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HMOAU

10 Chiof, FLANS

10 Janunry 1962

Mono Ro. 1301

SUBJECT , ALCOHOL ANTAGONISTS

A 1. Rooently I requostad ,OSI. to provide the available informtion on alcohol antagonists and the effect of Bentadrino, in particular. The initinl atudiea indicate four posoiblo appronchos to the problom which havo not been exhaustivoly stu-lied.

a. Uso of alcohol antagonists bofaro drin'ing.

l. Bonzodrina

2. Forvitin

b. Adsorption of alcohol in the digoativo trnct.

1. Charconl

2. Alùinu fol proparntions

e. Hoavy Sating of storchcs and sucars befora cnd whilo drinking.

d. Accolcrutod alcohol oxidntion (eliminntion).

l. Ensyne adjuvants, such aa nicotinio acid.

2. If it is anticipated that a proparation in liquid pill or cspsulo form ahould be providod for uoe, has suggostod that further ronenrch could bo inotigated at and culminatod quite rapidly to doternine tho most effoctiy modiun, Thie vork might ba conducted as part of the "ARTICHOKE" progran.

3. A svnary of tho initial tochnical findings aro ettnched for information purposos. It docs not represont an extensive coverage of tho aubjoot.

Attachyont: Intoxication end Alcohol Absorption and Antagoniats

A/B,I,64,24

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1. Tho dogree of intoxication is a function of the blood-alcohol level. This rolationship was detorminod during the incroasint and docroasing phases of the symptons, and it was shown to bo approximatoly lizear.

2. Tho aponranco of symptoms occurrod when tho "eppearanco threahold" was attainod (0.31 to 0.65 nlcohol/blood). Tho diaappoarod whon tho "disnpponrance throshold" (0.36 to 0.753) vas ronchod.

3. Attempts to niniaize tho intoxicativo nffoots folloving the ingestion of alcohol havo been concontratod upon the follaving mechanisus.

a. Absorption at tho gastrio mucooa

b.'Accaloration of the oxidation of alcohol by the litor.

e. Retardation of assinilation by the colls of the body (particulnrly corticnl brain colls).

d. Incronsed rnpidity of oxcrotion.

Of thoso, only roaeareles involving the firot tro have provon at all fruitful and studies of adsorption have beon most thorouchly considcred.

4. Some of the-oarliest work on tho absorption of alcohol (19l6) shows that aboorption is prolonged and appears later when the alcohol is taken after food. The sane workers found that tho intake of food with alcohol not only dolnyod absorption but that tho abaorption nover reachod valucà found whon alcohol wvas givon on an empty stomach. It is claimod that. this disappearanoo of alcohol is dhuo in part to tho alcohol novor boing, nbsorbod as such. The elnimants ascribe thie to Lhe alcohol boing bound to some constituent parts of the food such as protoins end amino-acids. This thoory of dilution seens to be confirmd sinca the blood-alcohol levol varies with the quantity of food ingastod.

5. loro gorncno to tho problem at hand than the physiolofical mechanism of abcorption is tho conrch for a spocific substanco to lossen tio absorption rato and henco loror the blood-alcohol lavol. Of tho limited number of foods teated, milr had tho greatest offoot.

6. Attempta to roduco intoxicetion vith drigo usunllynin at an ineranse in the rato of oxidation of the alcohol in tho livor. This rato is cstablishod ly an eneymo process in the livor «hich can be influanccd by drugs. Tho onsyme procosg is a nicotinic acid-riboflavin pysten that ic resnonsible for tho oxidntion of alcohol to acotaldotyde and aldclydc-mutase in tho axidation of acotaldohydo to ncotie acid.

7. Prugs ahich accolernto alcohol motabolism include alanino and insulinclucoce. It io clnincd that incylin and insulin-froo pancroatic oxtract aro cnpablo of incroasing the rate of nlcohol motabolism approxinatoly GO, in thorapeutio dosea in man.

Intoxioation and Alcohol /bsorption ad Antagonists

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ü. Autononlo drugs such ns ndronorpic oubstences liko onnhotaxine sulfato (tonzodriro) are foumd to bo nost offeotim. It hos boon glvon in mounts ronging fron 0.5 to 0.7 grems/kilo-body voight to 17 subjoota nad found to show a definite inhibiting effect vhich was grestost efter 30 ninutes but thon diminiahed. Tho drug vas civon both orally ond intravenously with conaistent results that wore relntod dirootly and exclusivoly to the amount of rphotamine given. Faredrine, edronalin and atropino culfato wore also tooted and foumd to bo offoctivo in tho order listod.