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EP3585367A1 - Composition renfermant du cinéol utilisée pour traiter des maladies nasales - Google Patents

Composition renfermant du cinéol utilisée pour traiter des maladies nasales

Info

Publication number
EP3585367A1
EP3585367A1 EP18711300.6A EP18711300A EP3585367A1 EP 3585367 A1 EP3585367 A1 EP 3585367A1 EP 18711300 A EP18711300 A EP 18711300A EP 3585367 A1 EP3585367 A1 EP 3585367A1
Authority
EP
European Patent Office
Prior art keywords
composition
rhinosinusitis
nasal polyps
nitric oxide
sinuum
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.)
Pending
Application number
EP18711300.6A
Other languages
German (de)
English (en)
Inventor
Markus UNKAUF
Barbara WOLLENBERG
Ralph Pries
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Maria Clementine Martin Klosterfrau Vertriebs GmbH
Original Assignee
Maria Clementine Martin Klosterfrau Vertriebs GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Maria Clementine Martin Klosterfrau Vertriebs GmbH filed Critical Maria Clementine Martin Klosterfrau Vertriebs GmbH
Publication of EP3585367A1 publication Critical patent/EP3585367A1/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61K31/33—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
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/348—Cannabaceae
    • A61K36/3482—Cannabis
    • 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
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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

Definitions

  • the present invention relates to the technical or medical field of treatment or therapy of rhinosinusitis with nasal polyps, in particular of chronic rhinosinusitis with nasal polyps.
  • the present invention relates to a composition, in particular a pharmaceutical composition, or a medicament for use in the prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps, in particular of chronic rhinosinusitis with nasal polyps, or a corresponding use of this composition or this drug for the stated prophylactic or therapeutic purpose.
  • the present invention also relates to the use of a cineole, in particular 1, 8-cineole, containing composition or a medicament thereof for the prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps, especially chronic rhinosinusitis with nasal polyps, and cineole, in particular 1, 8-cineole, as a pharmaceutical active ingredient in this regard.
  • the present invention also relates to an active ingredient combination, in particular in the form of a kit (kit-of-parts), for the prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps, in particular of chronic rhinosinusitis with nasal polyps, or a related kit for use in prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps, in particular of chronic rhinosinusitis with nasal polyps.
  • kit-of-parts for the prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps, in particular of chronic rhinosinusitis with nasal polyps.
  • the present invention also relates to cineol, in particular 1,8-cineol, for reducing or regulating the activity of a nitric oxide (NO) metabolism, in particular at least one nitric oxide synthase (NOS), preferably endothelial nitric oxide synthase (eNOS) in particular for use in the prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps, in particular of chronic rhinosinusitis with nasal polyps.
  • NO nitric oxide
  • eNOS endothelial nitric oxide synthase
  • the present invention also relates to cineol, in particular 1,8-cineol, for use in the prophylactic or therapeutic treatment of nitric oxide (NO) metabolism, in particular of at least one nitric oxide synthase (NOS), preferably of the endosome.
  • NO nitric oxide
  • NOS nitric oxide synthase
  • thelial nitric oxide synthase (eNOS) related or associated diseases, which are in particular rhinosinusitis with nasal polyps, in particular chronic rhinosinusitis with nasal polyps.
  • Rhinosinusitis (medical and synonymously also referred to as rhinosinusitis with nasal polyps or RSwNP) with nasal polyps or chronic rhinosinusitis with nasal polyps (medically and synonymously also referred to as chronic rhinosinusitis with nasal polyps or CRSwNP) is an independent disease with a complex clinical picture
  • a rhinosinusitis with nasal polyps or chronic rhinosinusitis with nasal polyps thereby represents a subgroup of rhinosinusitis (RS) in general or chronic rhinosinusitis (CRS) in particular, whereby the RSwNP or the CRSwNP are caused by the occurrence of nasal polyps is marked.
  • rhinosinusitis of the aforementioned type can be based on both clinical and imaging or endoscopic parameters, the clinical signs of an inflammatory change in the nasal cavities and paranasal sinuses are nasal obstruction and an anterior or posterior rhinorrhea. Furthermore, a rhinosinusitis of the aforementioned type is also associated with sometimes massive occurring nasal polyps (medically and synonymously as polyposis nasi et sinuum or shortened only referred to as polyposis nasi), which can be manifested for example by means of endoscopy. Chronic rhinosinusitis is especially present with persistence of symptoms over a period of at least twelve weeks.
  • chronic rhinosinusitis represents a significant health problem, with recent data showing that around 5% to 15% of the population in Europe and the US is affected by chronic rhinosinusitis.
  • RSwNP nasal polyps
  • chronic rhinosinusitis with nasal polyps or CRSwNP chronic rhinosinusitis with nasal polyps or CRSwNP is concerned, this is associated in particular with an inflammatory condition of the nasal and paranasal sinuses, which is chronic in CRSwNP and which is characterized in particular by grape-like or polypous Structures especially in the upper nasal cavity is characterized.
  • Typical histological features of the underlying nasal polyps associated with the disease are the presence of dense inflammatory infiltrates, loose fibrous connective tissue with significant tissue edema, and a thickened basement membrane mostly covered by respiratory pseudostratified epithelium.
  • nasal polyps associated with rhinosinusitis with nasal polyps (RSwNP) or chronic rhinosinusitis with nasal polyps (CRSwNP) are generally soft and generally benign or benign growths of the nasal mucosa, which may partially protrude into the nasal cavities.
  • Nasal polyps sprout, so to speak, from the nasal mucosa of the nose, with which they are connected via a kind of stem.
  • Some nasal polyps are only a few millimeters in size and do not disturb or hardly, whereas others can grow into extensive structures, which can then even lay the nasal spaces. As this not least restricts nasal breathing, the underlying disease of especially chronic rhinosinusitis with nasal polyps may therefore be very stressful and severely limit the quality of life.
  • the nasal polyps present in rhinosinusitis with nasal polyps or RSwNP chronic rhinosinusitis with nasal polyps or CRSwNP are, in a pathophysiological sense, generally pale grayish protrusions of chronically inflamed and edematous mucous membranes in the nasal cavity, which predominantly consist of the ethmoid region, middle Nasal pass and the middle turbinate impress.
  • it is benign growths, which emanate from a persistent inflamed nasal mucosa, such as is present in a particular chronic rhinosinusitis.
  • the protuberances in question generally consist of mucous membrane, which originates in particular from the ethmoidal cells or from the maxillary sinuses.
  • eosinophilic polyps which correspond to about 65 to 90% of the cases of the patient, and neutrophilic polyps.
  • the increased tissue eosinophilia is based in particular on increased transendothelial migration and inhibition of programmed cell death or apoptosis in eosinophils.
  • nasal polyps usually grows out of one of the paranasal sinuses into the main nasal cavity. Mainly the nasal polyps develop in the maxillary sinus (maxillary sinus) or the ethmoidal cells (cellulae ethmoidales). They come out of the excretory ducts and lie mostly in the middle nasal passage under the middle turbinate.
  • nasal polyps apart from the previously mentioned obstruction or restriction of nasal breathing - also lead to a loss of sense of smell and other diseases of the paranasal sinuses.
  • disease symptoms or health impairments often also from a limited nasal breathing.
  • such patients do not get enough air through the nose and therefore breathe more often through the mouth, which also leads, for example, to excessive snoring and associated sleep disturbances, along with a decrease in performance.
  • the air breathed through the mouth is not sufficiently filtered, so that the general risk of infection is increased.
  • Nasal polyps are a benign neoplasm of the nasal mucosa, which leads to reduced respiratory capacity and reduced olfactory perception.
  • Affected patients often feel that they have a so-called "stuffy" nose, which can also lead to a nasal voice.
  • these patients often suffer from recurrent or permanent Inflammation of the sinuses (sinusitis) and dull headache.
  • the sense of smell may be limited and thus also the sense of taste, which in turn results in a further loss of quality of life.
  • nasal polyps especially in children also lead to middle ear infection (otitis media) as a scurvy disease.
  • the current model of the pathogenesis of nasal polyps in particular associated with rhinosinusitis with nasal polyps (RSwNP) or with chronic rhinosinusitis with nasal polyps (CRSwNP), comprises significantly four steps, starting with a deficit of the person subsequently affected by the disease, which leads to a disturbed release of molecules of the innate defense of the patient, followed by a colonization by bacteria with loss of natural barrier function.
  • the local enhancement of pathogen-associated molecular patterns and the antigen-driven activation of the adaptive immune system (superantigen effect) create an inflammatory local microenvironment that per se drives the onset of inflammation and autoimmunity.
  • RSwNP nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • RSwNP nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • nasal polyps Depending on how severe the symptoms of the nasal polyps are, either a conservative, especially drug therapy or surgical treatment of the nasal polyps is performed.
  • nasal polyps For example, an operative removal of nasal polyps can often improve the acute symptoms quickly; nevertheless, in about 75% of the patients treated in this way, nasal polyps form again in the first years after removal. Therefore, it is provided in the prior art, even after nasal polyp surgery long-term corticosteroids topically (eg as cortisone-containing nasal sprays) or systemically applied (along with a variety of undesirable side effects) to prevent recurrence of polyps in the nose (which is often not achieved).
  • corticosteroids topically (eg as cortisone-containing nasal sprays) or systemically applied (along with a variety of undesirable side effects) to prevent recurrence of polyps in the nose (which is often not achieved).
  • corticosteroids or glucocorticoids have an anti-inflammatory effect and in this way relieve the inflammatory reactions, which include the swelling of the nasal mucosa.
  • corticosteroids should be used regularly for several months. Often the symptoms improve after a few weeks of use.
  • nasal polyps associated with eosinophilia are characterized by a severe inflammatory response characterized by cytokines (such as IL-5) and chemokines (such as eotaxin and RANTES).
  • Corticosteroids are typically particularly effective in eosinophil-associated Inflammation, which is why the parameter "eosinophilia” is often referred to as an indicator for the use of these drugs.
  • steroids induce apoptosis of these inflammatory cells, with the magnitude of the suppressive effect on IL-5 production from T cells being a decisive parameter.
  • the symptomatic treatment of nasal polyps has already been established by studies with the first topically administered corticosteroids. In recent years, clinical observations have been increasingly supported by objective parameters (rhinomanometry, rhinometry, peak nasal inspiratory flow PNIF, magnetic resonance tomography).
  • the recurrence rates and the time of recurrence after surgery could be improved or delayed in some studies, but the investigations do not go beyond the period of one year.
  • the dosage of topical steroids used in the trials is often above the recommended dosage for allergic rhinitis.
  • surgical therapy eg, infundibulotomy
  • infundibulotomy is usually required to effectively treat nasal obstruction and odor loss.
  • such surgeries are performed endonasally and preferably minimally invasively, and can provide healing rates of up to about 50% and improvement in up to about 90% of cases.
  • the ducts of the paranasal sinuses are usually also expanded, so that they are better ventilated and less likely to ignite.
  • nasal polyps and chronic polypous sinus diseases are prone to relapse, several operations are often required during the course of the disease.
  • Such minimally invasive sinus surgery is one of the most challenging procedures in ENT and is often associated with a multi-day hospital stay and intensive follow-up treatment, which includes in particular the use of topical corticosteroids over several months as a treatment for relapse prophylaxis. Under a postoperative steroid therapy lasting several months, there also appears to be an improved wound healing after a surgical therapy; However, controlled examinations of wound healing after sinus surgery are not available.
  • nasal polyps polyposis nasi et sinuum
  • rhinosinusitis and “diagnosis and therapy of sinusitis and polyposis nasi” German Society of Otolaryngology, Head and Neck Surgery.
  • the therapeutic concepts of the prior art either rely on surgical methods for the removal of RSwNP or CSwNP associated nasal polyps and / or corticosteroid-based conservative therapy concepts, these methods of the prior art are associated with considerable inconvenience and side effects for the patients concerned.
  • the therapy concepts of the prior art often a recurrence of the nasal polyps, especially after postoperative conditions, can not be prevented in an efficient manner, so that affected patients must undergo multiple surgical interventions of recurrent nasal polyps.
  • conservative therapy concepts based on corticosteroids especially in postoperative conditions, especially in the treatment of children, especially infants, undesirable because of the not insignificant side effect profile of these drugs.
  • RSwNP nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • CCSwNP chronic rhinosinusitis with nasal polyps
  • a pharmaceutical composition wherein the previously described disadvantages of the prior art are at least largely avoided or at least mitigated.
  • a still further object of the present invention is also to provide a corresponding therapeutic concept, in particular based on a relevant composition, in particular pharmaceutical composition, which or which a high efficacy with good compatibility in the context of prophylactic or therapeutic treatment of Rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP).
  • the therapy concept provided according to the invention or the relevant composition, in particular pharmaceutical composition should be associated with fewer side effects and / or inconveniences for the affected patients than conventional therapy methods or provide an at least comparable, preferably even improved, effectiveness.
  • the present invention proposes - according to a first aspect of the present invention - a cineol restroom composition, in particular a cineol restroom pharmaceutical composition, according to claim 1 before; Further, particularly advantageous embodiments of the composition according to the invention are the subject of the relevant sub and independent claims.
  • the present invention - according to a second aspect of the present invention - cineol, in particular 1, 8-cineol, for use in the prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with Nasal polyps (Polyposis nasi et sinuum) (CRSwNP), according to the related claim (claim 33); Further, particularly advantageous embodiments of this aspect of the invention are the subject of the relevant subclaim (claim 40).
  • the present invention according to a third aspect of the present invention - the use of a cineole, preferably 1, 8-cineole, as a pharmaceutical active ingredient-containing composition, in particular pharmaceutical composition, according to the relevant claim (claim 34); Further, particularly advantageous embodiments of this aspect of the invention are the subject of the relevant subclaim (claim 40).
  • the present invention - according to a fourth aspect of the present invention - relates to the use of cineol, preferably 1,8-cineol, as pharmaceutical active substance for the prophylactic or therapeutic treatment of rhinosinusitis with polyps (Polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP), according to the claim (claim 35) thereof;
  • RSwNP Polyposis nasi et sinuum
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • particularly advantageous embodiments of this aspect of the invention are the subject of the relevant subclaim (claim 40).
  • the present invention likewise relates, according to a fifth aspect of the present invention, to a medicament for the prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP) , according to the related claim (claim 36); Further, particularly advantageous embodiments of this aspect of the invention are the subject of the relevant subclaim (claim 40).
  • the present invention also relates to a combination of active ingredients, in particular in the form of a kit (kit-off-parts), for the prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP). , in particular chronic rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (CRSwNP) or for the corresponding use according to the corresponding claim (claim 37); Further, particularly advantageous embodiments of this aspect of the invention are the subject of the relevant subclaim (claim 40).
  • the related disease of rhinosinusitis with polyposis nasi et sinuum (RSwNP), in particular chronic nasal polyps rhinosinusitis (CRSwNP), one with a nitric oxide (NO ) Metabolism, in particular with at least one nitric oxide synthase (NOS), preferably with the endothelial nitric oxide synthase (eNOS), related invention.
  • RSwNP polyposis nasi et sinuum
  • CRSwNP chronic nasal polyps rhinosinusitis
  • NOS nitric oxide synthase
  • the present invention similarly focuses on influencing, as set forth below, of the quoted NO metabolism or the underlying proteins or enzymes.
  • the present invention also relates to cineol, in particular 1,8-cineol, for regulation, in particular reduction and / or downregulation and / or suppression and / or inhibition (inhibition), in accordance with another seventh aspect of the present invention.
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • the present invention - according to yet another, eighth aspect of the present invention also cineol, in particular 1, 8-cineole, for use in the prophylactic and / or therapeutic treatment with a nitric oxide synthase (NOS), in particular the endothelial nitric oxide synthase (eNOS), associated or associated, in particular thereby induced or favored diseases, in particular rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (CRSwNP), according to the related claim (claim 39); Further, particularly advantageous embodiments of this aspect of the invention are the subject of the relevant subclaim (claim 40).
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • drug (synonymously also “pharmaceutical”), as used in the context of the present invention, is to be understood as very broad and does not only encompass pharmaceuticals or pharmaceuticals as such (ie in terms of pharmaceutical law ), but above all so-called medical devices and beyond, but also homeopathic and nutritional supplements, as well as cosmetics and utensils.
  • the composition according to the invention may be present in a non-limiting manner in the form of a pharmaceutical (pharmaceutical), medical device, homeopathic, nutritional supplement, cosmetic or in the form of a commodity.
  • the present invention - according to a first aspect of the present invention - is thus a composition, in particular a pharmaceutical composition, for use in the prophylactic and / or therapeutic treatment of rhinosinusitis with nasal polyps (Polyposis nasi ei sinuum) (RSwNP), in particular chronic rhinosinusitis Nasal Polyps (Polyposis nasi et sinuum) (CRSwNP),
  • composition contains as active ingredient, in particular pharmaceutical active substance, cineol, preferably 1, 8-cineole, and
  • rhinosinusitis with nasal polyps Polyposis nasi et sinuum
  • CRSwNP chronic nasal polyps rhinosinusitis
  • NO nitric oxide
  • eNOS endothelial nitrogen monoxide synthase
  • the present invention or the present invention based therapy concept for the treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP) is associated with a variety of advantages and specifics which are set out below in a non-limiting, non-exhaustive manner:
  • the present invention focuses on a separate disease in the form of rhinosinusitis with nasal polyps (RSwNP) or chronic rhinosinusitis with nasal polyps (CRSwNP), namely, in which there is a chronic inflammatory condition of the nasal and paranasal sinuses, which with the formation of nasal polyps in the form Grape-shaped structures in the upper nasal cavity is accompanied, in this regard, there is also a specific pathogenesis, as stated herein.
  • RSwNP or CRwNP is therefore also associated with an independent or characteristic pathological appearance as well as a special pathogenesis, which distinguishes it from other diseases.
  • a novel therapeutic concept for the prophylactic or therapeutic treatment of the autonomous disease of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis, which can be distinguished from other diseases of the nose or sinuses, will be introduced for the first time with nasal polyps (polyposis nasi et sinuum) (CRSwNP), with which the previously described disadvantages of the prior art can at least be further avoided or at least mitigated.
  • the present case is particularly such that the rhinosinusitis in question with nasal polyps or the chronic rhinosinusitis with nasal polyps is such a disease, which also with a particular endogenous or physiological nitric oxide (NO) metabolism or a in particular the body's own or physiological nitric oxide synthase (NOS), in particular the endothelial nitric oxide synthase (eNOS), or is associated with or influenced thereby, in particular to the effect that in the presence of the disease - by the Applicant in a completely surprising way - the nitric oxide (NO) meta- bolism or the activity of the corresponding nitric oxide synthases (NOS), in particular the endothelial nitric oxide synthase (eNOS), is increased or in this regard, there is a desegulation, so that in this context in the pathological state in particular increased upregulation is present, in particular in the underlying polyp tissue or in polypose tissue.
  • NO
  • the Applicant has likewise found that the increase in nitric oxide (NO) metabolic activity or the increased activity of the corresponding nitric oxide synthases (NOS), in particular endothelial nitric oxide synthase (eNOS), is local or tissue-specific in nature Local or tissue-specific occurs, in particular in the associated with RSwNP or CRSwNP nasal polyps (Polyposis nasi et sinuum) or in the nasal polyp underlying tissue, so that in this case a local (over) production of NO is present, which in turn In particular, local inflammatory or disease modulating effects may be associated.
  • NO nitric oxide
  • NOS nitric oxide synthases
  • eNOS endothelial nitric oxide synthase
  • the present invention is based on a normalization or reduction (and thus on a downregulation or inhibition) of the NO metabolism or of the NOS in question, in particular eNOS, as a result of the special pharmacological action of cineol, in particular 1, 8-Cineol, as described by the applicant for the first time.
  • the normalization or reduction can take place equally and in particular at the local level.
  • cineole in particular 1,8-cineole
  • a purposely directed, in particular local normalization or downregulation or inhibition of the activity, a NO metabolism, in particular a NOS, in particular eNOS is turned off.
  • nitric oxide (NO) as a bioactive molecule can induce or enhance local inflammatory processes as part of a destructive effect.
  • the expression according to which the underlying RSwNP or CRSwNP is associated with the activity or regulation of an NO metabolism, in particular at least one nitric oxide synthase (NOS), preferably endothelial nitric oxide synthase (eNOS) or associated disease is to be understood very broadly.
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • the expression in question can be understood to mean that the disease is influenced by the activity or regulation of the stated NO metabolism or NOS, in particular eNOS, or hereby is accompanied or that with increased (local) activity or regulation of the cited NO metabolism or NOS, in particular eNOS, the disease is caused or induced and / or at least favors or at least maintained or strengthened.
  • RSwNP or RCSwNP is influenced by an NO metabolism or by a nitric oxide synthase (NOS), in particular by endothelial nitric oxide synthase (eNOS).
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • the disease is accompanied by a change, in particular an increase in the activity or regulation, of the NO metabolism in question or of NOS, in particular eNOS, which in turn can further worsen the pathological situation.
  • the nitric oxide synthase (NOS) in question in particular the endothelial nitric oxide synthase (eNOS) or the physiological NO metabolism or NO signaling pathway associated therewith, represents a corresponding pharmacological target or a corresponding pharmacological starting point for the treatment of the underlying Disease dar.
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • the physiological NO metabolism or NO signaling pathway associated therewith represents a corresponding pharmacological target or a corresponding pharmacological starting point for the treatment of the underlying Disease dar.
  • cineole especially 1, 8-cineole, has a corresponding profile of action and in this regard can be used as a special-acting pharmacological substance or drug.
  • nitric oxide synthases NOS
  • eNOS endothelial nitric oxide synthase
  • the term refers to the biological function and the underlying biomolecule and / or its control, preferably with regard to its function as an enzymatically active substance, in particular with its function as NO synthase and thus the (catalytic) production of nitric oxide (NO) and thus in particular with regard to its function in corresponding physiological signaling pathways or the like, such as the NO metabolism in question, in particular NO signaling pathway.
  • NO nitric oxide
  • an increased activity or an increased regulation or an activation and / or upregulation in particular with a correspondingly increased or enhanced biological function (in particular with respect to the underlying enzyme activity with the production of NO or the activity in the context of NO Metabolism or NO signaling pathway).
  • an inhibition (inhibition) or downregulation as caused by the administration of cineol, in particular 1, 8-cineol, caused, in particular accompanied by a reduced or normalized function.
  • an increased activity or an increased regulation or a downregulation in the context of the present invention should be understood in particular such that in this regard there is an increased activity or regulation compared to the non-pathological or healthy state, in particular where the increased activity may also relate to a comparison of disease-affected tissue, such as nasal polyps or polypous tissue associated with the disease, on the one hand, with non-disease tissue, such as lower turbinate tissue or the like.
  • the concept underlying the present invention in summary and as stated below, particularly aims to reduce or down-regulate or neutralize the activity in question of NOS, in particular eNOS, in order to thereby also improve the disease situation.
  • NO metabolism or nitric oxide synthases NOS
  • eNOS endothelial nitric oxide synthase
  • the pharmaceutical active substance Cineol preferably 1, 8- Cineole
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • the protein endothelial nitric oxide synthase belongs to the enzyme family of NO synthases. It catalyzes the formation of nitric oxide (NO) from the amino acid L-arginine and is thus of relevance for nitric oxide (NO) metabolism.
  • endothelial nitric oxide synthase eNOS
  • Nitric oxide (NO) and its potentially endogenously produced form as an endothelium-derived factor is a gaseous molecule which acts as a mediator in corresponding signaling pathways of the organism.
  • NO plays an important role in the physiological regulation of the cardiovascular system and has physiological functions in the nervous and immune systems, such as the defense mechanisms against infectious diseases and tumors.
  • Endothelial nitric oxide synthase (eNOS) in addition to inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS), is the most important isoform for regulating vascular function.
  • Multiple stimuli can initiate or enhance the activity of eNOS and, consequently, the production of nitric oxide (NO) in a calcium dependent and independent manner.
  • eNOS endothelial nitric oxide synthase
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • the applicant could show in a completely surprising manner that the phosphorylation of nitric oxide synthase (NOS), in particular endothelial nitric oxide synthase (eNOS), in rhinosinusitis with nasal polyps, especially chronic rhinosinusitis with nasal polyps, especially locally in the so associated nasal polyps or polyperiam tissue and especially in comparison to the non-affected disease tissue of the lower turbinate, resulting in the pathological state in particular locally increased (enzymatic) activity of the underlying protein, in particular with regard to its function as NO synthase, which in turn leads to an increased (local) NO metabolism with a corresponding activation of NO signaling pathways.
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • Endothelial nitric oxide synthase increases the permeability of vascular endothelium and plays an important role in regulating blood flow, nasal secretion and ciliary movement.
  • the increased phosphorylation of endothelial nitric oxide synthase and the associated (protein) activity can - without wishing to be limited or limited to this theory - in patients with chronic rhinosinusitis with nasal polyps an increased or excessive vascular permeability result Edema and increased inflammatory reactions may be linked.
  • cineole in particular 1,8-cineole, reduces the activity of the nitric oxide synthase in question, in particular in that the phosphorylation of nitric oxide synthase (NOS), in particular the endothelial Nitric oxide synthase (eNOS) is significantly reduced at serine 1 177, thus playing an important role in the pathogenesis of rhinosinusitis with nasal polyps, in particular chronic rhinosinusitis with nasal polyps.
  • NOS nitric oxide synthase
  • eNOS endothelial Nitric oxide synthase
  • a lower activity of, in particular, endothelial nitric oxide synthase is associated with decreased vascular permeability, which may prevent or reduce edema formation and increased inflammation.
  • NOS nitric oxide synthases
  • eNOS endothelial nitrogen monoxide synthase
  • cineole in particular 1,8-cineole, has a significant effect on the activation of endothelial nitric oxide synthase (eNOS) or its activation, which is equally important in the management of the disease underlying increased inflammation and edema, in particular by regulation of vascular permeability.
  • eNOS endothelial nitric oxide synthase
  • a special or new patient group which is specifically affected by a RSwNP or a CRSwNP, with rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular the chronic Rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (CRSwNP), one with a nitric oxide (NO) metabolism, preferably one with the activity and / or regulation of at least one nitric oxide synthase (NOS), in particular endothelial nitric oxide synthase (eNOS) , related and / or associated disease.
  • RSwNP nasal polyps
  • COSwNP chronic Rhinosinusitis with nasal polyps
  • NO nitric oxide
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • cineole in particular 1, 8-cineol
  • the purposive use of cineole, in particular 1, 8-cineol, as provided according to the invention represents a new therapeutic approach in respiratory diseases and in particular in chronic rhinosinusitis with nasal polyps, based in this respect on the basis of the active ingredient used according to the invention also a phytotherapeutic alternative or a natural product / natural agent-based alternative to, for example, glucocorticosteroids may be provided, based on an effective and low-therapy therapeutic concept.
  • glucocorticosteroids may be provided, based on an effective and low-therapy therapeutic concept.
  • Eucalyptol cineole especially 1, 8-cineole, it is a natural monoterpene.
  • 1,8-Cineol belongs to the bicyclic epoxy-monoterpenes, more precisely to the lime oxides.
  • 8 0 are eucalyptol, limonene-1, 8-oxide, 1, 8-epoxy-p-menthane or 1, 3,3-trimethyl-2-oxabicyclo [2.2.2] octane.
  • 1, 8-cineole as the main component of eucalyptus oil (eucalyptus oil contains up to 85 wt .-% 1, 8-cineole), but also in other plants before, such. In mint, healing sage, thyme, basil and tea tree.
  • 1,8-cineole is included, for example, in niaouli, juniperus, piper, cannabis, cajeput, sage, myrtle, and other essential oils.
  • 1,8-cineole Purified or pure 1,8-cineole, which is generally 99.6 to 99.8% pure, is generally obtained by fractional distillation of eucalyptus oil.
  • 1, 8-Cineol is used in the prior art in particular as an expectorant in bronchial catarrh and other respiratory diseases mainly in veterinary medicine, but also as a flavoring in the perfume industry.
  • 1, 8-cineole is used in dentistry in the revision of root fillings.
  • Pharmacologically, 1,8-cineole is active in the upper and lower respiratory tract, especially in the lungs and paranasal sinuses, expectorant and bactericidal. It also inhibits certain neurotransmitters, which, for. B.
  • 1, 8-cineole can - as stated below - in principle both topically, z. B. (intra) nasally and / or by inhalation, or systemically, in particular perorally (eg., In the form of capsules) are used. As an active ingredient, 1,8-cineole therefore has expectorant and anti-inflammatory effects.
  • 1, 8-cineol When systemically applied, 1, 8-cineol is easily absorbed and passes through the bloodstream in the respiratory organs to effect.
  • 1,8-cineole can liquefy inflammatory secretions and tough mucus in the airways and counteract inflammatory processes in the respiratory tract. In the area of the upper airways obstruction of nasal breathing in case of cold and dizziness of the head disappear.
  • 8-cineol For further details on the active ingredient 1, 8-cineol can be referenced, for example, Römpp Chemielexikon, Georg Thieme Verlag, Stuttgart / New York, 10th edition, Volume 1, 1996, page 752, keyword: "Cineol", and the lectured there Literature.
  • the active ingredient cineole is an effective therapeutic approach in the treatment of rhinosinusitis with nasal polyps, especially chronic rhinosinusitis with nasal polyps, cineole as a natural agent, for example, not associated with corticosteroids has serious side effects.
  • the cineol can be used as a monotherapeutic or, for example, in the treatment of more serious cases, also in combination with corticosteroids, the effect of which is intensified or the dose thereof is not significantly reduced by the joint or combined use of cineol can, and this with the same effective efficiency.
  • the underlying agent may also be used in the treatment of postoperative conditions, in which respect the rate of recurrence may be reduced, as further noted below.
  • the active ingredient cineol can be administered topically (eg, intranasally) and / or systemically (eg, orally). Both topical application, in which the cineol is generally applied directly to the nasal mucosa, as well as systemic (eg, peroral) application may also be the anti-inflammatory, corticosteroid-like profile of action of cineole come into play.
  • inventive concept is equally suitable for the treatment of recurrent forms of the underlying disease, in particular with regard to nasal polyps associated with the invention (Polyposis nasi et sinuum), which could not be treated satisfactorily or not always satisfactorily when using conventional therapy concepts.
  • nitric oxide synthase NOS
  • eNOS endothelial nitric oxide synthase
  • diseases of the aforementioned type can be treated which are involved in connection with corresponding physiological signaling pathways or signal transduction pathways involving the nitric oxide synthase (NOS) in question, in particular endothelial nitric oxide synthase (eNOS) , stand or accompany it.
  • the present invention thus provides an efficient therapy concept which can be used flexibly, which resort to a therapeutic agent (namely cineol, in particular 1,8-cineole), with which no appreciable undesired side effects are associated.
  • a therapeutic agent namely cineol, in particular 1,8-cineole
  • the therapy concept according to the invention can also be combined in an efficient and flexible manner with conventional therapy concepts;
  • the therapeutic concept according to the invention can be used after a surgical removal of nasal polyps in the underlying diseases to prevent recurrence, or it can be combined with conventional, systemic and / or topically applied corticosteroids, the therapy, the principle of action of the inventive therapy concept to increase or reduce their dose and thus also the side effect profile of these corticosteroids.
  • RSwNP nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • eNOS endothelial nitric oxide synthase
  • the nitric oxide (NO) metabolism may be constituted by or comprise at least one nitric oxide (NO) signaling pathway, in particular nitric oxide (NO) signal transduction pathway.
  • This may be, for example, a tissue affected by the disease, in particular the nasal polyps associated with the disease or the polypous tissue in question, nitric oxide (NO) metabolism or NO signaling pathway in question.
  • nitric oxide (NO) metabolism or the relevant signaling pathway may be a cGMP-dependent and / or cGMP-independent pathway.
  • NOS nitric oxide synthase
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • nitric oxide synthase NOS
  • eNOS endothelial nitric oxide synthase
  • the abovementioned signaling pathways or signal transduction pathways can also take the form of affecting, in particular, the tissue affected by the disease, in particular the nasal polyps or the polypous tissue associated with the disease, or being localized in the tissue in question.
  • rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP), one with increased activity or increased regulation, in particular upregulation, of nitric oxide (NO). Metabolism-related or concomitant, in particular thereby induced or favored disease be.
  • the increased activity or regulation may be localized and in particular affect the tissue affected by the disease, in particular the nasal polyps or polypous tissue associated therewith.
  • composition according to the invention or cineol can be used for the prophylactic or therapeutic treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) associated with nitric oxide (NO) metabolism or, in particular, induced or promoted therewith (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP).
  • RSwNP induced or promoted therewith
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • the nitric oxide (NO) metabolism or the underlying signaling pathways, in particular as defined above have increased regulation, in particular upregulation.
  • RSwNP nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • composition according to the invention or the cineol can be used for the prophylactic or therapeutic treatment of increased or increased regulation, in particular upregulation, of nitric oxide synthase (NOS), in particular endothelial nitric oxide synthase (eNOS) . associated therewith, in particular thereby induced or favored rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (CRSwNP), are used.
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • the rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular the chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP), one with an increased phosphorylation, preferably at Serine-1 177, the nitric oxide synthase (NOS), in particular the endothelial nitric oxide synthase (eNOS), related or associated, in particular thereby induced or favored disease.
  • RSwNP sinus nasi et sinuum
  • COSwNP chronic rhinosinusitis with nasal polyps
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • the composition according to the invention or cineol can be used for the prophylactic or therapeutic treatment of increased phosphorylation, preferably of serine 1 177, of nitric oxide synthase (NOS), in particular of endothelial nitric oxide synthase (eNOS).
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • RSwNP rhinosinusitis associated with nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • CCSwNP chronic rhinosinusitis with nasal polyps
  • the composition or cineol is used for the prophylactic or therapeutic treatment of recurrent forms of, or associated with, or associated with rhinosinusitis (RSwNP), in particular chronic rhinosinusitis (CRSwNP) Nasal polyps (Polyposis nasi et sinuum) is used.
  • RSwNP rhinosinusitis
  • CRSwNP chronic rhinosinusitis
  • Nasal polyps Polyposis nasi et sinuum
  • the underlying disease is in particular rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP) and, in particular, chronic nasal polyps rhinosinusitis (CRSwNP).
  • the cineole used according to the invention in particular 1,8-cineole, also has an activity against the nasal polyps underlying or accompanying the disease.
  • the use of the active substance used according to the invention in the form of cineole, in particular 1,8-cineol can reduce or avoid the underlying inflammatory or proliferative processes, which leads to a further improvement of the disease state.
  • the composition or cineol, in particular 1,8-cineol for the regulation, in particular reduction and / or downregulation and / or suppression and / or inhibition, of the activity of a nitric oxide (NO) metabolism , in particular at least one nitric oxide synthase (NOS), preferably endothelial nitric oxide synthase (eNOS), in particular for the regulation, in particular reduction and / or downregulation and / or suppression and / or inhibition, of the phosphorylation of at least one nitric oxide synthase (NOS) , in particular endothelial nitric oxide synthase (eNOS), preferably on serine-1 177.
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • composition according to the invention and / or cineol, in particular 1,8-cineol can be used for the prophylactic or therapeutic treatment of postoperative conditions.
  • the use of cineole, in particular 1,8-cineole, in the context of the therapy concept according to the invention also reduces or minimizes the formation of recurrences in an effective manner.
  • the composition or cineol is used for the prophylactic or therapeutic treatment of nasal polyps (polyposis nasi et sinuum), in particular recurrent forms, after prior surgical removal of the nasal polyps.
  • the composition of the invention or cineole may equally be used to reduce the risk or likelihood of recurrence, especially in postoperative conditions and / or post surgical removal conditions associated with rhinosinusitis (RSwNP), especially chronic Rhinosinusitis (CRSwNP), standing and / or nasal polyps associated therewith and / or caused thereby.
  • the composition or the cineol according to the invention may be used for the prophylaxis of recurrence, in particular in postoperative conditions or conditions following prior surgical removal of the patches associated with rhinosinusitis (RSwNP), in particular chronic rhinosinusitis (CRSwNP) or associated therewith Nasal polyps, are used.
  • composition according to the invention and / or cineol may also be used to prevent recurrence, in particular in postoperative conditions and / or conditions after previous surgical removal of or associated with rhinosinusitis (RSwNP), especially chronic rhinosinusitis (CRSwNP) and / or nasal polyps produced therefrom.
  • RSwNP rhinosinusitis
  • CRSwNP chronic rhinosinusitis
  • the composition according to the invention contains the cineole as pure substance, in particular free from other terpenes, preferably with a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight. %, more preferably at least 98 wt .-%, most preferably at least 99 wt .-%, even more preferably at least 99.5%, based on the cineole.
  • the cineole is present as pure substance or is used or if the cineole is free of other terpenes or contains no other terpenes.
  • the cineole used has a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight, particularly preferably at least 98% by weight, completely more preferably at least 99% by weight, more preferably at least 99.5%, based on the cineole.
  • the composition according to the invention contains the cineole as 1,8-cineole or the cineole is present as 1,8-cineol.
  • the cineole may be present in liposome-surrounded and / or liposomally packaged form.
  • the composition according to the invention it is preferred according to the invention for the composition according to the invention to contain cineol as the sole active ingredient, in particular as sole pharmaceutical active ingredient, or when the cineole is used as the sole active ingredient, in particular as sole pharmaceutical active ingredient. In this way, unwanted side effects and interactions can be avoided, while at the same time a high efficiency of action of the underlying drug is present.
  • the composition according to the invention does not contain non-steroidal anti-inflammatory drugs (NSAIDs) and / or is free of non-steroidal anti-inflammatory drugs (NSAIDs) and / or that cineol is absent or absent nonsteroidal anti-inflammatory drugs (NSAID). In this way, unwanted NSAID side effects and unpredictable interactions with cineol can be avoided.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • cineol is absent or absent nonsteroidal anti-inflammatory drugs
  • the composition according to the invention contains the cineole, in particular 1,8-cineole, in effective, in particular pharmaceutically effective amounts.
  • the amount of cineol in the composition according to the invention can vary widely, in particular depending on the form of therapy (eg topical or systemic) and the severity and peculiarity of the disease to be treated.
  • the cineole when the composition of the invention, the cineole, based on the composition, in relative amounts in the range of 0.0001 to 80 wt .-%, in particular 0.001 to 75 wt .-%, preferably 0.005 to 70 wt. -%, preferably 0.01 to 60 wt .-%, particularly preferably 0.05 to 55 wt .-%, most preferably 0.1 to 50 wt .-%, contains. In this way good efficiency on the one hand and good compatibility on the other hand are guaranteed. Nevertheless, it may be intended to deviate from the stated values without departing from the scope of the present invention; this is at the expert's discretion in each individual case.
  • the cineole when the composition according to the invention, in relative amounts of at least 0.0001 wt .-%, in particular of at least 0.001 wt .-%, preferably of at least 0.005 wt. %, preferably of at least 0.01 wt .-%, particularly preferably of at least 0.05 wt .-%, most preferably of at least 0.1 wt .-%, contains.
  • the cineole based on the composition, in relative amounts of at most 80 wt .-%, in particular of at most 75 wt .-%, preferably of at most 70 wt .-%, preferably of not more than 60% by weight, more preferably not more than 55% by weight, most preferably not more than 50% by weight.
  • the composition according to the invention contains the cineol together with at least one physiologically acceptable carrier (excipient) or that the cineole is used together with at least one physiologically acceptable carrier (excipient).
  • physiologically acceptable carriers excipients
  • all physiologically acceptable carriers (excipients) can be used.
  • the carrier used (excipient) miscible with 1, 8-Cineol and / or soluble therein and / or if the carrier (excipient) at 20 ° C and at atmospheric pressure in the liquid or solid state is present.
  • 1, 8-Cineol miscible and / or soluble herein, in particular liquid at 20 ° C and atmospheric pressure carriers are for example compounds from the group of fatty oils, preferably triglycerides, more preferably medium-chain triglycerides (Medium Chain Triglycerides, MCT ), most preferably triglycerides with C6-C12 fatty acid residues.
  • MCT Medium Chain Triglycerides
  • composition according to the invention or the cineol can in principle be administered topically (eg intranasally and / or by inhalation) and / or topically (eg systemically) within the scope of the therapy according to the invention, specifically as a function of the individual therapy or the form to be treated, the severity of the disease, the particular patient, etc.
  • topically e.g intranasally and / or by inhalation
  • topically eg systemically
  • the composition according to the invention or the cineol can in principle be administered topically (eg intranasally and / or by inhalation) and / or topically (eg systemically) within the scope of the therapy according to the invention, specifically as a function of the individual therapy or the form to be treated, the severity of the disease, the particular patient, etc.
  • a high efficiency of action with regard to the particular locally present increased activity of NOS or eNOS, in particular with respect to the disease affected Tissues, such as nasal polyps or polypous tissue associated with
  • composition according to the invention and / or the cineol is applied topically, in particular intranasally or by inhalation, and / or that the composition according to the invention and / or the cineol is prepared for topical, in particular intranasal or inhalative administration.
  • the composition according to the invention and / or the cineol can be administered in the form of an intranasally administered dosage form.
  • the combination according to the invention Settling and / or the cineole can be prepared in an intranasal administration form.
  • the composition of the invention may be applied in the form of nasal sprays, nasal drops, nasal gels, nasal ointments, nasal rinses, nasal creams, inhalants or the like, preferably nasal sprays.
  • the composition according to the invention and / or the cineol can be prepared in the form of nasal sprays, nose drops, nasal gels, nasal ointments, nasal irrigations, nasal creams, inhalants or the like, preferably nasal sprays.
  • the composition and / or the cineol can also be administered systemically, in particular orally or parenterally (for example intravenously, intraarterially, intramuscularly, subcutaneously, etc., for example in the form of a parenteral dosage form, such as injection, infusion, etc.), preferably perorally.
  • parenterally for example intravenously, intraarterially, intramuscularly, subcutaneously, etc., for example in the form of a parenteral dosage form, such as injection, infusion, etc.
  • the composition according to the invention and / or the cineole can be prepared for systemic, in particular peroral or parenteral, preferably peroral application.
  • the composition according to the invention and / or the cineol can be administered in particular in the form of a dosage form to be administered perorally, ie the composition according to the invention and / or the cineole can in this case be prepared in a dosage form to be administered perorally.
  • the composition according to the invention and / or cineol can be applied in particular as an enteric but small intestine-soluble systemic dosage form, preferably as a capsule, dragee, pill, tablet or the like, ie the composition according to the invention and / or the cineole can be used in this embodiment as enteric-coated but small intestine-soluble systemic dosage form, preferably as capsule, dragee, pill, tablet or the like.
  • the composition according to the invention and / or the cineol can in particular also be prepared as an injection, infusion or the like.
  • the daily dose of applied cineol can vary within wide ranges.
  • the amounts of cineole used can likewise vary widely.
  • the cineole is administered systemically with a daily dose in the range from 10 to 5,000 mg / diem, in particular in the range from 50 to 3,000 mg / diem, preferably in the range from 100 to 2,500 mg / diem, preferably in the range from 150 to 2,000 mg / diem, more preferably in the range of 200 to 1,500 mg / diem, and / or that the composition according to the invention and / or cineol are administered for administration at a daily dose in the range of 10 to 5,000 mg / diem, in particular in the range of 50 to 3,000 mg / diem, preferably in the range of 100 to 2,500 mg / diem, preferably in the range of 150 to 2,000 mg / diem, more preferably in the range of 200 to 1, 500 mg / diem.
  • the cinexoses used can vary within wide ranges.
  • the cineole is topically administered at a daily dose in the range from 0.1 to 2000 mg / d, in particular in the range from 0.5 to 1500 mg / d, preferably in the range from 1 to 1.
  • 000 mg / diem preferably in the range of 2 to 1 500 mg / diem, more preferably in the range of 5 to 1 000 mg / diem, or that the composition and / or cineol for administration with a daily dose in Range of from 0.1 to 2000 mg / d, in particular in the range of 0.5 to 1500 mg / d, preferably in the range of 1 to 1000 mg / d, preferably in the range of 2 to 150000 mg / that, especially preferably in the range of 5 to 1, 000 mg / diem, can be prepared.
  • provision may be made for departing from the stated values without departing from the scope of the present invention (which is at the discretion of the skilled person in each individual case).
  • composition according to the invention may also contain at least one further ingredient, in particular a further ingredient, in particular at least one excipient and / or an additive.
  • a further ingredient in particular at least one excipient and / or an additive.
  • the cineole according to the invention is used with at least one further ingredient, in particular at least one excipient and / or additive.
  • the at least one further ingredient, in particular adjuvant and / or additive in particular be selected from the group of processing aids, stabilizers, emulsifiers, antioxidants, humectants, thickeners, disinfectants, pH adjusters, pH buffering agents, preservatives, antiseptics, Dyes, flavorings, fragrances, fragrances, extenders, binders, wetting agents, vitamins, trace elements, mineral substances, micronutrients and / or essential oils and combinations thereof.
  • the composition according to the invention and / or the cineol can be used in supplementation, preferably in combination, with corticosteroids, in particular systemic or topical corticosteroids.
  • composition according to the invention and / or cineol can be used as an adjunctive therapeutic (co-therapeutic), preferably as a combination therapeutic, with corticosteroids, in particular systemic or topical corticosteroids.
  • composition according to the invention and / or cineole especially in co-therapy or in combination with corticosteroids, for reducing the need or replacement of corticosteroids in the prophylactic and / or therapeutic treatment of can be used in conjunction with rhinosinusitis with nasal polyps (RSwNP), in particular chronic rhinosinusitis with nasal polyps (CRSwNP), standing and / or associated nasal polyps (polyposis nasi et sinuum).
  • RSwNP nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • standing and / or associated nasal polyps polyposis nasi et sinuum
  • composition according to the invention and / or cineol in particular in co-therapy or in combination with corticosteroids, for increasing the activity and / or reducing the dose of corticosteroids in the prophylactic and / or therapeutic treatment of in Can be used in conjunction with rhinosinusitis with nasal polyps (RSwNP), in particular chronic rhinosinusitis with nasal polyps (CRSwNP), standing and / or associated and / or induced nasal polyps (Polyposis nasi et sinuum).
  • RSwNP rhinosinusitis with nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • standing and / or associated and / or induced nasal polyps Polyposis nasi et sinuum
  • composition according to the invention and / or cineol in particular in co-therapy or in combination with corticosteroids, for reducing or avoiding side effects of corticosteroids in the prophylactic and / or therapeutic treatment of nasal polyps (polyposis nasi et sinuum) which are related to and / or caused by rhinosinusitis with nasal polyps (RSwNP), in particular chronic rhinosinusitis with nasal polyps (CRSwNP).
  • nasal polyps polyposis nasi et sinuum
  • RSwNP rhinosinusitis with nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • the composition and / or the cineol is not used in supplementation, in particular not in combination, with non-steroidal anti-inflammatory drugs (NSAID) and / or wherein the composition and / or cineol are not Complementary therapeutic agent (co-therapeutic agent), in particular not as a combination therapy, with non-steroidal anti-inflammatory drugs (NSAID) is used.
  • NSAID non-steroidal anti-inflammatory drugs
  • co-therapeutic agent Complementary therapeutic agent
  • NSAID non-steroidal anti-inflammatory drugs
  • the cineol can be used in the form of a monotherapy or based on a monotherapeutic approach.
  • the present invention also relates to a composition, in particular a pharmaceutical composition, for use in the prophylactic and / or therapeutic treatment of rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (Polyposis nasi et sinuum ) (CRSwNP), preferably a composition as defined above, wherein the composition contains as active ingredient, in particular pharmaceutical active substance, cineol, preferably 1, 8-cineole, and
  • rhinosinusitis with polyps polyposis nasi et sinuum
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • CO nitric oxide
  • STAT protein Signal Transducers and Activators of Transcription Prote ' m
  • the Applicants has equally found that in the presence of the disease and the STAT proteins in question, in particular STAT 3, are up-regulated or excessively phosphorylated and that cineole has a regulating effect in this regard.
  • the activity or expression of NOS, in particular eNOS can be influenced by STAT, in particular STAT 3, without specifying or restricting this theory, namely, in particular, that STAT, in particular STAT 3, possibly as a transcription factor NOS, in particular eNOS.
  • the rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular the chronic rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (CRSwNP), one with an increased activity and / or increased regulation, in particular upregulation, and / or increased phosphorylation of the STAT protein (Signal Transducers and Activators of Transcription Prote ' m), in particular of STAT 3, related and / or associated, in particular induced thereby and / or favored disease.
  • composition and / or cineol may be used for prophylactic and / or therapeutic treatment of increased activity and / or increased regulation, particularly upregulation, and / or increased phosphorylation of the STAT (Signal Transducer and Activators of Tran Script of protein), in particular of STAT 3, related and / or associated thereby, in particular thereby induced and / or favored rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP).
  • STAT Signal Transducer and Activators of Tran Script of protein
  • composition and / or the cineol for regulating, in particular reducing and / or down-regulation and / or suppression and / or inhibition, of the activity of STAT protein (Signal Transducers and Activators of Transcription-Prote 'm), especially STAT 3 , are used.
  • Another object of the present invention - according to another aspect of the present invention - is cineole, in particular 1, 8-cineol, for use in the prophylactic and / or therapeutic treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic Nasal polyps (polyposis nasi et sinuum) (CRSwNP) rhinosinusitis, wherein rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP), one with a nitric oxide
  • the present invention is therefore in other words the use of cineol, in particular 1, 8-cineole, for the prophylactic and / or therapeutic treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular of chronic rhinosinusitis Polyposis nasi et sinuum) (CRSwNP), where rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP), one with a nitric oxide (NO) Metabolism, preferably a disease associated with the activity and / or regulation of at least one nitric oxide synthase (NOS), in particular endothelial nitric oxide synthase (eNOS).
  • RSwNP nasal polyps
  • Yet another object of the present invention - according to another aspect of the present invention - is also the use of a cineole, preferably 1, 8-cineole, as a pharmaceutical active ingredient-containing composition, in particular pharmaceutical composition, in particular as defined above, for prophylactic and / or therapeutic treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP), where rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), especially chronic rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (CRSwNP), one with a nitric oxide (NO) metabolism, preferably one with the activity and / or regulation of at least one nitric oxide synthase (NOS), in
  • RSwNP nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • rhinosinusitis is associated with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps ⁇ Polyposis nasi et sinuum) (CRSwNP), one with a nitric oxide (NO) metabolism, preferably one with the activity and / or regulation of at least one nitric oxide synthase (NOS), in particular endothelial nitric oxide synthase (eNOS), related disease and / or for the manufacture of a medicament for the prophylactic and / or therapeutic treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP), wherein rhinosinusitis with nasal polyps (Polyposis n
  • Yet another object of the present invention - according to another aspect of the present invention - is also a medicament for the prophylactic and / or therapeutic treatment of rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (CRSwNP), wherein rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP), one with a nitric oxide (NO) metabolism, preferably one with activity and / or regulation of at least one nitric oxide synthase (NOS), in particular endothelial nitric oxide synthase (eNOS), and / or for use in the prophylactic and /
  • a further subject of the present invention - according to a further aspect of the present invention - is an active ingredient combination, in particular in the form of a kit (kit-of-parts),
  • RSwNP nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • CRSwNP chronic rhinosinusitis with nasal polyps
  • eNOS endothelial nitric oxide Synthase
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide Synthase
  • nasal polyps polyposis nasi et sinuum rhinosinusitis
  • CRSwNP chronic nasal polyps rhinosinusitis
  • nasal polyps rhinosinusitis RSwNP
  • chronic rhinosinusitis RSwNP
  • nasal polyps rhinosinusitis RSwNP
  • chronic rhinosinusitis RSwNP
  • nasal polyps rhinosinusitis RSwNP
  • chronic rhinosinusitis with nasal polyps polyposis nasi et sinuum
  • NO nitric oxide
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • the combination of active substances in particular as spatially separated, but functionally coherent and / or components intended for co-medication or combination therapy, comprises
  • At least one corticosteroid preferably in the form of a corticosteroid-containing, topically or systemically to be administered pharmaceutical
  • another object of the present invention - according to a further aspect of the present invention cineol, in particular 1, 8-cineole, for the regulation, in particular reduction and / or reduction and / or suppression and / or inhibition, the activity of a Nitric oxide (NO) metabolism, in particular at least one nitric oxide synthase (NOS), preferably endothelial nitric oxide synthase (eNOS), in particular for regulation, in particular reduction and / or downregulation and / or suppression and / or inhibition, phosphorylation of at least one Nitric oxide synthase (NOS), in particular endothelial nitric oxide synthase (eNOS), preferably at serine-1 177, in particular for use in the prophylactic and / or therapeutic treatment of rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (RSwNP), in particular chronic rhinosinusitis with nasal polyps (Polyposis n
  • another object of the present invention - according to another aspect of the present invention - cineole, in particular 1, 8-cineole, for use in the prophylactic and / or therapeutic treatment of nitric oxide (NO) metabolism, preferably at least one Nitric oxide synthase (NOS), preferably endothelial nitric oxide synthase (eNOS), related and / or associated diseases, in particular induced and / or favored diseases thereof, in particular rhinosinusitis with nasal polyps (Polyposis nasi et sinuum) (RSwNP), preferably chronic rhinosinusitis with nasal polyps (polyposis nasi et sinuum) (CRSwNP), in particular rhinosinusitis with nasal polyps (polyposis nasi e
  • the cineole in particular as a regulator, preferably inhibitor and / or suppressor and / or inhibitor (inhibitor), at least one nitric oxide synthase (NOS), in particular endothelial nitric oxide synthase (eNOS), preferably as a regulator and / or reducer the phosphorylation of at least one nitric oxide synthase (NOS), in particular the endothelial nitric oxide synthase (eNOS), preferably on serine-1 177 used.
  • NOS nitric oxide synthase
  • eNOS endothelial nitric oxide synthase
  • cineole in particular 1, 8-cineole
  • the phosphorylation can be significantly reduced in particular at serine-1 177, which in turn leads to a reduction in the activity of NOS or eNOS, which in turn leads to a reduced synthesis of nitric oxide ( NO) and thus leads to a lower activity or downregulation of the relevant signal pathways. Consequently, those with the underlying symptoms associated with increased activity, or the condition as such.
  • Also according to this aspect of the invention can be very specific or selectively treat specific disease states, which conventional forms of therapy is not readily accessible or with such a specific or selective mode of action.
  • Nostrin and caspase 8 are in particular regulatory or effector proteins for eNOS, which in each case have an inhibiting effect on the activity of eNOS;
  • FIG. 2A is an expression profile determined on the basis of a Western blot analysis
  • FIG. 2B Results or evaluation of the Western blot analysis of the protein expression of eNOS or p-eNOS shown in FIG. 2A in the underlying nasal polyps (unshaded bars) on the one hand and lower turbinate (hatched bars) on the other hand in FIG decadic logarithmic plot; protein expression of eNOS in healthy lower turbinates serves as baseline; the Y-axis shows the percentage of control ("% of control”) in decadic logarithmic plot;
  • FIG. 4 shows relative expression of the genes (mRNA level) of nostrin (NOSTRIN), eNOS and caspase 8 (CASP8) in nasal polyp tissue in CRSwNP; the unshaded bars show the values determined without treatment with cineol (non-stimulated nasal polyps), and the shaded bars show the values determined under treatment with cineol (stimulated nasal polyps); the y-axis shows the relative expression in decadic logarithmic plot;
  • Figure 6A phosphokinase phosphorylation level of eNOS in nasal polyps in CRSwNP treated with cineole (NP 1, 8-cineole) in relation to non-cineol-treated and non-stimulated nasal polyps (NP); the y-axis shows the p-eNOS
  • FIG. 6B shows, by Western blot analysis, the degree of phosphorylation of eNOS at serine-1 177 in nasal polyp tissue in CRSwNP under treatment with cineole in relation to non-cineol-treated and non-stimulated nasal polyps; the Y axis shows the relative phosphorylation rate of eNOS at serine-1 177 (p-eNOS (1 177)) in decadal logarithm plots.
  • the y-axis shows the change in the phosphorylation rate of eNOS under cineole treatment in relation to non-cineol-treated or non-stimulated nasal polyps in decadic logarithmic application (y-fold change in the degree of phosphorylation or of the p-eNOS (1177) protein). expression).
  • the aim of the therapy concept according to the invention is, in particular, also a sustained relapse-free or at least an extension of the recurrence-free interval, in particular also due to the anti-inflammatory and corticosteroid-like action of cineol, in particular 1,8-cineole.
  • cineol in particular 1,8-cineole
  • cineol is capable of normalization in the presence of RSwNP or CRSwNP disinhibition of NOS metabolism, in particular eNOS metabolism.
  • the chronic rhinosinusitis with nasal polyps represents a significant health problem with a negative impact on the quality of life of patients dar.
  • the Applicant has the role of endothelial nitric oxide synthase (eNOS) with regard to the pathogenesis of rhinosinusitis with nasal polyps or investigated the nasal polyps associated with rhinosinusitis, in particular the gene and protein expression of eNOS and the related phosphorylation status in the presence of the disease has been investigated.
  • eNOS endothelial nitric oxide synthase
  • 1, 8-cineol on the presence of regulation of the eNOS signaling pathway and thus of NO production was investigated.
  • the influence of 1, 8-cineol on the cited gene or protein expression of eNOS in nasal polyps as well as the related influence of 1,8-cineole on the phosphorylation status of eNOS in nasal polyps.
  • eNOS as well as regulatory and effector proteins, namely nostrin (NOSTRIN) and caspase 8 (CASP8), were determined by total genome microarray, immunohistochemistry and Western blot.
  • NOSTRIN nostrin
  • CAP8 caspase 8
  • nasal polyps tissue samples from patients with CRSwNP incubated with 100 ⁇ 1, 8-cineol were analyzed using quantitative real-time PCR, Western blotting, and phosphorylation arrays.
  • CRSwNP or the associated nasal polyps have an increased activity or an increased phosphorylation of eNOS, which is of importance for the Vascular permeability, associated edema and increased inflammation may be.
  • 1, 8-cineol has a significant influence on eNOS and in this respect leads to a lower activity of eNOS, in particular the phosphorylation of eNOS is reduced. This may be, without wishing to be limited or limited to this theory, of importance in controlling or influencing the increased inflammation and edema formation caused by regulation of vascular permeability.
  • 1, 8-cineole acts as a potent inhibitor of eNOS activity and leads to a sharp decline in the cellular development of nasal polyps.
  • Applicant's data show that 1,8-cineol reduces the phosphorylation of eNOS, which likewise results in a decrease in the activity of eNOS and thus downregulation of the synthesis of nitric oxide (NO), so that the NO signaling pathways in this respect be inhibited.
  • the active ingredient 1, 8-cineol in particular, therefore, can lead to a weakening of the underlying disease symptoms or to a healing of the disease, in which case the risk of recurrence can be reduced.
  • Nasal polyp tissue, the corresponding lower turbinate tissue as an internal control and healthy lower nasal tissue were obtained from a total of 34 patients with a mean age of approximately 46 ⁇ 15 years, including 23 men (mean age approximately 43 ⁇ 15 years) and 1 1 women (mean age about 53 ⁇ 14 years) or 26 patients with CRSwNP (mean age about 50 ⁇ 14 years) and 8 healthy patients (mean age about 34 ⁇ 14 years) undergoing functional endoscopic sinus surgery (FESS) or a septoplasty with a reduction of the lower turbinate.
  • the fresh tissue samples were snap frozen immediately after resection in liquid nitrogen, stored at -80 ° C prior to RNA and protein extraction or used for experiments with 1,8-cineol.
  • nasal polyp tissue and lower nasal tissue were representatively analyzed by 8 patients (7 males and 1 woman, mean age about 54 ⁇ 13 years).
  • RNA samples were subjected to Agilent Whole Human Genome Microarray analysis (4x44K).
  • the RNA was extracted using standard RNA extraction protocols (Trizol) and quality controlled by the Agilent 2100 Bioanalyzer platform (Agilent Technologies).
  • the RIN value was calculated using RNA with a RIN> 6.
  • the Rosetta Resolver® gene expression data analysis system (Rosetta Biosoftware) was used to compare two individual intensity profiles in a ratio experiment. These experiments were performed in accordance with the "Minimal Information About a Microarray Experiment" (M IAME) guidelines.
  • the Proteome Profiler Human Phospho Kinase Array Kit (R & D Systems Inc, Minneapolis, Minnesota) allows for the simultaneous detection of the relative extent of phosphorylation of a total of 46 kinase phosphorylation sites. Capture and control antibodies were pipetted onto nitrocellulose membranes in duplicate. Tissue homogenates from polyp samples from five patients with chronic polypous rhinosinusitis (CRSwNP) and the lower turbinate as an internal control (250 ⁇ g total protein per array) were added to the phosphoprotein array according to the manufacturer's instructions. The pictures were taken using Fusion FX 7. Pixel density was analyzed using the Bio-1 D software (both Vilber Lourmat, Marne-Ia-Vallee, Cedex, France).
  • the tissues were homogenized and the proteins of all tissues were isolated by RIPA buffer (Cell Signaling, Danvers, MA, USA) containing 60 ⁇ aprotinin, 20 ⁇ PMSF, 20 ⁇ pepstatin A, 20 ⁇ leupeptin and 20 ⁇ phosphatase inhibitor Contained cocktail. Equal amounts of protein were separated by SDS-polyacrylamide gel electrophoresis using a 10% gel with internal standards (Protein Marker V, Peqlab, Er Weg, Germany) and transferred to a nitrocellulose membrane (0.45 ⁇ , Bio-Rad, Hercules, CA, USA).
  • the blots were blocked in TBS-T with 5% BSA for 60 min at room temperature and overnight at 4 ° C with specific antibodies to eNOS (1: 1000, # 5880, Cell Signaling, Danvers, MA, USA), p-eNOS (1: 1000, # 9570, Cell Signaling, Danvers, MA, USA), NOSTRIN (1: 500, SC-365031, Santa Cruz Biotechnology, Inc., Dallas, TX, USA) and CASP8 (1: 1000, # 4790, Cell Signaling, Danvers, MA, USA) in TBS-T with 3% BSA.
  • eNOS 1: 1000, # 5880, Cell Signaling, Danvers, MA, USA
  • p-eNOS 1000, # 9570, Cell Signaling, Danvers, MA, USA
  • NOSTRIN 500, SC-365031, Santa Cruz Biotechnology, Inc., Dallas, TX, USA
  • CASP8 1: 1000, # 4790, Cell Signaling, Danvers, MA, USA
  • Glyceraldehyde-3-phosphate dehydrogenase (# 21 18, Cell Signaling, Danvers, MA, USA) was used as a loading control.
  • Frozen tissue sections were air-dried and fixed for 10 min at 4 ° C in ice-cold (-20 ° C) methanol. The sections were washed three times in PBS overnight with primary antibodies to eNOS (1: 100, # 5880, Cell Signaling, Danvers, Mass., USA) and p-eNOS (1: 100, ab75639, Abcam PLC, Cambridge, MA). USA), washed three times in PBS and incubated for 45 min with anti-mouse Cy2 (1: 100, Jackson Immuno Research, West Grove, PA) and anti-rabbit Cy3 (1: 200, Jackson Immuno Research, West Grove, PA, USA). In addition, nuclear staining was performed with DAPI (Roche, Mannheim, Germany). Additional controls were added. The cells were examined under a microscope of the type Axiovert 200M (Carl Zeiss AG, Oberkochen, Germany).
  • Tissue samples were washed in phosphate buffered saline (PBS) (Gibco TM, Thermo Scientific, Waltham, Mass. USA), cautiously cut into small pieces with a scalpel blade, and enzymatically treated in an enzyme mixture solution of collagenase type II (31, 5 mg / ml).
  • PBS phosphate buffered saline
  • GIBCO Eggenstein, Germany
  • hyaluronidase (3.99 mg / ml, Sigma, Kunststoff, Germany
  • dispase 33.4 mg / ml, Sigma, Kunststoff, Germany).
  • Each 1 ml of enzyme is added to 15 ml of high purity serum-free DMEM (Gibco TM, Thermo Scientific, Waltham, MA USA) containing 1% L-glutamine and containing 10% FCS and 5% to 10% of antibiotics / antimycotics Solution (Gibco TM, Thermo Scientific, Waltham, MA USA).
  • the tissue sections were mixed with the digestive medium and incubated with shaking at 37 ° C for 120 min. After the enzymatic treatment, the cells were washed and centrifuged.
  • the dissociated cells were washed in PBS and filtered through a 70 ⁇ and a 40 ⁇ cell strainer made of nylon (Falcon, Becton Dickinson Labware, Heidelberg, Germany) to to prepare a single cell suspension.
  • the resulting cell suspension was cultured and subsequently either unstimulated or stimulated for 24 h with 100 ⁇ l of 1, 8-cineol (Klosterfrau Healthcare Group, Cassella-med GmbH & Co. KG, Cologne, Germany).
  • the proteins were isolated and the phosphorylation of the kinases is analyzed by the Proteome Profiler Human Phospho Kinase Array Kit (R & D Systems Inc, Minneapolis, Minnesota).
  • Tissue samples were washed in phosphate buffered saline (PBS) (Gibco TM, Thermo Scientific, Waltham, MA USA) and gently chopped into small pieces with a scalpel blade.
  • Tissue sections were cultured for 24 h in high glucose DMEM medium (Gibco TM, Thermo Scientific, Waltham, MA USA) containing 1% L-glutamine, 10% FCS, 5% antibiotic / antimycotic and either 100 ⁇ M of stimulant agent 1, 8-cineol (Klosterfrau Healthcare Group, Cassella-med GmbH & Co. KG, Cologne, Germany) or no stimulant (control). Subsequently, the mRNA was isolated for analysis of the eNOS signaling pathway.
  • PBS phosphate buffered saline
  • the Human eNOS Signaling TaqMan® Array allows the analysis of 92 genes associated with the eNOS signaling pathway and four endogenous control genes.
  • the transcriptional activity of the genes studied was analyzed using a LightCycler 96 (Roche, Mannheim, Germany).
  • the mRNA was isolated using a RNeasy Plus Mini Kit (Qiagen, Hilden, Germany) and cDNA-amplified using the RevertAid TM First Strand cDNA Synthesis Kit (Thermo Scientific, Waltham, MA USA). The experiments were carried out according to the manufacturer's instructions. Beta-actin was invariantly expressed under the experimental conditions, therefore mRNA levels of all selected genes in the patient were measured and normalized to ⁇ -actin. For analysis of the qPCR data, the 2 "AACt method was used. Statistical analysis
  • the Prism software (GraphPad, San Diego, USA) was used for statistical analysis and graphics. Mean and standard deviations were compared by Wilcoxon matched-pairs signed rank test, Mann-Whitney test or double ANOVA with Bonferroni post tests. P-values of ⁇ 0.05 were considered statistically significant.
  • a microarray analysis of the tissue of eight pairs of nasal polyps and the corresponding lower turbinates shows reduced gene expression of nostrin (NOSTRIN) and caspase (CASP8) as well as enhanced gene expression of eNOS in nasal polyps.
  • nostrin and caspase 8 are downregulated at the RNA level in nasal polyp tissue compared to the corresponding turbinate.
  • Nostrin and caspase 8 are proteins that affect the activity of eNOS, in that the proteins in question are capable of decreasing the activity of eNOS (see Figure 1).
  • a Western blot analysis shows the respective protein expression level of eNOS and p-eNOS (compare Fig. 2A, Fig. 2B).
  • NP nasal polyps
  • hIT the expression of eNOS in the nasal turbinate
  • eNOS is activated by phosphorylation on Ser-1 177 (p-eNOS (Ser1 177) and p-eNOS-1 177, respectively).
  • FIG. 2C shows the degree of phosphorylation of eNOS in nasal polyps and corresponding lower nasal turbinates, with each data point corresponding to a patient, and with each nasal turbinate including a nasal polyp, based on a phosphokinase array.
  • the carriage-like strokes correspond to the median, with a significant increase in the corresponding p-eNOS value (p-eNOS-1 177 (phosphorylation to serine-1 177)) being evident in the median.
  • Fig. 3 shows a clear staining of eNOS and p-eNOS-1 177 in nasal polyps, whereas in the lower turbinate the staining of eNOS and p-eNOS-1 177 is less pronounced and hardly exceeds the background signal.
  • FIG. 4 shows the relative expression of the respective genes under cineol treatment.
  • Figure 5 shows the expression of NOSTRIN, eNOS and CASP8 at the protein level in the nasal polyp after treatment with 1,8-cineol ( Figure 5).
  • FIG. 6A shows the phosphorylation status of eNOS after cineol treatment, with a significant reduction of the phosphorylation at the activating serine site 1 177 (serine-1 177) under the influence of cineole in the underlying phospho-kinase array.
  • the non-cineol-treated nasal polyps show significant phosphorylation of eNOS on serine-1 177.
  • a Western blot analysis performed in this context confirms this result (FIG. 6B).
  • CRSwNP a multifactorial disease
  • NO Nitric oxide
  • air pollutant is an extremely reactive chemical compound with a short half-life of a few seconds. Interestingly enough, it has been shown to act as a biological regulator in humans and animals. NO is present in almost all mammalian organ systems and is also present in the exhaled air of all humans. In addition, NO plays an important role in the biology of the lung and is involved in various lung diseases, including asthma.
  • eNOS increases the permeability of the vascular endothelium and in particular has a function in regulating blood flow, nasal secretion and ciliary movements.
  • the increased phosphorylation of eNOS and the associated protein activity in patients with chronic rhinosinusitis and nasal polyps may result in increased vascular permeability, which is associated with edema and increased inflammation.
  • Inhaled corticosteroids are an important treatment option in asthma.
  • CRSwNP may require a combination of drug and surgical treatment.
  • glucocorticosteroids are used as a primary therapy or for postoperative prophylaxis against recurrences.
  • Glucocorticosteroids have anti-inflammatory effects through protein / protein interactions, but they increase NO levels in the nose, with prolonged use increasing side effects.
  • 1,8-cineole in particular in the nasal polyp tissue in patients with chronic rhinosinusitis or CRSwNP, according to which 1, 8-cineol in particular the phosphorylation of eNOS which plays an important role in the pathogenesis of chronic rhinosinusitis with nasal polyps.
  • Lower eNOS activity is associated with decreased vascular permeability, which may counteract edema or excessive inflammation.
  • eNOS vascular permeability
  • 1, 8-cineole is shown to have an effect, in particular, on the phosphorylation of eNOS and thus on its activation, namely in that its excessive phosphorylation is particularly pronounced in the Polyp tissue and thus its activity is reduced, which is of particular importance in the management of increased inflammation and edema by regulating vascular permeability.
  • the potential etiological function of nasal nitric oxide is also taken into account in the mediation of persistent sinusitis, its reduction by 1, 8-cineol opening new perspectives with respect to its therapeutic use in RSwNP or CRSwNP, also as a phytotherapeutic alternative to glucocorticosteroids - steroids.
  • Preoperative CT images were scored according to the Lund Mackay score. The patients were asked to rate their complaints by means of a questionnaire (SNOT20 - German adapted version).
  • 1, 8-Cineol is thus a valuable supplement to the medical follow-up after sinus surgery.
  • the previously promising clinical application tests on the new effects and treatment options of 1,8-cineol found by the applicant are being continued and all patients previously treated with 1,8-cineol are regularly examined for the development of possible recurrences.

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Abstract

L'invention concerne une composition présentant une teneur en monoterpène, utilisée pour traiter des maladies du nez. Cette invention concerne en particulier une composition, notamment une composition pharmaceutique, destinée à être utilisée pour la prophylaxie et/ou le traitement d'une rhinosinusite avec polypes nasaux, en particulier une rhinosinusite chronique avec polypes nasaux, le principe actif de la composition se présentant sous la forme de cinéol, en particulier de 1,8-cinéol.
EP18711300.6A 2017-06-21 2018-03-13 Composition renfermant du cinéol utilisée pour traiter des maladies nasales Pending EP3585367A1 (fr)

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DE102017005865 2017-06-21
DE102017117836.8A DE102017117836A1 (de) 2017-06-21 2017-08-07 Cineolhaltige Zusammensetzung für die Behandlung von nasalen Erkrankungen
PCT/EP2018/056186 WO2018233884A1 (fr) 2017-06-21 2018-03-13 Composition renfermant du cinéol utilisée pour traiter des maladies nasales

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* Cited by examiner, † Cited by third party
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WO2022049581A1 (fr) * 2020-09-06 2022-03-10 M.H Medicane Ltd. Composition comprenant des cannabinoïdes, et/ou des terpènes, et ses méthodes d'utilisation

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DE102015119541A1 (de) * 2015-10-23 2017-04-27 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Monoterpenhaltige Zusammensetzung zur Behandlung von Erkrankungen der Nase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022049581A1 (fr) * 2020-09-06 2022-03-10 M.H Medicane Ltd. Composition comprenant des cannabinoïdes, et/ou des terpènes, et ses méthodes d'utilisation

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