AU611961B2 - Pharmaceutical preparation for curing multiple sclerosis and lateral amyotrophic sclerosis - Google Patents

Description

AU-AI -24247/88 P CT Me a .10 o L a ME)K4YHAPOUH1A5 3ASIBZA, 0 J1111IZO1311I111 CWTEtB1 C aUOVOBOPOM Q IATEHTHIOI KOORTEPAII14 (PCT) II3o6pQTCIM 4: A61K( 37/02 (11) Homlep mewpi apomiof uy6.rniiatuii WO 89/02745 Al (43) AlaTa NmewapiyHponiflhoI ny6aiinaujuti: 6 anpen.9 1989 (06.04.89) (21) Homtep mte*'ayiapo0Aii6f1 3aMBKzt: PCT/$U88/00162 (22) /AaTa Miew.iyiiapouitofi nojialm: 19 ajryCra 1988 (19,08,88) (31) HoNtep nPHOPiIrreTJ1o0 3ajiumuI 4312985/28 (32) /IaTa npIuopir'u: 2 oKT.916psi 1987 (02,10,87) (33) CTPalla n13IHOPIUeTa; SU (71) 3laXBH 'TeXb (0,1.1 68CeVyK3nuitbxZacydapcm6, KPOAle US,, BCECOIO3HhIfl TKAPaH1.IOOFIECK14f1 HA' Yt.I1'IbIf UIEHTP AKAAIEMI4I14 MEJ141.0IHH1 CI'.I4X I-AYFN CCCP [SU/SUI; Moct 1215S2, y3 Tpooo g a. 1a (SU) [VSESO~JUZNY KARDIOLOQICHESKY NAIJCH-NY TSENTR AKADEMII MEDITSINSKIKHi NAUK SSSR, Mos' Cow (StJ)I, (72) 1l306PeTftTCA'hr, i f13o0ipT4.eJII/3a"RnITeJw1 (tloaibKo PYCEB EWr1H~ 1VI fioputi [SUISUI;, Mocmoa 117571, ,iletaic~ti( rp,, i 156, KB. 277 (SU) [GUSEY, Evgeny IvnoVich, Moscow (SUYj. 3ABARTI4HU11iH K'roph Ajlewceeom (SLI/SU]; 4e~roBCtc 143530, Mjoc- KO~t~~f OJI, ',1,Komapo~a, a. 1, KB. 9 (SUJ) [ZAI VAL.ISHIN, Igor Alexeevich, Dedovsk (SU)j, ALE- MWHHA T1rbq*ia1 JleQ011QBti,1 [SU/SUI; XMIKI 14100, MIoc~oOc~a o5jj, yn. Moci~onlcKuT, 7/1, x 33 (SUW [DEMIINA, Tatiinai Leondovnt, Khirnkl IIEflCKASI OiRoa Mtuxafuioutw S/S noq. ManlaxoBKa 140090, MocKoBcKaRI o6n, EbIKOBc~oe maocce, D. 30, JKB. 64 (SU) [NEVSKAYA, Olga Mikhailovna, pos, Malakhovka THTOB M~xatin I4HBH, [SU/SU], Mocicaa 121609, yxi OceHn~i KB. 117 (SU) [TITOV, Mikhail Ivanovich, Moscow (SU)I, BECflAJlOBA Wa~HHaj 4LMHTPIeB~ia [SUI/SU]; MocKoa 121351, KyHtuemcas KB. 229 [BESPALOVA, Zhanna Dmitrievna, Moscow (SU)J, B3HHOPPAULOB Banreliii AHTOfHoB1w1 [SUISUJ; MocKpa 123007, XopoWea3cKoeL wtocce, 34, KB, 38 [VINOGRADOV, Valentin Antonovich, Moscow (SU)I. HIOJIoHCKI'WI Bna- 'Ntmp MapKoBI4q(SU/SU]; Moci;nit 123056,yji,Kpa- PHH4a, A. 14, NB. 25 (SU) (POLONSKY, Vladimir Mar kovich, Moscow (74) Areirr; ToProl3O-TPOMbILIIJIEHHIA5 H1AJATA CCCP; MfovKna 103735, yAKYC. 1'y4Mena, 5/2(SU3) [THEF USSR CHAMBER OF COMMERCE AND INDUSTRY, Moscow (SUAj, (01) YKa3aiiIube rocyglapCTrBa: AT (enpoieprcipnfi WOTe), AU, BE (eapor0ndC1Mf rIwrewr), CHj (eoporie1ci94.

ilwreffT), DE, (epponlefcKiii flaTeniT), FR (eponej]- VKPWi IIBTeIT), Q13 (epponeiivKwth naTerni, IT (eBpo, necKH Uaref!r), JP, LI) (CHne'CK01 mUTeHT), NL (daponeo'ivc;i nMWrew), SE(eprecci Tr), US C oniqe"10t a "ie')10010POdlloA notieKe (54) Tilec PHARiACEUTICAL PREPARATION FOR CURING MIULIL SCEROSIS AND LATERAL ANIYOTROPH-IC SCLROSIS (54) Haipn1iweIOpCq i1 JIEI(APCTBH1IIHLWJ IIpEIIAT JTO814~EI-I'U PACCE11iH-Iru CK1 0EP3A H BOIOBQFO AMHOITrQ(l)1MECIjOrO CK;IEPO3A Abstract A phrMnoetlu prepartiflor' for ctring mnulttpt Iceroli~ anrd 1teral aryotrophic sclerosis contaiin$.s poptide octivo stibstanc rh olwp srtir yr)-AaGIyPhv.Leu-Ar# and4 opharmicepitical. diluentl.

t JUN, 1989 AUS1'TRAUAN APR 1989 PATENT OFPICE I 1'sobpeTeHme OTHOCflTCR It o~iaCTII eim u Jle.KapCTBenHmEfl nperiapaT =3I Aiet.eE~x pacoesimoro cxzepo- 3a x dOMOBoro aDMzoTpoc~tecxcoro ciwieposa COCTOIIT M3 ge4CTBYIOiero BeigeOTBa nen~zga cjiegyorlef cTpyKTypu: Ty.x-f-A1 a-G-ly-Phe -Le u-Axrg x epma1eBTm~ecitoro pa3daBXTeJiF.

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AT A13CPtf* FR 'Dpta ML Mtarn AIU ABC'rPanIHR 08 ra5QH MR, Woaimts BE Lojibrit Huq~ivi NO ttmamiarig~ DR Bpai tmtsi1(P KOP~kKaRI~p~o~MaHIa SD Cyai CfV LJOITPaAbn~aop 114111M,)~~i~ PeciynyJiIKa SE Wtiliq CG' 1KHro KR Kopkaq Puy6mmH SN 4lcIHatM CHi UlatEaapiisi LI AixJILTib Stl COOUIIt O Ot KamoppYi LK Hipt Jlaim D aa DE lP0PTlfptta Pootty4nitta repmamot LU 110~a~p TG Toro 1~6 Mp1~ DK gaami NIC Iaoam US C00qj1M~oIAM4lltth M4t FT NIGt~ Maarac~ap

IEDICINAIJ

2 PREPARATION FOh TREAT11ENT OF ULEE SIJEROSIS AIUD AM''YOTROPHIC LATERAL SCLEROSIS Technical Field The present invention relates generally to medicine and r.more specifically to a novel medicinal preparation for treatment of' rultiple aclerosis and amnyotrophic lateral sclerosis.

TO Prior Art At present treatinent. of' multiple sclevos'is incorrorates action on the principal ptbogenetic nehissand administration of' symptomatic drugs. In the exacerbat'Aonr stage there are instituted su~'ch medicines as corticostero- IS id hormones, stimulants of' endogenous interf'eron production (Proper-maylPoiisa) deoxyribonuclease interf'eron Hughes R.A.A. Immunological treatment of multi',Ple sclerosis, J. INeurol., 1963, 230, 2, pp.73-80). Use is also made of' drugs infliieicing tissue retaboli~n (Pyra- 2Q qeta, Pyriditol, Qerebro ly sine), microcirculation oorn7gento (Dipynidamol, Pent oxyphi llin) antiaroat~oA darugs (acetylsalicylic acid, phytin a rixtuve of' calcium and, niagnesium salts of' inositol-phosphoric acids), immuinomodtUatn&ag eiits (T-activin, Thymalin) (cf. Gu iV PI, Az'iona V. Ya. Anistova R.A* et al. Treatment of' maltipls sclerosis Patients with Tattvin,, jourmia1 of' neuropath loyand psyciiiatry named. aften K oroakov, 193 cow, 1,10atsina Publi-sher4, 84, 2, ppJ16'a-I73)G A t tlf- preeit time amnyotiropic lateral 8cleposios ha,an adequately effcaciQL1o et-4olo, ic or patjoCentit trnett,4ezit. Vnhe co-TplQem of redies ue nldsatoi dants and oa,)tance_ thlat ativate )otoin taoit thef oentral nervous011 system, as" 'tell as symptoX.a tli drtlt"0 reulatinC t1he myo~eziia tontis,, resp -aion aild cardtao aotiVityr (cf. Treatje, t of' ner'vous diseaseQs. 'Edited 1 y 2- V.K. '.Iiederlholt, 1984, I'oscow, "Veditsina Publishers, pp.

336-339 (in Russian).

The cQ'nfly adoted methods of treatine multiple sclerosis and arnyotrophic lateral sclerosis are but lovi effective a. fail to poreve t further progressing and activation of the ;,orbid~ process. On th.e othler ha-id, corticosteroids and intprferon e~nployed f'or tr-at..,ent of multiple sclerosis are fraught with unto,;ward side react aons.

A peptide of the,, follo'VainZ structure has been described in litera, ;ture: tyr D Ala Gly Phe Leu Arg (cf. Cohavk-in, Goldstein, Proc. Niatl. Acad- aci. USA, 10,81, 73, pp. 6543-6547) WithouIt reference to a posaible field. of its adctoAfterv.,ards thepre has been dete-cted. an antiuloerous effect of the peptide in question (cf. Applcation PCT/SU 83/00039).

At nresent tLore is eo-me evidence of a favourable aotioQr- Produ~ced hy the vgive peptide on the development of oxperim'entally induced pancreoneorosis (of. Georcadze A.jC., Perrniaiov NK-, Penin If.A. qt al. CQ:.paratilve assessment of- the eifeot of Contrykcal, 5-Phthorurao l and a no-Tel USsR-developed dru~g Da2larin on couz'sirn,, of expet.aerital pancreatitis, Pharmacology a-nd Toxioogy, 1986, osco%, Ile d i ts. P~jh~ (in Rssian), a~s w~ell as of its i.mmunjomod,4at ing acto Los 'as1o orra"&ov V. A.I QpOiqiJ peptides ais v iaine syutem ,,ultrs, 3t~lVi o ,-UIo IoiO 'iosearc; G7eatre tindler tho UCISI Aoaderny of 1al-i~res 97, :,!oocolv, ~edit~na ~Ushero 'o1I PP.3- XQ (in R'ussian)- '4!ow,ledsge the ie of Iall peptide fIor I.r-at,-.eont of orc-anlo la~~of thle nplvots sytri xtt2±~ ltip2,e and amyotrophlo laterfl soleroses, has.! oo foar been a~vailable, D±aclosure of thq eto The Md io.Ln&L preparzationt3 disloned in the procent iliventi~on io therefQOr a novel One all laao not been dzcqrbd inl~eaue t I 3- It is therefore an object of the present iriventicn to provide a novel medicinal preparation~ for treatl,*aent of multiple sclerosis and arnyothropic lateral sclerosis, featuring high efficacy, improving tlhe conduction of a neutral im-oulse and causinc-*no untoward side reactions.

Said object is a-coomplished due to the fact that a mnedicinal preparation for treatmnent Of 7iUltiple sclerosis a'.ai amnyo".rophic lateral sclerosis, co~nprisinL an active prinQ~ople and an excipient, according to t..e iriven-tion, in- I0 corporates as thI-e active principle the peptide havil'- the following structure: T~yr D Ala Gly Phe Lieu, Arg.

The proposed drug is aprlicable in the most dlivevse mediciLnal forms, such as an injectiori solution, d ritraniaqal aerosols, suppositories, tablets, andl others, thaou-gh the druLg is preferable to be administered as injection. solutaons with a single dose of the active principle ranginag bet*ween, I and 5 rng- Used as an excipienit is preferenitially a dilluent, viz,, a Q.9-peroent aqueous, :Taol solti-von.

When in the tablet form the drug contains prefer~ably I0 to 15 mg of the active principle per tablet, whe, reaa starch, glucose or lactose is iused preferentia~lly as an excipient fori tablets, The- drug in the form of an iritraflasal aorol contains preferably I to 5 me; of tbhe active priLncuple per- zsin~le dlose, arid ,,ay incorwporate a 0,9-peroent aqueous 1.1aGC1 solvtion ag an eOnipierIt to wich tterei may be added any h- .aaceitically accepaledtrgns ,~hen applied for troat-neqt of multiPle scl~eroas~ oar- O ried out ag i-nst t,-e bac%,7round of' a basivs t1herapy, the pv'oposed dz'ur is conducive to clinica, a-elirto of th strate of' a majority of patientS troated$ positive d!Ynamios of all a-treated functions of the 11ovvouo system an-d, molre sex'iou-9 still, d minicJing of ani increasqed m~o :wac tols 1~sePronotllod oorebellar symiptoms, a-nd better~ ftuntional I4 state of the brain stem conduction path.

Treatment of a-nyotrophic lateral sclerosis with the proposed drug against the bacicground of a basis therapy results in prevention of further progressing of the disease in a majority of 'treated patients, a positive change in the patients' neurological status, avid less pronounced depressive reactions.

The drug is low-toxic (LD 5 being 520 mng/kg) features low single- and course doses and possesses a wide therap-eutic range.

Preferred Embodiment of the Invention The proposed drug for treat-menit of multiple sclerosis and amyotrophic lateral sclerosis has been trialled on humnans under Clinical conditions.

Treatment of' multiple sclerosis with the proposed drug was effected against the bac: gzound of the basis therapy which included the group 3 vitamins, glutamic acid, nicotinic acid, Cerebroly,,,ine, TUIydocalm, sniae Th proposed druEg has been administered to patients reu~ oularlY in a dose of' I to 5 m~of' tbe active prinoinye dissolved on one mijllilitre of physiological. saline tv tiLmes daily for five days.

Treatment of arnyotz'oPhio latteral sclercIs With the4 oe drug was effectedi agaitist tl~e background of' tat; therapy which includes Qerebrolysine, Retabolil, the group 3viteains, v a 1 (tocopheirol, ac'etate), antichiolinesterase ctrugs, myorela: ants, and biOsti'rTulant-- T~he propolsed dr'ug has beea -iven to patients intravenously or iz~tramuatoularly in a doaQ of' I to 5 ",If of' ti~e aot~ve prirlciple dissolved in one rilli~itlo of physiological saline twice a day for 14 days. Aftervara5s the treat:1-ent courseo have been repeated one to three times at ten-day interlvalq, Effect of' the propooed,. drug apt, ied for treat;.t f miltiple sclerosis was comapared with the, effect Of' T-acti- Vin which wa adft.inisteved against the backc~rund of' the TV c

I

:1 same basis therapy as in treatment with the prop)osed drug.

T-activin was injected to patients intramuscularly once a day in a dose of I ml of a 0.1-percent solution for five days. After a seven-day interval T-activin was administered in the same dose for anothevL two days.

In treat:men-t of multiple sclerosis with the proposed drug and with T-activin use was made, apart from, clini4cal analysis of the neuroloc'ical symptoms, also of th-e -tethod of registering short-latont induced audio potentials res- To ponding to acoustic stiaiulation. Dynamics of the neurological sympto-,ms was evaluated in terms of points of the Ku_ rtzke's scale. An analysis was made of the sum of points on the neurologic deficiency, as well as on the disalblement scale (progress of a morbid process) with due account of -patient's social adaptation. .hen studyina6 short-latent induced audio po~tentials there were stumTmed up three thousand responses and bees reeistered 7 co.,,ponents representing the functional state of th'e following auriculL_ r analyzer levels: I auditory nerve cochlea; I! cochlear comrplex nuclei; ITT superior olivary nuclei; ITV acoustic lemniscus nuolei4; V -nuclei of the posterior quadrigeminal tubercles; VI nuclei of the medial geniculate body; VII auditory cortex nuclei. All the componernts have been ailalyzed according to the values of peak-to-peak, intervals and those of, ratios between -peak Wc~plitudes. Twelve practically healthy persons were used as tlhe control roup for- zstadies into short-latent induced audio potentials.

The patierits were exa-.ined before i~ititui4" ti te dru& 3, as wiell as 5 an~d 14 clays, after niCthr admixdstratioQn.

It shouli be noted that no ohange.- in t1 eir- nelurolo- Cical, status were exhibited by the patns admiai:stered -the, proposed drug and T-activin whithin, t 4 e r'ecent twio mionths, which. allows one to consider an ii .proVeraert in the state as the effect of the abovesaidc d'u&.

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6 The main group of the patients given the proposed drug included 24 persons (6 males and 18 females) aged from 20 to 49, suffering from cerebrospinal multiple sclerosis, the 'duration of the disease ranging from 2 5 to 7 years. The proposed drug was ad:ministered to the patients intramuscularly in a dose of I or 2 mg twice a day for 5 days. The group of patients given T-activin consisted of 14 persons (6 males and 8 females) aged from 23 to 47, suffering from cerebrospinal multiple scle- IC rosis, the duration of the disease ranging from 2 to 7 years.

T-activin was administered to the patients intramuscularly in a dose of one millilitre of a 0.I-percent solution once a day for 5 days.

As a result of treatment ofimultiple sclerosis with the proposed drug a considerable clinical improvement was noted in 89 percent of the patients treated. Practically the improvement was manifested by a reduced sum of points on the scale of neurological deficiency by 2.9 and 3.8 points in 5 and 14 days respectively after the beginning of the treatment. The index on the illness progress scale was reduced by 1.3 points in 14 days after the comnencement of the treatment. Data on the efficicy' o treatment with the proposed drug versus the illness progress and degree of severity of multiple sclerosis are presented in Table I, A considerable clinical effect was detected in a sinle female patient who was admitted in the exacerbation stage of multiple sclerosis, the sum of points on the scale of neurological deficiency and the index on the illness progress scale were reduced by 10 and 3 points, respectively by the I5th day of treatment, which in combination meant the onset of remission.

A reliable reduction of the sum of points on the scale of neurological deficiency was observed in the group of patients exhibiting a remitting illness coursing in the Table I Dynamias of nrieuroloical statug of :,atients treated with~ the nvonoce a drug with1 due account of thne type of illness coursing C'roup of ~'unber of '3efore treatmeat patients r) tien ts Sum Of 1points Index on on neutrological illness deficiency scale prog'ress sc alie According, to illness coursing 1. Reitting Exaoerbation C)Rms 5:1;on dary ;re qsing 2. propg]ressive T53. 11I7 ±1.0 10,7 T-14 4.3 ~'0.8 3.7 ;~0.4 6.1 0 to of aeveriLty sevelle -i II able I (c,7l tinued) Group of patients ber of' ent s Cn the 6th day On t:~e 15th day Sumr of points !.ndex on aeurolo-i- on illcal defic.lcn- ness cy -,cale prog~res scale Su_,i of points on .,euro lo-,cal deficiericy scale Index on illness propgrecs scale According to illness coursing Thxa- IS cerbat i on laemisil 2Q c0e C orvdary Prgressin 10,7± 1.0 303±0.5 11 0 0 9 x 314 2.ProinF,; to degree of se- 0evere 12 132-0;t 1.2- 12.4"4 1 -3~ 4, D II.7±I.l 4,0±I.5 C. 9 2. 3't o 4 3 M16 A~fxence fromt~ th( initl level. io relliablt. at th _e cent oinifi~c#c ltvej P~40.05).

remission phase (by 3.1 points) and a seconidary progressing of the morbid process (by 6.3 points). 3esides, in th-e latter case there was noted a reliable reduction of the index on the illness progress~ scale (by 2.4 points); however, the curative effect attained was a delayed one and was observed lar~ely after ceasing the administration of' the proposed drug on the 15th day of' its ap~ilication. An Improved neurolog-ical status under the effect of th-e proposed drug vraa noted in the patie-Its with t1~e mild a.,d moderately severe forms of multiple sclerosis. In tl*eP latter2? case the favourable effect ,as more markedly pronounced and conlcerned both the sum of points on the scale of neurological deficiency Fand the idex on the illness progress scale, which were reditced respectively 'bY 4.3 anid 1.2 points on the 6th day of treat.iient. An itmpro'Ivemett in the paLtients, clinical Qtate resuti*'g from the treatnent withn the proposed. drug manif es.ted itself in diminished disorders, largely pyramidal dysfuinction arid dyEsesthesia, as nelas in better furotitons of the2 brali stem, cerebellumi, and pelvic Or,,_Ltis.

Apart from clinical bett, rment thlere was reveale d the abilityr of the proposed drug to :L-mp.rcve the f'w'ctional State of the conduciitlon pathq of' tlie br-in ateen, which was detected with the aid of' the met-od Qf reitrn hrt- 9e.'Ore instituio ofIh rpsd drii the patientz oxhibited. some ohnsin ohort-Jntent inrduced aicio potentia13 appearIne; aQ airitorted aurve olhape, intiorecs.ed peakcto-peak intervA ,Itd~) reauood pea.< &-plitudoe, a,114 alt,-redl ratio betweenar piudL Dota on teef'fst Of' darti on the pvinci-p.-. charCot-riotics asscessed Nitht the i4 of the aor'ecaid method ar'e CI'ven in Table 2.

1'htis ,,/eere riotej. arairis-t thie background of' the tpoeatment with the propooed dz't4- dimiaished aoyrnt,netryr of' cerebralO hemipheres ard partial rsttoration of' the I shape of the short-l~atent induced audio potential curve. The The maxim~um effect of the druig treatment was observed on the 15th day afts-'r the beginning of the treatment coirse, af.e., on the I0th day after its cessation ,,ibre a confident increase in the ratio between the amnplitudes of peak V and Peak I Was noted.

Table 2 Effect of' the proposed drug on relative charact,.-ris- IC tics of the !-.ethod of recgisterizzig short-latent indiaced, audio potentials responding to acoustic stimulation.

EFxamination Difference between latency valUes NTO te Peakc I.TI Peak V Peak '1 Peak T Peak II Pak I '5efoQJe treatment a 2TI- 0,07 2.-49±0, 33 4-70' 0.14 2 On the 6th day 2. 22* 0 05 2,3.3 4-50f Q.IX 3On the '43t1h da 2.20± 0.06 13" 4.3 Qz± 0Q.I2X Tale£ (continuation) ,~Exaranantiot flat.i betweoen a~rnp)4tttdes t~ePeak I! Peak VJ Peak V X 3efoz'e tleat:'ent Q,75 t Q -7 I± 0 ,1*7 0.4-1± O..TI 2On the 6th aaLy OwL?4 4 0, X5 0, 94* C "T 0. o, 1 SOn tjhe Xtj aa~ 0. 67* C.15 T-53" 0-3' 0,9: 0-,2 oC±n~j±,anace 2vel (F~4 0.05).

As a re~sdlt of a 5-day course of treatment -:ith Tactivin only an insignificant clinical effect obtained? which was manifested in an unreliable reductiori f sum of points on the schle of neurological deficiency (by 0.8 point on the average in the patients' group). It was predominantly the pyramidal symptoms and the degree of markedness of the, brain stem afftect~on that were found to diminish. Such changes were observed mainly in the group Qf patients with progressive coursing of' multiple sclerosis, TO though they were not statistically significant even i-n that group (for tl-e numerical data refer to Table ).An analys s of the neurological status of the pationits with due account of the degree of illness coursing there was observed but an insignificant positive dynamics both in the patients with4 a mild 'form of the disease and in thoqe with a moderately severe form. X4 days after the start Of treao-tment wlt'4, T-actiYJnI there was noted more clear-cQut improveaient in the patients'I neurologiqEal status, The =uM of points on the scale of neurojogial defec wa e duced by 2,4 points and the inde-x on the illness progress scale, by 0,7 point on tho average in the patientofsi Sroup, However, tho aforesaid rediuotion bore the nature of atrend only and ,a therefor'e not statistically s~ii cant.

Administration of T-activin to patients wihthe 1mild and ioclerately ceve re for-mg of' multiple sclerosic dil fez'ed Widely as to eff'icacy. Thtus, T-activi-n administered to the it~om tent du4ced r -iably (by 3.1 points) S the sumr of pointo an tbesh e of nturoloE&,cal deficiency, ~owheveas its effmat on patients with modnrately seveZ'e form of the_ divca,.- was- but neli~ible!. As a whole clinical.are Jlioratiozi resultin from a Qoutroe of tr-atmaent with T-acti- Vin wao observe-d in 56 Percent of thv pa.tiento. An' anlalysisof j4sort-l.Atont lnduotd aua1io pote ntialo againsot the bacl- Frotxd of t-ativin treatmncrt h avo! evidaenoe of an unrinbj_ V 12 Table 3 Dynamics of neurological status of patients treated with T-aotivin with due account of the type of ilnea coursing GroUp o f YTuber of Bef ore treatment patients patients um of poiats Index on on neurological ilness doficiency progress scale scale According to iJjne S Couro- 1, Remitting Ea9~rba~'.

tion 2 IQQ T-2 3,5 Remissiozi 4 X ,5 T.2 4,3 0.4 ie 27 5 1.a 6.5 4' 2# IrQreoplvo 6 13.7 Z-~3 4, 3 .0 Aco~rdng to degree or soverity 1 91 Xtl a 1.0 1.7 0,4 svr,51 X$.4 7'I, 6.0 1.

Oont fnued or, pae~n 13) IV i.N i

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13 Table 3 (continuation) on the 6th dlay On. the 15th dlay Group of patients ber of0. pat ients Sum of points On nei~aologi- Cal defiQc4Lency scale Index on illpro- Cgess scale Sum o f Index points on illon nu- ness rologica. progress def.scale scale According to illnessq couirsiflg batiaon 2 9 5' I 3,5+0,5 5, 5±0,.8 2. 5±0.5 Fernii-sion, 4 13.Q 1.3' Secondryr pzo~esi~ 2 T6,5 T- 2 4.3±0.4 I.0~t.2 6,5±215 X4,5±I*5 3.5±0. 6.0±3t, 0 3.7;tI degee of' Oeve- T. Mild, 2. 11od(-rat~iy 9 _T0.5 1.1 17.i2 T. .9 Q,4 7.9 .S 2.9:0,6, 5'$ 4 Z.4 16.2±I.7 XDffrnoe fr'om the- initia&l love As reliable- at the- 301 9-pe~rxcnt sienificance level (P4 0.05)i ww o -14increase in the peak III amplitude and of' a tendency toward an increased ratio of thet peak III amplitude to that of peak I, which meant stimulation of the structural elements at the level of the brain stem pons.

'Thus, it was found,,as a result of' the studies carried out, thct a clinical effect resulting from a short-time course of treatment %ith T-activin was dependent uopor the degree of' severity and type of coursi~ng of'mtil crosi~s, and on how loae, an organic deficiency had existed.

Mtore pronouniced, improv, rrent was observed in patients with a short duiration of' the cligease (uinder three years), in those with a relatively low degree of neuirological deficiency, and predominantly (acording to o'oservat,,n fi~ndi'ngs obtained on the, 15th day of tiveatmaent) in patien~ts inte IS remisaion phase in the ca;4ef of' the remitting illness Cou~rsing. 4uch an i-mprovement onzcerned largely the pyramidal, sy-mptorns and the brain stem affection signs,. T-activin produ-ced no substantial effeot unont the iyoge-nic tonlut8 and qerebellar dyqfw -ntion. AocordinC to the dataL obtaintd by the metlhod of ve~isterine ohort-latent indxiodaiopttials, effect o1' T-activin. on the functional statn of thebrai-n tim condutction paths was di,splayed in nono-pecific stimu~lation of the megodieneephalic stiuctwz'e and was trahsient, being probably, as a rule, dtui to prooesse!s of nonpecific stimu~lation of the- organismfo acaptat4-an veactionq.

Tre-atmnent of !nultipl.e sclerosis ith e aid of te, propos-E!d dr1AC had a nwibr of advantaC-s ovnir tzieatr-,enit wvith T--aotivin, such as ia e pirc!ntag-e of ~nc~ ie liorsAtion (89 and 56, r eotively) and th- f'a~t t ouch a,aelioration' wc in.-ndn of theo dce-rt of the ilessa amvez'ityr and th-e dUrationi Of~t dis~a 'ej tr r waa note-d, favourablEe oange s ini all aisturb !d 4untiona thi nf-,r vous- oys tem (rPedtzo,-d pyrt,,nidal dyzf.uiotion and dy-rsethaa4a, improved furntiono of' the brain stm qor btllum n~nd pli B4tial1.Y valuvblc Proporty pseedby tChe pro.posed dru but not+ chaactritic o-f' T~-ctiv is isability to reduce increased myogenic tonus, to render the cere'oellar symptoms less pronounced and to improve the functional state of the brain stern conduction paths.

In treatment of amyotrophic lateral sclerosis the proposed drug was administered against the background of the -enerally adopted therayicungCrroyn, Retabolil, the group B vitamins, vitamlin. E (tocopherol acetate), antiacholine st erase agents, inyorelay~ants, biostimulants, and th",e effect of the proposed drug was compared.

with that of the aforesaid complex of mredicines alone.

A- clinical pictuire of the ci; ease was the typical one for amyotrophic lateral sclerosis, being oharacterized 'ry the syrnptoma of a combined affection, of the anterocornuaJ.

IS and bulbar nuclear structuries and of the pyramidal conduction paths, the supranu~olear one icl-sve On the ground of a c2-4inio-anatomical. cifference, viz., pr~edominant affection of the anteroaorniaa. end bulbar nuclcar structures or pyramidal conduction pathis, as viell, as 2o the, initial disease symptoms, which aq a, wholle orrespond~s to a definite anatomioo-topoeraphic level of the ONS, there are recognized the following fortis of the disease: aerviothoracI lunbosacral, b tlb4ar, hgand the so-call0 p0lyomyitjic vmrsion.

The principal group of patiezits given the proposed drug against the hackground of a nomspecific tlhe-rpy ilriporated 62 patients affeced by amyotrophic lateral scl.erosis (39 malesa and 23 femalos) ac~ed fC,,rqm 2Z to 65 with the duration of the d,easoe from 3 monthso to 4.5 years. 28 patients 1Q had the Seneralized form of the diseas? 14 patients, the oervicothoraoic forma, 7 patients, tbe lumbosacral for~i$ IP patients, the bulbar 44d one Patient had the high fo-rm of amyot3rophil~aata'ral oltroa'-is.

The propo4ed dz'uj was ad:m-inis-tered, to theo patients inlin a dCose Of I oil 2 Mg twi ce a d y f oz X4 da 16 Whenever it became necessary the treatment course was repeated.

The croup of natients affected by arnyotrophic lateral sclerosis and given nonspecifi~c treatment consisted of persons (19 mnales and II females) aged fromr 24 to 68, the disease duration ranging between 4 months a-nd 5 years. ,.s for the degree of severity of the, CINS affection the patients of the control group did not differ substantially from those treated wit'li the proposed drug. 18 patients had the generalized form of the aisease, 5 patients, the cervicothoracic form, 4 patients, the lumbosacral form, and 3 patients had the bulbar form of amyotrophic lateral Sclerosis.

The results of studies into the effeat of the proposed dru~g on the coursing of aryotrophic latoral sclerosis are pres.,ented in Table 4.

Effect of the'l proposed drug and of Table 4 nonspecific therapy on the coursing of amyotrophic lateral sclerosis Treatmen-t N~umbe r of' Improvement To Progreas- Prono-, Mode- ig of diapplied patients chnei unced rate chnesease Proposed drug plus 62 8 16 28 11osei fio thxerapy (100%) (I6M fic therapyT 30 1 6 23 80011) (77%) As oan be seen from the above Table no symptoms of fther pmrcsaifg of thm diaease were rev7ealcd In a majority of the patients treated with, the proposed drug, In 52 Persons (84 percent). Only 10 patients (16 MW I: I i I Cr*--FL 17 percent) exhibited progressing of amyotrophic lateral sclerosis, while in 28 patients (45 percent) their state remained stationary, and in 24 patients (39 percent) there was noted an improved state.

Positive changes in the neurological status of the patients affected by amyotropnic lateral sclerosis were characterized by an increased force in the paralysed limbs resulting in a greater scope of motions, less pronounced bulbar disorders, including dysphagia and dysarthria. In some patients there was inoted improvement in the respiratory process accompanied by an increased vital capacity of the lungs (by IQ to 15 percent). In 8 patients (12,9 percent) there was noted a higher degree of amelioration manifested itself in extended motor skill, resulting in an ability of the'patient to take meals and seat, and even to walk within the hospital room unassistedly.

It is worth noting as an important fact that a great majority of the patients exhibited less pronouned depressive reactions against the background of administration of the proposed drug.

Positive changes were observed predominantly in the patients with relatively shorter duratiO.n of the disease (under two years) and in those patients whose clinical picture was featured by prevailing symptoms of affection of the pyramidal structures and the cervicothoratic spinal cord, The majority of the patients of the control group (23 persons or 77 percent) to whom the generally adopted complex therapy of amyotrophio lateral sclerosis was instituted, exhibited further progressing of the pathologic process, whereas in only 6 patients (20 percent) there was observed the stationary state. In one patient (3 percent) there were noted improved neurological symptoms, which incorporated some increase in the scope of motions in the legs and ability to walk due to a reduced spastic tonus in the muscles 1 -1 18 of the lower extremities. In no case there was observed a pronounced improvement in the patients' state accompanied by increased motor skill.

Thus, a comparative analysis in the state of the patients of both groups those treated with the proposed drug in combination with a generally adopted complex of medicines and with said complex alone) demonstrated that progressing of the disease was noted much less frequently (4.8 times) in the patients given the proposed drug than in those of the control group. The stationary or improved state was developed in 84 percent of the patients given the proposed drug and only in 23 percent of the patients in the control group. Moreover, none of the patients of the control group developed a pronounced improvement of their state and increased motor'skill, whereas such improvements were observed in 13 percent of the patients treated with the proposed drug.

The findings thus obtained give evidence to the fact that when used for treatment of amyotrophic lateral sclerosis the proposed drug promotes inhibition of further progressing of the pathologic process and conduces to a improvement in the patients' state.

Thus, the proposed drug exhibits high efficacy when used for treatment of such grave neurological diseases as multiple solerosis and amyotrophic lateral sclerosis. 89 percent of patients with multiple sclerosis treated with the proposed drug developed clinical amelioration, whereas only 56 percent of patients treated with T-activin did so, Besides, the efficacy of the proposed drug did not depend on the degree of severity and duration of the disease.

Moreover, the proposed drug manifested a quite novel property when applied for treatment of multiple solerosis, viz., ability to improve the fnctional state of the brain stem conduction paths.

High efficacy is exhibited by the proposed drug when 1 '1: 9 used for treatment of amyotrophic lateral sclerosis which has not so far had any pathogenetic specific therapy and is characterized by a steadily progressive coursing ending in a quickly set-in lethal outcome. Thus, application of' a generally adopted nonspecific therapy alone brought about stabilization of' the morbid process or clinical amelioration in 23 Percent of' the treated patients, whereas combined therapy usilig the conventional treatment and administration of the proposed drug resulted in that 84 percent of' the patients, the absolute majority, developed the aforesaid positive results, and in some patients there was attained a considerable deglree, of' improvement manifested itself' in, extended motor skill.

N'o untoward side reactions a.re obse_- ved during treatment with the Proposed drug. M~edicinal forms of' the proposed drug are prepared according to commonly known procedures.

The active principle of~ the proposed drug, can be synthesized by the standard, techni~ques u-ed in peptide chemistry, in, particular, by the method of stepped growth of' the puiptidc chain, beginning. with the: C-terminal free arginine, with the aid of' activated esters of' protecated amino-acids, through the following interme~diate compounds: carbo-b ,.nzoxy- Jleucylarginine; carbobenizoxcy-phenylalanyl-leucylarginine; carbobenizo.y-glycyl-phenyalanylleucylargij~ne; carbob enzoxy-D-alanyl-glycyl-phenylalanyl-le.,euylarg~njn~o carbob enzoxy-O-b( I nzyl-tyro syl-D-alanyl-GJlycyl-phenylalany,- To pr~omote understanding of thm prnajent invenztion given below is a detailed description of somec specific exemplary clinical trials of' thea propoised dlru.g to illuistrate the efficacy off its application.

Exam~rple XI FerIle patient 46,t the diagnosis being one of 3MIfultiple solerosiu in t1le cerebrosp~nal, form and with progressive coursing. bisease duration, 27 years. The disease runs with alternating exacerbations and remissions and features steady progressing of the morbid process. The p ati-nt is assigned group I disablement.

Neurological status on admission: affected visual acuity; smoothed-out nasolabial fold; nystagmus, difficulty in food swallowiiig; lower spastic paraparesis involving motor restriction in the talocrural and knee joints; bilateral feet clonus; -pathological pyramidal signs; the pa- JO tient could not walk, muscle strength of the arms reduced t'o 3 or 4 points; bilateral Jacobsonts and Rossolirno's reflexes; pronounce-d intention when performing coordination tests; truncal ataxia; deep sensibility disturbances in the legs. The sum of points on thez scale of neurological deficiency I8) the illness progress scale index-, 6.

Study into short-latent induced audio potentials revealed the symptoms of the braiin stem lesion; electroenceplaalogram of the dis-ynchr.onous type, On admission to the hoFspital tIe patient was presaribed vitamin B 1 1 glt' tamic acid, 4Mydocalm, shr-ietreatment cottrses with Pyracetam, and, Essentiale. Thnn a f tveday course of treatment with the proposed dru~g waz3 instituted, which was administered in a sin4gle dose of one! mg twice a day.

Upon the treatment qourse with the proposed drug the mus9cle strength in the legs incrnased, the cerebellar dysfunction became less pronotmacd, &as Nfell a.s the brain stem afotion symptoms. The sumr cif points On the eroo gicaj. deioienoy scale 10, th,- index-- on the illness progress scale -4 The pati n~t v/as able to wal1 with somIebody's help; there Were noted positivt changes on thT part of EGl and short-:Latevt indiced audio potentas Exampl~e 2 Male, patient K. I 20, thle diagnoslis being one oaf nultiple socrosis in the* feezopia.orm and r'emittinc -21coursing at the remission stapge. Disease duration 6 years, starting from the right-side hemiparesthesia. Afterwards the disease runs an undulant courhing attended by cerebellar symptoms, lower spastic paraparesis, brain stem symptoms, dysopsia, dysfunction of the pelvic organs. The patlent is assigned group III disablement.

N~eurological status on admission: reduced visual acuity in the right eye; diplopia at gacing to the right; nystagmus; lower spastic paraparesis involving reduced Io muscle strength down to 3 Points; bilateral increase in the tendon reflexes accompanying, by pathological pyramidal signs; truncal ataxia; intention in performing coordination tests; the patient walks only ywith somebody's help; dysfunction of the pelvic organs; disturbed vibratory sensibility in the right limbs. Thd sum Of points On the neurological deficiency scale T1 the index on thei illness pr'ogress scale Study into shjort-latent induced audio potentials revealed the symptoms of the bvain stem lesion.

Consderale dfftusion changes appeared on the eeton ce!phalog-ram.

On AdmIlssionl to the 1hosp!tal the patient was given vitamins B 1 and B 6 and glutaniQ acid; lie received Cerebro- Iysine for one month and was tr~eated witlh 91!ort-trme Qo14' sez with, M1ydocaltn and Esocntiale. Then the patient Was preoc:'ibed a five-day course of tzveatment with thi proposed di~u~g administ-ered intramuscula~rly in a sizigl!! ttose of 2 mg tviqe a day, After the tz.-tn'-n cotirse with t.11 prop~os-ed, drqeg Cerebelar ysf~ict~n dsapea ed completely, ml-otor dijturban subsided partially; the patient walkced linassistedly and auz'eIy; there wvera no aensib~li ty di tuz'bance-; diplopla reduced consdira1bly. Positive oha.ngeq ,Ver* displarec ori the n-*BG and .5hozt-latent induoa audio potentials. The sum O~f' Points Ola the soale of neUroloicvl, deLJ.Qienay the nde.z oif the Illn-mo progreas aoalc

WV

r 4 It 22- Exanp Ie 3 ,Male patient G. 50, the- diagnosis being one of aflyatrophic lateral sclerosis. ThI'e illness started f-om dysphonia which was attended, several mionths later, byp dysphagia. The patient's state aggravated proE-ressively. A year later there wmre develored myasthenia in the legs and the left arm, as vell as respiratory disturbances.

IT-urological status on adminssion: anarthria; glossal aldnecia; dysphonia; th e patient could, not swallow soonta- Tc neously; the- soft palate iznmorable; facial ,.qyasthenia. Tetraparesis (largtllr corcerned with. the arms) with dyskinesia in the hUMerval joints (to 4 points). Masthenlia in theM legs (to 2 points), the, patienrt wallking over tthe hospital rooma with difficulty, Generali~ed muscular hypertrophy and fasin the mscles. Uigh tendon ro~lezep, bilateral pat .ological aigits. Stensibility and funotion'so the pelvic org.ans unaffecte-d. qaic%, shallow breathling; re-duced cotugh :impulsn. Vital capaci~ty of thei lungs Z.32 litr (30 Percant of tht normal).

2Q Under hospi~tal conditions, the patin was ven tre-atset wiith the group ~3vitamin,j 04rbarnazepin, deoy2ibunuclease, Y~ydooal Thn he patienit was ad:-vn stere-d, against th ,e bac~cgr'ouid. of thle aforesqaid therapy, oropoced azu.

given intrazularJly in a dope of I m[ diluted with a 0.qqueotus Ya~l soluti±,n twice a day for %-ecks it succeisioui. After a I0-day interval thle Qour-- of~ trea- -tment with- th- pvoose.d :drug was rconated, As a r!!2ult of t1.e ahov.es-aidtatt the auol atrength in th ~et~ arms &.nd lo r gre so that part- Osi~s dr oppe!d dovin t1o one poin-t aM-, to ztro,retvly the patient ooculd wakbeyrond the- hospital. t rrt-tozy andJ Fo up and down thm ti'~fsds tq faie. Q~l p rmn so0Me spontantoUa 4wallcwin- motions, 4 vXIIP3.e 4.

gale Patient S,i 41, the diknoos-q beta- on,, of tuotvopic j 23 If lateral iclerosis. disease began wiivocal hoarseness, whereas myasthenia in the left foot appeared 2 or 3 ,Icnths later. Afterwards t,,v as developed -myesthenia in thle arms accompanied by pain in the left ar-m, as ,,ell as mouscular atrophy in thv shoulder girdle a-nd art-s, and diffused muscular twitching. All. the phenomena mentioned above piogressed. and were attendiqed, within th1 e cent half-year, also by myastlhenia in, thr legs anid dyspnea.

Neurological status on admis.in hoiona ysan IC mus; dysarthria; tonel~ess voice, tho patient could spmalc incessantly for only 5 to 7 minutes. When takine, rraeals the patient cou.ghed interm-ittently. Iaresis, of the soft palate.

Facial myasthenia. Tetraparesis, more pronounced in the distal portions of t: e gs (to 4 points). Fibrillation of the glossal musoles '7ling was daifficuJtj the patient could not go up the, staiLrs. Reduced tenson r'eflexes, Sens:ib ility and Luncti'ons of the pelvic orEgans unaffeacted.

Ujnder Hospital conitions the patient was assig-ned.

therapy with vita-nins B6and tocophero]. acetate, Carbamazepin 1 Baclophen, Retgbolil. Thereupon the patie-nt was administerdagit the baclc round. of the af'ores~aid therapy, the proposed d: ,ig g-iVen intramuscularly in a -dose of- 2 :nC diluted with a 0.9l-percent aqueous 'Na~l SOJUtion twoV tim--es daily for two weeks in s-i-jaession. After a IC-day in- 25terval2 th couirse of treat-mezt wirth the prornoced 'ru, was repeated.

Theq poatlertt-s $teato was irmproved aa a r5512.t of the treatment condtuted.: theI W1ecle strongt in th roial portion3 of the less and ar,48 inOVeas48( so tll-L-t degroo of paresis dro~pped d.Qvin to zorQ; the pattent could Vo up and down the staira, h4", voice beo cleaz'er, the mobility of the Coft palate s~menewhat onreac-ed and dy, arthzria wao x'edto- Ed, with thoe resul t t "It tl'e patien~t col'ld spakl in-.ceSsantly muAh )lcngez bE~incE practically not vrest oted in holdino. C' A4V~ -24 Exam~ple, Male poatient the diagnogis being one of anyc,thropic lateral qclerosis. The disease be-an. with myasthlenia in the legs durin-, welJx~,. Five month.- later there appeared~ myasth4,enia in the fol"Lowed by dysphonia.

The patient'Is state 'vsimpaire 1 progressivelya.

ANeuiroloEgica. statuis on first adnlis.zion; Idysarthria; Paresis, of the sor t Palate; tet raparesq, more pronouwnced in the aris (4 PQirlts); muzcidlar hy:)otrophy in the arms, and thLe shoulder, girdle; high tendon reflexes; bilateral pathologixal signs; diffsed, fasciculatixnu; sy..iptoms Of orlatoaim 'niility and T,not~on of t+,e pelvic organ s unaff'ected.

tUnder holspital Qorajd4ots the patienrt was 94bjQotr-d to therapy wit-'- vitam~ins B I and B 1 2 1 Pyraotari, Carbanoazepin, rtibonucleio ac~d. Agaist the: baccgroil-d of the aforesald treat-.,ent t'he ntixnt wadinistered the )ronoSed dri~g -i.,ven itramntisctilrly i,n a dose of I diluted w ,,th a Q.9-percent actueous 'TaO) solutlon tlwo t ,ge, da~ly for two weeks in siuooessiori.

.As: a result of thie treatment conducted the ,,at ient Is Otate was improved, whioi mnifesteo1 itself in a-n inozroased, muscle ,tren th in thre l.ees co tlhat pnnres ix :Ain-shed from', 3 to I point.

On dicmzaal, the )atiprnt ncyted no L ixps-.ient 4 Otate f'or 2 or 3 month-s, whereacm t1e_reaftez1 tpeoc.1 dittur- 1 ance antd m a t n a in thc,. a= 0 appe .red achixL 'w Vatod1 byr a oc naaoerb'.z2. injUry, StPtu- or, Cec xv3ary adminsion; dysa-,+1ria, dysphapi fibrltlation of tl sa mwxclee.

701'r PatIt le ulc1 Croak"I x'thOut OtOPp±i,% -'Qr OnlY2 or 3 lin t! di±t4 or-ln (Up to 4 point--), involvinL- r e s9triotod ad1cliit-,n of' the" finger,- and theo-r z' t e n2 ".on and ±nPOotbi2%ty of~ opoo7,ton of t*h0, firWt dii toth fth one in the 4,h ad a't~ pt w onoi the az'l; the palt-ont 0ould wa).k whout peat 0z ~'lc tance of up to 300 mn. 17uscular' hypotrophy in the.- 31,houlder Cirdle andl the arms; diffused fasciculatiois. Sern;bility a~nd functioilo of the :)elvic Qr-Fms ur.,affected.

Ajeainlst the bac~cground of a, therapy with the group -a vitamins, vitarmin Carbamnazepinj Pyprtcetan and laclop~jn the patient was pres-cribed thie proposed dvrg U-ven Jintraraus~ulzi;rly in a dos if I mg, iutedwiha09pr cernt ao,4eotis Z'aC2. solutjon two times daily for two wteks i~n succession. Afte3r a IQ-day iatex'valteces Ltet XQ ment with thae proposel drug was :repoated.

As a result of the treat:.1ent itt dteewsnt ed inc~reased qU,,Oj.~ strthi the 14nPaei i h lesa dli-inishe tozr;te patient was aWe to -alk ,vitlcut rest for a di;stanoIe of uip to 1. 5 km ~1,Iculr st.-eng~th I n the armTs ilnceased, the _-)tient could pevform-, adduti-on and extension of the finger's. 'Dysarthria decreased1, tho patient cooil opeak incesenty for much lonrer time, boe.ing praiially naot _vstrlcotd in h1,oldqnc- a txa~s, tal'c.

The medicinal pZ'epOatiaf accordin- to tb,.rese~at in- Vleflt-1O hao found appication in, nelurol- +r tr-:itmeit multiple scerosiq and amotrophic 1LtQe-'aI.~ero

Claims (3)

1. 2. A method, according to clai. 1 Wherein the peptide is administered in the form of an inject-ak]e solution. A method according to claim I or 2 wherein, the pepti~de is administered, in a concentration of I~ to 5 mg/mi. A method according to claim 2 or 3 wherein the 0:7 peptide is administer-ed in a 0.9% a0QUsts NaC2. solution, I 5 A method according to cl.aim I. wherein the peptide is administered in -the -form of a tabolet. s" A method acqordinq to cl.aim 5 wherein the peptide is in an amou~nt of 10 to 15 mg per tacblet.. 7, A method according to claim 5 or 6 wherein, the tabe further omprises starch, glucose Or 1zkctose. 0 A method according to claim 2I wherein the poptide Is dministbred in the forM of intraa$AI. aerosol., 9, meho a o dng to p~lain 8 wherein the pqpt~dQ is admini.stered in an, amrounht of I, to 5 mgj per single I 2 7
2. 10. A method of treatment of multiple sclerosis or amyotrophic, lateral sclerosis substantially as herein described with a reference to any one of examples 1 to DATED this 26th day of February 1991 VSESOJUZNY KARDIOLOGTCHESKY NAUCHNY TSENTR AKADEMII MEDTTSINSKIKH NAUK SSSR By their Patent Attorneys GRIFFITH HACK CO 0S* 9 *9 9S 0@ 9 9 S SO,. 95 9 a. S. 0 ~2 5
3. 555. S. 9* 0 a 95 9 9. 4 3Q 6t 9SO 99 9 9 95 99 025S/tLT INTERNATIONAL SEARCH REPORT International Application No pcr-/sur RR1OO162 1. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, Indicate all) According to International Patent Classification (IPC) or to both National Classillcation and IPC TPC 4- A 61 K37/02 1t, FIELDS SEARCHED Minimum Documentation Searched7 Classification system jClassification Symbols A41 70 IPC A6 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searcheda 111. DOCUMENTS CONSIDERED TO HE RELEVANT' Category citation of Document, 11 with Indication, where appropriate, of the relevant passages i2 Relevant to Claim No,' A W0,Al,86/00622,(VSESOJUZNY KARIOLOGICHESKY TSENTR 11-6 AKADEMII MEDITSINSKTKH NAUK SSSR)30 January t 1986(30.01.86),see the abstract A WO, Al184/02470, (VSE~SoUZNY KARDIOQLOGTCHE6KY TSENTR AKADEMIJ MEDITSINSKIKH NAUK SsSR) 05 July 1984 (05.07.84),see the claims cited in the description Sir GBAf 2141627, (03.01.85) 'Spe'lj categories of citedt documents: is 'IT" later document Published After the international filing date document defining the general state of the art which Is not or priority date and not in conflict with the, application but considered to be of particular irelevance cited to understand the principle or theory, underlying the IIE"earr dcumet bt Pkillhedon r afer he nteratinal Invention arler ocumnt ut ubl~hedot~or atertheintenatona "I document of Particular relevance, the claimed Invention filin datacannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or Involve an Inventive step which is ctied to establish the pubication date of another document of particular relevance;' the claimed Invention citation or other special reasont (as specified) cannot be considered to Involve an Inventive step when the I'0" document reering to Ani oral disclosure, use, exhibition or document is combined with one or more other such docu. other Means merits, such combination being obvious to a pers ,on shilled 1114 document Published prnt to the Interilonal filing date but In the art. later than the priority date claimed document member of the caine Patent family IV. CERTIFICATION Pate, of the Actual Completion of the International Search Date of Mailing of this International Search Report December 1.988(20.12.$8) 28 December 1988(28.12.88) International Sqarchlnu AttortY- Signature ot Authorized Officer ;t$AU Form PtOT/tSAI2tO (sec 11h1e90 (January 1985) 000? -1 or Ol ,LAu' UUU *~ltI 02M14% Ii* flS/V% I i -AI* 3IMHI OJO4wwbkmCo*4trOj "HUVOU HU mocpo VOH~OU dtm~twofl 0OXI H O04Hbo hoR8Lh W~b4rnowgagU i41oAHotf osiidnmA. vti tn o 1 on -mhtv~~ou 1044X01 1J.tvVD0 t"R4,WV I jHnjtMH .%XJ4M01 1919V OVt t390)4HH~pAu 'IHeklx)40V d~' *u~cbu oSotnt9X'8LtgO 'UhNi iiVrV C)HVHBae lq V 1 4, ao4ei:±iq9 c*w4o~msd Ow3wvov SH4M8±0hOD 0X1u '014N0090CH o~oxAHW loHkimdHod Artokio x wU)H~tuEookio IH~gap0v 'os ,OhIM RHeOUdA q~i~doIi*odoU jiii -0400040 M0400OU Hl49I HII NMuM MH0 looV4me)xr 14HHVJA~hO 11 LWUYIANIOV 'Yg4*0U kjsojbdU H4 A di s~i owe w O+ IviNW34oV ~oV*Hoq~ oi -eMOKtO 0OXSHut9 00itbP914 0H1hUMMH j Jq4)V .A OjpdV wom$vUHIq~u FmitV ewuoe~e~gi: o~qii.i z irwodx woiwvoawdu 140dOoNo wVH 'isimcowdu VM (uOHN nH~te~t1ed~~M 4~H0H mW~wo e "U 0m"H04nO3 M"VOB6OU '114W'tA)40V .1j Q44HOI~dPotO GOHH0UianCIODWOHU &kNViOdu 34 6414 1SO4 evU -OfliO~lO eOOHHq O~uo94v V~40mmmgq lmomhi~oV HMH HhVVou ODHONdekAtften A±Ut? 314 lqwwnHoe ioHO~d-0oH jrNOW emOlo YndoimH u4 '44d -AIrpAUo oN Hena".NOV L4MH1Hilo±U iHNud emutop 03 -001 H1 UHhH~du ONN~fl$OU VIWV 1MHeVeudu ON 4 AxMuc MHrT13hbdou q4 H V!1H1dolidU inVA U)o44ou Kientrdu Nl IHHSomio HkgH mhVVOCt mo4HA)+oli mqRjrV O JO24I4II oj ~eH sOpH isaoH e4 "4'dolom ~fl MW~ue0omWuqAuo #.woA~iob p4,ftwu qelioD La -xei. qHeuoM em~po ymH t1qije~u'o .LHOtA)40t eve o904awVdA~ )(ihum midoje±3Hi esp-z (mmolu6 a ~i 1 &Sd diowo I(9eO 0) 9861 BrEI 0 cOOD HIXVJ X14O4T/qtCm FIEM~V1 d~llt KI ~V1 p~~ohJIt~l&) pII3oDO) .9 V WA V 9-1 zeda ~Had xdo o(q8j~Od C 94 H dvaHN0C ry)iOHou KL~vv1adUi N so!I1~flOHIO fqIHDWANOtV '11 qioL~ipo e .lHitOX8 rHo O~qVDNO)LH 'eden Hol 9 'HlbilHeywA)sol1 MAIMMHHM 0 ILsIMBHV'0X9 e H IW)DHOU MUUNHh!9X0 'MM3IlenANDt! 901 I H 19 V V4hA mNi4dplAd SOqHMOH~m)442H3mu'} Z£nODHOU M4OHMHLh38XO 'HH~rM.I49lA1OV MqA1HHHVJ YNIDNOU MIDVU!O f g,0/a~ H1119 V M 9 "M HVM HHw )43!edos tiH .4H~reV~1~4H!f4 o Omn qatoo ,(eOI eiH)4{E)A 9aO:)4egtHH XrqHHOH1 H4epm:D3IrH onquf0)me" imoN4eHo du 64tr3e) 54UMdOCH YINI 9gO 5Yri~C)IM 3YUN I XDHOU YfOHt1OdVHAV1XKaW 0 13' 10 I I ?Jt