[go: up one dir, main page]

WO2008001055A1 - Procédé de traitement et/ou de prévention d'une maladie pulmonaire inflammatoire - Google Patents

Procédé de traitement et/ou de prévention d'une maladie pulmonaire inflammatoire Download PDF

Info

Publication number
WO2008001055A1
WO2008001055A1 PCT/GB2007/002354 GB2007002354W WO2008001055A1 WO 2008001055 A1 WO2008001055 A1 WO 2008001055A1 GB 2007002354 W GB2007002354 W GB 2007002354W WO 2008001055 A1 WO2008001055 A1 WO 2008001055A1
Authority
WO
WIPO (PCT)
Prior art keywords
polyether polyol
aqueous solution
treating
medicament
preventing
Prior art date
Application number
PCT/GB2007/002354
Other languages
English (en)
Inventor
Gareth Ackland
Alexander V. Gourine
Original Assignee
University College London Hospitals Nhs Foundation Trust
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University College London Hospitals Nhs Foundation Trust filed Critical University College London Hospitals Nhs Foundation Trust
Publication of WO2008001055A1 publication Critical patent/WO2008001055A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

Definitions

  • the present invention relates to a medicament for the treatment and/or prevention of inflammatory lung disease (such as asthma) and to the use of such a medicament for the treatment and/or prevention of inflammatory lung disease.
  • inflammatory lung disease such as asthma
  • Inflammation is an effective defence mechanism, it is a non-specific immune response that occurs in reaction to any type of bodily injury; be it irritation, infection or disease.
  • cystic fibrosis cystic fibrosis
  • emphysema chronic obstructive pulmonary disorder
  • COPD chronic obstructive pulmonary disorder
  • Asthma is a chronic, inflammatory lung disease involving recurrent breathing problems.
  • Asthma is a complex syndrome, and is recognised and defined by characteristics such as a variable degree of airway obstruction, bronchial hyperresponsiveness and airway inflammation. Allergen-induced mechanisms mediate about 80% of childhood asthma and approximately 40-50% of adult asthma.
  • a defining mechanism of activation in allergic asthmatics is the initial activation of mast cells by allergen specific Immunoglobulin E (IgE). This activation subsequently causes the release of mediators such as histamines, prostaglandins, leukotrines and cytokines, which mediate the so- called early phase asthmatic reaction, characterised by constriction of airway smooth muscle, vascular leakage and mucus production.
  • the late phase reaction which follows 4 to 6 hours later, is characterised by excessive inflammation of the airways resulting in airway narrowing. Airway inflammation evokes mediators that cause epithelial airway tissue damage.
  • mast cells are involved in the pathopysiology of asthma, through their ability to secrete a wide variety of cytokines and other mediators after activation, either by cytokines or allergens.
  • cytokines and other mediators after activation either by cytokines or allergens.
  • mast cells are present in the airway smooth muscles, the submucosa and the airway epithelium.
  • asthmatics the number of mast cells in these tissues is strongly increased.
  • Chronic obstructive pulmonary disease is a group of lung diseases that cause swelling of the airways. Emphysema and chronic bronchitis are the most common forms of COPD. Chronic bronchitis is an inflammation, or irritation, of the airways in the lungs. Cigarette smoking is the main cause of chronic bronchitis and emphysema. When tobacco smoke is inhaled into the lungs, it inflames and irritates the airways and they produce mucus. People who have been exposed for a long time to other things that irritate their lungs, such as chemical fumes, dust and other substances, can also get chronic bronchitis or emphysema.
  • COPD chronic obstructive pulmonary disease
  • Chronic bronchitis or emphysema can cause obstruction (narrowing) of the airways. Chronic bronchitis and emphysema commonly occur together.
  • a driving factor in the pathophysiology of COPD is the inflammatory process, which contributes to the narrowing of the small airways and other underlying mechanisms of the disease process. Recent evidence suggests that the inflammatory response results in a number of effects, including an influx of inflammatory cells, such as macrophages, neutrophils, and lymphocytes; thickened airways; and structural changes such as increased smooth muscle and fibrosis (Barnes. N Engl J Med. 2000;343:269).
  • Airway inflammation is recognised as a major factor in the pathogenesis of cystic fibrosis lung disease.
  • the inflammatory process in the CF lung is dominated by a neutrophil influx.
  • Accumulation of neutrophils in the airways is associated with high concentrations of neutrophil-derived mediators, in particular pro-inflammatory cytokines such as IL-8 and TNF- ⁇ .
  • neutrophil-derived mediators in particular pro-inflammatory cytokines such as IL-8 and TNF- ⁇ .
  • neutrophil-derived mediators in particular pro-inflammatory cytokines such as IL-8 and TNF- ⁇ .
  • neutrophil-derived mediators in particular pro-inflammatory cytokines such as IL-8 and TNF- ⁇ .
  • neutrophil-derived mediators in particular pro-inflammatory cytokines such as IL-8 and TNF- ⁇ .
  • neutrophil-derived mediators in particular pro-inflammatory cytokines such as IL-8 and TNF- ⁇ .
  • neutrophil-derived mediators in particular pro-inflammatory cytokines such as
  • inflammatory mediators can directly activate the neutrophils to carry out their cytotoxic activities. It is hypothesised that the persistent and excessive inflammation in the lungs of CF patients involves a failure of the mechanisms that control the inflammatory response. An altered regulation of cytokine production by neutrophils is certainly an important factor that promotes continued inflammation and injury.
  • Other lung diseases that involve an undesirable inflammatory component include interstitial lung disease (ILD, may also be called interstitial pulmonary fibrosis or pulmonary fibrosis), bronchiolitis (inflammation that involves the bronchioles), alveolitis (inflammation that involves the alveoli), vasculitis, sarcoidosis and acute respiratory distress syndrome (ARDS).
  • ILD interstitial lung disease
  • bronchiolitis inflammation that involves the bronchioles
  • alveolitis inflammation that involves the alveoli
  • vasculitis vasculitis
  • sarcoidosis acute respiratory distress syndrome
  • corticosteroid drugs anti-inflammatory drugs
  • COPD chronic obstructive pulmonary disease
  • Polyether polyol in particular polyether glycol, and most particularly polyethylene glycol, is a widely used substance for both household and industrial purposes. It possesses some remarkable properties that have been explored in several laboratory-based scenarios, although the mechanisms through which polyethylene glycol acts under different experimental conditions are unclear. Polyethylene glycol improves function in experimental transplant organs (JP Faure et al, American Journal of Transplantation 2004 vol 4; 495-504) reverses experimental spinal cord injury (R Borgens and R Shi, FASEB J. vol 14, 27-35, 2000) and protects against experimentally-induced colonic cancer (DE Corpet et al, Carcinogenesis vol.20 no.5 pp.915-918, 1999).
  • FR-A-2316923 discloses complex solutions comprising a number of components (urethane, ethylene glycol, etc) including high molecular weight (6000) polyethylene glycol in a high concentration (2.5%). There is no evidence given that the beneficial effect of this solution is related to the properties of polyethylene glycol.
  • DE-A-10204696 discloses the use of polyethylene glycol in a nasal spray (comprising several other substances) to treat viral infections causing coughs and sneezes. This does not suggest that there is any utility for treating or preventing inflammatory lung diseases.
  • WO-A-2004/047778 discloses a solution based on a high molecular weight, at least 5,000 daltons, polyethylene glycol given in a very high concentration in an experimental model of microbe-mediated epithelial disorders.
  • the pathogen Pseudomonas aeruginosa
  • high molecular weight; high concentration polyethylene glycol prevents contact of pathogens with the epithelial surface.
  • the disclosure has no relevance to the treatment or prevention of inflammatory lung diseases.
  • polyethylene glycols are known for use as bowel purgatives in common clinical practice.
  • None of these prior disclosures addresses the treatment of inflammatory lung disease in an individual, in particular for medical emergencies, for chronic inflammation associated with asthma, COPD, cystic fibrosis (CF), interstitial lung disease (ILD), bronchiolitis, alveolitis, vasculitis, sarcoidosis and acute respiratory distress syndrome (ARDS).
  • COPD chronic inflammation associated with asthma
  • COPD 1 cystic fibrosis CF
  • interstitial lung disease ILD
  • bronchiolitis alveolitis
  • vasculitis vasculitis
  • sarcoidosis acute respiratory distress syndrome
  • the present invention at least partially aims to meet at least one of those needs.
  • the present invention provides the use of an aerosolised aqueous solution of at least one polyether polyol for the treatment and/or prevention of inflammatory lung diseases.
  • the present invention provides a method of treating and/or preventing inflammatory lung diseases, said method comprising inhaling an aqueous solution of at least one polyether polyol.
  • said aqueous solution is administered as an aerosol.
  • the polyol polyether of the any aspect of the present invention can be of any suitable molecular weight for treating and/or preventing inflammatory lung disease in a subject, but it is preferred that it has a molecular weight of from 100 to 10,000, preferably 200 to any one of 5,000, 6,000, 7,000 or 8,000, or most preferably, 200 to 4000.
  • the molecular weight may be any one of 200, 400, 600, 800, 1 ,000, 1,500, 2,000, 2,500, 3,000, 3,500 or 4,000, and may be a range between any one of these points (i.e. 200 to 1,000).
  • Molecular weight is represented in Daltons (Da).
  • the present invention may employ a "low molecular weight polyethylene glycol", meaning the range of molecular weight of the polyethylene glycols is from 200 to 1000, or alternatively the present invention may employ a "medium molecular weight polyethylene glycol", meaning the range of molecular weights of the polyethylene glycol is from 1000 to 4000.
  • a mixture of such a "low molecular weight polyethylene glycol” and a “medium molecular weight polyethylene glycol” may alternatively be employed.
  • One preferred polyethylene glycol has a molecular weight of 400 Da.
  • the polyol polyether of any aspect of the present invention can be of any suitable concentration for treating and/or preventing inflammatory lung disease in a subject.
  • the concentration of the polyol polyether falls within the range of 0.01 to 1000 mg/ml, more preferably, 0.01 to 500 mg/ml, most preferably 0.01 to 100 mg/ml.
  • the polyether polyol is at a concentration of 0.01 to 10 mg/ml.
  • the polyether polyol can be present in the aqueous solution at a level of 0.01, 0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg/ml, or a range including 2 or more of these points (i.e. 0.1 to 7 mg/ml).
  • the concentration of the at least one polyether polyol in the aqueous solution is from 1 to 10 mg/ml.
  • the final dosage to be administered will depend on the precise mode of administration, but will preferably be such as to provide between 10 mg and 5 g to a typical subject of 70kg. Most preferably it will provide between 35 mg and 3.5g, or between 100 mg and 3g, or between 1g and 2g.
  • the present invention provides the use of an aerosolised aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing inflammatory lung disease.
  • the present invention provides the use of an aerosolised aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing asthma.
  • the present invention provides the use of an aerosolised aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing COPD.
  • the present invention provides the use of an aerosolised aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing cystic fibrosis.
  • the present invention provides the use of an aerosolised aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing acute respiratory distress syndrome.
  • the present invention provides the use of an aerosolised aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing interstitial lung disease.
  • the present invention provides the use of an aerosolised aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing sarcoidosis.
  • the present invention provides the use of a composition comprising at least one polyether polyol and an aqueous solution for administration via inhalation to a mammal for the manufacture of a combined preparation for the simultaneous, separate or sequential use as a medicament for treating and/or preventing inflammatory lung disease.
  • the present invention provides a composition comprising an aqueous solution of at least one polyether polyol for administration via inhalation to a mammal as a combined preparation for use as a medicament, in particular for treating and/or preventing inflammatory lung disease.
  • the term "inflammatory drug disease” applies to any disease or disorder of the lung which has an inflammatory component.
  • the inflammation is chronic - an inflammatory response of prolonged duration. It is preferred that this inflammatory component of the disease is unwanted or undesired, i.e. the inflammatory response is not contributing to the resolution of the disease/disorder.
  • the diseases treated according to the present invention may be characterised by chronic pathological inflammation.
  • the inflammatory lung disease treated according to the present invention is any one of the following diseases or disorders: interstitial lung disease (ILD, may also be called interstitial pulmonary fibrosis or pulmonary fibrosis), bronchiolitis (inflammation that involves the bronchioles), alveolitis (inflammation that involves the alveoli), vasculitis, sarcoidosis and acute respiratory distress syndrome (ARDS), asthma, COPD or cystic fibrosis (CF).
  • ILD interstitial lung disease
  • bronchiolitis inflammation that involves the bronchioles
  • alveolitis inflammation that involves the alveoli
  • vasculitis inflammation that involves the alveoli
  • ARDS acute respiratory distress syndrome
  • asthma COPD
  • cystic fibrosis cystic fibrosis
  • the solution of the present invention may be used to treat or prevent inflammatory lung diseases.
  • preventing a disease
  • exacerbations are avoided or reduced (“prevented”).
  • prevention of asthma means the prevention of an asthmatic episode.
  • An acute exacerbation of asthma is referred to as an asthma attack, and it this exacerbation that the invention seeks to prevent.
  • IN COPD an exacerbation involves the shortness of breath associated with this disease getting suddenly much worse.
  • a COPD exacerbation can be mild to life-threatening.
  • Pulmonary exacerbations also occur in cystic fibrosis sufferers.
  • exacerbations in inflammatory lung diseases can be viewed as exacerbations of inflammation.
  • the present invention extends to the prevention of exacerbations of inflammatory lung diseases.
  • the composition or medicament described herein is for administration to a mammal, the medicament or composition comprising at least one polyether polyol in aqueous solution, the at least one polyether polyol consisting of the sole active therapeutic constituent of the composition or medicament, wherein the at least one polyether polyol preferably has a molecular weight of from 200 to 4000 and is dissolved in an aqueous fluid selected from an aqueous solution of one or more crystalloids, an aqueous colloid suspension of one or more colloids, or a mixture of such an aqueous solution of one or more crystalloids and such a colloid suspension of one or more colloids.
  • the concentration of the at least one polyether polyol in the aqueous solution is from 0.01 to 10 mg/ml, more preferably from 1 to 10 mg/ml.
  • the polyether polyol may comprise a single polyether polyol, or may comprise a mixture of at least two polyether polyols.
  • the polyether polyol is preferably a polyether glycol, most preferably polyethylene glycol.
  • the polyethylene glycol preferably has a molecular weight of from 200 to 4000, most preferably, 200 to 1000.
  • the invention most preferably has medical use for administration to human beings, although it may also have veterinary use for treating other mammals, such as domestic pets (cats, dogs, etc.), horses, farm animals (cattle, etc.).
  • the aqueous fluid for administration to a human being or a mammal is a medical-grade liquid, such as an aqueous fluid for nebulisation.
  • the fluid comprises an aqueous solution of one or more crystalloids, an aqueous colloid suspension of one or more colloids, or a mixture of such an aqueous solution of one or more crystalloids and such a colloid suspension of one or more colloids.
  • Preferred aqueous crystalloid solutions include Ringer's lactate solution, compound sodium lactate solution (for example comprising sodium 131 mmol/l, potassium 5 mmol/l, calcium 2 mmol/l, chloride 111 mmol/l, lactate 29 mmol/l; pH 6-7; osmolarity 278 m ⁇ smol/l) and normal saline solution (for example 0.9% sodium chloride in water), or mixtures of two or more of these solutions.
  • a most preferred fluid for administration contains sodium lactate.
  • Preferred aqueous colloid suspensions include succinylated gelatine suspended in, for example 0.9% saline solution and starch based colloid preparations (including hydroxyethylated starch) in aqueous suspension.
  • the preferred crystalloid-colloid solutions include one or more aqueous crystalloid solutions in admixture with one or more aqueous colloid suspensions.
  • the polyether polyol solution of the present invention is a polyether polyol-saline solution.
  • the solution of the invention is polyether polyol in hypertonic saline.
  • the solution according to the present invention is polyethyle glycol - saline.
  • the at least one polyether polyol is dissolved in the aqueous fluid for administration to a human being or mammal is in a concentration (with respect to the volume of the initial aqueous fluid) of from 0.01 to 10 mg/ml, more preferably from 1 to 10 mg/ml.
  • the present invention provides a method of treating and/or preventing inflammatory lung disease, the method comprising administering to a patient an aqueous solution of at least one polyether polyol via inhalation. Most preferably, this inhalation is via a nebuliser.
  • the aqueous solution of polyether polyol is applied directly to the lung tissue, e.g. via pulmonary delivery.
  • the aqueous solution of polyether polyol may thus be administered topically, preferably by inhalation. It is most preferred that the aqueous solution of polyether polyol is administered through oral inhalation (the patient breathes through their mouth). Inhalation allows the delivery of the inventive solution to the deep part of the respiratory tract.
  • aqueous solution of polyether polyol may be inhaled as an aerosol.
  • aerosolised refers to the conversion of the solution according to the present invention into an aerosol or fine mist/droplets. Aerosolised drugs are a standard way of treating lung diseases such as asthma and COPD, and can be defined as a solution of a drug that can be atomised into a fine mist/droplets for inhalation therapy.
  • a nebuliser is a machine that changes liquid drugs into fine droplets (in aerosol form) that are inhaled through a mouthpiece or mask. It is a preferred aspect of the present invention that the polyether polyol solution is administered to the patient/subject as an aerosol; most preferably, the polyether polyol solution is administered using a nebuliser. In a preferred aspect of the present invention, the aerosolised solution may be considered to be nebulised.
  • Aerosolised drugs may be delivered to the lower airway either through the nasal cavity or the oropharynx (the cavity formed by the pharynx at the back of the mouth); however, the oropharynx (or intrapulmonary) route is preferable for several reasons. Particularly, pulmonary mucociliary clearance mechanisms are minimal in the alveolar region of the lungs. Unlike the terminal portions of the lung, however, the mucociliary clearance of the nasal passages are much more effective. Intrapulmonary administration, which is the preferred mode of administration for the present invention, is associated with less rapid elimination of medications compared to intranasal, allowing prolonged deposition time. For these reasons, intrapulmonary inhalation is emerging as the optimal route for administration of aerosolised solutions. In a most preferable embodiment, the solution of the present invention is administered as an aerosolised solution via the oropharynx. Alternatively put, the solution is aerosolised and inhaled via the oral route.
  • low molecular weight polyethylene glycol administered in low concentration of from 1-10 mg/ml, inhibits production and/or release of major endogenous pro-inflammatory mediators (cytokines).
  • cytokines major endogenous pro-inflammatory mediators
  • the inventors postulate that the solutions of the present invention may act to reduce/prevent inflammatory lung disease by reducing the production and/or release of pro-inflammatory cytokines that are thought to be involved with the initiation/development of inflammatory lung disease.
  • the solution is thought to act via attenuation of cytokine production/release.
  • the present invention is predicated on the finding by the inventors that there is a marked benefit resulting from the administration of polyether polyol, in particular polyethylene glycol-saline solutions in experimental models of acute inflammation.
  • the present invention therefore is based in part on the discovery of a new and unexpected medical use of a known compound, which, according to the experimental data obtained by the present inventors, has profound properties which decrease the production of the pro-inflammatory cytokines, which to the inventors' knowledge was previously unrecognised by those skilled in the art.
  • the polyethylene glycol-saline solution can be administered easily, safely and effectively.
  • the inventors believe that because polyethylene glycol has previously been recognised as being safe for human use, being used widely in foods and drugs (categorised as a "GRAS" (Generally Recognised as Safe) substance by The United States Food and Drug Administration), there is an immediate clinical opportunity to develop polyethylene glycol solutions for use to pre-empt, mitigate, prevent or treat inflammatory lung disease.
  • the administration of the polyether polyol solutions may readily be achieved using a standard mode of care (for example, a nebuliser) to deliver the anti-inflammatory benefits of the polyether polyol compounds.
  • the medicament of the present invention may be used to treat any one of the inflammatory lung diseases mentioned herein.
  • the invention will now be further described with reference to the following non-limiting Figures and Examples. Other embodiments of the invention will occur to those skilled in the art in the light of these.
  • Figure 1 shows the relationship between body temperature and time, and thus demonstrating inflammatory response, for rats treated with a medicament in accordance with Example 1 of the present invention and in a comparative control sample;
  • Figures 2 (a), (b) and (c) show the relationship between blood plasma levels of the respective cytokines and composition of the injection for rats treated with a medicament in accordance with Example 2 of the present invention and in comparative control samples.
  • Figure 3 shows the effect of different routes of administering test item on LPS (a) or PBS (b) -induced bronchoalveolar lavage fluid (BALF) TNF ⁇ levels.
  • Figure 4 shows the effect of different routes of administering test item on LPS or PBS- induced bronchoalveolar lavage fluid (BALF) granulocyte levels.
  • Figure 5(a) shows that the release of the inflammatory mediators MIP-1 , lnterleukin-6 and PGE2 by human peripheral blood mononuclear cells is reduced when these immune cells are treated with PEG, compared with a control [vehicle] solution in a comparative control sample.
  • Figure 5(a) also shows that at the same concentration, higher molecular weight PEG (>4000) was not efficacious, but MW ⁇ 2000 had a significant anti-inflammatory effect on cytokine production.
  • Figure 5(b) shows that the most efficacious concentration of PEG that reduced prostaglandin E2 production was between 7-10mg/ml. * denotes significant difference (p ⁇ 0.05).
  • An isotonic solution of polyethylene glycol in compound sodium lactate solution in accordance with the present invention was prepared.
  • the solution had a concentration of 6.2 mg/ml of the polyethylene glycol in compound sodium lactate solution, and the polyethylene glycol had an average molecular weight of 200, and is available in commerce from the company Sigma, of Poole, UK (amongst many others).
  • This polyethylene glycol solution is referred to hereinafter in these Examples as PEG 200- saline
  • the temperature of the rats was measured for a period of two hours.
  • the results are summarised in Figure 1.
  • the temperature data for each time measurement are presented as mean temperature values ⁇ standard error of the mean value. It was found that body temperature of rats treated with both polyethylene glycol 200- saline solution and lipopolysaccharide was significantly lower than of rats injected with saline and lipopolysaccharide (p ⁇ 0.05). The data demonstrate that one of the major indicators of systemic inflammation, i.e. fever, is markedly reduced following a single intraperitoneal injection of polyethylene glycol-saline in accordance with the invention. The attenuation of inflammation was thus measured by the febrile response.
  • bacterial endotoxin lipopolysaccharide LPS
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-6 interleukin-6
  • TNF ⁇ tumour necrosis factor- ⁇
  • Plasma IL-1 ⁇ , IL-6 and TNF ⁇ concentrations were measured after a period of 1 hour following injection of the respective solutions (either containing LPS or not).
  • the results are summarised in Figures 2 (a), (b) and (c), which show data presented as means + standard errors of the means. Numbers in parentheses indicate sample sizes.
  • IL-1 ⁇ , IL-6 and TNF ⁇ levels in plasma of rats treated with both polyethylene glycol 200-saline solution and lipopolysaccharide were significantly lower than in plasma of rats injected with saline and lipopolysaccharide (p ⁇ 0.05).
  • This Example shows that administration of a polyethylene glycol-saline solution in accordance with the present invention can substantially reduce the production and/or release of major pro-inflammatory cytokines during systemic inflammation evoked by bacterial endotoxins.
  • PEG 400 was supplied by Sigma as a viscous liquid. Stock PEG 400 was prepared in sterile PBS to the appropriate concentration (5mg/ml). The IV dosage was 10 ml/kg (200 ⁇ l). The IN dosage was 35 ⁇ l.
  • Dexamethasone was supplied by Sigma as a white powder. Stock solution was prepared in ethanol and diluted with PBS.
  • Lipopolysaccharide was supplied by Sigma as an off-white powder. LPS was dissolved in
  • the test system was Mouse/BALB/c from Harlan UK. Animals were female young adults
  • the normal cell constitution of a naive lung wash would be expected to be 80-90% macrophages, less than 5% lymphocytes with epithelial cells, eosinophils, neutrophils, natural killer cells and mast cells making up the remainder.
  • cytokines such as TNF and IL-1 which in turn recruit inflammatory cells.
  • the majority of cells that respond to LPS are neutrophils. Neutrophils and eosinophil numbers are categorised in these experiments as "granulocytes" based upon their size and granularity.
  • test items were administered at time Oh.
  • Each animal in groups 1 M-4M was subjected at 1 h to an intranasal administration of LPS at a volume of 35 ⁇ l (0.5 ⁇ g/mouse).
  • All mice in groups 5M-8M were subjected to an administration of PBS at a volume of 35 ⁇ l.
  • Mice were lightly anaesthetised by an inhaled general anesthetic (Halothane, Merial Animal Health Ltd) and the LPS or PBS was placed drop-wise on the nares using a pipette. The animals spontaneously breathed in the liquid and were observed to fully recover from the anesthetic within 2 minutes. All groups were 8 animals.
  • mice 4h after LPS/PBS administration all mice were culled and bronchoalveolar lavage was carried out.
  • the bronchoalveolar lavage fluid (BALF) was used to analyse the cell influx via FACS analysis and to study cytokine levels via Luminex.
  • Figure 3 shows 2 graphs depicting TNF ⁇ after either LPS or PBS instillation into the lungs.
  • Figure 4 shows that IV-administered PEG400 reduced the levels of inflammatory cells to the lungs from 74% to 64%, although this did not reach statistical significance. Dexamethasone did significantly reduce the cell influx when compared to vehicle.
  • Examples in accordance with the invention show that treatment with polyethylene glycol-saline solutions can markedly reduce the levels of pro-inflammatory cytokines in experimental models of inflammation.
  • the polyethylene glycol-saline was found to inhibit endotoxin-induced production of pro-inflammatory cytokines. From these data the inventors conclude, without wishing to be bound by theory, that the effect of polyethylene glycol infusion in inflammatory conditions is due to inhibition of overzealous production and/or release of harmful quantities of pro-inflammatory cytokines.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Otolaryngology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne l'utilisation d'une solution aqueuse contenant au moins un polyol de polyéther destinée à traiter et/ou à prévenir des maladies pulmonaires inflammatoires, en particulier l'asthme, une fibrose kystique et une MPOC. La solution de l'invention est administrée de manière topique, par inhalation.
PCT/GB2007/002354 2006-06-27 2007-06-25 Procédé de traitement et/ou de prévention d'une maladie pulmonaire inflammatoire WO2008001055A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0612748.4 2006-06-27
GBGB0612748.4A GB0612748D0 (en) 2006-06-27 2006-06-27 Treatment and/or prevention of inflammatory lung disease

Publications (1)

Publication Number Publication Date
WO2008001055A1 true WO2008001055A1 (fr) 2008-01-03

Family

ID=36888165

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/002354 WO2008001055A1 (fr) 2006-06-27 2007-06-25 Procédé de traitement et/ou de prévention d'une maladie pulmonaire inflammatoire

Country Status (2)

Country Link
GB (1) GB0612748D0 (fr)
WO (1) WO2008001055A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007101264A3 (fr) * 2006-02-28 2008-07-17 Univ Chicago Procédé servant à traiter des troubles des cellules endothéliales et épithéliales en administrant des composés de type peg de poids moléculaire élevé

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038699A2 (fr) * 1996-04-15 1997-10-23 Charlotte-Mecklenburg Hospital Authority Doing Business As Carolinas Medical Center Traitement de l'inflammation pulmonaire chronique a l'aide de polymeres d'alcool d'alkylarylpolyether
WO2002083113A2 (fr) * 2001-04-17 2002-10-24 Dey, L.P. Compositions bronchodilatatrices a base de formoterol et de steroide et methodes d'utilisation de celles-ci
DE10204696A1 (de) * 2002-02-06 2003-08-21 Sonomed Gmbh Verwendung von Polyethylenglykol zur Prävention oder Behandlung von Erkältungskrankheiten
WO2004047778A1 (fr) * 2002-11-26 2004-06-10 Uc Tech Materiaux et procedes pour la prevention et le traitement de troubles epitheliaux a mediation microbienne
WO2006003078A1 (fr) * 2004-06-29 2006-01-12 Boehringer Ingelheim International Gmbh Medicaments pour inhalation comprenant des steroides et un anticholinergique
WO2006067502A1 (fr) * 2004-12-23 2006-06-29 University College London Hospitals Nhs Foundation Trust Traitement de maladies inflammatoires

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038699A2 (fr) * 1996-04-15 1997-10-23 Charlotte-Mecklenburg Hospital Authority Doing Business As Carolinas Medical Center Traitement de l'inflammation pulmonaire chronique a l'aide de polymeres d'alcool d'alkylarylpolyether
WO2002083113A2 (fr) * 2001-04-17 2002-10-24 Dey, L.P. Compositions bronchodilatatrices a base de formoterol et de steroide et methodes d'utilisation de celles-ci
DE10204696A1 (de) * 2002-02-06 2003-08-21 Sonomed Gmbh Verwendung von Polyethylenglykol zur Prävention oder Behandlung von Erkältungskrankheiten
WO2004047778A1 (fr) * 2002-11-26 2004-06-10 Uc Tech Materiaux et procedes pour la prevention et le traitement de troubles epitheliaux a mediation microbienne
WO2006003078A1 (fr) * 2004-06-29 2006-01-12 Boehringer Ingelheim International Gmbh Medicaments pour inhalation comprenant des steroides et un anticholinergique
WO2006067502A1 (fr) * 2004-12-23 2006-06-29 University College London Hospitals Nhs Foundation Trust Traitement de maladies inflammatoires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KARLSSON P C ET AL: "Polyethylene glycol reduces inflammation and aberrant crypt foci in carcinogen-initiated rats", CANCER LETTERS, NEW YORK, NY, US, vol. 223, no. 2, 8 June 2005 (2005-06-08), pages 203 - 209, XP004894639, ISSN: 0304-3835 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007101264A3 (fr) * 2006-02-28 2008-07-17 Univ Chicago Procédé servant à traiter des troubles des cellules endothéliales et épithéliales en administrant des composés de type peg de poids moléculaire élevé

Also Published As

Publication number Publication date
GB0612748D0 (en) 2006-08-09

Similar Documents

Publication Publication Date Title
JP3263723B2 (ja) 喘息を治療するための組成物、及び喘息にかかった患者を治療するための気管支内薬物の製造における超低分子量ヘパリンの使用
JP2001513078A (ja) 吸入により新生物を治療する製剤とその方法
JP2002526451A (ja) 急性肺傷害の予防方法
JP2009529539A (ja) 呼吸器障害を治療するための方法および組成物
JP2011225625A (ja) 肺障害の治療
CN112533589A (zh) 用于治疗粘液高分泌的含有粘液溶解剂的组合物及其给药装置
AU2002323191B2 (en) Method for treating bronchial constriction and bronchospasm
JP2022521558A (ja) ペラミビル溶液吸入剤およびその製造方法
BG65818B1 (bg) Циклесонид-съдържащ фармацевтичен състав за прилагане върху мукоза
AU2002323191A1 (en) Method for treating bronchial constriction and bronchospasm
JP7483050B2 (ja) ヒアルロナンコンジュゲートの使用
JP2024506840A (ja) 化学ガス曝露を処置する方法
PT866711E (pt) Montirelina para inibição da apneia do sono
WO2008001055A1 (fr) Procédé de traitement et/ou de prévention d'une maladie pulmonaire inflammatoire
KR101924162B1 (ko) 기도의 염증 및 이상성 점액섬모 전달의 치료법으로서의 에어로졸화 댑손
KR102606504B1 (ko) 니클로사마이드를 포함하는 폐고혈압의 예방 및 치료용 조성물
AU2021262813A1 (en) Compositions and methods for treating cytokine storms
JP2021176903A (ja) イソグリチルリチン酸またはその塩の吸入製剤および呼吸器疾患を治療する薬物の製造におけるそれらの応用
US20080292580A1 (en) Treatment of Inflammatory Diseases
EA032116B1 (ru) Новое применение n,n-бис-2-меркаптоэтил-изофталамида
RU2805512C2 (ru) Композиция, содержащая муколитический агент, для лечения гиперсекреции слизи и устройство для ее дозирования
CN120478399B (zh) 一种金制剂在制备用于治疗猫传染性腹膜炎药物中的应用
EP4051307B1 (fr) Peptide pour la prévention ou le traitement du covid-19
CN117442588A (zh) 一种吸入用人干扰素α2b溶液及其制备方法
CN112089721A (zh) 一种腺苷的新应用及含有其的药物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07733349

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07733349

Country of ref document: EP

Kind code of ref document: A1