Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents Volume 1 (1982) / Chapter Skim
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Appendix I: Digest Report--Anticholinergic Chemicals-- by Henry Wills, Ph.D.
Appendix I: Digest Report--Anticholinergic Chemicals-- by Henry Wills, Ph.D.
Pages 117-262
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From page 117... ...
Diethylaminoethy 1 Benzilate Effect s on Han Human Data f rom Edgewood Arsenal S',nmary Esters of Phenylcyclopentylglycolic Acid tJ-He thyl-4-piperidinyl-( pheny~cyclopentyl) -glycolate (EA 3443)
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From page 118... ...
"TAB' Mixture Di scussion No te: The chemical nomenc lature may dif fer f rom that given in the master file. The EA or other number serves for t~entification of the compound in the master file.
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From page 119... ...
The ~ 7 esters represented in the 58 reports mentioned above belong to seven series of compounds: esters of tropic acid, of benzylic acid, of phenylisopropy~glycolic arid, of phenylcyclopenty~glycolic acid, of 3-quinuc lidinol, of ethyl-4-piperi:dinol, and of N-diethylaminoethanol. Esters of tropic acid occur in nature and have a comparatively long history of use as drugs.
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From page 120... ...
Quaternization of these alk~Ioide removes much of their ability to penetrate into the central nervous system and to affect its functions. However, the same variation in chemical structure increases the weak ability of these materials to interfere with the action of acety~choline at the motor end plates of skeletal muscles.
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From page 121... ...
These compounds seem to attach to the same receptors to which acety~choline usually attaches itself and thus to interfere with the ability of acety~choline to produce changes in the properties of cellular membranes. The actions of atropine and Scopolamine to block synaptic transmission within some areas of the central nervous sytem and Lo induce c oma were applied to the treatment of I 3
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From page 122... ...
(22) reported on 51 psychoneurotic and psychotic patients treated with intramuscular inJectione of 10-220 mg of atropine sulfate every other day during a period of 3-7 ok.
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From page 123... ...
dada _ al. stated that trepro~rement, when it occurred, began with the third to the seventh injection and increased with later injections.
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From page 124... ...
In the cases of compounds that hat been administered to man previously, the effects could be described quite accurately; if the only previous recipients had been experimental animals, the description of possible effects had to be somewhat hypothetical but usually could be re ~sonably accurat e . Before a discussion of the specific groups of anticholinergic compounds, it may be worth while to have a general view of the procedure of the experiments carried out wit}` human volunteers at Edgewood Arsenal and followed also by contractors.
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From page 125... ...
, the light reflex of the iris, salivation, ant heart rate. The compounds administered to dogs included a eropine, scopolamine, and a methylatropinium salt.
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From page 126... ...
A dose of scopolamine at 0.05 mg/kg rendered four of four dogs ataxic and caused them to engage in obstinate progression. This dose also resulted in abolition of the light reflex of the iris, paralysis of salivation between 45 and 135 min after the dose, and a 5 9X increase in heart rate.
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From page 127... ...
reported that pregnant rats given daily subcutaneous injections of atropine sulfate at 0.1 or 0.5 mg/kg-d from day Il to day IS of pregnancy had low heart rated, hypothermia, and greater than usual slowing of the heart by a dose of pilocarpine for about a week after the end of administration of atropine. The progeny of these rats had tachycardia for 2 wk after birth and mydriasis for a week after their eyes opened.
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From page 128... ...
- In addition to the more or less standard actions of anticholinergic compounds due to their ability to interfere with the actions of acety~choline on muscarinic receptors (resulting in acceleration of the heart; relaxation of smooth muscles in bronchi and bronchioles, intestinal tract ~ urinary trace, iris and cil.tary body of the eye, bile ducts and gall bladder, and some cutaneous blood vessels; and decrease or abolition of secretion by glands of the gastrointestinal tract and skin) , these substances may have pronounced effect!
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From page 129... ...
Schallek and Smith (52) reported that intravenous injection of atropine at 0.01 mg~kg into togs anestbetlced with thiopental had no detectable effect on their EEGs or their cardiovascular systems.
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From page 130... ...
of a particularly large affinity of the muscarinic receptors in brain for 3-quinuclidinyl benzilate was applied to the assay of the quantity of muscarinic receptor in a sample of tissue (60, 61~. Intramuscular injection of atropine 30 mitt before intravenous injection of f 3H]
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From page 131... ...
, strongly inhibited the binding of labeled benzilate by homogenates of rat brain, binding of this compound was proposed as an indicator of the presence of muscarinic receptors in particuJ-ar brain structures. In the nine~embered series of corpus striatum, cerebral cortex, hippocampus, superior-inferior colllcull, pons~idbrain, thalamus, hypothalamus, cer~rlcal con-medulla oblongata, and cerebellar cortex, Yamamura and Sayder (61)
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From page 132... ...
benzilate within the various regions studied earlier. In the cerebral cortex, the most ac tive areas of benzilate binding were the occipital cortex and the cortex of the cingulate gyrus.
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From page 133... ...
(72) compared the distribution in the rat brain of tritium-labeled atropine sulfate ant methylatropinium nitrate inJec ted intraperi toneally at 10 mg/kg.
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From page 134... ...
Deaplte this negative report on the Influence of atropine on acetylcholine concentration In the brain, Berry and Storz (74) stated in 1956 thee intraperltoneal iaJecelon of atropine at 6 ~g/kg decreased the mean concentration of acetylcholine in the ret brain from 365 ug/g to 204 ug/g at 30 min after injection.
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From page 135... ...
Although doses of ~ethylatropinium nt era te of 0.25~0.75 mg/leg produced sli ghtly greater release of acety~choline into the ~ c ollecti~ cups than the same doses of atropine sulfate, the former drug in dose-e up to 10 mg/kg produced a maximal increase in motor activity of 2.33 times basal activity, whereas atropine sulfate produced an increase in motor activity of 6.75 dimes basal activity. By using atropine and ~ethylatropinium labeled with trirlum, Aquilonius et al.
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From page 136... ...
Beerine and arecoline induced lacreased concentrations, whereas atropine and acopolamine induced decreases. These data indicate that a suboutaneousI, injected dose of scopolamine about one-f if teenth that of atropine administered similarI,r produced the same decrease in acety~choline concentration in the brain as the larger dose of atropine.
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From page 137... ...
Intravenous injections of tetratydro-5-aminoacr:~ine [THAI at ~ mg/kg and yohimbine at O.S mg/kg were found to produce some recovery from the effects of atropine, TEA being more effective than yohimbine [86~. These authors did not find that small intravenous doses of physostigeine OF neostigmine (0.02 mg/kg)
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From page 138... ...
In addition tO atropine itself, at least three other substances containing i4C appeared in the urine of the mouse. At 30 On af ter intravenous injection of labeled atropine into elce, the structures found to have the highest concentrations of 14C were the gall blaster ant the bile, the urinary bladder, and the duodenum and jedunum.
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From page 139... ...
The progressive shif t of the segment of the tntestical tract with the highest concentration of t4C from the duodenum and jeJunum to the ileum and then to the large bowel reflects the movement of a bolus of art especially high concentration of the isotope don the tract during a period of about 24 h. The failure to f ind \4co: in the expired air of the mice indicates that the tropic acid moiety in the at.ropine molecule is Doe metabolized -- in accord with the f inding that labeled tropic acid itself was excreted without loss in the urine.
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From page 140... ...
No tropic acid or unaltered atropine was f ound in bile. ~tabolites of atropine appeared in the bile Ethic 10 min after intravenous injection of that alkaloid .
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From page 141... ...
~103) used atropine labeled with 3H in the pare po~t~n of the benzene ring in the tropic acid moiety of atropine to follow the disposition of that alkaloid in the rat.
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From page 142... ...
Two Bale and two female subjects received intramuscular inJectione of 2 mg of one of these labeled atropines. One subject received ladi~ridual injections of each labeled atropine on two different days.
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From page 143... ...
(104) after intramuscular injection of tropine-labeled atropine were treated similarly, the half-~imes were I.8 and 16.5 h.
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From page 144... ...
Because tropic acid was the only substance found after alkaline hydrolysis of urine from subjects given tropate-labeled atropine and a substance that was either tropine or a close relative was the only one f ound in large quantities af ter alkaline hydrolysis of urine from subjects given tropine-labelet atropine, it is apparent that atropine did not undergo drastic metabolic modification in human subjects. Oxidative deall~ylation, with excretion of i4CO2 in the expired air, probably led to the temporary formation of noratropine.
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From page 145... ...
told of three children weighing 14-24 kg who livet after taking 600 mg of atropice. Report s of cases of serf ous, nonf atal intoxication by tropic acid esters indicate that recovery f ram such episodes is reasonably rapid.
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From page 146... ...
The f test sign of action by atropine in many subjects was a slight, temporal decrease in heart rate, followed by a gradual increase. Intravenous injection produced effects more rapidly than the other routes of administration.
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From page 147... ...
Using salivary secretion as the Indicator, tfiratchur ( 118 ~ f ound that atropine and scopolamine were about 2 and 4-5 times as active, respectively, after intramuscular injection as after ingestion. When heart rate was used as the indicator, both alkaloids were about twice as active after intramuscular injection as after ingestion.
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From page 148... ...
Atropine i greased heart rate by 60: and tecre aged the amount of saliva produced during ~ min by 6BX. Five subjects complained of mild difficulty in urinating.
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From page 149... ...
Ostfeld ant Aruguete (127) performed a similar study in which 54 volunteers were subjected to subcutaneous injections of 150~800 us of scopolamine hydrobromide.
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From page 150... ...
, 750 mg of P2S, 750 fig of P2S with 2 fig of atropine sulfate, or 2 me of atropine sulfate. The initial rate of absorption was Judged by the time after injection required for attainment of the maximal reduction in heart rate.
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From page 151... ...
followed up this work by comparl~g the effects of intramuscular injections of 2 fig of atropiac sulfate alone and mixed filth 750 fig of P2S on heart rate and sweating in nine exercising men. These volunteers worked at 25°C and a relative humidity of 65-751 until their heart rates had risen to \~0-~30 beat/ and then got injections of atropine alone or of atropine and P2S.
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From page 152... ...
Of three women who had taken scopolamine during the f irat trimester j two delivered apparently normal children. There is no way of determining from the paper what other drugs the women who used these two anticholinerg to substances may beve taken, except that one of seven babies with both congenital heart disease and another unspecified malformation was born to a woman who had used chlorpromazine, di~enhydrinate, meperidine, morphine, and secobarbital sodium in addition to scopolamine .
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From page 153... ...
In addition to the effects on the reproductive functions of the female, there has been some study of the effects of tropic acid esters and related compounds on sexual function in the male. One paper on this topic (125)
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From page 154... ...
Atropine aulfate by either route of adeiniatration induced an increase in heart rate, an increase in akin resiatance, an increase in pupil size, dryness of the skin, and an increased sensation of dryness of the mouth. In general, the effects appeared earlier after intravenous than after intra~uacular injection.
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From page 155... ...
Thereafter, the heart rate decreased gradually, the mean at 7-8 h after the injection being 66.1 beats/. The mean was below that during the control period from the third hour to the eighth hour after injection.
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From page 156... ...
0~5 .85 me . The ineracist ernal injections induced no charges in heart rate or blood pressure within 30 min after injection.
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From page 157... ...
Although tnhalations of 5 me of atropine sulfate latticed an increase in heart rate coo~parable with that induced by the injection of 2 ma, all subjects reported headaches, glddinese, tlretneas, lethargy, ant muscular wea~esa or incoortination after inhaling the 5- mg doses. it took 24 h for all the subjects to feel able to return to their usual acti~ritiea after inhaling the larger dose of atroplne sulfate, ant several reposed visual hallucinations ~ euphoria, and tysuria.
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From page 158... ...
No correlation between body size and decrease tn the Number Facility Test was found. Cummings and Craig (IS5)
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From page 159... ...
The pert ordnances in the Number Facility Test of the untreated group and the group treated with physontigo~ine became essentially identical at about 6 ~ after the dose of scopolamine. The heart rate decreased within 30 min after the dose of physostigeine, but this drug had little effect on pupil size.
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From page 160... ...
Behavior was rated with a checklist. The performances of the subjects in the Number Facility Tests a manual-texterity testy and a vigi lance test were evalua~ced.
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From page 161... ...
If atropine and scopolamine are taken as representative of the group of tropic acid esters, the best indexes of performance in the Number Facility Teat under the lnf luence of such esters are the scores in the lie, hypochondriasis, and mania scales of the ~Pl. After a similar analysis for fire antlcholinergic compound, three other substances with atropine and scopolamine, Clapper en a,.
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From page 162... ...
The increase in heart rate induced by scopolamine methy~bromide was greater than those induced by the same amounts of Scopolamine hydrobromide or atropine sulfate. The decreases in performance in the Number Facility Test induced by atropine or scopolamine were antagonized rapidly by intramuscular injections of physostigmine at 15-60 ug/kg, but the antagonistic effect wore off after 3-4 h.
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From page 163... ...
studied the effectiveness of intravenous administration of physostig~ine as an antagonist of the central ~ Number Facility Test) and peripheral (heart rate)
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From page 164... ...
Symptoms and signs of the action of the tropic acid esters on h''man subjects include complaints of mouth dryness and decreased secretion of saliva; increase in heart rate, possibly preceded by a short period of decrease In heart rate; dryness and flushlog of ache skin' particularly in the "blush area"; difficult urination; ataxia; disorientation; hallucination; delirium; dilated pupils, possibly nonreactive to light; prostration; and coma. The greatest hazard to life arises from suppression of the ability to secrete sweat, which can give rise to fatal hyperthermia if body temperature is not controlled artificially during hot weather or strenuous activity.
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From page 165... ...
, including benzilic acid. The esters were ex~ined for their ability to induce relaxation of isolated rabbit intestine that was made to contract by acety~choline; the esters of 3~quinuclidino]
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From page 166... ...
studied the effects of fire spasmolytic substances, including 3~qutnuclidinyl benzilate and its quaternized font, on the electroencephalogram, the electrocardiogram, and the blood pressure of the dog. Intravenous injection of 3~quinuclidiny!
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From page 167... ...
reported that rats placed into at3~0apheres contalai~g 3-quinuclitinyl benzilate tispereet as a tust, as a thermally generated smoke, or as an aerosol of a 1: solution of the benzilic acid ester in methyleae ttehlorite for concentration-time (Ct) products up to 29,508 mg.min/~3 experienced no permanent effects from the exposures, except occasional teethe randomly distributed with respect to intensity of exposure.
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From page 168... ...
(192) recorded the infrared spectra of seven esters of benzilic acid, of eight esters of 3-quinuclidinol, and of atropine and scopolamine and attempted to correlate the relative a~crengtho of the intramolecular hydrogen bond with the threshold doses of the various compounds in producing paychotomimeelc effects in toga.
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From page 169... ...
' both inhibitors of chollneaterases. The anticholinergic compounds used were N~ethyl-4-piperidinyl- (phenylcyclopentyl)
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From page 170... ...
Me optimal pa for adsorption of 3~quinuclidinyl benzilate was about 8.0, whereas that for atropine was about 9.7; at these pils, the adsorption of the two anticholinergic compounds was about the same. TEA decreased the adsorption of the benzilate by mitochondria9 but a ratio of 100 ~ (T~: 3-quinucItdi"l benzilate)
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From page 171... ...
Another possibility mentioned He that there may be no presynaptic muscari~c sites in the hippocampus. The ATPase in microsomes prepared from whole rat brain, from rat cerebral cortex, and from cerebral cortex of rats that had received 3~quinuclidinyl benzilate intraperitoneally at mg/kg an hour before they were killed was found (196)
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From page 172... ...
examined the effects of 3-quinuclidinyl benzilate on beagles. There were dose-related responses to doses of 10 and 50 ~g/kg in autonomic functions (heart rate, pupil diameter, flow of saliva, etc.)
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From page 173... ...
found that intravenous injection of 3~quinuclidiny! benzilate at 50 ug/tcg into dog e induced intoxication that persisted for more than 5 h.
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From page 174... ...
may looked also for reverse mutations in yeast cells exposed in vitro at 5 x 10~4 M and 5 x lo-2 It, for host~ediated transformations in yeast cells injected into the peritoneal casualties of mice that were then given 50 or lOO o~g/kg subcutaneously, and for dominant-lethal effects in mice after single intraperitoneal injections at lO or 40 mg~kg or repeated tn jectione -- ~S at 2 mg/kg, 15 at 10 mg/kg, or 5 at 20 mg/kg. The yeast cells exposed to 3~quinuclidiny} benzilate in vitro gave evidence of weak mutagenic activity.
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From page 175... ...
No lealons attributable to bencllate were found in the testes of the dogs that had been given that compound. DIE~NOET~L MNZI~TE The only other member of the group of esters of benzilic acid on whose effects there is a considerable body of information is diethylamis~oethy!
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From page 176... ...
McColl ant Rice (213) found that intraperitoneal injection of mice with diethylaminoethyl benzilate at 10 mg/kg 15 In before similar administration of tremorine increased the ED50 of tremorlne from 5.8 to 38.0 mg/k8.
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From page 177... ...
Intentional ad=~stratione of diethylaminoethyl benzilate to human subjects had shown (218) that the psychotomimetic state lasted for 4-12 h and was accompanied by a decrease in urinary excretion of 5-hydroxyi~doleacetic acid.
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From page 178... ...
The animals were killed 24 h later, ant the cells of their bone marrow were examined for chroo~oso~l aboor~slities. The lowest dose of the benzilate did not give rise to any detectable chromosomal abcomalities; ~ mg/kg resulted in a 50: increase ~ 60 fou" to inhibit monoamine i oroniazid .
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From page 179... ...
studied the effects of diethylaminoethyl benzilate on a group of 43 outpatients and 10 normal subjects. Patients given daily oral doses of the drug of ~ mg three times a day (t.i.~.)
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From page 180... ...
(224) reported the findings in an experiment in which 52 patients were given tablets containing fig of diethylaminoethyl benzilate and were instructed to take Five tablets a day, but were allowed to decrease that to three tablets a day if it seemed desirable and, for abort times, to two a day.
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From page 181... ...
Sldell's description of the effects induced by 3~quinuclidinyl benzi'ate is as follows: At low doses, the effects include a dry mouth, decreased gastric mobility, inhibition of sweating, an increase in heart rate, papillary dilatation and lose of ac~o~odation, mild sedation and mental slowing. At high doses these effects are intensified.
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From page 182... ...
After doses of 2,ug/lt,g, there were slight decrements tn performance in some of the tasks, a deflate increase tn heart rate, a decrease in systolic blood pressure, and a slight increase in diastolic blood pressure. The subjects given 4 ug/kg all made lower scores on the performance tests and exhibited definite functional changes, including increased heart rate, dizziness, drowsiness, mydrtasis, and difficulty in accommodating the eyes for near vision.
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From page 183... ...
Tetrahydroaminoacridine (TEA) had been found to decrease heart rate when tachycardia was present, to increase secretion of saliva, to increase sweating and lower core temperature If le had become high, to reduce Secular rigidity, and to improve, at least temporarily, the mental status of an intoxicated subject.
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From page 184... ...
Kitzes am Vancil estimated that the MED related to performance in the N - ber Facility Test was 2.54 ug~kg, with 9St confidence limits of 2.31 and 2.80 ug~kg, and that the HED for inducing changes in somatic functions (~1on, heart rate, and blood pressure) was about 2.7 ug~kg.
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From page 185... ...
5o for inductr~g a decrement in performance in the Number Facility Test of at least 25% was about 3.l ug/kg, that for increasing heart rate to at least 100 beato/min was about 5.6 ug/kg, and that for reducing performance in the Number Facility Test by at least 90: was about 5.9.ug/kg. For men given L-2-alpha-tropinyl benzilate at a mean dose of 6.l,ug/kg, the mean duration of severe effects of the compound was 2.5-3.l }I, and the mean.
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From page 186... ...
At that time, the heart rate, skis temperature, rectal temperature, and inhibition of sweat secretion were locreased in relation to the dose of bensllate administered. The highest rectal temperature was 380 3°C, an increase of lese than I°C above the mean normal temperature.
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From page 187... ...
SUM.~Y ~3-Quinuclidinyl benzilate, the benzilic acid ester that has been studied the most by Edgewood Arsenal, has effects similar in general to those of the tropic acid esters, but more prolonged. Two other benzilic acid esters have similar actions.
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From page 188... ...
M though 3-quinuclidiny} benzilate has been found Lo have weak mutagenic activity for yeast cells in culture and to produce gaps and breaks in chromosomes of bone marrow cells, it has not been proved to produce heritable changes in mammals. Diethylaminoethy} benzilate was more toxic cytogenetically than 3~quinuclidinyl benzilate, despite the lower anticholinergic activi ty of the former compound.
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From page 189... ...
to be effective both prophylactically and therapeutically in reducing the adsorption of 3-quinuclidinyi benzilate by the cat's motor cortex, caudate nucleus, and sensory cortex after intravenous injections of the benzilate and the glycolate. When given after the benzilate, EA 3443 reduces the retention of that compound by the medial and lateral geniculates.
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From page 190... ...
Mydrisaia occurred to a gild degree. There vea no consistent dose-reaponse relationship for the heart rate, but that rate may have been decreased, rather than increased.
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From page 191... ...
(163) found that the scale of the MNPI that was the best correlated with the degradation of performance of volunteers in the Ember Facility Test after intramuscular doses of EA 3443 (~ix volunteers, I.S,ug/kg; five volunteers, 2.4 ~ug~kg)
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From page 192... ...
The moat common complaints of subjects given dosea of Ditran by intramuscular injection or by mouth, or by both routes ~ were of hallucination, confusion, and impaired contact. Gershon and Olarlu found that Tacrine was able to antagonize both the peripheral and CNS effects of Ditran tn man, but was incapable of preventing those due to SernyI.
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From page 193... ...
Arecoline (150 Aging) restored salivation and heart rate to normal, but had co other detectable antagonistic actions when injected intravenously 30 min after Ditran.
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From page 194... ...
Mbanus (42) reported that subcutaneous injection of Ditran at 0.5 mg/kg into ll dogs resulted in the development of ataxia after a mean of 22 In, of obstinate progression after a mean of 31 min.
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From page 195... ...
Both inhibitors of cholinesterases were found to be effective in overcoming changes in the Ilumber Facility Test Induced by Dieran.
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From page 196... ...
Depression of general motor activity and depression of respiratory activity were the principal effects observed in the two test species during the estimations of LDsos. A range-fir~din8 test with intravenous injection of the glycolate into monkeys yielded an Ills probably between 10 and 20 mg/kg.
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From page 197... ...
Groups of four dogs were given daily intravenous injections at 0, 0.8, 6.0, and 20.0 mg~kg 5 d/wic for a month, receiving 21 doses during 29 d. Each group contained two Bales and two feeler.
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From page 198... ...
The heart rates of the dogs given the glycolate all increased during the first 15 min after administration of the first doses, whereas those of the control animals, given intravenous inJectiona of saline, decreased slightly on the average. After the first weekend, after three injections during the previous week and before injection of another dose of the beRzi]
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From page 199... ...
Their heart rates were increased markedly for more than 24 h after injection, but the peak of the tachycardia (+85X) occurred about 12 h after injection.
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From page 200... ...
The estimate of the HE:Dso was 1.96 ug/kg, with 95^ confidence limits of 1.45 and 2.66.ug/kg. Significant change in performance in the Number Facility Test usually began at about I.5 h at the highest dose administered (2.7 ug/l~g)
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From page 201... ...
Ataxia in this species appeared after intravenous doses of 3 mg/kg, ant prostration ant con~rulaion occurred after doses of Il-16 mg/kg. In the cat, mytriasis, decreased activity, increased heart rate, ant ataxia all occurred after intravenous doses of 10~100 ug/kg.
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From page 202... ...
It ended at 4 p.m. A battery of sects (heart rate, blood pressure, rectal temperature, Number Facility Test, and behavioral checklist)
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From page 203... ...
The hydrochiori-de of EA 3634 had no measurable effect on rate of sweating or performance in the Number Facility Test. When EA 3834 base was applied to the skin, the time to onset of inhibition of sweating (38~170 min)
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From page 204... ...
When a dose of 3 fig of physostigs~ne was inJec ted in~eramuscularI' 10 gin after intravenous injection of 302, 66S, there was rapid recovery from about 35% of baseline performance to about 921, but perfoneame in the ~ber Facility Test was don to about 20: of baseline by 2 h after the injection of 302,668. When the phycostig~ine was not injected until 45 ~n after the agent, performance in the Number Facility Test rose from zero to about 85: within about 45 min and to a peak of I 86
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From page 205... ...
One subject in each of the two highest ranges of retstned agent vomited, and eight others, tocluding subjects from all ranges of retained agent, complained of nausea. The heart rate was not altered significantly among the volunteers in the three groups with the lowest ranges of retention, but three of four sub Jects in the other group had heart rates above 100 beats/.
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From page 206... ...
Extrapolation of Lavallee's graphs suggests that the doses of 302,66B and of scopolamine that would be able to lower performance in the Number Facility Test to zero would be identical.
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From page 207... ...
The maximal increase occurred at about 15—n, and the heart rate was close to the baseline value by 4-6 h after Intramuscular injection. The mean blood pressure was tacreased slightly, with a time course similar to that of heart rate.
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From page 208... ...
With the production of at least a 25X decrement in performance tn the Number Facility Test as the criterion of a significant effect, the MED'o wee calculated to be 1.47 ug/~g. After a dose of 2 ug/kg, alg~lflcant decrement of performance extended from about 3 to about 12 h after injection; the maximal decrement after this tose (mean of four cases)
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From page 209... ...
suff ered significant decrements in their scores in the Number Facility Test in 45.5: and 53.~: of the cases, respectively. It seems probable that body weight played no important role in conditioning the response.
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From page 210... ...
The time to onset of incapacitation was about 2 h, and spontaneous recovery from severe effects required about 9 h from their inception. The effects induced by inhalation of aerosolized EA 3580 were the aame as those induced by latramuscular lnJectlon of this agent.
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From page 211... ...
compared the temporal characteristics of intoxication induced by intramuscular injections of 0.25 mg of EA 3580 in ache bydrochiorlde form is men resting in the laboratory and in men considerably more active in connection with field testing. me subjects in both aituations developed their initial deficits in performance in the ember Facility Test at the same rate, but the subjects in the f ield test experienced a somewhat aver deficit and returned toward comal more rapidly.
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From page 212... ...
The results were reported by Copelan (272) , who gave 24 volunteers intravenous doses of 1~0~605,ug/kgo Doses of 3.8 ~gJkg and less of this agent had only alight effects on performance in the Number Facility Test by the 12 men given these doses.
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From page 213... ...
In the one graph for a man given a dose of 7.S,ug/kg, incapacitation, indicated by reduction of score in the Number Facility Test to below 10% of his baseline score, occurred about 90 man after the injection. Intramuscular injection of 3 ma of physostigo~ne about 7 h after the injection of 302, 537 induced a marked, but temporary, improvement in the subJect's performance in the Number Facility Test.
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From page 214... ...
Complaints of dryness of the mouth were elicited by questioning, but were not made spontaneously. The heart rate did not change u~ess or until excitement and hyperactivity developed.
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From page 215... ...
There were vl8U8 illusions and a slightly increased activity of tendon reflexes. The heart rate and pupil diameter did not change.
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From page 216... ...
Janssen and Niemegeers (280) , on the basis of testo with prophylactic administration of benzetimide to rats given pilocarpine hydrochiorlde intravenously at 80 mg/kg, concluded that benzetimide had sufficten~c action on the central nervous system to Justify its conaideration as a t}leraupeutlc agent in parkinsonism.
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From page 217... ...
Urinary urgency and an increase of 10.8 fig in glean diastolic pressure were particularly strlklag effects. Me mean Systolic pressure increased by 5.9 ~ fig, ant the ocean heart rate by 45.3 beats/mln.
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From page 218... ...
were below those for the subjects given either compound alone for systolic and diastolic blood pressures and were above those for the subjects given either compound alone for the rate of respiration and the near point of vision. The change in the mean pupil diameter for the subjects given both compounds was the same as that due to mepiperphenidol alone and greater than that due to atropine alone, whereas the change in mean heart rate for the subjects given both agents was almost precisely halfway between those due to the individual compounds.
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From page 219... ...
summarized the results of experiments in which rats, rabbits, togs, ant monkeys were given intramuscular injections of graded single doses of TAB. Rate of the two sexes were studied separately.
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From page 220... ...
in which four volunteers were given intramuscular injections of 2 m} of TAB solution and another four were given 4 mI. The smaller dose resulted in a decrease in the mean score in the Number Facility Test of 40% during the 15 min after injection, whereas the larger dose resulted in a decrease of 78Z during the Awe Scone.
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From page 221... ...
The maxima change in heart rate occurred 10-20 win after injection and lasted for about 4 h after the larger dose. After the smaller dose, the subjects continued to be able to estimate time reasonably well and to respond effectively to visual signals in the vigilance port ion of the task.
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From page 222... ...
studied several synthetic anticholinergic compounds that had seemed in preliminary test. with animale deco have some superiority over atropine in an;tagonlsin8 the toxic effects of inhibitors of cholinesterases.
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From page 223... ...
among compounds that had disruptive actions on the normal functions of the central nervous system, anticholinergic compounds because of interest again, because of the well-known activities of atropine and acopola~ne in producing a temporary toxic, psychotomimetic state. Itost of the reports in this survey belong no this later period, which starlet in about 1958.
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From page 224... ...
Among the compounds adminlotered to volunteers by intramuscular injection, the most active in inducing a degradation in normal function-~ost commonly assessed on the basis of the dose required to cause loss of at least 25X of the predose score in the Number Facility Test by 50X of a group of subJecte-~as EA 3443, followed fairly closely by EA 3580, EA 3834, and 3~quinuclidiny] benzilate.
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From page 225... ...
The most actively incapacitating of the intravenously injected compounds was 302, 212; itS i~apacitati~ dose was larger than that of 3~quinuclidinyI-L-( pheny~cyclopentyI) glycolate, so it probably fits into the series of compounds given by intramuscular injection two or more compounds below 3-quinuclidinyl-L- |
From page 226... ...
As ~ group, these compounds are not particularly rapid inducers of whatever changes follow their administration; even after intravenous injections 302,212 and 302,S37 required 4 and I.5 h, respectively, to induce incapacitation. After intramuscular injection, 3-quinuclidinyl benzilate, EA 3167, and 301,060 required i.25, 2, and 5 h, respectively, to induce incapacitation.
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From page 227... ...
has been studied, but no detailed studies of its detoxification, pharmacol~netice, and molecular pharmacology have been fount for use in this review. Little or no information on the biochemical aspects of the activities of the anticholinergic compounds surveyed here has been found.
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From page 228... ...
investigated the drugs responsible for "certain' and "probable" reactions in 335 patients in a total of 817 patients treated during a parlor of years, findlog that 51X of all the reactions were canaet by drug a that hat actions on the central nervous system. The most common of these reactions were droweiness, nausea, dizziness.
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From page 229... ...
It should be noted, however, that two-thirds of the accidents of reproduction found in this survey were related to the use of antihistaminic bugs, many of which have some anticholinergic activity . Although anticholinergic drugs are useful in ameliorating the results of lack of inhibition of contractions of the detrusor muscles of the bladder, the danger of causing the development of hydronephrosis by using such drugs in cases with obstruction of urinary outflow from the bladder has been noted ~318)
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From page 230... ...
Mice and guinea pigs given five subcutaneoua doses per week of 3-quinuclidinyl benzilate at 150 ug/kg for 3 wk (total maximal dose, 2.25 mg/kg) were reported (~84)
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From page 232... ...
- ce es · c o o J · 0 · _ · N · - y , _ C o · C O O Len ~ 1 ~:1 1 :^ O ~ C — .
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From page 233... ...
TABLE I-3 Single-Dose LD,o. of Phenylisopropylglycolic Acid Esters Route of LDsos~, mg/k~ Animal Administration EA 3834 302,668 Mouse I.Y.
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From page 234... ...
970.0 305 Rae Icy. -- 37.6 O_ ~0 __ __ S O C O P.OO Guinea Pig S.Ce P.O.
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From page 235... ...
TABLE I-5 Single-Dose Minimal Effective and Lethal Intramuscular Doses of TAB teal Hale mice Male rats Female rats Male rabbits Dogs Monkeys 36 (27, 48)
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From page 236... ...
REFERENCES 1. Herbert , J
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From page 237... ...
1971: The Mechanism of Excitation by Acety~chollne in the Cerebral Cortex.
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From page 238... ...
2 ~ . Bachrach, W .
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From page 239... ...
1970: Central And Peripheral Effects of Anticholinergic Compounds. Ac ta phar~acol.
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From page 240... ...
1965: The Uptake of Atropine and Related Drugs by Intestinal Smooth Muscle of the Guinea Pig in Relation to Acety~choline Receptore.
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From page 241... ...
H 1974: Muscarinic Chol~inergic Receptor Binding in the Longitudinal Muscle of the Guinea Pig Ilium with [3~]
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From page 242... ...
1955: Tne Metabolism of Ci4-Labeled Atropine and Tropic Acid in Mice.
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From page 243... ...
94. Jager, B.V.
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From page 244... ...
1955: The Effects of Atropine Sulphate Upon Healthy Male Sub jects. Quart.
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From page 245... ...
1962. Central Nervous System Effects of Hyoscine in Man.
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From page 246... ...
de V 1973: Atropine Sulfate Aboorption From an Intramuscular InJection of a Mixture of the Oxime, P2S, and Atropine in Exercising Humans.
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From page 247... ...
1967: The Treatment of Scopolamine-Induced Delirium With Physostig~ine. Edgewood Arsenal Technical Report 4115.
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From page 248... ...
l, F.R. 1974: Modification by Diluento of Effects of Intramuscular A~cropine on Heart Rate in Man.
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From page 249... ...
1955: The General Phar~acology of Benzilic Acid Diethylaminoethy] Ester lIydrochioride [Benaceyzine NFN, Suavitil, Parasan]
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From page 250... ...
1967: The Human Assessment of BE Disseminated Onder Field Conditions. Edgewood Arsenal Technical Report 4140.
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From page 251... ...
19-66 : Studies of Brain Microsomal ATP-ase Activity and lon Transpose in Tissues Treated with BZ. Edgewood Arsenal Technical Report 4043.
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From page 252... ...
1955: The Autonomic Reaction of Psycho-neurotles to a New Sedative: Benaceyzin NFN, Suavitil [Benzilic Acid Diethylaminoethylester ECL]
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From page 253... ...
1966: CS27,349: Estimate of the Incapacitating Dose in Man. Edgewood Arsenal Tech~cal Memorandum Il4-2.
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From page 254... ...
Edgewood Arsenal Te chnical Hemorandum 75001.
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From page 255... ...
1967: CAR 301,060: Estimate of Minimal Effective Dose in Man. Edgewood Arsenal Technical Hen~orandum Il4-12.
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From page 256... ...
1968: Estimate of Incapacitating Dose of Compound 302,282 in Han. Edgewood Arsenal Technical Memorandum 114-21.
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From page 257... ...
Fink, H 1960: Effect of Anticholinergic Compounds on Post-Convulst~e Electroencephalogram and Behavior of Psychiatric Patients.
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From page 258... ...
1976: Fourteen Day Acute Toxicities of TAB Mixture and Each of Its Constituents Following a Single Intramuscular Dose in Hale Mice. Part M of Investigational New Drug ADD1ICatiOn PP .
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From page 259... ...
297. PJalland, 8., Nielsen, I.M.
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From page 260... ...
3080 Burnett, G.B., Prange, A.J., Jr., Wilson, I.CO Jolliff 9 L.A., Creese , I C., Snyder' S.H.
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From page 261... ...
321. Reallne, S
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Key Terms
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