ABSTRACT
Effective removal of organic UV filters from aquatic environmental compartments and swimming waters is very important because these substances are hazardous to humans and wildlife at low concentrations and act as endocrine disruptors. Therefore, the aim of the present article is to determine the extraction efficiencies of hydrophobic deep eutectic solvents (HDES) for the selected UV filters based on benzophenone structure (benzophenone, 2,4-dihydroxybenzophenone, 2,2´,4,4´-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2,2´-dihydroxy-4-methoxybenzophenone, 4-methacryloxy-2-hydroxybenzophenone) from aqueous matrices. For this purpose, six HDESs based on dl-menthol in combination with caprylic, decanoic and lauric acid are prepared and compared with referent terpene solvents such as terpineol and linalool. The effect of various parameters such as HDES composition, volume ratio, frequency and shaking time are studied. The highest extraction efficiency is shown by HDES of menthol:caprylic acid (1:1) composition at the aqueous:organic phase volume ratio of 1:1, shaking frequency of 1500â¯rpm and shaking time of 15â¯min. The achieved extraction efficiencies are higher than 99.6â¯% for all benzophenones studied in the purification of stagnant pond water, swimming pool water and river water samples. After a simple and fast sample treatment, the residual levels of benzophenones in the waters are controlled by a newly developed sensitive HPLC-MS/MS method with LOQs in the range of 0.7 - 5.0â¯ng/mL.
Subject(s)
Benzophenones , Deep Eutectic Solvents , Hydrophobic and Hydrophilic Interactions , Sunscreening Agents , Water Pollutants, Chemical , Water Purification , Benzophenones/chemistry , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/chemistry , Sunscreening Agents/chemistry , Sunscreening Agents/toxicity , Water Purification/methods , Deep Eutectic Solvents/chemistry , Menthol/chemistry , Caprylates/chemistryABSTRACT
BACKGROUND: Differences in neonatal pharmacokinetics are known to cause systemic accumulation of levobupivacaine with adverse effects during epidural analgesia. Therefore, it is not recommended to surpass 48 hours of administration in neonates. Free and total levobupivacaine levels are considered as predictors of toxicity. OBJECTIVE: The aim of the LEVON pilot study was to detect the accumulation of levobupivacaine during epidural analgesia exceeding 48 hours in neonates. METHODS: Ten neonates received a loading dose of levobupivacaine (1.25 mg/kg) followed by a continuous infusion (0.2 mg/kg/hour) epidurally. Free and total levobupivacaine concentrations were measured 0.5, 1, 6, 12, 36, 72 and 144 hours after the start of infusion. Cumulative doses of levobupivacaine, pain scores and clinical signs of toxicity were used for assessing efficacy and safety. RESULTS: The median concentrations of total levobupivacaine were 586.0, 563.0, 837.5, 957.0, 1930.0, 708.5 and 357.5 ng/ml. The median concentrations of free levobupivacaine were 4.0, 3.6, 5.5, 3.6, 5.5, 0.8 and 0.0 ng/ml. Three patients reached concerning concentrations of total levobupivacaine. Levels of free levobupivacaine remained low. No signs of toxicity were observed. CONCLUSION: Caudal epidural analgesia with levobupivacaine lasting longer than 48 hours appears to be safe providing that free levobupivacaine levels are below the presumed threshold for toxicity (Tab. 1, Fig. 1, Ref. 29). Text in PDF www.elis.sk Keywords: free levobupivacaine, total levobupivacaine, neonate, caudal continuous epidural analgesia, postoperative pain.
Subject(s)
Analgesia, Epidural , Infant, Newborn , Humans , Levobupivacaine , Analgesia, Epidural/adverse effects , Anesthetics, Local/adverse effects , Anesthetics, Local/pharmacokinetics , Bupivacaine/adverse effects , Pilot Projects , Pain Measurement , Double-Blind Method , Pain, PostoperativeABSTRACT
Branched chain amino acids (BCAAs), alanine and glutamine are determined in human plasma by capillary electrophoresis with contactless conductivity detection (CE/C4 D). The baseline separation of five amino acids from other plasma components is achieved on the short capillary effective length of 18 cm in 3.2 mol/L acetic acid with addition of 13% v/v methanol as background electrolyte. Migration times range from 2.01 min for valine to 2.84 min for glutamine, and LODs for untreated plasma are in the interval 0.7-0.9 µmol/L. Sample treatment is based on the addition of acetonitrile to only 15 µL of plasma and supernatant is directly subjected to CE/C4 D. Circulating amino acids are measured in patients with pancreatic cancer and cancer cachexia during oral glucose tolerance test. It is shown that patients with pancreatic cancer and cancer cachexia syndrome exhibit low basal circulating BCAAs and glutamine levels and loss of their insulin-dependent suppression.
Subject(s)
Amino Acids , Pancreatic Neoplasms , Amino Acids, Branched-Chain , Cachexia , Electric Conductivity , Electrophoresis, Capillary , Glutamine , HumansABSTRACT
In spite of use of cannabidiol (CBD), a non-psychoactive cannabinoid, in pediatric patients with epilepsy, preclinical studies on its effects in immature animals are very limited. In the present study we investigated anti-seizure activity of CBD (10 and 60 mg/kg administered intraperitoneally) in two models of chemically induced seizures in infantile (12-days old) rats. Seizures were induced either with pentylenetetrazol (PTZ) or N-methyl-D-aspartate (NMDA). In parallel, brain and plasma levels of CBD and possible motor adverse effects were assessed in the righting reflex and the bar holding tests. CBD was ineffective against NMDA-induced seizures, but in a dose 60 mg/kg abolished the tonic phase of PTZ-induced generalized seizures. Plasma and brain levels of CBD were determined up to 24 h after administration. Peak CBD levels in the brain (996 ± 128 and 5689 ± 150 ng/g after the 10- and 60-mg/kg doses, respectively) were reached 1-2 h after administration and were still detectable 24 h later (120 ± 12 and 904 ± 63 ng/g, respectively). None of the doses negatively affected motor performance within 1 h after administration, but CBD in both doses blocked improvement in the bar holding test with repeated exposure to this task. Taken together, anti-seizure activity of CBD in infantile animals is dose and model dependent, and at therapeutic doses CBD does not cause motor impairment. The potential risk of CBD for motor learning seen in repeated motor tests has to be further examined.
Subject(s)
Anticonvulsants/pharmacology , Cannabidiol/pharmacology , Cannabidiol/pharmacokinetics , N-Methylaspartate/pharmacology , Pentylenetetrazole/pharmacology , Seizures/drug therapy , Animals , Brain/drug effects , Disease Models, Animal , Epilepsy/drug therapy , Male , Rats , Rats, WistarABSTRACT
Riociguat is novel antihypertensive drug for treatment of pulmonary hypertension. As such, it is still being tested in many clinical and pharmacokinetic trials. Existing methods that determine serum riociguat and desmethylriociguat (DMR) are based solely on liquid chromatography with mass spectrometry. Therefore, we present a novel capillary electrophoresis with mass spectrometry method (CE-MS) for their determination in human serum as alternative method for ongoing trials. Complete resolution of both analytes was achieved by means of pH optimization of ammonium formate background electrolytes that are fully compatible with ESI/MS detection. Simple liquid-liquid extraction was used as sample pretreatment. The calibration dependence of the method was linear (in the range of 10-1000 ng/mL), with adequate accuracy (90.1-114.9%) and precision (13.4%). LOD and LOQ were arbitrarily set at 10 ng/mL for both analytes. Clinical applicability was validated using serum samples from patients treated with riociguat in pharmacokinetic study and the results corresponded with reference HPLC-MS/MS values. Capillary electrophoresis proved to be sensitive and selective tool for the analysis of riociguat and DMR.
Subject(s)
Electrophoresis, Capillary/methods , Pyrazoles/blood , Pyrimidines/blood , Spectrometry, Mass, Electrospray Ionization/methods , Electrolytes , Humans , Limit of Detection , Linear Models , Liquid-Liquid Extraction , Pyrazoles/chemistry , Pyrazoles/isolation & purification , Pyrazoles/pharmacokinetics , Pyrimidines/chemistry , Pyrimidines/isolation & purification , Pyrimidines/pharmacokinetics , Reproducibility of ResultsABSTRACT
Riociguat is a novel antihypertensive drug for the treatment of pulmonary hypertension. We present electrophoretic characterization, i.e. migration behavior of riociguat and metabolite M1 as support for optimized CZE/MS assay. Fundamental separation parameters, such as peak width, symmetry, and resolution are studied in a series of ammonium formate buffers within pH range 2.60-5.61. The narrow region of peak symmetry lies close to pH 4.0 for both analytes. Accordingly, the value of resolution maximizes in a background electrolyte adjusted to pH 4.10. Basic calibration parameters estimated from CZE experiments with absorption photometric and mass spectrometric detection of riociguat and metabolite M1 were evaluated. More than three orders lower LOD was achieved with high resolution mass spectrometric detection. The observed difference in the sensitivity of both detection techniques gives priority to the utilization of CZE/MS in practice. The values of dissociation constants of riociguat and metabolite M1, pKBH , were determined from CZE measurements in lithium formate and lithium acetate background electrolytes with constant ionic strength. The value of pKBH = 4.30 ± 0.02 for riociguat corresponds well to the value already presented in the literature. According to our observation, metabolite M1 behaves like a slightly stronger base with estimated pKBH = 4.40 ± 0.02.
Subject(s)
Electrophoresis, Capillary/methods , Mass Spectrometry/methods , Pyrazoles/analysis , Pyrazoles/metabolism , Pyrimidines/analysis , Pyrimidines/metabolism , Humans , Limit of Detection , Linear Models , Pyrazoles/blood , Pyrazoles/chemistry , Pyrimidines/blood , Pyrimidines/chemistry , Reproducibility of ResultsABSTRACT
Cannabis consumption has individual influence to cognitive and psychomotor functions of drivers and it has been generally accepted that driving under influence is risky in the perspective of traffic safety. However, rules how to assess fitness to drive are not quite clear. The psychoactive compound delta-9-tetrahydrocannabinol (THC) impairs cognition, psychomotor behaviour and driving performance in a dose-related manner approximately. After a single drug dose, THC blood concentration peaks within minutes, before the end of smoking, with a subsequent rapid decrease to the analytical limit of detection. Peak euphoria is delayed compared to THC peak blood concentration and physiological and behavioural effects return to baseline within 3-5 hours. In chronic users, the lipophilic THC accumulates in fat tissues, where its slow redistribution into blood is the rate limiting process in its terminal elimination. In our experimental study we have attempted to contribute to this discussion with results obtained from human volunteers - cannabis consumers in Czech Republic. Aim of our study was to document the time profile of serum THC level in occasional and chronic cannabis users. The observational interval covered the time immediately after the drug consumption (an own cigarette/joint) till 24 hours after. Our preliminary results have shown that in occasional users, THC serum levels cannot be detected already 4 hours after usual cannabis dose, whereas in chronic users measurable THC concentrations in serum persist longer. Moreover, some chronic consumers were practically with permanent THC detection during our observation period and also the chronic users consumed higher THC doses significantly related to doses in occasional ones. Presented results of the experimental study with human volunteers confirm a great individual variability of the kinetic profile of THC in blood due to complicated redistribution. The practical forensic question is how long the psychotropic effects of THC can persist after the last drug dose. In chronic users there are well documented indications of long term adverse effects to neurocognitive functions. THC blood level itself can not directly document the intensity of impairment of a driver. Moreover, the concentration of THC in blood at the time of driving is probably substantially higher than at the time of blood sampling. Therefore due to the prevention of traffic risk, some countries adopted per se traffic legislation based on analytical principle with minimum tolerance to illegal drugs in blood of drivers at driving. Low blood concentrations of THC close to the limit of detection of a specific toxicological method (GC-MS or LC-MS) are justified in an effective traffic legislation.
Subject(s)
Automobile Driving , Dronabinol/blood , Marijuana Smoking/blood , Psychotropic Drugs/blood , Accidents, Traffic/prevention & control , Cognition/drug effects , Dronabinol/adverse effects , Dronabinol/pharmacokinetics , Humans , Marijuana Smoking/adverse effects , Psychomotor Performance/drug effects , Psychotropic Drugs/adverse effects , Psychotropic Drugs/pharmacokineticsABSTRACT
We report the forensic case of a 42-year-old man, a known drug user, who died at home and whose body was only discovered 2 months later. Autopsy was performed on a corpse in the late postmortem stage where no apparent cause of death was found. A toxicological screening of biological materials (blood, urine and gastric content) using liquid chromatography with different types of mass detection (ion trap and high-resolution) revealed the presence of methoxetamine (MXE), a ketamine analog, and its metabolites. MXE and a number of its metabolites (e.g., O-desmethyl, N-desethyl, hydroxy, glucuronides and sulfates) were identified in urine. Based on the results, a method using liquid chromatography with tandem mass spectrometry was developed and validated for the determination of MXE concentration in biological materials. The following values of MXE concentration were found: blood-3.6 ng/mL, urine-70.5 ng/mL and gastric content-18.0 ng/mL. Given the absence of other drugs, medications and poisons, it can be inferred that despite relatively low blood concentrations, MXE contributed to the victim's death. The present case demonstrates that even after 2 months, MXE and its several metabolites can be detected and determined in the human cadaver at a relatively advanced stage of decomposition.
Subject(s)
Body Fluids , Cyclohexanones , Cyclohexylamines , Male , Humans , Adult , Cyclohexanones/analysis , Cyclohexanones/metabolism , Autopsy , Cadaver , Body Fluids/metabolismABSTRACT
Electrophoretic stacking is developed for sensitive determination of three zwitterionic antiepileptics, namely vigabatrin, pregabalin and gabapentin, in human serum. CE separation is performed in a 25 µm fused silica capillary covalently coated with the copolymer of acrylamide with 5% content of permanently charged 3-acrylamidopropyl trimethylammonium chloride (PAMAPTAC). In background electrolyte of 500 mM acetic acid, the 5% PAMAPTAC generates an anodic electro-osmotic flow with a magnitude of (-18.6 ± 0.5) · 10-9 m2V-1s-1, which acts against the direction of the electrophoretic migration of the analytes. A sample of the antiepileptic prepared in a 25% v/v infusion solution and 75% v/v acetonitrile is injected into the capillary in a large volume attaining a zone length of up to 270 mm. After turning on the separation voltage, the antiepileptics are isotachophoretically focussed behind the zone of Na+ ions with a sensitivity enhancement factor of 78. For the clinical determination of antiepileptics, the human serum is diluted with acetonitrile in a ratio of 1:3 v/v and a zone with a length of 90 mm is injected into the capillary. The method is linear in the 0.025-2.5 µg/mL concentration range; the attained limit of quantification is in the range 18.3-22.8 nmol/L; the within-day precision for the migration time is 0.8-1.2% and for the peak area 1.5-2.4%.
Subject(s)
Anticonvulsants , Chlorides , Electrophoresis, Capillary , HumansABSTRACT
Pharmacokinetic data for riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have previously been reported from randomized clinical trials, which may not fully reflect the population encountered in routine practice. The aim of the current study was to characterize the pharmacokinetic of riociguat and its metabolite M1 in the patients from routine clinical practice. A population pharmacokinetic model was developed in NONMEM 7.3, based on riociguat and its metabolite plasma concentrations from 49 patients with CTEPH. One sample with riociguat and M1 concentrations was available from each patient obtained at different time points after last dose. Age, bodyweight, sex, smoking status, concomitant medications, kidney and liver function markers were tested as potential covariates of pharmacokinetic of riociguat and its metabolite. Riociguat and M1 disposition was best described with one-compartment models. Apparent volume of distribution (Vd/F) for riociguat and M1 were assumed to be the same. Total bilirubin and creatinine clearance were the most predictive covariates for apparent riociguat metabolic clearance to M1 (CLf,M1/F) and for apparent riociguat clearance through remaining pathways (CLe,r/F), respectively. CLf,M1/F, CLe,r/F, Vd/F of riociguat and M1, and clearance of M1 (CLe,M1/F) for a typical individual with 70 mL/min creatinine clearance and 0.69 mg/dL total bilirubin were 0.665 L/h (relative standard error = 17%)), 0.66 (18%) L/h, 3.63 (15%) L and 1.47 (19%) L/h, respectively. Upon visual identification of six outlying individuals, an absorption lag-time of 2.95 (6%) h was estimated for these patients. In conclusion, the only clinical characteristics related to riociguat exposure in patients with CTEPH from routine clinical practice are total bilirubin and creatinine clearance. This confirms the findings of the previous population pharmacokinetic studies based on data from randomized clinical trials.
ABSTRACT
Recreational use of the potent synthetic opioid 3,4- dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide (U-47700) is rising, accompanied by increasingly frequent cases of serious intoxication. This article reports a case of near-fatal U-47700 intoxication. A man was found unconscious (with drug powder residues). After 40 h in hospital (including 12 h of supported ventilation), he recovered and was discharged. Liquid chromatography/high-resolution mass spectrometry (LC/HRMS) or gas chromatography/mass spectrometry (GC/MS) were used to detect and quantify substances in powders, serum and urine. Powders contained U-47700 and two synthetic cannabinoids. Serum and urine were positive for U-47700 (351.0 ng/mL), citalopram (Subject(s)
Benzamides/adverse effects
, Drug Overdose
, Illicit Drugs/adverse effects
, Adult
, Benzamides/analysis
, Benzodiazepines/analysis
, Chromatography, Liquid
, Citalopram/analysis
, Czech Republic
, Forensic Toxicology
, Gas Chromatography-Mass Spectrometry
, Humans
, Illicit Drugs/analysis
, Male
, Mass Spectrometry
, Midazolam/analysis
, Substance Abuse Detection
ABSTRACT
In the last decade there has been a dramatic increase in the availability and abuse of synthetic cathinones - new amphetamine-like stimulants. Even though their abuse during pregnancy could have serious adverse effects on the fetus, cathinones are not readily included in neonatal toxicological screenings. Meconium (first neonatal stool) is the specimen of choice to reveal long term drug exposure, however as it is a highly complex matrix, the sample preparation is a critical step before the instrumental analysis. The aim of this work was to develop a suitable meconium sample extraction technique using the advantages of salting-out assisted liquid-liquid extraction (SALLE) and using only MS-friendly organic ammonium salts. We further developed and validated liquid chromatography tandem-mass spectrometry method for the determination of 'traditional' stimulants (methamphetamine, amphetamine, MDMA) and cathinones (mephedrone, methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP), methylone, butylone, flephedrone, and naphyrone). Matrix-matched calibration was prepared in the concentration range 10-2000 ng/g. The limits of quantification were determined as 10 ng/g, recoveries ranged from 48.2% to 94.3% and the matrix effect was between 60.2% and 101.4%. Accuracy (86.1-114.5%) and precision (4.9-14.9%) were determined and all validation criteria were met for all analytes except for naphyrone. Finally, our analytical method was tested on a set of real meconium samples, which were found positive for amphetamine, methamphetamine and methylone, thus demonstrating the validity of the method.
Subject(s)
Amphetamines/analysis , Central Nervous System Stimulants/analysis , Liquid-Liquid Extraction/methods , Meconium/chemistry , Substance Abuse Detection/methods , Ammonium Compounds/chemistry , Chromatography, High Pressure Liquid/methods , Feasibility Studies , Female , Humans , Infant, Newborn , Limit of Detection , Pregnancy , Pregnancy Complications/diagnosis , Substance-Related Disorders/diagnosis , Tandem Mass Spectrometry/methodsABSTRACT
BACKGROUND: Cannabis, and specifically one of its active compounds delta-9-tetrahydrocannabinol in recreational doses, has a variety of effects on cognitive processes. Most studies employ resting state functional magnetic resonance imaging techniques to assess the stationary effects of cannabis and to-date one report addressed the impact of delta-9-tetrahydrocannabinol on the dynamics of whole-brain functional connectivity. METHODS: Using a repeated-measures, within-subjects design, 19 healthy occasional cannabis users (smoking cannabis ⩽2 per week) underwent resting state functional magnetic resonance imaging scans. Each subject underwent two scans: in the intoxicated condition, shortly after smoking a cannabis cigarette, and in the non-intoxicated condition, with the subject being free from cannabinoids for at least one week before. All sessions were randomized and performed in a four-week interval. Data were analysed employing a standard independent component analysis approach with subsequent tracking of the functional connectivity dynamics, which allowed six connectivity clusters (states) to be individuated. RESULTS: Using standard independent component analysis in resting state functional connectivity, a group effect was found in the precuneus connectivity. With a dynamic independent component analysis approach, we identified one transient connectivity state, characterized by high connectivity within and between auditory and somato-motor cortices and anti-correlation with subcortical structures and the cerebellum that was only found during the intoxicated condition. Behavioural measures of the subjective experiences of changed perceptions and tetrahydrocannabinol plasma levels during intoxication were associated with this state. CONCLUSIONS: With the help of the dynamic connectivity approach we could elucidate neural correlates of the transitory perceptual changes induced by delta-9-tetrahydrocannabinol in cannabis users, and possibly identify a biomarker of cannabis intoxication.
Subject(s)
Brain/drug effects , Dronabinol/pharmacology , Hallucinogens/pharmacology , Marijuana Smoking/psychology , Adult , Brain/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging , Male , Young AdultABSTRACT
Perampanel is a novel antiepileptic drug used in paediatric patients. Existing methods that determine serum perampanel are of limited practicability. We developed a novel capillary electrophoresis (CE) method using a new version of acetonitrile stacking for on-line sample pre-concentration, and fluorescence detection (FD). CE separations were performed in a fused-silica capillary where the electroosmotic flow was reduced by coating the inner surface using a INST coating solution. The optimised background electrolyte composition was 50 mM chloroacetic acid with addition of 0.5% m/v polyvinylalcohol (pH 2.15) and separation was driven by application of positive voltage + 30 kV. Serum samples (25 µL) treated by the addition of acetonitrile in a ratio of 1:3 v/v were each injected into the capillary at a large volume that corresponded to the length (129 mm) of the sample zone (hydrodynamic pressure impulse 6000 mbars). Acetonitrile stacking is based on the forcing the sample zone out of the capillary with simultaneous application of the separation voltage. Under such conditions, the enhancing factor achieves the value 57 for peak area compared to the small sample injection length (3.2 mm, hydrodynamic pressure impulse 150 mbar.s). A fluorescence detector with a broad excitation filter (240-400 nm) and an emission filter (495 nm) was used for visualisation of the native fluorescence of perampanel. The calibration dependence of the method was linear (in the range of 10-1000 ng mL-1), with adequate accuracy (99.8-103.3 %) and precision (13.1%). LOD and LOQ for perampanel were 2.9 ng mL-1 and 9.5 ng mL-1, respectively. Clinical applicability was validated using serum samples from patients treated with perampanel and the results corresponded with reference LC-MS/MS values. Our method offers a promising alternative for determining serum perampanel with several advantages. In particular, the low quantity of serum (25 µL) required means that testing can be performed on samples obtained for monitoring other antiepileptic medications, and thus reduces the test-burden on paediatric patients.
Subject(s)
Acetonitriles/chemistry , Drug Monitoring/methods , Electrophoresis, Capillary/methods , Pyridones/blood , Anticonvulsants , Calibration , Fluorescence , Humans , Limit of Detection , NitrilesABSTRACT
Synthetic cannabinoid compounds are marketed as "legal" marijuana substitutes, even though little is known about their behavioral effects in relation to their pharmacokinetic profiles. Therefore, in the present study we assessed the behavioral effects of systemic treatment with the two synthetic cannabinoids JWH-073 and JWH-210 and the phytocannabinoid Δ9-THC on locomotor activity, anxiety-like phenotype (in the open field) and sensorimotor gating (measured as prepulse inhibition of the acoustic startle response, PPI), in relation to cannabinoid serum levels. Wistar rats were injected subcutaneously (sc.) with JWH-073 (0.1, 0.5, or 5 mg/kg), JWH-210 (0.1, 0.5, or 5 mg/kg), Δ9-THC (1 or 3 mg/kg) or vehicle (oleum helanti) in a volume of 0.5 ml/kg and tested in the open field and PPI. Although JWH-073, JWH-210, Δ9-THC (and its metabolites) were confirmed in serum, effects on sensorimotor gating were absent, and locomotor activity was only partially affected. Δ9-THC (3 mg/kg) elicited an anxiolytic-like effect as suggested by the increased time spent in the center of the open field (p < 0.05). Our results further support the potential anxiolytic-like effect of pharmacological modulation of the endocannabinoid system.
ABSTRACT
High anion gap metabolic acidosis frequently complicates acute paracetamol overdose and is generally attributed to lactic acidosis or compromised hepatic function. However, metabolic acidosis can also be caused by organic acid 5-oxoproline (pyroglutamic acid). Paracetamol's toxic intermediate, N-acetyl-p-benzoquinoneimine irreversibly binds to glutathione and its depletion leads to subsequent disruption of the gamma glutamyl cycle and an excessive 5-oxoproline generation. This is undoubtedly an underdiagnosed condition because measurement of serum 5-oxoproline level is not readily available. A simple, cost effective, and fast capillary electrophoresis method with diode array detection (DAD) for simultaneous measurement of both paracetamol (acetaminophen) and 5-oxoproline in serum was developed and validated. This method is highly suitable for clinical toxicology laboratory diagnostic, allowing rapid quantification of acidosis inducing organic acid 5-oxoproline present in cases of paracetamol overdose. The calibration dependence of the method was proved to be linear in the range of 1.3-250µgmL-1, with adequate accuracy (96.4-107.8%) and precision (12.3%). LOQ equaled 1.3µgmL-1 for paracetamol and 4.9µgmL-1 for 5-oxoproline.
Subject(s)
Electrophoresis, Capillary , Acetaminophen , Acidosis , Analgesics, Non-Narcotic , Humans , Pyrrolidonecarboxylic AcidABSTRACT
3-Methoxy-phencyclidine (3-MeO-PCP) is a structural derivative of the dissociative hallucinogen phencyclidine (PCP). Although PCP toxicity is well documented, little is known about this new psychoactive substance despite being available on the black market even in central Europe. The objective of this case report is to present clinical and laboratory data of analytically confirmed non-fatal intoxication of two subjects with 3-MeO-PCP. A preliminary assessment of potential metabolites excreted into urine was enabled using the liquid chromatography high resolution mass spectrometric method.
Subject(s)
Hallucinogens/toxicity , Illicit Drugs/toxicity , Phencyclidine/analogs & derivatives , Chromatography, Liquid , Europe , Hallucinogens/urine , Humans , Illicit Drugs/urine , Phencyclidine/toxicity , Phencyclidine/urine , Substance Abuse DetectionABSTRACT
Metabolic and behavioural effects of, and interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are influenced by dose and administration route. Therefore we investigated, in Wistar rats, effects of pulmonary, oral and subcutaneous (sc.) THC, CBD and THC+CBD. Concentrations of THC, its metabolites 11-OH-THC and THC-COOH, and CBD in serum and brain were determined over 24h, locomotor activity (open field) and sensorimotor gating (prepulse inhibition, PPI) were also evaluated. In line with recent knowledge we expected metabolic and behavioural interactions between THC and CBD. While cannabinoid serum and brain levels rapidly peaked and diminished after pulmonary administration, sc. and oral administration produced long-lasting levels of cannabinoids with oral reaching the highest brain levels. Except pulmonary administration, CBD inhibited THC metabolism resulting in higher serum/brain levels of THC. Importantly, following sc. and oral CBD alone treatments, THC was also detected in serum and brain. S.c. cannabinoids caused hypolocomotion, oral treatments containing THC almost complete immobility. In contrast, oral CBD produced mild hyperlocomotion. CBD disrupted, and THC tended to disrupt PPI, however their combination did not. In conclusion, oral administration yielded the most pronounced behavioural effects which corresponded to the highest brain levels of cannabinoids. Even though CBD potently inhibited THC metabolism after oral and sc. administration, unexpectedly it had minimal impact on THC-induced behaviour. Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, if confirmed in humans and given the increasing medical use of CBD-only products, might have important legal and forensic ramifications.
Subject(s)
Brain/metabolism , Cannabidiol/pharmacokinetics , Dronabinol/pharmacokinetics , Exploratory Behavior/drug effects , Prepulse Inhibition/drug effects , Acoustic Stimulation , Administration, Inhalation , Administration, Oral , Analysis of Variance , Animals , Brain/drug effects , Cannabidiol/administration & dosage , Dronabinol/administration & dosage , Drug Administration Routes , Drug Combinations , Gas Chromatography-Mass Spectrometry , Injections, Subcutaneous , Male , Rats , Rats, Wistar , Time Factors , Tissue Distribution/drug effectsABSTRACT
A simple, sensitive and robust method for simultaneous determination of antiepileptic drugs (gabapentin, pregabalin and vigabatrin) in human serum using GC-MS was developed and validated for clinical toxicology purposes. This method employs an emerging class of derivatization agents - alkyl chloroformates allowing the efficient and rapid derivatization of both the amino and carboxylic groups of the tested antiepileptic drugs within seconds. The derivatization protocol was optimized using the Design of Experiment statistical methodology, and the entire sample preparation requires less than 5 min. Linear calibration curves were obtained in the concentration range from 0.5 to 50.0 mg/L, with adequate accuracy (97.9-109.3%) and precision (<12.1%). The method was successfully applied to quantification of selected γ-aminobutyric acid analogs in the serum of patients in both therapeutic and toxic concentration ranges.
Subject(s)
Amines/analysis , Anticonvulsants/analysis , Cyclohexanecarboxylic Acids/analysis , Pregabalin/analysis , Vigabatrin/analysis , gamma-Aminobutyric Acid/analysis , Amines/blood , Anticonvulsants/blood , Calibration , Computer-Aided Design , Cyclohexanecarboxylic Acids/blood , Formates/chemistry , Gabapentin , Gas Chromatography-Mass Spectrometry , Humans , Pregabalin/blood , Vigabatrin/blood , gamma-Aminobutyric Acid/analogs & derivatives , gamma-Aminobutyric Acid/bloodABSTRACT
OBJECTIVES: A simple, cost-effective, and fast gas chromatography method with mass spectrometry detection (GC-MS) for simultaneous measurement of ethylene glycol, 1,2-propylene glycol and glycolic acid was developed and validated for clinical toxicology purposes. DESIGN AND METHODS: Successful derivatization of glycolic acid with isobutyl chloroformate was achieved directly in serum/urine while glycols are simultaneously derivatized by phenylboronic acid. The entire sample preparation procedure is completed within 10 min. RESULTS: The assay was proved to be quadratic in the range of 50 to 5000 mgL(-1) with adequate accuracy (96.3-105.8%) and precision (CV ≤ 8.9%). CONCLUSION: The method was successfully applied to quantify the selected compounds in serum of patients from emergency units and the results correlated well with parallel GC-FID measurements (R(2) 0.9933 for ethylene glycol and 0.9943 for glycolic acid).