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WO2003028717A1 - A drugs association against influenza virus - Google Patents

A drugs association against influenza virus Download PDF

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Publication number
WO2003028717A1
WO2003028717A1 PCT/EP2002/008584 EP0208584W WO03028717A1 WO 2003028717 A1 WO2003028717 A1 WO 2003028717A1 EP 0208584 W EP0208584 W EP 0208584W WO 03028717 A1 WO03028717 A1 WO 03028717A1
Authority
WO
WIPO (PCT)
Prior art keywords
ribavirin
nac
influenza virus
association
against influenza
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.)
Ceased
Application number
PCT/EP2002/008584
Other languages
French (fr)
Inventor
Domenico Ungheri
Giovanni Battista Colombo
Luciano Licciardello
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.)
Zambon Group SpA
Zambon SpA
Original Assignee
Zambon Group SpA
Zambon SpA
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 Zambon Group SpA, Zambon SpA filed Critical Zambon Group SpA
Priority to EP02800058A priority Critical patent/EP1505991A1/en
Publication of WO2003028717A1 publication Critical patent/WO2003028717A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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 or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom

Definitions

  • the present invention relates to a drugs association against flu virus and more particularly it relates to the association of N-acetyl-cysteine and Ribavirin and the use of that association to treat influenza virus disease.
  • N-acetyl-cysteine (The Merck Index, XII Ed., page 16, No. 89) is a known drug with mucolitic and anti-oxidant activity. Among the various properties of the molecule, a certain activity to protect the laboratory animals infected with the flu virus has been described. Ribavirin (The Merck Index, XII Ed., page 1409, No. 8365) is a known drug with antiviral activity.
  • NAC N-acetyl-cysteine
  • Ribavirin even if it has meaningful antiviral properties, is not completely effective against flu virus [Antimicrobial Agents and Chemotherapy, 31(8), 1285 (1987)].
  • NAC can increase significatively and in a synergistic manner the antiviral activity of Ribavirin.
  • Object of the present invention therefore is a pharmaceutical composition containing NAC and Ribavirin to antagonise flu virus by increasing Ribavirin efficacy.
  • a second object of the present invention is the use of NAC for preparing pharmaceutical compositions to administer in combined therapy with Ribavirin to antagonise flu virus.
  • a third object of the present invention is a kit containing an effective amount of
  • NAC and Ribavirin or multiples thereof, in a form for administration are provided.
  • compositions object of the invention are preferably those suitable by oral administration (tablets, capsules, syrups, water-soluble forms), by aerosol (especially ready or extemporaneous solutions to be administered by suitable inhalers) or by injective route (ready solutions or to be prepared at the moment of use from lyophilized).
  • the doses which will change following to the selected pharmaceutical form, the seriousness of the infection and the patient response, will ensure an amount of Ribavirin between 1 and 5 g/die and of NAC between 1,2 and 6 g/die.
  • Example 1 Effect of NAC and Ribavirin association on the lethality of flu virus in mice
  • the animals were infected intranasally with a viral flu suspension (strain PR/8, suspension in 0.05 ml of culture medium) in a dose of 2-3 LD 50 and therefore they were randomly assigned (12 animals each group) to the following groups:
  • Group 1 treated with vehicle (physiological solution) per os or intraperitoneal without active ingredients
  • Group 2 treated with Ribavirin 100 mg/kg i.p.
  • Group 3 treated with NAC 1000 mg/kg p.o.
  • Group 4 treated with Ribavirin 100 mg/kg i.p. and NAC 1000 mg/kg p.o. Treatments (once daily) were started 4 hours after the infections and prolonged for 4 days. The animals were observed until the 14 th day and the total number of the dead animals were registered day by day.
  • Example 2 A kit for aerosol comprising a solution of Ribavirin at 20 mg/ml concentration and a solution of NAC 10% was prepared.
  • the kit contains also the instructions for use, suitable instruments to open the vials containing the solutions and if need a small bottle where to mix the solutions before administering the aerosol.
  • Example 3 A kit containing Ribavirin in injectable solution (1200 mg) and effervescent tablets of NAC (2x600 mg, FLUIMUCIL ® ) was prepared.
  • the kit contains the instructions for use and a sterilized syringe for i.v. injection of Ribavirin.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

A drugs association against flu virus and more particularly the association of N-acetyl-cysteine and Ribavirin and the use of that association to treat influenza virus disease is described.

Description

A DRUGS ASSOCIATION AGAINST INFLUENZA VIRUS
The present invention relates to a drugs association against flu virus and more particularly it relates to the association of N-acetyl-cysteine and Ribavirin and the use of that association to treat influenza virus disease.
N-acetyl-cysteine (The Merck Index, XII Ed., page 16, No. 89) is a known drug with mucolitic and anti-oxidant activity. Among the various properties of the molecule, a certain activity to protect the laboratory animals infected with the flu virus has been described. Ribavirin (The Merck Index, XII Ed., page 1409, No. 8365) is a known drug with antiviral activity.
N-acetyl-cysteine (from now on briefly indicated as NAC) does not have an antiviral activity such as to be effectively used it alone for this aim.
Ribavirin, even if it has meaningful antiviral properties, is not completely effective against flu virus [Antimicrobial Agents and Chemotherapy, 31(8), 1285 (1987)].
We have surprisingly found that NAC can increase significatively and in a synergistic manner the antiviral activity of Ribavirin.
Object of the present invention therefore is a pharmaceutical composition containing NAC and Ribavirin to antagonise flu virus by increasing Ribavirin efficacy. A second object of the present invention is the use of NAC for preparing pharmaceutical compositions to administer in combined therapy with Ribavirin to antagonise flu virus.
Furthermore, a third object of the present invention is a kit containing an effective amount of
NAC and Ribavirin or multiples thereof, in a form for administration.
The pharmaceutical compositions object of the invention are preferably those suitable by oral administration (tablets, capsules, syrups, water-soluble forms), by aerosol (especially ready or extemporaneous solutions to be administered by suitable inhalers) or by injective route (ready solutions or to be prepared at the moment of use from lyophilized).
The doses, which will change following to the selected pharmaceutical form, the seriousness of the infection and the patient response, will ensure an amount of Ribavirin between 1 and 5 g/die and of NAC between 1,2 and 6 g/die.
To better illustrate the present invention but without limiting it, the following examples are now given.
Example 1 Effect of NAC and Ribavirin association on the lethality of flu virus in mice The animals were infected intranasally with a viral flu suspension (strain PR/8, suspension in 0.05 ml of culture medium) in a dose of 2-3 LD50 and therefore they were randomly assigned (12 animals each group) to the following groups:
Group 1: treated with vehicle (physiological solution) per os or intraperitoneal without active ingredients
Group 2; treated with Ribavirin 100 mg/kg i.p. Group 3: treated with NAC 1000 mg/kg p.o.
Group 4: treated with Ribavirin 100 mg/kg i.p. and NAC 1000 mg/kg p.o. Treatments (once daily) were started 4 hours after the infections and prolonged for 4 days. The animals were observed until the 14th day and the total number of the dead animals were registered day by day.
The test results are reported in the following Table 1. Table 1 Effect of NAC and Ribavirin on the lethality of flu virus in mouse.
Figure imgf000003_0001
The data reported in the table show how NAC alone has a reduced antiinflu activity and as NAC in association with Ribavirin increase in a synergistic way the antiviral activity of this latter.
Example 2 A kit for aerosol comprising a solution of Ribavirin at 20 mg/ml concentration and a solution of NAC 10% was prepared.
The kit contains also the instructions for use, suitable instruments to open the vials containing the solutions and if need a small bottle where to mix the solutions before administering the aerosol.
Example 3 A kit containing Ribavirin in injectable solution (1200 mg) and effervescent tablets of NAC (2x600 mg, FLUIMUCIL®) was prepared.
The kit contains the instructions for use and a sterilized syringe for i.v. injection of Ribavirin.

Claims

Claims
1. A pharmaceutical composition containing NAC and Ribavirin to antagonise the flu virus by increasing the efficacy of Ribavirin.
2. Use of NAC to prepare a pharmaceutical composition to be administered in combined therapy with Ribavirin to antagonise the flu virus.
3. A kit containing an effective amount of NAC and Ribavirin or multiples thereof, and a form for administration.
PCT/EP2002/008584 2001-09-05 2002-08-01 A drugs association against influenza virus Ceased WO2003028717A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP02800058A EP1505991A1 (en) 2001-09-05 2002-08-01 A drugs association against influenza virus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2001MI001863A ITMI20011863A1 (en) 2001-09-05 2001-09-05 ASSOCIATION OF DRUGS AGAINST THE VIRUS OF INFLUENCE
ITMI01A001863 2001-09-05

Publications (1)

Publication Number Publication Date
WO2003028717A1 true WO2003028717A1 (en) 2003-04-10

Family

ID=11448332

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/008584 Ceased WO2003028717A1 (en) 2001-09-05 2002-08-01 A drugs association against influenza virus

Country Status (3)

Country Link
EP (1) EP1505991A1 (en)
IT (1) ITMI20011863A1 (en)
WO (1) WO2003028717A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4142774A4 (en) * 2020-05-01 2024-05-29 Mucpharm Pty Ltd PREVENTION AND TREATMENT OF VIRAL INFECTIONS

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990008540A1 (en) * 1989-01-26 1990-08-09 Zambon Group S.P.A. Treatment of disease associated with hiv-infections
US5580577A (en) * 1990-01-11 1996-12-03 Herzenberg; Leonard A. Method of treating the symptoms of human rhinovirus infection
WO1998030228A1 (en) * 1997-01-13 1998-07-16 Emory University Compounds and their combinations for the treatment of influenza infection
EP1046399A1 (en) * 1999-04-19 2000-10-25 Schering Corporation HCV combination therapy, containing ribavirin in association with antioxidants

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990008540A1 (en) * 1989-01-26 1990-08-09 Zambon Group S.P.A. Treatment of disease associated with hiv-infections
US5580577A (en) * 1990-01-11 1996-12-03 Herzenberg; Leonard A. Method of treating the symptoms of human rhinovirus infection
WO1998030228A1 (en) * 1997-01-13 1998-07-16 Emory University Compounds and their combinations for the treatment of influenza infection
EP1046399A1 (en) * 1999-04-19 2000-10-25 Schering Corporation HCV combination therapy, containing ribavirin in association with antioxidants

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FLORA DE S ET AL: "ATTENUATION OF INFLUENZA-LIKE SYMPTOMATOLOGY AND IMPROVEMENT OF CELL-MEDIATED IMMUNITY WITH LONG-TERM N-ACETYLCYSTEINE TREATMENT", EUROPEAN RESPIRATORY JOURNAL, MUNKSGAARD INTERNATIONAL PUBLISHERS, COPENHAGEN, DK, vol. 10, July 1997 (1997-07-01), pages 1535 - 1541, XP002912424, ISSN: 0903-1936 *
HENNET T ET AL: "ALTERATIONS IN ANTIOXIDANT DEFENCES IN LUNG AND LIVER OF MICE INFECTED WITH INFLUENZA A VIRUS", JOURNAL OF GENERAL VIROLOGY, SOCIETY FOR GENERAL MICROBIOLOGY, READING, GB, vol. 73, January 1992 (1992-01-01), pages 39 - 46, XP002912421, ISSN: 0022-1317 *
TODISCO T ET AL: "PROTECTIVE EFFECT OF N-ACETYLCYSTEINE ON IMMUNE SYSTEM OF ELDERLY PATIENTS IN ACUTE REPIRATORY VIRAL INFECTIONS", ANNUAL CONGRESS. EUROPEAN RESPIRATORY SOCIETY ERS. ABSTRACTS, XX, XX, 25 September 1993 (1993-09-25), pages 559S, XP002912419 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4142774A4 (en) * 2020-05-01 2024-05-29 Mucpharm Pty Ltd PREVENTION AND TREATMENT OF VIRAL INFECTIONS

Also Published As

Publication number Publication date
ITMI20011863A0 (en) 2001-09-05
ITMI20011863A1 (en) 2003-03-05
EP1505991A1 (en) 2005-02-16

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