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.

Femoral blood concentrations of flualprazolam in 33 postmortem cases.

Flualprazolam is a novel designer benzodiazepine, structurally related to alprazolam, flubromazolam and triazolam. In the last couple of years, it has been frequently detected in seizures and in forensic cases in Sweden and Finland. However, there is a lack of published blood concentrations for the drug, which presents difficulties when assessing its relevance for the cause of death. A quantitative method for the determination of flualprazolam in post-mortem blood was developed and validated, and subsequently used to analyse samples from 33 deaths previously screened as testing positive for flualprazolam in Sweden and Finland. Most of the cases in the study were accidental deaths (61 %) or suicides (18 %). The median (range) flualprazolam concentration was 18.0 (3.0-68) ng/g. The majority of the deceased were male (82 %) and the median age was 30 years. The median age in the Swedish cases was significantly higher (35 years) than in the Finnish cases (23 years) (p< 0.05). Poly-drug use and particularly the concomitant use of flualprazolam and opioids were very common in the study population. Most of the cases that were positive for flualprazolam were fatal poisonings by a drug (N=23), and in 13 cases, flualprazolam was implicated in the cause of death. Combining the resources of two countries in which all post-mortem toxicology is centralised provided a more comprehensive insight into the toxicology of flualprazolam. Research on novel psychoactive substances, such as flualprazolam, is required in order to be able to provide scientific evidence on the risks of these new substances for drug administration and potential users.

Acute intoxication by triazolam and promazine: a case report.

A fatality due to ingestion of triazolam and promazine is reported. Triazolam is a benzodiazepine widely prescribed as a hypnotic drug for the treatment of sleep disorders. Promazine is a neuroleptic drug. There is no previous evidence in the literature of death due to an overdose related to the contemporaneous intake of these two drugs. In this report the authors present the case of a 76-year-old woman who was found deceased at home with no evidence of trauma or asphyxia; near the body several empty pharmaceutical boxes containing triazolam and promazine were noticed. Toxicological analyses were performed and drug levels measured by means of gas chromatography coupled with mass spectrometry. The triazolam concentration in each specimen was as follows: blood 1100ng/ml; gastric content 1300ng/ml; the promazine concentration in blood and in gastric content was 3450ng/ml and 5800ng/ ml respectively. Based on the autopsy findings, patient history and toxicological results, the cause of death was determined to be acute intoxication due to the effect of triazolam and promazine and the manner of suicide.

Relative abuse liability of triazolam: experimental assessment in animals and humans.

The abuse liability of a drug is a positive, interactive function of the reinforcing and adverse effects of the drug. The relative abuse liability of the hypnotic benzodiazepine, triazolam, has been controversial. This paper reviews animal and human studies bearing on its relative abuse liability, including data on pharmacological profile, reinforcing effects, liking, speed of onset, discriminative stimulus effects, subjective effects, physiological dependence, rebound and early morning insomnia, drug produced anxiety, lethality in overdose, psychomotor impairment, interactions with ethanol, anterograde amnesia, impaired awareness of drug effect, and other psychiatric and behavioral disturbances. It is concluded that the abuse liability of triazolam is less than that of the intermediate duration barbiturates such as pentobarbital. Although there are considerable data indicating similarities of triazolam to other benzodiazepines, there is also substantial speculation among clinical investigators and some limited data suggesting that the abuse liability of triazolam is greater than that of a variety of other benzodiazepines, and virtually no credible data or speculation that it is less. Further research will be necessary to clarify definitively the abuse liability of triazolam relative to other benzodiazepines.

Abnormal ventricular repolarization mimicking myocardial infarction after heterocyclic antidepressant overdose.

In 2 young adult women who experienced acute heterocyclic antidepressant intoxication, we found a quite unusual electrocardiographic pattern characterized by abnormal ST-tract elevation in the right precordial leads associated with a marked QRS widening (right bundle branch block and left anterior fascicular block type). Because serum electrolyte imbalance and acute myocardial ischemic events were excluded, the mechanism by which antidepressant overdose may produce such elevation of the ST tract remains unclear.

Death attributed to the toxic interaction of triazolam, amitriptyline and other psychotropic drugs.

A 71-year-old man was found dead in a car into which exhaust fumes had been introduced. His wife who was in the same car recovered consciousness following hospitalization. She claimed that they had both attempted suicide by taking a large number of sleeping pills. Autopsy revealed no significant external injuries or medical disorders that would have led to the husband's death. The concentrations of alcohol and carbon-monoxide hemoglobin in his whole blood were 0.26 mg/ml and < 10%, respectively. Therefore, poisoning by carbon monoxide from the exhaust fumes was ruled out, and further toxicological examinations were undertaken. Triazolam, pentobarbital, amitriptyline and bromazepam were all detected in the tissues of the victim; whole blood concentrations were 45.60, 386.4, 521.2 and 166.7 ng/g, respectively. Triazolam (7.350 ng/g) and pentobarbital (288.2 ng/g) were also detected in the whole blood of the wife, collected 17 h after admission to hospital. When evaluating these results in the light of existing literature, we concluded that the victim and his wife had indeed attempted suicide by taking triazolam and pentobarbital. However, only the man had died of triazolam poisoning due to its apparently lethal combination with amitriptyline and other psychotropic drugs which had been prescribed to treat his depression.

The quantitation of triazolam in postmortem blood by gas chromatography/negative ion chemical ionization mass spectrometry.

A specific and sensitive assay has been developed to quantitate triazolam in postmortem blood using 2H6-triazolam as an internal standard. Triazolam is isolated from whole blood by adsorption on an Amberlite XAD-2 resin and subsequent elution with an organic solvent. The extract is analyzed by gas chromatography/mass spectometry using selected ion monitoring (GC/MS/SIM) in the negative chemical ionization mode (Cl-). The procedure is presently being used in case work and the results from 36 cases are presented.

Distribution of triazolam and alpha-hydroxytriazolam in a fatal intoxication case.

The case of a 77-year-old woman who was found dead in her bathtub with her head clearly above the water line is presented. The decedent had a medical history of depression, liver disease, spinal stenosis, and diabetes mellitus. An empty medication bottle of triazolam was found in the trashcan. At autopsy, no injury or evidence of drowning was found. Toxicological analysis identified triazolam at a concentration of 0.12 mg/L in the heart blood. Triazolam and alpha-hydroxytriazolam were quantitated in the specimens received. The medical examiner ruled that the cause of death was triazolam intoxication and the manner of death was suicide.

Triazolam blood concentrations in forensic cases in Canada.

Triazolam has been a controversial drug since its appearance on world markets as a hypnotic more than ten years ago. Whole blood concentrations of triazolam as found in forensic cases are cited in several categories; that is, impaired driving: 17 cases; sexual assault: four cases; death due to drugs: 45 cases; drug-related death (drugs contributed to the death but were not the ultimate cause): 20 cases; drug-involved death (drugs were present but were not felt to be a contributing factor): six cases; miscellaneous: one case. The data was gleaned from a forensic toxicology database designed and used by the Forensic Toxicology Sections of the Royal Canadian Mounted Police (RCMP) laboratories in Canada. Triazolam concentrations from selected references are included for comparison.

A case of fatal triazolam overdose.

A 57-year-old man was found dead lying down in a bamboo thicket. Moderate to severe petechiae were present on his conjunctivae, buccal mucosa, and laryngeal mucosa at autopsy. Cardiac chambers contained a normal volume of fluid blood. Moderate atherosclerosis and fatty liver were observed. No remarkable changes, other than congestion in other organs, were observed. Gas chromatographic screening of the stomach contents, blood and urine was positive for triazolam and alpha-hydroxytriazolam that were confirmed by gas chromatography-mass spectrometry. Blood concentrations of triazolam and free alpha-hydroxytriazolam were 62-251 and 10-66 ng/ml, respectively. A substantial amount of triazolam was detected in bile (1130 ng/ml), but not in urine. Free and total alpha-hydroxytriazolam concentrations were 3920 and 7050 ng/ml, respectively, in the bile and 3710 and 9670 ng/ml, respectively, in urine. Organs contained 216-583 ng/g triazolam. The concentration of free alpha-hydroxytriazolam in the kidney (246 ng/g) was higher than in any other organ. Free alpha-hydroxytriazolam was not detected in the liver. The concentrations of total alpha-hydroxytriazolam in the liver and kidney were 784 and 381 ng/g, respectively. Free to total ratios of alpha-hydroxytriazolam were 0.14-0.56 in fluid samples and 0.56-0.92 in tissue samples, except for the liver. A large quantity of triazolam (8.4 mg) remained in the stomach. The victim probably died of postural asphyxia caused by triazolam poisoning.

Anterograde amnesia in triazolam overdose despite flumazenil treatment: a case report.

Anterograde amnesia, possibly accompanied by acute brain syndrome, is a potential side-effect of certain benzodiazepines, particularly triazolam. Flumazenil is a benzodiazepine antagonist that is highly effective in reversing the central nervous system effects of benzodiazepine overdose. We report a case of triazolam overdose resulting in anterograde amnesia after flumazenil administration had restored clear consciousness. The defect in memory may have been due to too little flumazenil being given or failure of memory consolidation affected by the character of triazolam during the induced lucent period. We feel that physicians should be aware of the potential occurrence of acute brain syndrome in patients with benzodiazepine overdose despite treatment with flumazenil.

[Acute adult respiratory distress syndrome (ARDS) in a patient with amitriptyline poisoning]. / Akut lungeparenkymsvigt (ARDS) hos en amitriptylinforgiftet patient.

A case of "adult respiratory distress syndrome" after amitriptyline overdosage is reported. Amitriptyline is rapidly absorbed from the intestinal tract and the drug is concentrated in the tissues, particularly the brain, heart and lungs. It is suggested that in large quantities it may inhibit surfactant production and thus cause the clinical picture described. The ventilatory treatments are discussed. It seems that inversed ratio ventilation (IRV) has something to offer, avoiding the use of high oxygen fractions in inspired air and high peak airway pressures. Our patient improved with IRV.

[Triazolam (Halcion) poisoning]. / Forgiftninger med triazolam (Halcion).

Benzodiazepines have been regarded as relatively "safe" drugs where fatal poisonings are concerned. The very potent benzodiazepines have, to a certain extent, changed this viewpoint and since triazolam was introduced in Denmark in 1978, six fatal intoxications have occurred in East Denmark. Triazolam analyses were performed by capillary gas chromatography with an electron capture detector. In the only case where no ethanol was present, a blood triazolam concentration of 0.3 mumol/kg was detected. In one case no blood was available because of putrefaction, and muscle was analysed for triazolam instead of blood. The concentration range in the four cases with an ethanol concentration of 1-2 mg/g is 0.1-0.6 mumol/kg. The blood concentrations from these six fatal intoxications are compared to blood concentrations from living persons. The whole blood concentrations from living persons were in the range 0.005-0.08 mumol/kg (n = 28) with an average concentration of 0.034 mumol/kg.

Postmortem changes of triazolam concentrations in body tissues.

Postmortem changes of triazolam concentrations in body tissues were examined using rats, in order to find the most suitable tissue samples for toxicological analysis. Triazolam was orally given to rats (5 mg/kg), and then the rats were sacrificed 1 hour after administration. Tissue samples were collected 0, 1 and 2 days after storage at 22-24 degrees C, and the triazolam concentration in each sample was measured using gas chromatography with a nitrogen phosphorus detector. Triazolam concentrations were markedly increased in the spleen, the abdominal muscle, the liver and the kidney, and were slightly increased in the blood and the lung. On the other hand, no changes were observed in the thigh muscle or the brain, and the value in the thigh muscle was similar to those in the blood samples collected immediately after death. The results indicate that triazolam diffuses into the surrounding tissues through the stomach wall after death, so that the thigh muscle and the brain have to be analyzed as well as the blood for a correct diagnosis of triazolam ingestion.

A case of torsades de pointes induced by severe QT prolongation after an overdose of eperisone and triazolam in a patient receiving nifedipine.

INTRODUCTION: Eperisone hydrochloride is a centrally acting muscle relaxant, and triazolam is a short-acting benzodiazepine. Although commonly prescribed, cardiotoxicity induced by a single overdose of either drug is comparatively rare. A patient receiving nifedipine developed torsades de pointes (TdP) because of prolongation of the corrected QT (QTc) interval after an overdose of eperisone hydrochloride and triazolam. CASE REPORT: A 60-year-old man receiving nifedipine was admitted in a comatose condition 3 h after ingesting 5,000 mg of eperisone and 2.5 mg of triazolam. Electrocardiogram showed sinus rhythm with prolongation of the QTc interval (820 ms). The serum electrolyte levels were as follows: potassium, 3.8 mEq/L; magnesium, 2.4 mg/dL. The serum drug concentrations were high: eperisone, 15,360 ng/mL; triazolam, 110.8 ng/mL. A temporary cardiac pacemaker was implanted immediately after the development of TdP, 11 h after the ingestion. The serum triazolam concentration normalized on day 2. The QTc interval and eperisone concentration normalized on day 6. CONCLUSION: Eperisone and triazolam overdose can cause life-threatening cardiotoxicity. Electrocardiographic monitoring and serial determination of QTc interval are likely the best way to observe these patients and evaluate the risk of cardiotoxicity.