Carbapenems as Antidotes for the Management of Acute Valproic Acid Poisoning.

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.

Viper envenomation in Central and Southeastern Europe: a multicentre study.

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.

Rise of Pregabalin Poisoning and Abuse Cases in Serbia: A Ten-Year Retrospective Study.

Purpose: 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.

New insight into the perplexing toxic features of PCBs: A study of nephrotoxicity in an animal model.

The present study investigated the effects of PCBs on the rat kidneys with attention given to the determination critical effect dose (CED) using the Benchmark dose (BMD) approach. Male albino Wistar rats (7 animals per group) were given by oral gavage Aroclor 1254 dissolved in corn oil at doses of 0.0, 0.5, 1, 2, 4, 8, or 16 mg/kg b.w./day for 28 days. The PCB nephrotoxicity was manifested by a dose-dependent changes in serum urea levels. The study has also revealed PCB-induced oxidative stress induction in kidneys. The observed nephrotoxic effects can be partly explained by oxidative damage of lipids and proteins in the kidneys due to observed reduced CuZnSOD activity and disturbances in antioxidant protection. Аll the renal oxidative stress parameters showed dependence on PCB oral doses as well as internal, measure kidney PCB levels. Calculated BMDL values were lower than estimated no observed adverse effect levels (NOAEL) based on the study, suggesting the importance of BMD approach use in future risk assessment.

Acute organophosphate and carbamate pesticide poisonings - a five-year survey from the National Poison Control Center Of Serbia.

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.

Olanzapine poisoning in patients treated at the National Poison Control Centre in Belgrade, Serbia in 2017 and 2018: a brief review of serum concentrations and clinical symptoms.

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.

Advice on assistance and protection provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 3. On medical care and treatment of injuries from sulfur mustard.

Blister agents damage the skin, eyes, mucous membranes and subcutaneous tissues. Other toxic effects may occur after absorption. The response of the Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) to a request from the OPCW Director-General in 2013 on the status of medical countermeasures and treatments to blister agents is updated through the incorporation of the latest information. The physical and toxicological properties of sulfur mustard and clinical effects and treatments are summarised. The information should assist medics and emergency responders who may be unfamiliar with the toxidrome of sulfur mustard and its treatment.

Early diagnosis of nerve agent exposure with a mobile test kit and implications for medical countermeasures: a trigger to react.

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.

Carbon monoxide poisoning.

Carbon monoxide (CO) is the leading cause of poisoning deaths in many countries, including Japan. Annually, CO poisoning claims about 2000-5000 lives in Japan, which is over half of the total number of poisoning deaths. This paper discusses the physicochemical properties of CO and the toxicological evaluation of CO poisoning.

Advice on assistance and protection provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 1. On medical care and treatment of injuries from nerve agents.

The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice on assistance and protection in relation to the Chemical Weapons Convention. In this, the first of several papers describing the SAB's work on this topic, we describe advice given in response to questions from the OPCW Director-General in 2013 and 2014 on the status of available medical countermeasures and treatments to organophosphorus nerve agents. This paper provides the evidence base for this advice which recommended to the OPCW pretreatments, emergency care, and long-term treatments that were available at the time of the request for this class of chemical warfare agent (CWA). It includes a bibliography of over 140 scientific references, which can be used as a platform for watching future medical countermeasure developments. The information provided in this paper should serve as a valuable reference for medical professionals and emergency responders who may have no knowledge of the symptoms and treatment options of exposure to nerve agents.

Advice on assistance and protection from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 2. On preventing and treating health effects from acute, prolonged, and repeated nerve agent exposure, and the identification of medical countermeasures able to reduce or eliminate the longer term health effects of nerve agents.

The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice in relation to the Chemical Weapons Convention on assistance and protection. We present the SAB's response to a request from the OPCW Director-General in 2014 for information on the best practices for preventing and treating the health effects from acute, prolonged, and repeated organophosphorus nerve agent (NA) exposure. The report summarises pre- and post-exposure treatments, and developments in decontaminants and adsorbing materials, that at the time of the advice, were available for NAs. The updated information provided could assist medics and emergency responders unfamiliar with treatment and decontamination options related to exposure to NAs. The SAB recommended that developments in research on medical countermeasures and decontaminants for NAs should be monitored by the OPCW, and used in assistance and protection training courses and workshops organised through its capacity building programmes.

Clinical and analytical experience of the National Poison Control Centre with synthetic cannabinoids.

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.

Advice from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons on riot control agents in connection to the Chemical Weapons Convention.

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.

Oxidative stress and renal toxicity after subacute exposure to decabrominated diphenyl ether in Wistar rats.

Fully brominated diphenyl ether (BDE-209) is a flame retardant widely used in plastics and textiles. Because of its high persistence, humans are exposed to it continuously, mainly via dust ingestion. We investigated effects of BDE-209 on renal function and oxidative stress development in the kidney after subacute exposure in rats. Five groups of animals were given by oral gavage 31.25-500 mg BDE-209/kg b.w./day for 28 days, and relative kidney weight, serum urea and creatinine, and oxidative stress parameters in the kidney were determined. Benchmark-dose approach was used for dose response modeling. Serum creatinine was increased, while results obtained for serum urea were inconclusive. Relative kidney weight was not affected by BDE-209. Kidney reduced glutathione was elevated, while superoxide dismutase activity was not changed after BDE-209 treatment. Also, levels of thiobarbituric acid reactive substances (TBARS) were increased and total -SH groups were decreased, which indicated oxidative imbalance. The critical effect dose (CED)/CEDL ratios for the effects on TBARS and total -SH groups indicated estimated CEDs for these markers can be used in risk assessment of BDE-209. Our study results have shown that a relatively low dose of BDE-209 affects kidney function and that oxidative stress is one of the mechanisms of its nephrotoxicity.

Environmental exposure to organophosphorus nerve agents.

Exposure to organophosphorus nerve agents, the most deadly chemical warfare agents, is possible in a variety of situations, such as destruction of chemical warfare agents, terrorist attacks, armed conflicts or accidents in research laboratories and storage facilities. Hundreds of thousands of tons of chemical munitions were disposed of at the sea in the post World War II period, with European, Russian, Japanese and US coasts being the most affected. Sulfur mustard, Lewisite and nerve agents appear to be the most frequently chemical warfare agents disposed of at the sea. Addressing the overall environmental risk, it has been one of the priorities of the world community since that time. Aside from confirming exposure to nerve agents in the alleged use for forensic purposes, the detection and identification of biological markers of exposure are also needed for the diagnosis and treatment of poisoning, in addition to occupational health monitoring for specific profiles of workers. When estimating detrimental effects of acute or potential chronic sub-lethal doses of organophosphorus nerve agents, released accidentally or intentionally into the environment, it is necessary to understand the wide spectra of physical, chemical and toxicological properties of these agents, and predict their ultimate fate in environmental systems.

Interactions between cadmium and decabrominated diphenyl ether on blood cells count in rats-Multiple factorial regression analysis.

The objective of this study was to assess toxicity of Cd and BDE-209 mixture on haematological parameters in subacutely exposed rats and to determine the presence and type of interactions between these two chemicals using multiple factorial regression analysis. Furthermore, for the assessment of interaction type, an isobologram based methodology was applied and compared with multiple factorial regression analysis. Chemicals were given by oral gavage to the male Wistar rats weighing 200-240g for 28days. Animals were divided in 16 groups (8/group): control vehiculum group, three groups of rats were treated with 2.5, 7.5 or 15mg Cd/kg/day. These doses were chosen on the bases of literature data and reflect relatively high Cd environmental exposure, three groups of rats were treated with 1000, 2000 or 4000mg BDE-209/kg/bw/day, doses proved to induce toxic effects in rats. Furthermore, nine groups of animals were treated with different mixtures of Cd and BDE-209 containing doses of Cd and BDE-209 stated above. Blood samples were taken at the end of experiment and red blood cells, white blood cells and platelets counts were determined. For interaction assessment multiple factorial regression analysis and fitted isobologram approach were used. In this study, we focused on multiple factorial regression analysis as a method for interaction assessment. We also investigated the interactions between Cd and BDE-209 by the derived model for the description of the obtained fitted isobologram curves. Current study indicated that co-exposure to Cd and BDE-209 can result in significant decrease in RBC count, increase in WBC count and decrease in PLT count, when compared with controls. Multiple factorial regression analysis used for the assessment of interactions type between Cd and BDE-209 indicated synergism for the effect on RBC count and no interactions i.e. additivity for the effects on WBC and PLT counts. On the other hand, isobologram based approach showed slight antagonism for the effects on RBC and WBC while no interactions were proved for the joint effect on PLT count. These results confirm that the assessment of interactions between chemicals in the mixture greatly depends on the concept or method used for this evaluation.

Therapeutic and reactivating efficacy of oximes K027 and K203 against a direct acetylcholinesterase inhibitor.

As oxime-based structures are the only causal antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE), the majority of studies on these have been directed towards their synthesis and testing. In this study, experimental bispyridinium oximes K027 and K203, which have shown promising results in the last decade of research, were examined in vivo for their therapeutic and reactivating ability in acute poisoning by the direct AChE-inhibitor dichlorvos (DDVP), used as a dimethyl OP structural model. Additionally, the efficacy of oximes K027 and K203 was compared with the efficacy of four oximes (pralidoxime, trimedoxime, obidoxime and HI-6), already used in efficacy experiments and human medicine. To evaluate therapeutic efficacy, groups of Wistar rats were treated with equitoxic doses of oximes (5% LD50, i.m.) and/or atropine (10mg/kg, i.m.) immediately after s.c. DDVP challenge (4-6 doses). Using the same antidotal protocol, AChE activity was measured in erythrocytes, diaphragm and brain 60min after s.c. DDVP exposure (75% LD50). The oxime K027 was the most efficacious in reducing the DDVP induced lethal effect in rats, while the oxime K203 was more efficacious than trimedoxime, pralidoxime and HI-6. Significant reactivation of DDVP inhibited AChE was achieved only with oxime K027 or its combination with atropine in erythocytes and the diaphragm. Moreover, the acute i.m. toxicity of oxime K027 in rats was lower than all other tested oximes. The results of this study support previous studies considering the oxime K027 as a promising experimental oxime structure for further testing against structurally-different OP compounds.

Adverse Effects of Plant Food Supplements and Plants Consumed as Food: Results from the Poisons Centres-Based PlantLIBRA Study.

Plant food supplements (PFS) are products of increasing popularity and wide-spread distribution. Nevertheless, information about their risks is limited. To fill this gap, a poisons centres-based study was performed as part of the EU project PlantLIBRA. Multicentre retrospective review of data from selected European and Brazilian poisons centres, involving human cases of adverse effects due to plants consumed as food or as ingredients of food supplements recorded between 2006 and 2010. Ten poisons centres provided a total of 75 cases. In 57 cases (76%) a PFS was involved; in 18 (24%) a plant was ingested as food. The 10 most frequently reported plants were Valeriana officinalis, Camellia sinensis, Paullinia cupana, Melissa officinalis, Passiflora incarnata, Mentha piperita, Glycyrrhiza glabra, Ilex paraguariensis, Panax ginseng, and Citrus aurantium. The most frequently observed clinical effects were neurotoxicity and gastro-intestinal symptoms. Most cases showed a benign clinical course; however, five cases were severe. PFS-related adverse effects seem to be relatively infrequent issues for poisons centres. Most cases showed mild symptoms. Nevertheless, the occurrence of some severe adverse effects and the increasing popularity of PFS require continuous active surveillance, and further research is warranted. Copyright © 2016 John Wiley & Sons, Ltd.

Cadmium and decabrominated diphenyl ether mixture: In vitro evaluation of cytotoxic, prooxidative and genotoxic effects.

In order to look into the combined effects of Cd and BDE-209 in vitro, this study was aimed at examining cytotoxic and genotoxic effects using the human colon carcinoma cell line (SW 480) as a biological test system as well as to determine if ROS production was one of the possible mechanisms of their mixture action. This cell line was chosen since ingestion of contaminated food/water represents an important route of exposure to both Cd and BDE-209, which is why intestinal cells are a common target for the contaminants present in food and water. Cells were treated with single Cd in concentrations of 2.5, 7.5 or 15µg Cd/mL (corresponding to 22, 67 or 134µM), single BDE-209 in concentrations of 2.5, 5 or 10µg BDE209/mL (corresponding to 2.5, 5 or 10µM), and their mixtures (design 3×3). Mixture of Cd and BDE-209 has shown clear potential to reduce the viability of SW 480 cells, as evidenced by cytotoxicity associated with ROS generation. Factorial regression models used to identify type of interaction revealed synergism related to mixture citotoxicity and additive interaction for the effect on ROS production. The results from this introductory study could contribute to the issue of possible adverse effects associated with co-exposure and body burden with two persistent environmental pollutants, Cd and BDE-209.