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Olanzapine is a thienobenzodiazepine class antipsychotic that strongly antagonises the 5-HT2A serotonin receptor, but acute poisonings are reported rarely. Symptoms of an overdose include disorder of consciousness, hypersalivation, myosis, and coma. Serum concentration higher than 0.1 mg/L is toxic, while concentration above 1 mg/L can be fatal. Here we report key data about 61 patients admitted to the National Poison Control Centre in Belgrade, Serbia over olanzapine poisoning in 2017 and 2018. The ingested doses ranged from 35 to 1680 mg, and time from ingestion to determination from two to 24 hours. In 34 patients olanzapine serum concentrations were in the therapeutic range and in 27 in the toxic range. In five patients they were higher than fatal, but only one patient died. The most common symptoms of poisoning were depressed consciousness (fluctuating from somnolence to coma), tachycardia, hypersalivation, hypotension, myosis, and high creatine kinase. All patients but one recovered fully after nonspecific detoxification and symptomatic and supportive therapy.

Introduction: Ogilvie syndrome and gastrointestinal bleeding as complications after reversal of typical clinical picture of acute Clozapine overdose is described. Case Report: A previously healthy 31-year-old man was found unconscious with Glasgow Coma Score of 6, non-reactive miotic pupils, hypersalivation and heart rate of 115 bpm. In the blood, the presence of Clozapine, Diazepam, haloperidol and biperiden were confirmed. The patient was referred to the intensive care unit for symptomatic and supportive treatment. Clinical signs registered on admission, except for sinus tachycardia, were completely resolved by the day 3. The patient began to eat and had regular bowel movements. From the seventh day, gastrointestinal complications were noticed. Nonobstructive dilatation of the stomach and intestine was confirmed on computed tomography scan. Nasogastric suction, the usage of laxatives and prostigmin injections as well as colonic irrigation was performed with a good clinical response. Conclusion: Clinicians should be aware of the potential of atypical antipsychotics to cause ileus, particulary in combination with other drugs with antimuscarinic properties, and ready to rapidly detect and treat intestinal atony thus preventing life-threatening complications. Serum Clozapine levels may not equate to clinical toxicity and the drug-näive patient require more careful observation for complications in Clozapine toxicity settings.

Background/Aim. Acute intoxication by ethanol constitutes a significant part of the acute pathology caused by toxic chemicals, which require medical care in specialized health care institutions. The aim of the study was to determine some principal characteristics of the patients treated after acute ethanol poisoning, such as: participation in the total number of patients treated after acute poisoning by all chemical agents, age, sex, severity of poisoning and capacities for ambulatory or hospital treatment. Methods. A five-year retrospective case study was conducted on 20,891 acute poisoned patients, of which 10,731 were treated after acute ethanol poisoning during the period 2011–2015. All the subjects satisfied the diagnostic criteria of poisoning according to the World Health Organization International Classification of Diseases-10 and standardized Poison Severity Score scale. Results. Monitored parameters were analyzed in 10,731 patients acutely poisoned by ethanol, and their average number during one study year was 2146.2 ± 437.95. The average number of treated patients due to poisoning by ethanol (51.47 ± 2.86%) was statistically significantly higher than that of other causes of acute poisoning (p < 0.001). The majority of poisoned patients were men, aged 19 to 65 years, with mild to moderate symptoms of acute ethanol intoxication. The highest number of patients poisoned by ethanol had Poison Severity Score 1 (70.25 ± 5.04%, p < 0.001). Very few acute poisoned with ethanol required hospital treatment (1.05%). Anticipated number of patients acutely poisoned by ethanol had high percentage of increase for the period 2016–2020 (slightly more than 20%), which is worrying, primarily due to their high absolute number. Conclusion. Acute alcohol poisoning represents a significant part of the pathology in the total number of patients treated due to acute poisoning with various chemical substances. The results of this analysis showed that certain populations are particularly vulnerable to abuse of alcohol to the level requiring health care (male population, age 19˗65 years). Only a small number of patients (1% of all patients treated for acute alcohol poisoning) required clinical treatment. The obtained data provided the basis for a more targeted preventive action in certain population groups, as well as the adequate planning of professional medical staff engagement, material, spatial and other capacities. These data, also, provided the basis for additional detailed social, economic, health and other researches in this area as well as a more detailed registration of this type of poisoning and establishing a monitoring system and database.

Introduction: Valproic acid (VPA) is a broad-spectrum drug primarily used in the treatment of epilepsy and bipolar disorder. It is not an uncommon occurrence for VPA to cause intoxication. The established treatment of VPA poisoning includes supportive care, multiple doses of activated charcoal, levocarnitine and hemodialysis/hemoperfusion. There is a clinically significant interaction between carbapenem antibiotics and VPA. By affecting enterohepatic recirculation, carbapenems can increase the overall VPA clearance from the blood of intoxicated patients. It is suggested that carbapenems could successfully be used as antidotes in the treatment of acute VPA poisonings. The aim: To evaluate the effectiveness of carbapenems in the treatment of patients acutely poisoned by VPA. Patients and methods: This retrospective study included patients acutely poisoned by VPA and treated with carbapenems at the Department of Clinical Toxicology at the Military Medicinal Academy in Serbia for a two-year period. Results: After the admission, blood concentrations of VPA kept increasing, reaching their peak at 114–724 mg/L, while the mental state of the patients continued to decline, prompting a decision to introduce carbapenems. After the introduction of carbapenems, the concentrations of the drug dropped by 46–93.59% (average 72%) followed by rapid recovery of consciousness. Ten out of eleven patients had positive outcomes, while one patient died. The most commonly observed complication in our group of patients was bronchopneumonia. Conclusions: The application of carbapenems for the management of acute VPA poisoning might be a useful and effective treatment option. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Background/Aim. Based on numerous studies in animals, the most prominent toxic effects of decabrominated diphenyl ether (BDE-209) are observed in the liver, thyroid hormone homeostasis, reproductive and nervous systems. BDE-209 exhibits its toxic effects partly through the aryl hydrocarbon (Ah) receptor and consequent induction of hepatic microsomal enzymes. The aim of this study was to assess the hepatotoxic effect vs target tissue dose of BDE-209 in the subacutely orally exposed Wistar rats. Methods. Effects were examined on male Wistar rats, weighing 200-240 g, exposed to doses of 1,000, 2,000 or 4,000 mg BDE-209/kg body weight (bw)/day by gavage during 28 days. Animals were treated according to the decision of the Ethics Committee of the Military Medical Academy, No 9667-1/2011. Evaluation of the hepatotoxic effect was based on: relative liver weight water and food intake, biochemical parameters of liver function [aspartate amino transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gama glutamyl transferase (γ-GT)], and oxidative stress parameters in liver homogenates [malondialdehiyde (MDA), superoxide dismutase (SOD), -SH] and morphological and pathohistological changes in the liver. For the assessment of internal dose - response relationship, lower confidence limit of Benchmark dose (BMDL) of 5% or 10% i.e. BMDL5 or BMDL10, were calculated using PROAST software. Results. After the application of 1,000, 2,000 or 4,000 mg BDE-209/kg bw/day, the concentrations of BDE-209 measured in liver were 0.269, 0.569 and 0.859 mg/kg of liver wet weight, (ww) respectively. Internal doses correlated with external (r = 0.972; p < 0.05) according to equation: internal dose (mg BDE-209/kg of liver ww) = 0.0002 x external dose (mg/kg bw/day) + 0.0622. Hepato-toxicity was demonstrated based on significant increase in AST and γ-GT activities and the degree of histopathological changes. The lowest BMDL5 of 0.07228 mg BDE-209/kg of liver ww, correlating to external dose of 39 mg/kg/day, indicated the increase of AST activity as the most sensitive biomarker of BDE-209 hepatotoxicity in subacutely exposed rats. Conclusion. The results of the present work add up to the issue of BDE-209 toxicity profile with a focus on relationship between internal dose and hepatotoxicity. Critical internal dose for the effect on AST of 0.07 mg/kg of liver ww, corresponding to external dose of 39 mg/kg/day, is the lowest dose ever observed among the studies on BDE-209 hepatotoxicity. For the persistent substances with low absorption rate such as BDE-209, critical effect based on internal dose in majority of cases is considered as more precisely defined than the effect established based on external dose, particularly. [Projekat Ministarstva nauke Republike Srbije, br. III 46009]

Background/Aim. Rhabdomyolysis (RM) is potentially lethal syndrome, but there are no enough published data on its frequency and characteristics in acute poisonings. The aim of this study was to determine the causes and severity of RM in acute poisonings. Methods. Patients hospital charts were retrospectively screened during a one-year period in order to identify patients with RM among 656 patients treated due to acute poisonings with different agents. All the patients with RM were selected. Entrance criterion was the value of creatine kinase (CK) over 250 U/L. The severity of RM was assessed according to the Poison Severity Score. The patients were divided into three groups: the first one with mild RM (CK from 250 to 1,500 U/L), the second with moderate RM (CK from 1,500 to 10,000 U/L) and the third with severe RM (CK greater than 10,000 U/L). Results. RM occurred in 125 (19%) of the patients with acute poisonings. It was mainly mild (61%), or moderate (36%), and only in 3% of the patients was severe RM. The incidence of RM was the highest in poisonings with opiates (41%), pesticides (38%), neuroleptics (26%), anticonvulsants (26%), ethyl alcohol (20%), and gases (19%). Psychotropic agents were the most common causes of poisoning, and consequently of RM. Fatal outcomes were registered in 32 (25.60%) of all RM patients. The incidence of fatal outcomes in poisonings with mild, moderate and severe RM was 19.73%, 31.11% and 75%, respectively. Conclusion. RM syndrome occurs at a relatively high rate in acute poisonings. Although agent’s toxicity is crucial for the outcome, severe RM and its complications may significantly influence the clinical course and prognosis of poisoning. Routine analysis of CK, as a relevant marker for RM may indicate the development of RM in acute poisoning and initiate prompt therapeutic measures in preventing acute renal failure as the most frequent consequence of extensive rhabdomyolysis.

Introduction. Intermediate syndrome (IMS) was described a few decades ago, however, there is still a controversy regarding its exact etiology, risk factors, diagnostic parameters and required therapy. Considering that acute poisonings are treated in different types of medical institutions this serious complication of organophosphate insecticide (OPI) poisoning is frequently overlooked. The aim of this paper was to present a case of IMS in organophosphate poisoning, which, we believe, provides additional data on the use of oxime or atropine. Case report. After a well-resolved cholinergic crisis, the patient developed clinical presentation of IMS within the first 72 h from deliberate malathion ingestion. The signs of IMS were weakness of proximal limb muscles and muscles innervated by motor cranial nerves, followed by the weakness of respiratory muscles and serious respiratory insufficiency. Malathion and its active metabolite were confirmed by analytical procedure (liquid chromatography-mass spectrometry). Pralidoxime methylsulphate, adiministered as a continuous infusion until day 8 (total dose 38.4 g), and atropine until the day 10 (total dose 922 mg) did not prevent the development of IMS, hence the mechanical ventilation that was stopped after 27 h had to be continued until the day 10. Conclusion. Continuous pralidoxime methylsulphate infusion with atropine did not prevent the development of IMS, most likely due to the delayed treatment and insufficient oxime dose but also because of chemical structure and lipophilicity of ingested OPI. A prolonged intensive care monitoring and respiratory care are the key management for the intermediate syndrome. [Projekat Ministarstva nauke Republike Srbije, br. OI 176018, No. 46009]

Polychlorinated biphenyls (PCBs) and brominated flame retardants, polybrominated diphenylethers (PBDEs), are widespread environmental contaminants as a result of anthropogenic activities and due to their persistency and resistance to degradation. Both groups of chemicals are placed on the list of persistent organic pollutants (POPs), covered by the Stockholm convention which is aimed to limit or ban the production, use, emission, import and export of POPs in order to protect human health and the environment. Taking into account the structural similarity between PCBs and PBDEs, and the known effects of PCBs, these two groups of chemicals could have similar mechanisms of action. Also, because of real simultaneous exposure to these compounds, an examination of possible interactions is of great importance. Interactions of the compounds from these groups are likely at the system level of hormones, particularly thyroid and reproductive ones. As there are mechanisms of adverse effects of both groups of chemicals on the nervous system, including functional, neurological and behavioral changes, there are influences on neurotransmiters, changes in signal transduction and apoptosis. There are interactions affecting the occurrence of metabolic disorders as well. Data on the toxicity of mixtures of PCBs and PBDEs, as well as interactions of these chemicals would contribute to the processes of risk evaluation and risk characterisation. [Projekat Ministarstva nauke Republike Srbije, br. III 46009]

The aim of this study was to compare the protective effect of two individual oximes (HI-6 and trimedoxime) with their combination in mice acutely poisoned with tabun, dichlorvos or heptenophos. Oxime HI-6 did not protect experimental animals against either dichlorvos, heptenophos or tabun. Trimedoxime was very effective against all three OPs. The ED-500 doses of trimedoxime necessary to protect 50% of animals after the simultaneous administration of OPs and oxime were 42.18, 14.97 and 32.08 μmol/kg in dichlorvos, heptenophos and tabun poisoning, respectively. Half-time of efficacy in the tabun protocol was approximately three and two times longer than in the protocol for heptenophos and dichlorvos, respectively indicating also that trimedoxime is very potent in counteracting tabun toxicity. Addition of trimedoxime significantly improved the protective effect of HI-6 in acute tabun poisoning. When dichlorvos or heptenophos were used, addition of trimedoxime generally improved the antidotal effect of HI-6, but still lower protection was obtained than in the case when trimedoxime alone was administered. The investigations of different oxime combinations have indicated that application of a mixture of two oximes represents a promising antidotal approach.

Background/Aim. Saliva represents an alternative specimen for substances abuse determination in toxicology. Hence, the aim of this study was to optimize a method for saliva specimen preparation for heroin metabolites, morphine and 6-monoacetylmorphine (6-mam), and codeine determination by liquid chromatography-mass spectrometry (LC/MS), and to apply this method on saliva samples taken from the patients. Methods. Saliva specimen was prepared using liqiud/liquid extraction of morphine, codeine and 6- mam by mixture of chloroform and isopropanol (9 : 1; v/v). Extracts were analysed by HPLC/MS technique: separation column Waters Spherisorb® 5 μm, ODS2, 4.6 × 100 mm; mobile phase: ammonium acetate : acetonitile (80 : 20; v/v), mobile phase flow rate 0.3 mL/min; mass detection range: 100-400 m/z. Regression and correlation analyses were performed with the probalility level of 0.05. Concentrations of morphine, codeine and 6-mam were determined in saliva samples of the patients with “opiates” in urine identified by the test strips. Results. Calibration for each analysed substance was done in the concentration range from 0.1 to 1 mg/L and the coefficient of correlation was R2 > 0.99. We obtained following calibration curves: y = 385531x + 14584; y = 398036x + 31542; and y = 524162x - 27105, for morphine, codeine and 6-mam, respectively. Recovery for morphine and codeine determination was 99%, while for 6- mam it was 94%. Limits of detection and quantification of a proposed method were 0.01 mg/L and 0.05 mg/L, respectively. Concentration of morphine in the saliva of the heroin users ranged between 0.54 and 5.82 mg/L, concentration of codeine between 0.05 and 5.33, and 6-mam between 0.01 and 0.68 mg/L. A statistically significant correlation between codeine and 6-mam concentrations was obtained. Conclusion. A proposed HPLC/MS method for morphine, codeine and 6-mam determination in saliva is accurate, simple, cheap and suitable for routine analysis and monitoring of heroin abuse.

Background/Aim. Saliva is a body fluid which, like serum, can be used for determination of concentrations of certain drugs, both in pharmacotherapy as well as in acute poisonings. The aim of this study was to determine carbamazepine concentrations in both saliva and serum in acute poisoning in order to show if there is a correlation between the obtained values, as well as to monitor toxicokinetics of carbamazepine in body fluides. Methods. Saliva and serum samples were obtained from 26 patients treated with carbamazepine and 20 patients acutely poisoned by the drug immediately after their admission in the Emergency Toxicology Unit. Determination of salivary and serum carbamazepine concentrations was performed by the validated high pressure liquid chromatographyultraviolet (HPLC-UV) method. Results. A significant correlation of salivary and serum carbamazepine concentrations in both therapeutic application and acute poisoning (r = 0.9481 and 0.9117, respectively) was confirmed. In acute poisonings the mean ratio between salivary and serum concentrations of carbamazepine (0.43) was similar to the mean ratio after its administration in therapeutic doses (0.39), but there were high inter-individual variations in carbamazepine concentrations in the acutely poisoned patients, as a consequence of different ingested doses of the drug. In acute poisoning the halftime of carbamazepine in saliva and serum was 12.57 h and 6.76 h, respectively. Conclusion. Our results suggest a possible use of saliva as an alternative biological material for determination of carbamazepine concentrations in therapeutic application and acute poisoning as well, and a possible extrapolation of the results obtained in saliva to serum concentrations of carbamazepine.

Introduction/Aim. In acute organophosphate poisoning the issue of special concern is the appearance of muscle fasciculations and convulsions that cannot be adequately antagonised by the use of atropine and oxime therapy. The aim of this study was to examine atidotal effect of obidoxime or HI-6 combinations with memantine in mice poisoned with soman, dichlorvos or heptenophos. Methods. Male Albino mice were pretreated intravenously (iv) with increasing doses of oximes and/or memantine (10 mg/kg) at various times before poisoning with 1.3 LD-50 of soman, dichlorvos or heptenophos, in order to determine the median effective dose and the efficacy half-time. In a separate experiment, cerebral extravasation of Evans blue dye (40 mg/kg iv) was examined after application of memantine (10 mg/kg iv), midazolam (2.5 mg/kg intraperitonealy - ip) and ketamine (20 mg/kg ip) 5 minutes before soman (1 LD-50 subcutaneously - sc). Results. Coadministration of memantine induced a significant decrease in median effective dose in null time of both HI-6 (7.96 vs 1.79 mmoL/kg in soman poisoning) and obidoxime (16.80 vs 2.75 mmoL/kg in dichlorvos poisoning; 21.56 vs 6.63 mmoL/kg in heptenophos poisoning). Memantine and midazolam succeded to counteract the soman-induced proconvulsive activity. Conclusion. Memantine potentiated the antidotal effect of HI-6 against a lethal dose of soman, as well as the ability of obidoxime to antagonize the toxic effects of dichlorvos and heptenophos probably partly due to its anticonvulsive properties.

Background/Aim. Quantitative analysis of amoxicillin and clavulanic acid in biological matrices requires sensitive and specific methods which allow determination of therapeutic concentration in μg/mL range. Analytical methods for determination of their concentrations in body fluids described in literature include high performance liquid chromatography coupled to UV detector (HPLC-UV) and liquid chromatography-mass spectrometry (LC-MS). The aim of this study was to develop sensitive and specific ultra performance liquid chromatography/ mass spectrometry (UPLC/MS) method which could be used for the spectral identification and quantification of the low concentrations of amoxicillin and clavulanic acid in the human plasma. Method. A sensitive and specific UPLC/MS method for amoxicillin and clavulanic acid determination was developed in this study. The samples were taken from the adult healthy volunteers receiving per os one tablet of amoxicillin (875 mg) in combination with clavulanic acid (125 mg). Results. Plasma samples were pretreated by direct deproteinization with perchloric acid. Quantification limit of 0.01 μg/ml for both amoxicillin and clavulanic acid was achieved. The method was reproducible day by day (RSD < 7 %). Analytical recoveries for amoxicillin ranged from 98.82% to 100.9% (for concentrations of 1, 5 and 20 μg/mL), and recoveries for clavulanic acid were 99,89% to 100.1% (for concentrations of 1, 2 and 5 μg/mL). This assay was successfully applied to a pilot pharmacokinetic study in healthy volunteers after a single-oral administration of amoxicillin/ clavulanic combination. The determined plasma concentrations of both amoxicillin and clavulanic acid were in the range of the expected values upon the literature data for HPLC-UV and LC-MS methods. Conclusion. The described method provided a few advantages comparing with LC/MS-MS method. The method is faster using running time of 5 minute, has lower limit of quantification (LOQ ) and it could be used in pharmacokinetic studies of both amoxicillin and clavulanic acid.

Background/Aim. Analysis of organophosphosphorus compounds and their metabolites in a biological material includes the use of numerous methods, covering both preparation of samples for analysis and their identification that is considered to be very complex. Low concentrations monitoring requires implementation of highly sensitive analytical techniques. The aim of this study was to develop and validate an original and sensitive method for the detection and quantitation of organophosphorus pesticides (dimethoate, diazinon, malathion and malaoxon) in human biological matrices (serum, urine). Methods. This method was based on a solid-phase extraction procedure, a chromatographic separation using an ACQUITY UPLC ® HSST3 column and mass spectrometric detection in the positve ion mode. Mobile phase: was consited of Solvent A (5 mM ammonium formate pH 3.0) and Solvent B (0.1% acetic formate in methanol), in a linear gradient (constant flow-rate 0.3 mL/min). Results. The standard curve was linear in the range of 0.05-5.00 mg/L for malathion and malaoxon, 0.10-5.00 mg/L for dimethoate and 0.05-2.50 mg/L for diazinon. The correlation coefficient was r ≥ 0.99. Extraction recoveries were satisfactory and ranged between 90-99%. The limits of detection (LOD) was between 0.007- 0.07 mg/L and the limits of quantitation (LOQ) ranged between 0.022-0.085 mg/L. Intra- and interassay precision and accuracy were satisfactory for all of the pesticides analyzed. Conclusion. The method of liquid chromatography - mass spectrometry is simple, accurate, and useful for the determination of organophosphorus pesticides in both clinical and forensic toxicology.

Introduction. Clinical picture of severe glyphosatesurfactant poisoning is manifested by gastroenteritis, respiratory disturbances, altered mental status, hypotension refractory to the treatment, renal failure, shock. Single case report indicated possible neurotoxic sequels of glyphosatesurfactant exposure with white matter lesions and development of Parkinsonism. We described a patient with massive white matter damage which led to vigil coma and lethal outcome. Case report. A 56-year old woman ingested about 500 mL of herbicide containing glyphosate isopropylamine salt. The most prominent manifestation of poisoning included hypotension, coma, hyperkaliemia, respiratory and renal failure. The patient was treated in intensive care unit by symptomatic and supportive therapy including mechanical ventilation and hemodialysis. The patient survived the acute phase of poisoning, but she developed vigil coma. Nuclear magnetic imagining revealed extensive bilateral lesions of the brain stem white matter and pons. Conclusion. The outcome of reported poisoning may be the consequence of glyphosate-surfactant neurotoxic effect or/and ischemia, especially in the episodes of marked hypotension during hemodialysis. Considering recommendation of early hemodialysis as the treatment of choice, even before renal failure development, we point out the importance of careful planning of dialysis modality in hemodynamically instable patient and recommend continuous dialysis methods.

Background/Aim. The majority of symptoms and signs of acute diazepam poisoning are the consequence of its sedative effect on the CNS affecting selectively polisynaptic routes by stimulating inhibitory action of GABA. The aim of the present study was to examine the effects of combined application of theophylline and flumazenil on sedation and impaired motor function activity in acute diazepam poisoning in rats. Methods. Male Wistar rats were divided in four main groups and treated as follows: group I - with increasing doses of diazepam in order to produce the highest level of sedation and motor activity impairment; group II - diazepam + different doses of flumazenil; group III - diazepam + different doses of theophylline; group IV - diazepam + combined application of theophylline and flumazenil. Concentrations of diazepam and its metabolites were measured with LC-MS. The experiment was performed on a commercial apparatus for spontaneous motor-activity registration (LKBFarad, Sweden). Assessment of diazepam- induced neurotoxic effects and effects after theophylline and flumazenil application was performed with rotarod test on a commercial apparatus (Automatic treadmill for rats, Ugo Basile, Italy). Results. Diazepam in doses of 10 mg/kg and 15 mg/kg produced long-time and reproducible pharmacodynamic effects. Single application of flumazenil or theophylline antagonized effects of diazepam, but not completely. Combined application of flumazenile and theophylline resulted in best effects on diazepaminduced impairment of motoric activity and sedation. As a result of theopylline application there was better elimination of diazepam and its metabolites. Conclusion. Combined application of flumazenil and theophylline resulted in the best antidotal effects in the treatment of diazepam poisoned rats. These effects are a result of different mechanisms of their action, longer half-life of theophylline in relation to that of flumezenil and presumably the diuretic effect of theophylline.

Background/Aim. Pneumonia is the most frequent complication in acute psychotropic drugs poisoning, which results in substantial morbidity and mortality, but which also increases the costs of treatment. Risk factors for pneumonia are numerous: age, sex, place of the appearance of pneumonia, severity of underlying disease, airway instrumentation (intubation, reintubation, etc). The incidence of pneumonia varies in poisoning caused by the various groups of drugs. The aim of this study was to determine the incidence and risk factors for pneumonia in the patients with acute psychotropic drugs poisoning. Methods. A group of 782 patients, out of which 614 (78.5%) with psychotropic and 168 (21.5%) nonpsychotropic drug poisoning were analyzed prospectively during a two-year period. The diagnosis of pneumonia was made according to: clinical presentation, new and persistent pulmonary infiltrates on chest radiography, positive nonspecific parameters of inflammation, and the microbiological confirmation of causative microorganisms. To analyze predisposing risk factors for pneumonia, the following variables were recorded: sex, age, underlying diseases, endotracheal intubation, coma, severity of poisoning with different drugs, histamine H2 blockers, corticosteroids, mechanical ventilation, central venous catheter. The univariate analysis for pneumonia risk factors in all patients, and for each group separately was done. The multivariate analysis was performed using the logistic regression technique. Results. Pneumonia was found in 94 (12.02%) of the patients, 86 of which (91.5%) in psychotropic and 8 (8.5%) in nonpsychotropic drug poisoning. In the psychotropic drug group, pneumonia was the most frequent in antidepressant (47%), and the rarest in benzodiazepine poisoning (3.8%). A statistically significant incidence of pneumonia was found in the patients with acute antidpressant poisoning (p < 0.001). Univariate analysis showed statistical significance for the following parameters: sex (p < 0.05), chronic alcohol intake (p < 0.05), underlying diseases (p < 0.01), central venous catheter (p < 0.05) vasopressors (p < 0.05), coma (p < 0.001), H2 blockers (p < 0.001) and corticosteroids (p < 0.001). The multivariate analysis retained endotracheal intubation and antidepressant drug poisoning as an independent risk factor for pneumonia. Conclusion. Using univariate and multivariate analysis, risk factors for developing pneumonia were disclosed. Some of these factors may be modified by simple medical procedures, thus the incidence and mortality rate of pneumonia in drug poisoning might be substantially reduced.

In order to determine the frequency, severity of poisoning, and the efficacy of the applied therapeutic measures, retrospective study of 391 patients treated for acute drug poisoning was performed during one-year period at the Clinic for Emergency and Clinical Toxicology and Pharmacology. In 49 (12.5%) patients cardiovascular agents were the cause of poisoning, most frequently beta-blockers and calcium antagonists (77.5%). Poisoning with antihypertensive agents was registered in 12.2% of patients, antiarrhythmics in 8.2%, and cardiotonics in 2.1%. Beta-blockers and calcium antagonists caused severe poisoning in over 40% of cases. Predominant clinical manifestations were registered on cardiovascular system, while central nervous system effects occured secondary to cardiotoxicity. Symptomatic and supportive measures were performed most frequently, while specific agents, glucagon, calcium salts, and others, were used less often.

Pesticide poisonings, intentional as well as accidental, are common, especially in undeveloped and developing countries. The goal of this study was to analyze the clinical presentation of patients hospitalized due to acute organophosphate (OPP) or carbamate pesticide (CP) poisoning as well as to analyze the factors that potentially influenced the severity and outcome of the poisonings. A retrospective cross-sectional study was performed. The age and gender of each patient were recorded, the type of ingested pesticide, whether the poisoning was intentional or accidental, number of days of hospitalization, the severity of the poisoning, and the outcome of the treatment (i.e., whether the patient survived or not). Clinical aspects of poisonings were analyzed, as well as the therapeutic measures performed. 60 patients were hospitalized due to acute OPP or CP poisoning, out of 51 (85.00%) were cases of intentional self-poisoning. The majority of patients were poisoned by OPPs (76.67%), in one-third the causative agent was malathion, followed in frequency by chlorpyrifos and diazinon. Dimethoate poisonings were manifested with the most severe clinical picture. A 70% or lower activity of reference values of acetylcholinesterase and butyrylcholinesterase was found in 50% and 58% of patients, respectively. The most common symptom was miosis (58.33%), followed by nausea and vomiting. Pralidoxime reactivated acetylcholinesterase inhibited by chlorpyrifos or diazinon, but not with malathion or dimethoate. Impairment of consciousness and respiratory failure, as well as the degree of acetylcholinesterase and butyrylcholinesterase inhibition, were prognostic signs of the severity of poisoning. The lethal outcome was more often found in older patients (t = 2.41, p = 0.019). The type of ingested pesticide significantly affects the severity and outcome of poisoning as well as the effectiveness of antidotes. [ABSTRACT FROM AUTHOR]

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A rising number of patients are being treated for overdosing with new psychoactive substances (NPS) available at the illegal drug market in Serbia. The aim of this study was to report clinical and analytical experience of the National Poison Control Centre of Serbia (NPCC) with synthetic cannabinoids (SCs) and point to the NPS available at the illegal drug market in our country. From January 2013 to December 2016, 58 patients (aged between 14 and 25) were treated for the effects of synthetic cannabinoids at the NPCC. Tachycardia was established in 53, mydriasis in 31, somnolence, nausea, vomiting, and agitation in 16, dizziness in 10, disorientation in 9, dyspnoea and chest pain in 4, and loss of consciousness, pallor, paraesthesia, muscle twitches, and short-term memory impairment in 2 patients. After receiving symptomatic and supportive treatment in the emergency ward, all patients had fully recovered within 8 h and were discharged shortly afterwards. Another part of the study was focused on the analysis of the products known under their local street names as "Biljni tamjan" (herbal incense), "Beli slez", and "Rainbow Special" and the analysis of urine sampled from the patients with gas chromatography - mass spectrometry and high performance liquid chromatography. The detected synthetic cannabinoids were AB-PINACA, JWH-018, JWH-122, JWH-210, 5F-AKB48, and MDMB-CHMICA in herbal products and AB-FUBINACA, AB-CHMINACA, and MDMB-CHMICA in the urine samples. Our findings have shown the great capacity of NPCC to I) monitor NPS abuse in Serbia, II) reliably detect SCs in illicit products and biological samples, and III) clinically manage the adverse effects in their users. Future commitments of the NPCC will include systematic collection of relevant data on SCs and their adverse effects, detection of changes in purity and composition of the controlled NPS-based products, and raising the public awareness of NPS to improve the effectiveness of the national Early Warning System. [ABSTRACT FROM AUTHOR]

Despite improvements to intensive care management and specific pharmacological treatments (atropine, oxime, diazepam), the mortality associated with organophosphate (OP) poisoning has not substantially decreased. The objective of this examination was to describe the role of fresh frozen plasma (FFP) in acute OP poisoning. After a deliberate ingestion of malathion, a 55-year-old male suffering from miosis, somnolence, bradycardia, muscular fasciculations, rales on auscultation, respiratory insufficiency, as well as from an inhibition of red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE), was admitted to hospital. Malathion was confirmed in a concentration of 18.01 mg L-1. Apart from supportive measures (including mechanical ventilation for four days), antidotal treatment with atropine, oxime - pralidoxime methylsulphate (Contrathion®), and diazepam was administered, along with FFP. The potentially beneficial effects of FFP therapy included a prompt increase of BuChE activity (from 926 IU L-1 to 3277 IU L-1; reference range from 7000 IU L-1 to 19000 IU L-1) and a reduction in the malathion concentration, followed by clinical recovery. Due to BuChE replacement, albumin content, and volume restitution, FFP treatment may be used as an alternative approach in patients with acute OP poisoning, especially when oximes are not available. [ABSTRACT FROM AUTHOR]

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The need for an official pharmaceutical vehicle or carrier of drug based on natural sugar emulsifiers that protect and regenerate natural barriers of the skin lipid layer is constantly increasing. This article studies the specific structures of emulsions and two manners of water binding that provide prolonged skin moisturization and delayed or prolonged release of drugs insoluble in water. Natural emulsifiers of an alkylpolyglucoside (cetearyl alcohol and cetearyl glycoside) and estar-type (sorbitan stearate and sucrose cocoate) are used for manufacturing vehicle/carriers of drugs (diclofenac diethylamine). Specific hydrofilic groups in emulsifiers, such as glycozide and ester, are capable of binding in different manners and variable quantities of water by hydrogen bonds within the cream, which is responsible for water distribution and prolonged skin moisturization. This lyotropic potential of natural emulsifiers—alkylpolyglucoside and estar type—may affect the physical stability of topical vehicles by determining the colloidal structure, further reflecting the drug delivery from the pharmaceutical excipient to the skin. The aim of this article is to evaluate whether the type of emulsifier influences the structural characteristics of emulsion systems and how the content and availability of water within the cream reflects the delivery of diclofenac diethylamine (1.16%) from the topical vehicles. Freeze-fracture transmission electron microscopy, wide-angle x-ray diffraction, thermogravimetric analysis, and continual and oscilatory rheological measurements are employed for characterization of emulsion system colloidal structure. Diclofenac diethylamine release profiles from investigated emulsion systems were evaluated using the rotation paddle apparatus, modified by addition of diffusion cells (enhancer cell). There is an important difference in water distribution within the creams with emulsifiers of different chemical types. In the sample with ester-type sugar emulsifiers, the quantity of interlamellar-bound water is four times less than bulk and secondary water, while in the sample with alkylpolyglucoside emulsifier, approximately two thirds of total water are bound inside the system and one third is poorly bound, that is, bulk water. It can also be seen that diclofenac diethylamine is gradually released from the vehicle during 6 hours of testing. Formulation of topical vehicle as dermopharmaceutical drug carrier system, with natural emulsifier, like cetearyl alcohol, cetearyl glucoside, sorbitan stearate, and sucrose cocoate, is recommended. [ABSTRACT FROM AUTHOR]

Two sugar-based emulsifiers, cetearyl alcohol & cetearyl glycoside and sorbitan stearate & sucrose cocoate, known as potential promoters of lamellar liquid crystals/gel phases, were investigated in order to formulate an optimal vehicle for amphiphilic drug - diclofenac diethylamine (DDA). Physico-chemical characterization and study of vehicle's physical stability were performed. Then, the in vitro DDA liberation profile, dependent on the mode of drug incorporation to the system, and the in vivo, short-term effects of chosen samples on skin parameters were examined. Droplets size distribution and rheological behavior indicated satisfying physical stability of both types of vehicles. Unexpectedly, the manner of DDA incorporation to the system had no significant influence on DDA release. In vivo study pointed to emulsion's favorable potential for skin hydration and barrier improvement, particularly in cetearyl glycoside-based vehicle. [ABSTRACT FROM AUTHOR]

OBJECTIVE: During the last decade, besides the use of “classic recreational drugs”, there has been an increase of new psychoactive substances throughout the world. Illegal laboratoires constanly change the chemical structure of these substances. JWH-122 and JWH-210 are synthetics cannabinoids, found in herbal products (incense). Synthetic cannabinoids are cannabinoid receptor agonists that target the CB1 and CB2 marijuana receptors. These compounds are several times more potent than tetrahydrocannabinol. Among other products, JWH-122 and JWH-210, added to dried leaves, are sold as air refhresheners, with the remark “not for human consumption”. MATERIALS & METHODS: JWH-122 and JWH-210 were isolated using the liquid-liquid extraction. The sample solutions were qualitatively analyzed by using a liquid chromatography-electrospray ionization-mass spectrometer with XTerra column. Source temperature 125°C, desolvation temperature 430°C, fl ow gas: desolvatacion 400 L/h, cone 50 L/h. The mobile phase: 5 mM ammoniumacetate (pH 3.5): acetonitril. RESULTS: MS data were recorded in the full scan mode (m/z 100-500). For qualitative analysis of JWH-122 and JWH-210 the protonated molecular peaks of these compounds were monitored in the scan mode. The monitoring ions were as follows: JWH-122 m/z 355, 214, 169, 141; JWH-210 m/z 370, 214, 183. (Cone Voltage 50V). CONCLUSION: New psychoactive substances, which are pharmacologically active and toxic, are appearing in herbal products. Changing of NPAS chemical structure is a constant challenge for forensics and medical services, which need to be alert and ready to keep up with these diagnostic and detection problems. [ABSTRACT FROM AUTHOR]

Background/Aim. Saliva is a body fluid which, like serum, can be used for determination of concentrations of certain drugs, both in pharmacotherapy as well as in acute poisonings. The aim of this study was to determine carbamazepine concentrations in both saliva and serum in acute poisoning in order to show if there is a correlation between the obtained values, as well as to monitor toxicokinetics of carbamazepine in body fluids. Methods. Saliva and serum samples were obtained from 26 patients treated with carbamazepine and 20 patients acutely poisoned by the drug immediately after their admission in the Emergency Toxicology Unit. Determination of salivary and serum carbamazepine concentrations was performed by the validated high pressure liquid chromatography-ultraviolet (HPLC-UV) method. Results. A significant correlation of salivary and serum carbamazepine concentrations in both therapeutic application and acute poisoning (r = 0.9481 and 0.9117, respectively) was confirmed. In acute poisonings the mean ratio between salivary and serum concentrations of carbamazepine (0.43) was similar to the mean ratio after its administration in therapeutic doses (0.39), but there were high inter-individual variations in carbamazepine concentrations in the acutely poisoned patients, as a consequence of different ingested doses of the drug. In acute poisoning the halftime of carbamazepine in saliva and serum was 12.57 h and 6.76 h, respectively. Conclusion. Our results suggest a possible use of saliva as an alternative biological material for determination of carbamazepine concentrations in therapeutic application and acute poisoning as well, and a possible extrapolation of the results obtained in saliva to serum concentrations of carbamazepine. [ABSTRACT FROM AUTHOR]

Background/Aim. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are important biomarkers of exposure to organophosphorus and carbamate insecticides. Since the estimation of the level of cholinesterase inhibition depends on the normal values which may vary in different populations, it is important to determine them in our population, which so far has not been done. Therefore, the aim of this study was to determine the reference values for AChE and BuChE in a healthy population of adults in the Republic of Serbia. Methods. The AChE activity was measured by spectrophotometry (λ = 412 nm), using a modified Ellman's method. BuChE activity was determined by the integrated chemical system (Dimension RxLMax) with ready-made reagent cartridge for analysis. The examinees were healthy voluntary blood donors from the Institute of Transfusiology and Hemobiology, Military Medical Academy in Belgrade, Serbia. Statistical Package for Social Sciences (SPSS) software program was used for data processing. Results. In the group of 851 persons, there were 728 males and 123 females. The mean age was 39.1 ± 11.6 years. For all of them, erythrocyte AChE activity was done while BuChE was determined in 205 persons (169 males and 36 females). Their mean value of acetylcholinesterase activity was 8,090.6 ± 1,976.7 IU/L, and of butyrylcholinesterase activity was 14,556.6 ± 4,078.1 U/L. Due to lack of normal data distribution in male group (both enzymes), reference ranges were estimated as 2.5 and 97.5 percentiles. Conclusion. The results of this pilot study on cholinesterase in healthy population in the Republic of Serbia which has now been done for the first time, indicate the need for considering their wider ranges of when estimating the severity of poisoning. However, further study for BuChE with the inclusion of a larger number of females and data for body weight of the examinees, in order to get more precise reference limits, is suggested. [ABSTRACT FROM AUTHOR]

Recent uses of nerve agents underline the need of early diagnosis as trigger to react (initiating medical countermeasures, avoiding cross-contamination). As organophosphorus (OP) pesticide poisoning exerts the same pathomechanism, that is, inhibition of the pivotal enzyme acetylcholinesterase (AChE), a portable cholinesterase (ChE) test kit was applied in an emergency room for rapid diagnosis of OP poisoning. OP nerve agents or pesticides result in the inhibition of AChE. As AChE is also expressed on erythrocytes, patient samples are easily available. However, in most clinics only determination of plasma butyrylcholinesterase (BChE) is established which lacks a pathophysiological correlate, shows higher variability in the population and behaves different regarding inhibition by OP and reactivation by oximes. The ChE test kit helped to diagnose atypical cases of OP poisoning, for example, missing of typical muscarinic symptoms, and resulted in administration of pralidoxime, the oxime used in Serbia. The ChE test kit also allows an initial assessment whether an oxime therapy is successful. In one case report, AChE activity increased after oxime administration indicating therapeutic success whereas BChE activity did not. With only BChE at hand, this therapeutic effect would have been missed. As inhibition of AChE or BChE activity is determined, the CE-certified device is a global diagnostic tool for all ChE inhibitors including carbamates which might also be misused as chemical weapon. The ChE test kit is a helpful point-of-care device for the diagnosis of ChE inhibitor poisoning. Its small size and easy menu-driven use advocate procurement where nerve agent and OP pesticide exposure are possible., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Compounds that cause powerful sensory irritation to humans were reviewed by the Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) in response to requests in 2014 and 2017 by the OPCW Director-General to advise which riot control agents (RCAs) might be subject to declaration under the Chemical Weapons Convention (the "Convention"). The chemical and toxicological properties of 60 chemicals identified from a survey by the OPCW of RCAs that had been researched or were available for purchase, and additional chemicals recognised by the SAB as having potential RCA applications, were considered. Only 17 of the 60 chemicals met the definition of a RCA under the Convention. These findings were provided to the States Parties of the Convention to inform the implementation of obligations pertaining to RCAs under this international chemical disarmament and non-proliferation treaty., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)