EP1212047A2 - Use of charged dextran as a mucoactive agent and methods and pharmaceutical compositions relating thereto - Google Patents
Use of charged dextran as a mucoactive agent and methods and pharmaceutical compositions relating theretoInfo
- Publication number
- EP1212047A2 EP1212047A2 EP00954242A EP00954242A EP1212047A2 EP 1212047 A2 EP1212047 A2 EP 1212047A2 EP 00954242 A EP00954242 A EP 00954242A EP 00954242 A EP00954242 A EP 00954242A EP 1212047 A2 EP1212047 A2 EP 1212047A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- dextran
- mucus
- charged
- animal
- charged dextran
- 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.)
- Withdrawn
Links
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/721—Dextrans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/12—Mucolytics
Definitions
- the invention relates to a use of charged dextran, preferably dextran sulfate, as a mucoactive agent and methods and pharmaceutical compositions relating thereto.
- Mucus is produced and secreted by animals.
- the secretion of mucus is a critical component of the defense mechanism of the respiratory tract, trapping inhaled particulate and microbial material for removal via the mucociliary system. When this mechanism fails to clear sufficiently, mucus accumulates, and is coughed up as sputum or retained in the respiratory tract, encouraging colonization by microorganisms, which may lead to chronic lung inflammation and obstruction.
- Many lung diseases are associated with impaired mucus clearance, mucus retention and /or mucus hypersecretion, including without limitation, cystic fibrosis, bronchitis, bronchiectasis, bronchiohtis and bronchial asthma. Mucus airway obstruction has long been considered the most insidious agent of morbidity and mortality in such diseases, especially in cystic fibrosis.
- Airway mucus clearance depends on the physical properties of the mucous gel as well as interactions between mucus and airflow or mucus and cilia [1]. Mucus retention in the airway usually occurs because of a combination of mucus hypersecretion and impaired mucociliary clearance, and is generally associated with infected mucus and airway inflammation. Mucoactive medications are treatments designed to enhance the clearance of mucus from the respiratory tract in disorders where mucus clearance impairment is an important feature [2]. Mucokinetic therapy combating mucus retention is a major consideration in the treatment of cystic fibrosis (CF), and other chronic lung diseases in which mucus hypersecretion and impaired airway clearance produce symptoms.
- CF cystic fibrosis
- Mucus is a nonhomogeneous, adhesive, viscoelastic gel consisting of water and high molecular weight, crosslinked glycoproteins mixed with serum and cellular proteins (albumin, enzymes, and immunoglobulins), ions and lipids.
- the physical, three-dimensional structure that forms the mucous gel is dependent upon a number of forms of bonding: 1) intramolecular disulfide bonds [3, 4]; 2) entanglements with neighboring macromolecules [5]; 3) hydrogen bonds between oligosaccharide side-chains [6]. Although each bond is weak, the number of bond sites make hydrogen-bonding a potentially important target for mucolytic therapy; 4) ionic interactions between fixed negative charges [7, 8]; 5) extra networks of high molecular weight DNA and actin filaments released by dying leukocytes [8 - 10]. Each of these elements is a potential target for mucoactive therapy.
- rhDNase which has been found to improve lung function in a broad spectrum of patients [13, 14].
- the action of DNase is to degrade the three-dimensional network by mucolysis, or molecular weight disruption. Combined with other therapies, there are many possibilities for enhancement of potential benefits of this form of therapy [15].
- Ionic agents such as hypertonic saline
- hypertonic saline are believed to be mucoactive by shielding the fixed charges along the macromolecular core of the mucin polymer, making it less stiff and less extended and thus reducing the number of entanglement crosslinks with neighbouring macromolecules [8].
- the tolerability and potential for interfering with bacterial killing may limit the value of hypertonic saline as a therapeutic agent.
- Nonionic agents such as sugar derivatives reduce the crosslink density of sputum, probably by disrupting the hydrogen bonds between mucin molecules [6].
- oligosaccharides neutral dextran, lactose and mannitol have all been considered as potential therapeutic agents [6, 11, 12].
- the present inventor with others has shown that low molecular weight neutral dextran (m.w. 4000 or less) is a mucolytic agent, reducing the viscoelasticity and spinnability of CF sputum and improving its mucociliary clearability in in vitro testing and that the effects on viscoelasticity and spinnability were concentration-dependent, being greater at 4% than at 0.4% (wt./vol.) of dextran [6].
- heparin a charged oligosaccharide, low molecular weight heparin
- heparin had a greater mucolytic and mucokinetic capacity than the neutral saccharide polymer, dextran. This was seen both in in vitro rheological testing [17] and in excised frog palate clearance measurements [18].
- heparin is expensive to produce and could potentially have toxic side effects such as pulmonary hemoptysis (bleeding of the tracheobronchial mucosa).
- mucoactive agents known to date have limitations, there is a need for an improved mucoactive agent to improve mucus viscoelasticity and clearability.
- the present invention provides an improved mucoactive agent and methods and uses therefor.
- the improved mucoactive agent is a charged oligosaccharide.
- the charged oligosaccharide is charged dextran.
- the charged dextran is dextran sulfate or dextran phosphate.
- the charged dextran is dextran sulfate. It is herein shown that the charged dextran decreases mucus viscoelasticity and increases mucociliary clearability. The present invention relates to these unexpected findings.
- the present invention relates to a method of decreasing viscoelasticity of mucus from the respiratory tract of an animal by administering to the mucus an effective amount of a charged dextran, preferably dextran sulfate.
- the present invention provides a method of improving mucus clearance in an animal, preferably a human, in need thereof comprising administering to the respiratory tract of the animal an effective amount of a charged dextran, preferably dextran sulfate.
- the animal, preferably human, in need thereof may have a disease characterized by impaired mucus clearability, mucus retention, and /or mucus hypersecretion, such as cystic fibrosis, chronic bronchitis, bronchitis, bronchiectasis, bronchiohtis, or bronchial asthma, but most preferably cystic fibrosis.
- the disease may be an equine condition such as heaves.
- the charged dextran preferably dextran sulfate
- the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, including without limitation diluents and/or excipients.
- the pharmaceutical composition is a topical composition and most preferably an aerosol.
- the pharmaceutical composition comprises between about 6.5 mg/ml to
- a charged dextran preferably dextran sulfate.
- the charged dextran, preferably dextran sulfate is administered in a concentration of between about 6.5 mg/ml to 65 mg/ml charged dextran per composition, preferably per aerosol composition and in one embodiment at a dose of about 6 to 8.5 mis, and preferably about 7 to 8 mis.
- the dose is preferably administered over a period of about 15 to 30 minutes. In another embodiment the dose is administered from about 1 to 4 times daily.
- the charged dextran preferably dextran sulfate
- Figure 1 is a bar graph illustrating the effects on tracheal transepithelial potential difference (PD (-mV) by agar bridge technique) in 7 healthy mongrel dogs after 30-minute Ringer aerosol, and after increasing concentrations of aerosolized DexS0 (6.5 mg/ml; 20 mg/ml; and 65 mg/ml) in Ringer vehicle.
- the PD was significantly more negative for all three concentrations of DexS0 .
- Values are plotted as the mean ⁇ SEM.
- Figure 2 is a bar graph illustrating the effect of Dextran sulfate on Tracheal
- TMV Mucociliary Velocity
- Viscoelasticity as determined by magnetic rheometry, expressed as the average log G* over 1-100 rad/s, in 7 healthy mongrel dogs during and after 30-minute Ringer aerosol, and during and after increasing concentrations of aerosolized DexS0 (6.5 mg/ml; 20 mg/ml; and 65 mg/ml)in Ringer vehicle.
- DexS0 4 administration resulted in a significant decrease in average log G* at 6.5 and 65 mg/ml compared with the respective Ringer control.
- Figure 4 is a linear graph illustrating the effect of dextran sulfate on mucus % solids content (%SC of collected airway secretion in 7 healthy mongrel dogs during and after 30-minute Ringer aerosol and increasing concentrations of DexS0 (6.5 mg/ml; 20 mg/ml; and
- FIG. 5 is a bar graph illustrating the effect of heparin and dextran sulfate on Tracheal Mucus Viscoelasticity (TMV) of sputum from 7 cystic fibrosis human patients as determined by magnetic rheometry, expressed as the average log G* over 1-100 rad/s after treatment with saline, heparin (MW 6000), Dextran Sulfate (MW 5000, about 17% sulphur by weight), heparin (dimer, highly (fully) sulfated, H-9267: C 12 H 13 N0 19 S 3 Na 4 ), or heparin (dimer, low sulfate, partially de-sulfated H-9142, C 12 H 18 N0 13 SNa) to a final concentration of about 8 mg/ml ( or 0.4% wt/vol) of sputum.
- TMV Tracheal Mucus Viscoelasticity
- the highly sulfated heparin dimer showed significant decrease in viscoelasticity as compared to saline control. The effect was similar to heparin, M.W. 6000.
- the de-sulfated heparin dimer showed no significant improvement as compared to the control. Dextran sulfate was even more efficient in increasing viscoelasticity than any of the heparins used.
- the present invention describes a method of decreasing the viscoelasticity of mucus, comprising contacting the mucus with a mucoactive agent, a charged dextran, such as dextran phosphate or dextran sulfate, more preferably a dextran sulfate, most preferably a low molecular weight charged dextran, such as low molecular weight dextran sulfate.
- a charged dextran such as dextran phosphate or dextran sulfate, more preferably a dextran sulfate, most preferably a low molecular weight charged dextran, such as low molecular weight dextran sulfate.
- the administration of the mucoactive agent of the invention to the mucus can be done in vivo or in vitro. Possible in vitro applications include, diagnostic purposes, and testing mucus to determine optimum dosage and treatment regimes.
- a method for diagnosing an animal with impaired mucus clearance could comprise obtaining a sample of the animal's mucus and treating it in vitro with charged dextran, and determining the effect of the charged dextran on the viscoelasticity of the mucus to determine whether the animal may have impaired mucus clearance.
- a method for determining a dosage regime of an animal with impaired mucus clearance could comprise: ( a) obtaining a mucus sample from the animal; (b) subjecting aliquots of the mucus sample to different concentrations of charged dextran;
- the present invention further describes a method of improving mucus clearance from the respiratory tract of an animal comprising administering to the animal, an effective amount of a charged dextran of the invention, preferably dextran sulfate.
- the present invention further describes a method of improving mucus clearance in an animal with impaired mucus clearance, mucus retention and /or mucus hypersecretion, such as animals with lung diseases or conditions including without limitation: cystic fibrosis, chronic bronchitis, bronchitis, bronchiectasis, bronchiohtis (diffuse panbronchiolitis) or bronchial asthma, comprising administering to the animal an effective amount of a charged dextran, preferably dextran sulfate, to an animal in need thereof.
- lung diseases or conditions including without limitation: cystic fibrosis, chronic bronchitis, bronchitis, bronchiectasis, bronchiohtis (diffuse panbronchiolitis) or bronchial asthma
- low molecular weight dextran sulfate (about m.w. 5000 or less) administered to the respiratory tract in aerosol form through inhalation has been specifically shown to reduce viscoelasticity and increase mucociliary clearability of mucus in the respiratory tract of healthy dogs. It has also been shown to reduce viscoelasticity of mucus obtained from human patients with cystic fibrosis.
- compositions which can be used in the methods of the invention comprising the mucoactive agent of the invention and a pharmaceutically acceptable carrier and may include, diluents and excipients.
- “Mucoactive agent” as used herein refers to an agent which can reduce the viscoelasticity of mucus and /or improve or potentially improve the clearance of mucus from the respiratory tract.
- the mucoactive agent of the invention is a charged dextran, preferably a low molecular weight charged dextran.
- charged dextrans suitable for use in the present invention include without limitation, dextran phosphate and dextran sulfate
- the charged dextran is dextran sulfate.
- Charged dextran as used herein may include fully or partially charged dextran.
- the degree of phosphorylation or sulfation can vary from low (10-20% of monomer units) to high (fully sulfated or phosphorylated - one sulfate per sugar residue].
- Low molecular weight charged dextran such as low molecular weight dextran sulfate as used herein means charged dextran or dextran sulfate, as the case may be, with a molecular weight of between about 500 (dimer) and 5000.
- Animal as used herein is any living organism which has a respiratory tract and secretes mucus into the respiratory tract and is susceptible to conditions or diseases involving impaired mucus clearance.
- the animals are mammals, preferably rats, mice, horses, dogs, or humans, and most preferably dogs or humans.
- Effective amount means an amount of the mucoactive agent, effective at dosages and for periods of time necessary to achieve the desired result.
- An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the animal being treated.
- dosage regimes are described in the examples herein, a person skilled in the art would appreciate that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
- dosages by aerosol are generally indicated by concentration of the agent in the nebulizer, and the dose is regulated by the ventilation rate (volume of air per minute) of the animal, which is roughly proportional to body weight.
- the mucoactive agents of the invention are preferably administered in a concentration of between about 6.5 mg/ml to 65 mg/ml mucoactive agent per composition administered, preferably per aerosol composition and in one embodiment at a dose of about 6 to 8.5 mis (i.e. from about 39 mg to 552.5 mg of mucoactive agent), and preferably about 7 to 8 mis.
- the dose is preferably administered over a period of about 15 to 30 minutes. In another embodiment the dose is administered from about 1 to 4 times daily.
- “Clearance and clearability” as used herein refers to the ability of the mucus to be cleared from the respiratory tract of an animal. This can include without limitation to mucociliary clearance or cough.
- the mucoactive agents of the invention may be administered by topical administration to the mucus or respiratory tract of the animal in a known manner, such as in the form of an aqueous aerosol, dry powder inhaler, metered dose inhaler (with non-aqueous propellant), or direct topical instillation (to intubated patients, or through nasal or sinus irrigation). Most preferably administration is in the form of an aerosol by inhalation.
- the mucoactive agents of the invention can be administered in the form of pharmaceutical compositions which may also comprise pharmaceutically acceptable carriers, diluents and excipients.
- suitable pharmaceutical carriers which can be used in the invention are Ringer's solution, water, and sterile saline (0.9% NaCl).
- the pharmaceutical compositions of the invention can be prepared by per se known methods for the preparation of pharmaceutically acceptable compositions. Suitable methods and pharmaceutical carriers which can be used in the preparation of pharmaceutical compositions of the invention are described in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA, 1985).
- the pharmaceutical composition comprises between about 6.5 mg/ml to about 65 mg/ml of charged dextran, preferably dextran sulfate.
- charged dextran i.e. dextran sulfate
- administration of dextran sulfate by aerosol could increase the rate of mucociliary clearance.
- a charged macromolecule applied to the mucosal surface could alter epithelial ion currents, the changes in tracheal potential difference as an index of epithelial ion transport [19] was also studied. It was shown that dextran sulfate exhibited significant mucolytic capacity.
- dextran sulfate exerts its effect by modification of both bulk rheological properties and surface effects.
- dextran sulfate is believed to interfere with hydrogen bond interactions between mucin macromolecules, as well as with ionic interactions in the mucous gel. The net result is a stimulation of mucociliary clearance.
- dextran such as dextran sulfate
- mucoactive agent has the advantage of being considerably cheaper to produce than heparin or other charged oligosaccharides.
- dextrans have antimicrobial activities, this with the addition of mucoactive effects has added benefits in the treatment of patients with airway infections.
- a charged dextran such as dextran sulfate
- other therapies such as Pulmozyme (rhDNase) and /or N-acetylcysteine derivatives in the treatment of diseases with impaired mucus clearance, such as cystic fibrosis, bronchitis, chronic bronchitis, bronchiectasis, bronchiohtis, and bronchial asthma.
- rhDNase Pulmozyme
- N-acetylcysteine derivatives in the treatment of diseases with impaired mucus clearance, such as cystic fibrosis, bronchitis, chronic bronchitis, bronchiectasis, bronchiohtis, and bronchial asthma.
- the methods of the present invention using charged dextran could be combined with a true mucolytic agent (e.g. rhDNase or N-acetylcysteine) that reduces molecular chain length, to improve both mucociliary and
- the dogs were anesthetized with sodium pentobarbital (ca 30 mg/kg i.v., supplemented as required) and intubated with a cuffed endotracheal tube. They were administered Ringer aerosol first, followed by 6.5 mg/ml dextran sulfate, 20 mg/ml dextran sulfate, and 65 mg/ml dextran sulfate by aerosol. Each aerosolization was of 30 minutes duration, with a rest period of 30 minutes before the beginning of the next aerosol delivery.
- the aerosols were generated and delivered by a Pari LC STAR nebulizer using an air flow rate of 8 1/min, which results in an output of 0.58 ml/min and particles of 2.0 ⁇ m mass median diameter.
- the nebulizer was loaded in each case with 10 ml of solution. The amount of solution remaining in the nebulizer after 30 minutes was recorded.
- a T-tube connection was provided to the endotracheal tube during aerosol delivery to ensure a minimal deadspace for ventilation and adequate delivery of the aerosol. The dogs breathed spontaneously throughout the experiment.
- TMV Tracheal mucus velocity
- PD tracheal potential difference
- Dextran sulfate, sodium salt (DexS0 4 ) was obtained from Sigma-Aldrich, St. Louis,
- MO catalog* D7037, lot# 88H0725
- Its nominal molecular weight was 5000, and the sulfur content was 17.7%.
- DexS0 was dissolved in Ringer solution as vehicle. Ringer solution comprises NaCl, as well as KCl and CaCl 2 in approximate physiological concentration as found in plasma.
- PD Transepithelial Potential Difference
- TMV Tracheal Mucociliary Velocity
- TMV was determined twice for each aerosolization period, once during the aerosol, starting after 15 minutes had elapsed, and a second time starting about 10 minutes after the aerosolization had been completed.
- a T-connector with a seal was employed to allow for bronchoscopic visualization during the delivery of the aerosols.
- Mucus Collection Weight (MCW, mg/30 min): Tracheal mucus was collected by the endotracheal tube (ETT) method, which involves the removal of mucus adherent to the ETT after extubation [24]. Mucus collections were performed twice after each aerosol, once by immediately removing the ETT following aerosol inhalation, and the second 30 minute after inhalation, after re-installing a clean ETT. The mucus samples, which had been frozen, were thawed and weighed by microbalance, to determine MCW, an index of flux, and indirectly of the rate of secretion [20].
- ETT endotracheal tube
- Mucus Viscoelasticity Measurements The magnetic microrheometer technique was used to measure the viscosity and elasticity of the dog mucus samples [21]. A 100 ⁇ m steel ball was positioned in a 5-10 ⁇ L sample of mucus, and the motion of this sphere under the influence of an oscillating electromagnetic field gradient was used to determine the rheological properties of the mucus. The image of the steel ball was projected via a microscope onto a pair of photocells, whose output was amplified and transmitted to an oscilloscope. By plotting the displacement of the ball against the magnetic driving force, the viscoelastic properties of the mucus were ascertained. The parameters of mucus viscoelasticity determined were the rigidity index or mechanical impedance, i.e.
- Solids content (wefcdry weight ratio): A drying apparatus and microbalance were used to calculate the dry weight and wet weight of the collected secretion, from which the percent solids content (%SC) was calculated. The mucus samples, free of oil, were weighed on previously weighed glass slides. The samples were then dried in a microwave oven (750 W for 30 minutes) and allowed to cool. These dried samples were then reweighed, and % SC was calculated from ratio of dry to wet weight [23].
- the osmotic pressures of the DexS0 solutions were determined by means of a Wescor model 5500 vapor pressure osmometer.
- the excess osmolarity over Ringer's was as follows: 6.5 mg/ml: 15 mOsm; 20 mg/ml: 45 mOsm; 65 mg/ml: 141 mOsm.
- the delivered volume of aerosol from the Pari LC STAR nebulizer averaged 9.0 ⁇ 0.8 ml, and did not change with increasing dose.
- heparin decreases mucus viscoelasticity by 1) interaction of its negative charge on the amino groups of the mucin molecule, thereby reducing its entanglement with neighboring sulfate groups, and/or 2) interfering with intermolecular hydrogen bonding due to its short-chain oligosaccharide character (similar to dextran), and/or 3) ionic shielding effects of sodium and heparin on the polyionic moieties of the mucin molecule.
- DexS0 4 has been used to induce experimental colitis in rodents [33]; the mechanism probably involves erosion of the protective intestinal mucus layer.
- DexS0 4 m.w. 40,000
- dextran sulfate m.w. 7000
- dextran sulfate has also been administered orally to human subjects, with little anticoagulant effect because of its poor absorbablity, and no other apparent safety concerns [34].
- the potential of dextran sulfate as a therapy with no or minimal toxic effects is a question of dose, route of administration, molecular weight, and charge.
- Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc. Natl. Acad. Sci. U.S.A. 87:9188- 9192.
- TMV Tracheal mucociliary velocity,TMV by charcoal particle displacement, in 7 dogs during and after 30 minute Ringer aerosol, and during and after increasing concentrations of aerosolized DexS0 4 in Ringer vehicle. There were no significant differences in TMV with
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Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15060599P | 1999-08-26 | 1999-08-26 | |
US150605P | 1999-08-26 | ||
PCT/CA2000/000989 WO2001015672A2 (en) | 1999-08-26 | 2000-08-25 | Use of charged dextran as a mucoactive agent and methods and pharmaceutical compositions relating thereto |
Publications (1)
Publication Number | Publication Date |
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EP1212047A2 true EP1212047A2 (en) | 2002-06-12 |
Family
ID=22535267
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP00954242A Withdrawn EP1212047A2 (en) | 1999-08-26 | 2000-08-25 | Use of charged dextran as a mucoactive agent and methods and pharmaceutical compositions relating thereto |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1212047A2 (en) |
AU (1) | AU6679300A (en) |
CA (1) | CA2382259A1 (en) |
HK (1) | HK1047246A1 (en) |
WO (1) | WO2001015672A2 (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002102403A1 (en) * | 2001-06-14 | 2002-12-27 | Novo Nordisk A/S | Mucosal repair by tff dimer peptides |
WO2003068254A1 (en) * | 2002-02-18 | 2003-08-21 | University Of Southampton | Glycosaminoglycan-dnase combination therapy |
GB0327723D0 (en) * | 2003-09-15 | 2003-12-31 | Vectura Ltd | Pharmaceutical compositions |
GB2430881B (en) | 2005-10-06 | 2010-10-13 | Ntnu Technology Transfer As | Oligoelectrolyte polyols for the treatment of mucosal hyperviscosity |
GB0707096D0 (en) | 2007-04-12 | 2007-05-23 | Ntnu Technology Transfer As | Method |
JP5639475B2 (en) | 2007-11-27 | 2014-12-10 | アルギファルマ アイピーアール エーエス | Use of alginate oligomers in combating biofilms |
EP2391209A4 (en) * | 2009-01-27 | 2014-03-26 | Teleflex Medical Inc | Sputum dissolving suctioning solution for endotracheal and tracheostomy tubes |
GB0904942D0 (en) | 2009-03-23 | 2009-05-06 | Ntnu Technology Transfer As | Composition |
GB0904941D0 (en) | 2009-03-23 | 2009-05-06 | Ntnu Technology Transfer As | Composition |
CA2764195C (en) | 2009-06-03 | 2017-09-26 | Algipharma As | Treatment of acinetobacter with alginate oligomers and antibiotics |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1991015216A1 (en) * | 1990-04-05 | 1991-10-17 | Kennedy Thomas P | Method and medicament for prevention or medication of human leucocyte elastase-mediated pulmonary diseases |
US5514665A (en) * | 1993-12-30 | 1996-05-07 | University Of British Columbia | Method of preventing or reducing the risk of infection by bacterial pathogens utilizing simple and conjugated dextrans |
-
2000
- 2000-08-25 CA CA002382259A patent/CA2382259A1/en not_active Abandoned
- 2000-08-25 EP EP00954242A patent/EP1212047A2/en not_active Withdrawn
- 2000-08-25 AU AU66793/00A patent/AU6679300A/en not_active Abandoned
- 2000-08-25 WO PCT/CA2000/000989 patent/WO2001015672A2/en not_active Application Discontinuation
-
2002
- 2002-12-11 HK HK02108959.0A patent/HK1047246A1/en unknown
Non-Patent Citations (1)
Title |
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See references of WO0115672A2 * |
Also Published As
Publication number | Publication date |
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WO2001015672A2 (en) | 2001-03-08 |
HK1047246A1 (en) | 2003-02-14 |
AU6679300A (en) | 2001-03-26 |
WO2001015672A3 (en) | 2002-02-28 |
CA2382259A1 (en) | 2001-03-08 |
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