US20110257138A1 - Monoterpenes for treating respiratory tract diseases, in particular bronchopulmonary diseases - Google Patents

Monoterpenes for treating respiratory tract diseases, in particular bronchopulmonary diseases Download PDF

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US20110257138A1
US20110257138A1 US13/062,388 US200913062388A US2011257138A1 US 20110257138 A1 US20110257138 A1 US 20110257138A1 US 200913062388 A US200913062388 A US 200913062388A US 2011257138 A1 US2011257138 A1 US 2011257138A1
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respiratory
cineol
monoterpene
therapeutic
inhalative
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Harold Greve
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Maria Clementine Martin Klosterfrau Vertriebs GmbH
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Maria Clementine Martin Klosterfrau Vertriebs GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the medicinal field of respiratory disorders, in particular bronchopulmonary disorders, and to their treatment.
  • the present invention relates in particular to the joint use of, firstly, systemically, in articular orally, administrable monoterpenes together with, secondly, topically, in particular inhalatively, administrable respiratory therapeutics for the prophylactic and/or therapeutic treatment, in particular combination therapy or comedication, of respiratory disorders or bronchopulmonary disorders.
  • the present invention furthermore relates to a combination therapeutic, in particular in the form of a kit, or a combination therapy for prophylactic and/or therapeutic treatment of bronchopulmonary disorders or respiratory disorders using a comedication of, firstly, systemically administrable, in particular oral, monoterpenes and, secondly, topically administrable, in particular inhalative, respiratory therapeutics.
  • respiratory disorders is to be understood as meaning a general term which refers to all, in particular inflammatory, disorders of both the upper and the lower respiratory tracts and which encompasses both acute and chronic disease states.
  • respiratory disorders of the upper respiratory tract are, for example, inflammations of the paranasal sinuses (e.g. rhinosinusitis), and examples of respiratory disorders of the lower respiratory tract are, for example, bronchial asthma, bronchitis and COPD.
  • bronchopulmonary disorders is a generic term in particular for all, inflammatory and non-inflammatory disorders of the lower respiratory tract (i.e. the bronchial and pulmonary respiratory tracts) including in particular bronchial asthma, bronchitis and also chronic obstructive pulmonary diseases (“COPD”), and, in the context of the present invention, is used synonymously with the term “respiratory disorders of the lower respiratory tract”.
  • COPD chronic obstructive pulmonary diseases
  • Bronchial asthma is a chronic inflammatory disorder of the respiratory tract with chronic bronchial hypersensitivity or hyper-reactivity, inflammation or the bronchi and also lack of bronchial clearance, where, as a result of the bronchial obstruction, there may be episodes of respiratory distress, a general distinction being made between non-allergic (intrinsic) and allergic (extrinsic) asthma; in addition, mixed types of allergic and non-allergic asthma and mixed types of asthma and COPD are also known.
  • GINA 2006 Global Initiative for Asthma
  • stage 1 being intermittent asthma
  • stage 2 being mild asthma
  • stage 3 being moderate asthma
  • stage 4 being severe asthma.
  • the priority is asthma control, and a distinction is thus made between controlled, partially controlled and uncontrolled asthma.
  • bronchitis generally refers to an inflammation of the bronchi, in particular the bronchial mucosa, a distinction being made between acute bronchitis on the one hand and chronic bronchitis on the other.
  • WHO World Health. Organization
  • chronic bronchitis is defined as cough and election on most days during at least three months in two successive years, and it is one of the most frequent chronic disorders world-wide (about 15 to 25%) with consequently great relevance from a health-economical perspective.
  • chronic obstructive bronchitis there is a persistent bronchial obstruction which in most cases develops from a chronic bronchitis.
  • bronchopulmonary disorders in particular of respiratory disorders of the type mentioned above, in cases of mild to moderate severity use is frequently made of topical or local, in particular inhalative or inhalable, respiratory therapeutics.
  • inhalative bronchodilators and bronchospasmolytics such as inhalative beta-2-sympathomimetics, inhalative anticholinergics, inhalative corticosteroids or the like.
  • the inhalative respiratory therapeutics mentioned above are frequently not capable of deploying the desired therapeutic action, so that in most cases relatively high doses have to be administered to achieve the desired therapeutic results, or else in more serious cases systemic therapeutics, in particular based on corticosteroids, have to be coadministered when required or even on a permanent basis.
  • systemic therapeutics in particular based on corticosteroids, have to be coadministered when required or even on a permanent basis.
  • unwanted side-effects are observed, too.
  • an insufficient sensitivity of the abovementioned inhalative respiratory therapeutics with respect, to the respiratory disorders to be treated is observed.
  • inhalative respiratory therapeutics does not always result in sufficient deposition in the peripheral respiratory tract since she smallest branches of the respiratory tract, such as, for example, terminal and respiratory bronchioli, can, in general, not be reached by inhalative therapy, in particular when pulmonary function is reduced, such as, for example, in severe COPD.
  • corticosteroids are used from a certain degree of severity.
  • corticosteroids are additionally employed.
  • inhalable or inhalative corticosteroids in particular inhalable or inhalative glucocorticoids, synonymously also referred to as “inhalative corticosteroids” or simply by the acronym “ICS”, belong to the most important therapeutics for the topical or local, in particular inhalative, treatment of inflammatory respiratory disorders, in particular for bronchial asthma and COPD.
  • ICS inhalative corticosteroids
  • the principle of action in the case of regular inhalation consists in a primarily topical or local deposition in the respiratory tract, combined with a simultaneous effective anti-inflammatory action by relatively small amounts of steroids.
  • inhalable corticosteroids reduce respiratory inflammation by inhibition of cytokines and arachidonic acid metabolites (AA metabolites) which are released from activated respiratory epithelial cells and distal macrophages lining she respiratory tract, i.e. alveolar macrophages.
  • AA metabolites arachidonic acid metabolites
  • various white blood cells enter the respiratory tract causing either eosinophile infiltration in the case of bronchial asthma or primary granulocyte infiltration in the case of COPD. This cell infiltration is known to be an important determinant in the development of respiratory inflammation in bronchial asthma and bronchitis.
  • ICS are not employed during early stages of respiratory disorders, but in particular only for mild persistent asthma (GINA II) and for moderate to severe COPD (GOLD III and IV), where in most cases continuous therapy is required [cf., for example: (1) Global Initiative for Chronic Obstructive Lung Disease, GOLD 2004, National Institute of Health NIH and National Heart, Lung and Blood. Institute NHLBI, Bethesda, USA, www.goldcopd.com; (2) National institutes of Health (Ed.), Global Strategy for Asthma Management and Prevention, NHLBI/WHO Workshop Report, Bethesda, USA, U.S.
  • ICS are, depending on the severity of the respiratory disorder, recommended at even higher dosages and in combination with other therapeutics including oral glucocorticoids for a period of two to three weeks.
  • the actual cause of this is the insufficient deposition of ICS in the peripheral respiratory tract and, at least in COPD, a non-steroidal anti-inflammatory therapy which is additionally required.
  • the smallest branches of the respiratory tract such as terminal and respiratory bronchioli, have only been able to be reached by a systemic therapy.
  • oils or oil mixtures are also used inhalatively for a relatively short period of time for the symptomatic treatment of, for example, bronchitic conditions, and to facilitate expectoration in cases of hypersecretion, in particular for colds.
  • this is a therapy which does not address the causes and which is used in particular only for mild, especially acute, respiratory disorders and can be used for chronic and in particular severe respiratory disorders only in a supportive manner, if at all.
  • the prior-art treatment methods of bronchopulmonary disorders or respiratory disorders often do not give the desired therapeutic result, or only with unwanted side-effects.
  • the topical or local, in particular inhalative or inhalable, respiratory therapeutics used according to the prior art do not always have the desired therapeutic effect.
  • an improved and/or more efficient therapy for the treatment of respiratory disorders in particular bronchopulmonary disorders, is to be provided.
  • an improved efficacy or a broader application spectrum is to be enabled or achieved locally or topically, in particular inhalatively administrable respiratory therapeutics of the type mentioned above (such as for example, inhalative bronchodilators and/or bronchospasmolytics including sympathomimetics, phosphodiesterase inhibitors, parasympatholytics and/or vagolytics, anticholinergics, corticosteroids etc.).
  • inhalatively administrable respiratory therapeutics of the type mentioned above (such as for example, inhalative bronchodilators and/or bronchospasmolytics including sympathomimetics, phosphodiesterase inhibitors, parasympatholytics and/or vagolytics, anticholinergics, corticosteroids etc.).
  • a systemic, in particular orally administered monoterpene is capable of any interaction with a respiratory therapeutic which, in distinction thereto, is administered only locally or topically, in particular inhalatively, and is additionally then also capable of enhancing the activity of the latter in an unexpected manner, preferably in a synergistic manner.
  • a respiratory therapeutic which, in distinction thereto, is administered only locally or topically, in particular inhalatively, and is additionally then also capable of enhancing the activity of the latter in an unexpected manner, preferably in a synergistic manner.
  • the present invention provides—according to a first aspect of the present invention—the use of, firstly, at least one systemically administrable, in particular oral, monoterpene and, secondly, at least one topically administrable, in particular inhalative, respiratory therapeutic for the prophylactic and/or therapeutic treatment, in particular combination therapy and/or comedication, of respiratory disorders, in particular bronchopulmonary disorders.
  • the present invention provides the use of, firstly, at least one monoterpene and, secondly, at least one respiratory therapeutic for the prophylactic and/or therapeutic treatment, in particular combination therapy or comedication, of respiratory disorders, in particular bronchopulmonary disorders, where the monoterpene is administered systemically, in particular orally, and the respiratory therapeutic is administered topically, in particular inhalatively.
  • the efficiency or activity of the topical or inhalative respiratory therapeutic can be enhanced significantly, in particular in a synergistic manner.
  • the systemically, in particular orally, administered monoterpene is capable of enhancing the activity or efficiency of the topical or inhalative respiratory therapeutic in the manner found, since two entirely different, separate types of administration—namely systemic on the one hand and locally or topically on the other hand—are used for the two active compounds to be combined (i.e. monoterpene on the one hand and respiratory therapeutic on the other hand).
  • the sensitivity to the topical or inhalative respiratory therapeutic can be enhanced significantly; as a consequence, it may be possible to not only reduce the dose of the topical or inhalative respiratory therapeutic, but under certain circumstances also to make the topical or inhalative respiratory therapeutic in question available in the first place for certain respiratory disorders or for certain stages of the respiratory disorders mentioned above, where hitherto it has been impossible to use the topical or inhalative respiratory therapeutics in question owing to the lack of sensitivity.
  • the activity enhancement of the topical or inhalative respiratory therapeutic as such can probably—again without wishing to adhere to a certain theory—be attributed to the steroid-like activity potential, surprisingly found by the applicant, of the systemically employed monoterpenes, in particular with respect to the inhibition of inflammation mediators which are formed by various infectious, allergic and/or inflammatory stimuli and—owing to mucus hypersecretion—effect an increase or exacerbation of the respective respiratory inflammation.
  • isolated monoterpenes such as, for example, 1,8-cineol, menthol etc.
  • the applicant has, surprisingly, for the first time succeeded in providing an efficient combination therapy for the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders, which proposes or realizes, in the context of a comedication, the joint use of, firstly, at least one monoterpene which is to be administered systemically, in particular orally, and, secondly, —in combination therewith—at least one respiratory therapeutic be administered topically, in particular inhalatively.
  • the person skilled in the art is aware that, in the context of the combination therapy according to the invention or in the context of the use according to the invention, firstly, the monoterpene to be administered systemically, in particular orally, and, secondly, the respiratory therapeutic to be administered topically, in particular inhalatively, can be administered at the same time or else at different times.
  • a single daily dose may be suitable, or else it may be preferred to divide the respective total daily doses into two or more individual administrations over the course of the day; the decision is at the discretion of the person skilled in the art.
  • this may be selected in particular from mono- and bicyclic monoterpenes, preferably from the group consisting of monocyclic monoterpene alcohols, preferably menthol (for example L-menthol), and bicyclic epoxy-monoterpenes, preferably limonene oxides, preferably 1,8-cineol, and also mixtures thereof, particularly preferably from the group consisting of menthol and 1,8-cineol.
  • monocyclic monoterpene alcohols preferably menthol (for example L-menthol)
  • menthol for example L-menthol
  • bicyclic epoxy-monoterpenes preferably limonene oxides
  • 1,8-cineol preferably 1,8-cineol
  • Very particular preference according so the invention is given to using the monoterpene 1,8-cineol.
  • the monoterpene as an isolated or single active substance (i.e. not to use a mixture of different monoterpenes or ethereal oils or oil mixtures), of course together with a suitable pharmaceutical carrier or excipient and optionally together with other customary pharmaceutical auxiliaries and/or additives.
  • a suitable pharmaceutical carrier or excipient i.e. not to use a mixture of different monoterpenes or ethereal oils or oil mixtures
  • other customary pharmaceutical auxiliaries and/or additives i.e. not to use a mixture of different monoterpenes or ethereal oils or oil mixtures.
  • the terpenes are a highly heterogenous and very large group of chemical compounds which can be derived biosynthetically from isoprene or isopentenyl units, where the biosynthesis takes place via activated forms of these molecules, namely dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP); the units consist of five carbon atoms (C 5 units). More than 8000 terpenes and more than 30 000 of the closely related terpenoids are known. In the systematic classification of Organic Chemistry, the terpenes belong to the lipids (secondary natural products). The common building block of all terpenes is isoprene. The terpenes belong to the secondary plant products.
  • DMAPP dimethylallyl pyrophosphate
  • IPP isopentenyl pyrophosphate
  • monoterpenes More than 900 monoterpenes are known. All are synthesized by monoterpene synthases from geranyl pyrophosphate (2,6-dimethyloctane). In she context of the present invention, preference is given to using mono- and bicyclic monoterpenes. Most monocyclic monoterpenes which can be derived from p-menthane have a cyclohexane skeleton, whereas the bicycles carane, thujane, pinane, bornane and fenchane and, more generally, also isobornylane and isocamphane are the most important parent compounds of the bicyclic monoterpenes.
  • the monoterpene is usually employed in an oral administration form, preferably in the form of capsules.
  • an oral enteric preparation in particular capsule, which does, however, dissolve in the smell intestine.
  • oral enteric preparations in particular capsules, which dissolve in the small intestine, and which contain a single monoterpene, preferably 1,8-cineol.
  • the monoterpene is employed in effective, in particular pharmaceutically effective, amounts.
  • the dose of monoterpene may vary within wide ranges.
  • the systemically, in particular orally, administered monoterpene is administered in daily doses of from 100 to 2000 mg/die, in particular from 200 to 1200 mg/die, preferably from 300 to 1000 mg/die.
  • the monoterpene which is to be administered systemically or orally is generally prepared for administration in a daily dose of from 100 to 2000 mg/die, in particular from 200 to 1200 mg/die, preferably from 300 to 1000 mg/die. It is to be under stood that, if required, the person skilled in the art may deviate from the amounts mentioned above for individual cases or relating to certain applications without leaving the scope of the present invention.
  • the monoterpene to be administered systemically or orally is 1,8-cineol in the form of enteric capsules which dissolve in the small intestine, preferably in daily doses in the range of from 100 to 2000 mg/die, in particular from 200 to 1200 mg/die, particularly preferably from 300 to 1000 mg/die.
  • the daily doses mentioned above can advantageously be divided into one, two, or more individual administrations.
  • a respiratory therapeutic to be applied topically is administered as comedication.
  • the respiratory therapeutic to be administered topically is employed in effective, in particular pharmaceutically effective, amounts, too, where the person skilled in the art selects the respective doses depending on the respiratory disorder which is the subject of the therapy and its severity and depending on the topical respiratory therapeutic used.
  • the respiratory therapeutic to be administered topically and which is used according to the invention is an inhalative or inhalable respiratory therapeutic.
  • respiratory therapeutic to be administered topically in particular inhalatively
  • inhalatively is to be understood very broadly and encompasses in particular all medicaments and medicament combinations known to the person skilled in the art for treating bronchopulmonary disorders or respiratory disorders and which are suitable for topical, in particular inhalative, administration.
  • the respiratory therapeutic to be administered topically is selected from bronchodilators and bronchospasmelytics.
  • bronchodilators refers to substances which widen or dilate bronchi and bronchioli and, in this manner, reduce respiratory resistance
  • bronchospasmolytics refers to substances which reduce the bronchial muscle tone and in some cases inhibit the release of mediator substances from mast cells and increase mucociliary clearance.
  • the respiratory therapeutic to be administered topically is selected from the group consisting of (i) corticosteroids, in particular glucocorticoids; (ii) sympathomimetics, in particular betasympathomimetics, preferably beta-2-sympathomimetics; (iii) phosphodiesterase inhibitors; (iv) parasympatholytics and/or vagolytics; (v) anticholinergics; and also mixtures and combinations of the compounds mentioned above.
  • corticosteroids in particular glucocorticoids
  • sympathomimetics in particular betasympathomimetics, preferably beta-2-sympathomimetics
  • phosphodiesterase inhibitors phosphodiesterase inhibitors
  • parasympatholytics and/or vagolytics preferably anticholinergics
  • anticholinergics and also mixtures and combinations of the compounds mentioned above.
  • the topical, in particular inhalative, respiratory therapeutic is selected from the group consisting of corticosteroids, in particular glucocorticoids, beta-2-sympathomimetics and anticholinergics and also their mixtures and combinations.
  • the topically administrable, in particular inhalative, respiratory therapeutic may be a topical or inhalative corticosteroid, in particular glucocorticoid.
  • the topical or inhalative corticosteroid, in particular glucocorticoid may in particular be a compound from the group consisting of beclometasone, mometasone, budesonide, flunisolide, fluticasone, triamcinolone and their physiologically acceptable derivatives, in particular salts and esters, and also mixtures and combinations.
  • the corticosteroids are a group of about 50 steroid hormones formed in the adrenal cortex and also chemically comparable synthetic compounds, all corticosteroids being formed from the starting material cholesterol and having progesterone (delta-pregn-4-ene-3,20-dione) as a common skeleton. According to their biological action and the site at which they are formed, the corticosteroids can be divided into three groups, namely the mineralocorticoids, the glucocorticoids and the androgens. The glucocorticoids preferably used in accordance with the invention thus belong to the corticosteroids.
  • the doses at which the topical or inhalative corticosteroids, in particular glucocorticoids, are employed may vary within wide ranges.
  • the topical or inhalative corticosteroid, in particular glucocorticoid is usually administered in daily doses of from 50 to 1000 ⁇ g/die, in particular from 75 to 800 ⁇ g/die, particularly preferably from 100 to 600 ⁇ g/die, or is prepared in particular for administration in a daily dose of from 50 to 1000 ⁇ g/die, in particular from 75 to 800 ⁇ g/die, particularly preferably from 100 to 600 ⁇ g/die. It is to be understood that, if required, the person skilled in the art may deviate from the values mentioned above for individual cases or relating to certain applications without leaving the scope of the present invention.
  • the topical or inhalative respiratory therapeutic may be a sympathomimetic, in particular betasympathomimetic, preferably beta-2-sympathomimetic.
  • a sympathomimetic in particular betasympathomimetic, preferably beta-2-sympathomimetic.
  • betasympathomimetic preferably beta-2-sympathomimetic.
  • inhalative beta-2-sympathomimetics particular preference is given to the use of inhalative beta-2-sympathomimetics.
  • sympathomimetics denotes substances which mimic the action of the sympathetic nervous system.
  • betasympathomimetics (synonymously also referred to as “betamimetics”) act mainly on betareceptors.
  • beta-2-sympathomimetics which are preferred in accordance with the invention, relax smooth muscles (beta-2-receptors) and have brochospasmolytic action.
  • SABA short-acting betamimetics
  • LA long-acting betamimetics
  • SABA short-acting betamimetics
  • fenoterol hexoprenal in, levalbuterol, metaproterenol, orciprenalin
  • pirbuterol reproterol
  • salbutamol and/or terbutalin examples of long-acting betamimetics
  • long-acting betamimetics are in particular salmeterol and/or formoterol.
  • the topical or inhalative respiratory therapeutic may be an anticholinergic.
  • Anticholinergics are substances which suppress the action of acetylcholine and also have bronchospasmolycic activity.
  • Topical or inhalative anticholinergics which are preferably employed in accordance with the invention are ipratropium, tiotropium and/or their physiologically acceptable derivatives, preferably salts, particularly preferably ipratropium bromide and/or tiotropium bromide.
  • topical or inhalative respiratory therapeutics mentioned above may also be combined with one another.
  • systemic, in particular oral, active compound may be selected in particular from the group consisting of systemic phosphodiesterase inhibitors, in particular theophylline; systemic leukotriene receptor antagonists, in particular montelukast, zaforlukast and pranlukast; systemic corticosteroids; and also mixtures and combinations thereof.
  • the bronchopulmonary disorder may be an inflammatory or non-inflammatory, in particular inflammatory, disorder of the upper or lower respiratory tract.
  • the bronchopulmonary disorder may be an inflammatory respiratory disorder, in particular a respiratory disorder which is infection-exacerbated and/or requires steroids for treatment.
  • the bronchopulmonary disorder may be bronchial asthma or bronchitis.
  • the bronchopulmonary disorder may be chronic obstructive pulmonary disorder (COPD), in particular a chronic obstructive bronchitis or a pulmonary emphysema.
  • COPD chronic obstructive pulmonary disorder
  • the bronchopulmonary disorder may be a tobacco smoke-induced, in particular nicotine-induced, acute or chronic respiratory inflammation.
  • the present invention furthermore relates to the use of at least one systemically administrable, in particular oral, monoterpene, preferably 1,8-cineol, in particular as described above, for the in particular synergistic enhancement of the activity of at least one topically administrable, in particular inhalative, respiratory therapeutic in the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders.
  • the present invention relates to the use of at least one systemically administrable, in particular oral, monoterpene, preferably 1,8-cineol, in particular as described above, for the in particular synergistic enhancement of the anti-inflammatory and/or antioxidative activity of topical, in particular inhalative, corticosteroids, in particular glucocorticoids.
  • the present invention relates to the use of at least one systemically administrable, in particular oral, monoterpene, preferably 1,8-cineol, in particular as described above, for reducing the dose of topically administrable, in particular inhalative, respiratory therapeutics, preferably inhalative corticosteroids, in the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders.
  • the present invention relates to the use of at least one systemically administrable, in particular oral, monoterpene, preferably 1,8-cineol, in particular as described above, for inducing and/or enhancing the steroid-permissive effect of topically administrable, in particular inhalative, respiratory therapeutics, preferably inhalative corticosteroids, in the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders.
  • at least one systemically administrable in particular oral, monoterpene, preferably 1,8-cineol, in particular as described above, for inducing and/or enhancing the steroid-permissive effect of topically administrable, in particular inhalative, respiratory therapeutics, preferably inhalative corticosteroids, in the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders.
  • the present invention also relates to the use of at least one systemically administrable, in particular oral, monoterpene, preferably 1,8-cineol, in particular as described above, for avoiding or reducing habituation to betasympathomimetics in the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders, in particular with continuous therapy of all degrees of severity of COPD and bronchial asthma.
  • at least one systemically administrable in particular oral, monoterpene, preferably 1,8-cineol, in particular as described above, for avoiding or reducing habituation to betasympathomimetics in the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders, in particular with continuous therapy of all degrees of severity of COPD and bronchial asthma.
  • the present invention relates to the use of at least one systemically administrable, in particular oral, monoterpene, preferably 1,8-cineol, in particular as described above, in combination with at least one topically administrable, in particular inhalative, respiratory therapeutic, in particular in combination with an inhalative corticosteroid, for reducing the need for or for replacing systemic corticosteroids or other antiinflammatory and/or immunosuppressive systemic substances in the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders.
  • the present invention relates to the use of at least one systemically administrable, in particular oral, monoterpene, preferably 1,8-cineol, in particular as described above, in combination with at least one topically administrable, in particular inhalative, respiratory therapeutic, in particular in combination with an inhalative corticosteroid and optionally further with an inhalative beta-2-sympathomimetic, to optimize the basic therapy of bronchial asthma and COPD.
  • the use according to the invention likewise serves to modulate and inhibit COPD-dependent and/or COPD-independent ageing processes, in particular with the aim of reducing morbidity, increasing the quality of life and/or life expectancy (“anti-ageing”).
  • the monoterpene in particular 1,8-cineol, can be used as an inducer of NO-production for the treatment of primary and secondary pulmonary-arterial hypertension (PAH) in COPD and bronchial asthma.
  • PAH pulmonary-arterial hypertension
  • the monoterpene in particular 1,8-cineol, can be used for improving tissue perfusion and/or microperfusion and also bronchodilation in NO-deficiency situations.
  • the monoterpene in particular 1,8-cineol
  • the monoterpene can be used for inducing NO-production in recurrent infections of the upper and lower respiratory tracts or in infection-independent exacerbations, in particular owing to cigarette smoking and/or the action of ozone, or for normalizing noxious substance-dependent or -independent NO-deficiency situations.
  • the monoterpene in particular 1,8-cineol
  • the monoterpene in particular 1,8-cineol
  • the monoterpene can be used for the combined anti-inflammatory and/or antioxidative, therapy of the persistent and/or progressive inflammation of the respiratory tract after cessation of smoking, if appropriate with comedication with other respiratory therapeutics, in particular with the aim of delaying the development of emphysemas, respiratory insufficiency and/or the development, of peripheral airway obstructions.
  • the monoterpene in particular 1,8-cineol, can be used for modulating the entire multiorgan ageing process by virtue of anti-inflammatory and/or antioxidative effects in an early long-term therapy.
  • the present invention furthermore provides, according to vet a further aspect of the present invention, the use of at least one systemically administrable, in particular oral, monoterpene and at least one topically administrable, in particular inhalative, respiratory therapeutic as combination therapeutic and/or for the purpose of comedication for the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders.
  • the present invention yet further provides the use of at least one systemically administrable, in particular oral, monoterpene and at least one topically administrable, in particular inhalative, respiratory therapeutic for preparing a combination therapeutic, in particular in the form of a kit, for the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders.
  • the present invention also provides a combination therapeutic, in particular in the form of a kit, preferably for the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders, where the combination therapeutic comprises, firstly, at least one systemically administrable, in particular oral, monoterpene and, secondly, at least one topically administrable, in particular inhalative, respiratory therapeutic, in particular as spatially separate components (“kit-of-parts”).
  • the present invention furthermore also provides a method for treating the human or animal body, in particular a method for the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders, where at least one monoterpene and at least one respiratory therapeutic are each used in effective, in particular pharmaceutically effective, amounts, where the monoterpene is administered systemically, in particular orally, and the respiratory therapeutic is administered topically, in particular inhalatively.
  • the present invention yet further provides the use of at least one systemically administrable or administered, in particular oral, monoterpene, preferably 1,8-cineol, for the prophylactic and/or curative treatment of respiratory disorders, in particular bronchopulmonary disorders, in smokers and/or former smokers (i.e. in active as well as passive smokers) and for the preparation of a medicament for the prophylactic and/or curative treatment of respiratory disorders, in particular bronchopulmonary disorders, in smokers or former smokers.
  • the monoterpene can optionally be employed together with at least one topically administrable, in particular inhalative, respiratory therapeutic, in particular as a combination therapy and/or in comedication.
  • the present invention likewise provides the use of at least one systemically administrable or administered, in particular oral, monoterpene, preferably 1,8-cineol, for the prophylactic and/or curative treatment of anti-oxidative and/or anti-inflammatory processes in the human body in particular of smokers or for preparing a medicament for the prophylactic and/or curative treatment of antioxidative and/or anti-inflammatory processes in the human body in particular of smokers.
  • the monoterpene can be employed together with at least one topically administrable, in particular inhalative, respiratory therapeutic, in particular as a combination therapy and/or in comedication.
  • the present invention also provides the use of at least one systemically administrable, in particular oral, monoterpene, preferably 1,8-cineol, for increasing the corticosteroid sensitivity of smokers, in particular in the prophylactic and/or therapeutic treatment of respiratory disorders, in particular bronchopulmonary disorders.
  • the monoterpene can optionally be employed together with at least one topically administrable, in particular inhalative, respiratory therapeutic, in particular as combination therapy and/or in comedication.
  • a systemic or oral monoterpene preferably 1,8-cineol
  • An additional therapy for smokers, in particular those having bronchopulmonary disorders, such as COPD, with a monoterpene, preferably 1,8-cineol, or else a therapy of smokers or former smokers not having respiratory disorders with 1,8-cineol surprisingly prevents the development of bronchopulmonary disorders, such as, for example, COPD, or, in the case of existing respiratory disorders, reduces exacerbations and a progressive course.
  • 1,8-cineol is also suitable for protection against harmful environmental effects.
  • Systemic administration of the monoterpene, preferably 1,8-cineol allows—as discussed below—a significant improvement of pulmonary function, in particular in the context of a combination therapy with inhalative or topical respiratory therapeutics, which can be attributed inter ails, to the anti-inflammatory and/or anti-oxidative action of the monoterpene, preferably 1,8-cineol.
  • the systemic monoterpene, preferably 1,8-cineol inhibits the prooxidative actions of topical corticosteroids and for its part mediates a non-steroid-like antioxidative action.
  • the desired steroid sensitivity is increased, in particular also in cases of reduced steroid sensitivity in COPD.
  • the positive effects relate mainly to inhalative steroids.
  • FIG. 1 illustrates the stimulation of the action of the inhalative corticosteroid beclometasone by the monoterpene 1,8-cineol (10 ⁇ 6 mol/l) in LPS-stimulated human monocytes in vitro.
  • FIG. 2 illustrates the effects of 1,8-cineol on the IL1beta inhibition by beclometasone in vitro.
  • FIG. 3 illustrates the concentration-dependent modulating effects of 1,8-cineol on O 2 ⁇ and NO production in stimulated human monocytes in vitro
  • FIG. 4 illustrates the stimulation of monocyte O 2 ⁇ production with high concentrations 10 ⁇ 2 mol/l) of beclometasone.
  • FIG. 5 illustrates the comparative actions of beclometasone and 1,8-cineol regarding the inhibition/stimulation of superoxide (O 2 ⁇ ).
  • FIG. 6 illustrates the effect on O 2 ⁇ — inhibition provided by beclometasone (alone), 1,8-cineol (alone) and their combination.
  • FIG. 7 provides data illustrating that the activity of 1,8-cineol is weakened by the properties of beclometasone.
  • the essential clinical meaning is that the antiinflammatory action of minimal concentrations, which decrease in the periphery of the lung, of common ICS (metered aerosols and powder preparations) becomes more intensive.
  • systemic monoterpene and topical respiratory therapeutic in particular topical glucocorticoid, (for example oral 1,8-cineol and ICS or beclometasone) is advantageous in particular in the therapy of a peripheral respiratory inflammation in bronchial asthma and COPD as a novel therapeutic concept and for modulating the steroid-refractory progression of the pulmonary disorder, to prevent the development of irreversible respiratory insufficiency.
  • systemic monoterpene and topical respiratory therapeutic in particular topical glucocorticoid (for example oral 1,8-cineol and ICS or beclometasone)
  • topical glucocorticoid for example oral 1,8-cineol and ICS or beclometasone
  • the steroid-refractory respiratory inflammation caused by cigarette smoke and also other harmful proinflammatory or oxidative environmental substances such as, in particular, ozone (O 3 )
  • COPD ozone
  • a further essential aspect of the present invention is in particular also the prophylactic and alleviating effect of monoterpenes, in particular 1,8-cineol, in combination with topical respiratory therapeutics, in particular topical glucocorticoids, or else of monoterpenes on their own, in particular 1,8-cineol, on inflammations in smokers for the prevention and amelioration of the damage to the respiratory tract caused by cigarette smoke.
  • This damage occurs in particular even many years after smoking cessation or after the action of other noxious substances and is characterized clinically by a progressive obstruction and the development of emphysema with respiratory insufficiency during ongoing antiobstructive therapy.
  • 1,8-cineol enhances anti-inflammatory and antiobstructive effects of topical respiratory therapeutics, in particular topical glucocorticoids, so that even hitherto unknown pharmaceutical combinations of, for example, ICS and 1,8-cineol or another monoterpene, LABA and 1,8-cineol, SABA and 1,8-cineol and also of ICS, SABA and 1,8-cineol or of ICS, LABA and 1,8-cineol are suitable as a therapeutical alternative to the therapy of asthma and COPS of all degrees of severity and for the additional treatment of the active systemic component in COPS by the systemic availability of monoterpenes, in particular in capsules which dissolve in the small intestine or as powders.
  • NO is known to be an anti-inflammatory mediator, vasodilator, inhibitor of inflammatory mediators, histamine, granulocyte adhesion and platelet aggregation and also as an activator of ciliary function and mucosal clearance and protects comprehensively against respiratory infections and exacerbations of asthma and COPD in all disease stages.
  • 1,8-cineol is suitable as a continuous therapeutic which, in chronic bronchitis, COPD, emphysema and rhinosinusitis, by modulation, normalizes and adequately adapts to the respective requirements a suppressed NO production by favourable degradation of O 2 ⁇ radicals with induction of NO.
  • the conventional temporally limited therapy with in most cases ineffective substances targets only actual mucus hypersecretion and that therefore a long-term therapy to prevent the development and progression of respiratory inflammation in COPD and asthma by early use of effective substances with combined antioxidative and anti-inflammatory activity profile and a non-steroidal anti-inflammatory mechanism of action for enhancing the activity of topical respiratory therapeutics, in particular glucocorticoids, and also good compatibility without steroid side-effects in contrast to the general guidelines of national and international lung associations should be proposed as a matter of urgency.
  • NSAIM Non-Steroidal Airway Inflammation Modifier
  • monoterpenes here specifically: 1,8-cineol
  • glucocorticoids here specifically: beclometasone
  • Table 1 shows the synergistic activity of 1,8-cineol (10 ⁇ 6 mol/l) and beclometasone on the LPS-stimulated production of IL-1beta in human monocytes in vitro.
  • cineol and beclometasone synergistically inhibit IL-1beta production more than beclometasone on its own.
  • the IL-1beta production is also inhibited synergistically and to a significantly more pronounced degree by addition of beclometasone (p ⁇ 0.05).
  • 1,8-Cineol and beclometasone synergistically inhibit the IL-1beta production, more strongly than beclometasone on its own.
  • cineol (10 mol/l) the IL-1beta production is also inhibited synergistically and to a significantly more pronounced degree by addition of beclometasone (p ⁇ 0.05).
  • FIG. 1 shows the stimulation of the action of the inhalative corticosteroid beclometasone by the monoterpene 1,8-cineol (10 ⁇ 6 mol/l) in LPS-stimulated human monocytes in vitro; the addition even of small amounts of 1,8-cineol effects a significant increase of the activity of beclometasone, associated with an increased inhibition of IL-1beta.
  • FIG. 1 shows the stimulation of the action of the inhalative corticosteroid beclometasone by the monoterpene 1,8-cineol (10 ⁇ 6 mol/l) in LPS-stimulated human monocytes in vitro; the addition even of small amounts of 1,8-cineol effects a significant increase of the activity of beclometasone, associated with an increased inhibition of IL-1beta.
  • FIG. 1 shows the stimulation of the action of the inhalative corticosteroid beclometasone by the monoterpene 1,8-cineol (10 ⁇ 6 mol/
  • the LPS-stimulated production is inhibited to a significantly more pronounced degree (p ⁇ 0.031) by a combination of 1,8-cineol (10 ⁇ 6 mol/l) plus beclometasone (10 ⁇ 11 -10 ⁇ 9 mol/l) than by beclometasone on its own.
  • 1,8-Cineol intensifies in particular the action of subtherapeutic concentrations of beclometasone which are relevant for the peripheral respiratory tract.
  • FIG. 2 shows the effects of 1,8-cineol on the IL-1beta inhibition by beclometasone in vitro.
  • the activity of therapeutically relevant concentrations of beclometasone is inhibited significantly (p ⁇ 0.01) more strongly by 1,8-cineol compared to beclometasone plus 1,8-cineol. To achieve this activity, concentrations of the two substances which are at least 10 times higher have to be present.
  • a further essential novel aspect of the present data is the prophylactic and alleviating effect of 1,8-cineol in combination with topical glucocorticosteroids or else by 1,8-cineol on its own on inflammations in smokers for the prevention and amelioration of the damage to the respiratory tract caused by cigarette smoke.
  • This damage occurs in particular even many years after smoking cessation or after the action of other noxious substances and is characterized clinically by a progressive obstruction and the development of emphysema with respiratory insufficiency during ongoing antiobstructive therapy.
  • 1,8-cineol improves anti-inflammatory and antiobstructive effects of ICS plus LABA, so that hitherto unknown pharmaceutical combination products or kiss consisting, for example, of ICS+1,8-cineol or another monoterpene, LABA+1,8-cineol, SABA+1,8-cineol or else ICS+SABA+1,8-cineol or ICS+LABA+1,8-cineol, and also modern combinations with long-acting vagolytics will be suitable in the future as a therapeutic alternative for the therapy of asthma and COPD in all degrees of severity and for the additional treatment of the active systemic component in COPD owing to the systemic availability of monoterpenes in the form of capsules which dissolve in the small intestine or as powders.
  • Table 2 shows the effect of 1,8-cineol on the PMA-stimulated superoxide production (O 2 ⁇ production) (in RPMI 1640) of normal human monocytes in vitro.
  • the O 2 ⁇ production was not stimulated by PHA (500 mmol/l).
  • the non-parametric Mann & Whitney test was used (p ⁇ 0.05).
  • NO is known to be an anti-inflammatory mediator, vasodilator, inhibitor of inflammatory mediators, histamine, granulocyte adhesion and platelet aggregation and also as an activator of ciliary function and mucosal clearance and protects comprehensively against respiratory infections and exacerbations of asthma and COPD in all disease stages.
  • 1,8-cineol is suitable as a continuous therapeutic which, in chronic bronchitis, COPD, emphysema and rhinosinusitis, by modulation, normalizes and adequately adapts to the respective requirements a suppressed NO production by favourable degradation of O 2 ⁇ radicals with induction of NO.
  • monoterpenes in particular 1,8-cineol
  • a relatively high, systemically effective daily dose to regulate organ perfusion and to protect the upper and lower respiratory tracts including the lung against noxious substances acting as pathogens, in particular cigarette smoke and other emissions or fine dusts, respiratory infections and allergic and non-allergic respiratory inflammations in cases of hyperactivity, asthma and rhinitis.
  • pathogens in particular cigarette smoke and other emissions or fine dusts
  • respiratory infections and allergic and non-allergic respiratory inflammations in cases of hyperactivity, asthma and rhinitis.
  • These hitherto unknown properties associated with the action of monoterpenes, in particular 1,8-cineol may contribute in establishing in the future, for the first time, the additional therapy with 1,8-cineol in the literature and the therapy guidelines.
  • the persistent bronchial asthma had stabilized to such an extent that in 7 of the 10 patients the inhalative glucocorticoid required could be reduced by up to 60% and in 2 of the 10 patients the inhalative glucocorticoids could be discontinued altogether at times.
  • the therapy was tolerated well, without any side-effects.
  • the betamimetics required too, could be reduced by up to 40%.
  • a further 12 patients 59 to 78 years of age with persistent bronchial asthma (GINA TIT) treated with a combination therapy of inhalative glucocorticoid (beclometasone, 2 ⁇ 400 ⁇ g/die by inhalation) and inhalative long-acting beta-2-sympathomimetics (LABA, salmeterol) and also oral theophyllin were given 1,8-cineol (Soledum® capsules) 4 ⁇ 200 mg/die orally for one week. Even after a one-week therapy at the dose mentioned above, in 9 of the 12 subjects a slight to moderate improvement of lung function was achieved.
  • the persistent bronchial asthma had stabilized to such an extent that in 9 of the 12 patients the inhalative glucocorticoid required could be reduced by up to 30%.
  • the therapy was tolerated well, without any side-effects.
  • the betamimetics required too, could be reduced by up to 25%.
  • the lung function (FEV1) in the verum group (+5.1%) had improved significantly compared to the placebo group ( ⁇ 1%).
  • Clinical parameters such as the St. George's Respiratory Questionnaire (SGRQ), too, had improved significantly more in the verum group ( ⁇ 10.4 units) compared to the placebo group ( ⁇ 5 units).
  • SGRQ St. George's Respiratory Questionnaire
  • the results show, for the first time, that an additional therapy with 1,8-cineol in the form of capsules which dissolve in the small intestine reduces the decrease, reported in the literature, in the frequency of exacerbations by the known combined therapeutic approaches involving budesonide and formoterol ( ⁇ 24%, 13) and fluticasone and salmeterol ( ⁇ 25%, 14) by a further
  • 1,8-cineol and ICS are advantageous in particular in the therapy of a peripheral, respiratory inflammation in COPD as a novel therapeutic concept and for modulating the steroid-refractory progression of the pulmonary disorder, to prevent the development of irreversible respiratory insufficiency.
  • the therapeutic use of 1,8-cineol for the prophylaxis and therapy of early forms of COPD i.e. GOLD 0 or GOLD I
  • GOLD 0 or GOLD I early forms of COPD
  • the applicant was able to demonstrate antioxidative actions of the active compound 1,8-cineol, in addition to anti-inflammatory actions.
  • the antioxidative action is based primarily on an inhibition of superoxides and an additional action by inhibition of the superoxide dismutase activity (SOD activity), accompanied by a resulting inhibition of hydroperoxides (H 2 O 2 ) which act in a proinflammatory manner on the transcription, with formation of cytokines and other inflammation mediators.
  • Systemic 1,8-cineol for example in the form of Soledum® capsules, can be employed—as discussed above—for example as additional therapy firstly for severe COPD (for example GOLD III/IV) and/or as monotherapy for mild forms (for example GOLD I/II), i.e. also for chronic and acute bronchitis.
  • severe COPD for example GOLD III/IV
  • monotherapy for mild forms for example GOLD I/II
  • 1,8-cineol (4 ⁇ 10 ⁇ 6 mol/l and 6 ⁇ 10 ⁇ 6 mmol/l) is to be tested by co-incubation with therapeutically relevant concentrations (10 mol/l, 10 ⁇ 10 mol/l, 10 ⁇ 9 mol/l) and higher concentrations (10 ⁇ 8 mol/l, 10 ⁇ 7 mol/l, 10 ⁇ 6 mol/l) of beclometasone (“becl.”).
  • beclometasone beclometasone
  • the active compounds beclometasone and 1,8-cineol were diluted with ethanol up to a maximum concentration of 0.01%.
  • the active compounds were incubated together with freshly isolated monocytes (10 5 /ml) and the FCS stimulus (10%, from Sigma) for 20 hours in a cell culture medium (RPMI-1640, from Sigma).
  • the culture supernatants were then obtained after treatment of the cell membranes with Triton-X 100 and immediately examined for production of O 2 ⁇ radicals.
  • the determination of the cytosolic superoxide production is based on the reduction of the dye p-iodonitrotetrazolium violet (INTV), which reacts specifically with superoxide ions, to iodonitrotetrazolium formazan (formazan).
  • INTV is taken up by the cells into the cytosol. Intracellularly, the nitrogen cycle of the INTV is reduced by free superoxide radicals, giving rise to a water-soluble intermediate and the water-soluble formazan, which have their absorption maxima at 505 and 490 nm, respectively. In contrast, INTV does not absorb light of these wavelengths.
  • the cell lysate is (after treatment with hydrochloric acid) measured at 492 nm in a photometer.
  • the absorption of light is proportional to the amount of intracellularly accumulated INT-formazan which can then be determined using a formazan calibration curve.
  • the INT-formazan accumulation for its part is determined as a measure for the intracellular production of superoxide.
  • Monocytes (10 5 /ml) were incubated with different concentrations of beclometasone (10 ⁇ 12 to 10 ⁇ 6 mol/l, n 10-11) for 20 hours together with the FCC stimulus (10%).
  • a borderline significant inhibition ( ⁇ 10.5 ⁇ 5%, p 0.0910) of the O 2 ⁇ production was demonstrated only for beclometasone 10 ⁇ 9 mol/l (see Table 3).
  • an inhibition of the O 2 ⁇ production could not be demonstrated for beclometasone.
  • a therapeutically relevant borderline concentration of 1,8-cineol 6 ⁇ 10 ⁇ mol/l was determined as lowest antioxidatively active concentration for 1,8-cineol, and this concentration inhibited the O 2 ⁇ production significantly ( ⁇ 50.2 ⁇ 5%, ⁇ 0.0001).
  • beclometasone 10 ⁇ 11 to 10 ⁇ 9 mol/l on its own had no detectable effect on the O 2 ⁇ production (see Table 6).
  • Another novel, aspect of the present invention is the systemic inflammation, hitherto underestimated, in COPS, which inflammation is induced by smoking cigarettes, but also by the severity of the disorder.
  • COPS systemic inflammation
  • the inhalative local therapy is presumably not sufficient to actually control the course of COPS.
  • the present data may also explain the lack of any effects of a systemic therapy of COPT) with prednisolone which, in the presence of a nicotine-induced steroid resistance, promotes inflammation prooxidatively. Accordingly, in the future a new importance may be attributed to the substance 1,8-cineol.

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CN105250245A (zh) * 2015-10-15 2016-01-20 北京神州泰洁生物科技有限公司 一种治疗呼吸系统疾病的雾化吸入剂

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DE102010022174A1 (de) * 2010-05-12 2011-11-17 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Neue Darreichungsformen für Cineol
PL2723344T3 (pl) * 2011-08-19 2016-03-31 Maria Clementine Martin Klosterfrau Vertriebsges Mbh Złożony środek leczniczy zawierający monoterpen
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PL2320878T3 (pl) 2015-07-31
EA201170405A1 (ru) 2011-10-31
DE102009037359A1 (de) 2010-06-17
US20160338990A1 (en) 2016-11-24
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US11123323B2 (en) 2021-09-21
EA022312B1 (ru) 2015-12-30
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SI2320878T1 (sl) 2015-05-29

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