Synthesis of bifunctional cabbage flower-like Ho3+/NiO nanostructures as a modifier for simultaneous determination of methotrexate and carbamazepine.

Cabbage flower-like Ho3+/NiO nanostructure (CFL-Ho3+/NiO NSs) with significant electrocatalytic oxidation has been published for the first time. First, structure and morphology of CFL-Ho3+/NiO-NSs have been described by XRD, SEM, and EDX methods. Then, CFL-Ho3+/NiO-NSs have been applied as a modifier for simultaneous electrochemical detection of methotrexate (MTX) and carbamazepine (CBZ). Functions of the modified electrode have been dealt with through electrochemical impedance spectroscopy (EIS). It has been demonstrated that the electrode response has been linear from 0.001-310.0 µM with a limit of detection of 5.2 nM and 4.5 nM (3 s/m) through DPV for MTX and CBZ. Diffusion coefficient (D) and heterogeneous rate constant (kh) have been detected for MTX and CBZ oxidation at the surface of the modified electrode. Moreover, CFL-Ho3+/NiO-NS/GCE has been employed for determining MTX and CBZ in urine and drug specimens. Outputs showed the analyte acceptable recovery. Therefore, the electrode could be applied to analyze both analytes in drug prescription and clinical laboratories. Graphical abstract Electrochemical sensor based on bifunctional cabbage flower-like Ho3+/NiO nanostructures modified glassy carbon electrode for simultaneous detecting methotrexate and carbamazepine was fabricated.

Cyclodextrin-assisted dispersive liquid-liquid microextraction for the preconcentration of carbamazepine and clobazam with subsequent sweeping micellar electrokinetic chromatography.

A new version of dispersive liquid-liquid microextraction, namely, cyclodextrin-assisted dispersive liquid-liquid microextraction, with subsequent sweeping micellar electrokinetic chromatography has been developed for the preconcentration and sensitive detection of carbamazepine and clobazam. α-Cyclodextrin and chloroform were used as the dispersive agent and extraction solvent, respectively. After the extraction, carbamazepine and clobazam were analyzed using micellar electrokinetic chromatography with ultraviolet detection. The detection sensitivity was further enhanced using the sweeping technique. Under optimal extraction and stacking conditions, the calibration curves of carbamazepine and clobazam were linear over a concentration range of 2.0-200.0 ng/mL. The method detection limits at a signal-to-noise ratio of 3 were 0.6 and 0.5 ng/mL with sensitivity enhancement factors of 3575 and 4675 for carbamazepine and clobazam, respectively. This developed method demonstrated high sensitivity enhancement factors and was successfully applied to the determination of carbamazepine and clobazam in human urine samples. The precision and accuracy for urine samples were less than 4.2 and 6.9%, respectively.

Human Exposure to Wastewater-Derived Pharmaceuticals in Fresh Produce: A Randomized Controlled Trial Focusing on Carbamazepine.

Fresh water scarcity has led to increased use of reclaimed wastewater as an alternative and reliable source for crop irrigation. Beyond microbiological safety, concerns have been raised regarding contamination of reclaimed wastewater by xenobiotics including pharmaceuticals. This study focuses on carbamazepine, an anticonvulsant drug which is ubiquitously detected in reclaimed wastewater, highly persistent in soil, and taken up by crops. In a randomized controlled trial we demonstrate that healthy individuals consuming reclaimed wastewater-irrigated produce excreted carbamazepine and its metabolites in their urine, while subjects consuming fresh water-irrigated produce excreted undetectable or significantly lower levels of carbamazepine. We also report that the carbamazepine metabolite pattern at this low exposure level differed from that observed at therapeutic doses. This "proof of concept" study demonstrates that human exposure to xenobiotics occurs through ingestion of reclaimed wastewater-irrigated produce, providing real world data which could guide risk assessments and policy designed to ensure the safe use of wastewater for crop irrigation.

Pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers.

PURPOSE: Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers. METHODS: Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers. KEY FINDINGS: Mean eslicarbazepine Cmax,ss (in µm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0-τ (in µmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio eslicarbazepine plasma exposure (µmol h/L) to ESL daily-dose (µmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively. SIGNIFICANCE: ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss ) of eslicarbazepine and similar extent of plasma exposure (AUCss,0-τ ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine.

Determination of carbamazepine in human urine and serum samples by high-performance liquid chromatography with post-column Ru(bipy)2(3+)-Ce(SO4)2 chemiluminescence detection.

A novel, sensitive and rapid CL method coupled with high-performance liquid chromatography separation for the determination of carbamazepine is described. The method was based on the fact that carbamazepine could significantly enhance the chemiluminescence of the reaction of cerium sulfate and tris(2,2-bipyridyl) ruthenium(II) in the presence of acid. The chromatographic separation was performed on a Kromasil® (Sigma-Aldrich) TM RP-C18 column (id: 150 mm × 4.6 mm, particle size: 5 µm, pore size: 100 Å) with a mobile phase consisting of methanol-water-glacial acetic acid (70:29:1, v/v/v) at a flowrate of 1.0 mL/min, the total analysis time was within 650 s. Under optimal conditions, CL intensity was linear for carbamazepine in the range 2.0 × 10(-8) ~ 4.0 × 10(-5) g/mL, with a detection limit of 6.0 × 10(-9) g/mL (S/N = 3) and the relative standard detection was 2.5% for 2.0 × 10(-6) g/mL (n = 11). This method was successfully applied to the analysis of carbamazepine in human urine and serum samples. The possible mechanism of the CL reaction is also discussed briefly.

Novel micro-extraction by packed sorbent procedure for the liquid chromatographic analysis of antiepileptic drugs in human plasma and urine.

A method for the simultaneous determination of the antiepileptic drugs, phenobarbital (PHB), phenytoin (PTN), carbamazepine (CBZ), primidone (PRM) and oxcarbazepine (OXC) in human plasma and urine samples by using micro-extraction in a packed syringe as the sample preparation method connected with LC/UV (MEPS/LC/UV) is described. Micro-extraction in a packed syringe (MEPS) is a new miniaturized, solid-phase extraction technique that can be connected online to gas or liquid chromatography without any modifications. In MEPS approximately 1 mg of the solid packing material is inserted into a syringe (100-250 µL) as a plug. Sample preparation takes place on the packed bed. The bed can be coated to provide selective and suitable sampling conditions. The new method is very promising, easy to use, fully automated, inexpensive and quick. The standard curves were obtained within the concentration range 1-500 ng/mL in both plasma and urine samples. The results showed high correlation coefficients (R(2) >0.988) for all of the analytes within the calibration range. The extraction recovery was found to be between 88.56 and 99.38%. The limit of quantification was found to be between 0.132 and 1.956 ng/mL. The precision (RSD) values of quality control samples (QC) had a maximum deviation of 4.9%. A comparison of the detection limits with similar methods indicates high sensitivity of the present method. The method is applied for the analysis of these drugs in real urine and plasma samples of epileptic patients.

A novel microextraction by packed sorbent-gas chromatography procedure for the simultaneous analysis of antiepileptic drugs in human plasma and urine.

A simple, accurate, and sensitive microextraction by packed sorbent-gas chromatography-mass spectrometry method has been developed for the simultaneous quantification of four antiepileptic drugs; oxcarbazepine, carbamazepine, phenytoin, and alprazolam in human plasma and urine as a tool for drug monitoring. Caffeine was used as internal standards for the electron ionization mode. An original pretreatment procedure on biological samples, based on microextraction in packed syringe using C(18) as packing material gave high extraction yields (69.92-99.38%), satisfactory precision (RSD < 4.7%) and good selectivity. Linearity was found in the 0.1-500 ng/mL range for these drugs with limits of detection (LODs) between 0.0018 and 0.0036 ng/mL. Therefore, the method has been found to be suitable for the therapeutic drug monitoring of patients treated with oxcarbazepine, carbamazepine, phenytoin, and alprazolam. After validation, the method was successfully applied to some plasma samples from patients undergoing therapy with one or more of these drugs. A comparison of the detection limit with similar methods indicates high sensitivity of the present method over the earlier reported methods. The present method is applied for the analysis of these drugs in the real urine and plasma samples of the epileptic patients.

Pharmacokinetics of the monohydroxy derivative of oxcarbazepine and its enantiomers after a single intravenous dose given as racemate compared with a single oral dose of oxcarbazepine.

Oxcarbazepine (OXC) is an antiepileptic drug. In humans, OXC is metabolized via reduction and conjugation. Monohydroxy derivative of OXC (MHD) is the major pharmacologically active component after OXC ingestion. This study was performed to characterize the disposition of the two enantiomers of MHD after oral and intravenous administration and to estimate the bioavailability of MHD after a single oral dose administration of OXC compared to a single intravenous administration of MHD. The study was performed in two parts. In a first pilot study, three intravenous doses were given in an ascending manner (150, 200, and 250 mg of MHD; one subject per dose level) to assess the safety, tolerability, and basic pharmacokinetics. Part two was an open, single-center, randomized, two-way crossover, single-dose trial in 12 healthy adult subjects (n = 6 males and n = 6 females) given OXC orally (one film-coated 300-mg tablet of OXC) and MHD intravenously (250 mg infused over 30 min). Concentrations of OXC and its metabolites were measured by means of high-performance liquid chromatography methods. OXC given as a tablet is completely absorbed in man under fasting conditions. When MHD is given intravenously, (S)-MHD predominates as free compound in plasma. When OXC is administered orally, the ratio of the area-under-the-curve values of (S)-MHD over (R)-MHD equals 3.8, indicating an enantioselective reduction of the prochiral carbonyl group of OXC.

A Rapid LC-MS-MS Method for the Quantitation of Antiepileptic Drugs in Urine.

Epilepsy is a common neurologic disease that requires treatment with one or more medications. Due to the polypharmaceutical treatments, potential side effects, and drug-drug interactions associated with these medications, therapeutic drug monitoring is important. Therapeutic drug monitoring is typically performed in blood due to established clinical ranges. While blood provides the benefit of determining clinical ranges, urine requires a less invasive collection method, which is attractive for medication monitoring. As urine does not typically have established clinical ranges, it has not become a preferred specimen for monitoring medication adherence. Thus, large urine clinical data sets are rarely published, making method development that addresses reasonable concentration ranges difficult. An initial method developed and validated in-house utilized a universal analytical range of 50-5,000 ng/mL for all antiepileptic drugs and metabolites of interest in this work, namely carbamazepine, carbamazepine-10,11-epoxide, eslicarbazepine, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, 4-hydroxyphenytoin, and topiramate. This upper limit of the analytical range was too low leading to a repeat rate of 11.59% due to concentrations >5,000 ng/mL. Therefore, a new, fast liquid chromatography-tandem mass spectrometry (LC-MS-MS) method with a run time under 4 minutes was developed and validated for the simultaneous quantification of the previously mentioned nine antiepileptic drugs and their metabolites. Urine samples were prepared by solid-phase extraction and analyzed using a Phenomenex Phenyl-Hexyl column with an Agilent 6460 LC-MS-MS instrument system. During method development and validation, the analytical range was optimized for each drug to reduce repeat analysis due to concentrations above the linear range and for carryover. This reduced the average daily repeat rate for antiepileptic testing from 11.59% to 4.82%. After validation, this method was used to test and analyze patient specimens over the course of approximately one year. The resulting concentration data were curated to eliminate specimens that could indicate an individual was noncompliant with their therapy (i.e., positive for illicit drugs) and yielded between 20 and 1,700 concentration points from the patient specimens, depending on the analyte. The resulting raw quantitative urine data set is presented as preliminary reference ranges to assist with interpreting urine drug concentrations for the nine aforementioned antiepileptic medications and metabolites.

Ionic Liquid-Based Dispersive Liquidâ€"Liquid Microextraction for the Simultaneous Determination of Carbamazepine and Lamotrigine in Biological Samples.

This paper describes a new approach for the determination of carbamazepine and lamotrigine in biological samples by ionic liquid dispersive liquid-phase microextraction prior to high-performance liquid chromatography with ultraviolet detection. The effects of different ionic liquids (ILs) on the extraction efficiency of carbamazepine and lamotrigine were investigated. The highest extraction efficiencies of carbamazepine and lamotrigine were obtained using 30 ?L of 1-me-thyl-3-octylimidazolium hexafluorophosphate [C8MIM][PF6]. Several factors affecting the microextraction efficiency, such as the type and volume of extracting solvent, type and volume of disperser solvent, salt concentration, and pH of the sample solution have been optimized. The calibration plots were linear in the range of 0.1-20 mg L-1 for carbamazepine and 0.3-40 mg L-1 for lamotrigine with detection limits of 0.04 mg L-1 for carbamazepine and 0.07 mg L-1 for lamotrig-ine in plasma samples. The results confirm the suitability of the presented method as a sensitive method for the analysis of the target analytes in urine and plasma samples.

High-throughput quantitative analysis by desorption electrospray ionization mass spectrometry.

A newly developed high-throughput desorption electrospray ionization (DESI) source was characterized in terms of its performance in quantitative analysis. A 96-sample array, containing pharmaceuticals in various matrices, was analyzed in a single run with a total analysis time of 3 min. These solution-phase samples were examined from a hydrophobic PTFE ink printed on glass. The quantitative accuracy, precision, and limit of detection (LOD) were characterized. Chemical background-free samples of propranolol (PRN) with PRN-d(7) as internal standard (IS) and carbamazepine (CBZ) with CBZ-d(10) as IS were examined. So were two other sample sets consisting of PRN/PRN-d(7) at varying concentration in a biological milieu of 10% urine or porcine brain total lipid extract, total lipid concentration 250 ng/microL. The background-free samples, examined in a total analysis time of 1.5 s/sample, showed good quantitative accuracy and precision, with a relative error (RE) and relative standard deviation (RSD) generally less than 3% and 5%, respectively. The samples in urine and the lipid extract required a longer analysis time (2.5 s/sample) and showed RSD values of around 10% for the samples in urine and 4% for the lipid extract samples and RE values of less than 3% for both sets. The LOD for PRN and CBZ when analyzed without chemical background was 10 and 30 fmol, respectively. The LOD of PRN increased to 400 fmol analyzed in 10% urine, and 200 fmol when analyzed in the brain lipid extract.

Effect of antiepileptic drug polytherapy on urinary pH in children and young adults.

OBJECTS: The relationship between antiepileptic drugs (AEDs) polytherapy and urinary pH was studied to demonstrate the effect and difference of AED polytherapy compared to monotherapy. MATERIALS AND METHODS: A total of 271 urine samples from patients receiving AED polytherapy aged from 7 months to 35 years were enrolled. Two AEDs were co-administered to 215 patients, three AEDs to 45 patients, four AEDs to ten patients, and five AEDs to one patient. RESULTS: The distribution of urinary pH shifted to the alkaline range with increasing numbers of co-administered AEDs (p < 0.0001). The distribution of urinary pH shifted to the alkaline side with AED polytherapy that included valproate (p < 0.05) or acetazolamide (p < 0.03). The distribution of urinary pH did not change with or without zonisamide, carbamazepine, phenobarbital, phenytoin, or clonazepam. CONCLUSIONS: Urinary pH should be monitored in patients receiving AED polytherapy, particularly those receiving valproate, acetazolamide, or various AEDs in combination.

Selective recognition and enrichment of carbamazepine in biological samples by magnetic imprinted polymer based on reversible addition-fragmentation chain transfer polymerization.

A well-defined molecularly imprinted polymer (Fe3O4@CS@MIP) was synthesized via reversible addition-fragmentation chain transfer polymerization for magnetic solid-phase extraction coupled with high-performance liquid chromatography-diode array detector to detect carbamazepine (CBZ) in biological samples. The composition of Fe3O4@CS@MIP was selected by a two-step screening method. 4-vinyl pyridine, divinylbenzene and dimethylformamide were chosen as the functional monomer, cross-linker and porogen, respectively. The imprinted layer was coated on the surface of the chain transfer agent-modified magnetic chitosan nanoparticles. The prepared Fe3O4@CS@MIP was characterized by scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller measurement and vibrating sample magnetometer. The results indicated that Fe3O4@CS@MIP had a large surface area (265.8 m2/g), high saturation magnetization (19.88 emu/g) and uniform structure. Besides, the binding property of the Fe3O4@CS@MIP was studied in detail. The Fe3O4@CS@MIP showed high imprinting factor (IF = 4.83) and desirable adsorption capacity (323.10 µmol/g) to CBZ. Under the optimum conditions, the developed method exhibited excellent linearity (R2>0.999) in the range of 0.01-0.5 mg/L and 1.0-30.0 mg/L, and the limits of detection were 1.0 µg/L and 9.6 µg/L for the urine and serum samples, respectively. Good recoveries (88.22%-101.18%) were obtained with relative standard deviations less than 4.83%. This work provided a practical approach for the selective extraction and detection of CBZ in real samples.

Relative bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension.

BACKGROUND AND OBJECTIVE: Maintenance of effective drug concentrations is essential for adequate treatment of epilepsy. Some antiepileptic drugs can be successfully administered rectally when the oral route of administration is temporarily unavailable. Oxcarbazepine is a newer antiepileptic drug that is rapidly converted to a monohydroxy derivative, the active compound. This study aimed to characterise the bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension using a randomised, crossover design in ten healthy volunteers. METHODS: Two subjects received 300 mg doses of oxcarbazepine suspension via rectal and oral routes and eight received 450 mg doses. A washout period of at least 2 weeks elapsed between doses. The rectal dose was diluted 1:1 with water. Blood samples and urine were collected for 72 hours post-dose. Adverse effects were assessed at each blood collection time-point using a self-administered questionnaire. Plasma was assayed for oxcarbazepine and monohydroxy derivative; urine was assayed for monohydroxy derivative and monohydroxy derivative-glucuronide. Maximum plasma concentration (C(max)) and time to reach C(max) (t(max)) were obtained directly from the plasma concentration-time curves. The areas under the concentration-time curve (AUCs) were determined via non-compartmental analysis. Relative bioavailability was calculated and the C(max) and AUCs were compared using Wilcoxon signed-rank tests. RESULTS: Mean relative bioavailability calculated from plasma AUCs was 8.3% (SD 5.5%) for the monohydroxy derivative and 10.8% (SD 7.3%) for oxcarbazepine. Oxcarbazepine and monohydroxy derivative C(max) and AUC values were significantly lower following rectal administration (p < 0.01). The total amount of monohydroxy derivative excreted in the urine following rectal administration was 10 +/- 5% of the amount excreted following oral administration. Oral absorption was consistent with previous studies. The most common adverse effects were headache and fatigue with no discernible differences between routes. CONCLUSIONS: Monohydroxy derivative bioavailability following rectal administration of oxcarbazepine suspension is significantly lower than following oral administration, most likely because of poor oxcarbazepine water solubility. It is unlikely that adequate monohydroxy derivative concentrations can be achieved with rectal administration of diluted oxcarbazepine suspension.

[Extended suicidal poisoning with carbamazepine and phenothiazine derivatives]. / Rozszerzone samobójcze zatrucie karbamazepina i fenotiazynami.

UNLABELLED: Two cases (woman and man) of the extended suicidal poisonings with carbamazepine and phenothiazine derivatives are presented. Drug's blood concentrations during poisoning were monitored. We examine correlation between patient's general status and the drug's blood concentrations, carbamazepine and phenothiazine derivatives interaction due to young, healthy people who received no earlier treatment. MATERIAL AND METHODS: blood samples for toxicological examinations were collected at 0, 12, 24 and 48 hours after admission. Carbamazepine was determined using FPIA method and phenothiazines derivatives by HPLC-DAD. The highest blood concentrations were for carbamazepine: 30.92 mg/l (woman) and 20.95 ng/ml (man); for phenothiazine derivatives: 927 ng/ml (woman) and 733 ng/ ml (man). CONCLUSIONS: In both cases severe central nervous depression was observed due to summed action of the drugs. Sex and individual differences in cytochromes activities should have influence to carbamazepine metabolism and faster elimination time in woman. In the case of phenothiazine derivatives faster elimination time in man was observed. The differences in elimination times between compared drugs confirm their different metabolic routes.

An imprinted interpenetrating polymer network for microextraction in packed syringe of carbamazepine.

An imprinted interpenetrating polymer network (IPN) was synthesized and used as a medium for isolation of carbamazepine from urine samples. The polymer network consisted of a homogeneous polystyrene-sol gel hybrid constructed by in-situ radical polymerization method. In this process, within the sol-gel reaction duration, styrene monomer could penetrate into the reaction mixture and after the polymerization initiation, a monolithic IPN structure was prepared. The scanning electron microscopy (SEM) image and energy dispersive spectroscopy (EDX) are indications of the polystyrene dispersion at nano- to micro-meter level in the sol gel matrix. Eventually, the synthesized IPN was used as a sorbent in microextraction in packed syringe (MEPS) combined with high performance liquid chromatography (HPLC) for isolation of carbamazepine, naproxen and dexamethasone from urine samples. The molecularly imprinted IPN showed some degree of selectivity towards carbamazepine. To assess the important parameters influencing the extraction and desorption processes, an experimental design strategy was used. By the current method, low limits of detection (1.3-1.5µgL-1) and quantification (4.2-5µgL-1) were achieved (hydrocortisone as the internal standard). The intra- and inter-day precision data at 50 and 300µgL-1 were 1.3-7.4%, while the working linear dynamic range was from 4.2 to 500µgL-1.

Environmental exposure to pharmaceuticals: A new technique for trace analysis of carbamazepine and its metabolites in human urine.

Pharmaceutically active compounds are taken up and accumulate in crops irrigated with treated wastewater. This raises the concern of chronic human exposure to pharmaceuticals via food consumption. Thus, there is a need to develop a reliable technique to detect and quantify pharmaceuticals at environmentally relevant concentrations in human biological matrices, particularly urine. In this study, we focus on carbamazepine, an antiepileptic drug and recalcitrant compound that is taken up by crops-making it an excellent model compound for this study. This paper presents a new analytical technique enabling quantification of trace concentrations of carbamazepine and its metabolites in the urine of individuals who have been environmentally exposed. Sample preparation included extraction with acetonitrile followed by clean-up through mixed-mode ion-exchange cartridges and analysis using LC/MS/MS. This technique, which was validated for a wide range of concentrations (5-2000 ng L(-1)), exhibits low limits of quantification (3.0-7.2 ng L(-1)), acceptable recovery levels (70-120%), and low relative standard deviation (<20%). Unlike currently available methods for the analysis of water or treated wastewater that require large volumes (up to 1 L), the new method uses only 10 mL of urine. Moreover, relative to available methods for carbamazepine detection in the urine of individuals who are chronically treated with this drug, the limit of quantification values with our method are six orders of magnitude lower. The newly developed method has been successfully applied for the quantification of carbamazepine and its metabolites in the urine of healthy people exposed to this pharmaceutical through their diet. Our analytical protocol can provide the scientific community and stakeholders with real data for risk assessments and the design of policies ensuring safe use of wastewater for crop irrigation.

Chemical and biochemical characterization and in vivo safety evaluation of pharmaceuticals in drinking water.

The water constituents that are currently subject to legal control are only a small fraction of the vast number of chemical substances and microorganisms that may occur in both the environment and water resources. The main objective of the present study was to study the health impact resulting from exposure to a mixture of pharmaceuticals that have been detected in tap water at low doses. Analyses of atenolol, caffeine, erythromycin, carbamazepine, and their metabolites in blood, urine, feces, fat tissue, liver, and kidney after exposure to a mixture of these pharmaceuticals in treated drinking water were performed. The effects of this exposure were assessed in rats by measuring biochemical markers of organ injury or dysfunction. Simultaneously, the selected pharmaceuticals were also quantified in both physiological fluids and organ homogenates by liquid chromatography-tandem mass spectrometry (performed in multiple reaction monitoring mode and full scan mode). Following exposure of rats to a concentration of a pharmaceutical which was 10 times higher than the concentration known to be present in tap water, trace levels of some pharmaceuticals and their metabolites were detected in biological samples. This exposure did, however, not lead to significant organ injury or dysfunction. Thus, the authors report an experimental model that can be used to characterize the safety profile of pharmaceuticals in treated drinking water using a multiorgan toxicity approach. Environ Toxicol Chem 2016;35:2674-2682. © 2016 SETAC.

Comparative assessment of blood and urine analyses in patients with acute poisonings by medical, narcotic substances and alcohol in clinical toxicology.

Acute poisonings by medical, narcotic substances and alcohol are actual in Russia in the recent years. Comparison of analytic facilities of modern analytical techniques: chromatographic (HPLC, GC, GC-MS) and immuno-chemical (FPIA) in clinical toxicology for urgent diagnostics, assessment of the severity of acute poisoning and the efficacy of the treatment in patients with acute poisonings by psychotropic drugs, narcotics and alcohol have been done. The object of the study were serum, blood, urine of 611 patients with acute poisonings by amitriptyline, clozapine, carbamazepine, opiates and also alcohol. Threshold concentrations (threshold, critical and lethal) of the toxicants and their active metabolites which corresponded to different degrees of poisoning severity have been determined. The most comfortable and informative screening method for express diagnostics and assessment of severity of acute poisonings by psychotropic drugs and narcotics showed the HPLC with using automatic analyzers. FPIA using the automatic analyzer could be applied for screening studies, if group identification is enough. GC-FID method is advisable in case of poisoning by medical substances and narcotics in view of repeated investigation for assessment of the efficacy of the therapy. GC-MS could be advisable for confirming the results of other methods. GC-TCD possess high sensitivity and specificity and is optimal for express differential diagnostics and quantitative assessment of acute poisoning by ethanol and other alcohols.

Solidified floating organic drop microextraction combined with high performance liquid chromatography for the determination of carbamazepine in human plasma and urine samples.

Solidified floating organic drop microextraction (SFODME) in combination with high performance liquid chromatography was used for separation/preconcentration and determination of carbamazepine (CBZ) in human plasma and urine samples. Parameters that affect the extraction efficiency such as the type and volume of extraction solvent, ionic strength, sodium hydroxide concentration, stirring rate, sample volume and extraction time, were investigated and optimized. Under the optimum conditions (extraction solvent, 40 µL of 1-undecanol; sodium hydroxide concentration, 1 mol/L; temperature, 50 °C; stirring speed, 400 r/min; sample volume, 8 mL; sodium chloride concentration, 3% (w/v) and extraction time, 60 min) the calibration curve was found to be linear in the mass concentration range of 0.4-700.0 µg/L. The limit of detection (LOD) was 0. 1 µg/L and the relative standard deviation (RSD) for six replicate extraction and determination of carbamazepine at 100 µg/L level was found to be 4.1%. The method was successfully applied to the determination of CBZ in human plasma and urine samples.