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EP0690709A1 - Composition pharmaceutique destinee au traitement de certains virus et de certaines maladies auto-immunes, et son procede de preparation - Google Patents

Composition pharmaceutique destinee au traitement de certains virus et de certaines maladies auto-immunes, et son procede de preparation

Info

Publication number
EP0690709A1
EP0690709A1 EP94904353A EP94904353A EP0690709A1 EP 0690709 A1 EP0690709 A1 EP 0690709A1 EP 94904353 A EP94904353 A EP 94904353A EP 94904353 A EP94904353 A EP 94904353A EP 0690709 A1 EP0690709 A1 EP 0690709A1
Authority
EP
European Patent Office
Prior art keywords
water
solution
treatment
calcium
sodium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94904353A
Other languages
German (de)
English (en)
Inventor
Constantin Romulus Dinu
Ileana Dana Dinu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from RO9301803A external-priority patent/RO111245B1/ro
Application filed by Individual filed Critical Individual
Publication of EP0690709A1 publication Critical patent/EP0690709A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione

Definitions

  • the present invention refers to a pharmaceutical composition, in the form of an aqueous injectable, or orally administered solution, for the treatment of AIDS, and for the treatment of one of the neuroviruses selected from herpes simplex recurrens, herpes Zoster, encephalomyelitis, polyradiculoneuritis, cranial nerve paralysis, or for the treatment of the autoimmune disease- multiple sclerosis.
  • a pharmaceutical composition in the form of an aqueous injectable, or orally administered solution, for the treatment of AIDS, and for the treatment of one of the neuroviruses selected from herpes simplex recurrens, herpes Zoster, encephalomyelitis, polyradiculoneuritis, cranial nerve paralysis, or for the treatment of the autoimmune disease- multiple sclerosis.
  • Background Art The manipulation of metal ions equilibria, so important in the health-disease correlation investigated in laboratory trials (D.D. Perrin and H. St ⁇ nzi, Pharma
  • the best known multidentate ligand is EDTA (ethylenedia inetetraacetate) with six donor atoms and DTPA (diethylenetriaminepentaacetate) with eight donor atoms.
  • a metal ion M and a ligand L may combine reversibly to form complexeS'ML n where the equilibrium concentrations of the different species depend on the total concentrations of M and L and the stabilities of the complexes. In the presence of two or more different ligands mixed complexes ML'L' 'L 1 ' ' may be very important, increasing the stability of the complexes.
  • Example I Four examples are given below on the making of the pharmaceutical composition according to the invention.
  • the pharmaceutical composition of the present invention consisting essentially of: a) the calcium disodium salt of ethylenediaminetetraacetic acid b) calcium gluconate c) reduced glutathione d) sodium metabisulfite wherein the weight ratio for the active ingredients ranges from 5-10.5 g to 0.2-2.0 g to 0.01-0.1 g to 0.01-0.2 g, respectively per 100 ml of water.
  • the advantages of the preparation as per the invention are the following:
  • the drug has a specific curative effect in AIDS, and some other viruses, as well as in autoimmune diseases.
  • Reduced glutathione (glutamil-cysteinyl-glycine) natural tripeptide found in all animal tissues, is involved in the organism's defence mechanisms and considered to have the ability to bind through its thiols groups the metal ions being thus a mild chelating agent. It is also an antioxidant substance with a proeminent role in the immunologic and inflammatory processes.
  • the association of reduced glutathione with calcium sodium edetate and calcium gluconate leads to an extensive formation of mixed-ligands, where the metal-complexes are more stable, thus increasing the antiviral action of the drug.
  • Sodiummetabisulfite is a glutathione stabilizer, but at the same time the system glutathione-reduced- metabisulfite is a redox system intensified by the S 2 0 -2
  • composition of ingredients for 100 ml of solution as per the invention is the following:
  • the preparation of 1000 ml solution for injection or for orally administration as per the invention is the following:
  • All the water used for the manufacturing was water for injection purged with nitrogen gas.
  • 78 g ethylenediaminetetraacetic acid (EDTA) p.a. was dissolved in 600-700 ml water in a borosilicate glass container at 110°C.
  • 26.7g calcium carbonate p.a. was added little by little during l h by continuous stirring.
  • 106.5 ml 5 N sodium hydroxide (2l.3g) was gradually added into the solution that containes CaH 2 EDTA.
  • the solution has been purged with nitrogen gas for 30 minutes and it turned clear.
  • 6g calcium gluconate were dissolved in 50 ml water at approximately 80°C by minimal stirring and thereafter it was added to the initial solution.
  • the pharmaceutical composition of the present invention consisting essentially of: a) the calcium disodium salt of ethylenediaminetetraacetic acid b) calcium gluconate c) L-histidine wherein the weight ratio for the active ingredients ranges from 5-10.5 g to 0.3-1 g to 0.05-0.2 g, respectively per 100 ml of water.
  • the advantages of the preparation as per the invention are the following: The drug has a specific curative effect in AIDS and other viruses and autoimmune diseases.
  • Histidine is included in the composition of the present invention because the mixed complexes with metal- histidinate are more stable than expected. For instance, for the complex copper-histidinate-phosphonoacetate the stability is enhanced by a factor of 16 (Perrin and St ⁇ nzi Pharmac.Ther.Vol.12,p.262,PergamonPress 1981) . Histidine proved also to be the best stabilizer of the complex EDTA- Me *2 , hence bringing about an increased capacity of EDTA to bind metal ions like zinc, included in the structure of HIV (human immunodeficiency virus) .
  • the pharmaceutical composition is neither metabolized nor stored in the organism, the product is rapidly eliminated and it is toxicity-free in the dosage prescribed for the mentioned diseases. See below a concrete example.
  • composition of ingredients for 100 ml of solution as per the invention is the following: Calcium and sodium salt of the ethylenediaminetetraacetic acid lOg Calcium gluconate 0.5g
  • composition as per the present invention formulated as injectable solution or orally administered solution contains the calcium and sodium salt of diethylenetriaminepentaacetic acid (DTPA.Na 3 Ca)asociated with calcium gluconate, as a source of calcium and mild chelating agent, with L-cysteine hydrocloride, and sodium metabisulfite; the association weight ratio of the 4 active ingredients is 5-10 g to 0.4-1 g to 0.03-0.15 g to 0.05-0.15 g respectively per 100 ml of water.
  • the advantages of the preparation as per the invention are the following:
  • the drug has a curative effect in AIDS and other viruses and autoimmune diseases.
  • composition of ingredients for 100 ml solution of the invention is the following: Calcium and sdium salt of the diethylenetriaminepentaacetic acid 7.5g
  • Example IV The pharmaceutical composition of the present invention consisting essentialy of: a) the calcium disodium salt of ethylenediaminetetraacetic acid b) calcium gluconate c) L-cysteine hydrochloride d) sodium metabisulfite wherein the weight ratio for the four active ingredients ranges from 9-11 g to 0.4-0.8 g to 0.1-0.3 g to 0.1-0.3 g respectively per 100 ml. of water.
  • the advantages of the preparation as per the invention are the following:
  • the drug has an antiviral, anti-inflammatory, immunomodulatory and neurotrophic effect in AIDS, herpes simplex, herpes Zoster, and some other neuroviruses as cranial nerves paralysis, encephalomyeliti ⁇ , polyradiculoneuritis as well as in multiple sclerosis.
  • L-cysteine was included as a mild metal chelating agent, that strongly increases the chelating capacity of EDTA. In the presence of two or more different ligands, mixed complexes are more stable. The administration of EDTA-cysteine-gluconate lower zinc level in serum leading thus to the use of such mixed ligands to control viral diseases .
  • the importance of thiols groups in immunological and inflammatory processes is known very well already.
  • the cysteine-metabisulfite system is also a redox system potentated by the anion S 2 O s "2 with a beneficia synergia in the inflammatory process.
  • the pharmaceutical composition is neither metabolized nor stored in the organism, being rapidly eliminated and toxicity-free in the dosage prescribed (10-15 mg/Kg of body weight) for the above mentioned diseases. See below a concrete example:
  • composition of ingredients for 100 ml solution of the invention is the following:
  • the preparation of 1000 ml solution for injection or for orally administration as per the invention is the following:
  • EDTA ethylenediaminetetraacetic acid
  • the pH was redetermined and readjusted with sodium hidroxide to about 6.4-6.7.
  • Water was added up to 1000 ml.
  • the solution was filtered through a Millipore R filter under a steam of nitrogen gas.
  • the solution was divided in borosilicate colourless 10 ml ampoules under nitrogen gas and the vials were sterilized at 120°C for 30 minutes.
  • THE DOSAGE AND ADMINISTRATION OF THE DRUG AS PER INVENTION Genital or labial herpes a series of 4-6 i.m. injections, or in orally administration (one ampoule/day) .
  • Recurrent old herpes one series of 6 ampoules (one/day) i.m. administered according to the first symptoms of a relapse (burns, pruritus, pain) . After the first series, with the occurence of the first symptoms of a relapse, 6 ampoules (one/day) orally administered.
  • Viral peripheral facial paralysis series of 10-12 i.m. injections, with an interval of 4-5 days between the two series, if and when a follow-up of the treatment was required (one injection/day).
  • Multiple sclerosis 6 i.m. injections (one/day) monthly, or at longer intervals, according to the clinical type of MS, the evolution of the symptoms and the medical advice.
  • AIDS After the diagnosis was set and the immunological determinations were performed through the tests of the total lymphocytes and the CD 4 and CD 8 subpopula ions, the therapy is commenced by one or two ampoules per day, according to the case, orally administered, over a 10-day period, monthly. After 2-3 months of treatment, the immunological survey must be performed. The treatment is continual with no time limit. In some cases, a slight decrease of CD 4 after 1-3 months of treatment can be seen, followed-up by a significant increase of CD 4 values.
  • the CD ⁇ (the cytotoxic subpopulation) proves an evolution specific to the treatment: it often grows exceeding the normal values, beginning with the first series of treatment.
  • the treatment is non toxic, very well tolerated by children and adults, with no notable side effects.
  • the serum and urinary level of calcium is not modified under the treatment. During the period of treatment any medicinal calcium product and dairy product is forbidden.
  • the pharmaceutical preparation as per this invention has "in vivo" antiviral, antiinflammatory, immunomodulatory and neurotrophic action.
  • THE HYPOTHESIS on the antiviral mechanism of action is supported by the fact that the chelating agents exert an antiviral action by binding certain metal ions involved in the structure of the viruses and in their multiplication.
  • chelating agents as EDTA show "in vitro" antiviral effects include RNA-dependent DNA polymerases (reverse transcriptases) , zinc enzymes, by zinc complexation (D.D.Perrin and H.Stunzi, Pharmac. Ther. vol.12,p 267, 1981) .
  • the "in vivo" capacity of EDTA to bind zinc ions in stable complexes is much increased by the presence of other different types of ligands such as cysteine, histidine and reduced glutathione from the given examples as per this invention.
  • Zinc is directly involved in HIV (human immunodeficiency virus) structure. HIV-l has got a viral nucleoid core - the capsid - that contains the most stable element of the virus the nucleocapsid. This nucleocapsid is constituted of many small molecules of NC p 7 protein which binds directly to the genomic RNA through two zinc fingers structural motif.
  • nucleocapsid contains also various preformed viral enzymes, including the reverse-transcriptase, a zinc enzyme (Medecine/sciences, 1993,9,p.952-8 Greene W.C., N.Engl. J.Med.1991, v.324, 5,p.308-17) .
  • Our hyphotesi ⁇ is based on the "in vivo" removing of zinc from the nucleo capsid of HIV-l and from its zinc-enzymes, with the multi-ligand systems as presented in the invention.
  • the viral genome can be affected, involving an instability of the virus and its deterioration by the nucleases. Consequently, the attack target of zinc-chelating agents, presented in this invention, might be in AIDS, simply the zinc-protein of the nucleocapsid, whose plurifunctionality was demonstrated (Medecine/sciences, 1993,9,p.952-8) .
  • the drug according to the present invention acts on contractile protein systems, on cell membrane receptors, and signal transduction enzymes - protein kinase C - by a manipulation of the sulphide groups.
  • the antiviral and immunomodulatory actions of the pharmaceutical composition from the present invention at least at a fundamental level may be better understood.
  • the entry of calcium into cell may be considerered the first molecular event in the immunological modulation of lymphocytary subpopulation CD 4 and CD S .
  • the pharmaceutical composition consisting of the calcium disodium salt of ethylenediaminetetraacetic acid, calcium gluconate, L-cysteine and sodium metabisulfite in certain weight ratio is a very strong stimulator of lymphocytes involved inAIDS (CD 4 , CD e , total lymphocytes) .
  • the drug stimulates successiveively first the cytotoxic subpopulation CD 8 (suppresor) which starts,possibly, to eliminate the infected CD 4 cells.
  • the lymphocytes CD ⁇ called also CD 4 demographic control, proved "in vitro" their capacity to attack the HIV infected CD 4 cells. (Le journal du SIDA,Mars 1993,no.48 p.9).
  • the level of CD 8 grows exceeding the normal values after 1-2 series of oral administration of 10 ampoules (one/day) monthly of the above mentioned pharmaceutical composition. This CD ⁇ growth is in some cases associated with a small, temporary, diminution of the CD 4 subpopulation. But after 2-3 month of treatment the CD 4 begins to grow towards a normal level.
  • the problem the present invention resolves, consists in the "in vivo" antiviral action and in the stimulation of the lymphocytes involved in AIDS and, first of all, the cytotoxic subpopulation CD 8 , that commences to carry on an activity on the infected CD 4 cells, this stimulation being continuous for the rise of the CD 4 /CD 8 ratio up to a normal value.
  • an autoimmune process is being launched, controled by the pharmaceutical composition from the present invention.
  • the neurotrophic effect of the claimed pharmaceutical composition is based on the correcting of the effects of cellular Ca 2* deficiency, in the case of an injured nerve, by facilitating its in-flow into the nervous cell, re ⁇ establishing the nervous in-flow.
  • the depolarizationphenomena increase by accumulating Ca 2* in the synapses and neural transmission also by facilitating the discharge of acetylcholine quanta.
  • the anti-inflammatory effect was determined by means of preclinical pharmacology and clinically manifested as a decrease of pain in herpes and herpes Zoster, as a diminishing of neuroganglia inflammation. Clinical trials
  • the control group showed a progressive decrease in TL and in all T subpopulations within 4-17 months of survey.
  • the drug according to the invention was highly efficacious in the treatment of a group of 150 patients with recurrent herpes accompanied by neuralgia, under the dosage regime described. Pain rapidly diminishes after 24-48 hours, cutaneous lesions are arrested and rapidly evolve to epithelization (2.6 ⁇ 0.4 days) (p ⁇ 0.001; significant according to Student's test) .
  • the drug increases the intervals between relapses and the remission speed increases after the administration of two or three series of 6 injections (or oral administration) , simultaneously with the first symptoms of a relapse. In the most cases, relapses occur, if at all, after 200% longer periods, with an eruption reduced "miscarried" .
  • herpes Zoster The most important event in herpes Zoster is pain cessation (6.45 days) . Even if intense, pain was influenced within 24-48 hours after initiation of the therapy.
  • the test group(I) consisted of 27 patients, with idiopathic facial paralysis and one case with post-zosterian paralysis (Ramsey-Hunt syndrome) . These patients started the treatment up to 11 days since onset without having previously followed any other treatments.
  • the control group (II) consisted of 17 patients. These patients started the treatment from an average of 42.0 days since onset, having previously been treated with corticoid, vitamins, physiotherapeutic procedures with hardly any or no effects at all.
  • the drug was administered in daily i.m. injections in series of 6- 10 ampoules.
  • the clinical examination produced a score calculated on the basis of remanent motility and blink reflex measurements.
  • the electro-physiological examination produced the prompt reflex (PR) and delayed reflex (DR) .
  • PR prompt reflex
  • DR delayed reflex
  • Full recovery in group II was obtained in only 24% of the cases and the reflex response was absent in 33% of the cases. In the test group postparalytic spasms were not observed with a follow-up period of one year.
  • the treatment with corticosteroids is very hazardous in the case of herpetic encephalitis, Zoster or varicellosus encephalitis.
  • the great efficacy in neuroviruses of the drug according to the invention determined successful application of this treatment in more than 30 encephalitis cases which we ' re cured. After 10-12 i.m.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Nouvelle composition pharmaceutique et son procédé de préparation. La composition est utile dans le traitement du SIDA, de certains virus et de certaines maladies auto-immunes, et se présente sous la forme d'une solution aqueuse injectable ou buvable. On a mis au point quatre variantes de réalisation de ladite composition pharmaceutique: (I) composition pharmaceutique composée du sel double de calcium et sodium de l'acide éthylènediaminetétraacétique, associé au gluconate de calcium, au glutathion réduit et au métabisulfite de sodium, le rapport pondéral des ingrédients allant respectivement de 5 à 10,5 g, à 0,2 à 2 g, à 0,01 à 0,1 g, à 0,01 à 0,2 g par 100 ml d'eau; (II) composition pharmaceutique composée du sel disodium de calcium de l'acide éthylènediaminetétraacétique, associé au gluconate de calcium et à la L-histidine, le rapport pondéral des ingrédients actifs allant respectivement de 5 à 10,5 g, à 0,3 à 1 g, à 0,05 à 0,2 g par 100 ml d'eau; (III) composition pharmaceutique composée du sel de calcium et de sodium de l'acide diéthylènetriaminepentaacétique (DTPA Na3Ca), associé au gluconate de calcium, à l'hydrochlorure de L-cystéine et au métabisulfite de sodium, le rapport pondéral de l'association des ingrédients allant respectivement de 5 à 10 g, à 0,4 à 1 g, à 0,03 à 0,15 g, à 0,05 à 0,15 g par 100 ml d'eau; et (IV) composition pharmaceutique composée du sel disodium de calcium de l'acide éthylènediaminetétraacétique, associé au gluconate de calcium, à l'hydrochlorure de L-cystéine et au métabisulfite de sodium, le rapport pondéral des quatre ingrédients actifs allant respectivement de 9 à 11 g, à 0,4 à 0,8 g, à 0,1 à 0,3 g, à 0,1 à 0,3 g par 100 ml d'eau.
EP94904353A 1993-03-26 1993-12-29 Composition pharmaceutique destinee au traitement de certains virus et de certaines maladies auto-immunes, et son procede de preparation Withdrawn EP0690709A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
RO9300414 1993-03-26
RO9300414 1993-03-26
RO9301803A RO111245B1 (ro) 1993-12-28 1993-12-28 COMPOZIȚII MEDICAMENTOASE PENTRU TRATAMENTUL IJNOR VIROZE Șl BOLI AUTOIMUNE
RO9301803 1993-12-28
PCT/RO1993/000006 WO1994022438A1 (fr) 1993-03-26 1993-12-29 Composition pharmaceutique destinee au traitement de certains virus et de certaines maladies auto-immunes, et son procede de preparation

Publications (1)

Publication Number Publication Date
EP0690709A1 true EP0690709A1 (fr) 1996-01-10

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EP94904353A Withdrawn EP0690709A1 (fr) 1993-03-26 1993-12-29 Composition pharmaceutique destinee au traitement de certains virus et de certaines maladies auto-immunes, et son procede de preparation

Country Status (3)

Country Link
EP (1) EP0690709A1 (fr)
CA (1) CA2159116A1 (fr)
WO (1) WO1994022438A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4431175A1 (de) * 1994-09-01 1996-04-11 Medico Pharma Vertriebs Gmbh Neue, Chelatbildner enthaltende Arzneimittel
DE19533477C2 (de) * 1995-09-12 1997-10-23 Pharma Beratung Dr Klaus Hoffm Verwendung von Diethylentriaminpentaessigsäure (DTPA) mit immunsuppressiver Wirkung
DE19615461C2 (de) * 1996-04-19 1998-05-14 Detlef Schiele Mittel zur Ausleitung und Entfernung von Schwermetallspuren aus dem menschlichen Organismus
DE19725178A1 (de) * 1997-06-13 1998-12-17 Sorin Dr Sarzea Zusammensetzung zur Redoxkontrolle
BR122015008513B1 (pt) * 2005-11-09 2017-01-31 Ajinomoto Kk uso de um ou mais tipos de substâncias, composição de alimento, método para produzir alimento ou bebida conferido(a) com kokumi, e, alimento ou bebida conferido(a) com kokumi
JP5757674B2 (ja) 2005-11-09 2015-07-29 味の素株式会社 カルシウム受容体活性化剤
DE602006017421D1 (de) 2005-11-09 2010-11-18 Ajinomoto Kk Screening-verfahren für kokumi-vermittelnde agentien
US8420144B2 (en) 2005-11-09 2013-04-16 Ajinomoto Co., Inc. Kokumi-imparting agent, method of using, and compositions containing same
KR101491995B1 (ko) 2007-05-08 2015-02-10 아지노모토 가부시키가이샤 저지방 식품

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1110392A (en) * 1964-09-28 1968-04-18 Yamanouchi Pharma Co Ltd Composition containing glutathione and an amino acid or amino acids, and salts thereof
RO79426B1 (ro) * 1982-02-23 1984-07-30 Romulus Constantin Dinu Compozitie medicamentoasa pentru tratamentul unor neuroviroze
HU209973B (en) * 1988-03-09 1995-01-30 Biorex Kutato Fejlesztoe Kft Process for production of antiviral and immunstimular pharmaceutical composition
IT1246328B (it) * 1989-11-09 1994-11-17 Asta Pharma Ag Medicamenti contenenti acidi carbossilici contenenti zolfo quali agenti attivi nonche' procedimento per la loro produzione e loro impiego per la lotta ai retrovirus.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9422438A1 *

Also Published As

Publication number Publication date
CA2159116A1 (fr) 1994-10-13
WO1994022438A1 (fr) 1994-10-13

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