Fatal intoxication involving 2-methyl AP-237

Novel synthetic opioids contribute considerably to the opioid epidemic, especially with the frequent emergence of structurally similar compounds. This case report describes a fatal intoxication involving 2-methyl AP-237. A 54-year-old Caucasian male was found deceased from an apparent drug overdose. A plastic container labeled “2MAP” and a cut straw were found in the decedent's backpack at the scene. A white substance found in the container tested positive for fentanyl by field testing. According to his medical history, the decedent was treated for a drug overdose 3 years prior to his death. With no diagnostic findings at autopsy, the case was submitted for toxicological analysis. An unknown substance was detected in peripheral blood and urine using gas chromatography with nitrogen phosphorous detection (GC-NPD). Further testing was conducted using gas chromatography–mass spectrometry (GC–MS) and liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) which confirmed the presence of 2-methyl AP-237 and potential metabolites in blood and urine. Quantitation by GC-NPD revealed concentrations of 2-methyl AP-237 in blood and urine at 480 ng/mL and 4200 ng/mL, respectively. The toxicological analysis also identified and quantitated alprazolam in the blood at 55 ng/mL. Additionally, the metabolism of 2-methyl AP-237 was investigated and three hydroxylated metabolites were identified in peripheral blood and urine. Limited literature is available for the detection and quantitation of 2-methyl AP-237 in postmortem specimens. Given the toxicological findings with unremarkable autopsy findings, this case is an example of a fatal intoxication involving 2-methyl AP-237.     

Homicidal Poisoning in China Using Several Anesthetic Drugs

The authors describe a case of a well‐designed homicidal poisoning in China. A male was treated with starvation, intravenous fluids and antibiotics while in the hospital for acute diarrhea. He suddenly suffered from shortness of breath and subsequently died. A forensic autopsy was carried out, and several specimens were collected for toxicological screening. Propofol was tentatively identified in the blood by GC‐MS. Based on the presence of propofol in the blood, a suspect confessed that two other drugs, namely midazolam and vecuronium, were involved in this murder. Analytical drug quantification was then performed by GC‐MS and LC‐MS/MS. Blood analysis revealed the following: propofol at 0.5 μg/mL, midazolam at 0.098 μg/mL, and vecuronium at 0.10 μg/mL. These results suggest that the cause of death was respiratory depression due to the acute combined effect of several anesthetic drugs administered by the victim's companion.     

Fatal mephenesin intoxication

This report describes a death related to the abuse of and intoxication by mephenesin. To the best of our knowledge, this is the first report case of lethal intoxication involving solely mephenesin and reporting mephenesin blood concentrations. The victim was a 48-year-old woman found unconscious at home. Resuscitation was unsuccessful. Toxicological analysis was performed on a blood sample collected during resuscitation. The results being negative, the body was exhumed for an autopsy, which revealed bronchial inhalation syndrome. Analysis in a second laboratory has revealed the presence of mephenesin in samples collected during autopsy. No other drug/toxin was found, and alcohol was negative. Reanalysis of the peripheral blood collected during resuscitation found a mephenesin concentration of 15.81 microg/mL (15-fold greater that the maximum concentration that would result from a single intake of a 500 mg formulation). The pathologist has concluded on a bronchial inhalation syndrome consecutive to a mephenesin overdose as the cause of death. The manner of this death is discussed in the light of the toxicological hair analysis and the medical past of the victim.     

An autopsy case of combined drug intoxication involving verapamil,metoprolol and digoxin

We present here a fatal poisoning case involving verapamil, metoprolol and digoxin. A 39-year-old male was found dead in his room, and a lot of empty packets of prescribed drugs were found near the corpse. The blood concentrations of verapamil, metoprolol and digoxin were 9.2 microg/ml, 3.6 microg/ml and 3.2 ng/ml, respectively. The cause of death was given as cardiac failure, hypotension and bradycardia due to a mixed drug overdose of verapamil, metoprolol and digoxin, based on the results of the autopsy and toxicological examination. We speculate that the toxicity of verapamil is potentiated by drug interaction with metoprolol and digoxin.     

Distribution of dimethoate in the body after a fatal organophosphate intoxication

Many organophosphate pesticides (OPs) such as dimethoate are used to eradicate household pests, and those occurring in agriculture and forestry sectors. Combinations of two or more different insecticides have been manufactured to increase their effectiveness. A case of death is presented as suspected organophosphates intoxication. Autopsy was unremarkable except for grayish fluid in the stomach, with garlicky odor. A systematic toxicological analysis on post-mortem specimens revealed high concentrations of dimethoate in blood 38 microg/mL, urine 0.47 microg/mL, brain 2.2 microg/g, myocardial muscle 7.6 microg/g, liver 4.6 microg/g, lung 7.6 microg/g, skeletal muscle 21 microg/g, kidney 55 microg/g and gall bladder 31 microg/g. Blood alcohol was 2.85 g/L, cyclohexanone and cyclohexanol were also detected in the blood but not quantified. The cause of death was determined as organophosphate intoxication.     

A fatality due to propofol poisoning.

This report describes a suicide by self-administration of propofol in a 29-year-old female radiographer. This is the first published report of death by overdosage with propofol. Propofol was detected in tissues using high performance liquid chromatography. Post mortem femoral blood and liver concentrations of propofol were 0.22 mg/L and 1.4 mg/kg, respectively. The scene suggested that a dose of 400 mg was used.     

Fatal intoxication with tianeptine (Stablon)

Tianeptine (Stablon), although structurally similar to tricyclic antidepressants, acts by enhancing the reuptake of serotonin. A fatal case is presented involving a 26-year-old man, found lying in bed with a "mushroom of foam" around his mouth. Empty blister packs of Stablon and a suicide note were found next to the body. A liquid-liquid extraction procedure with n-hexane: ethyl acetate and n-hexane: 2-propanol, followed by LC-DAD-MS analysis, using positive mode electrospray ionization was performed. The detection limit was 0.001 microg/mL. The toxicological results revealed the following tianeptine concentrations in the post-mortem samples: blood 5.1 microg/mL; urine 2.0 microg/mL; liver 23 microg/g; stomach contents 22 mg. Femoral blood analyses also revealed an ethanol concentration of 0.53 g/L. The present method was also developed and validated for the other post-mortem specimens, since no previous published data had confirmed the post-mortem distribution of tianeptine. The absence of other suitable direct causes of death (macroscopic or histological) and the positive results achieved with the toxicological analysis led the pathologist to rule that death was due to an intoxication caused by the suicidal ingestion of tianeptine in combination with alcohol.     

Intoxication due to 1,4-butanediol

We report a case of intoxication resulting from the ingestion of a liquid, sold in the illicit market as "liquid ecstasy," which was found to contain 1,4-butanediol, a metabolic precursor of gamma-hydroxybutiric acid (GHB). Identification of the substance in the liquid was performed by gas chromatography-mass spectrometry (GC-MS).The toxicological analysis of blood, urine and gastric content of the victim was performed by immunoassay and gas chromatography with nitrogen-phosphorus detection as screening techniques and by means of GC-MS for confirmation and quantitation of 1,4-butanediol and GHB. The following drug concentrations were found: 82 microg/ml (blood), 401 microg/ml (urine) and 7.4 microg/ml (gastric content) for 1,4-butanediol and 103 microg/ml (blood), 430.0 microg/ml (urine) for GHB. In addition to these, other drugs detected and their blood concentration found in this case were methylenedioxymethylamphetamine (MDMA) 0.23 microg/ml and its metabolite methylenedioxyphenylamphetamine (MDA) 0.10 microg/ml. In the urine, a concentration of 0.10 microg/ml of benzoylecgonine was also found.     

Suicide due to oral ingestion of lidocaine: a case report and review of the literature

The Authors describe a rare case of suicide in a 31-year-old woman, due to oral ingestion of lidocaine; the histological and toxicological findings are discussed to provide useful information to the present experience with this particular modality of death. Histological examination revealed generalized stasis. In the myocardium we observed segmentation of the myocardial cells and/or widening of intercalated discs and associated group of hypercontracted myocardial cells with "square" nuclei in line with hyperdistended ones. Non-eosinophilic bands of hypercontracted sarcomeres alternating with stretched, often apparently separated sarcomeres, small foci of paradiscal contraction band necrosis, and perivascular fibrosis were observed too. Lidocaine was detected in the subject's urine through immunoenzymatic screening. Toxicological analysis by solid-liquid extraction and gas chromatography-mass spectrometry (GC-MS) analysis, was carried out to identify and quantify the individual substances present in the biological fluids and organs. Lidocaine concentrations were as follows: blood 31 microg/mL, gastric content 2.5 g, liver 10 microg/g, kidney 12 microg/g, brain 9 microg/g, spleen 24 microg/g, lung 84 microg/g, heart 9 microg/g, urine 9 microg/mL, and bile 6 microg/mL. No other drugs or alcohol were detected. When blood lidocaine reaches toxic levels, serious toxic symptoms associated with the central nervous system and cardiac system are noted. The overdose of lidocaine produces death from ventricular fibrillation or cardiac arrest. In this case, according to macroscopic and microscopic findings, the cause of death was most likely cardiac and possibly related to ventricular fibrillation.     

GC-MC法测定血液中丙泊酚

目的 建立血液中丙泊酚的气相色谱-质谱联用(GC-MS)分析方法.方法 血液以2,4-二甲基-6-叔丁基苯酚为内标,用乙醚进行液液萃取,离心后取有机层,水浴下挥干,GC-MS检测.结果 血液中丙泊酚与内标分离良好,在0.02～10 μg/mL范围内线性良好,线性方程为y=0.3136 x-0.0068,相关系数为0.9...     

Fatal intoxication following self-administration of a massive dose of buprenorphine

Several drug packages, including Subutex (high-dose buprenorphine, as sublingual tablets) boxes, were found near the corpse of a 25-year-old male drug addict, who apparently had committed suicide. The autopsy revealed a fatal respiratory depression. The toxicological investigations concluded that death resulted from massive burpienorphine intoxication. The determination of buprenorphine (BU) and norbuprenorphine (NBU) in all biological specimens was performed by liquid chromatography-electrospray mass spectrometry (LC-ES-MS) after hydrolysis (for solid tissues), deproteinization of the matrices, and solid-phase extraction of the compounds. Exceptionally high concentrations of BU and NBU were found in blood (3.3 and 0.4 mg/L, respectively), urine (3.4 and 0.6 mg/L), bile (2035 and 536 mg/L and brain (6.4 a nd 3.9 microg/g). The high concentration of BU (899 mg/L) and the absence of NBU in gastric liquid suggested oral intake. High concentrations of amino-7-flunitra/epam, the main metabolite of flunitra/epam, were also found in blood, urine and gastric liquid. This benzodiazepine may have been a co-factor in the toxic effects of BU.     

Determination of morphine in postmortem rabbit bone marrow and comparison with blood morphine concentrations

The aim of this study is to predict how long after time of death a buried body could be analyzed for opiates in soft tissues and to show the accessibility and suitability of bone marrow as a useful toxicological specimen from buried bodies. Morphine solutions were injected in nine albino rabbits. Doses ranged from 0.3 to 1.1 mg/kg with 0.1 mg/kg increments. One hour after the injections, the rabbits were sacrificed. Blood, urine and bone marrow samples were collected for analysis. After the whole bodies were buried, femur bone marrow specimens were collected on the seventh and fourteenth days. CEDIA was used to monitor morphine contents of the collected samples. All experimental cases showed that the increase in the given morphine doses correlated with the increase in blood and bone marrow morphine concentrations. High morphine concentrations were detected in urine samples, but there was no correlation between the urine and blood or urine and bone marrow morphine concentrations. Statistically meaningful increases in bone marrow morphine concentrations were found parallel to increase of blood morphine concentrations. Seventh and fourteenth day postmortem morphine concentrations also followed this correlation. Morphine concentrations in bone marrow at 7 and 14 day postmortem decreased consistently when compared with bone marrow morphine concentrations collected immediately after death. We conclude that in sudden death when other specimens are unavailable due to degradation, bone marrow can be a most useful specimen. Further experimental research in this area is required to validate bone marrow as an alternative tissue.     

Olanzapine concentrations in clinical serum and postmortem blood specimens--when does therapeutic become toxic?

The concentration of olanzapine (Zyprexa) was determined in 1653 clinical serum specimens during routine drug monitoring, and in 58 postmortem whole blood specimens as part of routine toxicological analysis. The analysis of olanzapine was performed by the solid-phase extraction of 1.0 mL of buffered serum or blood, followed by gas chromatography separation with nitrogen-phosphorus detection. The analysis of the clinical serum samples showed that 86% of positive serum values were within the range of 5 to 75 ng/mL, with a mean and median of 36 and 26 ng/mL, respectively. These data suggest that the concentrations of olanzapine expected during therapy may be higher than those previously reported. In 58 postmortem whole blood specimens the mean olanzapine concentration was 358 ng/mL with a range of 10 to 5200 ng/mL. Further, investigation of deaths involving olanzapine suggest that potential toxicity should be considered at concentrations above 100 ng/mL. Although the majority of the olanzapine-related deaths were associated with many other drugs, death primarily due to olanzapine toxicity was determined at concentrations in post-mortem blood as low as 160 ng/mL.     

Fatal accidental mixed poisoning of 3 men at the same time]

The case history presented reports on three 30- to 40-years-old men, who were found dead in a party like situation in the living room. The toxicological investigation proved alcohol and THC as well as therapeutic Flunitrazepam- and Pentobarbital levels and toxic 7- Amino-Flunitrazepam concentrations. The background of this surprising scene led up to the conclusion of an accidental death caused by a mixed intoxication.     

An Examination of the Postmortem Redistribution of Fentanyl and Interlaboratory Variability,

Fentanyl is a synthetic opioid agonist used for pain control. Often administered as a transdermal patch, it is an interesting drug for study of postmortem redistribution. We hypothesized that fentanyl concentrations would increase over time after death, as measured in blood drawn on the day prior to autopsy and in blood drawn at the time of autopsy in ten cases where fentanyl patches were identified at the scene. Concentrations were compared, and heart blood to femoral blood ratios were calculated as markers of postmortem redistribution. Fentanyl concentrations measured in peripheral blood drawn the day of autopsy (peripheral blood 2 [PB2]) were higher than those drawn the day prior to autopsy (peripheral blood 1 [PB1]) with a mean ratio (PB2/PB1) of 1.80. The ratio of heart blood concentrations (HB) to femoral blood concentrations drawn at autopsy (PB2) had a mean ratio (HB/PB2) of 1.08. Some cases had blood from the same source analyzed at two different laboratories, and concentrations of fentanyl in those samples showed inter‐ and intralaboratory differences up to 25 ng/mL. Postmortem fentanyl concentrations may be affected by antemortem factors, postmortem redistribution, and laboratory variability. Forensic pathologists must use caution in interpreting fentanyl levels as part of death investigation.     

Fatal intoxication with labetalol (Trandate)

The dead body of a 44-year-old woman, previously known for depression and alcoholism, has been discovered at her place of residence by her husband. A forensic autopsy has been carried out. The results indicated unspecific histological lesions (alveolar oedema, liver steatosis and interstitial nephritis) but did not reveal any apparent cause of death. Several boxes of medicines have been found near the body, justifying a toxicological analysis. This has been performed on peripheral blood and urine samples using liquid chromatography with diode array and mass spectrometric detections, in conjunction with gas chromatography coupled with mass spectrometry. Ethanol has been found (1.24 g/L in blood, 2.63 g/L in urine and 1.33 g/kg in gastric content), as well as therapeutic concentrations of meprobamate (14.1mg/L) and low concentrations of nordazepam (0.12 mg/L) in blood. On the other hand, particularly high levels of labetalol, a widely used beta-blocker, have been found both in blood (1.7 mg/L) and urine (20.2mg/L), which led us to measure labetalol levels in available viscera samples (liver, heart, kidney, and lung) and gastric content. Measured concentrations were 14.2 microg/g, 7.8 microg/g, 5.4 microg/g, 5.2 microg/g and 31.1 microg/g, respectively. We describe here the first report of a fatal intoxication attributed to labetalol that is linked to its acute toxicity, with tissue distribution of this beta-blocker.     

Fentanyl concentrations in 23 postmortem cases from the hennepin county medical examiner's office

The purpose of this study was to compare blood fentanyl concentrations in fentanyl-related deaths with fentanyl concentrations found incidentally at autopsy, as well as with fentanyl concentrations found in hospitalized patients receiving fentanyl. Between the years 1997 to 2005, 23 fentanyl-positive postmortem cases were identified. Nineteen of 23 (82.6%) cases were deemed to be drug overdoses. Fentanyl alone was responsible for 8 of the 19 (42.1%) overdose deaths. Mean and median fentanyl concentrations were 36 (SD 38) microg/L and 22 microg/L, respectively, range 5-120 microg/L. Seven of the cases were accidental, one undetermined. The remaining 11 of the 19 (57.9%) cases were mixed drug overdoses. Fentanyl concentrations in these cases were 31 (SD 46) microg/L, range 5-152 microg/L. All of the mixed drug overdoses were determined to be accidental. Four cases where fentanyl was considered an incidental postmortem finding were determined to be natural deaths. In hospitalized inpatients (n = 11) receiving fentanyl 2 of the patients receiving fentanyl for chronic pain for more than 3 months had concentrations of 8.5 microg/L and 9.9 microg/L. The other nine inpatient concentrations were less than 4 microg/L. In conclusion, blood fentanyl concentrations found in cases where fentanyl alone was determined to be the cause of death were similar to cases where fentanyl was part of a mixed drug overdose. There was also considerable overlap between fentanyl concentrations in fentanyl-related overdose deaths compared to hospitalized patients being treated for chronic pain. Fentanyl concentrations in postmortem cases must be interpreted in the context of the deceased's past medical history and autopsy findings.     

Postmortem diffusion of drugs from the bladder into femoral venous blood.

We describe significantly elevated drug concentrations in the femoral venous blood due probably to postmortem diffusion from the bladder. A 16-year-old deceased male was found in a shallow ditch in winter. The estimated postmortem interval was 9 days and putrefaction was not advanced. The cardiac chambers contained fluid and coagulated blood and a small amount of buffy coat clots. Diffused hemorrhages were found in the gastric mucosa. The bladder contained approximately 600 ml of clear urine. Gas chromatographic-mass spectrometric analysis of the urine disclosed allylisopropylacetylurea (a fatty acid ureide sedative), diphenhydramine, chlorpheniramine and dihydrocodeine. The cause of death was considered to be drowning due to a drug overdose and cold exposure. The concentrations of diphenhydramine, free dihydrocodeine and total dihydrocodeine in the femoral venous blood (1.89, 3.27 and 3.30 microg/ml, respectively) were much higher than those in blood from the right cardiac chambers (0.294, 0.237 and 0.240 microg/ml, respectively). Urine concentrations of diphenhydramine, free dihydrocodeine and total dihydrocodeine were 22.6, 37.3 and 43.1 microg/ml, respectively. The stomach contained negligible amounts of diphenhydramine, free dihydrocodeine and total dihydrocodeine (0.029, 0.018 and 0.024 mg, respectively); concentrations of these drugs in the femoral muscle were 0.270, 0.246 and 0.314 microg/g, respectively. These results indicate that postmortem diffusion of diphenhydramine and dihydrocodeine from the bladder resulted in the elevated concentrations of these drugs in the femoral venous blood. Not only high urinary drug concentrations but also a large volume of urine in the bladder might accelerate the postmortem diffusion.     

Interpretation of a 3,4-methylenedioxymethamphetamine (MDMA) blood level: discussion by means of a distribution study in two fatalities

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy" is a currently used or abused designer drug and fatalities are frequently encountered in forensic practice. However, the question remains open whether an MDMA blood level can be toxic or even potentially lethal. In order to provide insight in the interpretation of a detected MDMA concentration, the distribution of MDMA and its metabolite 3,4-methylenedioxyamphetamine (MDA) in various body fluids and tissues was studied and discussed in two different fatalities. Apart from peripheral blood samples (such as femoral and subclavian blood), various blood samples obtained centrally in the human body and several body fluids (such as vitreous humour) were examined. In addition, various tissues such as cardiac muscle, lungs, liver, kidneys, and brain lobes were analysed. In contrast to the peripheral blood levels, high MDMA and MDA levels were found in cardiac blood and the majority of the organs, except for the abdominal adipose tissue. The high concentrations observed in all lung lobes, the liver and stomach contents indicate that post-mortem redistribution of MDMA and MDA into cardiac blood can occur and, as a result, blood sampled centrally in the body should be avoided. Therefore, our data confirm that peripheral blood sampling remains "the golden standard". In addition, a distinct difference in peripheral blood MDMA concentrations in our two overdose cases was established (namely 0.271 and 13.508 microg/ml, respectively). Furthermore, our results suggest that, if a peripheral blood sample is not available and when putrefaction is not too pronounced, vitreous humour and iliopsoas muscle can be valuable specimens for toxicological analysis. Finally, referring to the various mechanisms of death following amphetamine intake, which can result in different survival times (e.g. cardiopulmonary complications versus hyperthermia), the anatomo-pathological findings and the toxicological results should be considered as a whole in arriving at a conclusion.     

Dependence of acute opiate poisoning lethal outcome on the gender, age, and duration of addiction

The article presents toxicological characteristics of 198 cases of acute parenteral poisoning with morphine and heroin in the range of concentrations of their metabolites in the blood and urine which occur in practice. Risk of death is quantified in the range of possible morphine concentrations in the blood in acute opiates intoxication with reference to gender and age. Assessment of the criteria of quantitative opiates toxicity was made according to the method of logit regression and dose-effect curve suitable for analysis of correlations between probability of death and blood concentrations of opiates metabolites. Conditional lethal doses in respect to gender and age are calculated.