阿维菌素在急性中毒死家兔体内的再分布研究

目的考察阿维菌素在急性中毒死家兔体内的再分布。方法按最小致死量一次性灌胃250mg/kg阿维菌素,HPLC法检测家兔死后0h、24h、48h和72h中阿维菌素的含量。结果给家兔一次性灌胃250mg/kg阿维菌素的临床死亡时间为120.6±9.2min(±s,n=10);测定了阿维菌素的致死血浓度和致死组织浓度;家兔死后0h~72h心血和各主要脏器组织中阿维菌素含量存在体内再分布现象;确定肝、肾、肺为最佳组织检材。结论阿维菌素在急性中毒死家兔体内的再分布数据,对法医办理此类案件具有重要参考价值。     

Disopyramide and Mianserin Intoxication: A Unique Fatal Case – Review of the Literature

Lethal occurrence is exceptional after disopyramide or mianserin poisoning. A case of intentional lethal intoxication with these drugs was reported, as well as a review of the literature. Pre‐ and postmortem blood concentrations of disopyramide or mianserin were assessed in a woman who died from acute cardiac failure after ingestion. The premortem blood concentration of disopyramide alone was considered lethal, and a toxic premortem concentration of mianserin was observed that may have increased cardiovascular failure induced by disopyramide because the metabolism of both drugs is mediated via cytochrome P450. Moreover, it was shown that the postmortem redistribution of disopyramide was limited, as pre‐ and postmortem concentrations were 48 and 65 mg/L, respectively. As regards mianserin, redistribution was observed after death with pre‐ and portmortem concentrations at 0.23 and 0.79 mg/L, respectively. This case illustrates that if postmortem blood concentration of disopyramide is known, the premortem concentration can be deduced.     

Nitrous Oxide Determination in Postmortem Biological Samples: A Case of Serial Fatal Poisoning in a Public Hospital*

Abstract: In a public hospital, eight cases of fatal poisoning by nitrous oxide (N₂O) occurred under oxygen administration, due to an erroneous swapping of the lines in the gas system. The aim of the study was to clarify the factors involved in asphyxia by characterizing gases from different lines and measuring N₂O concentrations in postmortem biological samples from bodies exhumed. Analyses carried out on the gas system confirmed the erroneous substitution of O₂ line with N₂O and air line with O₂. Consequently, high N₂O amounts were revealed in several tissues and gaseous biological samples. All specimens were analyzed by headspace gas chromatography technique. A rigorous quantitative analysis was possible only in blood (11.29–2152.04 mg/L) and urine (95.11 mg/L) and in air samples from stomach and trachea (from 5.28 to 83.63 g/m³). This study demonstrates that N₂O can be detected in biological samples even 1 month after death.     

Bupropion Overdose Resulted in a Pharmacobezoar in a Fatal Bupropion (Wellbutrin®) Sustained‐release Overdose: Postmortem Distribution of Bupropion and its Major Metabolites

Bupropion (BUP) overdose commonly causes generalized seizures and central nervous system depression. The case of a 28‐year‐old woman who died from a massive lethal overdose with sustained‐release bupropion (Wellbutrin^® 300 mg) is herein presented. The autopsy revealed the presence of a pharmacobezoar consisting of at least 40 tablets in the stomach. Determination of bupropion and its active metabolites (hydroxybupropion, threobupropion, erythrobupropion) was achieved by a liquid chromatographic mass spectrometry (LC‐MS/MS) method. Postmortem concentrations for bupropion, hydroxybupropion, threobupropion, and erythrobupropion were obtained in intracranial blood, urine, bile, liver, kidney, and vitreous humor. In this case, intracranial blood level of the parent drug was 1.9 mg/L. Threobupropion was the most abundant metabolite in both blood and urine, 59.3 and 890.6 mg/L. Tissue distribution showed the highest concentration in the liver, 12.3 mg/kg. The 0.8 bupropion concentration ratio vitreous/blood suggested that vitreous could be a valuable specimen for toxicological analysis should postmortem blood be unavailable.     

Rare Death Via Histamine Poisoning Following Crab Consumption: A Case Report

Histamine poisoning (scombroid food poisoning) is a toxicity syndrome that results from eating spoiled fish. To date, however, few poisoning (or mortality) cases have been reported in relation to crab consumption. Here, we describe a very uncommon case in which a 37‐year‐old woman and her 14‐year‐old son ate cooked crabs (Scylla serrata), resulting in the death of the female. Samples of vomitus, food residue, liver tissue, gastric content, intestinal content, and cardiac blood were analyzed by high‐performance liquid chromatography. Toxicological analysis revealed that histamine concentrations were very high in the cooked crab (47.08 mg/100 g) and intestinal content (22.54 mg/100 g). Comparing our toxicological results, police investigations, and family member statements, it can be assumed that the decedent ingested spoiled crabs, and by excluding other causes of death, lethal intoxication with histamine poisoning was confirmed.     

Acute Benztropine Intoxication and Fatality

A woman was found unresponsive with an empty bottle of Cogentin^® prescribed to another. Admitted to an area hospital, her condition steadily declined until death 29 h after admission. Following toxicological screening on hospital (admission) whole blood, the only significant compound detected was benztropine. Benztropine was confirmed at 0.28 mg/L – the highest antemortem blood concentration recorded in a case of toxicity or fatality uniquely associated with benztropine. A second serum antemortem specimen showed a benztropine concentration of 0.19 mg/L. Despite over 24 h in the hospital, benztropine was also found in the postmortem specimens collected at autopsy. Peripheral blood, central blood, liver, and gastric concentrations were 0.47 mg/L, 0.36 mg/L, 9.6 mg/kg, and 44 mg, respectively. These results indicate that benztropine exhibited a potential difference between whole‐blood and serum (plasma) concentrations. Additionally, in consideration of literature data, benztropine was found indicative of a compound prone to at least some postmortem redistribution.     

CYP2D6 and CYP2C19 genotypes and amitriptyline metabolite ratios in a series of medicolegal autopsies

In a series of 202 postmortem toxicology cases, the CYP2D6 and CYP2C19 genes were genotyped, and the concentrations of amitriptyline (AT) and six metabolites were analyzed. The polymorphic CYP2D6 and CYP2C19 genes encode enzymes participating in the metabolism of several potentially toxic drugs, and mutations in these genes may lead to adverse drug reactions, possibly even intoxications. AT was chosen as the substrate of interest because it is mainly metabolized by these enzymes, is considered relatively toxic, and ranks among the major causes of fatal drug poisoning in Finland. Our objective was to evaluate genetically determined interindividual variation in conjunction with metabolite ratios of drugs found in toxicological analysis in a series of medicolegal autopsies. Positive correlations were found between the proportion of trans-hydroxylated metabolites and the number of functional copies of CYP2D6 and between the proportion of demethylated metabolites and the number of functional copies of CYP2C19. None of the accidental or undetermined AT poisonings coincided with the CYP2D6 or CYP2C19 genotype which predicts a poor metabolizer phenotype. However, an unusually high femoral blood concentration of AT, 60mg/l, was found in one suicide case with no functional CYP2D6 genes. Our study shows a concordance of AT metabolite patterns with CYP2D6 and CYP2C19 genotypes in the presence of confounding factors typical for postmortem material. This result demonstrates the feasibility of postmortem pharmacogenetic analysis and supports the dominant role of genes in drug metabolism.     

Fatal Overdose of Gamma‐hydroxybutyrate Acid After Ingestion of 1,4‐Butanediol

We report a case of fatal intoxication from 1,4‐butanediol (1,4‐BD), which was ingested by a young and “naïve” gamma‐hydroxybutyrate (GHB) consumer during a party with the co‐ingestion of alcohol, cannabis, and methylene‐dioxy‐methamphetamine. The following drug concentrations were found using gas chromatography coupled with mass spectrometry on autopsy samples and on a cup and a glass found at the scene: 20,350 mg/L (bottle) for 1,4‐BD; 1020 mg/L (femoral blood), 3380 mg/L (cardiac blood), 47,280 mg/L (gastric content), and 570 mg/L (vitreous humor) for GHB. The concentration of GHB is difficult to interpret in forensic cases due to the possibility of an endogenous production of GHB. The variable tolerance of the user may also modify the peri‐ and postmortem GHB concentrations. This case underscores the need to have many different sources of toxicology samples analyzed to avoid the hypothesis of endogenous production of GHB.     

Fatal intoxication with 1,4-butanediol: Case report and comprehensive review of the literature

A fatal case of 1,4-butanediol (1,4-BD) oral ingestion is reported here, in which a 51-year-old man was found dead in his bed. According to the police report, the deceased was a known drug user. A glass bottle labeled (and later confirmed to be) “Butandiol 1,4” (1,4-BD) was found in the kitchen. Furthermore, the deceased's friend stated that he consumed 1,4-BD on a regular basis. The autopsy and histological examination of postmortem parenchymatous organ specimens did not revealed a clear cause of death. Chemical-toxicological investigations revealed gammahydroxybutyrat (GHB) in body fluids and tissues in the following quantities: femoral blood 390 mg/L, heart blood 420 mg/L, cerebrospinal fluid 420 mg/L, vitreous humor 640 mg/L, urine 1600 mg/L, and head hair 26.7 ng/mg. In addition, 1,4-BD was qualitatively detected in the head hair, urine, stomach contents, and the bottle. No other substances, including alcohol, were detected at pharmacologically relevant concentrations. 1,4-BD is known as precursor substance that is converted in vivo into GHB. In the synoptic assessment of toxicological findings, the police investigations and having excluded other causes of death, a lethal GHB-intoxication following ingestion of 1,4-BD, can be assumed in this case. Fatal intoxications with 1,4-BD have seldom been reported due to a very rapid conversion to GHB and, among other things, non-specific symptoms after ingestion. This case report aims to give an overview to the published of fatal 1,4-BD-intoxications and to discuss the problems associated with detection of 1,4-BD in (postmortem) specimens.     

Disposition of quetiapine in biological specimens from postmortem cases

Quetiapine is a new atypical antipsychotic that was approved in 1997 by the U.S. Food and Drug Administration for the treatment of schizophrenia. It possesses a high affinity for 5-HT2 receptors and a low affinity for D1 and D2 dopamine receptors. Because quetiapine has only been released recently to the U.S. market, little information exists regarding therapeutic, toxic, and lethal concentrations. This study reports the detection of quetiapine in 13 postmortem cases. Following a basic liquid-liquid extraction, quetiapine was identified and quantitated by capillary gas chromatography with nitrogen phosphorus detection. Confirmation was accomplished by full scan electron impact gas chromatography/mass spectrometry. Heart blood quetiapine concentrations ranged from 0.07 to 18.37 mg/L (N = 12, mean +/- SD = 3.42 +/- 5.67, median 0.62) and femoral blood concentrations ranged from 0.06 to 19.25 mg/L (N = 10. mean +/- SD = 3.89 +/- 6.12, median 0.81). The average heart blood/femoral blood ratio was 1.31 (range 0.55 to 2.57, N = 10). Urine, bile, and gastric contents were assayed in all cases in which they were submitted. In three cases, the cause of death was determined to be quetiapine toxicity. In these cases heart blood concentrations ranged from 0.72 to 18.37 mg/L (N = 3). These data may provide a basis for establishing levels associated with quetiapine toxicity as well as therapeutic concentrations in postmortem specimens.     

“Bath Salts” the New York City Medical Examiner Experience: A 3‐Year Retrospective Review

“Bath salts” are synthetic derivatives of cathinones, compounds found in the leaves of Catha edulis, which possesses amphetamine‐like properties. At the New York City Office of Chief Medical Examiner, we conducted a 3‐year retrospective analysis of deaths in which cathinones were detected. Two categories emerged; those in which cathinones were a contributory cause of death (15 cases) and those in which they were an incidental finding (15 cases). Of the former group, 13 were associated with additional intoxicants; two deaths were attributed solely to cathinone intoxication, both survived 10 h: a man whose postmortem blood methylone concentration was 0.71 mg/L and a woman whose postmortem blood ethylone concentration was 1.7 mg/L. In the latter category, there were several individuals who had higher concentrations of cathinones than the above two, the highest being a blood methylone of 4.8 mg/L. Based upon our data and the literature presented, lethal concentrations of cathinones cannot be established.     

A case of suicide by ingestion of sodium nitroprusside.

The study reports a case of suicide by ingestion of sodium nitroprusside which resulted in acute cyanide poisoning. Analyses carried out on body fluid yielded the quantitation of total (5.00 mg/L) and free (3.30 mg/L) cyanide in blood and of methemoglobin (blood = 10.5%). At the scene, some solid reddish-brown material was found in a glass, which on toxicological analysis was found to contain sodium nitroprusside; about 9 g of the same substance was identified in stomach contents. The detection and quantification of cyanide and methemoglobin in biological samples from the case indicated that the lethal effect was due to both metabolic products (cyanide and methemoglobin).     

A Rare Case of Poisoning with a Volatile Substance: Quantitative Determination of n‐Butane in Postmortem Tissue

Poisoning with volatile substances remains exceptional. Authors report the case of a married couple who were found in a car with a butane gas bottle: the woman was dead and her husband alleged it was an unsuccessful suicide pact. A specific research of volatile substances on postmortem samples with headspace gas chromatography–mass spectrometry following a quantitative determination was performed. The n‐butane concentrations detected were composed of 610 μg/L (cardiac blood), 50 μg/kg (brain), 134 μg/kg (lungs), 285 μg/kg (liver), and 4090 μg/kg (heart) and were compatible with the rare lethal concentrations evoked in the literature. The cause of death was determined to be asphyxiation through n‐butane criminal poisoning. Authors recommendation therefore is to take samples immediately and place them in properly sealed containers and hence analyzing the samples as soon as possible after collecting them or storing them under ?30°C (?22°F) if analyses cannot be performed immediately.     

A Fatal Case of Poisoning with Fentanyl Transdermal Patches in Japan

Fentanyl transdermal patches have been used to treat cancer‐ and noncancer‐related chronic pain. However, its inappropriate or illegal application may cause fatal poisoning. We herein present the case of a Japanese woman in her 40s who was found dead with seven 25‐μg/h fentanyl transdermal patches on her body. We established a detailed toxicological analysis procedure to quantify fentanyl, and its metabolite norfentanyl, and other drugs (acetaminophen, allylisopropylacetylurea, celecoxib, estazolam, promethazine, and sertraline) in human whole blood by ultra‐high‐performance liquid chromatography–tandem mass spectrometry. The measured fentanyl and norfentanyl concentrations in the femoral and cardiac blood were 0.051 and 0.072 μg/mL and 0.033 and 0.076 μg/mL, respectively. The decedent's fentanyl concentrations were consistent with previously reported postmortem blood levels for fatal cases of poisoning by fentanyl transdermal patches. Based on the decedent's case history, autopsy findings, and toxicological analyses, the cause of death was identified as intoxication with transdermal fentanyl.     

Postmortem hydroxychloroquine concentrations in nontoxic cases

Hydroxychloroquine (HCQ) is a 4-aminoquinoline compound used to treat malaria and chronic autoimmune disorders and is not uncommonly found in the medical examiner setting. Studies have shown HCQ to have a long half-life (32-56 days in blood), high volume of distribution (580-815 L/kg), and therapeutic concentrations ranging from 0.03 to 15 mg/L, depending on the chronicity of treatment. Previous reports have shown that the toxic concentration of HCQ ranges from 3 to 26 mg/L, whereas the lethal concentration ranges from 20 to 104 mg/L. A report addressing nontoxic postmortem concentrations of HCQ in individuals known to be taking the medication, and in whom there is no evidence of toxicity, has not been previously undertaken. This study found that postmortem concentrations in nontoxic cases can range from 0.3 to 39 mg/L, which is well within the reported range of both lethal and toxic concentrations. It is recommended that all investigative and autopsy data be considered and that the cause of death not be certified based purely on blood HCQ concentrations.     

Methyl tert‐Butyl Ether (MTBE) Detected in Abnormally High Concentrations in Postmortem Blood and Urine from Two Persons Found Dead Inside a Car Containing a Gasoline Spill

Two deep frozen persons, a female and a male, were found dead in a car. There had been an explosive fire inside the car which had extinguished itself. On the floor inside the car were large pools of liquid which smelled of gasoline. The autopsy findings and routine toxicological analyses could not explain the cause of death. Carboxyhemoglobin levels in the blood samples were <10%. Analysis with a headspace gas chromatography revealed methyl tert‐butyl ether (MTBE) concentrations of 185 mg/L (female victim) and 115 mg/L (male victim) in peripheral blood. The urine MTBE concentrations were 150 mg/L and 256 mg/L, respectively. MTBE is a synthetic chemical which is added to gasoline as a fuel oxygenate. Gasoline poisoning is likely to be the cause of the death in these two cases, and MTBE can be a suitable marker of gasoline exposure, when other volatile components have vaporized.     

Death of an infant involving benzocaine

This report describes the death of a four-month-old Hispanic male which may be related to benzocaine toxicity. A toxicological evaluation revealed benzocaine at a concentration of 3.48 mg/L, and postmortem methemoglobin of 36% (normal 0.4-1.5). Methemoglobinemia is a complication of benzocaine toxicity. In light of the toxicology findings, the coroner investigated the source of the benzocaine and discovered that the child was treated with Zenith Goldline Allergen Ear Drops containing 0.25% w/v benzocaine and 5.4% w/v antipyrine. There was an admission by a caregiver that on the day prior to the child's death, he had been treated with three times the prescribed dose. Blood benzocaine concentrations in nine other unrelated cases were determined and concentrations ranged from <0.05-5.3 mg/L (mean 1.48 mg/L). Seven of the nine cases were positive for drugs of abuse, and one additional case was described as a known drug user. Methemoglobin in these benzocaine positive cases ranged from 6-69%; however, methemoglobin concentrations in postmortem cases are frequently elevated and should be interpreted with caution. The unknown significance of the benzocaine, and the circumstances of the case raise questions about the ultimate attribution of this death to SIDS.     

Postmortem atropine concentrations in resuscitation cases

The medications used during resuscitation are often in and of themselves toxic. Several reports have been published regarding toxicities of these drugs, including lidocaine, procainamide, and atropine. But how does a forensic pathologist or toxicologist differentiate a possible intoxication from therapeutic or resuscitory use especially given that the concentrations of such drugs, when used in the setting of resuscitation, have not been studied? Concentrations of a well-known resuscitation medication, atropine, were assessed in cases where it was administered before death during attempted resuscitation in an effort to address this deficiency. A review of deaths occurring in 2009 was undertaken to identify cases where drugs known to be used during resuscitation were present on toxicological analysis. Autopsy reports and medical records were examined to determine how much atropine was administered, the timing and route of administration, the time the sample was drawn (antemortem and postmortem), the source of the sample, and the ultimate cause of death. Eighty-nine cases were identified in which atropine was given before death during attempted resuscitation and was detected in the blood on postmortem toxicological screening; 11 cases were identified in which atropine was administered before death yet was not detected on the postmortem toxicological screening. Mean age was 41 years, and there were 65 males and 35 females. The overall median dose of atropine given was 3 mg, the median difference between the time of last administration of the atropine to the time of death (or draw for antemortem samples) was 15 minutes, and the median atropine concentration was 0.1 mg/L. Analysis failed to reveal significant differences in the atropine concentration based on the route of administration (intravenous or intraosseus), the cause of death, or the time since administration (within the first 2 hours). Analysis did reveal a difference between the atropine concentrations in peripheral versus central blood sources and with prolonged postmortem interval (>24 hours) suggesting postmortem redistribution.