WO2017127810A1 - Méthodes pour la réparation de tissus pulmonaires - Google Patents

Méthodes pour la réparation de tissus pulmonaires Download PDF

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Publication number
WO2017127810A1
WO2017127810A1 PCT/US2017/014577 US2017014577W WO2017127810A1 WO 2017127810 A1 WO2017127810 A1 WO 2017127810A1 US 2017014577 W US2017014577 W US 2017014577W WO 2017127810 A1 WO2017127810 A1 WO 2017127810A1
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WO
WIPO (PCT)
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subject
administered
amd3100
phenylenebis
methylene
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PCT/US2017/014577
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English (en)
Inventor
Irina Petrache
Houssam QUEINI
Keith March
Hal Broxmeyer
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Indiana University Research & Technology Corporation
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Publication of WO2017127810A1 publication Critical patent/WO2017127810A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins

Definitions

  • the present disclosure relates generally to treating chronic obstructive pulmonary disease (COPD), and in particular, emphysema, in subjects in need thereof. More particularly, the present disclosure relates to repairing lung tissue damage caused by emphysema. In one aspect, the emphysema is a result of cigarette smoking.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • Emphysema and chronic bronchitis can be difficult to tell apart, but each presents problems with breathing and other lung symptoms.
  • the difference between emphysema and chronic bronchitis lies in how each disease affects the lungs.
  • Emphysema involves the gradual destruction of the air sacs in the lungs (alveoli), hindering breathing. Alveoli are responsible for providing oxygen to the bloodstream. Over time, emphysema weakens the alveoli and destroys the elasticity of pulmonary airways. As a result, emphysema sufferers experience shortness of breath and a constant struggle to breathe.
  • Chronic bronchitis is the opposite of emphysema. This condition causes a person's lungs to become very inflamed. Bronchitis commonly affects the windpipe and passageways of the lungs and is the result of severe irritation or infection. It can be a brief illness, or ongoing (chronic). The body's natural reaction to chronic bronchitis is to clear the air passages, resulting in severe coughing. [0007] Mistakenly, many believe that asthma is a type of COPD. Although COPD and asthma are both respiratory diseases characterized by underlying inflammation, the nature of the inflammation is quite different in each case.
  • COPD inflammation is characterized by inflammatory cells such as neutrophils, CD8+ T-lymphocytes and macrophages and the disease is associated with airflow limitation that is not fully reversible.
  • airflow limitation is often fully reversible, either spontaneously or with treatment and has a different profile of inflammatory cells, namely eosinophils and CD4+ T-lymphocytes.
  • both the airways and lung parenchyma are affected by the disease and airflow limitation is progressive.
  • Asthma is usually present from childhood, whereas COPD is predominantly diagnosed in patients greater than 40 years old.
  • the present disclosure is directed to a method for treating COPD in a subject in need thereof.
  • the method comprises administering a compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) to the subject.
  • the compound is 1,1'- [ 1 ,4-Phenylenebis(methylene) ]bis- 1 ,4 ,8 , 11 -tetraazacyclotetradecane octahydrochloride.
  • the present disclosure is directed to a method for repairing lung tissue in a subject in need thereof.
  • the method comprises chronically administering a compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) to the subject.
  • the compound is 1,1 '- [1 ,4-Phenylenebis(methylene)]bis- 1 ,4,8 , 11 -tetraazacyclotetradecane octahydrochloride.
  • the present disclosure is directed to a method for treating myelosuppression in a subject in need thereof.
  • the method comprises chronically administering a compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) to the subject.
  • the compound is l,l'-[l,4-Phenylenebis(methylene)]bis-l,4,8,l l- tetraazacyclotetradecane octahydrochloride.
  • FIG. 1 depicts SDF-1 levels as analyzed in the Example.
  • FIG. 2 depicts lung volumes as analyzed in the Example.
  • FIG. 3 depicts airspace enlargement, measured by mean linear intercept, as analyzed in the Example.
  • FIG. 4 depicts progenitor cells as analyzed after six months in the Example.
  • FIG. 5 depicts progenitor cells as analyzed after one week in the Example.
  • methods for treating COPD and in particular emphysema, are disclosed.
  • methods for repairing lung tissue damaged by COPD in a subject in need thereof are disclosed.
  • methods for treating myelosuppression in a subject in need thereof are disclosed.
  • Target organ injury is thought to be "sensed" by bone marrow progenitor cells (BMPCs) that actively participate in the repair through direct migration to the site of injury.
  • BMPCs bone marrow progenitor cells
  • a major player in recruiting bone marrow-derived circulating cells to injured organs is the cytokine stromal cell-derived factor (SDF)-1.
  • SDF cytokine stromal cell-derived factor
  • CXCR-4 also known as fusin or CD184 (cluster of differentiation 184)
  • CD184 cluster of differentiation 184
  • Cigarette smoking is the main risk factor for chronic obstructive pulmonary disease (COPD), and particularly, emphysema. It has now been found that CS has a direct suppressive effect on bone marrow progenitor cell number and proliferation, which may decrease their ability to repair the lung. Based on the foregoing, it was believed that mobilization of bone marrow progenitor cells following lung injury would be sufficient to enhance lung repair and improve outcomes during cigarette smoke exposure.
  • COPD chronic obstructive pulmonary disease
  • the present disclosure is generally directed to administering to a subject in need thereof, a compound capable of inhibiting the binding of cytokine stromal cell- derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4), and in particular, to administering AMD3100.
  • a compound capable of inhibiting the binding of cytokine stromal cell- derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) may be used in the methods of the present disclosure.
  • the methods are directed to be used with a subject in need thereof.
  • the methods of the present disclosure are to be used with a subset of subjects who are suspected of having and/or have COPD, and in particular, emphysema caused by cigarette smoking, and/or are suffering from myelosuppression.
  • Subjects may be susceptible to or at elevated risk for COPD (e.g., emphysema) and/or myelosuppression due to family history, age, environment, and/or lifestyle (e.g., cigarette smoking).
  • compositions comprise AMD3100 as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • compositions of this disclosure can be administered to humans and other animals orally, parenterally, intravenously, subcutaneously, intracisternally, intraperitoneally, buccally, as an oral or nasal spray, or the like, depending on the severity of the disorder being treated.
  • Another suitable delivery to subjects is airway delivery of AMD3100.
  • Suitable airway delivery methods include inhalation as aerosols, nebulized liquids and dry-powder formulations.
  • Other suitable methods of administration include, for example, by intratracheal inhalation and insufflation.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyl glycol, 1,3-butyl glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethyl glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can contain inert diluents commonly used in the art such as,
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • AMD3100 of the present disclosure In order to prolong the effect of AMD3100 of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of AMD3100 then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered AMD3100 is accomplished by dissolving or suspending AMD3100 in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of AMD3100 in biodegradable polymers such as polylactide- polyglycolide.
  • the rate of AMD3100 release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping AMD3100 in liposomes or microemulsions that are compatible with body tissues.
  • Suitable concentrations of AMD3100 administered include from about 1.0 mg/kg to about 160 mg/kg per day, including about 2.0 mg/kg to about 75 mg/kg.
  • a particularly suitable concentration of AMD3100 includes about 5 mg/kg per day.
  • AMD3100 is chronically administered to the subject.
  • “chronically administered”, “chronically administering” or “chronic administration” refer to administering AMD3100 more than one time (i.e., multiple dosages over a time period) to a subject in need thereof.
  • AMD3100 is administered continuously over a time period.
  • AMD3100 is administered repeatedly, but intermittently, over a time period.
  • AMD3100 can be administered to the subject daily for at least 3 days, or at least 5 days, or at least 7 days or more.
  • AMD3100 can be administered periodically for a period of at least 1 week, at least 12 weeks, at least 24 weeks or more.
  • the total daily/weekly usage of AMD3100 and compositions of the present disclosure (also referred to herein as "effective amount”) will be decided by the attending physician within the scope of sound medical judgment. More particularly, as used herein, the phrase "effective amount" of AMD3100 and/or compositions used in the methods of the present disclosure refers to a sufficient amount of AMD3100 to treat COPD and/or repair lung tissue damage caused by COPD as defined herein, at a reasonable benefit/risk ratio applicable to any medical treatment. It can be understood, however, that the total usage of AMD3100 and pharmaceutically acceptable compositions including AMD3100 for use in the methods of the present disclosure can be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject can depend upon a variety of factors including the severity of lung tissue damage being treated; the specific pharmaceutically acceptable composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of AMD3100 from the subject; the duration of the treatment; drugs used in combination or coincidental with AMD3100; and like factors well-known in the medical arts.
  • the present disclosure is directed to a method for treating COPD in a subject in need thereof.
  • the method comprises chronically administering 1,1 '-[1,4- Phenylenebis(methylene)]bis-l,4,8,ll-tetraazacyclotetradecane octahydrochloride to the subject.
  • the subject in need thereof is or was a cigarette smoker and is suffering (i.e., diagnosed as having emphysema) or at risk of suffering from emphysema.
  • the present disclosure is directed to a method for repairing lung tissue in a subject in need thereof.
  • the method comprises chronically administering 1,1'- [l,4-Phenylenebis(methylene)]bis-l,4,8,ll-tetraazacyclotetradecane octahydrochloride to a subject in need thereof.
  • the subject in need thereof is or was a cigarette smoker and has lung damage caused by COPD.
  • the present disclosure is directed to a method for treating myelosuppression.
  • the method comprises chronically administering 1,1 '-[1,4- Phenylenebis(methylene)]bis-l,4,8,ll-tetraazacyclotetradecane octahydrochloride to a subject in need thereof.
  • Myelosuppression is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes).
  • C57BL/6 mice were exposed to cigarette smoke (CS) for six months with or without subcutaneous injection of AMD3100.
  • AMD3100 was administered subcutaneously 5 mg/kg daily for 5 days during weeks 1, 12, and 24.
  • Mice were harvested after 24 weeks of CS exposure, when lung function, lung morphometry, SDF-1 levels in bronchial alveolar lavage fluid (BALF), as well as bone marrow progenitor cells, were measured.
  • BALF bronchial alveolar lavage fluid
  • CFU bone marrow progenitor cell colony forming units
  • emphysema-like morpho-functional manifestations in the lung Treatment of CS exposed mice with AMD3100 significantly ameliorated CS-induced increases in lung volumes (16% improvement; p ⁇ 0.05; FIG. 2), static lung compliance (15% improvement; p ⁇ 0.05), and airspace enlargement, measured by mean linear intercept (p ⁇ 0.05; FIG. 3).
  • AMD3100 treatment significantly increased, by 2.5-fold, the number of progenitor cells (CFU) in the bone marrow, despite ongoing CS exposure (p ⁇ 0.05; FIG. 4). Even after only one week, AMD3100 showed shielding from cigarette smoke-induced myelosuppression (p ⁇ 0.05; FIG. 5).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des méthodes permettant de traiter une bronchopneumopathie chronique obstructive (BPCO), et plus particulièrement un emphysème. La présente invention concerne des méthodes pour la réparation des lésions des tissus pulmonaires provoquées par une BPCO par l'administration d'AMD3100.
PCT/US2017/014577 2016-01-22 2017-01-23 Méthodes pour la réparation de tissus pulmonaires WO2017127810A1 (fr)

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US201662286041P 2016-01-22 2016-01-22
US62/286,041 2016-01-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110123742A (zh) * 2019-03-29 2019-08-16 四川汇宇制药有限公司 一种高品质普乐沙福注射液的制备方法
WO2022234054A1 (fr) * 2021-05-05 2022-11-10 4Living Biotech Utilisation d'un composé tel que le plérixafor pour le traitement d'une maladie pulmonaire virale

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090274687A1 (en) * 2008-05-02 2009-11-05 University Of Miami Attenuation of hypoxia induced cardiovascular disorders
US20140219952A1 (en) * 2010-03-23 2014-08-07 The Johns Hopkins University Methods of treatment using stem cell mobilizers
WO2016120369A1 (fr) * 2015-01-28 2016-08-04 Universite de Bordeaux Nouvelles compositions et méthodes de traitement et/ou de prévention de la maladie pulmonaire obstructive chronique

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Publication number Priority date Publication date Assignee Title
US20090274687A1 (en) * 2008-05-02 2009-11-05 University Of Miami Attenuation of hypoxia induced cardiovascular disorders
US20140219952A1 (en) * 2010-03-23 2014-08-07 The Johns Hopkins University Methods of treatment using stem cell mobilizers
WO2016120369A1 (fr) * 2015-01-28 2016-08-04 Universite de Bordeaux Nouvelles compositions et méthodes de traitement et/ou de prévention de la maladie pulmonaire obstructive chronique

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LANIADO-LABORIN, R.: "Smoking and Chronic Obstructive Pulmonary Disease (COPD): Parallel Epidemics of the 21st Century", INT. J. ENVIRON. RES. PUBLIC HEALTH, vol. 6, no. 1, 9 January 2009 (2009-01-09), pages 209 - 224, XP055400228 *
MODAK ET AL.: "Plerixafor Plus Granulocyte-Colony Stimulating Factor for Autologous Hematopoietic Stem Cell Mobilization in Patients With Metastatic Neuroblastoma", PEDIATR BLOOD CANCER, vol. 58, 17 March 2011 (2011-03-17), pages 469 - 471, XP055400229 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110123742A (zh) * 2019-03-29 2019-08-16 四川汇宇制药有限公司 一种高品质普乐沙福注射液的制备方法
WO2022234054A1 (fr) * 2021-05-05 2022-11-10 4Living Biotech Utilisation d'un composé tel que le plérixafor pour le traitement d'une maladie pulmonaire virale

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