[Intoxication with a tricyclic antidepressant]. / Intoxikation mit einem trizyklischen Antidepressivum.

A 48-year-old woman with a major depression and treatment with doxepin was found comatose in her flat. Her son last saw her 48 h prior to being found. On arrival of the emergency physician, she presented a generalized seizure. The patient underwent endotracheal intubation and mechanical ventilation due to respiratory insufficiency and severe cyanosis. Empty packages of tablets (doxepin ca. 4000 mg and zolpidem 100 mg) were found in the flat. On hospital admission the doxepin blood concentration was 1.2 microg/ml. No life-threatening arrhythmia occurred at any time. On the advice of the poison information center, hemoperfusion was performed for extracorporeal elimination. Within several hours the doxepin blood concentration could be lowered to 0.8 microg/ml and although still above the therapeutic range the patient was extubated. However, the patient developed a generalized seizure which required re-intubation. As a consequence of the high distribution volume and re-distribution phenomena, the doxepin blood concentration had increased again to 1.2 microg/ml. Approximately 72 h later she was extubated again while the doxepin blood concentration was 0.9 microg/ml and 3 days later, the doxepin blood concentration was lowered to 0.3 microg/ml and the patient was transferred to the psychiatric ward the following day. This case report questions the efficacy of hemoperfusion during acute doxepin intoxication in the given constellation of a non-life-threatening arrhythmia.

Interactions of melatonin with the liver microsomal cytochrome P450 system of rats and humans in vitro and effects on the P450 system and the antioxidative status in rat liver after acute treatment.

In vitro melatonin binds to human and rat liver microsomal cytochrome P-450 (P450) according to a type II substrate. The affinity is similar to that of aniline with a general left-shift. Melatonin interferes with model monooxygenase reactions indicative of different P450 forms in humans and rats (in humans according to the lower specific P450 content less pronounced): the strongest inhibition was found for ethoxyresorufin O-deethylation, indicating the binding to P450 1A, the binding to P450 2B (ethoxycoumarin O-deethylation) was less pronounced, the least inhibition was found for P450 3A (ethylmorphine N-demethylation) reaction. The oxidase function was also inhibited: luminol amplified chemiluminescence was more inhibited than the lucigenin amplified one, hydrogen peroxide formation was inhibited at concentrations higher than 10(-4) M, microsomal NADPH/Fe stimulated lipid peroxidation was inhibited at concentrations higher than 10(5) M. In vivo melatonin prolonged hexobarbital sleeping time in rats in a dose dependent manner (ip. co-administration of 1, 5 and 20 mg/kg b.w. melatonin with 100 mg/kg hexobarbital). Immediately after awakening the animals were sacrificed: a small increase in P450 concentrations cannot be explained, no changes in P450 monooxygenase or oxidase activities nor in microsomal lipid peroxidation or GSH status could be observed.

Effect of ketamine on the neuromagnetic mismatch field in healthy humans.

Mismatch negativity (MMN) is a component of the auditory evoked event-related potentials (ERP) that assesses automatic sound change detection and is disturbed in schizophrenic patients. Animal experimental evidence has linked the generation of MMN to the N-methyl-D-aspartate (NMDA) receptor. We investigated the neuromagnetic mismatch field (MMF) in healthy volunteers before and after intravenous application of a subanesthetic dose of the NMDA receptor antagonist ketamine (0.3 mg/kg). Ketamine had a significant influence on latency and dipole moment of the MMF, whereas the N100m latency of the standard tone was not prolonged and its dipole moment remained stable. Our results suggest that ketamine interferes with aspects of preattentive information processing and is in line with the view that disturbed NMDA receptor function may mediate the deficient auditory mismatch response in patients with schizophrenia.

Cytochrome P450 (P450) isoforms expression, P450 concentration, monooxygenase activities, reactive oxygen species formation, lipid peroxidation, and glutathione content in wild catch carp and tench liver--influence of a two weeks exposure to phenobarbital.

Carps, both sexes, 3 years old, weighing about 1 kg, and tenches of both sexes, 6 years old, weight about 250 g, were caught from a Thuringian lake without industrial pollution in November 1995 (fish without food uptake, water temperature at about 10 degrees C) and kept for 2 weeks in basins with clean water and addition of 0, 0.1, 1.0 or 10.0 mg/l phenobarbital-Na (PB). The concentration of PB was controlled during and at the end of the exposure period. The animals were fed pellets, but no food uptake was observed. After 24-48 h in fresh water the fish were sacrificed and the following hepatic parameters were immediately determined biochemically: monooxygenase functions: cytochrome P450 (P450) content, ethylmorphine N-demethylation (EN), ethoxycoumarin O-deethylation (ECOD), ethoxyresorufin O-deethylation (EROD), 7-benzyloxy-4-methyl-coumarin O-debenzylation (BCDB); oxidase function indicators: microsomal Fe2+/NADPH dependent hydrogen peroxide formation (H2O2), microsomal Fe2+/NADPH dependent luminol and lucigenin amplified chemiluminescence (LMCL, LCCL), microsomal Fe2+/NADPH dependent lipid peroxide formation (LPO); oxidative state: lipid peroxidation products (TBARS) and GSH and GSSG. Additionally, the expression of three P450 isoforms, 1A1, 2B and 3A, was assessed immunohistochemically in tissue samples from brain, gill, heart, spleen, liver, gut and ovary of both fish species and in kidney of tenches. PB did not influence body or liver weights, but increased liver P450 concentration in both species by 50-100%, though not significantly. Carp: PB increased both EN and EROD significantly, but not ECOD and BCDB; H2O2 and TBARS were enhanced significantly. LPO, LMCL and LCCL were not significantly influenced. Tench: PB increased all monooxygenase reactions (EN, ECOD, BCDB and EROD), though only significantly ECOD; H2O2 was elevated only after treatment with 0.1 mg/l PB, whereas LPO was decreased (!) after treatment by all three concentrations, though significantly only after 1.0 mg/l PB. LMCL was depressed (not significantly), but LCCL increased 5fold. TBARS were significantly enhanced. P450 1A1 subtype expression was concentration dependently elevated by PB in gill and liver of both fish and in the heart and kidney of tenches, P450 2B and 3A isoforms expression was induced in brain, gill, heart, liver and gut of both fish and in the kidney of tenches. In summary, the increased activities of the monooxygenase reactions tested and the elevated expression of all three P450 isoforms investigated in certain tissues indicate an induction of the P450 families 1, 2 and 3 by PB in fish.

Fatal poisoning with detajmium: identification of detajmium and its metabolites and artifacts by gas chromatography-mass spectrometry and quantification by high-performance liquid chromatography.

After ingestion of an unknown dose of detajmium, a 14-year-old female collapsed with asystolia. Resuscitation efforts were not successful. A medicolegal autopsy was carried out, and blood, liver and gastric content were extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). After derivatization with acetic anhydride, detajmium and twelve of its derivatives and metabolites were identified. The main metabolic pathways include hydroxylation and subsequent O-methylation of the indol ring, and oxidation as well as reduction of the C-21 hydroxyl function. Cleavage of the N-alkyl side-chain is a further, possibly non-enzymatic degradation pathway. Artifact formation induced by acetylation included dehydratation of the hydroxyl function of C-21 and the N-alkyl side-chain. The detajmium concentration in blood of the decreased was determined by high-performance liquid chromatography with fluorimetric detection (12 micrograms/ml).

[In vitro studies of the adsorption behavior of Wofatit Y 88 in relation to various drugs]. / In-vitro-Untersuchungen zum Adsorptionsverhalten von Wofatit Y 88 gegenüber verschiedenen Arzneimitteln.

The adsorber Wofatit Y 88 (VEB Chemiekombinat Bitterfeld) was tested regarding its adsorption properties in comparison with Hämoresin (B. Braun, Melsungen, FRG) Hemosorbent SKN-2K (USSR) and the own product Wofatit UH 91. As adsorptives the hypnotics Metaqualon, Pyrithyldion, Crotylbarbital and Phenobarbital were used. The investigation have been performed in a single-pass system in a relation of 1:25 to the clinical practice conditions. The concentration measurements to the estimation of adsorbed amounts were made by UV-VIS spectrometry. It was found that Wofatit Y 88 is superior to Hämoresin with regard to adsorbed amounts and adsorption speed. For all drugs Wofatit Y 88 was superior to UH 91.

[In vitro studies on the adsorption of various resins of the Wofatit type for drugs]. / In vitro-Untersuchungen zur Adsorption verschiedener Harze vom Typ Wofatit für Arzneimittel.

The capacities of the resins Wofatit Y 29, Y 55 and Y 56 (VEB Chemiekombinat Bitterfeld) to adsorb various medicaments were compared with that of the resin XAD-4. Methaquelone, diazepam, krotylbarbital, promazine phosphate and ethyloxamine were used as test substances. The resin Y 56 proved to have an adsorption capacity similar to that of XAD-4 (e.g. maximum saturation for methaquelone 98%, half-maximum saturation at 7 minutes). In further tests on various batches of this resin the best results were given by the resin Y 56/7. Adsorption was quite clearly shown to be dependent on concentration. At a blood-flow of 100 ml/min clearance values of 34.5 ml/min for krotylbarbitol and 22.1 ml/min for methaquelone were calculated. According to these findings the resin Y 56/7 is suitable for further testing in a haemoperfusion system with a view to clinical use.

[Detoxication by hemoperfusion]. / Detoxikation mittels Hämoperfusion.

In 13 patients (2 males, 11 females, 15-70 years of age) on account of severe intoxications with hypnotics sedatives, psychopharmaca, in most cases mixed intoxications, with propranolol and halogenized hydrocarbons a 4--8-hour haemoperfusion treatment with amberlite XAD-4-Resin was performed. 11 patients survived, 1 patient died in irreversible cardiogenic shock of a propranolol intoxication, another patient of the sequels of a crotylbarbital and methaqualone intoxication. The curves of the course of the blood concentration of the individual substances showed a good elimination for phenobarbital and crotylbarbital, methaqualone, meprobamat and didropyridine as well as trichlorethylene, a less good elimination for nitrazepam, propranolol and tetrachlorethylene, Altogether the effectiveness of the detoxication clearly higher in the time unit, compared with the dialysis.

Dialysability of benzodiazepines by haemodialysis and controlled sequential ultrafiltration (CSU) in vitro.

The efficacy of haemodialysis and controlled sequential ultrafiltration (CSU) for the elimination of three hypnotic and 6 benzodiazepine drugs was compared in vitro. In comparison to haemodialysis the efficacy of ultrafiltration by CSU was poor, as the mean per cent of CSU/haemodialysis (mg/hr) for 5 benzodiazepines was only 0.6-4.0% and for three hypnotics, phenobarbital 3.4%, pyrithyldione 8.2% and glutethimide 2.5% of the haemodialysis values. In haemodialysis in vitro phenobarbital, pyrithyldione, glutethimide and chlordiazepoxide were significantly and markedly more dialysable than 5 other benzodiazepines. The mean clearance of six benzodiazepine derivatives was about 2 to 3 times higher at blood flow rates of 200 ml/min. than 100 ml/min. In CSU experiments in vitro it was possible to remove approximately (as the mean percent of the initial dose) only the amount of five benzodiazepines corresponding to the per cent of the protein unbound fraction in the plasma (correlation r = 0.975, P less than 0.01). Only low amounts of three hypnotics, especially glutethimide, were removed by CSU in vitro.

Comparative in vitro investigations on the dialysability of hypnotic and psychotropic drugs by hemodialysis and controlled sequential ultradiffusion.

The efficiency of hemodialysis and controlled sequential ultradiffusion (CSU) for the elimination of toxic drug concentrations was tested by in vitro-investigations. In the 6 benzodiazepin derivatives tested, the clearance is markedly higher at a blood flow of 200 ml/min than at 100 ml/min. Pyrithyldione, glutethimide and phenobarbital are better dialysed than the benzodiazepines with exception of chlordiazepoxide. In comparison with hemodialysis, hemofiltration by means of CSU was less effective because of the small amount of ultrafiltrate obtained.