A case report on fatal intoxication by tapentadol: Study of distribution and metabolism.

We report a case in which a tapentadol acute intoxication was suspected as the cause of death of a 39-year-old man: approximately two days after death, cardiac and femoral blood, as well as urine, bile, gastric content and chest hair, were collected during the autopsy. Tapentadol was detected before and after hydrolysis in femoral (530 ng/mL unconjugated and 1570 ng/mL conjugated) and cardiac (680 ng/mL unconjugated and 3440 ng/mL conjugated) blood, and additionally in bile (3200 ng/mL), urine (9300 ng/mL), chest hair (2850 pg/mg) and gastric content. LC-QTOF screening analysis confirmed the presence of five different tapentadol metabolites (tapentadol-O-glucuronide, tapentadol-O-sulfate, N-desmethyltapentadol, N-desmethyltapentadol-glucuronide and N-desmethyltapentadol-O-sulfate), in urine, bile, cardiac and femoral blood. Positivity of body hairs allowed us to conclude that the man had used tapentadol in the last weeks/months. Autopsy and toxicological results (also positive for clotiapine, diazepam and chlordesmethyldiazepam) suggested that tapentadol could have caused, even at low concentrations, a severe respiratory depression, which contributed to the death of the subject. This is one of the few cases in literature where tapentadol was detected in blood, together with its metabolites, and the only one in which the parent drug was identified in hairs.

Fate of beta blockers and psycho-active drugs in conventional wastewater treatment.

The removal of beta blockers and psycho-active drugs was investigated in a representative conventional German WWTP by long-term measurement campaigns along different biological treatment processes. The activated sludge treatment with an elevated SRT of 18 d was the only process which led to a significant removal of certain beta blockers and psycho-active drugs. The removal efficiency was below 60% for all compounds except for the natural opium alkaloids codeine and morphine being removed by more than 80%. Primary biological transformation and sorption onto sludge as the main removal mechanisms were examined in lab-scale batch experiments. Sorption onto activated sludge was found to be negligible (<3%). The biological transformation could be described by pseudo-first order kinetics and the transformation constants k(biol) were used to predict the removal of beta blockers and psycho-active drugs in an activated sludge unit with a model. For most compounds the removal efficiencies measured on the full-scale WWTP were within the 95% confidence intervals predicted by the model. The results from full-scale measurements and modeling indicate that biological transformation in the nitrification tank together with parameters such as the sludge retention time and the temperature is crucial regarding the biological transformation of beta blockers and psycho-active drugs in conventional WWTPs.

Determination of 105 antibiotic, anti-inflammatory, antiparasitic agents and tranquilizers by LC-MS/MS based on an acidic QuEChERS-like extraction.

A procedure for screening 105 veterinary drugs in foods by liquid chromatography tandem mass-spectrometry (LC-MS/MS) is presented. Its scope encompasses raw materials of animal origin (milk, meat, fish, egg and fat) but also related processed ingredients and finished products commonly used and manufactured by food business operators. Due to the complexity of the matrices considered and to efficiently deal with losses during extraction and matrix effects during MS source ionisation, each sample was analysed twice, that is 'unspiked' and 'spiked at the screening target concentration' using a QuEChERS-like extraction. The entire procedure was validated according to the European Community Reference Laboratories Residues Guidelines. False-negative and false-positive rates were below 5% for all veterinary drugs whatever the food matrix. Effectiveness of the procedure was further demonstrated through participation to five proficiency tests and its ruggedness demonstrated in quality control operations by a second laboratory.

[Determination of three tranquillizer residues in animal foods by QuEChERS-high performance liquid chromatography-tandem mass spectrometry].

A method for simultaneous determination of chlorpromazine, diazepam and metolazone residues in porcine muscle, fish, liver and kidney was developed using QuEChERS and HPLC-MS/MS technique. The samples were extracted with ethyl acetate and cleaned up with C18, N-propylethylendiamine (PSA) and NH2 sorbents after using Na2SO4 as dehydrating agent. The analytes were separated by a special C18 column, Atlantis T3, and gradiently eluted with a mixed solution of 5 mmol/L formic acid and acetonitrile at a flow rate of 0.35 mL/min. The mass spectrometric analysis that quantified using isotope internal standard, was carried out with electrospray positive ion source (ESI+) and multiple reaction monitoring mode (MRM). The linearity of the calibration curves was good in the range of 0.2-5.0 µ g/L. The recoveries at three different spiked levels (0.5, 1 and 5 µ g/kg) in four matrices were in the range of 92.5%-117.8%. The repeatability expressed as relative standard deviations (RSDs) ranged from 0.7% to 11.6% (n=6). The method, with wide matrix range of application, is highly effective and sensitive and suitable for the rapid analysis of large quantities of samples.

The first year of the toxicology program.

The CAP Toxicology Survey Program's initial year is reviewed. Four series of samples, each consisting of five specimens with approximately 12 different drugs, were sent to almost 200 participants and as many as seven referees. They reported the presence or absence of more than 16 different compounds, and identified specific barbiturates when present. In each series, two serum samples were for qualitative identification and quantitative analysis. The remainder were urine samples for qualitative analysis. The aim of the survey is to enhance the "current state of the art" among participants. Drug-abuse toxicology and therapeutic monitoring of drugs were given priority. Clinically relevant samples reflecting current drug abuse, especially mixed-drug abuse, were provided, including serum for quantitative determination as is required in treatment of barbiturate overdose and for therapeutic drug monitoring. The Committee has interacted with participants by critiques of surveys, by questionnaires, and by responding to queries from participants.

Multiresidue method for the detection of tranquillisers, xylazine, and a beta-blocker in animal production by liquid chromatography-tandem mass spectrometry.

Tranquillisers are often used in animal production, especially in pigs to calm them before transport to the slaughterhouse. The use of certain substances (derived from phenothiazine) is totally prohibited, whilst other compounds (butyrophenone and beta-blockers) are regulated through the establishment of MRLs. A physico-chemical detection method based on liquid chromatography-tandem mass spectrometry is described. Validation was carried out according to the criteria laid down in Directive 2002/657/EC. The method was also used to detect and quantify these substances in treated animals.

High-pressure liquid chromatographic identification of drugs used in management of arthritis.

A screening procedure was developed for the identification of drugs used in the clinical treatment of arthritis. Each glucocorticoid, nonsteroidal anti-inflammatory agent, or tranquilizer was characterized by its retention on a reversed-phase high-pressure liquid chromatographic column and by the ratio of the response of dual UV detectors (254 and 280 nm). Although the retention times of all 14 drugs examined were less than 4 min. each drug could be distinguished easily from the other drugs in the series.

Enthalpies of hydrogen bonding in psychotropic drugs.

The enthalpy of hydrogen bonding of some antipsychotic, antidepressant, anticonvulsant, and antianxiety agents with phenol, as determined from IR and NMR spectroscopic measurements, was shown not to be responsible for differences in activity within the drug classes. These results support a theoretical prediction advanced for anticonvulsant activity.

Analysis of certain tranquilizers in biological fluids.

A review with 282 references is presented that deals with the reported methods of analysis of phenothiazines, thioxanthenes, and benzodiazepine derivatives of pharmaceutical interest. The review includes the methods adapted in biological fluids.

Potential interference of cyclobenzaprine and norcyclobenzaprine with HPLC measurement of amitriptyline and nortriptyline: resolution by GC-MS analysis.

Cyclobenzaprine and its major metabolite, norcyclobenzaprine, differ from amitriptyline and nortriptyline only by the presence of a double bond in the cycloheptane ring. Three patients developed sufficient levels of cyclobenzaprine and norcyclobenzaprine because of either rapid or long-term ingestion of cyclobenzaprine to cause positive interferences in both a Syva EMIT assay and a high-performance liquid chromatographic (HPLC) assay for identification and quantitation of tricyclic antidepressants in serum. Cyclobenzaprine coeluted with amitriptyline, and norcyclobenzaprine eluted slightly earlier than, but was poorly resolved from, nortriptyline in this HPLC assay. We found that cyclobenzaprine could be distinguished from amitriptyline and that norcyclobenzaprine could be distinguished from nortriptyline on the basis of gas chromatographic retention times upon gas chromatographic-mass spectrometric analyses after derivatization with trifluoroacetic anhydride. The compounds were also distinguishable by mass spectrometric criteria.

Problems associated with drug residues in beef from feeds and therapy.

Drug residues in beef have been reported internationally. These include antimicrobials, anti-inflammatories, growth promotants, parasiticides and insecticides. The main factors associated with residues are animal age and use, and failure to observe withdrawal time for regular or extra-label use. Public health concerns include toxic and anaphylactic reactions, and development of drug-resistant strains of bacteria. The maximum residue level (MRL) is the current standard for residues in food adopted by the Codex Committees of the Food and Agriculture Organisation and World Health Organisation, but is not universally accepted or standardised. Detection of residues at slaughter is a critical point in residue control. Several live animal tests are available, but these vary in reliability and usage. After slaughter, tissues sampled and tests used are more uniform. To prevent international trade barriers associated with drug residues in beef, the following conditions should be implemented: standardisation of testing methods used to detect drug residues; standardisation of methods for determining MRLs; establishment of active surveillance programmes to monitor residues.

Determination of propionylpromazine hydrochloride in formulation matrixes using reversed-phase ion-pair small bore liquid chromatography.

Propionylpromazine hydrochloride (PPZHCl) has been investigated for use with leghold traps to reduce the amount of self-inflicted trauma experienced by animals restrained by these traps. Three types of PPZHCl formulations made with Karo dark syrup, K-Y Jelly, and Vaseline were used in 2 types of tranquilizer trap devices (TTDs). A reversed-phase ion-pair liquid chromatography (LC) method using a small bore C18 column was used to: (1) determine the purity of the PPZHCl material used in these formulations, and (2) to determine the resulting PPZHCl content of each formulation. Analyte quantitation was done using UV absorption at 280 nm. Regression analysis of calibration standard solutions indicated a linear and directly proportional relationship between analyte response and PPZHCl concentration over the range evaluated. Recovery data from: (1) Vaseline formulations containing 38.8, 16.2, and 8.78% PPZHCl were 104, 92.9, and 90.2%, respectively, (2) Karo dark syrup formulations containing 26.5, 18.1, and 10.3% PPZHCl were 97.7, 99.3, and 106%, respectively, and (3) K-Y Jelly formulations containing 33.0, 23.5, and 13.4% PPZHCl were 100, 99.4, and 88.7%, respectively. The relative standard deviation (RSD) values from triplicate analysis of these formulations ranged from 0.7 to 6.7%. The PPZHCl content from 9 manufactured TTDs, 3 for each formulation type, were analyzed in triplicate and produced RSD values ranging from 0.7-6.8%. These results indicate that the formulation extraction presented could be used to evaluate the PPZHCl content in TTDs prior to field use. The use of a small bore LC column reduced the amount of solvents consumed and hazardous waste generated, compared to sample analysis that uses a more conventional analytical LC column.

Detection of drugs using XAD-2 resin. III:A routine screening procedure for bile.

The ability of bile to concentrate drugs and metabolites coupled with its general availability make it suitable for analysis and often the fluid of choice in postmorten cases requiring drug screening. Bile (5 to 10 ml) was diluted with water, sulfuric acid was added, and the mixture was autoclaved. The precipitated bile salts were easily removed by filtration and the filtrate (pH adjusted to 8.0 to 8.5) extracted with XAD-2 resin. Drugs were eluted with a mixture of ethyl acetate/1,2-dichloroethane and analyzed with thin-layer chromatography. Varying the dilution of bile improved the recovery of morphine, codeine, methadone, amobarbital, and phenobarbital. Excessive dilution, however, caused a washing phenomenon and reduced recovery of some drugs, as shown with morphine and codeine. The procedure described is useful for the rapid screening of bile specimens for drugs.

Toxicological findings in victims of traumatic deaths.

The toxicological findings from 6037 analyses of viscera obtained from victims of traumatic death are used to correlate the relative incidence of carbon monoxide, ethyl alcohol, narcotics, hypnotics, analgesics, and tranquilizers-antidepressants in deaths occurring under the following circumstances: fire related, asphyxia by hanging, by use of plastic bags, from physical obstruction of trachae, and by drowning; traumatic injury from impact of moving train, fall from height, and occupational accident; traumatic injury to pedestrian, driver, and passenger from vehicular accidents; and from violent death by shooting, stabbing, strangulation, and beating. The influence of alcohol, narcotic drugs, and tranquilizers on carbon monoxide can be seen in some of these traumatic deaths. Ethanol alone and in combination with other drugs was present in 42.3% and 19.5% of driver and pedestrian victims, respectively, of vehicular accidents in the year 1974. Comparative analysis is presented for the toxicological data obtained on victims of homicide (shooting, stabbing, strangulation, and beating) in New York City and similar data reported for victims of homicide in Detroit. In New York City 45.9% of such victims died while under the influence of alcohol or narcotic drugs, or both, with methadone predominating in the latter category. Tissue concentrations of drugs found in victims of traumatic death are presented. Diphenylhydantoin, diazepam, meperidine, and slow-acting barbiturates were found in normal therapeutic levels. Higher concentrations of amitriptyline, chlorpromazine, propoxyphene, short-acting barbiturates, and methadone were observed. The concentration of methadone in blood and brain (0.13 +/- 0.14 mg/100 ml) and in liver (0.53 +/- 0.42 mg/100 ml) in cases of traumatic death are not different from those observed in deaths classified as due to methadone overdose.

[Determination of psoralen and isopsoralen in tincture of fructus Psoraleae by HPLC].

A reversed-phase HPLC method was described for the determination of psoralen and isopsoralen in tincture of Fructus Psoraleae. After adding the internal standard and diluting the sample to a definite volume, the sample was injected and analysed. The RSDs were within 2% and the minimum working concentrations below 1 microgram/ml; the average recoveries of psoralen and isopsoralen 102.8% and 99.5% respectively and the linear ranges of psoralen and isopsoralen 12-200 micrograms/ml and 13-210 micrograms/ml (r = 0.999) respectively.

Evaluation of certain veterinary drug residues in food.

This report presents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of residues of certain veterinary drugs and to recommend maximum levels for such residues. The first part of the report considers an approach to assessing the safety of antimicrobial drug residues and their effects on the human intestinal microflora and general issues relating to the recommendation of Maximum Residue Levels (MRLs) for veterinary drug residues in food. A summary follows of the Committee's evaluations of toxicological and residue data on a variety of veterinary drugs: one beta-adrenoceptor-blocking agent (carazolol), one anthelminthic agent (doramectin), four antimicrobial agents (dihydrostreptomycin, streptomycin, neomycin and thiamphenicol), two insecticides (deltamethrin and phoxim), four production aids (estradiol-17 beta, progesterone, testosterone and porcine somatotropins) and one tranquillizing agent (azaperone). Annexed to the report are a summary of the Committee's recommendations on these drugs, including Acceptable Daily Intakes and MRLs, and other information required.

Development and validation of a confirmatory method for the determination of tranquilisers and a ß-blocker in porcine and bovine kidney by LC-MS/MS.

A method for the confirmation of the tranquilisers azaperone and its metabolite azaperol, of chlorpromazine, propionylpromazine and acepromazine, haloperidol, xylazine and the ß-blocker carazolol in porcine and bovine kidney with LC-MS/MS was developed. Various solvents and extraction techniques and different ways of clean-up were tested and verified with incurred pig kidney from an animal study. The best extraction efficiency was reached by extraction with a mixture of ammonia in ethyl acetate and overhead shaking without SPE clean-up. The optimised method with a twofold sample extraction was validated according to Commission Decision 2002/657/EC in a matrix-comprehensive in-house validation supported by the InterVal software, taking into account the defined MRLs and recommended concentrations. The validated method can be used for residue control of the above-mentioned analytes in bovine and porcine kidney of food-producing animals in accordance with Council Directive 96/23/EC.

Chemiluminescence and electrochemiluminescence detection of controlled drugs.

We review the determination of various controlled drugs (opioids, tranquilizers, stimulants, and hallucinogens) using flow-analysis methodologies (flow injection analysis, high performance liquid chromatography, capillary electrophoresis, and microfluidic devices) with chemiluminescence and electrochemiluminescence reagents such as luminol, diaryloxalates, tris(2,2'-bipyridine)ruthenium(II), permanganate, manganese(IV), and sulfite, for industrial, clinical, pharmaceutical, and forensic science applications.