WO2009040849A1 - Utilisation de l'acide aminé l-kynurénine et de ses dérivés pour le traitement de pathologies inflammatoires chroniques - Google Patents

Utilisation de l'acide aminé l-kynurénine et de ses dérivés pour le traitement de pathologies inflammatoires chroniques Download PDF

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Publication number
WO2009040849A1
WO2009040849A1 PCT/IT2008/000553 IT2008000553W WO2009040849A1 WO 2009040849 A1 WO2009040849 A1 WO 2009040849A1 IT 2008000553 W IT2008000553 W IT 2008000553W WO 2009040849 A1 WO2009040849 A1 WO 2009040849A1
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Prior art keywords
derivatives
kynurenine
acid
chronic inflammatory
allergy
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PCT/IT2008/000553
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English (en)
Inventor
Paolo Puccetti
Francesco Bistoni
Luigina Romani
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Paolo Puccetti
Francesco Bistoni
Luigina Romani
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Publication of WO2009040849A1 publication Critical patent/WO2009040849A1/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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention concerns the use of the L-kynurenine amino acid and derivatives thereof for the treatment of chronic inflammatory pathologies. More particularly, the invention refers to the use of the L-kynurenine amino acid and derivatives thereof for the treatment of chronic inflammatory pathologies like, for example, chronic granulomatous disease (CGD) and allergies.
  • Chronic granulomatous disease (CGD) is a pathology affecting phagocytes, white blood cells "scavengers" attacking and incorporating dead microorganisms and cells.
  • phagocytes are unable in killing some types of microorganisms: phagocytes normally move towards organism areas wherein an infection occurs, but are unable to carry out a reaction cascade resulting in microorganism "digestion". Due to this deficit, CGD affected patients are extremely susceptible to serious infections from bacteria and fungi (1).
  • infections can affect various tissues and organs: pneumonias, liver, spleen and lymphonode enlargement. Frequently the disease results in the development of granulomas (inflammatory tissues masses), which can occur in any part of the body. More often granulomas occur in skin, lungs, lymphonodes, liver or bone and, occasionally, they can block digesting or urinary tract.
  • CGD is inherited as chromosome X- linked recessive form. Only males are susceptible to this disease form, while females are healthy carriers (2).
  • An healthy carrier mother will have 25 % probability to conceive an affected male, 25 % probability for an healthy carrier daughter, 50 % probability for male or female healthy and not carrier.
  • a recessive autosomic inheritance occurs and, in this case, the disease indifferently affects males and females: an affected child can only be born if both parents are healthy carriers of the genetic modification.
  • An pair of healthy carriers will have 25% of possibility, at every pregnancy, to conceive an affected son or daughter, 50% of possibility to have an healthy son or daughter carriers, 25% of possibility for an healthy son or daughter and not carriers (3).
  • the healthy carriers can be identified with specific tests on a blood withdrawal.
  • the disease generating mutation i.e. the genetic error
  • DNA analysis it is possible to carry out the prenatal diagnosis; the possibility must carefully be evaluated at specialized Centres before the pregnancy onset.
  • CGD is a very serious disease and until some years ago affected persons had insufficient survival possibilities.
  • a therapy often resulting in successful results is based on gamma-interferon, a substance stimulating the immune system and limiting the occurrence of infections (5).
  • the bone marrow transplant can be used in order to recover from the disease definitively (6).
  • the present invention concerns the use of L-kynurenine amino acid and derivatives thereof for the treatment of chronic inflammatory pathologies.
  • chronic inflammatory pathologies there are allergies too.
  • Allergies are an excessive response to substances that generally are not dangerous for humans, representing parossistic immune response in comparison to normal.
  • immune system protects humans against pathogenic organisms, like bacteria, viruses or toxic substances.
  • the allergy is the response that an hyper-sensible immune system directs towards not pathogenic organisms. It is the first allergen exposure that provokes the individual allergic reaction and it results in that the same recognises allergen at every contact later on.
  • the symptoms occur at the second and subsequent exposures and are strictly dependent not only on the involved allergen in issue, but also on involved body portion and immune response intensity.
  • the allergen comes into contact with the individual immune system, it stimulates the antibody production, which bind to histamine containing cells. It is the production of this substance that results, for allergic patient, in typical symptoms generation: pruritus, affected tissue swelling, mucus hyper-secretion, muscular spasms.
  • the gravity and multiplicity of these symptoms are strongly subjective being variable depending on affected patient.
  • the more common allergens are food, drugs, various cosmetic contained compounds, various jewel or costume jewel contained metals bug punctures, dust mites, pollens and mildews, domestic animals.
  • Symptoms can vary as to intensity and typology depending on the response, involved body portion and patient immune system sensitivity. In general terms, however, some symptoms are common: rhinitis, cough, respiration difficulties, increased tearing, pruritus at contact zone (eyes, nose, throat, skin), cutaneous rash, vomit, diarrhoea, headache can occur.
  • the allergen is a drug or food
  • the or elimination test the suspected substance is respectively suspended or introduced in the patient therapy (in the case of drug) or diet (in the case of food) waiting for a reduction or exacerbation of the immune response.
  • high levels of antibodies and immunoglobulin (particularly IgE) or eosinophil increase indicate that the immune system already has come in contact with the allergen.
  • the therapies against allergies usually comprise, respectively, a short term therapy, aiming the elimination of the immediate symptoms, and a long term therapy, aiming the prevention of future allergic crises.
  • the allergies are treated with antihistaminic drugs, succeeding to alleviate light and moderated symptoms but, unfortunately, resulting in sleepiness, therefore the same are not appropriate when the patients are involved in managing potentially dangerous equipments, or driving, or whichever other situation wherein the attention is an essential requirement.
  • the nasal congestion it is advisable to use decongestant products, even if care is to be taken when these sprays are chronically used, because it can result in addiction.
  • the contact with the allergen in any case avoiding the contact with the allergen by far remains the better treatment for allergy (mainly where alimentary or pharmacological allergies are involved).
  • the allergic diseases result from the induction of helper (Th) 2 T-cells and IgE specific responses for the environmental common antigens (allergens) in susceptible individuals.
  • Th helper
  • IgE regulatory T-cell populations
  • Treg can actively prevent Th2 responses to allergens occurring in not-atopic individuals and function thereof can be weakened in allergic patients.
  • the therapies can act by means of modulation of Treg function.
  • Current searches aim the understanding of the mechanisms involved in the generation and function of allergen-specific Tregs.
  • a primary object is to promote the development of therapeutic regimes aiming the induction of inhibitory allergen-specific but at the same time long-lasting and localised mechanisms.
  • the immunotherapy consists of several injections over the time containing increasing doses of response triggering allergen in order that the organism is desensitised with respect to involved substance. Subcutaneous injections containing various allergen concentrations resulting in IgE decrease and IgG increase are carried out. Many patients took advantage of this type of treatment, and some thereof experienced a decrease of the allergy symptoms already one year after the therapy initiation. Usually immunotherapy is suspended after 3 years; although on one hand some patients have experienced good results also after the treatment suspension, on the other there are others which have showed a symptom worsening. In the most cases, however, immunotherapy has revealed an effective therapy for the treatment of allergic rhinitis, asthma and insect bites.
  • the allergic persons substantially consists of two large classes: one comprises people experimenting only annoying disturbs resulting from allergy (rhinitis, eye redness, mucus hypersecretion,...) and another comprises people unfortunately life threatening when contact the allergen, i.e. are subjected to the usually named anaphylactic shock. Most allergies are treated timely and successfully, but only as far as the current crisis; a later contact with the allergen will trigger another crisis anyway.
  • the desensitisation of the immune system resulting from immunotherapy can optimally prevent future allergic crises, but it is to be considered that injections can provoke cutaneous rash or, in some subjects, also anaphylactic shock.
  • this method can be only used for some allergens, like pollens, dust and similar ones, but not, as an example, for food allergies. It is also true anyway that the immunotherapy is proved to be effective in 2/3 cases, although a long term treatment is required.
  • the authors of the present invention have been studied new therapeutic approaches aiming the control of chronic inflammatory condition accompanying the allergic condition.
  • the attention has been focused on the immunological component controlling the inflammation and limiting the harmful effects thereof.
  • the authors of the present invention have demonstrated that by means of the treatment with exogenous kynurenine and gamma-interferon the allergic inflammatory symptoms are ameliorated.
  • L- kynurenine amino acid and derivatives thereof both natural, for example 3-hydroxykynurenine, anthranijic acid, 3-hydroxyanthranilic acid, quinolinic acid, and synthetic for use in medical field.
  • the present invention concerns moreover a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of L-kynurenine amino acid and/or derivatives thereof, both natural, for example 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and synthetic, possibly in combination with gamma-interferon, as active principle(s) in association with one or more pharmaceutically acceptable adjuvant and/or excipient.
  • These compositions can be advantageously used for the preparation of a medicament for the treatment of chronic inflammatory pathologies like, as an example, the chronic granulomatous disease and allergy, for example, allergic asthma.
  • the present invention therefore comprises also the use of the L-kynurenine amino acid and/or its it derivatives both natural, as for example 3-hydroxykynurenine, anthranilic acid, 3-hydrixyantranilic acid, quinolinic acid, and synthetic, eventually in combination with gamma- interferon, for the preparation of a medicament for the treatment of chronic inflammatory pathologies as, as for example, chronic granulomatous disease and allergy, as for example, allergic asthma.
  • L-kynurenine amino acid and/or derivatives thereof both natural, for example 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and synthetic, and ⁇ -interferon.
  • the invention concerns said combination for simultaneous, separated or sequential use in the therapy of chronic inflammatory pathologies like, for example, the chronic granulomatous disease and allergy, for example, allergic asthma. Therefore, the use of combination, as above defined, for the preparation of a medicament for the treatment of chronic inflammatory pathologies like, for example, chronic granulomatous disease and allergy, for example, allergic asthma, is a further object of the present invention.
  • FIG 1 shows that L-kynurenine is the first product of tryptophan metabolic degradation by an enzyme known as IDO. In CGD affected patients, this reaction does not occur due to the absence of "superoxide” cofactor.
  • Figure 2 shows the decrease of allergic parameters inflammation as the local production of hydroxyproline, mucin and IgE antibodies as a result of the treatment with kynurenine (L-kyn) and ⁇ interferon in comparison to treatment with placebo, kynurenine or ⁇ -interferon.
  • Figure 3 shows the decrease of eosinophils occurring in BAL as a result of the treatment with kynurenine (L-kyn) and ⁇ -interferon in comparison to treatment with placebo, kynurenine or ⁇ -interferon.
  • Example 1 Study on the effectiveness of the substitution therapy with exogenous kynurenine in CGD mouse
  • CGD mouse display an increased susceptibility to the pulmonary infection by Aspergillus fumigatus fungus, such that their intratracheal fungus colonization leads unavoidably to a lethal form of invasive aspergillosis. Therefore the working hypothesis has been that the correction of the metabolic defect (not production endogenous kynurenine) could be corrected by means of substitution therapy with exogenous kynurenine (i.e. synthetic, completely similar to natural one lacking in CGD mouse).
  • exogenous kynurenine has been administered to these animals, alone or in combination with ⁇ -interferon (IFN- ⁇ which promotes further metabolism thereof according to reaction scheme as shown in Fig. 1 , and the pharmacokinetic profile of exogenous kynurenine as well as the possible protection against a challenge otherwise lethal with A. fumigatus have been monitored.
  • Table 1 shows the kynurenine metabolism and survival of L-kynurenine treated mouse when infected with A. fumigatus.
  • CGD and healthy control mouse received subcutaneous implants with placebo or kynurenine (indicated as L-KYN) at day - 1 , and all the groups were infected intratracheally with A. fumigatus (5 x 10 6 ) at day 0.
  • Groups of L-KYN treated mouse received also IFN- ⁇ by subcutaneous way at day 1, 3 and 5 (20000 U/mice daily).
  • This second experimental model demonstrates that the restored infection resistance in CGD mouse by means of combination treatment with kynurenine and interferon substantially results from a restored microbicidal activity of those cells that, as above reported, characterise CGDI as a phagocyte affecting pathology, white blood cell "scavengers" attacking and incorporating microorganisms.
  • Example 3 Study on the effectiveness of the substitution therapy with exogenous kynurenine in ABPA expehmental model
  • L-KYN placebo or kynurenine
  • Total IgE in serum samples has been measured by means of immunoenzymatic assay (9).
  • Results clearly show a drastic reduction of the allergic inflammation parameters like local production of hydroxyproline and mucin as well as IgE antibodies (Figure 2) following the treatment with kynurenine and IFN- ⁇ .
  • Cienfuegos V. Hernandez-Bautista, and F. Espinosa-Rosales. 2006.

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  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

L'invention concerne l'utilisation de l'acide aminé L-kynurénine et de ses dérivés, à la fois naturels et synthétiques, pour le traitement de pathologies inflammatoires chroniques comme, par exemple, une granulomatose chronique familiale (CGD) et des allergies.
PCT/IT2008/000553 2007-08-21 2008-08-21 Utilisation de l'acide aminé l-kynurénine et de ses dérivés pour le traitement de pathologies inflammatoires chroniques WO2009040849A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITRM2007A000447 2007-08-21
IT000447A ITRM20070447A1 (it) 2007-08-21 2007-08-21 Uso dell'amminoacido l-chinurenina e dei suoi derivati per il trattamento delle patologie infiammatorie croniche.

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WO2009040849A1 true WO2009040849A1 (fr) 2009-04-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018044724A1 (fr) * 2016-08-31 2018-03-08 Ampio Pharmaceuticals, Inc. Traitement d'une maladie avec de la n-acétyl-kynurénine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1369114A1 (fr) * 2002-06-07 2003-12-10 Peter Priv. Doz. Dr. Terness Utilisation de métabolites du tryptophane comme agents pharmaceutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1369114A1 (fr) * 2002-06-07 2003-12-10 Peter Priv. Doz. Dr. Terness Utilisation de métabolites du tryptophane comme agents pharmaceutiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HEYLIGER S O ET AL: "The anti-inflammatory effects of quinolinic acid in the rat", LIFE SCIENCES, vol. 64, no. 14, 26 February 1999 (1999-02-26), pages 1177 - 1187, XP002515837, ISSN: 0024-3205 *
ROMANI LUIGINA ET AL: "Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease", NATURE (LONDON), vol. 451, no. 7175, January 2008 (2008-01-01), pages 211, XP002515838, ISSN: 0028-0836 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018044724A1 (fr) * 2016-08-31 2018-03-08 Ampio Pharmaceuticals, Inc. Traitement d'une maladie avec de la n-acétyl-kynurénine
US11478441B2 (en) 2016-08-31 2022-10-25 Ampio Pharmaceuticals, Inc. Treatment of disease with n-acetyl kynurenine

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