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WO1993011763A1 - Utilisation de cytochalasines pour inhiber la replication virale - Google Patents

Utilisation de cytochalasines pour inhiber la replication virale Download PDF

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Publication number
WO1993011763A1
WO1993011763A1 PCT/CA1992/000526 CA9200526W WO9311763A1 WO 1993011763 A1 WO1993011763 A1 WO 1993011763A1 CA 9200526 W CA9200526 W CA 9200526W WO 9311763 A1 WO9311763 A1 WO 9311763A1
Authority
WO
WIPO (PCT)
Prior art keywords
cytochalasin
dextran
hiv
cell
pharmaceutical preparation
Prior art date
Application number
PCT/CA1992/000526
Other languages
English (en)
Inventor
Thomas C. Usher
Lionel Resnick
Mariano Busso
Original Assignee
Usher Thomas C
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 CA002057289A external-priority patent/CA2057289A1/fr
Application filed by Usher Thomas C filed Critical Usher Thomas C
Priority to EP92923649A priority Critical patent/EP0616530A1/fr
Publication of WO1993011763A1 publication Critical patent/WO1993011763A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof

Definitions

  • This invention relates to a pharmaceutical preparation and method for inhibiting replication of a family of viruses know as human immunodeficiency virus HTLV-III (AIDS) virus.
  • AIDS human immunodeficiency virus
  • HTLV family of retroviruses A group of these viruses designated as HTLV-III has been isolated from patients with Acquired Immune Deficiency Syndrome (AIDS) and has become considered to be responsible for the development of this condition in humans. These are also known as HIV, particulary HIV-1 and HIV-2.
  • a cell line representative of this group has been deposited under ATCC No. CRL 8543 by an agency of the U.S. Department of Health and Human Services.
  • Azidothymidine a drug that inhibits reverse transcriptase prolongs the lives of patients with AIDS and many patients who receive AZT have temporary increases in the numbers of circulating helper (CD4 + ) T- lymphocytes.
  • CD4 + circulating helper
  • the invention provides for a pharmaceutical preparation for inhibiting in vivo the replication of viruses which comprises a complex of dextran-cytochalasin D in an appropriate pharmaceutical dosage form.
  • the invention also provides a method for inhibiting in vivo the replication of HIV viruses comprising the administration of a dextran-cytochalasin D complex in a pharmaceutically appropriate dosage form and quantity.
  • figure 1 is a graph indicating the anti-HIV effects of cytochalasin-D
  • figure 2 is a schematic diagram of a cell with a dextran sulphate-cytochalasin-D complex
  • figure 3 comprises graphs of FPLC and HPLC of dextran and dextran-dialdehyde
  • figure 4 comprises graphs of FPLC and HPLC of dextran sulphate and dextran sulphate-dialdehyde
  • figure 5 comprises graphs of FPLC and HPLC of a coupling sample
  • figure 6 is a graph of a complex of dextran and cytochalasin-D in different coupling times.
  • the cell-to-cell transmission of HIV represents a major obstacle in the development of effective anti-viral therapy.
  • This method of provirus spread bypasses the requirements of reverse transcription, thereby rendering inhibitors of reverse transcriptase, such as the nucleoside analogs, inactive.
  • the level of CD4 + T-cell depletion and the amount of HIV production could be reduced if the cell-to-cell spread of HIV was blocked by inhibiting conjugate formation.
  • Dextran sulphate has now been shown to inhibit syncytia formation and exert a potent inhibitor effect against HIV-1.
  • the cytochalasins especially cytochalasin-D, have now been shown to posses anti-HIV effects.
  • the cytochalasins are a class of mold metabolites which have now been shown to exhibit inhibitory effects on cell processes.
  • Six cytochalasins have been isolated. Major biological effects are (1) blockage of cytoplasmic cleavage resulting in multinucleate cell formation; (2) inhibition of cell movement; (3) induction of nuclear extrusion; (4) inhibition of glucose transport, thyroid secretion, growth hormone release, phagocytosis, as well as platelet aggregation and clot contraction.
  • cytochalasin D (C 30 H 37 NO 5 ) a polycyclic hydroxylated hydrocarbon appears to be the preferred compound as regards its cytotoxi ⁇ ity by inhibition of cell processes.
  • cytochalasin-D The anti-HIV effects of cytochalasin, especially cytochalasin-D may be noted from Figure 1.
  • MT-2 cells were infected with HIV-1 at a multiplicity of infection of 0.001 for 1 h followed by exposure to cytochalasin-D.
  • SFU syncytium forming units
  • HIV p24-positive cells indirect immunofluorescence was determined and compared to controls.
  • 0 represents the number of HIV infected cells: [] represents the percentage inhibition of HIV induced syncytium formation.
  • the HIV envelope glycoprotein contains fusogenic domains that are important for virus infection and syncytium formation.
  • the initial event in cell to cell interactions usually involves the formation of cellular conjugates.
  • the integrins are a family of cell-surface structures that mediate conjugate formation and facilitate the development of specific cellular interactions, such as cell mediated cytolysis and antigen presentation.
  • Leucocyte function associated antigen-1 (LFA-l) an integrin molecule that mediates cell to cell binding, has been reported to have a role in HIV induced syncytium formation.
  • the capacity to form syncytia may not, therefore, be solely dependent on the density of CD4 receptors of HIV envelope glycoprotein expressed on cell surfaces. In these studies, experiments were performed to determine the role of cell surface molecules, other than CD4 and the HIV envelope glycoprotein, in the development of HIV induced syncytium formation.
  • the significance of in vivo syncytium formation is suspect.
  • the cell to cell transmission of HIV is likely to be a major contributor to virus spread and CD4 T-cell depletion within the host.
  • Factors that lead to an increase in the level of expression of adhesion molecules would be expected to favour the cell to cell spread of HIV.
  • opportunistic infections can function as cofactors in the progression of HIV disease by their effect on the activation of T-lymphocytes, leading to an up regulation in the expression of LFA-1 on cell surfaces.
  • the coinfection of HTLV and HIV retroviruses accelerates the progression of HIV disease.
  • HTLV-1 transformed cell lines MT-2 and C- 8166
  • MT-2 and C- 8166 The common feature of HTLV-1 transformed cell lines (MT-2 and C- 8166) is their enhanced expression of integrins and conjugate formation. This results in a mechanism whereby the coinfection of HTLV and HIV retroviruses favours the cell to cell spread of HIV.
  • cytochalasin especially cytochalasin- D
  • cytochalasin-D a complex of cytochalasin, especially cytochalasin-D and dextran 40,000 molecular weight (blood plasma extender FDA approved)
  • a complex of cytochalasin, especially cytochalasin-D and dextran sulphate usherdex 8,000 molecular weight
  • Dextrans of any molecular weight may be used in the preparation of a dextran-cytochalasin-D complex having therapeutic value.
  • the usefulness of the instant invention includes topical application for the treatment of ulcers and viruses including genital ulcers and viruses, and mouth ulcers.
  • the invention is also useful in the treatment of Karposisarchoma and other tumours. The invention promotes inactivation of such tumours. Similar polysaccharides having the property of slow release mechanism such as dextrin, cyclodextrin etc. may also be as effective as those already above mentioned.
  • cytochalasin-D By complexing or coupling cytochalasin-D with dextran, dextran sulphate or other suitable polysaccharides the cytotoxicity of the cytochalasin-D to the host is reduced due to its slow release from the complex.
  • the complex of dextran and cytochalasin-D be useful in inhibiting virus replication in vivo , but in addition such a complex will also be useful in the treatment (in vivo ) of a variety of different types of cancers.
  • Dextran-cytochalasin-D as a macromolecular compound has excellent metabolic stability, resulting in a more effective treatment.
  • Dextran is useful not only as a "transfer weapon", but also as an immunologically active material which has now been used in the treatment study of AIDS.
  • the complex provides an effective weapon which will be able to attack and kill the harmful cells of several severe diseases including AIDS and carcinoma.
  • Figure 2 illustrates the effect of dextran sulphate-cytochalasin-D complex 10 on an abnormal cell 12, having a receptor 14.
  • cytochalasin-D contains a -NH group, it suggests that coupling will be possible if dextran is modified to dextran dialdehyde.
  • the principle of coupling of dextran and cytochalasin-D by dialdehyde may be represented by the following formula:
  • the mixture was dialysed against distilled water for more than 24 hours.
  • Figure 3 illustrates the FPLC and HPLC of dextran and dextran-dialdehyde
  • figure 4 illustrates the FPLC and HPLC of dextran sulphate and dextran sulphate-dialdehyde.
  • the results show that the amount of complex of dextran- cytochalasin-D increases with coupling time.
  • the area rate of A to G is increased from 0.55 at 4 hours to 0.96 at 24 hours.
  • Figure 6 shows the FPLC of complex of dextran and cytochalasin-D in different coupling times.
  • E-Aminocaproic acid 200 mg was added and the solution stirred with a magnetic bar for 24 hr at room temperature. The product was dialysed against three changes (12 hours each) of 0.1 M sodium carbonate.
  • cytochalasin D 10 mg
  • ethanol 1.5 ml
  • dimethyl sulfoxide 1.5 ml
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 400 mg was added with vigorous stirring.
  • the pH was adjusted to 6.0 by addition of 2N hydrochloric acid and stirring was continued for 24 hr.
  • the product was dialysed exhaustively against water and freezedried.
  • the dextran had M.W. 10,000 and in the coupling with cytochalasin D, the solvent was ethanol.
  • [ 3 H]cytochalasin B (2.5 uCi) was present as a marker to permit estimation of the extent of coupling by measurement of 3 H in the product.
  • the dextran had M.W. 40,000 and the solvent was dimethyl sulfoxide.
  • the recovery of dextran was quantitative.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur une préparation pharmaceutique et sur un procédé permettant d'inhiber in vivo la réplication de virus. Dans une variante, la préparation pharmaceutique se compose d'un complexe de dextrane et de cytochalasine-D susceptible d'être administré selon un dosage, une quantité et une posologie appropriés à un patient souffrant d'une maladie virale telle que le SIDA.
PCT/CA1992/000526 1991-12-09 1992-12-08 Utilisation de cytochalasines pour inhiber la replication virale WO1993011763A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP92923649A EP0616530A1 (fr) 1991-12-09 1992-12-08 Utilisation de cytochalasines pour inhiber la replication virale

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CA2,057,289 1991-12-09
CA002057289A CA2057289A1 (fr) 1991-12-09 1991-12-09 Preparations pharmaceutiques inhibant la replication de divers virus
US93931792A 1992-09-02 1992-09-02
US07/939,317 1992-09-02

Publications (1)

Publication Number Publication Date
WO1993011763A1 true WO1993011763A1 (fr) 1993-06-24

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1992/000526 WO1993011763A1 (fr) 1991-12-09 1992-12-08 Utilisation de cytochalasines pour inhiber la replication virale

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EP (1) EP0616530A1 (fr)
WO (1) WO1993011763A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000177A1 (fr) * 1993-06-17 1995-01-05 Dextran Products Limited Preparation pharmaceutique et procede permettant d'inhiber la replication de differents virus
WO1995005199A1 (fr) * 1993-08-19 1995-02-23 Dextran Products Limited Preparation pharmaceutique et son procede de production
WO2018038425A1 (fr) * 2016-08-24 2018-03-01 (주)아모레퍼시픽 Composition de blanchiment de la peau contenant de la cytochalasine d

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4855416A (en) * 1983-07-25 1989-08-08 Polydex Pharmaceuticals, Ltd Method for the manufacture of dextran sulfate and salts thereof
WO1990013293A1 (fr) * 1989-04-28 1990-11-15 Syracuse University Compositions de cytochalasine et procedes therapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4855416A (en) * 1983-07-25 1989-08-08 Polydex Pharmaceuticals, Ltd Method for the manufacture of dextran sulfate and salts thereof
WO1990013293A1 (fr) * 1989-04-28 1990-11-15 Syracuse University Compositions de cytochalasine et procedes therapeutiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AIDS vol. 5, no. 12, December 1991, pages 1425 - 1432 BUSSO,MARIANO E. ET AL 'HIV-INDUCED SYNCYTIUM FORMATION REQUIRES THE FORMATION OF CONJUGATES BETWEEN VIRUS- INFECTED AND UNINFECTED T-CELLS IN VITRO.' *
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY vol. 34, no. 10, October 1990, pages 1991 - 1995 BUSSO, MARIANO E. ET AL 'ANTI-HUMAN IMMUNODEFICIENCY VIRUS EFFECTS OF DEXTRAN SULFATE ARE STRAIN DEPENDENT AND SYNERGISTIC OR ANTAGONISTIC WHEN DEXTRAN SULFATE IS GIVEN IN COMBINATION WITH DIDEOXYNUCLEOSIDES' *
THE JOURNAL OF ANTIBIOTICS vol. 45, no. 5, May 1992, pages 686 - 691 LINGHAM, RUSSELL B. ET AL 'L-696,474, A NOVEL CYTOCHALASIN AS AN INHIBITOR OF HIV-1 PROTEASE III. BIOLOGICAL ACTIVITY' *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000177A1 (fr) * 1993-06-17 1995-01-05 Dextran Products Limited Preparation pharmaceutique et procede permettant d'inhiber la replication de differents virus
WO1995005199A1 (fr) * 1993-08-19 1995-02-23 Dextran Products Limited Preparation pharmaceutique et son procede de production
WO2018038425A1 (fr) * 2016-08-24 2018-03-01 (주)아모레퍼시픽 Composition de blanchiment de la peau contenant de la cytochalasine d

Also Published As

Publication number Publication date
EP0616530A1 (fr) 1994-09-28

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