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A non-interventional retrospective study in ambulatory patients was conducted at the emergency department of the Division of internal medicine. In 2 months, 266 suspected adverse drug reactions (ADRs) were identified in 224/3453 patients (6.5 %). In 158/3453 patients (4.6 %), an ADR was the reason for emergency department visit and in 49 patients (1.4 %), ADRs led to hospitalisation. A causality assessment algorithm was developed, which included Naranjo algorithm and levels of ADR recognition by the treating physician and the investigators. Using this algorithm, 63/266 ADRs (23.7 %) were classified as “certain”, whereas using solely the Naranjo score calculation, only 19/266 ADRs (7.1 %) were assessed as “probable” or “certain”, and the rest of ADRs (namely, 247/266 = 92.9 %) were assessed as “possible”. There were 116/266 (43.6 %) ADRs related to potential drug-drug interactions (DDIs), stated in at least one of the literature sources used. Based on the causality relationship, the rate of the clinically expressed DDIs was 19.0 %, or 12/63 “certain” ADR cases. Of these, 10 cases presented serious DDI-related ADRs. In summary, ADR causality assessment based exclusively on Naranjo algorithm demonstrated low sensitivity at an ambulatory emergency setting. Additional clinical judgment, including the opinion of the treating physician, proved necessary to avoid under-rating of the causality relationship, and enabled the determination of clinically expressed DDIs.

Objective: Chlorobenzylidene malononitrile (CS) is the tear gas used by the police. The aim was to evaluate an amphoteric, hypertonic, and chelating rinsing solution in CS exposure. Methods: The first (CS) group of six police officers was exposed to CS only. The second (preexposure) group of eight sprayed their faces with an aqueous, hypertonic, amphoteric, and chelating solution before CS exposure. The third (postexposure) group of eight sprayed their faces with an aqueous, hypertonic, amphoteric, and chelating solution after CS exposure. The time between exiting the CS cloud and arriving at the “ready for action” checkpoint was measured. Their facial pain both inside the CS cloud and at the checkpoint was assessed (0–10 points). Results: The pain level inside the CS cloud was significantly lower in the preexposed group (5.6 ± 1.1; p = 0.01) than in the CS group (9.7 ± 0.5) and in the postexposure group (9.1 ± 0.4) where it was similar. The time interval between CS exposure and arrival at the checkpoint in the preexposure group (1:26 ± 0:44 min) was significantly shorter than both in the CS group (2:28 ± 0:25 min; p = 0.04) and postexposure group (2:30 ± 0:48 min; p = 0.02) where it was not different. The residual pain at the checkpoint in the preexposure (1.1 ± 0.4) and postexposure (1.4 ± 0.7) groups was similar with a significant lower pain level than in the CS group (2.3 ± 0.5; p = 0.02). Conclusion: CS decontamination with an aqueous, hypertonic, amphoteric, and chelating solution reduces facial pain, whereas prevention with it reduces pain and recovery time. [ABSTRACT FROM AUTHOR]

Background: Severe benzodiazepine overdose can result in coma and respiratory depression that might cause brain hypoxia, necrosis and delayed post-anoxic leucoencephalopathy with permanent neurological sequelae. The aim of this study was to assess the possible role of S100B, a structural protein of astroglial cells, as a biochemical marker of brain injury in acute benzodiazepine overdose. Methods: Serum S100B determination was performed in 38 consecutive patients admitted to the emergency department (ED) in Ljubljana with benzodiazepine overdose. The level of consciousness and respiratory insufficiency on the scene were assessed by responsiveness to a verbal stimulus and pulse oximetry. Blood samples were taken immediately after arrival at the ED and S100B concentrations were measured with a commercial immunoluminometric assay. 20 healthy sexand age-matched volunteers formed a control group. Results: There were significant differences in S100B levels between the control group and the patients with benzodiazepine overdose according to their responsiveness to a verbal stimulus. Post hoc test results showed that S100B levels in patients with benzodiazepine overdose who were unresponsive to a verbal stimulus were significantly higher than those in patients responsive to a verbal stimulus (median 0.31 vs 0.11 μg/l; p=0.001). Both groups of patients with benzodiazepine overdose had significantly higher S100B levels than the control group (median 0.07 mg/; both p=0.001). Arterial oxygen saturation of patients with benzodiazepine overdose unresponsive to a verbal stimulus was significantly lower than in patients responsive to a verbal stimulus (median 83% vs 94%; p=0.001). There was no significant difference in the systolic blood pressure of patients with benzodiazepine overdose responsive or unresponsive to a verbal stimulus. Conclusion: Raised levels of S100B protein are associated with depressed levels of consciousness and respiratory insufficiency in patients with benzodiazepine overdose. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate S100B, an astroglial structural protein, during normobaric and hyperbaric oxygen therapy of conscious carbon monoxide (CO)-poisoned rats. So far, the usefulness of hyperbaric oxygen therapy in conscious CO-poisoned patients has been shown with neuropsychological testing. The S100B protein has been demonstrated as a possible biochemical marker and prognostic parameter in CO-poisoned rats. DESIGN: Randomized, controlled interventional trial. SETTING: University laboratory. SUBJECTS:: Male Wistar rats weighing 254 +/- 14 g. INTERVENTIONS: The rats were exposed to a mixture of 3,000 ppm CO in air for 60 mins. After CO exposure, the first group of eight conscious rats was exposed to ambient air for 30 mins, the second group of six conscious rats was exposed to 100% normobaric oxygen for 30 mins, and the third group of six conscious rats was exposed to 100% hyperbaric oxygen at 3 bars for 30 mins. Blood samples were taken from the jugular vein just before CO exposure and immediately after oxygen therapy. The level of consciousness was evaluated at the end of exposure, and the survival rate was monitored for 14 days. The S100B concentrations were measured with a commercial immunoluminometric assay. MEASUREMENTS AND MAIN RESULTS: Analyses of differences in S100B levels between different kinds of therapy before and after treatment showed a global significant difference (p = .002). The post hoc test results showed that S100B levels after therapy of the first group treated with ambient air (0.16 +/- 0.07 microg/L) and the second group treated with normobaric oxygen (0.19 +/- 0.05 microg/L) were similar (p = .741), and both of them were significantly different, with much higher values of S100B levels after therapy, from the third group treated with hyperbaric oxygen (0.06 +/- 0.03 microg/L; p = .018 and p = .002, respectively). All the rats survived. CONCLUSIONS: S100B is elevated in conscious CO-poisoned rats left on ambient air or treated with normobaric oxygen, but not in conscious CO-poisoned rats treated with hyperbaric oxygen. [ABSTRACT FROM AUTHOR]

Over the past decade, quetiapine has become one of the most commonly used psychotropic drugs in acute intoxication events worldwide. A structured literature review and analysis were conducted to assess the relationship between the kinetic and dynamic profiles in acute quetiapine intoxication. The correlation between dose and peak serum concentration (c max ) was determined using Pearson's correlation coefficient. Binary logistic regression was used to evaluate dose and c max as predictors of the most common clinical events, signs and symptoms. One hundred and thirty-four cases of acute quetiapine ingestion were included in the analysis, with a median ingested dose of 10 g and a median c max of 4 mg/L. The typical half-life was estimated to be 16.5 h, significantly longer than at therapeutic doses. For the immediate-release formulation, a biphasic disposition could not be excluded. Dose and c max demonstrated a weak but significant correlation (r = 0.256; N = 63; p = 0.043). Central nervous system depression and tachycardia were the most common clinical signs. Higher doses and concentrations increased the risk of severe intoxication and were good predictors of intubation, tachycardia, hypotension, QT c prolongation and seizures, but not QRS prolongation, arrhythmia, heart block, hypokalaemia or acidosis. The thresholds for dose and c max that increased the risk for individual signs and symptoms varied widely. However, doses > 3 g or c max > 2 mg/L can be considered as alert levels that represent a high risk for severe clinical course of acute quetiapine intoxication.

Profound and transient thrombocytopenia of functional platelets without bleeding was observed in patients envenomed by Vipera a. ammodytes ( Vaa ). This condition was rapidly reversed by administration of F(ab) 2 fragments of immunoglobulin G targeting the whole venom, leaving platelets fully functional. To investigate the potential role of snake venom C-type lectin-like proteins (snaclecs) in this process, Vaa -snaclecs were isolated from the crude venom using different liquid chromatographies. The purity of the isolated proteins was confirmed by Edman sequencing and mass spectrometry. The antithrombotic effect was investigated by platelet agglutination and aggregation assays and blood coagulation tests. Using flow cytometry, the platelet activation and binding of Vaa -snaclecs to various platelet receptors was analyzed. Antithrombotic efficacy was tested in vivo using a mouse model of vascular injury. Two Vaa -snaclecs were purified from the venom. One of them, Vaa -snaclec-3/2, inhibited ristocetin-induced platelet agglutination. It is a covalent heterodimer of Vaa -snaclec-3 (α-subunit) and Vaa -snaclec-2 (β-subunit). Our results suggest that Vaa -snaclec-3/2 induces platelet agglutination and consequently thrombocytopenia by binding to the platelet receptor glycoprotein Ib. Essentially, no platelet activation was observed in this process. In vivo, Vaa -snaclec-3/2 was able to protect the mouse from ferric chloride-induced carotid artery thrombosis, revealing its applicative potential in interventional angiology and cardiology., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Alcohol hangover (veisalgia) is a fairly common phenomenon. The pathogenesis of veisalgia is not understood and treatment has not yet been established. Occasionally, students take N-acetylcysteine (NAC) before binge drinking to alleviate hangover. The aim of this study was to evaluate the effect of NAC on serum levels of electrolytes, enzymes, oxidative stress biomarkers and symptoms of veisalgia in binge drinking. In this randomized, double-blind, placebo-controlled study, healthy students were randomly assigned into two groups: one receiving NAC and the other receiving a placebo. Blood samples were taken before drinking, 30 min after a 1.5 h long drinking session, and the subsequent morning. Serum levels of electrolytes, urea, enzymes, ethanol, 8-Hydroxydeoxyguanosine (8-OHdG) and N-epsilon-hexanoyl-lysine were measured. The participants completed the Acute Hangover Severity Scale (AHSS) assessment based on symptoms, and 40 students (20 male), aged 23 ± 2 years, were included in the study. Their mean blood ethanol concentration was 1.4 g/kg. Serum sodium levels were increased after drinking, and urea decreased the following morning compared to their levels before drinking in both groups. Serum 8-OHdG levels were increased after drinking and remained elevated until the following morning, compared to the levels before drinking, in both groups. NAC had no effect on sodium, urea and 8-OHdG levels or the symptoms of veisalgia. In conclusion, binge drinking causes a transient increase in serum sodium and as a prolonged increase in oxidative marker 8-OHdG levels. NAC had no effect on the sodium and 8-OHdG levels.

Introduction: Cannabis is the most common recreational drug worldwide and synthetic cannabinoid receptor agonists are currently the largest group of new psychoactive substances. The aim of this study was to compare the clinical features and outcomes of lone acute cannabis toxicity with lone acute synthetic cannabinoid receptor agonist toxicity in a large series of presentations to European emergency departments between 2013-2020., Methods: Self-reported drug exposure, clinical, and outcome data were extracted from the European Drug Emergencies Network Plus which is a surveillance network that records data on drug-related emergency department presentations to 36 centres in 24 European countries. Cannabis exposure was considered the control in all analyses. To compare the lone cannabis and lone synthetic cannabinoid receptor agonist groups, univariate analysis using chi squared testing was used for categorical variables and non-parametric Mann-Whitney U- testing for continuous variables. Statistical significance was defined as a P value of <0.05., Results: Between 2013-2020 there were 54,314 drug related presentations of which 2,657 were lone cannabis exposures and 503 lone synthetic cannabinoid receptor agonist exposures. Synthetic cannabinoid receptor agonist presentations had statistically significantly higher rates of drowsiness, coma, agitation, seizures and bradycardia at the time of presentation. Cannabis presentations were significantly more likely to have palpitations, chest pain, hypertension, tachycardia, anxiety, vomiting and headache., Discussion: Emergency department presentations involving lone synthetic cannabinoid receptor agonist exposures were more likely to have neuropsychiatric features and be admitted to a psychiatric ward, and lone cannabis exposures were more likely to have cardiovascular features. Previous studies have shown variability in the acute toxicity of synthetic cannabinoid receptor agonists compared with cannabis but there is little comparative data available on lone exposures. There is limited direct comparison in the current literature between lone synthetic cannabinoid receptor agonist and lone cannabis exposure, with only two previous poison centre series and two clinical series. Whilst this study is limited by self-report being used to identify the drug(s) involved in the presentations, previous studies have demonstrated that self-report is reliable in emergency department presentations with acute drug toxicity., Conclusion: This study directly compares presentations with acute drug toxicity related to the lone use of cannabis or synthetic cannabinoid receptor agonists. It supports previous findings of increased neuropsychiatric toxicity from synthetic cannabinoid receptor agonists compared to cannabis and provides further data on cardiovascular toxicity in lone cannabis use.

The growing threat of antibiotic resistance necessitates accurate differentiation between bacterial and viral infections for proper antibiotic administration. In this study, a Virus vs. Bacteria machine learning model was developed to distinguish between these infection types using 16 routine blood test results, C-reactive protein concentration (CRP), biological sex, and age. With a dataset of 44,120 cases from a single medical center, the model achieved an accuracy of 82.2 %, a sensitivity of 79.7 %, a specificity of 84.5 %, a Brier score of 0.129, and an area under the ROC curve (AUC) of 0.905, outperforming a CRP-based decision rule. Notably, the machine learning model enhanced accuracy within the CRP range of 10-40 mg/L, a range where CRP alone is less informative. These results highlight the advantage of integrating multiple blood parameters in diagnostics. The "Virus vs. Bacteria" model paves the way for advanced diagnostic tools, leveraging machine learning to optimize infection management., Competing Interests: Marko Notar is the CEO of Smart Blood Analytics SA. Mateja Notar, Sašo Moškon, Tim Smole, Žiga Osterc, Marjeta Tušek Jelenc and Manca Köster hold positions at Smart Blood Analytics Swiss SA. Matjaž Kukar, Peter Černelč, and Gregor Gunčar serve as advisors to Smart Blood Analytics Swiss SA. The remaining authors declare no competing interests., (© 2024 The Authors.)

Psychotropic prescription drugs are commonly involved in intoxication events. The study's aim was to determine a comparative risk for intoxication in relation to prescribing rates for individual drugs. This was a nationwide observational study in Slovenian adults between 2015 and 2021. Intoxication events with psychotropic drugs were collected from the National Register of intoxications. Dispensing data, expressed in defined daily doses, were provided by the Health Insurance Institute of Slovenia. Intoxication/prescribing ratio values were calculated. The correlation between trends in prescribing and intoxication rates was assessed using the Pearson correlation coefficient. In total, 2640 intoxication cases with psychotropic prescription drugs were registered. Anxiolytics and antipsychotics were the predominant groups. Midazolam, chlormethiazole, clonazepam, sulpiride, and quetiapine demonstrated the highest risk of intoxication, while all antidepressants had a risk several times lower. The best trend correlation was found for the prescribing period of 2 years before the intoxication events. An increase of 1,000,000 defined daily doses prescribed resulted in an increase of fifty intoxication events for antipsychotics, twenty events for antiepileptics, and five events for antidepressants. Intoxication/prescribing ratio calculation allowed for a quantitative comparison of the risk for intoxication in relation to the prescribing rates for psychotropic drugs, providing additional understanding of their toxicoepidemiology.

Introduction: Snakebite incidence varies across Europe. However, there is limited research from Central and Southeastern Europe. These regions are notable for the presence of the common European adder ( Vipera berus ) and the more venomous nose-horned viper ( Vipera ammodytes ). No standard European antivenom protocol exists. The aim was to assess the epidemiology and treatment of viper bites in this region, focusing on a comparison of bites from Vipera berus and Vipera ammodytes ., Methods: We conducted a prospective multicenter study in Central and Southeastern Europe from 2018 to 2020. This study included poison centres and toxicology-associated hospital wards in Poland, the Czech Republic, Slovakia, Hungary, Slovenia, Croatia, Serbia, and Bulgaria. The following data were collected: age, gender, Vipera species, snakebite site, clinical picture, laboratory results, Audebert's clinical severity grading score, and antivenom therapy., Results: The annual incidence of viper bites in Central and Southeast Europe was estimated at 2.55 bites per million population. Within their respective geographical distribution areas, the incidence of Vipera ammodytes bites (1.61 bites per million population) was higher than Vipera berus bites (1.00 bites per million population). Patients bitten by Vipera ammodytes more frequently reported local pain and developed thrombocytopenia. Antivenom treatment was more commonly administered in Vipera ammodytes bites (72%) compared to Vipera berus bites (39%). The incidence of Vipera ammodytes bites treated with antivenom within its geographical distribution area was three times higher than Vipera berus bites treated with antivenom (1.16 bites per million population versus 0.39 bites per million population). No deaths were reported., Conclusions: The estimated incidence of viper bites in Central and Southeastern Europe is at least 2.55 per million population. Vipera ammodytes bites are more common and severe, characterized by higher frequencies of pain and thrombocytopenia. Antivenom is needed more often for Vipera ammodytes bites. It is vital that enough European Medicines Agency-approved Vipera ammodytes antivenom is produced and offered affordably.

The influence of cannabidiol (CBD) on brain development is inadequately understood. Since CBD is considered a non-intoxicating drug, it has attracted great interest concerning its potential medical applicability, including in pregnant women and children. Here, we elucidated the response of perinatal rat cortical neurons and astrocytes to CBD at submicromolar (0.1, 0.5, 1, 5 µM) concentrations attainable in humans. The effect of CBD was concentration- and time-dependent and cell-specific. In neurons, 0.1 µM CBD induced an early and transient change in mitochondrial membrane potential (ΔΨm), ATP depletion, and caspase-8 activation, followed by rapid ATP recovery and progressive activation of caspase-9 and caspase-3/7, resulting in early apoptotic cell death with reduction and shortening of dendrites, cell shrinkage, and chromatin condensation. The decrease in neuronal viability, ATP depletion, and caspase activation due to CBD exposure was prevented by transient receptor potential vanilloid 1 (TRPV1) antagonist. In astrocytes, 0.5 µM CBD caused an immediate short-term dysregulation of ΔΨm, followed by ATP depletion with transient activation of caspase-8 and progressive activation of caspase-9 and caspase-3/7, leading to early apoptosis and subsequent necroptosis. In astrocytes, both TRPV1 and cannabinoid receptor 1 (CB 1 ) antagonists protected viability and prevented apoptosis. Given that CBD is a non-intoxicating drug, our results clearly show that this is not the case during critical periods of brain development when it can significantly interfere with the endogenous cannabinoid system.

Introduction: Colchicum autumnale (autumn crocus) is a plant that contains highly toxic alkaloid colchicine. The aim was to evaluate accidental C autumnale poisoning and assess serum troponin as a prognostic parameter., Methods: In this study, we retrospectively included all adult patients with a history of accidental C autumnale ingestion and serum colchicine confirmation during the study period from 2000 to 2019. The medical files of enrolled patients were reviewed. Literature search of accidental ingestions of C autumnale was done., Results: Over the study period of 20 years, 16 adult patients were admitted to the University Medical Centre Ljubljana due to acute colchicine poisoning after ingestion of C autumnale . They all mistakenly ingested C autumnale 's leaves instead of Allium ursinum in the spring and had confirmed colchicine in serum by GC-MS or LC-MS/MS (15.5 µg/L (0.5-80 µg/L)). They developed vomiting and diarrhoea within 1-9 h after the meal. Vomiting within 2 h was associated with lethality ( p =.04). Bone marrow suppression developed in 15 patients (94%). Acute myocardial injury with positive troponin I (>0.10 µg/L) developed in five patients; lethal cardiogenic shock with decreased cardiac output and hypotension occurred in four of these patients despite supportive therapy. Positive troponin I ultra (>0.10 µg/L) was associated with need for intensive support therapy ( p =.01), decreased cardiac output ( p =.01) and death ( p =.01). The mortality was 4/16 (25%). On review, we found 58 cases; 95% cases accidently ingested leaves of C autumnale instead of A ursinum. Troponin I was reported in 3% cases. The lethality of this and reviewed cases was 35% (26/74)., Conclusions: In unexplained gastroenterocolitis after ingestion of wild plants as a salad or spice in the spring, especially when wild garlic is mentioned, we should always consider C autumnale poisoning. Cardiogenic shock can be predicted by a positive serum troponin I measurement.

Physicians taking care of patients with COVID-19 have described different changes in routine blood parameters. However, these changes hinder them from performing COVID-19 diagnoses. We constructed a machine learning model for COVID-19 diagnosis that was based and cross-validated on the routine blood tests of 5333 patients with various bacterial and viral infections, and 160 COVID-19-positive patients. We selected the operational ROC point at a sensitivity of 81.9% and a specificity of 97.9%. The cross-validated AUC was 0.97. The five most useful routine blood parameters for COVID-19 diagnosis according to the feature importance scoring of the XGBoost algorithm were: MCHC, eosinophil count, albumin, INR, and prothrombin activity percentage. t-SNE visualization showed that the blood parameters of the patients with a severe COVID-19 course are more like the parameters of a bacterial than a viral infection. The reported diagnostic accuracy is at least comparable and probably complementary to RT-PCR and chest CT studies. Patients with fever, cough, myalgia, and other symptoms can now have initial routine blood tests assessed by our diagnostic tool. All patients with a positive COVID-19 prediction would then undergo standard RT-PCR studies to confirm the diagnosis. We believe that our results represent a significant contribution to improvements in COVID-19 diagnosis.

Vipera ammodytes ( V. ammodytes ) is the most venomous European viper. The aim of this study was to compare the clinical efficacy and pharmacokinetic values of intravenous Vipera berus venom-specific (paraspecific) Fab fragments (ViperaTAb) and intramuscular V. ammodytes venom-specific F(ab') 2 fragments (European viper venom antiserum, also called "Zagreb" antivenom) in V. ammodytes -envenomed patients. This was a prospective study of V. ammodytes -envenomed patients that were treated intravenously with ViperaTAb or intramuscularly with European viper venom antiserum that was feasible only due to the unique situation of an antivenom shortage. The highest venom concentration, survival, length of hospital stay and adverse reactions did not differ between the groups. Patients treated with intravenous Fab fragments were sicker, with significantly more rhabdomyolysis and neurotoxicity. The kinetics of Fab fragments after one or more intravenous applications matched better with the venom concentration in the early phase of envenomation compared to F(ab') 2 fragments that were given intramuscularly only on admission. F(ab') 2 fragments given intramuscularly had 25-fold longer apparent total body clearance and 14-fold longer elimination half-time compared to Fab fragments given intravenously (2 weeks vs. 24 h, respectively). In V. ammodytes -envenomed patients, the intramuscular use of specific F(ab') 2 fragments resulted in a slow rise of antivenom serum concentration that demanded their early administration but without the need for additional doses for complete resolution of all clinical signs of envenomation. Intravenous use of paraspecific Fab fragments resulted in the immediate rise of antivenom serum concentration that enabled their use according to the clinical progress, but multiple doses might be needed for efficient therapy of thrombocytopenia due to venom recurrence, while the progression of rhabdomyolysis and neurotoxic effects of the venom could not be prevented.

Snakebites are a relatively rare medical emergency in Europe. In more than half of the annual cases caused by Vipera ammodytes , Vipera berus , and Vipera aspis , immunotherapy with animal-derived antivenom is indicated. Among eight products recently identified as available against European medically relevant species, only Zagreb antivenom, Viperfav, and ViperaTAb have been used almost exclusively for decades. Zagreb antivenom comprises V. ammodytes -specific F(ab') 2 fragments. Viperfav is a polyspecific preparation based on F(ab') 2 fragments against V. aspis , V. berus , and V. ammodytes venoms. ViperaTAb contains Fab fragments against the venom of V. berus . In 2014 the production of Zagreb antivenom was discontinued. Additionally, in the period of 2017 to 2018 a shortage of Viperfav occurred. Due to a lack of the product indicated for the treatment of V. ammodytes bites, other antivenoms were implemented into clinical practice without comparative assessment of their eligibility. The aim of our work was to identify a high-quality antivenom that might ensure the successful treatment of V. ammodytes and V. berus bites at the preclinical level. Differentiation between bites from these two species is difficult and unreliable in clinical practice, so the availability of a unique antivenom applicable in the treatment of envenoming caused by both species would be the most advantageous for Southeastern Europe. Zagreb antivenom, Viperfav, and ViperaTAb, as well as Viper venom antitoxin for V. berus envenoming and the in-development Inoserp Europe, which was designed to treat envenoming caused by all medically important European snakes, were comparatively tested for the first time. Emphasis was placed on their physicochemical properties, primarily purity and aggregate content, as well as their in vivo protective efficacies. As Zagreb antivenom is no longer available on the European market, Viperfav is the highest-quality product currently available and the only antivenom whose neutralisation potency against V. ammodytes and V. berus venoms was above regulatory requirements.

Free fatty acid receptor 3 (FFA3, previously GPR41) is activated by short-chain fatty acids, mediates health effects of the gut microbiota, and is a therapeutic target for metabolic and inflammatory diseases. The shortage of well-characterized tool compounds has however impeded progress. Herein, we report structure-activity relationship of an allosteric modulator series and characterization of physicochemical and pharmacokinetic properties of selected compounds, including previous and new tools. Two representatives, 57 (TUG-1907) and 63 (TUG-2015), showed improved solubility and preserved potency. Of these, 57 , with EC 50 = 145 nM and a solubility of 33 μM, showed high clearance in vivo but is a preferred tool in vitro. In contrast, 63 , with EC 50 = 162 nM and a solubility of 9 μM, showed lower clearance and seems better suited for in vivo studies. Using 57 , we demonstrate for the first time that FFA3 activation leads to calcium mobilization in murine dorsal root ganglia.

Introduction: Tiamulin is a semisynthetic pleuromutilin diterpene veterinary antibiotic, widely used in farms. We present a case of prolonged QT-interval and ventricular tachyarrhythmia after tiamulin inhalation. Case presentation: A 43-year-old veterinarian without previous medical history was dividing granulated powder of antibiotic gravimetrically without wearing personal protective equipment. Half an hour after exposure, nausea occurred; four hours later he started to vomit and soon after that he experienced syncope. He was unconscious three minutes; afterwards he became somnolent, dizzy and nauseated with sweating and salivation. On admission to hospital five hours after exposure, he was conscious and had heart rate 70 beats/min and blood pressure 140/80 mmHg. Initial laboratory results were normal. Electrocardiography showed a prolonged QTc-interval of 730 ms with numerous polymorphic ventricular extrasystoles and episodes of non-sustained polymorphic ventricular tachycardia that resolved after treatment with lidocaine and magnesium. Subsequent electrocardiography revealed gradual shortening of QTc-interval with QTc-interval normalization (430 ms) between 24 and 32 hours after tiamulin exposure. Laboratory tests, morphologic heart diagnostics and genetic testing excluded other potential causes of QTc-interval prolongation. Subsequent toxicology analysis by LC-MS/MS confirmed tiamulin in his serum samples on admittance (500 ng/mL). Conclusion: Tiamulin inhalation can be associated with prolonged QT-interval and ventricular tachyarrhythmia. QT-interval prolongation could be expected in overdoses of emerging human pleuromutilins.

Chemokines undergo post-translational modification such as N-terminal truncations. Here, we describe how N-terminal truncation of full length CCL3 (1-70) affects its activity at CCR1. Truncated CCL3 (5-70) has 10-fold higher potency and enhanced efficacy in β-arrestin recruitment, but less than 2-fold increased potencies in G protein signaling determined by calcium release, cAMP and IP 3 formation. Small positive ago-allosteric ligands modulate the two CCL3 variants differently as the metal ion chelator bipyridine in complex with zinc (ZnBip) enhances the binding of truncated, but not full length CCL3, while a size-increase of the chelator to a chloro-substituted terpyridine (ZnClTerp), eliminates its allosteric, but not agonistic action. By employing a series of receptor mutants and in silico modeling we describe residues of importance for chemokine and small molecule binding. Notably, the chemokine receptor-conserved Glu287 7.39 interacts with the N-terminal amine of truncated CCL3 (5-70) and with Zn 2+ of ZnBip, thereby bridging their binding sites and enabling the positive allosteric effect. Our study emphasizes that small allosteric molecules may act differently toward chemokine variants and thus selectively modulate interactions of specific chemokine subsets with their cognate receptors., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Introduction: Treatment of acute organophosphorus or carbamate insecticide self-poisoning is often ineffective, with tens of thousands of deaths occurring every year. Researchers have recommended the addition of magnesium sulfate or calcium channel blocking drugs to standard care to reduce acetylcholine release at cholinergic synapses., Objective: We aimed to review systematically the evidence from preclinical studies in animals exposed to organophosphorus or carbamate insecticides concerning the efficacy of magnesium sulfate and calcium channel blocking drugs as therapy compared with placebo in reducing mortality or clinical features of poisoning. We also systematically reviewed the evidence from clinical studies in patients self-poisoned with organophosphorus or carbamate insecticides concerning the efficacy of magnesium sulfate and calcium channel blocking drugs as therapy compared with placebo, in addition to standard therapy, in reducing mortality, atropine requirement, need for intubation and ventilation, and intensive care unit and hospital stay., Methods: We performed a systematic review for articles on magnesium sulfate and calcium channel blocking drugs in organophosphorus or carbamate insecticide poisoning using PubMed and China Academic Journals Full-text (Medicine/Hygiene Series) databases and keywords: "organophosphorus or organophosphate poisoning", "cholinesterase inhibitor poisoning" OR "carbamate poisoning" AND "magnesium", "calcium channel blocker", or generic names of different calcium channel blocking drugs. Review of titles and abstracts revealed 2262 papers of potential relevance. After review of the full papers, a total of 19 papers relevant to the question were identified: five preclinical studies, nine case reports or small case series, and five clinical studies and trials. We also obtained primary data from three unpublished clinical trials of magnesium sulfate, providing data from a total of eight clinical studies and trials for analysis. All studies were of organophosphorus insecticides; no studies of carbamates were found. No pre-clinical or clinical studies of calcium channel blocking drugs and magnesium sulfate in combination were found. We extracted data on study type, treatment regimens, outcome, and side effects. Pre-clinical studies: Two rodent studies indicated a benefit of calcium channel blocking drugs treatment on mortality if given before or soon after organophosphorus exposure, in addition to atropine and/or oxime. In poisoned minipigs, treatment with magnesium sulfate after organophosphorus insecticide poisoning reduced cholinergic stimulation and hypertension. Of note, magnesium sulfate further suppressed serum butyrylcholinesterase activity in one rat study. Observational clinical studies: Calcium channel blocking drugs and magnesium sulfate have been used to treat cardiac dysrhythmias and hypertonic uterine contractions in organophosphorus poisoned patients. A small neurophysiological study of magnesium sulfate reported reversion of neuromuscular junction effects of organophosphorus insecticide exposure. Comparative clinical studies: Only four of eight studies were randomized controlled trials; all studies were of magnesium sulfate, of small to modest size, and at substantial risk of bias. They included 441 patients, with 239 patients receiving magnesium sulfate and 202 control patients. The pooled odds ratios for magnesium sulfate for mortality and need for intubation and ventilation for all eight studies were 0.55 (95% confidence interval [CI] 0.32-0.94) and 0.52 (95% CI 0.34-0.79), respectively. However, there was heterogeneity in the results of higher quality phase III randomized controlled trials providing more conservative estimates. Although a small dose-escalation study suggested benefit from higher doses of magnesium sulfate, there was no evidence of a dose effect across the studies. Adverse effects were reported rarely, with 11.1% of patients in the randomized controlled trials receiving the highest dose of magnesium sulfate requiring their infusion to be stopped due to hypotension., Conclusions: Both preclinical and clinical data suggest that magnesium sulfate and calcium channel blocking drugs might be promising adjunct treatments for acute organophosphorus insecticide poisoning. However, evidence is currently insufficient to recommend their use. Mechanistic and large multi-center randomized controlled trials testing calcium channel blocking drugs and magnesium sulfate are required to provide the necessary evidence, with careful identification of the insecticides ingested and measurement of surrogate markers of toxicity, including butyrylcholinesterase activity.

The succinate receptor 1 (SUCNR1) is a receptor for the metabolite succinate, which functions as a metabolic stress signal in the liver, kidney, adipose tissue and the retina. However, potent non-metabolite tool compounds are needed to reveal the physiological role and pharmacological potential of SUCNR1. Recently, we published the discovery of a computationally receptor-structure derived non-metabolite SUCNR1 agonist series with high target selectivity. We here report our structure-activity exploration and optimisation that has resulted in the development of agonists with nanomolar potency and excellent solubility and stability properties in a number of in vitro assays. Ligand-guided receptor models with high discriminative power between binding of active and inactive compounds were developed for design of novel chemotypes.

Quick and accurate medical diagnoses are crucial for the successful treatment of diseases. Using machine learning algorithms and based on laboratory blood test results, we have built two models to predict a haematologic disease. One predictive model used all the available blood test parameters and the other used only a reduced set that is usually measured upon patient admittance. Both models produced good results, obtaining prediction accuracies of 0.88 and 0.86 when considering the list of five most likely diseases and 0.59 and 0.57 when considering only the most likely disease. The models did not differ significantly, which indicates that a reduced set of parameters can represent a relevant "fingerprint" of a disease. This knowledge expands the model's utility for use by general practitioners and indicates that blood test results contain more information than physicians generally recognize. A clinical test showed that the accuracy of our predictive models was on par with that of haematology specialists. Our study is the first to show that a machine learning predictive model based on blood tests alone can be successfully applied to predict haematologic diseases. This result and could open up unprecedented possibilities for medical diagnosis.

Objective: Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools., Methods and Results: Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a substructure-based search query, which, combined with molecular docking, was used in virtual screening of the ZINC database to pick two serial mini-libraries of a total of only 245 compounds from which sub-micromolar, selective GPR91 agonists of unique structures were identified. The best compounds were backbone-modified succinate analogs in which an amide-linked hydrophobic moiety docked into the side-pocket next to succinate as shown by both loss- and gain-of-function mutagenesis. These compounds displayed GPR91-dependent activity in altering cytokine expression in human M2 macrophages similar to succinate, and importantly were devoid of any effect on the major intracellular target, succinate dehydrogenase., Conclusions: These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)

In Central Europe, reports of human envenomation by Cheiracanthium punctorium, commonly known as the yellow sac spider, are sporadic, despite the fact that this species is widespread in Europe. However, in recent years, C. punctorium has been repeatedly described globally in medical and toxicological literature. Its venom was found to possess insecticidal, haemolytic, cytotoxic, and membrane-damaging activities. Its bite is often very painful, frequently associated with local and transient cutaneous and neurotoxic effects, but sometimes also with systemic symptoms which require medical help. The main objective of this article is to introduce more details about C. punctorium, the clinical manifestations and circumstances of its bite, the characteristics of its venom and proposed clinical management. The authors provide case reports of patients bitten by C. punctorium during the 10-year observational period. All patients presented in this article showed generally mild clinical manifestations and recovered completely without sequelae. No further treatment in terms of hospital surveillance or specific clinical measures was necessary in any of the reported cases.

The discovery and synthesis of new tyrosine-based inhibitors of DNA gyrase B (GyrB), which target its ATPase subunit, is reported. Twenty-four compounds were synthesized and evaluated for activity against DNA gyrase and DNA topoisomerase IV. The antibacterial properties of selected GyrB inhibitors were demonstrated by their activity against Staphylococcus aureus and Enterococcus faecalis in the low micromolar range. The most promising compounds, 8a and 13e, inhibited Escherichia coli and S. aureus GyrB with IC 50 values of 40 and 30 µM. The same compound also inhibited the growth of S. aureus and E. faecalis with minimal inhibitory concentrations (MIC 90 ) of 14 and 28 µg/mL, respectively., (© 2017 Deutsche Pharmazeutische Gesellschaft.)

Background: European viper bite is relatively uncommon but can cause serious envenoming, particularly swelling and hemorrhage spreading from limb to trunk that can cause long term disability. Systemic features are relatively mild compared to many other venomous species. Moderate-to-severe envenoming requires antivenom, which is given many hundreds of times each year across the continent. Several Vipera spp antivenoms are produced in Europe, but there is little comparative information available for the antivenoms and none is licensed with the European Medicines Agency. We aimed to collect descriptive data on European viper antivenoms and assess their relative effectiveness., Methods: A systematic review of articles relating to antivenom in Europe was performed using the Medline medical database. The following keywords "Europ*" or the individual names of each European country and "antiven*" or "immun*" or "envenom*" and "snake" or "viper*" or "adder" were used. Articles published between 1 January 1996 and 11 March 2016 pertaining to clinical outcome, including case reports, were selected. Referenced articles in the indexed articles were explored for suitability and included if they met any of the criteria: specific antivenom used, route of antivenom administration, adverse reactions to antivenom therapy and length of hospital admission. All accepted abstracts from EAPCCT conferences since 2000 were searched and abstracts relating to Vipera spp envenoming were assessed for suitability. We extracted data on study type, safety and effectiveness. We sought information on antivenoms from manufacturers and individual patient data from authors of publications. Since individual patient data were only rarely available, we compared median length of stay between case series reporting each antivenom. We identified 40 papers and six published abstracts, and one unpublished paper that reported clinical cases and case series of envenomed patients treated with antivenom. No publication reported randomized controlled trials comparing any European Vipera antivenom with either placebo or another antivenom. 25 reports were of retrospective hospital- (n = 13) or poison center-based (n = 12) case series including five or more patients; a further 12 reports were either case reports or case series with less than five patients and one paper was a limited literature review. An additional nine papers reported prospective data; seven collected data remotely through poison service telephone communication with the attending physicians. Antivenoms available in Europe: Eight antivenoms are available for European Vipera spp envenoming; a material safety data sheet providing information on manufacture was available for seven. Six are raised against V. berus or V. ammodytes venom; the seventh is raised against a mixture of V. ammodytes, V. aspis and V. berus venom and the eighth is raised against V. ammodytes, Macrovipera lebetina and Montivipera xanthina venom. Six manufacturers recommended intramuscular administration while two recommended intravenous administration. No randomized control trials comparing the effectiveness of antivenoms were identified. Pre-clinical data: We found two papers presenting comparative preclinical data. Clinical data: Clinical studies were predominantly retrospective and contained clinical data on antivenom used in 2602 patients; where the antivenom was identified (n = 2174), 2061 (94.8%) received Zagreb, ViperFAV or ViperaTAb antivenoms. There were few published data on the other antivenoms. Repeated use of antivenom: Repeat doses were reported in 230/1491 of cases (15.4%) where this information was recorded. Outcome and length of hospital stay: Intravenous administration of antivenom was associated with shorter length of hospital stay (median length of hospital stay in studies of intravenous ViperFAV or ViperaTAb ranged from 1 to 4.8 days versus 2 to 18 days for intramuscular Bulbio or Zagreb antivenoms). Antivenom versus no antivenom: Some small studies demonstrated no difference in the length of hospital stay in patients with equivalent envenomation grading who either did or did not receive antivenom. Adverse events: Adverse reactions were reported in 37 of 2408 cases (1.5%) including seven cases of anaphylaxis., Conclusions: There are very limited pre-clinical comparative data and no randomised controlled trials assessing effectiveness of the antivenoms against different Vipera species. Most descriptive data suggest the efficacy of Zagreb, ViperFAV and ViperaTAb antivenoms by the intravenous route but not intramuscular route, although this is level D evidence. Reported adverse reactions were rare, suggesting that the modern intravenous antivenoms are of good quality. Better and more systematic data, including perhaps randomized controlled trials comparing different antivenoms, are required for the many hundreds of antivenom administrations that occur annually across Europe.

Purpose: Drug-drug interaction (DDI) screening systems report potential DDIs. This study aimed to find the prevalence of probable DDI-related adverse drug reactions (ADRs) and compare the clinical usefulness of different DDI screening systems to prevent or warn against these ADRs., Methods: A prospective cohort study was conducted in patients urgently admitted to medical departments. Potential DDIs were checked using Complete Drug Interaction®, Lexicomp® Online™, and Drug Interaction Checker®. The study team identified the patients with probable clinically relevant DDI-related ADRs on admission, the causality of which was assessed using the Drug Interaction Probability Scale (DIPS). Sensitivity, specificity, and positive and negative predictive values of screening systems to prevent or warn against probable DDI-related ADRs were evaluated., Results: Overall, 50 probable clinically relevant DDI-related ADRs were found in 37 out of 795 included patients taking at least two drugs, most common of them were bleeding, hyperkalemia, digitalis toxicity, and hypotension. Complete Drug Interaction showed the best sensitivity (0.76) for actual DDI-related ADRs, followed by Lexicomp Online (0.50), and Drug Interaction Checker (0.40). Complete Drug Interaction and Drug Interaction Checker had positive predictive values of 0.07; Lexicomp Online had 0.04. We found no difference in specificity and negative predictive values among these systems., Conclusion: DDI screening systems differ significantly in their ability to detect probable clinically relevant DDI-related ADRs in terms of sensitivity and positive predictive value.