Compositions and methods for treating obesity, obesity related disorders and for inhibiting the infectivity of human immunodeficiency virus

Abstract

The present invention relates to methods and pharmaceutical compositions for treating obesity or obesity-related disorders in a subject suffering from or predisposed to developing obesity or an obesity-related disorder, or for inhibiting the infectivity of HIV, by administering oleuropein, an analogue or derivative thereof, or the major metabolites of oleuropein including oleuropein aglycone, hydroxytyrosol, and elenolic acid or their analogues, or derivatives thereof, an iridoid glycoside, or a secoiridoid glycoside or analogues or derivatives thereof, or any combination of the foregoing including olive leave extract. The invention also relates to methods for screening/diagnosing a subject having, or predisposed to having obesity or a related disorder by measuring the expression profiles of an adipogenic gene selected from PPARγ2, LPL and αP2 gene and gene product, or other adipogenic, lipogenic, or lipolytic genes and gene products in an individual. The invention further provides for screening for novel oleuropein analogues.

1 . A method of modulating adipocyte differentiation or adipogenic gene or gene product expression or lipolytic gene or gene product expression, comprising administering a therapeutically effective amount of oleuropein or an analogue, derivative, or oleuropein aglycone or their analogues, or derivatives thereof, or hydrotyrosol, or dihydroxy phenol or their analogues, or derivatives thereof, or elenolic acid or their analogues, or derivatives thereof, or an iridoid glycoside, or a secoiridoid glycoside or their analogue, derivative, or any combination thereof including but not limited to olive leave extract to a mammalian subject in need thereof. 
     
     
         2 . A method of treating, controlling or preventing obesity, or of reducing body weight, or of inhibiting fat accumulation in vivo, or of promoting fat burning in vivo, comprising administering a therapeutically effective amount of oleuropein or an analogue, derivative or oleuropein aglycone or their analogues, or derivatives thereof, or hydrotyrosol, or dihydroxy phenol or their analogues, or derivatives thereof, or elenolic acid or their analogues, or derivatives thereof, or an iridoid glycoside, or a secoiridoid glycoside or their analogue, derivative, or any combination thereof including but not limited to olive leave extract to a mammalian subject in need thereof. 
     
     
         3 . A method of treating, controlling or preventing the onset of one or more obesity related disorders or conditions selected from the group consisting of diabetes mellitus, hyperglycemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertension, hypertriglyceridemia, insulin resistance, or hyperinsulinemia, in a mammalian subject in need of treatment, comprising administering a therapeutically effective amount of oleuropein or an analogue, derivative or oleuropein aglycone or their analogues, or derivatives thereof, or hydrotyrosol, or dihydroxy phenol or their analogues, or derivatives thereof, or elenolic acid or their analogues, or derivatives thereof, or an iridoid glycoside, or a secoiridoid glycoside or their analogue, derivative, or any combination thereof including but not limited to olive leave extract. 
     
     
         4 . A method of treating, controlling or preventing the onset of one or more obesity related disorders or conditions selected from the group consisting of Asthma and related diseases including but not limited to, Allergy, Atopic Dermatitis (Eczema), Gastroesophageal Reflux Disease, Pneumothorax, Airway, Pulmonary and Lung disorders, Churg-Strauss Syndrome in a mammalian subject in need of treatment, comprising administering a therapeutically effective amount of oleuropein or an analogue, derivative or oleuropein aglycone or their analogues, or derivatives thereof, or hydrotyrosol, or dihydroxy phenol or their analogues, or derivatives thereof, or elenolic acid or their analogues, or derivatives thereof, or an iridoid glycoside, or a secoiridoid glycoside or their analogue, derivative, or any combination thereof including but not limited to olive leave extract. 
     
     
         5 . A method of treating, controlling or preventing the onset of one or more obesity related disorders or conditions selected from the group consisting of AIDS and HAART related diseases including but not limited to lipodystrophy in a mammalian subject in need of treatment, comprising administering a therapeutically effective amount of oleuropein or an analogue, derivative or oleuropein aglycone or their analogues, or derivatives thereof, or hydrotyrosol, or dihydroxy phenol or their analogues, or derivatives thereof, or elenolic acid or their analogues, or derivatives thereof, or an iridoid glycoside, or a secoiridoid glycoside or their analogue, derivative, or any combination thereof including but not limited to olive leave extract. 
     
     
         6 . A method of treating, controlling or preventing the onset of one or more viral infection related disorders or conditions selected from the group consisting of viral infection related diseases including but not limited to the AIDS virus HIV-1, and other viruses with type I transmembrane envelope glycoprotein, such as simian immunodeficiency viruses (SIV), Sendai virus, feline immunodeficiency virus (FIV), respiratory syncytial virus (RSV), measles virus, Ebola virus, Nipah and Hendra viruses, the severe acute respiratory syndrome associated coronavirus (SARS-CoV), and the avain flu virus in mammalian, avian, poultry, non human primates subjects in need of treatment, comprising administering a therapeutically effective amount of oleuropein or an analogue, derivative or oleuropein aglycone or their analogues, or derivatives thereof, or hydrotyrosol, or dihydroxy phenol or their analogues, or derivatives thereof, or elenolic acid or their analogues, or derivatives thereof, or an iridoid glycoside, or a secoiridoid glycoside or their analogue, derivative, or any combination thereof including but not limited to olive leave extract. 
     
     
         7 . The method of  claim 1 , wherein the adipogenic genes and gene products whose expression is modulated includes, but is not limited to, PPARγ, PPARγ2, LPL and the αP2 genes and gene products. 
     
     
         8 . The method of  claim 1 , wherein the lipolytic genes and gene products whose expression is modulated including but not limited to PPAR δ and its modulated genes and gene products. 
     
     
         9 . The method of  claim 1 , wherein the lipogenic or lipolytic genes whose expression is modulated including but not limited to PPAR α and its modulated genes and gene products. 
     
     
         10 . A method of de-differentiation and transdifferentiating adipocytes into osteoblasts (bone cells), myoblasts (muscle cells), and chondrocytes (cartilage cells), the method comprising administering to a mammal in need thereof a therapeutically effective amount of oleuropein or an analogue, derivative or oleuropein aglycone or their analogues, or derivatives thereof, or hydrotyrosol, or dihydroxy phenol or their analogues, or derivatives thereof, or elenolic acid or their analogues, or derivatives thereof, or an iridoid glycoside, or a secoiridoid glycoside or their analogue, derivative, or any combination thereof including but not limited to olive leave extract. 
     
     
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         18 . The method of  claim 2  further comprising administering a second agent in combination with oleuropein, or an analogue or oleuropein aglycone or their analogues, or derivatives thereof, or hydrotyrosol, or dihydroxy phenol or their analogues, or derivatives thereof, or elenolic acid or their analogues, or derivatives thereof, or an iridoid glycoside, or a secoiridoid glycoside or their analogue, derivative, or any combination thereof including but not limited to olive leave extract. 
     
     
         19 . The method of  claim 18 , wherein the second agent is selected from the group consisting of a different PPAR modulating agent, a cholesterol or lipid lowering agent, a biguanide, insulin, an antihyperglycemic agent and any agent useful for treating metabolic syndrome or type 2 diabetes. 
     
     
         20 . The method of  claim 19 , wherein the different PPAR modulating agent is selected from the group consisting of troglitazone, pioglitazone and rosiglitazone. 
     
     
         21 . The method of  claim 19 , wherein the cholesterol or lipid lowering agent is a HMG-CoA reductase inhibitor, and wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of atorvastatin, bervastatin, cerivastatin, dalvastatin, fluvastatin, itavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatin and simvastatin. 
     
     
         22 . The method of  claim 19 , wherein the biguanide is selected from the group consisting of metformin, phenformin, and buformin. 
     
     
         23 . The method of  claim 19 , wherein the antihyperglycemic is a prandial glucose regulator or an alpha-glucosidase inhibitor. 
     
     
         24 . The method of  claim 23 , wherein the prandial glucose regulator is repaglinide or nateglinide. 
     
     
         25 . The method of  claim 23 , wherein the alpha-glucosidase inhibitor is selected from the group consisting of acarbose, voglibose and miglitol. 
     
     
         26 . The method of  claim 19 , wherein the agent useful for treating metabolic syndrome or type 2 diabetes is a sulfonylurea selected from the group consisting of glimepiride, glibenclamide (glyburide), gliclazide, glipizide, gliquidone, chloropropamide, tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolcylamide and tolazamide. 
     
     
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