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USE OF ANTI-EPERTENSIVE AND ANTI-CHOLDE CCPOUHDSFUR THE COTIROL OF STESS RESCTICAS

Cbjoct of Lnvoatiration

The odjeet  ths pcsent project Le to findi tho most effcctito method  inhihiting the alars reaotio stiralated throegh th autonciie narrouo systen in individuals undsr atrens. The psthod af approcch ia to derise chezical blockirg agents or drugs which may ba adsinistered at the proper tizs to provont both cholinergic and adrerorgie nanifastations of the zutoncnic rsrrous systen.

Ganoral Censidersticas

In individtualz under stress both cholinorgic and adrerargic rescponses ocur. "Tho syepatho-adrenal tysten frequantly diseharges as a unit and. this ccurs erpecially under circnnstancas of rage and fright (Canncn, l932). Ts autonozic structurss all ovar the body aro affectod at ths sam tize. Ths hart is accelerated; the blooi prossue risos! red blood cells are poured into ths cireulation froa tha spleon; tho blood redistributes itaclf fra the skin and splenchic bod to the akelstal muscles; thz bloci sugar rises; the palpebral fissures vidan; ths papils dilatej and, cn the whole, tho organisa is botter prepared for fighe cr flight,"(Goodnn & Gilran)

Ths splmchnic imervation  the adrenal modulla which liberatso epinephrin into the systes is triggored by tho relezse of scotyleholine. This relosss a asstylcholine is a prias notivater of ths alars respemes

OIMECTONS

orricens: /2/

Projoct

(bx3)

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in both ths sympathetic and parasyapathetic divisiors of the autoncaic nervow systen. The acetylcholir relecss therefore affects all the categories of fibers of the parasypathotic systea and also all itoncic preganglicnic nerves, whether syapathstio or parasyapathetic, the splanchnic (preganglionic) fibers to ths adrenal podulla, tho "syxpzthetic" fibers to sxcat glands and certain blood vessels, and the somatic notor nerves to skeletal mucles.

Plan of Frocedure

It is obvious that to arrive at the objective of these investigations, suitable facilities for clinical testing must be provided. It is understood that these will be available elserhere, but that preliminary clinical screening will be performed by the principal invessigator to determins the mcet effective cozbination of anti-cholinergic and antiedrenergio coupounds for inhibiting alara resporses.

At present the standard anti-cholinergic and anti-adrenergic drug preparatiors usually combine phenobarbital and belladonna with or withcut the additicn of xanthina derivatives or hycscyamine. Among the available proparations marketed by drug concerns, the follosing may be listed:

BELLADONAL The alkaloids of belladonna leaf Phenobarbital

.25 ng. 50

BEIBARB Phenobarbital Hyoscine Hydrobronide Atropine Sulfate Hyoscyaaine Hydrobroside

1/4 gr. (16 mg.)
0.0072 g.
0.U2LU ng.
0.1280 g.

.2-

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It is planrsd to adainister these preparations first, in ordsr to get a base lirs to determins hox far beyond these presently availabls materials the researchers must go to produce satisfactory results. The methods that rs will uss here to screen the effectiveness of these cozpounds will be the control of blood pressure in hopertensive patients, in patients under exciterent, and also the effect of these copounds on the palaar swsating test. This test is perforped by placing the paln of the subject'a hand on filter paper previously dipped in tannic acid and dried. The anount of the inprint left by the hand is a measure of palnar sweating. The best of thess preliminary compounds will be given the grade "lo", and new experimental preparations will have their effectiveness expressed munerically according to their relative effectiveness as copared to the best of theso copounds.

The use of new conpounds, available either ccmercially or synthesi: by the investigater, will fall into two groups: The first group will be labeled "Anti-hpertensive Agents." The second group will ba labcled "Anti-cholinargic Agents."

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The anti-rportenaie aganta rill inclnde ptueluine derivatives, a group o pugesiua selts R alylaino phtbalates d of ths double iss dorivatives of opanol.  mabor of these ceapanda havs beon pre pared by ths chier investigatar. Otbars will be dtained frns lesding pheranesteal copunise, such as priseoline, shich is a syapatbolytis ageat nrkated by CB, and Dibydrrgocorine araable froa Sandos.

Laong the asti-chalirorgie proparstios, ace of th ó-mothey quinolire derivatives prepared by the principal investigater will bo tosted alcog with blocking agents devised for pilocarpins and eserin. Those aro an outgroath of anti-ssthmatic thsrapeutic agents devised by tha principel inrostigator.

In addition, fron commercially available supplies, such ccapcunds a9 Banthino rill bo investigated.

Ths objoct, as previously stated,'is to find the most effectivo corbinatios of anti-cholinergic and anti-adrenergic ccpounds which il prevent the relsase wndor strsss of the chemical effectors which prodace the alars resporse in individuals. 7

The principal investigator will conduct both acate and chronic taxicity studies on all coapounds subnitted for clinical investigatiop. In addition to this, preliminary pharmacological studies on the relative anti-hypertensivs and anti-cholinorgic effects of these compcunds wlll be carried out.

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The folloring badgot is propoeod for thase inrostigations:

Adsinistratic, office overhsad and trarel..... \$3,000.co

Chenical Assistants and Consultation part-tize..... 3,600.00

Laboratory tochnicien for pathologio sections, chroaic taxicity, etc. ...... 2,400.00

Clinical techmician for clinical laboratory deterinztion ..... 3,000.00

Equipent, supplies and chenicals..........3,C00.00

USE CP ANTIFTFZRTENSTE AND ANTI-CHOLDE COMPOUDSFUA TES CCRTECL C STESS PEACTIORS

Noverber 13, 1951

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Atropico

Sytr

Banthize

Other standard syathstic Atropines

Bistrius

Veraloid

Aprosaline (CIA)

Experiestal coupounds vill be tried only after evalustion of acute and chronic toxicity dsts (aod other pertinent dats) by the responsible Medical Officer on the project.

Typical pateriala to be Evaluated in Project