The general toxicology unknown. II. A case report: doxylamine and pyrilamine intoxication

A general toxicology unknown case is presented to demonstrate our systematic approach. A 20-year-old male was found dead with multiple suicide notes. Overdose was suspected but substances were not known. Blood alcohol was negative. Urine was analyzed by enzyme-multiplied immunoassay technique and was negative for all drugs assayed. Urine was then extracted with ethyl acetate:hexane (1:1) at pH 10 and back-extracted into 1.0N sulfuric acid. The acidic layer was adjusted to pH 10, and re-extracted with ethyl acetate:hexane (1:1). The residue was analyzed by gas chromatography (GC) on a 3% OV-101 column. It was found to be negative for all commonly screened substances. However, several unknown peaks were observed. Electron impact mass spectra of these unknown peaks were obtained and searched for in our computer library of more than 25000 mass spectra. These unknown peaks were identified as doxylamine and pyrilamine by gas chromatography/mass spectrometry. The base peak and molecular ion for pyrilamine were at m/z 121 and 285, respectively. The base peak for doxylamine was at m/z 58. No molecular ion was observed for doxylamine. Both doxylamine and pyrilamine are antihistamines, but are promoted and used in the management of insomnia. Quantitation was performed on a GC using dexbrompheniramine as an internal standard. Blood concentrations for doxylamine and pyrilamine were 0.7 and 7.0 mg/L, respectively. Concentrations in other tissues were determined. Death was caused by combined doxylamine and pyrilamine intoxication; the manner of death was suicide.     

Fatal intoxications in the Nordic countries. A forensic toxicological study with special reference to young drug addicts

Fatal intoxications in the 15-34 age group in the five Nordic countries during the years 1984 and 1985 (Sweden only in 1984) were investigated. The known drug addicts were studied separately. The highest incidence of intoxications, calculated per 10(5) population, was found in Finland (11.3), followed by Denmark (10.3), Sweden (8.5), Iceland (7.2) and Norway (6.6). The percentage of intoxications caused by drugs was 92 in Denmark, 71 in Norway, 66 in Sweden, 50 in Finland and 17 in Iceland. Ethanol intoxications were seen 5-7 and 2-3 times as frequently in Finland and in Iceland, respectively, than in the other three countries. Carbon monoxide intoxications accounted for two-thirds of all fatal intoxications in Iceland. Drug addicts accounted for 62% of all fatal intoxications in the Danish material. The corresponding figures were 33% in the Norwegian, 16% in the Swedish and 5% in the Finnish material. No deaths in drug addicts were found in Iceland. Most drug addicts in Denmark, Norway and Sweden died of hard drugs and most in Norway and Sweden, from heroin or morphine, whereas in Denmark other strong analgesics, such as methadone, dextropropoxyphene and ketobemidone, accounted for 40% of all hard-drug-related fatal intoxications. To a certain extent the results reflect differences in the legal autopsy routines in the various Nordic countries. However, the ascertainment of drug addicts is assumed to be near-complete in each country.     

Possible role of pseudoephedrine and other over-the-counter cold medications in the deaths of very young children

The Philadelphia Medical Examiners Office has reported a series of 15 deaths between February 1999 and June 2005 of infants and toddlers 16 months and younger in which drugs commonly found in over-the-counter (OTC) cold medications were present. A total of 10 different drugs were detected: pseudoephedrine, dextromethorphan, acetaminophen, brompheniramine, carbinoxamine, chlorpheniramine, ethanol, doxylamine and the anticonvulsants, phenobarbital, and phenytoin. The drugs were confirmed and quantified by gas chromatography (GC)-mass spectrometry, with the exception of ethanol, which was analyzed by headspace GC and of phenobarbital and phenytoin that were quantified by GC with a nitrogen phosphorus detector. The most predominant drug was pseudoephedrine, which was found in all of the cases (blood concentration, n=14, range=0.10-17.0 mg/L, mean=3.34 mg/L) and was the sole drug detected in three cases. Acetaminophen was detected in blood from each of the five cases with sufficient sample. Other drugs (with frequency of detection) were dextromethorphan (five cases), carbinoxamine (four cases), chlorpheniramine (two cases) and brompheniramine, doxylamine, and ethanol (one case each). In the majority of the cases, toxicity from drugs found in easily available OTC medications was listed either as the direct cause of death or as a contributory factor. The manner of death was determined to be natural in only two of the cases. This postmortem study supports previous evidence that the administration of OTC cold medications to infants may, under some circumstances, be an unsafe practice and in some cases may even be fatal. The treating physicians and the general public need to be made more aware of the dangers of using OTC cold medications to treat very young children so that these types of tragedies might be avoided.     

Cases of fatal poisoning in post-mortem examinations at the Institute of Forensic Medicine in Greifswald--analysis of five decades of post-mortems

Apparently, fatal poisoning as cause of death are still rarely found in unnatural deaths investigated in the institutes of forensic medicine. In the Institute of Forensic Medicine at the University of Greifswald, 10-15% of the post-mortem autopsies displayed an intoxication during the last several decades with a possible decreasing tendency. Thirteen thousand eight hundred and nineteen autopsies were carried out in our institute-situated in a low populated rural area-during the last 50 years with the confirmed death cause intoxication in 1,589 times. In this study, especially the intoxication causes and the substance classes of the poisonous agents have been investigated. In addition, we analyzed the frequency of intoxications as well as sex and age of the deceased. Surprisingly, CO-intoxications were found most frequently with an incidence of 49% followed by alcohol intoxications with 21%. The latter was not unexpected taking into account the habits of the local population. Medical drugs and narcotics take only the third place, although the abuse of modern narcotics drugs is already visible even in the far east of Germany. The spectrum of substances which are abused, taken accidentally or deliberately is continuously changing, reflecting scientific progress in the pharmaceutical industry as well as fashion tendencies. Therapeutic use is almost always followed by abuse. Our results confirm prior experience concentrating mostly on other poisons like heavy metals or herbicides, etc. In addition, we could demonstrate the influence of political conditions on use and distribution of illegal drugs in Germany. Our study clearly demonstrates that insufficient equipment or analytical methods are no longer the reason for any problems uncovering lethal intoxications. They are rather due to insufficient investigations of the corpses (without considering the possibility of an intoxication as differential diagnosis) and to frequent mistakes of the prosecutor's office in death without signs of physical violence. These facts may explain the above mentioned decreasing tendency of intoxications, but they also clarify that this tendency probably does not correspond to reality.     

Fatal intoxications in a Swedish forensic autopsy material during 1992-2002

Compilations of substances detected in fatal intoxications are important in order to observe changes in intoxication patterns, to monitor effects of preventive work and to discover new trends in drug usage. The aim of the present study was to describe the current pattern of substances detected in fatal intoxications in Sweden. Fatal intoxications investigated at the Department of Forensic Chemistry, Link?ping, Sweden, during 1992-2002, were analysed. All suicides, uncertain cases and accidents where the cause of death were fatal intoxications (ICD-9: E950, E980 and E859) were included and substances detected in more than 50 fatal intoxications (in femoral blood) were listed. For each substance, a cut off value was set, above which concentrations were considered toxic. Fatal intoxications were detected by forensic-chemical analyses in 12% (6998/60,314) of the forensic autopsies during the study period. Among the suicides, an average of 3.8 substances were detected per case, the corresponding figure for uncertain cases and accidents were 3.5 and 4.1 substances, respectively. Ethanol was by far the most frequently detected substance, detected in 43% (3039) of the fatal intoxications, of which 32% (960) had toxic concentrations, followed by propoxyphene, detected in 27% (1863) of the fatal intoxications of which 74% (1370) had toxic concentrations. The number of cases where ethanol and propoxyphene were detected decreased during the study period. Moreover, other CNS-active drugs such as antidepressants, analgesics and anxiolytics were also frequently detected. The drugs with high proportions of cases with toxic concentrations detected were propoxyphene, amitriptyline, zolpidem, carisoprodol, alprazolam, thioridazine, methadone and ketobemidone. Selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) were detected in 12% (833) and 10% (665), respectively. A significantly (P <0.001) higher proportion of cases where TCA were detected had toxic concentrations when compared with cases where SSRI were detected (64% versus 31%).     

Colchicine poisoning by accidental ingestion of meadow saffron (Colchicum autumnale): pathological and medicolegal aspects

Although intoxications with colchicine, the alkaloid of Colchicum autumnale (meadow saffron), are well known, in most cases the intoxications are evoked by oral or parenteral preparations traditionally used as medication against gout. The accidental ingestion of Colchicum autumnale, on the other hand, is a rare event and has to our knowledge only twice been described in detail. We report a further case in which two persons confused this highly poisonous plant with wild garlic (Allium ursinum), a popular spice in the Central European cuisine. While one person merely complained about a 3-day episode of nausea, vomiting and watery diarrhea, the second person died of multi-organ system derangements 48 h after the ingestion of the colchicum leaves. At autopsy hemorrhagic lung oedema, hypocellular bonemarrow, centrilobular fatty necrosis of the liver and necrosis of the proximal convoluted tubuli of the kidneys were observed. A colchicine concentration of 7.5 micrograms/ml was found in the bile whereas no substance was detected in the postmortem blood.     

The Identification of Ingested Dandelion Juice in Gastric Contents of a Deceased Person by Direct Sequencing and GC–MS Methods*

Abstract: DNA and chemical analysis of gastric contents of a deceased person were handled in this work. The body of the victim was discovered in his car, submerged in a lake. We were asked to determine whether or not the gastric contents of the victim harbored drugs and dandelion material. It was suspected that the victim had been murdered by poisoning with an excess amount of sleeping medication (doxylamine), which had been homogenized with dandelion. The concentrations of 11.4 and 27.5 mg/kg of doxylamine detected from spleen and liver of the victim were far higher than the assumed therapeutic concentration. Via gas chromatography–mass spectrometry (GC–MS) analysis and direct sequencing analysis of plant genetic markers such as intergenic transcribed spacer, 18S ribosomal RNA (rRNA), rbcL and trnLF, it was confirmed that the gastric contents of the victim contained taraxasterol, which is one of the marker compounds for dandelion and contained dandelion species‐specific rbcL and trnL‐trnF IGS (trnLF) sequences. The initial PCR of the genomic DNA isolated from the gastric contents showed insufficient quantity, and the second PCR, of which the template was a portion of the initial PCR products, exhibited a sufficient quantity for direct sequencing. rbcL and trnLF located in the cpDNA resulted in the successful determination of dandelion DNA in a decedent’s stomach contents. GC–MS identifies the actual presence of a taraxasterol at 28.4 min. Raw dandelion was assumed to be used as a masking vehicle for excess sleeping drug (doxylamine).     

Fatal unintentional intoxications with tramadol during 1995-2005

Tramadol is an extensively used centrally acting analgesic and is considered a safe drug devoid of many serious adverse effects of traditional opioids. However, recently, toxicity and an abuse potential of tramadol have been reported. This study examined fatal unintentional tramadol intoxications among Swedish forensic autopsy cases between 1995 and 2005. All fatal intoxications were selected, in which toxic concentrations of tramadol (>1 microg/g femoral blood) had been detected, and where the forensic pathologist considered the intoxication unintentional and the fatal outcome at least partly explained by tramadol. Toxicology analyses, police reports, autopsy protocols and medical records were scrutinized. A total of 17 cases (eleven men and six women) of fatal unintentional tramadol intoxications were identified. For these cases the median age was 44 years (range 18-78 years) and the median tramadol concentration was 2.0 microg/g (range 1.1-12.0 microg/g). Other pharmaceutical substances, illicit drugs or ethanol were detected in addition to tramadol in all of these cases. In fact, intoxication with multiple drugs was considered the cause of death in 10 (59%) cases. However, in seven cases tramadol was the only substance present in toxic concentrations. A history of substance abuse was identified in 14 (82%) subjects and a present tramadol abuse in 8 (47%). These results suggest that fatal intoxications with tramadol may occur unintentionally and that subjects with a history of substance abuse may be at certain risk. Precaution is therefore warranted when prescribing tramadol in such patients.     

Fatal ethanol poisonings in 1984-1986

Analysis of statistical data on the number of fatal ethanol intoxications in 1984-1986 is presented. A steady tendency to reduction in fatal ethanol intoxications is stressed.     

An Unusual Case of Strychnine Poisoning

Strychnine‐related death has been described since the 19th century. This alkaloid was discovered in 1818. Historically, strychnine was used by the South‐East Asian autochthones on their arrows. However, its production was modified by legislation, which was used to protect people against accidental intoxications. Here, we present the case of a 69‐year‐old man who was found dead at home. During the autopsy, we found a blue substance in the stomach. Toxicological analysis measured strychnine at 0.29 μg/mL in the blood sample, which is a relatively low level in comparison with the results given in the literature. However, histologic examination and toxicological findings permitted the conclusion of strychnine poisoning.     

Histomorphometric indices of the pancreas in intoxication with alcohol and narcotics

The results of histomorphometric examinations of the pancreas in drug- and alcohol-addiction as well as in acute intoxications are described. They show that, in chronic alcoholic intoxication as compared with opiomania, there are more pronounced interlobular sclerosis and lipomatosis, which is manifested by an enlarged middle lobe of the stroma (containing fat and connective tissue fibers), by a higher density of islands of Langerhans and by their higher sectional area. Autolysis and edema of the stroma are more severe in an acute intoxication with drugs than in other cases of fatal outcome. A possibility is demonstrated to differentiate between various types of the so-called long-term exogenous intoxication and to discriminate between different types of thanatogenesis typical of various cases of acute intoxications. Data are presented that demonstrate the advantage of the quantitative analysis of histological preparations over the qualitative one.     

Toxicological characteristic of neuroleptics--substituted benzamides

At present in the medical practice the group of neuroleptics, substituted benzamides is widely used. According to literature data they cause acute intoxications under particular conditions. The group of substituted benzamides includes drugs such as amisulpride, tiapride, sulpiride and sultoprid. Substituted benzamides intake causes toxic actions: psychotropic and neurotoxic. The neuroleptic intoxication is an effect of overdosage, abuse and hypersensitization. Severe intoxications with drugs of this group may cause lethal outcome.     

Pesticide intoxications in the Centre of Portugal: three years analysis

Pesticides are used in most countries around the world to protect agricultural and horticultural crops against damage. Poisoning by these toxicant agents occurs as a result of misuse or accidental exposure, and also by oral ingestion (voluntary or not). In Portugal, pesticide intoxications are still a cause of death, found in a considerable number of cases. The authors retrospectively examined the cases of pesticide poisoning in the Centre of Portugal, from autopsies performed in the Forensic Pathology Service of Coimbra's Delegation of the National Institute of Legal Medicine (NILM) and from other autopsies carried out in the Centre of Portugal, as well as some samples taken in hospitals in cases of suspected intoxication. In this study, the positive cases have been especially studied, in order to identify the pesticide used, as well as the etiology. The frequency of intoxications and its distribution by sex and age were also analyzed. Between January 2000 and December 2002, the Forensic Toxicology Laboratory received 639 pesticide analysis requests. In 2000, in a total of 149 analysis requests, 30 cases were positive, 63.3% from male individuals and 36.7% from female. In 2001, the analysis requests increased to 240 as well as the positive cases (43), 74.4% from male individuals and 25.6% from female and in 2002, the total cases analyzed also increased to 250, with 38 positive (73.6% from male individuals and 26.4% from female). Among the pesticides, organophosphorus insecticides still constitute the most important class detected in forensic intoxications, representing 63% of the total positive cases, followed by herbicides, with 33% of the positive results. Quinalphos is the most important organophosphorus insecticide, present in 32 of the 111 positive cases, followed by the herbicide paraquat, detected in 31 cases. The study emphasizes the increasing number of pesticide analyses, particularly relevant for the organophosphorus compounds and herbicides. Intoxication suspicion, accidental or voluntary, seems to be the most common cause of the incidents, for which analyses are requested, but it is also evident that the putative cause is unknown in a large number of cases. Therefore, more stringent legislation and enforcement regarding the sale and distribution of these toxic substances are needed.     

Increased lung weight in fatal intoxications is not unique to opioid drugs

Fatal intoxications with opioids are known to be associated with an increased lung weight, as well as with brain and pulmonary edema and urinary retention. However, there is evidence to suggest that fatal intoxications with non-opioid substances are also associated with increased lung weight; however, the latter aspect has not been comprehensively analyzed. To determine to what extent opioid and non-opioid substances are associated with increased lung and brain weight, we studied these organs in cases where the cause of death was attributed to intoxication with a single agent. Using data from cases autopsied at the National Board of Forensic Medicine (NBFM) in Sweden from 2009 through 2019 where the cause of death was attributed to a single substance, we created models of combined lung weight and brain weight. The models used age and sex as predictors as well as nested varying effects for the specific intoxicant and category of intoxicant. Suicidal hanging with negative toxicology cases served as controls. The population majority was male among both intoxications (68%) and controls (83%). The most common single substance group was opioids. All tested substances were associated with heavier lungs than controls, with the largest effect in the opioid group. Our findings show that several substances are associated with increased lung weight and that among intoxication deaths there is no difference in expected brain weight between substances. Hence, heavy lungs, without a reasonable explanation, should prompt a broad toxicological screening.     

Acute and subacute fetal CO-poisoning

The main principles of placental CO exchange in cases of CO intoxications of pregnant women are shown. Fetal COHb lags behind maternal COHb by several hours depending on the exposure pattern. During CO elimination the fetal COHb levels again lag behind the mother's. A case of a lethal CO intoxication of a pregnant woman, mens IX, with exposure time of 10-12 h and COHb of 75% for the mother and 46% for the fetus allows to make conclusions about process of intoxication and about different times of death for mother and fetus. In highly acute lethal intoxications of the mother COHb in fetal blood is low or negative. A vital danger of the fetus is not probable when mother survived a short CO exposure.     

Fatal intoxications in the age group 15-34 years in Denmark in 1984 and 1985. A forensic study with special reference to drug addicts

This survey deals with the Danish part of a study on fatal intoxications conducted in the Nordic countries in 1984 and 1985 with special reference to drug addicts. There were 315 cases of fatal intoxications in people 15-34 years of age. These were examined at the Forensic Institutes in Denmark and described with reference to cause of death, sex, age and drug addiction. Of the deceased, 194 were drug addicts according to a specific definition of this term. Women accounted for 28% of all the fatalities investigated in the study and 24% of those in addicts. More than 90% of the deaths were caused by drugs, with ethanol as a contributory factor in approximately 40% of cases. Deaths caused by heroin/morphine predominated, causing 50% of the deaths among drug addicts, but legal drugs, such as dextropropoxyphene, methadone and ketobemidone were also frequent causes of death in this group. In half the cases the concentration of morphine in blood following injection of heroin/morphine was found to be equal to or less than 0.5 mumol/kg, and in only about one-tenth of cases was the blood concentration above 2.0 mumol/kg.     

Fatal inhalation of butane-propane gas

Fatal intoxications with butane and/or propane are rare although the inhalation of such liquid gases in order to induce hallucinations is not uncommon amongst youngsters, the number of which is difficult to evaluate. Thus the possibility of gas intoxication should be taken into consideration in all cases of unclear death of youngsters, in which case the macroscopic and histological findings will be unspecific whereas the chemical-toxicological analyses, especially of the native brain, lung and liver tissue, lead to definite conclusions.     

Fatal intoxication by dextromethorphan: a report on two cases

A report is given of two young people who died after intake of dextromethorphan, one by suicide and the other for uncertain reasons. To our knowledge this is the first reported fatal intoxications with this drug.