High haloperidol concentrations in a traffic suicide

High concentrations of haloperidol are seen in a psychiatric patient who ran from a health care facility into traffic. Haloperidol concentrations were found to be 1.2 mg/L in heart blood, 2.7 mg/L in brain, and 10.8 mg/L in liver. No other drugs were detected.     

Determination of several psychiatric drugs in whole blood using capillary gas-liquid chromatography with nitrogen phosphorus detection: comparison of two solid phase extraction procedures

A simple and reliable gas chromatographic method with nitrogen-phosphorus detection without derivatization was developed for the detection of several psychiatric drugs in whole blood as part of systematic toxicological analyses (STA). Drugs included mirtazapine, chlorpromazine, methotrimeprazine (levomepromazine), clothiapine, olanzapine, clozapine, haloperidol, and thioridazine. All drugs were studied at concentrations of 100-2,000 microg/L, except haloperidol that was studied at concentrations of 400-8,000 microg/L. In order to select the best blood purification procedure and therefore increase the signal to noise ratio we have compared two solid-phase extraction (SPE) columns, Chem Elut and Bond Elut Certify, for their recovery, precision, sensitivity and matrix purification efficiency. Recoveries for these drugs using Chem Elut columns at 500 and 2,000 microg/L (2,000 and 8,000 microg/L for haloperidol) were in the range 21-65%, with intra-assay and inter-assay precisions of less than 17% and 19%, respectively. Limits of detection (LODs) and limits of quantitation (LOQs) for mirtazapine, chlorpromazine, methotrimeprazine, clothiapine, olanzapine, clozapine, and thioridazine ranged from 62 to 161 microg/L and from 205 to 531 microg/L, respectively. LOD and LOQ for haloperidol were 442 and 1,458 microg/L, respectively. Recoveries of these compounds using Bond Elut Certify columns at 500 and 2,000 microg/L (2,000 and 8,000 microg/L for haloperidol) were in the range 44-97%, with intra-assay and inter-assay precisions of less than 7% and 14%, respectively. LODs and LOQs for mirtazapine, chlorpromazine, methotrimeprazine, clothiapine, olanzapine, clozapine, and thioridazine ranged from 37 to 66 microg/L and from 122 to 218 microg/L, respectively. LOD and LOQ for haloperidol were 156 and 515 microg/L, respectively. Linearity was observed in the studied range for all compounds with r(2) values of >0.999. The use of the mixed-mode bonded-silica Bond Elut Certify columns showed advantages comparing with Chem Elut columns for the screening of these psychotropic agents such as higher recoveries, cleaner extracts, better sensitivity, better precision and less solvent consumption and subsequent disposal.     

Identification of haloperidol and tiapride in the urine with thin layer chromatography

How to identify haloperidol and tiapride in the urine by thin layer chromatography was proposed. Optimal systems of solvents were selected by chromatographic mobility of the substances studied in 14 solvents with different polarity. The findings allowed making an optimal choice of the composition and proportion of the solvents. Diethylamine, as a basic modifier, was introduced in the system of solvents. This improved chromatographic mobility of haloperidol and tiapride. Optimal mobile phases, developers were found, the threshold of detectability of the substances in the given conditions was established. The techniques were used for identification of haloperidol and tiapride in the samples from model urine mixture in the presence of non-identified endogenic compounds. They are characterized by rapid performance, selectivity, sensitivity and good reproducibility and can be introduced into practice of chemicotoxicological laboratories.     

Comparative investigations on the uptake of basic substances into the human keratinocyte cell line HaCaT--a model for the uptake of xenobiotics into the keratinocytes of the hair follicle

The human cell line HaCaT was used to study drug uptake by keratinocytes as an in-vitro model to elucidate drug incorporation into anagen hair follicle. The basic drugs under investigation were taken up very rapidly resulting in a concentration plateau in the keratinocytes which was dependent on the drug concentration in the cell culture medium. The results obtained for HaCaT clearly demonstrated the existence of a partition-equilibrium between the extracellular and intracellular drug concentrations. Only small amounts of the offered drugs were taken up and remarkable differences were observed showing a decreasing uptake for imipramine > haloperidol > cocaine/benzoylecgonine. Total protein content in the culture medium was 3.5 +/- 0.3 mg/mL and the protein binding of the drugs to the foetal serum proteins was found to be negligible in the experiments. Overall, the in vitro findings were consistent with previous observations for in vivo drug incorporation into hair. In particular, an explanation was found for the correlation between the AUC-value and hair concentration observed in animal studies as well as for the generally low drug concentrations in non-pigmented hair.     

Evidence of Haldol (haloperidol) long-term intoxication

A case of intoxication by haloperidol is reported. Haloperidol is a butyrophenone derivative commonly used in many hospital units as an antipsychotic agent. Adverse reactions due to haloperidol intoxication include drowsiness, blurred vision, extrapyramidal effects, tardive dyskinesia, tachycardia, hypotension and muscular rigidity. In August 2008, a 49 year-old female nurse started feeling various symptoms such as muscular rigidity, drowsiness and buccal dyskinesia. After 3 months, she was hospitalized for the worsening of these symptoms. Four months later, she showed once more the same symptoms. Two open water bottles from which the nurse used to drink in the hospital were confiscated and analyzed. Moreover, the nurse was asked to give a sample of her hair for executing the inherent toxicological analyses. Haloperidol was found in both bottles 1 and 2 at a concentration of 31.5 μg/mL and 43.6 μg/mL, respectively. Based on segmental hair analysis, it was deduced that the nurse consumed haloperidol in the approximate period from August 2008 to March 2009. The higher levels of haloperidol in hair were found in accordance with the periods of most severe appearance of symptoms, requiring the hospitalization of the nurse. The analysis of preservatives and excipients led us to conclude that the pharmaceutical drug was probably added to the water bottles as "Haldol 2mg/mL oral solution".     

Detection of antidepressant and antipsychotic drugs in human hair

The presence of therapeutic drugs and their metabolites in the hair of psychiatric patients was investigated using gas chromatography (GC)-mass spectroscopy (MS)-electron ionization (EI) and GC-MS-chemical ionization (CI). In hair samples tested from 35 subjects, carbamazepine, amitriptyline, doxepin, trihexyphenidyl, chlorpromazine, chlorprothixene, trifluoperazine, clozapine and haloperidol were detected, with maximal concentrations of 22.5, 57.7, 183.3, 15.6, 68.2, 30.0, 36.8, 59.2 and 20.1 ng/mg of hair sample, respectively. Chlorpromazine and clozapine concentrations in the hair were found to be dependent on the dosage used and their correlation coefficients were 0.8047 (P<0.001, n=16) and 0.7097 (P<0.001, n=16), respectively. Segmental analysis demonstrated that there was a correlation between the history of subject's drug exposure and the distribution of drug along the hair shaft. Our results also show that drug analysis in hair may provide useful information about drug treatment and the history of usage, and that drugs can be detected in normally kept hair for at least 16 months after intake.     

The time-dependant post-mortem redistribution of antipsychotic drugs

The post mortem redistribution of ten commonly prescribed antipsychotic drugs (APs) was investigated. Femoral blood was collected from 273 cases at admission to mortuary (AD) and at post-mortem (PM). The PM samples were collected at various times up to nine days after admission and the sample pairs analysed using LC-MS/MS. The drugs included in this study were 9OH-risperidone (paliperidone), amisulpride, chlorpromazine, clozapine, haloperidol, olanzapine, promethazine, quetiapine, risperidone, and zuclopenthixol. Haloperidol, quetiapine and risperidone showed minimal changes between AD and PM specimens, whereas the majority of drugs showed significant changes between the sample pairs collected at different time points post mortem (p<0.01) in addition to an average concentration change greater than the uncertainty of measurement of the applied method. Average increases in blood concentrations after admission to the mortuary ranged up to 112% (chlorpromazine and olanzapine) but also decreases up to -43% (9OH-risperidone) were seen. There were large standard deviations between sample pairs and substantial day-to-day unpredictable changes that highlight the difficulty in the interpretation of drug concentrations post-mortem. Based on the presented data, we recommend that specimens for toxicological analysis should to be taken as soon as possible after admission of a deceased person to the mortuary in order to minimise the effects of the PM interval on the drug concentration in blood.     

Chemico-toxicological analysis of haloperidol in blood with high-performance liquid chromatography in combined poisoning

Haloperidol is widely used in psychiatric practice both in monotherapy and in combination with neuroleptics, phenothiazine derivatives (chlorpromasin, levomepromasin) and antidepressants (amitriptilin, imipramin). We have developed techniques of haloperidol isolation from blood in combined poisonings with phenothiazine derivatives (chlorpromazine, levomepromasine) and antidepressants (amitriptilin, imipramin), their identification and quantitation with high-performance liquid chromatography. The highest output of the substances studied was achieved in alkaline hydrolysis. The techniques are expressive, sensitive and well reproducible. This makes them convenient for practice of forensic-chemical and chemico-toxicological laboratories.     

A rapid and simplified extraction of haloperidol from plasma or serum with bond elut C18 cartridge for analysis by high performance liquid chromatography

This method for the determination of haloperidol (HAL) in plasma is based on high-performance liquid chromatography (HPLC) with a reversed-phase column, ODS-C18. HAL is rapidly extracted from human plasma by using Bond Elut C18 cartridge and its recovery is over 90%. The mobile phase is a mixture of 1% acetate/acetonitrile/tetrahydrofuran/triethylamine (69.5: 28.2:1.9:0.4, by vol.). The method is rapid, simple and free from intereferences and gives good precision.     

反相高效液相色谱分离抗精神失常药物

作者采用反相高效液相色谱法对氯丙嗪、三氟拉嗪、异丙嗪、奋乃静、氟奋乃静、氯氮平、氟哌啶醇、安泰乐,多虑平等九种常见抗精神失常药物进行分离。并对色谱条件流动相中甲醇比例,二乙胺浓度,pH值及柱温对药物保留时间的影响进行考察,选择出一种能良好分离九种药物的色谱系统,对这类药物中毒时鉴别药物品种具有实用意义。     

Black Esophagus: Acute Esophageal Necrosis in Fatal Haloperidol Intoxication

Herein, we present a case of 53‐year‐old psychotic woman with acute esophageal necrosis (black esophagus), who was found lying on the floor in the living room of her flat. Pillboxes of antipsychotic drugs were located in the bin. External examination of the body was unremarkable. On internal examination, we found acute esophageal necrosis. Histologically, there was complete epithelial necrosis with focal involvement of muscularis mucosae, dense infiltrate of leukocytes, and ulcerations without any viable cells. There was no evidence of underlying organic diseases or trauma. Toxicological analysis revealed a fatal blood level of antipsychotics (haloperidol, zotepine, and chlorprothixene). Death of the deceased was attributed to fatal intoxication with three various types of antipsychotics. As far we know, this is the first described association between so‐called black esophagus and fatal blood level of neuroleptics.     

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.     

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.     

The effect of lethal electrical shock on postmortem serum myoglobin concentrations

Postmortem serum myoglobin concentrations in blood from the femoral vein (peripheral withdrawal) and the heart (central withdrawal) of nine electrical fatalities were compared with those of 74 individuals who had died of other causes. Independent of the cause of death or topographical site, serum myoglobin concentrations rose dramatically with the passage of postmortem time (maximum concentrations in the control group: 975,100 micrograms/l). In 59% of the total sample (electrical fatalities plus controls), serum myoglobin concentrations were higher in the central blood, in the other 41% the concentrations were higher in the peripheral blood. The differences in concentrations between the peripheral and the central withdrawal area correlated with neither the postmortem interval nor the cause of death. Up to the second day postmortem there was a statistically significant difference in serum myoglobin concentrations between electrical fatalities and controls. The individual values within each group, however, varied widely and overlapped between groups. Controls who had also suffered muscle injury (polytrauma, myocardial infarction) did not have significantly higher serum myoglobin concentrations than controls without muscle injury. Myoglobin concentrations appear to be greatly influenced by the extent and duration of the muscle cramps induced by the electrical current. Correct interpretation of serum myoglobin concentrations depends on the knowledge of events surrounding the lethal electrical shock. Postmortem determination of serum myoglobin concentrations alone is, therefore, not sufficient to establish intravital exposure to electrical current and can aid the diagnosis only in special cases.     

Postmortem investigation of lamotrigine concentrations

Lamotrigine is a relatively new anticonvulsant. Therapeutic plasma concentrations generally range from 1 to 4 mg/L, although several studies have shown that good control of epilepsy has been achieved with concentrations reaching 10 mg/L generally, with little toxicity. In overdose, however, the drug has been linked to ECG changes that may suggest a possible arrythmogenic effect and hence cardiac toxicity. Lamotrigine has also been shown to cause encephalopathy and thus neurotoxicity. There is no information concerning postmortem lamotrigine concentrations and their interpretation. We describe lamotrigine concentrations in postmortem specimens including blood, liver, bile, vitreous humour, and urine from eight cases. A high performance liquid chromatography (HPLC) method is described with extraction procedures for the various tissues. Two possible groups were identified. The first being the "broader therapeutic" group with blood concentrations ranging from 0.9 to 7.2 mg/L and corresponding liver concentrations ranging from 16 to 36 mg/kg. The second being a "supratherapeutic" group with blood concentrations ranging from 20 to 39 mg/L and corresponding liver concentrations ranging from 53 to 350 mg/kg. Although none of the eight cases described were attributed to overdose by lamotrigine alone, the cause of death for one of the three cases in the "supratherapeutic" group was given as mixed drug toxicity. Cause of death for the remaining two cases in this group was reported as epilepsy. However, both these cases showed elevated concentrations of lamotrigine and both were co-medicated with valproic acid. Such co-administration has been shown in the literature to lead to elevated lamotrigine concentrations and a reduction in lamotrigine dose has been recommended. With such data, we highlight the importance of monitoring lamotrigine concentrations in cases co-medicated, particularly with valproic acid.     

Correlation between 'on admission' blood toluene concentrations and the presence or absence of signs and symptoms in solvent abusers

For 1 year, from June 1987 to June 1988, toluene concentrations in blood samples of patients admitted to a psychiatric hospital after inhaling solvent vapor, collected on admission and 4 h later, were analyzed by gas chromatograph. Toluene levels in the first urine samples collected after admission were also analyzed and case histories were kept listing age, sex and physical and psychiatric effects. In all, 51 cases were studied--34 males and 17 females. (1) The average age of the males was 21.4 years and of the female 16.2 years. (2) The toluene concentrations in the blood collected on admission ranged from 0.3 to 22.8 micrograms/g. (3) Physical signs were observed in 9 patients with an "on admission" blood toluene concentrations of more than 3.0 micrograms/g; twice as many subjects (18), however, with blood toluene concentration greater than 3.0 micrograms/g were without physical signs. (4) The blood toluene concentrations of three cases in the condition known as twilight state were more than 10.0 micrograms/g. (5) In 24 cases with blood toluene concentrations below 3.0 micrograms/g, there were no physical signs. (6) Five subjects with blood toluene concentrations in the 0.8-5.2 micrograms/g range showed neuropsychiatric effects; however, 23 subjects in the same blood toluene concentration range did not exhibit psychiatric effects, and none of the subjects with blood toluene concentrations greater than 5.2 micrograms/g, 15 in all, had such effects.     

Concentrations of Opiates and Psychotropic Agents in Polydrug Overdoses: A Surprising Correlation Between Morphine and Antidepressants

Abstract: The relationship between postmortem concentrations of morphine and co‐detected psychoactive drugs in fatal overdoses is examined. Morphine and other drugs were detected in 161 medicolegal autopsy cases. Subsets of these morphine‐positive cases based on drug class were established, including opioids, antidepressants, ethanol, benzodiazepines, and “other.” Each subset was split into high or low concentration groups based on median drug concentrations. Morphine concentrations of the [high] and [low] groups were compared, with no significant difference in morphine concentration identified in the opioid, ethanol, or benzodiazepine subsets. The “other” drug class was too heterogeneous for statistical assessment. Morphine concentrations did show a significant direct relationship (p = 0.01) with antidepressants, namely increased concentrations of antidepressant drugs are associated with an increased concentration of morphine. This trend probably remains even after excluding cocaine‐positive cases. The unsuspected finding that postmortem concentrations of antidepressants positively correlate with morphine levels may be important in the treatment of depression in drug addicts.     

Post-mortem cases involving amphetamine-based drugs in The Netherlands. Comparison with driving under the influence cases

In this study we reviewed the post-mortem cases in the years 1999-2004 that were presented at the Netherlands Forensic Institute. The concentrations of amphetamine-based drugs in femoral blood from cases of suspected unnatural death were compared with concentrations in whole blood from non-fatal cases of driving under the influence (DUI cases) and with literature. Furthermore, the combinations with other drugs and/or alcohol were investigated. Amphetamine-based drugs were present in 70 post-mortem cases and 467 DUI cases. The most detected amphetamine-based drug was MDMA, followed by amphetamine. The presence of MDA could usually be explained by metabolism of MDMA. Methamphetamine and MDEA were rarely present. Frequently, the amphetamine-based drugs were taken in combination with alcohol and/or other non-amphetamine-based drugs such as cocaine or cannabinoids. The 70 post-mortem cases were divided into 38 amphetamine-based drug caused (i.e. the amphetamine-based drug directly caused or contributed to the death) and 32 amphetamine-based drug related deaths (i.e. death was not directly caused by the amphetamine-based drug). In the latter category, other (poly)drug intoxications and death by violence or drowning were the most frequent causes of death. In 30 cases, MDMA caused death directly. The range in blood concentrations of MDMA in these cases was substantial, i.e. 0.41-84 mg/L with a median concentration of 3.7 mg/L (n=30). MDMA blood concentrations in the MDMA related deaths (n=20) and in the DUI cases (n=360) varied up to 3.7 and 4.0 mg/L, respectively. Seven victims died from the direct effects of amphetamine; the blood concentration of amphetamine ranged from 0.24 to 11.3 mg/L, with a median concentration of 1.7 mg/L (n=7). The median concentrations of amphetamine in the amphetamine related deaths (n=13) and the DUI cases (n=208) were much lower, i.e. 0.28 and 0.22 mg/L, respectively. Amphetamine blood concentrations up to 6.0 and 2.3 mg/L were seen in the drug related deaths and DUI cases, respectively. The most frequently encountered amphetamine-based drugs in the investigated deaths were MDMA and amphetamine. The majority of MDMA- and amphetamine-caused deaths, i.e. 90% of these deaths, occurred with blood concentrations above 1.5 and 0.80 mg/L, respectively. MDMA and amphetamine blood concentrations in drug related deaths and DUI cases, however, overlap the range of fatal concentrations. Therefore, MDMA or amphetamine concentrations should never be used alone to establish the cause of death.     

Quantification of Methamphetamine in Mouse Thighbones Buried in Soil

Bone samples are used for analysis of drugs in decomposed or skeletonized bodies. Toxicological analyses of buried bones are important for determining the causes and circumstances of death. In this study, methamphetamine and amphetamine concentrations in heart blood, thigh muscles, and thighbones were analyzed using solid‐phase extraction with liquid chromatography–tandem mass spectrometry. Methamphetamine concentrations in heart blood, thigh muscle, and thighbone ranged from 0.041 to 0.873 μg/mL, 0.649 to 2.623 μg/g, and 56.543 to 643.371 μg/g, respectively. Thighbone concentrations were significantly higher than those in heart blood or thigh muscles were. Methamphetamine concentrations in buried thighbone (4.010–45.785 μg/g) were significantly lower than those of unburied thighbones were (56.543–643.371 μg/g). Methamphetamine and amphetamine were detected in thighbones buried for 7–180 days. These findings indicate that the methamphetamine concentrations in bone are higher and decrease after burial in soil.     

Determination of drug levels in larvae of Lucilia sericata (Diptera: Calliphoridae) reared on rabbit carcasses containing morphine

This study concerns the determination of morphine concentrations in fly larvae reared on rabbits administered different concentrations of morphine and a correlation between concentrations of the drug in larvae and tissues. Three rabbits (R1, R2 and R3) were given dosages of 12.5, 25.0 and 50.0 mg/h of morphine over a 3 h period via continuous ear artery perfusion. These dosages and time of perfusion were calculated to create tissue concentrations of morphine similar to those encountered in human death due to overdose. Morphine blood level plateau was attained after 1 h of perfusion. A fourth rabbit was used as a control. To evaluate drug concentrations, tissues were sampled using a coelioscopic technique. Approximately 400 eggs of Lucilia sericata, all of the same age category, were placed in eyes, nostrils and mouth of each rabbit carcass. Larvae and puparia were regularly collected from each rabbit for toxicological analysis. The concentrations of the drug in the tissues sampled were determined to be similar to those normally encountered in human overdoses and were correlated with the dosage of morphine that had been administered. Morphine was detected in all larvae and pupae fed on tissues from carcasses administered morphine, except for puparia from the colony fed on the R1 animal which received 12.5 mg/h dosage of morphine. All samples from the control rabbit were negative for morphine. Concentrations of morphine in larvae reared on rabbit carcasses containing morphine were 30 to 100 times lower than the concentrations found in the tissues. A correlation between the tissue concentrations and larval concentrations was found in only 3rd instar larvae (80 to 140 h following hatching). No correlations were found between administered dosages, tissue concentrations and younger larvae, prepuparial larvae or puparia.