http://exhibits.library.stonybrook.edu/mfp/files/original/f8b5cf3cf6b847561379d21a8181ceef.pdf 550c4683b921dafa008583e1e9dd5aff PDF Text Text ��COPY Clinical Release PRODUCT Combination of 'Thorazine' and Diparcol (SKF #1026-A) Diparcol alone 'Thorazine' mg/cag. ca . FORMULAS 50.0 mg. H01 2.0 Magnesium.Stearate Lactose 200.0 -__- ---- mg. mg. 300.0 mg. is. Restricted Medical Utility Studies - Dr. Herman Denber TOXICITY Acute Intravenous Toxicity The intravenous acute toxicity of a combination of SKF #1026—A ('Diparcol') and 'Thorazine' in the ratio of 5:1 was determined. Intravenous LD50'S in male mice (CFl) were determined for SKF #1026-A, 'Thorazine' and a combination of SKF #1026-A and ‘Thorazine' in the ratio of 5:1. The mice were observed for a 2h hour period, at which time all surviving mice appeared — normal. Combination significantly more toxic than SKF #1026-A (T.R. = 1.2) 'Thorazine' ngt_significantly'more toxic than combination. (T.R. 'Thorazine' significantly more toxic than - 1.36) SKF #1026-A (T.R. = 1.13) acute intravenous toxicity in mice of a combination of 'Thorazine' and ‘Diparcol', in the ratio of 1 part of 'Thorazine' to 5 parts of 'Diparcol', did not differ significantly from that of 'Thorazine' alone. Such a comparison is valid since the slopes of the toxicity curves are parallel. The combination is significantly more toxic than 'Diparcol' alone, but the comparison is subject to criticism.that the slopes of the toxicity curves are not parallel. The December 9, 1955 �DIPARCOL In answer to your request an attempt has been made to find data comparing the anticonvulsant activity of Diparcol (Diethazine, SKF #1026) with.that of other phenothiazine derivatives: Phenergan (SKF 1&98), 'Thorazine‘ (SKF 2601), Promazine (SKF 3h06), 'Compazine' (SKF h657), SKF 5277 and SKF 5116. No such studies have been done in our laboratory. The only SKF lab report on Diparcol gives its toxicity as LDSO * 31.2 mg/Kg I.V. as compared with 22.9 mg/Kg I.V. for 'Thorazine'. Balestrieri (1955) compared Diethazine, Phenergan, Parsidol and chlorpromazine with respect to their protective action against electroshock and Metrazol seizures in rabbits. Phenergan and chlorpromazine showed no anticonvulsant action against electroshock seizures; Diethazine, 5 mg/Kg I.V. protected 2/5 animals and at 10 mg/Kg I.V. 3/5 animals. Parsidol protected 2/5 animals at both doses. These results confirm SKF data obtained using maximal electroshock seizures in mice which showed no anticonvulsant activity for SKF lh98, 2601, h657 or 5116. SKF 3h06 did protect mice against seizures; the ED§Q was 155 mg/Kg p.o. SKF 5277 also demonstrated anticonvulsant activity with an oral ED50 of 71.0 mg/Kg. , Balestrieri snowed chlorpromazine to be Metrazol seizures. Phenergan was inactive inactive in protecting at 5 mg/Kg I.V. rabbits against but a 10 mg/kg I.V. protected h/5 animals. Diethazine protected h/5 animals at 5 mg/Kg and 5/5 at 10 mg/kg. ParSidol protected 5/5 animals at both doses. ’No similar SKF data are available. The experiments of Anticonvulsant action and molecular structure of phenothiazine derivatives. .krch. Int. Pharmacodynam. 103:1-11, 1955 Balestrieri, HLM:pz hc A. �COPY- PHARMACOLOGY REPORT November 8, 1956 10-(2'-Diethy1aminoethyl)-Phenothiazine Hydrochloride 0R (Diparcol) SKF No. 1026-A Compound: Code No. Lot No. 99 Structure: )W ii /” '\\ K\//h\§v/\ EV 1 9H2 l c H2.N-( 02H37~2 mignzim.R.T.Cmma' Tested for: Dose Range - .HCl Mmda Studies in mice after intravenous administration (11/10/55) Observations Dose rug/kg side effects 2.5 No 5.0 2/2 slight depression, loss of pinnal reflex 2/2 ataxia, sl. depression, loss of pinnal reflex, 'Thorazine' walk. 2/2 ataxia, marked depression, dyspnea, 'Thorazine' walk, loss of pinnal reflex. 10.0 15.0 6/6 clonic convulsions, apnea, prostration, ataxia after recovery, hypotonicity, 3/6 dead 2/2 clonic convulsions, apnea, prostration, ataxia after re- 20.0 25.0 . cover h otonicit Note-—all animals recovered from.prostration within 60 minutes.. Summary: exhibited 'Thorazine'-like side effects after intravenous administration in mice. Slightly higher doses were required to produce depression than with 'Thorazine' and the depression produced was of shorter duration. SKF #1026—A 'Thorazine'-like Activity: Charge: Biological screening GW/IB/m/mh �LILLY LABORATORY FOR CLINICAL RESEARCH INDIANAPOLIS GENERAL HOSPITAL INDIANAPOLIS 7, U. S.A. December 29, 1955 Max Fink, MOD. Hillside Hospital 75-59 263rd Street Glen Cake, New York Dear Dr. Fink: In answer to your recent request, Storey et a1. (Antibiotic Med. & Clin. Therapy, 2c258, September, I§§STI though they do not report electroencephalogram findings, do discuss the behavioral effects of cycloserine. There have been no publications, to my knowledge, reporting EEG findings in patients receiving 'Seromycin' (Cycloserine, Lilly). Veterans Administration hospitals have been doing EEG tracings but their reports have not yet been published. They will probably present their data at the Veterans Administration Conference on the Chemotherapy of Tuberculosis to be held in St. Louis in February. do be not we of further please may assistance, any If hesitate to w rite us. The Very truly yours, f th, M.D. ri Clinical esearch Division R. mlw 18760EIGHTIETH ANNIVERSARY-1956 �TELEPHONE: LEHIBH Form 90a-Adm. 4-1300 State of New York Department of Mental Hygiene MANHATTAN STATE HOSPITAL JOHN H. TRAVIS, M. D. DIRECTOR IN Ward’s Island, New York City 35, N. Y. ANSWERING REFER To ______.______._____ Dr. Max Fink June 20, 1957 Hillside Hospital 75-59 263rd Street Glen Oaks, N. Y. Dear Max: your findings on I should like very much to include Chloram on I that writing the final in paper the 'Diparcol' me send Could of you Treatment Depression. promazine-Diethazine diethazine I.V. of the effects in general, note indicating, a brief on the EEG? Were there any concomitant psychological effects? of "personal reference under the of note I will course, this, communication." Many thanks. Sincerely yours, [/7 HD:SS Herman C. B. Denber, M. D. Director of Psychiatric Research �4;:- x} June a?) 1957. Dr. Hem 6. B. Ember, Dimmr of Payehiatma Bsmmh, Mahatma; State ammm, ”55W"! 1818M, ”at. f: , Dear Hm Itwaaaplmto Atlantic city. I am aomr that mm we We withyouandymwfiein mum could not. get. smother for "mucus“ much. Johanna and cmvisit. I social enjoyed bht very Mb: 5.3 who: moth with a wry Might. boy, But this yw' almdy may: Mahala, Ina 1mm. A9 fer our “parlance with your suggestion in 1 obtained some intmous manual from SKI. In the last 1w ‘mths we hm given it. to six ”news intmmly. Evin subject and tt. {um at" electroshock therapy and the trim of the I. of much. In sank instance high height. of m: mo 1n In: an the premix "mag abatmmphdogm u’mrity tam. the but situation, in which I and an we qmamm 3 and than remand after the parlour M the Watt-attests cf the d 50 2 of the The rate was mm. dosage drug gvmat smnmum. and than abuut for thirty ”cording a at. of the air. rate mast how the to for eight Manama unplug :pprmntnly mm hour. mm. mm mm, W 93.03th m m mm W» 6!me We: m. mum WW m W m ma Way m hiring the ministmtion, each patient Moped, batman the coma um fourth cc. m epdseda of waging. mare m macaw in breathing which an trunnion. This was the mat untoward attach a: m m alaotromcophnlosnphia ohms pared gradually but was mt. M: the: tho of minutes n injection. within tan 150 ace mm apparent. to thin tin mm veto mead rm a may a! than mansions 70 rum rmmyms toammcf in mm» Wt.- mmumm. tamper-u MWalimdzm;wnwegemmWoffimSma cent. tin 691th, however, mad about the sum. Mb 3:: «that peanut! far one to an hours and in :1]. WWW 1n the maples “loan about four to time: hours liter the Gilt: activity at at the pro-injection m1. In an. “outpatient:mdauutifltymmotthaomrofhto66330.3“ caplofion of the Winn in value” of he to 70 UN. mm the delta activity am: ”My ma in pomnt tiny and in voltage u: that. m an: amount! mam- him he Waits. nun appeand stupor-impound film �Dr» new at Bar mr, #2 a clearly defined 25 cpl. nativity... Tlmm records the the was an ”alerting? following. report Warmly animated by an incmaad methane” ai‘ we patient and a crust. “ibis greater difficulty in having the patient maintain his eyes gazed, ma tbs change in hm patients from: a "Home for this alerting phenm effect to a mgative am)... The changes in language after positive were the reverse of the changes in language which we have axperlmcod 131ml 1n the past after tho amatmtion a! mama-him. Since we use the identical w scone the changes in 11am in an Mammal fashion. In maimaim, three Mamas the questions prior to the of Dime}. wen 11-. and therefore to ovum.“ the changes in Imam. negative Waible & “manure" In one manna tha max-d changed in to an 1mm. mama clung» of the kind tkmt we see: with mbarbim. This dinmponcy I. cannot explain. m m m1 m 1mm W10 rm manna; am eontinning this study and I would 11m to pmmt the behavioral and electroeneephalog‘aphia effects My in the £111 to the Eastern EEG Association. Thaw observations are, of eourse, migratory and I am not 8m 8 UT the next batch or patients may not shot-7 us some other patterns. To tho flat extent. that. this inmatigation has confirmed the observations of Leann”, I an moat yieased. Ha I have no objection to war reporting some of this itfl'omtian in outline. If is of any help ta you, I will be pleased to see the paragraph: as yen intend to report, them and give you my reaction as to how they reflect. it our axpoziemaa, Sincerely yours,Kn: Fink, Dani-haunt at MFtJB mammal Pnyuhiatry. H.130 �“,f ‘i? ziirect i v . i of Diethazine on EEG ’5‘ 0+3 qt I for and Significance Theory of Convulsive Therapy Mauougflwk.fldb Previous studies of the role of EEG changes in convulsive therapy delta activity for have demonstrated the significance of the induced the behavioral re3ponse. Investigations concerning the biochemical substrate of delta in electroShock and convulsions EEG have indicated significance for the cholinesterase - acetylcholine system. reports on by Ulett concerning the effects of atropine and Recent 00’ scogfilflhine the delta response-effihe-EEE-showed a reversal of the-induced patterns. Boncurrent iswmvafi. reports by r and of diethazine on normal EEG and that following Lechner on the EEQ effects trauma provided the stimulus for the study of the effects of this drug in electroshock. Subjects: Twenty voluntary psychiatric patient in an openyward/psychiatric hospital have been tested to date. d " £5? During recording, at various maturing (Biparcol) is administred intravenously at per minuteI Maw “'5’57- £155; xi treatmen . rmi 94°" " the rate of 25 milligrams ‘1 250 milligrams, {My diethazime 70.,qu * �Observations : a) by the of All dryness cmgling, respond subjects Behavioral“ mouth and thickness of speech. Feelings of weakness of extremities illusory sensations are and There common. is an increase in rest- lessness and difficulty in maintaining eyes closed. In patients who have had sufficient electroshock to manifest syntactic and orientation language changes indicative of altered cerebral function, is there ‘ b) EEGSq a reversal of language patterns. . In all subjects there is desynchronization of frequencies \ and decrease in voltage. Alpha rhythms are less prominent. ! low Occasionally, \ -—-a c" In voltage “ILA 577’ frequencies appear. \ voltages-a25of delta with degrees varying activity, patients in decrease‘, frequencies decrease and burst activity disappears. Irregular alpha and beta frequencies of low voltage become c) The EEE and persist clinical effects consist for gradually disappear. one mmminent. to three hours, and �Discussion: The pharmacologic effects of diethazine are described as "anti- cholinergic" and "atropine-like," and in patients with altered brain function may be h described as "allert‘ electroshock induced m (Ulett). EEG delta is P The action of diethazine an 0 . scopfll ine similar to atropine and eeelpalemine (Zinc floss observations era‘similar to those in subjects with head injury (Jeéhker and Lechner). Conclusion: ‘1'“ Based on this data, as well as the cerebr¢{:§pinal fluid cholin- esterase studies of Bornstein) and Tower and McEachern, . fuedJLb£1 diethazine hes-e ready that: (l) ' ' it is .: enter the central axrhnL; and trauma induced electroshock by by delta system3(2) a . concluded nervous 4' may similar A have biochemical substrate;(3) electroshock may be looked upon as a controlled 6F Alana; method tc.indnge ce ebral dysfunction for The its induced behavioral significance of these observations for EEG studies of head trauma and the mode of action of gin-ilpconvulsiVe therapy discussed. effects. will be �//— £3th at Diethuine on 3%: and Significance for Theory at Germanium mm Previous studies of the rule of have demtrnted EEG changes in convulsive thenpy the eigmfieam or the induced delta activity for the behwioral response. Imeatigetions containing the substrate of EEG 1:10ch delte 1n electroshock and convulsions have inflated significance for the eholinestemae - mtwlchonne system. reports Ulatt concerning the «treats a! atropine and by anthedalta patterns, response otheEEGshemdamml of napalm theinducedm Goncurrent reports by Jemkner and Lochner an the offliethum «1110;14:11me Recent. effects mtrmmmmmmm atimelua for the study of the effects or this drug in electmahock. Subagetet Twenty voluntary psychiatric patimte in en upward/psychiatric hospital have been tested to date. Electroencephalogm have been obtained mutant. During the recording, at. various fines during (limit) is administer! intmemualy per me until at. the 250 Milligrams have been rate of Metered. diethume 25 milligrams a an �¢2~ mumations: a.) Behavioral - 51]. subjects respand by coming, dryness (J the math and thickness of speech. Feelings of weakness of extremities and mm. illusory sensations are Mamas is news in mt. an difficulty in maintaining eyes closed. In pgtients 3nd who have had There Mficient ehctmhwk to manifest syntactic and onentation language changes indicative of altamd cerebral function, them in a reversal of language pattern» b) EEG ~ In all subjects than in Voltage. and decrease Damionflly, 10w is «synchronization Alpha W of Inqueneies are less prominent. tnqmncies appear. voltnga In pstinnta with varying dogma of delta activity, voltaga is deemed, tmquemiea in “cram am} burst wtivity disappears; Irregular alpha and but: fmqmnoioa of law voltage become more a) Tho W and liy clinical eflwta diuppnr. . pox-stat mm gamut. for om to than hours, and �A! mammalian The phnmaeolog'ic effects of diethuine are described as ”anti- cholinergia“ and “atmpimlflm,” and in patients with altered brain function may be doacribod an ”martini." The action of electroshock induced (Butt). EEG delta is 3min:- to atropine Also, than. observations with hast! 11131211 («bunker and m diothum 8nd n W napalm 51:11” to than in subdue“ Mr). 091191113th Band on this data, us all 0 as the carom spinal fluid wanna «tea-am swarms of Bernstein and Tower and IicEnchem, it is minded that: (1) diothuine has a randy ability to enter the central nervous system (2) delta induud by electroshock and by trauma my have similar Mommioal substrate (3) electroshock my be loolwd upon as a controlled m’chod to induce cerebral dysfunction for Ema tm its induced behavim'al effects. hand for'EEG of atxfiias of these obsamtiona significant: and the mode of discussed. act-.1031 of electmcomluvo therapy will. be �MM or blow swam m and Gmmlaim Therapy on m m, for 1119on of 24.13. me changes in wmulsive therapy have the signifiam of the induced delta actdxiw for the biochemm umoarning the Invasfigatlans tome. have EEG and indicated electroshock emulsions of delta in mutate nignfimm tor the ahonmuem - mmdcholine system mm. Pruvioua studies Wand 1:6de at the rails of. otatropdmandaoopolmo Wbymttcommmgmeflw EEG induced showed EEG or cloctrashook a moral in an pattom. am: Comm-rent reparts by Janka»: and Lechner an the: extent: of on mm]. EEG and that. following tram provided this stimulus far the study of the effects at this drug in electroshock. mm Salaam” treatment various during ht stages patina“ puma-lo in an open—ward voluntary psychiatric hospital have been tested to (Dimmol) is manicured date. "During EEG recording, int-.mwaly at the rate of 25 milligrams- por minute, for a total at 2% Twenty diam W0 Mmtionu ' : a) %: b) m m All subjects respond by coughing, dryness of the thickness of mach. Feelings of weakness of emu-mitten mm and illusory marathons are cam. more is an immune 1h restless. mas and mamty 1n maintaimng eyes clued. In patients who have had sufficient. electroshock to manila“ syntactic and orientation language changes indicative of album earabral function, there is a reversal of language patterns. more 13a doaynchrmiuuon of rmmdes down» in voltage. Alpha rhythms are less lament. Occasionally, 1m? voltage theta frequencies appear. In all subjects In patients with varying demos of delta activity, voltageand burnt increase frequencies activity disappears. Irregular decmo, alpha and beta Imumcies of low voltage become prominent. c) The EEG and clinical effects persist for one to three hours, and gradually disappear. Fm Department of men Oaks, ELY. than 1.1-6.5? - EAEEG mmm Psychiatry, Hillside Hospital, �‘5 of downbeat afloat: dawn» m Wohgie u ”antiwhonmtgie" and 'ttropine‘uka," and in patina“ With slated brain imam any be 6030de as ”wrung.” the mum at on ahctroshack induced EEG delta is amm to atropine 610mm um! £39me (010%). mm ebmmfiom an aim similar to firm in aubjccta with bud injury (Janina: and helmet). The cmcluaiam Mac! on this duh, as «11 as this cerebmspinal fluid cholimatamso studios of Ben-MW, and Tower and Wuhan, is wmludod that: (1) damn» mam entm the «antral nervous system; (2) delta nativity inducod kw alwtrodmck and and by tram may ham: 3 similar (3) mutate: mm be lookad upon an o. watt-0119c! ”that! of naming «mural to: its behaviaral affaa‘w. it mmwu m Wanna The «:1ng the or action of convulsive: therapy will trauma and node of thew than mamtiom for m ”adieu or had be animated. �v -r:‘V?\'(‘r.uv' w--w—ILW|>L‘»V‘V'~B—w"y:mm w—r-mw-vwn»vww.,u—A » v —.-.r. -- .vr. w—y ~ w — "av/\— <7 r ,rw-I'IWK . aw u 'mwl' - - - "a.“ AM'HV'Wwv _,,, A was �wan-my r'm ��Form 90-Adm. éhhft$nk jfluh fisgrlfiatrit gustitute 722 WEST 188'"! STREET. LAWRENCE B. KDLI, M. D. nlnlm'run NEW YORK December 4, 1957 Dr. Max Fink Dept. of Experimental PSychiatry Hillside Hospital 75—59 263rd Street Glen Oaks, New York Dear Max: feelings about Saturday night are reciprocal. Weihoroughly enjoyed the gracious company of you and Martha. With the intuitive perceptiveness of the female, Yetta informed me of a forthcoming event in your family, and we Wish you the best of everything. I indeed look forward to the reprints on your Work which you described in your letter and our discussing them together. The next edition of the Kalinowsky and Hoch will be expanded to include tranquilizers, and I would also appreciate any reprints of yours in this area. I have enclosed my own reprint on the clinical effects of Win-2299 and the basic paper by Luduena and Lands. As you will note, the compound is a peripheral anticholinergic and produces a "disorientative" reaction in cats by central action. Its psychotomimetic action in man appears basically to be an acute toxic reaction type. I would imagine that its central mech~ anism of action is similar to that of atropine (which also produces acute confusional states in high doses). Win—2299 is effective at much lower dosages than atro— pine. Possibly both atropine and Win—2299 both produce central effects by an anticholinergic action but, as far as I know, this modus operandi has not been pinned down crucially as far as the C.N.S. is concerned. I would not expect all anticholinergic agents to be psychotomimetic, of course. Win-2299 is a tertiary amine. Monodral is a closely related drug, differing only by quaternization of the terminal nitrogen in Win—2299. It is Win~4369 in the paper of Luduena and Lands (p.283), i.e. the methobromide form. According to Winthrop-Sterling, it is a peripheral anticholinergic in man in doses of 5-40 mg. per day. Central or psychic actions are not mentioned in their account. Presumably, quaternization reduces central activity by reducing permeability. Our �Dr. Max Fink (cont'd) ’ -2— I imagine that other agents in the Win series with central effects in cats might also be active as psychotomimetics in man. I am not familiar with the formula of diparcol and if you have it available would appreciate learning where to look it up. The drug is not covered by Goodman and Gilman. I would appreciate return of the Luduena and Lands paper when it has served your needs. We gave the Win—2299 the orally, The compound being drug was supplied as the supplied in tablet form. racemic mixture, the asymmetric carbon atom being terminal in the aliphatic chain. Sterling—Winthrop may have it for intravenous use and I suggest that you write M. L. Tainter, M.D., Director, Sterling-Winthrop Research Institute, Rensselaer, N.Y. about it. Our oral supply was used up in the study. As you know, all psychotomimetics not only create new symptoms in mental patients but also intensify or revive pre-existent symptoms. Best of luck. Cordially, ”2a Harry Pennes, H. HHP/ys Encl. M.D. �PA if .. _ * (on 1M5? I Effect of Diethazine on EEG and we Significance for Theory of Convulsh M Therapy MD Mow In a previous report to-this society we noted the relationship between the degree of induced delta activity during the course of therapy and the behavioral reSponse to electroshock. Those patients, in delta activity were induced early, and were degrees of behavioral change, as well as a significantly greater percentage W gm vial £64414a Law In. Box} EH: acetylcholine and in whom only low degrees were induced (Fink and Kahn, 1957). activity 1, (ii; '1.) high degrees of sustained, manifested the greatest of improvement and recovery than those patients of delta whom ,hML-wQA‘O‘ . a, W" , ‘Jawc‘z MM L Mkfil‘g‘f‘” ’M‘Af‘z‘ mv’efrff " in!“ (.4 Mfianges infree” ' a variety é‘fu‘reports, cholinesterase in the Spinal fluids of patients (Sachs, 9. Ward) and animals (Bdrnstein, Tower and McEachern) following head Wig; . . I the observations that by trauma M o (Bfrnstein, flue/4% In 1956 .c‘ E agents liq—alter the EEG patterns induced Ward, Jenkner-Lechner) and by electroshock ( “knew“at?mp (Ulett)pu_l Ulett reported that atropine g’scbpolaminerwhea-aéiénéstered— / W, blocked the appearance of the delta wea»...have come to associate with - _,-.,..«-'V'F-r -v~ WWW ahaaul,” "‘4“qu w. traumalawfl electroshock therapy. A!” 791’] am’LlLJ/g/J M ’L “‘2‘“ 4“““4/ié’MWrrW ”“an“ j?” activity {lama/Wye? v» �-ebeervetions~ Previously, ward (193) following the suggestion of Bornsteiny (19h6) had noted that atropine altered both the EEG patterns and the neurologic signs induced in.man by head trauma. afiereT-tee, the side ZZ,AQA7V ~effects were marked. In 1955: Jenkner and Lechner reported that EEG behavioral effects similar to atropine were achieved by diethazine istered in patients with head trauma.‘ They and admin— also reported the effect‘of diethazine in normal subjects. It is the purpose of this report to describe the effects of intravenous diethazine on the EEG of patients during electroshock therapy; and to relate their these findings to the present neurophysiologic-adaptive hypothesis of the ndde of~action of convulsive therapy. w ‘flwmwmflmwwwfl_fl____.imm 3" Diethazine is a soluble phenothiazine compound with phamacologic properties similar to atropine. In experimental animals, (19h?) have noted that diethazine blocks vagal slowing of the heart‘) M suppresses the bradycardia, bronchospasm, salivation, and fasciculation and seizures induced by acetylcholine, DFP ‘‘‘‘‘ ‘wywwflfimgimww‘fizoxsum-“:- w' ”mm—«MA..- and pilocaxxfixg and induces dry mouth, mydriasis and hypotension. L/——' / Heymans EE.E£ a“: nevus-aw» 4.: '2‘ YW',‘47"’~"5‘W1‘-05 Emma-gwhz - .— ' .~_4~:_MD~J �93" ”w W Subjects: Twenty-two psychiatric 42‘ patients,” various stages of electro- shock treatment in an open-ward, voluntary psychiatric hOSpital have been studied. the laboratory. Following a routine EEG administered intravenously at the rate of of 2630 to 250 mgm, the i Tl’br.‘ EEG 25 mgm per minute, for a total effects. Prior to the historical interview and a structured questionnaire period were tape-recorded. EEG recording, diethazine was depending upon the behavioral drug administration, an unstructured both EEG gubjects were tested in Following drug administration, recording‘ and recorded interview periods were continued until record again manifested.the pre-injection patterns on visual inspection. Mm New. ‘>IIVW~.. Qbservations: in Le ,, (a) Clinical: AH su jects manifesm Spontaneous coughing mutual-i33- @ followed by a dryness of the mouth and a thickness of speech. flgrtrf They note‘, ' 3'37 a feeling of lassitude and weakness of the extremities? soon followed by increased restlessness and difficulty in maintaining eyelid closure. phenomena were PSymW/clearly between 15 and 30 minutes . manifested in after some subjects. In the rest period drug administration, six subjects spontan- ..,. _‘ ... _ A �4,. eously voiced feelings of unreality, visual and haptic illusions, and delusional thoughts about their illness, the setting of the test procedures or our identity. Such patterns were transient and had disappeared In by the termination of the experiment,-asaallyhiééfifiurdfinnxrdnmzns. three subjects, increasing agitation . and panic led to a cessafion of the recording. éHere7-tccy—restétation_a£—pme—énjenfifinnrdnfiuufiuuaauua I 'li' g“, , I! i . fiilliwuwfi (b) In previous studies, the intimate relationship we had noted between changes in syntactic language patterns with alteration in cerebral function induced by electroshock. In subjects tested prior to electroshock, diethazine induced changes in syntactic pattern of an "alerting" variety. I - gal [5% In subjects with elta activity‘ with clinical syntactic patterns indicative of an alteration in cerebral function, diethazine induced a transient dis- appearance or minimzation of Such language in language (c) was concurrent with changes EEG Patterns: In all patterns. The period of changes in electroencephalogram. records, there is a decrease in voltage and desynchronization of frequencies. There is a decrease in prominence of prevailing rhythms. In patients without delta activity (pre-electrodhock)’ �-s5‘ 4/ this deéhronization and voltage decrease is occasionally accompanied by the appearance of small amounts of low voltage These are demonstrated in Slides 1, not appear to be altered. The and 2. The 5’7 '5' cps activity. basic alpha rate does build-up in voltages and appearance of thm slower frequencies with hyperventilation is blocked. In patients with varying degrees of induced high voltage activity voltage”, both random and 4 This change It and 3 dub is a decrease in burst delta activity disappears; and irregular, / low voltage alpha and beta frequencies become prominent. are noted in Slides delta These changes LL. 5W in is manifest in appears during drug administration, and all electroshock subjects. persists for awe. [WM filwwx 13% 2/1. floncurren WithAelectroencephalographic hours vtwv ‘ ”fly to three age MM» Wrens-em fiith the 8&3 17TH 770 n moustita—tion— of the pre-injectionEl'I} patterns, the pre-injection behavioral and language patterns again appeared. �DISCUSSION: report of Jenkner and Lechner of the t”t.¥£~£ dikd/“4lz‘ijzz7' effects of diethazine in"normal" subjects. 'Wa.alsa—nnta_tha§21iethazine These observations confirm the alters records-snd-fiith electroshock induced delta activity in‘a fashion similar to atropine and scopolamine, as described by Ulett, A Mada» W was. . 1%,. is apparent, therefore, thatngfi readily affects the central nervous and.é53 duration system, ofiactivity is most useful for experimental purposes. The-previeusiy—eitnd studies by numerous Observers of nervous system effects of head trauma point to an intimate relationship between the degree of neurologic dysfunction, the degree of EEG alterationjgand the level of free acetylcholine in the spinal fluid. The effect of atropine both the Echand ill on concomitantly on behavior in subjects with head trauma lends further support to the significance of figs: acetylcholine as the biochemical basis for the observed EEG patterns. In these studies of diethazine electroshock, the intimate relationship between EEG patterns and and behavior �-7have been reported. We note the parallel to the observations in head \ trauma. On the basfis of these observations, as well as studies of Spinal fluid Woholinesterase levels; (Tower we would and HoEachern, Fink and Goldenberg)‘ suggest that the biochemical substrate of the electroshock process. is isimilar to that of head controlled trauma.9 method of inducing ectroshock hLauri. may be looked upon cerebral dysfunction for its as a behavioral effects. Previous studies have demonstrated that alteration in cerebral function provides the physiologic basis for the behavioral changes in electroshock (Fink and Kahn, 1957). Such alteration in cerebral function provides the milieu for a change in the organism's adaptation to his environment. aSpects of behavior, as perception, language, mood, recall, memory, All affect, undergo change, and provide the basis for the therapist's evaluation of improvement. The studies of diethazine amplify this neurophysiologic 9.39.9. adaptive hypothesis of electroshock by suggesting the type of biochemical substrate that underlies both the physiologic and the behavioral changes. �Mm= 0 Diethazine, a pftent anti-cholinergic compound, u was experimentally introduced intravenously in psychiatric subjects,;fi various stages of convulsive therapy. Electroencephalograms manifested a desynchmnization of frequenciesfue («C decrease in voltage records without prior delta activity. Records with delta activity showed similar changes with disappearance of delta burst activity. Concomitant with the electrographic patterns indicative of It is concluded a effects, behavioral reversal of the electroshock effect enters the central nervous System upon intravenous (b) The biodemical basis for that of head trauma; (c) therapy The may EEG compound that readily adninistration. changes in electroshock is similar and biochemical basis of the lie in were observed. that: (a) Diethazine is a Bitent anti-cholinergic to and language mode of action of convulsive the acetylcholine-cholinesterase system. a, �@ Research and Development Division SMITH, KLINE & FRENCH LABORATORIES PHILADELPHIA - I ESTABLISHED I84| December 11, 1956 Max Fink, M.D. Director of Research Hillside Hospital 75—59 263rd Glen Oaks, Street New York Dear Doctor Fink: associate, Mr. C. W, French, has referred your letter of November 12 requesting a supply of diethazine to me for reply. It has taken me a little While to uncover-sufficient supplies for the short clinical trial you want to conduct since our interest in diethazine alone and in come bination with 'Thorazine' isn't too great at this time. My not have this compound available in 500 mg. capsules as you requested. It is only available in 250 mg. tablets. A supply of this strength has been sent to you together with a supply of the intravenous we do material so that you is all the literature we this will be of some help. Enclosed hope the may Observe EEG effects on 10 have available on Sincerely yours, .\ to 15 patients. diethazine. I , J”, Meagan? Ms (,7 . John F. Buckley a Research Associate / ’ ' Medical Department JFB:hc Enclosures P.S. Will you kindly sign the enclosed FDA card and return so that we may keep our files up-to-date. it to us � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effects of Diethazine on EEG and significance for theory of convulsive therapy. Electroencephalogr Clin Neurophysiol. 10 207-208. (abstract). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-29a-004 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource 13 items. 1: Handwritten notes. 2: Clinical Release. 3: Diparcol. 4: Pharmacology Report. 5: Letter to Fink from R. S. Griffith. 6: Letter to Fink from Herman C. B. Denber. 7: Letter to Denber from Fink. 8: Draft with edits. 9: Two drafts. 10: Handwritten notes. 11: Letter to Fink from Harry H. Pennes. 12: Draft with edits. 13: Letter to Fink from John F. Buckley Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published