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Background: Given the importance of achieving optimal therapeutical concentration in patients treated with antidepressants, this study investigates a novel technique for the simultaneous determination of trazodone (TRZ) and doxepin (DOX) in human plasma and serum samples for the first time., Results: To achieve simultaneous determination of two antidepressants, TRZ and DOX, a novel detection system was designed: a non-enzymatic voltammetric biosensor based on boron-reduced graphene oxide/manganese oxide nanoparticles (GCE/B-rGO/MnO NPs). The detection was accomplished after pre-concentration and extraction trace amounts of the analytes using the thin film-solid phase microextraction (TF-SPME) technique, which employed polyvinyl alcohol/polyvinyl acetate/copper oxide nanoparticles (PVA/PVAc/CuO NPs) electrospun nanofibers. The successful preparation of composite nanofibers and modified electrodes was confirmed using the evaluation of field emission-scanning electron microscopy (FE-SEM) and energy-dispersive X-ray spectroscopy (EDX). Also, the composite nanofibers were characterized with attenuated total reflectance-Fourier transform-infrared (ATR-FT-IR) and X-ray diffraction (XRD). In the solution of TRZ and DOX, under optimum experimental conditions, the linear dynamic ranges (LDRs) were 0.1-20.0 μmol L -1 and 0.5-27.0 μmol L -1 , respectively. Also, the limit of detection (LOD) values of TRZ and DOX were 0.032 and 0.150 μmol L -1 ., Significance: PVAc acts as a cross-linking agent for PVA, and their mixture is effective for sample preparation and pre-concentration of analytes in complex matrices. Also, adding CuO NPs to this polymeric mixture enhanced the adsorption efficiency. Taking advantage of the high surface area of MnO NPs and the high electrical conductivity of B-rGO, and considering the superiority of their simultaneous utilization, the constructed electrochemical biosensor is both cost-effective and rapid. It demonstrates excellent stability, repeatability, and sensitivity for the simultaneous determination of TRZ and DOX under optimal conditions. This biosensor, the first of its kind, is specifically designed for the simultaneous determination of TRZ and DOX in human plasma and serum samples, representing a significant advancement in biosensing technology., 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 © 2024 Elsevier B.V. All rights reserved.)

The study's objective is to establish an eco-friendly, sensitive and economical quantitative methodology for the concurrent analysis of donepezil HCl (DPZ) and trazodone HCl (TRZ) in raw materials, tablets and human plasma. The first derivative synchronous fluorescence spectroscopic (FDSFS) technique was applied at constant wavelength difference (∆λ = 120) for assessment of DPZ and TRZ at each other's zero-crossing point at 279 nm and 297 nm, respectively. The submitted technique was validated in accordance with ICH Q2 R1 guidelines and the linearity of the standard calibration curve was observed over the concentration range of 10-500 ng/ml for DPZ and 20-1,000 ng/ml for TRZ. The detection limits (LOD) were found to be 2.65 and 5.4 ng/ml, and the limits of quantitation (LOQ) were 8.05 and 16.3 ng/ml for DPZ and TRZ, respectively. This technique was used further to quantify the studied medications in their laboratory-prepared mixtures, commercial tablets and spiked plasma samples. The results obtained were not significantly different from those acquired from the comparison methods, indicating the high accuracy and precision of the proposed method. Furthermore, the ecological friendliness of the suggested method was evaluated and proven to be excellent using Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE) evaluation tools., (© 2024 John Wiley & Sons Ltd.)

Background: Trazodone (TRZ) is a second-generation non-tricyclic antidepressant derived from a triazolopyridine derivative, which is mainly used to treat emotional disorders and conditions related to depressive disorders., Purpose: This study investigated the design, development and characteristics of polyvinyl chloride (PVC) membrane sensors for trazodone HCl (TRZ)., Methods: The developed sensing membranes were constructed using β-cyclodextrin (β-CD; sensor 1), γ-cyclodextrin (γ-CD; sensor 2) or 4- tert -butylcalix[8]arene ( t -BC8; sensor 3) ionophores as sensing materials in addition to ionic sites and dioctyl phthalate in the PVC matrix., Results: Sensors 1, 2 and 3 displayed fast, stable and near-Nernstian response over a relatively wide trazodone concentration range (7.0×10 -6 -1×10 -3 , 5.0×10 -5 -1×10 -3 and 8.0×10 -6 -1.0×10 -3  M, respectively), with detection limits of 2.2×10 -6 , 1.5×10 -5 and 2.42×10 -6  M, respectively in the pH range of 3.0-6.0. The sensors demonstrated good selectivity for TRZ in the presence of different ionic compounds. The accuracy and precision of the proposed sensors were assessed by the determination of 40.7 μg/ml of TRZ, which showed average recoveries of 99.6%, 99.1% and 98.5% with mean relative standard deviations of 2.4%, 2.5% and 2.6% for sensor 1, 2 and 3 respectively. Molecular modeling was used to calculate the host-guest binding energy. The lowest free binding energy was -6.243, -5.752 and -5.7105 kcal/mol for 1:1 stoichiometry host-guest complexes of trazodone and β-CD, γ-CD and t -BC8, respectively, which was in-line with a Nernstian response., Conclusion: The investigated methods can be applied for the determination of TRZ in pharmaceutical preparations. The results of investigated dosage-form of TRZ show good agreement with those using the US Pharmacopeia method., Competing Interests: All authors declared they have no conflict of interest in regard to this work.

Objectives: Elderly people with dementia are commonly suffered from sleep disorders. So, the use of Donepezil hydrochloride as anti-Alzheimer drug and Trazodone hydrochloride as antidepressants with hypnotic action is very important in these cases. This study reports about novel and sensitive RP-HPLC method with fluorescence detection for simultaneous bioanalytical determination of Donepezil hydrochloride (DON) and co-administered, Trazodone hydrochloride (TRA) in their pure forms, spiked human plasma and tablets., Materials and Methods: Elution of both drugs was achieved with excellent resolution using a RP-C18 Hypersil Gold column and an isocratic mobile phase consisting of phosphate buffer (50mm, pH 4.6): methanol: acetonitrile (60:35:5) with a flow rate of 1.5mL/min and 20μL as injection volume. A Fluorescence detector at 300nm for excitation and 400nm for emission was used., Results: Retention times were 4.3 and 6.3min for Donepezil hydrochloride and Trazodone hydrochloride, respectively. Linearity ranges of the assay were 25-1000 and 50-5000ng/mL and the limits of detection (LOD) and quantitation (LOQ) were 8.52, 15.47 and 25.81, 46.89ng/mL for Donepezil hydrochloride and Trazodone hydrochloride, respectively., Conclusion: The high sensitivity of the proposed method enabled the successful determination of the cited drugs in spiked human plasma with mean percentage of recoveries of 91.58±3.34 and 100.30±5.11 for Donepezil hydrochloride and Trazodone hydrochloride, respectively., (Copyright © 2019 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Environmental contamination with pharmaceuticals has received growing attention in recent years. Several studies describe the presence of traces of drugs in water bodies and soils and their impacts on nontarget organisms including plants. Due to these facts investigations of the uptake and metabolism of pharmaceuticals in organisms is an emerging research area. The present study demonstrates the analysis of three selected antidepressants (sertraline, clomipramine, and trazodone) as well as metabolites and transformation products in a cress model (Lepidium sativum). Cress was treated with tap water containing 10 mg/L of the parent drugs. Employing an analytical approach based on high performance liquid chromatography coupled with quadrupole time of flight or Orbitrap mass spectrometry in MS and MS² modes, in total 14 substances were identified in the cress extracts. All three parent drugs were taken up by the cress and translocated from the roots to the leaves in specific patterns. In addition to this, eleven metabolite species were identified. They were generated by hydroxylation, demethylation, conjugation with amino acids, or combinations of these mechanisms. Finally, the inclusion of control cultures in the experimental setup allowed for a differentiation of "true" metabolites generated by the cress and transformation products generated by plant-independent mechanisms., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new sensitized chemiluminescence method by acidic permanganate oxidation was developed for the sensitive determination of trazodone. A fluorescent dye as used rhodamine 6G to increase a chemiluminescence intensity. Under optimum conditions, the liner range of the calibration curve was obtained for 1-5000 nmol/L. The limit of detection was calculated from 3σ of a blank was 0.23 nmol/L. The coexistent ions and substances had no interference with the chemiluminescence measurement. The chemiluminescence spectra were measured to elucidate a possible mechanism for the system. The present method was satisfactorily used in the determination of the drugs in pharmaceutical samples and animal serums., (Copyright © 2017 John Wiley & Sons, Ltd.)

Alternative specimens have been occasionally considered as substitutes for whole blood for postmortem toxicology testing. We studied the applicability of vitreous humor, and evaluated whether it would be suitable to replace (or augment) whole blood for routine drug screening. Results showed that from 51 autopsy cases, we were able to identify an aggregate of 209 findings in whole blood compared with 169 in vitreous. The total number of compounds identified was 71 for whole blood and 60 for vitreous humor. Quantitative analysis showed that whole-blood concentrations of trazodone were several fold higher than vitreous humor concentrations (1.42 ± 0.57 vs. 0.15 ± 0.05 mg/L, respectively) and similar results were also obtained for diazepam (0.37 ± 0.06 vs. 0.13 ± 0.01, respectively). For other drugs such as oxycodone, hydrocodone and doxylamine, a trend suggesting higher concentrations in vitreous humor vs. whole blood was observed; however, this was not significant. Our results are consistent with the limited work of other investigators, and suggest that vitreous humor could be an appropriate matrix for drug screening in postmortem toxicology., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Non-toxic postmortem trazodone tissue (liver) concentrations have not been previously described. Liver trazodone concentrations were compared to peripheral blood and central blood concentrations in 19 medical examiner cases. Postmortem blood specimens were initially screened for alcohol and simple volatiles, drugs of abuse, and alkaline drugs. Trazodone, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a high performance liquid chromatography procedure. Re-analyses showed that there may be degradation of trazodone in postmortem blood stored at 4°C. There was, on average, about a 20% decrease in samples stored up to eight months. These data suggest that postmortem trazodone peripheral blood concentrations may be considered non-toxic to at least 1.0mg/L with liver concentrations to at least 2.2mg/kg. Overall, trazodone concentrations ranged from 0.08-6.1mg/L in peripheral blood, 0.07-7.1mg/L in central blood, and 0.39-26mg/kg in liver. The median trazodone central blood to peripheral blood ratio was 0.98 (N=19). The liver to peripheral blood ratios showed a median value of 2.8L/kg (N=18). Given that a liver to peripheral blood ratio less than 5L/kg is consistent with little to no propensity for postmortem redistribution, these data demonstrate that trazodone is unlikely to show significant redistribution., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

A simple and rapid electrochemical method was developed for the determination of trace-level trazodone, based on the excellent properties of multi-walled carbon nanotubes (MWCNTs). The MWCNT-modified glassy carbon electrode was constructed and the electrochemical behavior of trazodone was investigated in detail. The cyclic voltammetric results indicate that MWCNT-modified glassy carbon electrode can remarkably enhance electrocatalytic activity towards the oxidation of trazodone in neutral solutions. It leads to a considerable improvement of the anodic peak current for trazodone, and allows the development of a highly sensitive voltammetric sensor for the determination of trazodone. Trazodone could effectively accumulate at this electrode and produce two anodic peaks at about 0.73 V and 1.00 V. The electrocatalytic behavior was further exploited as a sensitive detection scheme for the trazodone determination by differential-pulse voltammetry. Under optimized conditions, the concentration range and detection limit are 0.2-10 microM and 24 nM, respectively for trazodone. The proposed method was successfully applied to trazodone determination in pharmaceutical samples. The analytical performance of this sensor has been evaluated for detection of analyte in urine as a real sample.

A trazodone-selective electrode for application in pharmaceutical quality control and urine analysis was developed. The electrode is based on incorporation of a trazodone-tetraphenylborate ion exchanger in a poly(vinyl chloride) membrane. The electrode showed a fast, stable and Nernstian response over a wide trazodone concentration range (5 x 10(-5)-1 x 10(-2) M) with a mean slope of 59.3 +/- 0.9 mV/dec of concentration, a mean detection limit of 1.8 x 10(-5) +/- 2.2 x 10(-6) M, a wide working pH range (5-7.5) and a fast response time (less than 20 s). The electrode also showed good accuracy, repeatability, reproducibility and selectivity with respect to some inorganic and organic compounds, including the main trazodone metabolite. The electrode provided good analytical results in the determination of trazodone in pharmaceuticals and spiked urine samples; no extraction steps were necessary. Dissolution testing of trazodone tablets, in different conditions of pH and particle size, based on a direct potentiometric determination with the new selective electrode is presented as well.

A specific liquid chromatography-mass spectrometric (LC-MS) method using an ion trap spectrometer was developed for the quantitation of articaine in human plasma. Articaine and the internal standard (trazodone) were extracted in a single step with diethyl-ether from 0.5 mL of alkalinized plasma. The mobile phase consisted of acetonitrile with 0.1% formic acid (40:60, v/v). It was delivered at a flow rate of 0.3 mL/min. The effluent was monitored by MS in positive-ion mode. Ionisation was performed using an electrospray ion source operating at 200 degrees C. Articaine was identified and quantified in SIM mode at m/z 185. Calibration curves were linear over the concentration range of 78.1-5000 ng/mL with determination coefficients>0.996. This method was fast (total run-time<3 min), accurate (bias<16%), and reproducible (intra-assay and inter-assay precision<14%) with a quantitation limit of 78.1 ng/mL. The good specificity and sensitivity achieved by this method allowed the determination of articaine plasma levels in patients following a submucosal infiltration injection of articaine in the patients undergoing a third molar surgery.

A simple and rapid spectrophotometric method has been developed for the determination of tricyclic anti-depressant drugs such as trazodone (TZH), amineptine (APH) and amitriptyline (ATPH) hydrochlorides in pure form and in different pharmaceutical preparations. The charge transfer (CT) reaction between TZH, APH and ATPH as electron donors and TCNQ as electron acceptor was utilized for their spectrophotometric determination. The optimum experimental conditions, like time, temperature, stoichiometry, solvents, for the CT complex formation are established. The method permits the determination of TZH, APH and ATPH over a concentration range of 10-400, 10-440 and 10-300 microg ml(-1), respectively. The sensitivity (S) is found to be 0.09, 0.087 and 0.069 g cm(-2) for TZH, APH and ATPH, respectively. The SD values are found to be 0.146-0.293, 0.154-0.285 and 0.091-0.212 and RSD values are 0.142-1.92, 0.297-1.92 and 0.212-0.915 for TZH, APH and ATPH, respectively. The low values of the relative standard deviation indicate the high accuracy and precision of the method. The mean recovery values obtained together with a high correlation coefficient values, amount in the range 98-101.5, 98.7-102.9 and 93-101.9 for TZH, APH and ATPH, respectively. The method is applicable for the assay of the investigated drugs in different dosage forms and the results are in good agreement with those obtained by the official method.

A simple and reliable liquid chromatographic procedure is described for the determination of trazodone in pharmaceutical formulations and urine samples. The optimized procedure uses fluorimetric detection, a C18 column and a micellar mobile phase of sodium dodecyl sulfate (SDS) and 1-butanol. The mobile phase selected for use was 0.2M SDS and 8% 1-butanol fixed at pH 3 with phosphate buffer. The total analysis time was 10 min. For the analysis of urine samples, one great advantage of the method is that no extraction step is required. The quantification limit was 9.5 ng mL(-1), ensuring the analysis of the drug in biological fluids. The procedure shows good accuracy, repeatability and selectivity. Repeatability and intermediate precision were tested for several concentrations of the drug. Good claim percentages were obtained in the analysis of pharmaceutical formulations. Calibration repeatability in urine matrix was also studied in the 0.06-22.4 microg mL(-1) range. Good recoveries were obtained from spiked urine samples. No interferences from common additives frequently administered with trazodone or from endogenous compounds in urine samples were found. The results show that the procedure is suitable for routine analysis of the drug.

A novel micro-extraction procedure was developed through the use of an electrospun polymer nanofiber as a solid-phase extraction (SPE) sorbent to directly extract trazodone from human plasma. The target compound was then monitored by a high performance liquid chromatography with ultraviolet detector (HPLC-UV) system. Parameters of influencing the extraction efficiency, such as fiber diameter, fiber packing amount, eluted solvent, pH and ionic strength were investigated. Under the optimized conditions, a linear response for trazodone over the range of 20-2000 ng mL(-1) was achieved with a gamma(2) value of 0.9996. The precision of the method was examined with relative standard deviations of 5.7, 2.7, 2.2% corresponding to 50, 200, and 500 ng mL(-1), respectively, of trazodone spiked into 0.1 mL of plasma samples. The extraction recoveries of 58.3-75.2% and the relative recoveries of 94.6-105.5% were obtained. The limit of detection (LOD) was determined to be 8 ng mL(-1). A 15 min of HPLC gradient was successfully applied to determine trazodone from human plasma. Due to its simplicity, selectivity and sensitivity, the method may be applied to pharmacokinetic and pharmacodynamic studies of drugs.

A fatal suicidal ingestion of drugs, together with activated charcoal, is reported. The death occurred 31 hours after the self-administration. The autopsy revealed a large amount of gastric content that appeared to be a compact mass of black color. Toxicologic analyses showed the presence of toxic levels of desalkylflurazepam and trazodone; metamizole and pridinol were also detected. The obtained results supported the hypothesis of a death due to acute intoxication delayed by the self-administration of activated charcoal, which elimination was probably hindered by the action of pridinol.

Two simple, rapid and sensitive extractive spectrophotometric methods have been developed for the assay of trazodone hydrochloride (TRH) in pure and pharmaceutical formulations. These methods are based on the formation of chloroform soluble ion-association complexes of TRH with bromothymol blue (BTB) and with bromocresol purple (BCP) in KCl-HCl buffer of pH 2.0 (for BTB) and in NaOAc-AcOH buffer of pH of 3.6 (for BCP) with absorption maximum at 423 nm and at 408 nm for BTB and BCP, respectively. Reaction conditions were optimized to obtain the maximum color intensity. The absorbance was found to increase linearly with increase in concentration of TRH, which was corroborated by the calculated correlation coefficient values (0.9996, 0.9945). The systems obeyed Beer's law in the range of 0.2-14.5 and 0.2-14.1 microg/ml for BTB and BCP, respectively. Various analytical parameters have been evaluated and the results have been validated by statistical data. No interference was observed from common excipients present in pharmaceutical formulations. The proposed methods are simple, accurate and suitable for quality control applications.

Background: Amino acid neurotransmitters represent a major class of compounds that are involved in neuronal communication at CNS synapses., Methods: Twelve amino acids were separated after precolumn derivatization with dansyl chloride. The biologically important amino acids, taurine, aspartate, glutamate, glycine, alanine and gamma-aminobutyric acid were determined in rat brain tissue and rabbit plasma., Results: The major modifications to previous methods included isocratic elution instead of gradient elution to reduce time and cost of serial analyses; optimization of mobile phase to improve the separation of free dansyl with derivatives, so as to elide complex steps for the clean of the chromatogram; and selection of an internal standard (Trazodone) to improve the reproducibility and the reliability of procedures. Twelve amino acids were assayed within 35 min. Other alpha-amino acids that are relevant to the make-up of mammalian proteins did not interfere with the determination. The standard curve, recovery, analytical precision and detection limits for each neuroactive amino acid were determined., Conclusion: This assay separated 12 amino acids in a single run. Six neuroactive amino acids were also simultaneous measured by isocratic HPLC with UV detection. The method is applicable in determination of Tau, Glu, Asp, Gly, Ala and GABA in biological samples.

ZD6474 (N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy] quinazolin-4-amine) is a tyrosine kinase inhibitor with anti-angiogenic and anti-tumor activity that is currently undergoing human trials for cancer treatment. Pharmacokinetic studies in animal models are an important component in clinical development of this agent to relate pre-clinical models to patient treatment. A liquid chromatography tandem mass spectrometry method was developed for the determination of ZD6474 levels in mouse plasma and tissues. Plasma (0.05 mL) and tissue homogenates (0.1 mL of 10 mg/mL) were extracted under alkaline conditions with ethyl acetate:pentane (1:1, v/v) after addition of the internal standard (trazodone, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridine-3(2H)-one). Separation was achieved on a C18, 50 mm x 2 mm column with quantitation by internal standard reference and multiple reaction monitoring of the ion transitions m/z 475-->112 (ZD6474) and m/z 372-->176 (trazodone). The calibration curve was linear from a range spanning 20-20,000 ng/mL in plasma and 10-320 ng/mg in tissue homogenates. Mean recoveries from plasma and tissue homogenates were 88 and 90%, respectively. The accuracy in plasma was 88% at the lower limit of quantitation (20 ng/mL with a 50 microL plasma sample) with high precision (R.S.D.%<10%). Assay performance in liver and other tissue homogenates is also reported. The assay was applied to a pharmacokinetic study in mice to determine dosing schedules that would approximate therapeutic ZD6474 levels determined in humans.

Purpose: The purpose of this study was to establish an automated approach to salt selection and to search for unique trazodone salts for new applications., Methods: Automated procedures were developed on a Biomek 2000 automation workstation with stacker and plate reader capabilities. Trazodone was dispensed into 96-well plates, and an automated method was set up to form 104 trazodone salts. Salts were observed under a polarized light microscope to determine crystallinity. After stepwise eliminations, the remaining salts were scaled-up and subjected to differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), hygroscopic, pH-solubility, density, surface area, and particle size analyses., Results: Oils formed in several cases resulting in preliminary elimination of mesyl and esyl salts and four crystallizing solvents. Crystallinity was observed in 34 of 44 scaled-up trazodone salts. PXRD, DSC, and hygroscopic analyses indicated a number of new salts that were comparable in physicochemical parameters to the marketed HCl salt. Among them, the tosylate salt showed uniqueness for new applications., Conclusions: Automated procedures can be developed to increase the efficiency of pharmaceutical salt selection. The new tosylate salt gave a unique pH-solubility profile with low solubility over the entire pH range making it a potential candidate for a suspension or prolonged action formulation.

Two sensitive and simple spectrophotometric methods are developed for the determination of trazodone HCl, famotidine, and diltiazem HCl in pure and pharmaceutical preparations. The methods are based on the oxidation of the cited drugs with iron(III) in acidic medium. The liberated iron(II) reacts with 1,10-phenanthroline (method A) and the ferroin complex is colorimetrically measured at 510 nm against reagent blank. Method B is based on the reaction of the liberated Fe(II) with 2,2-bipyridyl to form a stable colored complex with lambda(max )at 520 nm. Optimization of the experimental conditions was described. Beer's law was obeyed in the concentration range of 1-5, 2-12, and 12-32 microg mL(-1) for trazodone, famotidine, and diltiazem with method A, and 1-10 and 8-16 microg mL(-1) for trazodone and famotidine with method B. The apparent molar absorptivity for method A is 1.06x10(5), 2.9x10(4), 1.2x10(4) and for method B is 9.4x10(4 )and 1.6x10(4), respectively. The suggested procedures could be used for the determination of trazodone, famotidine, and diltiazem, both in pure and dosage forms without interference from common excipients.

The electrochemical oxidative behavior of piribedil (PR) was described. It was investigated by cyclic, linear sweep, differential pulse (DPV) and square wave (SWV) voltammetric techniques. The redox behavior of PR was found irreversible. Different parameters were tested to optimize the conditions for the determination of PR. The dependence of intensities of currents and potential on pH, concentration, scan rate, nature of the buffer was investigated. Two sensitive methods for the measurement of PR were described. For analytical purposes, a very well resolved diffusion controlled voltammetric peak was obtained in 0.1 M H(2)SO(4) and pH 5.7 acetate buffer. The determination peaks are obtained at 1.27 and 0.95 V for differential pulse and 1.29 and 0.97 V for SWV in 0.1 M H(2)SO(4) and pH 5.7 acetate buffer, respectively. The linear response was obtained in the ranges of 2 x 10(-6)-1 x 10(-3) M in 0.1 M H(2)SO(4) and 2 x 10(-6)-8 x 10(-4) M in pH 5.7 acetate buffer for both techniques. The proposed techniques were successfully applied to the determination of PR in tablet dosage forms and human serum. Excipients did not interfere in the determination. The necessary statistical validation reveals that the proposed methods are free from significant systematic errors.

The voltammetric behavior of trazodone (TRZ) HCl was studied using direct current (DC(t)), differential pulse (DPP) and alternating current (AC(t)) polarography. The drug manifests cathodic waves over the pH range of 10-14. The waves were characterized as being irreversible, diffusion-controlled with limited adsorption properties. At pH 10, the diffusion current-concentration relationship was found to be rectilinear over the range 4-32 and 0.8-24 microg ml(-1) using DC(t) and DPP modes, respectively, with minimum detectability (S/N=2) of 0.104 microg ml(-1) (2.45 x 10(-6) M) and 0.314 microg ml(-1) (7.397 x 10(-6) M) using the DPP and DC(t) modes, respectively. The diffusion-current constant (I(d)) is 4.31+/-0.02 (n=6). The proposed method was successfully applied to the determination of the studied compound either in pure form or in formulations. The results obtained were favorably compared with those given using a reference method. Furthermore, the proposed method was applied to the determination of TRZ in spiked human urine and plasma adopting the DPP technique. No prior extraction step is needed in case of urine. The percentage recoveries were 98.43+/-0.79 and 97.44+/-0.705 (n=4) in spiked human urine and plasma, respectively. A pathway for the electrode reaction was postulated.

Ion-associate complexes of furaltadone, methadone and trazodone hydrochlorides with [Cd(SCN)(4)](2-) and [Zn(SCN)(4)](2-) were precipitated and the excess unreacted cadmium or zinc complex was determined. A new method using atomic emission and atomic absorption spectrometry for the determination of the above drugs in pure solutions and in pharmaceutical preparations is given. The drugs can be determined by the affort method in the ranges 7.2-72.16, 6.9-69.18 and 8.1-81.6 microg/ml solutions of the three drugs, respectively.

Trazodone is a popular antidepressant medication that has been available for approximately 30 years. It has a reputation as a safe drug with relatively few reported fatalities attributed solely to it. We review the pharmacology and forensic toxicology of trazodone and report toxicology and cause and manner of death in a series of 37 deaths in which trazodone was detected. Although the normal upper therapeutic blood concentration for trazodone is about 2 mg/L, fatalities are rarely attributed solely to it at blood concentrations below 9 mg/L. Considering the pharmacology of the drug, potential interactions between other drugs with serotonin reuptake properties need to be considered, as does the increased susceptibility to the toxic effects in patients with pre-existing heart disease. In the cases reviewed, none were attributed solely to trazodone, although trazodone was frequently present together with other serotonergic drugs, such as the selective serotonin reuptake inhibitors like fluoxetine and sertraline. Ten cases had blood trazodone concentrations above 2 mg/L. Of these cases, trazodone played a primary role in the death of three subjects, with blood concentrations all greater than 9 mg/L. We confirm the conclusions of others that trazodone is a relatively safe drug except in massive overdose, although its toxicity may be influenced by the presence of other drugs and underlying pathophysiology.

The aim of this study was to investigate the brain pharmacokinetics and pharmacodynamics of trazodone. Sensitive microbore high-performance liquid chromatographic methods with electrochemical detection (LC-ED) were developed for the determination of trazodone, serotonin (5-HT), and their respective metabolites. The feasibility of microdialysis coupled with LC-ED system for direct analysis of these compounds in the rat striatum was investigated. Striatal dialysates were automatically injected onto a cyano microbore column, through an on-line injector, for the determination of trazodone and its metabolite or onto a reversed phase microbore column for the determination of 5-HT and its metabolite. A monophase phenomenon with a first-order elimination rate constant was observed for trazodone. The brain pharmacokinetics of trazodone appear to conform to a one-compartment model. Surprisingly, no significant changes in striatal 5-HT or its metabolite were observed following the same dosage and time course. The present results suggest that brain microdialysis methods may be applicable to pharmacokinetic and pharmacodynamic studies of psychotrophic agents.

The voltammetric behaviors of trazodone using a platinum electrode in stationary or rotating conditions and its determination in tablets by DP rotating electrodes are described in this study. The experiments were conducted in the supporting electrolyte consisting of 0.2 M KCl and 0.2 M acetate or phosphate buffer. No adsorption was observed at +300 mV. The factor affecting the voltammetric current was diffusional in the range of 200-2000 rpm for rotating, and 2-10 mV potential rate for stationary conditions; and the calibration dependence was linear between 1x10-5-5x10-5 M trazodone solutions. The detection limit was found to be 2.5x10-6 M (sb=5.03, n=5) for stationary and 1.7x10-6 M (sb=2.12, n=5) for rotating electode assuming a signal to noise ratio of 3. According to the statistical evaluations, acceptable results were obtained at the 95% probability level. Therefore, the proposed method is practicable, sensitive and accurate for the analysis of trazodone preparations in quality control laboratories.

A coated wire trazodone-selective electrode based on incorporation of trazodone-tetraphenylborate ion pair in a poly(vinylchloride) coating membrane was constructed. The influences of membrane composition, temperature, pH of the test solution, and foreign ions on the electrode performance were investigated. The electrode showed a Nernstian response over a trazodone concentration range from 1.41 x 10(-5) to 0.89 x 10(-2) M, at 25 degrees C, and was found to be very selective, precise, and usable within the pH range 2.4-9.0. The standard electrode potentials, E degree, were determined at 20, 25, 30, 35, 40 and 45 degrees C and used to calculate the isothermal temperature coefficient (dE degree/dT) of the electrode. Temperatures higher than 45 degrees C seriously affected the electrode performance. The electrode was successfully used for potentiometric determination of trazodone hydrochloride both in pure solutions and in pharmaceutical preparations.

The potentials and limitations of high-performance liquid chromatography-photodiode array detection are highlighted in respect to its use in the analysis of different biological matrices followed by the identification of unknowns. The logical analytical approach used in clinical and forensic toxicology, vital for the identification of one or more toxic substances as a cause of intoxication, is largely based on both simple and fast "general unknown screening" methods which cover most relevant drugs and potentially hazardous chemicals. In this field of systematic toxicological analysis, a literature overview shows that HPLC can play a substantial role. Both column packing material and eluent composition have their impact on intra- and interlaboratory reproducibility. In view of the sometimes different retention characteristics of various HPLC columns, several possibilities are addressed to enhance the discriminating power of primary retention parameters. The advantages of photodiode array detection as compared to UV detection have been of paramount importance to the success of HPLC in toxicological analysis. Dedicated libraries with spectral information and searching software are powerful tools in the process of identification of an unknown substance. In the present paper, these aspects are also verified in a number of real cases, i.e., trazodone and dothiepin, azide, chloroquine and cocaine, in which we illustrate from our own experience the potentials of HPLC-photodiode array detection in systematic toxicological analysis.

Calliphora vicina larvae were fed on drug-laden muscle from three suicides involving amitriptyline, temazepam and a combination of trazodone and trimipramine; triplicate daily harvestings were analysed. The limit of detection for all four drugs was 0.01 micrograms drug/g larvae. Mean drug concentrations (microgram/g) in the initial muscle were:amitriptyline, 2.68; temazepam, 4.04; trazodone, 21.56; and trimipramine, 19.58. Larval rearings for days 4-8 (15 larval samples per drug) had mean and ranges of drug concentrations (microgram/g) of 0.10 (r, 0.02-0.24) for amitriptyline; 0.52 (r, 0.26-0.78) for temazepam; 0.13 (r, 0.05-0.32) for trazodone; and 0.28 (r, 0.10-0.59) for trimipramine. After day 8 there was a precipitous fall in larval drug concentrations associated with pupariation. At day 11 ranges of drug concentrations (microgram/g) were: amitriptyline, < 0.01-0.01; temazepam, 0.01-0.08; trazodone, < 0.01-0.01; and trimipramine, 0.04-0.04. Day 16 pupae had corresponding ranges (microgram/g) of < 0.01, 0.01-0.01, < 0.01 and < 0.01-0.02. Transfer to drug-free food at day 5 led to similar falls in drug concentrations (microgram/g) from day 5 to day 6: 0.08-0.03 for amitriptyline, 0.61-0.09 for temazepam, 0.13-0.01 for trazodone, and 0.30-0.02 for trimipramine. The results show considerable variation in larval drug concentrations, both at the same developmental stage and at different stages of the life cycle, under conditions which closely reflect case situations. In practice, the precipitous decrease in drug concentrations in non-feeding larvae and at pupariation make it desirable to sample only larvae actively feeding on a corpse.

A plastic membrane ion-selective electrode applicable to many basic drugs has been developed. The electrode developed was constructed with tricresyl phosphate and a poly(vinyl chloride) matrix on a polytetrafluoroethylene film. The electrode showed a near-Nernstian response to chlorpromazine, trihexyphenidyl, imipramine, dibucaine, papaverine, propranolol, tetracaine, trazodone, quinidine and cinnarizine. The determination of 50 to 3000 micrograms/ml of trazodone hydrochloride in a pH 4.0 acetate buffer solution showed an average recovery of 99.4% (mean standard deviation 0.7%) by direct potentiometry. Inorganic cations and pharmaceutical excipients did not interfere with the determination. Trazodone hydrochloride and trihexyphenidyl hydrochloride in tablets were determined, and the results compared favorably with those obtained by conventional methods.

A specific and highly sensitive method for the measurement of trazodone in plasma and brain of rat is presented. The compound and the internal standard were extracted from alkalinized samples with hexane and analysed by capillary gas chromatography with nitrogen-selective detection. The method was demonstrated to be accurate and precise. The limits of determination were 2 ng/ml for plasma and 24 ng/g for brain, which makes this procedure suitable for pharmacokinetic analysis.

A selective and sensitive high-performance liquid chromatographic assay with ultraviolet detection for the determination of the antidepressant drug etoperidone and two active metabolites in plasma is described. The drug, metabolites and internal standard are isolated from plasma using a two-step liquid-liquid extraction procedure. The resulting sample is chromatographed on a C18 column (10 cm x 2.1 mm I.D.) with ultraviolet detection at 254 nm. Standard curves are linear for each compound over the concentration range 2-1000 ng/ml. The accuracy and precision of the assay, expressed as the percentage deviation of measured values from the true value and the relative standard deviation (inter-run), are less than or equal to 10% at all concentrations except the minimum quantification limit. Using an automated injector and computerized data acquisition, eighty samples can be routinely processed in one day. The assay has been successfully used for the analysis of plasma samples from pharmacokinetic studies in mice, rats, dogs and humans.

1 A simple and specific procedure is described for the determination of the new anti-depressant trazodone in human plasma utilising reverse-phase HPLC which is sensitive to 20 ng ml-1. 2 Following oral administration of single 50 mg doses of two formulations of trazodone on separate occasions to healthy fasted volunteers, the peak plasma concentration, time to peak concentration, area under the curve, elimination rate constant and half-life were determined. 3 The two formulations are closely similar and they are considered to have comparable bioavailability.

A sensitive and rapid method for the analysis of trazodone (TZD) and its metabolite, 1-(m-chlorophenyl)piperazine (m-CPP), in the serum and urine of rabbits treated with the drug was developed. The assay requires extraction from the biological fluids with adequately buffered organic solvents followed by HPLC. The assay allows good reproducibility, fair recovery, and excellent linearity in the range of 0.6 to 10 micrograms/mL for TZD and 1.2 to 20 micrograms/mL for m-CPP.

A simple assay procedure for the quantitation of trazodone hydrochloride in tablets, without prior separation, has been developed using a trazodone-selective electrode. The electrode was based on a trazodone:tetrakis(p-chlorophenyl)borate ion-pair complex, dioctyl phthalate, and polyvinyl chloride matrix that were mounted on a PTFE membrane. The electrode showed a near-Nernstian response in the range of 10(-2) to 5 x 10(-6) M trazodone over the pH range of 2.5 to 5.0, with a cationic slope of 58 mV/concentration decade. The durability of the electrode and the reproducibility of the performance among the electrodes were sufficient. The electrode was used for the determination of the pKa value of trazodone. The selectivity of the electrode to a number of interferences was investigated. Many inorganic cations (alkali and alkaline earth metals) and pharmaceutical excipients did not interfere, but some organic ammonium compounds interfered according to their extractability. Determination of 10 to 3000 micrograms/mL of trazodone hydrochloride in aqueous solution showed an average recovery of 100.6% (mean standard deviation 0.4%) by direct potentiometry. This assay was applied to determine trazodone hydrochloride in tablets and the results compared favorably with those obtained by high-performance liquid chromatography.

A simple and specific method is presented for the capillary gas chromatographic determination of trazodone in postmortem blood and tissues. The drug and trimethobenzamide, which was used as an internal standard, were extracted with 1% isopropanol in n-butyl chloride. Chromatography was accomplished with a short (4-m) methyl silicone capillary column and hydrogen carrier gas. This combination of extraction solvent and chromatographic conditions was demonstrated to be both accurate and precise. Since trazodone is a relatively new drug, additional thin layer and packed column gas chromatographic data is presented to augment the incorporation of trazodone into routine analytical protocols.

A method for the determination of the antidepressant drug trazodone is presented. 8-Hydroxyloxapine is used as the internal standard. A simple solid-phase extraction procedure utilizing disposable reversed-phase C18 columns is described. Samples are analyzed by gas chromatography with nitrogen-selective detection using a wide-bore capillary column with a permanently bonded, nonpolar stationary phase. The assay possesses linearity to 3.0 micrograms/mL, sensitivity to at least 0.25 microgram/mL, recovery averaging 96%, and between-run precision reflected by a CV of 5.6%. We conclude that the method reported here is ideally suited for monitoring therapeutic and toxic levels of trazodone.