Experienced researcher in the scientific area of Pharmacology, Toxicology and Clinical Pharmacology. Research interests include toxicology of cholinesterase inhibitors and cardiovascular pharmacology.
Organophosphorus compounds induce irreversible inhibition of acetylcholinesterase, which then pro... more Organophosphorus compounds induce irreversible inhibition of acetylcholinesterase, which then produces clinically manifested muscarinic, nicotinic and central effects. The aim of the study was to analyse the clinical signs of acute paraoxon poisoning in rats and to determine the relationship between the intensity of signs of poisoning and the dose of paraoxon and/or the outcome of poisoning in rats. Animals were treated with either saline or atropine (10 mg/kg intramuscularly). The median subcutaneous lethal dose (LD50) of paraoxon was 0.33 mg/kg and protective ratio of atropine was 2.73. The presence and intensity of signs of poisoning in rats (dyspnoea, lacrimation, exophthalmos, fasciculations, tremor, ataxia, seizures, piloerection, stereotypic movements) were observed and recorded for 4 h after the injection of paraoxon. Intensity of these toxic phenomena was evaluated as: 0 – absent, 1 – mild/moderate, 2 – severe. Fasciculations, seizures and tremor were more intense at higher...
Introduction: Oganophosphorus compounds (OP) bind to acetylcholinesterase (AChE) and inactivate i... more Introduction: Oganophosphorus compounds (OP) bind to acetylcholinesterase (AChE) and inactivate it. In the synaptic cleft, undestroyed and accumulated acetylcholine produce the acute cholinergic effects. The aim of this study was to determine the frequency, speed of onset and intensity of certain signs of paraoxon poisoning depending on dose and outcome of poisoning. Methods: The study was conducted in adult Wistar rats. The median lethal dose (LD50) of paraoxon as well as protective ratio (PR) of atropine (10 mg/kg intramuscularly) was determined. Clinical signs of poisoning were observed: fasciculations, tremor, seizures, ataxia, piloerection, lacrimation, exophthalmos, bizzare/stereotypic behaviour and dyspnoea. The time from paraoxon injection to the first appearance of the sign of poisoning was recorded as well as the intensity of poisoning with evaluation at 10 time intervals throughout the 4 h observational period. Results: The LD50 of paraoxon was 0.33 mg/kg (subcutaneously)...
ABSTRACT Background: The ASPOC Project (ASPPOC, Antibiotic Surveillance Project on Perioperative ... more ABSTRACT Background: The ASPOC Project (ASPPOC, Antibiotic Surveillance Project on Perioperative Chemoprophylaxis) is a multicentric study carried out in European countries, aiming at establishing an evidence-based perioperative chemoprophylaxis. Objectives: The aim of this study, which is part of ASPPOC, was to check conformance to the guidelines for perioperative chemoprophylaxis in Neurosurgery, and to trace out changes that must be made in European countries to improve its quality. Methods: 6 European countries participated in the study: Greece, Italy, Denmark, Serbia, Croatia and Montenegro. The conformance to the recommended guidelines and the quality of perioperative prophylaxis were checked by use of the same questionnaire in each country. The following criteria of quality were checked: application of perioperative prophylaxis, duration and time of initiation of prophylaxis, and the kind of antibiotics used. Results: A different practice on the quality of perioperative prophylaxis was observed in each country. The duration of prophylaxis exceeded the maximum recommended time of 24 hours in many cases in all countries except Denmark and Italy. The quality of prophylaxis was generally good in Denmark. In Serbia, Croatia, Montenegro, Greece and Italy discrepancies in the duration of prophylaxis and the kind of antibiotics were observed, with use of 3rd generation cephalosporins — and even 4th generation cephalosporins in Croatia. Aminoglycosides were used in Denmark, Italy, Serbia and Montenegro. Conclusions: The conformance to the guidelines and the quality of perioperative prophylaxis were not satisfactory. Dynamic changes are required to improve the quality and establish an evidence-based perioperative prophylaxis in Neurosurgery.
Tiazofurin and 8-Cl-cAMP are novel antineoplastic agents that have been shown to be effective aga... more Tiazofurin and 8-Cl-cAMP are novel antineoplastic agents that have been shown to be effective against various cancer cells in vitro and in vivo. Through specific mechanisms of action they modulate the cellular signal transduction pathway, thereby causing growth inhibition, cell differentiation, apoptosis and downregulation of c-ras and c-myc gene expression. We examined the effects of 8-Cl-cAMP and tiazofurin, either separately or together, on apoptosis induction and c-fos and c-myc expression in melanoma cells. 8-Cl-cAMP and tiazofurin inhibited the growth of melanoma cells in a dose-responsive manner. Whether used separately or together, each agent induced apoptotic cell death. Apoptosis was accompanied by a marked inhibition of c-fos and c-mye gene expression. RT-PCR analysis showed that 8-Cl-cAMP, together with tiazofurin, promoted 61% and 75% decreases of c-myc and c-fos expression in melanoma cells respectively. These results clearly indicate that the combination of 8-Cl-cAMP and tiazofurin could provide a promising therapeutic approach for melanoma treatment
Background: It is well established that thrombolytic therapy improves the functional recovery by ... more Background: It is well established that thrombolytic therapy improves the functional recovery by reducing disability measured as National Institutes of Health Stroke Scale (NIHSS) and Rankin score in patients with ischemic stroke. However, the role of alteplase treatment on anxiety and depression in those patients is less clear. Therefore, the aim of this study was to determine whether patients treated with thrombolytic therapy had a better quality of life, less anxiety and depression compared to patients who were not treated with thrombolysis. Subjects and methods: In this "single canter study" 60 patients with acute ischemic stroke were divided into two groups: alteplase treated (AT) group, and not treated (NT) group. The sociodemographic data including gender, age, marital status, education, employment, financial status, place of residence, refugee status were collected at the beginning of study. The NIHSS score and modified Rankin score (mRS) were performed on admission and at discharge from hospital. Six months following discard from hospital the Beck's Anxiety Inventory (BAI), Beck's Depression Inventory (BDI) and the Short Form 36 quality of life (SF-36 QoL) were performed. Results: There were no differences in mean NIHSS and mRS at admission to hospital between the groups. At discharge from hospital patients in AT group had significantly lower NIHSS and mRS than patients in NT group. In post-stroke period the patients from AT group had significantly less anxiety and depression than patients from NT group (BAI in AT 6.4+4.17 vs BAI in NT 14.27+7.01 and BDI in AT 9.20+6.61 vs BDI in NT 18.0+7.49). Patients in AT group had significantly better SF-36 QoL score in all components than NT group. Conclusion: The results of this study showed that thrombolytic therapy reduced the intensity of anxiety and depression and improves the quality of life of patients six months after ischemic stroke.
Abstract Carboxylesterases (CarbE) represent an important factor in studying the new antidotes ag... more Abstract Carboxylesterases (CarbE) represent an important factor in studying the new antidotes against G-agents, tabun, sarin, and especially soman. Its isoenzymes exist in many mammalian tissues, but the most important is blood, as it is a medium for transportation of nerve agents to the target organs, such as the central nervous system and respiratory muscles. Rodent species used extensively in such research contain high plasma CarbE activity (mice, rats) or medium level (guinea pigs). At the same time, a low level of plasma CarbE activity was found in marmosets and there was practically no such activity in the plasma of rhesus monkeys and humans. In order to obtain results that would be easily extrapolated to humans, either nonhuman primates with naturally minimal plasma CarbE activity or rodents pretreated with CarbE inhibitors (TOCP, CBDP) should be utilized. In such animals, the LD50 of nerve agents is very similar, as is the efficacy of the prophylactic/postexposure antidotes. CarbEs are also potential stoichiometric scavengers of nerve agents and can be used intravenously to bind organophosphorus compound molecules.
Memantine is the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, used in the tre... more Memantine is the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, used in the treatment of Alzheimer's disease. It also known that memantine pretreatment assured protection of skeletal muscles from poisoning with nerve agents and an interaction between memantine and AChE was proposed. In the study presented we examined interactions of memantine and its main metabolite (1-amino-3-hydroxymethyl-5-methyl adamantine, Mrz 2/373) with AChE in vitro as well as their effect on kinetics of the soman-induced AChE inhibition and aging. The results have shown that memantine and Mrz 2/373 exerted concentration-dependent inhibition of AChE, with Mrz 2/373 being a more potent inhibitor than the parent compound. Addition of soman 7.5 nmol/l induced gradual AChE inhibition that became almost complete after 20 min. Memantine (0.1, 0.5 and 1 mmol/l) and Mrz 2/373 (0.1, 0.5 and 1 mmol/l) concentration-dependently slowed down the AChE inhibition. After 30 min of incubation of AChE with soman, 5 min of aging and 20 min of reactivation by asoxime (HI-6 dichloride), AChE activity was 8.1% in control medium, 30.7% and 41.9% after addition of 1 and 10 mmol/l memantine, and 16.1% after addition of 1 mmol/l Mrz 2/373. It was concluded that it is possible that memantine and Mrz 2/373 can prevent AChE from inhibition by soman, which could, along with known memantine's neuroprotective activity, explain its potent antidotal effect in soman poisoning. The potential effect on aging of the soman-AChE complex warrants further studies.
Organophosphorus compounds induce irreversible inhibition of acetylcholinesterase, which then pro... more Organophosphorus compounds induce irreversible inhibition of acetylcholinesterase, which then produces clinically manifested muscarinic, nicotinic and central effects. The aim of the study was to analyse the clinical signs of acute paraoxon poisoning in rats and to determine the relationship between the intensity of signs of poisoning and the dose of paraoxon and/or the outcome of poisoning in rats. Animals were treated with either saline or atropine (10 mg/kg intramuscularly). The median subcutaneous lethal dose (LD50) of paraoxon was 0.33 mg/kg and protective ratio of atropine was 2.73. The presence and intensity of signs of poisoning in rats (dyspnoea, lacrimation, exophthalmos, fasciculations, tremor, ataxia, seizures, piloerection, stereotypic movements) were observed and recorded for 4 h after the injection of paraoxon. Intensity of these toxic phenomena was evaluated as: 0 – absent, 1 – mild/moderate, 2 – severe. Fasciculations, seizures and tremor were more intense at higher...
Introduction: Oganophosphorus compounds (OP) bind to acetylcholinesterase (AChE) and inactivate i... more Introduction: Oganophosphorus compounds (OP) bind to acetylcholinesterase (AChE) and inactivate it. In the synaptic cleft, undestroyed and accumulated acetylcholine produce the acute cholinergic effects. The aim of this study was to determine the frequency, speed of onset and intensity of certain signs of paraoxon poisoning depending on dose and outcome of poisoning. Methods: The study was conducted in adult Wistar rats. The median lethal dose (LD50) of paraoxon as well as protective ratio (PR) of atropine (10 mg/kg intramuscularly) was determined. Clinical signs of poisoning were observed: fasciculations, tremor, seizures, ataxia, piloerection, lacrimation, exophthalmos, bizzare/stereotypic behaviour and dyspnoea. The time from paraoxon injection to the first appearance of the sign of poisoning was recorded as well as the intensity of poisoning with evaluation at 10 time intervals throughout the 4 h observational period. Results: The LD50 of paraoxon was 0.33 mg/kg (subcutaneously)...
ABSTRACT Background: The ASPOC Project (ASPPOC, Antibiotic Surveillance Project on Perioperative ... more ABSTRACT Background: The ASPOC Project (ASPPOC, Antibiotic Surveillance Project on Perioperative Chemoprophylaxis) is a multicentric study carried out in European countries, aiming at establishing an evidence-based perioperative chemoprophylaxis. Objectives: The aim of this study, which is part of ASPPOC, was to check conformance to the guidelines for perioperative chemoprophylaxis in Neurosurgery, and to trace out changes that must be made in European countries to improve its quality. Methods: 6 European countries participated in the study: Greece, Italy, Denmark, Serbia, Croatia and Montenegro. The conformance to the recommended guidelines and the quality of perioperative prophylaxis were checked by use of the same questionnaire in each country. The following criteria of quality were checked: application of perioperative prophylaxis, duration and time of initiation of prophylaxis, and the kind of antibiotics used. Results: A different practice on the quality of perioperative prophylaxis was observed in each country. The duration of prophylaxis exceeded the maximum recommended time of 24 hours in many cases in all countries except Denmark and Italy. The quality of prophylaxis was generally good in Denmark. In Serbia, Croatia, Montenegro, Greece and Italy discrepancies in the duration of prophylaxis and the kind of antibiotics were observed, with use of 3rd generation cephalosporins — and even 4th generation cephalosporins in Croatia. Aminoglycosides were used in Denmark, Italy, Serbia and Montenegro. Conclusions: The conformance to the guidelines and the quality of perioperative prophylaxis were not satisfactory. Dynamic changes are required to improve the quality and establish an evidence-based perioperative prophylaxis in Neurosurgery.
Tiazofurin and 8-Cl-cAMP are novel antineoplastic agents that have been shown to be effective aga... more Tiazofurin and 8-Cl-cAMP are novel antineoplastic agents that have been shown to be effective against various cancer cells in vitro and in vivo. Through specific mechanisms of action they modulate the cellular signal transduction pathway, thereby causing growth inhibition, cell differentiation, apoptosis and downregulation of c-ras and c-myc gene expression. We examined the effects of 8-Cl-cAMP and tiazofurin, either separately or together, on apoptosis induction and c-fos and c-myc expression in melanoma cells. 8-Cl-cAMP and tiazofurin inhibited the growth of melanoma cells in a dose-responsive manner. Whether used separately or together, each agent induced apoptotic cell death. Apoptosis was accompanied by a marked inhibition of c-fos and c-mye gene expression. RT-PCR analysis showed that 8-Cl-cAMP, together with tiazofurin, promoted 61% and 75% decreases of c-myc and c-fos expression in melanoma cells respectively. These results clearly indicate that the combination of 8-Cl-cAMP and tiazofurin could provide a promising therapeutic approach for melanoma treatment
Background: It is well established that thrombolytic therapy improves the functional recovery by ... more Background: It is well established that thrombolytic therapy improves the functional recovery by reducing disability measured as National Institutes of Health Stroke Scale (NIHSS) and Rankin score in patients with ischemic stroke. However, the role of alteplase treatment on anxiety and depression in those patients is less clear. Therefore, the aim of this study was to determine whether patients treated with thrombolytic therapy had a better quality of life, less anxiety and depression compared to patients who were not treated with thrombolysis. Subjects and methods: In this "single canter study" 60 patients with acute ischemic stroke were divided into two groups: alteplase treated (AT) group, and not treated (NT) group. The sociodemographic data including gender, age, marital status, education, employment, financial status, place of residence, refugee status were collected at the beginning of study. The NIHSS score and modified Rankin score (mRS) were performed on admission and at discharge from hospital. Six months following discard from hospital the Beck's Anxiety Inventory (BAI), Beck's Depression Inventory (BDI) and the Short Form 36 quality of life (SF-36 QoL) were performed. Results: There were no differences in mean NIHSS and mRS at admission to hospital between the groups. At discharge from hospital patients in AT group had significantly lower NIHSS and mRS than patients in NT group. In post-stroke period the patients from AT group had significantly less anxiety and depression than patients from NT group (BAI in AT 6.4+4.17 vs BAI in NT 14.27+7.01 and BDI in AT 9.20+6.61 vs BDI in NT 18.0+7.49). Patients in AT group had significantly better SF-36 QoL score in all components than NT group. Conclusion: The results of this study showed that thrombolytic therapy reduced the intensity of anxiety and depression and improves the quality of life of patients six months after ischemic stroke.
Abstract Carboxylesterases (CarbE) represent an important factor in studying the new antidotes ag... more Abstract Carboxylesterases (CarbE) represent an important factor in studying the new antidotes against G-agents, tabun, sarin, and especially soman. Its isoenzymes exist in many mammalian tissues, but the most important is blood, as it is a medium for transportation of nerve agents to the target organs, such as the central nervous system and respiratory muscles. Rodent species used extensively in such research contain high plasma CarbE activity (mice, rats) or medium level (guinea pigs). At the same time, a low level of plasma CarbE activity was found in marmosets and there was practically no such activity in the plasma of rhesus monkeys and humans. In order to obtain results that would be easily extrapolated to humans, either nonhuman primates with naturally minimal plasma CarbE activity or rodents pretreated with CarbE inhibitors (TOCP, CBDP) should be utilized. In such animals, the LD50 of nerve agents is very similar, as is the efficacy of the prophylactic/postexposure antidotes. CarbEs are also potential stoichiometric scavengers of nerve agents and can be used intravenously to bind organophosphorus compound molecules.
Memantine is the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, used in the tre... more Memantine is the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, used in the treatment of Alzheimer's disease. It also known that memantine pretreatment assured protection of skeletal muscles from poisoning with nerve agents and an interaction between memantine and AChE was proposed. In the study presented we examined interactions of memantine and its main metabolite (1-amino-3-hydroxymethyl-5-methyl adamantine, Mrz 2/373) with AChE in vitro as well as their effect on kinetics of the soman-induced AChE inhibition and aging. The results have shown that memantine and Mrz 2/373 exerted concentration-dependent inhibition of AChE, with Mrz 2/373 being a more potent inhibitor than the parent compound. Addition of soman 7.5 nmol/l induced gradual AChE inhibition that became almost complete after 20 min. Memantine (0.1, 0.5 and 1 mmol/l) and Mrz 2/373 (0.1, 0.5 and 1 mmol/l) concentration-dependently slowed down the AChE inhibition. After 30 min of incubation of AChE with soman, 5 min of aging and 20 min of reactivation by asoxime (HI-6 dichloride), AChE activity was 8.1% in control medium, 30.7% and 41.9% after addition of 1 and 10 mmol/l memantine, and 16.1% after addition of 1 mmol/l Mrz 2/373. It was concluded that it is possible that memantine and Mrz 2/373 can prevent AChE from inhibition by soman, which could, along with known memantine's neuroprotective activity, explain its potent antidotal effect in soman poisoning. The potential effect on aging of the soman-AChE complex warrants further studies.
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