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.

Pink urine.

A 55-year-old man was admitted after a suspected hypnotic overdose of valerian extracts. In addition to altered consciousness, the first clinical symptoms included not only diffuse rash on the face, trunk, and limbs, but also an inspiratory dyspnea with a marked hypoxemia. A major laryngeal edema was noted during orotracheal intubation. After correction of hypoxemia, the patient became agitated and propofol was administered by continuous infusion. In addition, the patient passed pink urine staining the urine collection bag. The presence of an unidentified toxic substance was suspected.

Voltammetric determination of promethazine hydrochloride at a multi-wall carbon nanotube modified glassy carbon electrode.

A simple and sensitive method is described for voltammetric determination of promethazine hydrochloride (PMZ), a widely used phenothiazine drug, based on its electrochemical oxidation at a multi-wall carbon nanotube (MWCNT) modified glassy carbon electrode (GCE). Compared with bare GCE, the MWCNT-modified GCE exhibited excellent enhancement effect on the electrochemical oxidation of PMZ. PMZ yielded two anodic peaks at about 0.61 V and 0.78 V, and the peak at 0.61 V was applied to the determination. Under optimized conditions, the anodic peak current was linear to the concentration of PMZ in the range from 5.0 × 10(-8) to 4.0 × 10(-4) M with the detection limit of 1.0 × 10(-8) M. The relative standard deviation (RSD) was 2.28% for 8.0 × 10(-6) M PMZ (n = 10). To further validate its possible application, the proposed method was successfully used for the quantification of PMZ in pharmaceutical formulations and biological fluids with satisfactory results.

Joint modeling of performance and subjective reporting to assess sensitivity to drug-induced sleepiness.

In an NASA ground study, two forms of cognitive tests were evaluated in terms of their sensitivity to sleepiness induced by the drug promethazine (PMZ). Performance for the two test modes (Y(1) and Y(2)), PMZ concentration, and a self-reported sleepiness using the Karolinska Sleepiness Scale (KSS) were monitored for 12 h post dose. A problem arises when using KSS to establish an association between true sleepiness and performance because KSS scores are discrete and also because they tend to concentrate on certain values. Therefore, we define a latent sleepiness measure X as an unobserved continuous random variable describing a subject's actual state of sleepiness. Under the assumption that drug concentration affects X, which then affects Y(1), Y(2), and KSS, we use Bayesian methods to estimate joint equations that permit unbiased comparison of the performance measures' sensitivity to X. The equations incorporate subject random effects and include a negativity constraint on subject-specific slopes of performance with respect to sleepiness.

An autopsy case of rhabdomyolysis related to vegetamin and genetic analysis of the rhabdomyolysis-associated genes.

We report an autopsy case of a man who died 2 days after taking an overdose of vegetamin. The autopsy findings were as follows: the epidermis on the axillary fossa and the inguinal skin had become macerated. Skeletal muscle was discolored. Concentrations of urea nitrogen, creatinine and urine myoglobin were 1.95 g/day, 0.66 g/day and 1100 ng/mL, respectively. Immunohistochemically, myoglobin was strongly stained at the Bowman's capsule, and tubular lumen and epithelium. 8-OH-dG was strongly stained in renal tubular epithelium in which cell nuclei were strongly stained. ORP-150 was observed in intraglomerular cells and renal tubular epithelium. The concentrations of phenobarbital, promethazine and chlorpromazine ranged from therapeutic to toxic levels, from toxic to lethal levels and toxic level, respectively. His cause of death was considered to be vegetamin-induced rhabdomyolysis. In genetic analysis of this subject, there were two heterozygous silent mutations in the three hot-spot regions in the RYR1 gene. In the CPT II gene, the subject was found to be heterozygous for an amino acid substitution in exon 4, (1203)G>A causing a (368)Val>Ile amino acid substitution. There was no mutation in the VLCAD gene or CYP2C19 gene. The subject was heterozygous for CYP2D6*1 and CYP2D6*2.

Influence of simulated weightlessness on the intramuscular and oral pharmacokinetics of promethazine in 12 human volunteers.

The National Aeronautics and Space Administration (NASA) recommends using promethazine to prevent and treat space motion sickness, but pharmacologic responses in space and on Earth are different. Twelve volunteers were given 50 mg promethazine orally or intramuscularly before and after 48 hours of bed rest to simulate weightlessness. The maximum measured plasma concentration (C(max)), time to C(max) (t(max)), and area under plasma concentration versus time curve from 0 to infinity (AUC(inf)) were determined, and the bioequivalence was tested between bed-rest and ambulatory status for the intramuscular and oral routes as well as between both routes for bed-rest and ambulatory position. Simulated weightlessness did not influence the ratio AUC(bed rest)/AUC(ambulatory) after intramuscular injection, whereas a significant increase (26%) in the ratio was seen after oral administration, probably because of a prolonged contact time between promethazine and the intestinal wall associated with an increase in the intestinal transit time. The AUC was 3-fold higher when the drug was administered by the intramuscular route during both positions. Thus, intramuscular administration could be a good alternative to the oral route.

Interaction of surface-active drugs in rabbits.

The interaction of chlorpromazine and promethazine in vivo has been investigated. The drugs were administered to the rabbit orally as a single dose (100 mg of each drug) as well as simultaneously with an interval of 15 min. The presence of multiple peaks at the separate administration of promethazine and chlorpromazine on the one hand, and increase of number of peaks, symbathic character of kinetic curves of mentioned drugs and its prolonged appearance in the systemic circulation of the blood by simultaneous administration on the other hand, may be explained by the intensive presystem metabolism and surface-activity ability of these drugs, and by the periodic 'lassitude' of liver for their capture and elimination (either presystem or systemic). The micelle formation from these drugs in the gastro-intestinal tract and formation of the mixed micelles on simultaneous administration were also taken into consideration. Chlorpromazine is more strongly captured by the liver at its first pass through it than promethazine, from comparison of pharmacokinetics of these drugs administered separately. Therefore, chlorpromazine on simultaneous administration occupies the sites of the liver which were covered by promethazine at single dose, thereby substituting promethazine and promoting its transferral into the systemic blood circulation. This results in a large increase in promethazine content in blood, additional peaks appear and the presence of promethazine in the blood is prolonged. The influence of chlorpromazine on the kinetics of promethazine is especially obvious when chlorpromazine enters the organism first and more easily occupies those sites in the liver which participate in the capture and elimination of both drugs. Concerning influence of promethazine on the kinetics of chlorpromazine, promethazine reinforces in some way the ability of liver to capture chlorpromazine, thereby intensifying the presystem metabolism of chlorpromazine and inhibiting its own metabolism. The analogous effect was observed in the study of the influence of promethazine on the kinetics of carbamazepine.

Recovery, enrichment and selectivity in liquid-phase microextraction comparison with conventional liquid-liquid extraction.

Mathematical descriptions for extraction recovery and enrichment were applied for liquid-phase microextraction (LPME) and comparison with conventional two- and three-phase liquid-liquid extraction techniques (LLE) was made. The LPME theoretical calculations were verified by experimental determination of actual partition coefficients and by data obtained with LPME in a robust hollow fibre formate. With hollow fibre LPME operated in the two-phase mode, analytes were extracted from 1 to 4 ml aqueous samples into 25-50 microl of an organic solvent present in the pores and in the lumen of the porous hollow fibres. Compared with conventional two-phase LLE, two-phase LPME provided substantially higher enrichments for compounds with relatively large partition coefficients (K(org)/d>500). In contrast, because of the large volume of organic solvent relative to the sample volume, LLE provided high recovery and moderate enrichment even for compounds with relatively low partition coefficients (K(org)/d>5). Thus, two-phase LPME may be used for substantially enhanced extraction selectivity and enrichment of relatively hydrophobic analytes as compared with LLE whereas conventional two-phase LLE is superior for more hydrophilic analytes. Similar results were found for three-phase LPME where analytes where extracted from 1 to 4 ml aqueous samples through approximately 20 microl organic solvent immobilized within the pores of the hollow fibre and into 25 microl of an aqueous acceptor solution inside the lumen of the hollow fibre. The fundamental differences of LPME and LLE were further demonstrated with practical experiments on extraction of the basic drugs promethazine, methadone, and haloperidol from human plasma and urine.

Liquid-phase microextraction of protein-bound drugs under non-equilibrium conditions.

Recently, we introduced an inexpensive and disposable hollow fiber-based device for liquid-phase microextraction (LPME) where ionic analytes typically were extracted and preconcentrated from 1-4 mL aqueous samples (such as plasma and urine) through an organic solvent immobilized in the pores of a polypropylene hollow fiber and into a 10-25 microL volume of acceptor phase present inside the lumen of the hollow fiber. Subsequently, the acceptor phase was directly subjected to the final analysis by a chromatographic or electrophoretic method. In the present work, attention was focused on LPME of the basic drugs amphetamine, pethidine, promethazine, methadone and haloperidol characterized by substantial differences in the degree of protein binding. Drug-protein interactions in plasma resulted in reduced recoveries and substantially increased extraction times compared with extraction of the drugs from a pure water matrix. However, by addition of 5-50% methanol to the plasma samples, recoveries were comparable with LPME from water samples and ranged between 75 and 100%. The addition of methanol was found not to speed up the LPME process and extractions from plasma were performed in 45 min to reach equilibrium. Because approximately 55-70% of the final analyte concentrations were achieved within the initial 10 min of the LPME process, validation was accomplished after 10 and 45 min of LPME. In general, the results with 10 and 45 min were almost comparable, with precision data in the range 1.2-11.1% (RSD) and with linearity in the concentration range 20-1000 ng mL(-1) (r = 0.999). In conclusion, excellent LPME results may be achieved in a short time under non-equilibrium conditions with a minor loss of sensitivity. In cases of drug-protein interactions, methanol may be added to ensure a high extraction recovery.

A liquid chromatographic method for the simultaneous determination of promethazine and three of its metabolites in plasma using electrochemical and UV detectors.

A new assay method has been developed for the quantitation of promethazine (PMZ) with a sensitivity and reproducibility as good as any previously reported method. This method is also capable of quantitatively determining three metabolites of PMZ (monodemethylated, sulphoxidated, and monodemethylated sulphoxidated PMZ), which has not been previously described. The method uses high-performance liquid chromatography with amperometric and UV detection simultaneously and requires only one extraction step from serum with chloroform. The method uses trifluoperazine as the internal standard. The limit of detection level for PMZ is 1.0 ng/ml when a 0.2-mL specimen of plasma is assayed. A validation study is also conducted for evaluating the recovery, precision, linearity of response, sensitivity, and selectivity of the method.

A new capillary electrophoresis end-column amperometric detection system without the need for capillary/electrode alignment.

A self-aligning end-column amperometric detection system for capillary electrophoresis was constructed. In this system, the electrode and capillary were exchanged easily and the capillary/electrode alignment procedure is not required. Gold, gold/mercury amalgam, copper and carbon fiber could be used as the working electrode. The principle is in the use of two disk holders with the capillary and the electrode in the center, so that by inserting the disk holders into a groove in the working electrode port, the capillary and the electrode are automatically aligned and the distance between the capillary and the electrode is assured at 0.24 mm. The relative standard deviation obtained using five different gold/mercury amalgam microdisk electrodes for determination of cysteine was 1.5% for the migration time and 3.3% for the electrophoretic peak current. The simple and convenient system was attractive for the routine analysis by capillary electrophoresis with electrochemical detection. The system was applied to the determination of promethazine hydrochloride in human serum.

The pharmacokinetics of promethazine after intravenous administration in camels.

The pharmacokinetics of promethazine were determined in seven camels (Camelus dromedarius) after an intravenous dose of 0.5 mg kg body weight.-1 The data obtained (median and range) were as follows: the elimination half-life (t1/2 beta) was 5.62 (2.84-6.51) h; the steady state volume of distribution (Vdss) was 8.90 (7.10-12.00) L kg-1, total body clearance (CT) was 24.5 (17.22-33.65) ml kg-1 min-1 and renal clearance (Clr) was 4.81 (1.97-5.48) ml kg-1 min-1.

Redistribution of basic drugs into cardiac blood from surrounding tissues during early-stages postmortem.

The objective of this study was to elucidate the mechanism(s) responsible for increases in the concentrations of basic drugs in cardiac blood of bodies in a supine position during early-stages postmortem. The concentrations of basic drugs in cardiac blood and other fluids and tissues of three individuals who had used one or more basic drugs were examined. The results were compared with those obtained in experiments using rabbits. In the first case, autopsy of whom was performed approximately 12 h after death, methamphetamine was detected and its concentrations were in the order: lung >> pulmonary venous blood > blood in the left cardiac chambers (left cardiac blood) >> pulmonary arterial blood > blood in the right cardiac chambers (right cardiac blood). In the second case, autopsy of whom was performed approximately 9 h after death, methamphetamine and morphine were detected and their concentrations in the left cardiac blood were roughly twice those in the right cardiac blood. The methamphetamine and morphine concentrations in the lung were 2 to 4 times higher than those in cardiac blood samples. In the third case, autopsy of whom was performed approximately 2.5 days after death, the pulmonary veins and arteries were filled with chicken fat clots. Toxicological examination revealed the presence of four basic drugs: methamphetamine, amitriptyline, nortriptyline and promethazine. Their concentrations in the lung were 5 to 300 times higher than those in cardiac blood, but postmortem increases in the concentrations of these drugs in the cardiac blood were not observed. In the animal experiments, rabbits were given 5 mg/kg methamphetamine intravenously or 20 mg/kg amitriptyline subcutaneously and sacrificed 20 min or 1 h later, respectively. The carcasses were left in a supine position at the ambient temperature for 6 h after or without ligation of the large vessels around the heart. For the groups with ligated vessels, the mean ratios of the drug concentrations in both left and right cardiac blood samples 6 to 0 h postmortem were about 1, whereas in those without ligated vessels, these ratios were about 2 and 1, respectively. The order of the methamphetamine and amitriptyline concentrations in blood and tissue samples were roughly: lungs > myocardium and pulmonary venous blood > cardiac blood, inferior vena caval blood and liver. Our results demonstrate that when bodies are in a supine position, (1) basic drugs in the lungs diffuse rapidly postmortem into the left cardiac chambers via the pulmonary venous blood rather than simply diffusing across concentration gradients, and (2) basic drugs in the myocardium contribute little to the increases in their concentrations in cardiac blood during the early postmortem period.

Quantitation of promethazine enantiomers in human serum using a chiralcel OJ-R column and mixed-mode disc solid-phase extraction.

A liquid chromatographic method was developed for the assay of R(+)- and S(-)-promethazine enantiomers from human serum. The method involves the use of the mixed mode disc solid-phase extraction technique for sample clean-up. Chromatographic resolution of the enantiomers was performed on a reversed-phase cellulose-based chiral column (Chiralcel OJ-R) under isocratic conditions using a mobile phase consisting of 0.5 M aqueous sodium perchlorate/acetonitrile (63:37, v/v) at a flow rate of 0.5 ml min-1. Recoveries in the range of 97-99% at 20 ng ml-1 levels were obtained for both promethazine enantiomers. Intra-day and inter-day precision calculated as R.S.D.% was in the 3-8% ranges for both enantiomers. Intra-day and inter-day accuracy calculated as percent error was in the 0-10 and 1-7% ranges for both enantiomers, respectively. Linear calibration curves were obtained for each enantiomer in serum in the concentration range 5-90 ng ml-1. The limit of quantitation of each enantiomer was 10 ng ml-1. The detection limit for each enantiomer in serum using UV detection at 249 nm was 2 ng ml-1 (S/N = 2).

A liquid chromatographic method for the determination of promethazine enantiomers in human urine and serum using solid-phase extraction and fluorescence detection.

A LC method was developed for the concurrent assay of R(+) and S(-) promethazine from human urine and serum. The method involves the use of solid-phase extraction for sample clean-up. Chromatographic resolution of the enantiomers was performed under isocratic conditions using a mobile phase of hexane-1,2-dichlorethane-absolute ethanol-trifluoroacetic acid (400:150:100:1, v/v/v/v) at a flow rate of 1 ml min-1 on a brush-type column KK-CARNU. The enantiomers were detected by fluorescence using an excitation wavelength of 250 nm and a 280 nm emission cutoff filter. Chlorpromazine was used as the internal standard for urine analysis. Standard addition was used for promethazine analysis from serum. Drug to internal standard ratios were linear from 0.25 to 10 micrograms ml-1 in urine. Serum levels were linear from 2 to 10 ng ml-1.

Quantification of chlorprothixene, levomepromazine and promethazine in human serum using high-performance liquid chromatography with coulometric electrochemical detection.

Isocratic reversed-phase high-performance liquid chromatography with coulometric electrochemical detection was optimised to quantify the neuroleptic drugs chloroprothixene, levomepromazine, and promethazine in human serum. The method involves extraction of the neuroleptic drugs in n-heptane-isoamylalcohol from the alkalinized serum, followed by chromatographic separation on a Nucleosil CN column with acetonitrile-pyridine-sodium acetate buffer as the mobile phase. The extraction recovery was > 85% for each neuroleptic drug. The sensitivity and selectivity required for pharmacokinetic studies was obtained with a dual coulometric analytical cell operating in the oxidative screen mode. The lower limit of detection in human serum for chlorprothixene, levomepromazine, and promethazine, was 0.5, 0.2 and 0.1 ng/ml, respectively. A linear relationship (r2 > 0.99) was obtained between the concentrations of each neuroleptic drug and the detector signal. The accuracy of the quality control samples was +/- 7% for each neuroleptic drug with a precision within 9.5%, 8.1% and 13.5% for chlorprothixene, levomepromazine, and promethazine, respectively. The neuroleptic drugs were stable in acetonitrile and human serum for at least six months when stored at -20 degrees C. This method is applicable to analyze a large number of serum samples for pharmacokinetic studies of the neuroleptic drugs.

Rapid, sensitive high-performance liquid chromatographic method for the quantification of promethazine in human serum with electrochemical detection.

A method of analysis has been developed to quantify promethazine in human serum with a sensitivity that was suitable for bioavailability studies following a 50.0-mg rectal dose. The limit of quantification from 1.0 ml of serum for promethazine using electrochemical detection was 0.200 ng/ml. At this concentration, the total coefficient of variation obtained from seven replicates over the course of three days of validation was 7.53%. The amount of serum required, the ease of sample preparation and the precision of the method at the limit of quantification demonstrated an improvement over previous assays. A validation study was completed that included an evaluation of recovery, ruggedness, linearity of response, accuracy, precision, sensitivity, stability and selectivity. The method was then used to determine promethazine serum levels in a 36-subject bioavailability study following a 50.0-mg suppository dose.

Applications in drug analysis of carbon paste electrodes modified by fatty acids.

The oxidation of promethazine as a model compound has been studied by adsorptive stripping voltammetry at carbon paste electrodes (CPE). A modification of the carbon paste matrix with fatty acids allows greater preconcentration of the molecule at the electrode surface. Several fatty acids of different chain length have been tested. The modification of the CPE with lauric acid has been successfully applied in the quantitative analysis of promethazine in standard serum samples. The influence of several parameters affecting the accumulation step has been investigated such as: pH, ionic strength, interfering ions, paste composition. The detection limit in phosphate buffer at pH 9.0 (tacc = 5 min) has been found to be 1 x 10(-10) M.