Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2 Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants (1984) / Chapter Skim
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Appendix B. Digest Reports: Oximes
Appendix B. Digest Reports: Oximes
Pages 263-332
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From page 263... ...
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 organophosphorus 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.
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From page 264... ...
Similar results have been obtained with d-tubocurarine,l9 gallamine,:9 and piperidyl methylandrostanediol.20 Crone23 reported that d-tubocurarine chloride in vitro at 10~4 M completely prevented for 6 h the aging of red-cell acety~cholinesterase that was inhibited by sarin and that gallamine triethiodide at the same concentration markedly slowed the aging of similarly inhibited cholinesterase. 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.
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From page 265... ...
Skeletal muscles become unable to maintain a tetanic response to repetitive indirect stimulation at doses of Roman below those that affect significantly cardiovascular 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.
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From page 266... ...
being considerably 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.
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From page 267... ...
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)
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From page 268... ...
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)
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From page 269... ...
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.
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From page 270... ...
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.
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From page 271... ...
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.
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From page 272... ...
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 physiologic saline at 0.2 mI;/kg. The solutions were sterilized by filtration through a Seitz filter.
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From page 273... ...
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.
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From page 274... ...
Hyperventilation, mentioned above as the most frequent sign of intoxication, was stated to occur only during injections of the oximes and to stop immediately after the end of the injection. All the dogs given intravenous injections of an osime had decreases in their blood concentrations of hemoglobin (mean, -23.2X)
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From page 275... ...
No alterations that seemed to be related to ingestion of the oxides were found in hematologic values, blood chemistry, urinalysis, organ weights, organ: body weight ratios, or gross and microscopic appearances of tissues and organs removed at necropsy. AIL additional study of daily intravenous injection into rats and dogs of IV at 35 mg/kg 5 d/wk for 4 wk used groups of 10 rats and four doga -- two males arid two females.56 The only visible signs of toxicity observed in the rats were wheezing, hype Apnea, and "awelling in the throat." Wheezing, recorded I]
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From page 276... ...
7 Both rabbits and dog e received daily doses of 2-PAM T at 30 mg/kg and of III at 10 mg/kg. Two dogs and two rabbits received intravenous injections of physiologic saline on the same schedule fo1lowed for injecting oximes.
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From page 277... ...
If the plasma concentration of an oxime 5 min after intravenous injection was taken as the initial value, at 30 minutes it had fallen to 21.~% (2-PAM I)
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From page 278... ...
Convulsions have been reported after V.59~63 Moderately marked increases in systolic and diastolic blood pressures with increased pulse pressures and tachycardia have been reported to follow intravenous administration of 2-PAM I, I, and II.59~63~69~72~73 The increases after II were not as great as those after I The two bisquater~ary bis-oximes (III and IV)
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From page 279... ...
Facial paresthesia and headache were the principal complaints of the 13 subjects, in a group of 24, who mentioned symptoms after oral doses of 1.84-7.36 g of IV. Sidel1 _ al.~° reported that intramuscular injection of I or sodium chloride into normal human subjects resulted in increases in serum creatine phosphokinase activity.
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From page 280... ...
Me thy] nicotir~ium hydrodynamic acid iodide ah later 2-PAM I~both having a quaternized nitrogen atom removed by about two carbon atoms from a hydroxylated nitrogen atom-were found to be effective Deactivators of chollnesterase inactivated by organophosphorus inhibitors.2~4~82 Although the truth of the basic assumption was not demonstrated until 1959,84 the general success of quateraization in increasing the reactivating potencies of hydroxamic acids and oxides with pyridine skeletons made it almost certain before then.
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From page 281... ...
Ho lees and Robins45 reported that 2-PAM I overcame neuromuscular blockade induced by DFP, TEPP, or satin, but this could be demonstrated with the isolated phrenic nerve-diaphragm preparation from the rat only after washing away excess OP compound. Intravenous injection of 2-PAM I overcame slowly neuromuscular blockade induced by OP compounds.
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From page 282... ...
It Is apparent from Table 3 that addition of 2-PAM I to atropine increased cholinesterase reactivation by 40.5% in the parotid gland, by 127.~% in the gastrocnemius muscle, and by 8.2% in the brain. The especially large change in cholinesterase activity in skeletal muscle suggests tat this may be the principal site at which 2-PAM ~ antagonizes inhibition of cho linest era se .
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From page 283... ...
TABLE 3 Recovery of Cholinesterase Activity in Parotid Glands, Gastrocnemius Muscles, and Brains of Rats Poisoned with Subcutaneous Vat at 40 llg/kg and Treated 20 Min Later with Intraperitoneal Atropine Sulfate at 7 mg/kg or with Intraperitoneal Atropine Sulfate and 2-PAM I at 17.5 mg/kga Reactivation, X of inhibition by VX Parotid Gastrocnemius Go and Muscle Therapy Atropine sulfate 39.0 Atropine sulfate + 2-PAM I 54.8 25.2 57.4 Brain 8.5 9.2 a Samples of tissue were removed 3 h after therapy, or 20 min after VX if no therapy was administered. Groups of rats contained a mean of ~ (6-15)
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From page 284... ...
The patient was still unconscious, however, with markedly constricted pupils. At that time, intravenous injection of 0.5 g of 2-PAM I in a 1% solution relieved both residual effects immediately, and no further treatment was required.
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From page 285... ...
The latter possibility is related to the proposal of Erdmann _ al.98 that restoration by 2-PAM I of the righting reflex after its abolition by parathion is effected by the oxime's modifying inhibition of chow nesterase in some peripheral site important for activity of the refiles. Rajapurkar and Koelle99 reported that intravenous V at 40 mg/kg, but not at 4 mg/kg, induced reactivation of cholinesterase in the surfaces of cells of the casts superior cervical ganglion after the animal had been given DFP at 3.7 mg/kg 20 min earlier; there was no significant reactivation of the cholinesterase in the ganglion as a whole (after homogenization)
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From page 286... ...
Apparently on the other aide of the picture iB a report by Meeter 04 that intraperitoneal injection of either III or IV at 40 mg/kg, given to rats when their body temperatures had fallen 2-2.5°C after intravenous injections of DFP at I.2 mg/kg, blunted the fan , which might proceed in untreated rats to a decrease of nearly 6 °C. These doses also shortened the return of body temperature to its normal value.
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From page 287... ...
These animals survived; those given paragon alone al, died in convulsions within 3-8 min. Badgar et al.~07 found that acety'cholinesterase activity in the pontomedul~ary area of the mouse brain was possibly a direct linear function of the dose of IV (2.5-35.0 mg/kg)
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From page 288... ...
and an increase in pulse prensure.~3 The mean blood pressure, after a small dip immediately after the injection, returned approximately to the control value. With repeated doses of 5 and 10 mg/kg, the heart rate decreased after each dose and then returned gradually to its normal value e After a cumulative dose of 100 mg/kg, there was marked lowering of the heart rate and a decrease in the voltage of the T-wave of the EGG.
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From page 289... ...
was a more potent antagonist of d-tubocurarine than this dose of 2-PAM I Partial blockades of neuromuscular transmission induced by intravenous injections of decamethonium bromide at 20 ~g/kg, neostigmine bromide at 1 mg/kg, or succiny~choline chloride at 50 ~g/kg were intensified by intravenous injection of 2-PAM I at 5 mg/kg, in about the same way in which they were enhanced by intravenous doses of edrophonium bromide at 0.2 mg/kg.
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From page 290... ...
revealed that the peak systolic blood pressure paralleled more faithfully the peripheral resistance than it did any of the other variables and that the peripheral resistance increased more abruptly after a third dose of I at 30 mg/kg than after the second such dose, which in turn induced a larger increase than the first dose. The blood flow decreased to 55% of the original value during the 76 min between the peak flow after the second dose of I and the third dose.
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From page 291... ...
until their blood pressures became approximately the same as they had been before the infusions began were then given intravenous injections of I at 20 or 40 mg/kg, tyramine at 0.l or 0.5 mg/kg, or nicotine at 0.5 mg/kg.il~ The concentration of norepinephrine in carotid arterial blood was estimated before and at intervals after the injection of one of the test compouada. Except after the lower dose of tyramine, when the maximal locrease in the concentration of norepinephrine in the blood appeared at 5 min after the injection, the peak concentration of norepinephrine in carotid arterial blood occurred at 3 min after injection.
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From page 292... ...
In view of the fact that none of the possible antagonists was able to prevent more than about 68.5% of the increase in peripheral resistance induced by I, this oxime may well have direct stimulant effects on vascular smooth muscle. III, unlike I, was fouad49 to lower blood pressure and produce bradycardia in cats anesthetized with sodium pentobarbital.
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From page 293... ...
Bayl20 nude a more extensive study of the erects of III on blood pressure, respiration, and ganglionic and neuromuscular transmission. Intravenous doses of 25 mg/kg or more decreased systolic and diastolic pressure in anesthetized cats and dogs.
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From page 294... ...
~ increased the ef fects of injected epinephrine on blood pressure aM contraction of the nictitating membrane, but decreased the response of the nictitating membrane to stimulation of the cervical sympathetic trunk. These findings fairly well loca~ized the blocking action of this oxime to the ganglion itself.
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From page 295... ...
Intravenous injection of IV into a cat at 15 mg/kg decreased the response of the heart to stimulation of the vague nerve and completely blocked contractions of the nictitating membrane in response to stimulation of the cervical sympathetic chain. An intravenous dose of 50 mg/kg decreased blood pressure am1 respiratory activity.
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From page 296... ...
Heat sterilization of an aqueous solution of II was found to result in the formation of small amounts of cyanide and in a change in the color of the solution from pale yellow to orangebrown. A homogenate of liver from the rat was found to decompose II slowly; other biologic samples (whole blood-, kidney, skeletal muscle, urine, and feces)
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From page 297... ...
Information on the atorage stabilities of IV and V has not been found, other than a note that, when stored at 37°C at an unspecified pH, both 2-PAM I and V had half-lives greater than 7 mot After oral administration of I to dogs at nearly Too mg/kg in an aqueous solution, the -concentration of oxime in the plasma ~ h later was as great as was measured at any later time.~35 By 5 h after the dose, the plasma concentration had decreased to 51.3: of that at ~ h; by 13 h, it was only I8X of that at ~ h. When approximately the same -297~
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From page 298... ...
Kunkel et al.l39 found that three of six rabbits Riven intramuscular injections of atropine sulfate at 6 mg/kg 55 min before intravenous injection of nomad at l.5 times the LD,o lived for 7 ~ thereafter. When the atropine was accompanied by I at 15 mg/kg, yielding a plasma concentration of office of about 4.8 ~g/mI, two of six rabbits lived for 7 d.
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From page 299... ...
in the urine of one cat. lrhe urine of mice was believed to contain at least six chromatographical~y separable metabolites of 2-PAM I, in addition to the unchanged oxide, whereas the urine of the one cat seemed deco contain only unchanged oximee Only O.~8X of the label was found in the expired air of mice during 6 h after intravenous injection of labeled onetime.
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From page 300... ...
to rats at 500 or 100 mg/kg, respectively, increased by many times the urinary excretion of thiocyanate. From the amount of thiocy~anate excreted above the base line, the quantity of hydrogen cyanide produced in metabolism of the oxime was calculated to be 0.l mg/kg -- a little more than one-third the LD,o for rats by intraperitoneal injection.
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From page 301... ...
Using this method, Way et al.~43~~46 identified N-methy~pyridini ~-2-Ditri~e, _ _ _ N-methy~pyridinium-2-one, and N-methylpyridinium-2-aminocarbonyI-4one as metabolic products of 2-PAM in the perfusate from isolated rat livers. They also found, but did not identify, an N-methylpyridini~'m2-0-conjugate, which was not hydrolyzed by either ~glucuronicase or phenol sulfatase.
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From page 302... ...
Alkalinization of the urine by administration of ace~cazolamide had no effect on the urinary excretion of the osime. Probenecid (priming with 25 mg~kg followed by infusion at 40 mg/kg per hour)
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From page 303... ...
, both systolic and diastolic blood pressures were increased immediately after the end of the infusion (usual duration, 15 min.)
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From page 304... ...
A subject who inhaled aerosols of lob and 50% aqueous solutions of I did not develop hypertension or detectable oximemia. Oral administration of 1 or 2 g every 6 h for 5 ~ to eight subjects resulted 1n no significant changes in blood pressure or heart rate.
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From page 305... ...
When I and II were administered in equimolar doses, the peak plasma concentrations of oxime were reached ater 2 h. With doses of 0.31 mmol/kg, IT gave a peak concentration greater than that given by I by about 4.6 M
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From page 306... ...
doses of 3-9 g of I to a total of 28 men. Although these doses were not adjusted to the body weights of the subjects, there was a general tendency for the mean peak plasma concentration of oxime to increase as the dose increased.
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From page 307... ...
TABLE 4 Biologic Half-Li~res of 2-PAM Salts Given Orally to Man Half-Life, h Concentration Based on Urinary 2-PAM Salt in Plasma Excretion Iodide 2.
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From page 308... ...
It is likely that exposure to the higher temperature at rest resulted in increased blood flow to the kidneys by vasodilatation, that exercise at the lower ambient temperature decreased blood flow to the kidneys by shunting of blood to the active muscles and possibly to the skin to permit dissipation of the extra heat produced during the exercise, that the greater heat load imposed by the combination of higher ambient temperature aM exercise resulted in an eared larger shunting of blood away from tile kidneys to the skin, and that the resultant of vasodilatatioD in the active skeletal muscles and in the skin was a sharply decreased blood flow to the kidneys and, consequently, lower tubular secretion of p-~minohippurate and I After being found to be healthy on a thorough physical examination accompanied by a broad range of laboratory examinations, 22 men were used in studies of the renal clearance of I, after intravenous injection at 5 mg/kg under a variety of conditions.~6' Alkalinization of the urine to a pH above 7.5 by administration of bicarbonate and acidification of the urine to a pH below 5.0 by administration of ammonium chloride both reduced urinary excretion of I
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From page 309... ...
They found initiallyi62 that an infusion of thiamine at 100 mg/h during 2.5 h led to a greater plasma concentration of oxime after intravenous injection of I at 5 mg/kg than when the injection of I was not accompanied by an infusion of thiamine. The renal clearance of I and the urinary excretion of I were greater during the first 1.5 h of infusion of thiamine than during the corresponding period after injection of I without infusion of thiamine.
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From page 310... ...
Four of the men also complained of fatigue and drowainess; two complained of "vitamin gustatory sensation." The two men who had hypertension after the infusion of I with thiamine had mean increases in systolic blood pressure of 34 mm Hg and in diastolic pressure of 24 mm Hg. lathe mean maximal increase in heart rate of these two men and of the one other man who had only an increase in heart rate was 25 beats/mint In all five men, the mean plasma concentration of oxime was always greater in the experiments in which the infusion included thiamine than in those In which ache infusion contained I alone, by about l-~1 ug/mI.
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From page 311... ...
Oral doses of I (form not specified) produced peak plasma concentrations of oxime sooner after ingestion than after ingestion of the tablets of II; the peak plasma concentration from a given dose of I usually was larger than that from a similar dose of II in the form of -311
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From page 312... ...
Doses of 2, 4, 6, and g of II were taken by the fasted subjects, and doses of 4 and 6 g by those who had broken their fasts. Peak plasma concentrations of the onetime were reached within 2-3 h after the tablets were ingested.
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From page 313... ...
The half-eime of urinary excretion was about 84.5 + 10 min. Dose-re~ated increases in the heart rate and systolic and diastolic blood pressures were alto produced by IV.
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From page 314... ...
ache minimal time required for reaching the peak plasma concer~tration of the oxime after intramuscular injection. The half-time for urinary excretion of IV may be about ~ h after intravenous injection.
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From page 315... ...
Whereas the most striking cardiovascular response to the monopyridinium monoximes is hypertension, that to the bispyridinium bisoximes is prolonged hypotension after an initial, short hypertensive response. The hypertension and tachycardia that have been induced by initial —315—
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From page 316... ...
The principal lack in the available information perceived in this review is the absence of any significant attempt to determine whether a delayed toxic effect becomes evident after administration of these compounds. Although hydrogen cyanide is a metabolic product of the monopyridinium monoximes and a nitrite has been found in the urine of rats given III, the production of these compounds has not been great enough to cause obvious toxic effects near the times of administration of the oximes.
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From page 317... ...
1967. Reactivation by pyridinium aldoxime methochloride (PAM)
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From page 318... ...
1966. Reirereal of a soman-induced ef feet on neuromuscular function by oximes.
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From page 319... ...
1965. Penetration of guinea pig atop rabbit skin by dimethyl sulfoxide solutions of a quaternary oxime .
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From page 320... ...
1965. Effects of 2-PAM and IMB-4 on neuromuscular transmission.
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From page 321... ...
injection of hype rtortic solutions of P2S and sodium chloride.
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From page 322... ...
1974. Serum crea tine phosphokinase activity after intramuscular injection.
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From page 323... ...
1956. The effect of oximes on neuromuscular block produced by sarin in the rat.
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From page 324... ...
1963. Spontaneous and pralidoxime induced reactivation of brain cholinesterase in the chick after fatal nitrostigmine poisoning.
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From page 325... ...
1972. The influence of obidoxime on acety~cholinesterase activity in different parts of the mouse brain following isopropylmethylphosphonofluoridate into2rication.
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From page 326... ...
1963. Experimental analysis of the rise in blood pressure in dogs OOOsed by intravenous 2-PAM chiorlde.
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From page 327... ...
and pralidoxime chloride (PAM C1) in aqueous solutions.
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From page 328... ...
1976. lathe metabolism of C14 2-PAM in the isolated perfused rat liver.
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From page 329... ...
1970. Modification of the effects of atropine on h~an heart rate by pralidoxime.
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From page 330... ...
Plasma concentrat ions of the after repeated oral and in~cra33:43-46. Pralidoxime methane sulfonate: plasma berets and pharmacokinetce in man after oral administration of a new preparation.
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From page 331... ...
Plasma concentrat ions of the after repeated oral and in~cra33:43-46. Pralidoxime methane sulfonate: plasma berets and pharmacokinetce in man after oral administration of a new preparation.
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From page 332... ...
Plasma concentrat ions of the after repeated oral and in~cra33:43-46. Pralidoxime methane sulfonate: plasma berets and pharmacokinetce in man after oral administration of a new preparation.
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