PROJECT - USE OF ANTI-HYPERTENSIVE AND ANTI-CHOLINE COMPOUNDS FOR THE CONTROL OF STRESS REACTIONS

• Document Type: SPECIALCOLLECTION
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): 00144864
• Release Decision: RIPPUB
• Original Classification: U
• Document Page Count: 6
• Document Creation Date: November 22, 2024
• Document Release Date: January 15, 1983
• Publication Date: November 15, 1951

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Project
USZ OF ANTI-HYFERTZNSIVE AND Arfl-CEOLIIE =FOUNDS'
-1:17 1ri.3 Ot� SMS at-AMC-WS
Object of Invsctizaticn
� The object of the prevent project is to find the most.effectivy
method of ieMbiting the alarm reaction stiwolated through the autoncaie
nervous eyiten in individuals under etreee. The method of approach iv
to devise cheeical blocking agents or drug= atIch nay be adminietered at
the proper tins to prevent both cholinorgic and adrerorgic menifectatious
of the automcmic rervecs system.
General Considerati=e
In individuals! under stress both-cholinergic and adremorgic
responses occur. "The Sympatho-adrenal eyst4m frequently disoharges aa
a unit and this =cure erpecially under circumatances of rage and fright
(Cann, 1932)c The autonomic structures all ovor the bof are affected
at the eamc time. The heart is accelerated; the blood preF.tantre rimf;;
red blood cells are poured into the circulation from the spleon; the blood
_redistributes itself from the skin and splanchnic bed to the skeletal
muecles; the blood sugar risee; the palpebral 'fissures midsn; ihe ppile
� dilate.; and, on the whole, the organism is better prepared for Light,cr
flight." (Dooduan tc Gilman)
The splanchnde innervation of the adrenal medulla.which-liberateo
epinephrin into the system is triggered by the release of acetylcholine.
Thie release of acetylcholine in a prime motivator of the alarm respvnee
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in both the sympathetic and parasympathetic divisions of the autopocic
nervous system. The acetylcholiee release therefore affects all the
categories of fibers of the parasympathetic ystem and also all autonic
preganglicnic nerves, whether sympathetic or paraSyepathetic, the splanchnic
(preganglionic) fibers to the adrenal medulla, the "eympetheticn fibers
to sweat glands and certain blood vessels, and the scmatic motor nerves to
skeletal muecles.
Plan of Procedure
It is obvious that to arrive at the objective of these investiga-
tions, suitable facilities for clinical testing must be provided. It is
understood that these will be available elsewhere, but that preliminary
clinical screening will be performed by the principal inveseigator to
determine the mcet effective combination of anti-cholinergic and anti-
adrenergie compounds for inhibiting alarm responses.
, �
At present the standard ant i-cholinergic and anti-adrenergic drug
pre4aratione usually combine phenobarbital and belladonna with or without
;the addition of xanthime derivatives or hyoecyamine. Among the available
preparations marketed by drug concerns, the follcwing nay be listed: .
BELLADONAL
The alkaloids of belladonna leaf .25 mg
Phenobarbital � 50 mg.
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BELBABB
- Phenobarbital 1/4 gr.:(16 mg.)
Hy-oscine liydrobromide 0.0072 mg.
Atropine Sulfate 0.0210 ng.
Xyoscyamine Wdrobromide 0.1280 mg.
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PUROBARB
khenobarbital
� Theobra,1n.1 Calcium
1/6 gre.
3.25 gre.
NEUBUTAL AND BELLIDONNI
immoutai Sccium 1/4 gr. (15 mg.)
Ertract Belladonna 1/6 gr. (10 mg.)
DONNATAL
1.170.1cyx21rie eulfato
Atropine sulfate
gyoecime hydrobromlde
Phenobarbital (1/4 gr.)
0.1037 mg.
0.0194 leg-
� 0.0065 mg.
16.2 mg.
It is planmsd to administer these preparations first, in order to
get a base lima to determine how far beyond these presently available
materic2s the researchers must go to produce satisfactory results. The �
methods that ve will use here to screen the effectiveness of these compoundS
will be the control cf blood pressure in 1&rtensive patients, in patients
under excitem'ent, and also the effect of these compounds on the palmar
sweatir4; test. This test is perfcrmed by placing the palm of the subject's
hand on filter paper previously dipped in tannic acid and dried. The =aunt
of the imprint left by the hand is a measure of ppl-lar sweating. The best
of these preliminary compounds will be given the grade "10, and new experi-
mental preparaticne will have their effectiveness expressed numerically
according to their relative effectiveness as ccmpared to the best of 'these
corpounds.
The use of new compounds, available either ccemercially or synthesi:
by the investigator, will fall into two groups: The first group will be
labeled "Anti-hypertensive Agents." The second group will be labeled
"Anti-cholinergic Agents."
The anti-17partensive agents will incloiap derivatives,
A group of =mg:cesium salts ce al*711-Rinn phthalataa and of tbedouble
amina derivative: of propaaol. rmmber of thee* c=po=.414 have bean pre.-
wed bryttm chief investigator. Cet.se will be obtained from leading
pharmazastlael comps:lisle, such as prisoolime, which IX a sympstbolytis
agent marketed by CBA, and Dilrdroargocornine available from Sandoz.
Amcog the anti-cholimergis prow:reticles, some of the 6-methc7
gam-line derivatives prepared by the principal immatigator will be
tested along with blocking agents devised for pilocarpine and eserin.
These arc an outgrowth of anti-asthmatic therapeutic agents devised by the
principal investigator.
In addition, from commercia1:1,y available cupplies, such compounds
as 13anthine will be investigated..
The object, as previously stateds'is to find the most effective
combination of anti-cholinergic and anti-adrenereic conToundc which mill'
prevent the release under stress of the chemical effectors which produce
the Alarm response in individuals.
The principal investigator will conduct both acute and chronic
toxicity studies on all compounds submitted for clirir.al investigation.
In addition to this, preliminary pharmacological studies on the relative
anti-kvpertensive and anti-cholinergiceffects of these compcunds will
be carried out..
US3 CF ANTIFITZRTZNSTVS AND ANTI-CHOLINZ cwouNrs �
17-�,A TilS COMO"; OF STRESS itz:aci101;5
The following budgat i3 propmed for these invelstigations:
P-onistratiom, office oltrhead
and trave1 $ 3,000.00
Cbonical Assistanta and Consultation
part-t .3,6U0.00
Laboratory technician for pathologic
sections, chromic toxicity, etc. 2,400.00
Clinical technician for cliniCal
laboratory detarmination 3,000.00
Equipment, supplies and chemicals 3,000.00
$ 15,000.00
November 13, 1951
$1,��
Typical gaterialn to b..". Evaluated in Project
Atropin*
Syntropan
Banthine
Other standard synthetic Atropines
Bistrium
Veraloid
Apresaline (CI)
Experimental compounds vU be tried only after evaluation of acute
and Chronic toxicity dsts (and other pertinent data) by the responsible
Nedical Officer on the project.
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