[go: up one dir, main page]

WO1986003412A1 - Ameliorations du traitement et de la prevention des infections par rhinovirus - Google Patents

Ameliorations du traitement et de la prevention des infections par rhinovirus Download PDF

Info

Publication number
WO1986003412A1
WO1986003412A1 PCT/GB1985/000555 GB8500555W WO8603412A1 WO 1986003412 A1 WO1986003412 A1 WO 1986003412A1 GB 8500555 W GB8500555 W GB 8500555W WO 8603412 A1 WO8603412 A1 WO 8603412A1
Authority
WO
WIPO (PCT)
Prior art keywords
interferon
antiviral substance
combination according
enviroxime
phases
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/GB1985/000555
Other languages
English (en)
Inventor
David Arthur John Tyrrell
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 GB848430883A external-priority patent/GB8430883D0/en
Priority claimed from GB858511658A external-priority patent/GB8511658D0/en
Application filed by Individual filed Critical Individual
Publication of WO1986003412A1 publication Critical patent/WO1986003412A1/fr
Priority to NO863165A priority Critical patent/NO863165L/no
Anticipated expiration legal-status Critical
Ceased 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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]

Definitions

  • This invention relates to the treatment, control and prevention of viral respiratory infections and especially the common cold infections caused by rhinoviruses.
  • interferons The inherent ability of the interferons to suppress colds and to be effective in prophylaxis when applied in sufficient amounts has undoubtedly been established and with increasing knowledge of the various species of interferon which exist, alpha, beta and gamma, antiviral activity against respiratory viruses has been confirmed with all known members of the alpha species and is likely to be similarly proven for beta and gamma species of interferon.
  • the present invention comprises the synergistic combination of a non-interferon antiviral substance active against rhinoviruses and an interferon for simultaneous, separate or sequential use in the treatment or prevention of- rhinovirus infection. Also included within the scope of the present invention is the use of a non-interferon antiviral substance active against rhinoviruses and an interferon for the manufacture of a synergistic medicament combination of the antiviral substance and the interferon for application in the treatment or prevention of a rhinovirus infection.
  • a method of treating or preventing rhinovirus infection in which a non-interferon antiviral substance active against rhinoviruses and an interferon are administered to a patient whereby rhinovirus infection in the patient is treated or prevented by synergistic activity against the rhinovirus of the non-interferon activiral substance and the interferon.
  • This example shows the inhibition of replication of a rhino ⁇ virus type 2 by gamma interferon in combination with the drug enviroxime in WISH cells.
  • Table 1 shows the antiviral activities of human type IFN ⁇ and enviroxime when applied separately and the levels of these substances required to produce the same antiviral effect when applied in combination.
  • the effects on virus yield are shown of progressive dilution of the active substances when applied separately or in combination.
  • Part A of Table 1 shows the effect of progressively reducing IFN ⁇ concentrations in the absence of - 3 - enviroxime whereas part B reproduces this for enviroxime in the absence of IFN ⁇ .
  • Part C of Table 1 progressive dilution of each of the components of a mixture of the two substances is shown.
  • Part A of Table 1 shows a hundred-fold reduction in virus yield (from 6.5 to 4.5) in the presence of two units/ml of IFN ⁇ .
  • Part B shows a similar reduction in the presence of between 0.03 and 0.15 mg/ml of enviroxime (2-amino-1-(isopropylsulphonyl)-6- ( ⁇ -hydroxyimiobenzyl) benzimidazole; equal proportion of syn and anti isomers) .
  • Part C of Table 1 shows that the same reduction is produced by a mixture containing 0.03 units of IFN ⁇ and about 0.0003 (deduced) mg of enviroxime. This dramatic effect is also shown by the two right-hand columns which give the dilution reductions from stock solutions of the two components.
  • Table 1 also shows the Combination Index (CI) which is calculated as described by Spector et al (1982), Am. J. Med. J___ suppl 1A, 36-39, from the equation (Drug 1) (Drug 2)/[Drug 1 + Drug 2) (VC)] .
  • (Drug 1), (Drug 2), (Drug 1 + Drug 2) and (VC) are yield of treated virus with (Drug 1), (Drug 2) combination of Drug 1 and Drug 2 and untreated virus control respectively.
  • CI Combination Index
  • IFN was added 24 hours before virus. Enviroxime was added with virus. The cultures were inoculated with moi 10 TCID__ of ' RVg, harvested after 24 hours and then titrated. Recombinant human IFN ⁇ was E.coli-derived (D0002) with a titre of 6.8 x 10 7 IU/ml. WISH cells were grown at 37°C in MEM(Gibco) supplemented with 10% foetal bovine serum (FBS), 1% glutamine, penicillin 100 unit/ml and streptomycin 0.1 mg/ml. A laboratory passaged strain of RV_ was grown in Ohio HeLa cell monolayers maintained in BME supplemented with 2% FCS. Cultures were harvested at full cytopathic effect (CPE), frozen and thawed, clarified by centrifugation and the supernatant was stored at -70C.
  • CPE cytopathic effect
  • This example demonstrates the inhibition in WISH cells (grown as described in Example 1) of a rhinovirus type 9 (grown and harvested as for RV in Example 1) (100 TCID_ 0 /ml) by human type gamma interferon in combination with each of the three antiviral drugs enviroxime, ,6-dichloroflavan (DCF) and a chalcone (4'-ethoxy- 2 , -hydroxy-4,6 , -dimethoxy-chalcone.
  • DCF ,6-dichloroflavan
  • the numbers in the first two columns indicate the end points of one drug in the presence of the indicated concentration of the other, and again it is seen that over a wide range of concentrations the amount of both drugs which is required is greatly reduced compared with that when they are acting alone.
  • the size of these reductions is shown directly in columns 3 and 4 and the combined inhibitory effect is also expressed as the FIC index, as shown in the last column.
  • the FIC index (MIC of drug A in combination)/(MIC of drug A alone) + (MIC of drug B in combination)/(MIC of drug B alone).
  • FIC index ⁇ 0.5 significant synergism
  • FIC index 0.5-0.9 suggestive of synergism
  • FIC index * A Effects are additive
  • FIC index 1.1-1.9 Indifference or ' partial antagonism
  • FIC index >2 Antagonism.
  • the broken line shows the merely additive effect on the inhibition of virus replication to be expected from the interferon and non-interferon antiviral and the unbroken line the actual synergistic effect.
  • FIG. 2 shows the inhibition of a rhinovirus type 9 (100 TCID n /ml) by enviroxime in combination in turn with human type alpha, beta and a hybrid beta-like interferon, (hybrid IFN ⁇ x 410: normal HuIFN ⁇ in which some of the N-terminal sequence has been removed and replaced with HuIFN ⁇ - sequence) 90% pure and containing 5 x 10 IU/ml) the results being presented, respectively, in sections (a), (b) and (c) of the Figure.
  • Hybrid IFN ⁇ x 410 normal HuIFN ⁇ in which some of the N-terminal sequence has been removed and replaced with HuIFN ⁇ - sequence
  • Figure 3 shows the counterpart experiments to those of Figure 1 but using a rhinovirus type 2 (100 TCID- 0 /ml), sections (a), (b) and (c) of the Figure relating, respectively, to the chalcone, dichloroflavan and enviroxime.
  • Non-interferon antiviral substances which are particularly suitable for carrying the invention into effect are organic compounds such as the chalcones and enviroximes which contain no heavy metals and which have a low degree of mammalian toxicity relative to the dose synergistically effective with the interferon to prevent or treat rhinovirus infection.
  • the cytotoxic concen ⁇ tration of such substances in vitro is generally at least one and preferably at least three orders of magnitude greater than the effective concentration of the substance alone.
  • interferon and the other antiviral substance will be administered at about the same time either separately or in compounded form and in proportions calculated to achieve a pronounced synergistic effect. They will be administered to the patient by any of the known methods for achieving protection against the common cold e.g. by nasal drops or sprays or powders although orally administrable forms are also envisaged.
  • the combination of the present invention may be presented in the form of a pack which comprises two phases for simultaneous, separate or sequential oral or intranasal application, "the said phase being isolated from one another, one phase comprising a non-interferon antiviral substance active against rhinoviruses together with a vehicle and the other phase comprising an interferon together with a vehicle, the construction of a container housing the phases or the arrangement of 'the phases relative to one another being such as to facilitate and encourage either simultaneous application of the phases or the application of first one of said phases and then the other, whereby in normal use of the contents of the pack a dose of the non-interferon antiviral substance and the interferon will be applied which is synergistically effective to treat or prevent rhinovirus infection.
  • interferon e.g. INF ⁇ or 6
  • antiviral e.g. enviroxime
  • the daily dosage of inter ⁇ feron is usually divided into 2 or 3 applications and of the antiviral into 3 to 5 applications.
  • interferon e.g. INF ⁇ with a potency of 2.5 MU/ml
  • interferon antiviral e.g. enviroxime

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Bidet-Like Cleaning Device And Other Flush Toilet Accessories (AREA)

Abstract

Combinaison synergique d'une substance antivirale sans rapport avec l'interféron et active contre les rhinovirus et d'un interféron, pour une utilisation simultanée, séquentielle ou séparée dans le traitement ou la prévention des infections provoquées par le rhinovirus.
PCT/GB1985/000555 1984-12-06 1985-12-06 Ameliorations du traitement et de la prevention des infections par rhinovirus Ceased WO1986003412A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NO863165A NO863165L (no) 1984-12-06 1986-08-05 Fremgangsmaate ved forbedret bekjempelse av rhinovirusinfeksjon.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB848430883A GB8430883D0 (en) 1984-12-06 1984-12-06 Treatment/control of rhinoviruses
GB8430883 1984-12-06
GB8511658 1985-05-08
GB858511658A GB8511658D0 (en) 1985-05-08 1985-05-08 Treatment control/prevention of rhino-virus infection

Publications (1)

Publication Number Publication Date
WO1986003412A1 true WO1986003412A1 (fr) 1986-06-19

Family

ID=26288545

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1985/000555 Ceased WO1986003412A1 (fr) 1984-12-06 1985-12-06 Ameliorations du traitement et de la prevention des infections par rhinovirus

Country Status (6)

Country Link
EP (1) EP0207116A1 (fr)
AU (1) AU5234586A (fr)
ES (1) ES8700940A1 (fr)
GB (1) GB2168608A (fr)
NO (1) NO863165L (fr)
WO (1) WO1986003412A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5093116A (en) * 1988-06-02 1992-03-03 Boehringer Ingelheim Int. Gmbh Method of treating viral infection utilizing inteferon α and pipyridamole

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820515A (en) * 1982-12-13 1989-04-11 Texas A&M University System Method of using interferon in low dosage to regulate appetite and efficiency of food utilization
US4820514A (en) * 1985-12-30 1989-04-11 Texas A&M University System Low dosage of interferon to enhance vaccine efficiency

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080032A2 (fr) * 1981-11-20 1983-06-01 Enzo Biochem, Inc. Préparation pharmaceutique pour le traitement de lésions herpétiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080032A2 (fr) * 1981-11-20 1983-06-01 Enzo Biochem, Inc. Préparation pharmaceutique pour le traitement de lésions herpétiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 102, No. 23, 10 June 1985, Columbus, Ohio, (US) Y. NINOMIYA et al.: "Comparative Studies on the Modes of Action of the Antirhinovirus Agents Ro-090410, Ro-09-0179, RMI-15, 731, 4' ,6-Dichloroflavan and Enviroxime", see Abstract No. 197597d & Antimicrob. Agents Chemother. 1985, 27 (4), 595-9 (Eng) *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5093116A (en) * 1988-06-02 1992-03-03 Boehringer Ingelheim Int. Gmbh Method of treating viral infection utilizing inteferon α and pipyridamole

Also Published As

Publication number Publication date
ES549671A0 (es) 1986-11-16
EP0207116A1 (fr) 1987-01-07
AU5234586A (en) 1986-07-01
NO863165D0 (no) 1986-08-05
ES8700940A1 (es) 1986-11-16
GB8530152D0 (en) 1986-01-15
NO863165L (no) 1986-08-05
GB2168608A (en) 1986-06-25

Similar Documents

Publication Publication Date Title
Canonico et al. Inhibition of RNA viruses in vitro and in Rift Valley fever-infected mice by didemnins A and B
US4462986A (en) Synergistic anti-herpes compositions
JP2009102370A (ja) グリシルリジン酸及び抗ウイルス活性を有する蛋白質を少なくとも一つ含む、抗ウイルス薬剤組成物
US5080909A (en) Anti-viral compositions
Wyde et al. The antiviral activity of SP-303, a natural polyphenolic polymer, against respiratory syncytial and parainfluenza type 3 viruses in cotton rats
Ahmad et al. Synergism between anti-rhinovirus antivirals: various human interferons and a number of synthetic compounds
KR960000432B1 (ko) 제약학적 생성물
NL8501995A (nl) Werkwijze voor het remmen van acuut stralingssyndroom en het optreden van septiceem en daarvoor te gebruiken preparaat.
WO1986003412A1 (fr) Ameliorations du traitement et de la prevention des infections par rhinovirus
English et al. Attenuation of experimental tobramycin nephrotoxicity by ticarcillin
KISHIMOTO et al. Prevention of murine coxsackie B3 viral myocarditis and associated lymphoid organ atrophy with recombinant human leucocyte interferon αA/D
US4902678A (en) Anti-viral compositions
US5869446A (en) Preparation of lactoferrin (or serotransferrin or ovotransferrin) and desferrioxamine methanesulfonate (or other low molecular weight metal ion chelators) for the therapy of viral infections
US4344937A (en) Antiviral agent comprising 1-β-D-arabinofuranosylthymine
EP1473037A1 (fr) Ribavirin pour le traitement des infections dues au hMPV
Stevenson et al. Recombinant alpha interferon in retreatment of two patients with pulmonary lymphoma: Dramatic responses with resolution of pulmonary complications
US5262174A (en) Anti-viral compositions
WO1983002723A1 (fr) Compositions anti-virales
SK282983B6 (sk) Použitie aminopurínových protivírusových látok
Tyrrell et al. Prophylaxis and treatment of rhinovirus infections
Viertel et al. Treatment of severe systemic lupus erythematosus with immunoadsorption and intravenous immunoglobulins.
JPS62501074A (ja) ライノウイルス感染の治療、抑制および予防に関する改良
Takahashi et al. The Japanese Interferon Study Group (JISG) has established the efficacy of human interferon‐β for serious CMV pneumonitis in kidney recipients
JPH0441427A (ja) 骨粗鬆症治療剤
Jenkins et al. Azathioprine in 50 rheumatoid arthritic patients intolerant or unresponsive to gold or penicillamine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU JP NO US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BE CH DE FR IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 1986900179

Country of ref document: EP

ENP Entry into the national phase

Ref country code: AT

Ref document number: 1985 9051

Date of ref document: 19860619

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1986900179

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1986900179

Country of ref document: EP