Pharmaceutical Residues in Edible Oysters along the Coasts of the East and South China Seas and Associated Health Risks to Humans and Wildlife.

The investigation of pharmaceuticals as emerging contaminants in marine biota has been insufficient. In this study, we examined the presence of 51 pharmaceuticals in edible oysters along the coasts of the East and South China Seas. Only nine pharmaceuticals were detected. The mean concentrations of all measured pharmaceuticals in oysters per site ranged from 0.804 to 15.1 ng g-1 of dry weight, with antihistamines being the most common. Brompheniramine and promethazine were identified in biota samples for the first time. Although no significant health risks to humans were identified through consumption of oysters, 100-1000 times higher health risks were observed for wildlife like water birds, seasnails, and starfishes. Specifically, sea snails that primarily feed on oysters were found to be at risk of exposure to ciprofloxacin, brompheniramine, and promethazine. These high risks could be attributed to the monotonous diet habits and relatively limited food sources of these organisms. Furthermore, taking chirality into consideration, chlorpheniramine in the oysters was enriched by the S-enantiomer, with a relative potency 1.1-1.3 times higher when chlorpheniramine was considered as a racemate. Overall, this study highlights the prevalence of antihistamines in seafood and underscores the importance of studying enantioselectivities of pharmaceuticals in health risk assessments.

Subnanomolar detection of promethazine abuse using a gold nanoparticle-graphene nanoplatelet-modified electrode.

A simple, sensitive, and effective adsorptive stripping voltammetric sensor for the detection of trace-level promethazine was created based on a gold nanoparticle-graphene nanoplatelet-modified glassy carbon electrode (AuNP-GrNP/GCE). AuNP-GrNP nanocomposites were synthesized using an electroless deposition process, and the morphology was characterized using UV-vis spectroscopy, Fourier transform infrared spectroscopy, field emission scanning electron microscopy, and energy-dispersive X-ray spectroscopy. The electrochemical behavior and detection of promethazine at the AuNP-GrNP/GCE were investigated utilizing cyclic voltammetry and adsorptive stripping voltammetry. The AuNP-GrNP/GCE showed outstanding synergistic electrochemical activity for promethazine oxidation, a highly active surface area, great adsorptivity, and outstanding catalytic properties. The electrolyte pH, amount of AuNP-GrNP nanocomposite, preconcentration potential (vs. Ag/AgCl), and time were optimized to obtain a high performance electrochemical sensor. Under optimal conditions, the proposed sensor displayed two linear concentration ranges from 1.0 nmol L-1 to 1.0 µmol L-1 and from 1.0 to 10 µmol L-1. The limits of detection and quantitation were 0.40 and 1.4 nmol L-1, respectively. This sensor displayed high sensitivity, a capability for rapid analysis, and excellent repeatability and reproducibility. The developed sensor was effective and practical for promethazine detection in biological fluids and forensic samples, and the obtained results exhibited excellent agreement with the results obtained using the method described in the British Pharmacopoeia. Graphical abstract.

Fast determination of codeine, orphenadrine, promethazine, scopolamine, tramadol, and paracetamol in pharmaceutical formulations by capillary electrophoresis.

Paracetamol is an active ingredient commonly found in pharmaceutical formulations in combination with one of the following compounds: codeine, orphenadrine, promethazine, scopolamine, and tramadol. In this work, we propose a unique analytical method for determination of these active ingredients in pharmaceutical samples. The method is based on capillary electrophoresis with capacitively coupled contactless conductivity detection. The separation was achieved on a fused silica capillary (50 cm total length, 40 cm effective length, and 50 µm id) using an optimized background electrolyte composed of 20 mmol/L ß-alanine/4 mmol/L sodium chloride/4 µmol/L sodium hydroxide (pH 9.6). Each sample can be analyzed in a single run (≤2 min) and the limits of detection were 2.5, 0.62, 0.63, 2.5, 15, and 1.6 µmol/L for scopolamine, tramadol, orphenadrine, promethazine, codeine, and paracetamol, respectively. Recovery values for spiked samples were between 94 and 104%.

Measurement analysis of two radials with a common-origin point and its application.

In spectral analysis, a chemical component is usually identified by its characteristic spectra, especially the peaks. If two components have overlapping spectral peaks, they are generally considered to be indiscriminate in current analytical chemistry textbooks and related literature. However, if the intensities of the overlapping major spectral peaks are additive, and have different rates of change with respect to variations in the concentration of the individual components, a simple method, named the 'common-origin ray', for the simultaneous determination of two components can be established. Several case studies highlighting its applications are presented.

Multiple Time-of-Flight/Time-of-Flight Events in a Single Laser Shot for Improved Matrix-Assisted Laser Desorption/Ionization Tandem Mass Spectrometry Quantification.

Quantitative matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF) approaches have historically suffered from poor accuracy and precision mainly due to the nonuniform distribution of matrix and analyte across the target surface, matrix interferences, and ionization suppression. Tandem mass spectrometry (MS/MS) can be used to ensure chemical specificity as well as improve signal-to-noise ratios by eliminating interferences from chemical noise, alleviating some concerns about dynamic range. However, conventional MALDI TOF/TOF modalities typically only scan for a single MS/MS event per laser shot, and multiplex assays require sequential analyses. We describe here new methodology that allows for multiple TOF/TOF fragmentation events to be performed in a single laser shot. This technology allows the reference of analyte intensity to that of the internal standard in each laser shot, even when the analyte and internal standard are quite disparate in m/z, thereby improving quantification while maintaining chemical specificity and duty cycle. In the quantitative analysis of the drug enalapril in pooled human plasma with ramipril as an internal standard, a greater than 4-fold improvement in relative standard deviation (<10%) was observed as well as improved coefficients of determination (R2) and accuracy (>85% quality controls). Using this approach we have also performed simultaneous quantitative analysis of three drugs (promethazine, enalapril, and verapamil) using deuterated analogues of these drugs as internal standards.

Simultaneous determination of three banned psychiatric drugs in pig feed and tissue using solid-phase reactor on-line oxidizing and HPLC-fluorescence detection.

The banned addition of psychiatric drugs such as phenothiazines to animal feed and foodstuffs increases the risk of human organ lesion. Phenothiazines usually exhibit weak native fluorescence and can be oxidized to strongly fluorescent compounds. In this study, a novel, sensitive and convenient method of HPLC-fluorescence detection based on post-column on-line oxidizing with lead dioxide solid-phase reactor has been developed for simultaneous determination of three banned psychotropic drugs, promethazine, chlorpromazine and thioridazine. Three compounds were successfully separated on an Agilent TC-C18 column with mobile phase of acetonitrile (A) and water (B), both containing 0.5% (v/v) formic acid. A gradient elution was programmed and fluorimetric detection was performed at λex /λem of 332/373 nm for promethazine, 340/380 nm for chlorpromazine and 352/432 nm for thioridazine. The calibration graphs gave good linearity over the concentration ranges of 30.0-4976.4 µg/L for promethazine, 2.0-2153.2 µg/L for chlorpromazine, and 15.0-3088.0 µg/L for thioridazine, and correlation coefficients (r) were ≥0.995. The method was applied to the determination of phenothiazines in pig feed and pig tissue, and the average spiked recoveries were in the range 69.1-115.4%.

[Rapid identification 15 effective components of anti common cold medicine with MRM by LC-MS/MS].

This paper reports the establishment of a method for rapid identification 15 effective components of anti common cold medicine (paracetamol, aminophenazone, pseudoephedrine hydrochloride, methylephedrine hydrochloride, caffeine, amantadine hydrochloride, phenazone, guaifenesin, chlorphenamine maleate, dextromethorphen hydrobromide, diphenhydramine hydrochloride, promethazine hydrochloride, propyphenazone, benorilate and diclofenac sodium) with MRM by LC-MS/MS. The samples were extracted by methanol and were separated from a Altantis T3 column within 15 min with a gradient of acetonitrile-ammonium acetate (containing 0.25% glacial acetic acid), a tandem quadrupole mass spectrometer equipped with electrospray ionization source (ESI) was used in positive ion mode, and multiple reaction monitoring (MRM) was performed for qualitative analysis of these compounds. The minimum detectable quantity were 0.33-2.5 microg x kg(-1) of the 15 compounds. The method is simple, accurate and with good reproducibility for rapid identification many components in the same chromatographic condition, and provides a reference for qualitative analysis illegally added chemicals in anti common cold medicine.

Identification and determination of ketotifen hydrogen fumarate, azelastine hydrochloride, dimetindene maleate and promethazine hydrochloride by densitometric method.

Conditions for determination of: ketotifen hydrogen fumarate, azelastine hydrochloride, dimetindene maleate and promethazine hydrochloride by densitometric method in substances and pharmaceuticals were provided. Maximum wavelenghts were: 228 nm for ketotifen hydrogen fumarate, 295 nm for azelastine hydrochloride, 265 nm for dimetindene maleate and 255 nm for promethazine hydrochloride. The limits of quantification were in the ranges of 0.2-5 microg/spot. The statistical data showed adequate accuracy and precision of developed methods.

Ultrasonication-aided synthesis of nanoplates-like iron molybdate: Fabricated over glassy carbon electrode as an modified electrode for the selective determination of first generation antihistamine drug promethazine hydrochloride.

The innovation of novel and proficient nanostructured materials for the precise level determination of pharmaceuticals in biological fluids is quite crucial to the researchers. With this in mind, we synthesized iron molybdate nanoplates (Fe2(MoO4)3; FeMo NPs) via simple ultrasonic-assisted technique (70 kHz with a power of 100 W). The FeMo NPs were used as the efficient electrocatalyst for electrochemical oxidation of first-generation antihistamine drug- Promethazine hydrochloride (PMH). The as-synthesized FeMo NPs were characterized and confirmed by various characterization techniques such as XRD, Raman, FT-IR, FE-SEM, EDX and Elemental mapping analysis and electron impedance spectroscopy (EIS). In addition, the electrochemical characteristic features of FeMo NPs were scrutinized by electrochemical techniques like cyclic voltammetry (CV) and differential pulse voltammetry technique (DPV). Interestingly, the developed FeMo NPs modified glassy carbon electrode (FeMo NPs/GCE) discloses higher peak current with lesser anodic potential on comparing to bare GCE including wider linear range (0.01-68.65 µM), lower detection limit (0.01 µM) and greater sensitivity (0.97 µAµM-1cm-2). Moreover, the as-synthesized FeMo NPs applied for selectivity, reproducibility, repeatability and storage ability to investigate the practical viability. In the presence of interfering species like cationic, anionic and biological samples, the oxidation peak current response doesn't cause any variation results disclose good selectivity towards the detection of PMH. Additionally, the practical feasibility of the FeMo NPs/GCE was tested by real samples like, commercial tablet (Phenergan 25 mg Tablets) and lake water samples which give satisfactory recovery results. All the above consequences made clear that the proposed sensor FeMo NPs/GCE exhibits excellent electrochemical behavior for electrochemical determination towards oxidation of antihistamine drug PMH.

A novel technique for NACE coupled with simultaneous electrochemiluminescence and electrochemical detection for fast analysis of tertiary amines.

A simultaneous electrochemiluminescence (ECL) and electrochemical (EC) detection scheme for NACE was presented for fast analysis of tertiary amines. Both ECL and EC signals were generated at the same Pt electrode. Triethylamine (TEA), tripropylamine (TPrA), chlorpromazine, promethazine, and dioxopromethazine (DPZ) were selected to validate NACE-ECL/EC dual detection strategy. The linear ranges for TEA and TPrA were 0.01-500 and 0.01-10 microM with the detection limits of 8.0 and 5.0 nM (S/N=3), respectively. The RSDs (n=6) of the migration time and the ECL intensity for 1 microM TEA and 0.5 microM TPrA were 0.1 and 2.8%, and 0.2 and 1.8% with theoretical plate numbers of 180,000 and 700,000 per meter, respectively. These two analytes could be separated within 92 s and the Pt electrode did not need reactivation during the experiments. Chlorpromazine, promethazine, and DPZ could be well separated by NACE. The proposed method was also demonstrated for fast determination of DPZ in human urine with simple sample preparation. The results indicated that NACE-ECL/EC had the advantages of simple and fast analysis with more information, wide linear range, high sensitivity, and compatibility with real urine sample.

A validated HPLC method for separation and determination of promethazine enantiomers in pharmaceutical formulations.

A simple, rapid, and validated method for separation and determination of promethazine enantiomers was developed. Promethazine was separated and quantitated on a Vancomycin Chirobiotic V column (250 x 4.6 mm), using a mixture of methanol, acetic acid, and triethylamine (100:0.1:0.1%, by volume) as a mobile phase at 20 degrees C and at a flow rate of 1 mL/min. The UV-detector was set to 254 nm. Acetyl salicylic acid (Aspirin) was used as an internal standard. The applied HPLC method allowed separation and quantification of promethazine enantiomers with good linearity (r > .999) in the studied range. The relative standard deviations (RSD) were 0.29 and 0.36 for the promethazine enantiomers with accuracy of 100.06 and 100.08. The limit of detection and limit of quantification of promethazine enantiomers were found to be 0.04 and 0.07 microg/mL, respectively. The method was validated through the parameters of linearity, accuracy, precision, and robustness. The HPLC method was applied for the quantitative determination of promethazine in pharmaceutical formulations.

Development and validation of a HPLC method for the analysis of promethazine hydrochloride in hot-melt extruded dosage forms.

A simple and rapid stability-indicating HPLC method was developed for determination of promethazine hydrochloride (PMZ) in hot-melt extruded (HME) films and sustained release tablets. Chromatographic separation was achieved on a 150 mm x 4.6 mm i.d., 3 microm particle size, C8 (2) column with acetonitrile-25mM phosphate buffer (pH 7.0), 50:50 (v/v) as mobile phase at a flow rate of 1 mL min(-1). Quantitation was achieved with UV detection at 249 nm based on peak area. The method was validated in terms of linearity, precision, accuracy, robustness specificity, limits of detection and quantitation according to ICH guidelines. Specificity was validated by subjecting the drug to acid, base, oxidative, reductive and dry heat degradations. None of the degradation products obtained by forced degradation interfered with the PMZ peak. The method was successfully applied for assessing the stability of the drug in the HME films and sustained release tablet formulations. In addition, uniformity of PMZ content in HME films was also determined using the method developed. Excipients present in either of the dosage forms analyzed did not interfere with the analysis indicating the specificity of the method. Due to its simplicity and accuracy, the method is suitable for application to various dosage forms.

Quantitative online detection of low-concentrated drugs via a SERS microfluidic system.

Herein, quantitative online monitoring of concentration fluctuations of different interesting drugs, namely, the phenothiazine promethazine as well as the anti-cancer agent mitoxantrone via surface enhanced Raman scattering assay based on a microfluidic device is demonstrated. With the applied liquid/liquid two-phase-segmented flow system we succeed in preventing the adhesion of nanoparticle aggregates to the channel walls which is necessary for a quantitative analysis. Even after repeated cycles no carry-over due to sedimentation of colloid particles is observed. To the best of our knowledge these are the first measurements applying a combination of a microfluidic device with SERS detection for quantitative online monitoring of fluctuations in drug concentrations over hours without use of aggressive chemicals for rinsing the chip surfaces prior to each measurement.

Electrochemical determination of trace promethazine hydrochloride by a pretreated glassy carbon electrode modified with DNA.

A highly sensitive electrochemical biosensor for the detection of trace amounts of promethazine has been designed. Double stranded (ds)DNA molecules are immobilized onto a pretreated glassy carbon electrode (GCE(ox)) surface. The voltammetric behaviors of promethazine on DNA-modified electrode were explored by means of cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The promethazine gave rise to a pair of well-defined peaks, which appeared at E(pc) = 52 mV and E(pa) = 96 mV (vs. Ag/AgCl) in 0.10 M acetate buffer (pH 5.0). The peak current was linearly enhanced with increasing the concentration of promethazine. The calibration was linear for promethazine over the range of 4.7 x 10(-10) to 9.3 x 10(-9) M with a correlation coefficient of 0.999. The limit of detection (LODs) was 3.0 x 10(-10) M (S/N = 3). The modified electrode was applied to determine promethazine in human blood samples with satisfactory results.

Methadone toxicity fatalities: a review of medical examiner cases in a large metropolitan area.

Over the past several years, Medical Examiners in Kentucky and around the nation have observed a dramatic rise in drug intoxication deaths involving the prescription medication methadone. This documented rise in methadone-related deaths requires a better understanding of methadone's pathophysiology and the ways it contributes to significantly increase morbidity and mortality. This study reviews 176 fatalities ascribed to methadone toxicity by the Office of the Chief Medical Examiner in Kentucky between 2000 and 2004. Postmortem toxicological analysis recorded a more than 10-fold increase in methadone toxicity fatalities, rising from 6 cases in 2000 to 68 cases in 2003. Of the 176 methadone-related fatalities, methadone was the only drug detected in postmortem blood and urine toxicological analyses in 11 (6.25%) cases. The mean methadone blood concentration of all 176 cases was 0.535 mg / L (0.02-4.0). The following psychoactive medications were detected: antidepressants (39.8%), benzodiazepines (32.4%), and other opioids in addition to methadone (27.8%). Cannabinoids were detected in 44 (28.4%) cases and cocaine or metabolite in 34 (21.9%) cases. Of the 95 cases with a known history of methadone use, 46 (48.4%) involved prescription by private physician. The interpretation of blood methadone concentrations alone or combined with other psychoactive drugs requires consideration of the subject's potential chronic use of and tolerance to the drug. A thorough investigation into the practices of procurement and use/abuse of methadone is essential to arrive at the proper designation of the cause of death.

Triage test and HPLC assay for analysis of vegetamin, an antipsychotic agent, using gastric contents and blood specimens.

Vegetamin is an antipsychotic agent composed of phenobarbital, promethazine and chlorpromazine. While phenobarbital can be detected by the Triage kit for screening drugs of abuse, the other two components cannot. We describe here the detection of promethazine and chlorpromazine using either a high performance liquid chromatography (HPLC) unit equipped with an ultraviolet, a photodiode array (PDA), or an electrochemical detector (ECD), or gas chromatograph-mass spectrometry (GC-MS). The absorption and mass spectra of promethazine and chlorpromazine were nonspecific, and thus the ECD-HPLC system was best equipped to quantitate these components. Comparison of the chromatograms of blood and gastric contents aids the identification of drug metabolites.

Determination of promethazine hydrochloride and its preparations by highly accurate nephelometric titration.

A highly accurate nephelometric titration for the determination of promethazine hydrochloride and its preparations was presented. The titration operating conditions were studied and the solubility product constant of promethazine tetraphenylboron precipitation was determined. The result of the titration is comparable to those of control experiments. The proposed method has been found to be accurate, precise, specific and linear.

Determination of promethazine hydrochloride in pharmaceuticals by capillary isotachophoresis.

Capillary isotachophoresis (ITP) in cationic regime of the separation with conductometric detection has been used for the separation and determination of promethazine hydrochloride (PRO) in commercial mass-produced pharmaceutical preparations. Several electrolyte systems of different compositions and pH were examined and the optimized ITP electrolyte system consisted of 10 mmol/l of potassium acetate adjusted to pH 4.8 with acetic acid as the leading electrolyte with electroosmotic flow (EOF) suppressing additive, 0.2% (w/v) methylhydroxyethylcellulose (m-HEC), and 5 mmol/l of beta-alanine as the terminating electrolyte. The proposed electrophoretic method was successfully validated. It was convenient for the sensitive, simple, rapid, and highly reproducible assay of promethazine. The calibration graph relating the ITP zone length to concentration of the analyte was rectilinear in the range of 40-200 mg/l of the drug standard, with a coefficient of determination r(2)=0.9992. The relative standard deviation (RSD) was 1.12% (n=6) when determining 100 mg/l of PRO in standard sample. Good quantitation was obtained in short analysis time (a single analysis took 6 min). The recoveries of drug from samples were found to be 97.22% (tablets), 99.72% (injections), and 99.14% (syrup). The minimal sample pretreatment and low running cost make the proposed ITP method a good alternative to commonly used analytical methods.

Forensic toxicological analyses of drugs in tissues in formalin solutions and in fixatives.

Forensic toxicological drug analyses of human specimens are usually performed immediately after autopsy or on frozen preserved tissues. Occasionally, cases require analysis of drugs from tissues fixed in formalin solution. To improve the estimation of the level of drug in tissues following formalin fixation, we studied drug concentrations in human tissues, liver and kidney, that were collected from a drug-positive autopsy case. Parts of tissues were preserved in formalin solution for 1, 3, 6 and 13 months. Tissues obtained before and after preservation, along with tissue-exposed fixatives, were assayed using gas chromatography-mass spectrometry; all of the samples were assayed for the presence of drugs and changes in the drug concentrations both before and after preservation in formalin. Concentrations of assayed drugs decreased upon fixation in formalin; levels of these drugs did not necessarily show further decreases during subsequent storage in fixative, up to 13 months. Distinct trends in drug levels were found in liver and kidney. In liver, the levels of chlorpromazine, levomepromazine, and promethazine decreased to 23-39% at 1 month after preservation; all 3 of these drugs were detected at all tested time points of preservation. Bromazepam was not detected at 13 months after preservation. Milnacipran was the most unstable after preservation in formalin solution among all of the assayed drugs. In kidney, all assayed drugs exhibited reduced stability during preservation compared to levels in liver. Methamphetamine and methylenedioxymethamphetamine were not detected in any time points of tissues. The proportions of the drugs that remained within the tissues differed between liver and kidney. Also, S-oxide compounds of chlorpromazine and levomepromazine, which were not observed before preservation, were detected in fixed liver tissues and their fixatives at 3, 6 and 13 months of preservation. These results suggest that analyses in formalin-fixed tissues need to include analysis of various organ-tissues and their fixatives at multiple time points for the duration of preservation. These analyses should include detection of chemical degradation/denaturation products, such as S-oxides of chlorpromazine and levomepromazine.

The use of on-line and off-line chromatographic extraction techniques coupled with mass spectrometry for support of in vivo and in vitro assays in drug discovery.

We have investigated various sample chromatographic extraction and sample preparation methods for liquid chromatography mass spectrometry analysis in order to increase the throughput of various in vivo and in vitro assays in support of drug discovery. The results indicated that direct plasma injection, although certainly faster than conventional protein precipitation for sample preparation, had problems associated with column longevity and overall robustness. Frequently a single study could not be completed without column replacement. On-line solid phase extraction, on the other hand, compared well with off-line solid phase extraction, using our LC extraction column design, as contamination of the extraction column was minimized by back flushing using the Gilson syringe pump. Finally, on-line solid phase extraction for support of Caco-2 permeability studies worked very well for both single components and mixtures as the matrix was much simpler, presenting fewer contamination problems.