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OCR for page 263
APPENDIX B
DIGEST REPORT
OXIMES
by
J. Henry Wills
INTRODUCTION
The group of oximes that has been administered to human volun-
teers by or under the auspices of the Biomedical Laboratory of the
Edgewood Arsenal at Aberdeen Proving Ground includes several salts
of N-methylpyridinium-2-formyl oxime, N,N'-trimethylene-bis-~4-
formy~pyridinium oxime~biabromide and -bischloride, N,N'-methyI-
eneoxymethylene-bis(4-formylpyridinium oxime~bischioride, and the
ketoxime diacetylmonoxime. Two of the widely used salts of the
monopyridini~ oxime are the chloride (pralido2cime chloride),
referred to here as I, and the methane suffocate (contrathion),
referred to as II ~ or P2S ~ . The bispyridinium bisoximes above are
known, respectively, as trimedoxime bromide (III), trimedoxime chlo-
ride, and obidoxime chloride (IV). The ketoxime is known as DAM
(V). The designations by Roman numerals are used hereafter for
these oximes.
Other Batty of N-methy~pyridinium-2-formyl oxime are identified
by the abbreviation 2-PAM followed by the common symbols for ele-
mental anions (such as 2-PAM I for the iodide) or the names of orga-
Other salts of N,N'-trimethyl-
nic anions (such as 2-PAM tartrate).
ene-bis-~4-formylpyridinium oxime) are identified by appending the
designation for the anion to the abbreviation TMB-4.
These and other oximes were developed to be Deactivators of
cholinesterase that had been inhibited by organophosphorus anti-
cholinesterase compounde;~4 they were considered initially and
briefly to be complete antagonists of the toxic actions of these
substances. This idea had to be abandoned when 2-PAM I was
founders to be much more effective as an adjunct to atropine than
as a sole therapeutic agent in antagonizing intoxication by organo-
phosphorus anticho~ nesterase agents. Furthermore, 2-PAM I and I
antagonized particularly the blockage of nicotinic chat inergic
neuromuscular transmission at the motor endplate on skeletal
muscle--an ef feet that can be reproduced to some extent with
d-tubocurarine and other curare~imetic agents.
The efficacy of crimes as adjuncts to atropine in treating
intoxication by anticho~inesterase agents depends on both the agent
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and the oxime. For instance, I is potent as an adjunct to atropine
in treating experimental animals intoxicated by sarin or VX, but is
only mildly effective as an adjunct to atropine in treating intoxi-
cation by tabun6~8 and almost completely ineffective in treating
intoxication by soman,9 whereas III is moderately effective as an
adjunct to atropine in treating experimental intoxication by tabun.
None of the oximee considered here is outstandingly effective as an
adjunct t' atropine in treating intoxication of laboratory animals
by Roman. ~
The failure of these oximes to antagonize the alterations in
normal function induced by Roman has been attributedl4 to hydroly-
tic dealkylation of the phosphorus atom in the phosphony] residue
attached to the active center of cholinesterase; that results in an
alteration in the electronic field around the phosphorus atom that
renders oximate ions unable to sever the bond between the phospho ws
atom and the serine residue in the active center of the enzyme. The
aging reaction, identified first with DFP,l5 has been found to pro-
ceed particularly rapidly in the phosphonyl residue from Roman on
inhibited cholinesterase.~3~6 A large dose of I was fouadi7 to
stop the aging process in experimental animals, but reactivated only
a part of the chow nesterase that had been inhibited. The amount of
I required for this purpose was so large (104 mg/kg intravenously)
as to carry a high hazard of toxic action. Furthermore, there is
some uncertainty about the importance of aging in the response of an
organism to Roman. For example, the repetitive depolarization of
skeletal muscle fibers after a single indirect stimulus that follows
a dose of Roman was stopped by TMB-4 Cl' without detectable reacti-
vation of cholinesterase in the vicinity of the motor endplate.
Similar results have been obtained with d-tubocurarine,l9 galla-
mine,:9 and piperidyl methylandrostanediol.20 Crone23 reported
that d-tubocurarine chloride in vitro at 10~4 M completely pre-
vented for 6 h the aging of red-cell acety~cholinesterase that was
inhibited by sarin and that gallamine triethiodide at the same con-
centration markedly slowed the aging of similarly inhibited choli-
nesterase. Because the response of skeletal muscle after a dose of
Roman was affected by a dose of d-tubocurarine that would have yielded
a concentration in the blood of no more than 0.45 ~ lo-6 M, it is
difficult to believe that Crone's effect can explain fully the in viva
action of d-tubocurarine in antagonizing the neuromuscular blocking
action of soman.
In 17 rats, twitch contraction of the anterior tibialis muscle in
response to single indirect stimuli continued until a mean dose of
soman had been given that was more than 2 100 times the minimal dose
that altered the magnitude of the twitch. Eventual failure of the
twitch response was seen to be always connected with marked alow-
ing of the heart. This observation raises the possibility that the
effect of Roman on the twitch response of skeletal muscle depends on
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a deficient supply of blood: to the muscle, rather than on an effect
on neuromuscular transmission. However, a similar indirect action
seems not to explain the effect of soman on the response of skeletal
muscle to repetitive indirect stimulation. Skeletal muscles become
unable to maintain a tetanic response to repetitive indirect stimu-
lation at doses of Roman below those that affect significantly car-
diovascular function. The indication that TMB-4 C1: can antagonize
the effect without inducing reactivation of cholinesterase at the
neuromuscular Junctionl~ illustrates the importance of knowing what
actions other than reactivation of cholinesterase may reside in the
molecules of not only III but also the other crimes with which this
review is concerned.
LETHALITY OF SINGLE DOSES IN EXPERIMENTAL ANIMALS
Several compilations of the toxicities of oximes have been
published.23~29 Additional information on the toxicities of the
oxides under consideration is available from several sources,
including Namba,30 Lindsey et al.,3' Wills,32 and Crook and
Cresthul' .33 Tab' e 1 summarizes the avail ate' e information on the
single-dose ~ ethalities of the oximes by giving typical values, with-
out attribution to specific investigators. In comparing lethal doses
of the various oximes, assuming that the oximate radical is the bio-
logically active portion of the molecule, knowledge of the relative
amounts of thi 8 radical in the various compounds is important. Tab] e
2 gives values for this measure; the last column of the table gives
values for the relative lethal activities of the compounds derived
from the data in Table 1. It is obvious that there 1e no measurement
in Table 1 on which all eight oximes can be compared, so that the
relative lethality values in Table 2 should not be taken too
seriously; they may be approximately correct in order. Lethality
after oral administration was omitted from the consideration of
relative lethality because it obviously differed qualitatively from
lethality by other routes of administration; e.g., all five of the
oximes given to mice orally were less toxic than 2-PAM I, although
all were more lethal than SPAN I by any other route of administra-
Lion. When the two rankings in Table 2 are compared by means of
Kendall's rank correlation coefficient, there is only a 90% chance
that the ranks in the two measurements are significantly correlated
Thus, the relative amounts of the oximate radical in the molecules
of the different oximes may not explain completely their comparative
lethalities .
Seven of 14 dogs given sing' e intravenous doses at IB7 mg/kg of
2-PAM I died.33 Vomiting, weakness, tremor, salivation, loss of
reflexes, and convulsion were the most common signs of intoxication
in these animals. Seven of 16 dogs given single intravenous doses
of III at 57.5 mg/kg by the same investigators died. Weakness, con-
wlaion, tremor, salivation, loss of reflexes, and vomiting were the
-2 65-
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most common effects. In general, the 8igD8 of toxicity appeared in
approximately the following order after each osime: staggering weak-
ness, collapse, relaxation of muscles, urination, defecation, tremor,
convulsion, gasping, salivation, loss of reaction to touch, sound, or
pricking with a needle, loss of eye reflexes, apnea, cyanosis, and
death. The principal difference in effects between 2-PAM I and III
was that muscular weakness was a less immediate response after 2-PAM
I than after III.
Cholinolytic drugs have ~ en found34~35 to increase the letha-
lities of II, III, and a 1:l mixture of II and III in mice given
intramuscular injections. The changes in the Logos of II and III
induced by a constant dose of atropine were 17.9% and 17.8X, respec-
tively, despite the fact that the LDsos of the oximes alone dif-
fered by a factor greater than 2. Parpanit and several mixtures of
cholinoly tic drugs had effects qualitatively similar to those of
atropine. Duke and deCandole36 reported that intramuscular indec-
tion into rabbits of equal 408e8 (30 mg/kg) of I, II, and III
resulted in peak plasma concentrations of the oximes about 9 min
after the injections, the peak concentration of II] being consider-
ably greater than those of I and II. These investigators reported
also that, whereas the plasma concentrations of I and III after
intravenous injections decreased more slowly than that of II, the
pi asma concentration of all three after intramuscular injections
decreased at about the same rate. Inasmuch as ~ and II had similar
peak blood concentrations (lower than that of III) after intravenous
injections, I and II seem to have somewhat larger volumes of distri-
bution ire the body of the rabbit than Ill.
In the rat, absorption of III from a single-loop intestinal prep-
aration during ~ h was found to be only about 13% of that of 2-PAlI
1.37 The rate of absorption of I was somewhat lower than that of
the iodide; II was absorbed at nearly the same rate as the
iodide.38 Three hours after the oximes were put into intestinal
loops, slightly more than one-third as much of III had been absorbed
as of 2-PAM I.
Brown39 found that lntracister~al injection of II, after injec-
tion of sarin by the same route, was ineffective in overcoming respi-
ratory paralysis and vasomotor stimulation resulting from satin, but
that an intravenous dose of atropine was effective. Edery40
extended this sort of study with severe' organophosphorus compounds,
atropine, I, III, and V. He found that intraventricular atropine
and, to a minor extent, oximes were able to antagonize the effects of
intraventricularly injected ethyl pyrophosphate. Intravenous injec-
tion of ~ at 25 mg/kg I-2 min after intraventricular injection of
ethyl pyrophosphate did not modify the effects induced by the organo-
phosphorus compound. Intravenous injection of III at 20 mg/kg or,
especially, of 2-PAM I at 50 mg/kg had definite antagonistic effects
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TABLE 1
Representatlve LD,o Values of
Eight Osimes Administered to Seven Animal Species
LD~. m~/kg
YAK C1 P2S 2-PAM 1~-4 Br2 Obidoxime DAM
Species Rout ea 2-PAM I (I) (I1) lactate (III) T~-4 C12 (IV) (V)
Mouse IV 133 155 -- 122 44 -- 130 --
IP 210 140 -- 60 110 139 68
IM 230 180 231 - - 80 130 160 --
SC 257 222 16S -- 83 183
PO 1,650 2,S90 3,700 1,920 2,000 — 3,390 --
Rat IV 147 96 109 -- 89 104 140
IF 300 199 -- -- 165 -- 195
IM -- 150 218 -- 137 ~ 189
SC —— —— 332 —— — —— ——
PO —- - - 7,000 - - - - - - 4,000
Guinea IM -- 168 305
pig
79
Rabbi t IV -- 94 133 -- -- 44 83
245 - - __
Cat IV -- -- -- -- -- -- 100 --
IM —— —— —— —— 117 —— 188
Don IV 190 - - - - -- 60 -- 70
IM -- -- 356 -- --
a IV, intravenous; IP, intraperitonea~l; IM, intramuscular; SC, subcutaneous; PO, by mouth.
—2 67—
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TABLE 2
Relative Oximate Content and Relative Lethality of Eight Oximes
Relay ive Oximate Relat lve
Oxime Content Lethality
2-PAM I 1.00 1.00
P2S (II) 1.13 1.27
2-PAM lactate 1.17 1.10
TMB-4 Br2 (III) 1.18 2.56
Obidoxime ( IV) 1. 47 1.39
TMB-4 C12. 1.48 1.67
2-PAM C1 (I) 1.53 1.33
DAM (V) 2.61 3.13
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on the responses induced by prior lntraventricular injection of ethyl
pyrophosphate. In interpreting these findings, it is pertinent to
point out that the doses of the various oximes used correspond with
0.044 mmol/kg of III, 0.~89 mmol/kg of 2-PAM I, and 0.248 mmol/kg of
V. On the basis of these values, Edery' ~ conclusion that 2-PAM I
was the most active antagonist of ethyl pyrophosphate may be
quest ionable .
These aM other findings have raised the question of whether qua-
ternary pyridini~ osimes can enter the CNS from the general circula-
tion. Kalser,43 in a study with rats and cats given intravenous
injections of I tagged with i4C in the quateraizing me tiny] group,
found that the cerebrum, the cerebellum, the medulla oblongata, and the
spinal cord contained only traces of i4C at times at which the blood
contained the label at 19-53 ~Ci/kg. However, Firemark et al.42
found that the brain of the rat had a concentration of i4--2-PAM I
about one-tenth that in plasma 10 min after intravenous injection of
labeled oxime at 20 mg/kg. In the brain, the cerebral and cerebellar
cortices had the highest concentrations of the label; the caudate
nucleus, the thalamus, and the hypothalamus contained concentrations
a little less than half those in the cortices. Rats pretreated with
the anthe~mintic organophosphate trichiorfon and killed 10 min after
intravenous injection of labeled 2-PAM I had a concentration of the
label in their brains about twice that found in normal rata. The
brain appears, therefore, to be somewhat permeable by 2-PAM I, but
distinctly less so than leg muscle, diaphragm, liver, and kidneys
according to Ka1ser's data, and to have that permeability increased
by an organophosphorus anticholinesterase compound.
Freshly prepared 80iUtioU8 of II (150 mg/mI) in water or DMSO
were applied to the skins of guinea pigs and rabbits, except that on
the head awl legs.43 The II in DMSO entered ache blood of the rab-
bit at a peak rate about 3 times that at which lI in water penetrated
the skin. No uptake of II from the aqueous solution by the guinea
pig was detected. The rate of uptake of II from the DMSO solution by
the guinea pig was about two-thirds that by the rabbit. Guinea pigs
that had been anointed with the DMSO solution of II were given sarin
subcutaneously at 200 mI/kg and immediately thereafter atropine sul-
fate intramuscularly at 15 mg/kg. Similarly anointed rabbits were
given sarin intravenously at 100 ~g/kg and then atropine sulfate
intramuscuairly at 15 mg/kg. For the guinea pigs, the shortest
interval between skin application of II in DMSO and sarin administra-
tion at which death occurred was 12 h. For the rabbits, the corre-
sponding time was 5 h. It is apparent, therefore, that DMSO can
facilitate the movement through guinea pig and rabbit skin of suffi-
cient II to maintain protective blood concentrations of II for
reasonab' e times.
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The LDso of I, injected intravenously, for rabbits was
decreased by prior intravenous injections of d-tubocurarine at 0.1
mg/kg or atropine sulfate at 2 mg/kg by 63.4% and 9.3:, respec-
~ci~rely.44 Prior intravenous injection of neostigmine bromide at
0.1 mg/kg increased the LDso by 31.2X. These findings indicate
that I exerts its principal action on the neuromuscular junction in
skeletal muscles and has only a minor effect on muscarinlc choliner-
gic junctions. This conclusion agrees generally with that from
Kalser's work. It is reinforced by reports that I blocks transmission
in the isolated rat phrenic nerve-diaphragm preparation;45 that it
antagonizes the stimulant action of acety~choline on isolated frog
muscle;46 that it decreases the response of the frog rectus abdo-
minls muscle to decamethonium and to carbamylcholine, in addition to
the response to acetylcholine, but in large concentrations increases
partial blockade of transmission in the rat phrenic nerve-diaphragm
preparation induced by prolonged exposure to decamethonium;47 and
that it increases, and in high concentrations decreases, the endplate
potential.48
Wagley48 found that V produced a dose-related decrease in the
endplate potential of the curarized illofibularis muscle of the frog
at 1-3 ~ 10-2 M. A similar effect of 2-PAM ~ was found at 1-3 ~
10~3 M, whereas concentrations below 10-3 M produced dose-related
increases in the endplate potential. Fleisher et al.47 found that
III, unlike I, had no excitatory action on the isolated frog rectus
abdominis, but had a more potent effect than I in inhibiting the
response of that muscle to decamethonium, carbamylcholine, and
acety~choline.
Junket et al.49 found that intravenous administration of III
at 5 and 10 mgTg had no effect on the response of the cat gastroc-
nemius-soleus muscle group to supramaximal indirect stimulation at
either slow (0.5/~) or tetanizing frequencies. An intravenous dose
of 20 mg/kg produced a marked temporary decrease in the response to
a tetanizing frequency without altering the twitch response. An
intravenous dose of 40 mg/kg almost abolished for 25 min or more the
response to delivery of a tetanizing frequency to the motor nerve
and decreased by about BOX the tension developed in the twlLch
response. That dose of III alto blocked partially the response of
the heart to stinmiatioD of the vague nerves, but did not modify the
changes in blood pressure induced by bilateral occlusion of the
carotid arteries or by intravenous injection of acety~choline
chloride or epinephrine chloride at 3 ~g/kg. The effect of III,
like that of I, seems to be predominantly on nicotinic cholinergic
junctions. The effects of TMB-4 Con on the response of the cat
heart to stimulation of the vagi and on contraction of the nictitat-
lng membrane after pregang~ionic stimulation of the superior cervical
ganglion were more marked than those of the same intravenous dose
(15 mg/kg) of I. 50
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Dultz et al.23 infused V intravenously into dogs at 50 mg/kg
per minute and I at 30 mg/kg per minute. The mean times to death
after infusions of the two oximes were 10 and about 33 min. respec-
tive~y. These times correspond with relative lethal doses of 100
and 196.5, respectively. These values are not far from those for
intraperitoneal injections of the two opines into mice.~00~206
After V, the heart rate rose initially and then, after about 3 min
of infusion, began a slow decrease. The diastolic pressure
decreased progressively from the start of infusion, whereas the
systolic pressure remained fairly steady during the first 4 min of
infusion and then began to decrease sharply. The rate of breathing
and the tidal volume were reasonably constant during the first 5 min
of infusion; the rate of breathing then increased, after an initial
brief decrease, to nearly 3 times its original value by 9.5 min after
the start of infusion. During the same period, the tidal volume
decreased to about one-tenth its original value. At 10 min after
the start of infusion, the animal became apneic, the pulse pressure
fell to zero, there was a brief period of arrhythmia associated ~ th
an elevation of the J segment of the EGG, and then the dog died.
The most striking changes during the early minute e of infusion
of I were increases in systolic and pulse pressures. These were
accompanied by an increase in breathing rate without much change in
tidal volume or heart rate. After about 28 min of infusion, systolic
pressure and heart rate began to decrease. About 3 min later, both
systolic and diastolic blood pressures fell precipitously with heart
rate and tide' volume. Breathing rate had begun to decrease sharply
after about 28.5 min of infusion. Terminally, the T wave of the ECG
was increased and prolonged, and the voltage of the QRS complex was
markedly reduced. Death followed apnea by only a few minutes. The
changes reported by these investigators suggest that V kills by CNS
depression, whereas I kills by interfering with Depolarization and
contraction of cardiac muscle.
Ba11 ant yore et al. 5' gave rabbits intramuscul ar or intravenous
injections of II at the LDso. They found that plasma II maintained
at less than 90 ~g/~1 was not lethal. Concentrations of 90-160 l~g/ml
were not lethal if they persisted for only a few minutes. If concen-
tratioDe in that range were maintained for 40-SO min. there might be
a sudden increase to above 200 ug/mi. A plasma II concentration
above that loci t generally led to death. The II concentrat ion in
the aqueous humor of the eye increased slowly, but an hour after
injection was nearly the same as that in the plasma. Thereafter,
the II concentration in the plasma and-in the aqueous humor
decreased at similar rates.
TOXICITY OF REPEATED DOSES IN EXPERIMENTAL ANIMALS
. .
Rats and rabbits received intramuscular injections of solutions
of II in saline 5 d/wk for ll and 9 wk. respectively.S2 Dogs were
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given gelatin capsules of II by mouth 5 d/wk for 17 wk. Control
groups of rats and rabbits were given physiologic saline intramuscu-
larly on the same schedules as those which received II. No control
dogs were included in the experiment; comparisons were made between
the dogs given II and "normal" animals. The daily doses of II
injected into rats were 50 and 150 mg/kg; those injected into the
rabbits were 50 and 100 mg/kg. Dogs weighing 13-17 kg received
daily doses of ~ g, or about 59-77 mg/kg.
The rats given II seemed to be normal both grossly and by micro-
acopic esaminatlon of sections of tissues at the end of the study.
The rabbits had no abnormality clearly attributable to lI other than
puNIent, indurative myositis at the site of injection in nine of 10
animals. Inasmuch as the solutions injected were not stated to have
been sterilized, the myositis is not astonishing. The stomachs of
the three dogs all had fibrosed mucous membranes at the cardiac and/or
pylorlc regions. The plasmas of these dogs had subnormal concentra-
tions of albumin and total protein and low albumin: globulin ratios.
lathe rats given either of the doses of II grew normally, and indeed
somewhat more than the controls. The rabbits, as is not unusual, had
coccidial infestations of their livers and intestines, but had no
lesions attributable specifically to the oxime. The plasma II
concentrations of the dogs shortly before they were killed at the end
of the exposure period were around 60-90 ~g/mI. One of the three dogs
had roundworms (Tosascaris leonine) in its intestines and
granulomatous nodules in its kidneys and pancreas due to this
infestation.
The same investigators made a comparative study of the toxicities
of I and TMB-4 CI2 in rabbits and dogs, published as an interim
report by FOA ~ (Cl024-FlOO) in April 1963 and as a paper in April
1964.53 Groups of eight rabbits received intramuscular injections 5
d/wk for 12 wk of I at 65 mg/kg, 11IB-4 C12 at 30 mg/kg, or physi-
ologic saline at 0.2 mI;/kg. The solutions were sterilized by filtra-
tion through a Seitz filter. Groups of four young beagles (9-~1 kg)
were given capsules containing ~ g of IMB-4 Cl2 or of I 5 d/wk. For
TMB-4 CI2, this dose was continued throughout the 15 wk of the
study; for I, the daily dose was reduced to 0.75 g after the first 2
wk and kept there until the end of the 15-wk study.
Except for local changes at the site of injection, the rabbits
given I intravenously suffered no detectable toxic effect other than a
minor loss of weight. Those given TMB-4 Cl2 began to die during the
third week of the study, six of eight rabbits having died by the end
of the 15-wk period. The blood of the rabbits given either oxime
was seen to clot rapidly, the effect being more marked after TMB-4
C12 at 30 mg/kg than after I at 65 mg/kg and lasting for 4-5 h after
an intramuscular injection. The dogs given capsules of TMB-4 Cl2
had no signs of intoxication by the oxime, whereas those given
cannules of I had dime nished activity, ataxia, and head drop starting
—272—
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2-3 h after they were given their capsules. After the daily dose of
I was reduced, these Aims of intoxication disappeared; they became
evident again in three of the four dogs during weeks 10-12 of the
study. The signs of renewed intoxication appeared on only a few days
in each dog and then disappeared again, although administration of I
continued. The curves of gain of body weight by the dogs were unaf-
fected by the oximes, and all were judged to be in a normal state of
nutrition at the end of the 15-wk period.
At the sites of injection of oxime in the rabbits, various
extents of hemorrhage and of purulent, indurative myositis and muscle
necroals were seen. The rabbits that received physiologic saline and
five that received intramuscular injections of 2.15 M sodium chloride
on ~ ~ in a satellite experiment had waxy degeneration of muscle at
the site of injection. Five rabbits that received in~cramuscular
injections of 2.15 M I on ~ ~ also had wary degeneration of muscle
at the site of injection. This was stated to be more extensive than
that seen in the rabbits given equimolar sodium chloride. No other
lesions in the rabbits that seem to be attributable to the oximes
were described.
The dogs given capsules of the o~cimes were found to have hypere-
mia in their stomachs and intestines. Four of the eight dogs had
erosions of gastric mucosa, evident particularly in the apices of
the rugae in the fundus and found in animals given I an well as in
those given TMB-4 CI:. ~ ~ the dogs had epithet al defects and
proliferation of the connective tissue of the lamina propria. Atro-
phy of stomach glands was seen sometimes. The brains of both the
dogs and the rabbits were described as having peculiar, slightly
granular, basophilic structures in the white matter of the brain
stem. These could appear as spheres or clouds. The figure purport-
ing to demonstrate these structures does not do so clearly enough to
permit a guess as to their nature; they may be nothing more than fix-
ation artifacts.
Inasmuch as myositls was reported in the second paper53 as
well as in the first,52 this response must be induced by the oxides
and not by bacteria. The second paper showed that oral doses of I
and TMB-4 Cl;: induced the same sort of scar formation as II in the
gastric mucosa, 80 that this response may be induced by either the
oximino group or the quater~ary nitrogen atom. It would be informa-
tive in this regard to have the results of an experiment in which
capsu] es of pyridine-2-a~ doxime and of N-methy~pyridinium chloride
were administered in a similar fashion.
The toxicities of repeated intravenous doses of I and II in rab-
bits and dogs have been estimated.54 Six rabbits were given I at
50 mg/kg 5 d/wk for 6 wk; four rabbits were given II at the same dose
on the same schedule. Three 60g8 were given I at 25 mg/kg b.i.~. 5
-27 3—
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69. Namba, T. 1958. Toxicity of PAM (pyridine-2-aldoxime methio-
dide). Naika no Ryoiki 6:437-441.
70. Qul~by, G.E. 1964. Further therapeutic experience with pralid-
oximes in organic phosphorus poisoning. J. Am. Med. Assn. 187:
202-206.
71. Taylor , W. J.R., Llewellyn-Thomas , E., Walker, G. C ., Sellers ,
E.~. 1965. Effects of a combination of atropine, metaraminol,
and pyridine aldoxime methanesulfonate (AMP Therapy) on normal
human subjects . Canad. Med. Asen. J. 92: 957-961.
72. Caleenick, B., Christensen, J.A., Richter, M. 1967. Human toxi-
city of various oximes. Arch. Rev. Hlth. 15: 599-608.
73. Wirth, W. 1968. Schidigungsmo'glichkeiten durch Antidote. Arch.
To2rikol . 24: 71-82.
74. Quinby, G.E. 1968. Feasibility of prophylaxis by oral pralid-
oxime. Arch. Env. Hlth. 16: 812-820.
75. Sidel l, F.R., Groff , W.A., Ellin, R. I. 1969. Blood levels of
onetime, excretion rates, and side effects produced by single oral
doses of N-methy~pyridinium-2-aldo~cime methanesulfo~te (P2S) in
heads. EAIR 4256.
76. Sidell, F.R., Grof f , W.A., Ellin, R. I . 1969. Blood levels of
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muscular administration. Brit. J. Indust. Med.
167. Sidell. F.R. ~ Groff, W.A., Kaminakis, A. 1972.
Plasma concentrat ions of the
after repeated oral and in~cra-
33:43-46.
Pralidoxime
methane sulfonate: plasma berets and pharmacokinetce in man after
oral administration of a new preparation. EATR 4596 and J.
Pharmaceut . Sci. 61: Il36-~140.
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Oximes and related cho~nesterase Deactivators.
15:33-42.
/
-330—
V. The effect of
Teratology
OCR for page 331
161. Swartz , R. D., Side' i, F.R. 1974. Renal tubular secretion of
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162. Josselson, J., Sidell, F.R. 1976. The ef feet of intravenous
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EB-TR-7 6118 .
165. Hold and, P., Parke , D. C., Reeve , A. 1971. Dose response in
hens of slow and rapid release P2S tablets. CDE TN 58.
166. Holland, P., Parks , D. C. 1976.
Oxime pralidoxime mesylate (P2S)
muscular administration. Brit. J. Indust. Med.
167. Sidell. F.R. ~ Groff, W.A., Kaminakis, A. 1972.
Plasma concentrat ions of the
after repeated oral and in~cra-
33:43-46.
Pralidoxime
methane sulfonate: plasma berets and pharmacokinetce in man after
oral administration of a new preparation. EATR 4596 and J.
Pharmaceut . Sci. 61: Il36-~140.
168. Sidell, F.R., Groff, W.A. 1970. To~cogonin: oral administra-
tion to man. EATR 4397.
169. Sidell, F.R., Groff, W.A., Sr., Kaminakis, A. 1972. Toxigonin
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stration to man. EATR 4625 and J. Pharmaceut. Sci. 61:1765-
1769.
170. Gabourel, J.D., Cometock, J. P. 1962. Effect of diacetylmon-
oxime on the action of convulsant and sedative-hypnotic barbitu-
rates . J. Pharmacol. Exp. Therap. 137 :122-126.
171. Landauer, W. 1977. Cholinomimetic teratogens .
Oximes and related cho~nesterase Deactivators.
15:33-42.
/
-330—
V. The effect of
Teratology
OCR for page 332
161. Swartz , R. D., Side' i, F.R. 1974. Renal tubular secretion of
pralidoxime in man. EB-TR-73017 and Proc. Soc. Exp. Biol. Med.
146: 419-424.
162. Josselson, J., Sidell, F.R. 1976. The ef feet of intravenous
thiamine hydrochloride on pra~idoxime pharmacokinetics in man.
EB-IR-7 6115.
163. Josselson, J., Sidell, F.R. 1977. Dose-response ef fects of
intravenous thiamine hydrochloride on pralido~cime pharmacoki-
netics in man. EB-TR-76117.
164. Josselson, J., Sidell, F.R. 1977. Thiamine hydrochloride as an
adjunct to pralidoxime in a simulated therapeutic setting.
EB-TR-7 6118 .
165. Hold and, P., Parke , D. C., Reeve , A. 1971. Dose response in
hens of slow and rapid release P2S tablets. CDE TN 58.
166. Holland, P., Parks , D. C. 1976.
Oxime pralidoxime mesylate (P2S)
muscular administration. Brit. J. Indust. Med.
167. Sidell. F.R. ~ Groff, W.A., Kaminakis, A. 1972.
Plasma concentrat ions of the
after repeated oral and in~cra-
33:43-46.
Pralidoxime
methane sulfonate: plasma berets and pharmacokinetce in man after
oral administration of a new preparation. EATR 4596 and J.
Pharmaceut . Sci. 61: Il36-~140.
168. Sidell, F.R., Groff, W.A. 1970. To~cogonin: oral administra-
tion to man. EATR 4397.
169. Sidell, F.R., Groff, W.A., Sr., Kaminakis, A. 1972. Toxigonin
and pralidoxime: a kinetic comparison after intravenous admini-
stration to man. EATR 4625 and J. Pharmaceut. Sci. 61:1765-
1769.
170. Gabourel, J.D., Cometock, J. P. 1962. Effect of diacetylmon-
oxime on the action of convulsant and sedative-hypnotic barbitu-
rates . J. Pharmacol. Exp. Therap. 137 :122-126.
171. Landauer, W. 1977. Cholinomimetic teratogens .
Oximes and related cho~nesterase Deactivators.
15:33-42.
/
-330—
V. The effect of
Teratology
Representative terms from entire chapter:
blood pressure
