US20140105985A1 - Topical use of levofloxacin for reducing lung inflammation - Google Patents
Topical use of levofloxacin for reducing lung inflammation Download PDFInfo
- Publication number
- US20140105985A1 US20140105985A1 US14/134,348 US201314134348A US2014105985A1 US 20140105985 A1 US20140105985 A1 US 20140105985A1 US 201314134348 A US201314134348 A US 201314134348A US 2014105985 A1 US2014105985 A1 US 2014105985A1
- Authority
- US
- United States
- Prior art keywords
- levofloxacin
- aerosol
- pulmonary
- concentration
- ofloxacin
- 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.)
- Abandoned
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to methods and compositions for the treatment of pulmonary inflammation.
- methods and compositions using aerosol levofloxacin or ofloxacin to reduce pulmonary inflammation are provided.
- Inflammation is a response of vascularized tissue to injury; it is perceived as redness, heat, swelling, and pain and is usually accompanied by loss of function to varying degrees. In its acute form it is of short duration, involving increased vascular transudation and interstitial edema and infiltration of inflammatory cells, predominantly of neutrophils. In moist mucosal tissues, such as that which lines the respiratory tract, there may also be loss of surface epithelial cells and secretion of mucus. This form of inflammatory response is considered protective and is, therefore, in the short term, beneficial to the host. However, if the injury is repeated or severe, the character of the inflammatory infiltrate may change to one predominantly of mononuclear cell (i.e., lymphocytes, monocytes, and macrophages) and it may become persistent.
- mononuclear cell i.e., lymphocytes, monocytes, and macrophages
- Chronic inflammation may develop from unresolved symptomatic acute inflammation or may evolve insidiously over a period of months without apparent acute onset of clinical manifestations.
- Histopathologic features of chronic inflammation include the predominance of macrophages and lymphocytes, proliferation of nurturing structurally heterogeneous and hyperpermeable small blood vessels, fibrosis, and necrosis.
- Activated macrophages and lymphocytes are interactive in releasing inflammatory mediators or cytokines that amplify immune reactivity.
- Cytokines include a family of biologic response modifiers including interleukins, chemokines, interferons, growth factors, and leukocyte colony-stimulating factors.
- cytokines are secreted by leukocytes, connective tissue cells, and endothelial cells.
- Chemokines consist of 8- to 10-kd proteins that stimulate leukocyte recruitment and migration as part of the host response to antigenic insults. In chronic inflammation, the protracted inflammatory response is often accompanied simultaneously by tissue destruction and repair.
- Some embodiments include methods for treating a pulmonary inflammation in a subject in which the methods include administering to the subject in need thereof an aerosol of a solution including levofloxacin or ofloxacin and a divalent or trivalent cation.
- Some embodiments include methods for treating a pulmonary inflammation in a subject, wherein the pulmonary inflammation is induced by one or more pro-inflammatory cytokines, in which the methods include administering to the subject in need thereof an aerosol of a solution including levofloxacin or ofloxacin and a divalent or trivalent cation to achieve a reduction in the pulmonary concentration of said cytokine by at least 10%.
- Some embodiments include methods for treating a pulmonary inflammation in a subject in which the methods include administering to the subject in need thereof an aerosol of a solution including levofloxacin or ofloxacin and a divalent or trivalent cation to achieve a reduction in the pulmonary concentration of one or more pro-inflammatory cytokines including IL-1 ⁇ , IL-6 and IL-8, whereby the pulmonary inflammation is reduced or suppressed.
- FIG. 2A shows a graph of IL-6 levels produced by HBE135 cells in response to treatment with control, LPS, and LPS with levofloxacin, moxifloxacin, or ciprofloxacin.
- FIG. 2B shows a graph of IL-8 produced by HBE135 cells in response to treatment with control, LPS, and LPS with levofloxacin, moxifloxacin, or ciprofloxacin.
- FIG. 3A shows a graph of percentage cell survival for NL20 cells treated with increasing concentrations of levofloxacin, moxifloxacin, or ciprofloxacin.
- FIG. 3B shows a graph of percentage cell survival for HBE135 cells treated with increasing concentrations of levofloxacin, moxifloxacin, or ciprofloxacin.
- FIG. 6 shows a graph of IL-6 and IL-8 levels produced by HBE135 cells in response to treatment with LPS, and LPS with increasing concentrations of levofloxacin or tobramycin.
- FIG. 7C shows a graph of IL-6 levels in THP-1 cells treated with control; LPS; and 10 ⁇ g/ml, 30 ⁇ g/ml, 100 ⁇ g/ml, 300 ⁇ g/ml levofloxacin and LPS.
- FIG. 7D shows a graph of IL-8 levels in THP-1 cells treated with control; LPS; and 10 ⁇ g/ml, 30 ⁇ g/ml, 100 ⁇ g/ml, 300 ⁇ g/ml levofloxacin and LPS.
- FIG. 9 shows shows a graph of the relative luciferase activity of a NFkB promoter construct in NL20 cells stimulated with control; TNF ⁇ ; TNF ⁇ and 100 ⁇ g/ml levofloxacin; and TNF ⁇ and 100 ⁇ g/ml levofloxacin.
- Cells were transfected with the reporter plasmid, and after 24 h treated with TNF ⁇ alone or TNF ⁇ with antibiotics, then incubated for an additional 8 h.
- NFkB-dependent luciferase activity was measured using a commercial assay. The results were expressed as means ⁇ SD of six replicates.
- the present invention relates to methods and compositions for the treatment of disorders and diseases associated with pulmonary inflammation.
- methods and compositions to reduce inflammation using aerosol levofloxacin or ofloxacin formulated with a divalent or trivalent cation are provided.
- Some embodiments include treating acute or chronic inflammation of the lung or the upper airway by topically administering aerosol levofloxacin or ofloxacin formulated with a divalent or trivalent cation directly to the inflammation site.
- levofloxacin topical administration of levofloxacin formulated with divalent or trivalent cations can significantly decrease the level of cytokine and chemokine production in vitro and in vivo. Such decreases in the levels of pro-inflammatory cytokines may produce a reduction in neutrophil-mediated inflammations. Examples of pro-inflammatory cytokines include IL-1, IL-6, IL-7, and IL-8. High concentrations of levofloxacin can be administered to the lungs and upper airways by inhalation. Surprisingly, formulations of levofloxacin with divalent or trivalent cations have greater availability in the lungs compared to formulations of levofloxacin only.
- the present invention relates to methods and compositions for reducing inflammation in the lungs and upper airway by administration of aerosolized fluoroquinolones, such as levofloxacin, formulated with divalent or trivalent cations, such as Mg 2+ .
- NSAID non-steroidal anti-inflammatory drugs
- azithromycin have been associated with benefits in certain CF patient subgroups (Flume P A, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007; 176:957-969, incorporated by reference in its entirety).
- the antibiotic erythromycin reduces the incidence of pulmonary exacerbations in COPD patients (Seemungal T A, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008; 178:1139-1147, incorporated by reference in its entirety).
- the efficacy of azithromycin and erythromycin in these settings are likely due in large part to immunomodulatory and anti-inflammatory effects rather than antibacterial effects.
- fluoroquinolones may have an immunomodulatory activity as well as an anti-bacterial activity. These activities may be distinct and only apparent in vivo at concentrations that are also cytotoxic. Some fluoroquinolones may affect their immunomodulatory activity through various signaling pathways that relate to the production and secretion of various cytokines and chemokines. However, not all fluoroquinolones show immunomodulatory activity. Moreover, different fluoroquinolones illicit different responses, such as the induction or inhibition of particular cytokines and chemokines. The immunomodulatory activity may also depend on cell type, immune stimulant, and concentration of the fluoroquinolone.
- fluoroquinolones such as moxifloxacin and grepafloxacin, but not ciprofloxacin, can inhibit secretion of pro-inflammatory factor such as IL-8, IL-6, ERK1/2, MK, and NF ⁇ B in human lung epithelia cells (Blau, H., K. et al. 2007.
- Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, MK, and NF-kappaB activation in a cystic fibrosis epithelial cell line.
- Levofloxacin inhibits TNF- ⁇ and IFN ⁇ production in tonsillar lymphocytes at 50 mg/L, and IL-8 production at 5 mg/L.
- levofloxacin inhibits RANTES-release in nasal epithelial cells from patients of nasal polyposis.
- the inhibitory activity of levofloxacin on the production of pro-inflammatory factors is much lower than that for other fluoroquinolones such as ciprofloxacin and moxifloxacin.
- the inhibitory activity of levofloxacin on the production of pro-inflammatory factors such as TNF- ⁇ , IL-1 and IL-8 requires 100 mg/L levofloxacin.
- immortalized human airway epithelia cells retain certain features of airway epithelium and have been extensively used to characterize immunomodulatory effects of other antibiotics (Blau H, et al. Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, MK, and NF-kappaB activation in a cystic fibrosis epithelial cell line. Am J Physiol Lung Cell Mol Physiol 2007; 292:L343-352; and Donnarumma G, et al.
- IL-6 and IL-8 are of high importance in regulating inflammatory response in CF lungs, with latter having the strongest potential to induce neutrophil chemotaxis (Strieter R M. Interleukin-8: a very important chemokine of the human airway epithelium. Am J Physiol Lung Cell Mol Physiol 2002; 283:L688-689, incorporated by reference in its entirety). It has been discovered that levofloxacin produces a dose-dependent reduction of TNF ⁇ - and LPS-induced IL-6 and IL-8 levels in cultured human airway epithelia cells. Levofloxacin also decreases LPS-induced IL-1 ⁇ , IL-6 and IL-8 production in human monocytic cells. In addition, levofloxacin reduces IL-6 and IL-8 production in vivo.
- administering refers to a method of giving a dosage of an anti-inflammatory pharmaceutical composition to a vertebrate.
- the preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the inflammation, and the severity of an actual inflammation.
- a “carrier” or “excipient” is a compound or material used to facilitate administration of the compound, for example, to increase the solubility of the compound.
- Solid carriers include, e.g., starch, lactose, dicalcium phosphate, sucrose, and kaolin.
- Liquid carriers include, e.g., sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil, peanut and sesame oils.
- various adjuvants such as are commonly used in the art may be included.
- mamal is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, and cats, but also includes many other species.
- pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable.
- the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
- Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, naphtoic acid, oleic acid, palmitic acid, pamoic (emboic) acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, glucoheptonic acid, glucuronic acid, lactic acid, lactobioic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
- Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, histidine, arginine, lysine, benethamine, N-methyl-glucamine, and ethanolamine.
- Other acids include dodecylsufuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, and saccharin.
- Solidvate refers to the compound formed by the interaction of a solvent and fluoroquinolone antimicrobial, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
- a therapeutically effective amount or “pharmaceutically effective amount” is meant a fluoroquinolone anti-inflammatory agent, as disclosed for this invention, which has a therapeutic effect.
- the doses of fluoroquinolone anti-inflammatory agent which are useful in treatment are therapeutically effective amounts.
- a therapeutically effective amount means those amounts of fluoroquinolone anti-inflammatory agent which produce the desired therapeutic effect as judged by clinical trial results and/or model animal anti-inflammatory studies.
- the fluoroquinolone anti-inflammatory agent are administered in a pre-determined dose, and thus a therapeutically effective amount would be an amount of the dose administered.
- This amount and the amount of the fluoroquinolone anti-inflammatory agent can be routinely determined by one of skill in the art, and will vary, depending on several factors, such as the particular inflammation involved, for example, the site of inflammation, the severity of inflammation. This amount can further depend upon the patient's height, weight, sex, age and medical history. For prophylactic treatments, a therapeutically effective amount is that amount which would be effective to prevent a particular inflammation.
- a “therapeutic effect” relieves, to some extent, one or more of the symptoms of the inflammation, and includes curing an inflammation. “Curing” means that the symptoms of inflammation are eliminated. However, certain long-term or permanent effects of the inflammation may exist even after a cure is obtained (such as extensive tissue damage). As used herein, a “therapeutic effect” is defined as a statistically significant reduction in an inflammation, emergence of inflammation, or improvement in inflammation symptoms as measured by human clinical results or animal studies.
- Treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
- prophylactic treatment refers to treating a patient who is not yet having an inflammation, but who is susceptible to, or otherwise at risk of, a particular inflammation such that there is a reduced onset of an inflammation.
- therapeutic treatment refers to administering treatment to a patient already suffering from an inflammation.
- treating is the administration to a mammal (either for therapeutic or prophylactic purposes) of therapeutically effective amounts of a fluoroquinolone anti-inflammatory agent.
- dosing interval refers to the time between administrations of the two sequential doses of a pharmaceutical's during multiple dosing regimens.
- dosing intervals are 12 hours and 24 hours, respectively.
- the “peak period” of a pharmaceutical's in vivo concentration is defined as that time of the pharmaceutical dosing interval when the pharmaceutical concentration is not less than 50% of its maximum plasma or site-of-inflammation concentration. In some embodiments, “peak period” is used to describe an interval of anti-inflammatory dosing.
- the “respirable delivered dose” is the amount of drug inhaled during the inspiratory phase of the breath simulator that is equal to or less than 5 microns using a simulator programmed to the European Standard pattern of 15 breaths per minute, with an inspiration to expiration ratio of 1:1.
- pulmonary concentration can include the concentration of a substance in the lung of a subject, the concentration of a substance in the sputum of a subject, and/or the concentration of a substance in the bronchial alveoial lavage of a subject. As will be understood, “pulmonary concentration” can be measured by various methods.
- a method for treating an inflammation in an animal, specifically including in a mammal, by treating an animal suffering from such an inflammation with a fluoroquinolone anti-inflammatory agent formulated with a divalent or trivalent cation and having improved pulmonary availability.
- fluoroquinolone anti-inflammatory agents may be administered following aerosol formation and inhalation.
- this method of treatment is especially appropriate for the treatment of pulmonary inflammations that are difficult to treat using an anti-inflammatory agent delivered parenterally due to the need for high parenteral dose levels (which can cause undesirable side effects), or due to lack of any clinically effective anti-inflammatory agents.
- this method may be used to administer a fluoroquinolone anti-inflammatory agent directly to the site of inflammation. Such a method may reduce systemic exposure and maximizes the amount of anti-inflammatory agent to the site of inflammation.
- the aerosol fluoroquinolone therapy may be administered as a treatment or prophylaxis in combination or alternating therapeutic sequence with other aerosol, oral or parenteral antibiotics.
- this may include aerosol tobramycin and/or other aminoglycoside, aerosol aztreonam and/or other beta- or mono-bactam, carbapenems, aerosol ciprofloxacin and/or other fluoroquinolones, aerosol azithromycin and/or other macrolides or ketolides, tetracycline and/or other tetracyclines, quinupristin and/or other streptogramins, linezolid and/or other oxazolidinones, vancomycin and/or other glycopeptides, erythromycin, and chloramphenicol and/or other phenicols, and colisitin and/or other polymyxins.
- compositions and methods provided herein can include the aerosol fluoroquinolone therapy administered as a treatment or prophylaxis in combination or alternating therapeutic sequence with an additional active agent.
- additional agents can include antibiotics.
- More additional agents can include bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, and combinations thereof.
- glucocorticoids examples include prednisone, fluticasone, budesonide, mometasone, ciclesonide, and beclomethasone.
- eicosanoids examples include montelukast, pranlukast, zafirlukast, zileuton, ramatroban, and seratrodast.
- More additional agents can include pulmozyme, hypertonic saline, agents that restore chloride channel function in CF, inhaled beta-agonists, inhaled antimuscarinic agents, inhaled corticosteroids, and inhaled or oral phosphodiesterase inhibitors.
- More additional agents can include CFTR modulators, for example, VX-770, atluren, VX-809. More additional agents can include agents to restore airway surface liquid, for example, denufosol, mannitol, GS-9411, and SPI-8811 More additional agents can include anti-inflammatory agents, for example, ibuprofen, sildenafil, and simavastatin. More additional agent include anti-inflammatory agents. Examples of anti-inflammatory agents include steroidal and non-steriodal anti-inflammatory agent.
- steroidal anti-inflammatory agents include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, chloroprednisone, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desciclesonide, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone
- nonsteriodal anti-inflammatory agents include COX inhibitors (COX-1 or COX nonspecific inhibitors) (e.g., salicylic acid derivatives, aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine and olsalazine; para-aminophenol derivatives such as acetaminophen; indole and indene acetic acids such as indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin; anthranilic acids (fenamates) such as mefenamic acid and meloxicam; enolic acids such as the oxicams (piroxicam, meloxicam) and
- the divalent or trivalent cation concentration can be from about 25 mM to about 400 mM, from about 50 mM to about 400 mM, from about 100 mM to about 300 mM, from about 100 mM to about 250 mM, from about 125 mM to about 250 mM, from about 150 mM to about 250 mM, from about 175 mM to about 225 mM, from about 180 mM to about 220 mM, and from about 190 mM to about 210 mM.
- the chloride concentration can be from about 25 mM to about 800 mM, from about 50 mM to about 400 mM, from about 100 mM to about 300 mM, from about 100 mM to about 250 mM, from about 125 mM to about 250 mM, from about 150 mM to about 250 mM, from about 175 mM to about 225 mM, from about 180 mM to about 220 mM, and from about 190 mM to about 210 mM.
- the magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride can have a concentration from about 5% to about 25%, from about 10% to about 20%, and from about 15% to about 20%.
- the ratio of fluoroquinolone to divalent or trivalent cation can be 1:1 to 2:1 or 1:1 to 1:2.
- Non-limiting fluoroquinolones for use as described herein include levofloxacin, ofloxacin, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, lomefloxacin, moxifloxacin, norfloxacin, pefloxacin, sparfloxacin, garenoxacin, sitafloxacin, and DX-619.
- the formulation can have a fluoroquinolone concentration, for example, levofloxacin or ofloxacin, greater than about 50 mg/ml, about 60 mg/ml, about 70 mg/ml, about 80 mg/ml, about 90 mg/ml, about 100 mg/ml, about 110 mg/ml, about 120 mg/ml, about 130 mg/ml, about 140 mg/ml, about 150 mg/ml, about 160 mg/ml, about 170 mg/ml, about 180 mg/ml, about 190 mg/ml, and about 200 mg/ml.
- levofloxacin or ofloxacin greater than about 50 mg/ml, about 60 mg/ml, about 70 mg/ml, about 80 mg/ml, about 90 mg/ml, about 100 mg/ml, about 110 mg/ml, about 120 mg/ml, about 130 mg/ml, about 140 mg/ml, about 150 mg/ml, about 160 mg/ml, about 170 mg/ml, about
- the formulation can have a fluoroquinolone concentration, for example, levofloxacin or ofloxacin, from about 50 mg/ml to about 200 mg/ml, from about 75 mg/ml to about 150 mg/ml, from about 80 mg/ml to about 125 mg/ml, from about 80 mg/ml to about 120 mg/ml, from about 90 mg/ml to about 125 mg/ml, from about 90 mg/ml to about 120 mg/ml, and from about 90 mg/ml to about 110 mg/ml.
- a fluoroquinolone concentration for example, levofloxacin or ofloxacin
- the formulation can have an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg, from about 325 mOsmol/kg to about 450 mOsmol/kg, from about 350 mOsmol/kg to about 425 mOsmol/kg, and from about 350 mOsmol/kg to about 400 mOsmol/kg.
- the osmolality of the formulation is greater than about 300 mOsmol/kg, about 325 mOsmol/kg, about 350 mOsmol/kg, about 375 mOsmol/kg, about 400 mOsmol/kg, about 425 mOsmol/kg, about 450 mOsmol/kg, about 475 mOsmol/kg, and about 500 mOsmol/kg.
- the formulation can have a pH from about 4.5 to about 8.5, from about 5.0 to about 8.0, from about 5.0 to about 7.0, from about 5.0 to about 6.5, from about 5.5 to about 6.5, and from 6.0 to about 6.5.
- the formulation can comprise a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like), or auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
- the formulation can lack a conventional pharmaceutical carrier, excipient or the like.
- Some embodiments include a formulation lacking lactose. Some embodiments comprise lactose at a concentration less than about 10%, 5%, 1%, or 0.1%. In some embodiments, the formulation can consist essentially of levofloxacin or ofloxacin and a divalent or trivalent cation.
- a formulation can comprise a levofloxacin concentration between about 75 mg/ml to about 150 mg/ml, a magnesium chloride concentration between about 150 mM to about 250 mM, a pH between about 5 to about 7; an osmolality of between about 300 mOsmol/kg to about 500 mOsmol/kg, and lacks lactose.
- a formulation comprises a levofloxacin concentration about 100 mg/ml, a magnesium chloride concentration about 200 mM, a pH about 6.2 an osmolality about 383 mOsmol/kg, and lacks lactose.
- a formulation consists essentially of a levofloxacin concentration about 100 mg/ml, a magnesium chloride concentration about 200 mM, a pH about 6.2 an osmolality about 383 mOsmol/kg, and lacks lactose.
- a formulation consists of a levofloxacin concentration about 100 mg/ml, a magnesium chloride concentration about 200 mM, a pH about 6.2 an osmolality about 383 mOsmol/kg, and lacks lactose.
- the fluoroquinolone anti-inflammatory agents formulated with divalent or trivalent cations and having improved pulmonary availability may be administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described.
- a therapeutically effective dosage e.g., a dosage sufficient to provide treatment for the disease states previously described.
- the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the inflammation, the manner and schedule of administration and the judgment of the prescribing physician; for example, a likely dose range for aerosol administration of levofloxacin would be about 20 to 300 mg per day, the active agents being selected for longer or shorter pulmonary half-lives, respectively. In some embodiments, a likely dose range for aerosol administration of levofloxacin would be about 20 to 300 mg BID (twice daily).
- fluoroquinolone antimicrobial agents disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, aerosol inhalation. Methods, devices and compositions for delivery are described in U.S. Patent Application Publication No. 2006/0276,483, incorporated by reference in its entirety.
- compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, for example, powders, liquids, suspensions, complexations, liposomes, particulates, or the like.
- the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
- the fluoroquinolone anti-inflammatory agent can be administered either alone or in some alternatives, in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
- a conventional pharmaceutical carrier e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
- the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate,
- the pharmaceutical formulation will contain about 0.005% to 95%, preferably about 0.5% to 50% by weight of a compound of the invention.
- Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
- the compositions will take the form of a unit dosage form such as vial containing a liquid, solid to be suspended, dry powder, lyophilate, or other composition and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
- a diluent such as lactose, sucrose, dicalcium phosphate, or the like
- a lubricant such as magnesium stearate or the like
- a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
- Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
- a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
- Solutions to be aerosolized can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to aerosol production and inhalation.
- the percentage of active compound contained in such aerosol compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
- composition will comprise 1.0%-50.0% of the active agent in solution.
- compositions described herein can be administered with a frequency of about 1, 2, 3, 4, or more times daily, 1, 2, 3, 4, 5, 6, 7 or more times weekly, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times monthly.
- the compositions are administered twice daily.
- Pulmonary drug delivery may be accomplished by inhalation of an aerosol through the mouth and throat.
- Particles having a mass median aerodynamic diameter (MMAD) of greater than about 5 microns generally do not reach the lung; instead, they tend to impact the back of the throat and are swallowed and possibly orally absorbed.
- Particles having diameters of about 2 to about 5 microns are small enough to reach the upper- to mid-pulmonary region (conducting airways), but are too large to reach the alveoli. Smaller particles, i.e., about 0.5 to about 2 microns, are capable of reaching the alveolar region.
- Particles having diameters smaller than about 0.5 microns can also be deposited in the alveolar region by sedimentation, although very small particles may be exhaled.
- a nebulizer is selected on the basis of allowing the formation of an aerosol of a fluoroquinolone anti-inflammatory agent disclosed herein having an mMAD predominantly between about 2 to about 5 microns.
- the delivered amount of fluoroquinolone anti-inflammatory agent provides a therapeutic effect for respiratory infections.
- the nebulizer can deliver an aerosol comprising a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns, a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns, and a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.
- the aerosol can be produced a jet nebulizer.
- the aerosol can be produced using a vibrating mesh nebulizer.
- An example of a vibrating mesh nebulizer includes the PART E-FLOW® nebulizer. More examples of nebulizers are provided in U.S. Pat. Nos. 4,268,460; 4,253,468; 4,046,146; 3,826,255; 4,649,911; 4,510,929; 4,624,251; 5,164,740; 5,586,550; 5,758,637; 6,644,304; 6,338,443; 5,906,202; 5,934,272; 5,960,792; 5,971,951; 6,070,575; 6,192,876; 6,230,706; 6,349,719; 6,367,470; 6,543,442; 6,584,971; 6,601,581; 4,263,907; 5,709,202; 5,823,179; 6,192,876; 6,644,304; 5,549,102; 6,083,922; 6,161,536; 6,264,922; 6,557,549; and 6,612,303
- nebulizers that can be used with the formulations described herein include Respirgard II®, Aeroneb®, Aeroneb® Pro, and Aeroneb® Go produced by Aerogen; AERx® and AERx EssenceTM produced by Aradigm; Porta-Neb®, Freeway FreedomTM, Sidestream, Ventstream and I-neb produced by Respironics, Inc.; and PAM LC-Plus®, PAM LC-Star®, produced by PAM, GmbH.
- Respirgard II®, Aeroneb®, Aeroneb® Pro, and Aeroneb® Go produced by Aerogen
- AERx® and AERx EssenceTM produced by Aradigm
- Porta-Neb® Freeway FreedomTM, Sidestream, Ventstream and I-neb produced by Respironics, Inc.
- PAM LC-Plus® PAM LC-Star®, produced by PAM, GmbH.
- U.S. Pat. No. 6,196,219 is hereby incorporated
- the amount of levofloxacin or ofloxacin that can be administered to the lungs can include at least about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg,
- the aerosol can be administered to the lungs in less than about 120 minutes, about 100 minutes, about 90 minutes, about 80 minutes, about 70 minutes, about 60 minutes, about 20 minutes, about 10 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, and about 1 minute.
- the inflammation can be acute or chronic inflammation of the lung or the upper airway.
- pulmonary inflammation can refer to acute or chronic inflammation of at least a portion of the respiratory tract, such as the lungs and upper airway.
- disorders and diseases associated with pulmonary inflammation can include asthma, cystic fibrosis, pulmonary fibrosis, chronic bronchitis, bronchiectasis, chronic granulomatous disease, sinusitis, chronic obstructive pulmonary disease, and pneumonia.
- Some embodiments include methods to achieve a reduction in pulmonary inflammation.
- a reduction can include reducing the signs and symptoms of a pulmonary inflammation.
- methods include achieving a reduction in the levels of pro-inflammatory cytokines in the lungs.
- a reduction in the levels of pro-inflammatory cytokines in the lungs can be measured by various methods, such as a reduction in the levels of pro-inflammatory cytokines in sputum and/or BAL.
- methods include achieving a reduction in the levels of IL-1 ⁇ , IL-6, and IL-8 in the lungs.
- NL20 cells and HBE135 cells are immortalized human airway epithelial cells that retain certain features of airway epithelium and have been extensively used to characterize immunomodulatory effects of other antibiotics (Blau H, et al. Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, JNK, and NF-kappaB activation in a cystic fibrosis epithelial cell line. Am J Physiol Lung Cell Mol Physiol 2007; 292:L343-352; and Donnarumma G, et al.
- NL20 cells were maintained in Ham's F12 medium with 2 mM L-glutamine, 0.1 mM nonessential amino acids, 5 ⁇ g/ml insulin, 10 ng/ml epidermal growth factor, 1 ⁇ g/ml transferrin, 500 ng/ml hydrocortisone and 4% FBS.
- HBE135 cells were routinely grown in keratinocyte-serum free medium with 5 ng/ml of human recombinant EGF and 0.05 mg/ml of bovine pituitary extract (Invitrogen, San Diego, Calif.) supplemented with 5 ⁇ g/ml insulin and 500 ng/ml hydrocortisone.
- NL20 cells were seeded on 24-well tissue culture plates at 2 ⁇ 10 4 cell/ml. The day after seeding, cells received normal growth medium without serum for an additional 24 h. The same serum-free media was used for all subsequent treatments of NL20 cells.
- IL-6 and IL-8 production in NL20 monolayers was induced by treatment with 10 ng/ml of TNF ⁇ .
- HBE135 Cells were aliquoted into 24-well tissue culture plates at 1 ⁇ 10 5 cells/ml and were used for cytokine production experiments approximately 24 hours after plating without additional media changes.
- IL-6 and IL-8 production in HBE135 cells was induced by treatment with 5 ⁇ g/ml of LPS from P. aeruginosa.
- TNF- ⁇ induced a several-fold increase in IL-6 and IL-8 production in NL20 cells ( FIGS. 1A and 1B ).
- LPS induced an increase in the level of IL-8 in HBE135 cells ( FIG. 2B ).
- IL-8 levels were reduced by approximately 20-30% ( FIGS. 1A and 1B ).
- No significant change in IL-6 levels was observed in cells treated with levofloxacin or ciprofloxacin.
- an increase in IL-6 levels was observed.
- FIGS. 2A and 2B show the levels of IL-6 and IL-8 in cells.
- HBE135 cells treated with 10 ⁇ g/ml and 30 ⁇ g/ml levofloxacin, moxifloxacin or ciprofloxacin. This experiment shows that low concentrations of levofloxacin can reduce the levels of IL-8 in HBE135 cells stimulated with LPS.
- cytotoxicity of levofloxacin, moxifloxacin and ciprofloxacin on NL20 and HBE135 cell lines were measured using an Alamar Blue assay. After 48 hour incubation with the antibiotic, cells were incubated in fresh growth media containing 5% Alamar Blue dye and fluorescence was recorded at 0 h and 4 h to assess antibiotic cytotoxicity. Higher levofloxacin concentrations were less cytotoxic to either NL20 or HBE135 cells compared to moxifloxacin and ciprofloxacin ( FIGS. 3A and 3B ). Moxifloxacin and ciprofloxacin were significantly cytotoxic to NL20 cells at 300 ⁇ g/ml.
- NL20 cells induced with TNF ⁇ and HBE135 cells induced with LPS were treated with 300 ⁇ g/ml levofloxacin or 300 ⁇ g/ml levofloxacin formulated with MgCl 2 .
- TNF ⁇ -induced NL20 cells and LPS-induced HBE135 cells were treated with 10-300 ⁇ g/ml levofloxacin, or tobramycin. No significant changes in cell viability in cytotoxicity assays were observed between any treatment (data not shown).
- FIG. 5A In NL20 cells treated with 10 ng/ml TNF ⁇ , an increase in IL-6 production from 3.4 ⁇ 0.2 pg/ml to 40.3 ⁇ 2.3 pg/ml was observed ( FIG. 5A ). IL-8 production increased from 3.3 ⁇ 0.2 pg/ml to 197.3 ⁇ 28.9 pg/ml ( FIG. 5B ). Incubation of NL20 cells with 5 ⁇ g/ml LPS did not produce significant increases in either IL-6 or IL-8 production (data not shown). The addition of 10 ⁇ g/ml or 30 ⁇ g/ml levofloxacin did not significantly change the level of IL-6 and IL-8 produced by NL20 cells.
- levofloxacin demonstrates an ability to reduce pro-inflammatory cytokine production in vitro in NL20 cells
- HBE135 cells with 5 ⁇ g/ml LPS increased IL-6 production from 46.1 ⁇ 6.4 pg/ml to 86.3 ⁇ 6.4 pg/ml and IL-8 production from 280.7 ⁇ 54.9 pg/ml to 541.9 ⁇ 54.8 pg/ml.
- Incubation of HBE135 cells with 10 or 30 ⁇ g/ml levofloxacin and LPS cells did not significantly change IL-6 and IL-8 levels.
- 100 ⁇ g/ml and 300 ⁇ g/ml levofloxacin resulted in a 45% and 40% decrease in IL-6 levels, respectively ( FIG. 6 ).
- Levels of IL-8 decreased by 30% and 20% in HBE135 cells treated with 100 ⁇ g/ml and 300 ⁇ g/ml levofloxacin, respectively ( FIG. 6 ). Incubation of cells with 10 ⁇ g/ml, 30 ⁇ g/ml, or 100 ⁇ g/ml tobramycin did not affect the levels of IL-6, while 300 ⁇ g/ml of tobramycin increased levels of IL-6 by 30%. Treatment with 30 ⁇ g/ml to 300 ⁇ g/ml tobramycin increased IL-8 production by 20% to 30% (p ⁇ 0.05).
- levofloxacin can induce a dose-related reduction in the production of the pro-inflammatory cytokines, IL-6 and IL-8, in cultured human lung epithelial cell lines.
- 300 ⁇ g/ml levofloxacin reduced levels of IL-6 by 4-fold and IL-8 by 2-fold (p ⁇ 0.05); in contrast, tobramycin increased IL-6 levels by 50%, but had no effect on IL-8.
- THP-1 The human monocyte cell line, THP-1 is an established in vitro model of human monocytic cells and is capable to secrete a greater variety of cytokines compared to NL20 and HBE135 cells.
- THP-1 cells were cultured in RPMI-1640 medium with 10%FBS, 0.05 mM 2-mecraptoethanol.
- THP-1 cells were seeded on 24-well tissue culture plates at 1 ⁇ 10 6 cells/ml in growth media without serum. The following day, 100 ng/ml LPS from P. aeruginosa and antibiotics were added and cells incubated for 24 hours before media collection to assess cytokine production. Quantification of IL-6, IL-8, IL-1 ⁇ and TNF ⁇ production was performed as described above for NL20 cells.
- FIGS. 7A , 7 B, 7 C, and 7 D Stimulation of THP-1 with 10 ng/ml of LPS increased IL-1 ⁇ , TNF ⁇ , IL-6 and IL-8 levels by 60-, 200-, 30- and 600-fold, respectively.
- FIGS. 7A , 7 B, 7 C, and 7 D Co-incubation of LPS and at 100 ⁇ g/ml and 300 ⁇ g/ml levofloxacin resulted in a 40% and 70% decrease in IL-1 ⁇ levels, respectively ( FIG. 7A ).
- 300 ⁇ g/ml levofloxacin increased TNF ⁇ production ( FIG. 7B ).
- the human monocyte cell line, THP-1 is an established in vitro model of human monocytic cells and is capable to secrete a greater variety of cytokines compared to NL20 and HBE135 cells.
- IL-8 mRNA expression in NL20 monolayers was induced by treatment with 10 ng/ml TNF ⁇ . Levofloxacin was added simultaneously with TNF ⁇ . After 24 h incubation, the cell monolayer was washed with PBS, total cellular RNA was prepared and reverse transcription was performed using a human IL-8 specific primer and the “Cells-to-cDNA” kit from Ambion (Austin, Tex.).
- cDNA was subjected to real-time PCR analysis using PowerSYBR Green PCR master mix and a GeneAmp 5700 Instrument (Applied Biosystems; Warrington, UK). All data were normalized to the housekeeping gene ⁇ -actin. Stimulation of NL-20 cells with TNF ⁇ , produced a statistically significant (p ⁇ 0.005) 20-fold increase in IL-8 mRNA levels ( FIG. 8 ). This increase correlates with the increased levels of IL-8 protein induced by TNF ⁇ . Addition of 100 ⁇ g/ml and 300 ⁇ g/ml levofloxacin had no significant effect on the level of IL-8 mRNA expression ( FIG. 4 ). These results suggest that levofloxacin reduces levels of the IL-8 secreted protein by modulating processes that include protein translation and/or protein secretion.
- the human monocyte cell line, THP-1 is an established in vitro model of human monocytic cells and is capable to secrete a greater variety of cytokines compared to NL20 and HBE135 cells.
- Cells were seeded on 96-well plate at 3 ⁇ 10 4 cells/well and transfected the following day with a pMetLuc-NFkB reporter plasmid (Clontech) encoding a secreted luciferase protein under the control of a NFkB-regulated promoter.
- a pSEAP-Control plasmid (Clontech) encoding a secreted alkaline phosphatase under the control of a strong constitutive promoter.
- Chronic bronchitis patients having acute or chronic pulmonary inflammation are administered aerosol levofloxacin formulated with MgCl 2 . After treatment, a reduction in the acute inflammation is observed. A reduction in the levels of pro-inflammatory cytokines is observed. A reduction in the levels of IL-1 ⁇ , IL-6, and IL-8 in the lungs is observed. A reduction in the levels of IL-1 ⁇ , IL-6, and IL-8 in the sputum and/or BAL is observed.
- Bronchiectasis patients having acute or chronic pulmonary inflammation are administered aerosol levofloxacin formulated with MgCl 2 . After treatment, a reduction in the acute inflammation is observed. A reduction in the levels of pro-inflammatory cytokines is observed. A reduction in the levels of IL-1 ⁇ , IL-6, and IL-8 in the lungs is observed. A reduction in the levels of IL-1 ⁇ , IL-6, and IL-8 in the sputum and/or BAL is observed.
- Non-CF bronchiectasis patients having acute or chronic pulmonary inflammation are administered aerosol levofloxacin formulated with MgCl 2 . After treatment, a reduction in the acute inflammation is observed. A reduction in the levels of pro-inflammatory cytokines is observed. A reduction in the levels of IL-1 ⁇ , IL-6, and IL-8 in the lungs is observed. A reduction in the levels of IL-1 ⁇ , IL-6, and IL-8 in the sputum and/or BAL is observed.
- a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise.
- a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.
- the articles ‘a’ and ‘an’ should be construed as referring to one or more than one (i.e., to at least one) of the grammatical objects of the article.
- ‘an element’ means one element or more than one element.
Abstract
Description
- This application is a continuation of U.S. Ser. No. 12/574,666 entitled “TOPICAL USE OF LEVOFLOXACIN FOR REDUCING LUNG INFLAMMATION” filed on Oct. 6, 2009 which claims priority to U.S. Provisional Application No. 61/103,496, entitled “Topical Use of Levofloxacin for Reducing Lung Inflammation,” filed on Oct. 7, 2008, which are hereby incorporated by reference in their entireties.
- The present invention relates to methods and compositions for the treatment of pulmonary inflammation. In particular, methods and compositions using aerosol levofloxacin or ofloxacin to reduce pulmonary inflammation are provided.
- Inflammation is a response of vascularized tissue to injury; it is perceived as redness, heat, swelling, and pain and is usually accompanied by loss of function to varying degrees. In its acute form it is of short duration, involving increased vascular transudation and interstitial edema and infiltration of inflammatory cells, predominantly of neutrophils. In moist mucosal tissues, such as that which lines the respiratory tract, there may also be loss of surface epithelial cells and secretion of mucus. This form of inflammatory response is considered protective and is, therefore, in the short term, beneficial to the host. However, if the injury is repeated or severe, the character of the inflammatory infiltrate may change to one predominantly of mononuclear cell (i.e., lymphocytes, monocytes, and macrophages) and it may become persistent.
- Inflammatory diseases afflict millions of people across the world leading to suffering, economic loss and premature death. As well as inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), other inflammatory diseases include allergic rhinitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and psoriasis. Inflammatory sinus diseases include sinusitis due to infections of acute, subacute and chronic duration; allergic rhinitis; and inflammation due to other underlying causes such as allergies, hay fever, allergic rhinitis, rhinitis, and asthma, affecting the nasal cavity or the four sinuses, each which have left and right halves, the frontal sinuses, the maxillary sinuses the ethmoid sinuses, and the sphenoid sinuses.
- Chronic inflammation may develop from unresolved symptomatic acute inflammation or may evolve insidiously over a period of months without apparent acute onset of clinical manifestations. Histopathologic features of chronic inflammation include the predominance of macrophages and lymphocytes, proliferation of nurturing structurally heterogeneous and hyperpermeable small blood vessels, fibrosis, and necrosis. Activated macrophages and lymphocytes are interactive in releasing inflammatory mediators or cytokines that amplify immune reactivity. Cytokines include a family of biologic response modifiers including interleukins, chemokines, interferons, growth factors, and leukocyte colony-stimulating factors. The cytokines are secreted by leukocytes, connective tissue cells, and endothelial cells. Chemokines consist of 8- to 10-kd proteins that stimulate leukocyte recruitment and migration as part of the host response to antigenic insults. In chronic inflammation, the protracted inflammatory response is often accompanied simultaneously by tissue destruction and repair.
- The present invention relates to methods and compositions for the treatment of pulmonary inflammation. In particular, methods and compositions using aerosol levofloxacin or ofloxacin to reduce pulmonary inflammation are provided.
- Some embodiments include methods for treating a pulmonary inflammation in a subject in which the methods include administering to the subject in need thereof an aerosol of a solution including levofloxacin or ofloxacin and a divalent or trivalent cation.
- Some embodiments include methods for treating a pulmonary inflammation in a subject, wherein the pulmonary inflammation is induced by one or more pro-inflammatory cytokines, in which the methods include administering to the subject in need thereof an aerosol of a solution including levofloxacin or ofloxacin and a divalent or trivalent cation to achieve a reduction in the pulmonary concentration of said cytokine by at least 10%.
- Some embodiments include methods for treating a pulmonary inflammation in a subject in which the methods include administering to the subject in need thereof an aerosol of a solution including levofloxacin or ofloxacin and a divalent or trivalent cation to achieve a reduction in the pulmonary concentration of one or more pro-inflammatory cytokines including IL-1β, IL-6 and IL-8, whereby the pulmonary inflammation is reduced or suppressed.
- Some embodiments include methods for treating a pulmonary inflammation in a subject, wherein the pulmonary inflammation is induced by one or more mediators including TNFα and LPS, in which the methods include administering to the subject in need thereof an aerosol of a solution including levofloxacin or ofloxacin and a divalent or trivalent cation.
- Some embodiments include methods for reducing the pulmonary concentration of a pro-inflammatory cytokine in a subject, in which the methods include administering to the subject in need thereof an aerosol of a solution including levofloxacin or ofloxacin and a divalent or trivalent cation, whereby the pulmonary concentration of the cytokine is reduced.
-
FIG. 1A shows a graph of IL-6 levels produced by NL20 cells in response to treatment with control, TNFα, and TNFα with levofloxacin, moxifloxacin, or ciprofloxacin.FIG. 1B shows a graph of IL-8 produced by NL20 cells in response to treatment with control, TNFα, and TNFα with levofloxacin, moxifloxacin, or ciprofloxacin. -
FIG. 2A shows a graph of IL-6 levels produced by HBE135 cells in response to treatment with control, LPS, and LPS with levofloxacin, moxifloxacin, or ciprofloxacin.FIG. 2B shows a graph of IL-8 produced by HBE135 cells in response to treatment with control, LPS, and LPS with levofloxacin, moxifloxacin, or ciprofloxacin. -
FIG. 3A shows a graph of percentage cell survival for NL20 cells treated with increasing concentrations of levofloxacin, moxifloxacin, or ciprofloxacin.FIG. 3B shows a graph of percentage cell survival for HBE135 cells treated with increasing concentrations of levofloxacin, moxifloxacin, or ciprofloxacin. -
FIG. 4A shows a graph of relative IL-6 levels produced by NL20 cells treated with TNF-α in response to increasing concentrations of levofloxacin and levofloxacin formulated with MgCl2.FIG. 4B shows a graph of relative IL-8 levels produced by NL20 cells treated with TNF-α in response to increasing concentrations of levofloxacin and levofloxacin formulated with MgCl2.FIG. 4C shows a graph of relative IL-6 levels produced by HBE135 cells treated with LPS in response to increasing concentrations of levofloxacin and levofloxacin formulated with MgCl2.FIG. 4D shows a graph of relative IL-8 levels produced by HBE cells treated with LPS in response to increasing concentrations of levofloxacin and levofloxacin formulated with MgCl2. -
FIG. 5A shows a graph of IL-6 levels produced by NL20 cells in response to treatment with control, TNF-α, and TNF-α with 10 μg/ml, 30 μg/ml, 100 μg/ml, or 300 μg/ml levofloxacin or tobramycin.FIG. 5B shows a graph of IL-8 levels produced by NL20 cells in response to treatment with control, TNFα, and TNFα with 10 μg/ml, 30 μg/ml, 100 μg/ml, or 300 μg/ml levofloxacin or tobramycin. Results are means±SD of three replicates. *P<0.005. -
FIG. 6 shows a graph of IL-6 and IL-8 levels produced by HBE135 cells in response to treatment with LPS, and LPS with increasing concentrations of levofloxacin or tobramycin. IL-6 and IL-8 levels are shown relative to cells treated with LPS only (n=3). *P<0.05, cells treated with LPS and antibiotics compared to LPS only. **P<0.005, cells treated with LPS and antibiotics compared to LPS only. -
FIG. 7A shows a graph of IL-1β levels in THP-1 cells treated with control; LPS; and 10 μg/ml, 30 μg/ml, 100 μg/ml, 300 μg/ml levofloxacin and LPS.FIG. 7B shows a graph of TNFα levels in THP-1 cells treated with control; LPS; and 10 μg/ml, 30 μg/ml, 100 μg/ml, 300 μg/ml levofloxacin and LPS.FIG. 7C shows a graph of IL-6 levels in THP-1 cells treated with control; LPS; and 10 μg/ml, 30 μg/ml, 100 μg/ml, 300 μg/ml levofloxacin and LPS.FIG. 7D shows a graph of IL-8 levels in THP-1 cells treated with control; LPS; and 10 μg/ml, 30 μg/ml, 100 μg/ml, 300 μg/ml levofloxacin and LPS. Cells were incubated with LPS alone or LPS with levofloxacin for 24 h. Cytokine concentration in cell media was determined by ELISA. The results were expressed as mean±SD (n=3). *P<0.05, cells treated with LPS and antibiotics compared to LPS only. **P<0.005, for cells treated with LPS and antibiotics compared to LPS only. -
FIG. 8 shows a graph of the relative level of IL-8 mRNA in NL20 cells stimulated with control; TNFα; TNFα and 100 μg/ml levofloxacin; and TNFα and 100 μg/ml levofloxacin. Cells were seeded, serum-starved for 24 h and TNFα alone or TNFα with antibiotic were added and incubated for 24 h. Levels of mRNA were measured by real-time PCR. The results were expressed as means±SD of four replicates. -
FIG. 9 shows shows a graph of the relative luciferase activity of a NFkB promoter construct in NL20 cells stimulated with control; TNFα; TNFα and 100 μg/ml levofloxacin; and TNFα and 100 μg/ml levofloxacin. Cells were transfected with the reporter plasmid, and after 24 h treated with TNFα alone or TNFα with antibiotics, then incubated for an additional 8 h. NFkB-dependent luciferase activity was measured using a commercial assay. The results were expressed as means±SD of six replicates. -
FIG. 10A shows a graph of MIP-2 levels in BAL of mice treated with 60 mg/kg saline, 60 mg/kg levofloxacin formulated with MgCl2, or 60 mg/kg tobramycin.FIG. 10B shows a graph of IL-6 levels in BAL of mice treated with 60 mg/kg saline, 60 mg/kg levofloxacin formulated with MgCl2, or 60 mg/kg tobramycin. - The present invention relates to methods and compositions for the treatment of disorders and diseases associated with pulmonary inflammation. In particular, methods and compositions to reduce inflammation using aerosol levofloxacin or ofloxacin formulated with a divalent or trivalent cation are provided. Some embodiments include treating acute or chronic inflammation of the lung or the upper airway by topically administering aerosol levofloxacin or ofloxacin formulated with a divalent or trivalent cation directly to the inflammation site.
- Damage to the lungs and subsequent decline in pulmonary function that occurs in chronic inflammation is mediated primarily by neutrophil tissue infiltration that induces subsequent damage through the release of various hydrolytic and oxidative enzymes. This inflammatory cascade at the mucosal surface is mediated by bacteria producing lipopolysacchararide (LPS), and the LPS inducing TNFα release from macrophages or directly at the lung epithelial surface. Release of both TNFα, as well as inflammatory cytokines, for example IL-8 and IL-6, results in neutrophil activation and chemotaxis. While bacterial infections plays a large role in the inflammatory process, it is also believed that impaired chloride secretion in cystic fibrosis or other diseases is also partially responsible for increased cytokine levels (Perez A. et al, Am J. Physiol. Lung Cell Mol Physiol (2007) 292:383-395, incorporated by reference in its entirety).
- It has been discovered that topical administration of levofloxacin formulated with divalent or trivalent cations can significantly decrease the level of cytokine and chemokine production in vitro and in vivo. Such decreases in the levels of pro-inflammatory cytokines may produce a reduction in neutrophil-mediated inflammations. Examples of pro-inflammatory cytokines include IL-1, IL-6, IL-7, and IL-8. High concentrations of levofloxacin can be administered to the lungs and upper airways by inhalation. Surprisingly, formulations of levofloxacin with divalent or trivalent cations have greater availability in the lungs compared to formulations of levofloxacin only. Accordingly, the present invention relates to methods and compositions for reducing inflammation in the lungs and upper airway by administration of aerosolized fluoroquinolones, such as levofloxacin, formulated with divalent or trivalent cations, such as Mg2+.
- Therapeutic approaches for decreasing chronic inflammation are a viable strategy to improve lung function in CF and COPD patients. Anti-inflammatory properties of non-steroidal anti-inflammatory drugs (NSAID) (e.g., ibuprofen) and azithromycin have been associated with benefits in certain CF patient subgroups (Flume P A, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007; 176:957-969, incorporated by reference in its entirety). In addition, the antibiotic erythromycin reduces the incidence of pulmonary exacerbations in COPD patients (Seemungal T A, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008; 178:1139-1147, incorporated by reference in its entirety). The efficacy of azithromycin and erythromycin in these settings are likely due in large part to immunomodulatory and anti-inflammatory effects rather than antibacterial effects.
- Some fluoroquinolones may have an immunomodulatory activity as well as an anti-bacterial activity. These activities may be distinct and only apparent in vivo at concentrations that are also cytotoxic. Some fluoroquinolones may affect their immunomodulatory activity through various signaling pathways that relate to the production and secretion of various cytokines and chemokines. However, not all fluoroquinolones show immunomodulatory activity. Moreover, different fluoroquinolones illicit different responses, such as the induction or inhibition of particular cytokines and chemokines. The immunomodulatory activity may also depend on cell type, immune stimulant, and concentration of the fluoroquinolone. For example, fluoroquinolones such as moxifloxacin and grepafloxacin, but not ciprofloxacin, can inhibit secretion of pro-inflammatory factor such as IL-8, IL-6, ERK1/2, MK, and NFκB in human lung epithelia cells (Blau, H., K. et al. 2007. Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, MK, and NF-kappaB activation in a cystic fibrosis epithelial cell line. Am J Physiol Lung Cell Mol Physiol 292:L343-52; Donnarumma, G., I. et al. 2007. Anti-inflammatory effects of moxifloxacin and human beta-
defensin 2 association in human lung epithelial cell line (A549) stimulated with lipopolysaccharide. Peptides 28:2286-92; Hashimoto, S., K. et al. 2000. Grepafloxacin inhibits tumor necrosis factor-alpha-induced interleukin-8 expression in human airway epithelial cells. Life Sci 66:PL 77-82, incorporated by reference in their entireties). However, in all studies cells were treated with antibiotic concentrations less than 50 μg/ml, which corresponds to serum drug concentrations that may be attained after systemic dosing. - Levofloxacin inhibits TNF-α and IFNγ production in tonsillar lymphocytes at 50 mg/L, and IL-8 production at 5 mg/L. In addition, levofloxacin inhibits RANTES-release in nasal epithelial cells from patients of nasal polyposis. However, the inhibitory activity of levofloxacin on the production of pro-inflammatory factors is much lower than that for other fluoroquinolones such as ciprofloxacin and moxifloxacin. For example, the inhibitory activity of levofloxacin on the production of pro-inflammatory factors such as TNF-α, IL-1 and IL-8 requires 100 mg/L levofloxacin.
- As described herein, immortalized human airway epithelia cells retain certain features of airway epithelium and have been extensively used to characterize immunomodulatory effects of other antibiotics (Blau H, et al. Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, MK, and NF-kappaB activation in a cystic fibrosis epithelial cell line. Am J Physiol Lung Cell Mol Physiol 2007; 292:L343-352; and Donnarumma G, et al. Anti-inflammatory effects of moxifloxacin and human beta-
defensin 2 association in human lung epithelial cell line (A549) stimulated with lipopolysaccharide. Peptides 2007; 28:2286-2292, incorporated by reference in their entireties). IL-6 and IL-8 production in those cells can be strongly induced by TNFα or by bacterial LPS that is present in high concentrations in lung fluids of CF and COPD patients (Sagel S D, et al. Sputum biomarkers of inflammation in cystic fibrosis lung disease. Proc Am Thorac Soc 2007; 4:406-417, incorporated by reference in its entirety). Both IL-6 and IL-8 are of high importance in regulating inflammatory response in CF lungs, with latter having the strongest potential to induce neutrophil chemotaxis (Strieter R M. Interleukin-8: a very important chemokine of the human airway epithelium. Am J Physiol Lung Cell Mol Physiol 2002; 283:L688-689, incorporated by reference in its entirety). It has been discovered that levofloxacin produces a dose-dependent reduction of TNFα- and LPS-induced IL-6 and IL-8 levels in cultured human airway epithelia cells. Levofloxacin also decreases LPS-induced IL-1β, IL-6 and IL-8 production in human monocytic cells. In addition, levofloxacin reduces IL-6 and IL-8 production in vivo. - The term “administration” or “administering” refers to a method of giving a dosage of an anti-inflammatory pharmaceutical composition to a vertebrate. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the inflammation, and the severity of an actual inflammation.
- A “carrier” or “excipient” is a compound or material used to facilitate administration of the compound, for example, to increase the solubility of the compound. Solid carriers include, e.g., starch, lactose, dicalcium phosphate, sucrose, and kaolin. Liquid carriers include, e.g., sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil, peanut and sesame oils. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, N.J. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, incorporated by reference herein in its entirety.
- The term “mammal” is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, and cats, but also includes many other species.
- The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, naphtoic acid, oleic acid, palmitic acid, pamoic (emboic) acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, glucoheptonic acid, glucuronic acid, lactic acid, lactobioic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, histidine, arginine, lysine, benethamine, N-methyl-glucamine, and ethanolamine. Other acids include dodecylsufuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, and saccharin.
- “Solvate” refers to the compound formed by the interaction of a solvent and fluoroquinolone antimicrobial, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
- By “therapeutically effective amount” or “pharmaceutically effective amount” is meant a fluoroquinolone anti-inflammatory agent, as disclosed for this invention, which has a therapeutic effect. The doses of fluoroquinolone anti-inflammatory agent which are useful in treatment are therapeutically effective amounts. Thus, as used herein, a therapeutically effective amount means those amounts of fluoroquinolone anti-inflammatory agent which produce the desired therapeutic effect as judged by clinical trial results and/or model animal anti-inflammatory studies. In particular embodiments, the fluoroquinolone anti-inflammatory agent are administered in a pre-determined dose, and thus a therapeutically effective amount would be an amount of the dose administered. This amount and the amount of the fluoroquinolone anti-inflammatory agent can be routinely determined by one of skill in the art, and will vary, depending on several factors, such as the particular inflammation involved, for example, the site of inflammation, the severity of inflammation. This amount can further depend upon the patient's height, weight, sex, age and medical history. For prophylactic treatments, a therapeutically effective amount is that amount which would be effective to prevent a particular inflammation.
- A “therapeutic effect” relieves, to some extent, one or more of the symptoms of the inflammation, and includes curing an inflammation. “Curing” means that the symptoms of inflammation are eliminated. However, certain long-term or permanent effects of the inflammation may exist even after a cure is obtained (such as extensive tissue damage). As used herein, a “therapeutic effect” is defined as a statistically significant reduction in an inflammation, emergence of inflammation, or improvement in inflammation symptoms as measured by human clinical results or animal studies.
- “Treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. The term “prophylactic treatment” refers to treating a patient who is not yet having an inflammation, but who is susceptible to, or otherwise at risk of, a particular inflammation such that there is a reduced onset of an inflammation. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from an inflammation. Thus, in preferred embodiments, treating is the administration to a mammal (either for therapeutic or prophylactic purposes) of therapeutically effective amounts of a fluoroquinolone anti-inflammatory agent.
- The term “dosing interval” refers to the time between administrations of the two sequential doses of a pharmaceutical's during multiple dosing regimens. For example, in the case of orally administered ciprofloxacin, which is administered twice daily (traditional regimen of 400 mg b.i.d) and orally administered levofloxacin, which is administered once a day (500 mg or 750 mg q.d.), the dosing intervals are 12 hours and 24 hours, respectively.
- As used herein, the “peak period” of a pharmaceutical's in vivo concentration is defined as that time of the pharmaceutical dosing interval when the pharmaceutical concentration is not less than 50% of its maximum plasma or site-of-inflammation concentration. In some embodiments, “peak period” is used to describe an interval of anti-inflammatory dosing.
- The “respirable delivered dose” is the amount of drug inhaled during the inspiratory phase of the breath simulator that is equal to or less than 5 microns using a simulator programmed to the European Standard pattern of 15 breaths per minute, with an inspiration to expiration ratio of 1:1.
- As used herein “pulmonary concentration” can include the concentration of a substance in the lung of a subject, the concentration of a substance in the sputum of a subject, and/or the concentration of a substance in the bronchial alveoial lavage of a subject. As will be understood, “pulmonary concentration” can be measured by various methods.
- In some embodiments, a method is provided for treating an inflammation in an animal, specifically including in a mammal, by treating an animal suffering from such an inflammation with a fluoroquinolone anti-inflammatory agent formulated with a divalent or trivalent cation and having improved pulmonary availability. In some embodiments, fluoroquinolone anti-inflammatory agents may be administered following aerosol formation and inhalation. Thus, this method of treatment is especially appropriate for the treatment of pulmonary inflammations that are difficult to treat using an anti-inflammatory agent delivered parenterally due to the need for high parenteral dose levels (which can cause undesirable side effects), or due to lack of any clinically effective anti-inflammatory agents. In one such embodiment, this method may be used to administer a fluoroquinolone anti-inflammatory agent directly to the site of inflammation. Such a method may reduce systemic exposure and maximizes the amount of anti-inflammatory agent to the site of inflammation.
- In some embodiments, the aerosol fluoroquinolone therapy may be administered as a treatment or prophylaxis in combination or alternating therapeutic sequence with other aerosol, oral or parenteral antibiotics. By non-limiting example this may include aerosol tobramycin and/or other aminoglycoside, aerosol aztreonam and/or other beta- or mono-bactam, carbapenems, aerosol ciprofloxacin and/or other fluoroquinolones, aerosol azithromycin and/or other macrolides or ketolides, tetracycline and/or other tetracyclines, quinupristin and/or other streptogramins, linezolid and/or other oxazolidinones, vancomycin and/or other glycopeptides, erythromycin, and chloramphenicol and/or other phenicols, and colisitin and/or other polymyxins.
- In addition, compositions and methods provided herein can include the aerosol fluoroquinolone therapy administered as a treatment or prophylaxis in combination or alternating therapeutic sequence with an additional active agent. As discussed above, some such additional agents can include antibiotics. More additional agents can include bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, and combinations thereof. Examples of bronchodilators include salbutamol, levosalbuterol, terbutaline, fenoterol, terbutlaine, pirbuterol, procaterol, bitolterol, rimiterol, carbuterol, tulobuterol, reproterol, salmeterol, formoterol, arformoterol, bambuterol, clenbuterol, indacterol, theophylline, roflumilast, cilomilast. Examples of anticholinergics include ipratropium, and tiotropium. Examples of glucocorticoids include prednisone, fluticasone, budesonide, mometasone, ciclesonide, and beclomethasone. Examples of eicosanoids include montelukast, pranlukast, zafirlukast, zileuton, ramatroban, and seratrodast. More additional agents can include pulmozyme, hypertonic saline, agents that restore chloride channel function in CF, inhaled beta-agonists, inhaled antimuscarinic agents, inhaled corticosteroids, and inhaled or oral phosphodiesterase inhibitors. More additional agents can include CFTR modulators, for example, VX-770, atluren, VX-809. More additional agents can include agents to restore airway surface liquid, for example, denufosol, mannitol, GS-9411, and SPI-8811 More additional agents can include anti-inflammatory agents, for example, ibuprofen, sildenafil, and simavastatin. More additional agent include anti-inflammatory agents. Examples of anti-inflammatory agents include steroidal and non-steriodal anti-inflammatory agent. Examples of steroidal anti-inflammatory agents include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, chloroprednisone, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desciclesonide, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, any of their derivatives, analogues, and combinations thereof. Examples of nonsteriodal anti-inflammatory agents include COX inhibitors (COX-1 or COX nonspecific inhibitors) (e.g., salicylic acid derivatives, aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine and olsalazine; para-aminophenol derivatives such as acetaminophen; indole and indene acetic acids such as indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin; anthranilic acids (fenamates) such as mefenamic acid and meloxicam; enolic acids such as the oxicams (piroxicam, meloxicam) and alkanones such as nabumetone) and selective COX-2 inhibitors (e.g., diaryl-substituted furanones such as rofecoxib; diaryl-substituted pyrazoles such as celecoxib; indole acetic acids such as etodolac and sulfonanilides such as nimesulide).
- For purposes of the method described herein, a fluoroquinolone anti-inflammatory agent formulated with a divalent or trivalent cation having improved pulmonary availability may be administered using an inhaler. In some embodiments, a fluoroquinolone anti-inflammatory agent disclosed herein is produced as a pharmaceutical composition suitable for aerosol formation, good taste, storage stability, and patient safety and tolerability. In some embodiments, the isoform content of the manufactured fluoroquinolone may be optimized for tolerability, anti-inflammatory activity and stability.
- Formulations can include a divalent or trivalent cation. The divalent or trivalent cation can include, for example, magnesium, calcium, zinc, copper, aluminum, and iron. In some embodiments, the solution comprises magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride. In some embodiments, the divalent or trivalent cation concentration can be from about 25 mM to about 400 mM, from about 50 mM to about 400 mM, from about 100 mM to about 300 mM, from about 100 mM to about 250 mM, from about 125 mM to about 250 mM, from about 150 mM to about 250 mM, from about 175 mM to about 225 mM, from about 180 mM to about 220 mM, and from about 190 mM to about 210 mM. In some embodiments, the chloride concentration can be from about 25 mM to about 800 mM, from about 50 mM to about 400 mM, from about 100 mM to about 300 mM, from about 100 mM to about 250 mM, from about 125 mM to about 250 mM, from about 150 mM to about 250 mM, from about 175 mM to about 225 mM, from about 180 mM to about 220 mM, and from about 190 mM to about 210 mM. In some embodiments, the magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride can have a concentration from about 5% to about 25%, from about 10% to about 20%, and from about 15% to about 20%. In some embodiments, the ratio of fluoroquinolone to divalent or trivalent cation can be 1:1 to 2:1 or 1:1 to 1:2.
- Non-limiting fluoroquinolones for use as described herein include levofloxacin, ofloxacin, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, lomefloxacin, moxifloxacin, norfloxacin, pefloxacin, sparfloxacin, garenoxacin, sitafloxacin, and DX-619.
- The formulation can have a fluoroquinolone concentration, for example, levofloxacin or ofloxacin, greater than about 50 mg/ml, about 60 mg/ml, about 70 mg/ml, about 80 mg/ml, about 90 mg/ml, about 100 mg/ml, about 110 mg/ml, about 120 mg/ml, about 130 mg/ml, about 140 mg/ml, about 150 mg/ml, about 160 mg/ml, about 170 mg/ml, about 180 mg/ml, about 190 mg/ml, and about 200 mg/ml. In some embodiments, the formulation can have a fluoroquinolone concentration, for example, levofloxacin or ofloxacin, from about 50 mg/ml to about 200 mg/ml, from about 75 mg/ml to about 150 mg/ml, from about 80 mg/ml to about 125 mg/ml, from about 80 mg/ml to about 120 mg/ml, from about 90 mg/ml to about 125 mg/ml, from about 90 mg/ml to about 120 mg/ml, and from about 90 mg/ml to about 110 mg/ml.
- The formulation can have an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg, from about 325 mOsmol/kg to about 450 mOsmol/kg, from about 350 mOsmol/kg to about 425 mOsmol/kg, and from about 350 mOsmol/kg to about 400 mOsmol/kg. In some embodiments, the osmolality of the formulation is greater than about 300 mOsmol/kg, about 325 mOsmol/kg, about 350 mOsmol/kg, about 375 mOsmol/kg, about 400 mOsmol/kg, about 425 mOsmol/kg, about 450 mOsmol/kg, about 475 mOsmol/kg, and about 500 mOsmol/kg.
- The formulation can have a pH from about 4.5 to about 8.5, from about 5.0 to about 8.0, from about 5.0 to about 7.0, from about 5.0 to about 6.5, from about 5.5 to about 6.5, and from 6.0 to about 6.5.
- The formulation can comprise a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like), or auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). In some embodiments, the formulation can lack a conventional pharmaceutical carrier, excipient or the like. Some embodiments include a formulation lacking lactose. Some embodiments comprise lactose at a concentration less than about 10%, 5%, 1%, or 0.1%. In some embodiments, the formulation can consist essentially of levofloxacin or ofloxacin and a divalent or trivalent cation.
- In some embodiments, a formulation can comprise a levofloxacin concentration between about 75 mg/ml to about 150 mg/ml, a magnesium chloride concentration between about 150 mM to about 250 mM, a pH between about 5 to about 7; an osmolality of between about 300 mOsmol/kg to about 500 mOsmol/kg, and lacks lactose.
- In some embodiments, a formulation comprises a levofloxacin concentration about 100 mg/ml, a magnesium chloride concentration about 200 mM, a pH about 6.2 an osmolality about 383 mOsmol/kg, and lacks lactose. In some embodiments, a formulation consists essentially of a levofloxacin concentration about 100 mg/ml, a magnesium chloride concentration about 200 mM, a pH about 6.2 an osmolality about 383 mOsmol/kg, and lacks lactose. In some embodiments, a formulation consists of a levofloxacin concentration about 100 mg/ml, a magnesium chloride concentration about 200 mM, a pH about 6.2 an osmolality about 383 mOsmol/kg, and lacks lactose.
- The fluoroquinolone anti-inflammatory agents formulated with divalent or trivalent cations and having improved pulmonary availability may be administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the inflammation, the manner and schedule of administration and the judgment of the prescribing physician; for example, a likely dose range for aerosol administration of levofloxacin would be about 20 to 300 mg per day, the active agents being selected for longer or shorter pulmonary half-lives, respectively. In some embodiments, a likely dose range for aerosol administration of levofloxacin would be about 20 to 300 mg BID (twice daily).
- Administration of the fluoroquinolone antimicrobial agents disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, aerosol inhalation. Methods, devices and compositions for delivery are described in U.S. Patent Application Publication No. 2006/0276,483, incorporated by reference in its entirety.
- Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, for example, powders, liquids, suspensions, complexations, liposomes, particulates, or the like. Preferably, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
- The fluoroquinolone anti-inflammatory agent can be administered either alone or in some alternatives, in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). Generally, depending on the intended mode of administration, the pharmaceutical formulation will contain about 0.005% to 95%, preferably about 0.5% to 50% by weight of a compound of the invention. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
- In one preferred embodiment, the compositions will take the form of a unit dosage form such as vial containing a liquid, solid to be suspended, dry powder, lyophilate, or other composition and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
- Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Solutions to be aerosolized can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to aerosol production and inhalation. The percentage of active compound contained in such aerosol compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 90% in solution are employable, and will be higher if the composition is a solid, which will be subsequently diluted to the above percentages. In some embodiments, the composition will comprise 1.0%-50.0% of the active agent in solution.
- Compositions described herein can be administered with a frequency of about 1, 2, 3, 4, or more times daily, 1, 2, 3, 4, 5, 6, 7 or more times weekly, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times monthly. In particular embodiments, the compositions are administered twice daily.
- Aerosol delivery
- For pulmonary administration, the upper airways are avoided in favor of the middle and lower airways. Pulmonary drug delivery may be accomplished by inhalation of an aerosol through the mouth and throat. Particles having a mass median aerodynamic diameter (MMAD) of greater than about 5 microns generally do not reach the lung; instead, they tend to impact the back of the throat and are swallowed and possibly orally absorbed. Particles having diameters of about 2 to about 5 microns are small enough to reach the upper- to mid-pulmonary region (conducting airways), but are too large to reach the alveoli. Smaller particles, i.e., about 0.5 to about 2 microns, are capable of reaching the alveolar region. Particles having diameters smaller than about 0.5 microns can also be deposited in the alveolar region by sedimentation, although very small particles may be exhaled.
- In one embodiment, a nebulizer is selected on the basis of allowing the formation of an aerosol of a fluoroquinolone anti-inflammatory agent disclosed herein having an mMAD predominantly between about 2 to about 5 microns. In one embodiment, the delivered amount of fluoroquinolone anti-inflammatory agent provides a therapeutic effect for respiratory infections. The nebulizer can deliver an aerosol comprising a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns, a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns, and a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns. In some embodiments, the aerosol can be produced a jet nebulizer. In some embodiments, the aerosol can be produced using a vibrating mesh nebulizer. An example of a vibrating mesh nebulizer includes the PART E-FLOW® nebulizer. More examples of nebulizers are provided in U.S. Pat. Nos. 4,268,460; 4,253,468; 4,046,146; 3,826,255; 4,649,911; 4,510,929; 4,624,251; 5,164,740; 5,586,550; 5,758,637; 6,644,304; 6,338,443; 5,906,202; 5,934,272; 5,960,792; 5,971,951; 6,070,575; 6,192,876; 6,230,706; 6,349,719; 6,367,470; 6,543,442; 6,584,971; 6,601,581; 4,263,907; 5,709,202; 5,823,179; 6,192,876; 6,644,304; 5,549,102; 6,083,922; 6,161,536; 6,264,922; 6,557,549; and 6,612,303 all of which are hereby incorporated by reference in their entireties. More commercial examples of nebulizers that can be used with the formulations described herein include Respirgard II®, Aeroneb®, Aeroneb® Pro, and Aeroneb® Go produced by Aerogen; AERx® and AERx Essence™ produced by Aradigm; Porta-Neb®, Freeway Freedom™, Sidestream, Ventstream and I-neb produced by Respironics, Inc.; and PAM LC-Plus®, PAM LC-Star®, produced by PAM, GmbH. By further non-limiting example, U.S. Pat. No. 6,196,219, is hereby incorporated by reference in its entirety.
- The amount of levofloxacin or ofloxacin that can be administered to the lungs can include at least about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, and about 800 mg.
- The aerosol can be administered to the lungs in less than about 120 minutes, about 100 minutes, about 90 minutes, about 80 minutes, about 70 minutes, about 60 minutes, about 20 minutes, about 10 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, and about 1 minute.
- Some embodiments of the methods and compositions described herein relate to treating particular disorders and diseases associated inflammation. In particular embodiments, the inflammation can be acute or chronic inflammation of the lung or the upper airway. As used herein “pulmonary inflammation” can refer to acute or chronic inflammation of at least a portion of the respiratory tract, such as the lungs and upper airway. Examples of such disorders and diseases associated with pulmonary inflammation can include asthma, cystic fibrosis, pulmonary fibrosis, chronic bronchitis, bronchiectasis, chronic granulomatous disease, sinusitis, chronic obstructive pulmonary disease, and pneumonia.
- Some embodiments include methods to achieve a reduction in pulmonary inflammation. A reduction can include reducing the signs and symptoms of a pulmonary inflammation. In some embodiments, methods include achieving a reduction in the levels of pro-inflammatory cytokines in the lungs. A reduction in the levels of pro-inflammatory cytokines in the lungs can be measured by various methods, such as a reduction in the levels of pro-inflammatory cytokines in sputum and/or BAL. In some embodiments, methods include achieving a reduction in the levels of IL-1β, IL-6, and IL-8 in the lungs.
- Example 1
- NL20 cells and HBE135 cells are immortalized human airway epithelial cells that retain certain features of airway epithelium and have been extensively used to characterize immunomodulatory effects of other antibiotics (Blau H, et al. Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, JNK, and NF-kappaB activation in a cystic fibrosis epithelial cell line. Am J Physiol Lung Cell Mol Physiol 2007; 292:L343-352; and Donnarumma G, et al. Anti-inflammatory effects of moxifloxacin and human beta-
defensin 2 association in human lung epithelial cell line (A549) stimulated with lipopolysaccharide. Peptides 2007; 28:2286-2292, incorporated by reference in their entireties). IL-6 and IL-8 production in the NL20 and HBE135 cells was induced by adding TNFα or Lipopolysaccharide (LPS) from Pseudomonas aeruginosa, respectively. The effect of antibiotics on cytokine levels was assessed by ELISA assay. - NL20 cells were maintained in Ham's F12 medium with 2 mM L-glutamine, 0.1 mM nonessential amino acids, 5 μg/ml insulin, 10 ng/ml epidermal growth factor, 1 μg/ml transferrin, 500 ng/ml hydrocortisone and 4% FBS. HBE135 cells were routinely grown in keratinocyte-serum free medium with 5 ng/ml of human recombinant EGF and 0.05 mg/ml of bovine pituitary extract (Invitrogen, San Diego, Calif.) supplemented with 5 μg/ml insulin and 500 ng/ml hydrocortisone.
- NL20 cells were seeded on 24-well tissue culture plates at 2×104 cell/ml. The day after seeding, cells received normal growth medium without serum for an additional 24 h. The same serum-free media was used for all subsequent treatments of NL20 cells. IL-6 and IL-8 production in NL20 monolayers was induced by treatment with 10 ng/ml of TNFα. HBE135 Cells were aliquoted into 24-well tissue culture plates at 1×105 cells/ml and were used for cytokine production experiments approximately 24 hours after plating without additional media changes. IL-6 and IL-8 production in HBE135 cells was induced by treatment with 5 μg/ml of LPS from P. aeruginosa. After 48 h, cell medium was collected, clarified and the amount of IL-6 and IL-8 released into the medium was quantified using QuantiGlo chemiluminescent ELISA kits (R&D Systems, Minneapolis, Minn.). To test the effect of antibiotics on IL-6 and IL-8 secretion, antibiotics were added to culture media along with LPS or TNF-α and processed as described above.
- TNF-α induced a several-fold increase in IL-6 and IL-8 production in NL20 cells (
FIGS. 1A and 1B ). LPS induced an increase in the level of IL-8 in HBE135 cells (FIG. 2B ). In NL20 cells treated with 10 μg/ml and 30 μg/ml levofloxacin, moxifloxacin or ciprofloxacin, IL-8 levels were reduced by approximately 20-30% (FIGS. 1A and 1B ). No significant change in IL-6 levels was observed in cells treated with levofloxacin or ciprofloxacin. However, in NL20 cells treated with 30 μg/ml ciprofloxacin, an increase in IL-6 levels was observed.FIGS. 2A and 2B show the levels of IL-6 and IL-8 in cells. In HBE135 cells treated with 10 μg/ml and 30 μg/ml levofloxacin, moxifloxacin or ciprofloxacin. This experiment shows that low concentrations of levofloxacin can reduce the levels of IL-8 in HBE135 cells stimulated with LPS. - The cytotoxicity of levofloxacin, moxifloxacin and ciprofloxacin on NL20 and HBE135 cell lines were measured using an Alamar Blue assay. After 48 hour incubation with the antibiotic, cells were incubated in fresh growth media containing 5% Alamar Blue dye and fluorescence was recorded at 0 h and 4 h to assess antibiotic cytotoxicity. Higher levofloxacin concentrations were less cytotoxic to either NL20 or HBE135 cells compared to moxifloxacin and ciprofloxacin (
FIGS. 3A and 3B ). Moxifloxacin and ciprofloxacin were significantly cytotoxic to NL20 cells at 300 μg/ml. - NL20 cells induced with TNFα and HBE135 cells induced with LPS were treated with 300 μg/ml levofloxacin or 300 μg/ml levofloxacin formulated with MgCl2. An approximate 10-fold and 5-fold reduction in IL-6 and IL-8 levels, respectively, was observed in NL20 cells treated with 300 μg/ml levofloxacin or 300 μg/ml levofloxacin formulated with MgCl2. (
FIGS. 4A and 4B ). In addition, reductions in IL-6 and IL-8 levels were observed in HBE cells treated with 300 μg/ml levofloxacin or 300 μg/ml levofloxacin formulated with MgCl2 (FIGS. 4C and 4D ). Levofloxacin and levofloxacin formulated with MgCl2 had similar activity in vitro. - TNFα-induced NL20 cells and LPS-induced HBE135 cells were treated with 10-300 μg/ml levofloxacin, or tobramycin. No significant changes in cell viability in cytotoxicity assays were observed between any treatment (data not shown).
- In NL20 cells treated with 10 ng/ml TNFα, an increase in IL-6 production from 3.4±0.2 pg/ml to 40.3±2.3 pg/ml was observed (
FIG. 5A ). IL-8 production increased from 3.3±0.2 pg/ml to 197.3±28.9 pg/ml (FIG. 5B ). Incubation of NL20 cells with 5 μg/ml LPS did not produce significant increases in either IL-6 or IL-8 production (data not shown). The addition of 10 μg/ml or 30 μg/ml levofloxacin did not significantly change the level of IL-6 and IL-8 produced by NL20 cells. However, 100 μg/ml and 300 μg/ml levofloxacin resulted in 2- to 4-fold reductions in IL-6 levels, respectively (p<0.005) (FIG. 5A ). Levels of IL-8 decreased by 50% and 60% in NL20 cells treated with 100 μg/ml and 300 μg/ml levofloxacin, respectively (p<0.005) (FIG. 5B ). 10 μg/ml to 100 μg/ml tobramycin did not significantly affect production of IL-6 or IL-8 (FIGS. 5A and 5B ). However, 300 μg/ml tobramycin produced an increase in IL-6 production (FIG. 5A ). Thus, levofloxacin demonstrates an ability to reduce pro-inflammatory cytokine production in vitro in NL20 cells - Incubation of HBE135 cells with 5 μg/ml LPS increased IL-6 production from 46.1±6.4 pg/ml to 86.3±6.4 pg/ml and IL-8 production from 280.7±54.9 pg/ml to 541.9±54.8 pg/ml. Incubation of HBE135 cells with 10 or 30 μg/ml levofloxacin and LPS cells did not significantly change IL-6 and IL-8 levels. However, 100 μg/ml and 300 μg/ml levofloxacin resulted in a 45% and 40% decrease in IL-6 levels, respectively (
FIG. 6 ). Levels of IL-8 decreased by 30% and 20% in HBE135 cells treated with 100 μg/ml and 300 μg/ml levofloxacin, respectively (FIG. 6 ). Incubation of cells with 10 μg/ml, 30 μg/ml, or 100 μg/ml tobramycin did not affect the levels of IL-6, while 300 μg/ml of tobramycin increased levels of IL-6 by 30%. Treatment with 30 μg/ml to 300 μg/ml tobramycin increased IL-8 production by 20% to 30% (p<0.05). - These in vitro studies demonstrated that levofloxacin can induce a dose-related reduction in the production of the pro-inflammatory cytokines, IL-6 and IL-8, in cultured human lung epithelial cell lines. 300 μg/ml levofloxacin reduced levels of IL-6 by 4-fold and IL-8 by 2-fold (p<0.05); in contrast, tobramycin increased IL-6 levels by 50%, but had no effect on IL-8. These findings suggest that high concentrations of levofloxacin obtained in pulmonary tissues following treatment with aerosol levofloxacin formulated with MgCl2 will provide antinflammatory benefits in patients with chronic pulmonary infections.
- The human monocyte cell line, THP-1 is an established in vitro model of human monocytic cells and is capable to secrete a greater variety of cytokines compared to NL20 and HBE135 cells. THP-1 cells were cultured in RPMI-1640 medium with 10%FBS, 0.05 mM 2-mecraptoethanol. THP-1 cells were seeded on 24-well tissue culture plates at 1×106 cells/ml in growth media without serum. The following day, 100 ng/ml LPS from P. aeruginosa and antibiotics were added and cells incubated for 24 hours before media collection to assess cytokine production. Quantification of IL-6, IL-8, IL-1β and TNFα production was performed as described above for NL20 cells.
- Stimulation of THP-1 with 10 ng/ml of LPS increased IL-1β, TNFα, IL-6 and IL-8 levels by 60-, 200-, 30- and 600-fold, respectively (
FIGS. 7A , 7B, 7C, and 7D). Co-incubation of LPS and at 100 μg/ml and 300 μg/ml levofloxacin resulted in a 40% and 70% decrease in IL-1β levels, respectively (FIG. 7A ). 300 μg/ml levofloxacin increased TNFα production (FIG. 7B ). Incubation with increased concentrations of levofloxacin caused dose-dependent decrease of IL-6 production, with 300 μg/ml levofloxacin reducing IL-6 levels by five-fold (FIG. 7C ). Levels of IL-8 were significantly decreased by 100 μg/ml and 300 μg/ml levofloxacin (FIG. 7D ). - The human monocyte cell line, THP-1 is an established in vitro model of human monocytic cells and is capable to secrete a greater variety of cytokines compared to NL20 and HBE135 cells. IL-8 mRNA expression in NL20 monolayers was induced by treatment with 10 ng/ml TNFα. Levofloxacin was added simultaneously with TNFα. After 24 h incubation, the cell monolayer was washed with PBS, total cellular RNA was prepared and reverse transcription was performed using a human IL-8 specific primer and the “Cells-to-cDNA” kit from Ambion (Austin, Tex.). cDNA was subjected to real-time PCR analysis using PowerSYBR Green PCR master mix and a GeneAmp 5700 Instrument (Applied Biosystems; Warrington, UK). All data were normalized to the housekeeping gene β-actin. Stimulation of NL-20 cells with TNFα, produced a statistically significant (p<0.005) 20-fold increase in IL-8 mRNA levels (
FIG. 8 ). This increase correlates with the increased levels of IL-8 protein induced by TNFα. Addition of 100 μg/ml and 300 μg/ml levofloxacin had no significant effect on the level of IL-8 mRNA expression (FIG. 4 ). These results suggest that levofloxacin reduces levels of the IL-8 secreted protein by modulating processes that include protein translation and/or protein secretion. - NFkB and AP-1 are important regulators in the transcriptional activity of some pro-inflammatory cytokines. This example relates to the effect of levofloxacin on the transcriptional regulatory activity of NFkB.
- The human monocyte cell line, THP-1 is an established in vitro model of human monocytic cells and is capable to secrete a greater variety of cytokines compared to NL20 and HBE135 cells. Cells were seeded on 96-well plate at 3×104 cells/well and transfected the following day with a pMetLuc-NFkB reporter plasmid (Clontech) encoding a secreted luciferase protein under the control of a NFkB-regulated promoter. To normalize transfection efficiency, cells were cotransfected with a pSEAP-Control plasmid (Clontech) encoding a secreted alkaline phosphatase under the control of a strong constitutive promoter. 24 hours after transfection, media was replaced with fresh serum-free media containing 10 ng/ml TNF-α and levofloxacin. 8 hours after incubation, cell supernates were collected, and luciferase and alkaline phosphatase activities were measured using the “Ready-to-Glow Dual Secreted Reporter assay” (Clontech, Mountain View, Calif.). Cells transfected with the reporter plasmid encoding luciferase gene under control of NFkB transcription factor produced a low basal level of luciferase activity. Stimulation with TNFα, a known activator of the NFkB pathway, resulted in an almost 20-fold increase in promoter activity (
FIG. 9 ). Addition of 100 μg/ml and 300 μg/ml levofloxacin did not produce a significant effect on the level of reporter gene activity. This suggests that levofloxacin did not affect TNFα-stimulated transcriptional activity of NFkB. - Mice (n=4) were injected with 50 μg LPS by an intraperitoneal route. Thirty minutes after LPS treatment, mice were treated using a microspray aerosol device (PennCentury, Philadelphia) with 60 mg/kg saline control, levofloxacin formulated with MgCl2, or tobramycin. Mice were sacrificed 6 hours after aerosolized treatment, and bronchoalveolar (BAL) fluid was collected by lavage with 1 ml saline. IL-6 and MIP-2 (murine homolog of human IL-8) levels were determined by ELISA.
- Treatments with saline, levofloxacin formulated with MgCl2, and tobramycin resulted in mean MIP-2 levels of 515 pg/ml, 233 pg/ml, and 502 pg/ml, respectively (
FIG. 10A ). Treatment with levofloxacin formulated with MgCl2 resulted in more than a 2-fold reduction in MIP-2 levels relative to the saline control. Moreover, the reduction was significantly greater than both saline and tobramycin treated mice (p<0.05). A similar trend was observed in IL-6 levels (FIG. 10B ). Treatment with levofloxacin produced IL-6 levels more than 2-fold lower than IL-6 levels in the saline control (p<0.05). Treatment with tobramycin resulted in an increase in IL-6 levels compared to the saline control. This in vivo data is consistent with the in vitro data of Example 5, where treatment with levofloxacin decreased levels of IL-6 and IL-8, while tobramycin had no significant effect on IL-8 levels and a trend towards increasing IL-6 levels. - This in vivo study shows that treatment with high concentrations of levofloxacin formulated with MgCl2 can reduce pro-inflammatory cytokines that include IL-6 and IL-8. Accordingly, these findings suggest that in addition to potent antibacterial effects, high concentrations of levofloxacin may have anti-inflammatory benefits in patients susceptible to acute and chronic inflammations, for example patients with CF and COPD.
- CF patients having acute or chronic pulmonary inflammation are administered aerosol levofloxacin formulated with MgCl2. After treatment, a reduction in the acute inflammation is observed. A reduction in the levels of pro-inflammatory cytokines is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the lungs is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the sputum and/or BAL is observed.
- COPD patients having acute or chronic pulmonary inflammation are administered aerosol levofloxacin formulated with MgCl2. After treatment, a reduction in the acute inflammation is observed. A reduction in the levels of pro-inflammatory cytokines is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the lungs is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the sputum and/or BAL is observed.
- Chronic bronchitis patients having acute or chronic pulmonary inflammation are administered aerosol levofloxacin formulated with MgCl2. After treatment, a reduction in the acute inflammation is observed. A reduction in the levels of pro-inflammatory cytokines is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the lungs is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the sputum and/or BAL is observed.
- Bronchiectasis patients having acute or chronic pulmonary inflammation are administered aerosol levofloxacin formulated with MgCl2. After treatment, a reduction in the acute inflammation is observed. A reduction in the levels of pro-inflammatory cytokines is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the lungs is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the sputum and/or BAL is observed.
- Non-CF bronchiectasis patients having acute or chronic pulmonary inflammation are administered aerosol levofloxacin formulated with MgCl2. After treatment, a reduction in the acute inflammation is observed. A reduction in the levels of pro-inflammatory cytokines is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the lungs is observed. A reduction in the levels of IL-1β, IL-6, and IL-8 in the sputum and/or BAL is observed.
- To the extent publications and patents or patent applications incorporated by reference herein contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
- Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein.
- Terms and phrases used in this application, and variations thereof, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as ‘known’, ‘normal’, ‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like ‘preferably,’ preferred,‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise. In addition, as used in this application, the articles ‘a’ and ‘an’ should be construed as referring to one or more than one (i.e., to at least one) of the grammatical objects of the article. By way of example, ‘an element’ means one element or more than one element.
- The presence in some instances of broadening words and phrases such as ‘one or more’, ‘at least’, ‘but not limited to’, or other like phrases shall not be read to mean that the narrower case is intended or required in instances where such broadening phrases may be absent.
- All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term ‘about.’ Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
- Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.
Claims (49)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/134,348 US20140105985A1 (en) | 2008-10-07 | 2013-12-19 | Topical use of levofloxacin for reducing lung inflammation |
US15/729,930 US11020481B2 (en) | 2008-10-07 | 2017-10-11 | Topical use of levofloxacin for reducing lung inflammation |
US17/240,273 US20220080047A1 (en) | 2008-10-07 | 2021-04-26 | Topical use of levofloxacin for reducing lung inflammation |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10349608P | 2008-10-07 | 2008-10-07 | |
US12/574,666 US8629139B2 (en) | 2008-10-07 | 2009-10-06 | Topical use of Levofloxacin for reducing lung inflammation |
US14/134,348 US20140105985A1 (en) | 2008-10-07 | 2013-12-19 | Topical use of levofloxacin for reducing lung inflammation |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/574,666 Continuation US8629139B2 (en) | 2008-10-07 | 2009-10-06 | Topical use of Levofloxacin for reducing lung inflammation |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/729,930 Continuation US11020481B2 (en) | 2008-10-07 | 2017-10-11 | Topical use of levofloxacin for reducing lung inflammation |
Publications (1)
Publication Number | Publication Date |
---|---|
US20140105985A1 true US20140105985A1 (en) | 2014-04-17 |
Family
ID=41397491
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/574,666 Active 2030-08-21 US8629139B2 (en) | 2008-10-07 | 2009-10-06 | Topical use of Levofloxacin for reducing lung inflammation |
US14/134,348 Abandoned US20140105985A1 (en) | 2008-10-07 | 2013-12-19 | Topical use of levofloxacin for reducing lung inflammation |
US15/729,930 Active US11020481B2 (en) | 2008-10-07 | 2017-10-11 | Topical use of levofloxacin for reducing lung inflammation |
US17/240,273 Abandoned US20220080047A1 (en) | 2008-10-07 | 2021-04-26 | Topical use of levofloxacin for reducing lung inflammation |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/574,666 Active 2030-08-21 US8629139B2 (en) | 2008-10-07 | 2009-10-06 | Topical use of Levofloxacin for reducing lung inflammation |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/729,930 Active US11020481B2 (en) | 2008-10-07 | 2017-10-11 | Topical use of levofloxacin for reducing lung inflammation |
US17/240,273 Abandoned US20220080047A1 (en) | 2008-10-07 | 2021-04-26 | Topical use of levofloxacin for reducing lung inflammation |
Country Status (14)
Country | Link |
---|---|
US (4) | US8629139B2 (en) |
EP (1) | EP2346509B1 (en) |
JP (4) | JP2012505222A (en) |
CN (1) | CN102325532B (en) |
CA (1) | CA2739893C (en) |
DK (1) | DK2346509T3 (en) |
ES (1) | ES2809177T3 (en) |
HR (1) | HRP20201150T8 (en) |
HU (1) | HUE050147T2 (en) |
IL (1) | IL212189A0 (en) |
PL (1) | PL2346509T3 (en) |
PT (1) | PT2346509T (en) |
SI (1) | SI2346509T1 (en) |
WO (1) | WO2010042549A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140066441A1 (en) * | 2005-05-18 | 2014-03-06 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US10149854B2 (en) | 2008-10-07 | 2018-12-11 | Horizon Orphan Llc | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US10231975B2 (en) | 2009-09-04 | 2019-03-19 | Horizon Orphan Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
US11020481B2 (en) | 2008-10-07 | 2021-06-01 | Horizon Orphan Llc | Topical use of levofloxacin for reducing lung inflammation |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RS60205B1 (en) | 2005-12-28 | 2020-06-30 | Vertex Pharma | Pharmaceutical compositions of the amorphous form of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
CN102711760A (en) * | 2009-08-19 | 2012-10-03 | Mpex医药有限公司 | Use of aerosolized antibiotics for treating chronic obstructive pulmonary disease |
AU2015275224C1 (en) * | 2009-09-04 | 2017-11-16 | Horizon Therapeutics U.S. Holding Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
US9572774B2 (en) | 2011-05-19 | 2017-02-21 | Savara Inc. | Dry powder vancomycin compositions and associated methods |
GB201113662D0 (en) * | 2011-08-08 | 2011-09-21 | Prosonix Ltd | Pharmaceutical compositions |
US20160051526A1 (en) * | 2013-04-09 | 2016-02-25 | Cresset Biomolecular Discovery Ltd | The Local Treatment of Inflammatory Ophthalmic Disorders |
KR20170063954A (en) | 2014-10-07 | 2017-06-08 | 버텍스 파마슈티칼스 인코포레이티드 | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
US9968616B2 (en) | 2014-10-25 | 2018-05-15 | The Chinese University Of Hong Kong | Discovery of FDA-approved drugs as inhibitors of fatty acid binding protein 4 using molecular docking screening |
WO2023003003A1 (en) * | 2021-07-20 | 2023-01-26 | 興和株式会社 | Novel inhalant |
WO2023022198A1 (en) * | 2021-08-19 | 2023-02-23 | 国立大学法人東北大学 | Novel prophylactic or therapeutic agent for novel coronavirus infection-related disease |
CN116270525A (en) * | 2023-02-22 | 2023-06-23 | 南京华盖制药有限公司 | Inhalable bionic nano material for treating pulmonary bacterial infectious pneumonia and preparation method and application thereof |
CN116925997B (en) * | 2023-07-27 | 2024-04-02 | 湖北医药学院 | Application of levofloxacin in preparing medicine for promoting cell proliferation |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090247458A1 (en) * | 2007-10-25 | 2009-10-01 | Revalesio Corporation | Compositions and methods for treating cystic fibrosis |
US7838532B2 (en) * | 2005-05-18 | 2010-11-23 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8357696B2 (en) * | 2005-05-18 | 2013-01-22 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8629139B2 (en) * | 2008-10-07 | 2014-01-14 | Mpex Pharmaceuticals, Inc. | Topical use of Levofloxacin for reducing lung inflammation |
US8815838B2 (en) * | 2008-10-07 | 2014-08-26 | David C. Griffith | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
Family Cites Families (265)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US696219A (en) | 1901-08-23 | 1902-03-25 | Paul Willemain | Building containing acetylene-gas-generating apparatus. |
US2587215A (en) | 1949-04-27 | 1952-02-26 | Frank P Priestly | Inhalator |
BE555319A (en) | 1956-03-21 | 1900-01-01 | ||
US2858691A (en) | 1956-09-04 | 1958-11-04 | Mosler Lock Company | Key changed tumbler clamp |
BE556587A (en) | 1957-01-31 | 1957-04-11 | ||
GB901107A (en) | 1959-06-29 | 1962-07-11 | Pfizer | Therapeutic composition and method of preparing same |
US3669113A (en) | 1966-03-07 | 1972-06-13 | Fisons Ltd | Inhalation device |
US3507277A (en) | 1966-09-17 | 1970-04-21 | Fisons Pharmaceuticals Ltd | Inhalation device |
US3456644A (en) | 1967-01-19 | 1969-07-22 | Dart Ind Inc | Inhalation-actuated aerosol dispensing device |
US3456645A (en) | 1967-01-19 | 1969-07-22 | Dart Ind Inc | Inhalation-actuated aerosol dispensing device |
US3456646A (en) | 1967-01-19 | 1969-07-22 | Dart Ind Inc | Inhalation-actuated aerosol dispensing device |
GB1268051A (en) | 1968-06-07 | 1972-03-22 | Fisons Pharmaceuticals Ltd | Inhalation device |
US3565070A (en) | 1969-02-28 | 1971-02-23 | Riker Laboratories Inc | Inhalation actuable aerosol dispenser |
US3636949A (en) | 1969-08-08 | 1972-01-25 | Armstrong Kropp Dev Corp | Inhalation-initiated aerosol dispenser |
BE758834A (en) | 1969-11-13 | 1971-05-12 | Riker Laboratoires Inc | AEROSOL DISPENSER ACTIVATED BY INHALATION |
GB1383761A (en) | 1971-02-25 | 1974-02-12 | Woodcraft Dc | Inhalation device for use with an aerosol container |
US3732864A (en) | 1971-06-07 | 1973-05-15 | Schering Corp | Inhalation coordinated aerosol dispensing device |
IT941426B (en) | 1971-07-17 | 1973-03-01 | Isf Spa | SWIRL-CHAMBER INHALER FOR POWDER-SHAPING MEDICINAL SUBSTANCES |
US3826255A (en) | 1972-06-22 | 1974-07-30 | Hudson Oxygen Therapy Sales Co | Intermittent positive pressure breathing manifold |
FR2224175B1 (en) | 1973-04-04 | 1978-04-14 | Isf Spa | |
IT1016489B (en) | 1974-03-18 | 1977-05-30 | Isf Spa | INHALER |
US3971377A (en) | 1974-06-10 | 1976-07-27 | Alza Corporation | Medicament dispensing process for inhalation therapy |
IT1017153B (en) | 1974-07-15 | 1977-07-20 | Isf Spa | APPARATUS FOR INHALATIONS |
YU41046B (en) | 1974-08-22 | 1986-10-31 | Schering Ag | Medicine inholating device |
SU628930A1 (en) | 1974-11-26 | 1978-10-25 | Московский научно-исследовательский институт туберкулеза | Device for introducing medicinal powders |
US3948264A (en) | 1975-05-21 | 1976-04-06 | Mead Johnson & Company | Inhalation device |
US4147166A (en) | 1977-05-02 | 1979-04-03 | American Cyanamid Company | Oral inhalator powder dispenser |
US4268460A (en) | 1977-12-12 | 1981-05-19 | Warner-Lambert Company | Nebulizer |
US4253468A (en) | 1978-08-14 | 1981-03-03 | Steven Lehmbeck | Nebulizer attachment |
US4263907A (en) | 1979-05-14 | 1981-04-28 | Lindsey Joseph W | Respirator nebulizer |
BR8007911A (en) | 1979-12-06 | 1981-06-16 | Glaxo Group Ltd | PERFECTED INHALER |
JPS5746986A (en) | 1980-09-02 | 1982-03-17 | Dai Ichi Seiyaku Co Ltd | Pyrido(1,2,3-de)(1,4)benzoxazine derivative |
SI8110592A8 (en) | 1981-03-06 | 1996-06-30 | Pliva Pharm & Chem Works | Process for preparing of n-methyl-11-aza-10-deoxo-10-dihydroerythromycine a and derivatives thereof |
SE438261B (en) | 1981-07-08 | 1985-04-15 | Draco Ab | USE IN A DOSHALATOR OF A PERFORED MEMBRANE |
US4688218A (en) | 1981-07-15 | 1987-08-18 | Etablissement Public De Diffusion Dit "Telediffusion De France" | Multiplex channels for continuous flow for numerical signal |
US4470412A (en) | 1982-03-19 | 1984-09-11 | Trutek Research, Inc. | Inhalation valve |
US4510929A (en) | 1982-04-30 | 1985-04-16 | Bordoni Maurice E | Disposable radioactive aerosol inhalation apparatus |
US4730000A (en) | 1984-04-09 | 1988-03-08 | Abbott Laboratories | Quinoline antibacterial compounds |
US4994599A (en) | 1987-11-20 | 1991-02-19 | Abbott Laboratories | Intermediates for producing quinolone-3-carboxylic acids |
US4649911A (en) | 1983-09-08 | 1987-03-17 | Baylor College Of Medicine | Small particle aerosol generator for treatment of respiratory disease including the lungs |
GB8328808D0 (en) | 1983-10-28 | 1983-11-30 | Riker Laboratories Inc | Inhalation responsive dispensers |
JPS60202822A (en) | 1984-03-28 | 1985-10-14 | Dai Ichi Seiyaku Co Ltd | Antiviral agent |
US4624251A (en) | 1984-09-13 | 1986-11-25 | Riker Laboratories, Inc. | Apparatus for administering a nebulized substance |
US4648393A (en) | 1984-11-02 | 1987-03-10 | Ackrad Laboratories, Inc. | Breath activated medication spray |
FR2575678B1 (en) | 1985-01-04 | 1988-06-03 | Saint Gobain Vitrage | PNEUMATIC POWDER EJECTOR |
US4805811A (en) | 1985-03-29 | 1989-02-21 | Aktiebolaget Draco | Dosage device |
NO166131C (en) | 1985-06-20 | 1991-06-05 | Daiichi Seiyaku Co | ANALOGUE PROCEDURE FOR THE PREPARATION OF S (-) - PYRIDOBENZOKSAZINE COMPOUNDS. |
US4811731A (en) | 1985-07-30 | 1989-03-14 | Glaxo Group Limited | Devices for administering medicaments to patients |
US4977154A (en) | 1985-12-12 | 1990-12-11 | Warner-Lambert Company | 5-amino and 5-hydroxy-6-fluoroquinolones as antibacterial agents |
US4809692A (en) | 1986-01-31 | 1989-03-07 | Trudell Medical | Pediatric asthmatic medication inhaler |
IT1204826B (en) | 1986-03-04 | 1989-03-10 | Chiesi Farma Spa | INHALATION PHARMACEUTICAL COMPOSITIONS |
US4926852B1 (en) | 1986-06-23 | 1995-05-23 | Univ Johns Hopkins | Medication delivery system phase one |
US4790305A (en) | 1986-06-23 | 1988-12-13 | The Johns Hopkins University | Medication delivery system |
JPS63188627A (en) | 1987-01-31 | 1988-08-04 | Rooto Seiyaku Kk | Antiallergic and antiphlogistic agents |
DE3704907A1 (en) | 1987-02-17 | 1988-08-25 | Bayer Ag | TOPICALLY APPLICABLE PREPARATIONS OF GYRASE INHIBITORS IN COMBINATION WITH CORTICOSTEROIDS |
US5119806A (en) | 1987-05-12 | 1992-06-09 | Glaxo Inc. | Inhalation device |
KR910000142B1 (en) | 1987-05-29 | 1991-01-21 | 니혼 다바고 상교오 가부시기가이샤 | Filter for cigarette |
RU2066324C1 (en) | 1987-07-09 | 1996-09-10 | Пфайзер Инк. | Crystalline azithromycin dehydrate, and process for preparation thereof |
US4857311A (en) | 1987-07-31 | 1989-08-15 | Massachusetts Institute Of Technology | Polyanhydrides with improved hydrolytic degradation properties |
US4907538A (en) | 1988-05-09 | 1990-03-13 | Little Suamico Products Inc. | Multiple bin cow feeder |
US4832015A (en) | 1988-05-19 | 1989-05-23 | Trudell Medical | Pediatric asthmatic inhaler |
IT1217890B (en) | 1988-06-22 | 1990-03-30 | Chiesi Farma Spa | DOSED AEROSOL INHALATION DEVICE |
FR2636716B1 (en) | 1988-09-21 | 1990-12-07 | Staubli Sa Ets | DEVICE FOR COUPLING ELEMENT HOLDER PLATES OF MULTIPLE FITTINGS |
EP0363060B1 (en) | 1988-10-04 | 1994-04-27 | The Johns Hopkins University | Aerosol inhaler |
DK479189D0 (en) | 1989-01-06 | 1989-09-28 | Hans Gernot Schenk | INHALER |
US5012803A (en) | 1989-03-06 | 1991-05-07 | Trudell Medical | Modular medication inhaler |
US5012804A (en) | 1989-03-06 | 1991-05-07 | Trudell Medical | Medication inhaler with adult mask |
GB8908647D0 (en) | 1989-04-17 | 1989-06-01 | Glaxo Group Ltd | Device |
ES2087911T3 (en) | 1989-04-28 | 1996-08-01 | Riker Laboratories Inc | DRY DUST INHALATION DEVICE. |
US4955371A (en) | 1989-05-08 | 1990-09-11 | Transtech Scientific, Inc. | Disposable inhalation activated, aerosol device for pulmonary medicine |
IT1237118B (en) | 1989-10-27 | 1993-05-18 | Miat Spa | MULTI-DOSE INHALER FOR POWDER DRUGS. |
WO1991009525A1 (en) | 1989-12-29 | 1991-07-11 | Abbott Laboratories | Quinolone carboxylic acid--metal ion--acid complexes |
US5113855A (en) | 1990-02-14 | 1992-05-19 | Newhouse Michael T | Powder inhaler |
US5192548A (en) | 1990-04-30 | 1993-03-09 | Riker Laboratoires, Inc. | Device |
GB9015077D0 (en) | 1990-07-09 | 1990-08-29 | Riker Laboratories Inc | Inhaler |
GB9015522D0 (en) | 1990-07-13 | 1990-08-29 | Braithwaite Philip W | Inhaler |
IT1243344B (en) | 1990-07-16 | 1994-06-10 | Promo Pack Sa | MULTI-DOSE INHALER FOR POWDER MEDICATIONS |
US5060643A (en) | 1990-08-07 | 1991-10-29 | Tenax Corporation | Breath-activated inhalation device |
FR2665635A1 (en) | 1990-08-10 | 1992-02-14 | Merck Sharp & Dohme | FLUID PHARMACEUTICAL COMPOSITION BASED ON METAL COMPLEX AND PROCESS FOR PREPARING THE SAME. |
GB9026025D0 (en) | 1990-11-29 | 1991-01-16 | Boehringer Ingelheim Kg | Inhalation device |
US5258528A (en) | 1990-11-30 | 1993-11-02 | Warner-Lambert Company | Individual stereoisomers of pyrrolidine methanamines substituted on the ring nitrogen by a 1-phenylethyl group |
US5217004A (en) | 1990-12-13 | 1993-06-08 | Tenax Corporation | Inhalation actuated dispensing apparatus |
US5040527A (en) | 1990-12-18 | 1991-08-20 | Healthscan Products Inc. | Metered dose inhalation unit with slide means |
US5404871A (en) | 1991-03-05 | 1995-04-11 | Aradigm | Delivery of aerosol medications for inspiration |
US5164740A (en) | 1991-04-24 | 1992-11-17 | Yehuda Ivri | High frequency printing mechanism |
AU651882B2 (en) | 1991-05-14 | 1994-08-04 | Visiomed Group Limited | Aerosol inhalation device |
ES2158911T5 (en) | 1991-06-10 | 2009-12-09 | Schering Corporation | FORMULATIONS IN AEROSOL WITHOUT CHLOROFLUOROCARBONOS. |
ATE359842T1 (en) | 1991-07-02 | 2007-05-15 | Nektar Therapeutics | DISPENSING DEVICE FOR MIST-FORMED MEDICATIONS |
IT1250691B (en) | 1991-07-22 | 1995-04-21 | Giancarlo Santus | THERAPEUTIC COMPOSITIONS FOR INTRANASAL ADMINISTRATION INCLUDING KETOROLAC. |
ATE155695T1 (en) | 1991-11-07 | 1997-08-15 | Ritzau Pari Werk Gmbh Paul | NEBULISER, PARTICULARLY FOR USE IN DEVICES FOR INHALATION THERAPY |
DE4140689B4 (en) | 1991-12-10 | 2007-11-22 | Boehringer Ingelheim Kg | Inhalable powders and process for their preparation |
DE4142238A1 (en) | 1991-12-20 | 1993-06-24 | Boehringer Ingelheim Kg | POWDER INHALATOR WITH POWDER SUPPORT FROM REGULAR MICROSTRUCTURES |
DE9307115U1 (en) | 1992-05-29 | 1993-09-02 | Ggu Gesundheits Umweltforsch | Device for producing inhalable active substances |
US5785049A (en) | 1994-09-21 | 1998-07-28 | Inhale Therapeutic Systems | Method and apparatus for dispersion of dry powder medicaments |
US5284133A (en) | 1992-07-23 | 1994-02-08 | Armstrong Pharmaceuticals, Inc. | Inhalation device with a dose-timer, an actuator mechanism, and patient compliance monitoring means |
EG20543A (en) | 1992-10-30 | 1999-07-31 | Procter & Gamble | Process for preparing of novel antimicrobial -5- (n-heterosubstituted amino) quinolones |
NZ250105A (en) | 1992-11-09 | 1996-07-26 | Monaghan Canadian Ltd | Inhalator mask; one-way valve opens upon exhalation |
CZ287848B6 (en) | 1992-12-18 | 2001-02-14 | Schering Corp | Inhalator of powder substances |
US5934272A (en) | 1993-01-29 | 1999-08-10 | Aradigm Corporation | Device and method of creating aerosolized mist of respiratory drug |
US5558085A (en) | 1993-01-29 | 1996-09-24 | Aradigm Corporation | Intrapulmonary delivery of peptide drugs |
US5364838A (en) | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
US5709202A (en) | 1993-05-21 | 1998-01-20 | Aradigm Corporation | Intrapulmonary delivery of aerosolized formulations |
US5532239A (en) | 1993-08-02 | 1996-07-02 | Assistance Publique - Hopitaux De Paris | Therapeutic application of fluoroquinolone derivatives |
US5688792A (en) | 1994-08-16 | 1997-11-18 | Pharmacia & Upjohn Company | Substituted oxazine and thiazine oxazolidinone antimicrobials |
MY115155A (en) | 1993-09-09 | 2003-04-30 | Upjohn Co | Substituted oxazine and thiazine oxazolidinone antimicrobials. |
GB9322014D0 (en) | 1993-10-26 | 1993-12-15 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
US5388572A (en) | 1993-10-26 | 1995-02-14 | Tenax Corporation (A Connecticut Corp.) | Dry powder medicament inhalator having an inhalation-activated piston to aerosolize dose and deliver same |
US5404781A (en) | 1994-06-09 | 1995-04-11 | Ko Shin Electric And Machinery Co., Ltd. | Anti-sway means for a saw web |
US5642730A (en) | 1994-06-17 | 1997-07-01 | Trudell Medical Limited | Catheter system for delivery of aerosolized medicine for use with pressurized propellant canister |
US5820873A (en) | 1994-09-30 | 1998-10-13 | The University Of British Columbia | Polyethylene glycol modified ceramide lipids and liposome uses thereof |
US5508269A (en) | 1994-10-19 | 1996-04-16 | Pathogenesis Corporation | Aminoglycoside formulation for aerosolization |
GB9501841D0 (en) | 1995-01-31 | 1995-03-22 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
WO1996025918A1 (en) | 1995-02-24 | 1996-08-29 | Nanosystems L.L.C. | Aerosols containing nanoparticle dispersions |
US6427682B1 (en) | 1995-04-05 | 2002-08-06 | Aerogen, Inc. | Methods and apparatus for aerosolizing a substance |
US5758637A (en) | 1995-08-31 | 1998-06-02 | Aerogen, Inc. | Liquid dispensing apparatus and methods |
US5586550A (en) | 1995-08-31 | 1996-12-24 | Fluid Propulsion Technologies, Inc. | Apparatus and methods for the delivery of therapeutic liquids to the respiratory system |
US5921237A (en) | 1995-04-24 | 1999-07-13 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US6672304B1 (en) | 1995-06-08 | 2004-01-06 | Innovative Devices, Llc | Inhalation actuated device for use with metered dose inhalers (MDIs) |
ATE209518T1 (en) | 1995-06-21 | 2001-12-15 | Asta Medica Ag | MEDICINAL POWDER CARTRIDGE WITH INTEGRATED DOSING DEVICE AND POWDER INHALER |
CA2176298C (en) | 1995-06-27 | 2009-01-27 | Dennis D. Copeland | A single high dose fluoroquinolone treatment |
AUPN417395A0 (en) | 1995-07-14 | 1995-08-10 | Techbase Pty. Ltd. | An improved spacer |
JP5042447B2 (en) | 1995-07-21 | 2012-10-03 | 第一三共株式会社 | Mixed preparation |
GB9515182D0 (en) | 1995-07-24 | 1995-09-20 | Co Ordinated Drug Dev | Improvements in and relating to powders for use in dry powder inhalers |
US6209538B1 (en) | 1995-08-02 | 2001-04-03 | Robert A. Casper | Dry powder medicament inhalator having an inhalation-activated flow diverting means for triggering delivery of medicament |
SE9502799D0 (en) | 1995-08-10 | 1995-08-10 | Astra Ab | Device in inhalers |
CZ293747B6 (en) | 1995-12-21 | 2004-07-14 | Pfizer Inc. | Aqueous pharmaceutical solution suitable for injection into a host and use thereof |
US5694920A (en) | 1996-01-25 | 1997-12-09 | Abrams; Andrew L. | Inhalation device |
US6026809A (en) | 1996-01-25 | 2000-02-22 | Microdose Technologies, Inc. | Inhalation device |
US5823179A (en) | 1996-02-13 | 1998-10-20 | 1263152 Ontario Inc. | Nebulizer apparatus and method |
US6083922A (en) | 1996-04-02 | 2000-07-04 | Pathogenesis, Corp. | Method and a tobramycin aerosol formulation for treatment prevention and containment of tuberculosis |
FR2747311B1 (en) | 1996-04-10 | 1998-08-14 | Pf Medicament | POWDER AND COMPRESSED AIR INHALER |
US6838552B1 (en) | 1997-08-14 | 2005-01-04 | Vanderbilt University | Diagnosis and management of infection caused by Chlamydia |
US6579854B1 (en) | 1996-08-14 | 2003-06-17 | Vanderbilt University | Diagnosis and management of infection caused by chlamydia |
AU743174B2 (en) | 1997-10-08 | 2002-01-17 | Sepracor, Inc. | Dosage form for aerosol administration |
US5906202A (en) | 1996-11-21 | 1999-05-25 | Aradigm Corporation | Device and method for directing aerosolized mist to a specific area of the respiratory tract |
CA2227314A1 (en) | 1997-01-24 | 1998-07-24 | Hoechst Aktiengesellschaft | Preparation of concealed taste preparations of antibacterially active quinolone derivatives |
US6349719B2 (en) | 1997-02-24 | 2002-02-26 | Aradigm Corporation | Formulation and devices for monitoring the efficacy of the delivery of aerosols |
US6006747A (en) | 1997-03-20 | 1999-12-28 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US6406880B1 (en) | 1997-05-02 | 2002-06-18 | Integrated Research Technology, Llc | Betaines as adjuvants to susceptibility testing and antimicrobial therapy |
US6664239B2 (en) | 1997-05-06 | 2003-12-16 | Vanderbilt University | Diagnosis and management of infection caused by Chlamydia |
US6756369B2 (en) | 1997-05-06 | 2004-06-29 | Vanderbilt University | Diagnosis and management of infection caused by Chlamydia |
US6890526B2 (en) | 1997-05-06 | 2005-05-10 | Vanderbilt University | Methods and reagents for the treatment of multiple sclerosis |
US6884784B1 (en) | 1997-05-06 | 2005-04-26 | Vanderbilt University | Diagnosis and management of infection caused by chlamydia |
US5855564A (en) | 1997-08-20 | 1999-01-05 | Aradigm Corporation | Aerosol extrusion mechanism |
US20010044584A1 (en) | 1997-08-28 | 2001-11-22 | Kensey Kenneth R. | In vivo delivery methods and compositions |
US6293279B1 (en) | 1997-09-26 | 2001-09-25 | Trudell Medical International | Aerosol medication delivery apparatus and system |
US20030082107A1 (en) | 1997-10-01 | 2003-05-01 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating an infectious disease or cancer |
US6003512A (en) | 1997-11-13 | 1999-12-21 | Lovelace Respiratory Research Institute | Dust gun-aerosol generator and generation |
EP1149602B1 (en) | 1997-11-19 | 2015-01-07 | Aptar France SAS | Spray device for an inhaler suitable for respiratory therapies |
ID21415A (en) | 1997-12-05 | 1999-06-10 | Upjohn Co | QUINOLON MAGNESIUM ANTIBIOTIC COMPOUNDS |
US6192876B1 (en) | 1997-12-12 | 2001-02-27 | Astra Aktiebolag | Inhalation apparatus and method |
US6223746B1 (en) | 1998-02-12 | 2001-05-01 | Iep Pharmaceutical Devices Inc. | Metered dose inhaler pump |
US6026807A (en) | 1998-02-27 | 2000-02-22 | Diemolding Corporation | Metered dose inhaler cloud chamber |
GB9810299D0 (en) | 1998-05-15 | 1998-07-15 | Glaxo Group Ltd | Use of nitric oxide synthase inhibitors |
US6257233B1 (en) | 1998-06-04 | 2001-07-10 | Inhale Therapeutic Systems | Dry powder dispersing apparatus and methods for their use |
NZ509328A (en) | 1998-07-24 | 2002-11-26 | Jago Res A | Medicinal aerosol formulations |
DE69932313T2 (en) | 1998-08-21 | 2007-07-19 | Senju Pharmaceutical Co., Ltd. | AQUEOUS LIQUID PREPARATIONS |
DK1674107T3 (en) | 1998-09-25 | 2016-12-19 | Cubist Pharmaceuticals Llc | Use of daptomycin |
US6395746B1 (en) | 1998-09-30 | 2002-05-28 | Alcon Manufacturing, Ltd. | Methods of treating ophthalmic, otic and nasal infections and attendant inflammation |
GB2343122B (en) | 1998-10-26 | 2003-01-08 | Medic Aid Ltd | Improvements in and relating to nebulisers |
US6070575A (en) | 1998-11-16 | 2000-06-06 | Aradigm Corporation | Aerosol-forming porous membrane with certain pore structure |
US6584971B1 (en) | 1999-01-04 | 2003-07-01 | Medic-Aid Limited | Drug delivery apparatus |
US6350199B1 (en) | 1999-03-16 | 2002-02-26 | International Game Technology | Interactive gaming machine and method with customized game screen presentation |
US7919119B2 (en) | 1999-05-27 | 2011-04-05 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US6338443B1 (en) | 1999-06-18 | 2002-01-15 | Mercury Enterprises, Inc. | High efficiency medical nebulizer |
CA2282066C (en) | 1999-06-29 | 2010-09-07 | Smithkline Beecham Corporation | Methods of use of quinolone compounds against atypical upper respiratory pathogenic bacteria |
US20020061281A1 (en) | 1999-07-06 | 2002-05-23 | Osbakken Robert S. | Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis |
US6576224B1 (en) * | 1999-07-06 | 2003-06-10 | Sinuspharma, Inc. | Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis |
US6586008B1 (en) | 1999-08-25 | 2003-07-01 | Advanced Inhalation Research, Inc. | Use of simple amino acids to form porous particles during spray drying |
ATE313318T1 (en) | 1999-10-29 | 2006-01-15 | Nektar Therapeutics | DRY POWDER COMPOSITIONS WITH IMPROVED DISPERSITY |
US6294178B1 (en) | 1999-11-01 | 2001-09-25 | Robert E. Weinstein | Method and device for coordinating topical and oral sinusitis treatments |
MXPA02004349A (en) | 1999-11-01 | 2003-09-22 | Alcon Inc | Pharmaceutical compositions containing a fluoroquinolone antibiotic drug and xanthan gum. |
US6962151B1 (en) | 1999-11-05 | 2005-11-08 | Pari GmbH Spezialisten für effektive Inhalation | Inhalation nebulizer |
US20010049366A1 (en) | 2000-02-09 | 2001-12-06 | Alcon Universal Ltd. | Topical solution formulations containing an antibiotic and a corticosteroid |
US6544555B2 (en) | 2000-02-24 | 2003-04-08 | Advancis Pharmaceutical Corp. | Antibiotic product, use and formulation thereof |
US6667057B2 (en) | 2000-02-24 | 2003-12-23 | Advancis Pharmaceutical Corp. | Levofloxacin antibiotic product, use and formulation thereof |
US6730320B2 (en) | 2000-02-24 | 2004-05-04 | Advancis Pharmaceutical Corp. | Tetracycline antibiotic product, use and formulation thereof |
US6669948B2 (en) | 2000-02-24 | 2003-12-30 | Advancis Pharmaceutical Corp. | Antibiotic product, use and formulation thereof |
US6667042B2 (en) | 2000-02-24 | 2003-12-23 | Advancis Pharmaceutical Corp. | Fluroquinilone antibiotic product, use and formulation thereof |
US6663890B2 (en) | 2000-02-24 | 2003-12-16 | Advancis Pharmaceutical Corp. | Metronidazole antibiotic product, use and formulation thereof |
US6663891B2 (en) | 2000-02-24 | 2003-12-16 | Advancis Pharmaceutical Corp. | Erythromyacin antibiotic product, use and formulation thereof |
CA2733850C (en) | 2000-04-11 | 2013-10-22 | Trudell Medical International | Aerosol delivery apparatus with positive expiratory pressure capacity |
US20020076437A1 (en) | 2000-04-12 | 2002-06-20 | Sanjeev Kothari | Flashmelt oral dosage formulation |
US6608078B2 (en) | 2000-05-08 | 2003-08-19 | Wockhardt Limited | Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment |
US6716819B2 (en) | 2000-05-19 | 2004-04-06 | University Of Iowa Research Foundation | Use of xylitol to reduce ionic strength and activate endogenous antimicrobials for prevention and treatment of infections |
PE20020044A1 (en) | 2000-06-16 | 2002-01-30 | Upjohn Co | THIAZINE OXAZOLIDINONE |
US6492328B2 (en) | 2000-06-28 | 2002-12-10 | The University Of Iowa Research Foundation | Novispirins: antimicrobial peptides |
AU2001278864A1 (en) | 2000-06-30 | 2002-01-30 | University Of Cincinnati | Peptides with antioxidant and antimicrobial properties |
AU2001282988B2 (en) | 2000-07-26 | 2006-01-05 | Atopic Pty Ltd | Methods for treating atopic disorders |
WO2002018345A1 (en) | 2000-08-29 | 2002-03-07 | Chiron Corporation | Quinoline antibacterial compounds and methods of use thereof |
TWI290053B (en) | 2000-09-19 | 2007-11-21 | Daiichi Seiyaku Co | Medicinal composition for preventing the generation of a disagreeable taste |
US6298656B1 (en) | 2000-09-29 | 2001-10-09 | Siemens Westinghouse Power Corporation | Compressed air steam generator for cooling combustion turbine transition section |
US6601581B1 (en) | 2000-11-01 | 2003-08-05 | Advanced Medical Applications, Inc. | Method and device for ultrasound drug delivery |
JP2004518677A (en) | 2000-12-21 | 2004-06-24 | ファルマシア・アンド・アップジョン・カンパニー | Antibacterial quinolone derivatives and their use to treat bacterial infections |
US6626173B2 (en) | 2001-01-08 | 2003-09-30 | Iep Pharmaceutical Devices Inc. | Dry powder inhaler |
BR0207930A (en) | 2001-03-05 | 2004-03-02 | Ortho Mcneil Pharm Inc | Masked flavor liquid pharmaceutical compositions |
US6523536B2 (en) | 2001-03-12 | 2003-02-25 | Birdsong Medical Devices, Inc. | Dual-canister inhaler having a spacer and easy to operate lever mechanism |
CN1322528A (en) * | 2001-04-19 | 2001-11-21 | 刘文通 | Rhinitis treating medicine |
US6878713B2 (en) | 2001-04-25 | 2005-04-12 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
US6589955B2 (en) | 2001-06-20 | 2003-07-08 | Bristol-Myers Squibb Company | Pediatric formulation of gatifloxacin |
US6681768B2 (en) | 2001-06-22 | 2004-01-27 | Sofotec Gmbh & Co. Kg | Powder formulation disintegrating system and method for dry powder inhalers |
US20030138403A1 (en) | 2001-06-29 | 2003-07-24 | Maxygen Aps | Interferon formulations |
TR200401980T4 (en) | 2001-07-02 | 2004-09-21 | Chiesi Farmaceutici S.P.A. | Tobramycin formulation optimized for aerosol administration |
ATE395042T1 (en) | 2001-08-16 | 2008-05-15 | Baxter Int | DOSAGE FORMS WHICH CONTAIN MICROPARTICLES AND PROpellant GAS |
EP1438019A1 (en) | 2001-10-24 | 2004-07-21 | PARI GmbH Spezialisten für effektive Inhalation | Kit for the preparation of a pharmaceutical composition |
AU2002364562A1 (en) | 2001-12-13 | 2003-06-30 | Activbiotics, Inc. | Metal complexes and formulations of rifamycin analogues and uses therof |
US20030143265A1 (en) | 2001-12-19 | 2003-07-31 | Seiichi Araki | Method for treatment of sepsis |
US20030171340A1 (en) | 2002-02-07 | 2003-09-11 | Jenefir Isbister | Methods of disease treatment using metal-complexed tetracycline antibiotics |
JP2005530704A (en) | 2002-03-05 | 2005-10-13 | トランセイブ, インク. | Inhalation system for preventing and treating intracellular infections |
EP1484061A4 (en) | 2002-03-11 | 2009-12-23 | Eisai R&D Man Co Ltd | Drugs containing riboflavin-type compounds |
JP4290381B2 (en) | 2002-04-11 | 2009-07-01 | 学校法人 聖マリアンナ医科大学 | Emulsion containing pyridonecarboxylic acid compound |
US7607436B2 (en) | 2002-05-06 | 2009-10-27 | The Research Foundation Of State University Of New York | Methods, devices and formulations for targeted endobronchial therapy |
WO2003094890A1 (en) | 2002-05-07 | 2003-11-20 | Nektar Therapeutics | Capsules for dry powder inhalers and methods of making and using same |
US7423153B2 (en) | 2002-05-10 | 2008-09-09 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of gatifloxacin |
US20040045546A1 (en) | 2002-09-05 | 2004-03-11 | Peirce Management, Llc | Pharmaceutical delivery system for oral inhalation through nebulization consisting of inert substrate impregnated with substance (S) to be solubilized or suspended prior to use |
US20040152701A1 (en) | 2002-12-02 | 2004-08-05 | Dr. Reddy's Laboratories Limited | Novel anhydrous crystalline form of Levofloxacin and process for preparation there of |
AU2003285625A1 (en) | 2002-12-16 | 2004-07-09 | Ranbaxy Laboratories Limited | Pure levofloxacin hemihydrate and processes for preparation thereof |
MXPA05007466A (en) | 2003-01-09 | 2006-03-08 | Arizeke Pharmaceuticals Inc | Methods of treating lung diseases. |
RU2373937C9 (en) | 2003-02-10 | 2010-07-27 | Байер Шеринг Фарма Акциенгезельшафт | Therapy of respiratory apparatus bacteriosis by local application of fluoroquinolones |
US20060258677A1 (en) | 2003-02-15 | 2006-11-16 | Teva Pharmaceutical Industries Ltd. | Novel crystalline forms of gatifloxacin and processes for preparation |
DE60318384T2 (en) | 2003-03-19 | 2009-02-19 | The Jordanian Pharmaceutical Manufacturing Co. Ltd. | Non-hygroscopic pharmaceutical compositions containing non-hydrated quinolone carboxylic acids |
DE10318235A1 (en) | 2003-04-22 | 2004-11-11 | Clariant Gmbh | Easily dispersible pigments with rapid color strength development |
US20070248693A1 (en) | 2003-08-02 | 2007-10-25 | Elizabeth Mazzio | Nutraceutical composition and method of use for treatment / prevention of cancer |
WO2005019434A2 (en) | 2003-08-26 | 2005-03-03 | The Regents Of The University Of Colorado, A Body Corporate | Serine protease inhibitors for treatment of bacterial infections |
SE0302665D0 (en) | 2003-10-07 | 2003-10-07 | Astrazeneca Ab | Novel Process |
CN1312076C (en) | 2003-10-14 | 2007-04-25 | 长沙理工大学 | Ceramic glass pigment produced by using ferrochrome alloy as raw material and production method thereof |
AU2004281532B2 (en) | 2003-10-15 | 2010-03-18 | Pari Pharma Gmbh | Liquid preparation containing tobramycin |
ES2327935T3 (en) | 2003-11-17 | 2009-11-05 | Nektar Therapeutics | INTRODUCTION OF AN AEROSOL IN A FAN CIRCUIT. |
US7452524B2 (en) | 2004-01-27 | 2008-11-18 | Gilead Sciences, Inc. | Method for improvement of tolerance for therapeutically effective agents delivered by inhalation |
JP2008500965A (en) | 2004-03-17 | 2008-01-17 | エムペックス・ファーマシューティカルズ・インコーポレーテッド | Use and administration of bacterial efflux pump inhibitors |
US7148404B2 (en) | 2004-05-04 | 2006-12-12 | Novozymes A/S | Antimicrobial polypeptides |
AU2005245962A1 (en) | 2004-05-21 | 2005-12-01 | Mpex Pharmaceuticals, Inc. | Bacterial efflux pump inhibitors and methods of treating bacterial infections |
US7632869B2 (en) | 2004-05-24 | 2009-12-15 | Bausch & Lomb Incorporated | Antimicrobial compositions and uses thereof |
WO2006002140A2 (en) | 2004-06-21 | 2006-01-05 | Nektar Therapeutics | Compositions comprising amphotericin b |
ATE464883T1 (en) | 2004-07-22 | 2010-05-15 | Bend Res Inc | FLAVOR-COVERING FORMULATION WITH A RETARDED-RELEASE INGREDIENT FORMULATION AND/OR QUICKLY SOLUBLE CYCLODEXTRIN |
WO2006033713A2 (en) | 2004-08-09 | 2006-03-30 | Chiron Corporation | Methods for ciprofloxacin inhalation |
US7388077B2 (en) | 2004-11-12 | 2008-06-17 | Novozymes A/S | Polypeptides having antimicrobial activity and polynucleotides encoding the same |
AU2006206274A1 (en) | 2005-01-20 | 2006-07-27 | Sirtris Pharmaceuticals, Inc. | Use of sirtuin-activating compounds for treating flushing and drug induced weight gain |
CN101128206A (en) | 2005-01-21 | 2008-02-20 | 沃纳奇尔科特公司 | Tetracycline metal complex in a solid dosage form |
KR101483297B1 (en) | 2005-03-24 | 2015-01-21 | 다이이찌 산쿄 가부시키가이샤 | Pharmaceutical composition |
WO2006108075A2 (en) | 2005-04-05 | 2006-10-12 | The Scripps Research Institute | Compositions and methods for enhancing drug sensitivity and treating drug resistant infections an diseases |
KR101488403B1 (en) | 2005-05-18 | 2015-02-04 | 엠펙스 파마슈티컬즈, 인코포레이티드 | Aerosolized fluoroquinolones and uses thereof |
JP2009500054A (en) | 2005-07-01 | 2009-01-08 | シンベンション アーゲー | Medical device containing reticulated composite material |
US7547692B2 (en) | 2005-12-14 | 2009-06-16 | Activbiotics Pharma, Llc | Rifamycin analogs and uses thereof |
WO2007085057A1 (en) | 2006-01-25 | 2007-08-02 | The Council Of The Queensland Institute Of Medical Research | A medical protocol |
WO2007090123A2 (en) | 2006-01-30 | 2007-08-09 | University Of Chicago | Mgra is a redox regulator of antibiotic sensitivity and virulence |
RU2008136460A (en) | 2006-02-10 | 2010-03-20 | Пари Фарма ГмбХ (DE) | PHARMACEUTICAL AEROSOL |
EP2028936A4 (en) | 2006-02-13 | 2014-02-26 | Univ Boston | Compositions and methods for antibiotic potentiation and drug discovers |
US20070197548A1 (en) | 2006-02-17 | 2007-08-23 | Murthy Yerramilli V S | Fluoroquinolone compositions |
EP2436381A1 (en) | 2006-06-27 | 2012-04-04 | Sandoz AG | Crystallization of hydrohalides of pharmaceutical compounds |
WO2008025560A1 (en) | 2006-09-01 | 2008-03-06 | Pari Pharma Gmbh | Methods for taste masking of nebulised compositions for nasal and pulmonary inhalation therapy |
US20080276935A1 (en) | 2006-11-20 | 2008-11-13 | Lixiao Wang | Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs |
EP1938822A1 (en) * | 2006-12-21 | 2008-07-02 | Novartis AG | Combination therapy for the treatment of airways disease |
US8080394B2 (en) | 2007-04-27 | 2011-12-20 | Brigham And Women's Hospital | Method for determining predisposition to pulmonary infection |
EP2030644A1 (en) * | 2007-08-31 | 2009-03-04 | PARI Pharma GmbH | Aerosols for sinunasal drug delivery |
GB0719248D0 (en) | 2007-10-03 | 2007-11-14 | Generics Uk Ltd | Compounds and methods for pharmaceutical use |
US20090197212A1 (en) | 2008-02-04 | 2009-08-06 | Maxitrol Company | Premix Burner Control System and Method |
US8834930B2 (en) | 2008-05-15 | 2014-09-16 | Novartis Ag | Pulmonary delivery of a fluoroquinolone |
SG10201811494SA (en) | 2009-04-24 | 2019-01-30 | Horizon Orphan Llc | Methods of treating a pulmonary bacterial infection using fluoroquinolones |
KR20120102587A (en) | 2009-08-19 | 2012-09-18 | 엠펙스 파마슈티컬즈, 인코포레이티드 | Riboflavin based aerosol and use as placebo in trials |
CN102711760A (en) | 2009-08-19 | 2012-10-03 | Mpex医药有限公司 | Use of aerosolized antibiotics for treating chronic obstructive pulmonary disease |
MX353288B (en) | 2009-09-04 | 2018-01-08 | Raptor Pharmaceuticals Inc | Use of aerosolized levofloxacin for treating cystic fibrosis. |
US20150299122A1 (en) | 2012-08-31 | 2015-10-22 | Alectos Therapeutics Inc. | Glycosidase inhibitors and uses thereof |
JP6981961B2 (en) | 2015-07-30 | 2021-12-17 | ホライズン オルファン エルエルシー | Fucosidase inhibitor |
JP6966835B2 (en) | 2016-02-05 | 2021-11-17 | ホライズン オーファン リミテッド ライアビリティ カンパニー | Fluoroquinolone preparation for cystic fibrosis |
-
2009
- 2009-10-06 PL PL09740571T patent/PL2346509T3/en unknown
- 2009-10-06 US US12/574,666 patent/US8629139B2/en active Active
- 2009-10-06 EP EP09740571.6A patent/EP2346509B1/en active Active
- 2009-10-06 HU HUE09740571A patent/HUE050147T2/en unknown
- 2009-10-06 ES ES09740571T patent/ES2809177T3/en active Active
- 2009-10-06 CA CA2739893A patent/CA2739893C/en active Active
- 2009-10-06 DK DK09740571.6T patent/DK2346509T3/en active
- 2009-10-06 JP JP2011531125A patent/JP2012505222A/en active Pending
- 2009-10-06 PT PT97405716T patent/PT2346509T/en unknown
- 2009-10-06 CN CN200980142471.3A patent/CN102325532B/en not_active Expired - Fee Related
- 2009-10-06 WO PCT/US2009/059740 patent/WO2010042549A1/en active Application Filing
- 2009-10-06 SI SI200932074T patent/SI2346509T1/en unknown
-
2011
- 2011-04-06 IL IL212189A patent/IL212189A0/en unknown
-
2013
- 2013-12-19 US US14/134,348 patent/US20140105985A1/en not_active Abandoned
-
2014
- 2014-05-02 JP JP2014095077A patent/JP2014159461A/en active Pending
- 2014-10-09 JP JP2014208156A patent/JP6099609B2/en active Active
-
2016
- 2016-11-02 JP JP2016215046A patent/JP2017025106A/en active Pending
-
2017
- 2017-10-11 US US15/729,930 patent/US11020481B2/en active Active
-
2020
- 2020-07-23 HR HRP20201150TT patent/HRP20201150T8/en unknown
-
2021
- 2021-04-26 US US17/240,273 patent/US20220080047A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7838532B2 (en) * | 2005-05-18 | 2010-11-23 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8357696B2 (en) * | 2005-05-18 | 2013-01-22 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8524734B2 (en) * | 2005-05-18 | 2013-09-03 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US20090247458A1 (en) * | 2007-10-25 | 2009-10-01 | Revalesio Corporation | Compositions and methods for treating cystic fibrosis |
US8629139B2 (en) * | 2008-10-07 | 2014-01-14 | Mpex Pharmaceuticals, Inc. | Topical use of Levofloxacin for reducing lung inflammation |
US8815838B2 (en) * | 2008-10-07 | 2014-08-26 | David C. Griffith | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
Non-Patent Citations (2)
Title |
---|
Dal Negro et al., "Tobramycin Nebulizer Solution in Severe COPD Patients Colonized with Pseudomonas Aeruginosa: Effects on Bronchial Inflammation" Advances in Therapeutics (2008) vol. 20 pp. 1019-1030 * |
Geddes, D. M., "5. Bronchiectasis and Cystic Fibrosis" Airways Obstruction (published 1981 by MTP Press Ltd) pp. 40-50 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140066441A1 (en) * | 2005-05-18 | 2014-03-06 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US10987357B2 (en) | 2005-05-18 | 2021-04-27 | Horizon Orphan, LLC | Aerosolized fluoroquinolones and uses thereof |
US10149854B2 (en) | 2008-10-07 | 2018-12-11 | Horizon Orphan Llc | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US10722519B2 (en) | 2008-10-07 | 2020-07-28 | Horizon Orphan Llc | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US11020481B2 (en) | 2008-10-07 | 2021-06-01 | Horizon Orphan Llc | Topical use of levofloxacin for reducing lung inflammation |
US10231975B2 (en) | 2009-09-04 | 2019-03-19 | Horizon Orphan Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
US10792289B2 (en) | 2009-09-04 | 2020-10-06 | Horizon Orphan Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
Also Published As
Publication number | Publication date |
---|---|
PT2346509T (en) | 2020-08-05 |
CN102325532B (en) | 2015-06-17 |
ES2809177T3 (en) | 2021-03-03 |
US20100087386A1 (en) | 2010-04-08 |
JP6099609B2 (en) | 2017-03-22 |
US20180085462A1 (en) | 2018-03-29 |
JP2017025106A (en) | 2017-02-02 |
WO2010042549A1 (en) | 2010-04-15 |
IL212189A0 (en) | 2011-06-30 |
US20220080047A1 (en) | 2022-03-17 |
JP2014159461A (en) | 2014-09-04 |
EP2346509A1 (en) | 2011-07-27 |
CA2739893A1 (en) | 2010-04-15 |
JP2015044825A (en) | 2015-03-12 |
HUE050147T2 (en) | 2020-11-30 |
CA2739893C (en) | 2016-10-04 |
SI2346509T1 (en) | 2020-08-31 |
CN102325532A (en) | 2012-01-18 |
US8629139B2 (en) | 2014-01-14 |
PL2346509T3 (en) | 2021-03-08 |
DK2346509T3 (en) | 2020-08-03 |
EP2346509B1 (en) | 2020-05-13 |
HRP20201150T8 (en) | 2021-06-25 |
HRP20201150T1 (en) | 2021-01-22 |
JP2012505222A (en) | 2012-03-01 |
US11020481B2 (en) | 2021-06-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220080047A1 (en) | Topical use of levofloxacin for reducing lung inflammation | |
JP7169693B2 (en) | Treatment of respiratory diseases | |
AU2002351181B2 (en) | Methods and compositions for treating lesions of the respiratory epithelium | |
ES2739979T3 (en) | Use of levofloxacin spray for the treatment of cystic fibrosis | |
WO2002085308A3 (en) | Antisense and anti-inflammatory based compositions to treat respiratory disorders | |
US20090227511A1 (en) | Methods and compositions for treating lesions of the respiratory epithelium | |
CA2888428C (en) | Ciclesonide for the treatment of airway disease in horses | |
JP2021533156A (en) | Compositions Containing Mucolytics for the Treatment of Excessive Mucus and Devices for Dosing thereof | |
Rozanski et al. | Advances in respiratory therapy | |
TW201016215A (en) | Compositions and uses of antiviral active pharmaceutical agents | |
US20220105128A1 (en) | Methods of treating viral infections affecting the respiratory tract using topically administered lithium agents | |
AU2015275224C1 (en) | Use of aerosolized levofloxacin for treating cystic fibrosis | |
J Ragavan | Advances in Mucomodulator Therapy for Treatment of Excess Airway Mucus in Patients with Asthma, Chronic Obstructive Pulmonary Disease and Cystic Fibrosis | |
Peng et al. | Blocking intrapulmonary activation of complement cascade on the development of airway hyperresponsiveness: Utility in sight? | |
JPWO2020201038A5 (en) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: MPEX PHARMACEUTICALS, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DUDLEY, MICHAEL N;TSIVKOVSKI, RUSLAN Y;GRIFFITH, DAVID C;AND OTHERS;SIGNING DATES FROM 20091118 TO 20091201;REEL/FRAME:032752/0265 |
|
AS | Assignment |
Owner name: TRIPEX PHARMACEUTICALS, LLC, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MPEX PHARMACEUTICAL, INC.;REEL/FRAME:036906/0924 Effective date: 20150819 |
|
AS | Assignment |
Owner name: RAPTOR PHARMACEUTICALS INC, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:TRIPEX PHARMACEUTICALS, LLC;REEL/FRAME:037102/0573 Effective date: 20151001 |
|
AS | Assignment |
Owner name: CITIBANK, N.A., AS COLLATERAL AGENT, NEW YORK Free format text: SECURITY AGREEMENT;ASSIGNOR:RAPTOR PHARMACEUTICALS INC.;REEL/FRAME:040479/0578 Effective date: 20161025 |
|
AS | Assignment |
Owner name: HORIZON ORPHAN LLC., CALIFORNIA Free format text: CHANGE OF NAME;ASSIGNOR:RAPTOR PHARMACEUTICALS INC.;REEL/FRAME:040827/0163 Effective date: 20161025 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |
|
AS | Assignment |
Owner name: HORIZON THERAPEUTICS U.S. HOLDING LLC (FKA RAPTOR PHARMACEUTICALS INC.), ILLINOIS Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:CITIBANK, N.A.;REEL/FRAME:065178/0955 Effective date: 20231006 |