Fatal cyclobenzaprine overdose with postmortem values

There are only two published cases of overdose with postmortem blood cyclobenzaprine concentrations, both with confounding factors. We report two additional cases of fatal cyclobenzaprine overdose with postmortem values. Case 1: a 56-year-old female was found in full cardiopulmonary arrest after a verbal suicide threat to a friend. Postmortem blood concentrations were cyclobenzaprine 0.96 mg/L and diazepam 0.3 mg/L. Case 2: a 37-year-old male was found in full arrest by a family member after an intentional ingestion of cyclobenzaprine. Postmortem blood concentrations were cyclobenzaprine 0.8 mg/L and ethanol 0.174 gm/dL. The concentrations of diazepam and ethanol reported in these two patients were not found in quantities usually associated with a fatal outcome, suggesting that the cyclobenzaprine was the primary cause of the fatality. Additionally, the blood was drawn from a femoral site, so that postmortem redistribution is not a likely factor. Blood concentration of > or = 0.8 mg/L cyclobenzaprine may be associated with a fatal outcome.     

Determination of ethchlorvynol in body tissues and fluids after embalmment

A 54 year-old female expired at her residence. Her husband, a physician, signed a certificate stating that her death was due to cerebrovascular accident (CVA) and released her body to a funeral home, where she was embalmed. Since the deceased had a long history of medical problems and drug abuse, an autopsy was performed and no evidence of CVA was found. Toxicological analyses of body fluids and tissues revealed the presence of ethchlorvynol in high concentration in the bile (112 mg/l). The bloody fluid collected from the heart contained a concentration of ethchlorvynol below the limit for quantitation. Other findings included phenobarbital (32.8 mg/l) in heart bloody fluid and methanol (an ingredient of embalming fluid). The significance of the findings is discussed in relation to embalmment prior to autopsy and toxicological analyses. Ethchlorvynol concentration in the bile is compared to other fatal cases due to ethchlorvynol overdose.     

Swollen Lips After a Night of Partying—An Allergic Reaction to Ecstasy?

Ecstasy (MDMA) is a mood‐lifting drug with numerous somatic side effects, for example, dehydration or continuous chewing and biting. We describe the case of a young woman who underwent a forensic medical examination for suspected sexual assault. She claimed to have suffered from a memory lapse, and she had a painful swelling of her lips with a plaque‐like coating on her lips and buccal mucosa. The attending physician suspected that these findings might have been caused by strong sucking pressure on her lips within the context of a sexual assault. A toxicological examination of a blood specimen verified that she had been under the influence of an extremely high dose of ecstasy (1.456 mg/L MDMA and 0.0213 mg/L MDA). Pursuant to the forensic medical assessment, the described findings on her lips, and buccal mucosa were interpreted as an allergic and mechanical reaction (through continuous chewing and biting) to ecstasy.     

Acute intoxication caused by overdose of flunitrazepam and triazolam: high concentration of metabolites detected at autopsy examination

ABSTRACT: A 52-year-old woman was found dead on the floor of the living room on the first floor of a house, which belonged to the man with whom she shared the house. On visiting the site, her clothes were found to be undisturbed. Packages of flunitrazepam (Silece, 2 mg/tablet) and triazolam (Halcion, 0.25 mg/tablet) were found strewn around the victim. Toxicological analysis was performed, and the concentrations of flunitrazepam, triazolam, and their metabolites in the victim's blood and urine were measured by high-performance liquid chromatography coupled with photodiode array and mass spectrometry. A high blood concentration of 7-aminoflunitrazepam was detected (1,270 ng/g), and further metabolites such as 7-acetamidoflunitrazepam, 7-acetamidodesmethylflunitrazepam, and 7-aminodesmethylflunitrazepam were detected in the blood and urine samples. In addition, 4-hydroxytriazolam and α-hydroxytriazolam were detected in her urine at a concentration of 950 and 12,100 ng/mL, respectively.On the basis of the autopsy findings and toxicology results of high concentrations of both flunitrazepam and triazolam derivatives, the cause of death was determined to be acute intoxication from flunitrazepam and triazolam.     

Fatality caused by a combined trimipramine-citalopram intoxication

A 53-year-old woman who was diagnosed as suffering from depression was found dead in her bed. The autopsy revealed no morphological changes sufficient to explain death. Toxicological analysis was performed and the drugs trimipramine (2.33 mg/l), citalopram (4.81 mg/l) and zolpidem (0.07 mg/l) were identified in the femoral blood. A combined drug intoxication resulting in synergistic effects to cardiovascular disorders was proposed as the cause of death. An acute overdose and suicide was suggested by calculation of the parent drug to main metabolite ratios in femoral blood and liver tissue. The trimipramine to desmethyltrimipramine ratios were calculated to be 2.06 and 3.18, the citalopram to desmethylcitalopram ratios were 1.96 and 2.02.     

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).     

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.     

Fatal outcome of poisoning with the benzodiazepines flunitrazepam and diazepam

On a wintry day a 29-year-old woman was found dead beside her car showing head injuries and signs of hypothermia. Several empty packets of sedative and hypnotic drugs were lying inside the car. Toxicological analysis revealed the presence of flunitrazepam (heart blood of the left and right chamber 0.033 mg/L each), norflunitrazepam (left heart blood 0.029 mg/L, right heart blood 0.027 mg/L), 7-amino-flunitrazepam (left heart blood 0.090 mg/L, right heart blood 0.104 mg/L), diazepam (left heart blood 0.395 mg/L, right heart blood 0.386 mg/L), nordazepam (left heart blood 0.112 mg/L, right heart blood 0.115 mg/L) and temazepam (left heart blood 0.034 mg/L, right heart blood 0.033 mg/L). Neither alcohol nor other drugs were found. It was concluded that benzodiazepine intake led to a disturbance of consciousness. Whether the woman died in this situation due to the icy temperature as a result of hypothermia or whether she died or would have died solely due to benzodiazepine overdosage could not be clarified.     

Methcathinone: a new postindustrial drug

Methcathinone, a methyl derivative of cathinone, is an illicit drug also known as ephedrone. It is a stimulant found in the "khat" plant, Catha edulis, which can easily be synthesized from pseudoephedrine. Its intoxication is difficult to diagnose and cure properly for two reasons: (i) target consumers are usually "well-educated people" aware of the risks and precautionary measures and (ii) intoxication by cathinone derivatives of synthetic or natural (derived from the khat) origin induce misleading symptoms. As a result, documented reports of methcathinone intoxication that are based on reliable analyses are rare. This paper describes a case of reiterated coma due to an overdose of methcathinone dissolved in alcohol that was taken with bromazepam. A 29-year-old woman was admitted to an emergency department for a coma of toxic origin. Medical files showed that it was her second such episode to occur that month. Moreover, the family indicated signs of depression, incoherent behaviour and intake of "amphetamine-like" drugs. Clinical examination revealed a Glasgow coma score of 9, symmetrical reactive pupils with mydriasis and no convulsions. The patient presented with rapid respirations and her blood pressure was 93/53 mmHg. The ionogram and the blood gas analyses were normal, while the blood alcohol level was 0.167 g/dL. Urinalysis revealed the presence of benzodiazepines and a high concentration of amphetamines (methcathinone: 17.24 mg/L, ephedrine: 11.60 mg/L and methylephedrine: 11.10 mg/L). In addition, serum analysis revealed bromazepam (8.89 mg/L), methcathinone (0.50 mg/L) and methylephedrine (0.19 mg/L). This case showed that the consumption of bromazepam and alcohol altered the typical clinical symptoms of cathinone derivative intoxication, namely hypertension and convulsions. Methylephedrine, an impurity resulting from the alkylation of a primary amine, can be considered a chemical tag indicating fraudulent synthetic origin of the drug. This case describes a documented example of new addictive behaviour of "well-educated" people involving the intake of methcathinone, a postindustrial psychostimulant intentionally combined with an anticonvulsant benzodiazepine. However, this specific case suggests that in spite of a very high bromazepam concentration in presence of the potentiator alcohol, the vital respiratory function would be probably maintained, thanks to the association with methcathinone.     

Collective poisoning with hallucinogenous herbal tea

An incident wherein more than 30 people were poisoned with a herbal infusion during a meditation session is described. The clinical features observed were hallucinations, aggression, agitation, amnesia, mydriasis, dry skin, tachycardia, hyperthermia, hypotension, collapse, coma and respiratory depression. All patients recovered, although mechanical ventilation was required in some instances. A portion of the herbal infusion was found to contain atropine (hyoscyamine), scopolamine (hyoscine), harmine, and other alkaloids. The estimated ingested doses (free bases) were atropine 4 mg, harmine 27 mg, and scopolamine 78 mg. The mean concentrations in 21 serum samples obtained approximately 6h after ingestion of the infusion were atropine 5 ng/ml, harmine 8 ng/ml, and scopolamine 13 ng/ml.     

Detection of amitriptyline, nortriptyline and bromazepam in liver, CSF and hair in the homicidal poisoning of a one-month-old girl autopsied 8 months after death

We reported on the death by poisoning of a one-month-old baby that had followed the death of one of her sister (due to cyamemazine overdose). Exhumation of the corpse was done 8 months after burial and revealed the presence of amitriptyline. Parent drug and its metabolite were analysed by HPLC-MS/MS in positive ionisation mode on a C(18) analytical column using a gradient of acetonitrile and 2mM formate buffer at pH=3. Quantification is based on the main ion m/z=233, the common product ion of nortriptyline (MH(+), m/z 264), amitriptyline (MH(+), m/z 278) and nortriptyline D3 used as internal standard (MH(+), m/z 267). Amitriptyline and nortriptyline in the liver were measured at a concentration of 29.8 and 3.6 μg/g, respectively. Hair analyses revealed the presence of amitriptyline and nortriptyline at concentrations of 1811 and 43 pg/mg, respectively, while complementary analyses showed the presence of bromazepam in the hair at a concentration of 740 pg/mg, thus documenting previous administrations. The mother confessed later having used the drinkable form of the pharmaceutical LAROXYL(?) by pouring the content of a 20 ml bottle (at 40 mg/ml) into the feeding-bottle of her child. The milk was sweet but still bitter and following the testimony of a close relative, the whole family helped to feed the crying baby.     

High urine ethanol and negative blood and vitreous ethanol in a diabetic woman: a case report, retrospective case survey, and review of the literature

Several studies have shown that ethanol can be produced in urine infected with yeast or bacteria in vitro. We present the unusual case of a diabetic woman in whom ethanol was produced in her urine in vivo. The decedent was a 19-year-old woman who was noncompliant with her diabetes treatment. She presented to a local hospital in severe diabetic ketoacidosis and died shortly thereafter. Upon arrival at the hospital, a blood glucose of 553 mg/dL was detected. A urinalysis was positive for ketones (> 80 mg/dL), glucose (> 1000 mg/dL), and large budding yeast forms. A drug screen performed on the urine was positive for ethanol. At the coroner/medical examiner office, an autopsy was negative for significant anatomic findings. Toxicology analysis revealed a urine ethanol level 0.32 g/dL, although no ethanol was detected in blood or vitreous samples. A urine gram stain and culture identified Candida glabrata. A retrospective case review of all deaths related to diabetes examined at the coroner/medical examiner office from 1986 to 2003 did not reveal other cases with similar findings. This case of a noncompliant, juvenile-diabetic woman illustrates a rare finding of apparent in vivo glucose fermentation by C. glabrata to form ethanol in the urine. This case also highlights a potential difficulty in toxicologic analysis and interpretation using urine only.     

A Multi-Drug Intoxication Fatality Involving Xyrem® (GHB)

Abstract:  Gamma-hydroxybutyrate (GHB) is best known as a recreational depressant drug, whose use has also been implicated in drug facilitated sexual assault cases. It is also available as a therapeutic agent (Xyrem^®) used for the treatment of daytime sleepiness or cataplexy associated with narcolepsy. This is a report of a case of a 53-year-old woman undergoing treatment with Xyrem^® for narcolepsy. The decedent was also prescribed tramadol, gabapentin, cetirizine, modafinil, carisoprodol, and Xyrem^®. Toxicological analysis of the blood revealed GHB 165.6 mg/L, and 90.7 mg/L in the urine. Blood GHB concentrations in the range 156–260 mg/L have been reported to induce moderately sound sleep. The combined use of central nervous system depressant drugs, together with her problematic sleep apnea, and snoring (both contraindications for GHB use) were determined to have caused this subject's death. The manner of death was determined to be accidental.     

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.     

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.     

Identification of alprazolam in hair in two cases of drug-facilitated incidents

The use of a drug to modify a person's behaviour for criminal gain is not a recent phenomenon. However, the recent increase in reports of drug-facilitated crimes (sexual assault, robbery) has caused alarm by the general public. Among the drugs that can be used, alprazolam (Xanax), an anxiolytic benzodiazepine, has been seldom observed. To document two cases involving this drug, we have developed an approach based on hair testing by LC-MS/MS. After pH 8.4 buffer incubation and extraction with methylene chloride/diethyl ether (80/20, v/v), hair extracts were separated on a XTerra MS C18 column using a gradient of acetonitrile and formate buffer. Alprazolam and diazepam-d5, used as internal standard, were detected by electrospray tandem mass spectrometry. In the first criminal case, alprazolam tested positive in two consecutive 2 cm hair segments at 4.9 and 2.4 pg/mg, from a 12-year-old girl, assaulted by her father who had sedated her three or four times. In the other case, alprazolam was detected in four consecutive 1cm hair segments at 3.1-0.4 pg/mg, obtained from an adolescent who had been forced to prostitute herself.     

A forensic toxicological dilemma: the interpretation of post-mortem concentrations of central acting analgesics

Dora V., a 88-year-old pensioner suffering from a hiatus hernia, died at the home of an orthopaedist and his wife, an anaesthetist, immediately after she had received a dose of 300 mg pethidine via intravenous infusion in a timeframe of about 90 min. One day before her death a befriended notary of the couple visited Dora V. and obtained a blank signature. After her death, a will was forged using this signature, rendering the couple sole heirs of Dora V.'s estate with a value of several million euros. Post-mortem toxicology was performed in three different institutes of legal medicine. The concentrations of pethidine in peripheral venous blood were between 6.1 and 6.5mg/l and 9.5 and 17.2mg/kg in brain. Pharmacokinetic calculation confirms the given dose. There was no doubt that the cause of death was acute pethidine intoxication. The accused couple claimed that this dose of pethidine was indicated to relief pain, and as the pathologists said in their expert opinions that the hiatus hernia could explain her death, the court had to acquit the accused. This very special case demonstrates that preconceived murder of a sick person with suitable analgesics cannot be proven--at least not with the methods available to forensic toxicology and pathology. This has to be taken into consideration if euthanasia will be legalised under special circumstances.     

Fatal Oral Methylphenidate Intoxication with Postmortem Concentrations

Methylphenidate (MPD) is a widely prescribed stimulant used primarily for the treatment for attention‐deficit/hyperactivity disorder (ADHD). Suicide attempts involving MPD ingestion have been well described; however, deaths attributed solely to MPD ingestion have not been reported. A 62‐year‐old woman was found dead on her floor. The only discrepancy in among her medication quantities was that >three hundred 10 mg MPD tablets were missing. Analysis utilizing gas chromatography–mass spectrometry revealed elevated postmortem MPD peripheral and central blood, liver and vitreous humor concentrations. Considering both the central blood to peripheral blood ratio (0.89) and the liver to peripheral blood ratio (3.3), MPD does not appear subject to significant postmortem redistribution. With no other identifiable cause of death, we report what appears to be the first isolated MPD ingestion associated with a fatality.     

Toxicologic findings in suicide with doxepin and paroxetine]

A young nurse was found dead in her flat. In chemical-toxicological analysis the following femoral blood drug concentrations were determined: paroxetine 0.176 mg/l, doxepine 82.12 mg/l, desmethyldoxepine 0.34 mg/l. Additionally the drug concentrations were determined in various body fluids and organs. The results of the described fatality are discussed. For interpretation of toxicologic results in antidepressant fatalities ratios of parent drug to metabolite and postmortem drug redistribution should be taken into account.