WO1996006639A2 - Nouveaux medicaments contenant des agents formant des chelates - Google Patents

Nouveaux medicaments contenant des agents formant des chelates Download PDF

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Publication number
WO1996006639A2
WO1996006639A2 PCT/EP1995/003426 EP9503426W WO9606639A2 WO 1996006639 A2 WO1996006639 A2 WO 1996006639A2 EP 9503426 W EP9503426 W EP 9503426W WO 9606639 A2 WO9606639 A2 WO 9606639A2
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WO
WIPO (PCT)
Prior art keywords
complex
edta
medicament according
mentioned
cana2
Prior art date
Application number
PCT/EP1995/003426
Other languages
German (de)
English (en)
Other versions
WO1996006639A3 (fr
Inventor
Serban Al. Bacanu
Iulian Ionescu
Sorin Sarzea
Stefan Teodor Tomas
Original Assignee
Medico Pharma Vertriebs Gmbh
Sicomed S.A.
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
Application filed by Medico Pharma Vertriebs Gmbh, Sicomed S.A. filed Critical Medico Pharma Vertriebs Gmbh
Priority to AU35194/95A priority Critical patent/AU3519495A/en
Publication of WO1996006639A2 publication Critical patent/WO1996006639A2/fr
Publication of WO1996006639A3 publication Critical patent/WO1996006639A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/30—Copper compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds

Definitions

  • the invention relates to new drugs, the chelating agents and essential amino acids or derivatives thereof, which are optionally complexed with divalent metal ions and contain divalent elements or compounds of divalent elements.
  • Chelating agents have long been used successfully as pharmaceuticals or components of pharmaceuticals in medicine or at least in the discussion, for example in the therapy of metal ion poisoning or in the inhibition of enzymes by binding cofactors. It is known that the steric conformation of the chelating agents and their ability to bind receptors have a strong influence on the therapeutic effects. However, many of the chelating agents known in the state of the art induce side effects which are contrary to a wide medical application (cf. for example Mazzarello et al., Schwe. Arch. Neurol. Psych. 131 (1982), 175-179). The furthest so far A common chelating agent used is azyclovir, which has already achieved considerable success in medical practice (eg Corey et al., New Engl.
  • the pharmaceuticals according to the invention are characterized by a lack of toxicity when the usual concentrations are administered with optimal results. Moreover, it has been shown for an already known drug to a similar composition which is however not claimed as such in the present invention and named RODILEMID ® that a prolonged administration carries no mutagenic potential. (Moralidhara et al., Food Chem. Toxicol. Dec. 12, 1991, 845-849). It is assumed that the mechanism of action of the pharmaceuticals according to the invention can be of different types. For example, the antiviral activity of the medicament according to the invention should be based on the fact that the withdrawal of zinc ions by the chelating agent brings about a disturbance in the zinc finger function of various retroviral proteins.
  • the amino acid component in the embodiment as cysteine could play an important regulatory role between T cells and macrophages and thus develop immunomodulatory effects.
  • the polyaminopolycarboxylic acids mentioned above in (a) and (a 1 ) are EDTA, DTPH, DCTA or derivative or complexes, preferably salts thereof, preferably EDTA CaNa2.
  • the amino acid mentioned in (b) and (b ') is cysteine, histidine or methionine and, as a derivative thereof, a precursor of cysteine or of histidi or of methionine or N-acetylcysteine, N-acetylhistidi or N- Acetylmethionine.
  • the divalent element mentioned in (c) is calcium and the derivative thereof is a calcium salt, preferably calcium lactate, calcium glucona or calcium levulinate.
  • the medicament according to the invention contains at least one of the following mixtures 1. EDTA-CaNa2, N-acetylcysteine and calcium gluconate;
  • the above percentages are based on the sum of the components (a), (b) and (c) or (a 1 ) and (b 1 ).
  • the invention further relates to the use of the medicament according to the invention for the treatment of in particular viral, preferably retroviral diseases.
  • the antiviral mechanism of action is based on a disruption of the viral metal ion availability induced by the medicament according to the invention.
  • the genomic RNA binds very strongly to nucleocapsid proteins, as a result of which the nucleocapsid structure is formed.
  • the so-called NC protein is used required for RNA dimerization, also for encapsulation and for initiation of reverse transcription in human retroviruses.
  • the NC7p7 protein of the HIV-1 nucleocapsid is necessary for the formation of infectious particles and contains two zinc fingers of the Cys-X2-Cys-X4-His-X4-Cys type.
  • the medicament according to the invention presumably causes the zinc fingers to lose their biological abilities either through a steric change in the binding structure or through loss of the zinc ions, whereby in any case the three-dimensional structure of the nucleotide sequence may be changed, which ultimately results in the loss of the three-dimensional binding activity and with it the loss of infectiousness.
  • the invention further relates to the use of the medicament according to the invention and a medicament containing the composition for treating AIDS mentioned in the disclaimer mentioned above.
  • the invention further relates to the use of the medicament according to the invention for the treatment of inflammation, preferably polyradiculonevritis.
  • the invention further relates to the use of a medicament according to the invention as an immunomodulator; e.g. Immune stimulation in flu and paragrippal infections.
  • an immunomodulator e.g. Immune stimulation in flu and paragrippal infections.
  • the invention also relates to the use of a medicament according to the invention for the treatment of autoimmune diseases.
  • the invention relates to the use of the medicament according to the invention for the treatment of multiple sclerosis, Nicolas-Barre syndrome, as well as herpes simplex, herpes zoster and facial paresis.
  • the invention relates to the use of a medicament according to the invention for the treatment of neurodegenerative diseases.
  • the invention relates to the use of a medicament according to the invention and a medicament which has the composition mentioned in the above disclaimer as an anti-cancer agent.
  • Figure 1 shows the effectiveness of the pharmaceuticals according to the invention.
  • Example 1 Inhibition of HIV-1 Infections by EDTA CaNa2-Cvstein-Calcium ⁇ luconat (RODILEMID ® )
  • the anti-HIV-1 activity and cytotoxicity of EDTA CaNa2 ⁇ cysteine calcium gluconate were measured in the MT-4 cell test (Harada et al., J. Immunol. Meth. 92 (1986), 177-181) and the results with the toxic and inactive anti-HIV-1 concentrations of four RODILEMID ® derivatives (1A1H, 1A09, 1A2N, 1A1N), DMSO / H 2 0 (blind test, M) and azidothymidine (3 '-azido-2', 3 '-dideoxythymidine, AZT) compared.
  • the infection of the MT-4 cells was propagated to the IIIB strain of the HIV-1 virus (Popovic et al., Science 224 (1984), 497-500) in CEM cells.
  • MT-4 and CEM cells (freely available, eg from ATCC) were grown in RPMI-1640 medium (Gibco, Düsseldorf, Germany) containing 20% by volume heat-inactivated fetal calf serum (FCS, Seromed, Berlin, Germany) and antibiotics had been added in the usual concentration.
  • FCS heat-inactivated fetal calf serum
  • the MT-4 cell test was performed in 9-well microtiter plates. To measure the cytopathogenicity of the active ingredients, serial dilutions of RODILEMID ® were incubated with 3 ⁇ 10 4 MT-4 cells per well. Anti-HIV-1 activity was measured in the presence of the virus. The final virus concentrations were 10 TCID50, with one unit TCID50 being defined as the infectious dose in cell culture that reduced the number of living cells by 50%. Fresh media was added to each well three days after infection. Four ⁇ l after infection, 0.1 ⁇ Ci H-thymidi (Amersham, Braunschweig, Germany) was added to each well.
  • RODILEMID ® was toxic to the MT-4 cells at a concentration of 1250 ⁇ g / ml ( Figure la, dashed line).
  • a RODILEMID ® concentration of 625 ⁇ g / ml had no influence on the cell growth and at this concentration a strong anti-HIV-1 activity could be determined via a strong 3 H thymidine incorporation (FIG. 1 a, solid line).
  • An anti-HIV-1 activity of RODILEMID ® could be determined at concentrations between 625 ⁇ g / ml and 39 ⁇ g / ml.
  • AZT was toxic to those in MT-4 cells at a concentration of 250 ⁇ M ( Figure 1b, dashed line).
  • the anti-HIV1 activity of AZT could be measured in the range of 25000 nM and 25 nM (Fibur lb, solid line). A measurable difference in the anti-HIV-1 activity of RODILEMID ® and the derivatives could not be determined. In terms of toxicity, only 1A1H is less toxic to MT-4 cells than RODILEMID ® : MT-4 cells died at a concentration of 2500 ⁇ g / ml 1A1H. The three other derivatives 1A09, 1A2N and 1A1N were toxic in the same range as RODILEMID ® (1250 ⁇ g / ml).
  • the selectivity index SI (see Table 1) defined as 100% cell toxicity concentration divided by 100% antiviral concentrations for a compound / composition was highest for AZT (10000).
  • RODILEMID ® was about 300 times less active than AZT and twice as active than the RODILEMID ® derivative 1A1H.
  • Selectivity index is defined as 100% cell toxicity concentration divided by 100% antiviral concentrations for a compound / composition No detectable antiviral activity and therefore no SI value.
  • Example 2 Treatment scheme for the use of the inventive drug in MS, AIDS.
  • Herpes Simplex, Herpes Zoster and the criz-Barre-Svndrom Herpes Simplex, Herpes Zoster and the criz-Barre-Svndrom
  • the treatment process consists of long-term treatment with the drug and depends on the development of the patient's clinical symptoms and other common para-clinical parameters.
  • the treatment regimen includes active periods that alternate with periods when the drug is not being used. Treatment is characterized by a phase of long alternating periods and a phase of short ones
  • SPARE BL ⁇ (RE ⁇ EL 26) alternating periods marked.
  • the daily doses vary between 7 and 70 mg per kg body weight, which are administered as intramuscular, intravenous injections or as an oral dose. If oral therapy is used, the dose described above can be doubled. After a break of 20 to 25 days, the therapy is started again cyclically. After therapy cycles of 12 to 15 days, a longer break of, for example, three months can be inserted, the length of which in turn depends on the clinical status and the usual para-clinical parameters.
  • the therapy begins with the appearance of the disease symptoms to be treated, in the case of multiple sclerosis of a relapse, 15 to 70 mg of the medicament according to the invention being administered per kg body weight as intramuscular or intravenous injections for 15 to 30 days. Thereafter, the treatment with doses of 7 to 35 mg of medicinal product per kilogram of body weight is continued for 3 to 6 months, it being possible to use the administration routes described above. Depending on the patient's clinical picture and the usual paraclinic parameters, the treatment can be repeated after one to six months.
  • apples, pears, bananas, cherries, peaches, watermelons, grapes, coffee, tea, cereals, potatoes, white beets, eggs, veal, poultry, fish, fat, rye bread, wheat bread, wheat starch, wheat, oatmeal, paddy rice, husked rice, rice starch, potato starch, flour are consumed.
  • the toxic activity of RODILEMID was determined: in rats the D50 is 4790 mg / k body weight, in mice even 5940 mg / kg body weight.
  • RODILEMID ® therapy started on the first day of immunological tests by intramuscular injection per day over a period of 10 days. After one month, the patients received an oral dose a day, 14 days a month. Therapy had to be stopped four months later. It was then continued with 10 AIDS patients, seven of whom belonged to the first group examined and three new patients were added. These patients were given 10 doses per month, with only one dose being given each day. The immunological examinations were carried out once every 45 days after the restart of the treatment and the clinical monitoring has taken 30 or 18 months (for the three newly added patients) since the start of the study.
  • HIV-1 infected patients identified as such 1 to 4.5 years earlier, were observed immunologically and clinically after starting oral therapy with RODILEMID®.
  • the therapy included the administration of 10 ampoules per month, one ampoule being administered per day.
  • Herpes zoster infections were cured within six to seven days, and patients responded well to both specific and complementary treatments for opportunistic infections, gaining weight.
  • the AIDS patients from the control group showed the following symptoms: progressive reduction in the total number of lymphocytes and in all T-lymphocyte subpopulations.
  • the number of T ⁇ cells in the most advanced clinical picture decreased by about half after 10 months.
  • Five patients in this group have since died and two patients who have been treated with AZT also showed a progressive decrease in T4 ⁇ lymphocytes. Thereby values of 130 / mm 3 and 250 / mm 3 reached, one of the two patients has since died. A somewhat slowed decrease in T4 lymphocyte counts on the hold was observed in this patient. Two of the patients are in the WR-6 phase.
  • RODILEMID ® has been treated for 26 months, one has died, but the others are still alive.
  • RODILEMID ® has unambiguously contributed to an improved clinical appearance and an extension of the lifespan of AIDS patients. In HIV-1 infected patients the transition to the disease stage could be prevented or at least slowed down. Treatment is easy to perform, inexpensive, and no toxic or other side effects have been observed.
  • the above-described differences in oral or intramuscular use in connection with the non-toxicity of RODILEMID ® leads to the conclusion that RODILEMID ® can be administered in double dose in adults, which could lead to even better treatment results.

Abstract

L'invention concerne de nouveaux médicaments contenant des agents formant des chélates ainsi que des acides aminés essentiels ou leurs dérivés, complexés le cas échéant avec des ions métalliques bivalents. Ces nouveaux médicaments contiennent en outre des éléments bivalents ou des composés d'éléments bivalents.
PCT/EP1995/003426 1994-09-01 1995-08-31 Nouveaux medicaments contenant des agents formant des chelates WO1996006639A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU35194/95A AU3519495A (en) 1994-09-01 1995-08-31 Novel drugs containing chelate-forming agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19944431175 DE4431175A1 (de) 1994-09-01 1994-09-01 Neue, Chelatbildner enthaltende Arzneimittel
DEP4431175.3 1994-09-01

Publications (2)

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WO1996006639A2 true WO1996006639A2 (fr) 1996-03-07
WO1996006639A3 WO1996006639A3 (fr) 1996-07-25

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009976A2 (fr) * 1995-09-01 1997-03-20 Washington University Procede d'attenuation de troubles dus a des neurotoxines par des chelatants du zinc
DE19735126C1 (de) * 1997-08-13 1999-01-21 Infectopharm Arzneimittel Und Verfahren zur Herstellung einer eine Zinkverbindung enthaltenden oralen Zusammensetzung und deren Verwendung zur Behandlung von Erkältungskrankheiten
US6013632A (en) * 1997-01-13 2000-01-11 Emory University Compounds and their combinations for the treatment of influenza infection
EP1085862A1 (fr) * 1998-06-19 2001-03-28 Thomas B. Bryan Procede servant a traiter une maladie auto-immune
ES2216709A1 (es) * 2003-04-08 2004-10-16 Mercedes Nubia Perez De Cabrales Composicion farmaceutica para tratar el herpes zoster.
US20110105419A1 (en) * 2008-02-21 2011-05-05 Mark Borisovich Balazovsky Pharmacological adjuvants based on coordination compounds of d-metals
WO2019172741A1 (fr) * 2018-03-09 2019-09-12 Instituto Tecnológico José Mario Molina Pasquel y Henriquez Complexes bimétalliques comprenant des cations bivalents ayant un effet inhibiteur de la réplication du vhs

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19641197C2 (de) * 1996-09-24 1999-02-18 Schering Ag Ionenpaare und ihre Verwendung als Kontrastmittel

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2827478A1 (de) * 1978-06-22 1980-01-17 Jozsef Dr Beres Arzneimittel, insbesondere zur heilung von und vorbeugung gegen geschwulstkrankheiten
WO1983002893A1 (fr) * 1982-02-23 1983-09-01 Dinu, Romulus, Constantin Composition medicinale pour le traitement de certaines nevroviroses
WO1992015329A1 (fr) * 1991-02-28 1992-09-17 The United States Of America, Represented By The Secretary, United States Department Of Commerce Procedes et compositions pharmaceutiques servant a inhiber la protease du virus de l'immunodeficience humaine
WO1994022438A1 (fr) * 1993-03-26 1994-10-13 Constantin Romulus Dinu Composition pharmaceutique destinee au traitement de certains virus et de certaines maladies auto-immunes, et son procede de preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2827478A1 (de) * 1978-06-22 1980-01-17 Jozsef Dr Beres Arzneimittel, insbesondere zur heilung von und vorbeugung gegen geschwulstkrankheiten
WO1983002893A1 (fr) * 1982-02-23 1983-09-01 Dinu, Romulus, Constantin Composition medicinale pour le traitement de certaines nevroviroses
WO1992015329A1 (fr) * 1991-02-28 1992-09-17 The United States Of America, Represented By The Secretary, United States Department Of Commerce Procedes et compositions pharmaceutiques servant a inhiber la protease du virus de l'immunodeficience humaine
WO1994022438A1 (fr) * 1993-03-26 1994-10-13 Constantin Romulus Dinu Composition pharmaceutique destinee au traitement de certains virus et de certaines maladies auto-immunes, et son procede de preparation

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
NEUROL PSYCHIATR (BUCUR), OCT-DEC 1986, 24 (4) P263-8, ROMANIA, XP002002404 DINU R ET AL: "Rodilemid therapy in peripheral palsy: a clinical and electrophysiological study." *
NEUROL. PSYCHIATR. REV. ROUM. MED., Bd. 21, Nr. 3, 1983, Seiten 307-308, XP002002403 R. DINU ET AL.: "Chelatotherapy with Rodilemid in some acute neuroviroses and multiple sclerosis" *
REV. ROUM. BIOL. SER. BIOL. ANIM., Bd. 34, Nr. 2, 1989, Seiten 129-132, XP002002405 ST. AGRIGOROAEI ET AL.: "Specific action of some biosynthesis products upon the body's defence capacity" *
SANTE PUBLIQUE (BUCUR), 1984, 27 (2) P99-114, ROMANIA, XP002002401 DINU R ET AL: "Herpes zoster and herpes simplex--public health matter;chelatotherapy in these acute neuroviroses." *
SANTE PUBLIQUE (BUCUR), 1985, 28 (1) P3-30, ROMANIA, XP002002402 DINU R ET AL: "Chelatotherapy in multiple sclerosis. Open preliminary study of a new therapeutical principle applied in multiple sclerosis--public health topic." in der Anmeldung erw{hnt *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009976A2 (fr) * 1995-09-01 1997-03-20 Washington University Procede d'attenuation de troubles dus a des neurotoxines par des chelatants du zinc
WO1997009976A3 (fr) * 1995-09-01 1997-05-22 Univ Washington Procede d'attenuation de troubles dus a des neurotoxines par des chelatants du zinc
US6013632A (en) * 1997-01-13 2000-01-11 Emory University Compounds and their combinations for the treatment of influenza infection
US6107281A (en) * 1997-01-13 2000-08-22 Nutri-Quest, Inc. Compounds and their combinations for the treatment of influenza infection
DE19735126C1 (de) * 1997-08-13 1999-01-21 Infectopharm Arzneimittel Und Verfahren zur Herstellung einer eine Zinkverbindung enthaltenden oralen Zusammensetzung und deren Verwendung zur Behandlung von Erkältungskrankheiten
EP1085862A1 (fr) * 1998-06-19 2001-03-28 Thomas B. Bryan Procede servant a traiter une maladie auto-immune
EP1085862B1 (fr) * 1998-06-19 2011-01-05 Thomas B. Bryan Traitement d'une maladie autoimmune
ES2216709A1 (es) * 2003-04-08 2004-10-16 Mercedes Nubia Perez De Cabrales Composicion farmaceutica para tratar el herpes zoster.
US20110105419A1 (en) * 2008-02-21 2011-05-05 Mark Borisovich Balazovsky Pharmacological adjuvants based on coordination compounds of d-metals
WO2019172741A1 (fr) * 2018-03-09 2019-09-12 Instituto Tecnológico José Mario Molina Pasquel y Henriquez Complexes bimétalliques comprenant des cations bivalents ayant un effet inhibiteur de la réplication du vhs

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Publication number Publication date
DE4431175A1 (de) 1996-04-11
AU3519495A (en) 1996-03-22
WO1996006639A3 (fr) 1996-07-25

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