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WO1996001627A1 - Utilisation de swinholide a pour detacher et depolymeriser l'actine - Google Patents

Utilisation de swinholide a pour detacher et depolymeriser l'actine Download PDF

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Publication number
WO1996001627A1
WO1996001627A1 PCT/US1995/008610 US9508610W WO9601627A1 WO 1996001627 A1 WO1996001627 A1 WO 1996001627A1 US 9508610 W US9508610 W US 9508610W WO 9601627 A1 WO9601627 A1 WO 9601627A1
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Prior art keywords
swinholide
actin
mucous
macrolide
respiratory
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PCT/US1995/008610
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English (en)
Inventor
Michael R. Bubb
Edward D. Korn
Ilan Spector
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THE GOVERNMENT OF THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTMENT OF HEALTH ANS HUMA SERVICES
Research Foundation Of The State University Of New York
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Application filed by THE GOVERNMENT OF THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTMENT OF HEALTH ANS HUMA SERVICES, Research Foundation Of The State University Of New York filed Critical THE GOVERNMENT OF THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTMENT OF HEALTH ANS HUMA SERVICES
Priority to AU29670/95A priority Critical patent/AU2967095A/en
Publication of WO1996001627A1 publication Critical patent/WO1996001627A1/fr

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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones

Definitions

  • This invention relates to methods for severing and depolymerizing filamentous actin and to therapeutic methods for conditions or diseases involving pathological
  • this invention provides a method for severing and depolymerizing filamentous actin
  • Cystic fibrosis is one of the most common, fatal, genetic diseases in the world today. The life
  • Cystic fibrosis is an autosomal recessive disease that causes abnormalities in fluid and electrolyte transport in exocrine epithelia in the lung.
  • cystic fibrosis the luminal border of the airway mucosal cell is unresponsive to cyclic-AMP dependent protein kinase
  • the cells are impermeable to chloride ions and as a result, sodium absorption across the cell membrane is accelerated.
  • the subsequent electrolyte imbalances tend to reduce the level of hydration of the airway mucous, thus contributing to the viscosity of the lung secretions characteristic of cystic fibrosis.
  • Bacteria and microplasma frequently establish colonies within the mucous.
  • mucosal clearance is reduced in cystic fibrosis patients, and therefore bacterial clearance is also reduced and lung congestion and infection are thus common.
  • Therapeutic agents that target the cytoskeleton are limited mostly to compounds that affect microtubules. Recently, however, several drugs that directly or indirectly affect the organization of the actin cytoskeleton have been investigated as potential therapies for neoplastic, immunologic and cardiovascular diseases (Senderowicz A.M.J. et al. (1994), Proc. Am. Assoc. Cane. Res . , 35:409; Bubb M.R. et al. (1994), J. Biol . Chem. , 269:4869; Van Leenen, D. et al. (1993), J. Immunol . , 151:2318; Rao, K.M.K. et al. (1988), J " . Cell .
  • Swinholide A is a cytotoxic 44-carbon ring dimeric macrolide isolated from the marine sponge, Theonella swinhoei (F. Carmeli and Y. Kashman, (1985), Tetrahedron Lett . , 26:511; Kobayashi M. et al. (1990), Chem Pharm. Bull . 38:2409-2418; Kobayashi M. et al. (1990) , Chem Pharm. Bull . 38:2960; Kitagawa, I. et al. (1990) J. Am. Chem. Soc . 112:3710-3712); Kobayashi, M., et al. (1994) Chem.
  • Swinholide A is capable of both severing and depolymerizing actin.
  • Swinholide A has the ability to both sever and depolymerize actin filaments.
  • This invention relates in general to a method of severing and/or depolymerizing filamentous actin by contacting the filamentous actin or a locus containing filamentous actin with an effective amount of Swinholide A or modification thereof.
  • This invention relates to the use of Swinholide A and modifications thereof in the treatment of mammals afflicted with diseases or conditions in which extracellular actin is pathological.
  • This invention also relates to the use of Swinholide A and modifications thereof in treatment of mammals afflicted with respiratory conditions or diseases involving thick mucous secretions or sputum accumulations in the respiratory passages.
  • This invention further relates to the use of Swinholide A and modifications thereof in the treatment of mammals afflicted with cystic fibrosis.
  • This invention also relates to methods of use of Swinholide A and modifications thereof in isolation and purification of cellular components.
  • This method also relates to a treatment method comprising administering therapeutically effective amounts of Swinholide A to patients afflicted with diseases characterized by accumulation of inflammatory cells and necrotic cellular debris in respiratory passages resulting in the accumulation of pathological thick mucous or sputum containing filamentous actin.
  • compositions suitable for pulmonary administration comprising effective amounts of Swinholide A and modifications thereof to sever and depolymerize the filamentous actin present in cystic fibrosis mucous or sputum.
  • FIG. 1A-E show the effect of Swinholide A on mouse fibroblasts. Fluorescence micrographs of Balb/C 3T3 (Fig.lA and Fig.IB) and Swiss 3T3 (Fig.lC and Fig.ID) cells labeled with TRITC-phalloidin. The decrease in fluorescence intensity in (Fig.IB) and (Fig.ID) was much greater than it appears to be because the exposure times were controlled automatically to optimize visualization.
  • FIG.lA Control cells grown to high density.
  • Fig.IB Cells grown to high density and then treated for 24 h with 50 nM Swinholide A.
  • Fig.lC Exponentially growing control cells.
  • Fig.ID Exponentially growing cells treated with 10 nM Swinholide A for 24 h.
  • FIG. 2A-C shows the sequestration of dimeric actin by Swinholide A.
  • Fig.2A Effect of Swinholide A on the apparent actin critical concentration.
  • Pyrenyl- labeled, gel-filtered skeletal muscle F-actin J.A. Spudich and S. Watt (1971), J " . Biol . Chem. , 246:4865; T. Kouyama and K. Mihashi (1981), Eur. J. Biochem. , 114:33
  • buffer F was diluted to the concentrations shown in the presence of 0 (D) , 0.3 ( ⁇ ) , 0.9 (o) or 1.8 (O) ⁇ M Swinholide A and the fluorescence determined at steady state.
  • Optical absorbance scans at 290 nm were obtained at 7-min intervals.
  • FIG.3A Time course of depolymerization of Mg 2+ -pyrenyl actin monitored by decrement in fluorescence intensity.
  • the samples were mixed by inversion of the cuvettes for 10 seconds (s) and fluorescence intensity was first measured 25 s after dilution. (Fig.3B) .
  • Figures 4A-4B show examples of isomers in which the size or the conformation of the macrocyclic dilactone ring has been altered.
  • Mammal includes, but is not limited to, humans, monkeys, dogs, cats, mice, rats, hamsters, cows, pigs, horses, sheep and goats.
  • filamentous actin we mean F-actin or - i/i - polymers of actin or polymeric actin.
  • effective amount amounts of Swinholide A and modifications thereof sufficient to sever and depolymerize filamentous actin.
  • Preferred Swinholide A effective amounts are in the range of about 5 nM to about 100 ⁇ m.
  • therapeutically effective amount dosages of Swinholide A and modifications thereof administered within pharmaceutical compositions as described herein and resulting in the severing and depolymerization of filamentous actin.
  • the therapeutically effective amount of Swinholide A and modifications thereof will depend, for example, upon the therapeutic objective, the rate of administration and the emulation of the patient. Accordingly it may be necessary for the therapist to titer the dosage and modify the rate of administration and dosage as required to obtain the optimal therapeutic effect.
  • modification includes isomers, stereo-isomers, derivatives, homologs, congners, chemical derivatives, and minor modifications, such as esters, ethers and amides, or any other chemical modifications resulting in compounds which are the functional equivalents of Swinholide A as described herein. Swinholide A and modifications thereof may be natural or synthetic in origin. - 9
  • R 1 H or optionally substituted lower straight chain or branched chain alkyl, said alkyl having 1 or more carbons, preferably having 1 to 6 carbon atoms and said optional substituents preferably are, for example, hydroxy; OR 4 wherein R 4 is lower alkyl or halo- alkyl; lower alkyl; haloalkyl; amino; monoalkylamino; dialkylamino; halogen; cycloalkyl; aryl or heteroaryl; R 2 , R 3 are each independently H, optionally substituted straight chain or branch chain alkyl, cycloalkyl, aryl, or heteroaryl; said optional substituents being the same as those mentioned hereinabove.
  • aryl is preferably phenyl or napthyl
  • heteroaryl includes, for example, aromatic hetero groups containing 1 or more oxygen, sulfur, or nitrogen atoms.
  • groups include pyridyl, quinolinyl and indolinyl.
  • Halogen is preferably chlorine, fluorine or bromine.
  • Such monomeric macrolides may have the general Formulas II and III :
  • R 2 being the same as those mentioned hereinabove.
  • Such derivatives can be obtained by acidic treatment of Swinholide A (Kobayashi, et al. (1994) Chem. Pharm Bull 42(1) 19-26, herein incorporated by reference) which may yield a mixture of compounds.
  • Swinholide A Korean, et al. (1994) Chem. Pharm Bull 42(1) 19-26, herein incorporated by reference
  • Such mixtures may include those compounds shown in Figures 4A and 4B and Formula IV below.
  • Such derivatives may have the general Formula IV:
  • R 2 and R 3 are the same as described hereinabove.
  • R is the same as described herein and abov .
  • R CH 2 0H or COOR 5 .
  • R 5 H or optionally substituted lower straight chain or branch chain alkyl and the optional substituents are mentioned herein above.
  • a still further embodiment of this invention is the octaformat which may have the structure shown in formula VI.
  • such compounds may be prepared by reacting Swinholide A with acyl chlorides at about a 2:1 equivalent ratio in pyridene for about 24 - 14 hours at room temperature, or may be prepared by reacting Swinholide A with dibasic acyl chlorides of the general type Z0 2 C- ( ) n -COCl or monobasic acyl chlorides of the ZNH- ( ) n -C0Cl type where Z is a protecting group which will be removed after the completion of the reaction which may be separated based on their cellular and in vitro effects.
  • Formula VI as shown below:
  • R 6 hydrogen or alkanoyl, preferably Cj - C 5 alkonoyl, typical formyl, acetyl or propionyl, preferably R 7 , R 8 are either jointly or independently alkanoyl or alkyl straight chain or branch chain lower alkyl which can be optionally substituted as described hereinabove.
  • epoxidized derivatives of any of the compounds shown as formulae I - VI in which some or all of the double bonds have been epoxidized as to form either c_, ⁇ or ⁇ , ⁇ - epoxides.
  • the epoxy group(s) may be ring-opened to provide hydroxy derivatives. - 15 -
  • Epoxidation products of Swinholide A with OH in the presence of H 2 0 2 will yield a, /3-epoxides, while epoxidation with known epoxidation reagents will yield ⁇ , ⁇ - expoxides.
  • Swinholide A modifications are modified so as to be more polar or bulky thus less able to pass through the cell membrane.
  • respiratory condition or disease an affliction in a mammal wherein there are accumulations of viscous mucous or sputum or pathological accumulations of mucous or sputum blocking the air passages of the afflicted mammal.
  • respiratory conditions or diseases that may be treated by the therapeutic methods described herein include, but are not limited to, cystic fibrosis, pneumonia, acute bronchitis, chronic bronchitis and any respiratory condition characterized by pathological accumulation of sputum resulting in obstruction of the afflicted mammal's airways.
  • Swinholide A a natural marine product, disrupts the actin cytoskeleton of cells grown in culture, severs F-actin with high cooperativity, depolymerizes actin filaments rapidly when the molar ratio of Swinholide A to actin subunits is approximately one and sequesters actin dimers in both polymerizing and non-polymerizing buffers.
  • the binding stoichiometry is one Swinholide A molecule per actin dimer.
  • This invention provides- a method of severing and depolymerizing filamentous actin by exposing or contacting the filamentous actin with an effective amount of Swinholide A or modifications thereof.
  • filamentous actin-containing biological materials include but are not limited to, a cell, continuous cell lines, - 16 - primary cultures of cells, cells, detergent-insoluble cell fractions and cell membrane preparations, cellular homogenates, nuclear homogenates, tissues, organs, extracellular actin, mucous or sputum samples isolated from mammals affiliated with respiratory conditions or diseases, and respiratory secretions.
  • cells include but is not limited to, fibroblasts, neutrophils endothelial, epithelial, leukocytes and platelets.
  • a suitable effective amount of Swinholide A to be used may be in the range of about 5 nM to about 100 ⁇ M, the most preferred range is about 30 nM to about 80 ⁇ m and the most preferable range is about 50 nM to about 100 nM.
  • Balb/c 3T3 cells and Swiss Wesbster 3T3 fibroblast cells are cultured under standard condition and exposed to Swinholide.
  • a preferred range of Swinholide A is about 5 nM to about 100 ⁇ M.
  • the cells are exposed to tetramethyl rhodaminyl-phalloidin (TRITC- phalloidin, Cano, Manuale et al., Cell Mot . and Cytoskel . (1992) 21:147-158) fluorescent derivative of the F-actin binding toxin, and cytological stains. Severing and depolymerization of actin is assessed by fluorescent microscopy.
  • Swinholide A or modifications thereof on filamentous actin may be assessed by conventional methods. Examples of such methods include but are not limited to, electron microscopy (Small, J.V. and Celis, J.E. (1978) Cytobiologie 16:308; Small, J.V. and Celis, J.E. (1978) J " . Cell Sci . 31:393); fluorescence microscopy with rhodamine- labeled phalloidin (Wang, K. et al.
  • mucous or sputum samples isolated from mammals afflicted with a respiratory - 17 - condition or disease such as cystic fibrosis are exposed to Swinholide A or modifications thereof.
  • Severing and depolymization of filamentous actin is assessed by the viscolacistity of the samples.
  • Assessment of severing and depolymerization of filamentous actin can also be determined by viscosity measurements of the filamentous actin contacted with Swinholide A or modifications thereof.
  • Viscosity assessment of biological samples can be performed by standard methods. Examples of such methods includes, but is not limited to, falling ball viscometry (Pollard, T.D.
  • the actin severing and/or depolymerizing effect of Swinholide A or modifications thereof is used in purification of cellular components or cellular fractions in biological preparations.
  • Swinholide A can be added to a biological preparation thereby allowing for the separation of plasma membranes from associated filamentous actin.
  • biological preparations include, but is not limited to, cellular homogenates, and membrane fractions prepared from them by differential centrifugation (Miyata H. et al. (1989) J " . Cell Biol . 109: 1519; Clarke, BJ et al. (1988) J. Protozool . 35:408) and detergent-insoluble membrane skeletons (Apgar J.
  • Suitable concentrations of Swinholide may be in the range of about 5 nM to about 100 ⁇ M.
  • Examples of cellular components include, but are not limited to, plasma membranes, nuclear membranes, and cytoskeletons. - 18 -
  • Swinholide A or modifications thereof may be used to therapeutically treat mammals afflicted with respiratory conditions or disease.
  • conditions that can be treated by the therapeutic methods disclosed herein include but are not limited to, pneumonia, acute bronchitis, chronic bronchitis and cystic fibrosis.
  • mammals preferably humans afflicted with cystic fibrosis are administered therapeutically effective amounts of Swinholide A which functions to sever and depolymerize the filamentous actin present in the pathological mucous or sputum in their lungs.
  • An individual having cystic fibrosis is initially administered amounts of Swinholide A in the range of about 0.10 mg to about 5 mg per dosage, twice daily.
  • Preferred dosages are in the range of about 0.25 mg to 1.0 mg, twice daily or as determined by the minimum effective concentration from sputum samples.
  • a pharmaceutical composition of the Swinholide A is administered as fluid containing Swinholide A deliverable as a spray from a nebulizer.
  • the Swinholide A composition is preferably to be delivered alone until mucous viscosity is decreased or together with other therapeutic agents such as antibiotics.
  • other therapeutic agents such as antibiotics.
  • dosage regime may be varied both in frequency and in quantity to a given patient. It is anticipated that this regime will be optimized for an individual in accordance with the conventional evaluation techniques. Efficacy will be determined by assaying for improved lung function in afflicted mammals. This assessment can include viscoelastic measurements of sputum, improvements in pulmonary function including - 19 - improvements in forced exploratory volume of sputum and maximal midexpirator flow rate.
  • the aforementioned therapeutic regime can be given in conjunction with adjunct therapies such as antibiotics, DNAse I or other current therapies for the treatment of cystic fibrosis.
  • Swinholide A is effective to reduce the viscosity of pulmonary mucous in a cystic fibrosis patient thereby facilitating lung clearance of the patients.
  • Swinholide A or modifications thereof can be coupled to hydrophilic elements or other molecules by standard methods so as to prevent entry of the Swinholide A or modifications thereof into the cells of the respiratory tract.
  • Swinholide A or modifications thereof can be administered to the afflicted mammal by means of a pharmaceutical delivery system for the inhalation route.
  • Swinholide A or modifications thereof may be formulated for administration as pharmaceutical compositions in physiologically acceptable carriers or excipient, optimally with supplementary therapeutic agents.
  • the compounds may be formulated in a form suitable for administration by inhalation.
  • the pharmaceutical delivery system is one that is suitable for respiratory therapy by topical administration of Swinholide A and analogs thereof to mucosal linings of the bronchi.
  • This invention can utilize a system that depends on the power of a compressed gas to expel the Swinholide A - 20 - from a container.
  • An aerosol or pressurized package can be employed for this purpose.
  • the term "aerosol" is used in its conventional sense as referring to very fine liquid or solid particles carried by a propellant gas under pressure to a site of therapeutic application.
  • the aerosol contains the therapeutically active compound, which can be dissolved, suspended, or emulsified in a mixture of a fluid carrier and a propellant.
  • the aerosol can be in the form of a solution, suspension, emulsion, powder, or semi-solid preparation. Aerosols employed in the present invention are intended for administration as fine, solid particles or as liquid mists via the respiratory tract of a patient.
  • suitable propellants include, but is not limited to, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a value to deliver a metered amount.
  • the present invention can also be carried out with a nebulizer, which is an instrument that generates very fine liquid particles of substantially uniform size in a gas.
  • a nebulizer which is an instrument that generates very fine liquid particles of substantially uniform size in a gas.
  • a liquid containing the Swinholide A or analogs thereof is dispersed as droplets.
  • the small droplets can be carried by a current of air or oxygen through an outlet tube of the nebulizer. The resulting mist penetrates into the respiratory tract of the patient.
  • a powder composition containing Swinholide A or analogs -thereof, with or without a lubricant, carrier, or propellant, can-be administered to a mammal in need—of therapy.
  • This embodiment of the invention can be carried out with a conventional device for administering a powder pharmaceutical composition by inhalation.
  • a powder mix of the compound and a suitable powder base such - 21 - as lactose or starch may be presented in unit dosage form in for example capsular or cartridges (e.g., - gelatin, or blister packs) from which the powder may be administered with the aid of an inhaler.
  • the patient to be treated can be a primate, such as a human, or any other animal exhibiting the described symptoms. While the method of the invention is especially adapted for the treatment of a human patient, it will be understood that the invention is also applicable to veterinary practice.
  • Balb/C 3T3 (American Type Culture Tissue Collection, Rockville, MD) and Swiss 3T3 (American Type Culture Tissue Collection, Rockville, MD) cells were grown in Dulbecco's modified Eagle's medium supplemented with 10% calf serum (Gibco) at 37 °C in a humidified atmosphere of 9% C0 2 in air.
  • Swinholide A (Carmely, F. and Kashman, Y. (1985) Tetrahedron Lett. 26:511; Kobayashi, M. et al.
  • the stained cells were examined with a Zeiss Axiphot microscope equipped with epifluoresence illumination and photographed using automatic exposure to optimize visualization.).
  • Swinholide A caused rounding of mouse embryo 3T3 fibroblast cells within 1 h and massive destruction of the actin cytoskeleton as monitored by TRITC-phalloidin, a fluorescent derivative of the F-actin-binding toxin. Partial cell retraction or arborization and diminution of microfilament bundles (stress fibers) began after exposure of cells to 10-50 nM Swinholide A for 2 to 4 h, with complete loss of stress fibers by 5 to 7 h.
  • Figs. 1A and IB The effect of 50 nM Swinholide A on cells grown to high density is shown in Figs. 1A and IB.
  • Exponentially growing cells (Fig. 1C) exposed to 10 nM Swinholide A for 24 h became arborized with diffusely distributed phalloidin-stainable F-actin in the cytoplasm in addition to fluorescent punctate structures (Fig. ID) . Almost all of the cells became binuclear (Fig.
  • Swinholide A did not interfere with the progression of cells through mitosis but inhibits cytokinesis, presumably by inhibiting formation and function of the contractile ring. Swinholide A did not affect the integrity and organization of the microtubule system (data not shown) .
  • Swinholide A Sequestration of actin dimers by Swinholide A
  • The. ability of Swinholide A to. sequester unpolymerized actin -subunits was quantified (Fig. 2A) by the increase in the apparent critical concentration of N- pyrenylcarboxyamidoethyl-labeled actin (pyrenyl-actin) in buffer containing 2.0 mM MgCl 2 , 0.1 mM CaCl 2 , 0.2 mM dithiothreitol (DTT), 0.1 mM ATP, 0.01% sodium azide, and - 23 -
  • actin in a non- polymerizing buffer was covalently crosslinked by N,N'- 1,4-phenylenedimaleimide (PDM) to a species (Fig. 2C, lanes 2 and 3) with an electrophoretic mobility identical to that of the actin dimer (apparent molecular mass, 86 kDa) formed when the crosslinking reagent was added - 24 - immediately after addition of MgCl 2 (Fig. 2C, lane 4 and Millonig, R. et. al., (1988), J. Cell Biol . , 106:785).
  • PDM N,N'- 1,4-phenylenedimaleimide
  • Swinholide A could actively destabilize F-actin by complexing to and increasing the off-rate of terminal subunits and/or by severing actin filaments thus creating more filament ends.
  • the first possibility is inconsistent with the observation that the depolymerization rate was not directly proportional to the concentration of Swinholide A (Fig. 3B) , and the observed increase in depolymerization rate with time (Fig. 3C) is most consistent with an increase in the number of filament ends as a result of severing.
  • the high degree of cooperativity with respect to Swinholide A concentration implies that Swinholide A must bind to several neighboring subunits before the filament breaks.
  • Swinholide A like the protein gelsolin, not only severed actin filaments but also capped the "barbed” ends (the two ends of the polarized filament are designated “barbed” and “pointed” from the arrowhead-like appearance of electron microscopic images of filaments decorated with myosin.) of severed filaments, the rates of depolymerization of uncapped and gelsolin capped filaments would.be expected to converge at high concentrations of Swinholide A. In fact, the opposite behavior-was-observed (Fig. 3B) indicating that the barbed ends of filaments severed in the absence of gelsolin remained uncapped.
  • the data presented for tolytoxin is consistent with the formation of a 1:1 complex with actin monomer.
  • Swinholide A on the actin cytoskeleton and cell morphology are more like those of latrunculins (Spector, I. et al. (1989), Cell Mot, Cytoskel . , 13:127) than of cytochalasins which, also, do not usually cause a decrease in the concentration of F-actin (A. Morris and J. Tannenbaum, (1980) Nature, 287:638; Wodnicka, M. et al. (1992), Folia Histochem. Cytobiol . 30:107).
  • Swinholide A in vi tro are in some ways similar to those of gelsolin in that the severing capacity of gelsolin also increases with increasing Mg 2+ concentration (J. Bryan and L.M. Coluccio, (1985) J. Cell Biol . , 101:1236) and the actin dimers complexed to gelsolin and Swinholide A have the same electrophoretic mobility when covalently crosslinked.
  • gelsolin caps actin filaments with high affinity and its severing activity is non-cooperative.
  • Actophorin an actin-severing protein from the soil amoeba, Acanthamoeba castellani , does show cooperativity qualitatively similar to Swinholide A but appears to sever much less effectively and apparently binds to actin monomers (Maciver, S.K. et al. (1991) J. Cell Biol . , 115:1611) .
  • Swinholide A may be efficacious in treating mammals afflicted with cystic fibrosis.
  • Swinholide A may be efficacious in treating mammals afflicted with cystic fibrosis.
  • Swinholide A may be administered to mammals afflicted with cystic fibrosis in the form of an inhalation or nebulizer device. Mammals can be administered ranges or doses of
  • Preferred dose ranges are 0.25 to 1.0 mg per dosage twice daily.
  • the mammals will be monitored for increased lung capacity, decreased viscosity of mucous or sputum by conventional clinical evaluation methods. Specific parameters to be expressed include the increased production of lung capacity.
  • Such treatments may be administered either alone or in conjunction with other adjuvants therapies, such as lavage, percussion, posteral drainage, antibiotics or DNAse I treatment. - 28 -

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Abstract

Cette invention concerne un procédé permettant de détacher et de dépolymériser l'actine filamenteuse à l'aide d'un produit d'origine marine appelé le Swinholide A; ainsi que des procédés de traitement de mammifères souffrant de pathologies ou de maladies impliquant l'actine extracellulaire pathologique et notamment de pathologies ou de maladies respiratoires dans lesquelles l'actine filamenteuse contribue aux viscosités pathologiquement élevées des mucosités ou des expectorations présentes dans les poumons de ces mammifères.
PCT/US1995/008610 1994-07-08 1995-07-10 Utilisation de swinholide a pour detacher et depolymeriser l'actine WO1996001627A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO1998053839A3 (fr) * 1997-05-30 1999-09-10 Centre Nat Rech Scient Produits anti-cancereux pour le traitement de la mucoviscidose
EP1249244A1 (fr) * 2001-04-13 2002-10-16 Universiteit Gent Compositions thérapeutiques pour le traitement d'une maladie influencée par l'équilibre G-actin / F-actin, p.e. une maladie respiratoire

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"Effect of macrolides on velocity of mucus transport in chronic asthmatics using Tc-99m HSA aerosol", J.NUCL.MED., vol. 35, no. 5 suppl., 8 June 1994 (1994-06-08), pages 240P - 241P *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998053839A3 (fr) * 1997-05-30 1999-09-10 Centre Nat Rech Scient Produits anti-cancereux pour le traitement de la mucoviscidose
US6635627B1 (en) 1997-05-30 2003-10-21 Centre National De La Recherche Scientifique (Cnrs) Anti-cancer products for treating cystic fibrosis
EP1249244A1 (fr) * 2001-04-13 2002-10-16 Universiteit Gent Compositions thérapeutiques pour le traitement d'une maladie influencée par l'équilibre G-actin / F-actin, p.e. une maladie respiratoire
WO2002083167A3 (fr) * 2001-04-13 2003-01-30 Univ Gent Compositions therapeutiques utilisees dans le traitement d'une maladie des voies respiratoires
US7432308B2 (en) 2001-04-13 2008-10-07 Universiteit Gent Therapeutic compositions for the treatment of a respiratory tract disease

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