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