Florian Eyer

Publications of Florian Eyer

• Enantioselective determination of R- and S-hyoscyamine in mammalian plasma and urine samples

  Authors: Harald John, Florian Eyer, Thomas Zilker, Horst Thiermann

  Naunyn-Schmiedebergs Archiv für Pharmakologie und experimentelle Pathologie. 03/2012; 385(Suppl 1):S42.

• Enantioselective determination of R- and S-hyoscyamine in mammalian plasma and urine samples

  Authors: Harald John, Florian Eyer, Thomas Zilker, Horst Thiermann

  Naunyn-Schmiedeberg´s Archives of Pharmacology. 03/2012; 385(Suppl. 1):S42.

• Enantioselective determination of R- and S-hyoscyamine in mammalian plasma and urine samples

  Authors: Harald John, Florian Eyer, Thomas Zilker, Horst Thiermann

  Naunyn-Schmiedeberg´s Archives of Pharmacology. 03/2012; 385 Suppl 1:S42.

• Clinical and analytical features of severe suicidal quetiapine overdoses--a retrospective cohort study.

  Authors: Florian Eyer, Rudolf Pfab, Norbert Felgenhauer, Tim Strubel, Bernd Saugel, Thomas Zilker

  Clinical toxicology (Philadelphia, Pa.). 11/2011; 49(9):846-53.

  Detailed data on severe overdoses with quetiapine are relatively sparsely reported in the literature. To describe a cohort of 20 acute quetiapine overdoses and provide additional data on theDetailed data on severe overdoses with quetiapine are relatively sparsely reported in the literature. To describe a cohort of 20 acute quetiapine overdoses and provide additional data on the pharmacokinetics and clinical features of intoxication with this drug. A retrospective study was conducted on patients with quetiapine poisoning admitted to our institution. We included moderate to severe overdoses between 2005-2011 who required admission to ICU. Predominantly female patients (n = 17) ingested a median dose of 9.8 g quetiapine. Poison Severity Score was moderate in 9 patients, severe in 10 patients and in one case fatal. Quetiapine was analytically confirmed in all cases. Clinical manifestations included drowsiness or coma (all patients), tachycardia (12 patients) and hypotension (10 patients). Seizures and arrhythmia occurred in 4 patients, each. Intubation and mechanical ventilation was required in 14 patients due to seizures, respiratory depression or loss of airway protection and 15 patients developed pneumonia. Hypokalaemia and hyperglycaemia were present at admission in 10 and 5 patients, respectively. Despite frequent prolongation of the QT(c) in 13 patients, QT interval was normal in most cases and QRS-interval was prolonged in only one patient. Presumably anticholinergic delirium was recognised in 8 patients and 6 patients received physostigmine with good clinical response. In 13 cases quetiapine was analysed quantitatively in serum with a relevantly prolonged half-life (16 ± 12 h) and a median peak serum concentration of 3074 ng/mL. In 4 of these 13 patients we observed an increase of quetiapine serum concentration in the further course. In this study, quetiapine overdoses were associated with significant toxicity and a fairly high number of complications. A careful and often prolonged clinical observation in the more severe cases of overdose seems mandatory.

• Atropine maintenance dosage in patients with severe organophosphate pesticide poisoning.

  Authors: Horst Thiermann, Dirk Steinritz, Franz Worek, Maria Radtke, Peter Eyer, Florian Eyer, Norbert Felgenhauer, Thomas Zilker

  Toxicology letters. 09/2011; 206(1):77-83.

  Although the importance of atropine in therapy of organophosphate (OP) poisoning is generally recognized, its dosing is a matter of debate. A retrospective analysis of atropine dosing was undertakenAlthough the importance of atropine in therapy of organophosphate (OP) poisoning is generally recognized, its dosing is a matter of debate. A retrospective analysis of atropine dosing was undertaken in 34 patients who had been enrolled in a clinical study assessing obidoxime effectiveness in OP-poisoning. All patients were severely intoxicated (suicidal attempts) and required artificial ventilation. Atropine was administered routinely by intensive care physicians for life-threatening muscarinic symptoms, with the recommendation to favor low dosage. The pharmacological active enantiomere S-hyoscyamine was determined by a radioreceptor assay. When RBC-AChE activity ranged between 10% and 30%, S-hyoscyamine plasma concentrations of approx. 5 nmol L⁻¹ were sufficient. This concentration could be maintained with about 0.005 mg h⁻¹ kg⁻¹ atropine. Only when RBC-AChE was completely inhibited, therapy of cholinergic crisis required atropine doses up to 0.06 mg h⁻¹ kg⁻¹. Elimination half-life of S-hyoscyamine was 1.5 h, showing occasionally a second slow elimination phase with t(½)=12 h. Malignant arrhythmias were observed in some 10% of our cases, which occurred late and often in the absence of relevant glandular cholinergic signs, when the S-hyoscyamine concentration was below 2.5 nmol L⁻¹. Arrhythmias mostly resolved on reinstitution of atropine.

• Patient-doctor interaction, psychobehavioural characteristics and mental disorders in patients with suspected allergies: do they predict "medically unexplained symptoms"?

  Authors: Constanze Hausteiner-Wiehle, Martine Grosber, Esther Bubel, Sylvienne Groben, Susanne Bornschein, Claas Lahmann, Florian Eyer, Bernadette Eberlein, Heidrun Behrendt, Bernd Löwe, Peter Henningsen, Dorothea Huber, Johannes Ring, Ulf Darsow

  Acta dermato-venereologica. 06/2011; 91(6):666-73.

  In approximately 20% of patients with suspected allergies, no organic symptom explanation can be found. Limited knowledge about patients with "medically unexplained symptoms (MUS)" contributes toIn approximately 20% of patients with suspected allergies, no organic symptom explanation can be found. Limited knowledge about patients with "medically unexplained symptoms (MUS)" contributes to them being perceived as "difficult" and being treated inadequately. This study examined the psychobehavioural characteristics of patients presenting for a diagnostic allergy work-up. Patients were interviewed and completed various self-rating questionnaires. Patient-Doctor interaction was evaluated, and the organic explicability of the patients' symptoms was rated by allergists. Patients with vs. those without MUS differed in several respects. Mental comorbidity, female sex, dissatisfaction with care, and a problematic countertransference (the interviewer's feelings towards the patient) independently predicted MUS. Patients whose symptoms could be explained organically reported more psychobehavioural problems than a control group of immuno-therapy patients. There were no differences in patient-doctor interaction. In patients with suspected allergies, recognition of psychological burden and concurrent mental disorders is important. Mental comorbidity and a difficult patient-doctor interaction may predict MUS.

• High-performance liquid-chromatographic tandem-mass spectrometric methods for atropinesterase-mediated enantioselective and chiral determination of R- and S-hyoscyamine in plasma.

  Authors: Harald John, Florian Eyer, Thomas Zilker, Horst Thiermann

  Analytica chimica acta. 11/2010; 680(1-2):32-40.

  S-hyoscyamine (S-hyo) is a toxic tropane alkaloid from plants of the solanacea family, which is extracted for pharmaceutical purposes thereby undergoing racemization (atropine). Merely the S-hyoS-hyoscyamine (S-hyo) is a toxic tropane alkaloid from plants of the solanacea family, which is extracted for pharmaceutical purposes thereby undergoing racemization (atropine). Merely the S-hyo enantiomer acts as an antagonist of muscarinic receptors (MR). Nevertheless, racemic atropine is clinically administered in e.g. ophthalmology and for symptomatic therapy of acute poisoning with organophosphorus compounds (OPCs, e.g. pesticides, nerve agents). However, very limited data are available of comparative pharmacokinetics of S- and R-enantiomers in humans or other species. Therefore, we developed an enantioselective LC-ESI-MS/MS assay making use of rabbit serum containing atropinesterase (AtrE, EC 3.1.1.10) which is suitable for stereospecific hydrolysis of S-hyo into tropine and tropic acid while R-hyo is unaffected. For sample preparation plasma was incubated with human serum (not containing AtrE, procedure A) and with rabbit serum (procedure B). Afterwards, hyoscyamines were quantified by a validated previously published non-chiral LC-ESI-MS/MS method. Following procedure A the concentration of total hyo and following procedure B remaining R-hyo were determined. S-hyo was calculated by the difference between these concentrations. This assay design allowed reproducible, precise (RSD 2-9%), accurate (93-101%) and selective determination of total and individual hyoscyamines. Potential therapeutics for OPC poisoning (carbamates, oximes) and thiono-pesticides did not interfere with the assay whereas some oxon-pesticides inhibited S-hyo hydrolysis. A control experiment was designed allowing to be aware of such interferences thus avoiding the use of false results. To validate this assay, results were compared to those from a novel isocratic chiral LC-ESI-MS/MS method. Separation of S-hyo (t(R) 31.1 ± 0.2 min) and R-hyo (t(R) 33.4 ± 0.2 min) was achieved on α-glycoprotein (AGP) chiral stationary phase at 40°C (selectivity factor α 1.07). Ammoniumformate (0.01 M, pH 8.0) with 3.75% (v/v) acetonitrile served as mobile phase (300 μL min(-1)). Hyoscyamines were detected in the positive multiple reaction monitor mode. The enantioselective assay was applied to the analysis of atropine degradation in diluted rabbit serum in vitro as well as to human in vivo plasma samples from a pesticide-poisoned patient treated with atropine.

• Assessment of neuromuscular dysfunction during poisoning by organophosphorus compounds.

  Authors: Horst Thiermann, Thomas Seeger, Sascha Gonder, Nadja Herkert, Bernd Antkowiak, Thomas Zilker, Florian Eyer, Franz Worek

  Chemico-biological interactions. 09/2010; 187(1-3):265-9.

  Dysfunction of respiratory muscles is a life-threatening complication in poisoning by organophosphorus compounds (OPs). It is both of central and peripheral origin due to impaired cholinergicDysfunction of respiratory muscles is a life-threatening complication in poisoning by organophosphorus compounds (OPs). It is both of central and peripheral origin due to impaired cholinergic signalling upon inhibition of acetylcholinesterase (AChE). The dysfunction at neuromuscular synapses is not amenable to anticholinergics and remains a therapeutic challenge. Thus, a clear understanding of the distinct mechanisms occurring at neuromuscular synapses is decisive for the development and improvement of therapeutic strategies, particularly with nerve agent poisoning, where clinical studies are prevented by ethical considerations. Using red blood cell AChE, the kinetics of OP induced inhibition, aging, and spontaneous and oxime-induced reactivation have been elucidated. In a dynamically working in vitro model with real-time determination of membrane-bound AChE, it was shown that the kinetic constants derived from erythrocyte AChE are comparable to muscle AChE in a given species. To assess, whether kinetic considerations of AChE activity are relevant for the neuromuscular function, organotypic spinal cord-skeletal muscle cocultures have been established. In this model neostigmine and VX affected neuromuscular transmission as anticipated from their known actions on AChE. Also oxime-induced restoration of the neuromuscular transmission was observed. These findings were confirmed by functional studies on diaphragm muscles of various species with determination of muscle force generation upon phrenic nerve or indirect electrical field stimulation techniques. Investigations with human intercostal muscles are in progress to assess the conditions in human tissue. The results obtained with paraoxon favourably correlate with data from clinical findings of parathion-poisoned patients where the correlation of neuromuscular transmission with the activity of erythrocyte AChE could be established. In conclusion, a variety of methods are available to follow the microscopic reactions occurring at the synaptic level. Due to the lack of clinical data with different OPs, e.g. nerve agents, well designed animal experiments, reflecting the human situation as close as possible, are indispensable for the development of new drugs against the deleterious OP effects.

• Characteristics of oligosymptomatic versus polysymptomatic presentations of somatoform disorders in patients with suspected allergies.

  Authors: Constanze Hausteiner, Dorothea Huber, Susanne Bornschein, Martine Grosber, Esther Bubel, Sylvie Groben, Claas Lahmann, Bernd Löwe, Florian Eyer, Bernadette Eberlein, Johannes Ring, Heidrun Behrendt, Ulf Darsow, Peter Henningsen

  Journal of psychosomatic research. 09/2010; 69(3):259-66.

  Psychobehavioral characteristics of patients with somatoform disorders (SFDs), are increasingly discussed as possible positive criteria for this diagnostic group. However, little is known aboutPsychobehavioral characteristics of patients with somatoform disorders (SFDs), are increasingly discussed as possible positive criteria for this diagnostic group. However, little is known about psychobehavioral differences, or similarities, between the different SFD presentations, i.e., polysymptomatic [multisomatoform/somatization disorders (MSD)] versus mono- or oligosymptomatic courses [pain disorder (PD), undifferentiated somatoform disorder (USD)]. This is a cross-sectional study including 268 consecutive allergology inpatients. After an Structured Clinical Interview for DSM-IV, patients completed several self-rating questionnaires. Results were compared within the different SFD presentations as well as between patients with versus without SFDs. We identified 72 patients with an SFD. There were fewer and smaller psychobehavioral differences within patients with the different SFD presentations (MSD, USDs, PDs) than between patients with undifferentiated versus no SFD. Patients with one of the three different SFD subdiagnoses scored similarly on many measures referring to psychosocial distress (e.g., psychological distress, mental health-related quality of life, dissatisfaction with care). The number of reported symptoms, somatic symptom severity, a self-concept of bodily weakness, the degree of disease conviction, and physical health-related quality of life discriminated the different SFD presentations not only from patients without SFDs but also from each other. Patients diagnosed with one of the different SFD subtypes share many psychobehavioral characteristics, mostly regarding the reporting of psychosocial distress. Perceived somatic symptom severity and physical impairment as indicators of bodily distress could either further define categorical subdivisions of SFD or dimensionally graduate one general SFD category defined by bothering bodily symptoms and disproportionate psychosocial distress.

• Predictors of treatment outcomes after removal of amalgam fillings: associations between subjective symptoms, psychometric variables and mercury levels.

  Authors: Wolfgang Weidenhammer, Susanne Bornschein, Thomas Zilker, Florian Eyer, Dieter Melchart, Constanze Hausteiner

  Community dentistry and oral epidemiology. 04/2010; 38(2):180-9.

  This analysis aimed to study predictors of different treatment outcomes and associations between subjective symptoms, psychometric variables and mercury levels in patients who subjectively attributedThis analysis aimed to study predictors of different treatment outcomes and associations between subjective symptoms, psychometric variables and mercury levels in patients who subjectively attributed their health problems to dental amalgam. A secondary and retrospective analysis of data of a recently published randomized clinical trial was performed. Seventy-eight patients [44% female, mean (SD) age 35 (6) years, randomly assigned to either amalgam removal or a health promotion program] were included into statistical analysis. Prior to intervention and 12 months later, questionnaires for assessing symptoms, psychological distress and health status were presented, and mercury levels in blood and urine were determined. The patients' personality profile at study onset was characterized by slightly reduced extraversion and slightly elevated emotional instability. Overall, subjective symptoms decreased slightly and there were no statistically significant differences in the decrease of symptoms after intervention between both groups. Decrease of mercury levels after intervention was closely associated with removal of amalgam fillings (r(mult) = 0.64 in regression analysis). Statistically significant correlations could be found between mercury levels and subjective symptoms with respect to baseline (r = 0.29-0.39) and to changes after intervention (r = 0.24-0.42), but not for psychological distress (r = 0.05-0.25) and health related quality of life (r = -0.03-0.18). Prediction of symptom improvement after intervention was poor (r(mult) = 0.44). Results contribute some new aspects to the inconsistent findings in the literature with respect to associations between symptoms and subtoxic mercury levels. More emphasis should be placed on exploring individual vulnerability for amalgam sensitivity.

• Free and Total Digoxin in Serum During Treatment of Acute Digoxin Poisoning With Fab Fragments: Case Study.

  Authors: Florian Eyer, Werner Steimer, Christine Müller, Thomas Zilker

  American journal of critical care : an official publication, American Association of Critical-Care Nurses. 10/2009;

  A woman ingested 10 mg of methyldigoxin in a suicide attempt and presented 19 hours after ingestion with clinical signs of glycoside intoxication. Her serum level of digoxin was 7.4 ng/mL, andA woman ingested 10 mg of methyldigoxin in a suicide attempt and presented 19 hours after ingestion with clinical signs of glycoside intoxication. Her serum level of digoxin was 7.4 ng/mL, and antidotal therapy with Fab antibody fragments was started. The manufacturer's recommended dosing scheme was modified, with 80 mg Fab administered intravenously within 15 minutes followed by a continuous infusion at 30 mg/h. Total serum concentration of digoxin increased markedly within minutes after Fab therapy was started, while the level of free digoxin immediately decreased into the nontoxic range without recrudescent toxic effects of digoxin. The cumulative amounts of free and bound digoxin that were excreted in urine within 30 hours after ingestion were 900 mug and 1600 mug, respectively. Half-life of bound digoxin in urine was 9.9 hours; mean rate of clearance of bound digoxin in the urine was 7.0 mL/min. On the basis of these kinetic data, a smaller initial bolus dose of Fab followed by a continuous infusion may be a more tailored, cost-effective, and relatively safe therapy for patients who have overdosed on cardiac glycosides.

• Risk assessment of severe tricyclic antidepressant overdose.

  Authors: Florian Eyer, Jochen Stenzel, Tibor Schuster, Norbert Felgenhauer, Rudi Pfab, Christian von Bary, Thomas Zilker

  Human & experimental toxicology. 10/2009;

  Prognostic factors for severe complications in tricyclic antidepressant (TCA) overdose remain unclear. We therefore evaluated the value of clinical characteristics and electrocardiograph (ECG)Prognostic factors for severe complications in tricyclic antidepressant (TCA) overdose remain unclear. We therefore evaluated the value of clinical characteristics and electrocardiograph (ECG) parameters to predict serious events (seizures, arrhythmia, death) in severe TCA overdose of 100 patients using logistic regression models for risk assessment. The overall fatality rate was 6%, arrhythmia occurred in 21% and 31% of the patients developed seizures. Using an univariable logistic regression model, the maximal QRS interval (OR 1.22; 95% CI 1.06-1.41; p = .005), the time lag between ingestion and occurrence of first symptoms of overdose (OR 1.13; 95% CI 0.99-1.29; p = .072) and the age (OR 0.73; 95% CI 0.55-0.98; p = .038) were determined as the solely predictive parameters. In the multivariable logistic regression model, the QRS interval could not be established as independent predictor, however, the terminal 40-ms frontal plane QRS vector (T40) reached statistical significance regarding prediction of serious events (odds ration [OR] 1.70; 95% confidence interval [CI] 1.02-2.84; p = .041), along with age and time lag between ingestion and onset of symptoms of overdose with a sensitivity and specificity of 71% and 70%, respectively. Evaluation of both clinical characteristics and ECG-parameters in the early stage of TCA overdose may help to identify those patients who urgently need further aggressive medical observation and management.

• Obidoxime in acute organophosphate poisoning: 1 - clinical effectiveness.

  Authors: Florian Eyer, Franz Worek, Peter Eyer, Norbert Felgenhauer, Mike Haberkorn, Thomas Zilker, Horst Thiermann

  Clinical toxicology (Philadelphia, Pa.). 09/2009;

  Objective. The effects of obidoxime in the treatment of organophosphate poisoning were assessed by comparing the clinical course with its effects on laboratory parameters relevant to poisoning. InObjective. The effects of obidoxime in the treatment of organophosphate poisoning were assessed by comparing the clinical course with its effects on laboratory parameters relevant to poisoning. In this article we report clinical findings and activity of cholinesterase in plasma and acetylcholinesterase (AChE) in red blood cells. In a linked paper we describe changes in neuromuscular transmission and atropine concentrations in the same patient cohort. Methods. We studied 34 atropinized patients with severe parathion, oxydemeton methyl, and dimethoate self-poisoning who were treated with obidoxime in a standard protocol. We measured the AChE activity in blood and related it to clinical features of organophosphate poisoning. Results. Patients poisoned with parathion responded promptly to obidoxime (250 mg bolus followed by continuous infusion at 750 mg/day up to 1 week) with improvement of neuromuscular transmission and increased AChE activity. The effects were only transient in cases with the other poisons. Death (7/34) occurred late and was mostly due to complications rather than due to ongoing cholinergic crisis. Conclusions. Obidoxime appeared safe and reactivated AChE in parathion poisoning.

• Obidoxime in acute organophosphate poisoning: 2 - PK/PD relationships.

  Authors: Horst Thiermann, Franz Worek, Peter Eyer, Florian Eyer, Norbert Felgenhauer, Thomas Zilker

  Clinical toxicology (Philadelphia, Pa.). 09/2009; 47(8):807-13.

  OBJECTIVE: The effects of obidoxime in the treatment of organophosphate poisoning were assessed by biochemical and biological effect monitoring. In this article we report effects on neuromuscularOBJECTIVE: The effects of obidoxime in the treatment of organophosphate poisoning were assessed by biochemical and biological effect monitoring. In this article we report effects on neuromuscular function, oxime and atropine concentration, and relate them to acetylcholinesterase (AChE) activity. METHODS: We measured the activity of cholinesterase in plasma and AChE in red blood cells (RBC) and related these data with neuromuscular transmission analysis (ulnar nerve stimulation). Concomitantly, poison and oxon along with plasma obidoxime and atropine levels were measured at regular intervals. RESULTS: We found a close correlation between RBC-AChE activity and neuromuscular transmission and a reciprocal correlation between both the atropine maintenance dose and/or its plasma concentration. The steady state of RBC-AChE activity of reactivation and re-inhibition followed the course predicted by laboratory-determined reaction constants. CONCLUSIONS: Intense monitoring of organophosphate-poisoned patients allowed assessment of why a given obidoxime concentration was, or was not, able to counteract the re-inhibition of the RBC-AChE. RBC-AChE activity mirrors the function of n-receptor- and m-receptor-mediated cholinergic signaling as measured by neuromuscular transmission and atropine requirements.

• Psychobehavioral Predictors of Somatoform Disorders in Patients With Suspected Allergies.

  Authors: Constanze Hausteiner, Susanne Bornschein, Esther Bubel, Sylvie Groben, Claas Lahmann, Martine Grosber, Bernd Löwe, Florian Eyer, Bernadette Eberlein, Heidrun Behrendt, Ulf Darsow, Johannes Ring, Peter Henningsen, Dorothea Huber

  Psychosomatic medicine. 08/2009;

  Objective: To explore a combination of health-related psychobehavioral features as potential positive criteria for somatoform disorders (SFD). Currently, SFD can only be diagnosed in the absence ofObjective: To explore a combination of health-related psychobehavioral features as potential positive criteria for somatoform disorders (SFD). Currently, SFD can only be diagnosed in the absence of sufficient organic symptom explanation, resulting in low criterion validity and delay of appropriate therapy. Methods: Cross sectionally, we studied various psychobehavioral characteristics of 197 inpatients with suspected allergies. At the beginning of the medical work-up, patients were interviewed and completed a set of self-rating questionnaires (Illness Perception Questionnaire-Revised, Whiteley Index-7, Cognitions About Body And Health Questionnaire, Scale for the Assessment of Illness Questionnaire, Health Attitude Survey, Reassurance Questionnaire, and Patient Health Questionnaire). Organic explicability of the presenting symptoms was assessed by allergists at the end of the work-up. Forty-eight patients with SFD were compared with 149 patients without SFD, and predictive models were set up. To control for effects of the work-up situation, we also investigated 47 patients with an established diagnosis of hymenoptera venom allergy. Results: In the work-up group, various self-reported psychobehavioral features discriminated patients with SFD from patients without SFD. In logistic regression analysis, self-reported dissatisfaction with medical care, disease conviction, reduced symptom controllability, and reduced body scanning independently predicted SFD. A predictive model based on these psychobehavioral characteristics had high sensitivity and specificity (area under the curve = 0.86, 95% Confidence Interval = 0.79-0.93; p < .001), which was comparable to the Patient Health Questionnaire-15, an established SFD screening tool assessing somatization. Conclusions: Psychobehavioral characteristics in patients with SFD cannot solely be attributed to the uncertainty of a work-up situation. Their predictive value is comparable to that of the traditional measuring of symptom number and severity; hence, they should be considered as SFD positive criteria in Diagnostic and Statistic Manual of Mental Disorders, 5th Edition.

• Plasma level of atropine after accidental ingestion of Atropa belladonna.

  Authors: Reinhard Bogan, Thomas Zimmermann, Thomas Zilker, Florian Eyer, Horst Thiermann

  Clinical toxicology (Philadelphia, Pa.). 08/2009; 47(6):602-4.

  BACKGROUND: Ingestion of toxic plant constituents still poses a challenge in clinical management. The amount of berries ingested is often unclear and in the case of Atropa belladonna may affectBACKGROUND: Ingestion of toxic plant constituents still poses a challenge in clinical management. The amount of berries ingested is often unclear and in the case of Atropa belladonna may affect clinical outcome. Plasma levels of atropine may thus be useful in confirming the cause of intoxication. CASE REPORT: A 48-year-old man had ingested three handfuls of Atropa belladonna. Within 6 h he experienced phases of disorientation, aggressiveness, and tachycardia. He was initially treated with diazepam, an intravenous infusion of physostigmine and activated charcoal. After temporary improvement his clinical condition worsened and he was transferred to our toxicological intensive care unit. Here, ongoing sedation and continuous administration of physostigmine was necessary because of disorientation. In the early phase of hospitalization, a blood sample was taken and a muscarinic receptor total binding equivalent to binding of 130 microg/L atropine was determined by a radio receptor technique. Within 2 days the patient recovered completely and was discharged in a good general condition. CONCLUSION: Receptor binding may help confirm diagnosis and elucidate mechanisms in this type of exposure.

• Extreme variability in the formation of chlorpyrifos oxon (CPO) in patients poisoned by chlorpyrifos (CPF).

  Authors: Florian Eyer, Darren M Roberts, Nicholas A Buckley, Michael Eddleston, Horst Thiermann, Franz Worek, Peter Eyer

  Biochemical pharmacology. 06/2009;

  Chlorpyrifos (CPF) is a pesticide that causes tens of thousands of deaths per year worldwide. Chlorpyrifos oxon (CPO) is the active metabolite of CPF that inhibits acetylcholinesterase. However, thisChlorpyrifos (CPF) is a pesticide that causes tens of thousands of deaths per year worldwide. Chlorpyrifos oxon (CPO) is the active metabolite of CPF that inhibits acetylcholinesterase. However, this presumed metabolite has escaped detection in human samples by conventional methods (HPLC, GC-MS, LC-MS) until now. A recently developed enzyme-based assay allowed the determination of CPO in the nanomolar range and was successfully employed to detect this metabolite. CPO and CPF were analysed in consecutive plasma samples of 74 patients with intentional CPF poisoning. A wide concentration range of CPO and CPF was observed and the ratio of CPO/CPF varied considerably between individuals and over time. The ratio increased during the course of poisoning from a mean of 0.005 in the first few hours after ingestion up to an apparent steady state mean of 0.03 between 30 and 72 hrs. There was a hundred fold variation in the ratio between samples and the interquartile range (between individuals) indicated over half the samples had a 5-fold or greater variation from the mean. The ratio was independent of the CPF concentration and the pralidoxime regimen. CPO was present in sufficient quantities to explain any observed acetylcholinesterase inhibitory activity. The effectiveness of pralidoxime in reactivating the inhibited acetylcholinesterase is strongly dependent on the CPO concentration. Differences in clinical outcomes and the response to antidotes in patients with acute poisoning may occur due to inter-individual variability in metabolism.

• [Caustic injuries of the eye, skin and the gastrointestinal tract.]

  Authors: Florian Eyer, Thomas Zilker

  Therapeutische Umschau. Revue thérapeutique. 06/2009; 66(5):379-86.

  Caustic injuries of the eye usually occur accidentally and can result in minor eye irritations to total loss of vision. All chemical exposures to the eye require immediate decontamination by copiousCaustic injuries of the eye usually occur accidentally and can result in minor eye irritations to total loss of vision. All chemical exposures to the eye require immediate decontamination by copious irrigation with an aqueous solution for at least 15 - 30 minutes up to two hours in single cases of massive exposure. Tap water is readily available, safe, and effective and, thus, the preferred irrigation fluid. Warmed lactated Ringer's solution is theoretically preferable to normal saline as an ocular irrigant because it has a more physiologic pH and osmolarity. Immediate ophtalmologic referral is recommended for all but the most trivial chemical burns to the eye. Specific treatments for decontamination depend on the underlying agent. Chemical burns of the skin usually occur accidentally. Initial treatment consists of copious water lavage commencing at the scene and removal of particles. While most caustic injuries are treated symptomatically, exposures to hydrofluoric acid (HFA) frequently necessitate specific topic, subcutaneous, intralesional, intravenous or intraarterial injections of calcium gluconate to bind fluoride ions until analgesia. A burn from HFA that involves more than 5% of total body-surface area, or more than 1% of total body-surface area if the concentration of HFA is greater than 50%, requires admission to an ICU for electrocardiographic monitoring and serial meas-urements of cal-cium levels, since life-threatening arrhythmias and hypocalcemia can occur. Caustic injuries of the gastrointestinal tract can occur due to inadvertent ingestion of mislabelled fluids or as a suicidal attempt. Ingestion of alkalis is generally thought to result in more severe injuries than ingestion of acids. The oropharynx needs to be first examined by laryngoscopy. A supraglottic or epiglottic burn with erythema and edema formation may be a harbinger of airway obstruction and should be seen as an indication of early endotracheal intubation or tracheostomy. Endoscopy should be performed preferably within 12 hours and generally not later than 24 hours and can serve as a prognostic tool to manage patients appropriately. The risk of procedure related perforation is generally accepted to be negligible. Existing data fail to support the routine use of steroids and antibiotics to prevent esophageal stricture formation and may mask signs of peritonitis. Esophageal strictures, stenosis or gastric outlet obstruction are formidably long-term complications. There is a 1000- to 3000-fold increase in the incidence of esophageal carcinoma after lye-ingestion with a latent period between the time of ingestion and the development of carcinoma as long as 60 years. Endoscopic dilatation or insertion of intraluminal stents should not be performed within the first 6 weeks. Patients with grade 3b injuries may underwent prompt surgical resection in single cases, even if no perforation is confirmed. Perforation, evolution of a mediastinitis or peritonitis with multi-organ failure are devastating complications with extremely high mortality and warrants immediate surgical treatment.

• Treatment of severe intravenous phenytoin overdose with hemodialysis and hemoperfusion.

  Authors: Florian Eyer, Norbert Felgenhauer, Rudi Pfab, Klaus Thurmel, Thomas Zilker

  Medical science monitor : international medical journal of experimental and clinical research. 01/2009; 14(12):CS145-148.

  Background: Phenytoin is a widely used anticonvulsant agent responsible for a number of intentional and unintentional overdoses. However, besides supportive care, specific treatment recommendationsBackground: Phenytoin is a widely used anticonvulsant agent responsible for a number of intentional and unintentional overdoses. However, besides supportive care, specific treatment recommendations to enhance elimination of the parent compound have been discussed controversially and effectiveness of hemoperfusion is under debate. Case Report: A women with a prehistory of cerebral seizures was presented following a severe iatrogenic phenytoin overdose with a peak plasma concentration of 117 mg/L. A Phenytoin overdose could be contributed to both inadequate dosing and missed repeated drug monitoring. Native phenytoin body clearance failed to relevantly lower phenytoin concentration. Thus, three sessions of a four-hour long combination of activated charcoal hemoperfusion and high-flux hemodialysis were performed resulting in considerably reduced half-life during these measures of about 7-13 hours compared to the native half-life wavering between 40-100 hours. This resulted in a substantial clinical improvement in terms of central nervous system toxicity. Conclusions: Hemodiaperfusion with activated charcoal seems to be a reasonable measure for forced lowering of highly toxic phenytoin plasma concentration and should be considered especially in circumstances following intravenous overdose (e.g. inadequate iatrogenic dosing). Its narrow therapeutic range enforces strictly adequate dosing and subsequent repeated drug monitoring of phenytoin.

• Enzyme-based assay for quantification of chlorpyrifos oxon in human plasma.

  Authors: Renate Heilmair, Florian Eyer, Peter Eyer

  Toxicology letters. 09/2008; 181(1):19-24.

  Chlorpyrifos oxon (CPO) is the active metabolite of the pesticide chlorpyrifos that inhibits cholinesterases at high reaction rates. Chlorpyrifos is of major concern because it causes some tenChlorpyrifos oxon (CPO) is the active metabolite of the pesticide chlorpyrifos that inhibits cholinesterases at high reaction rates. Chlorpyrifos is of major concern because it causes some ten thousand fatalities each year, mostly due to suicidal attempts. Notwithstanding, toxicokinetic studies on chlorpyrifos in humans are scarce and CPO has not been detected hitherto in human blood. Knowledge of the concentration and the time course of CPO in poisonings would be helpful to better design antidotal strategies, particularly with oximes. Owing to the exceptionally fast covalent binding to butyrylcholinesterase we searched for an enzyme-based assay for CPO determination. We succeeded in a simple procedure where CPO is titrated with purified equine butyrylcholinesterase. The assay requires less than 0.2 mL EDTA plasma and allows the quantification of CPO down to 0.5 nM. CPO is first extracted from plasma with n-pentane, thereby largely excluding the majority of the more hydrophilic pesticide oxons from possible cross-reactions. When chlorpyrifos incorporation is ascertained the assay may be considered largely specific. The new procedure enabled the assessment of the extent of reversible binding of CPO to human albumin, amounting to 85% under physiological conditions. The assay allowed the quantification of CPO in the plasma of a poisoned patient, where the active metabolite was about two orders of magnitude lower than chlorpyrifos. Similar to the parent compound its oxon showed the same tendency to persist for longer periods, thus calling for a change of the usual oxime dosage regimen.