CA1185528A - Pharmaceutical composition for the treatment of cardio-vascular diseases - Google Patents

Abstract

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT
OF CARDIO-VASCULAR DISEASES

A b s t r a c t A pharmaceutical composition for the treatment of cardio-vascular diseases comprising an active principle, viz. 3-(2,2,2-trimethylhydrazinium) propionate dehydrate of the following formula:

Description

Field of th~ Invention ~ he pre~e~t i~e~tio~ relates to medicine and, more particularly~ to a novel pharmaceutical compositio~ for the treatme~t of c~rdio-vascular ~ sease ~uch a~ c~rdiac in~ufficiency at valvular ~e~ects~ m~ocarditises, cardio sclero~is, i~chemic heart disea~e, rhythm di~orders (arrh~thmia) of diff~rent genesis.

Background of the Invention At pre~ent the principal selec~i~e cardiotonic pha~a-ceutical preparations are cardiac ~l~co~ides~ ~he~ cover preparation~ of digitalis, as well ~ chni8, ~tropha~thus ~nd may lily (cf. M~Yu~Mashkov~ky~ Ph~rmaceutical Pr~p~rs~
tion~, M., Meditsina Phblishing ~ous~ 1977)o ~ a~ic disadvantage of gl~coside~ i~ their low therapeu tical indcx. Overdosage o~ the pr~paratio~s c~u~a~ seriou~
complic~ion~: acute brad~cardia~ pol~to~e extra~y~tole~
bigemi~y~ trigsmin~ deceleration of atriova~tricular condition 9 ~tricul~r ~lutter ~nd dia~kolic c~rdiac arrestO
A~ e~se~tial di~ad~tage r~ide~ o in the ab~ence of a di~ti~ct correlation bet~en the pr~paratio~ concen-tr~tio~ i~ blood and the e~fect obtainedO ~uxthermore~ gl~
cosides frequentl~ caus~ irritatio~ of mucous ~embrane of ; the ~tomach a~fect vomiting center re~ulting i~ dy~peptic di~turb~ce~
~ ler~e group of preparatio~ for the treat~e~t o~

.:

s~
cardio~va~cular di~eal3es is constitu~ed b~sr anti~rrhythmic prep~rations~ Orle of the mo8t widel;sr emplo~ed among them i8 novocainamide which is ~;ucce~3sfully Rdmini~tered at ~ariou~ kinds oî rh;stthm di~;turbances i~cludi~g e~ tra~ystole.
~Iowe~er, ~ven thi~ pre ?aration can cause ~ide effects ; ge ~eral w~akne~s; headache, nau~ea, vomiti~g, iD.somnia, dys-peptic phenome~ d, at the i~travenou~ mod~ GI adminis-tr~tio~,, possibt e dovelopment of ~ c~rdiogenic ~hock., Eurthermor~ ~ due to possible inhibitio~ of m~oc~rdial con-tr~ctibilit~r and reduction of arterial pre~s~re in the c~se of m~ocardial i~fsrction the preparation ~houl~ be admini~tered with ~reat cautionO
A ~imilar di~ad~a~ e is ixlher~nt in hig~ly e;~fi-cie~t preparation3 Aimalin a~d Et~moæin ~eth~l ester of

2-carbamic acid 10-(3-mor~hol;srlpropiongl)phenothiazino ~;ydrochlorid~) which al~o lower contr~ctile properties of m,yoc~rdium ~hus cau~i~g reductio~ of arteri~l pre~aure snd complicati~g their admi~istratio~ ak c~rdiog~nic ~hoc~
~nd h~rpote~ion~
,~-Adre~oblocker~ (Ideral, Benzodixin9 O~renolol) al~o h~ve ~ ~umber of negati~e ~ide effect~O ~hese compo-u~d~ ~re highl~ toxic (LD50. ~ Inderal i~ 30~50 m~ g for whit~ mice), provide a negative illotropic ~ffect; they are contrsi~dicated at ~ome heart dish~e~ ~uch ~8 ~inus br~d;yc~rdi~9 atrioventricul~x bloc~, cardiac insufficien-cy, bron~hi~l a~t~:ma ~ diabete~ mellitu~ and the like,.
~ o cut ~hort attac~c~ of bre~st pang use i6 ~uccess full;sr made of org~nic ~itrst~ amo~; which nitro~lycerin - ; 3 , .

, .... . . . . .

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has en~oyed mogt e~tensi~e application. ~he latter prepar~-tion i~proves to~us of coronar7 arterie~ ~nd ~djust~ re~is-ta~ce of perlpheral ~e~sel~, thug facilitati~g the heart's fu~ction of blood di~charge î~to aorta.
~ neg~tive propert~ of nitroglicerin is a short dura-tio~ of its effect and abilit~ of cau~ing 8trong cephalal-gia due to ch~nging tonu~ of skull ~eins~
Al~o known i8 a na~urally-occurring ~etabolite ~-but~robetain featuring ~ broad range of biolo~ical acti-vity including the effect on cardio-~ascu?ar sy~tem (~ature, 18~,3~8, ~959). HoweYer, ~-but~robet~in is rapidl~ metabo-li~ed in the orga~ism into carniti~e a~d, due to this ~act 9 i~ pos~e~se~ onl~ a short-time effect~

, . i It is an ob~ct of the present inve~tion to provide a novel pharmaceutical preparatio~ for the treatment o~ car~ I
dio~a~icular di~iea~e~i which would ~eature a low toxicity9 higher e~ficie~cy ~nd longer effect, and to eliminate ~ide . phenomena characteristic Or kno~n prep~rati~s i~tended ~or the ~re~tment of cardio-vascular d~sea~es. .
D~tailed De~cription Or the Invention ., . ~
~ he pha~maceutical co~po~itio~ according to the preA
sent i~rention i~ no~el snd hitherto unk~ow~ in the art~
~ hi~ object is accomplished by tha~ ~he novel pharmar ceutical composition for the treatment 9~ cardio ~a~cular di~ea~es comprising an acti~e pri~cipl~ and a pharmaceu~i-c~lly scceptabl0 dilue~t contain3 a6 ~he acti~e principl~, ~ 4 - :
1. :,....... .
. , :
. ~, ~, . . ........ .... . . .. .

accordi~g to the pre~3e~ inverLtion~ 3-(2~2~2~t~cimeth~1~;ydra-zinium) propio~te of the following formula:
(c~3)33~ C~2Cl~G~ ) ~2r In the ca~e of U8~ ; the m~dicated compound a~ injec-I;ions it co~ta~s the active principle i:n an amou~:Lt of 5 to 40~ b;y w~ight and, as th~3 pbarmace~atic~ll;r ~cceptable diluent ~ ~olYent di~tilled water ur ~ otonic solu~
ti~ O
Whell to be admini3tered a~ t~blets or capsule~, it contEIins the ~ctive principle in ~n amount of 00~ o 0,. 5 g per tablet or c~p~ule~, Special e~perime~tal studies have sho~ that the afî ect o~ the prep~sr~tion is ba~ed on its abilit;5r of dila tating coronar;sr ~rteries, thu3 accelerati:n~s a~imilation, b;y myoc~rdium9 of ener~-supplyi~g cub;tance~ a~d providing a pociti~ve e~fect on mitochondrial apparatu6 of m~oc~rdium cell which eventu~lly contribute~ to ~ pronounced de~relop~
ment of a po3itive inotro~ic ~fect of the cardiac mu~cle~, ~ he ph~ac~utical prep~ra~ion accordin~ to the pre~
~nt ~ention caII be u~eîul in the trea-~ent of ~uch di ~-~se~ a~ heart in~uf~icienc~r~ v~lcular de~ec t~ " m;yocarditi-~e~ 9 card~o~cl~ro~i'8, i~chemic :heart di~e~a q rh;~thm di~
~urbance~ o~ differe~t y;ene~isO In the~e casa~ it~ efîect i~ ~uperior to th~ therapeutic action of other pharmaceuti~
c~l preparation~ includin~;9 for exampl~, cardiac gl~co~de~, J~blocker~, Carb~crome~eO Especially pronou~ccd therapeu-tic xe~ult3 h~ve been ob~erved in ~e ca~e of chronical de-compen~3atio;n at rheu~aa~ic val~rul r defects 7 acu-~e circul~-, ~o:~y in~ufficiency at my~oc8rdi~1 in~arc-tio~O Also positi~re, though les~ pro~Lounced7 effect is obser~ed upon ~mini~tra~
tion of khe pharmaeeutic~l prepar~tion according to the preaent invention i~ ~hc case of paxo}c;y~mal tach~yoardia, fibrillation, ~V block, parox~m~O The preparatio~ accor din~ to the prese~t invention ha~; been tested in experiments on ~nimal~ ~nd in clinic~ on pa~i0n~3 with v~xious kinds of pathology~, ~ hus, the effect of the preparatio~ accordi~g to the pre~ent invelltion hs~ bee~ ~tudied relatiYe to vari~tion of ~he arrhy~hmogenic and lethal doses oî calcium chlorids.
thç experi~e~t was carried out o~ white mice of both ~exes w~ighing '19-~8 g which were narcotized by urethane a~d ECG w~
remetered in tran~thoracic lead. A ;~ ~olution of calcium chloride WhB ~dministered to tha te~t ~nimals into the tail ~rei~ at a co~st0~t rate (0u1 ml for 15 seco~ds). q!he ~verage do~e o~ c~lcium chloride cau~ing appearance of srrh~thmia and he~rt ~rre~ wa~ determined~ In the te~t group~ the ~tu~
die~ compoulld~ were ~dmini~tered 45, 60, '120~ '180 and 240 minutes befor~: the be~ ing of admini23tration of cslcium chlorid~ ~able 1 ) ~, It h~s been round t:h~t even ~ gle pre-limin~ry ~dmini~r~tio~ of the preparation based on 3-(2,2,2 t;rimethylh;~ zinium~-propionate intraperitoneall~ i~cresses ths arrh;~thmogenic and lethal dose~ of calcium chloride.
Though the prior art preparatiQ:~s :~o~oc~inamide and quini-d:Lne in ~ppropriate dose~ c~uses ~ more pronounced inor~ase oî the arrh;ythmogenic do~e oï calcium chloride, th~ preparfl-tion according to thc pre~ent inve~tion resul ts i~ a longer , ~

s~
a~tiarxh;ythmic effect alt a ~ub~3t~ntially lower toxicitg (Tsble 2).
~ he snti~rrh~thmic activity w~ ~ atudied in experi-ments on whit~ ratfi of both ~;e~es with ~ ma~ of 190 to 2~0 g ~arcotized b;y ureth~ne; for the~e ani~als :E:CG wa~
r~corded. I~to th~ f emoral v~in OI the rat~ aconitine wa~
irltroduc~d ~t a con~tan~ rate a~d it~ arrh;ythmogenic and lethal doses were determined 13lo~g with their variation under the protective effect of t}le preparation ~ccording to the present in~rentio~. It ha~ been rou~d that the pre-p~ration ha~ ~ pronounced protective ePfect ~l~o at the peror~l mode of ~dmini~tr~tion t~able ~0 ~ hus~ proph~lactic peroxal ~dministration of the pre-paration at the dail~ dose of 25 mg/kg during one wee~ ~ub-~tantiall~ increa~e~ ~he arrhythmoKenic and leth~l dos~s Or ~conitlne (by ~8.7 and 27.6% re~pecti~el~ Jected 1~
hour~ ~fter the last ~dmini~tr~tion of the preparation of the in~e~tionO At a moro la~ting admi~i~tr~tion protective proper~ies of the prep~ratio~ ~re ~ronounced even more clearly ~ble 3)~
~ he ef~ect of the prepar~t~on a¢co~ding to the pre-~ent in~ention on the ~ri~tion o~ the arrh~thmogenic do~e o~ Strophanthin G wa~ studie~ in experiments on rab-bit~ of both se~e~ wi~h a maa3 of 0~3 to 0~6 kg admini~te-red with Stro~ha~thin G i~ the do~e of 60 ~g~g into the marginal ~uric~l~r ~in and, after e~er~ 5-10 minutes, at do~e o~ 5~10 ~g~kg till the appearance of ~ ~table ~ent-ricular extras~6toleO I~ the test ~roup~ 20-30 minute~ be-, - 7 -.. .. . . . . ... . . ... . .... . .

.
~ f~3 fore administration of the glycoside a solution of 3-(2,2,2-trimethylhydrazinium) propionate was propholactically ad-ministered intravenously, the ECG was recorded in II standard lead.
It was found that in the dose of 10 mg/kg the pre-paration increased the arrhythmogenic dose of Strophanthin G from 67+9 to 90-15 ug/kg (Table 4). At a further in-crease of the dose of the preparation to the present inven-tion its protective effect was increased too.

Variation of arrthythmogenic and lethan doses of CaCl~with time after administration of the studied phar-maceutical compositions in experiments on mice.
Table 1 N Pharmaceutical Preventive Ti~e, minu-tes _ _ os composition dose, mg/kg intraperi- 45 60 toneal adminis- arrhy- arrhy-tration thmo- lethal thmo- let-genic gonic hal Doses of CaCl ~ 2~

~- __ _ In~ection form of 1091.5 101.7 103.4 122.2 the preparation o~
~he invention, 40~
solution of 3-(2,2, 2 2-trimethylhydrazi-nium)propionate in 30 106.7 122.8 0.3% solution of NaCl

3 Novocainamide 10 114.16 120.8 125.16 143 .. . .. .. . ..... . . . ~ . ....... . .

4 Quinidine 3 128.9 147.7 104.5 117.8 120.84 138.54 119.~8 12~.2 , _ , ., . .. . . .. .

~;

Table 1 (contd.) Control - 85 100.9 Nos. Time, minutes S

arrhyth- lethal arrhyth- lethal arrhyth- lethal mogenic mogenic mogenic __ Doses of CaC12 mg/kg _ 2 111.9 130 110.1 116 117.5 130.2 121.9 128 .
86.85 104.5 3 93.16 114.9 . _ 87.47 103.65 ~ 94.5 117.6 88.7 115.8 .

Table 2 Acute toxicity of pharmaceutical compositions in experiments on white mice at intravenous administration.

Pharmaceutical compo~ition LD50, mg/kg Injection orm of the preparation of this invention, 40~ solution of 3-(2,2,2-trimethylhydrazinium) propionate in distilled water 4,430(3,164.3-6.202) -.~,~.

Table 2 (contd.) Novocainamide 112 (97.39-128.8) Quinidine 58 (58.6-78.88) - 9a -, ~able 3 ~tisrrhythmogenic ~ckivit~ of the preparation according to the pre~ent in~en~ion ~t it~ repeated admini~tration in experime~t~ on rat~0 Do~e of the harmaceutical Aconitine dose ~ariation, compo~ition ~mg/kg) admi ni~t~red perorally and Administr~tion for contsining~ g:
1 wee~ 2 week~

3~(2,2 2-trlmethylhydr~ rh~t~ Lethal mogeYi~ hal zinium~propion~te 0.400û

Silica with pux~ty grade of 99u~ ~nd particle ~ize of 5-20 ~m 0.0340 potato ~t~rch 0.05B6 Meth~lcellulose 000024 M~gne~ium ~tearate 0.0050 ~8~7 i 270~ ~2.,26 2~.7 100 , 5506 16.2 3406 9.7 ., , , ~ 10 -.
`:~ . ., ~ble 4 Vari~tion of the arrhythmogenic dose of ~troph~nthin G under the action of the pharmac~utica1 prepar~tion of the pre~0nt in~ention Prepara Arrh~thmo Duratio~
Ph~rmaceutic~l tion do~e~ genic dose of arrhy-compo~ition mg/~g in- of Strop- thmi~, travenou~- hanthing mi~utas olution of the 10 90~15 '12~6 prep~ratioll ~coording ~ 25 ~lOG~'10 8~5 to the pre~e~t inven- 50 ~106~12 15 tion containing 3-~ ~, 2, 2-trimethylhydra-zin:L~m)propion~te ~he sctive principle - - 67~9 20+10 q~o i~veutigate the thex~peutic aff ect o~ the prepara~
tion ~ccording to the pre~ent i~ventiorl relatlve to th~
Stroph~nthin arrh;~hmia 9 another serie of expeximents W~18 c~rried outO Stroph~nth~ was intr~e~ou~ dmini~
re~ to rabbits o~ both ~e~e~ with a ma~ o~ 3~0 to 3.8 kg i~ the ~sener~l do~e o~ 80~ug/k~ wbich cauaed arrh;ythmia within 40-60 mi~utes~ ~he te~t preparation was i~atravenou~
tered at the ~c~ground of ~rrh~rthmi~ i~ th~ teat g~o~p O
It w~ found that ~he prep~ratio~ b~ed o~ 3-(2,2,2-trimethylhydr~zinium)propion~te in a ~o~e of 1 ~o 3 ~ ~g _, 11 -- ' ~' ' .

~ 5~in the mfl~orit~ o te~ts ~lread~ within 1-2 minute~ ~fter the intravenous admini~tr~tion ~emporaril~ arre~ted ventri-cul~r tachy~rrhythmia cau6ed by Stropha~thin G in r~bbit~O
Chsnges in the comp~ex QGS~ were also reduced; after the ~dmini~tr~tio~ of th~ prep~ration in the dose of 5 mg/kg the regular SynUS8l rh~thm w~s ret~ined ~or 12~5 minu~e~
o~ the average, whereafter arrhythmia wa~ gradually renewed, but it could be again elimin~ted b~ a repeat~d administra-tion o~ the prep~ration in a dose of 2-5 mg/kgO In such case~ the ~inusal rhythm was retained for 15 to 30 minute~
and in the ma~ority of tests srrhythmia wa~ ~ever renewed.
Furthermor~, a~ ~periment wa~ carried out o~ narcotized guinea pigs with a ma~ of 600-7~0 g to which Stroph~nthin -~ w~s admi~istered into ~he f~moral vein in the total do~e o~f 500 ug~kg.
~ he prep~ratio~ based o~ 3-~2,2,2-trimethylhy~xa~onium)-propion~te was intr~enousl~ ~dministered against the back-ground o~ arrhythmia in the te~t group. It was ~ound that ~
alread~ wi~hi~ 2-3 minutes a~ter the intr~venou9 adminiBtr~- i tion the teBt prepara~ion temporarily ~rr~ted the ventri-cular ~rrh~thmia caused b~ Stroph~nthin ~ e the gr~ph~.
~he ch~nges in the co~plex QRST were reduced ~nd the atxial fibrillation di~appesred which wes demo~tr~ted b~ the appe-~r~nce of the ~pt. ripple. I~ ~ome ca~e~ at a timel~ ~dmini-~tration of t~e prep~r~tion in a dose of 2-~ ~g~kg it wa~
po~sible to al~o eliminate the atrio-ven~ricul~r bloc~
c~u~ed b~ Strophanthin Kv ~he graph illustrate~ the recordi~g o~ ECG of a guinea p~,g, ~he ~fect of compound I on Stroph~nthi~ arrhynthmia i~ ~;uinea pig~.
A ~ ECG of a gUi3D ea pig in IX standard lesd and time mark of 1 8eCOnl~lo :B - r~cording cont:inued.
1 ~ ~t~rting ~:CG
2 ~ ECG 3 minut~s a~ter administr~tion of S1;rophan~hiIl X
in the do~;e of 0. 5 m~ g 3 - ECG ~ minute~3 after admini~tratio~ o~ the preparat;ion in the do~e oï 2 " 0 mg/kg 4 - recording of :3CG b;~r 8 minutea ls~t~r

5 -ECG 3 minutes after a~ tr~tion of the prepa~ation i~
the do~e of 5 mg/kg (18 minute~ af ter the begin~ing of t~e experimeilt )

6 :E:CG p~tter:~ 15 mi~ute~ af~er admini~tratio~ o~ the preparation in the do~e of 5 mg/k~

7 ~ ECG p~ttern 5 minutes after ~ repeated ~dminis~ration of t~c preparation in t~e dose of ~ mg/kg

8 - :ECG patter~ 5 minutes ~ter the repe~ted a~mini~tra tio~ of the p~ep~rat~on in th~ do~e of 5 mg~kg.
~urthermor~ 9 th~ prep~r~tion accordin~; to ~he present invention wa~ t~ted Ior a ~peci~ic anti~rr~thmic &nd anti-~ngi~l erfe~t~. ~or t~e purpo~e o~ compari~on also 1;ested were prior ~rt ~ntiarrhythmic prepar~tio~s ~ guinidine, novocain~mide 7 lidocain a~d a know~ antianginal agent -c~rbo.cromene~ ~he ef~ect of the no~rel ph~r~aceutical com-position ~ccording to the presen~ i~vention was studied ol~ c~r~ w~i~shing 20973~.6 kg; the pr~p~ration wa~ u6ed as ::.

~t . ,. :, ~ . ,i `

~ ~5~
a ~ agueous ~ol~tion corlt~ini~g 3-(2, 2, 2-tri~ethylh;ydra-zinium)propionate for th~ de~ermirla~ion of the thre~hold value of electric ~ibrilla tion of au:ricle ~nd ventricle~.
At arti~icial resp ~atio~ a.~ter openin~; of thor~x ~d perie~rdium needle-like eleotrode~ were applied to the right auricula and ~pex of the left ~entricle. The irritation w~ effected b~ ~iquaxe pul~es of 1 m. sO, 15 st/so ~he cur-rent pa~sing through the he~rt w~8 graduall~ increased till fibrillation~ ~ppe~red which were ev~luated b~ ECG and arterial preesure on a ph;srsiograph s~r~ilable from ~arco Bio S;yskems Co., The studied compo~md~ wer~ adminiætered intravenouslyO ~he results thus obtained are 8~10W~1 in ~ble 5 hereinbelow. It was found th~t the ph~rmaceutical composition sccording to the preserlt i~ventioll in a do~e of from 6 to 15 mg/kg upon intra venous admini~tr~tion incre~ed by 40~55% the threshold of alcctricaî ~ibrillation o~ suricle and ventricle~3 novoca-inamid~ provided the ~EIme ~ffect in ~ dose of 40-55 m~/~cg.
Quinidine ~nd lidocain, though exerting their effect at lower do~e~, had ~ ~ubst~ti~ r highsr toxicity.
For the compari~on of prep~r~tion~ 7 a~ the criterion o~ the r~n~e o~ t~erapeutic eff ect, there w~e used the ratio o~ the h~lf-leth~l do~e to the half effective dose ~D5of ;E:D5~) which was r~ferred to a~ the ~nti~rrh;ythmic ind~x~.
Th¢ ~llti33~;~thmic index of the pharmaceutical compo~ition ~ccord~ng t~ the preeent inven~ion in the Iorm o~ ~ '10% 60-lution containin~;, as the a~-ti~e p~inoiple~ 3 ~2~2~2~tri-meth~lhydr~inium~propionste ~443) for this paxticular t~pe of ~rrh~thmia w~ subsk~nti~lly higher than the ~ntiarrhyth-- 14 ~
.

5~

mic index of quinidine (26)~ lidoc~in (1~) and novoc~insmi-de (2.3)~ Th~ comparative study o~ th~ antiarrh~thmic aciti vit~ of ph~rmaceutical prep~ration8 using acotine model of arrh~thmia w~ effected in experiment~ on white r~ts weigh-.ing 190-240 g. The test prepsrations wer~ ad~inistered in traperito~eally ~0-40 minute~ before ~dministration of aco-nit.ineO ~he results are shown in ~able 5 hereinbelow.
For this ~odel o~ ~rrhythmia the ph~rmaceutical prepa-ration according to the pre6ent inventio~ show~ a sub~tan-ti~lly higher activity as compared to ~he known ~ntiarrhythmic prepMration~O ~hus; the anti~rrhythmic index for the pharma-ceutical preparation according to the pre~ent invention was 3~, whil~ for gui~idi~e and.novocai~amide ~hese ~alues were 16 ~nd 2.5 respectivel~J A~ the third model of arrh~thmia the~
re was u~ed ~trophanthin arrh~thmia in guinea pigs. ~o guine~
pig~ with a ma~ of 420 to 7~0 g Strophanthin-K wa9 admini~
~exed in the do~e of 450 ~/kg. In the oontrol ~roup this dose o~ Strophanthin caused ~ppe~r~nce of arrhythmia a~ i de~th o~ th~ anim~].s wit~i~ 1Z~20 minutes~ ~g~in~t the background of arr~ythmia the test prepsrations were adminis~
t~red intr~ve~ousl~ ~h~ result~ thus obt~in~d are sho~n in ~ble 5 hereinb~low. ~he test~ h~ve ~hown ~hst the intra~e~ou~ 1.
~dministr~tion of the pharm~ceuticsl Gomposition ~ccording '.
to the pre~ent inventio~ and novoc~n~mide cut~ ~hort the .:
Strophanthin-induced arrhythmia in guine~ plg5 for 5-20 minu te~ in 6 experime~ts out o~ 8, wherea~ the administratio~
o~ lidoc~n ~nd qu nidi~e cause~ improvement, accordlng to ECG data, rOr only 0.5-3 mi~ute~ in 4 out of 7 and in 4 out o~ 8 ~im~l~ re~ecti~el~. ~5 .

~ ha stud~ of the preparation according to the pre~ent invention for arterial pre~sure.g breathing and hemody~amic effects of ~orepinephrine~ neoepinephrine, no~oepinephrine 9 ~cet~lchcline and histamine wa~ carried out i~ e~periments on cats with a mass of 2~8 to 4.0 kg n~rcotized by chlor~se.
~here were then recorded the ~nimalsl arteri~l pressure~ res piration ~nd ~CG on a phy~iograph pro~uGed ~ rco Bio-Sy~-tem~ Co.
~nti~rrh~thmic ~cti~ity and aeute toxicity of the te~t ph~rmac0utic~l compo~ition~
~able 5 ~D 0 mg/kg ~ ~D5J~D50/
~0~ Ph~rmaceutical compo~ition Electric irri- Aconitine ar- i~
t~tion of cat 1 8 ~hgthmia in he~rt r~t~ ' .__________ ~_____~__~___ _ 4 10% ~queous solution of the ph~rm~ceutical pre~ 5 2 p~r8tion of this i~ven tion for i~jections containin~ 3-~2,2 2-tri meth~lhydr6~inium~pro-pion~te as the active principle 10~3.5 ~433J ~205~2.5/354 3 Quinidine 2~6tO.5 ~26~4.3~006 ~16J

4 Novocai~mide 46.0~60~ J2/ 45.0~5.0~2~5J

5 L1docai~ 3.o 0~3 J~3~

.

' ~abl e 5 ~contO) }:Dso mg~k~ D50/~D5o~ Acute to~i-~o~ ci~
Strophanthin ~rrh~th~ white mice mi~ in guinea pigsnous admi-nistration, I,D50 m~/k~

2 7.8~2~3 /568/ ~943 (3,164~3~69202) 3 2 0 3~0 ~ 4 ,~30~ 68 (5~"6-7~.88) ., i.
11~
7 ~ 2/ ( 97 ~ 9~128 . 8 ) ;
f 3 . 8~0 . 5 /11/ 40 ~3~.3;4~) ' ~
~t was fou~d that in doses of,0.5 to 2.0 m~3/kg the f~
prep~r~tion ~dministered intrave~ousl~ did ~ot re~ult i~
~ny essential ch~nge of arterial pre~sure, pul~e ~reguency and respir~tion. ~hs above-~peci~ied do~e~ of the prepera tlo~ neither chsnged the leYel of~ respon~es to biogenio ami~
nes. At higher dose~ of the preparation (15-25 mg/kg~ there w~ observed ~ ~hort-time reduction of arteri~l pres~ure by 5-20 mm ~g which in some c~;es wa~ changed to a more l~tinK (5-12 minutes) i:~crease of ~rterial pressure by 5-10 mm Hg as compared tv the initial valueu ~t the same t~me ther2 wa6 ob~erved a short time increase of the res- ;

~ 5~
ponse to hist~mi~e (by 5-10~) and ch~nge in response to ~he ~dmini~tration of neoepinephxine (by 5-1~%) and ~ce~yl choline ~by 10-15%)q A ~ur~her i~cre~se Or the prep~r~tion dose did not c~use changes of blood pres~ure or respon6e to the admini~tration of biogenic amines.
~ here were also carried out comp~rative ~tudies of the ~ffect on coron~ry circulation exerted by the pharmaceuti-cal compo~ition according to the present invention and car-bocrD~ene~ ~he pharmaceutical compo6îtio~ according to the inventio~ i~ used in the form of a 20% in~ection solution contsini~g 3-~(2,2,2~trimeth;~1h~dr~zinium)propion~te a~ the ac-ti~e princip~e in a 0O~% ~olution of sodium chloride.
I~ ~cute experiment~ o~ narcotized ~ats with a mass of from 2.9 to 4.1 kg under the conditions of ~rtificial re~pi-r~tion ~rteri~l pressure w~ recorded in common carotide , arter7, centr~l venou~ pre~sure - in right ~uricle, volu~e rate o~ blood ~low in the ~scending aortic arch and volume rate of t~e coronar7 blood flow~ At the sa~e time there was recorded the content of oxyhemoglobin in venou~ coronar~
blood~ ~he compar~tive dat~ on the efficienc~ of the pharma-ceu~ie~l compo~ition according to the present invention ~nd that of carbocro~bne are ~own in ~a~le 6 hereinbelowu it i~ 8e~n from the ~ble, the ph~rmsceutical compo-8ition ~ccording to the presenk invention ~nd c~rbocromene i~ e~ui~alent dose3 i~crease9 over a long timel th~ volu~e rate of coronary blood flow at a low effect exerted on the ~rterial pre~sureO oth preparation~ do not change'or o~l~ :
~lightl~ rea~0 the c~rdi~c output. ~urthermore, ~he pre-'I ~
, ',`' , .' . ' par~tion acç~rding to the present in~ention, likewi~e c~rbocro-mene, lastingl~ increase ~aturation of venous blood of corona-r~ sinu~ with oxygen, w~ereag toxici~ of the preparation of thi~ invention'i~ b~ 12 ~ime~ le3~er th~n th~t of carbocrome ne. ~or thi~ rea~on, the therapeutical index of the novel pharm~ceutical compo~itio~ i8 by approximately 3 time~ hi~her (314 v~. 130)o ~ here were ~l~o carrie~ out the tests of ~llerge~ic ca p~city of the prep~ration accordin~ to the invention; the test results have ~ho~n that the prepar~tion does not cau~e irritation of ve~sel walls when aclministered intravenously;
neithex it cause~ aller~ic re~ponses both at i~travenou~ and pero~al modes of ~dministration e~ther upon ~ si~le or long-time (up to ~0 da~) admini~tra~io~ thereof~
~ e prepar~tion doses of up to 10,000 mg/kg in e~peri-ments on white rats administered perorall~ on ~n~ day of pregna~cy cau~ed no embr~otoxic or teratogenic effect6, ~he stud~ of the mut~genous ~ctivit~ of the preparatîon based o~ 3-(2,2,2~trimeth~lhydrazinium)propionata dih~dr~te on ~ruit flies and ~almonellae h~s ~hown that the preparation of the pre~ent invention doe~ not h~ve mutagenous acti~it~J
Pharmaceutic~l preparatio~ based on 3-(2~2~2~rimeth~l-h~r~zinium)propionate dih~dr~te are stable in ~tor~ge at ths tempex~ture o~ ~5C for flt le~8t two yearsO
~ he prepsration h~ been ~tudied o~ more than 65 pati-ents suffering from YariOUs patholoEy of the cardio-vascular sy~tems such a8 heart rbythm disturb~nce~ ~arrhythmia) of different etiology, i~chemic hesrt disea~e, ~tenocardia, athero~clerosi~0 : _ ~9 _ , qhough the indication~ for admini~tration of the prepax~tion were con~iderabi~ low, during clinical tests it wa~ ~dministexed ~ainly to patients with ischemic he~rt dise~se (IHD)o Given hereinafter are the results of ~n~lysis of the preparation a~icie~cy in 20 men and women ag0d from 25 to 50 ~ear~.
All the patients h~d typical s~enocardia (angin~ pec-toris) ~ttacks, two patients h~d pronounced p~tholog~ of coronary ~rt~ries revealed by coronarograph~ and in 5 pati~
ents - a l~rge-focu~ myocardi~l infarction in ~n~mnesis with p~thological 0 in ECG~ ~11 patient~ were peror~lly ~dminis~
tered with the prepax~tion i~ ~ dose of 20 to 40 mg of the :~
~ctive principla per k~ of the bodyweight which each pati-e~t was given during the dayti~e with meals for 4 wee~s altogether which was 4~-96 g on the a~er~ge per the treat-ment cour~e.
~ he fo~lowing hemodgnamic~ parameters were studied.
r~te of the heart's ~aat (R~B), electroc~rdiogram (~CG)~
~11 kinds of ~rterial pr~ssure with the curve recording on ~ Mechanocardiograph 063 ~Savitsky' 8 model), beat ejectio~
accordi~g to the Wrem~er-Ranke metho~t ~peed o~ pulse w~e prop~ation, ph~e an~lysis of the left ventricle sy~tole o~ ~n in~trument Mingogrsph M 341 a~ well ~ amplitude time parameter~ (volume rate of e~ection VRE, speed of pr~ure ~row~h (SPG)~ rste of heart rela~ion (R~R~).
Duri~g the investi~ation the patients suffering from I~D continued their acti~e way of life, all other medicated compounds were calcelled, except for ~itroglycerin tabl~t~
when required~

~able 6 ~emodynamic characteristic~ and acut~ toxicit~
of the p~armaceutical preparatio~ containing 3 (2,2,2-trimethylh~drazinium)propionate a~
the active principle and the preparation C~rbocromene~

Pharm~ceutical Dose~ Volume rate of arterial pre~sure, %
No~ preparat1on mg/kg Perce~t Increase . of incre~- duration~
. se - mi~utes 1 ___________ ~Z________ ~ 4 20% in~ection solu- 2 15 20 tion contai~ing 2 3-(2,2,2-trimethyl- 10 40 45 hydrazinium~propio-nate as the active25 55 7 principle in 0.9 fiolution of NaCl 3 C~rbocromene 0O5 30 35 - 21 ~

Tabl a 6 (cont. ) Change of Change of Change of Ac~te toxicit;sr ~: arterial heart out- central for white mice os pressure, putg ~6 venou~ at intraperito-96 pres~ure 5 neal administ % . ratio~, ID
mg/~g 6 ~Z 8 ~ -5 ~~ +5 0 7 9 ~50 2 (~ '1.6+9,4~0) ~5 '10 -5 -8 - ~5 ~10 - 20 ~10 Q - ~5 +5 ~5 650 3 (500 ~ 845) ~5 +5 - 15 . 5 0 ~ +7 ~5 - 15 5 - 10 Ev~3n during the first week from the beginning of ad mini.~tration oî the ;pr~paration a considerable improv ement o~ th~ patient~ ' state of health was noted: retro3ter~al pain~, occurred les~ f'requentl~, dyspnea became less pxo-nouIlced, ~he rate of admini~tration of ~itrogl;s~cerin tablets per day wa~ sharpl;y reduced,, working capacit~ was incre~sed~ weakness in leg~ disappear~, heart inter-mis6ions became le~s frequentO
~ he eleGtrocardiographic investigations re~realed a slight decrea~ of the rate of the heart ' ~ beat, di~ppea-rance of auriculare snd ~rentricular ext:ras;y~toles3 rei;D-s~

Yer~ion of the T ripple ~nd inc~ease of it~ posi tiYe smp-litude. In the investigation o~ arterisl pressure there wa~ observed the growth of all ki~ds of ~P, especiall~
the value of hemodynamic imp~ct which pointed to the growth of kinetic energ~ of the hemod~amic flow. ~he ~rowth of the ~rterial pressure wa~ a~sociated mainly with the increase of beat ejection~ whPrea~ the tonus of vessels of ela~tic and mascular t~pe was not substantially ch~nged which was demol~trated by the values of the pro-pagation ~peed of the pulse w~ve~
In the phase analysis of the left ventricl2 duri~
the treatment the involution period ~ WAS definitel~ in-creesed the phase of expul~ion E wa~ reduced, the period of ten~ion PT shortened mainly due to a reduction of the period of isometric contraction (IC).
~or evaluation of contraction properties of myo~ -cardium ~eparately during its 8~5 tolic ~nd diastol~c pe-riod~ o~ its co~traction there were used amplitude~time ch~racteristics rate of heart e~ection (RH~), rate of pressure raise ~BP~) a~d rate o~ heart relaxation ~RER)~
~ he rate of heart ejection (~E) i~ determined by the fo~mula: B~6 , wherein BV - beat volume i~ ml~ E ~ time of the expul~ion phase in second~O
~ he value o~ RHE characterizes contraction proper tie~ of t~e myoc~rdium during the sy~tole period; incxease of this v~lue in the course of treatment b~ means of the prepar~tion according to the pre~ent invéntion demon~tra-~e~ improYement of inotropic p~operties of m~ocardium.
- ~3 ~

The rate of pre~sure xsi~e i8 determined by the for-mul~: RPR ~ wherein DP - diastolic pressure in mm, C

Hg, 5 - co~entional value of ~he final diastolic pressure in the aoxta, IC - isome~ric contraction. RPR characterized contracti~e prop~rties of the m~ocardium during the period of closed valves and it~ sbilit~ of rapidly surpassing the value of pre~sure in the aorta for ope~ing of the aortic valves.
The rate o~ beart relsxation (R~IR) characteri3es acti-vity of the m~ocardium at the moment of diastole and is determined b~ the foxmula: ~R = ~ , wherein SP -~tolic pressure in -the brachial artery in mm ~, 5 - conventional value of the final diastolic pressure in the aorta, D ~ duration of the diastolic period in secoIlds.
The re~ult~ of the inve~tig~tion are ~hown in ~able 7 hexein-below.
The antianginal and ~ntiarrh~thmic effects of the pre-paration accordin~ to the present invention were evaluated with the use of the ln~ectional pharmaceutical form oX the pr~psrstio~ administered intra~enously in an amou~t of 00 2 to 0.4 g based on the active principle~ In 8 cases of ste~ocardia attack in 5 patients -the prep~ration rapidly cut short retrosternal pain~ without an~ additional admi-nistrstion of nitrates, analgetics and narcotics. However, the analgetic effect was not alwa~s stable which necessits-ted a repeated administratio~ of the preparationO
The prep~ration efficiency in the case of extrasysto-lic srrh~thmia was studied on 7 patients~ ~he i~travenous , .

5~

Variatio~ OI hemod;y~amic parameters in patients with I~ID under the e~fect of ~M~m~ of the pero~al form o~ the pharmaceu~ical compo~;ition containirlg 3- ( 2, 2, 2-trimet~;srlh;~rdra zinium)propi onate dihydrate a6 the zctive principle ~abl e 7 Psrameter during the b sf ore Nos Parameker treatment 1 st week 2nd wee~
_ __ _~_ __ __ 2 , ~ _ _ 4 2 beeat/m~s 72. 3~ 5 67 . 8+1 ,, 8 64. 3+'1 . 3 3 beat ~rolume, l/min 70 ~ 2~5 .. ~ 72 ~ 2~3 . 7 74 0 4+~ . 7 . ~ minute blood volume, 5.6+0.3 4.9~1.3 4.8~5.1 l/min 5 f inal ~ysto-mm/Hg 130 ,.4+2. 0 134. 6+1. 6 143 . 5~1 . 8 6 lateral systo- 11508+0.5 1'16.4~2.1 1~l809~1~7 7. ~vera~e d~na- .
mic pres6ure 89 . 7~1 . 2 90 ~. 6~0 ~ 7 91 . 2~10 2 a d stol c 68 . 2+0 . 6 69 . 9+1 . ~ 70 0 3~0 r 9

9 pulse pres~ 47.6~0.6 46.5~1.1 48.~1.6 hemod;ynsmic '1*,.6~1.2 18.2~1.. 0~ 24.6~0.7 11 i~volution 830~26 . 873f33 933_~42b '12 expulsion phase,milli~ 222~4 . 225+2 230~3 13 te:~lsion period, milliseeond~ '109-~4 .104+2 ~100~4 ^5 .

~able 7 (cont.) ~ __ 4 5 14 as~nchxon.
contraction 56+2 55~4 54~2 i~ometric contraction, millisec. 53~2 49~3 46~4 16 diastol~, milIiseconds 499~14 543~21 603~21 17 volume of heart ejection, ml~sec 315~15 320+23 322~13 18 rate of pres~
sure raise, mm Hg/sec 1,188~30 1,326+45. 1~473~130 19 rate of heart relax~tion, mm Hg/sec 250~9 238~10 229~8 Note: certainty of difference p c 0.010 , -- 2b -- ' .

s~

~able 7 (contO) Parameter during the treatment ~os ~
3rd week 4th week _ 2 60.1+176~ 62.2+1.4 3 ~0~6+405 8400~.4 4 4.~+307 5.2+3~5 ~45.0~2.4~ ~50.6~2~7 6 120.1+1.4~ 125.6~007 7 92~0~1.8 92.2~1.0 8 7203+1.4 72.0~1~8¢
9 47.8+1.4 53.6+102 ~0 24.9~.5~ 25.~+0.7 ~1 1000+42~ 965~21 ~2 232~4 ~35~3 13 99~3~ 88*2 14 56~4 55~3 43+2 33~2 16 669~14~ 642~14 ~7 374+14~ 357+17 18 1,581~54~ 2,030+68 19 209~8 226~12 ~ote: ~cartainty of differe~ce P - 0.01 ~ 2?-administration o~ the prep~ration (1 ml of a L~~ solu-tion) arrested the rhythm disorder ~or 5-20 minutes.
~ herefore, the pharmaceutical preparation based on 3-(2,2,2-trimeth~lh~dr~zinium)propionate in patients with verified ischemic disease provides the inotropic effect on the myocardium, remo~es retrosternal pains and rhythm disorders ~uch as extrasystole.
Consequently, the ph~rmaceutical preparation according to the present invention fea-tures a special scope of activit~; it m~nifests itself a~ a ~asodilative prepa-ration relative to coronary arteries, facilitates imprQVe~
ment of the myocardial metabolism and posse6ses a clearly pronounced and stable positi~e inotropic ef~ect.
~ he pharmaceutical preparation ac~ording to the pre-sent invention is preferabl~ administered in the form of injectio~ solutions, tablets~ capsules, powders. It is in-dicated at the rate of 10 to ~0 m~kg of the bodyweight as tablets or cap~ules per da~ simultaneously with taking meals, or i~ the form of 10-40% injection solution~ ~he preparaticn of the present invention relates to low-toxic ~ubsta~ces ~ist B or even les~ strict).
Pharmaceutical forms o~ thc preparation for peroral administration are stable for two years at room temperatu-re and are to be stored in a dry~ ht-protected place Injection solutions should be stored for ~ot more than 2 years at a temperature of not more than +5C.
~ he active principle according to the present.in~en-tion, vizo 3-(2,2,2-trimetylhydrazinium)propionate is ....

~ a ~s~

prepared b~ a~y conven~ional me~hod; for ex~mple, a solutiono~ methyl-3-(272~2~trimeth~lh~drazi~iu~pr~pion~te chloride in .
water is passed through a co1umn with an îon exchange resin Amberli te IRA-400 /Registered ~rade Mark/. The solvent is re-moved and the residue is cr~stallized from eth~nol~ ~here are thus obtai~ed 140 g (85~) of 3-(2~2,2-trimethylh~draziniu~) propionate in the form of colourless c~stals with the M.p.
of 254-256C. ~MR spectrum ( ~ , ppm): 6.79 sin~let, (CH3)3~+; 6.89 triplet~ CH~; 7.77, triplet, CH2.
~ ound, %: C 39.56, ~ 10-10, ~ 15.36; C6H1~02~2~2~20 Calculated, %: C 39.56; H 9.89, N 15~30.
3 - ( 2 7 2~2 trimethyl~ydrasinium)propionate dih~drate comprises ~ htl~ h~groscopic white substances well solub-le in water, hot ethanol and methanol, insoluble in non-polar solvents, having a weak specific odour. When stored in closed ware at room temperature, it is stable fox at 2 ~ear~. ~pon heati~g above 40C the product loses crystsl-lization water and slowl~ decomposes.

-- 29 -~

Claims (4)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition possessing antiarrhyth-mic and antianginal activity comprising an active principle, viz. 3-(2,2,2-trimethylhydrazinium)propionate dihydrate of the following formula:

and a pharmaceutically acceptable diluent.

2. A pharmaceutical composition according to Claim 1 for injections, wherein the active principle is present in an amount of from 5 to 40% by weight.

3. A pharmaceutical composition according to Claim 1 for injections, wherein a the pharmaceutically acceptable diluent use is made of a solvent - distilled water or an isotonic solution.

4. Pharmaceutical composition according to Claim 1 in the form of tablets or capsules wherein the active principle is contained in an amount of from 0.1 to 0.5 g per tablet or capsule.