+

WO1998000119A2 - Utilisation nouvelle de principes actifs influant sur les fonctions d'acetylcholine non neuronale - Google Patents

Utilisation nouvelle de principes actifs influant sur les fonctions d'acetylcholine non neuronale Download PDF

Info

Publication number
WO1998000119A2
WO1998000119A2 PCT/EP1997/003415 EP9703415W WO9800119A2 WO 1998000119 A2 WO1998000119 A2 WO 1998000119A2 EP 9703415 W EP9703415 W EP 9703415W WO 9800119 A2 WO9800119 A2 WO 9800119A2
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
acetylcholine
active ingredient
skin
muscarinic
Prior art date
Application number
PCT/EP1997/003415
Other languages
German (de)
English (en)
Other versions
WO1998000119A3 (fr
Inventor
Ignaz Wessler
Original Assignee
Boehringer Ingelheim Pharma Kg
Boehringer Ingelheim International 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 Boehringer Ingelheim Pharma Kg, Boehringer Ingelheim International Gmbh filed Critical Boehringer Ingelheim Pharma Kg
Priority to AU32632/97A priority Critical patent/AU3263297A/en
Publication of WO1998000119A2 publication Critical patent/WO1998000119A2/fr
Publication of WO1998000119A3 publication Critical patent/WO1998000119A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline

Definitions

  • the present invention relates to a novel use of active ingredients with which the functions of non-neuronal acetylcholine - e.g. epithelial acetylcholine - can be influenced.
  • Acetylcholine acts as a central neurotransmitter in the central, peripheral and enteral nervous system. Accordingly, acetylcholine can be detected in the corresponding neurons.
  • acetylcholine does not only play a central role in neurons as a neurotransmitter, but that so-called non-neuronal acetylcholine plays an important role in human surface epithelium and is synthesized there by the enzyme choline acetyltransferase (ChAT).
  • ChAT choline acetyltransferase
  • non-neuronal acetylcholine can be detected in the surface epithelium of the human respiratory tract, the gastrointestinal tract - such as the small intestine, colon, sigma and gallbladder - in the vaginal mucosa, in the epidermis of human skin and in many other cells.
  • CONFIRMATION KDPIE Detection of ChAT enzyme activity in isolated epithelial cells - and detection of acetylcholine in epithelial cells using HPLC analysis.
  • the detection of non-neuronal acetylcholine can be done by simply "wiping" the corresponding surfaces with a cotton swab.
  • the cell material absorbed by the cotton contains so much acetylcholine that it is sufficient for analytical detection.
  • this method of sampling for example, neither the basement membrane (bronchi) nor the lamina muscularis mucosae (intestinum) is damaged, which prevents contamination of the extracts obtained from the cotton wool with cholinergic neurons.
  • the surface epithelium of human respiratory tract - like the human epidernis - is not innervated by cholinergic neurons.
  • Epithelial acetylcholine was surprisingly found along the entire intestinal tract - starting in the oral mucosa to the small and large intestine and in the gallbladder. The same applies to the respiratory tract, with acetylcholine being detected in both large and small bronchi. Epidermal acetylcholine was also found in the area of almost the entire body surface (upper and lower extremities, thorax, abdomen and back). A particularly pronounced ChAT-corresponding immunoreactivity was found in the growth zone of the hair, the hair follicles. In addition, acetylcholine was also detected directly in the human body hair.
  • acetylcholine was also used in epithelial cells to drain urine Pathways demonstrated, as well as in mesothelial cells (pleura, pericardium) as well as in certain immune cells (alveolar macrophages, mononuclear cells) and in glial lines.
  • non-neuronal acetylcholine regulates important functions of non-neuronal cells (epithelial cells): cell-cell contact, barrier function, lymphatic drainage, proliferation.
  • the present invention opens up the possibility of the aqueous diarrhea - as e.g. when cholera is observed - to be able to treat with topically acting antagonists on muscarinic receptors (non-selective and M1 -selective antagonists).
  • topically acting antagonists on muscarinic receptors non-selective and M1 -selective antagonists.
  • the therapy of inflammatory bowel diseases such as ulcerative colitis - with topically effective agonists at muscarinic / nicotine receptors, as this barrier disrupts the mucosal barrier function.
  • cystic fibrosis can be made possible according to the invention with topically acting agonists on muscarinic receptors, with non-selective or M1-selective agonists or topically active inhibitors of cholinesterase.
  • a therapeutic option for hypersensitivity with topically acting antagonists on muscarinic receptors (non-subtype-selective M1 receptors) is opened.
  • the present invention in skin diseases - such as, for example, wound healing disorders with - drugs that have a stimulating effect on the function of the epidermal cholinergic system - such as agonists on muscarinic or nicotine receptors, inhibitors of cholinesterase, activators of epidermal acetylcholine, activators for the release and enhancement with respect to the expression of the synthesizing enzyme ChAT - the access to a positive therapeutic effect.
  • the present invention enables the treatment of Alzheimer's disease by using activators of choline acetyl transferase (ChAT) in non-neuronal cells (glial cells).
  • acetylcholine In primary cultures of rat glial cells 2 + 0.7 pmol per 10 6 cells acetylcholine could be detected.
  • successful treatment for example atopic dermatitis, neurodermatitis, psorasis and, for example, cholinergic uterine artery - with active substances which have an inhibitory effect on the function of epidermal acetylcholine - such as antagonists on muscarinic or nicotine receptors , Inhibitors of choline acetyltransferase, inhibitors of epidermal acetylcholine release and reducers with regard to the expression of the synthesizing enzyme choline acetyltransferase.
  • Suitable topical agonists for the treatment of respiratory diseases are, for example, active substances such as those disclosed in German Offenlegungsschrift DE-OS 38 39 385 - in particular Wal 2014.
  • active substances such as those disclosed in German Offenlegungsschrift DE-OS 38 39 385 - in particular Wal 2014.
  • Compounds such as carbachol or acetylcholine themselves are considered.
  • DMPP dimethyl-4-phenylpiperazinium
  • DMPP dimethyl-4-phenylpiperazinium
  • topically active inhibitors of cholinesterase are, for example, compounds such as those in European Offenlegungsschrift EP-A-0 296 650 - in particular donepezil and its acid addition salts or active substances such as those in German Offenlegungsschrift DE-OS 38 05 744 - in particular SDZ -ENA-713 - are disclosed.
  • Topical antagonists on muscarinic receptors may be mentioned, for example - in addition to active ingredients as are known from the prior art - Atrovent, Propantelin, Buscopan, Alginor, Oxivent, Scopolamine and Atropine and compounds as are known from German Offenlegungsschrift 39 31 041 - in particular BA 679, BEA 2108 (bromide of endo-3 - [(hydroxy-di-2-thienylacetyl) oxy] -8,8-dimethyl-8-azonia-bicyclo [3.2.1] oct-6-ens) and BA 253 called.
  • nicotinic blockers such as, for example, tubocurarine, alcuronium, galamine and decamethonium and pancuronium.
  • tubocurarine alcuronium, galamin and decamethonium and pancuronium.
  • Sampling can be done, for example, by wiping the surface with a cotton swab.
  • the sample can be taken in such a way that the sample is obtained with a cotton wool roll, which may be moistened with a test liquid.
  • the so-called "cup” technique can be used to determine the acetylcholine from the skin, the oral mucosa and the vaginal mucosa.
  • a vessel suitable for sampling and charged with a liquid containing the acetylcholine is placed on the skin in such a way that the acetylcholine can diffuse into the device.
  • stimulation solutions known from the prior art can be used to determine the functionality of non-neuronal acetylcholine - such as solutions of nicotine, citric acid or ⁇ -adrenoreceptor agonists. Examples
  • Human tissue (bronchi, intestinal tissue) was obtained from surgical material that was obtained in the context of tumor and stone surgery.
  • Acetylcholine and ChAT activity was determined on mechanically or enzymatically isolated epithelial cells.
  • the luminal surface of the respective tissue was carefully wiped off with a cotton swab (Q-Tip).
  • the epithelial surface of intestinal tissue was examined in the same way, taking great care to ensure that the lamina muscularis mucosa with the underlying cholinergic, submucosal, plexus remained intact. A histological check was also carried out on this. Analogously, samples were taken from the epithelial surface of the oral mucosa or the vaginal mucosa.
  • the cotton swabs were extracted with 1 ml of a vol. 15% formic acid solution in acetone. The acetylcholine was then detected from this extract.
  • Epithelial cells of the human bronchi and small intestine were isolated enzymatically - by incubation (2 h at 36 ° C or 24 h at 4 ° C) with 0.1% pronase in a DMEM / F12 medium to isolate the epithelial cells and subsequent measurement of enzyme activity or for "western blot analysis" treated. Isolated epithelial cells were checked for their epithalial origin by staining with an antibody against pan-cytokeratin.
  • the acetylcholine content was determined in cotton swab extracts from surface epithelia and in homogenized human skin. The skin was placed in 1 ml of a 15% by volume solution of formic acid in acetone and crushed with a knife.
  • the extraction medium was centrifuged (10 min. 4000 rpm) and the supernatant was evaporated to dryness in a stream of nitrogen.
  • the sediment of the dried sample was resuspended in 300-500 ⁇ l of the mobile phase for the HPLC analysis.
  • a volume of 20 ⁇ l was injected, the acetylcholine being determined by cation exchange HPLC using electrochemical detection; the "BAS 481 Microbore System" was used for this. Choline and acetylcholine were chromatographed on a Sep Stik column (1 x 530 mm) with a mobile phase of a 40 mM phosphate buffer and 0.3 mM EDTA (adjusted to pH 8.5).
  • the analytical column was followed by a reaction step with an immobilized enzyme (Sep Stik IMER 2 / pkg), in which the acetylcholine was hydrolyzed.
  • the subsequent reaction with choline oxidase produced hydrogen peroxide, which washes around a platinum electrode (reference electrode Ag / AgCI, 0.5 V).
  • the resulting current is proportional to the amount of acetylcholine formed [Reinheimer, T., P. Bernedo, H. Klapproth, H. Oelert, B. Zeiske, K. Racke, and I. Wessler, 1996.
  • Acetylcholine in isolated airways of rat, guinea-pig, and human species differences in the role of airway mucosa, Am. J. Physiol. 14, L722-728], the detection limit for acetylcholine being 10 fmol per 20 ⁇ l injection volume [Ricny J., K.-D. Höhle, K. Racke and I. Wessler, 1995. Effect of inhaled steroids on cholinergic transmission in human isolated bronchi. Eur. Respir. J. 8: 587-589].
  • cotton swabs that had not come into contact with human tissue were extracted under analogous conditions. The extracts obtained in this way gave no signal for acetylcholine.
  • the ChAT protein could be detected immunohistochemically and by "Western blot analysis" using a polyclonal anti-ChAT antibody [Schemann, M., H. Sann, C. Schaaf, and M. Gurder, 1993, Identification of cholinergic neurons in enteric nerves by antibodies against choline acetyltransferase, Am. J. Physiol. 265, G1005-G1009].
  • a monoclonal anti-ChAT antibody was also used.
  • tumor-free, human tissue (bronchi, small intestine and stomach, skin) was flash-frozen with isopentane immediately after the operative isolation and then stored in liquid nitrogen. Frozen sections (4 ⁇ m) were made - each over a period of 15 min. - Permeabilized with 4% formaldehyde solution and by incubation with 0.1% Triton X-100 solution.
  • the visualization was carried out using the anti-ChAT antibody and the anti-rabbit IgG antibody-phosphatase conjugate.
  • ChAT enzyme activity was carried out in extracts of cotton swabs from smears of the intestinal surface or in extracts from enzymatically isolated epithelial cells (from human bronchi and small intestine) or from extracts of human skin.
  • ChAT assay was carried out according to methods which are known from the prior art [Reinheimer, T., P. Bemedo, H. Klapproth, H. Oelert, B. Zeiske, K. Racke, and I. Wessler, 1966. Acetylcholine in isolated airways of rat, guinea-pig, and human: species differences in the role of airway mucosa, Am. J. Physiol. In press and Ricny J., K.-D. Höhle, K. Racke and I. Wessler, 1995: Effect of inhaled steroids on cholinergic transmission in human isolated bronchi. Eur. Respir. J. 8: 587-589],
  • Enzymatically isolated epithelial cells were prepared from a DMEM / F12 medium by careful centrifugation (5 min, 200 rpm) and subsequent washing of the pellets thus obtained three times with 3 ml of phosphate-buffered saline solution.
  • the cell pellet or cotton swab was brought into contact with 0.5 1 ml of extraction buffer (10 mM Na2HP04, 100 NaCl, 2 mM EDTA, 0.5% (v / v) Triton X-100). After 15 minutes of ice cooling, the samples were centrifuged (3 min; 12,000 rpm; 0 ° C).
  • the selective inhibitor bromoacetylcholine was added to the assay buffer.
  • the protein content was determined according to Smith et al. [Smith, PK, R. Krohn, GT Hermanson, AK Mallia, FH Gärtner, MD Provenzano, EK Fujimoto, NM Goeke, BJ Olson, and DC Klenk (1985). Measurement of protein using bicinchoninic acid. Anal. Biochem. 150: 76-85].
  • acetylcholine in epithelial cells of the human respiratory tract indicates that important epithelial functions are regulated by non-neural acetylcholine (secretion, mucociliary clearance, barrier function, cell proliferation).
  • acetylcholine could be detected in the epithelial cells of the oral mucosa and the mucosa of the vagina.
  • the detection of epidermal acetylcholine and the observed cellular effects open up a new approach to the treatment of skin diseases - such as wound healing disorders - with pharmaceutical active substances which have a stimulating effect on the function of the epidermal, cholinergic system - such as e.g. Agonists on muscarinic or nicotine receptors, cholinesterase inhibitors, activators of epidermal acetylcholine, activators for the release and enhancement with regard to the expression of the synthesizing enzyme choline acetyltransferase.
  • skin diseases such as wound healing disorders - with pharmaceutical active substances which have a stimulating effect on the function of the epidermal, cholinergic system -
  • pharmaceutical active substances which have a stimulating effect on the function of the epidermal, cholinergic system -
  • e.g. Agonists on muscarinic or nicotine receptors e.g. Agonists on muscarinic or nicotine receptors, cholinesterase inhibitor
  • the unexpected findings described enable a new approach to the successful treatment of skin diseases - such as atopic dermatitis, neurodermatitis, psoriasis and cholinergic utricaria - with active substances that can inhibit the function of epidermal acetylcholine - such as Antagonists on muscarinic or nicotine receptors, inhibitors of choline acetyltransferase, inhibitors of epidermal acetylcholine release and inhibitors with regard to the expression of the synthesizing enzyme choline acetyltransferase.
  • active substances that can inhibit the function of epidermal acetylcholine - such as Antagonists on muscarinic or nicotine receptors, inhibitors of choline acetyltransferase, inhibitors of epidermal acetylcholine release and inhibitors with regard to the expression of the synthesizing enzyme choline acetyltransferase.
  • ChAT protein could be detected with both a poly and a monoclonal antibody.
  • a positive ChAT immunoactivity was also detected in mesothelial cells (eg pleura, pericardium). "Western blot analysis" for the ChAT protein in epithelial cells of human bronchi
  • the prominent band corresponds to the previously known 68 kd "neuronal" ChAT protein; in contrast, ChAT proteins with a lower molecular weight of 41 and 54 kd are found in epithelial cells of bronchial origin.
  • Bromoacetylcholine (30 uM), which is a specific ChAT inhibitor, reduced the enzyme activity by 80-90%.
  • the nutrient solution contained either the Addition of 1 ⁇ M atropine (blockade of muscarinic receptors) or 30 ⁇ M tubocurarine (blockage of nicotine receptors); the control was carried out without the addition of any medication. After 30 minutes and 2.5 hours, pieces of skin were removed from the medium and processed according to the prior art for electron microscopy.
  • tubocurarine control: 0.728 + 0.037 ⁇ m, count of 20 interfaces; tubocurarine: 0.926 + 0.118 ⁇ m, count of 20 interfaces, ⁇ ⁇ 0.001).
  • Small intestine pieces were obtained from fresh surgical material and incubated in an oxygenated nutrient solution in a manner similar to that described for skin. Instead of an electron microscopic examination, light microscopy was carried out after prior HE staining. It was found that atropine caused a significant expansion of small lymphatic vessels and lymphedema in the villous stroma compared to the control after 30 minutes of exposure. It is known that an intact function of "gap-juction" is necessary for the orderly contractile activity of small lymph vessels (Zawieja et al., Am J. Physiol 264, H1283-91, 1993). By blocking muscarinic receptors, ie by switching off the function of acetylcholine, a disturbance in the lymphatic flow was triggered. I 7
  • Bronchia were isolated from the surgical material and epithelial cells were obtained according to the state of the art (Reinheimer et al, Am J Physiol 270, L 722-8, 1996).
  • a standardized measuring method, the MTT method was used to measure cell proliferation (Bagge et al , J Immunol Meth 119, 203-10, 1989) It was found that added acetylcholine triggered a concentration-dependent increase in cell proliferation (0 1 nM - 10 ⁇ M), while bromoacetylcholine, an inhibitor of acetylcholine synthesis, causes antagonists of nicotine and antagonists Muscarinic receptors lead to an antiproliferative effect.
  • exogenous and endogenous acetylcholine inhibits the activation of mucosal mast cells in human bronchial tubes.However, this inhibitory control function takes place in a narrow concentration window, under the conditions of a highly regulated cholinergic system the functional control can be lost pro-inflammatory effect This can be enhanced by a stimulatory effect of acetylcholine on the synthesis and release of the pro-inflammatory cytokine GM-CSF from human bronchial epithelial cells. Exogenously applied acetylcholine increases the GM-CSF release from P ⁇ mark cultures more human bronchial epithelial cells two to three times. In an experiment on isolated human macrophages, it was found that after the blocking of nicotine and muscarinic receptors, an explosive migration with accompanying lysis of the cells occurred.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de détermination de l'état fonctionnel de l'acétylcholine non neuronale dans des tissus humains ou des cellules humaines directement accessibles ou accessibles par endoscopie, ainsi que l'utilisation de principes actifs susceptibles d'influer sur la synthèse, la libération, l'inactivation et la fonction de l'acétylcholine non neuronale.
PCT/EP1997/003415 1996-07-02 1997-07-01 Utilisation nouvelle de principes actifs influant sur les fonctions d'acetylcholine non neuronale WO1998000119A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32632/97A AU3263297A (en) 1996-07-02 1997-07-01 New use of active ingredients which affect non-neuronal acetylcholine functions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19626373A DE19626373A1 (de) 1996-07-02 1996-07-02 Neuartige Verwendung von Wirkstoffen, welche die Funktion von nichtneuronalem Acetylcholin beeinflussen
DE19626373.5 1996-07-02

Publications (2)

Publication Number Publication Date
WO1998000119A2 true WO1998000119A2 (fr) 1998-01-08
WO1998000119A3 WO1998000119A3 (fr) 1998-04-02

Family

ID=7798569

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/003415 WO1998000119A2 (fr) 1996-07-02 1997-07-01 Utilisation nouvelle de principes actifs influant sur les fonctions d'acetylcholine non neuronale

Country Status (4)

Country Link
AU (1) AU3263297A (fr)
DE (1) DE19626373A1 (fr)
WO (1) WO1998000119A2 (fr)
ZA (1) ZA975804B (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999008672A1 (fr) * 1997-08-15 1999-02-25 Shire International Licensing Bv Utilisateur d'un inhibiteur de cholinesterase pour traiter des maladies liees a l'activite de l'enzyme proteolytique
WO2001010427A3 (fr) * 1999-08-09 2001-09-20 Arakis Ltd Utilisation topique d'agents anti-muscarinique
WO2001080844A3 (fr) * 2000-04-21 2002-03-28 Inspire Pharmaceuticals Inc Methode de traitement de la keratoconjonctivite seche a l'aide d'agonistes des recepteurs de l'acetylcholine
WO2005072713A2 (fr) * 2004-01-27 2005-08-11 The Feinstein Institute For Medical Research Inhibiteurs de la cholinesterase pour traiter l'inflammation
US20070287733A1 (en) * 2004-10-12 2007-12-13 Ernir Snorrason Method of Treating Skin Diseases
US7994188B2 (en) 2001-03-13 2011-08-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg Compounds for treating inflammatory diseases
US20150297574A1 (en) * 2004-10-12 2015-10-22 I Ernir SNORRASON Method of treating skin diseases
JP2016510804A (ja) * 2013-03-15 2016-04-11 ヴェローナ ファーマ ピーエルシー 複合製剤
EP3456353A4 (fr) * 2016-05-09 2020-09-16 Nanoegg Research Laboratories, Inc. Composition pour le traitement ou la prévention de la dermatite atopique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066100A1 (fr) * 2002-02-07 2003-08-14 Eisai Co., Ltd. Stimulants de la pousse de cheveux, preparations percutanees et procede de stimulation de la pousse de cheveux

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1243729A1 (ru) * 1984-06-01 1986-07-15 Киевский государственный институт усовершенствования врачей Способ лечени нейродермита
US5084281A (en) * 1989-02-14 1992-01-28 Dillon Richard S Method and solution for treating tissue wounds
US5185350A (en) * 1991-09-23 1993-02-09 Hoechst-Roussel Pharmaceuticals Incorporated Substituted pyridinylamino-1h-indoles,1h-indazoles,2h-indazoles, benzo (b)thiophenes and 1,2-benzisothiazoles
US5550112A (en) * 1992-12-30 1996-08-27 Patent Biopharmaceutics, Inc. Hyaluronic acid-urea pharmaceutical compositions and uses

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999008672A1 (fr) * 1997-08-15 1999-02-25 Shire International Licensing Bv Utilisateur d'un inhibiteur de cholinesterase pour traiter des maladies liees a l'activite de l'enzyme proteolytique
WO2001010427A3 (fr) * 1999-08-09 2001-09-20 Arakis Ltd Utilisation topique d'agents anti-muscarinique
WO2001080844A3 (fr) * 2000-04-21 2002-03-28 Inspire Pharmaceuticals Inc Methode de traitement de la keratoconjonctivite seche a l'aide d'agonistes des recepteurs de l'acetylcholine
US7994188B2 (en) 2001-03-13 2011-08-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg Compounds for treating inflammatory diseases
WO2005072713A2 (fr) * 2004-01-27 2005-08-11 The Feinstein Institute For Medical Research Inhibiteurs de la cholinesterase pour traiter l'inflammation
WO2005072713A3 (fr) * 2004-01-27 2005-12-08 Long Island Jewish Res Inst Inhibiteurs de la cholinesterase pour traiter l'inflammation
US8003632B2 (en) 2004-01-27 2011-08-23 The Feinstein Institute For Medical Research Cholinesterase inhibitors for treating inflammation
US20070287733A1 (en) * 2004-10-12 2007-12-13 Ernir Snorrason Method of Treating Skin Diseases
US20150297574A1 (en) * 2004-10-12 2015-10-22 I Ernir SNORRASON Method of treating skin diseases
US9186345B2 (en) * 2004-10-12 2015-11-17 Hakon Hakonarson Method of treating skin diseases
US9730919B2 (en) * 2004-10-12 2017-08-15 Hakon Hakonarson Method of treating skin diseases
JP2016510804A (ja) * 2013-03-15 2016-04-11 ヴェローナ ファーマ ピーエルシー 複合製剤
US10471063B2 (en) 2013-03-15 2019-11-12 Verona Pharma Plc Drug combination of PDE3/PDE4 inhibitor and muscarinic receptor antagonist
EP3456353A4 (fr) * 2016-05-09 2020-09-16 Nanoegg Research Laboratories, Inc. Composition pour le traitement ou la prévention de la dermatite atopique

Also Published As

Publication number Publication date
WO1998000119A3 (fr) 1998-04-02
DE19626373A1 (de) 1998-01-08
AU3263297A (en) 1998-01-21
ZA975804B (en) 1998-01-02

Similar Documents

Publication Publication Date Title
DE10362194C5 (de) Verfahren zum Testen der Aktivität einer möglichen wirksamen Substanz, die die enzymatische Aktivität der Phospholipase A2 hemmen kann
DE3883035T2 (de) Saponinkomplexe mit Phospholipiden und sie enthaltende pharmazeutische und kosmetische Zusammensetzungen.
DE60029801T2 (de) Verwendung von einem produkt aus pflanzlichem öl zur erhöhung der hautlipiden produktion
DE60124715T2 (de) Verwendung von oligosacchariden zur stimulierung der produktion von beta-endorphin
EP0532465A1 (fr) Fraction protéinique pour les soins cosmétiques et dermatologiques de la peau
DE60019506T2 (de) Laminaria Algenextrakt, Verfahren zur Herstellung und diese enthaltende kosmetische oder pharmazeutische Zusammensetzungen
WO1998000119A2 (fr) Utilisation nouvelle de principes actifs influant sur les fonctions d'acetylcholine non neuronale
EP0095682B1 (fr) Procédé de préparation de produits régénérateurs de cellules et de tissus
DE69911614T2 (de) Komponenten mit niedrigem molekulargewicht aus knorpelgewebe von haien, verfahren zur herstellung und therapeutische verwendungen
WO2004075816A2 (fr) Procede pour produire des compositions contenant des flavonoides et leur utilisation
DE69430079T2 (de) Verfahren zur Herstellung von Oenothein-B aus Epilobium Parviflorum
EP0474597A2 (fr) Composés diphényls inhibiteurs du métabolisme de l'acide arachidonique et leur utilisation dans des compositions pharmaceutiques
EP0201053B1 (fr) Utilisation d'extraits de pollen pour préparer de compositions pharmaceutiques pour la prophylaxie d'allergies
EP0220453B1 (fr) Application d'extraits de pollen de plantes à la préparation de compositions pharmaceutiques ralentissant la croissance de cellules tumorales et procédé pour leur préparation
EP0145005B1 (fr) Tensio-actif pulmonaire, procédé de préparation et utilisation pharmaceutique
DE3787971T2 (de) Aktives prinzip, isoliert aus haigeweben.
DE2234832C2 (de) Proteinfreies Hormonkonzentrat von Säugetier-Nebenschilddrüsen, dessen Herstellung und dieses Hormonkonzentrat enthaltende pharmazeutische Präparate
DE69625804T2 (de) Aus aloe barbadensis isoliertes cinnamoyl-c-glykosid chromon
McLean The relation between the thromboplastic action of cephalin and its degree of unsaturation
DE2851629A1 (de) Biologisches peptolidpraeparat, verfahren zu seiner herstellung und dieses praeparat enthaltende arzneimittel
DE68928646T2 (de) Natriuretisches hormon
DE60000658T2 (de) Zusammensetzung zur behandlung von psoriasis
DE69724156T2 (de) Aus mycobacterium tuberculosis extrahierter kohlenwasserstoffkomplex und verfahren zu dessen herstellung
DE69015081T2 (de) Nicht-digoxinähnlicher Na+,K+-ATPaseinhibitorischer Faktor.
Gloor et al. Biochemical and physiological particularities on the skin surface of diabetics

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AU BG BR BY CA CN CZ EE HU IL JP KR KZ LT LV MX NO NZ PL RO RU SG SI SK TR UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AU BG BR BY CA CN CZ EE HU IL JP KR KZ LT LV MX NO NZ PL RO RU SG SI SK TR UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97532940

Format of ref document f/p: F

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载