[Show abstract][Hide abstract] ABSTRACT: Introduction
In order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. Therefore, it makes sense to offer a carefully referenced compilation of therapeutic and toxic plasma concentration ranges, as well as half-lives, of a large number of drugs and other xenobiotics for quick and comprehensive information.
Data have been abstracted from original papers and text books, as well as from previous compilations, and have been completed with data collected in our own forensic and clinical toxicology laboratory. The data presented in the table and corresponding annotations have been developed over the past 20 years and longer. A previous compilation has been completely revised and updated. In addition, more than 170 substances, especially drugs that have been introduced to the market since 2003 as well as illegal drugs, which became known to cause intoxications, were added. All data were carefully referenced and more than 200 new references were included. Moreover, the annotations providing details were completely revised and more than 100 annotations were added.
For nearly 1,000 drugs and other xenobiotics, therapeutic ("normal") and, if data were available, toxic and comatose-fatal blood-plasma concentrations and elimination half-lives were compiled in a table.
In case of intoxications, the concentration of the ingested substances and/or metabolites in blood plasma better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications, and to support forensic and clinical expert opinions.
[Show abstract][Hide abstract] ABSTRACT: The term “dumping” is used for the removal of corpses after a drug-related death, usually to public places not far from where death occurred, after they passed away in the presence of others or in someone elses home. Most of these deaths are habitual drug-addicts. We report 4 cases of “dumping” featuring particular characteristics. In 2 cases the deceased were 15-year-old female drug-addicts and the accomplices could be determined and were accused and convicted of not having helped the dying. In one of these cases the death scene implicated a crime of violence, as the decomposed body was removed to a hidden place after being wrapped in plastic foil and a quilt-over. The 2 other cases concerned “body packers” who died from cocaine intoxication after the drug-packages which they had transported in their gastrointestinal tract had ruptured. The bodies were dumped in a backyard and on a toilet of a motorway road house, respectively. Reviewing the literature, we point out the usual characteristics of cases of dumping and refer to the legal consequences (within the German Law).
[Show abstract][Hide abstract] ABSTRACT: In forensic toxicology, several fatal intoxications with fentanyl have occurred in the recent past, but there are rare discussions in the literature of postmortem fentanyl blood concentrations subsequent to lethal and non lethal applications. To study this problem, we analyzed postmortem blood concentrations (vena femoralis) of 118 cases with therapeutic use of fentanyl and compared them with serum levels of 27 living persons after therapeutic administration of fentanyl patches (Durogesic). Basically, blood concentrations in postmortem specimens cannot be directly compared with in vivo serum levels: in our study, we observed that postmortem fentanyl blood concentrations were on average up to nine times higher than in vivo serum levels at the same dose. These differences could be explained by postmortem redistribution, but they were higher than expected on the basis of the physical and chemical properties of fentanyl alone. The special pharmacokinetics of the drug after long term transdermal application seem to play an important role in this phenomenon. In addition, there was no clear correlation between transdermal fentanyl dose and blood or serum concentrations, either antemortem or postmortem. Our study provides extensive data for postmortem peripheral blood concentrations after therapeutic non-fatal fentanyl patch application and demonstrates once more that in forensic toxicology, blood concentrations must be holistically interpreted with respect to all aspects of a case.
No preview · Article · Apr 2012 · Journal of analytical toxicology
[Show abstract][Hide abstract] ABSTRACT: Besides the use of Gamma-Hydroxybutyrate (GHB) as a recreational drug, use of GHB as an agent in drug-facilitated crime should also be considered. In these cases, there is often a delay of several hours from the incident to collection of the samples. As GHB has a very short plasma half-life, the window of detection is small and in the majority of these specimens, levels of GHB are low. Because GHB is naturally occurring in humans, discrimination between endogenous and exogenous GHB is complicated, particularly in those samples with low concentrations. In this study, endogenous GHB levels of 50 serum and 50 urine samples were determined by GC-MS after conversion to trimethyl-silyl-derivatives. Concentrations in serum ranged from 0.62 to 3.24 mg/L (mean=1.14 mg/L; median=0.97 mg/L) and from 0.64 to 4.20mg/L (mean=1.21 mg/L; median=0.96 mg/L) in urine. Based on this substantial data, the current suggested lower cut-off of 4 mg/L in ante mortem serum samples could be confirmed. For urine, we propose the lower cut-off of 6 mg/L instead of 10mg/L to avoid false negative interpretation.
No preview · Article · Apr 2010 · Forensic science international
[Show abstract][Hide abstract] ABSTRACT: Somatic cell hybrids were made from mouse myeloma cells and spleen cells derived from BALB/c mice immunized with homogenized epithelial fractions of BPH. The screening by immunoperoxidase staining on human prostate and non-prostate tissue resulted in one monoclonal antibody identifying a prostate specific antigen. Upon SDS-PAGE and Western blot this antigen exhibited a single band at the position of 34 kDa molecular weight. The immunoreactivity of the prostate antigen was found to be localized excluxsively in the epithelial lining of ducts and secretions of normal prostate, BPH and prostate cancer. Anti-p34 antibody reacted with an antigenic determinant on the PSA molecule and inhibited the binding of Anti-PSA antibody to PSA by about 80 to 90% in the RIA.Zusammenfassung Die Lymphozyten-Hybridisierung erfolgte zwischen Myelomzellen und Milzzellen immunisierter BALB/c-Mäuse. Zur Immunisierung wurde eine homogenisierte Epithelfraktion aus BPH-Geweben verwandt. Das Screening-Verfahren erfolgte immunhistologisch von Prostata und nicht-prostatischen Organen. Mit dieser Technik konnte ein monoklonaler Antikörper identifiziert werden, der ein Prostata-spezifisches Antigen erkennt. Das Antigen hat ein Molekulargewicht von 34 kDa und ist in den Drüsenepithelien der normalen Prostata, der BPH und des Prostatakarzinoms lokalisiert. Der Antikörper reagiert mit antigenen Determinanten des PSA-Moleküls und inhibiert zu 80 bis 90% die Bindung des Anti-PSA-Antikörpers an PSA.
[Show abstract][Hide abstract] ABSTRACT: Despite the fact that glycerol is well known as a nontoxic substance, intoxication with this tertiary alcohol is possible. We report on a 72-year-old male who was referred to the Department of Neurology with progressive neurological symptoms that had developed 4 h prior to admission. Temporally associated was the so-called glycerol test or Klockhoff test, which was performed for the diagnosis of suspected Menière's disease. The test procedure starts with oral administration of glycerol, the maximal dose should not exceed 1.5 g/kg of body weight.
Because of an apparently pathologically highly elevated serum concentration of triglycerides (3,465 mg/dL) measured 10 h after glycerol administration, the suspicion of an overdose of glycerol rose. During the following day, the glycerol serum concentration was analyzed at three different times.
Based on these measurements, we determined pharmacokinetic parameters and estimated the initially ingested amount of glycerol of about 3.88-3.95 g/kg body weight.
We conclude that an accidental overdose of glycerol must have occurred during the glycerol test to the patient.
No preview · Article · May 2009 · Clinical Toxicology
[Show abstract][Hide abstract] ABSTRACT: Although 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a known serotonergic neurotoxin in different animal species, there is to date no conclusive evidence of its neurotoxicity in humans. MDMA use was associated with impairments of psychological well-being, verbal memory and altered serotonergic functioning in a number of crosssectional studies. Due to inherent methodological limitations, such as the notorious polydrug use of ecstasy users and lack of control of possible pre-existing differences between ecstasy users and control participants, researchers have called for well-controlled, prospective longitudinal studies to shed more light on the issue of MDMA neurotoxicity to the human brain.
No preview · Article · Apr 2006 · Journal of Psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Intoxications with carbachol, a muscarinic cholinergic receptor agonist are rare. We report an interesting case investigating a (near) fatal poisoning.
The son of an 84-year-old male discovered a newspaper report stating clinical success with plant extracts in Alzheimer's disease. The mode of action was said to be comparable to that of the synthetic compound 'carbamylcholin'; that is, carbachol. He bought 25 g of carbachol as pure substance in a pharmacy, and the father was administered 400 to 500 mg. Carbachol concentrations in serum and urine on day 1 and 2 of hospital admission were analysed by HPLC-mass spectrometry.
Minutes after oral administration, the patient developed nausea, sweating and hypotension, and finally collapsed. Bradycardia, cholinergic symptoms and asystole occurred. Initial cardiopulmonary resuscitation and immediate treatment with adrenaline (epinephrine), atropine and furosemide was successful. On hospital admission, blood pressure of the intubated, bradyarrhythmic patient was 100/65 mmHg. Further signs were hyperhidrosis, hypersalivation, bronchorrhoea, and severe miosis; the electrocardiographic finding was atrio-ventricular dissociation. High doses of atropine (up to 50 mg per 24 hours), adrenaline and dopamine were necessary. The patient was extubated 1 week later. However, increased dyspnoea and bronchospasm necessitated reintubation. Respiratory insufficiency was further worsened by Proteus mirabilis infection and severe bronchoconstriction. One week later, the patient was again extubated and 3 days later was transferred to a peripheral ward. On the next day he died, probably as a result of heart failure. Serum samples from the first and second days contained 3.6 and 1.9 mg/l carbachol, respectively. The corresponding urine concentrations amounted to 374 and 554 mg/l.
This case started with a media report in a popular newspaper, initiated by published, peer-reviewed research on herbals, and involved human failure in a case history, medical examination and clinical treatment. For the first time, an analytical method for the determination of carbachol in plasma and urine has been developed. The analysed carbachol concentration exceeded the supposed serum level resulting from a therapeutic dose by a factor of 130 to 260. Especially in old patients, intensivists should consider intoxications (with cholinergics) as a cause of acute cardiovascular failure.
Full-text · Article · Feb 2006 · Critical care (London, England)
[Show abstract][Hide abstract] ABSTRACT: Ecstasy use has often been found to be associated with psychopathology, yet this research has so far been based largely on subjective symptom ratings.
To investigate whether ecstasy users suffered from long-term psychopathological consequences.
We compared the prevalence of Diagnostic and Statistical Manual version IV (DSM-IV) mental disorders in 30 current and 29 former ecstasy users, 29 polydrug and 30 drug-naive controls. Groups were approximately matched by age, gender and level of education. The current ecstasy users reported a life-time dose of an average of 821 and the former ecstasy users of 768 ecstasy tablets.
Ecstasy users did not significantly differ from controls in the prevalence of mental disorders, except those related to substance use. Substance-induced affective, anxiety and cognitive disorders occurred more frequently among ecstasy users than polydrug controls. The life-time prevalence of ecstasy dependence amounted to 73% in the ecstasy user groups. More than half of the former ecstasy users and nearly half of the current ecstasy users met the criteria of substance-induced cognitive disorders at the time of testing. Logistic regression analyses showed the estimated life-time doses of ecstasy to be predictive of cognitive disorders, both current and life-time.
The motivation for ecstasy use is not likely to be self-medication of pre-existing depressive or anxiety disorders as these did not occur more frequently in the ecstasy users than in control groups or in the general population. Cognitive disorders still present after over 5 months of ecstasy abstinence may well be functional consequences of serotonergic neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA).
[Show abstract][Hide abstract] ABSTRACT: Actually, guidelines for treatment of substance-related disorders were written under the overall control of the DG-Sucht e. V. and the DGPPN e. V. This appears within the framework of the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaft (AWMF). The leading objective of these guidelines is the description of the current scientifically proven and evidence-based medicine in addiction to derive recommendations to therapy. In this context, the guideline for treatment of cocaine-, amphetamine-, ecstasy-, and halluzinogen-related disorders is introduced.
No preview · Article · Jan 2005 · Fortschritte der Neurologie · Psychiatrie
[Show abstract][Hide abstract] ABSTRACT: Despite increased blood sampling there is a slightly increased tendency for police suspicion and actual detection of drug use to coincide. This would indicate a considerable number of undetected cases of driving under the influence of drugs in Hamburg. Over the last few years, the frequency of detection for methadone flunitrazepam, clonazepane and amphetamine derivates changed due to an increase in availability of these substances on the black market. Given the data it is impossible to determine whether the detection frequency of cannabis is merely a result of proper police training in the early recognition of signs for drug use or whether it is a result of an alteration in cannabis consumption. Cannabis consumption exceeds opiate consumption and it can be assumed that this was the case in the past. Therefore the improved police training would enable a more realistic picture of actual drug consumption in road traffic today than would have been possible only a few years ago. As a rule all psychoactive substances were abused in combination with other drugs regardless of whether they acted pharmacologically alike or not (> 80% in combination). The only exception here would be cannabis, where other psychotropic substances could be detected in less than half of the cases (42.4%). In comparison with other drugs, however, a proportionately large number of cases of cannabis use in combination with only alcohol could be detected (26.6 %). A mixed consumption of drugs was found most frequently in combination with methadone and it can be assumed, as with benzodiazepine, that in most cases these were not prescription drugs prescribed by a physician. Road traffic accident findings would indicate that mixed consumption of drugs increase the probability of accidents. Methadone and Benzodiazepine were detected more frequently in road traffic accidents than in merely suspected driving under the influence of drugs. This is not applicable to any other substance with the exception of barbiturates, which are no longer relevant in number. Substances other than methadone and benzodiazepine, which are not listed in the existing § 24a StVG (German Traffic Law) are largely irrelevant to traffic offences. This would imply that prescription medication- when used properly - does not affect safe driving. Conclusion: It is therefore recommended to follow the recommendations by SCHÖCH  which state that proof of other drugs and alcohol (> 0.3‰) should be recorded in the appendix of § 24a section 2 StVG (German Traffic Law) Furthermore, benzodiazepines as well as methadone used in conjunction with either alcohol (> 0.3‰) or another psychoactive substance should be recorded in the latter.
[Show abstract][Hide abstract] ABSTRACT: Organophosphate compounds are widely used as pesticides. After ingestion by humans, organophosphates decompose into alkyl phosphates. Decomposition continues postmortem. We developed a rapid (< 3 h), quantitative, and sensitive analysis of the human organosphosphate metabolites O,O-dimethylphosphate (DMP), O,O-diethylphosphate (DEP), O,O-dimethylthiophosphate (DMTP), O,O-diethylthiophosphate (DETP), O,O-dimethyldithiophosphate (DMDTP), and O,O-diethyldithiophosphate (DEDTP). Urine is dried under azeotropic conditions with isopropanol and nitrogen. All metabolites are converted into their corresponding benzyl esters reacting with benzyl bromide and diazotoluene. The protocol prevents the isomerization of DMTP and DETP occurring when diazo compounds are used exclusively. The benzyl ester derivatives are purified on solid-phase extraction silica columns. The quantitative analysis is performed by gas chromatography-mass spectrometry. All metabolites can be identified by the parent molecular ions. Urine samples from eight cases of fatal suicidal poisoning dialkyl phosphates were quantitated. The limits of detection ranged from 3 to 6 ng/mL. Hence, this protocol is sufficiently sensitive to detect and quantitate organophosphate metabolites beyond cases of fatal poisoning, in the clinical setting, and even following average environmental exposure.
Preview · Article · May 2004 · Journal of analytical toxicology
[Show abstract][Hide abstract] ABSTRACT: In order to assess the significance of drug levels measured in clinical and forensic toxicology as well as for Therapeutic Drug Monitoring (TDM) it is essential that good collections of data are readily available. For more than 800 substances, therapeutic ('normal') and, if data was available, toxic, and fatal plasma concentrations as well as elimination half-lives were compiled in a table. The compilation includes data for hypnotics, benzodiazepines, neuroleptics, antidepressants, sedatives, analgesics, anti-inflammatory agents (e.g., NSAIDs), antihistamines, antiepileptics, betaadrenergic antagonists, antibiotics (penicillins, cephalosporins, aminoglycosides, gyrase inhibitors), diuretics, calcium-channel blockers, cardiac glycosides, antiarrhythmics, antiasthmatics, ACE-inhibitors, opiate agonists, and local anesthetics, among others. In addition, toxicologically relevant xenobiotics were listed. Data have been abstracted from published information, both compilations and primary sources and have been completed with data collected in our own forensic and clinical toxicology laboratories. Wherever possible, ranges for therapeutic plasma concentrations are expressed as trough concentration at steady state. The half-life values given for each drug are chosen to represent the terminal log-linear phase at most. It is the purpose to rapidly assess the significance of drug levels for the therapeutic monitoring of patients, and to facilitate the diagnostic and clinical assessment in case of intoxications.
[Show abstract][Hide abstract] ABSTRACT: Chronic recreational ecstasy (MDMA) use has often been reported to be associated with psychopathology, memory impairments and serotonergic alterations. However, the findings have not been consistent.
To attempt to replicate these findings, to investigate whether such alterations would be reversible and whether they could be predicted by parameters of previous drug use.
In a cross-sectional design, 30 current and 31 ex-ecstasy users with ecstasy abstinence of at least 5 months, and 29 polydrug and 30 drug-naive controls were compared on measures of psychopathology, cognitive performance and serotonin transporter availability.
The groups did not differ significantly in age, gender distribution, education level and premorbid intelligence. The ecstasy groups did not differ significantly from polydrug controls on most of the relevant parameters of concomitant illegal drug use. Reported drug use was confirmed by hair and urine analyses. All three groups of drug users exhibited significantly elevated psychopathology compared with drug-naive controls. Only ex-ecstasy users were significantly impaired on verbal recall. Current ecstasy users showed significantly reduced distribution volume ratios of serotonin transporter availability in the mesencephalon and caudate nucleus. Regression analyses indicated that psychopathology and serotonergic alterations were best predicted by the number of ecstasy tablets taken on a typical event.
The results indicate that verbal memory impairments were possibly aggravated after prolonged ecstasy abstinence while there was tentative evidence of serotonergic recovery. On the other hand, self-reported elevated psychopathology appeared to be associated with polydrug use in general and not specifically with ecstasy use.
No preview · Article · May 2003 · Psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Adenoviral vectors have been shown to efficiently transfer DNA into a wide variety of eukaryotic cells in vitro and in vivo. However, the therapeutic benefit of this approach is limited by severe side effects as a result of uncontrolled transgene expression.
A bi-directional promoter that controls the desired transgene as well as a tetracycline-suppressible transactivator (tTA) was cloned into the E1-region of E1-deleted recombinant adenoviral vectors. Autoregulation within this construct was obtained by tTA expression under control of the operator, to which tTA binds in the absence of tetracycline. Consequently, binding of tetracycline to tTA results in downregulation of tTA as well as the co-expressed transgene in the infected cell.
We were able to suppress luciferase-reporter gene expression by up to 16 000-fold in the presence of doxycycline (dox, 2 micro g/ml). Under control of this tetracycline-regulated system, single-chain interleukin-12 (scIL12) was expressed. Adenovirally mediated expression of this potentially lethal cytokine with strong activation of antitumoral immune response was downregulated by up to 6000-fold in the presence of dox. Subsequently, this downregulation also resulted in a highly significant reduction of interferon-gamma secretion by stimulated splenocytes. These mainly contribute to the toxicity of this immunotherapeutic approach.
With expression levels exceeding those of the cytomegalovirus (CMV) promoter in almost all cell lines tested, these new vectors will also contribute to the safety of adenoviral approaches by controlled expression without compromising on maximum expression levels.
No preview · Article · Apr 2003 · The Journal of Gene Medicine
[Show abstract][Hide abstract] ABSTRACT: The use of the illicit drug ecstasy (mainly containing methylenedioxymethamphetamine, MDMA) is widespread among young people in western Nations. Animal experiments indicate that MDMA is a potent neurotoxin specifically affecting the serotonergic system. A few functional neuroimaging studies revealed central nervous alterations after the repeated use of ecstasy. We examined 94 ecstasy users in comparison to 27 control subjects by means of positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG). The FDG uptake rates were globally reduced in ecstasy users, most pronounced in the striatum. The uptake rates tended to be negatively correlated with the cumulative ecstasy doses. The results indicate that younger ecstasy users may be more vulnerable with regard to neurotoxicity.
Full-text · Article · Mar 2002 · Toxicology Letters
[Show abstract][Hide abstract] ABSTRACT: Of the side effects occurring in temporal association with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), peptic ulcer disease is reported most often.
To (1) provide information on the temporal association between fatal peptic ulcer presenting as sudden death and NSAID use prior to death, and (2) to examine the diagnostic efficiency of postmortem determination of NSAID levels using high-pressure liquid chromatography.
Prospective autopsy study of all cases of sudden death associated with peptic ulcer disease from a total of 1139 medicolegal autopsies performed during a 12-month period.
Postmortem femoral blood samples were analyzed for NSAIDs using high-pressure liquid chromatography, and specimens of gastric and duodenal mucosa were examined for coexisting pathologic conditions.
Twelve fatalities that occurred out of hospital as a result of peptic ulcer disease and presented as sudden death were identified. Autopsy blood samples were positive for NSAIDs in 7 cases (ibuprofen in 4 cases, levels 0.8 to 1.4 microg/mL; diclofenac in 2 cases, levels 0.6 and 1.6 microg/mL; and ketoprofen in 1 case, level 0.3 microg/mL). The ages of the affected individuals (3 men, 4 women) ranged from 43 to 60 years. No other drugs, including corticosteroids, anticoagulants, salicylic acid, and salicylates, were present. Microscopic examination revealed no pathologic antemortem mucosal conditions in any of the cases.
For the postmortem elucidation of etiopathogenetic factors contributing to fatal peptic ulcer disease, high-pressure liquid chromatography to determine NSAID levels in autopsy blood samples is of considerable diagnostic benefit, especially when combined with histology. The number of cases of sudden death involving younger individuals dying as a result of peptic ulcer disease in temporal association with preceding use of NSAIDs seems to be underestimated from the clinical viewpoint due to the underrepresentation of out-of-hospital fatalities in the field of clinical pathology.
No preview · Article · Jan 2002 · Archives of pathology & laboratory medicine
[Show abstract][Hide abstract] ABSTRACT: Liver transplantation is the only available definite treatment of end-stage acute liver failure. We report 12 cases of toxin-induced acute liver failure that finally required transplantation. Apart from viral hepatitis, toxic actions of drugs or chemicals account for the majority of acute liver failures world-wide. In approximately 40% the responsible agent remains undetected. Paracetamol and phenprocoumon were thought to have caused liver injury in three cases each, α-amanitin in two cases as well as halothane, adriablastin and anti-tuberculous drugs in one case each. In one patient, the responsible substance remained unidentified. Transplantation was successful in 75% of all cases. The prognosis of toxin-induced acute liver failure strongly depends on the identification of the substance responsible. Thus, every effort has to be made to reduce the large number of undiagnosed cases. To achieve this, a close cooperation of clinical centres and institutions performing toxicological analyses is of overriding importance.