Revisited: Therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics.

In order to assess the significance of drug/substance levels measured in intensive care medicine and clinical and forensic toxicology as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. We revisited and expanded our 2012 compilation of therapeutic and toxic plasma concentration ranges as well as half-lives of now more than 1100 drugs and other xenobiotics.Data have been abstracted from original papers, text books, and previous compilations and have been completed with data collected in our own forensic and clinical toxicology laboratories. We compiled the data presented in the table and the corresponding annotations over the past 30+ years. A previous compilation was completely double-checked, revised, and updated, if necessary. In addition, more than 200 substances, especially drugs who have been introduced since 2012 to the market as well as illegal drugs and other xenobiotics which became known to cause intoxications were added. We carefully referenced all data. Moreover, the annotations providing details were updated and revised, when necessary.For more than 1100 drugs and other xenobiotics, therapeutic ("normal") and, if data was available, toxic, and comatose-fatal plasma/blood concentrations as well as elimination half-lives were compiled in a table.In case of intoxications, the blood concentration of the substance and/or metabolite 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 as well as to support forensic and clinical expert opinions.

Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics.

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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Fentanyl: toxic or therapeutic? Postmortem and antemortem blood concentrations after transdermal fentanyl application.

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.

Severe glycerol intoxication after Menière's disease diagnostic--case report and overview of kinetic data.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: We conclude that an accidental overdose of glycerol must have occurred during the glycerol test to the patient.

Case report: acute unintentional carbachol intoxication.

INTRODUCTION: Intoxications with carbachol, a muscarinic cholinergic receptor agonist are rare. We report an interesting case investigating a (near) fatal poisoning. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Highly suppressible expression of single-chain interleukin-12 by doxycycline following adenoviral infection with a single-vector Tet-regulatory system.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.