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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 -263-

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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 -264

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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 -266-

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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 -268 -

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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. 269-

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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 -27C-

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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 -271

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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 oxime and symptoms in hams after single and multiple oral doses of 2-pyridine aido~lme methochioride. J. Pharmaceut. Sci. 58: ~ 093-1098. 7 7. Sidell, F .R., Grof f 9 W.A. 1969. Tozogonin : blood levels and side effects after intramuscular administration in man. EATR 4344. 78. Boelcke, G., Creutsfeldt, W., Erd~sm, W.D., Gaaz, J.W., Jacob, G. 1970. Untersuchungen zur Frage der Lebertoxicitat von Obidoxin. (TosogoninR) am Menechen. Dtach. Med. Wachr. 95: 1175-1178. 79. Sidell, F.R., Groff, W.A. 1971. Tozogonin: oral administration to man. J. Pharmaceut. Sci. 60:860-863. 80. Sidell, F.R., Culver, D.L. , RamiO8ki8, A. 1974. Serum crea- tine phosphokinase activity after intramuscular injection. The ef feet of dose, concentration, and volume . J. Am. Med. Assn. 229:1 894-~897. 322

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