WO1999024025A2 - Anti-inflammatoire ou inhibiteur de cox-ii non steroidien presentant peu d'effets secondaires - Google Patents

Anti-inflammatoire ou inhibiteur de cox-ii non steroidien presentant peu d'effets secondaires Download PDF

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Publication number
WO1999024025A2
WO1999024025A2 PCT/EP1998/007104 EP9807104W WO9924025A2 WO 1999024025 A2 WO1999024025 A2 WO 1999024025A2 EP 9807104 W EP9807104 W EP 9807104W WO 9924025 A2 WO9924025 A2 WO 9924025A2
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WO
WIPO (PCT)
Prior art keywords
steroidal
tumors
preparation according
cox
benign
Prior art date
Application number
PCT/EP1998/007104
Other languages
German (de)
English (en)
Other versions
WO1999024025A3 (fr
Inventor
Gisela Jacobasch
Jürg HEMPEL
Katrin Schmehl
Original Assignee
Deutsches Institut für Ernährungsforschung
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 Deutsches Institut für Ernährungsforschung filed Critical Deutsches Institut für Ernährungsforschung
Publication of WO1999024025A2 publication Critical patent/WO1999024025A2/fr
Publication of WO1999024025A3 publication Critical patent/WO1999024025A3/fr

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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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam

Definitions

  • the invention relates to a pharmaceutical preparation for the prophylaxis and / or therapy of benign and / or malignant tumors of the gastrointestinal tract.
  • aspirin has a certain inhibitory effect on the development of colorectal cancer.
  • Aspirin is a non-steroidal anti-inflammatory drug of the cyclooxygenase inhibitor type. With this finding, a positive therapeutic contribution of an inflammatory drug for colon cancer patients was postulated for the first time.
  • non-steroidal anti-inflammatories have been a focus of chemical-synthetic drug discovery and pharmacological and clinical characterization. It was found that the non-steroidal anti-inflammatories of a broad molecular spectrum of active substances were inhibited by cyclooxygenase I (COX-I) and later
  • CONFIRMATION COPY discovered cyclooxygenase II (COX II) and the intensity of systemic side effects; see. for example OA-97/09 977.
  • compositions for the prophylaxis and / or therapy of benign and / or malignant tumors of the gastrointestinal tract are now provided, which are characterized by a non-steroidal non-steroidal anti-inflammatory inhibitor or a non-steroidal cyclooxygenase type II inhibitor (COX- II) are marked.
  • the invention is based on the surprising finding that in an apc-defective min-mouse model which is comparable to the human clinical picture of familial adenomatous polyposis (FAP) and in FAP patients the formation of mtestinal polyps by oral administration of a anti-inflammatory or COX-II inhibitor as aspirin, for example from meloxicam, m almost completely prevented in contrast to the control group.
  • a anti-inflammatory or COX-II inhibitor as aspirin, for example from meloxicam
  • One embodiment of the invention relates to a pharmaceutical preparation for the prophylase and / or therapy of benign and / or malignant tumors of the gastrointestinal tract, the preparation being characterized as an active ingredient by a non-steroidal anti-inflammatory agent with few side effects.
  • a non-steroidal anti-inflammatory agent with few side effects.
  • Such a preparation can be characterized by a known, in particular a non-steroidal anti-inflammatory inhibitor with low side effects known for pharmaceutical preparations, wherein aspirin is excluded.
  • Another embodiment of the invention relates to a pharmaceutical preparation for the prophylaxis and / or therapy of benign and / or malignant tumors of the gastrointestinal tract, the preparation being characterized by a low-side-effect non-steroidal inhibitor of cyclooxygenase type II (COX-II) is.
  • COX-II cyclooxygenase type II
  • Such a preparation can be characterized by a known, in particular a low-side-effect non-steroidal inhibitor of cyclooxygenase type II (COX-II) known for pharmaceutical preparation, wherein aspirin is excluded.
  • COX-II cyclooxygenase type II
  • a preparation according to the invention can be characterized by a non-side-effect non-steroidal anti-inflammatory agent or cyclooxygenase type II inhibitor with a benzothiazm structure, preferably by an oxicam, in particular meloxicam, Tenoxicam or peroxicam.
  • Meloxicam (such as Mobec R ) is often prescribed by doctors despite the relatively short approval period. It is considered to be the most effective drug for the treatment of FAP patients. This applies to both preventive treatment and aftercare after surgical removal of an adenoma or carcinoma. This active ingredient is also promising for the treatment of patients with colorectal polyp formation that can be attributed to a somatic apc gene mutation. It is also not improbable that meloxicam also has a cytostatic effect on other malignancies. It should therefore be seen as an example of a new era of cytostatics that belong to the group of non-steroidal anti-inflammatory drugs (NSAIDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • a preparation according to the invention can be characterized by Sulmdac or one of its salts as an active ingredient.
  • the preparation according to the invention can be in a form suitable for oral administration or can be administered encapsulated rectally.
  • the preparation according to the invention can be used for the prophylaxis and / or therapy of benign and / or malignant tumors of the gastrointestinal tract, specifically
  • non-steroidal anti-inflammatory agents with little side effects or non-steroidal cyclooxygenase type II inhibitors with few side effects are suitable for pharmaceutical
  • pharmaceutical preparations are suitable for the prophylaxis and / or therapy of benign and / or malignant tumors of the gastrointestinal tract, it is possible for a person skilled in the art to isolate other suitable active substances in addition to the active substances mentioned above, in that
  • one or more non-steroidal non-steroidal cyclooxygenase type II (COX-II) inhibitors are tested for their suitability for the prophylaxis and / or therapy of benign and / or malignant tumors of the gastrointestinal tract with the help of apc-defective mice and isolated a suitable active ingredient.
  • Apc-defective Min mice were treated with meloxicam, the preparation Mobec% T3 being used as the source of the meloxicam. It was offered to the animals in a concentration of 20 mg / 1 drinking water. This corresponds to an average daily intake of approximately 0.060 mg. None of the experimental animals developed intestinal polyps under a 59 to 61-day meloxicam release, in contrast to untreated apc-defective mice, which had 53.2 ⁇ 32.7 polyps in part as carcinoma. After killing the animals, an examination of the organs showed no evidence of toxic side effects at the selected concentration of the preparation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des préparations pharmaceutiques utilisées pour la prévention et/ou le traitement de tumeurs bénignes et/ou malignes du tractus gastro-intestinal qui se caractérisent en ce qu'elles contiennent un anti-inflammatoire non stéroïdien présentant peu d'effets secondaires ou bien un inhibiteur non stéroïdien, présentant peu d'effets secondaires, de la cyclooxygénase de type II.
PCT/EP1998/007104 1997-11-06 1998-11-06 Anti-inflammatoire ou inhibiteur de cox-ii non steroidien presentant peu d'effets secondaires WO1999024025A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19749096.4 1997-11-06
DE1997149096 DE19749096A1 (de) 1997-11-06 1997-11-06 Nebenwirkungsarmer nicht-steroidaler Entzündungshemmer oder COX-II-Hemmer

Publications (2)

Publication Number Publication Date
WO1999024025A2 true WO1999024025A2 (fr) 1999-05-20
WO1999024025A3 WO1999024025A3 (fr) 1999-07-01

Family

ID=7847842

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/007104 WO1999024025A2 (fr) 1997-11-06 1998-11-06 Anti-inflammatoire ou inhibiteur de cox-ii non steroidien presentant peu d'effets secondaires

Country Status (2)

Country Link
DE (1) DE19749096A1 (fr)
WO (1) WO1999024025A2 (fr)

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
BOOLBOL ET AL: "cox-2 overexpression and tumor formation are blocked by sulindac in a murine model of fap" CANCER RES, Bd. 56, Nr. 11, 1996, Seiten 2556-2560, XP002101825 *
DUBOIS ET AL: "NSAIDs, eicosanoids and colorectal cancer prevention" GASTROENTEROL CLIN NORTH AM, Bd. 25, Nr. 4, 1996, Seiten 773-791, XP002101819 *
ELDER ET AL: "induction of apoptotic cell death in human colorectal carcinoma cell lines by a cox-2 selective NSAID" CLIN CANC RES, Bd. 3, Nr. 10, - Oktober 1997 Seiten 1679-1683, XP002101829 *
FISCHBACH ET AL: "sulindac inhibits tumor incidence and causes tumor regression but does act on proliferation in DMH treated rat colon" GASTROENTEROLOGY, Bd. 108, Nr. 4, 1995, Seite 468 XP002101827 *
HIXSON LET AL: "antiproliferative effect of NSAIDs against human colon cancer cells" CANCER EPIDEMIOL BIOMARKERS PREV, Bd. 3, Nr. 5, 1994, Seiten 433-438, XP002101824 *
JACOBASCH ET AL: "inhibition of intestinal tumor development in min mouse by treatment with resistant starch and NSAIDs" FASEB J, Bd. 11, Nr. 3, April 1997, Seite 611 XP002101820 *
LUK G.D.: "prevention of GI cancer, the potential role of NSAIDs in colorectal cancer" SCHWEIZ MED WOCHENSCHR, Bd. 126, Nr. 19, 1996, Seiten 801-812, XP002101821 *
MORGAN G.: "the potentia of NSAIDs in the prevention and treatment of colorectal carcinoma" EUR J SURG ONCOL, Bd. 22, Nr. 5, 1996, Seite 560 XP002101828 *
PEREIRA ET AL: "NSAIDs inhibition foci of aberrant crypts and cancer in rat colon" FASEB J, Bd. 3, Nr. 4, 1994, Seite a95 XP002101822 *
PIAZZA ET AL: "selective apoptosis of neoplastic cells accompanies polyp regression in fap patients treated with FGN-1 (sulindac sulfone)" GASTROENTEROLOGY, Bd. 112, Nr. 4, April 1997, Seite 638 XP002101826 *
REDDY B.S.: "chemoprevention on colon cancer by minor dietary constituents and their synthetic analogues" PREV. MED., Bd. 25, Nr. 1, 1996, Seiten 48-50, XP002101823 *
TSUJII ET AL: "cox-2 expression in human colon cancer cells increases metastatic potential" PROC NATL ACAD SCI USA, Bd. 94, Nr. 7, April 1997, Seiten 3336-3340, XP002101830 *

Also Published As

Publication number Publication date
WO1999024025A3 (fr) 1999-07-01
DE19749096A1 (de) 1999-05-12

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