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2
CHOLINESTERASE REACTIVATORS
BACKGROUND
the nine teenth and tweet ieth
mustard gas as a toxic weapon
, ~ the warfare potential of chem-
ical agents. This led to support for research on lethal nerve agents
during and immediately after World War Il. The research was followed
by the development of treatment methods, and prominent among these
was the use of cholinesterase Deactivators to reverse the lethal
ef fec ts of anticholinesterase nerve gases .
Rapid advances in chemistry during
centuries, coupled with the success of
in Wnrl r1 War T attracted attention to
The terminal ion of World War II brought to light the highly
potent chemical-warfare agents of the organophosphorus ester class
that had been synthesized by both sides during the conflict. The
properties, pharmacology, and toxicology of these anticholinesterase
agents were discussed ire Volume 1 of the National Research Council
report . 17 Such agents as diisopropyl fluorophosphate ~ DFP), sarin
(GB), soman (GD), and tabun (GA) were a fascination to pharmacolo-
gists who conduc ted extensive studies in the early postwar years .
It soon became evident that no available antidotes could block the
pharmacologic activity of these chemicals, alleviate the signs and
symptoms of toxicity, or restore normal bodily functions after
exposure. Atropine readily antagonized the muscarinic actions,
including those in the central nervous system (CNS), but elicited no
reversal of the nicotinic effects. Better forms of therapy were
sought, particularly to alleviate the nicotinic effects of anticho-
linesterase agents.
_ ,.
The first suggestion of a practical form of antidotal therapy
came in 1949 from Hestrin,9 who found that acetylcholinesterase
(ACHE) catalyzed the formation of acetohydroxamic acid when incu-
bated with sodium acetate and hydroxylamir~e. Critical in vitro
studies in the next decade led to the development of a practical
approach to therapy. The crucial concept ire these studies was the
recognition that the compound formed when AChE reacted with a
phosphorus ester was a covalent phosphoryl-enzyme intermediate
similar to that formed in the hydrolysis of acetylcholine.23
Wilson and colleagues, beginning in 1951, demonstrated that AChE
inhibited by alkyl phosphate esters (tetraethyl pyrophosphate, TEPP)
could be reactivated by water, but that free enzyme formed much more
rapidly in the presence of hydroxylamir~e. 20 ~ 21 Similar results
—3—
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were obtained by Hobbiger.l0 In 1953, Wilson and Meislich26
synthesized nicotinehydroxamic acid and the corresponding meth-
iodide; these agents were far more potent Deactivators of Skye
phosphate-inhibited AChE than was hydroxylamine. In 1955, Wilson
described picolinehydroxamic acid as the best Deactivator among a
series of quaternary hydroxamic acids, noting that oximes also were
reactiva~cors. In in vitro studies, Davies and Green4 and Childs
et al. 3 reported that 2-formyl-N-methy~pyridinium iodide oxide
(2-PAM iodide form) was 170 times more active than picoline-
hydroxamic acid in reactivating TEPP-inhibited AChE in vitro, 30
times more active in reactivating DFP-inhibited AChE, and 400 times
more ac Live ire reactivating GB-inhibited AChE . Similar f indings
were reported by Wilson and Gineburg.24,25
The first investigators to show the marked antidotal properties
of pral idoxime compounds (Figure 2-~) were Kewitz and Wilson.13
Askew1 noted marked species differences in the rate and effec-
tiveness of oximes and hydroxamic acids in reactivating al kyl
phosphate-inhibited AChE. Other in viva studies demonstrated that
some oximes were effective in antagonizing the blockade of neuro-
muscular transmission at ter treatment of animals with TEPP, DFP, or
GB. 12 The methyl methanesulfonate derivative of 2-PAM, P2S
~ Figure 2-1), was shown to be very effective by virtue of greater
water solubillty. 5 Additional studies demonstrated that the most
effective treatment of organophosphonus ester-poisoned animates was
to use oximes concomi tantly wi th atropine . The general conclusions
were that atropine minimizes or abolishes the toxic actions of AChE-
inhibi tiny compounds on mu scarinic and central chorine rgic si tea and
the pyridini''m and other quater~ary hydroxamic acids and oxides
reverse the toxic ef fects of the organophosphorus esters by reac-
t ivating the inhibited AChE. 14 ,19
Success with the pyridinium oximes led to an intensive search
for more effective oximes and the discovery of an especially potent
derivative, 1, 3-bis(4-formy~pyridinium~propane dibromide biso2rime -
(~B-4) (Figure 2-1), which reactivated serum-inhibited AChE in
vitro more rapidly than 2-PAb1 or P2S.11,l8 l~lB-4 was an effective
chemi cad adjunct to atropine in sarin-poisoned mice, rats, rabbits,
cats, and dogs, 2 Further modifications of the bispyridinium
structure--insertion of dif ferent groups between the pyridinium
rings--led to the synthesis of bis(4-formyl-N-methylpyridinium
oxide) ether bichloride known originally as LuH6 and later as
toxogonin (Figure 2-1).' Its advantage was that it was less toxic
than 1~B-4 and also capable of reactivating AChE inhibited by a
variety of organophosphorus esters .6,15
With the demonstration of species variability in response to the
various oximes,\ it was noted that results obtained with a parti-
cular organophosphate were not obtained with other agents, ever if
—4—
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H-~-OH O(3
CH3
2-PAM. Pyrldine-2-aldoxime methiodide methyl chloride
LOU - H. N - H CH, so.O
— 1
CH,
P2S. Pyridine-2-aldoxime methyl methanesulfonate
CHAT - H CHAT - H
(3: e!
CH2 - H2-CH2
28r()
TMB-4. N,N-trimethylene bis~pyridine-4-aldoxime bromide)
HC- - OH HC--N—OH
0~ itch
CHINCH:
Toxogonin. Bis(4-formyl N-methylpyridini~,m oxime) ether dichloride
FIGURE 2-1 Structural formulas of cholinesterase Deactivators
tested at Edgewood
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they formed the same phosphorylated enzyme. This meant that
screening of the reactivators for suitable antidota1 properties
necessitated in viva testing with as many organophosphorus esters as
possible. It also meant that data from animal studies could not be
extrapolated to humans without considerable caution, necessitating
testing in humans. The ef fectiveness of oximes in treating poison-
ing by organophosphorus eater chemical - carfare agents stimulated the
U. S. Army to initiate studies with four compounds--2-PAM, P2S, TMB-4,
and tozogonin--in military volunteers from 1958 to 1975, to assess
their effectiveness against low doses of suitable militarily impor-
tant organosphates. This chapter examines some pertinent features of
the pharmacology and toxicology of the pralidoxime Deactivators
(Table 2-1~. It presents conclusions of the Panel on Cholinesterase
Reactivators as to the potential of these agents to impair chroni-
cally the health and well-being of the volunteers who participated
in the studies conducted by the Department of the Army. It focuses
on the four agents tented at Edgewood. A detailed report of the
pharmacology and toxicology of the four oxime Deactivators is in
Appendix B.
TABLE 2-l
Subjects Tested with Cholinesterase Reactivators at Edgewood
No . Sub; ec ts
Tox. No. EA No. Compound CAS NO. (Approx.)
D-1 217 0 2-PAM: pralidoxime 51-15-0 607
chloride ~ or iodide)
protopam chloride (or iodide);
2-f ormyl-N-me thylp yrid ini um
chloride [or iodide) oxime;
pyridine-2-aldoxime
methoch'oride (or methiodide)
D-2 P2S: methyl methanesulfonate 154-92-2 95
derivative of 2-PAM; pralidoxime
me thanesulf onat e; Prot opam
methanesulf orate
D-3 3475 Toxogonin: LuH6; bier 4-formyl- 114-90-9 41
Name thy~pyridini um o2rime ~ e ther
dichloride
D-4 1814 TMB-4; 1, 1 ~ -trimethylene- 56-9 7-3
bis ~ 4-formyl-pyridinium ~ bromide (bromide ~
~ or chloride ~ dioxide; 3613-81-9
trimedoxime; 1,3-bis (chloride)
~ 4-f ormy~pyridinium) propane
dibromide (or dichloride) bisoxime
—6—
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REFERENCES
-
1. Aslcaw, B.M. Oximes and hydroxamic acids as antidotes in
anticholinesterase poisoning. Br. J. Pharmacol. Chemo the r.
11:417-423, 1956.
2.
Bay, E., Krop , S . and Yates , L. F. Chemotherapeutic effec-
ti~reness of I,1 '-trimethylene bis (4-formy~pyridinium bromide)
dioxime (TMB-4) in experimental anticholinesterase poisoning.
Pro c . Soc. Exp . Biol. Med. 98 :107-110 ? 1958.
Childs , A. F., Davies, D.R., Green, A.L., and Rutiand, J. P.
reacti~ration by oximes and hydroxamic acids of cholinesterase
inhibi~ced by organophosphorus compounds. Br. J. Pharmacol.
Chemother. 10 :462-465, 1955.
Da~ries, D.R., and Green, A.L. General Discussion. Discuss.
Faraday Soc. No. 20: 269, 1955.
5. Davies, D.R., Green, A.L., and Willey, G.L. 2-Hydroxy-
imiIlomethyt -N~ethy~pyridini ~ me thanesulphonat e and atropine
in the treatment of severe organophosphate poisoning. Br. J.
Pharmacol. Chemother. 14: 5-8, 1959.
6. Engelhard, N., and Erdmann , W. D. Beziehangen zwischen
chemischer Struktur und Cholinesterase reaktivierender
Wirk~amkeit bei einen Reihe neuer bis-quartarer Pyridin-4-
aldoxime . Arzoem. Forsch. 14: 870-875, 1964.
Engelhard , H., and Erdmarm, W. D. Ein neuer Reaktivator fur
durch Alky~phosphat gehemmte Acetylcholinesterase. Klin.
Wochenschr. 41: 5 25-5 27, 19 63.
. Grob, D., and Johns , R. J. Use of oximes in the treatment of
intoarication by anticholinesterase compounds in normal subjects
Am. J. Med. 24:497-511, 1958.
9. Hestrin, S.J. Acylation reactions mediated by purified acetyl-
choline esterase . J. Biol . Chem. lB0: 879-~81, 1949.
10. Hobbiger, F. Inhibition of cholinesterases by irreversible
inhibitors in ~ritro and in vivo. Br. J. Pharmacol. Chemother.
6:21-30, 1951.
11. Hobbiger, F., O' Sullivan, D.G., and Sadler, P.W. New potent
reactivators of acetocholinesterase inhibited by tetraethyl
pyrophosphate. Nature 182: 1498-1499, 1958.
—7—
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Ho Ime ~ , R., and Robins , E . L. The reversal by oximes of neuro-
muscular block produced by anticholinesterases. Br. J.
Pharmacol. Chemother. 10: 490-495, 1955.
Kewitz, H., and Wilson, I.B. A specific antidote against lethal
a~y~phosphate intoxication. Arch. Biochem. Biophys. 60: 261-
263, 1956.
14. Kewitz , H., Wilson, I. B., and Nachmansohn, D. A specific anti-
dote against lethal alkyl phosphate intoxication. II. Antidotal
properties. Arch. Biochem. Biophys. 64: 456-465, 1956.
Milosevic , M., Andjelkovic , D., and Binenfeld, Z . Effete de
divers oximes, derives de chlorures de l-phenyle, 1-benzyle et
1-phenacyle pyridine et lea analogues de 4-formyle pyrldin dans
1' intoxication au paragon. Med. Exp. 10: 73-7B, 1964.
16. Namba, T., and Hiraki, K. PAM (pyridine-2-aldoxime methiodide)
therapy for alkylphosphate poisoning. J. Am. Med. Assoc.
16 6: 1834-1839, 1958.
17. National Research Council, Committee on Toxicology. Possible
Long-Term Health Ef fee ts of Short-Term Exposure to Chemical
Agents. Vol. I. Anticholinesterases and Anticholinergica.
Washington, D. C.: National Academy Press, 1982. 290 pp.
18. Poziomek, E.J., Hackley, B.E., Jr ., and Steinberg , G.M.
Pyridir~ium aidoximes. J. Org. Chem. 23:714-717, 1958.
19. Wills, J. H. Recent studies of organic phosphate poisoning.
Fed. Proc., Fed. Am. Soc. Exp. Biol. 18: 1020-1025, 1959.
20. Wilson, I. B. Acety~cholinesterase. XI. Reversibility of
tetraethyl pyrophosphate inhibition. J. Blol. Chem.
190:111-~17, 1951.
21. Wilson, I . B. Acety~cholinesterase . XTII. Reactivation of alkyl
phosphate-inhibited enzyme. J. Biol.- Chem. 199:~13-120, 1952.
22. Wilson, I. B. Promotion of acetylcho~nesterase activity by the
anionic site. Discus s. Faraday Soc. No . 20 :119-125, 1955.
23. Wilson, I.B., Bergman, F., and Nachmansohn, D. Acetyl-
cholinesterase. X. Mechanism of the catalysis of acylation
reactions. J. Biol. Chem. 186: 781-790, 1950.
24. Wilson, I.B., and Ginsburg, S. A powerful Deactivator of
alkyd phosphate-inhibited acetylchol inesterase . Biochim.
Biophys. Acta 18 :168-170, 1955.
_~_
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25. Wilson, I . B. -, and Ginsburg, S . Reactivation of acetyl-
cholinestera~e inhibited by aLky~phosphates. Arch. Biochem.
54: 569-5 71, 1955.
26. Wilson, I.B., and Meis~ich, E.K. Reactivation of acetyl-
cholinesterase inhibited by alky~phosphates. J. Am. Chem. Soc.
75: 4628-4629, 1953.
REVIEW OF ABLE INFO~TION ON
l
2-PAM P2S IMB-4 AND TOXOGONIN
~ ~ ,
CHARACTERISTICS
Pralidoxime chloride (EA 2170), [ C7HgN2O]C1 (Figure 2-1),
is a white, nonhygroscopic, crystalline powder, with a molecular
weight of 172. 63, a melting point of 226-227°C, and a solubility
in water of over 1 g/ml. It is a chorine st era se deactivator and was
tested alone and with anticholinesterase chemicals on human volun-
teers at Edgewood. It is manufactured by Ayerst Laboratories,
approved by the F1)A, and wide1 y used in the United States as an
antidote to alleviate the acute responses to poisoning by organo-
phosphorus insecticides and other anticholinesterase
chemicals.4,ll,73
Pralidoxime methanesulfonate (P2S), [C7HgN2O]CH3O3S,
consists of hydroscopic crystals with a molecular weight of 232.28
and a melting point of 155°C. 1~117 This is reportedly the
preferred oxime in the United Kingdom. 73
Toxogonin (EA 3475), [C14Hl6Cl2N4O3], is a grayish-
whi te powder that exists as ache chloride with a molecular weight of
359. 22, a melting point of 229°C, and free volubility in water. A
dibromide compound with a melting point of 202°C is also used
This oxime is much used in many European countries . 73
4 (EA 48~4~, [Cl5Hl8~4o2]Br2, exists as odorless,
light tan crystals with a molecular weight of 446.21 and a melting
pa int of 238-2 41°C and is also available as the chloride . 11, 7 3
Russian and Yugoslavian investigators have reported the use of TMB-4
as an antidote in anticholinesterase poisoning.l7~73
All four cholinesterase Deactivator compounds are
pralidoximes . The f irst two are monoquaternary oximes; the last two
are hi squat ernary oxime ~ .
_9_
l
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BIOCHEMISTRY
The body contains two main classes of cholinesterase: acety~cho-
linesterase (EC 3.~.~. 7) and butyry~cholinesterase (EC 3.~.~.~) .27
^The former, sometimes referred to as true cho1 inesterase, is mainly
a tissue enzyme and is found mainly in such tissues as the synapses
of the cholinergic system; it is also found in other tissues, such
as erythrocytes, where i ts function is uncertain. The latter,
referred to as peeudocholinesterase, is a soluble enzyme that is
synthesized in the liver and circulates in the plasma.
Acetylcholine is the optimal substrate for acetylcholinesterase,
whereas butyrY1choline is the optimal substrate for butyrylcholin-
esterase. 80~04 Acety~cholinesterase does not hydrolyze butyryl-
choline very ef f iciently.
Acetylcholinesterase can be extracted from tissues to various
extents by saline buf fers, but often a detergent is necessary to
solubi lize the larger part of the enzyme . Even a single tie sue
usually yields a number of enzyme forms with different sedimentation
coefficients. 72 Some of the forms are highly asymmetric; some
tend to aggregate, unless the salt concentration is high. Regard-
less of the source or the molecular form, the kinetic properties of
acety~cholinesterase are similar. Although it contains a number of
catal ytic subuni ts, there are no homotropic allosteric ef facts, nor
do there appear to be any physiologic regulators of i ts activity .
Acetylcholinesterase is sub] ect to substrate inhibition at high
concentrations, but Michaelis kinetics are observed at lower concen-
trations, because the substrate constant and the Michaelis constant
differ by a factor of 100. Turnover numbers run about 2-9 ~ 105
min~1, and Km (Michaelis constant) values are about 0.2
mM. 7616 Whatever the source, the enzyme is sub ject to inhibi-
tion by the same reversible and irreversible inhibitors. Most of
the kinetic work has been done with the saline-extracted 1iS enzyme
from electric eel and the detergent-extracted 6S enzyme from erythro-
cytes . The former is a tetramer derived f ram the net ive enzyme by
the action of proteases; the latter is a dimer.89
The following diagram illustrates the reaction of acety~cho-
linesterase (E) with acetylcholine (S ~ to produce an acetylenzyme
intermediate (E' ~ with later hydrolysis of the intermediate and
regeneration of the enzyme .113 ~ 114 KM is calculated as shown
in the diagram. The catalytic constant, kCat, refers to the
overall decomposition of the enzyme intermediate (E.S, E' ).
—10—
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EOH+S ken E S ken
k-1
H2Oi k3
E'+ Choline ELM
= k 1 + k~( I + k2 )
E + acetate ~( )
In acetylation, the enzyme acts as a nucleophi'e, and choline as
a leaving group; in deacetylation, water is the nucleophile, and the
enzyme is the leaving group. The enzymic nucleophile is the hydroxyl
group of a specific serine residue. The mechanisms of both acetyl-
at ion and deacetylat ion probably involve the formation of tetrahedral
intermediates. The active site contains an imidazole group that
functions first as a general base and than as a genera' acid in each
step and whose ionization determines in part the pH variation of
enzyme activity.
Details of enzyme-substrate and enzyme-inhibi tor reactions were
described in Volume 1 (p. 8~. In summary, organophosphate esters
wi th good leaving groups phosphorylate the enzyme by a mechanism
similar to acetylation of the enzyme.
RO O
\11
RG
E-OH + ,P-F ~ E-OH (ROXR'O)P(0)F 2~ E_o_p\ + HE
OR'
These substances are sometimes called irreversible inhibitors,
because the hydrolysis of the phosphorylated enzyme by water is slow.
Various nucleophiles containing a substituted ~mmorrium group will
dephosphorylate the phosphorylated enzyme much more rapidly than
water. This was recognized early in the quest for a practical reac-
t tvating agent when choline was found to be a Deactivator. Because
a hydroxyl group in an alcohol is a weak nucleophile at neutral pH,
the capacity of choline to function as a Deactivator must be a con-
sequence of its molecular complementarily with the enzyme and the
increased acidity of the alcohol. The idea arose of f inding a rigid
structure that would include a quaternary ammonium group and an
acidic nucleophile that would be complementary with the phospho-
rylated enzyme ire such a way that the nucleophilic oxygen would be
positioned close to the elec trophilic phosphorus atom. This led t o
the pralidoxime compounds ~ PAbls ~ . The syn isomer of 2-PAM
(2-PAM-ayn) turned out to be especially active. The reaction of
2-PAM with the phosphorylated enzyme is shown in the following
diagram.
—11—
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Representative terms from entire chapter:
phosphorylated enzyme
E O P/ + :` N-OH
+CH 3 H
OR
2 PAM EO-P\
KR |k OR
E + 0` `_o_p
+CH3 H
The pseudo-first-order rate constant for reac~ci~ration of ~ iS enzyme
is:
k (pseudo first-order ) = i;2
I +KR
2 -PAM
hen the oxime concentration is smaller than Kp (~2-PAM]
(cholinolytic effect),l5~35~5l or increase excretion of the
anticholinesterase agent.48~86 Some of the other possible
mechanisms are discussed later, but the interaction between oxime
an free or unbound organophosphorus ester is considered below.
The basic reaction believed to occur in the inhibition of
acetylcholinesterase by some alkylphosphates is shown in Reaction 1.
n
|~E + (go)} - ~ ~ (go)} - ~ + ~ (1)
active enzyme inhibitor inhibited enzyme
The inhibited enzyme is stable in aqueous environments, and
lethality results from a blocking of transmission at cortical
cholinergic synapses, such as those involved in breathing.
The reactivation or the inhibited enzyme can be achieved with
selected oximes (such as 2-PAM), as shown in Reaction 2.
(lD)2~01! ~ ~
CE-NOB
3]
SIDE ~ ;~'d-~_O~P-(08)2
cE3I
inhibited enzyme Deactivator active enzyme phosphorylated
oxime
The reactivation is an equilibria reaction. Under some
conditions--e."., when the oxime reacts directly with the
organophosphate ester (Reaction 3) or where the equilibria constant
is less than 1 (Reaction 21--the phosphorylated oxime can inhibit
the enzyme by driving the reaction to the lef t .
i+ CII-NOB
CE31
reactivator inhibitor
~ (~32P-! ~ ^~
~ =3
phosphorylated oxime
Thus, the phosphorylated oxime can itself be a potent cholin-
esterase inhibitor. Wilson and Ginsburg advanced this concept when
they noticed incomplete react ivation of acety~cholinesterase by 2-PAM
and suggested that the phosphorylated oxide reinhibited the enzyme
(according to Reaction 2~.
—13—
(3)
have been reported in the literature ~ and they are discussed in
Appendix B. In all but two instances (described below), moderate
effects disappeared within 24 h.
One volunteer (2307) received 2 g of P2S and ~ g of TMB-4 oral ly
68 mire before being given 1.5,ug of soman by intravenous infusion.
He had minor symp tome, but in 12 h became anxious, restless, and
agitated. He was transferred to Walter Reed Hospital. His Multi-
phasic Multiple Personali ty Inventory (MMPI) and psychiatric inter-
view before exposure were described as "doubtful in regard to suit-
abi ~ ity, but riot grossly pathological . " Postexposure physical and
necrologic examinations showed no organic signs of neurologic
disease. The discharge diagnosis from Walter Reed Hospital in 1961
specified acute, moderate anxiety reaction manifested by restless-
ness, anxiety, agitation, and hysterical reaction. He has experi-
enced further problems requiring inpatient and outpatient psychi-
atric care. The Veterans' Administration diagnoses between 1966 and
1980 noted infantile personality with strong paranoid trends, organic
brain syndrome, and severe a ~ iety neurosis with depression. This
subject was also noted in Volume 1 (p. 30~.
A second sub ject ~ 6849) experienced a grand Sal seizure 3 h af ter
receiving 300 mg of 2-PAM (chloride form) intramuscularly. He
regained consciousness within 5 mini he had bitten his tongue. He
was initially lethargic, but felt well 10 h later. He was trans-
ferred to Walter Reed Hospital, but followup records are not avail-
able. He had received 300 mg of 2-PA}1 intramuscularly 5 and 8 ~
before the episode. The only symptom on those occasions was local
pain at the injection site.
Although 2-PAM is an FDA-approved ding, data submitted to the FDA
to obtain approval are proprietary and were not released when
requests for them were made to the FDA and to the manufacturer. A
report of the FDA Adverse Drug Experiences Monitoring Program
~ October 30, 1983) contained one adverse reaction (hypotension
fol1 owing 1 g by intravenous injection).
In seminary, with the possible exception of those two cases, the
records contained no evidence of delayed or persistent effects after
administration of the chorine at erase Deactivators. Such data
cannot, however, address the issue of long-term effects or delayed
sequelae.
REFERENCES
1. Albanus, L., Jarplid, B., and Sundwall, A. The toxicity of some
cholinesterase reactivating oximes. Br. J. Exp. Pathol.
45: 120-127, 1964.
—36—
2. Aldridge, W.N., and Reiner, E. Enzyme Inhibitors as Substrates.
Frontiers of Biology, Volume 26. New York: American Elsevier
Publishing Co., Inc. 1972. p. 75-77.
3 . Amo ~ , W. C., Jr ., and Hal ~ , A. Malathion poisoning treated with
protopam. Ann. Intern. lied. 62 :1013-1016, 1965.
Ayerst Laboratories, Division of American Home Products Corp.,
New York, N.Y. Protopam(R) chloride (Pralidoxime chloride).
Professional brochure . 197 3. 39 p .
5. Barckow, D., Nenhaus, G., aid Erdmann, W.D. Zur Behandlung der
schweren Parathion-(E 605(R)~-Vergiftung mit dem Cholin-
esterase-Reaktivator Obidoxim (To~ogonin(R)~. Arch. Toxikol.
24:133-146, 1969. (English Summary)
6. Barkman, R., Edgren, B., and Sundwall, A Self-administration of
pralidoxime in nerve gas poisoning with a note on the stability
of the drug. J. Pharm. Pharmacol. 15:671-677, 1963.
Barr, A.M. Further experience in the treatment of severe
organic phosphate poisoning. tied. J. Aust. 1:490-492, 1966.
8.
Barr, A. M. Poisoning by antic ho1 inesterase organic phosphates:
Its significance in anaesthesia. Med. J. Aust. 1: 792-796, 1964.
^. Bay ~ E. PharmacodyDamice of 1,1'-trimethylene bis(4-formyl-
pyridirM um bromide) dioxime (TMB-4~. Fed. Proc. Fed. Ame SOC.
Exp. Biol. I8: 366, abet . no. 1445, 19 59.
10. Bay, E. lathe action of 2-formyl-1 Methyl pyridinium chloride
oxime ~ 2-PAM Cl) on catechlolamine induced response in rabbits.
Pharmacologist 4: 149, 1962.
11. Beilsteins Handbuch der Organischen Chemie, edited by Reiner
Luckenbach. Supplementary Series III/IV, Vol. 21, part 4, pp .
3514-3515, 3542-3543. Heidelberg: Springer-Veriag Berlin, 1978.
12. Bell, A., Barnes, R., and Simpe on, G.R. Cases of absorption and
poisoning by the pesticide "Phosdrin. " Med. J. Aust . 1: 178-180 ,
1968.
13. Bennett, B.G ., and Best , J. Successful use of an antidote in
phosphorus insecticide poisoning . Med. J. Aust . 2:150, 1962.
14 . Berglund , F., Elwin, C. E., and Sundwall , A. Studies on the
renal elimination of N~ethylpyridinium-2-aldo2rime. Biochem.
Pharmacol. 11: 383-388, 1962.
—37—
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CONCLUSIONS
0n the basis of an examination of toxicologic litera~cure, case
reports from Edgewood volunteers, and a review of mortality data
(reported in Volume 1), the Committee found no evidence of chronic
disease ir~ animals or humans associated with single or repeated
doses of the cholinesterase reactivators (oximes). The paucity of
chronic-exposure data from aMmals and the lack of follownp data on
volunteers prevent certainty in predicting occurrence or absence of
delayed ef fects. The compounds are eliminated very rapidly from the
body, but they produce a variety of acute effects that are short-
lived a~ re~rersible, such as gastrointestinal distress following
oral administration, pain at ar~ injection site, dizzir~ese, headache,
a~ ocular discomfort. The Committee found no data on the basis of
which to deter~ine or rule out carcinogenicity, mutagenicity,
teratogenici~cy, or reproductive ef fects of the four oximes and
therefore did not reach a conclusion in this area.
—46—
