WO2015114584A1 - Polydatine pour le traitement du vih chez des patients - Google Patents

Polydatine pour le traitement du vih chez des patients Download PDF

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Publication number
WO2015114584A1
WO2015114584A1 PCT/IB2015/050726 IB2015050726W WO2015114584A1 WO 2015114584 A1 WO2015114584 A1 WO 2015114584A1 IB 2015050726 W IB2015050726 W IB 2015050726W WO 2015114584 A1 WO2015114584 A1 WO 2015114584A1
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Prior art keywords
hiv
polydatin
patients
blood
cells
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PCT/IB2015/050726
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English (en)
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Mauro MATTEUZZI
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Ghimas SpA
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Ghimas SpA
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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
    • A61K31/70—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to uses of polydatin for the treatment of patients infected by HIV (HIV-positive) .
  • Our organism is not able to eradicate the HIV virus: the antibodies created cannot penetrate the contaminated lymphocyte and therefore the virus inside it cannot be neutralised .
  • the antiretroviral drugs currently available counter the action of the retroviruses, the group of viruses to which the HIV virus belongs. They are able to block the reproduction of the virus or slow down its progress. Different types of drugs exist with different specific actions: the therapy must therefore be prescribed and followed by a doctor able to dose and select the drug most suitable for the patient and the phase of the disease.
  • NRTI nucleoside reverse transcriptase inhibitors
  • NRTI non-nucleoside reverse transcriptase inhibitors
  • IP protease inhibitors
  • INR immunological nonresponders
  • Stilbenes of plant origin are part of the class of phytoalexins , natural molecules able to interact with the biological structures and activate repair processes and defence mechanisms against biotic stress, such as infections from pathogenic micro-organisms and abiotic stress such as oxidative stress.
  • resveratrol 3, 4 ',5- trans-tri-hydroxy-stilbene
  • resveratroloside a molecule that allows the existence of two conformational isomeric forms: cis and trans. Glycosylated forms of these isomers exist, such as resveratroloside and polydatin.
  • Polydatin (3, 5, 4 ' -dihydroxystilbene-3-0 ⁇ -D-glucopyranoside - also known as piceid) is a natural glucoside of resveratrol in which the glycoside group is bound in position C-3 where it substitutes a hydroxyl group.
  • glycoside group leads to conformational changes in the polydatin which are reflected in changes in the biological properties.
  • tumour models such as melanoma, breast cancer and colon cancer
  • its antitumoral activities are mediated via the modulation of various signal molecules, which regulate the progression of the cell cycle, the inflammation, proliferation, apoptosis, invasion, metastasization and angiogenesis of the tumour cells
  • Namasivayam N. Chemoprevention in experimental animals Ann N Y Acad Sci. 2011; 1215: 60-71; Shukla Y, Singh R. Resveratrol and cellular mechanisms of cancer prevention. Ann. N.Y. Acad. Sci. 2011; 1215: 1-8; Brisdelli F, D'Andrea G, Bozzi A.
  • Resveratrol a natural polyphenol with multiple chemopreventive properties. Curr Drug Metab. 2009; 10 (6) : 530-46; Lanzilli G, Cottarelli A, Nicotera G, Guida S, Ravagnan G, Fuggetta MP: Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation 2012, 35(1) :240-8; De Maria S, Scognamiglio I, Lombardi A, Amodio N, Caraglia M, Carteni M, Ravagnan G, Stiuso P. Polydatin, a natural precursor of resveratrol, induces cell cycle arrest and differentiation of human colorectal Caco-2 cell.
  • the object of the present invention is to provide new possibilities for the treatment of patients infected by HIV with low concentration of T CD4+ lymphocytes in the blood (in particular, patients immunologically not responding during the antiretroviral therapy) .
  • one object of the present invention is to provide a treatment for patients infected by HIV with low concentration of T CD4+ lymphocytes in the blood (in particular, patients immunologically not responding during the antiretroviral therapy) , said treatment being free from the drawbacks of the known art.
  • polydatin for use in the treatment of HIV a use of the polydatin for the production of a pharmaceutical preparation for the treatment of HIV, a method for the treatment of HIV according to the following independent claims and, preferably, in any one of the claims depending directly or indirectly on the independent claims.
  • polydatin is provided for use in the treatment (of HIV) of persons (patients) infected by HIV (HIV-positive) and with a concentration of T CD4+ lymphocytes (T CD4+ cells; a particular sub-group of lymphocytes) in blood lower than 500 (in particular, lower than 350) cells ⁇ L (of blood) .
  • the persons are human patients. More precisely, the patients are (have already been and are currently) subject to antiretroviral therapy.
  • the concentration of T CD4+ lymphocytes in the blood is measured by a method described in one of the following texts :
  • the concentration of T CD4+ lymphocytes in the blood is measured according to what disclosed in Mellors JW, Munoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, Kingsley LA, Todd JA, Saah AJ, Detels R, Phair JP, Rinaldo CR Jr. Plasma viral load and CD4p lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126: 983-985.
  • polydatin (or piceid) has the following structure :
  • the cited persons have a concentration of T CD4+ lymphocytes in the blood lower than 300 (in particular, lower than 200) cells ⁇ L (of blood) .
  • the concentration of T CD4+ lymphocytes in the blood is lower than 350 (more precisely, lower than 300; even more precisely, lower than 250) cells ⁇ L (of blood) after at least two years of highly active antiretroviral therapy (HAART) .
  • the cited persons have plasma HIV RNA values lower than 50 copies/ ⁇ (of blood) .
  • said plasma HIV RNA values remained below 50 copies/ ⁇ (of blood) for a period of at least 18 months.
  • the plasma HIV RNA values are measured with one of the methods described in one of the following documents: Hunt, PW, Cao, HL, Muzoore, C, Ssewanyana, I, Bennett, J, Emenyonu, N, Kembabazi, A, Neilands, TB, Bangsberg, D, Deeks, SG, Martin, JN. Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Kenyans initiating antiretroviral therapy. AIDS 2011;25;
  • C-reactive protein independently predicts HIV-related outcomes among women and children in a resource-poor setting. AIDS 21:2067-2075;
  • the plasma HIV RNA values are measured according to what is described in Mellors JW, Munoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, Kingsley LA, Todd JA, Saah AJ, Detels R, Phair JP, Rinaldo CR Jr. Plasma viral load and CD4p lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126: 983-985.
  • the persons (patients) are chosen from patients immunologically not responding during the highly active antiretroviral therapy (HAART) and non- responding patients that have been treated.
  • the persons (patients) are immunologically not responding during the highly active antiretroviral therapy (HAART) .
  • patients immunologically not responding during the highly active antiretroviral therapy it is meant patients with a concentration of T CD4+ lymphocytes in the blood lower than 350 (cells ⁇ L (of blood) ) after at least two years of highly active antiretroviral therapy and plasma HIV RNA values below 50 copies/ ⁇ (of blood) for at least 18 months .
  • non-responding patients that have been treated patients with a concentration of T CD4+ lymphocytes in the blood lower than 500 (cells ⁇ L (of blood) ) after at least two years of highly active antiretroviral therapy and at least one year of treatment with polydatin (at least 100 mg per day) and with plasma HIV RNA values below 50 copies/ ⁇ (of blood) for at least 18 months.
  • the highly active antiretroviral therapy is defined according to the contents of the "Italian guidelines on the use of antiretroviral drugs and diagnostic-clinical management of persons with HIV-1 infection" (Italian Ministry of Health, November 2013) .
  • each patient takes (in other words, is administered) a daily dose of polydatin of at least 100 mg (in particular, at least 120 mg) .
  • the daily dose is up to 500 mg of polydatin.
  • the daily dose is taken by (is administered to) each patient in at least 2 partial doses (in particular, up to 6 doses) .
  • the partial doses are taken at no more than 8 (more precisely, no more than 7) hours from one another.
  • said partial doses are taken (administered) at least 3 (more precisely, at least 4) hours from one another.
  • each partial dose is at least 20 (in particular, at least 40; more precisely, at least 60) mg of polydatin.
  • each partial dose is up to 120 (in particular, up to 100) mg of polydatin.
  • the polydatin is taken orally, in particular in tablet form.
  • the tablet normally comprises, furthermore, one or more pharmaceutically acceptable excipients (for example food grade fructose) .
  • a use of polydatin is provided for the production of a pharmaceutical preparation for the treatment (of HIV) of persons (patients) infected by HIV (HIV-positive) and with a concentration of T CD4+ lymphocytes (T CD4+ cells) in the blood lower than 500 (in particular, lower than 350) cells ⁇ L (of blood) .
  • polydatin (or piceid) has the following structure :
  • the cited persons are as defined according to the first aspect of the present invention.
  • each patient takes (in other words, to each patient is/are administered) doses of polydatin according to the first aspect of the first invention.
  • the polydatin is used for the production of a tablet.
  • the tablet furthermore normally comprises one or more pharmaceutically acceptable excipients (for example food grade fructose) .
  • a method for the treatment (of HIV) of persons (patients) infected by HIV (HIV-positive) and with a concentration of T CD4+ lymphocytes (T CD4+ cells; a particular sub-group of lymphocytes) in the blood lower than 500 (in particular, lower than 350) cells ⁇ L (of blood) .
  • polydatin (or piceid) has the following structure :
  • the cited persons are as defined according to the first aspect of the present invention.
  • each patient takes (in other words, to each patient is/are administered) doses of polydatin according to the first aspect of the first invention.
  • the polydatin is taken orally, in particular in tablet form.
  • the tablet normally comprises, furthermore, one or more pharmaceutically acceptable excipients (for example food grade fructose) .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de polydatine dans le traitement de patients séropositifs ne présentant pas de réaction immunologique à la thérapie antirétrovirale hautement active (HAART). L'administration expérimentale de polydatine à ces patients s'est avérée étonnamment efficace, du fait qu'elle a augmenté la concentration des cellules CD4 dans le sang des patients, au-delà même de 500 cellules/µL.
PCT/IB2015/050726 2014-01-31 2015-01-30 Polydatine pour le traitement du vih chez des patients Ceased WO2015114584A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITBO20140041 2014-01-31
ITBO2014A000041 2014-01-31

Publications (1)

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WO2015114584A1 true WO2015114584A1 (fr) 2015-08-06

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6479466B1 (en) * 1999-08-13 2002-11-12 University Of Maryland Compositions for treating viral infections, and methods therefor
WO2006019841A2 (fr) * 2004-07-13 2006-02-23 Government Of The United States Of America S
WO2009093007A2 (fr) * 2008-01-21 2009-07-30 The University Of York Immuno-modulation par des glycosides à modification régiosélective

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6479466B1 (en) * 1999-08-13 2002-11-12 University Of Maryland Compositions for treating viral infections, and methods therefor
WO2006019841A2 (fr) * 2004-07-13 2006-02-23 Government Of The United States Of America S
WO2009093007A2 (fr) * 2008-01-21 2009-07-30 The University Of York Immuno-modulation par des glycosides à modification régiosélective

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
"Italian guidelines on the use of antiretroviral drugs and diagnostic-clinical management of persons with HIV-1 infection", November 2013, ITALIAN MINISTRY OF HEALTH
"Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents", 12 February 2013, DEPARTMENT OF HEALTH AND HUMAN SERVICES, pages: 1 - 239
BRISDELLI F; D'ANDREA G; BOZZI A: "Resveratrol: a natural polyphenol with multiple chemopreventive properties", CURR DRUG METAB., vol. 10, no. 6, 2009, pages 530 - 46, XP009161382, DOI: doi:10.2174/138920009789375423
DE MARIA S; SCOGNAMIGLIO I; LOMBARDI A; AMODIO N; CARAGLIA M; CARTENI M; RAVAGNAN G; STIUSO P: "Polydatin, a natural precursor of resveratrol, induces cell cycle arrest and differentiation of human colorectal Caco-2 cell", JOURNAL OF TRANSLATIONAL MEDICINE, vol. 11, 2013, pages 264, XP021164423, DOI: doi:10.1186/1479-5876-11-264
DRAIN, P. K.; R. KUPKA; G. I. MSAMANGA; W. URASSA; F. MUGUSI; W. W. FAWZI: "C-reactive protein independently predicts HIV-related outcomes among women and children in a resource-poor setting", AIDS, vol. 21, 2007, pages 2067 - 2075
FELDMAN, J. G.; P. GOLDWASSER; S. HOLMAN; J. DEHOVITZ; H. MINKOFF: "C-reactive protein is an independent predictor of mortality in women with HIV-1 infection", J ACQUIR IMMUNE DEFIC SYNDR, vol. 32, 2003, pages 210 - 214
GOURLAY, A. J.; C. VAN TIENEN; S. S. DAVE; T. VINCENT; S. L. ROWLAND-JONES; J. R. GLYNN; H. C. WHITTLE; M. F. VAN DER LOEFF.: "Clinical predictors cannot replace biological predictors in HIV-2 infection in a community setting in West Africa", INT J INFECT DIS, vol. 16, 2012, pages E337 - 343
HUNT, PW; CAO, HL; MUZOORE, C; SSEWANYANA, I; BENNETT, J; EMENYONU, N; KEMBABAZI, A; NEILANDS, TB; BANGSBERG, D; DEEKS, SG: "Impact of CD8+ T-cell activation on CD4+ T- cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy", AIDS, 2011, pages 25
HUNT, PW; CAO, HL; MUZOORE, C; SSEWANYANA, I; BENNETT, J; EMENYONU, N; KEMBABAZI, A; NEILANDS, TB; BANGSBERG, D; DEEKS, SG: "Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy", AIDS, 2011, pages 25
JAFFAR, S.; M. S. VAN DER LOEFF; J. EUGEN-OLSEN; T. VINCENT; R. SARJE-NJIE; P. NGOM; A. M. MEYER; N. BERRY; P. AABY; H. WHITTLE: "Immunological predictors of survival in HIV type 2-infected rural villagers in Guinea-Bissau", AIDS RES HUM RETROVIRUSES, vol. 21, 2005, pages 560 - 564
KULLER, L. H.; R. TRACY; W. BELLOSO; S. DE WIT; F. DRUMMOND; H. C. LANE; B. LEDERGERBER; J. LUNDGREN; J. NEUHAUS; D. NIXON: "Inflammatory and coagulation biomarkers and mortality in patients with HIV infection", PLOS MED, vol. 5, 2008, pages E203
LANZILLI G; COTTARELLI A; NICOTERA G; GUIDA S; RAVAGNAN G; FUGGETTA MP: "Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation", INFLAMMATION, vol. 35, no. 1, 2012, pages 240 - 8, XP035016672, DOI: doi:10.1007/s10753-011-9310-z
MELLORS JW; MUNOZ A; GIORGI JV; MARGOLICK JB; TASSONI CJ; GUPTA P; KINGSLEY LA; TODD JA; SAAH AJ; DETELS R: "Plasma viral load and CD4p lymphocytes as prognostic markers of HIV-1 infection", ANN INTERN MED, vol. 126, 1997, pages 983 - 985
NAMASIVAYAM N.: "Chemoprevention in experimental animals", ANN N Y ACAD SCI., vol. 1215, 2011, pages 60 - 71
OSTROWSKI, S. R.; J. GERSTOFT; B. K. PEDERSEN; H. ULLUM: "Impaired production of cytokines is an independent predictor of mortality in HIV-1-infected patients", AIDS, vol. 17, 2003, pages 521 - 530
PFLIEGER AUDE ET AL: "Natural Stilbenoids Isolated from Grapevine Exhibiting Inhibitory Effects against HIV-1 Integrase and Eukaryote MOS1 Transposase In Vitro Activities", PLOS ONE, vol. 8, no. 11, November 2013 (2013-11-01), XP002729520 *
PHILLIPS; P. COLLABORATION: "Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes", LANCET, vol. 364, 2004, pages 51 - 62
SHUKLA Y; SINGH R: "Resveratrol and cellular mechanisms of cancer prevention", ANN. N.Y. ACAD. SCI., vol. 1215, 2011, pages 1 - 8
SOUSA, A. E.; J. CARNEIRO; M. MEIER-SCHELLERSHEIM; Z. GROSSMAN; R. M. VICTORINO: "CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load", J IMMUNOL, vol. 169, 2002, pages 3400 - 3406, XP055068484, DOI: doi:10.4049/jimmunol.169.6.3400
TAYLOR, JM; FAHEY, IL; DETELS, R; GIORGI, JV: "CD4 percentage, CD4 number, and CD4:CD8 ratio in HIV infection: which to choose and how to use", J ACQUIR IMMUNE DEFIC SYNDR, vol. 2, 1989, pages 114 - 124, XP000566938

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