An oxcarbazepine-related fatality with an overview of 26 oxcarbazepine postmortem cases

We present an oxcarbazepine-related fatality together with an overview of 26 postmortem cases involving oxcarbazepine observed during the period 2001-2006. The fatality case concerned a 27-year-old woman with epilepsy, who was found dead in her bed. Oxcarbazepine and its active metabolite, 10-hydroxycarbazepine, were the only compounds detected. The concentrations of oxcarbazepine were as follows: femoral blood, 2.9mg/kg; muscle, 1.8mg/kg; liver, 0.9mg/kg; gastric content (300ml), 860mg/kg; and vitreous humour, not detected. The concentrations of 10-hydroxycarbazepine were as follows: femoral blood, 66mg/kg; muscle, 40mg/kg; liver, 62mg/kg; gastric content, 27mg/kg; and vitreous humour, 25mg/kg. The analyses were performed by HPLC-DAD after liquid-liquid extraction. Oxcarbazepine intoxication was regarded as a possible cause of death. For the other 26 cases, the 10-hydroxycarbazepine concentrations ranged from 2.2 to 48mg/kg with a median of 25mg/kg.     

鲤醇硫酸酯钠急性中毒的实验病理研究

鲤醇硫酸酯钠（纯度99．2％），给小鼠腹腔注射，测得LD50为115．15mg／kg。40只小鼠随机分为4组，三个实验组分别以1．5LD50、1．0LD50和0．5LD50剂量腹腔注射染毒。结果表明，实验鼠肾小管上皮变性坏死；心肌细胞水变性，可见多发性肌溶灶；肝有单细胞性坏死。与草鱼胆汁中毒的病变基本相似。提示鲤醇硫酸酯钠是草鱼胆汁的主要毒性成分，主要损害肾，心肌，肝等脏器。     

Two tricyclic antidepressant poisonings: levels of amitriptyline, nortriptyline and desipramine in post-mortem biological samples

Two deaths due to amitriptyline and desipramine overdoses are reported. The first case deals with a 20-year-old Caucasian male who was found dead at his residence. Toxicological analysis of the blood, urine, liver and kidney revealed the presence of amitriptyline (1.7 mg/l, 0.13 mg/l, 36.0 mg/kg and 98.0 mg/kg) and nortriptyline (0.66 mg/l, 0.74 mg/l, 12.0 mg/kg and 37.0 mg/kg). The gastric content contained only 220 mg of amitriptyline. The urine also contained norverapamil, which was consistent with previous verapamil therapy. The second case involved a 19-year-old Caucasian male who attempted suicide earlier and was on desipramine medication. The blood, urine, liver and gastric content disclosed the presence of desipramine in the concentrations of 14.2 mg/l, 33.7 mg/l, 112.5 mg/kg and 180 mg, respectively. The levels of these tricyclics analyzed by high pressure liquid chromatography were in agreement with the levels reported in the literature. Though with the amitriptyline poisoning no significant anatomic changes were noted, the desipramine-caused death was further supported by the multisystem vascular congestion and ischemic changes consistent with cardiopulmonary failure.     

Thiodicarb and methomyl tissue distribution in a fatal multiple compounds poisoning

Abstract:  Thiodicarb is a nonsystemic carbamate insecticide whose acetylcholinesterase activity is related to its main methomyl degradation product. A 40-year-old woman was found dead in her car. Empty packages of medicines and an open bottle of Larvin^® containing thiodicarb were found near her body. No signs of violence nor traumatic injuries were noticed upon autopsy, and police investigations strongly suggested a suicide. Systematic toxicological analysis performed on postmortem specimens revealed the presence of various sedatives, hypnotics, and antipsychotic drugs in blood, urine, and gastric content. Some of the compounds identified were determined at blood concentrations well above the known therapeutic concentrations: zolpidem (2.87 mg/L), bromazepam (2.39 mg/L), nordazepam (4.21 mg/L), and levopremazine (0.64 mg/L). Specific analysis of thiodicarb and of its methomyl metabolite was then performed on all fluids and tissues collected during autopsy by liquid chromatography ion trap tandem mass spectrometry (LC-MS-MS). The anticholinesterase capacity of blood, urine, and gastric content collected at autopsy was 83%, 82%, and 32%, respectively (normal value: 0%). The presence of thiodicarb in the bottle found near the body corroborates the hypothesis of an intake of that compound. Although thiodicarb was only detected in gastric content (24.3 mg/L), its methomyl metabolite was quantified in most postmortem tissues and fluids: gastric content (19.9 mg/L), peripheral blood (0.7 mg/L), urine (8.5 mg/L), bile (2.7 mg/L), liver (0.7 mg/kg), kidney (1.7 mg/kg), lung (1.5 mg/kg), brain (9.3 mg/kg), and heart (3.6 mg/kg).     

氯胺酮致小鼠产生类精神分裂症与NRG1、ErbB4 mRNA表达的相关性

目的探讨氯胺酮连续给药致小鼠产生的类似精神分裂症症状,与精神分裂症易感基因神经调节蛋白1（neuregulin-1,NRG1）及其受体ErbB4 mRNA表达的相关性,为研究精神分裂症的可能发病机制提供参考依据。方法50只雄性昆明种小鼠,随机分为生理盐水组、氯胺酮小剂量（25 mg/kg）、中剂量（50 mg/kg）、大剂量（100 mg/kg）组和氯氮平治疗组,腹腔注射给药,1次/d,连续7 d。氯氮平组在连续腹腔注射7d氯胺酮（1次/d,每次100mg/kg）后,再用氯氮平灌胃7d（1次/d,每次20mg/kg）。HE染色观察海马神经元的变化;采用逆转录-聚合酶链反应（RT-PCR）检测海马中NRG1及ErbB4 mRNA的表达。结果注射7d氯胺酮后,大剂量组海马区NRG1及ErbB4 mRNA的表达显著减少。结论氯胺酮诱导小鼠产生类似精神分裂症的症状,可能与海马区NRG1及ErbB4 mRNA的表达减少相关联。     

Phenol: tissue distribution in a fatality

A case is reported where phenol, a disinfectant, was ingested and resulted in the death of a 40-year-old white female. Concentrations of phenol were determined in blood (130 mg/L), urine (47 mg/L), bile (187 mg/L), brain (486 mg/kg), kidney (331 mg/kg), muscle (204 mg/kg), liver (228 mg/kg), and stomach content (668 mg) and compared to other cases reported in the literature.     

氯胺酮致小鼠产生类精神分裂症的行为改变

目的对氯胺酮单次或连续给药后小鼠所产生的类似精神分裂症症状进行观察．以评价不同剂量氯胺酮造模的可行性。方法40只雄性昆明种小鼠,随机分为生理盐水对照组、氯胺酮小剂量（25mg／kg）、中剂量（50mg／kg）和大剂量（100mg／kg）组,腹腔注射给药,1次／d,连续7d。观察小鼠的行为学变化。结果单次注射氯胺酮后,大剂量组小鼠有明显的运动亢进、刻板行为及共济失调现象（P〈0．01）;连续注射7d氯胺酮后,中剂量组小鼠出现了运动亢进、刻板行为及共济失调（P〈0．05）,大剂量组小鼠刻板行为及共济失调现象更为显著（P〈0．01）。结论单次或连续注射氯胺酮均可诱导小鼠产生类似精神分裂症的症状,且大剂量时症状更为显著．连续注射后症状更为稳定。     

Fatal flecainide intoxication

A fatal case attributed to flecainide acetate (Tambocor), a class Ic antiarrythmic drug, is presented. Flecainide was detected by GC/MS in gastric contents, blood and liver as well. The urine analysis revealed the presence of its dealkylated metabolite. Body fluids and tissue concentrations determined by GC/ECD were 7.7 mg/kg in femoral blood, 0.26 mg/kg in bile, 18 mg/kg in liver, 0.17 mg/kg in cerebrospinal fluid, 0.22 mg/kg in brain cortex and 28.9 mg/kg in urine. The total amount of flecainide in gastric contents was about 43 mg. Even taking into account the postmortem redistribution of flecainide, its blood level still remains in the toxic range.     

Tissue distribution of trichloroethylene in a case of accidental acute intoxication by inhalation

This article describes the toxicological findings in a fatality due to an accidental inhalation of trichloroethylene which took place during wall coating of a poorly ventilated well using trichloroethylene. The man was wearing protective clothing and a mouthmask with adsorbent. He was found dead on the floor of the well 5h after descending. Trichloroethylene was added to the mortar to enhance drying. Identification and quantitation of trichloroethylene in the postmortem samples (blood, lung, liver, kidney, stomach content and bile) and identification of its metabolite trichloroacetic acid in urine was performed using static headspace gas chromatography with mass spectrometric detector. The compounds were separated on a CP-SIL 5CB Low Bleed/MS column using n-butanol as internal standard. The method was linear over the specific range investigated, and showed an accuracy of 104% and an intra-day precision of 11%. Trichloroethylene concentrations of 84mg/l in subclavian blood, 40mg/l in femoral blood, 72mg/kg in liver, 12mg/kg in kidney, 78mg/kg in stomach content, 104mg/l in bile and 21mg/kg in lung were found. Trichloroacetic acid was identified in the urine.     

Tissue distribution of tramadol and metabolites in an overdose fatality

Tramadol (Ultram) is a centrally acting, synthetic analgesic agent. Although it has some affinity for the opiate receptors, tramadol is believed to exert its analgesic effect by inhibiting the re-uptake of norepinephrine and serotonin. There are several published cases of tramadol's involvement in drug-related deaths and impairment. Reports of deaths involving tramadol alone with associated tissue concentrations are rare. This report documents a case in which tramadol overdose was identified as the cause of death. The following tramadol concentrations were found in various tissues: blood, 20 mg/L; urine, 110.2 mg/L; liver, 68.9 mg/kg; and kidney, 37.5 mg/kg. Tissue distributions of the two primary metabolites, N-desmethyl and O-desmethyl tramadol, are also reported. In each tissue or fluid except urine, the tramadol concentration was greater than either metabolite, consistent with other reports of drug-impaired drivers and postmortem cases. The O-desmethyl metabolite concentration was greater than the N-desmethyl metabolite concentration in all tissues; this is in contrast to other postmortem reports, in which the majority of cases report concentrations of O-desmethyl as less than those of N-desmethyl. This may be useful as an indicator of time lapse between ingestion and death.     

家兔氯敌鼠中毒死亡与体内含量的关系

用家兔作为实验动物，以3个给药剂量建立氯敌鼠中毒模型，采用反相高效液相色谱法测定染毒免各脏器组织中氯敌鼠的含量，探讨氯敌鼠中毒死亡与体内含量的关系。     

Endogenous methanol: variability in concentration and rate of production. Evidence of a deep compartment?

The endogenous methanol concentration was determined in 72 men aged between 18 and 35 years in the morning after a 12-h period of fasting and abstinence from alcohol. The distribution curve was found to be skewed to the right, the concentrations ranging from ‘0’ (below the detection threshold) to 3.4 mg/kg. The median was 0.1 mg/kg and the mean 0.35 mg/kg. Significant differences were found between three groups defined according to the duration of prior abstinence from alcohol (8 h, 30 h, and 5 days). The highest values were seen after the shortest period of abstinence and the lowest values after the longest period of abstinence. The course followed by the methanol concentration in the presence of blocking of methanol oxidation by orally or parenterally administered ethanol was observed over at least 10 h on two separate occasions in a further 8 subjects aged between 24 and 35 years. At blood ethanol concentrations of more than 0.20 g/kg, the rate of production of methanol, calculated by regression, ranged from 0.09–0.37 mg/kg/h (r = 0.970–0.554, S_y,x = 0.227–0.565 mg/kg). The rise in methanol concentration at the start of ethanol administration was significantly more rapid than the subsequent rise. It is hypothesised that there may be a so-called deep compartment for methanol that would explain the dependence of the endogenous methanol level on the duration of the preceding period of abstinence from ethanol, and the occurrence of an initial phase of faster rise in methanol concentration associated with the administration of ethanol.     

Potentiation of lethality and increase in body temperature by combined use of d-methamphetamine and morphine in mice

Lethality and change in body temperature in mice were examined after subcutaneous injection of d-methamphetamine and morphine alone or in combination. The LD50 values for methamphetamine and morphine were calculated to be 95 and 670 mg/kg body wt., respectively. When a non-lethal dose of morphine (300 mg/kg) was administered with various doses of methamphetamine, the LD50 for methamphetamine was reduced to 5 mg/kg, indicating a marked potentiation of toxicity by combined use of both drugs. Injection of 5 mg/kg of methamphetamine produced slight hyperthermia, while 300 mg/kg of morphine decreased the body temperature of mice. However, when both drugs were used concomitantly, a marked increase in body temperature was observed. Hyperthermia was also observed when the dose of morphine was reduced to 50 mg/kg. It is postulated that hyperthermia is probably one of the contributory factors in the potentiated toxicity by combined use of morphine and methamphetamine.     

Fatal cardiac arrhythmia after repeated exposure to 1,1-difluoroethane (DFE)

A 42-year-old man was found dead after repeated exposure to 1,1-difluoroethane (DFE, Freon 152a), a propellant found in CRC Duster, a product intended for the removal of dust and lint. Toxicologic analysis detected DFE in femoral blood 136.3 mg/L, brain 117.5 mg/kg, liver 87.6 mg/kg, lung 60.3 mg/kg, adipose 235.7 mg/kg, and vitreous fluid 25.1 mg/L. The cause of death was determined to be a fatal cardiac arrhythmia due to intoxication with 1,1-difluoroethane. After comparison to previously published cases involving DFE, we suggest that analysis of adipose tissue for DFE and similar compounds, along with blood and other tissues, may be useful in distinguishing between acute versus chronic exposure. Adipose may also be a valuable alternate specimen for detection in cases where loss or elimination from blood is likely to have occurred.     

Influence of Paraquat on Chrysomya megacephala (Fabricius) (Diptera: Calliphoridae) Infesting Minced‐beef Substrates in Kelantan,Malaysia

This study investigated the influence of paraquat, a prevalent poison used by suicides, on initial oviposition and development of Chrysomya megacephala (Fabricius) using minced‐beef substrates. Paraquat in lethal dose for human (40 mg/kg), two times the lethal dose (80 mg/kg) and five times the lethal dose (200 mg/kg) were mixed thoroughly with respective minced‐beef substrates (1 kg each) that were decomposed in a shaded habitat fully protected from rain. Results of four replications of the above experiment revealed that the presence of paraquat neither delayed initial oviposition nor prolonged the developmental stages of C. megacephala. Therefore, estimation of postmortem interval (PMI) based on empirical baseline data obtained using animal models devoid of any poisons would still be appropriate for estimating PMI in paraquat‐related deaths.     

Fatal outcome of Ecstasy overdose

Consumption of amphetamine derivatives has considerably increased in Germany since the early nineties. Again and again intoxications with lethal outcome have also been reported, especially after physical activities such as intensive dancing. The authors present a case of an obviously suicidal intoxication of a 21-year-old man who was found dead with marked cuts on the right forearm. Toxicological tests showed in particular 3, 4-methylene-dioxymethamphetamine (MDMA). The results of the hair analysis revealed chronic consumption, but no cellular liver damage could be demonstrated. When examining the body fluids and organs, the highest concentrations by far were measured in the lungs (36.6 mg/kg), the liver (29.7 mg/kg) and the brain (29.1 mg/kg). The concentration in heart blood amounted to 10.8 mg/kg and was thus markedly higher than in peripheral blood (7.2 mg/kg). In the muscles concentrations ranged between 14.3 mg/kg and 20.2 mg/kg. On the basis of these concentrations and the available pharmacokinetic data the amount of MDMA probably consumed is assessed. It is demonstrated that for this assessment the concentrations in the muscular system are of special importance, as redistribution of highly lipophilic substances from the surrounding tissue is possible also in peripheral blood.     

Bupropion and alcohol fatal intoxication: case report.

A fatality due to the ingestion of bupropion and ethanol is presented. Bupropion and its metabolites were extracted from several tissues and identified using gas chromatography with nitrogenphosphorus and mass spectrometry detection. The concentrations of bupropion, hydroxybupropion and the erythroamino and threoamino alcohol metabolites in heart blood were 4.2, 5.0, 0.6 and 4.6 mg/l, respectively. The heart blood ethanol concentration was 0.27 g/dl. In addition, bupropion was distributed as follows: subclavian blood, 6.2 mg/l; bile, 1.4 mg/l; kidney, 2.4 mg/l; liver, 1.0 mg/kg; stomach contents, 16 mg and urine, 37 mg/l.     

Peak blood-ethanol concentration and the time of its occurrence after rapid drinking on an empty stomach

Healthy men, 20 to 60 years old, drank a moderate dose of ethanol in the morning after an overnight fast. They consumed either neat whisky in amounts corresponding to 0.34, 0.51, 0.68, 0.85, or 1.02 g of ethanol per kilogram of body weight or 0.80 g/kg ethanol solvent diluted with orange juice. The peak blood-ethanol concentration (BEC) increased with the dose administered, but the time required to reach the peak was not markedly influenced over the range of doses studied. At a dose of 0.68 g/kg, the peak BEC ranged from 52 to 136 mg/dL (N = 83), and slow absorption (a late-occurring peak) produced a lower peak BEC. The peak BEC was reached between 0 and 45 min for 77% of the subjects (N = 152) and between 0 and 75 min for 97% of them. The time of peaking in venous blood occurred, on average, 10 min later than in capillary (fingertip) blood although the peak BEC was not appreciably different; the mean venous BEC was 97.0 mg/dL (range, 76 to 112 mg/dL), and the mean capillary BEC was 99.6 mg/dL (range, 75 to 123 mg/dL). When subjects drank 0.80 g/kg ethanol diluted with orange juice over 30 min, the average BEC increment between the end of drinking and the peak was 33 mg/dL (range, 0 to 58 mg/dL). The rate of absorption of ethanol was 1.78 mg/dL/min (range, 0.52 to 4.8 mg/dL/min), and the peak BEC occurred within 60 min after the end of drinking in 92% of the trials. The largest BEC increment (mean, 21 mg/dL; range, 0 to 44 mg/dL) was seen during the first 15 min after the drinking period.     

Quantification of Morphine,Codeine, and Thebaine in Home‐Brewed Poppy Seed Tea by LC‐MS/MS

Recently, medical examiners reported two cases of a 21‐year‐old male and 24‐year‐old male with high amounts of morphine in their blood at autopsy. It was suspected that the decedents ingested lethal amounts of morphine from home‐brewed poppy seed tea. No studies to date have investigated opium alkaloid content extracted from poppy seeds by home‐brewing methods. Various poppy seed products were purchased from online sources and extracted with four home‐brewing methods representative of recipes found on drug user forums. Morphine, codeine, and thebaine were quantified in the tea extracts by liquid chromatography‐tandem mass spectrometry using a validated analytical method. Morphine, codeine, and thebaine concentrations from seeds were <1–2788 mg/kg, <1–247.6 mg/kg, and <1–124 mg/kg, respectively. Alkaloid yield varied between extractions, but regardless of extraction conditions, lethal amounts of morphine can be rinsed from poppy seed coats by home‐brewing methods.