Methods for treating disorders using plant extracts

Abstract

The present invention provides materials and methods relating to mildly polar fluid extracts of plant materials, such as Artemisia plant species, useful in methods for treating diabetes and methods for modulating the activity of glucagon-like peptide-1 (GLP-1), and in methods for modulating phosphoenol pyruvate carboxykinase (PEPCK) activity in a diabetes-specific manner. The extracts are generally non-toxic and non-mutagenic and may be administered to diabetics with beneficial effect on blood glucose levels. The extracts may also be administered to non-diabetics without deleterious effect. The plants are easily grown with a minimum of time, labor, and cost. Extracts are inexpensively and quickly prepared without the need for fractionation to remove potentially deleterious compounds, and the extracts may be administered to mammals such as humans through various routes, in a variety of forms, and at convenient concentrations.

1 . A method of modulating blood glucose level in a mammal comprising administration of an effective dose of a mildly polar extract of  Artemisia.    
     
     
         2 . The method according to  claim 1  wherein the blood glucose level is decreased.  
     
     
         3 . A method of modulating glucagons-like peptide-1 (GLP-1) activity in a mammal comprising administration of an effective dose of a mildly polar extract of  Artemisia.    
     
     
         4 . The method according to  claim 3  wherein the GLP-1 activity is increased.  
     
     
         5 . A method of altering the appetite of a mammal comprising administering an effective dose of a mildly polar extract of  Artemisia  to the mammal.  
     
     
         6 . A method of promoting an ileal brake comprising administering an effective dose of a mildly polar extract of  Artemisia  to a mammal.  
     
     
         7 . A method of modulating the binding between GLP-1 and the GLP-1 receptor comprising administering an effective dose of a mildly polar extract of  Artemisia  to a mammal.  
     
     
         8 . A method of modulating α-glucosidase activity in a mammal comprising administration of an effective dose of a mildly polar extract of  Artemisia.    
     
     
         9 . A method of modulating insulin resistance in a mammal comprising administering an effective dose of a mildly polar extract of  Artemisia.    
     
     
         10 . The method according to  claim 9  wherein insulin resistance is decreased.  
     
     
         11 . A method of modulating the in vivo conversion of glucose to glycogen in a mammal comprising administering an effective dose of a mildly polar extract of  Artemisia.    
     
     
         12 . The method according to  claim 11  wherein the in vivo conversion of glucose to glycogen is increased.  
     
     
         13 . A method of modulating the expression of insulin receptor substrate-2 (IRS-2) polypeptide in a mammal comprising administering an effective dose of a mildly polar extract of  Artemisia.    
     
     
         14 . The method according to  claim 13  wherein the expression of IRS-2 polypeptide is increased.  
     
     
         15 . A method of modulating insulin-stimulated glucose uptake in a mammal comprising administering an effective dose of a mildly polar extract of  Artemisia.    
     
     
         16 . The method according to  claim 15  wherein the insulin-stimulated glucose uptake is increased.  
     
     
         17 . A method of modulating hepatic glucose output in a mammal comprising administering an effective dose of a mildly polar extract of  Artemisia.    
     
     
         18 . The method according to  claim 17  wherein the hepatic glucose output is decreased.  
     
     
         19 . The method according to  claim 17  wherein the mildly polar extract is an alcoholic extract that decreases phosphoenol pyruvate carboxykinase (PEPCK) expression.  
     
     
         20 . (canceled)  
     
     
         21 . A method of promoting increased cellular energy in non-adipose cells comprising administering an effective dose of a mildly polar extract of  Artemisia.    
     
     
         22 . The method according to  claim 21  wherein the increased cellular energy provides increased muscle cell strength.  
     
     
         23 . The method according to  claim 21  wherein the increased cellular energy provides increased muscle cell endurance.  
     
     
         24 . The method according to  claim 21  wherein the increased cellular energy prevents or reduces physiological distress.  
     
     
         25 . The method according to  claim 21  wherein the increased cellular energy prevents or reduces fatigue.  
     
     
         26 . The method according to  claim 21  wherein the increased cellular energy prevents or reduces a nutritional deficiency.  
     
     
         27 . The method according to  claim 21  wherein the non-adipose cells are selected from the group consisting of muscle cells and neurons.  
     
     
         28 . A method of preparing a mildly polar extract of  Artemisia  comprising the steps of: 
 (a) contacting  Artemisia  with an elicitor; and    (b) extracting the  Artemisia  with a mildly polar fluid.    
     
     
         29 . The method according to  claim 28  wherein the mildly polar fluid comprises at least 60% ethanol.  
     
     
         30 . The method according to  claim 28  wherein the  Artemisia  comprises a stern:leaf biomass ratio of at least 1.0.  
     
     
         31 . The method according to  claim 28 , further comprising disrupting  Artemisia.    
     
     
         32 . The method according to  claim 28  wherein the  Artemisia  is immature.  
     
     
         33 . The method according to  claim 28  wherein the extract comprises a compound selected from the group consisting of capillarisin, tetrahydroxy-methoxy flavanone, umbelliferone, sakuranin, a trihydroxy-methoxy flavanone and a trihydroxy flavanone.  
     
     
         34 . The method according to  claim 28  wherein the elicitor is selected from the group consisting of chitosan and  Trichoderma.    
     
     
         35 . The method according to  claim 28  wherein the elicitor is about 0.1% chitosan.  
     
     
         36 . The method according to  claim 28  wherein the elicitor is  Trichoderma harzianum.    
     
     
         37 . The method according to  claim 28 , further comprising drying the extract at an elevated temperature to reduce methyl eugenol concentration.  
     
     
         38 . The method according to claims  1 ,  3 ,  5 ,  6 ,  7 ,  8 ,  9 ,  11 ,  13 ,  15 ,  17 ,  21 , or 28, wherein the  Artemisia  is  Artemisia dracunculus.    
     
     
         39 . The method according to claims  1 ,  3 ,  5 ,  6 ,  7 ,  8 ,  9 ,  11 ,  13 ,  15 ,  17 ,  21 , or 28, wherein the mildly polar extract is an alcoholic extract.  
     
     
         40 . The method according to  claim 39 , wherein the alcoholic extract is an ethanolic extract.  
     
     
         41 . The method according to claims  1 ,  3 ,  5 ,  6 ,  7 ,  8 ,  9 ,  11 ,  13 ,  15 ,  17 ,  21 , or 28, wherein the extract lacks detectable mutagenic activity.  
     
     
         42 . The method according to claims  1 ,  3 ,  5 ,  6 ,  7 ,  8 ,  9 ,  11 ,  13 ,  15 ,  17 ,  21 , or 28, wherein the mammal is human.  
     
     
         43 . The method according to claims  1 ,  3 ,  5 ,  6 ,  7 ,  8 ,  9 ,  11 ,  13 ,  15 ,  17 ,  21 , or 28, wherein the administration comprises oral delivery.  
     
     
         44 . The method according to claims  1 ,  3 ,  5 ,  6 ,  7 ,  8 ,  9 ,  11 ,  13 ,  15 ,  17 ,  21 , or 28, wherein the extract has no acute oral toxicity at a dosage of up to 5000 milligram plant material per kilogram mammal body weight.  
     
     
         45 . A pharmaceutical composition comprising an effective dose of a mildly polar extract of  Artemisia.    
     
     
         46 . The composition according to  claim 45  wherein the  Artemisia  is  Artemisia dracunculus.    
     
     
         47 . The composition according to  claim 45  wherein the mildly polar extract is an alcoholic extract.  
     
     
         48 . The composition according to  claim 47  wherein the alcoholic extract is an ethanolic extract.  
     
     
         49 . The composition according to  claim 45  wherein the extract lacks detectable mutagenic activity.  
     
     
         50 . A pharmaceutical composition comprising an effective dose of a compound selected from the group consisting of capillarisin, tetrahydroxy-methoxy flavanone, umbelliferone, sakuranin, trihydroxy-methoxy flavanone and trihydroxy flavanone.  
     
     
         51 . The use of the composition according to  claim 49 , wherein the use is selected from the group consisting of modulating glucose level in a mammal, altering the appetite of a mammal, promoting an ileal brake, modulating the binding between GLP-1 and the GLP-1 receptor, modulating alpha-glucosidase activity in a mammal, modulating insulin resistance in a mammal, modulating the in vivo conversion of glucose to glycogen in a mammal, modulating the expression of insulin-receptor substrate-2 (IRS-2) polypeptide in a mammal, modulating insulin-stimulated glucose uptake in a mammal, modulating hepatic glucose level in a mammal, treating type 2 diabetes in a mammal and promoting increased cellular energy in non-adipose cells.  
     
     
         52 . A formulation for treating diabetes in a mammal comprising an  Artemisia  extract and at least one compound selected from the group consisting of  gymnema sylvestre , fenugreek, bitter melon, alpha-lipoic acid, alpha-lipoic acid salts, corosolic acid, ursolic acid, D-pinitol,  aloe vera , chromium picolinate, banaba leaf, yacou root,  momordica charantia , olive leaf extract,  pterocarpus marsupium, salacia reticulata , garlic, hawthorn, phosphatidylserine, omega 3 fatty acids, and resistant starch.  
     
     
         53 . A formulation for weight control in a mammal comprising an  Artemisia  extract and at least one compound selected from the group consisting of pyruvic acid, pyruvic acid salts, L-carnitine, hydroxycitric acid, ephedrine, caffeine, conjugated linoleic acid, aspirin, alpha-lipoic acid, and alpha-lipoic acid salts.  
     
     
         54 . A formulation for promoting increased cellular energy in non-adipose cells in a mammal comprising an  Artemisia  extract and at least one compound selected from the group consisting of creatine, creatine monohydrate, a creatine salt, creatine citrate, creatine pyruvate, phosphocreatine, caffeine, alpha-lipoic acid, glucosamine, chondroitin, hydrolyzed collagen, methylsulfonyl-methane, Whey protein, L-glutamine, phosphatidylcholine, choline, a choline salt, phosphatidylserine, beta-hydroxy beta-methylbutyrate, pyruvic acid, pyruvic acid salts, L-carnitine, D-ribose, an amino acid, a branched chain amino acid, S-Adenosylmethionine, taurine, conjugated linoleic acid, alpha-lipoic acid, alpha-lipoic acid salts, and glycerin.