Disease relevance of 4-(nitrosomethylidene)-1-[[4-(nitrosomethylidene)pyridin-1-yl]methoxymethyl]pyridine

• One of these reactivators, HI-6, was shown to be significantly more effective in treating soman toxicity than other oximes, such as 2-PAM, TMB4, and obidoxime [1].
• Six patients with organophosphorus compound intoxications developed an intermediate syndrome (weakness and fasciculations) and obidoxime was given on eight occasions [2].
• The protocol was based on relatively high doses of obidoxime, relatively low doses of atropine and overriding with a pacemaker in cases of ventricular arrhythmias and prolonged Q-T interval [3].
• We conclude that each drug should be titrated separately: atropine dosage should be adjusted to the severity of tracheobronchial secretions and bronchospasm, while full doses of obidoxime are justified for the period before "aging" sets in [3].
• The mean arterial blood pressure (MAP) response to obidoxime, measured in normal rats, was a transient hypotension, but to sarin an immediate hypertension [4].

High impact information on 4-(nitrosomethylidene)-1-[[4-(nitrosomethylidene)pyridin-1-yl]methoxymethyl]pyridine

• Using obidoxime as an "allosteric antagonist," evidence was found that dimethyl-W84 interacts with the postulated common allosteric site [5].
• The structural data clearly show analogous coordination of Ortho-7 and obidoxime within the active-site gorge of AChE [6].
• Crystal structures of the oximes HI-6, Ortho-7 and obidoxime in complex with Mus musculus acetylcholinesterase (mAChE) reveal different roles of the peripheral anionic site (PAS) in the binding of the oximes [6].
• The low efficiency of HI-6 and the significantly higher efficiency of Ortho-7 and obidoxime may be explained by the differential binding of the oximes in the PAS and active-site gorge of AChE [6].
• The central chain of Ortho-7 and obidoxime is loosely coordinated in the active-site gorge, whereas the second carboxyimino pyridinium ring is accommodated in the vicinity of the phenol ring of Tyr337 [6].

Chemical compound and disease context of 4-(nitrosomethylidene)-1-[[4-(nitrosomethylidene)pyridin-1-yl]methoxymethyl]pyridine

• Conversely, 91% of the 23-fold variation in the ability of the oximes pralidoxime and obidoxime to protect against the toxicity of OP compounds in guinea pigs was explained by the variation in the in vitro ability of oximes to reactivate OP-inhibited AChE [7].

Biological context of 4-(nitrosomethylidene)-1-[[4-(nitrosomethylidene)pyridin-1-yl]methoxymethyl]pyridine

• As introduced by Ellis and Seidenberg as a tool to check for a common allosteric site [Mol. Pharmacol. 42:638-641 (1992)], obidoxime was used to antagonize the actions of the test compounds [8].
• Pharmacokinetics and pharmacodynamics of obidoxime in sarin-poisoned rats [4].
• The significantly diminished glomerular filtration rate confirmed the retardation of obidoxime excretion in sarin poisoning [4].
• The serum oxime concentrations (ED50 values) for HI-6, obidoxime, and PAM against a 3 LD50 dose of sarin were 0.72, 9.05, and 2.56 micrograms/ml, respectively [9].
• Autocatalysis, a mechanism found only rarely in the degradation of pharmaceuticals, has not been reported in previous studies of obidoxime hydrolysis [10].

Anatomical context of 4-(nitrosomethylidene)-1-[[4-(nitrosomethylidene)pyridin-1-yl]methoxymethyl]pyridine

• Acetylcholine and cholinesterase in submandibular glands of rats given armin and obidoxime [11].
• Addition of native erythrocytes to sarin-treated plasma resulted in marked inhibition of EryAChE in the presence of obidoxime, suggesting a higher affinity of the POX for EryAChE [12].
• Effect of the bispyridinium compounds HGG12, HGG42, and obidoxime on synaptic transmission and NAD(P)H-fluorescence in the superior cervical ganglion of the rat in vitro [13].
• The effect of the oxime reactivator obidoxime chloride (obidoxime) on single frog neuromuscular junctions has been studied in order to clarify its action on the acetylcholine receptor (AChR) and on the acetylcholine esterase (AChE), both before and after blocking its enzymatic activity with the organophosphorus compound sarin [14].

Associations of 4-(nitrosomethylidene)-1-[[4-(nitrosomethylidene)pyridin-1-yl]methoxymethyl]pyridine with other chemical compounds

• Reactivators (oximes) of inhibited AChE are a mainstay of treatment, however, the commercially available compounds, obidoxime and pralidoxime, are considered to be rather ineffective against various nerve agents [15].
• The effects of obidoxime, a pyridinium oxime, on the cholinesterase activity and acetylcholine content of the submandibular glands of rats poisoned with armin, an organophosphorus anticholinesterase agent, were studied [11].
• Atropine and obidoxime in a parenteral injection device are determined by simple HPLC method simultaneously without any pretreatment at 228 nm [16].
• The pharmacokinetics and pharmacodynamics of the oxime obidoxime (Toxogonin, 50 mg/kg iv) were investigated in anesthetized normal rats and in sarin-poisoned (50 micrograms/kg iv) rats [4].
• Reactivation of paraoxon-, sarin-, soman- and VX-inhibited AChE by obidoxime was impaired by POX-induced re-inhibition whereas no deviation of pseudo first-order kinetics was observed with tabun, cyclosarin and VR [17].

Gene context of 4-(nitrosomethylidene)-1-[[4-(nitrosomethylidene)pyridin-1-yl]methoxymethyl]pyridine

• 3. The paraoxon concentrations measured fitted satisfactorily the values calculated from the kinetic constants previously obtained for AChE inhibition and obidoxime-induced reactivation in vitro [18].
• Obidoxime and 2-PAM were superior to HI 6 and HLö 7 in reactivating butyrylcholinesterase (BChE) [12].
• At serum concentrations of 3.6, 3.6, and 3.3 micrograms/ml for HI-6, obidoxime, and PAM, respectively, the 24-hr mortality following sarin poisoning was 0, 90, and 20% [9].
• Thus, the replacement of obidoxime by more effective acetylcholinesterase (AChE) reactivators is necessary to increase the neuroprotective efficacy of antidotal treatment in the case of soman poisonings [19].
• Only with obidoxime a significant increase in AChE activity was found [20].

Analytical, diagnostic and therapeutic context of 4-(nitrosomethylidene)-1-[[4-(nitrosomethylidene)pyridin-1-yl]methoxymethyl]pyridine

• The R.S.D. for the HPLC procedure of obidoxime in atropine-obidoxime injectors was 0.82% [21].
• Perfusion with 10(-3) M obidoxime caused a 19% increase in left ventricular stroke work and a 31% increase in total pressure-volume area [22].
• Internal standard high-performance liquid chromatography method for the determination of obidoxime in urine of organophosphate-poisoned patients [23].

References