C'.ARDIOVASCULAR. BlFICTS OF TlllMITHOBBNZAMIDI
by DON NOLAN BENSLAY
A TBISIS
submitted to
ORIGON STATI COLLIGB
in partial fulfillment of the re~uirementa for the degree of
MASTEl. Ol SCIENCE June 1961 AltlilDr
Redacted for Privacy & 0hrrfr r! il.rcr Redacted for Privacy
Redacted for Privacy
Redacted for Privacy
hGr tlrrt L ptrratrl .M/ r-/Z9o - tn a Dy Ydlr D. mrllln ACltNOWLEDGMDT
The author wishes to expre•e hie sincere thanks and gratitude to Dr. Rob s. McCutcheon for his efforts in securing the generous gz.-ant from Hoffmann•La Roche Laboratories, which made thia work pottible, and for his help throughout the couz.-se of the ttudy and writing of this paper.
Thankt is also due Boffmann•La Roche for their generoua eon• tributions and other pharmaceutical companies; named 1n the text, for theiz.- donations of drugs used 1n this study.
Special thanks and appreciation is felt for the help, encour ag•ent and patience given by my wife, Mary Lea, and her mother,
Velda D. Mullina, duri113 the paat year. TAILI or COHTIMTS
IITI.ODUCTIOM • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • . • • • • • • • • • • • • • • . • • • • 1
IUilliMD'lAL MITBODS ...... ' ...... 8 BI.OOD russuu STUDDS. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • a CAIDU.C STUDIES ...... 10 liSULTS AND DISCUSSION ...... 17 BLOOD PIKSSURI STUDY liSOLTS ••••••••••••••••••••••••••••••• 17 BLOOD PIISSUU STUDY DISCUSSION ••••••••••••••••••••••••••• 21 CARDIAC STUDY K!SULT AND DISCUSSION ••••••••••••••••••••••• 28 SUMKAU AND CONCLUSIONS ...... 31 LIST OJ TAlLIS AHD FIGUIIS
TAlLIS
TABLI 1 •••••••MJWf ARTIRUL BLOOD PRISSUU FALL t S'lARDA.ID DIVIATICII • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 33
FlGUUS
PlGURI l ••.•.•CBIMICAL STRUCTUJI IILATIONSHIP •••••••••••••••••••• 7
FIGUU 2A••••• BLOOD PRISSUU UCOID OF DXPHINIIYDIAMINI WITH TRIMITHOIDZAMIDI • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 34
FIGURJ 2B ••••• BLOOD PUSSUII UCORD Or ACITYLCHOLINI WITH. TRIM1'11101DZAMIDI. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 34 riGURB 2C •••••BLOOD PUSSURI IICOJlD or IIIWUMINE WITH TRIHITROIIIZAMIDI•••••••••••••••••••••••••••••• 34
FIGUU 3A ••••• BLOOD PUSSUU UCOa:D OP LIVARTBREHOL WITH T.RIMITBOBIHZAMIDI •••••••••••••••••••••••••••••• 35
FlGUU 3B •••••BLOOD PIISSUU IICORD OF PHIHOXYBIHZAMIDI WITH. TRIMITBOBINZAKIDI ••••••••••••••••••••••••••••• 35
FIGUU 3C ••••• BLOOD PIISSUU RICORD OF DICBLOiliSOPIDTIUHOL WITH Tll.IM£THOBDZAMIDI •••••••••••••••••••••••••••••• 35 riGUill 4A ••••• BLOOD PUSSUU UCOJlD or IJGOTAMINI WITH TB.IMITH~DZAKIDI • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 36 liGUU 4B ••••• BLOOD PUSSUU lliCOilD OP DICHLOUSOPIOTIUHOL WITH TRIMBTBOBIMZAMIDI •••••••••••••••••••••••••••••• 36
FIGURI 4C •••••BLOOD PIISSUU IliCOID OF DilHINHYDIAMlNI WITH Tlt.Itfl'lBOBINZAM.lDI ...... , .. • • • • • • • • • • • • • 36
FIGUill 5 ••••• ILICTROCAIDIOGIAM SHOWDC PILOtlliD AIUlHYTBHlA.. • • • • • 37
PtGURI 6 ••••• ILICTIOCAilDIOOllAK SHOWDC IHCUASID 0081 OF IJtiN'nBI.INI...... • • • • • • • • • • • • • • • • 38 CAllDIOVASCULd IPFICTS OF ftiMI~INZAMIDI
INTllODUCTION
Trimethobenzamide is the generic name of a compound ch•ically designated as 4•(2•dimethylam1noethoxy)•N•(3,4,5•trimetboxybenzoyl) benzylamine hydrochloride. It was first synthesized in the chemical reaearch laboratories of Hoffmann-La Roche, Inc., by Mr. s. Teitel and Dr. M. w. Goldberg. It is now conaidered a apecific antiemetic drug and ta marketed as such.
Nausea and vomiting constitute a primitive protective function to rid the body of harmful aubstancea. Clinically, however, nauaea and vomiting are seldom advantageoua. Often theae aymptoma are more distressing to the patient than the underlying disorder with which they are auociated; and in certain instances, the effects of pro longed nauaea and vomiting can be actually detrimental to the pa• tient'a recovery. While it would be moat deairable to eliDlinate the cauaea of nauaea and vomiting, thia ia not always feasible. There•
fore, in many inatances, aymptomatic relief become• the aim of therapy.
It has been atated that the baais for the evaluation of new anti· emetic druga abould be to find "agenta which will apeclfically depresa
the anetic mechaniaa with minimal effects elaewbere." (21, p. 339)
Many agenta have been uaed in the paat as antiemetic• and most can be claaaed in one of three categories: antthtataminea, reserpine and 2 phenothiAzine cled.vatlvee. Of theae, the phanotbiaatne de1."ivatlvee have been the most effective, but as with other eollpOUD.da, many un• wanted d.de e f fects are present. trf.methobenzamide seems to be the f irst 1pe.cUtc •ntiemetic/ant1nauseant qent that is virtually free o£ side e f fects and has no sedative or t~anquiliziug properties. (t6. p.270•271)
!oyd, !1!!• (3, p.299·309) (2, p.39~393) baa done con81derable vork .t.n checking the antt•etic properties of antih1atamtnea. In one paper, (3, p. ~99•309) 31 a.nt1h1sUmtne c~ounda were ecreened., and it was foUftd that ell but nine compounds showed positive antiemetic properties. 'l'heae C:OJi!Pounds were compared chemically and correlated aa to afttiemetic aettoo. Chen and IDeo~ in 1950 (7, p.245•251) coa• pared the antiemetf.e actlvtty of diphenhydramine tfith that of 4rar.&a• mine and found tt to be· equally effective.
Experimental work with th.e alkaloida of Rauwolfia eerpentina, re1erpine and alaeroxyn was dcnle 1n lndia by Malhorta and Sidhu tn
1955. (19, p.l28) They fo~d both drug• to be very eff~tive in
COiilbaU.ng apOCPOrphlne tnducecl ...... , but not: copper sulfate induced vomttlq, Boy4 and Caaael alao found the same to be true in 1957.
(2, p. 392)
Of c:ourae the greateat amount of work concemed with anttemet1c druga has been done wttb the phenotha•ln• clertvatlvea. tn 1954,
Brand, !! !!.. (4, p.86•92) r:epo1:ted that in dogs chlorprou.zine was effective asatnet those drugs whf.ch cauae •••te by atbaul•ti.xag the 3 chemoreceptor trigger zone, but not against those that stimulate the gastrointestinal tract or nodose ganglion, also it was stated that chlorpromazine was not effective at all in preventing emesis in the cat. Rosenkilde and Govier in 1957 (25, p.386) compared Sch•3940
(Trilafon) and prochlorperazine with chlorpromazine and found the first to be 24 tUnes and the latter to be 3 ttmes more effective than chlorpromazine (Thorazine) in inhibiting apomorphine induced emesis 1n dogs. Also mepazine and promazine showed little or no effect in the doses used.
In still other work, Glaviano and Wang (8, p.364) reported that chlorpromazine given subcutaneously, 2 mg/Kg, ia effective in rais• ing the threshold of emesis induced by apomorphine or hydergtne about ten fold. The primary mechanism was indicated as a selective action on the chemoreceptor trigger zone.
As has been stated, all three of t hese classes of compounds exhibit unwanted side effects. Some of these effects as listed by
Moyer and Wilson (21, p.329) are: sedation, dizziness, . dry mouth, weakness, fatigability, blurring of vision, incoordination, and lightheadedness as well as occasional headaches, insomnia, nervous• ness, constipation, and diarrhea. These side effects, although UBu• ally mild, occur in 20 to 75 percent of all patients and ·severity is
frequently proportional to the dosage. Other side effects that oc• cur, usually with phenothiazine derivatives and particularly chlor• promazine are: bone marrow depression, hepatic dysfunction and vas cular collapse. About 12 percent of the patients treated with 4
chlorpromazine experience a aignificant hypotenaion, and a smaller percent experience a reversible paralyaia agitana•like ayndroae.
Jaundice 18 seen in atill a smaller number of patients.
The untoward effects of rauwolfia alkaloids are a~ilar to
thoae already atated; nasal congestion, weight gain and laxative effecta are most frequently observed. Anorexia, nauaea, headache,
dizzineas and diarrhea have been reported leaa often. Laasitude,
drowsineaa and other evidence of central aedation are uaually aeen after large doaes and during prolonged therapy. (9, p.755) Trtmethobenzamide aeema to be the firat specific antiemetic/
antinauaeant that is practically free of theae side effects. (26,
p. 277)
The chemlatry of trimethobenzaaide 1& very intereating when
compared with the other compounda •entioned that have been uaed as antiemetic agenta. Trimethobenqmide containa a benzylamine nucleus to which a dtmethylaminoethoxy and a trimethoxybenzoyl group are attached. Diphenhydramine, which contains the dimethyl•
aminoethoxy group, protects dogs againat the emetic effecta of
apomorphine. (7, p. 245-251) (3, p. 308) However, both groupe of
authora obaerved signs of central excitation with thia drug.
Reaerpine containa the trimethoxybenzoyl group. Malhorta and Sidhu
and alao loyl and Caaaell (19, p.l23·129) (3, p.391) have reported the antiemetic activity of thia compound. The latter authora found s
that the minimum antiemetic dose of reserpine caused diarrhea and
lethargy lasting 48 hours. Phenotld.azine derivtlltiveJ co~tatn the
dtmethylamtno group and the antiemetic activity of these compounds
have been reported by several authors.. However, the central cleppes•
sant action of these drugs is well known.
It seems that the combination of these chemical groups 1n ,t:d
methobenzamide produced a strong antiemetic/antioauseant effect
while manifesting few, if any, of the aide effects observed in the
other compounds.
The mechanism of action of all of the antiemetic drugs seem to
be quite similar. Trimethobe~~amide has been compared to chlorprom•
azine (26, p.270-277) and it was found that the drugs resemble each
other in completely blocking the emetic effects .of apomo~hine in
the dog; doses of both drugs that abolish apomorphine induced emesis
· ·show · little or no e.ffect against emesis induced by inerugaatJ"ie cop"'
per sulfate. These facts provide some evidence as to the site of
the antiemetic action of these drugs. Wang and Borison (30, p. 20)
found that apomorphine acted on the chemoreceptor trigger zone lo•
cated on the dorsal surface of the medulla oblongata. Orally admin•
istered copper sulfate was found to set up afferent impulses which
excite the emetic center in the reticular formation of the medulla.
Glaviano and Wang (8, p.36S) observed that low doses of chlorproma
zine, which greatly raised the threshold of apomorphine ind1,1,ced 6 emesis, had little effect on the threshold for 4mt&sis induced by copper eulfate; higher doses were needed to depress this responae.
The authors concluded that the prtmary site of antiemetic action of chlorpromazine is the chemoreceptor trigger sone, and when large doses are used, the reticular vomiting center b alao depressed. A previoue study indicated the antiemetic action of trbnethobenzamide ia also exerted primarily on the chemoreceptor trigger zone. (26, p.276) Cardiovascular praperties of tritnethobenzamide have been com• pared with those of chlorpromazine by Sehallek, ~ !l· (26, p.273) They observed the following: when administered to dogs by rapid t.v. injection, chlorpromazine at 1 mg/kg. and trtmetbobenzamide at 4 mg/kg produced equivalent falls in blood pressure. Whereas the fall with trimethobenzamide was fleeting, that with chlorproma• zine was prolonged. At 10 mg/kg, trimethobenzamide produced an in creased blood pressure fall with longer duration; the longest dura tion obtained with trtmethobenzamide at 10 mg/kg equaled the shortest duration obtained with chlorpromazine at a dose of 1 mg/kg. Tri methobenza.mide showed no antagonism to the blo-od pressure eff.eets of acetylcholine, epinephrine or histamine. Chlorpromazine at 1 mg/ kg antagonized the effects of epinephrine and hiatamine.
It is tbe cardiovascular properties of trimethobenzamide with which this paper 1s primarily concerned. CHEMICAL STRUCTURE RELATIONSHIP 7 FIGURE 1
Clil.ORPROMAZ INE ,cH, s N-CH -CH -CH -N ' . l a. 'CHI
DIPHENHYDRAMINE r\ Rf, [\J__ Hf,N-ca,-ca,-o-~
CR -0 ~~ N H
RESERPINE
cR' 1
CH -0 ca,-:- -~-*-CRa- -o-cR1-CH1 -lRJ 0' 0' ~RJ CH,~-0- -- - TRIMETROBENZAMIDE 8
DPillJM!NTA.L METHODS
Blood Pressure Studies The object of the blood pressure studies was two-fold: first, to re-check the result• already obtained on blood pressure (26, p.273·275); second, to determine whether there is any type of blocking or 1timulation of the autonomic nervous syst-..
Exper~ents were conducted under six headings: (1) The expert- mental agent, in which tr~ethobenzamide was injected alone or pre cedtng any other drug. (2) Antihtstamtnic agents, in which chlor• promazine and diphenhydramine were admini1tered in conjunction with tr~ethobenzamide. (3) Sympathomimetic agent1, in which epinephrine and levarterenol were used with tr~ethobenzamide. (4) Sympatholytic agents, in which phenoxybenzamtne, dichlorisoproterenol and ergota• mine were adminiatered in conjunction with trbnethobenzaaide. (5) Parasympathomimetic aaeut, in which acetylcholine was injected ' in conjunction with triaethobenzamine. (6) Parasympatholytic agent, in which trimethobenzamide wa• administered after atropine had been injected. These experiaeats are treated 1n 110re detail under teault• ud Dlaeussion. Trimethobenz&mide infud.ons wer6 made in som~ expert• menta. When administered by infusion, the dose was approximately 0.7 me/kg/minute. The rate of infusion of other agents was deter mined by the rapidity of either the rise or fall tn the blood pres sure as indicated by the manometer. In all eases the blood pressure 9 level wae allowed to stabilize (the control level) before the next drug was injected.
Twenty-one mongrel doa• of either sa wetahtng betwe~ 10 and 25 kilograas with an average weight of 16 kilograme were u1ed in thb 1tudy. Each was anae•thetlzed with pentobarbital aodium solu tion, 30 mg/kg admtniatered 1ntraper1toneally. This waa 1upplemented, if needed, with ..all amounta of pentobarbital intravenou1ly. Blood pre1aure waa obtained pr~rily with a mercury -.noaeter u11Dg aodium citrate (41) in the ay1tem. Recordtna• were made on a smoked drum of an electric kymosraph throughout the entire experiment. In some caaes a Sandborn Recorder wa1 utilized in conjunction with a phyeio logical preseure traneducer to record blood preaaurea. The riaht com• mon carotid artery was exposed through an incision and caunulated with a glae1 arterial c.uula. Single doeea of drugs were adminiatered rapidly by injection via the femoral vein (5 to 10 eeconda). When two druga were admtnietered simultaneously, one was by constant in fuaion through an indwelling catheter in the femoral vein using a
Harvard Conatant Volume Infusion Pump. The rate of infuaion waa de• teratned uaually by the blood preasure response to the drug. Heparin sodium (Lilly ampoule No. 405) waa adminiatered in all exper~ents a1 an anticoagulant 1n a do1age of 2 mg/kg.
Druga u1ed in the blood pre1sure atudie1 were as follows: 10
Drug Manufacturer *Trtmethobenzamide (Tigan) Hoffmann• LaRoche *Chlorpromazine (Thorazine) Smith Kline &French *Epinephrine Winthrop Stearns Acetylcholine Merck & Company *Levarterenol (Levophed) Winthrop Stearns *Diphenhydramine (Benadryl) Parke Davil *Ergotamine (Gynergen) Sandoz Pharmaceuticals *Phenoxybenzamine (Dibenzyline) Smith Kline & French *Bichlorisoproterenol Eli Lilly Atropine s. B. Penick &Company llbtamine Diphosphate Abbott Laboratories
The pentobarbital sodium used to anaesthetize the dogs in all experiments was *Nembutal sodi~ sterile solution manufac~ured by
Abbott Laboratories.
Cardiac Studies The purpose of the cardiac studies was to determine the ability of trimethobenzamide to prevent or reverse cardiac arrhythmias. Ten mongrel dogs of either sex weighing between 12 and 23 kilo• grams were used in this study. Each was anaesthetized with pento• barbital sodium solution, 30 mg/kg administered intraperttoneally. This was supplemented, if needed, with small amounts of pentobarbital intravenously. The electrocardiogram was recorded using a Sanborn Model
150 Four-Channel recorder. The standard limb leads (6, p.29·31) were employed, the lead wires being connected to the animal by placing needles under the skin. In all experiments a Sanborn Vtso Scope
*Kindly donated by the manufacturer as indicated. 11 oscilloscope was employed so that one lead could be viewed continu• ously. ln some experiments the blood preasure was recorded simul taneously using a Sanborn Physiological Pre81ure Transducer connected to the right common carotid or the femoral artery and recorded on one channel of the recorder. When needed; a Harvard Respiration Pump Model
No. 607 was employed to support respiration. The pump, operating through a tracheal ·cannula, was set for 20 respirations per minute and the volume delivered varied dep.ending upon the size of the- animal.
The dog• were positioned on the dorsal side when epinephrine was used and on the ventral side when acetylcholine was used. Drugs were ad• ministered d1rectly into either the saphenous or the femoral vein, usually by rapid injection (5 to 10 seconds).
·An improvised defibrillator was used during the course of some of the expertments. This consisted of two wires connected to a male electric plug, a spring•loaded key was put in the circuit and copper wire electrodes were soldered to the ends of the wires. The electrodes were placed under the skin through incisions made on eac'tlr side of the chest and the circuit plugged into a llO•volt outlet.
Drugs used in the cardiac studies were as follows~ Manufacturer
Chloroform for anaesthesia E. a. S~uibb &Sons Epinephrine Winthrop Stearns Acetylcholine Merck & Company Neostigmine (Prostigmin) Hoffmann-La Roche 12
As pl"eviously stated, the object of this study was to determine the ability of trtmethobenzamide to prevent or reverse cardiac arrhy• thmias. Before the study could be started a method had to be devised to initiate an e,rrhythmia sufficiently prolonged to determine what, if any, effect trimethobenzamide had on an arrhythmia. A literatul"e study of some of the methods used 1n previous work was made to determine such a method, one in which the result could be predicted. Brill, --at al. f.n 1959 studied the effects of Vasoxyl in vantricu• lar arrhythmi.ils, (5, P·• 312) Ventricular arrhythmias were eetab1ished in clogs by ligation of the anterior descending coronary artery, by production of myocardial necros:l.a with the injection of zinc hyd1:oxide, by the •dministration of toxic doaes o·f various cardiac glycoaides, and by a procedure consisting of infusing amodiaquin solution until a bi"' geminal rhythm had been produced. These methods were unpredictable,. death sometimes ensuing before the arrhythmia was produced, .and in other cases the arrhythmia was of too short duration.
Leveque (16, p.l08·UO) produced atrial fibrillation 1n dogs by
thyroid administration and acetylcholine injection. When using acety:.. choline alone, arrhythmia was produced in 30 percent of the enima:ls~ tn the thyrotoxic dogs. 81 percent responded with an atrial fibrilla• tion. the average duration of time in both methods was ~bout 25 sec"' onc:ls. A problem cODUnOn to this method is respiratory embarrassment due to acetylcholine induced bronchiolar cons.triction and copious 13 salivation which may cause accidental death of the animal.
In 1955 too.is and lrop reported (17. p.396) that auricular fibrillation could be induced in the intact heart by the intravenous administration of acetylcholine to unanaesthethed noraal dogs,goats, and monlteys. ly the use of proper anaesthetic agents, and by the protection of injected acetylcholine from destruction through the use of anticholinesterase agents, injected acetylcholine or vagal st~lation produced auricular fibrillation of extended duration. The effect of aeetylehoU.ne or vagal sttmulation on such a pre existtaa fibrillation is to increase the rate of the fibrillation, and the fibrillation can be perpetuated by repeated injections of acetylcholine or by vagal stiaulation. Chloroform has been associated with death almost from the start of its use as an anaesthetic. In 1914, Levy (17, p.57) gave an anal ysis of 109 huaan deaths under chloroform anae1thesia. Be stated that when the heart is affected by low concentrations of chloroform it is thrown by the action of epinephrine into ventricular fibrilla• tion. He also said that one of the most important forma of cardiae sttmulation, which is liable to preduee a fatal reaction in the lightly chloroformed animal, is stimulation by excitation of the myoneuraljwnctions of the sympathetic cardiae nerves (cardiae accel erator nerves), as by epinephrine. Thia b a very powerful form of stimulation and almost tnvariably leads to ventricular fibrillation. 14
Moore and Swain (22, p.249) have shown that intratracheal ad ministration of 0.1 ml/kg of methyi chloroform, followed in 15 sec onds by 10 meg/kg of epinephrine i.v., induced ventricular fibrilla• t1on.
In discussing ventricular fibrillation, Bard (1 1 p.65-66) states that the condition resembles auricular fibrillation but occurs in the ventricles, and i f fully developed, stops all blood flow, in cluding that in the coronaries. It is then fatal. In eats spontan• eous recovery from experimentally-produced ventricular fibrillation may take place, but recovery from fully developed fibrillation is very rare in most of the larger mammals. The condition can be in• duced by an electric shock. It may also result from deficient blood supply through failure of the coronary circulation. Epinephrine may be a cause under certain circumstances. This substance causes hyper• excitability of the ventricular muscle and when injected i.v. or liberated by prolonged splanchnic stimulation in an animal under in•. halation anaesthesia may cause paroxyamal ventricular extrasystole&.
Under conditions of high blood preasure these paroxysmal ventricular extrasystole& may give rise to very aberrant electrical complexes with very feeble mechanical contractions. The changes fall short of fibrillation, and the heart may recover. An example of this effect is the action which epinephrine tends to have in the early stagea of chloroform anaesthesia. Here the heart is slowed by 15 hyperactivity of the vagus. The heart is damaged by the chloroform, an.d epinephrine, whether inject,ed or secreted, may induce ventricular fibrillation.
After condderation of the foregoing discussion o£ met~ods of
arrhythmias, two methode were decided upon. First, injection of ac tylcholine after use o f an anticholinesterase agent; and second, inj ction of blall doses of epinephrine during i,nhala-
These methods seemed to be the most dependable and produced a.r hythmias of a more prolonged duration.
Bard (1, p 66) states that ventricular fibrillation may some times be stoppe by a strong electrical stimulus applied to the heart, parttcul rly after cardiac massage. Similarly, an intense electrical shoe applied to the whole individual may break the irregular eireu movement of fibrillation and initiate normal rhythm. Sueh t eatment, though valuable, may itself start ventricu lar fibrillatio if applied in error to a heart which is not in fibrU~ation. 'fe effect depends on forcing simultaneous eon• tractions in nu1erous fibers which are in a relatively refractory state. Ventricular fibrillation may also be overcome experimentally by suppreeaing all contraction with exce1sive potassium chlo~ide; this is then an.tagontzed by calcium "Chloride, contraction ts reeumed at a normal rhythm~
In 1933 Hooker et al. (11, p.446) reported that high voltages 16
will not cause v~ntricular fibrillation but low voltages will. High voltages with high amperes act as a counter shock and defibrillator on the fibrillating heart. Uiggers in 1936 (31, p.l62) reported on massage followed by counter shock by stating that brief paeasge through a heart of 60•cycle alternating current, with Utinima.l strength of one ampere, stops fibrillation and is followed spontaneou~ly by strong coordinated contractions capable of restoring a normal blood pres• sure. this is only true, however, provided coronary occlu•ion is not present and fibrillation has not lasted more than two or three minutes.
In more recent work Stearns et al., 1951, (29, p.610) sum• marized their experiments by stating that 50 etherized dogs were sub•
jected to ventricular fibrillation by faradization of the heart mus cle. It was shown that cardiac massage would maintain mean arterial blood pressure of 40 to 60 mm Hg. but would not produce defibrilla tion during more than 30 minutes. Similarly, defibrillation did not result from intra-cardiac procaine given early during the course of ca~diac massage. The only dependable defibrillating agent teste~ was counter shock ~ith 1.5 amperes of 60•cycle alternating current. tt was clearly aho'~ that epinephrine and norepinephrine at 10 me~/ kg neither encouraged spontaneous refibrillation nor interfered with resumption of cardiac automaticity. These agents were fre• quently necessary for maintenance of the mean arterial pressure 17
during massage. No evi.dence of a beneficial action of procabae was
found. Attempts to keep these animals alive were generally unsuc
cessful. The few animals which did survive were characterized most frequently by short duration of f ibrillation (i.e•• early
counter shock) and by not having received intracardiac procaine.
In 1950, Southworth (27, p.717·720) reported the case of "E.F."
a white woman aged 25. Ventricular fibrillation had been preeipi• . tated by cardiac eatheretization. She was treated with procAine
and lidocaine intracardiac and seven electric shocks, applied
directly to the heart. The ahockll were 135 volts in strength.
Complete recovery after 45 minutes was reported.
RBSULTS AND DISCUSSION
Blood Pressure Study
(1) Experimental agent: Tr~ethobenzamide •• experiments in which
this drug preceded any other agent. Dosage: 4 mg/kg rapid t.v.
injection.
Dog 3. B.P. fall of 60 mm Hg. control level in 4 minutes. J.P. fall of 30 11111 Ba· c011trol level in 3 minutes. Dog 4. B.P. fall of 50 mm Hg. control level in 5 minutes. J.P. fall of 25 mm Bg. control level in 4 minutes. Dog 9. B.P. fall of 15 mm Bg. control level tn 3 minutes. Dog 10. B.P. fall of 30 mm Bl· control level in 1.S minutes. Dog ~3. B.P. fall of 0 tmn Hg. control level in 0. 5 tdnutes. J.P. fall of 30 mm Bg. control level in O.S minutes. B.P. fall of 30 mm Bg. control level f.n 0. 5 minutes. Dog 14. J.P. fall of SS 11111 Bg. did not recover control level. (adverse reaction to trimethobenzamtde) 18
Dog 15. B.P. fall of 80 11111. Bg. rose 55 11111. Bg. in 6 minutes. B.P. fall of 45 Dill lf3. rose 35 Dill Hg. in 6 minutes. Dog 16. B.P. fall of 20 Dill Hg. control level in 4 minutes. Dog 18. B.P. fall of 20 1lllll 113. control level in 2.5 minutes. B.P. fall of 20 1llll Hg. control level in 2. 5 minutes.
(2) Antihietaminic agents: Chlorpromazine and diphenhydramine in conjunction with tr~ethobenzamide.
Dog 1. Chlorpromazine 1 mg/kg t.v. B.P. fall of 30 11111 Bg. over 60-ainute period. Dog 2. Chlorpromazine 1 mg/lcg t.v. B.r. fall of 35 11111. Hg. over 60 minute period. Dog 3. Chlorpromazine 1 mg/k.g i.v. after two previous doses of trf.methobenzamide 4 mg/k.g t.v. B.P. fall of 35 1'IIID Hg. over 60-mtnute period. Dog 4. Chlorpromazine 1 mg/kg i.v. after two previoua doses of trf.methobenuaide 4 mg/kg t.v. B.P. fall of 40 11111 Hg. over 30•minute period. Dog 5. Chlorpromazine 1 mg/kg i.v. B.P. fall of 35 1IDil Hg. over 6~1nute period. Dog 6. Chlorpromazine 1 mg/kg t.v. B.P. fall of 35 mm Hg. over 45-minute period, followed by trtmethobenzamide 4 mg/kg t.v. B.P. fall of 25 mm Bg. control level in 3 minutes. Dog 12. Diphenhydramine 30 mg/kg t.v. B.P. fall of 15 ma Hg. froa 78 DID Hg. to 63 - Hg. control level in 3 min• utes, followed by trf.methobenzamide 4 mg/kg t.v. B.P. fall of 20 ._ Hg. control level in 4 minutes. Dtphenhy~ramine infusion t.v. B.P. stabilized at 75 11111 Bg. Trimethobenzamide 4 mg/kg t.v. B.P. fall of 10 mm Hg. control level in 3 minutes.
(3) Sympathomimetic aaents: Epinephrine and levarterenol.
Dog 7. Epinephrine infuaion t.v. B.P. stabilized at 80 mm Hg. trfmethobenzamide 4 mg/kg t.v. B.P. fall of 35 mm Hg. control level in 1 ainute. Trimethobenzam1de infusion t.v. B.P. stabilized: at 75 mm Bg. epineph rine 67 meg t.v. B.P. riae of 30 Dill Hg. control level in 2 minutes. Repeat B.P. rise of 30 ma Hg. control level in 2 minutes. 19
Dog 9. Trtmethobenzamide infusion t.v. approx. 0.7 mg/kg/minute J.P. stabilized. Levarterenol 67 meg. t.v. J.P. rise of 15 mm Hg. control level in 3 minutes. Levarterenol infusion i ••• J.P. stabilized. Trimethobenzamide 4 mg/ kg t.v. J.P. fall of 35 11111 If&. control level in 3 min utes x 2. Dog 10. Levarterenol infusion t.v. J.P. stabilized, trlmetho• benzamide 4 mg/kg i.v. J.P. fall of 40 mm Bg. control level in 3 minutes x 2. Trimethobenzamtde infusion t.v., levarterenol 67 meg t.v. J.P. rise of 40 mm Bg. control level in 5 minutes.
(4) Sympatholytic agents: Phenoxybenzamine, dichlorisoproternol and ergotamine.
Dog 13. Trimethobenzamide 4 mg/kg t.v. B.P. fall of 30 Dill Bg. control level in 0.5 minutes. aepeated 3 times, same results. lrgot~ine 0.5 mg t.v. J.P. rise of 20 mm Hg. stabilized. Trimetbobenzamide 4 mg/kg t.v. B.P. fall of 8 mm Bg. control level in 0.5 minutes. J.P. fall of 10 mm. Bg. control level in 1 minute. Repeat, B.P. fall of 10 mm Hg. control level in 5 minutes. Ergotamine 0.5 mg i.v. J.P. rise of 20 mm Hg. stabi lized. Trimethobenzamide 4 mg/kg i.v. B.P. fall of 10 mm Hg. Dose repeated 4 times with same results recovered to control level J.P. in 12 to 15 minutes. Dog 15. Phenoxybenzamine infusion t.v. J.P. etabilized. Trim.ethobenzamide 4 mg/kg i.v. B.P. fall of 40 mm Hg. rise of 30 mm Hg. in 6 minutes. Repeat, B.P. fall of 30 mm Hg. control level in 6 minute.. Repeat, J.P. fall of 30 Dill Bg. control level in 6 minutes. Dog 16. Trimethobenzamide 4 mg/kg i.v. B.P. fall of 20 mm Hg. control level in 4 minutes. Repeat, J.P. fall of 20 um Hg. rise of 10 mm Hg. in 4 minutes. Ergotamine 0.5 mg t.v. J.P. rise of 25 mm Bg. stabilized. Tri metbobenzamide 4 mg/kg t.v. B.P. fall of 8 mm Hg. con• trol level in 9 minutes. Repeat, J.P. fall of 6 1IID Hg. control level in 1 minute. Same results for 3 consecutive doses. Trtmethobenzamide 8 mg/kg t.v. B.P. fall of 10 mm Hg. rise of 7 mm Hg. tn 3 minutes. Dog 17. Phenoxybenzamine 50 mg 1.. v. 45 minutes previous to cannulation. Epinephrine 2 meg/kg t.v. J.P. fall of 35 mm Hg. (reversal) control level in 5 minutes. Trimethobenzamide 4 J118/kg B.P. fall of 20 mm Bg. 20
control level in 6 minutes. Repeat: B.P. fall of 23 mm Bg. control level in 5 minutes. Repeat: B.P. fall of 25 mm Hg. control level in 4 minutes. Repeat: B.P. fall of 25 mm Bg. control level in 5 minutes. Repeated 3 more times with same result in B.P. and time.
Dog 18. Trimethobenzamide 4 mg/kg i.v. B.P. fall of 20 ll1lll Hg. control level in 2. 5 minuteo. Repeated, same resul t, dichlorisoproterenol 70 mg i.v. B.P. fall of 40 mm Hg. raised 20 mm Hg. in 6 minutes. Trimethob zamide 4 mg/ kg 1.v. dose repeated 3 times at 3-, i nute intervals, all gave same result -- B.P. fall of 11 mm Hg. control level in 1 minute. Dog 19 . Dichlorisoproterenol 5 mg/kg 1ntraperitoneally 3 hours before cam&.'tlation. Trimethobenzamide 4 mg/kg B. P. abrupt fall of 70 mm Hg. control level ~n ~v minutes. Dichlorisoproterenol 5 mg/kg i.v. B.P. fall of 10 mm Hg. stabilized. Isoproterenol 2 meg/kg B.P. fall of 10 mm Hg. control level in 3 minutes (reversal). Trimethobenzamide 4 mg/kg t.v. B.P. fall of 15 mm Hg. control level 1n 2 minutes. Repeat: B.P. fall of 15 mm Hg. control level in 1 minute.
(5) Parasympathlmimetic agent: Acetylcholine.
Dog 11. Acetylcholine 2 mg. i.v. B.P. fall of 65 mm Hg. control level after 30 minutes. Repeat 1 mg i.v. B.P. fall of 40 mm Bg. control level in 2 minutes. Trimethobenzamide 4 mg/kg i.v. B.P. fall of 30 mm Bg. control level in 2 minutes. Acetylcholine in fusion i.v. B.P. stabilized. Trimethobenzamtde 4 mg/ kg B.P. fall of 30 mm Hg. control level in 4 minutes. Trimethobenzamide infusion i.v. B.P. stabilized. Acetylcbolin 1 mg t.v. B.P. fall of 70 mm Hg. control level tn 5 minutes. Repeat with same result. Acetylcholine 0.5 mg i.v. B.P. fall of 35 mm Hg. con trol level in 5 minutes.
(6) Parasympatholytic agent: Atropine.
Dog 8. Acetylcholine infusion was started but had to be counteracted with Atropine 0.05 mg/kg i.v. because 21
precipitous fall in B.P. and decrease in heart rate. B.P. stabilized. TrfmethobenHJnlde 4 mg/kg t.v. B.P. fall of 25 mm Sg. control level in 4 •tnutes.
As a result of 15 observations the average blood pressure fall, plus or minus the standard deviation, due to trtmethobenzamide was found to be -34.67 !' 20.83 mm Hg~ The. tim.e range for the blood pres• sure to fall, then raise back to non.nal, was 0. 5 to 6 minute·s. ta previous work, Schallek !!!l· found the mean fall in blood pressure to be •26. 0 '! 10.4 in six observations. (26, p. 275) In the present study it was noted that thel'e were four eases in whieh there was an abnormal blood pressure fall of 50 mm Hg. or more.
As can be seen in Table 1, the resulte give an indication that di~henhydramine block• the hypotension caused by trim.ethobenzamide.
Diphenhydramine, being an ant1h1at81Jl1ne. partially blocks the cardio• vascular effects of histamine. Goodman and Gilman (9, p.645) state that histamine is a powerful dilator of capillaries. The action is a direct one on the contractile mechanism• the respo~se is indepeu• dent of innervation, antagonbed by ep1uephr1ne, not blocked by atropine, and only partially blocked by antihistaminics. After larga doses the capillaries dilate to such a degree that their permeability b altered. It is also stated that in the dog, monkey, and man histamine causes arteriolar dilation. The extreme dilation 22 of arterioles and capillaries by histamine results in a marked fall in systemic blood pressure. Krantz and Carr (15, p.780•781) state that diphenhydramine was found to be capable of preventing most of the depressor response to histamine in the anaesthetized dog. A quantitative relationship appears to exist. When observing the dose• effect curve it can be seen that the inhibition increases sharply at low doses of diphenhydramine, and at a dose of about l mg/kg the curve rapidly approaches the base line, showing about 97 percent inhibition. It was pointed out that this type of dose-effect curve suggests that diphenhydramine exerts antihistaminic action through adsorption phen• omenon on the target cells. It would seem very 1ikely that if trimethobenzamide exhibited its hypotensive properties through the same mechanism as diphenhydra mine, that the initial dose of diphenhydramine would cause a fall in blood pressure that would mask, or seem to block, the hypotenaion usually caused by trtmethobenzamide t.v. injected alone.
Table 1 shows also that levarterenol gave an indication of having potentiated the blood pressure fall associated with t.v. injection of trimethobenzamide. Goodman and Gilman (9, p.501) state that when levarterenol (0.1 to 0.4 meg/kg/min) is administered by slow intravenous infusion, both systolic and diastolic arterial pressures are elevated; pulse pressure usually increases. Since cardiac output remains unchanged or decreases slightly, total 23 peripheral resista...rtce is 11ugmented. These facts indicate that the pressor response to levarterel}ol results chiefly from peripheral vasoconstYiction and that the cardiac effects are masked by compensa tory vagal bradycardia.
The indication of potentiation due to levarterenol is no doubt caused by the peripheral vasoconstriction and elevated blood pressure resulting from an injection of the drug . When the injection o f levar• terenol is followed by an injection of trimethobenzamide which then exhibits its hypotensive action, the blood pressure has further to fall, seeming to indicate that levarterenol potentiates the hypo tensive properties of trimethobenzamide.
Table l shows that there is a slight decrease in the blood pres.sure fall clue to trimethobenzami.de during and after p'benoxy benzamine injection. It is felt that this slight change is not significant and may be caused because of the initial drop in blood pressure which is caused by phenoxybenzamine when injected alone.
The blood pressure fall usually caused by trimethobenzamide would not be expected to be a.s great when hypotension is already present at the time o f injection.
Dichlorisoproterenol gave an indication of blocking the hypo tension caused by i.v . trimethobenzamide, as can be seen 1n Table 1.
Powell and Slater were the first workers to report on this analog of isoproterenol, Their findings (24, p.481) show that dichlorf.so proterenol in doses of 5 to 10 mg/kg i . v. caused either a transient 24 fall in blood pressure or no observable change. The degree of blood pre..ure fall seemed to be related to the rate of injection, for after rapid administration there was usually a definite lowering of blood pressurea whereas, tn other cases slow injection was asso• ciated with no change. The effect of various sympathomimetic amines was tested after the blood pressure had returned to a steady level.
At a dose of S 113/kg, the compound blocked only the seconclary de• pr•ssor effect of epinephrine, bad no effect on the preesor re•ponae to epinephrine or levarterenol, and decreased considerably the de• pressor effect of isoproterenol. However, after 10 mg/kg doses there seemed to be enhancement of epinephrine and levarterenol preasor responses as shown by an increased blood pressure and almost complete block of the depressor response to isoproterenol. These authors s~ marized by stating that their work suggested "a rather tight drug• receptor complex, and that it s~ed probable that dichloriaoproter• enol was combining with certain 'adrenergic inhibitory receptor sites' without itself causing much physlulogical effect, and yet was com• peting for these sites with physiologically active amines." If the terminology of other workers in this field is accepted, dichloriso· proterenol can be called a specific "beta receptor" blocking agent.
In the present study it was noted that t.he intraperitoneal in• jection of dichloriaoproterenol three hours previous to the injection of trimethobenzamide (dog 19) had no effect on the hypotensive 25 properties of trtmethobenzamide, but in four observations (dogs 18 and 19), when dichlorisoproterenol, 5 mg/kg., was injected rapidly i.v., it exhibited hypotensive action. Succeeding doses of trtmetho• benzamide then gave an indication of being blocked. This action seems to be s~ilar to that exhibited by diphenhydramine and probably arises from the same cause, and is not due to any nervous innervation or blocking action.
lrgotamine also gave an indication of blocking the hypotensive effects of i.v. trimethobenzamide in the studies made. Of the three drugs that indicated blocking action, ergotamine seemed to be the most effective. Goodman and Gilman (9, p.891·892) state that the ergot alkaloids exert complex actions on the cardiovascular system which are difficult to analyze, but common to all of them is the ability to cause peripheral vasoconstriction by a direct action on the vascular mu~culature. Ergotamine is an adrenergic blocking agent, reversing the pressor response to epinephrine and levarterenol. It could be termed an "alpha receptor" blocking agent.
Because of the indication from the table that tr~ethobenzamide had a cardiovascular action stmilar to that of histamine, it was de· cided to perform some additional exper~ts comparing histamine with dichlorisoproterenol and ergotamine. The blood pressure was recorded using the Sanborn recorder with the pressure transducer, as previously 26
described. The femoral artery was cannulated with a polyethylene
tube, and the tube was introduced into the aorta. Drugs were in•
jeoted, as before, into the femoral vein.
Dichlorieoproterenol was used in the first experf.dlent. In two
control observations. histamine itt a dose of 1 mg. i.v. caused the
blood pressure to fall 85 mm Hg. tn a 21.5 lg. male dog. A rapid
injection of dichlor:l.soproterenol 5 mg/kg i.v. caused the blood pres•
sure to fall 70 mm Hg. Histamine in a dose of 1 mg. :l..v. after the
dichlorisoproterenol caused an additional fall of 45 mm Hg. (avg. of
three observations). Diehlorisoproteranol 5 mg/kg i.v. was again
injected, thi• ttme causing the blood pressure to fall 20 mm Hg.
Histamine 1 mg i.v. was then injected, this ttme causing a fall of
35 1t1m llg. (avg .• of bwo observations). The dog was saved and used
two days later.
In the second exper~ent (same antmal) ergotamine 0.5 mg. t.v. was used. Ergotamine caused the blood pressure to rise 40 mm Hg. from
the control pressure. Histamine 1 mg. t.v. injected after the ergota• mine caused the blood pressure to fall 100 mm Hg. (avg. of three observa•
tions). After this, trtmethobenzamide, 4 mg/kg t.v. was injected to see
if the previous dose of ergotamine was sufficient to block its hypoten•
sive action. Tr~ethobenzam:l.de caused the blood presaure to fall 77 mm
Hg. (avg, of three observations). ltgotamtne 0.5 mg i.v. was again to• jected, causing the blood pressure to rise an additional 35 mm Hg. After 27 this tr~ethobenzamide 4 mg/kg t.v. was injected. This time the blood pressure fell only 12 mm Hg. (avg. of three observations), in• dicattng that the first dose of ergotamine (0.5 mg.) was not suffi• cient to block the hypotensive effects. This was no doubt true be cause of the size of the dog.
In the third experiment performed in this series, an additional dose of ergotamine was used in conjunction with histamine to try to prevent the hypotensive action of the histamine. The animal used was a female dog weighing 7. 75 kg. Histamine 1 mg. t.v. was injected to determine the control fall. It caused the blood pressure to fall
90 mm Bg. Ergotamine 0.5 ntg t.v. was then injected, causing the blood pressure to r1se 15 mm Hg. Histamine 1 mg. t.v. after this still caused a fall of 105 mm Hg. n additional dose of ergotamine,
0.5 mg. t.v., was injected; this time causing nc increase in the blood pressure. Histamine after this (1 mg. t.v.) caused the blood pressure to fall 105 mm Hg. A third dose of ergotamine, 0.5 mg. t.v., was given.
Histamine, 1 mg. t.v., again after the ergotamine caused the blood pressure to fall 95 mm Bg.
Thb last experit!lent indicated that no matter how great the strength of dose of ergotamine, it does not have the property of being able to prevent the hypotensive action of histamine. The first exper~ent also indicated that dichlorisoproterenol does not block the hypotension caused by histamine. 28
Cardiac Studies
In the first method used, the dog was placed on its ventral side and neostigmine was injected i.v. prior to injections of acetylcholine. Four animals died during t he process of determining the amounts of neostigmine and acetylcholine needed to precipitate a cardiac arrhythmia. It was finally determined that a dose of
0.5 mg of neostigmine i.v. followed by acetylcholine 0.1 mg/kg i.v. would initiate a cardiac arrhythmia in most antmals. The first time that a successful arrhythmia was produced by this method, tr~ethobenzamide, 4 mg/kg t.v., had been injected previously.
The same dose of acetylcholine that had induced arrhythmias in earlier dogs also induced arrhythmias in the animal treated with the experimental drug. Another dose of trimethobenzamide, 4 mg/kg i.v., was injected during the course of the arrhythmia but it had no effect upon shortening or reversing the condition. In the second experiment neostigmine, 0.5 mg/kg i.v., was administered prior to trtmethobenzamide, 4 mg/kg i.v., then acetylcholine 0.15 mg/kg t.v.
A ventricular arrhythmia ensued, which lasted for a period of 2.5 minutes before becoming normal. The same dose of acetylcholine was administered again, producing a ventricular arrhythmia as shown by the electrocardiogram. Trtmethobenzamide 4 mg/kg t.v. was then injected. The arrhythmia lasted for a period of seven minutes this time. Three different strengths of trimethobenzamide wer.e tried on this animal, 4.0, 8.0, and 16.0 mg/kg t.v..... they were administered both before and after doses of acetylcholine. In every case the dose of trimethobnnmide administered after aeetylcholine ·prolonged the. duration of the induced arrhythmia as $een by the longer period of time on the electrocardiogrem.
In the second method used, the dog was prepared as described previously. A, towel, with a chloroform-saturated piece of cotton tn it, 't Upon a second injection of epineph1'1.ne 1. 5 meg/kg t.v. tqe &ul'ie!ulalt a~rhythmia precipitated a ventricular fibrillation which rea.ulted in the death of thft animal. This dog died after having a total of two doses of epinephrine, 1. 5 meg/kg , .and t'rf.:methobenzamtde having been injected after initiation of the a~rhytbmia. ln the next dog, trimethobenzamtde, 4 mg/kg, was injected i.v. prior to admtniatratf.on of chloroform or epinephrine. Chlorofo.rm inhalation was started and 30 epineph~ine, 1.5 meg/kg 1.~., was injected. No arrhytbm~a was in• duced. the dose of epinephrine was then increased to 2.25 meg/kg without producing an arrhythmia. A third dose of epinephrine, 3. 0 meg/kg t.v., was injected still during chloroform inhalation and no arrhythmia was prod1.1ced. Another dose of trlmethobenzamtde, 4 mg/kg t.v. • was administered. Repeated doses of epinephrine were then ad• ministered. The doee was increased by 0.75 meg/kg each time until a total of 11 closes had been injected t.v. After the eleventh tnjec• tion a total of 9 meg/kg, an arrhythmia was initiated which went into a ventricular fibrillation and resulted tn the death of the animal. In this last experiment, the administration of trlmethobenzamide gave an indication of haviag protected the heart from the usual eff.ect of epinephrine during chloro.form inhalation. 1n order to check th18 effect more closely a controlled arrhythmia was induced, the threshold dose of epinephrine determined and trtmethobenzaaide administered to determine whether the threshold dose of epinephrine could be in• creased before an arrhythmia or fibrillation was produced. Attempts were then made to deft.brlllate the heart after it was in a state ef arrhythmia or fibrillation. In the present work counter shock was decided upon as a defib• rtllatf.ng agent. The apparatus previously described was used. 31 Only one experiment was carried out. In that case the. dog was prepared as previously described. chloroform and epinephrine were used as the fibrillating agents. A ventricular fibrillation was in• du~ed and interpreted by the electroc•rdiogram. After a fibrillation of approximately one minute, counter shock was applied. 'the fibrilla tion stopped and the rhythm returned to normal after one counter shock. After this, trimethobenzamide 4 mg/kg t.v. was. administered, at the usual rapid rate. The blood pressure fell to zero mm Hg. By no ... ~ \ t of effort was it possible to reestablith the blood pressure~ The dog expired evidently as a result of an adverse react1on to the · tr1m~th,Jb~~z amide. No more animals were available for experimental work at the time so this procedul"e was carried no further. StltMARY AND CONCLUSIONS lnvestf.gation of the cardiovascular properties of tr:Lmethobenza-· mide leads to the conclusion that the blood pressure fall caueed by the rapid i.v. inj.ection of the drug, in a dose of 4 mg/ks,. 1a medi ated by a direct action on the pel"ipheral blood vessels and not through any a~tton on the autonomic nervous system. lxamtnation and analyaia of electrocardiograms taken before, during and after injection of trimethobenzamide indicate that the hypoten1ion is not ca.uaed by any direct action on the heart. Cardiac arrhythmias were induced by two methods: acetylcholine 32 t.v. preceded by an injection of neostigmine and epinephrine injec• tion t.v. during chloroform inhalation. Intravenous injection of trimethobenzamide before and during the induced arrhythmias indicate that it only serves to prolong the time of a previously induced auric• ular fibrillation and it does not prevent the onset of an arrhythmia when administered prior to its induction. There ls an indication that trtmethobenzamide may protect the heart from progressing into a ventricular fibrillation once an arrhythmia has been induced by the epinephrine•chloroform method. 33 TABLE I Mean Arterial Blood Pressure Pall ! Standard Deviation N • Humber of Observations Dose i.v. B.P. ill Dill !s. ...!... Tr~ethobenzamide: 4 •'kg •34.67 ±20.83 15 Chlorpromazine: 1 mg/kg ·33.75 ±2.s 4 Tr~etbobenzamide: 4 mg/kg -25.0 1 after Chlorpromazine 1 mg/kg Chlorpr~zine: 1 mg/kg -37.50 ±2.5 2 after Trtmethobenzamide 4 mg/kg Diphenhydramine: 30 mg/kg ·15.0 1 Tr~ethobenzamide: 4 mg/kg ·20.0 1 after Diphenhydramine 30 mg/kg Tr~ethobenzamide: 4 mg/kg •10.0 1 during Diphenhydramine in£. Trimethobenzamide: 4 uag/kg -35.0 1 durina lpinepherine in£. 10 m.cg/kg/min Tr~ethobenzamide: 4 mg/q -37.5 t2.5 4 during Levarterenol in£. 10 meg/kg/min Tr~ethobenzamide: 4 mg/kg -8.55 t3.27 11 after Ergotamine 0.5 1111 ' Tr~ethobenzamide: 4 ms/kg -26.5 t5.79 10 during Phenoxybenzamine tnf. 30 meglkg/mtn" ·· .. ··· · · · Diehlorisoprotereaol 5 mg/kg •40.0 1 Trtmethobenzamide: 4 arg/kg -12.6 '!2.19 5 after Dichlorisoproterenol 5 mg/kg Trimethobenzamide: 4 mg/kg -30.0 1 during Acetylcholine tnf. Acetylcholine: l.Omg -40.0 1 Acetylcholine: 1.0 mg -7o.o to 2 during Trimethobenzamide tnf. 0. 7 mg/kg/min Trimethobenzamide: 4 mg/kg ·25.0 1 after Atropine 1 mg/kg 34 DIPHENHYDRAMINE WITH TRIMETHOBENZAMIDE FIGURE 2B ACETYLCHOLINE WITH TRIMETHOBENZAMIDE ERGOTAMINE WITH TRIMETHOBENZAMIDE \ 35 FIGURE 3A LEVARTERENOL WITH TRIMETHOBENZAMIDE FIGURE 3B PHENOXYBENZAMIDE WITH TRIMETHOBENZAMIDE FIGURE 3C DICHLORISOPROTERENOL WITH TRIMETHOBENZAMIDE 36 FIGURE 4A ERGOTAMINE WITH TRIMETHOBENZAMIDE FIGURE 4B DICHLORISOPROTERENOL WITH TRIMETHOBENZAMIDE FIGURE 4C PHENOXYBENZAMIDE WITH 'l:'RIMETHOBENZAMIDE ~~~: ~~~- ~~. ~:4_- 7-~-~- ~~~~~---~~~: -- ~~~-J. ~· ·~·-· ~· ·~- ~~~.l ~~~~~~ ~------' I . J : :. : : : : . ~j-~-·-~- ~~..;~----· --+-+-+=!--;.~- -:-- ·: . . . : : : ! : : : CACErl,gHOL J NE-== =~:=:J···--J==B±:f~r_.-;-;....;--;-..;-;-+-·f···· · --·····'-·····-i-+-i-+-H-1 · RECOVERY AFTER _,_: .., L.:i . . : : . .-+-+-+-H-++-H--·-"····H-++-,f-+,-!Hi+ +-f-,+l-,H,+,+-H++-:i-i.---t~ 2. 5 Il l ~UTES • 1 I ' .•:/\ : :T::.. .:. ,; =]: /\~ Tjlii + ! 1 1 j ' +' ! i· ; i 4 ..1. I .. ; ,_ l"'. j 1 + i .. j ____:_ ~ J ' i+J FIGURE 5. ELECTROCARDIOGRAM SHOOING PROLONGED ARRHYTHMIA FIGURE 6 . ELECTROCARDI BIBLIOGRAPBY 1. Bard. Philip. (ed.) Medical physiology. lOth ed. St. Louis, C.V. Mosby., 1956. 1421 p. 2. Boyd, Eldon M. and Wilfred A. Cassell. Agents affecting apomor• phine induced vomiting. Journal of Pharmacology and Experimental Therapeutics ll9:39Q-393. 1957. 3. Boyd, Eldon M. !1 !l• Inhibition of the apomorphine induced vomiting syndrome by antihistamine agents. Journal of Pharmacol• ogy and Experimental Therapeutics 113:299•309. 1955. 4. Brand, 1. 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