CYP2D6 increases toxicity of the designer drug 4-methylthioamphetamine (4-MTA)

4-Methylthioamphetamine (4-MTA) belongs to a group of new amphetamine derivatives that is usually sold as "ecstasy" or "flatliners" on the illicit drug market. Large interindividual differences in 4-MTA mediated toxicity have been reported in humans. Therefore, we tested whether CYP2D6 or its variant alleles as well as CYP3A4 influence the susceptibility to 4-MTA. For this purpose, we used the colony formation assay with Chinese hamster lung fibroblast V79 cells expressing human wild-type CYP2D6 (CYP2D6*1), the low activity alleles CYP2D6*2, CYP2D6*9, as well as human CYP3A4. The obtained results showed that the expression of wild type CYP2D6*1 clearly enhanced the susceptibility to the cytotoxic effects of 4-MTA compared with the parental cells devoid of CYP-dependent enzymatic activity. Toxicity in V79 CYP2D6*1 was also higher compared to the V79 cell lines expressing the low activity alleles CYP2D6*2 and CYP2D6*9. In contrast to CYP2D6, the CYP3A4 isoenzyme did not enhance 4-MTA toxicity. In conclusion, our results suggest that CYP2D6 rapid metabolizers may be more susceptible to 4-MTA toxicity than CYP2D6 poor metabolizers.     

4-MTA: a new synthetic drug on the dance scene

4-MTA (p-methylthioamphetamine) is a new synthetic sulphur derivative of amphetamine that has been associated with six deaths since it was first identified in Europe in 1997. Sold as 'ecstasy' or 'Flatliners', the drug like MDMA is a potent serotonin releaser. Using a self-nominated sampling methodology we accessed over 1000 dance drug users through a magazine survey. Ten percent of respondents thought that they had used 4-MTA. Those with experience of 4-MTA tended to come from a sub-population of heavy 'ecstasy'-users. Responses to the effects of the drug were mixed, although about a quarter of those who believed that they had tried 4-MTA thought that they would use it again.     

Fatal poisoning with verapamil

The toxicologic findings in a case of fatal poisoning with verapamil (Isoptin^®) are presented. For isolation of verapamil the biologic material was subjected to protein precipitation. The aqueous solutions were acidified with hydrochloric acid, prepurified by extraction with ether, and subsequently the basic drug verapamil was isolated by ion pair extraction with chloroform. Quantitative determination of verapamil was carried out by gas chromatography using a nitrogen specific flame ionization detector. The following concentrations of verapamil were measured: liver 5500 ng/g, kidney 2000 ng/g, blood 590 ng/g, urine 250 ng/g, gastric contents 3 mg (total). During examination by the police it was claimed by a witness that two tablets of Isoptin^® had been taken before death.After application of a therapeutic dose of Isoptin^® peak concentrations of 11 and 30 ng/g of blood cells and of 30 and 65 ng/g of plasma were measured in two healthy subjects; the latter figures corresponded well to previous findings of other authors, who investigated plasma concentrations of verapamil after therapeutic administration. In the case presented here, the blood concentration of 590 ng/g clearly demonstrated that an extreme overdose must have been taken before death.

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Zusammenfassung Es werden die Ergebnisse der toxikologischen Untersuchung bei einer tödlichen Vergiftung mit Verapamil (Isoptin^®) dargestellt. Die biologischen Materialien wurden wie folgt aufgearbeitet: Nach Eiweißfällung wurden die wäßrigen Lösungen mit Salzsäure angesäuert und durch Ätherextraktion vorgereinigt. Anschließend wurde das basische Verapamil durch Ionenpaarextraktion mit Chloroform isoliert. Die quantitative Bestimmung erfolgte durch Gaschromatographie mit Hilfe eines Stickstoff-spezifischen Flammenionisationsdetektors. Folgende Konzentrationen an Verapamil wurden bestimmt: Leber 5500 ng/g, Niere 2000 ng/g, Blut 590 ng/g, Urin 250 ng/g, Mageninhalt 3 mg (gesamt).Während der polizeilichen Vernehmung sagte ein Zeuge aus, daß vor dem Tod zwei Tabletten Isoptin eingenommen wurden.Nach Gabe einer therapeutischen Dosis Isoptin^® fanden sich bei zwei gesunden Versuchspersonen Maximalkonzentrationen von 11 und 30 ng/g Blutzellen und von 30 und 65 ng/g Blutplasma; die letzteren Zahlen stimmen gut überein mit Versuchsergebnissen anderer Autoren über die Plasmaspiegel nach therapeutischer Verapamilgabe. Die Blutkonzentration von 590 ng/g im vorliegenden Fall zeigt dagegen eindeutig, daß vor dem Tod Verapamil in extremer Überdosierung zur Anwendung gelangt sein muß.

     

Fatal poisoning with selenium dioxide

Two hours after suicidal ingestion of an unknown amount of selenium dioxide, a 17-year-old male was admitted to hospital with asystolia and apnea. Attempts at resuscitation failed and the patient was pronounced dead. Findings at autopsy included congestion of lungs and kidneys, diffuse swelling of the heart, and brain edema. The most impressive finding was an orange-brown discoloration of the skin and all viscera, probably due to hemolysis and/or pigmentation related to ingestion of selenium dioxide. Selenium blood and tissue levels were increased by a factor of 100-1000 as compared to normal. The highest concentrations were found in pancreas, spleen, liver, and adipose tissue. For elucidation of the chemical nature of selenium in tissues, a new analytical method which was based on carbon disulfide extraction was developed. Carbon disulfide is a good solvent for non-polar selenium compounds like elemental selenium and selenium disulfide, but not for polar compounds like selenite and selenoproteins. A major fraction of selenium in tissues was extractable by carbon disulfide, which seems to indicate the presence of elemental selenium and/or selenium disulfide. The color of these substances is red and orange, respectively. This might explain at least part of the discoloration of skin and tissues. In vitro experiments suggested that trace amounts of hydrogen selenide, which is an intermediate of selenite metabolism, probably induced hemolysis. For evaluation of the therapeutic value of hemoperfusion in selenium poisoning in vitro hemoperfusion experiments were performed, which revealed only a moderate effect on selenium blood levels.     

Fatal yew (Taxus sp) poisoning in Willamette Valley, Oregon, horses

Despite the well-founded reputation of plants of the genus Taxus as being amongst the most toxic plants for domestic livestock in the US, there are surprisingly few published case reports of yew poisoning in horses. This report documents 2 acute fatalities in horses in the central Willamette Valley, OR associated with the consumption of Taxus sp. The predominant features of the intoxication were peracute death, with no signs of struggling or convulsions, in otherwise fit and well managed adult horses. The most significant gross necropsy findings were limited to pulmonary congestion and hemorrhage, suggestive of acute circulatory disturbance. A diagnosis of Taxus sp poisoning was confirmed on the basis of a history of potential exposure, by the identification of yew leaves in the gastric contents of the horses, and by the subsequent identification of yew clippings in the pasture. The literature relevant to Taxus sp poisoning in horses is reviewed.     

Fatal overdosage with nefopam (Acupan)

This paper presents a fatality due to massive, intravenous self-administration of nefopam (Acupan), a non-opiate central analgesic, in a 37-year-old female. Nefopam was measured in various postmortem samples by means of high-pressure liquid chromatography coupled to mass spectrometry via an ionspray interface. Heart blood concentration was 4.38 microg/mL and exceeded by approximately 30 times the highest therapeutic levels with the usual reservations concerning possible postmortem redistribution. This is only the third case of death following nefopam overdose reported in the literature.     

Fatal poisoning by Rumex crispus (curled dock): pathological findings and application of scanning electron microscopy

A case of fatal poisoning due to ingestion of the plant Rumex crispus (curled dock) is described. The patient, a 53-year-old male, presented with gastrointestinal symptoms, severe hypocalcemia, metabolic acidosis and acute hepatic insufficiency. Despite therapeutic measures, the patient died 72 h after ingestion of the plant material. Noteworthy among the pathological findings were centrolobular hepatic necrosis and birefringent crystals in the liver and kidneys that were identified by histochemical techniques and scanning electron microscopy. These observations are compared with other reports in the medical literature, with an emphasis on the risk involved in the use of these plants for culinary or medicinal purposes.     

Fatal methadone poisoning in children: Maryland 1992-1996

The prevention of accidental poisoning by prescribed an over-the-counter medication has been successfully addressed by the use of child-resistant containers. Nevertheless. accidental methadone poisoning in children remains a problem. The Office of the Chief Medical Examiner for the State of Maryland has investigated four deaths in children due to methadone poisoning over a 4-year period. Three of the cases occurred within a 3-month period. Two victims accidentally ingested methadone within 3 days of each other. The authors address the continuing danger of methadone poisoning to children and identify factors contributing to this problem.