HI-6 in Man: Efficacy of the Oxime in Poisoning by Organophosphorus Insecticides

Abstract

<jats:p> The efficacy of the oxime HI-6 was studied as a treatment for organophosphorus poisoning. HI-6 was given four times daily as a single intramuscular injection of 500 mg accompanied by atropine and diazepam therapy. Oxime treatment was started on admission and continued for a minimum of 48 h and a maximum of 7 d. HI-6 rapidly reactivated human blood acetylcholinesterase inhibited by diethoxy organophosphorus compounds, while the dimethoxy-inhibited enzyme was mainly resistant to the treatment by HI-6. Although both HI-6 and pralidoxime chloride reactivated the red blood cell cholinesterase in quinalphos-poisoned subjects, the return of enzyme activities was more rapid following the use of HI-6. The general improvement of poisoned patients, which was sometimes more rapid than the rise of acetylcholinesterase activity, pointed to direct pharmacological effects of HI-6. No undesirable side-effects were noted in patients when HI-6 plasma concentrations were maintained at levels far above the 'therapeutic' concentration for up to 7 d. </jats:p>

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

“…Clinical data obtained in organophosphorus pesticide-poisoned patients provide evidence for the validity of this assumption. [82][83][84] As generally visualized, the oxime is oriented proximally to exert a nucleophilic attack on the phosphorus of the enzyme-inhibitor complex. Intermediate in the reactivation is a complex between the phosphylated enzyme and the reactivator.…”

“…No adverse effects were noted in patients treated with oximes. 82 Nine patients intoxicated with organophosphorus insecticides were treated with PAM-2 methylsulphate (Contrathion) using a dose of 4.42 mg/kg as a bolus injection followed by continuous infusion 2.14 mg/kg/h. 106 In patients with ethylparathion and methylparathion poisonings, enzyme reactivation could be obtained in some at oxime concentrations as low as 2.88 mg/L.…”

“…In patients poisoned by several organophosphorus insecticides, HI-6 ensured fast reactivation of erythrocyte AChE in almost all cases, except in the cases of dimethoate and phosphamidon. 82,103 However, AChE inhibited by several organophosphorus insecticides, including dimethoate, demethon, triamiphos, ethoprophos, profenofos, fenamiphos and pyridafenthion, resists any attempt at reactivation with any oxime, probably due to variations in phosphoryl moiety and distribution of electronic charge. 56,86,142 Finally, a systematic review of two randomized controlled clinical trials did not result in final proof of the efficacy of PAM-2 in the treatment of poisonings induced by organophosphorus insecticides in humans, 146 probably due to the methodological gaps in the trials included, as indicated in the original publication.…”

Kinetic prerequisites of oximes as effective reactivators of organophosphate-inhibited acetylcholinesterase: a theoretical approach

“…( Figure 1) was tested only in few cases of OP pesticide poisoning 10 . Apart from pralidoxime, only few oximes have been used in human OP-poisoning in the past 50 years 7 .…”

“…Apart from pralidoxime, only few oximes have been used in human OP-poisoning in the past 50 years 7 . Obidoxime ( Figure 1) was first used in the early 1960s 8 followed by trimedoxime (TMB-4, Figure 1) 9 while HI-6 ( Figure 1) was tested only in few cases of OP pesticide poisoning 10 . Although only very few oximes are used clinically a huge number of oximes were synthesized in the past decades mainly in Germany, USA, Croatia, Israel, Czech Republic, and Korea 7,11 .…”