Serotonin toxicity involving MDMA (ecstasy) and moclobemide

The use of MDMA (ecstasy) in Australia is a widespread and growing problem, promoting acute toxicity and disease which can lead to premature death in users. We report four cases of fatal serotonin toxicity caused by the combination of MDMA and moclobemide, a reversible MAO-A inhibitor with potent serotonergic activity. Despite the highly reported toxicity of this drug combination, there are very few reports of fatalities attributed to a MDMA and moclobemide interaction. Pathology and toxicology reports, initial police reports and coroners' findings were examined to determine the circumstances of the deaths. Symptoms of some of the four cases as reported by paramedics and medical staff included hyperthermia, hyperkalemia, profuse sweating, twitching and shaking. Two cases involved moclobemide concentrations consistent with common prescribed doses, while the other two cases involved much higher concentrations often associated with toxicity. Three of these cases presented with some form of heart disease.     

Potentiation of lethality and increase in body temperature by combined use of d-methamphetamine and morphine in mice

Lethality and change in body temperature in mice were examined after subcutaneous injection of d-methamphetamine and morphine alone or in combination. The LD50 values for methamphetamine and morphine were calculated to be 95 and 670 mg/kg body wt., respectively. When a non-lethal dose of morphine (300 mg/kg) was administered with various doses of methamphetamine, the LD50 for methamphetamine was reduced to 5 mg/kg, indicating a marked potentiation of toxicity by combined use of both drugs. Injection of 5 mg/kg of methamphetamine produced slight hyperthermia, while 300 mg/kg of morphine decreased the body temperature of mice. However, when both drugs were used concomitantly, a marked increase in body temperature was observed. Hyperthermia was also observed when the dose of morphine was reduced to 50 mg/kg. It is postulated that hyperthermia is probably one of the contributory factors in the potentiated toxicity by combined use of morphine and methamphetamine.     

Forensic toxicologic analysis of methamphetamine and amphetamine in body materials by gas chromatography/mass spectrometry

Qualitative and quantitative analysis of methamphetamine and amphetamine in biologic materials was carried out by gas chromatography/mass spectrometry. A deuterium-labeled methamphetamine was employed as an internal standard with a detection limit of 50 pg and absolute stability and reproducibility. Blood was found to be the best material for estimation of the toxicity of the stimulant drug. It can be replaced by muscle which contains methamphetamine concentrations close to those of blood. The authors' classification of the toxic blood levels of methamphetamine from therapeutic to fatal doses was confirmed by additional data obtained from new case studies.     

Dependence of acute opiate poisoning lethal outcome on the gender, age, and duration of addiction

The article presents toxicological characteristics of 198 cases of acute parenteral poisoning with morphine and heroin in the range of concentrations of their metabolites in the blood and urine which occur in practice. Risk of death is quantified in the range of possible morphine concentrations in the blood in acute opiates intoxication with reference to gender and age. Assessment of the criteria of quantitative opiates toxicity was made according to the method of logit regression and dose-effect curve suitable for analysis of correlations between probability of death and blood concentrations of opiates metabolites. Conditional lethal doses in respect to gender and age are calculated.     

Methadone toxicity causing death in ten subjects starting on a methadone maintenance program.

Methadone maintenance therapy is designed to reduce the need for addicts to use heroin or other illegal opiates. Death in patients starting on such a program has not previously been documented. We report the death of 10 persons who died within days of starting a methadone maintenance program administered by general practitioners. Their bodies were subject to a full autopsy by forensic pathologists, with a full toxicological examination. The mean starting dose had been 53 mg, which had been increased to a mean of 57 mg by the final dose. Death occurred after a mean of 3 days. The mean blood methadone concentration at death was 2.1 mumol/L. Complete toxicological analysis showed that six subjects had additional drugs present including two with alcohol, two with benzodiazepines and morphine, and one with benzodiazepines alone. Pathological examination revealed the presence of chronic persistent hepatitis in all subjects and bronchopneumonia in five. The causes of death were given as methadone toxicity or methadone toxicity in combination with bronchopneumonia. Our observations highlight the dangers of methadone in the first days of starting on a maintenance program, particularly when the starting doses are relatively high and subjects have no demonstrated tolerance to opiates.     

The new narcotic drug law and its effects on the panorama change of the drug scene of the Aachen border district

The situation in the region of Aix la Chapelle with its borders towards The Netherlands and Belgium has presented us with increasing problems in drug and narcotic delinquency during recent years. Because of the revised law on narcotic drugs in 1982 and recent decisions by the German Federal Supreme Court, forensic toxicologists are expected not only to define drugs qualitatively as well as quantitatively, but also to provide expertise on problems of effective doses, pharmacokinetics, toxicity and tolerance development with various narcotic drugs. Based on our own experience in this special forensic field, as well as on the data compiled by investigation authorities, our analytical findings are presented with regard to toxicological interpretation and the legal consequences.     

Loperamide as a Potential Drug of Abuse and Misuse: Fatal Overdoses at the Medical University of South Carolina

Loperamide is an over‐the‐counter, μ‐opioid receptor agonist commonly used as an antidiarrheal agent. Loperamide was thought to have minimal abuse potential due to its low bioavailability and limited central nervous system activity; however, there have been increasing reports of loperamide misuse in supratherapeutic doses to achieve euphoria and/or avoid opioid withdrawal. A literature review suggests a rise in loperamide abuse was inevitable, with substantial increases in reported cases over the last decade. Five fatal cases of toxic medication use where loperamide was listed as a primary or contributory cause of death were identified at the Medical University of South Carolina. The characteristic autopsy demographics and findings are described, and the mechanisms of abuse and toxicity of loperamide are reviewed. Loperamide overdoses are a growing concern from both a forensic and clinical standpoint, and the frequency of reported cases will likely increase as awareness grows within the medical and toxicological communities.     

The Pharmacokinetics of Morphine and Codeine in Human Plasma and Urine after Oral Administration of Qiangli Pipa Syrup

Papaveris pericarpium, a natural source of morphine and codeine, is the principal active component in many antitussive traditional Chinese medicines. We herein report the first PK study of papaveris pericarpium in human plasma and urine following oral administration of single (15, 30, 60 mL) and multiple dose (15 mL) of Qiangli Pipa Syrup (MOR 0.1 mg/mL, COD 0.028 mg/mL) by monitoring morphine and codeine using a HPLC‐MS/MS method. Their T_max and t_1/2 values are independent of dosages, while the AUC_0?t linearly increased with higher dosages, indicating linear PK characteristics. AUC_0?t increased obviously after multiple doses, indicating possible risk of accumulative toxicity. Urine studies suggested risks of positive opiate drug tests with a cutoff of 300 ng/mL, which lasted 6–14 h at different doses. These results provide important information for clinical safety, efficacy and rational drug use of Qiangli Pipa Syrup and also guide the related judicial expertise of its administration.     

Unexpected Serotonin Syndrome,Epileptic Seizures,and Cerebral Edema Following 2,5‐dimethoxy‐4‐bromophenethylamine Ingestion

4‐bromo‐2,5‐dimethoxyphenethylamine (2C‐B) is a designer drug. In Europe, 2C‐B is easily obtained and used for recreational purposes. It is known for its stimulating effects similar to those of 3,4‐methylenedioxymethamphetamine, although in higher doses it has more hallucinogenic effects. Here, we report a case of 2C‐B ingestion, confirmed by liquid chromatography‐tandem mass spectrometry, in an 18‐year‐old man. The neurological consequences were severe, including the development of serotonin syndrome and severe brain edema. Supportive therapy resulted in a stable condition, although, after several months, the patient still suffered from severe neurological impairment due to the drug‐induced toxicity. This case showed that 2C‐B could not be identified with the drugs of abuse screening routinely used in Dutch hospitals. The use of 2C‐B carries many risks, with potentially profound neurological damage, that both consumers and healthcare physicians are unaware of.     

Bone as a biomarker of acute fluoride toxicity

The use of bone as a biomarker for chronic and acute exposure to fluoride salts has been suggested, but there are no data published about its use to evaluate lethal intoxication. One hundred and sixty rats were divided into eight groups that received a single oral intubation dose from 0 (control) to 90 mg F/kg as NaF. The animals' time of death was recorded and their femurs were removed for fluoride analysis. Acid-soluble fluoride was determined in the whole bone and on the surface (periosteal), using an ion specific electrode. The data showed a statistically significant relationship between fluoride dose and the number of deaths (P<0.0001). A statistically significant relationship was also found between fluoride dose and fluoride concentration ([F]) in either the whole femur (P<0.0017), on the surface (P<0.0001) or for the ratio periosteal [F]/whole [F] (P<0.0001). However, the [F] on the femur surface was more closely correlated with mortality than that in the whole bone, showing statistically significant differences among the lethal doses and control (P<0.05). The data suggest that the ratio [F] periosteal bone/[F] whole bone, is a biomarker for acute fluoride toxicity.     

发光细菌在法医毒物检测中的应用

目的利用发光细菌-青海弧菌Q67对于法医毒物的敏感性,建立一种案发现场快速检测法医毒物的发光细菌检测方法。方法制备冷冻干燥青海弧菌Q67测试液,将法医毒物检材的不同浓度稀释液加入制备好的青海弧菌Q67测试液中,通过检测青海弧菌Q67反应前后的相对发光强度的变化,计算出样本对青海弧菌Q67相对发光强度的变化率或抑制率,对法医毒物检材的毒性进行生物影响的定性评价。结果通过对包含多种农药混合物的法医检材稀释液的测试,发现发光细菌检测结果呈阳性的4个检材对青海弧菌Q67的发光强度抑制率分别为：100.00%,90.41%,84.26%,88.81%。结论通过对包含多种农药混合物的法医检材的测试表明,青海弧菌Q67发光检测方法对法医毒物的毒性的检测是一种快速、灵敏的现场检测方法。     

Caffeine toxicity: a case of child abuse by drug ingestion

The case of a 14-month-old child who died of caffeine toxicity is presented. The evidence for prolonged toxicity associated with inappropriate delay in the seeking of medical care and the presence of various recent and healing injuries are diagnostic of child abuse. Fatal caffeine toxicity and child abuse by drug/substance administration are uncommonly reported. Relevant medical literature is reviewed.     

One hundred seventy two deaths involving the use of oxycodone in Palm Beach County

Oxycodone is a potent semi-synthetic narcotic prescribed for the management of pain. Previous investigators have reported that the abuse of oxycodone is most frequently seen in conjunction with the abuse of other drugs, although fatalities have been reported with oxycodone alone. We undertook a retrospective review of cases investigated by the Palm Beach County Medical Examiner's Office in which postmortem toxicologic studies indicated the presence of oxycodone. A total of 172 consecutive cases were studied, including 18 in which death was attributed to oxycodone toxicity, 117 to combined drug toxicity, 23 to trauma, 9 to natural causes and 5 to another drug or drugs. The postmortem blood concentrations of oxycodone overlapped among the groups. The mean blood oxycodone concentration among the cases of oxycodone toxicity was 0.69 mg/L, combined drug toxicity 0.72 mg/L and trauma 0.62 mg/L. Concentrations were lower in cases of deaths attributed to natural causes and to another drug or drugs (mean each 0.087 mg/L). Benzodiazepines, detected in 96 cases, were the most common co-intoxicants in the cases of combined drug toxicity, followed by cocaine, which was found in 41. The most frequently encountered benzodiazepine was alprazolam. This study confirms that deaths in which oxycodone is a factor are most commonly cases of combined drug toxicity. The high incidence of alprazolam as a co-intoxicant has not been previously recognized.     

Disposition of citalopram in biological specimens from postmortem cases

Citalopram is a bicyclic phthalate compound approved in 1998 by the U.S. Food and Drug Administration for the treatment of depression. It is a highly selective serotonin reuptake inhibitor that appears to have little effect on noradrenaline or dopamine reuptake. Since this drug has only recently been released on the U.S. market, information regarding therapeutic, toxic, and lethal concentrations is sparse. This study reports the detection of citalopram in 22 postmortem cases. Citalopram was identified and quantitated by capillary column gas chromatography with nitrogen phosphorus detection after basic liquid-liquid extraction. Confirmation was achieved by full scan electron impact gas chromatography/mass spectrometry. In the 22 cases studied, heart blood citalopram concentrations ranged from 0.09 to 1.64 mg/L (n = 22, mean +/- SD = 0.51+/-0.43, median = 0.34); femoral blood concentrations ranged from 0.09 to 0.76 mg/L (n = 14, mean +/- SD = 0.34+/-0.23, median = 0.28); and urine concentrations ranged from 0.05 to 276.00 mg/L (n = 13). Liver was analyzed in three cases with citalopram concentrations ranging from 2.22 to 8.08 mg/kg. The average heart blood/femoral blood ratio was 1.26 (range 0.75 to 1.98, n = 14). In each case, the cause of death was not considered to be related to citalopram toxicity. These data may therefore provide a basis for establishing post mortem citalopram concentrations following therapeutic doses.     

基于HPLC-TOF-MS代谢组学方法的溴鼠灵毒性作用评价

目的分析溴鼠灵中毒大鼠尿液的代谢特征,揭示溴鼠灵干预对大鼠毒性作用的分子机制。方法通过构建大鼠溴鼠灵中毒模型,采用高效液相色谱-飞行时间质谱(high performance liquid chromatographytime of flight mass spectrometry,HPLC-TOF-MS)获取大鼠尿液代谢轮廓,并用正交偏最小二乘法-判别分析(orthogonal partial least squares-discrimination analysis,OPLS-DA)进行多变量统计分析,找出与溴鼠灵毒性作用密切相关的差异代谢物。结果 OPLS-DA得分图显示给药前后不同时间的大鼠尿液样本代谢物轨迹在各时间段内相似度较好,呈现各自聚类现象。比较溴鼠灵给药前后大鼠尿液样本,筛选出22个与溴鼠灵毒性相关的差异代谢物。结论溴鼠灵主要通过干扰大鼠体内的三羧酸循环、糖酵解、鞘脂代谢和色氨酸代谢等代谢通路发挥毒性作用,且溴鼠灵毒性作用具有累积效应。基于尿液HPLC-TOF-MS代谢组学方法可为溴鼠灵毒性作用的分子机制研究提供新思路。     

Fatal acute selenium toxicity

Selenium is used widely in industry and as a dietary supplement. Reports of acute selenium toxicity are infrequent, however, and the relationship of toxicity to selenium concentrations in blood and tissues has not been established. We describe a patient who died eight days after ingesting selenious acid in the form of gun blueing. The patient's clinical course demonstrated many of the features of inorganic selenium toxicity described in animals; hypotension as a result of both vasodilation and decreased cardiac output, adult respiratory distress syndrome, severe myopathy which contributed to respiratory failure, and a garlicky odor to the breath. Four days after ingestion the serum selenium concentration was twenty times normal and urinary excretion seventy times normal. Postmortem tissue selenium concentrations were up to 40 times normal.     

Post-mortem toxicology

Studies examining post-mortem processes are difficult to conduct since changes will have already occurred when the body arrives at the mortuary. While control of collection site for blood can minimize changes in concentration it is very difficult to conduct experiments in humans aimed at understanding the mechanisms and determining the extent of such changes. The use of appropriate animal models can be useful in this regard providing the species and conditions are carefully chosen. Pharmacokinetic studies in humans are also very useful for understanding the changes in drug concentration with time in blood (and other fluids) and also for improving our understanding of drug effects. Unfortunately, doses of illicit drugs that can be given are relatively low to guarantee safety hence extrapolations are made to real life situations. Individual case studies can be useful to describe an unusual or particularly interesting circumstances but little useful information can be obtained when trying to ascertain the role of competing factors, e.g. role of individual drugs when multiple drugs are present, varying toxicity between route of administration, and the role of age or natural disease when drugs are also present. Epidemiological approaches by reviewing large numbers of related cases are the most powerful tool to obtain this information. All of these studies need to operate under the ethical and legal framework appropriate for a jurisdiction. This paper discusses the relative merits of scientific approaches to research in post-mortem toxicology and provides guidance on the most appropriate techniques for future studies.     

Alprazolam-related deaths in Palm Beach County

Alprazolam is a commonly prescribed benzodiazepine. The abuse of benzodiazepines is most frequently seen in conjunction with the abuse of other drugs. Only rare fatalities have been attributed to alprazolam alone. We undertook a retrospective review of cases investigated by the Palm Beach County Medical Examiner's Office in which postmortem toxicologic studies indicated the presence of alprazolam, to further study the pattern of alprazolam abuse. Our review consisted of 178 cases, including 87 in which death was attributed to combined drug toxicity, 2 to alprazolam toxicity alone, 44 to trauma, 12 to natural causes, and 33 to another drug or drugs. Cocaine and methadone were the most common cointoxicants in the cases of combined drug toxicity, while heroin was less frequently detected. There was considerable overlap in the postmortem blood alprazolam concentrations among the groups. The overlapping ranges of concentrations of alprazolam detected indicate that it may be difficult to define a lethal alprazolam range, and that it may not be possible to determine the actual role of alprazolam as a causal factor in cases of combined drug toxicity. This study confirms that alprazolam alone is rarely a cause of death, and that alprazolam abuse usually occurs within a polydrug use pattern. The high incidence of cocaine as a cointoxicant has not been previously reported.     

Anabolic androgenic steroids in police cases in Sweden 1999-2009

Anabolic Androgenic Steroids (AAS) are considered drugs of abuse and are controlled substances in Sweden since 1999. Traditionally AAS have been used by elite athletes to enhance performance, but in recent years it has become an increasing problem outside elite sport among athletes, bodybuilders and criminals. Use of AAS is associated with psychiatric side effects such as aggression, depression and violent behavior. Supraphysiological doses and long term use can cause serious physical harm such as cardiovascular toxicity and even premature death. We investigated and evaluated the drug analytical findings in forensic cases from suspected perpetrators in cases from the police where a screening for AAS was requested to get information about the prevalence of AAS use and the occurrence of poly-drug abuse. The study was based on samples submitted from the police authorities to the Department of Forensic Toxicology in Sweden during the period 1999-2009. Urines were analyzed by methods based on GC-MS and LC-MS-MS. We also analyzed the prevalence of AAS use at the prison and probation services. A total number of 12,141 urine samples (6362 police cases and 5779 inmates) were analyzed and 33.5% of the cases from the police and 11.5% of the inmates were tested positive for AAS. The users of AAS were mainly in 99.2% men with a mean age of 26.2±6.2 years whereas the women were 29.5±6.5 years old. The most frequently used AAS was nandrolone followed by testosterone and methandienone. Other illicit and licit drugs were detected in 60% of the cases from the police, strongly indicating a frequent poly-drug abuse among users of AAS.