We continue from Ukraine: Nerve Agent Civil Defense Part 3.

The  articles cited so far relate clinical experience, suggesting that the standard of  care may be wrong. There is another type of paper, which attempts to elucidate intricate biochemical mechanisms. See (PubMed) The treatment of Soman poisoning and its perspectives.

Until Novichok came into focus, soman was the odd man out of organophosphate nerve agents. While other agents require time to cement their holds on AChE, soman does so almost instantaneously, so that pralidoxime cannot rip it off. This paper identifies better oxime antidotes, HI-6, HGG-42 and BDB-27.   Yet in this specialty of toxicology, dialog between clinicians who disavow oximes, and biochemists looking for better ones is so notably lacking, each appears unaware of the literature of the other.

Like soman, novichok is/was alleged to bind AChE irreversibly. Why did the Skripals and Navalny survive? The only disclosure about the Skripals conforms to standard treatment, which was not supposed to work. If Porton Down knows more, they’re not saying, for good reason.

Another paper implies something we have to consider. See (PubMed) Release of dopamine, GABA and EAA in rats during intrastriatal perfusion with kainic acid, NMDA and soman: a comparative microdialysis study. The gist: Soman, and other nerve agents, blow up the brain by causing catastrophic levels of neurotransmitters, notably dopamine. Notable, because maybe something can be done about it.

In civil defense, it  has to do with the choice of antihistamine. Quoting from (NIH) Promethazine,

Promethazine…(1)antidopaminergic, (2)antihistamine, and (3)anticholinergic properties. … Promethazine is a direct antagonist at the mesolimbic dopamine receptors and (4)alpha-adrenergic receptors in the brain. Promethazine exhibits its antihistamine effects as an H1-receptor blocker.[12][13]

Note the red numbers. Besides blocking histamine, promethazine has three useful off-target effects, which could save a brain from blowing up. Conversely, diphenylhydramine has been described as making dopamine more potent, which we do not want, or of neutral effect. I’ll leave cyclizine to another time.

In terms of civil defense, the question is: Diphenylhydramine, or something else? There isn’t  data to show that promethazine is clinically better. Diphenylhydramine may be unique in medicine, in the power of a drug that is dirt cheap:

• The most powerful antihistamine known.
• Powerful anticholinergic.
• Possibly competitive with the nerve agent standard of care.
• A bottle of 600 tablets, 25mg, costs $4.49 at Sams Club.
• The only drug with world stocks that might be sufficient to protect a medium size country.

Notably missing is a means to administer by injection. Via the oral route, absorption is delayed by 15 minutes. Blood concentration peaks at about 4 hours. Autoinjectors are better, but unsustainable for repeated exposures. Recall the initial goal:

A civilian in the bulls-eye of a nerve agent munition, who receives the incredibly small lethal dose of a modern nerve agent, cannot be saved by anything other than an antidote kit. Visualize exposure zones as a set of concentric rings surrounding the bulls-eye.  There may be options for the next zone out, LD50, where half of those exposed die, and more distant rings: those who are sickened, and those exposed to the agent after a delay.

If this toxicology specialty had a decent dialog between clinicians and researchers, we might not be swimming in mystery. A comparison for scale. Iodine tablets provide very incomplete protection against nuclear reactor accidents, yet are considered worthwhile.

What is the difference? One is an accident. The other is the intentional work of man.