Electroneurophysiological monitoring as an early severity predictor in acute anticholinesterase poisoned patient and the effect of oxime therapy manipulation

The neuromuscular transmission failure in acute anticholinesterases [e.g. organophosphorus compounds and carbamates] poisoning occurs because of inactivation of the enzyme acetylcholinesterase located in the neuromuscular junction, and is distinguished by single electrical stimulus induced repetitive responses and decrement response upon high rate repetitive nerve stimulation [RNS]. Oxime therapy with its action at different sites in the neuromuscular junction would alter the neuroelectrophysiological findings in acute anticholinesterases poisoning. The aim of this study is to evaluate the usefulness of RNS as a prognostic indicator of severity in acute anticholinesterase poisoning and the recovery process and its use as a guide for oxime therapy continuation or discontinuation. The study was conducted on 32 patients with acute organophosphorus poisoning admitted to the poison control center, Ain Shams University Hospitals during the period from January 2007 to June 2007. Patients were subdivided into group I [mild group n=6], group II [moderate group n=20], and group III [severe group n=6]. All the cases were clinically evaluated, pseudocholinesterase levels were estimated and RNS was done before and after oxime therapy. The patients were classified according to the decremental response into 3 categories, type 1 response [initial improvement and subsequent lack of improvement], type 2 responce [Initial improvement and subsequent normalization of neuromuscular transmission] and type 3 response [lack of improvement with initial dose of toxogonin]. RNS is a sensitive prognostic test which can be used as an early predictor of acute anticholinesterase poisoning for grading its severity, and assessment of obidoxime [Toxogonin] therapy. As therapeutic benefit of obidoxime is limited by its short duration of action, it is recommended to be administered for a longer period of time under neuroelectrophysiological guidance

Improving the bioavailability of intranasal obidoxime chloride in rabbits by using liposomes

Obidoxime chloride is an oxime used in the treatment of organphosphorus pesticides toxicity. Obidoxime chloride is usually used parentrally by intramuscularly or intravenously injections. It has been suggested that the intranasal use of obidoxime may provide an easier route of administration. The experiments in rabbits showed that when used intranasally, obidoxime has a poor bioavailability, as obidoxime chloride is poorly absorbed from nasal mucosa. However, when incorporated into liposomes [Dehydrated Rehydrated Vesicles DRV s] obidoxime bioavailability, when used intranasally, has increased by 2 folds approximately. Intranasal and intramuscular bioavailabilities were determined from AUC values relative to that after intravenous dosing of the same dose. The intranasal route of administration differed significantly from the intramuscular and intravenous routes of administration. Intramuscular bioavailability was much greater than that of intranasal obidoxime chloride as solution [31% vs. 98.9%], when used in the same dose. Peak plasma concentration [C max] was 6.9375 micro g/ml [S.D. = 1.335], 34.74467 micro g/ml [S.D. = 0.81] and 62.855 micro g/ml [S.D. = 1.36] for the intranasal, intramuscular and intravenous routes, respectively. The time to achieve C max for the intranasal route [t max = 60 min] and for the intramuscular route [t max= 20 min]. Obidoxime chloride, when used intranasally as DRVs [made from PC only], has a bioavailability similar to its bioavailability when used as solution [31% vs. 33.7%], no significant difference for P=0.05. Whereas, when used intranasally as DRVs [made from PC/Cholesterol in equimolar proportions], obidoxime chloride bioavailability has increased to 67.6%, with extended effects. The results of this study show that intranasal DRVs, made from phosphatidyl choline/cholesterol [1/1], and containing obidoxime chloride, has a much greater AUC than intranasal obidoxime chloride when used as a solution and as DRVs made from phosphatidyl choline only

Role of obidoxime on the cardiotoxicity of organophosporus insecticides

Severe bradycardia was noted in Diazinon reared rats. Heart rate was significantly reduced in only Diazinon treated group of rats while the Selecron Obidoxime combination manifested the most significant prolongation of the QTc interval among the OP treated groups. A significant increase of AST [SCOT] was evident in Diazinon and Selecron treated group compared to control. A smaller rise of AST, though statistically significant was evident in Obidoxime Diazinon combination. A highly significant rise of CPK was evident in OP groups as well as Diazinon Obidoxime combination being significantly higher in Diazinon group. Both Diazinon and Selecron groups induced a highly significant rise of CPK/MB. Obidoxime combined to Diazinon produced a significantly smaller value of CPK/MB when compared with Diazinon. A smaller value was as well observed with Selecron Obidoxime combination. Pseudocholinesterase values significantly declined in both OP treated groups. Obidoxime did not significantly correct the decline of pseudocholinesterase level. Histopathology of myocardium revealed inflammatory cell infiltration, degeneration and foci of necrosis affecting more prominently Diazinon treated and less intensely Selecron treated rats. Obidoxime evidently greatly minimized the pathological findings though mononuclear cell infilteration was still apparent. Cardiac enzymes were closely correlated with the histopathological results. Obidoxime significantly reduced the rise of cardiac enzymes and the intensity and frequency of myocardial degeneration and necrosis. No correlation was evident between pseudocholinesterase level and biochemical and histopathological improvement. On the other hand, obidoxime produced a significant further prolongation of QTc interval on the ECG of rats treated with OP hence increasing the arrhythmogenic risk

Reactivation and aging of acetylcholinesterase in human brain inhibited by phoxim and phoxim oxon in vitro / 中华预防医学杂志

<p><b>OBJECTIVE</b>Inhibition of acetylcholinesterase (AChE) in human brain caused by phoxim or phoxim oxon, their reactivation with oxime and aging of phosphorylated AChE were studied and compared in vitro.</p><p><b>METHODS</b>Micro-colorispectrophotometric assay was used to determine the activity of AChE.</p><p><b>RESULTS</b>The pI(50) of inhibition of AChE in human brain by phoxim and phoxim oxon were 5.39 and 5.77, respectively, whereas the pI(90) were 4.60 and 5.00, respectively. The reactivation rate of 0.1 mmol/L of pralidoxime (2-PAM), obidoxime (LüH(6)), trimedoxime (TMB-4) and pyramidoxime (HI-6) for phoxim-inhibited AChE in human brain was 65%, 97%, 91% and 56%, respectively, and their reactivation rate for phoxim oxon-inhibited AChE in human brain was 97%, 87%, 99% and 89%, respectively. The optimal reactivator for phoxim and phoxim oxon-inhibited AChEs was LüH(6) and TMB-4, respectively. The half aging time of phoxim and phoxim oxon inhibited phosphorylated AChEs were 39 and 28 hours, respectively, and the 99% aging time were 256 and 186 hours, respectively.</p><p><b>CONCLUSIONS</b>LüH(6) or TMB-4 should be used at the earlier as possible after poisoning with phoxim and phoxim oxon, and the reactivator should be consecutively used for more than seven days, even after their acute symptoms have been well controlled.</p>

Study on the therapeutic effect of combined use of obidoxime and atropine with respiratory machine on respiratory muscle paralysis caused by omethoate poisoning of rats / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To examine the therapeutic effect of combined use of obidoxime and atropine with artificial ventilation on respiratory muscle paralysis caused by omethoate poisoning in rats.</p><p><b>METHODS</b>Rats were exposed to 2 times the dose of LD50 omethoate and treated with atropine (10 mg/kg) to counteract cholinergic symptoms. When the rats' respiratory frequency became slower and breathed with difficulty, the trachea intubation and artificial ventilation was carried out. The rats in group A were continuously treated with atropine. The dose of obidoxime for Group B, C and D were 8, 15, 20 mg/kg respectively, given at the same time as artificial ventilation and 1, 2, 3 hours later. The doses of atropine was reduced to 1/3 - 2/3 of the first dose so as to maintain the rats atropinized. If the rat survival was beyond 60 minutes after withdrawal of artificial ventilation, the combined treatment was considered successful. The function of isolated phrenic diaphragm of the rats was observed with MS-302 physiological and pharmacological analysis instrument.</p><p><b>RESULTS</b>None of the rats in Group A was successful after withdrawal from artificial ventilation and the function of phrenic diaphragm appeared poor; whereas > 80% of the rats in B, C, D Group were successful after withdrawal from artificial ventilation in 3 h and the function of phrenic diaphragm remained well. The survival rate in B, C and D groups were higher after withdrawal from artificial ventilation than that in Group A(P < 0.01). The function of phrenic diaphragm in Group B, C and D were gradually decreased after ACh was added into the container.</p><p><b>CONCLUSIONS</b>Combined use of suitable dose of obidoxime and atropine with artificial ventilation for respiratory muscle paralysis caused by omethoate poisoning could promote the recovery of diaphragm function and reduce the death rate in poisoned rats.</p>