Unequal efficacy of pyridinium oximes in acute organophosphate poisoning

The use of organophosphorus pesticides results in toxicity risk to non-target organisms. Organophosphorus compounds share a common mode of action, exerting their toxic effects primarily via acetylcholinesterase (AChE) inhibition. Consequently, acetylcholine accumulates in the synaptic clefts of muscles and nerves, leading to overstimulation of cholinergic receptors. Acute cholinergic crisis immediately follows exposure to organophosphate and includes signs and symptoms resulting from hyperstimulation of central and peripheral muscarinic and nicotinic receptors. The current view of the treatment of organophosphate poisoning includes three strategies, i.e. the use of an anticholinergic drug (e.g., atropine), cholinesterase-reactivating agents (e.g., oximes) and anticonvulsant drugs (e.g., benzodiazepines). Oximes, as a part of antidotal therapy, ensure the recovery of phosphylated enzymes via a process denoted as reactivation of inhibited AChE. However, both experimental results and clinical findings have demonstrated that different oximes are not equally effective against poisonings caused by structurally different organophosphorus compounds. Therefore, antidotal characteristics of conventionally used oximes can be evaluated regarding how close the certain substance is to the theoretical concept of the universal oxime. Pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LüH-6), HI-6 and HLö-7 have all been demonstrated to be very effective in experimental poisonings with sarin and VX.TMEM and LüH-6 may reactivate tabun-inhibited AChE, whereas HI-6 possesses the ability to reactivate the soman-inhibited enzyme. An oxime HLö-7 seems to be an efficient reactivator of AChE inhibited by any of the four organophosphorus warfare agents. According to the available literature, the oximes LüH-6 and TMB-4, although relatively toxic, are the most potent to induce reactivation of AChE inhibited by the majority of organophosphorus pesticides. Since there are no reports of controlled clinical trials on the use of TMB-4 in human organophosphate pesticide poisoning, LüH-6 may be a better option

Piridinijevi oksimi: razlozi za njihov odabir kao kauzalnih antidota protiv otrovanja organofosfatima i sadašnja rješenja za autoinjektore

During the last five decades, five pyridinium oximes were found to be worthy of use as antidotes against nerve agents in humans: pralidoxime, in a form of chloride or PAM-2 Cl and mesylate or P2S (against sarin, cyclosarin and VX), trimedoxime or TMB-4 and obidoxime or LüH-6 (both against tabun, sarin and VX), HI-6 (against sarin, soman, cyclosarin and VX) and HLö-7 (against all the five nerve agents). In order to provide the auto-injector with the best and most potent acetylcholinesterase reactivator, the Defence Research and Development Canada (DRDC) received in the 1990s a core funding from the federal government’s CBRN research and Technology Initiative (CRTI). Its ultimate result should be three products: (1) 3-in-1 auto-injector (atropine, HI-6 dimethanesulphonate and avizafone, as anticonvulsant), (2) 2-in-1 auto-injector (atropine and HI-6 dimethanesulphonate) and (3) HI-6 dimethanesulphonate in a vial for administration by the medically trained personnel. Previous experimental and clinical experience suggests that, among the oximes mentioned, only trimedoxime and obidoxime can be used for acetylcholinesterase reactivation and antidotal protection against most of the organophosphorus insecticides. The search for an “omnipotent” oxime, effective in reactivation of AChE inhibited with both nerve agents and organophosphorus insecticides, is still ongoing.Tijekom proteklih pet desetljeća, za pet piridinijevih oksima ustanovljeno je da zavređuju da budu upotrijebljeni kod ljudi kao antidoti protiv živanih bojnih otrova: pralidoksim, u obliku klorida, PAM-2 Cl ili mesilat, P2S (protiv sarina, ciklosarina i VX-otrova), trimedoksim ili TMB-4 i obidoksim ili LüH-6 (oba protiv tabuna, sarin i VX-otrova), HI-6 (protiv sarina, somana, ciklosarina i VX-otrova) i HLö-7 (protiv svih pet živanih bojnih otrova). Radi osiguranja autoinjektora s najboljim i najpotentnijim reaktivatorom acetilkolinesteraze, Kanadska uprava za obrambena istraživanja i razvoj (DRDC) primila je tijekom 1990-ih godina osnovnu financijsku potporu od Istraživačke i tehnološke inicijative u oblasti kemijske, biološke, radiološke i nuklearne zaštite (CRTI) Vlade Kanade. DRDC će primati financijsku i znanstvenu pomoć suradnjom šest zemalja (izmeu Kanade, Njemake, Nizozemske, Norveške, Švedske i Velike Britanije). Njezin bi krajnji rezultat trebala biti tri proizvoda: (1) “3-u-1” autoinjektor (atropin, HI-6 dimetansulfonat i avizafon, kao antikonvulzant), (2) “2-u-1” autoinjektor (atropin i HI-6 dimetansulfonat) i (3) HI-6 dimetansulfonat u bočici za primjenu od medicinski obrazovanog osoblja. Prethodna eksperimentalna i klinika iskustva sugeriraju da, među spomenutim oksimima, jedino trimedoksim i obidoksim, koji su relativno toksini per se, mogu osigurati reaktivaciju acetilkolinesteraze i antidotsku zaštitu protiv većine organofosfornih insekticida. Potraga za “omnipotentnim” oksimom, djelotvornim i protiv svih živanih bojnih otrova i protiv svih organofosfornih insekticida, još je u toku

EFFICACY AND SAFETY OF LOW-DOSE VERSUS STANDARD-DOSE ALTEPLASE REGIMENS IN PATIENTS WITH ACUTE ISCHAEMIC STROKE

Background: The use of intravenous recombinant tissue plasminogen activator, alteplase, at a dose of 0.9 mg/kg is an effective treatment for patients with acute ischaemic stroke; this dose is also associated with high intracerebral haemorrhage rates. The aim of this study was to evaluate whether the low-dose alteplase treatment is as effective and safe as the standard-dose regimen. Subjects and methods: This was a retrospective, single-centre study, and data were collected from the Hospital Stroke Registry. Based on the severity of stroke and the risk of intracerebral haemorrhage, patients were divided into two groups according to the alteplase doses given; the low-dose (0.6 mg/kg) group (n=45) and the standard-dose (0.9 mg/kg) group (n=165). Ninety-day outcomes measured as modified Rankin score and National Institute for Health Stroke Scale (NIHSS) score, as well as symptomatic intracerebral haemorrhage and mortality rates were analysed. Results: The standard-dose group had a slightly more favourable outcome (Rankin score 0-2) at 90 days after alteplase treatment than the low-dose group (64.24% vs. 53.33%), but the difference was not significant. The total intracerebral haemorrhage rate and mortality rate at 90 days were higher in the standard-dose group than in the low-dose group (21.2% vs. 13.3% and 6.1% vs. 0.0%, respectively), but these differences were not statistically significant. Conclusion: The low-dose alteplase treatment applied to the patients with high intracerebral haemorrhage risk had comparable efficacy and safety profile to the standard-dose regimen

EFFICACY AND SAFETY OF LOW-DOSE VERSUS STANDARD-DOSE ALTEPLASE REGIMENS IN PATIENTS WITH ACUTE ISCHAEMIC STROKE

Background: The use of intravenous recombinant tissue plasminogen activator, alteplase, at a dose of 0.9 mg/kg is an effective treatment for patients with acute ischaemic stroke; this dose is also associated with high intracerebral haemorrhage rates. The aim of this study was to evaluate whether the low-dose alteplase treatment is as effective and safe as the standard-dose regimen. Subjects and methods: This was a retrospective, single-centre study, and data were collected from the Hospital Stroke Registry. Based on the severity of stroke and the risk of intracerebral haemorrhage, patients were divided into two groups according to the alteplase doses given; the low-dose (0.6 mg/kg) group (n=45) and the standard-dose (0.9 mg/kg) group (n=165). Ninety-day outcomes measured as modified Rankin score and National Institute for Health Stroke Scale (NIHSS) score, as well as symptomatic intracerebral haemorrhage and mortality rates were analysed. Results: The standard-dose group had a slightly more favourable outcome (Rankin score 0-2) at 90 days after alteplase treatment than the low-dose group (64.24% vs. 53.33%), but the difference was not significant. The total intracerebral haemorrhage rate and mortality rate at 90 days were higher in the standard-dose group than in the low-dose group (21.2% vs. 13.3% and 6.1% vs. 0.0%, respectively), but these differences were not statistically significant. Conclusion: The low-dose alteplase treatment applied to the patients with high intracerebral haemorrhage risk had comparable efficacy and safety profile to the standard-dose regimen

HOW MEDICAL STUDENTS IN THEIR PRE-CLINICAL YEAR PERCEIVE PSYCHIATRY AS A CAREER: THE STUDY FROM BELGRADE

Background: Taking the Initiative to evaluate students’ affinity toward psychiatry seems to be a global issue and is an essential part of programs to improve the status of the profession. The aim of this study is to explore medical students’ attitudes toward psychiatry in comparison to other residencies (internal medicine, surgery, pediatrics, gynecology and general medicine) in the pre-clinical year and to observe which factors influence the creation of these attitudes. Subjects and methods: The survey included 114 students of the second year, School of Medicine in Belgrade (academic year 2007/08). The data was collected trough a 23-item questionnaire. Results: Fifteen percent of students stated that psychiatry was their career of choice, while 25% expressed a strong aversion. Psychiatry was ranked less attractive than internal medicine, surgery and pediatrics, but more attractive than general medicine or gynecology. Those who like psychiatry attributed more importance to an interesting and challenging job than to prestige and financial reward. Also, they found this field to be intellectually challenging and to rapidly expand the frontier of medicine. Students with negative attitude were convinced that psychiatry was lacking in scientific foundation and was clinically inefficient, they disliked intensive emotional involvement, exposure to stress and frequent unpleasant situations and had prejudices toward the patients or simply a lack of the interest. Conclusion: The present study is the first of its kind in Serbia which used a precise and internationally comparable methodological instrument and It shows that pre-clinical medical students at the University of Belgrade, have a stronger affinity towards psychiatry when compared to their peers from most countries worldwide. Also, the study points out the fact that prejudices toward patients with mental dysfunctions and lack of confidence in the efficacy of psychiatric treatment should be specially targeted by the curriculum in the later part of undergraduate education. How this will affect the attitude of clinical students and graduates is to be examined

6th Golden Helix Pharmacogenomics Day: pharmacogenomics and individualized therapy

The Golden Helix Pharmacogenomics Days are international scientific meetings aiming to educate healthcare professionals and biomedical scientists about pharmacogenomics and personalized medicine. In this meeting report, we provide an overview of the scientific lectures and the topics discussed during the 6th Golden Helix Pharmacogenomics Day that was held in Belgrade, Serbia last June 5, 2012. The scientific program included lectures by the local and international speakers from Europe and the United States

6th Golden Helix Pharmacogenomics Day: pharmacogenomics and individualized therapy

The Golden Helix Pharmacogenomics Days are international scientific meetings aiming to educate healthcare professionals and biomedical scientists about pharmacogenomics and personalized medicine. In this meeting report, we provide an overview of the scientific lectures and the topics discussed during the 6th Golden Helix Pharmacogenomics Day that was held in Belgrade, Serbia last June 5, 2012. The scientific program included lectures by the local and international speakers from Europe and the United States

Antidotski efekat kombinacija obidoksim/HI-6 i memantina kod miševa trovanih somanom, dihlorvosom ili heptenofosom

Introduction/Aim. In acute organophosphate poisoning the issue of special concern is the appearance of muscle fasciculations and convulsions that cannot be adequately antagonised by the use of atropine and oxime therapy. The aim of this study was to examine atidotal effect of obidoxime or HI-6 combinations with memantine in mice poisoned with soman, dichlorvos or heptenophos. Methods. Male Albino mice were pretreated intravenously (iv) with increasing doses of oximes and/or memantine (10 mg/kg) at various times before poisoning with 1.3 LD-50 of soman, dichlorvos or heptenophos, in order to determine the median effective dose and the efficacy half-time. In a separate experiment, cerebral extravasation of Evans blue dye (40 mg/kg iv) was examined after application of memantine (10 mg/kg iv), midazolam (2.5 mg/kg intraperitonealy - ip) and ketamine (20 mg/kg ip) 5 minutes before soman (1 LD-50 subcutaneously - sc). Results. Coadministration of memantine induced a significant decrease in median effective dose in null time of both HI-6 (7.96 vs 1.79 mmoL/kg in soman poisoning) and obidoxime (16.80 vs 2.75 mmoL/kg in dichlorvos poisoning; 21.56 vs 6.63 mmoL/kg in heptenophos poisoning). Memantine and midazolam succeeded 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.Uvod/Cilj. Poseban problem pri trovanju organofosfornim jedinjenjima predstavljaju mišićne fascikulacije i konvulzije, koje se ne mogu u potpunosti antagonizovati primenom atropina i oksima. Cilj ovog rada bio je ispitivanje antidotskog efekta kombinacije memantina i oksima HI-6 kod trovanja somanom, kao i kombinacije memantina sa obidoksimom kod trovanja dihlorvosom i heptenofosom. Metode. Albino miševima, mužjacima, u repnu venu date su rastuće doze oksima i/ili memantina (10 mg/kg) u različitim vremenskim intervalima pre intravenskog (iv) davanja 1,3 LD-50 somana, dihlorvosa ili heptenofosa. Praćenjem stepena preživljanja, izračunate su srednje efektivne doze i poluvreme efikasnosti. U odvojenom eksperimentu praćena je cerebralna ekstravazacija boje Evans plavo (40 mg/kg iv) nakon primene memantina (10 mg/kg iv), midazolama (2,5 mg/kg intraoperitonealno - ip) i ketamina (20 mg/kg ip) 5 min pre davanja somana (1 LD-50 supkutano - sc). Rezultati. Primenom kombinacija sa memantinom srednje efektivne doze u nultom vremenu i HI-6 (7,96 vs 1,79 mmoL/kg kod trovanja somanom) i obidoksima (16,80 vs 2,75 mmoL/kg kod trovanja dihlorvosom; 21,56 vs 6,63 mmoL/kg kod trovanja heptenofosom) bile su višestruko niže u odnosu na dozu samog oksima. Memantin i midazolam uspešno su suprimirali prokonvulzivni efekat somana. Zaključak. Rezultati ove studije pokazuju da primena memantina u kombinaciji sa oksimima obezbeđuje bolji zaštitni efekat nego sam oksim, a u osnovi ovog efekta verovatno leži i njegov antikonvulzivni potencijal