WO2009087602A1 - Compositions et procédés de traitement et de prévention de la rectocolite hémorragique - Google Patents

Compositions et procédés de traitement et de prévention de la rectocolite hémorragique Download PDF

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Publication number
WO2009087602A1
WO2009087602A1 PCT/IB2009/050081 IB2009050081W WO2009087602A1 WO 2009087602 A1 WO2009087602 A1 WO 2009087602A1 IB 2009050081 W IB2009050081 W IB 2009050081W WO 2009087602 A1 WO2009087602 A1 WO 2009087602A1
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WIPO (PCT)
Prior art keywords
thiocyanate
compound
ulcerative colitis
isothiocyanate
treatment
Prior art date
Application number
PCT/IB2009/050081
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English (en)
Inventor
Miklós GEISZT
Original Assignee
Geiszt Miklos
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Publication of WO2009087602A1 publication Critical patent/WO2009087602A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the invention provides compositions and methods for treating and preventing ulcerative colitis (or colitis ulcerosa).
  • the compositions and methods of the invention are based on a novel use of thiocyanate or isothiocya- nate comprising compounds and other compounds useful for enhancing thiocyanate or isothiocyanate levels in the serum and/or in the colon.
  • IBD is a chronic, recurrent disease characterized by inflammation involving the colon. Crohn's disease (the other major version of IBD) is a chronic, recurrent disease where inflammation can occur in any part of the gastrointestinal tract. Despite many years of intense research, the pathogenesis of both major versions of IBD is still poorly understood. Understanding the molecular events, which lead to the pathogenesis of IBD would be essen- tial for the development of more effective, new therapeutic strategies. There are many observations suggesting that increased production of reactive oxygen species (ROS) in the intestinal mucosa has an important role in the development of IBD ( 1>2 ). The production of a high amount of ROS was observed in clinical biopsy samples of patients with IBD ( 3 ' 4 ).
  • ROS reactive oxygen species
  • ROS specifically superoxide
  • O 2 " can also react with nitric oxide (NO ) and form the highly reactive metabolite, peroxynitrite (OONO ⁇ ).
  • NO nitric oxide
  • OONO ⁇ peroxynitrite
  • Peroxynitrite then induces cytotoxic processes, partially through the nitration of tyrosine residues of proteins. The formation of nitro tyro sine residues was demonstrated in the biopsy samples of IBD patients ( 5 ).
  • the peroxidase - halide/pseudohalide - hydrogen peroxide host defense systems synthesize potent antimicrobial compounds through the oxidation of halide/pseudohalide ions into reactive species.
  • the major components of the human peroxidase - halide/pseudohalide - hydrogen peroxide host defense systems are as follows. Peroxidases
  • Lactoperoxidase is a member of the family of mammalian peroxidases.
  • Peroxidases are heme- containing enzymes, which use hydrogen peroxide H 2 O 2 to oxidize different substrates ( 8 ).
  • the structure of peroxidases is highly conserved across the plant and animal kingdom. They all contain specific amino acids in highly conserved locations and these amino acids are responsible for the binding of heme ( 8 ).
  • Mammalian peroxidases include myeloperoxidase (MPO), eosinophil peroxidase (EPO), thyroid peroxidase (TPO), lactoperoxidase (LPO) and peroxidasin. LPO was first described in milk where it is present in high concentration ( 9 ).
  • LPO is also a component in other exocrine secretions including the saliva and bronchial secretion ( 10 ).
  • the presence of LPO in tear and cervical fluid was also suggested, although genetic or immunological evidence were not pro- vided.
  • LPO is produced by exocrine glands, which include salivary glands, mammary glands and submucosal glands of the trachea and bronchi. Under physiological conditions LPO is the dominant peroxidase in the airways. However, when inflammation occurs neutrophil or eosinophil granulocytes migrate to these tissues and these cells contain high amount of MPO or EPO.
  • Hydrogen peroxide H 2 O 2
  • the phagocytic NADPH oxidase provides hydrogen peroxide.
  • This H 2 O 2 -producing system is effectively activated by different inflammatory cytokines and bacterial products ( ⁇ ).
  • the H 2 O 2 -SOUTCe of the LPO system is less clear although recent data suggest that Dual oxidases, which are present on mucosal surfaces, provide H 2 O 2 for the LPO-catalyzed reactions ( 12 ' 13 ). It was recently described the Dual oxidases (Duox enzymes) are also effectively upregulated by inflammatory cytokines including interferon- gamma, suggesting that during airway inflammation Duox-based H 2 O 2 production increases ( 14 ). Excessive hydrogen peroxide production has dangerous consequences for the host organisms, since hydrogen peroxide can interfere with different signaling pathways and also affects cell proliferation.
  • SCN thiocyanate
  • NCS isothiocyanate
  • F iodide
  • SCN seems to be the major substrate of LPO (exocrine secretions contain much higher concentrations of SCN " than I " or NCS " ).
  • Thiocyanate is oxidized into hypothiocyanate in the following lactoperoxidase catalyzed reaction:
  • hypochlorous acid and hypothiocyanate are both potent antimicrobial substances against a wide range of Gram positive and negative bacteria. Hypochlorous acid is a more effective weapon that hypothiocyanate, but it is also more toxic to the host organism ( 16 ).
  • peroxidases Beside the oxidation of halids/pseudohalids, peroxidases also effectively catalyze a different kind of biochemical reaction. They can cross-link proteins through tyrosine residues in a reaction where two tyrosine rings become covalently attached, thus forming dityrosine residues. In lower species this biochemical reaction is used for the stabilization of the extracellular matrix (such as the stabilization of cuticle in C. elegans and formation of the fertilization envelope during sea urchin fertilization) ( 17 ' 18 ).
  • Thiocyanate ions are ubiquitously present in several tissues and secretions. Thiocyanate is formed in the body during the detoxification of cyanide by rhodanase and thiocyanate is also present in food, especially in cabbage, cauliflower, etc.
  • the concentration of SCN " in the human serum is 50-200 ⁇ M, and in the human saliva 500-2000 ⁇ M.
  • the serum (and salivary) level of SCN " is dependent on the dietary intake of the anion and on the smoking habit of the individual. Smokers have much higher SCN " concentration in their blood (up to 300 ⁇ M), which is the result of increased cyanide uptake by smoking and its conversion into SCN " ( 19 ).
  • Thiocyanate is en- riched in the saliva through the action of the Na-iodide symporter, which is also responsible for the accumulation of iodide into the thyroid gland ( 20 ). Since SCN " and I " compete at the transporter, SCN " can inhibit the uptake of iodide into the thyroid gland leading to the inhibition of thyroid hormone biosynthesis. This inhibition frequently occurs in individuals who consume thiocyanate-rich food while their iodide uptake is low.
  • the object of this invention is, therefore, to elaborate novel uses and methods for the treatment and prevention of ulcerative colitis involving the activation of the lactoperoxidase based host defense system.
  • the invention is based on our original finding that LPO is expressed in the epithelium of the colon. This finding together with the previous, and so far not at all interpreted, observation present in the art that heavy smokers tend to develop ulcerative colitis shortly after abandoning smoking (whilst they are seemingly protected against the same disease while still smoking) led the present inventors to the surprising conclusion that the LPO/thiocyanate system might inhibit the development of the disease. This conclusion is further strengthened by the also known observation that serum and saliva thiocyanate levels of heavy smokers are significantly higher than normal.
  • the present disclosure is the first to demonstrate the protecting effect of thiocyanate ions in a relevant animal model of colitis (i.e. the dextran sodium sulfate (DSS) induced colitis model in mice). DETAILED DESCRIPTION OF THE INVENTION
  • Smokers have higher thiocyanate levels because they inhale cyanide during smoking, which is then metabolized to thiocyanate through sulfuration with thiosulfate by mitochondrial rho- danase ( 19 ). (Since no beneficial effect of smoking was described in patients with Crohn's disease, enhancing thiocyanate serum concentrations might not be beneficial in this specific disorder).
  • elevated SCN " serum and/or colon level boosts the LPO mediated host protection system against toxic ROS com- pounds and, on the other hand, also activates the LPO mediated antimicrobial self-protection system ( 22 ).
  • Elevated serum SCN " and/or colon levels can also reduce the potentially harmful tyrosine based crosslinking of proteins that may also play a role in the development of the inflammatory condition in the colon.
  • elevating serum and/or colon SCN " levels can also reduce the production of harmful ROS by other peroxidases expressed in the colon.
  • the early stage treatment (or prevention) of ulcerative colitis by SCN " therapy may be especially important, because the destruction of the epithelium in later stages of the disease might interfere with LPO expression, which seems to be essential in the effectiveness of the therapy.
  • SCN SCN
  • NCS NCS
  • Drugs containing thiocyanate included: Asthmolytan (VEB Pharmamed Naumburg), Mucidan (KaIi- Chemie, Hannover/BRD), Rhodapurin, Rhodasept C.
  • Asthmolytan Asthmolytan
  • Mucidan KaIi- Chemie, Hannover/BRD
  • Rhodapurin Rhodasept C.
  • Thiocyanate containing drugs were used to treat asthma (although in Asthmolytan ephedrine seems to be the effective component), hypertension, inflammation of the oral cavity, pharingitis and were used in antiseptic formulations.
  • Serum and/or colon SCN “ (or NCS " ) concentrations may be advantageously elevated by the administration of SCN (or NCS) compounds (advantageously pharmaceutically acceptable salts) via the oral or parenteral route.
  • SCN or NCS
  • Other sources of serum thiocyanate might include glucosinolates, which are present in many plants (especially in the family of Brassicaceae).
  • Other compounds e.g. nitriloside
  • the metabolic conversion of which provides for the formation of thiocyanate ions might also be effective in elevating serum SCN " concentration.
  • a person skilled in the pertinent art can easily determine whether a candidate compound is suitable for elevating the thiocyanate or isothiocyanate ion concentrations in the serum or colon of a subject to be treated in accordance with the present invention.
  • Such compounds obviously include pharmaceutically acceptable thiocyanate or iso- thiocyanate salts, and compounds like different glucosinolates and nitriloside, the metabolic conversion of which is known to be resulting in the elevation of serum thiocyanate levels.
  • the present invention provides for a compound the dissolution or metabolic conversion of which provides for the formation of thiocyanate or isothiocyanate ions, for use in the prevention or treatment of ulcerative colitis.
  • the compound of the invention is advantageously selected from the group consisting of thiocyanate and isothiocyanate salts, glucosinolate compounds and nitriloside.
  • the compound of the invention is advantageously used as an active ingredient of a pharmaceutical composition or a food additive.
  • the invention further provides for the use of a compound, the dissolution or metabolic conversion of which provides for the formation of thiocyanate or isothiocyanate ions, for producing a pharmaceutical composition or a food additive suitable for the treatment or prevention of ulcerative colitis.
  • the used compound is advantageously selected from the group consisting of thiocyanate and isothiocyanate salts, glucosinolate compounds and nitriloside.
  • the invention also concerns pharmaceutical compositions or food additives for use in the prevention or treatment of ulcerative colitis, wherein said pharmaceutical composition or food additive comprises a compound the dissolution or metabolic conversion of which provides for the formation of thiocyanate or isothiocyanate ions.
  • compositions or food additives produced or applied in accordance with the invention are advantageously formulated for oral or parenteral administration and oral compositions according to the in- vention are advantageously optimized for releasing thiocyanate or isothiocyanate ions predominantly in the colon, thereby specifically providing for the elevation of the concentration of thiocyanate or isothiocyanate ions in the colon.
  • oral compositions with coatings ensuring the release of the effective ingredients mostly in the colon (see e.g. the well established art pertaining to the production of the so called "enteric coated” oral compositions), specifically providing thereby for e.g. the elevation of the concentration of thiocyanate or isothiocyanate ions therein.
  • the invention also enables the production of pharmaceutical compositions optimized for preventive administration to subjects who abandoned smoking and, therefore, are in enhanced risk of developing ulcerative colitis.
  • the invention also concerns a method for producing a pharmaceutical composition or a food additive suitable for the prevention or treatment of ulcerative colitis, said method comprising the mixing of a compound the dissolution or metabolic conversion of which provides for the formation of thiocyanate or isothiocyanate ions with pharmaceutically acceptable carriers and/or other additives.
  • the invention further provides for a method of treating or preventing ulcerative colitis comprising administering an effective amount of a composition comprising, as an active ingredient, a compound the dissolution or metabolic conversion of which provides for the formation of thiocyanate or isothiocyanate ions, to a patient suf- fering from or having a risk of developing ulcerative colitis.
  • a composition comprising, as an active ingredient, a compound the dissolution or metabolic conversion of which provides for the formation of thiocyanate or isothiocyanate ions
  • the administration of compositions comprising compounds the dissolution or metabolic conversion of which provides for the formation of thiocyanate or isothiocyanate ions is advantageously done via the oral or parenteral route.
  • the invention also concerns a method for preventing the onset of ulcerative colitis in individuals who abandoned smoking.
  • Fig. 1 shows the results of a Northern blot experiment performed on colon total RNA isolates, demonstrating the expression of LPO mRNA in both mouse and rat colon (the 957 bp Dra III fragment of the mouse LPO cDNA was used as an LPO specific probe).
  • Fig. 2 is a graph showing the effect of SCN treatment on the disease activity index (DAI) of mice having DSS-induced colitis.
  • Fig. 3 is a graph showing the effect of SCN treatment on DSS-induced mortality in mice.
  • Fig. 4 is a graph showing the effect of SCN treatment on colon length reduction induced by DSS in mice.
  • LPO mRNA in the mouse and rat colon was studied by Northern blot analysis.
  • a 957 bp fragment of the mouse LPO cDNA was generated by Dra III cut. Radioactive labeling was performed by Prime- It® Random Primer Labeling Kit (Stratagene) using [ ⁇ - 32 P]dCTP.
  • total RNA was prepared from mouse and rat colon, electrophoretically separated on a 1% agarose formaldehyde gel and transferred to nylon membrane. Membranes were probed at 60 0 C by standard hybridization protocols. As can be seen on Fig. 2, both rat and mouse colon RNA isolates proved to be positive for LPO mRNA expression.
  • DSS Dextran sodium sulfate

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention concerne des compositions et des procédés de traitement et de prévention de la rectocolite hémorragique. Les compositions et les procédés de l'invention reposent sur l'utilisation innovante de composés à thiocyanate ou à isothiocyanate et d'autres composés utiles pour augmenter les taux de thiocyanate ou d'isothiocyanate dans le sérum et/ou dans le colon.
PCT/IB2009/050081 2008-01-10 2009-01-09 Compositions et procédés de traitement et de prévention de la rectocolite hémorragique WO2009087602A1 (fr)

Applications Claiming Priority (2)

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HUP0800012 2008-01-10
HU0800012A HU0800012D0 (en) 2008-01-10 2008-01-10 Novel use and methods for the treatment and prevention of ulcerative colitis

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014049044A1 (fr) * 2012-09-26 2014-04-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la colite ulcéreuse

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2346325A (en) * 1999-02-02 2000-08-09 Wassen Int Ltd Formulation comprising a brassica extract or sulforaphane and resveratrol
WO2003068202A1 (fr) * 2002-02-15 2003-08-21 Dsm Ip Assets B.V. Compositions comportant du lycopene destinees au traitement et a la prevention des pathologies associees a l'angiogenese
WO2006006933A2 (fr) * 2004-07-15 2006-01-19 Glucogene Medical Hfm Ab Nouvelles compositions
US20070042061A1 (en) * 2005-08-18 2007-02-22 Ribnicky David M Anti-inflammatory activity of phenethylisothiocyanate (PEITC) and the Barbarea verna seed preparation containing this compound
CN101088497A (zh) * 2006-06-27 2007-12-19 张宏宇 一种含有番茄红素与硫葡萄糖甙的组合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2346325A (en) * 1999-02-02 2000-08-09 Wassen Int Ltd Formulation comprising a brassica extract or sulforaphane and resveratrol
WO2003068202A1 (fr) * 2002-02-15 2003-08-21 Dsm Ip Assets B.V. Compositions comportant du lycopene destinees au traitement et a la prevention des pathologies associees a l'angiogenese
WO2006006933A2 (fr) * 2004-07-15 2006-01-19 Glucogene Medical Hfm Ab Nouvelles compositions
US20070042061A1 (en) * 2005-08-18 2007-02-22 Ribnicky David M Anti-inflammatory activity of phenethylisothiocyanate (PEITC) and the Barbarea verna seed preparation containing this compound
CN101088497A (zh) * 2006-06-27 2007-12-19 张宏宇 一种含有番茄红素与硫葡萄糖甙的组合物

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DATABASE WPI Week 200835, Derwent World Patents Index; AN 2008-F02419, XP002527103 *
KRAFT DANIEL ET AL: "Interaction of cyanide with sulfide detoxification in the colonic mucosa: An explanation for the beneficial effect of smoking on ulcerative colitis?", GASTROENTEROLOGY, vol. 132, no. 4, Suppl. 2, April 2007 (2007-04-01), & DIGESTIVE DISEASE WEEK MEETING/108TH ANNUAL MEETING OF THE AMERICAN-GASTROENTEROLOGICAL-ASSOCIATION; WASHINGTON, DC, USA; MAY 19 24, 2007, pages A228, XP008105645, ISSN: 0016-5085 *
KRISTAL ALAN R ET AL: "Brassica vegetables and prostate cancer risk: a review of the epidemiological evidence.", NUTRITION AND CANCER 2002, vol. 42, no. 1, 2002, pages 1 - 9, XP008106063, ISSN: 0163-5581 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014049044A1 (fr) * 2012-09-26 2014-04-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la colite ulcéreuse

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