We continue from Ukraine: Nerve Agent Civil Defense Part 2.
Edit: Corrected link to (MMSL) Antihistamines: Promising Antidotes of Organophosphorus Poisoning.
All small-molecule drugs have off-target effects, a.k.a. side effects. Viewing nerve agents as “evil drugs”, the same is true. The “simple story” of Part 2 applies most directly to sarin, tabun, and VX, but not soman or novichok. How these differences complicate the simple story is at this level mostly, but not entirely a distraction, something to be sorted out by the CW defense establishments.
The challengers have their own simplification, study of organophosphate pesticide poisoning as a proxy for nerve agents. These pesticides are nerve agents for insects, specialized to insect AChE. They cross-react with human AChE, acting as weaker human nerve agents. Toxicity varies widely. You can drink malathion and get away with it; the active metabolite of parathion is paraoxon, which is 70% as toxic as sarin.
Treatment of parathion poisoning has mostly followed the orthodoxy of the simple story. But there have been doubters, motivated by poor survival rates with the simple story standard of care. Alternative treatments were used, based on the off-target anticholinergic effects of first generation antihistamines, resulting in some papers. There have been so many cases that it has been possible to extract some evidence-based medicine. The principle papers are:
- (MMSL) Antihistamines: Promising Antidotes of Organophosphorus Poisoning.
- (NIH) Protective effects of the antihistamine promethazine against acute paraxon-methyl and dicrotophos toxicity in adult rats.
- (NIH) Efficacy of pralidoxime in organophosphorus poisoning: revisiting the controversy in Indian setting.
Quoting the last,
Results: During the study period, 150 patients were screened following which 120 patients were randomized to either of the treatment arms. Add-on pralidoxime therapy did not offer any appreciable benefit over atropine alone in terms of reducing mortality (18.33% (11/60) versus 13.33% (8/60)) and ventilator requirement (5% (3/60) versus 8.33% (5/60)). However, patients randomized in the add-on pralidoxime arm experienced longer duration of hospital stay (7.02 ± 1.12 days) than those receiving atropine-alone therapy (5.68 ± 1.87 days) (P < 0.001).
This is an astonishing result of evidence based medicine, in strong contradiction to the theory of the simple story. If it transfers to human nerve agents, the possibility presents that current orthodox treatment of some or most nerve agents is fundamentally wrong. Which agents, if any, and why, is a mystery.
The antihistamines are:
- Cyclizine, Marezine, Valoid, Nausicalm, generic. OTC.
- Diphenylhydramine, the active ingredient of the U.S. (but not EU) formulation of OTC Benadryl, available as a generic.
- Promethazine, by prescription, generic or branded: Phenergan, Promacot.
Some readers may wonder why diazepam (Valium) has been omitted, when it is a frequent adjunct. Atropine is blocked from entry into the brain by the blood brain barrier, but nerve agents penetrate. Untreated, this results in a continual epileptic seizure, with high lethality. Diazepam is an anticonvulsant. Whether diazepam is specific treatment, or merely supportive, is an open question. The antihistamines enter the brain, where they are specific anticholinergics, possibly replacing diazepam. See (NIH) Diazepam in the treatment of organophosphorus ester pesticide poisoning and (PubMed) The role of diazepam in the treatment of nerve agent poisoning in a civilian population.
Why is atropine the historical choice? Perhaps because it appeared to be the cleaner drug. With the new awareness that nerve agents cause massive release of histamine, resembling the anaphylactic shock of a severe type 1 allergic reaction, anticholinergics that are also antihistamines become desirable.
Optimal treatments, which must be distinct for each agent, are not known. Since identification of the actual agent is delayed, optimality might not have practical utility.
Takeaway so far: Nerve agent poisoning in humans is so deadly, and experimentation so infeasible, the standard of care may be wrong.
Conclusion follows shortly.