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

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

Uticaj natrijum bikarbonata i standardnih antidota na acido-bazni status pacova trovanih dihlorvosom

The aim of the present work was to examine potential beneficial role of sodium bicarbonate (3 mmol/kg ip) on protective potency of trimedoxime (10 mg/kg im), obidoxime (10 mg/kg im) and atropine (10 mg/kg im) in rats poisoned with dichlorvos. Special attention was paid to the influence of co-administration of sodium bicarbonate on acid-base status in experimental animals poisoned with dichlorvos (1.3 LD50 sc). Coadministration of sodium bicarbonate significantly increased protective effect of standard antidotes in rats poisoned with dichlorvos. Sodium bicarbonate given along with atropine/oxime produced an increase in blood pH value and correction of acidosis. In conclusion, correlation between protective effect and biochemical outcome was evident when sodium bicarbonate was added to antidotes.Cilj rada je bio da se ispita efekat natrijum bikarbonata (3 mmol/kg ip) na zaštitni potencijal trimedoksima (10 mg/kg im), obidoksima (10 mg/kg im) i atropina (10 mg/kg im) u pacova trovanih dihlorvosom. Posebna pažnja je posvećena uticaju kombinacija natrijum bikarbonata i antidota na acido-bazni status eksperimentalnih životinja trovanih dihlorvosom (1.3 LD50 ). Primena kombinacija sa natrijum bikarbonatom zna- čajno je povećala zaštitne efekte standardnih antidota, a došlo je i do porasta vrednosti pH krvi i korekcije acidoze. Takođe, moglo se zaključiti da kada je natrijum bikarbonat dat zajedno sa atropinom/oksimom postoji jasna korelacija između dobijenih zaštitnih efekata i testiranih biohemijskih parametara

Effect of sodium bicarbonate in rats acutely poisoned with dichlorvos

The development of effective antidotes against organophosphates such as dichlorvos has been a persistent challenge over the past decades. Therapy of organophosphate poisoning is based on the administration of atropine and oxime as standard antidotes. The present study was undertaken to evaluate the ability of sodium bicarbonate to improve protective effects of standard antidotes in rats poisoned with dichlorvos. The aim of this experiment was to establish the correlation between protective effects and biochemical parameters relevant for acid-base status. In order to examine the protective effect of both standard antidotes and their combinations, groups of experimental animals were poisoned subcutaneously with increasing doses of dichlorvos. Immediately thereafter, rats were treated with atropine 10 mg/kg intramuscularly, oximes 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally. These antidotes were administered either as single doses or in combinations. In the biochemical part of the experiments, rats were poisoned with dichlorvos 1.3 LD50 (10.64 mg/kg) subcutaneously and immediately thereafter treated with atropine 10 mg/kg intramuscularly, oximes (trimedoxime or obidoxime) 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally either as single doses or in combinations. Parameters relevant for acid-base status were measured 10 minutes after the administration of antidotes. The results of our study indicate that addition of sodium bicarbonate to standard antidotes significantly improves protective effects of atropine, obidoxime and trimedoxime. Correlation between protection and biochemical outcome is clearly evident when sodium bicarbonate is being added to atropine