Pralidoxime is the only oxime acetylcholinesterase (AChE) reactivator stocked in the United Kingdom, for use as an antidote to organophosphate poisoning, for use in combination with atropine.
Organophosphates were initially developed by the Schrader group in Nazi Germany as pesticides. Reference Nepovimova and Kuca1 However, an accidental exposure resulted in Schrader being hospitalized for a fortnight, Reference Everts2 leading to the realization that organophosphates had an alternative use as chemical weapons against humans, and before long, Germany had developed and stockpiled sarin and Soman organophosphates. Reference López-Muñoz, Alamo and Guerra3 Resultantly, development of antidotes to this new class of chemical weapon began, Reference Kewitz, Nachmansohn and Wilson4,Reference Childs, Davies and Green5 in an early example of rational drug design. Reference Wilson and Ginsburg6 Oximes were shown to dephosphorylate organophosphate-inhibited AChE, with pralidoxime showing a favorable balance of high efficacy and low toxicity—leading to its use in humans by the mid-1950s—initially for patients exposed to pesticides. Reference Namba and Hiraki7,Reference Davies and Green8 Of particular importance, while antimuscarinics such as atropine block muscarinic receptors, only oximes such as pralidoxime directly reverse organophosphate inhibition of AChE—and so, theoretically, also have protective efficacy at both nicotinic and muscarinic receptors: protecting both the neuromuscular junction and parasympathetic autonomic nerve system.
Seventy years on from the rational design of pralidoxime, organophosphates have been used against civilians by the Iraqi Reference Balali-Mood and Shariat9 and Syrian Reference John, van der Schans and Koller10 armies, twice in terrorist attacks in Japan, Reference Yanagisawa, Morita and Nakajima11 and more recently, in the attempted assassinations of Sergei Skripal Reference Khavrutskii and Wallqvist12 and Alexei Navalny Reference Eddleston and Chowdhury13 in Europe. More impactfully, organophosphates are responsible for approximately 168,000 deaths per year: in 20% of suicides globally. Reference Mew, Padmanathan and Konradsen14
Despite the clear ongoing impact of organophosphate use, meta-analyses have found no benefit, and potential harm, from use of pralidoxime in organophosphate poisoning for attempted suicides Reference Buckley, Eddleston and Li15,Reference Kharel, Pokhrel and Ghimire16 ; with a 2009 World Health Organization (WHO) report concluding that “The current body of evidence does not appear to support the continued use of pralidoxime for the treatment of organophosphate poisoning”. Reference Bevan17 Nevertheless, the United Kingdom continues to stock pralidoxime as a therapy, alongside atropine, for organophosphate poisoning, despite this negative conclusion.
It is, therefore, necessary to assess the likely efficacy of pralidoxime in the United Kingdom, in substantially different contexts to the randomized controlled trials (RCTs) of pralidoxime use in attempted suicides in less economically developed countries. Reference Buckley, Eddleston and Li15,Reference Kharel, Pokhrel and Ghimire16
Therefore, one postulates and evaluates 3 scenarios that might occur in the United Kingdom, as illustrated on Figure 1: (1) accidental release of organophosphates from an industrial facility, (2) large scale terrorist/military attack, and (3) Skripal-like assassination attempts affecting few people.
Figure 1. Outline of the response, and oxime efficacy following organophosphate (OP) exposure.
Discussion
Wrong Place, Wrong Time
Oximes work by reactivating an initial inhibited organophosphate-AChE adduct before an irreversible secondary “ageing” dealkylation reaction occurs. Critically, if pralidoxime is administered after AChE has “aged,” it has zero “reactivating” efficacy. Reference Bevan17
The ageing half-lives of organophosphates vary substantially: VR has an ageing half-life of 139 h, tabun 19 h, parathion-methyl 4 h, sarin 3 h, but soman just 6 min, Reference Worek, Thiermann and Szinicz18 and cyanobacterial guanitoxin theoretically instantaneously. Reference Fiore, de Lima and Carmichael19,Reference Hyde and Carmichael20 Furthermore, the half-life of novichok agents (used in the Navalny and Skripal poisonings Reference Eddleston and Chowdhury13 ) is not reliably published, but is believed to occur rapidly. Reference Jeong and Choi21 Therefore, unless pralidoxime is administered within minutes of Soman exposure, or hours of sarin exposure, it is unlikely to have any clinical benefit.
This poses a major problem for the United Kingdom, as pralidoxime is a “Category C” antitoxin—meaning it is held “supra-regionally”. Indeed, approximately 2/3 of acute hospitals do not stock pralidoxime, and the mean estimated delivery time from holding centers to these hospitals was recently estimated to be 114 min. Reference Harnett, Vithlani and Sobhdam22 Therefore, in scenario 1, there is a possible near-2-h delay until drug is administered to victims. In scenario 2—the nature of the chemical would be initially unknown, likely leading to a further delay in diagnosis of organophosphate exposure. This happened in Matsumoto 1994, where it took 3 d to diagnose sarin release by terrorists. 23 Alternatively, with few victims, scenario 3 may be even more challenging to identify—as organophosphate poisoning presents similarly to opioid overdose—which may be presumed first to the rare nature of organophosphate exposure. Reference Eddleston and Chowdhury13 Indeed, in the Skripal poisoning, pralidoxime was not administered until the following day. Reference Eddleston and Chowdhury13,Reference Hulse, Haslam and Emmett24
Therefore, as illustrated on Figure 1, in scenario 1, pralidoxime is likely to have no benefit for soman poisoning, but possible efficacy for medium/slow ageing organophosphates. In scenario 2, a day-long delay is likely to reduce the efficacy of pralidoxime to most organophosphates, whereas in scenario 3, only the slowest-ageing organophosphates such as VR/VX will have reversal from pralidoxime administration.
Only with near instantaneous oxime administration can the fastest-ageing organophosphates such as soman be reversed. This was achieved through supply of 6.7m atropine-oxime auto-injectors to civilians in Israel during the Gulf War. Reference Bentur, Layish and Krivoy25 However, the much lower risk of organophosphate attack in the United Kingdom makes this economically unjustifiable here. Alternatively, whereas these delays might be inevitable for UK civilian use, in military contexts provision of auto-injectors, and a far higher index of suspicion of organophosphate exposure, may collectively enable faster recognition of attack, and administration of drugs—meaning these criticisms do not necessarily apply to military contexts.
One Size Does Not Fit All
Since the 1950s, it has been known that oximes may act particularly well (and better than pralidoxime) at reversing the poisoning of specific organophosphates. Reference Kozer, Mordel and Haim26 Additionally, K-series agents have been shown to have efficacy against GA—which is impressive as GA has a lone amide electron pair—making nucleophilic attack impossible for pralidoxime. Reference Kuca, Cabal and Musilek27,Reference Kassa, Jun and Karasova28 More recently, research on donor blood has allowed direct comparison of particular organophosphates with specific oximes. For every single organophosphate tested, an oxime better than pralidoxime has been found—and obidoxime, which is widely used globally, was found to be at least 3× better than pralidoxime for most G- and V-series agents. Reference Worek, Thiermann and Szinicz18 Further oximes are in development globally—although to date, pralidoxime, obidoxime, and trimedoxime have remained the key oximes licensed for use in humans.
In this context, even in scenarios 1 + 2, where pralidoxime might have efficacy, there likely exists an even better oxime—of which the UK stocks none for civilian use.
Ideally, multiple oximes would be stocked—and the best oxime for a specific organophosphate administered. Although there would inevitably be further delay in the context of time-critical ageing, in the 1995 Tokyo attack, sarin was identified by gas chromatography/mass spectrometry within 2 h of the initial release 23 —so this is not impossible.
Too Weak, or Too Dangerous?
There is some indication that the WHO recommended dosage of pralidoxime may be too low. Reference Bevan17 The target plasma oxime concentration appears to be based off early experiments in cats, Reference Bevan17,Reference Eddleston, Eyer and Worek29,Reference Sundwall30 which found anesthetized cats to be protected from organophosphates at this concentration—with further work showing this could be achieved in humans in 10 min with intramuscular injection of 20-30 μg/kg pralidoxime. Reference Sundwall31 A fundamental problem with this extrapolation is that major differences in oxime efficacy exist between species, Reference Davies, Green and Willey32 making application to humans very difficult.
Subsequent analysis in humans indicates this may not be appropriate.
First, an RCT in 2009 compared the WHO regimen with placebo in patients with pesticide poisoning and found no reduction in mortality with pralidoxime use. Reference Eddleston, Eyer and Worek29 However, mortality was significantly lower in the patients where AChE activity successfully recovered—which may indicate that reactivating AChE does reduce mortality, but the WHO dosage is too low to have this effect in most patients. This is supported by a 2006 RCT, which compared high dose (above the WHO regimen) with low dose (below the WHO regimen) pralidoxime—with mortality 87% lower in the high dose group. Further research is needed, but there is, therefore, some indication that pralidoxime may work well as an oxime, but only at concentrations higher than currently recommended.
There is an alternative risk that pralidoxime might be harmful in some cases—with a nonsignificant harmful hazard ratio found in numerous meta-analyses. Reference Buckley, Eddleston and Li15,Reference Kharel, Pokhrel and Ghimire16 Pralidoxime is toxic in excess, and early studies found that in rodents, pralidoxime has a minimum lethal dose of 100 μg/kg—at least 3× above that used in humans—causing death in 20 min through respiratory depression. Reference Kewitz, Nachmansohn and Wilson4 Although the mechanism is uncertain, as early as 1959, Reference Berry, Davies and Green33 and again more recently, Reference Kuca, Cabal and Musilek27 it has been shown that at high doses, oximes may paradoxically inhibit AChE. Additionally, there is some evidence that oximes are more toxic in patients exposed to carbamate pesticides (who may present clinically almost identically, as carbamates also inhibit AChE) rather than organophosphates, as oximes may augment inhibition of AChE in these scenarios. Reference Faff and Bak34,Reference Wille, Kaltenbach and Thiermann35
Conclusions
Organophosphates pose a major threat to human life, and have already been used for terrorist military means in the United Kingdom. Reference Eddleston and Chowdhury13 The need for an antidote to organophosphate poisoning is clear, but it is beyond doubt that there are major problems associated with the use of pralidoxime as an antidote to organophosphate poisoning in the United Kingdom.
Even in scenarios 1 and 2, where pralidoxime might be administered to patients within hours, pralidoxime may have little or no efficacy against the particular organophosphate the patient is exposed to, and be administered at a dosage too low to have clinically significant effect. In scenario 3, where longer delays highly probable, this is even more likely for all but the slowest-ageing organophosphates. In all cases, a superior oxime not currently stocked in the United Kingdom may exist—although substantial trial evidence of this is currently lacking. However, in this regard, even if alternative oximes were to be stockpiled for civilian use in the United Kingdom, without a change in the speed of drug distribution and administration, there may be no clinically significant benefit for patients, should organophosphate ageing be already complete.
These real-world hour-day long delays were never modeled in the original animal experiments used to design pralidoxime, Reference Kewitz, Nachmansohn and Wilson4,Reference Childs, Davies and Green5,Reference Davies, Green and Willey32,Reference Berry, Davies and Green33 which may explain the lack of efficacy seen in modern trials. Reference Buckley, Eddleston and Li15,Reference Kharel, Pokhrel and Ghimire16 Additionally, many novel organophosphates have been designed since the 1950s—meaning pralidoxime is used for organophosphates it was never designed to be used against.
Although higher-dosage regimens might prove to have better efficacy, this will raise drug costs—to around $400/patient in the case of the Pawar regimen, Reference Pawar, Bhoite and Pillay36 which may be unacceptable given the exceptionally rare organophosphate poisoning incidence in the United Kingdom.
Therefore, pralidoxime is largely unfit for its purpose as an antidote to organophosphate poisoning in the United Kingdom, and the discussed chemical, systematic, and temporal deficiencies in current antidote therapy may result in additional deaths in future organophosphate poisonings.
Competing interests
None.
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