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APPENDIX I 1)IGEST REPO RT--ANTICHOLIN.ERGI C CHEMICALS Introduc tion Es ters of Tropic Ac id Studies in Animals Human Data from General Li terature Human Oata f rom Edgewood Arsenal Summary Esters of Benzilic Acid Introduc tion Data from Experiments with Animals 3-Quinuclidinly Benzilate (BZ or EA 2277) 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) Di tran (CS 4297) 3-Qu inuc lidinyl-( pheny~cyc lopentyI) -glycolate ~ EA 3167 L -2-a lpha-Tropinyl-L-( pheny~cyclopenty] )-glycolate c i s-2-He thy 1-3-quinuc lidinyl-( pheny~cyclopentyI)-glycolate (301, 060) Esters of Phenylisopropylglycolic Acid N-bie thyl-4-piperidinyl-(phenyIlsopropyl~-glycolate (EA 3834 4-~1-Me thy I-1-l, 2, 3, 6-t e trahy dro pyri dinyl ) -phenyli sopro pyl- glycolate ~ 302, 668 ~ Esters of 1-Propyny~cyclopenty~glycolic Acld N-~* thy1-4-piperidyl-(phenylcyclobutyl)-glycolate (EA 3580) - Hi sc ellaneous Es ters 302, 282 302, 537 WIN 229 9 Nonester Anticholinergic Compounds ~ Benzetimide (CAS 14051-33-3) blepiperphenidol

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"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. e

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APPENDIX I DIGEST REPORT ANTICHOLINERGI C CHEMICALS by J. lIeary Wills, Ph.~. INTRODUCTION The Board on Toxicology and Environmental Health Hazards of the National Research Counct1 provided 58 reports that are related to the administration of anticholinergic compounds to human volunteers by personnel ant contractors of the Chemical Corps Medical Laboratories at Army Chemical Center, Md., and its successor organizations at Aberdeen Proving Ground, Edgewood, Maryland . Those report s recorded studies of the responses of humans, mostly ~en, to 19 individual substances and to a mixture- of atropine, benactyzine, and the oxime, trimedoxime (THB-4~. Two of the 19, benzetimide (Dioxotrine) and mepiperphenidol (Darstine), are N-all~ylated derivatives of piperidine, but the other 17 are esters. Anticholinergic substances not mentioned in these reports, but said to have been administered also to volunteers, are N-methy ltropiny~pheny~cyelopenty~glycolate, 3-quinuclidinyI-~-hydroxypheny~cyclopentylacetate, and N-die thy laminoe thy lphenylcyclopenty~carboxylate . 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. Atropine ~ I'L-hyoacyamine) and its optical isomers, the D- and L-hyoscyamines, anti scopolamine (L-hyoacine) and its optical isomer, D-hyoscine, have been obtained from such planes as deadly nightshade (Atropa belladonna) ~ jimsonweed (Datura stramonium), henbane (Ryoacyamus niger), horsenettle ~ Solanum , carol~inen~e), and various species of Scopolia. The L isomers of both esters are more potent than the D isomers. Both esters have peripheral and central anticholinergic activities; i.e., they interfere with the actions of acety~choline at peripheral ne~roeffector junctions on smooth and cardiac muscles and on cells of glands that produce external secretions and at synapses between some neural elements. Scopolamine is especially potent in the lest regard. whereas atropine and L-hyoacyamine are especially effective in blocking the action of acety~choline at peripheral neuroeffector junctions. Even at neuromuscular June tions on skeletal muscles, which atropine usually is considered not to affect significantly, a sufficiently high concentration (10~4 M) of this drug in vitro caused a shortening of the duration of end-plate currents ~ I) . I l

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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. Toxic psychoses and delirium from ingestion of atropine and acopola~ne have been Anon for many centuries; descriptions of the effects of these drugs antedate by long times the recognition of their mechanism of action. For example, henhane was reco~e-nded in the Ebere papyrus of about 1550 B.C. for the relief of abdominal distress. After -the first isolation of atropine from plant material in IB32, the actions of this group of alkaloids were identlfiet rapidly. By 1875, Ringer (2) vea able to give the following description (excerpted) of the actions of atropine belladonna): - Be lladonna employed either internally or externally checks or even suppresses the secreelon of the glance. This at least is true of the marry, sudoriparous and salivary glands, and possibly of other glands. les influence on the secretion of the submaxillary glance has been fully worked out. This gland reeei~res branches from the chords ~cympani nerve which is endowed with two sets of fibres, one acting immediately on the cells, the other causing the blood-vessels to dilate, being vaso-inhibitory. Belladonna acts through the nerves distributed to the cells, for after the injection of atropia, if the chords timpani nerve is irritated, the Vessels of the submaxillary gland become distended as usual, but the gland does cot secrete. The paralyzing effect of atropia is antedated by physostigma, for after the injection of physostigma, irritation of the chorda tympany causes the gland to secrete. Dropped into the eye, applied to the skin in its neighborhood, or taken by the stomach, preparations of belladonna very speedily produce extreme dilatation of the pupil. This is one of the most characteristic effects of belladonna. ~ full dose of belladonna produces great dryness of the tongue snd roof of the mouth, extending down the pharynx and larynx, inducing consequently cone difficulty in swallow) - , with hoarsenese, and even d" cough; and large dose will sometimes induce dryness of the Schneidarian membrane, and dryness of the conjunctive, with much injection. Belladonna often relieves colic of the intestines; and is especially serviceable in the colic of children. After a considerable dose of belladonna, the face becomes much flushed, the eye bright, d", and injected, the pupil dilated, the sight dim and hazy, while the power of accommodation in the eye for I 2

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distance in lost. The mind and senses are peculiarly affected. The ideas, at first rapid and connected, become incoherent and extravagant; there is often decided delirium, with pleasing illusions. Sometimes the patient is possessed with constant restlessness, keeps continually moving, and cannot be quieted. A kind of somnambulism is occasionally observed; thus cases are recorded where, under the inf luence of belladonna ~ the patient for a long time performs the movements customary to his occupation; thus, it is narrated of a tailor that he sat f or hours moving his hands and ares as if sewing and his lips as if talking, but without uttering a word. The delirium may be furious ant dangerous, requiring the patient to be restrained; nay, it is recorded of one poisoned by this drug that so violent did he become that he was ordered to be confined in a mat-house . The f irst effect of belladonna on the pulse ts to increase its quickness, fullness, and force to the extent even of 50 Lo 60 beats in the minute.... Meuriot is of opinion that belladonna paralyses the peripheral branches of the vagal nerve, and by this means accelerates the heart 's action. Ringer had this to say about the ef facts of hyoscyamus ~ scopolamine): Thus it produces dryness of the mouth and throat, dilatation of the pupil, presbyopia, lightness and swimming in the head, delirium and hallucinations, a drunken gait, and often a strong desire to fight. Sometimes there is aphonia, and often sleepiness, with oppressive disagreeable dreams. ~ red rash has been observed after large doses. The pulse at first is much lessened in frequency but soon recovers itself, sometimes becoming even quicker than before the medicine was taken . Hyoseyamus is generally used to produce sleep when opium disagrees. It has also been employed in neuralgia. It was only af ter the role of acetyJ.choline in the functioning of the autonomic nervous system, in neuroeffector transmission to the various entities innervated by that system and to skeletal muscles (3-~), and in synaptic ~cransmission within some areas of the central and peripheral nervous systems (12-3~7) had been demonstrated that the proximate mechanism of action of atroplne, scopolamine, and other compounds of similar activity could be understood. 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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mental disease by Forrer ( 18) and Goldner ( l9) . In 1950, Forrer published an account of a study of 16 schizophrenic patients treated intramuscularly with large doses of atropine sulfate on 3 days of each week for a long period. The doses of atropine sulfate were increased gradually during a course of treatment from 20~32 mg to 212 ma, to maintain the achievement of unconeciousness, with hyperreflexta and development of the Babinaki sign, despite a gradually developing tolerance to the Snug. In 1957, Hiller et al. (20) reviewed the cases of 206 mental patients treated in this general way, includlag 148 who had been ill for 2 ye or more before treatment. At the time of that report, the technique was to inject atropine sulfate at 3:00 a.m., so that the patient would recover sufficiently from the effect of the drug to be able to eat lunch and take part in organized activities in the hospital during the afternoon and evening of the same day. Four treatments were given each week, instead of the three that had been given initially. The desired state of coma was produced ult}`in 30~60 mic of intramuscu3.ar injection, and spontaneous recovery, with complete clearing of the sensorlum. required 6-9 h at ter the in Section. - Of 206 patients treated, Il5 (55.~) were considered to have improved moderately or markedly, 60 (29.1Z) to be unimproved, and 31 (15.01) to have imp roves only slightly. Six months after completion of a course of injections, 115 patients (55.8Z) were atoll improved moderately or markedly. In a series of about 500 patients treated with large doses of atropine, with about 10,000 individual inductions of coma, there was one death (21~. This fatality was attributed to the replacement, without notification of the physician, of the specially trained nursing and technical personnel on the treatment ward with persons who were Scat thoroughly familiar with the procedures for caring for comatose patients, and particularly the procedures for controlling febrile reac tions . The patient died of uncontrolled hyperthermia. Goldner ~19) reported that he had used tntraeuscular toses of 5-50 mg of scopolamine in treating beneficially an unspecified number of mental patients, but then had switched to atropine because of lts greater a~railabllity. He reported on a group of 20 patients treated with atropine-toxicity therapy, 13 (65%) of whom were considered to have benefited moderately or markedly. Goldner also gave a limited comparison of the results of electrocon~rulai~re therapy (ECT) and of a ~ropine-toxicity therapy, stating that several patients who had not benefited from ECT improved on substitution of atropice-induced coma. Dada et al. (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. The average dose was 30-50 tog. The longeat period of observation mentioned in the paper was 6 mot Of the 51 patients, 28 (S4.9%) seers considered to have improved detectably. The proportion that improved among the psychotic patients (53.3Z) was smaller than that among psychopathic and I 6

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psychoneurotic ones (66. 7Z). The greatest alterations in symptoms and signs of the patients' diseases were in psychomotor excitement, hallucination, euphoria, anxiety, compulsion, and delusion. dada _ al. stated that trepro~rement, when it occurred, began with the third to the seventh injection and increased with later injections. If no improvement occurred by the tenth injection, it was not likely t O appear. The authors concluded that atropine-toxicity therapy i s a relatively sat e type of shock therapy, but stated that it was successful in only about 53.3% of their psychotic patients and that its efficacy probably had been overestimated by Schwarz (23~. Schwarz had concluded that 25: of 155 cases of psychoneurosis and psychosis had improved markedly with atropine-toxicity therapy and that another 32% had improved moderately . Hiller et al. (20) described the phenomena experienced by patients given large doses of atropine to induce a toxic coma: The various stages are passed through quietly and comf ortably . Neurologically , there are in order: progressive muscular incoordination, decreased pain sensitivity, and hyperreflexia with the development of the Babinski sign. On the psychological side, we observed clouding of the sensorium, disorientation, loss of time-space relationship, distortion of perception by illusions and hallucinations, confusion, and coma which proceeds to but does not go further than the early fourth stage in one and one-half hours af ter the drug is admini stered . Although the sensorium is markedly clouded, there is no cessation of psychological phenomena . Patient s undergoing treatment indicate by their actions, and occasionally by word, that psychic processes continue even during the coma. Illusions seem to be experienced, inasmuch as patients attempt to pick up the bedclothing with their f ingers and later report that they saw, and attempted to pick up, flowers, bugs, snakes, et cetera. Conversations may be held with absent persons--indicative of an hallucinatory state. With both atropine-induced i llusions and hallucinat ions, highly signif icant past events in the patient's life seem to provide the mayor psychic stimuli. Behavior is correlated with psychological phenomena. Circumoral movements, including sucking and illusory "eating" and 'smoking," are commonly observed. When a sufficient degree of motor coordination i s re tained to accomplish the necessary movement, a progressive, coordinated, and purposeful series of events may of ten be observed. For example, a pantomime of striking a match, lighting a cigarette, and subsequently of smoking that cigarette is not infrequently observed. Affective lability and corresponding rapid alternation of facial expressions suggestive of pain, sadness, querulousness, and euphoria are commonly observed . This clinical experience indicating that even large and temporarily incapacitating hoses of atropine and scopolamine had no persistent deleterious effects on the health of human I 5

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beings made it seem that the administration of other' possibly more incapacitating, anticholinergice to huff volunteers was not unethical or immoral if two conditions had been fulfilled. These were that a compound to be administered to volunteers had been tested adequately in experimental animals to determine that the probability of its having persistent ill effects on health was small and that the volunteers had been informed as fully as possible of the possible effects of the c ompound . 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. The following description is a composite from two sources: a report from Edgewood Arsenal (24) and a report by a contractor (25~. Test subJec ts were selected in two stages. Groups of possible volunteers were acquainted with the general nature of the experimental program through a briefing, during which they could ask questions about the general conditions and procedures of the studies. Those who volunteered to take part in the experimental program after this general briefing were given thorough medical examinations, including psychologic or psychiatric assessment. The volunteers considered acceptable for a particular experiment were then given a specific briefing and an opportunity to volunteer to take part in that study. The studies were carried out in air-conditioned areas from which hazards of accidental injury hat been eliminated as thoroughly as possible (e.g., '~lass panels in doors were replaced with wood, electric outlets and cables shielded, ant sharp corners padded) . Beds and toilet, messing, and recreational facilities were provided within the research areas. The research was conducted under sur~reillance of qualified physicians, who administered all in Jections or oral doses of the test substances. Men volunteers were exposed to inhalation of vapors or aerosols, the concentrations of these substances in the air Lo be breathed by the sub jects were established by appropriate personnel. Breathing of the contaminated air by the ~ro1unteers was observed and supervised by physicians. After an exposure to an agent, the volunteers were observed continuously f or 8-24 h, and then intermittently for up to 14 d. In a few cases, followup studies were made 6 ma or more af ter the exposure. I 6

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ESTERS OF TROPIC ACID This group contains f ive of the substances said to have been administered to volunteers, but only three of these are mentioned in the 58 reports related to studies of the effects of anticholinergic compounds on human beings: aeropine, scopolamine, and methylscopolammonium. The ether two substances in this group that were administered Ho volunteers are D-hyoscyamine and methylatropinium. Atropine and scopolamine appear, respectively, in 18 and 11 reports, whereas methylscopolammonluss salts appear in only three. Atropine and scopolamine differ only in the basic moiety esterified with tropic acid. Scopolamine and the hyoscines have an oxygen bridge inserted between the two carbon atoms in the dihydropy~role ring of tropine that are not adjacent to the nitrogen atom, forming scopine, whereas atropine and the hyoscyamines have no such bridge. The facts that atropine is a racemic mixture of D- and L-hyoscyamines, that scopolamine is L-byoscine, and that the L f ores of both hyoscyamine and hyoscine have much greater biologic effectiveness than the D forms mean that atropine sulfate, with only 50~- of its active isomer, has only about 60Z as much active material per unit of weight as scopolamine hydrobromide, despite the addition of an oxygen atom in the bridge in the latter molecule. STUDIES IN ANIMALS Several relatively recent reviews of the actions and potencies of the solanaceous alkaloids are available (26-32~. Generally, they give a great deal of information about the medically useful or undesirable actions of the compounds without dealing with their toxicity in any quantitative manner. Table I-1 contains a sugary of information on the LDso doses for experimental animals of the f ive compounds in the group of esters of tropic acid, collected from a variety of published sources (33-41) and from internal reports of Bristol Laboratories, Lederle Laboratories, Maltby Laboratories, the Squibb Institute for Medical Research, Strasenburgh Laboratories, the Up John Company, and Sterling-Winthrop Research Institute . Albanus (42) studied the ef fects of subcutaneous in deco ions of 13 anticholinergic compounds on central and pert pheral cholinergic activities in the tog, recording such factors as the appearance of ataxia and of what he called "obstinate progression' (i.e., the failure of the animal to pull hack af ter encountering an obstacle in its path), the light reflex of the iris, salivation, ant heart rate. The compounds administered to dogs included a eropine, scopolamine, and a methylatropinium salt. A dose of atropine at 0.1 mg/kg produced no significant alterations in the dogs, but a dose of 0.2 mg/kg produced ataxia in three of four dogs and increased their heart rate by 76: ~ A dose of 0.3 mg/Icg mate five of five dogs ataxic ant causes three of five to engage in obstinate I 7

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progression. ~ dose of 0.5 mg/kg rendered seven of seven dogs both at.axic and out of contact with the environment,, as indicated by obstinate progression. This dose also abolished the light reflex of the iris, blocked salivation between 45 and 180 sin after the dose, and increased heart rate by 891. Scopolamine was considerably more active than a tropine in this series of experiments, a dose of 0.03 mg/kg producing ataxia in six of six dogs and increasing heart rate by 24%. 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. The methylatropinium salt was much less effective than either of the onetime alkaloids. A dose of 2.5 mg/kg produced ataxia in none of four dogs. A dose of 10 ~g/kg induced ataxia in f ive of eight dogs and obstinate progression in three of eight. It abolished both the light reflex of the iris and salivation between 45 min af ter the dose ant the end of the period of observation, at 315 win after the dose. Doubling that dose induced both ataxia and obstinate progression in four of four dogs. The only study of the subchronic toxicity of members of the group of esters of tropic acid f ound is one by Boyd and Boyd (43) with atropine. Groups of rabbits were given daily intramuscular injections of atropine sulfate at 44-118 mg/kg for 100 d. The daily dose required to cause death within 100 d was 78 + 5 mg/kg, whereas that required to cause death within 10 d was 127 + 9 mg/kg. The Boyts obtained a relationship between the number (y) of dally injections to produce death and the size of the daily dose (x): log y ~ 2. 35 - 0.343 log x. The principal sublethal ef f ec ~ ~ not iced i n the rabbi t ~ were ~ in the approximate order of their appearance): increased intraco10nic temperature, decreased drinking, decreased production of uri ne, and decreased growth. Three other papers were related to a special type of subehronic toxicity induced by atropine: alteration of cells, embryos, and fetuses exposed to the chemical. Ishidate ee al. (44) exposed cultures of fibrob1asts from Chinese hamsters Lo atropine sulfate at 2SO ug/ml in saline for 48 h. At the end of the period of incubation, I: of the cells were polyplold. Of cells examined for chromo~omal aberrations after incubation with atropine for 24 h, FEZ had gaps and breaks in their chromosomes. These percentages of polyplol~y and of chromosomal aberration were only slightly greater than those in cultures to which plain saline had been added. Examination of atropine sulfate for carcinogenicity in animals by the method specifies in Survey of Compounds Which Have Been Tested f or Care inogenic Ac tinily (U. S . Public Health Service Pu blication 149 ) and f or mutagenicity in bacteria yielded no evidence that atropine had either activity. I 8

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Butros (45) explanted 21- to 22-h chick blastoderms onto agar-containi~ substrates with atropine at 40~100 g/~1 for 24 h. Blastodems exposed at 40-8O,ug/~1 had alight but dose-related injury to the developing neural tube. Those exposed at 90 ug/mI hat arrested development with pyccosis and slight cytolysts of the cells of the brain wall and with somites that were smaller than noneal and that hat slightly opaque cells. Blastoderms exposed at 100 ~g/ml had their growth arrested and their brain walls wrinkled and folded, the cells evincing early cytolysis. In some of these blastoderms, the neural tube was completely cytolyzed; in others, eve neural tube was open at both its ends. Some 85% of the embryos had normal beating heart tubes; some heart primordia were incomplete and had lateral gaps. Grunf eld and Balass ~ 46) 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. No long-lasting effects on either the tams or the pups were repo reed . Scopolamine, added to the culture medium in a Petri dish at 1 ~g/plate after incubation with microsomes prepared from livers of rats, produced no change in the cultural characteristics of Salmonella typhimurtum strains TA 98 and TA 100 (47~. In agreement with this finding of non~utagenicity of scopolamine for bacteria, a study by Vrba (48) with HeLa cells, human leukocytes, and monkey renal cells revealed that scopolamine hydrobromide at a f ina1 concentration of I% in contact with these cells induced aberrations of the chromatics in the HeLa cells, but not in the monkey renal cells or the human leukocyte s. Vrba concluded that change ~ in chromatics in HeLa cells do not prove that a chemical is mutagenic in man. Campbell and Ramirez (49) gave three pregnant rats daily intraperitoneal injections of scopola~ ne at I. 2 mgJkg. Three other groups of two pregnant rats each were given nothing other than the usual food and water or daily intraperitoneal injections of physiologic saline or scopolamine at 2.4 mg/kg. All experimental procedures began on the tenth day of pregnancy ant were continued UDti1 parturition. Some of the of f spring of these dams, when 120 d old, were deprived of water for 18 h and then placed in a conflict situation in which they were exposed to continuous electric shock of variable voltage whenever they tried to drink. The voltage required to inhibit drinking was recorded. Offspring of the three dams that had received daily doses of scopolamine at I.2 mg/Icg were I 9

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208. Hughes, H.C., Bostrom, R.E., Goldstein, R.S., Ferrell9 JOFO 1969: The Effects of BZ on Spermatogenesis in the Dog. ~gewood Arsenal Technical Memorandum Il6-So 209. Jacobsen, E. ~ Skearup, Y. 1955: Experimental Induction of Conflict-Beha~riour in Cats: The Effect of Some Ar~ticholinergic Compounds. Ac ta pharmacol. toxicol. ll: 125-134. 210. Jacobsen, E., Sonne, E. 1955: The Effect of Benzilic Acid Diet}~riaminoethylester, ECl [8enaceyzine] on Stress-Induced Behaviour in the Rat. Acts pharmacol. ~oxicol. Il :- 135-147. 211. Jacobsen, E., Kehiet, H., Larsen, V., Mun~vad, I., Skinhod, K. 1955: The Autonomic Reaction of Psycho-neurotles to a New Sedative: Benaceyzin NFN, Suavitil [Benzilic Acid Diethylaminoethylester ECL]. Acta psychiat. neurol. scand. 30: 627-642. 212. Berger, FoMo ~ Hendley, COD., [ynes, TeEo 19S6 Pharmacology of the Psychotherapeutic Drug Benaceyzine [beta-diethylaminoethyI-benzilate hydrochloride]. Proc. Soc. Exp. Biol. Med. 92: 563-566. 213. McColl, J.~., Rice, W.B. 1962: Antagonism of Tremorine by Benaceyzine and Dioxolane Analogs. Toxicol. Appl. PhanmacolO 4: 263-268. 2140 Jacobsen, E., 1964: Benaceyzine. Chapter ~ in Gordon, tel., ed . 1964: Psychophar~acological Agents, tJol . I., Academic Press, New York and Lonton, pp. 287-300. 215. Shitov, E.E., 1965: itItyanie sulfate magnlya ~J kombinaschit ~ trank~ilizatorami na bioelecktricheskuyu i cholinesterasnuyu akti~rnost golovnogo mozga. Famakol . Tokaikol. 28: 13-17. 216. Banshchikov, V.M., Stoliarov, (;.~. 1966 : Patchotomimeticheskie Sredst~ra ~ Aneicholinergichessim l~eis tviem. Zh . Ite~rropaeol . Pai~hiat . Koroakeva 66:464-468. 217. Vojeechovsky, M. 1958: ~ Psychosis Caused by Benaceyzine [ntoxication. Acta paychiat. neurol. scand. 33: 514-518. 218. Vo~techov~ky, M., Vitek, V., Ryeanek, K., Bultasova, a. 1958: Psychotogenic and Hallucinogenic Properttes of Large Dosea of Benaceyzine. Experientia 14: 422-423. 219. Edel~on, J., Schiosser, A., Douglas, J.F. 1970: Benaceyzine Hetabolism in the Rat. Arch. Internat. Phanmacodyn, Therap. 187: 139-143. I 134

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220. Davies, E.B. 1956: A New Drug to Relieve Anxiety. Brit. Med . J. I: 48 0-484 . 2~ . ~ymond, H.J., Lucas, C.J. 1956: Benaceyzine in Psychoneurools, with a Note on the EEG Changes in Noneal SubJecto. Brit. Hed. J. I: 952-954. 222. Kinross-Wrlght, V., Moyer, J.~. l9S7 : Obeer~rations Upon the Therapeutic Use of Benactyzine Suavetil. Am. J. Psychiat. 114: 73-74. 223. Vo ~techovoly, Il., tJitek, V., Ry~anek, K. 1966: Experimentelle Psychose nach ~Jerabrelchung von Benacryzine. Arzniem. Forech. 16: 240~242. 224. Rickels, K., Gordon, P.E., Jenkins, B.tl., Sablosky, L., ~llachos, V.A., Iteise , C. C., Whalen, E . M., Wilson, I) .A. 1971: Combination of ldeprobamate ant Benaceyzine (Deprol) and Con~ei~uents in Neurotic Depressed Patiento. Dis. Nerv. Syst. 32: 457-467. 225. Sidell, F.R. undated: A Summary of the Investigatione in Man wi~h BZ Conducted by the U.S. Army, 1960-1969. CSt. 000~13 7. 226. Freedman, T. 1962: Effec-~s of ~Z on Pilot Performance. Final Report, Contract No. DA-~-108-C.YL-6644. 227. Authur unkno~ 1962: Posalble Buman Estimates for BZ Baset on Relationship Between BZ and A~ropine. C.C. Ied. Labs. Miscellaneous Paper. 228. Ketchum, J. 1963: rhe human Assessoaent of BZ. Chemical Re search and Development Laboratori es Techulcal ~femorandum 20~29. 229. Directorate of Medical Research, U.S. Army Edgewood Areenal I;965: Guide to the Management of BZ Cssualties. 230. Kitzes, D.~., Uancil, M.E. 1965: Estimate of Hinimal Effective Doses of BZ by the Intramuscular Route in Man. Chemical Research and Development Laboratories Technical Hemorandum 2-30. 231. Crowell, E.8., Jr. 1966: CS27,349: Estimate of the Incapacitating Dose in Man. Edgewood Arsenal Tech~cal Memorandum Il4-2. 232. Craig, F.N., t~cttichael, P.D., Robinson, P.F., Sldell, F.R. 1969: Effects of BZ on Temperature Regulation in Han. Edgewood Arsenal Technical Hemorandum 112-~. 233. Brown, H., 1965: A Review of the Phar~acology and Toxicology of C" 301, 060. Contract No. DA-~-108-AMC-lO 8( A) . I 135

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2340 Mennear, J., Samuel, G.K. 1963: Pre~clinical Pharmacology Study - Monkeys. EA 3443. Contract No. I'A-l8-1013-A~C-7 8(A) . 235. Mer~near, 3., Crews, L.M. 1963: Pre-clinical Pharmacology Study - Dogse EA 3443. Contract No. DA-18-108-"C-78(A)o 236. Mennear, Jew. 1962: Pre-clinical Pharmacology Study - Dogs. EA 2545 and EA 3167. Contract No. DA-13-108-405-QfL-826. 237. Kitzes, }AL., Ketchum, J.S. 1965: Estimate of Minimal Effective Dose of EA 3443 in ttan. Chemical Research and Development Laboratories Technical }memorandum 2-29. 238. Havoc, J.~., Salter, 1~. 1966: A Study of Possible Residual Effects of EA 3443 and EA 2S8O on Cognitive Ability. Edgewood Arsenal Technical Report 4044. 239. Armstrong, R.D., Meeker, L.WO, Somere' L., O'[eary, J.FO, 1975: Behavioral Dose~Response Studles of EA 3643 and EA 3580 ia Rat8 Trained in the Sequential Response Test. Edgewood Arsenal Te chnical Hemorandum 75001. 240. Abood, L.G., Ostfeld, A.}l., Biel, J. 1958: A New Group of Psychotomimetic Agents. Proc. Soc. Exp. Biol. Hed. 9 7: 483-486. 241. Ostfeld, A.N., Abood, L.G., Harcus, O.A. 1958: Studies with Ceruloplasmin and a New Hallucinogen. Arch. Neurol. Psychiat. 79: 317-322. 242. Abood, L.G., Ostfeld, A., Biel, J.~, 1959: S true ture-Ac tiv! ty Re lationships of 3-Pi peridyl Benzila~es with Paychotogenic Properties. Arch. Internat . Pharmacodyn. Therap 0 120: ~ ~ 6-2 00. 243. Usdin, E., Efron, 13.11. 1972: Paychotropic Drugs ant Related Compounts, Second Editlon, Washington, O.C. U.S. Goverament Printing Office, p. 224. 244. Gershon, S., Olartu, J. 1960: JB 329- A New Psychotomimetic. Its Antagonlam by Tetrahydroaminacrine and Its Comparison with LS0, Hescaline' and Sernyl. J. Neuropaychiat. 1:283-292. 245. Biel, J.~., Nuhfer, P.A., Hoya, W.K., Leiser H.A., Abood, L.G. 1962: Cholinergic Blockade as an Approach to the Development of New Paychotropic Agents. Ann. N. YO Acad. Sci. 96:251-262. 246. Brown, M.L., Gershon, S., Lang, W.J., Korol, B. 1966: The Effects of Paychoactive Druge on the Behavioral Response to Ditran in Dogs. Arch. Internat. Pharmacodyn. Therap. 160:407~423. 1 136

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247. Gershon, S., Angrist, B.M. 1973: Effects of Alterations of Cholinergic Function on Behavior. Chapter 2 in Proc. Of the 62nd Ann. Meet. Am. Paychopathol. Assoc., Cole, J.O., Freedman, A.M. , Friedhoff, A.J. , cd's, Baltimore, Johns Hopkins Press, pp 15-36. 248. Ketchum, J.S., Kitzes, D., Copelan, H. 1973: EA 3167: Effects in Han. Edgewood Arsenal Technical Report 6713. 249. Arthur D. Little, Inc., and Sterlin8-Winthrop Research Institute 1968: Supplement S. Additional Toxicity and Tolerance Tests with 226,086 and 226,169. Quarterly Report ~ Contract No. DA-~-lO8-AMC-103 (A) . 250. Hayes, A.H., Jr. 1967: CAR 301,060: Estimate of Minimal Effective Dose in Man. Edgewood Arsenal Technical Hen~orandum Il4-12. 251. Copelan, H.~. 1968: tfi050 of Agent 834. Flual Report, Contrac ~ No . DAAAl5~68-C~0627. 252. Averill }I.P., ldcHamara, B.P., Callahan, J.F., Oberet, F.W., Farrant, R.L. 1970: Toxicology of EA3834A in Animals. Edgewood Arsenal Technical Memorandum 106. 253. Sim, V.M. 19 71: Compound 302, 668: S~'nmary Report . Edgewood Arsenal Special Publication 100~95. 254. Sidell, F.R., Braun, B.G. 1972: EA 3834A: Effects in Man Af ter a Single Oral Dose. Edgewood Arsenal Technical Report 459 7. 255. McCarroll, J.E., Markis, J.E., Ketchum, J.S., Houff, C.W., Sim, V.~. 1972: EA 3834: Effects on Performance of a Small Inf entry Rif le Element ~Jnter Simulated Combat Conditions. Edgewood Arsenal Technical Report 4633. 256. Cucinell, S.A., Cummings, E.G., Holgate, S.H. 1975: Sweat Inhibition and Performance Decrements in Han Following Percutaneous Exposure to EA3834. Edgewood Arsenal Technical Report EB-TR-76004. Copelan, Hip. 1967: HE:DSO of Agent 668. Final Report, Contract No. DA-18-035-AMC-126 (A). 2S8. Karger, S. 1968: Incapacitating Dose of CAR 302, 668 in Man, and Efficacy of Physostigmine as an Antidote. Edgewood Arsenal Technical Hemorandum 116-20. 259. Sidell, F.R., Karger, S. ~ Simons, C.J., Weiner, J.T. 1970: Compound 302, 668: Aerosol Administration to Man. Edgewood Arsenal Te chnical Report 4395. 260. Copelan, H.W. 1967: MED50 of Agent CAR 302,212. Report No . I\t, Contrac ~ No . DA-18~035-A.MC-126 (A) . ~ 137

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