Galantamine Has New Role in Age of Terrorism
Galantamine Is an Antidote
to Lethal Nerve Agents
In combination with atropine, it provides total
protection from organophosphate war gases and pesticides
By Will Block
Life shrinks or expands in proportion to one’s courage.
— Anaïs Nin
cliché in pulp fiction is the one where the bad guy plans to use some kind of poison to disable or kill people but cannot avoid being exposed to it himself. Naturally, he will need an antidote—and it always turns out that he has one. How convenient! So he pops a pill or gulps a potion or inhales a whiff of some exotic gas, and—presto!—he remains unscathed while his victims drop like flies around him.
In real life, it’s seldom that easy. Let me rephrase that, lest it sound as though I have actual experience as a mass murderer. In real life, most poisons are difficult or impossible to counteract with antidotes. Naturally, scientists are interested in finding effective antidotes—whether preventive (before the fact) or therapeutic (after the fact)—for the poisons that threaten us.
How the Military Shapes Our World
No one is keener on this subject than the military. For millennia, armies have been developing poisons, both chemical and biological, to use against their enemies, while forever seeking better means to protect themselves from similar attacks. That effort requires the military’s support of much basic research in the natural sciences, from which all technologies (the practical applications of scientific knowledge) are derived.
The pursuit of chemical and biological warfare provides but one illustration of a profoundly important, paradoxical fact: the military, through its nearly limitless interests and funding capabilities, has throughout history been mankind’s premier wellspring for scientific discovery and creative (as well as destructive) invention, spinning off innumerable technologies that have permeated and enriched almost every aspect of our lives. We will encounter one small example in this article.
A Primer on Poisons . . .
There are many kinds of poisons, acting in different ways and with different outcomes. Some disable the victim temporarily, with no lasting effects. Some cause permanent damage, from minor to devastating. Some kill slowly, some quickly. Many, however, can also have the opposite effect: at subtoxic dosages, they can be used as drugs to treat diseases and perhaps save lives (e.g., atropine, quinine, curare, digitalis, strychnine, morphine, nitroglycerin, and aspirin). As the great Renaissance physician Paracelsus said, “Dosage alone determines poisoning.”
Among the most lethal of poisons are nerve agents, which disrupt the functioning of the body’s central nervous system (the brain and spinal cord) and peripheral nervous system (all the rest). They have been used in warfare by Iraq (against Iran and against its own people in the 1980s), by terrorists in Japan in the mid-1990s, and by terrorists in Iraq in 2004. The potential for their future use is great, because terrorists are highly motivated for it and because any competent chemist with a well-equipped laboratory could make them from readily available precursors.
The galantamine/atropine combina-
tion was 100% protective if the
galantamine was given up to 1 hour
before the soman, or up to 5 minutes
after the soman. By 10 minutes after
the soman, however, it was too late,
and galantamine had no effect.
Nerve agents for chemical warfare belong to a class of highly toxic compounds called organophosphates (OPs). The principal ones are soman, sarin, cyclosarin, tabun, and VX. All are liquids, but most can be dispersed as gases (they’re often called nerve gases). Some other OPs are widely used as insecticides, herbicides, and fungicides, and they pose substantial risks to agricultural workers. Every year, in fact, thousands of people throughout the world suffer OP poisoning, and hundreds die. The medical personnel caring for them can be poisoned by their excretions and even by the vapors they emit.
. . . And One on Acetylcholine
In parts of the central nervous system, the neurotransmitter acetylcholine (ACh) mediates neural signals underlying many higher functions, including memory and other cognitive processes. In the peripheral nervous system, ACh mediates the neural signals that make our skeletal muscles and smooth muscles contract when required. In both cases, it’s vital that appropriate levels of ACh—not too little and not too much—be maintained.
The task of keeping our ACh levels in check is accomplished by the enzyme acetylcholinesterase (AChE), which continually destroys used ACh molecules as new ones are being formed to transmit new signals. This system works well unless ACh levels fall too low (as occurs, e.g., in Alzheimer’s disease). Then it’s helpful to intervene with agents called acetylcholinesterase inhibitors, which bind to some of the AChE molecules, rendering them ineffective. This allows ACh levels to rise.
If the AChE inhibitor is too strong, however, there can be an overload of ACh, causing its target cells (neuronal or muscle) to become overstimulated and remain “switched on,” with potentially devastating consequences. That is what makes the organophosphate poisons (both nerve agents and pesticides) so lethal—they’re extremely powerful AChE inhibitors.
Warning: Gruesome Scenario
When OPs enter our system, they seize our AChE molecules in what amounts to a molecular death grip, causing a rapid rise in ACh levels. In the periphery, this leads to the profuse, uncontrollable release of bodily fluids (sweat, tears, nasal and respiratory mucus, saliva, vomit, urine, and feces; also blood), as well as dimmed vision, reduced heartbeat, low blood pressure, mucous congestion and constriction of the bronchial tubes (making breathing difficult), severe twitching of muscle fibers, and general weakness.
As if all that weren’t bad enough, the effects caused by ACh buildup in the central nervous system include anxiety, confusion, headache, ataxia (loss of muscle coordination), tremors, convulsive seizures, coma, and, finally, cardiorespiratory paralysis. It’s a gruesome death. Depending on the level of exposure, it can take anywhere from a few minutes to a few days. Those who survive may have suffered severe brain damage.
Until recently, there was no very good antidote for these terrible poisons. The military has tested many candidate substances, a few of which are somewhat effective and are routinely issued to soldiers in the field. They still leave much to be desired, though—especially in terms of preventing brain damage—and most have very serious side effects (albeit not as serious as death) at the high dosages required.
The three agents most commonly used are pyridostigmine bromide, atropine, and any of several compounds called oximes; benzodiazepines have also been used.* The search for something better has never let up.
Galantamine = Antidotal Gold
Now the search has struck gold, in the form of the plant alkaloid galantamine, an AChE inhibitor that turns out, when used together with atropine, to be an extremely effective antidote. (You’ve just become confused, right? For help, see the sidebar “Fighting Fire with Fire?”) Galantamine is best known as a treatment for mild to moderate Alzheimer’s disease, and it’s also useful for the precursor condition known as mild cognitive impairment (MCI). (See
“Galantamine Improves Memory in MCI” and
“Don’t Forget Your Galantamine” in the February 2005 and January 2006 issues, respectively.)
Fighting Fire with Fire?
There is a glaring paradox: both the organophosphate poisons and their antidote galantamine are acetylcholinesterase inhibitors. If that’s so, shouldn’t galantamine just be adding fuel to the fire? What gives?
The answer is complicated and not altogether certain. The study’s authors have speculated that some combination of the following factors probably explains the paradox:
- Whereas the OPs are irreversible AChE inhibitors (they cling tenaciously to AChE molecules once they’re attached), galantamine is a reversible inhibitor, meaning that it readily “comes and goes” on the AChE molecules, in a manner of speaking. This allows the AChE some opportunity, transiently, to keep ACh levels in check. The upshot is a certain “denial of access” of the OPs to AChE by virtue of galantamine’s less intense, more beneficial type of inhibitory action.
- The OPs inhibit not just AChE, but also a related enzyme, BuChE (butyrylcholinesterase), which can thus be considered a kind of OP scavenger, just as AChE is. By contrast, galantamine has a much greater affinity for AChE than for BuChE, so it doesn’t “waste” itself on the latter. That leaves BuChE more available to scavenge (irreversibly) the OP molecules that are being denied access to AChE by galantamine. The more the OPs latch onto BuChE instead of AChE, the better.*
Another factor may be that galantamine’s biochemical actions in the brain affect not just the cholinergic system—the neural system whose neurotransmitter is acetylcholine—but others as well, notably the glutamatergic and GABAergic systems. These systems (and others) are interwoven in highly complex and variable ways that differ markedly from one part of the brain to another, making any therapeutic agent’s effects both unique and very difficult to understand.
There’s more, but let’s stop here, except to mention that other AChE inhibitors that are used to treat Alzheimer’s disease have not panned out as organophosphate antidotes. For now, at least, galantamine stands alone.
- Albuquerque EX, Pereira EFR, Aracava Y, Fawcett WP, Oliveira M, Randall WR, Hamilton TA, Kan RK, Romano JA Jr, Adler M. Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc Natl Acad Sci USA 2006;103(35):13220-5.
Galantamine’s value as an OP antidote was discovered by a research team at the University of Maryland School of Medicine and the U.S. Army’s Medical Research Institute of Chemical Defense and its Medical Research and Materiel Command (both in Maryland); their study has just been published in the Proceedings of the National Academy of Sciences. Using young male guinea pigs, they tested various galantamine/atropine combinations against three organophosphate poisons: the nerve agents soman and sarin and a compound called paraoxon, the biologically active metabolite of the insecticide parathion. All substances were given by injection.
Galantamine Provides 100% Protection
The researchers first tried atropine alone, 1 minute after the OP injection. Although it provided some benefit, the animals nonetheless had intense convulsions within 15–30 minutes, and 89% of them died within 24 hours. The experiment was then repeated, but this time with a pretreatment of galantamine (as galantamine hydrobromide, the chemical form in which this substance is generally used in humans), given 30 minutes before the OP.
The results were stunning: the galantamine/atropine combination provided 100% protection against the lethal OP compounds. All the animals survived, with no ill effects, either before or after the OP injection—it was as though they hadn’t even been exposed to the poison. Atropine was essential to galantamine’s antidotal efficacy—without it, there were no survivors.
The results were dose-dependent, and the optimal dosage of galantamine for preventing OP toxicity yielded blood concentrations similar to those achieved in humans being treated for Alzheimer’s disease. Thus, the galantamine dosage is considered safe. (Nothing was said about the atropine dosage in this regard, but it is apparently safe as well.)
Galantamine Must Be Used Quickly
Using soman because it’s the fastest-acting of the three poisons tested and thus poses the greatest challenge, the researchers also found that the galantamine/atropine combination was 100% protective if the galantamine was given up to 1 hour before the soman, or up to 5 minutes after the soman. By 10 minutes after the soman, however, it was too late, and galantamine had no effect.
It’s noteworthy that the guinea pigs suffered no OP-induced brain damage when galantamine was used. This contrasts with pyridostigmine bromide, which does not protect against brain damage. That’s because PB does not readily cross the blood-brain barrier, and when it does,
it may even contribute to brain damage.
Galantamine, by contrast, easily crosses the blood-brain barrier (as do the OPs, of course), and it provides strong neuroprotection—a hallmark of its anti-Alzheimer’s action. (See
“Galantamine Helps Protect Your Neurons” in the April 2005 issue.)
The researchers’ next step is to test the treatment in nonhuman primates. Meanwhile, they summarized their current work as follows:
The present study demonstrates the remarkable potential of galantamine to improve antidotal therapy for even the most deadly OPs. In combination with atropine, well tolerated, clinically relevant doses of galantamine, administered acutely either before or soon after an exposure to the nerve agents soman and sarin or paraoxon, fully counteract the toxicity and lethality of these compounds. …
Development of effective and safe antidotes against OP toxicity will help improve the treatment of the victims of a terrorist attack with nerve agents, and it will help reduce the mortality associated with OP pesticide poisoning worldwide. The demonstration that an acute galantamine-based therapy effectively and safely counteracts OP poisoning is, therefore, of utmost relevance for farm workers and others who handle OP pesticides, for the general population under threat of OP exposure in terrorist attacks, and for soldiers, who, despite the Geneva Protocol, may be exposed to deadly nerve agents in the course of battle.
How Serious Is the Threat?
The overriding issue of our time is terrorism and the avowed threat of genocide—not just against Jews but against all of Western civilization. Terrorists seek to deprive us of liberty and the pursuit of happiness by destroying their necessary antecedent, life itself. Toward that end, they are aggressively seeking to obtain and use weapons of mass destruction: chemical, biological, radiological, and nuclear.
We now face the gravest threat to our survival in American history, owing to the unprecedented nexus of three factors, each of which is extremely dangerous by itself:
- WMDs in the hands of terrorists. The chances that a few anonymous, elusive fanatics could unleash WMDs anywhere, anytime, are growing. The days when such weapons could be possessed only by more or less civilized nation-states with whom one could engage in reasoned discourse are gone.
- Mass murder through suicide. The willingness—
desire, in fact—of terrorists to further their cause through suicide makes defensive measures incomparably more difficult than in the past, when one could take for granted the enemy’s natural desire for survival (with the notable exception of World War II’s kamikaze pilots).
- Ideological hatred fueled by religious fanaticism. This is the most irrational and fearsome of human motivations, against which diplomacy and appeals to reason have never been successful. It virtually guarantees war.
This unholy triad portends global disaster unless the civilized world unites to take every possible measure against it. But what can we as individuals do in our daily lives?
We can act on (not just agree with and then forget about) the advice of experts who recommend the stockpiling of supplies necessary for emergency preparedness.* It’s important to realize that, in the event of a major chemical or biological attack, there will be widespread panic and disorder, and emergency medical services could be severely limited or nonexistent for long periods. If nerve agents were used, even prompt assistance might come too late (especially with soman, for which the first 5 minutes after exposure are critical).
Thus, we will all be on our own. Although protecting ourselves against every form of attack is impossible, we now know that it probably will become possible to protect ourselves from nerve agents, using galantamine and atropine. Let us hope, however, that it never comes to that, and that we need use galantamine only for its primary purpose: protecting our cognitive functions from the ravages of aging.
*When the federal government proposed, a few years ago, that citizens prepare for an airborne chemical or biological attack by stockpiling plastic sheeting and duct tape with which to seal themselves into a room for a brief period (several hours, perhaps a day), the idea was widely derided, providing fodder for late-night comedians. Alas, people ridicule what they don’t understand. The idea is eminently sensible and could save many lives.
It’s human nature to ignore the threats we cannot see, but it behooves us all—for the sake of our own well-being as well as that of our fellow citizens—to do our best to confront them courageously and to act rationally in our best interest. One way to do that is to adopt the Boy Scouts’ motto: Be Prepared. That may soon become more feasible in one crucial arena, thanks to the new discovery regarding galantamine.
- Aas P. Future considerations for the medical management of nerve-agent intoxication.
Prehosp Disast Med 2003;18(3):208-16.
- Golomb BA. A Review of the Scientific Literature as it Pertains to Gulf War Illnesses. Volume 2: Pyridostigmine Bromide. MR-1018/2-OSD, The RAND Corporation, Santa Monica, CA, 1999.
- Albuquerque EX, Pereira EFR, Aracava Y, Fawcett WP, Oliveira M, Randall WR, Hamilton TA, Kan RK, Romano JA Jr, Adler M.
Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc Natl Acad Sci USA 2006;103(35):
Will Block is the publisher and editorial director of Life Enhancement magazine.