Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect.

BACKGROUND: Theta cordance is a novel quantitative electroencephalography (QEEG) measure that correlates with cerebral perfusion. A series of clinical studies has demonstrated that the prefrontal theta cordance value decreases after 1 week of treatment in responders to antidepressants and that this effect precedes clinical improvement. Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, has a unique rapid antidepressant effect but its influence on theta cordance is unknown. METHOD: In a double-blind, cross-over, placebo-controlled experiment we studied the acute effect of ketamine (0.54 mg/kg within 30 min) on theta cordance in a group of 20 healthy volunteers. RESULTS: Ketamine infusion induced a decrease in prefrontal theta cordance and an increase in the central region theta cordance after 10 and 30 min. The change in prefrontal theta cordance correlated with ketamine and norketamine blood levels after 10 min of ketamine infusion. CONCLUSIONS: Our data indicate that ketamine infusion immediately induces changes similar to those that monoamineric-based antidepressants induce gradually. The reduction in theta cordance could be a marker and a predictor of the fast-acting antidepressant effect of ketamine, a hypothesis that could be tested in depressive patients treated with ketamine.

Individual prolactin reactivity modulates response of nucleus accumbens to erotic stimuli during acute cannabis intoxication: an fMRI pilot study.

RATIONALE: Self-report studies indicate that cannabis could increase sexual desire in some users. We hypothesized that intoxication increases activation of brain areas responsive to visual erotica, which could be useful in the treatment of hypoactive sexual desire disorder, a condition marked by a lack of sexual desire. OBJECTIVES: The aim of this study is to assess the aphrodisiacal properties of cannabis. METHODS: We conducted an open-randomized study with 21 heterosexual casual cannabis users. A 3T MRI was used to measure brain activation in response to erotic pictures. Blood samples were collected to determine the serum levels of cannabinoids, cortisol and prolactin. Participants were grouped according to whether they had ever experienced any aphrodisiacal effects during intoxication (Group A) or not (Group non-A). RESULTS: Intoxication was found to significantly increase activation in the right nucleus accumbens in the Group A while significantly decreasing activation in the Group non-A. There was also a significant interaction between the group and intoxication, with elevated prolactin in the Group non-A during intoxication. No intoxication-related differences in subjective picture evaluations were found. CONCLUSION: Cannabis intoxication increases activation of the right nucleus accumbens to erotic stimuli. This effect is limited to users whose prolactin is not elevated in response to intoxication. This effect may be useful in the treatment of low sexual desire.

[Screening and identification of stimulant and psychedelic drugs as acetyl-derivatives by GC-MS]. / Záchyt a identifikace budivých a psychedelických bází ve forme acetylderivátu pomocí GC-MS.

With the increasing number of abused stimulant and psychedelic drugs, along with so called "dance drugs" and "new synthetic drugs" available on the Czech illegal market, there is a need to update methods in toxicological laboratories and therefore it is necessary to develop and optimalize screening and identification procedures for new toxic substances appearing in the laboratory practice. It is well known that relatively popular commercial screening immunoassays have some limits: for instance restricted amount of detectable substances, specificity and sensitivity of detection. Therefore, it is mandatory to combine or complete them with more specific methods based on a different principle. In this paper we have focused on collecting useful analytical data to introduce or complete the system of detection and identification of unknown drugs and their metabolites which can appear in biological samples by using gas chromatography-mass spectrometry (GC-MS) after preparation of relevant acetylated derivatives. The collection of experimental data involves retention indexes and mass spectra of acetylated phenylalkylamines, tryptamines and piperazines and some of their metabolites. These data are fundamental for laboratory diagnostics of drugs of abuse or intoxication and they can be useful for practical application in a number of toxicological laboratories. The mean limit of detection 0.1 ng analyte injected to GC-MS is low enough to allow the method to be successfully applied to real toxicological samples.

[Gamma-hydroxybutyrate (GHB) misuse or abuse and interpretation of toxicological findings]. / Zneuzití a abúzus gama-hydroxybutyrátu (GHB) a interpretace toxikologických nálezu.

Gamma-hydroxybutyrate (GHB) Misuse or Abuse and Interpretation of Toxicological Findings The paper presented is a review of important information on gamma-hydroxybutyrate abuse or misuse, its toxicological findings under various circumstances, endogenous concentrations and potentional neoformation, with stressing the difficulties of interpretation which shall be done very carefully.

Hair analysis for opiates: evaluation of washing and incubation procedures.

Hair analysis of drugs of abuse has been a subject of interest from a clinical, social and forensic perspective for years because of the broad time detection window after intake in comparison to urine or blood. However, the correct and reliable interpretation of opiates findings in an authentic hair sample requires optimalisation and standardisation of decontamination and incubation procedures. Comparing various published methods, we have found some variability in them and no unequivocal recommended procedure for starting with a method directly. Therefore, various combinations of solvents, of various polarity, as washing solvents were tested for removing opiates from the external surface of real hair samples. The yields of opiates from these washings were compared with the yields from the interior of the hair matrix after digestion with various procedures. The opiates after digestion were cleaned up from resulting solution on extraction columns with mixed solid-phase and analysed by GC-MS in standard EI mode after silylation. The efficiencies of neutral (Söerensen buffer, pH 7.4), acid (0.1 M HCl) and basic (1 M NaOH) digestion of the hair matrix were evaluated and the relative recoveries for morphine, codeine, dihydrocodeine and hydrocodone were compared. As it is very problematic to imitate the reference hair sample with a specific amount of analytes incorporated inside, which can be used for calibration to get a close estimate of the quantities of analytes inside the solid authentic sample, the total digestion of a hair sample in basic medium was considered to be a very important reference basis for quantitative determinations. The ratios of hydrolysis of labile 6-acetylmorphine or acetylcodeine were tested and evaluated in practical routine conditions of acid or neutral digestion of hair. Comparing the three methods of incubation of authentic hair samples, the methods using 1 M NaOH or 0.1 M HCl yielded higher recoveries of total equivalents of morphine or codeine, whereas the incubation in Söerensen buffer allowed the reflection of real ratios of labile metabolites and/or parent compounds in an original sample. This method has been shown to be capable of detecting hydrocodone in hair with other opiates concomitantly and to indicate the drug abuse pattern of a person at various time intervals in the past.

Plasma levels of dosulepine and heart electric field.

Antidepressants, particularly tricyclic (TCA) antidepressants, may have cardiotoxic effects, such as cardiac arrhythmias, especially in patients with cardiovascular diseases. For most of TCA, no exact correlation between dosage, plasma levels and changes of ECG parameters of standard ECG has been found. So far, no relationship between dosulepine plasma levels and heart electric field parameters has been studied. We selected 18 female outpatient subjects diagnosed with recurrent depressive disorders, currently in the remission phase (HAMD < 10), without any cardiovascular disease. Patients were treated with daily dosulepine doses of 25-125 mg for 4-8 weeks. 30 heart electric field parameters were analyzed by Cardiag 128.1 diagnostic system as part of BSPM (Body Surface Potential Mapping). Acquired data were correlated with dosulepine plasma levels by means of Spearman's rank order correlation test. Four ECG parameters showed a significant correlation with dosulepine plasma levels: QRS axis deviation in frontal plane (p=0.01), DIAM 40 max (p<0.05), QRS-STT angle in transversal and left sagittal plane (p<0.05). The demonstrated changes confirmed dosulepine influence on the early myocardium depolarization phase and the correlation of this effect with dosulepine dose (its plasma concentration). The higher the dosulepine level, the more marked are the changes of the QRS-STT angle in transversal and sagittal planes and the changes in the QRS axis deviation in frontal plane. Repeatedly recorded changes in the heart electric field were dosulepine-specific and dependent on its plasma levels.

Fatal opiates overdose. Toxicological identification of various metabolites in a blood sample by GC-MS after silylation.

A fatal opiates overdose, where ethylmorphine, hydrocodone, dihydrocodeine and codeine were consumed concomitantly, is reported. This case report may contribute to data on fatal blood concentrations of drugs with rare incidence. The relative retention times in capillary gas chromatography and full mass spectra of various opiates in their silylated forms, detected together in one sample, may serve as a helpful analytical reference for clinical and forensic toxicologists.

Chlorinated phenols as metabolites of lindane. Evaluation of the degree of conjugation in rat urine.

After lindane was administered to rats in a single oral dose, the time profile of the degree of conjugation of the main phenolic metabolites was evaluated. In all urine samples 2,3-dichlorophenol, 2,4,5- and 2,4,6-trichlorophenol, and 2,3,5,6-tetrachlorophenol were constantly present. 2,3,5,6-Tetrachlorophenol and then 2,4,6-trichlorophenol were the prevalent metabolites in all cases. The degree of conjugation did not correlate with the dissociation constant of individual chlorinated phenols. Phenol conjugation declined with time after administration.

[The sorption effectiveness of Czech-manufactured hemoperfusion sorbents for amatoxins]. / Sorpcní úcinnost ceských hemoperfuzních sorbentu pro amatoxiny.

BACKGROUND: Haemoperfusion was introduced in the treatment of intoxications with Amanita phalloides in 1974. Haemoperfusion over active charcoal is used most frequently. The objective of the present study was to compare the sorption capacity of Czech haemoperfusion sorbents of the charcoal and resin type for amatoxins extracted from dried Amanita phalloides. METHODS AND RESULTS: Haemoperfusion sorbents on the basis of charcoal-Chemviron SC XII and on the basis of synthetic resin--Amberlite XAD 2 were used in experiments in vitro. Recirculation of an aqueous extract of Amanita phalloides over a haemoperfusion column with a volume of 400 ml located in a closed system took 4 hours. Amanitin levels (alpha and beta) were assessed by HPLC. Two-hour perfusion over Amberlite XAD led to removal of the entire amount of both amanitins from the aqueous solution. Four-hour perfusion over charcoal, however, reduced the original alpha amanitin level by 24% (p < 0.05) and of beta amanitin by 8% (change not significant). Extraction of alpha and beta amanitin by the resin sorbent varied between 0.95-1.00. The type of charcoal used, produced from the shells of coconuts, had a low extraction activity, cca 12%. CONCLUSIONS: The assembled results provide evidence that the synthetic resin Amberlite XAD 2 has a more than ten times greater sorption capacity, as compared with charcoal (Chemviron SC XII) and that in experiments in vitro it removes rapidly and effectively alpha and beta amanitin from an aqueous solution. Although during sorption of mycotoxins from plasma or blood the sorption rate and total capacity declines amberlite resins (Czech haemoperfusion column Hemabsorb A2) can be recommended for use in clinical toxicology.

[Trends in toxicologic examinations in clinical practice]. / Vývojové trendy toxikologických vysetrení v praxi.

Review presented on the occasion of the significant life jubilee of Prof. J. Tesar, MD, DrSc., 16.12.2002 in the Medical House in Prague deals with the development and application of analytical technologies in toxicological practice in the last fifty years, with demands on decreasing the size of biological samples, detection limits achievable, with possibilities of interpretation deduced from analyses of alternative matrices. The paper also informs about scientific guidelines applied in Europe with attention focused on the reliable detection of illicit drugs in the workplace or drugs and driving. Based on more advanced analytical strategy, more complete and more precise information can be achieved and consequently more perfect interpretation based on objective evidence can be gained and it can comply to "Evidence Based Forensic Toxicology".

[Pitfalls in the interpretation of toxicologic analysis of psychoactive substances]. / Mozná úskalí interpretace analyticko-toxikologických nálezu psychoaktivních látek.

Toxicological examination of biological samples of a certain case is a complex task which demands knowledge not only of modern analytical methods but also of the fate and effects of xenobiotics in organism. The evidence of unknown drugs and poisons in biological material is a difficult matter due to the broad variety of harmful substances and their unlimited possible mixtures, due to variable concentrations in a broad unpredictable range. In toxicology, there is the important question of the completeness of evidence and correctness of chemical identification of individual substances. Generally, the validation of qualitative methods is less developed than the validation of quantitative methods. The evidence of unknown harmful substances in biological samples requires often the individual consideration about optimal attitude to a nonstandard toxicological case and prevent from application of uniform procedures in fixed combinations.

[Detection of the metabolite of delta-9-tetrahydrocannabinol in urine by means of GC/MS and interpretation of analytical findings]. / Prukaz metabolitu delta-9-tetrahydrocannabinolu v moei pomocí GC/MS a interpretace analytického nálezu.

Delta-9-tetrahydrocannabinol is one of many components of plants of Cannabis. In the human body it is susceptible to oxidation and its metabolites together with metabolites of other cannabinoids are excreted into urine and faeces. In this paper there is described our experience with the specific confirmation of the metabolite of the main psychoactive substance, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, using gas chromatography with mass spectrometry after urine alkaline hydrolisis, solid phase extraction and silylation. The preliminary immunochemical screening of cannabinoids in urine is performed by EMIT method.

[Evaluation of methods of trace analysis of various opiates including hydrocodone and hydromorphone in the blood and urine using gas chromatography-mass spectrometry]. / Zhodnocení metod stopové analýzy ruzných opiátu vcetne hydrokodonu a hydromorfonu v krvi a v moci pomocí GC-MS.

A GC-MS method suitable to conduct practical trace toxicological analyses of various opiates including hydrocodone or hydromorphone is presented both in scan and selected ion monitoring modes. Silylation can be a convenient reaction to derivatize unknown analytes in toxicological samples. However, silylation of drugs with tautomeric keto/enol groups in molecular structure can cause analytical problems due to poor reproducibility of conversion degree. After using N-Methyl-N-trimethyl-silyltrifluoracetamide (MSTFA) acceptable results were achieved.

[Sensitivity of GC-MS in the detection of benzodiazepines in the urine in the form of trimethylsilyl derivatives]. / Citlivý GC-MS prukaz benzodiazepinu v moci ve forme jejich trimethylsilylderivátu.

A sensitive evidence of trace concentrations of benzodiazepines and their metabolites in urine can be enabled after special sample preparation including enzymatic hydrolysis, special solid phase extraction, silylation and following analysis by gas chromatography with mass spectrometry in electron impact mode. After optimalization of the procedure the extraction recovery values in the range 50-85% are achieved. The scale of retention times with basic mass spectral data are presented for the spectrum of silylated benzodiazepines which can overlap some gaps in the standard toxicological literature up to now available.

[Contribution to the kinetics of ethanol absorption and elimination in the presence of hydrocarbons (n-hexane) in the rat]. / Prispevek ke kinetice vstrebávání a eliminace ethanolu za prítomnosti uhlovodíku (n-héxanu) v krysím organismu.

Increased ethanol blood level follows the administering of ethanol mixed with single hydrocarbons in a similar way as after cannulation of ethanol with benzol Ethanol blood level changes are stipulated by hydrocarbons, reducing benzol compounds are not decisive for increasing influence. Kinetic relations indicate that resorption speed is not influenced substantially. Increased ethanol blood level in rat seems to be caused by restricted elimination.

[Affecting the levels of ethanol by administering gasoline with ethanol]. / Ovlivnení hladiny etanolu podáním benzínu vedle etanolu.

Administering of benzene alone into rat stomach through a tube does not increase the amount of reducing compounds in blood above the physiological level and does not influence the Widmark test in spite of the fact that benzene in blood in vitro produces reducing compounds. The administration of benzene alone to rats is not sufficient for any conspicuous reducing compounds in blood above the level corresponding to the administration of ethanol alone. This elevation is due to the increased ethanol serum level according to the result of gas chromatography. Benzene components may influence ethanol resorption, metabolism and elimination. The administration of benzene alone to rats is not sufficient for any conspicuous blood level of reducing compounds. Findings in rats represent a first stage information which may be important for forensic medical expertise.

[A sensitive method for detection of sympathomimetic amines in pentafluorobenzamide form in biological samples using gas chromatography]. / Citlivý prukaz sympatomimetických aminu v biologických vzorcích ve forme pentafluorobenzamidu pomocí plynové chromatografie.

A toxicological method of sensitive and specific confirmation of methamphetamine and other primary and secondary amines in biological samples after extractive perfluorobenzoylation is described. The method is based on the principle of gas chromatography with parallel specific nitrogen detection and electron capture detection. The other alternative is the gas chromatography combined with mass spectrometry in chemical ionization mode. The method described allows the detection of methamphetamine and amphetamine in urine in concentrations below 10 ng/ml.

[Is absorption hemoperfusion effective in the treatment of baclofen poisoning?]. / Je sorpcní hemoperfúze úcinná pri lécení otravy baclofenem?

By six-hour sorption haemoperfusion over active charcoal in a 33-year-old woman intoxicated with baclofen (Baclofen Polfa) the initial plasma concentration was reduced by 87%, while from the blood only 3% of the ingested dose were removed. Therefore the capacity of baclofen elimination was tested by perfusion and dialysis in vitro. Two-hour dialysis with the Czechoslovak haemodialyzer Chiraplat was equally effective for removal of baclofen from an aqueous solution (21.2 mg) as four-hour perfusion over active charcoal and resin--Czechoslovak haemoperfusion columns Hemasorb 800 C (19.4 mg) and Hemasorb 800 A-4 (18.9 mg). Because during the first 30 minutes of perfusion the resin sorbent has a double extraction, as compared with dialysis, it is better to use in serious intoxication haemodialysis and haemoperfusion concurrently.