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

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.

An autopsy case of drowning under the influence of multiple psychotropic drugs.

A fatal case of drowning under the influence of multiple psychotropic drugs, such as quetiapine, escitalopram, aripiprazole and flunitrazepam, is presented. Quantitative toxicological analysis of a femoral blood sample revealed concentrations of quetiapine, escitalopram, aripiprazole and 7-aminoflunitrazepam (a metabolite of flunitrazepam) of 1.266 µg/ml, 0.609 µg/ml, 0.124 µg/ml and 0.055 µg/ml, respectively. From the autopsy findings, results of toxicological examination and investigation by the authorities, we concluded that the cause of death was drowning under the influence of mainly quetiapine and escitalopram.

Forensic toxicological implication of an autopsy case of mixed drug overdose involving clomipramine, chlorpromazine and flunitrazepam.

A case of fatal poisoning involving clomipramine, chlorpromazine and flunitrazepam is presented. Quantitative toxicological analysis showed that the concentrations of clomipramine, chlorpromazine and 7-aminoflunitrazepam (a metabolite of flunitrazepam) in the femoral blood were 3.24 microg/ml, 0.36 Kg/ml and 0.61 microg/ml, respectively, and large amounts of drugs were also detected from the stomach contents. We concluded that the cause of death was due to the combined use of clomipramine, chlorpromazine and flunitrazepam.

Benzodiazepine antagonist Ro 15-1788 in self-poisoning. Diagnostic and therapeutic use.

Thirteen patients with benzodiazepine overdosage received the specific benzodiazepine antagonist Ro 15-1788. Intravenous administration of 1.5 to 10 mg reversed the central nervous system depression induced by different benzodiazepine compounds within one to two minutes of injection. These case reports indicate that Ro 15-1788 may be an effective tool in the primary management of self-poisoning.

Postmortem distribution of flunitrazepam and its metabolite 7-aminoflunitrazepam in body fluids and solid tissues in an autopsy case: Usefulness of bile for their detection.

We experienced an autopsy case of a woman in her 70s, in which the direct cause of her death was judged as asphyxia due to the occlusion of food in the trachea. The postmortem interval was estimated at about 2days. The specimens dealt with were femoral vein blood, right heart blood, left heart blood, bile, brain, lung, heart muscle, liver, spleen, kidney, pancreas, skeletal muscle, and adipose tissue. By tentative drug screening, we found a high concentration of 7-aminoflunitrazepam in the femoral vein blood, which lead us to examine the postmortem distribution of flunitrazepam and its metabolite 7-aminoflunitrazepam in her body fluids and solid tissues. The extraction of flunitrazepam, 7-aminoflunitrazepam and internal standard nimetazepam was performed by a modified QuEChERS method, followed by the analysis by liquid chromatography-tandem mass spectrometry. Because this study included various kinds of human matrices with quite different properties, we used the standard additional method to overcome the matrix effects. The concentration of 7-aminoflunitrazepam were generally much higher than those of the parent drug flunitrazepam for most specimens except for the adipose tissue, showing that flunitrazepam is readily metabolized to its 7-amino metabolite after absorption into the body both antemortem and postmortem. The outstandingly highest concentration of 7-animoflunitrazepam was found in the bile, followed by the kidney, pancreas, left heart blood, spleen and liver. Although a majority of flunitrazepam was converted to 7-aminoflunitrazepam, the flunitrazepam concentration was highest in the pancreas, followed by the spleen, bile, left heart blood, and brain. In contrast to the results on synthetic cannabinoids, the levels of flunitrazepam and 7-animoflunitrazepam in the adipose tissue were relatively low. The present study showed that the bile may be a useful specimen for detection of unchanged benzodiazepines/their metabolites to be collected at autopsy.

Determination of flunitrazepam in plasma by liquid chromatography.

A reversed-phase liquid chromatographic method has been used to determine flunitrazepam in plasma. Extraction was simple and there was no need to hydrolyse the drug. Separation was achieved on a 150 x 3.9 mm i.d. column packed with 4-microns Nova Pack C18 using a mobile phase of water-acetonitrile-triethylamine (700:300:4, v/v/v) (adjusted to pH 7.5 with orthophosphoric acid). The method was shown to be rapid and reliable with a lower limit of detection of 5 ng ml-1. Results are reported of simple experiments on the effects of temperature and light on the stability of flunitrazepam in plasma kept on the laboratory bench.

Nutmeg (myristicin) poisoning--report on a fatal case and a series of cases recorded by a poison information centre.

In literature, cases of nutmeg abuse have been described repeatedly, but only one fatal case of poisoning was reported [1]. In the present case, myristicin (4 microg/ml) was detected for the first time in the postmortal serum of a 55-year-old woman. Identification was achieved with the aid of UV-VIS spectroscopy and TLC; for quantification, HPLC was used. Because also flunitrazepam (0.072 microg/ml) was found, death had probably been due to the combined toxic effect of both substances. From 1996 to 1998, in a series of cases, seven poisonings with nutmeg were recorded by the Erfurt Poison Information Centre. Even where higher doses (20-80 g of powder) had been ingested, a life-threatening situation was never observed. In one of these cases, a myristicin blood level of 2 microg/ml was measured 8h after ingestion of two to three tablespoonful of nutmeg powder (approx. 14-21 g, or 280-420 mg/kg).

Citalopram in fatal poisoning cases.

Citalopram, a selective serotonin reuptake inhibitor, is the most frequently prescribed antidepressant in Sweden. To investigate the extent to which citalopram in overdose is found in fatal poisoning cases compared with other drugs, all fatal poisonings in one forensic medicine district in Sweden during the years 1994-1999 were examined. Drugs found in overdose in more than 10 cases were included. The ratio between number of cases with each included drug and prescription of defined daily dose/1,000 inhabitants/day (DDD) was determined. Citalopram was the fourth most frequently found drug in overdose, occurring in 22 (6%) of the 358 fatal poisoning cases, after dextropropoxyphene (DXP), flunitrazepam and nitrazepam, which were present in 111 (31%), 56 (16%) and 31 (9%) cases, respectively. When related to the prescription rate, citalopram was significantly less represented than five of the other seven included drugs, namely DXP, flunitrazepam, nitrazepam, amitriptyline and clomipramine. Propiomazine and zopiclone occurred to the same extent as citalopram. According to the assessments of the forensic physicians, citalopram was the cause of death in five cases (1.4%) and contributed to death in another nine cases (2.5%). It is concluded that citalopram, in spite of its high prescription rate, has not become a drug of importance in fatal poisoning cases. Since, this result may not be generalisable to non-fatal poisoning cases, it is recommended that the prevalence of citalopram in these cases be examined separately.

Flunitrazepam: an evaluation of use, abuse and toxicity.

The benzodiazepine flunitrazepam is extensively prescribed to patients with insomnia in many countries, but has also become popular among alcohol- and drug abusers. Several reports indicate that it is used as a date rape drug and suggest that it may precipitate violent behavior. Furthermore, flunitrazepam is involved in many fatal intoxications in Sweden. This study was designed and conducted to explore the negative consequences of flunitrazepam abuse in Sweden, and to assess the trends in its use and abuse. The occurrence of flunitrazepam in cases referred to the Department of Forensic Chemistry in Linköping, Sweden 1992-1998, was investigated in detail. The detections were studied separately for different groups; medicolegal death investigations, drug abuse cases, driving under influence cases, and other medicolegal cases. These data were further compared with the sales, and seizures by the Swedish Customs and the Swedish Police. During 1992-1998, 641 fatalities occurred, where the cause of death was attributed to intoxication with flunitrazepam solely (130) or in combination with other drugs, or concomitant conditions (511). In 78% of all driving under influence cases, where flunitrazepam was detected, the analyses also disclosed the presence of illicit drugs. A similar association was seen in drug abuse cases. The seizures reported by the Swedish Customs revealed a substantial and increasing illegal trade. Cases, where flunitrazepam seemingly induced violent behavior were identified, and one of these is described in some detail. It is concluded that the abuse pattern and the toxicity of flunitrazepam should be kept in mind by forensic investigators and that this panorama also should be considered when decisions about the registration and classification of flunitrazepam are made in different countries.

Among fatal poisonings dextropropoxyphene predominates in younger people, antidepressants in the middle aged and sedatives in the elderly.

To compare the characteristics of dextropropoxyphene (DXP) poisoning victims with those of victims of poisonings by antidepressants and sedatives, we examined all fatal poisonings due to DXP, antidepressants or sedatives among autopsies performed at one department of forensic medicine in Sweden during the six-year period from 1992 to 1997. In 202 cases, death was classified as fatal poisonings by DXP, antidepressants or sedatives. DXP caused death in 78 cases (39%), antidepressants in 49 (24%), and sedatives in 75 (37%). DXP as a single preparation was predominant in causing death. The second compound, flunitrazepam, caused death in 30 cases (15%). The victims of poisonings by DXP, antidepressants, or sedatives shared a similar history of alcohol/drug abuse, depression and somatic illness. They were mostly living alone at the time of death (>60%), the majority died at home (81%), and suicide was the most frequent manner of death (73%). Age seemed to be an important characteristic regarding the choice of drug. Younger people predominantly died of DXP (mean age 43 years, 95% confidence interval, CI 39-47), and elderly people of sedatives (mean age 59 years, CI 55-63). Antidepressants were found mainly in middle-aged victims (mean age 51 years, CI 48-54). The predominance of sedatives among the elderly might be explained by a very high prescription rate of such drugs in older age groups, but prescription rate could not explain the DXP predominance among younger people. We hypothesize that younger people are more prone to abuse therapeutic drugs for euphoric reasons than elderly people, and that because of its high toxicity, DXP leads to accidental deaths more often than sedatives.

Flunitrazepam (Rohypnol) abuse in combination with alcohol causes premeditated, grievous violence in male juvenile offenders.

This study focuses on 19 juvenile offenders who were frequently intoxicated by flunitrazepam (FZ), almost exclusively under the brand name Rohypnol. Street names for Rohypnol tablets are Rophies, Ropies, Roofies, Ropes, Roches, Rochas, Rochas Dos, Rophs, Ropers, Ribs, R-25, Roach-2s, Trip and Fall, Remember All, Mind Erasers, Forget Pills, and the Date Rape Drug. An overdose of FZ gives an increased feeling of power and self-esteem, reduces fear and insecurity, and provides the belief that everything is possible. FZ is also associated with loss of episodic memory and with impulsive violence, particularly when combined with alcohol. The subjects were taken from a subpopulation of 47 male juvenile offenders from Swedish national correctional institutions. Background information for subjects was obtained by in-depth interviewing and personality inventories including the Zuckerman Sensation-Seeking Scales, the Eysenck Personality Questionnaire, and the Karolinska Scales of Personality. Data concerning previous criminal offenses was obtained from the Swedish National Police Board. Almost all of the FZ abusers had been previously sentenced for serious violent offenses. Our data suggest that FZ abused by psychiatrically vulnerable subjects (i.e., with high scores on boredom susceptibility and verbal aggression) poses a serious hazard both to the abusers as well as the community. Our results support the finding that FZ should be classified as a Schedule I drug (i.e., a drug similar to heavy narcotics).

[A drowsy child: benzodiazepine poisoning?]. / Een suf kind: benzodiazepine-intoxicatie?

In The Netherlands accidental intoxications in children due to benzodiazepines are regularly encountered. In 1987 of 1630 requests for information at the National Poison Control Centre about probable benzodiazepine intoxications 144 (8.8%) concerned children 0-12 years of age. The symptoms of this type of intoxication are non-specific and if the physician does not think of benzodiazepine intoxication extensive diagnostic procedures may be performed. If children show symptoms e.g. unconsciousness, ataxia and hypotonia, the physician should always think of benzodiazepine intoxication and try to confirm or to exclude this possibility by toxicological analysis. We discuss ways and means of the diagnosis and how to avoid pitfalls on the way.

[Tetraplegia in the course of coma from drug intoxication]. / Tétraplégie au décours d'un coma par intoxication médicamenteuse.

It is reported a case of quadriplegia occurring in a 67-year-old women after she commits suicide with flunitrazepam. The patient stayed during around twenty hours unconscious, in the sitting position, with an extreme flexion of the neck on the left side. After injection of flumazenil the patient's consciousness was restored. Nevertheless a complete sensitive and motor deficit at the C4 and C5 level was then observed. Several diagnosis such as peripheral neuropathy, infectious disease, or arterial occlusion were eliminated and we finally postulated that the regulation of the spinal blood flow had likely been disturbed by the prolonged flexion of the neck, the hypotension and the putative respiratory depression. The fact that the patient suffered from cervicarthrosis would have already impaired the spinal blood flow regulation and consequently had probably damaged the spinal cord. No clinical improvement of the quadriplegia was noticed and the patient died in the intensive care unit thirteen days after admission. Such an exceptional complication after a toxic coma remind us the necessity to avoid long lasting vicious position of the cervical spine in anaesthesia and emergency practice.

Rave drugs: pharmacological considerations.

An increasingly prevalent component of today's adolescent and young adult culture are the rave or club drugs, such as Ecstasy, Rohypnol, gamma-hydroxybutyric acid, ketamine, Fry, lysergic acid diethylamide (LSD), and methamphetamine. Considering the incidence of accidental injury in this age group, young patients admitted to the operating room in emergency situations may be under the influence of one of these drugs. Each of these illicit drugs has distinct adverse physiological effects that may be compounded by the administration of anesthetic agents. Thus, it is important for the anesthetist to be cognizant of these drugs, their effects, and the potential risk factors they pose.

[Plastic bag as the method in suicide and homicide]. / Plastikbeutel als Mittel der Selbst- und Fremdtötung.

The report describes a suicide and a homicide by suffocation in a plastic bag. Both cases were copy-cat acts. The suicide copied the method--taking medicines and pulling a plastic bag over his head from a personal model. In the homicide the perpetrator followed the example of a film sequence from the US feature film "Charade".

[Serial homicide in the Vienna-Lainz hospital]. / Die Mordserie im Krankenhaus Wien-Lainz.

Report on many cases of murder (the indictment included 41 cases) in the Clinical Centre of Lainz in Vienna. Two of the accused nurses were sentenced to life imprisonment, the other two to 15 and 12 years respectively. The operating modes are presented: intravenous administration of flunitrazepam, so called "oral hygiene", which proved to be forced aspiration of water, and injection of insulin. Possibilities of preventive measures against murder in hospital are discussed.

[Suicidal monointoxication with flunitrazepam. Further comment on coloration phenomena of the upper gastrointestinal tract]. / Suizidale Monointoxikation mit Flunitrazepam--ein Beitrag zu Färbungsphänomenen der Schleimhaut des oberen Gastrointestinaltrakts.

Fatal monointoxications with benzodiazepines, for instance with a suicidal intention, are exceptional findings. We report the autopsy case of an 82-year-old woman who died due to a suicidal monointoxication with Rohypnol 1 mg film tablets (therapeutical agent: flunitrazepam). 0.065 mg/L flunitrazepam and 0.34 mg/L 7-aminoflunitrazepam were detected in a postmortem heart blood sample and toxicological analysis revealed the metabolite 7-aminoflunitrazepam in gastric contents, too. At external examination, a bluish-turquoise coloration was seen around the woman's right nostril and within the oral cavity. At autopsy, similar coloration phenomena were seen on the mucosa of the distal esophagus and the stomach. Formerly, bluish stains on mouth and nostrils were considered indicative of intoxications with organophosphates such as parathion (E 605). More recently, case reports accumulate where an intoxication with Rohypnol 1 film tablets (containing the coloring agent indigocarmine in its core) have to be considered as a potential differential diagnosis of such coloration phenomena.

[Fatal outcome of poisoning with the benzodiazepines flunitrazepam and diazepam]. / Tödlich verlaufene Intoxikation unter Beteiligung der Benzodiazepine Flunitrazepam und 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.