Publications by authors named "Slavica Vucinic"

27 Publications

  • Page 1 of 1

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

BMJ Mil Health 2020 Apr 20;166(2):99-102. Epub 2020 Feb 20.

Military Medical Academy, National Poison Control Center, Belgrade, Serbia.

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.
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http://dx.doi.org/10.1136/jramc-2019-001310DOI Listing
April 2020

Carbon monoxide poisoning.

Toxicol Rep 2020 20;7:169-173. Epub 2020 Jan 20.

Department of Toxicology & Forensic Sciences, Medical School, University of Crete, Voutes Campus, Heraklion, 71003, Greece.

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.
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http://dx.doi.org/10.1016/j.toxrep.2020.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992844PMC
January 2020

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.

Toxicology 2019 03 9;415:56-69. Epub 2019 Jan 9.

OPCW Scientific Advisory Board Secretary, 2011-2016, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.tox.2019.01.004DOI Listing
March 2019

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.

Toxicology 2019 02 27;413:13-23. Epub 2018 Nov 27.

OPCW Office of Strategy and Policy, Intern Summer 2018, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.tox.2018.11.009DOI Listing
February 2019

Acute organophosphate poisoning: 17 years of experience of the National Poison Control Center in Serbia.

Toxicology 2018 11 25;409:73-79. Epub 2018 Jul 25.

Experta Consulting Belgrade, Serbia.

Based on human toxicity studies, by appropriate regulatory decisions, the number of organophosphates (OP) on Serbian market has reduced significantly over the last two decades, followed by a gradual decrease in the number of poisonings by organophoshates, treated at the National Poison Control Centre (NPCC).

Methodology: The aim of this retrospective study is to present data regarding the clinical management of poisoning with OP pesticides at the NPCC, that we collected during the 17 years period (1998-2014).

Results: In the period 1998-2014, about 17.250 patients were hospitalized at the NPCC, there were around 14.000 patients treated for poisoning by various toxic agents, and among them 410 cases (3%) due to poisoning with OP pesticides. In this period, 92% of OPI poisonings treated in the NPCC were suicidal by intention, while only 8% were due to accidental ingestion or inhalation. The most common clinical signs of poisoning in patients exposed to anticholinesterase pesticides, observed at Clinic of Toxicology of the NPCC were miosis (63.4%), bronchorrhoea (51.9%), vomiting and diarrhea (44.8%), hypotension (19.5%). Acute respiratory insufficiency was registered in 81 (19.7%) and acute cardiocirculatory failure in 16 (3.9%) patients. There were about 25% of most severely poisoned patients. Besides general supportive measures (decontamination, respiratory support), specific pharmacological treatment (atropine, oxime, diazepam) was applied. The highest total administered dose of atropine at NPCC was 6400 mg. However, the most patients received total doses of atropine up to 500 mg (32%).

Conclusion: Acute poisoning with OP pesticides is not frequent in Serbia, however, it represents important clinical feature due to severity, possible complications and their impact on duration and costs of hospitalization. Initial treatment involves prevention of further absorption and provision of supportive care, followed by administration of specific antidotes. According to its role, the National Poison Control Centre in Belgrade, in addition to treatment of acute poisonings, continuously performs toxicovigilance, i.e. the identification, investigation and evaluation of various toxic risks in the community in order to undertake adequate and timely procedures. Permanent efforts are being made in order to reduce availability and to improve control measures for pesticides marketing.
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http://dx.doi.org/10.1016/j.tox.2018.07.010DOI Listing
November 2018

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

Arh Hig Rada Toksikol 2018 Jun;69(2):178-185

National Poison Control Centre, Military Medical Academy, Medical Faculty University of Defense, Belgrade, Serbia.

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.
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http://dx.doi.org/10.2478/aiht-2018-69-3096DOI Listing
June 2018

Environmental exposure to organophosphorus nerve agents.

Environ Toxicol Pharmacol 2017 Dec 7;56:163-171. Epub 2017 Sep 7.

Faculty of Agriculture, University of Belgrade, Institute for Phytomedicine, Serbia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.etap.2017.09.004DOI Listing
December 2017

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

Toxicology 2017 Feb 12;376:120-125. Epub 2016 May 12.

University of Belgrade-Faculty of Pharmacy, Department of Toxicology "Akademik Danilo Soldatović", Vojvode Stepe 450, 11221 Belgrade, Serbia.

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.
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http://dx.doi.org/10.1016/j.tox.2016.05.011DOI Listing
February 2017

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

Neurotoxicology 2016 07 10;55:33-39. Epub 2016 May 10.

University of Belgrade, Faculty of Pharmacy, Department of Toxicology "Akademik Danilo Soldatović", Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuro.2016.05.006DOI Listing
July 2016

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

Phytother Res 2016 Jun 7;30(6):988-96. Epub 2016 Mar 7.

National Poisons Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1002/ptr.5604DOI Listing
June 2016

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

Environ Sci Pollut Res Int 2018 Mar 16;25(8):7223-7230. Epub 2015 Dec 16.

Department of Toxicology "Akademik Danilo Soldatovic", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia.

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.
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http://dx.doi.org/10.1007/s11356-015-5921-5DOI Listing
March 2018

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

Environ Toxicol Pharmacol 2014 Sep 4;38(2):663-71. Epub 2014 Aug 4.

Department of Toxicology "Akademik Danilo Soldatovic", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.etap.2014.07.021DOI Listing
September 2014

Causes of rhabdomyolysis in acute poisonings.

Vojnosanit Pregl 2013 Nov;70(11):1039-45

Clinic for Emergency and Clinical Toxicology, Military Medical Academy, Belgrade, Serbia.

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.
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http://dx.doi.org/10.2298/vsp1311039jDOI Listing
November 2013

Fresh frozen plasma as a successful antidotal supplement in acute organophosphate poisoning.

Arh Hig Rada Toksikol 2013 Jun;64(2):87-91

National Poison Control Centre, Medical Faculty, Military Medical Academy, University of Defence, Belgrade, Serbia.

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(R)), 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.
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http://dx.doi.org/10.2478/10004-1254-64-2013-2378DOI Listing
June 2013

Oxime and atropine failure to prevent intermediate syndrome development in acute organophosphate poisoning.

Vojnosanit Pregl 2013 Apr;70(4):420-3

National Poison Control Centre, Military Medical Academy, Belgrade, Serbia.

Introduction: Intermediate syndrome (IMS) was described a few decades ago, however, there is still a controversy regard ing 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) poison ing 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 ana lytical procedure (liquid chromatography-mass spectrometry). Pralidoxime methylsulphate, adiministered as a continuous in fusion 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 atro pine 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.
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http://dx.doi.org/10.2298/vsp120229037vDOI Listing
April 2013

Combined effects of cadmium and decabrominated diphenyl ether on thyroid hormones in rats.

Arh Hig Rada Toksikol 2012 Sep;63(3):255-62

Department of Toxicology Akademik Danilo Soldatović, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia.

The aim of this study was to see how a mixture of cadmium (Cd) and decabrominated diphenyl ether (BDE209) affect thyroid function, namely thyroid-stimulating hormone (TSH), thyroxin (T4), free thyroxin (FT4), triiodothyronin (T3), and free triiodothyronin (FT3) in Wistar rats (eight per group) receiving either a single substance or their combination by gavage for 28 days. Three groups were receiving Cd alone in the doses of 2.5 mg kg-1, 7.5 mg kg-1, or 15 mg kg-1 b. w. a day, three groups were receiving BDE209 in the doses of 1000 mg kg-1, 2000 mg kg-1, or 4000 mg kg-1 b. w. a day, while nine groups were receiving different mixtures of Cd and BDE209 in these doses (3x3 design). The results have indicated that the Cd+BDE209 mixtures more potently disrupt thyroid hormone homeostasis than would be expected from these chemicals alone.
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http://dx.doi.org/10.2478/10004-1254-63-2012-2179DOI Listing
September 2012

Toxicokinetics and correlation of carbamazepine salivary and serum concentrations in acute poisonings.

Vojnosanit Pregl 2012 May;69(5):389-93

National Poison Control Centre, Military Medical Academy, Belgrade, Serbia.

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 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.
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May 2012

[Determination of morphine, codeine and 6-monoacetylmorphine in saliva of substance-abuse patients using HPLC/MS methods].

Vojnosanit Pregl 2012 Feb;69(2):141-6

Agencija za hemikalije Republike Srbije, Beograd, Srbija.

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 microm, ODS2, 4.6 x 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.
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http://dx.doi.org/10.2298/vsp1202141mDOI Listing
February 2012

[Antidotal effect of combinations obidoxime/HI-6 and memantine in mice poisoned with soman, dichlorvos or heptenophos].

Vojnosanit Pregl 2011 Dec;68(12):1033-40

Univerzitet u Beogradu, Farmaceutski fakultet, Katedra za toksikologiju, "Akademik Danilo Soldatovid", Beograd, Srbija.

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 gmoL/kg in soman poisoning) and obidoxime (16.80 vs 2.75 micromoL/kg in dichlorvos poisoning; 21.56 vs 6.63 micromoL/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.
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http://dx.doi.org/10.2298/vsp1112033aDOI Listing
December 2011

[Simultaneous determination of amoxicillin and clavulanic acid in the human plasma by high performance liquid chromatography-mass spectrometry (UPLC/MS)].

Vojnosanit Pregl 2010 Nov;67(11):887-92

Vojnomedicinska akademija, Centar za kontrolu trovanja, Beograd, Srbija.

Background/aim: Quantitative analysis of amoxicillin and clavulanic acid in biological matrices requires sensitive and specific methods which allow determination of therapeutic concentration in 1 g/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 microg/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 microg/mL), and recoveries for clavulanic acid were 99.89% to 100.1% (for concentrations of 1, 2 and 5 microg/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.
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http://dx.doi.org/10.2298/vsp1011887cDOI Listing
November 2010

[Rapid simultaneous determination of organophosphorus pesticides in human serum and urine by liquid chromatography-mass spectrometry].

Vojnosanit Pregl 2010 Sep;67(9):717-22

Vojnomedicinska akademija, Centar za kontrolu trovanja, Beograd, Srbija.

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 positive 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 > or = 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.
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http://dx.doi.org/10.2298/vsp1009717zDOI Listing
September 2010

[Acute glyphosate-surfactant poisoning with neurological sequels and fatal outcome].

Vojnosanit Pregl 2009 Sep;66(9):758-62

Vojnomedicinska akademija, Centar za kontrolu trovanja, Beograd, Srbija.

Introduction: Clinical picture of severe glyphosate-surfactant 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 glyphosate-surfactant 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.
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http://dx.doi.org/10.2298/vsp0909758pDOI Listing
September 2009

[Pharmacodynamic and pharmacokinetic effects of flumazenil and theophylline application in rats acutely intoxicated by diazepam].

Vojnosanit Pregl 2009 Feb;66(2):141-8

Vojnomedicinska akademija, Centar za kontrolu trovanja, Beograd, Srbija.

Background/aim: The majority of symptoms and signs of acute diazepam poisoning are the consequence of its sedative effect on the CNS affecting selectively poli-synaptic 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 (LKB-Farad, 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 diazepam-induced 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.
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http://dx.doi.org/10.2298/vsp0902141sDOI Listing
February 2009

The physicochemical characterization and in vitro/in vivo evaluation of natural surfactants-based emulsions as vehicles for diclofenac diethylamine.

Drug Dev Ind Pharm 2007 Mar;33(3):221-34

Pharma product doo, Bul.vojvode Misića, Belgrade, Serbia.

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.
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http://dx.doi.org/10.1080/03639040601150179DOI Listing
March 2007

A randomized, open-label pharmacokinetic comparison of two oral formulations of fluconazole 150 mg in healthy adult volunteers.

Clin Ther 2005 Oct;27(10):1588-95

Institute of Toxicology and Pharmacology National Poison Control Centre, Belgrade, Serbia Montenegro.

Background: Because of its systemic action, fluconazole is prescribed for a variety of fungal infections. However, therapeutic failure might result when a patient is switched between an innovator drug and a nonbioequivalent generic formulation. Pharmacokinetic (PK) studies investigating the bioequivalence of generic and innovator drugs can minimize such risks.

Objective: The aim of this study was to compare the PK profiles and relative bioavailabilities of 2 oral formulations of fluconazole: Diflucan (reference; Pfizer Corporation Austria GmbH, Wien, Austria) and Funzol (test; Bosnalijek d.d., Pharmaceutical and Chemical Industry, Sarajevo, Bosnia and Herzegovina), both prepared as capsules containing 150 mg of active drug.

Methods: A single oral dose of fluconazole was given under fasting conditions to healthy, white volunteers aged 18 to 55 years in this open-label, randomized, crossover study. A 3-week washout period was applied between each of the 2 doses. Serum samples were obtained before dosing and at various time points after dosing up to 144 hours and were analyzed for fluconazole concentration using a high-performance liquid chromatography-UV method. PK parameters representing the extent (AUC(0-infinity)) and rate (CmaX and T(max)) of absorption of fluconazole were obtained. An analysis of variance, a power analysis, 90% CI, and two 1-sided tests were used for statistical analysis of relative differences between the 2 drugs. Bioequivalence was concluded if the 90% CIs for the geometric mean ratios of AUC(0-infinity) and C(max) were between 0.80 and 1.25. A study investigator monitored the volunteers for adverse effects at 5 defined time points during the clinical part of the investigation.

Results: Thirteen men and 11 women (mean age, 33.3 years; mean weight, 73.6 kg) completed the study. The respective point estimates of the ratios of geometric means of log-transformed C(max) and AUC0(0-infinity) of fluconazole (test vs reference) were 0.985 and 1.047, with 90% CIs of 0.894 to 1.085 and 0.927 to 1.182, respectively. Differences in T(max) also did not reach statistical significance. No adverse effects were reported by the subjects or revealed by clinical or laboratory tests.

Conclusions: The study failed to demonstrate any statistically significant differences in C(max) and AUCO(0-infinity) values between the test and reference formulations of oral fluconazole 150 mg in this small, select population of healthy volunteers. On that basis, and according to both the rate and extent of absorption, the test and reference formulations were considered bioequivalent.
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http://dx.doi.org/10.1016/j.clinthera.2005.10.016DOI Listing
October 2005

[Risk factors for the development of pneumonia in acute psychotropic drugs poisoning].

Authors:
Slavica Vucinić

Vojnosanit Pregl 2005 Oct;62(10):715-23

Vojnomedicinska akademija, Klinika za toksikologiju i farmakologiju, Beograd, Srbija i Crna Gora.

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.
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http://dx.doi.org/10.2298/vsp0510715vDOI Listing
October 2005

[Acute poisoning with cardiovascular agents].

Vojnosanit Pregl 2003 Nov-Dec;60(6):691-6

Vojnomedicinska akademija, Centar za kontrolu trovanja, Klinika za toksikologiju i klinicku farmakologiju, Beograd.

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 occurred secondary to cardiotoxicity. Symptomatic and supportive measures were performed most frequently, while specific agents, glucagon, calcium salts, and others, were used less often.
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http://dx.doi.org/10.2298/vsp0306691vDOI Listing
February 2004