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Marko Antunovic,1,2 Slavica Vucinic,1,2 Jelena Kotur-Stevuljevic,3 Kristijan Krstic,4 Jasmina Jovic-Stosic,1,2 Vesna Kilibarda,1,2 Natasa Perkovic-Vukcevic,1,2 Snezana Djordjevic1,2 1Medical Faculty Military Medical Academy, University of Defense, Belgrade, Serbia; 2National Poison Control Center, Military Medical Academy, Belgrade, Serbia; 3Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia; 4Department of Physical Medicine and Rehabilitation, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, SerbiaCorrespondence: Marko Antunovic, National Poison Control Center, Military Medical Academy, Crnotravska 17, Belgrade, 11040, Serbia, Tel +381 11 3608 264, Fax +381 11 367 21 87 264, Email antunovic.marko87@gmail.comPurpose: The aim of this study was to analyze data on gabapentinoid-related attendances to the National Poison Control Center of Serbia (NPCC), particularly abuse cases; to estimate its changes and to compare it with trends in national consumption rates of these drugs. We also aimed to analyze the main characteristics of the study population and to investigate the major clinical effects in poisoned patients.Patients and Methods: This is a retrospective study of patients admitted to the NPCC for acute poisoning involving gabapentinoids from 1 May 2012 to 1 October 2022.Results: There were 357 (95.5%) pregabalin-related and 17 (4.5%) gabapentin-related poisoning cases in 302 patients. Abuse of pregabalin was detected in 27.8% (84/302), while gabapentin abuse occurred in 0.7% (2/302) of all patients. A steady increase in rates of pregabalin poisoning and abuse cases strongly correlated with the increase in overall consumption of this drug, while there were no significant changes in rates of gabapentin consumption, poisoning and abuse rate during the study period. Most patients who abused pregabalin pregabalin were males (84.5%) and the median age was 26 years (range: 15– 45 years). Almost 60% of patients who abused pregabalin (48/84) belonged to the migrant population. Co-ingestions occurred in 89.4% of pregabalin-related cases (319/357), resulting in more severe poisoning. The most often co-ingested drugs were benzodiazepines and among them clonazepam was detected in the largest number of cases.Conclusion: The poisoning and abuse cases involving pregabalin are on the rise in Serbia, which coincided with an increase in its overall consumption during the study period. Isolated pregabalin ingestions resulted in mild poisoning, although severe symptoms such as coma and bradycardia were recorded. When prescribing pregabalin to patients at risk of abuse caution is needed. Strengthening the measures for dispensing of pregabalin may reduce the risks associated with its abuse.Keywords: gabapentinoids, overdose, misuse, drug consumption, psychoactive substances

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.

Introduction. During the last few years, intravenous lipid emulsions have been effectively used in treatment of acute poisonings with lipophilic substances, including verapamil. Case report. A 37-year-old women presented 1 hour after ingestion of 2.8 g verapamil with hypotension and complete heart block. Because of the applied standard therapy failure and further patients impairment, Intralipid® 20% was used. Sinus rhythm was restored, arterial blood pressure increased and verapamile concentrations, both total and free decreased. Conclusion. Intravenous lipid emulsion can be important in treatment of severe acute intoxication and cardiotoxicity caused by verapamil.

Backgound/Aim. Flumazenil is benzodiazepine receptor antagonist. It has been studied for a various indications, including reversal of sedation after surgery or diagnostic procedures, awakening of comatose patients in benzodiazepine overdose, or for symptomatic treatment of hepatic encephalopathy. Some drugs, like theophylline, may prolong its elimination half-life. Considering the long half-life of diazepam and its metabolites, concomitant use of theophylline may reduce the need for repeated dosing of flumazenil in patients with acute diazepam poisoning. The aim of this study was to introduce a reliable and accurate method for determining the concentration of flumazenil after therapeutic application in patients with acute poisoning, and using that method to assess whether the kinetics of flumazenil change in the presence of aminophylline (combination of theophylline and ethylenediamine in a 2 : 1 ratio) applied as concomitant therapy. Methods. Blood samples from patients with acute diazepam poisoning that received flumazenil at the dose of 0.5 mg, or the same dose with 3 mg/kg of body weight of aminophylline, were collected 1, 3, 10, 30, 60, 120 and 240 min after its intravenous administration. Samples were prepared by solid-phase extraction on Oasis HLB cartridges with ethylacetate as extracting agens. Flumazenil was determined by liquid chromatography with mass spectrometry (LC-MS) in single ion monitoring mode at m/z 304. Separation of flumazenil from matrix compound was performed on Lichrospher RP-8 column using the mixture of acidic acetonitrile and 20 mM of ammonium acetate in water (55 : 45) as a mobile phase. Results. The applied analitycal method showed excellent recovery (94.65%). The obtained extracts were much cleaner than the extracts obtained by the same extractant in the process of liquid-liquid extraction. The limit of detection of the LC-MS method described in this paper was 0.5 ng/mL and the limit of quantitation was 1 ng/mL. In the patients treated with both flumazenil and aminophylline, the elimination constant for flumazenil was significantly lower and the elimination half-life was longer (p < 0.05) in comparison with the same parameters in the patients who received flumazenil alone. Conclusion. The applied LC-MS method for the determination of flumazenil in serum samples of patients with acute diazepam poisoning is rapid, sensitive, precise and specific. Concomitant use with theophylline significantly prolonged elimination of flumazenil during the treatment of acute poisonings with diazepam.

Introduction. Calcium channel blockers and beta-blockers are among the most frequently ingested cardiovascular drugs in self-poisoning causing significant mortality. Intravenous lipid emulsion (ILE) is reported as a potentially novel antidote for treatment of acute poisoning caused by some of these drugs. Case report. We presented two cases of poisoning with these drugs. The case 1, a 24-year-old woman ingested amplodipine, metformin and gliclazide for self-poisoning. She presented with tachycardia and hypotension. Laboratory analyses revealed hyperglycaemia and metabolic acidosis. Despite the treatment which included fluid resuscitation, vasopressors, intravenous calcium, glucagon and ILE, circulatory shock occurred. The patient died 10 hours after admission due to cardiac arrest refractory to cardiopulmonary resuscitation. The case 2, a 41-year old man, was found in a coma with empty packages of nifedipine, metoprolol and diazepam tablets. On admission vital signs included Glasgow Coma Scale (GCS) of 3, weak palpable pulses, undetectable blood pressure, and irregular breathing with oxygen saturation of 60%. An electrocardiography showed AV block (Mobitz II) with ventricular rate of 44/min with progression to third degree of AV block. In attempt to increase heart rate and blood pressure the following agents were administered: atropine boluses, normal saline with dopamine, glucagon, calcium chloride and ILE. Temporary transvenous pacemaker was placed, electrical capture was recorded, but without improvement in haemodynamics. Three hours after admission cardiac arrest happened and cardiopulmonary resuscitation was unsuccessful. Conclusion. Intravenous lipid emulsion may be ineffective in acute poisonings with amlodipine, nifedipine or metoprolol.

Introduction. ‘Body packer’ syndrome with severe intoxication or sudden death may happen in persons who smuggle drugs in their body cavities. In case of lethal outcome when carrying cocaine, it is important, but sometimes difficult to determine whether death was due to intoxication or due to other causes. Therefore, it is necessary not only to quantify cocaine and its metabolites in biological material, but also based on their distribution in body fluids and tissues to conclude whether it is acute intoxication. We described a well-documented case of fatal poisoning in a body packer and post mortem distribution of the drug in biological samples. Case report. A 26-year-old man was brought to hospital with no vital signs. Resuscitation measures started at once, but with no success. Autopsy revealed 66 packets of cocaine in his digestive tract, one of which was ruptured. Hyperemia of the most of all internal organs and pulmonary and brain edema were found. High concentrations of cocaine, its metabolites benzoylecgonine and ecgonine methyl ester, as well as cocaine adulteration levamisole were proven in the post mortem blood and tissues by liquid chromatography-mass spectrometry (LC-MC) method with selective-ion monitoring. Conclusion. The ratio of cocaine and its metabolites concentrations in the brain and blood obtained by LC-MS method can be used for forensic confirmation of acute intoxication with cocaine.

Background/Aim. Benzodiazepines are among the most frequently ingested drugs in self-poisonings. Elderly may be at greater risk compared with younger individuals due to impaired metabolism and increased sensitivity to benzodiazepines. The aim of this study was to assess toxicity of benzodiazepines in elderly attempted suicide. Methods. A retrospective study of consecutive presentations to hospital after self-poisoning with benzodiazepines was done. Collected data consisted of patient's characteristics (age, gender), benzodiazepine ingested with its blood concentrations at admission, clinical findings including vital signs and Glasgow coma score, routine blood chemistry, complications of poisoning, details of management, length of hospital stay and outcome. According the age, patients are classified as young (15-40-year old), middle aged (41-65-year old) and elderly (older than 65). Results. During a 2-year observational period 387 patients were admitted because of pure benzodiazepine poisoning. The most frequently ingested drug was bromazepam, the second was diazepam. The incidence of coma was significantly higher, and the length of hospital stay significantly longer in elderly. Respiratory failure and aspiration pneumonia occurred more frequently in old age. Also, flumazenil was more frequently required in the group of elderly patients. Conclusion. Massive benzodiazepines overdose in elderly may be associated with a significant morbidity, including deep coma with aspiration pneumonia, respiratory failure, and even death. Flumazenil is indicated more often to reduce CNS depression and prevent complications of prolonged unconsciousness, but supportive treatment and proper airway management of comatose patients is the mainstay of the treatment of acute benzodiazepine poisoning.

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The hippocampus along with other structures of the medial temporal lobe plays an important role in the process of learning and memory consolidation. Bilateral hippocampal lesions lead to persistent anterograde amnesia while unilateral damage results in milder, content-specific forms of amnesia. Hippocampus may be affected by an acute or chronic pathologic process from a wide spectrum of neurological disorders. Case report. A 61-year-old female patient with a long history of hypertension, glucose intolerance, hypercholesterolemia and depression was hospitalized for acute anterograde amnesia, which led to repeated excessive drug taking. By further examinations that included laboratory tests, electroencephalography, Doppler sonography of intra- and extracranial vessels and neurovisualization methods [multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) of the brain] bilateral hippocampal ischemia that occurred at different times was detected. Cognitive and neuropsychological evaluation revealed an isolated severe damage of episodic memory with the inability of retention of new information which persisted at the control examination three months later. The assumed mechanism of occurrence of ischemia in this case could be arterio-arterial embolism. Conclusion. Although ischemic stroke is one of the most common neurological diseases, ischemic stroke of the hippocampus is rare, the isolated bilateral presentation with clinical signs of severe amnestic syndrome in particular. Timely recognition and modern therapeutic approach could have a favorable impact on the recovery from severe neurological, cognitive deficit. It could be suggested that in patients with the clinical image of acute anterograde amnesia and vascular risk factors the MSCT examination of the brain with computed tomography perfusion and angiography is performed immediately upon hospitalization.

Introduction. Glyphosate is the first widely used herbicide against weed in genetically modified crops. Though glyphosate itself has a low toxicity, commercial products are more dangerous because of increased toxicity due to surfactants addition. There is no specific antidote for the poisoning with glyphosate-surfactant (Gly-SH). In recent times, the efficacy of intravenous lipid emulsion (ILE) administration for the treatment of acute poisoning caused by Gly- SH has been investigated. Case Report. A 50-year-old man was admitted 3 hours after self-poisoning with herbicide containing glyphosate and polyoxyethyleneamine, as a surfactant. On admission, the patient was in a coma, hypotensive (80/50 mmHg) and without spontaneous breathing. Electrocardiogram showed widecomplex tachycardia, and arterial blood gas (ABG) revealed acidosis (pH 7.07). Conventional treatment included mechanical ventilation, intravenous fluids, bicarbonate and dopamine. As there was no improvement, ILE was started. The patient received 100 mL of 20% Intralipid® bolus followed by infusion of 400 mL over 20 minutes. Prior to expiration of infusion, a gradual rise in blood pressure was noted, and within 2 hours sinus rhythm was restored. Conclusion. This case report suggests that the use of ILE may be an additional option for the treatment of cardiocirculatory disturbances caused by commercial products of glyphosate herbicide. [Projekat Ministarstva nauke Republike Srbije, br. III4128]

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.

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.

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. Since the introduction of diquat in agriculture practice in 1960's, about 40 cases of poisoning have been described in detail in medical literature. Case report. We presented two cases. A case one, a 35-year-old, previously healthy, woman ingested 14% diquat solution. The poisoning had fulminant course, consisted of severe stomachache, vomiting, cardiocirculatory shock, respiratory failure and cardiac arrest 20 hours post-ingestion. Autopsy revealed myocardial infarction, bronchopneumonia and incipient renal damage. A case two, a 64-year-old man developed severe gastroenteritis, corrosive lesions of mucosal surfaces, acute renal injury, arrhythmias, brain stem infarction and bronchopneumonia. The diagnosis of diquat poisoning was made retrospectively upon the clinical picture and identification of pesticides he had been exposed to. The patient died 18 days post-exposure. The most prominent findings on autopsy were pontine hemorrhage and infarction, bronchopneumonia, left ventricle papillary muscle infarction and renal tubular damage. Conclusion. Cardiocirculatory disturbances led to fatal complications, the heart and brain infarction. We pointed out the heart as one of the most severely affected organs in diquat poisoning.

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. Glimepiride, as an antidiabetic from the group of sulfonylurea, is administered perorally in the treatment of diabetes mellitus. The aim of this study was to compare pharmacokinetic profiles and relative bioavailabilities of the two oral formulations of glimepiride, generic and innovator tablets, after a single dose of the active drug. Methods. An oral dose of 6 mg glimepiride was given under fasting conditions to 24 healthy volunteers. A one-week washout period was applied between the two consecutive periods. The serum samples obtained before dosing, and at various time points up to 48 hours, were analyzed for glimepiride concentration using the validated highperformance liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters representing early (maximal concentration, time to reach maximal concentration) and total exposure (area under the curve from the time 0 to the infinite time) to glimepiride were obtained and further analyzed using the multifactorial analysis of variance and the non-parametric Wilcoxon signed ranks test. Comparison of the secondary kinetic variables was only descriptive. Results. The point estimates of the ratios of geometric means (test/reference) of maximal concentrations and areas under the curve were 1.046 (90% confidence interval: 0.906−1.208) and 1.022 (90% confidence interval: 0.856−1.220), respectively, while the median values of times to reach maximal concentration, at 5% level of significance, did not differ significantly. Both formulations were well tolerated. Transient mild hypoglycaemia, which had been noted in 6 participants, resolved spontaneously within 30−60 minutes. Conclusion. Since all the parametric 90% confidence intervals for the log-transformed main variables of glimepiride were within the 0.80 and 1.25 interval, accepted as the definition of bioequivalence, and the differences in times to reach maximal concentration also did not reach statistical significance, studied tablets were considered bioequivalent.

Background: Carbamazepine is one of the most commonly used antiseizure medications. Although carbamazepine pharmacokinetics in epileptic patients is well described, much less is known about these processes in the patients who experienced self-poisoning episode by this drug. Therefore, the aim of our investigation was to perform population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults., Research Design and Methods: Software program NONMEM and the ADVAN2 TRANS2 subroutine were used for establishing a population toxicokinetic model for the estimation of clearance and volume of distribution based on of the sum values of carbamazepine and carbamazepine-10,11-epoxide concentrations., Results: Our results indicated that the adult patients' ability to eliminate carbamazepine and carbamazepine-10,11-epoxide following acute carbamazepine self-poisoning was strongly associated with the high levels of CRP and ASP, as well as by the treatment with sedation., Conclusions: Our study should provide better understanding of the toxicokinetics of carbamazepine taken in overdose and better management of patient population admitted to hospital.

Background: Propranolol is a highly lipid-soluble beta-blocker. We describe a case of severe propranolol overdose, with atypical dysrhythmia--wide complex tachycardia--which was successfully treated with lipid emulsion., Case Report: A 31-year-old woman ingested approximately 3.6 g of propranolol along with ethanol. Clinical manifestations of poisoning included coma, seizures, respiratory failure, hypoglycaemia, circulatory shock, and dysrhythmias. An ECG revealed nonspecific intraventricular conduction delay, followed by wide complex supraventricular tachycardia. Toxicological analysis of blood showed ethanol 2.42 g/L and propranolol 4.21 mg/L. The patient responded poorly to conventional therapy, so intravenous lipid emulsion was used. Apart from IV dopamine, the only treatment after the onset of wide complex tachycardia was 20% Intralipid. Transient improvement was noticed after the initial dose of 500 mL; during the infusion of further Intralipid, blood pressure returned to normal and sinus rhythm was re-established., Conclusion: We believe that lipid emulsion had a beneficial effect in the treatment of propranolol toxicity.