MEDICINAL COMPOSITION FOR THE TREATMENT OF CERTAIN NEUROVIROSES

Abstract: The pharmaceutical composition as per the present invention, formulated as injectable solution, is composed of the calcium and sodium salt of the ethylenediaminotetracetic acid, associated with calcium gluconate as a source of Ca<2+> ions and aminoacid, preferably cysteine, or a tripeptide-glutathion, the association ratio for the three ingredients being 8...12; 0.3,,,1; 0.05...0.2. This drug has a specific curative action in the treatment of certain neuroviroses: Herpes Zoster, herpes, encephalomyelitis, multiple sclerosis, polyradiculoneuritis, cranial nerves paralysis as well as certain types of dementia porphyriam Wilson's disease. The mechanism of action is based on the antivirotic action of chelators manifested by the modification of the equilibrium of metal ions involved in viruses multiplication and by the restoring of certain lesions of the cell membrane and, implicitly, of certain neuronal activities, through fluctuations of the extracellular Ca<2+> concentration. This drug is also effective in the autoaggressive processes, as it has a strong anti-inflammatory and trophic action. The calcium and sodium salt of the ethylenediaminotetracetric acid associated with calcium gluconate and cysteine is not toxic, if the prescribed dosage is observed.

Description: LiSDICIKlL OOLIPOSICIOK ΕGΛ TES TPi' Ii i-T OP CESS AIS LϊaϋSOVIROSS gJaofac_j-pja_ __j i 1 d he present invention refers to-.a medicinal composition for the treatment of certain neuroviroses; Herpes Zoster, herpes, encephalomyelit is, multiple sclerosis, poly- rεαiculo neuritis, cranial n rves paralysis as well as certain types of demεntis, porphyria, Wilson's disease. Be^^r ^ o^d ^ Ar^ Certain pharmac utical preparations are ow to be effective in herpes Z'ster, the antibiotic Syfamycin or the immune stimulating agent Isoprinosine (Lesourd B, Loude ϋ. Lleunier P., Dou erc P, Moulias H., - ϊraitemεnt du sona Zoster par isoprinosine - La nouv.Presse ϋo die ale, le 23 ganvier 1932 II nr.3, p * 191) and other chemothΞrapic compounds such as iάczruridine (Juel Jensen B.£. -Treatment of Zost-ar with idox - uridinc in ' iniώtylsulf oxide: result of two blind control trial 3r.Med.rJ.lS7o (4) p.776-780) cytDsine arabinosid-s (Pierle L.-li'. - CytosiDβ arabinoside for herpes Zoster - K.Snsl...ied. 197 , 29o p.40-- 10) and adenine arabinoside (Whitley E.J. et al - idenins arabinoside therapy for herpes Zoster - K ' .ingl. J.lύed. 176 - 2S4, p. 193-1199). Isoprinosine has a slow curative action upon Zoster eruption; its effect upon pains is practically insigni¬ ficant. The o ter substancc-s-idoxunidine, cytosine arabinoside and adenine. arabinoside ere αontraindicsteα on account of side effects. The antivirotic action of several classes of chelators has been ascertained as against a larg-:? εp-ctrum of_ viruses (perrin D.J . and Stiinzi H. , 1981 - Pha mac.T er . 22, 55 io in vitro studies or in animal studies; even certain compounds of the class of thiosemicarbαzon-ss were proved to be active " in the prophylaxis of chicken pox in an epidemic i Liaαraε. In our country, Gh.JJ.G-rigorescu wrot- (in 1955) t at di crceptc— ropanol (DI-IP; BϋL) is effective in herpes Zost ' r and in some other viroses (1973) ; however, Dlϋ? is not indica ted to humans owing to the fact that tiαe therapeutic dose is superposed on the .toxic dose (L. Goodman, -3 pharmacological basis of therapeutics, lyδo Ed. .G-oodman, .(iilman). The detoxifying action of ' the ethylenedia i -teiracetic acid is well-known; this product is used as an antidote in poisonings with b and trivalent metals ; its mec nism of action is explained by a cheiating process. The cheiating action of the ethyle edia ino tetracetic acid- and of its salts with various metal ions is dependant upon temperature, pH and the Sjjecific activity of the cheiating ag nt expressed by the stsbility cons snt of t resulting complex. Its antiviral effect has only been proved i in vitro studies on some viral e zym s-the polymerases of vi ral nucleic -acids and the nsuraminidasse of the A flu virus (Perrin D.D. and Stiinzi H. , 1981, Pha mac.Ther.22, 225)- who activity was inhibited by the ethylenediamino-t't ce ic aci thus, viruses multiplication and their penetration into cells was prevented; however, this cheiator has not been as ydt us in antiviral humma th rapy. Thε prior art.do≤s not mention pharmaceu ica or medicinal compositions meant- for antiviral therapy with t ethyiensdiasino-tetracetic acid as tiieir active ingredient. disc osure of β-^∑^ _"^,--5_-\ ■ The composition as per the prese t invention, formulated as injectable solution, contains the ca l cium an d - - 4 sodium salt of th ethylene diaι ino-tetracetic acid, associa- ted with calcium gluconate as a source of Ga 2+ i aons and -, a a inoacid (preferably cysteine) or a tripeptid (glutatnion) ; the association ratio of the ingredients is 8 .... 12; 0.3 .... 1; 0.05 .... 0. . Tjtie advantages of "σhe preparation as per the inversion are the fallowing : - tne aru lBS a specific curative effect in herpes Zoster, herpes and some other ne oviroses j cranial nerves paralysis, enc phalomyelitris , multiple sclerosis, poly radic lo euritis as well as certain types of dementia porphy- ria, Wilson's disease, - the use of cysteine and the ethylenediamin tetracetic acid under the form of double salt of calcium and sodium as chelauing agents provides an anti-in lammatory and trophic and antiviral erfect, ensures a rapid difzusion as we as a unixor disτriDution in tne tissues. Since it is not met bolized in rhe organism, the product is rapidly eliminated (5 a wichin the first hour from i.p. administration and 100 % within 24 hours in rats) . - the ϋa and Ca double salt of the ethylene- diamino-te trace tic acid and .cysteine are toxic ity-free in the dosage pre- scribed for the above mentioned neurovi otϊc disor¬ ders . •^ejg ^ le ^ l The composition of active ingredients for 100 of injectable- solution as per th? invention is the following : Calcium and sodium salt of τn in & ethyls edia ino-tetracetic acid Calcium gluconate r . -- Cysteine hydrochloride 0.1 g Distilled v.ater ad 100 ml In about 80 ml of fresh distilled water, dissolve, at 80 D C, th-? calcium and sodiuπ salt of the ethy- le edia ino-tetracetic acid and then 0.5 g of calcium gluco¬ nate and 0.1. of cysteine hyd ochl ide; add distilled water to I0Q ml, then filter through a Hiliipore fiitre. Divide the filtered solution in colourless lo ml ampoules; sterilize by keeping in the autoclave at 120 for 3 minutes. Exam_le2 The composition of active ingredients for 100 ml of inόectabie ' solution as per the invention is the -fol lowing ; Calcium and sodium salt of the 10 g ethylenediamino-tetracetic acid Calcium gluc n-ate 0.5 g jlutathion • 0.05g Distilled wator ad 100 ml In about 80 ml of fresh distilled water, dissolve at 80 C the- calcium and sodium salt of the ethylene— diamino-tetrεcetic acid, and than 0.5 g of calcium gluconate, then add the gluthation, previously dissolved in 5 ml of dis¬ tilled water. Idά water to 100 ml .and filter through a Hilii¬ pore fiitre. Divide the filtered solution in colourless 10 ml ampoules: sterilize by keeping in the autoclave at 120 G for 30 minutes. The inject able solution as p'- tha inven¬ tion should be intramuscularly εdministered, 10 ml in 24 hours, ovc-r a period 6-7 days. The hypotheses on the φechanis of action of the pharmace tical preparation as per this invention are based on several recent studies that have proved that the metal ions in the organism are both directly and indirectly involved in the synthesis and metabolism of proteins and virel nucleic acids. The chelation of several such ions by the chelators in this preparation inhibits viruses multipli¬ cation through the modi cation of the metal ions ballonce. Besides hindering the process of virus mult plication, the chelators in the c ain-d pharmaceutical prep ration also act in viral and autoimmune disorders - such as multiple sclerosis whose etiopathology is still unknown ; they determine the fluctuation of plasma Oa 2+ , thus restorin certain lesions of the cell membrane and i ylicity, certain neuronal activities. Consequently, the drug may be also effe tive in checking such autoaggr-essive processes. The asociattion of cystein-? to ethy -'n^dia tetr£?c?tic acid has a synergic effect upon the latter 's chel ting action, since c steinε- itself has the ability to fixate electrcphilic agents (cations) by the thiolic group, ko-tfe.-; over, cysteine has the property to form, with some transition metals, hardly soluble complex combinations in with the- nitro gen atom is coorάinativeiy linked to the metal. The initial exp rime ts on the effect of the ethyienediai-iino-tetracetic acid associat e d with calcium gluco nate upen certain n-r. uroviroses hav only -pointed out a tempo rary r e storing of the nc-rvous influx; th-~ association with cysteine has resulted in a long-lasting remission ofl rjaralysi in multiple sclerosis, a strong anti-icf iammatc-ry and trophic effect and as iut-'rsϋ ' ying of the antivli-:! action, Ilor- ovώr, cystciive uay reduce the uiitage nic effect of some cne ical conpounds (Il.Loriy , li.iato, I. iι±r-&su, - Lutation Soseor-ch 1972, 5>7 . ^ '5J> and there¬ fore pr-r-vant≤ the wut genic effec cf the phc-__jmaceutic.il pa- ion. .Reduced giuthation ("V- i taϋyl - cysteπyi - glycins) is a natural tripβptide to be f und in ail ani al and. ege al tissues; it is invoivid in the organism' defence ec-chaniεπj≤ and considered to have as εntiαutage ic effect by protecting -the nucleoph lic groups, r-os inform¬ ations! i_iεcro__; l cu.le.s (D1..) against strongly elεctrophyli ge nts . G-luthation capacity to ix-ate through its thiolic groups, eleetz-cphyl c agents (me * sai cations) may be compar -to a chela icn mechanism. Thus, "σ associating giuthation to "the ethylenεd aiaiπo-tetr-acetic acid, .the cheiating capacity of the latter is completed and enhanced and the product is provided with an antisu agsπic action. . - * In the structure cf gluta hion, an abnormal pepti αic link esc be noticed, .which is s m lar to e structure iϋ certain natural very strong a.ntibiotics (p__.cduc^ά bj bactϋxi .) a'-d which ara considered to be endowed with an a n ±vir Hi pr opor . ϋ 1.1 lire such antibiotics which εr-i highly toxic, gl trtϊoπ, which is a πor;_._l Ket ' abiλita of the hu__.an cr i£in, is evoid of tc- ici ..


Inventors: DINU ILEANA DANA, DINU ROMULUS CONSTANTIN, DINU, ILEANA, DANA, DINU, ROMULUS, CONSTANTIN
Applicants: CENTRALA IND MEDICAMENTE, CENTRALA INDUSTRIALA DE MEDICAMENTE, COSMETICE C
Application year: 1982
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K38, A61P17, A61P25, A61P29, A61P31