and instantaneous results. Among other devices, a Triage Drug of Abuse panel is considered to be highly reliable for its high specificity and sensitivity of abused drugs. Although it is known that a false positive amphetamine (AMP) result may be obtained from the urine samples containing putrefactive amines or ephedrine-related compounds, no clinical false negative methamphetamine results have been reported to date. However, a false negative Triage result was obtained from the urine of a fatal methamphetamine poisoning victim taking Vegetamine tablets. Further experimental analyses revealed that the cross-reactivity of methamphetamine and chlorpromazine metabolites, including nor-2-chlorpromazine sulfoxide, was the cause for a false negative Triage reaction for AMP. Forensic scientists and clinicians must be aware of the limitations of on-site drug testing devices and the need for the confirmatory laboratory tests for the precise identification and quantification of drugs in suspicious intoxication cases, as also recommended by the manufacturers.

High-performance liquid chromatography (HPLC) with tris(2,2'-bipyridyl)ruthenium(II) chemiluminescence detection methodology is reported for the determination of the atypical antipsychotic drug quetiapine and the observation of its major active and inactive metabolites in human urine and serum. The method uses a monolithic chromatographic column allowing high flow rates of 3 mLmin(-1) enabling rapid quantification. Flow injection analysis (FIA) with tris(2,2'-bipyridyl)ruthenium(II) chemiluminescence detection and HPLC time of flight mass spectrometry (TOF-MS) were used for the determination of quetiapine in a pharmaceutical preparation to establish its suitability as a calibration standard. The limit of detection achieved with FIA was 2 x 10(-11) molL(-1) in simple aqueous solution. The limits of detection achieved with HPLC were 7 x 10(-8) and 2 x 10(-10) molL(-1) in urine and serum, respectively. The calibration range for FIA was between 5 x 10(-9) and 1 x 10(-6) molL(-1). The calibration ranges for HPLC were between 1 x 10(-7)-1 x 10(-4) and 1 x 10(-8)-1 x 10(-4) molL(-1) in urine and serum, respectively. The quetiapine concentrations in patient samples were found to be 3 x 10(-6) molL(-1) in urine and 7 x 10(-7) molL(-1) in serum. Without the need for preconcentration, the HPLC detection limits compared favourably with those in previously published methodologies. The metabolites were identified using HPLC-TOF-MS.

The Uppsala University 5 MV Pelletron tandem accelerator has been used to study (14)C-labeled biological samples utilizing accelerator mass spectrometry (AMS) technology. We have adapted a sample preparation method for small biological samples down to a few tens of micrograms of carbon, involving among others, miniaturizing of the graphitization reactor. Standard AMS requires about 1 mg of carbon with a limit of quantitation of about 10 amol. Results are presented for a range of small sample sizes with concentrations down to below 1 pM of a pharmaceutical substance in human blood. It is shown that (14)C-labeled molecular markers can be routinely measured from the femtomole range down to a few hundred zeptomole (10 (-21) mol), without the use of any additional separation methods.

In the present work, hollow fiber liquid phase microextraction (HF-LPME) in conjunction with reversed-phase HPLC/UV was developed for extraction and determination of trace amounts of chlorpromazine in biological fluids. The drug was extracted from an 11 ml aqueous sample (source phase; SP) into an organic phase impregnated in the pores of the hollow fiber (membrane phase; MP) followed by the back-extraction into a second aqueous solution (receiving phase; RP) located in the lumen of the hollow fiber. The effects of several factors such as the nature of organic solvent, compositions of SP and RP solutions, extraction time, ionic strength and stirring rate on the extraction efficiency of the drug were examined and optimized. Under the optimal conditions, enrichment factor of 250, dynamic linear range of 1-500 microgl(-1), and limit of detection of 0.5 microgl(-1) were obtained for the drug. The percent relative intra-day and inter-day standard deviation (R.S.D.%) based on three replicate determinations were 6.7 and 10.3%, respectively. The method was applied to drug level monitoring in the biological fluids and satisfactory results were obtained.

This paper proposes a new and effective approach for the quantitative analysis of sulpiride, a significant antipsychotic drug, in human urine samples by the incorporation of excitation-emission matrix (EEM) fluorescence and second-order calibration methodologies based on the alternating fitting residue (AFR) and self-weighted alternating trilinear decomposition (SWATLD) algorithms. With the application of a second-order advantage, the proposed strategy could be utilized for a direct concentration determination of sulpiride with a simple pretreatment step, even in the presence of serious natural fluorescent interferences. The average recoveries of sulpiride in complex urine samples by using AFR and SWATLD with an estimated component number of three were 101.2 +/- 2.1 and 94.4 +/- 0.7%, respectively. Moreover, the accuracy of the two algorithms was also evaluated through elliptical joint confidence region (EJCR) tests as well as the figures of merit, such as sensitivity (SEN), selectivity (SEL) and limit of detection (LOD). The experimental results demonstrated that both algorithms, as promising quantitative alternatives, have been satisfactorily applied to the determination of sulpiride in human urine, but the performance of AFR was slightly better than that of SWATLD.

Introduction: This study deals with a new methodology of on-line solid-phase extraction (SPE), derivatization reaction and spectrophotometric measurement utilizing sequential injection analysis (SIA) technique. The method was applied for the assay of trifluoperazine in human urine., Methods: An SPE procedure was automated to perform sample clean-up, extraction and preconcentration into a homemade microcolumn connected to a SIA manifold. Unlike previous SIA methods, a simple SIA manifold included one syringe pump and one multi-position valve was constructed. This offered simplicity and rapidity to the proposed method (sampling frequency 11 sample h(-1)). Spectrophotometric measurement was based on a fast oxidation of trifluoperazine by Ce(IV) in sulfuric acidic media resulting in a spectrophotometrically detectable chromophore measured at wavelength 500 nm. The SPE procedure was optimized by the univariate method while the derivatization reaction and spectrophotometric measurement were optimized by multivariate methods., Results: The method was linear in a range of 70-200 ng ml(-1) and accurate with a recovery of 92.7%. Relative standard deviation of repeatability (n=10 in a day) and intermediate precision (n=5 over a week) did not exceed 4.3% indicating satisfactory precision. The limits of detection and quantification were 18.2 and 55.2 ng ml(-1), respectively. The sensitivity of the method was improved by the preconcentration, the use of extended pathlength in the detection device and the optimization of absorbance measurement. The method is selective in the presence of chlordiazepoxide, which is sometimes taken in combination with trifluoperazine., Discussion: The method is suitable for the application of overdose and therapeutic drug monitoring in human urine.

The in vivo metabolism of the antipsychotic agent mazapertine was studied after oral administration of mazapertine succinate (40 mg/subject) to two healthy volunteers, and urine (0-24 hours) was obtained for metabolite identification using API-ionspray LC/MS and MS/MS analysis. Unchanged mazapertine (12% of the sample) plus 10 metabolites were profiled, quantified, and tentatively identified on the basis of MS data, Glusulase-hydrolysis, and by comparison to synthetic samples. The formation of mazapertine metabolites are via seven metabolic pathways: (1) phenylhydroxylation, (2) piperidyl oxidation, (3) O-dealkylation, (4) N-dephenylation, (5) oxidative N-debenzylation, (6). depiperidylation, and (7) glucuronidation. Pathways 1, 2, 5 and 7 formed 4-OH-phenyl-mazapertine (M1, 18%) and 4-OH-piperidyl (M2, 14%)-mazapertine, carboxybenzoylpiperidine (M8, 10%) and its glucuronide (M9, 14%) as four major metabolites. Six moderate and minor metabolites (M3-M7 & M10; each < or =10%) formed via a combination of pathways 1-6. Mazapertine is extensively metabolized in humans.

The objective of this study was to evaluate the efficacy of olanzapine (OLA) in heroin-dependent patients affected by comorbid schizophrenia spectrum disorders (SSD). Sixty-one patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for heroin dependence and the criteria for SSD (schizophrenia and schizotypal and schizoaffective-bipolar disorders) were treated in a 12-week prospective observational trial of substitution treatment in combination with OLA or typical antipsychotic haloperidol. Patients were included into 2 subgroups, in relationship with treatment, for the evaluation of the end points at week 12: group 1, SSD treated with OLA (35 patients); group 2, SSD treated with haloperidol (26 patients). Efficacy measures were retention in treatment, Symptoms Checklist-90 score changes, negative urinalyses results, and craving reduction. The rate of patients who remained in treatment at week 12 in group 1 SSD, treated with OLA, was significantly higher (32[91.4%]) than that of group 2 SSD (13 [50%]), treated with the typical antipsychotic (P < 0.001). The decrease in Symptoms Checklist-90 total scores from baseline, as expression of an improvement in comorbid psychopathology in the patients who completed the treatment, was significantly more consistent in group 1 than in group 2 patients (P < 0.01). Among the patients who remained in treatment, 64.4% achieved early full substance abuse remission, whereas 35.6% achieved partial substance abuse remission, with a significant difference between 1 (78.13%) and 2 (46.1%) treatment subgroups (P = 0.04). Although obtained by an observational-open clinical study with multiple limitations, our findings suggest that OLA may be able to increase retention and negative urinalyses rates during opioid agonist maintenance treatment in the patients with SSD and to improve psychopathology symptoms and tolerability in these dually diagnosed heroin addicts. Preliminary accurate diagnostic assessment and appropriate psychoactive medication in addicted patients affected by schizophrenia and schizotypal and schizoaffective-bipolar disorders seem to obtain less adverse effects and a more successful outcome of drug dependence treatment.

The adsorptive and electrochemical behaviors of clozapine (CLZ) were investigated on a glassy carbon electrode that was electrochemically treated by anodic oxidation at +1.8 V, following potential cycling in the potential range from -0.8 to 1.0 V vs. Ag/AgCl reference electrode. Based on the obtained electrochemical results, an electrochemical-chemical (EC) mechanism was proposed to explain the electrochemical oxidation of CLZ. The resulting electrochemically pretreated glassy carbon electrode (EPGCE) showed good activity to improve the electrochemical response of the drug. CLZ was accumulated in a phosphate buffer (pH 6) at a certain time, and then determined by differential pulse voltammetry. The anodic and cathodic peak currents showed a linear function in the concentration ranges of 0.1 - 1, 1 - 10 and 10 - 100 microM with various accumulation times. The proposed method was successfully used for the determination of CLZ in pharmaceutical preparations. The preconcentration medium-exchange approach was utilized for the selective determination of the drug in spiked urine samples with satisfactory results. The recovery levels of the method reached 96% (RSD, 1.8%) and 90% (RSD, 2.8%) for urine and plasma samples, respectively.

Azaleptine detection and quantitation in cadaveric material in forensic-chemical tests using thin-layer chromatography, UV-spectrophotometry, gas chromatography-mass spectrometry are outlined.

Background: In clinical and forensic toxicology, general unknown screening is used to detect and identify exogenous compounds. In this study, we aimed to develop a comprehensive general unknown screening method based on liquid chromatography coupled with a hybrid triple-quadrupole linear ion trap mass spectrometer., Methods: After solid-phase extraction, separation was performed using gradient reversed-phase chromatography. The mass spectrometer was operated in the information-dependent acquisition mode, switching between a survey scan acquired in the Enhanced Mass Spectrometry mode with dynamic subtraction of background noise and a dependent scan obtained in the enhanced product ion scan mode. The complete cycle time was 1.36 s. A library of 1000 enhanced product ion-tandem mass spectrometry spectra in positive mode and 250 in negative mode, generated using 3 alternated collision tensions during each scan, was created by injecting pure solutions of drugs and toxic compounds., Results: Comparison with HPLC-diode array detection and gas chromatography-mass spectrometry for the analysis of 36 clinical samples showed that linear ion trap tandem mass spectrometry could identify most of the compounds (94% of the total). Some compounds were detected only by 1 of the other 2 techniques. Specific clinical cases highlighted the advantages and limitations of the method., Conclusion: A unique combination of new operating modes provided by hybrid triple-quadrupole linear ion trap mass spectrometers and new software features allowed development of a comprehensive and efficient method for the general unknown screening of drugs and toxic compounds in blood or urine.

The importance of P-glycoprotein (P-gp) in the pharmacokinetics of amisulpride and the effects of a P-gp inhibitor cyclosporine A (CsA) was investigated both, in vitro and in vivo. In vitro and in vivo results indicated amisulpride as a substrate of P-gp. Amisulpride was not metabolized by rat liver microsomes. Open field behavior showed time dependent abolishment in locomotion by amisulpride (50 mg kg(-1)). Co-administration of CsA (50 mg kg(-1)) resulted in a higher and significantly longer antipsychotic effect (24 h after drug administration). Accordingly, the area under concentration-time curve in serum and brain was higher in CsA co-treated rats (13.5 vs. 29.8 micromol h l(-1) for serum and 2.16 vs 2.98 micromol h l(-1) for brain tissue) while renal clearance was not affected. These results pointed to a pharmacokinetic drug interaction between CsA and amisulpride most likely caused by inhibition of P-gp.