Patent Application: US-201313964727-A

Abstract:
the present invention provides a method and composition for ameliorating or reducing the symptoms and signs and for the treatment of obesity , diabetes , and related conditions in a mammal in need thereof , said method comprising administering effective amounts of a pharmaceutically acceptable composition comprising a mixture of probiotic microorganisms with distinct but complementary pathways of carbohydrate metabolism , for a time sufficient to ameliorate , reduce or treat at least one sign or symptom of obesity , diabetes or cardiovascular disease . compositions having the desired properties , and methods for their use in pharmaceutical and nutritional formulations , are provided .

Description:
the body mass index ( bmi ) ( calculated as weight in kilograms divided by the square of height in meters ) is the most commonly accepted measurement for overweight and / or obesity . in adults , a bmi exceeding 25 is considered overweight , while obesity is defined as a bmi of 30 or more , with a bmi of 35 or more considered as serious co - morbidity and a bmi of 40 or more considered morbid obesity . for the purposes of this invention , “ obesity ” shall mean a bmi of 30 or more . one out of every five overweight people is affected by the “ metabolic syndrome ”. metabolic syndrome is one of the fastest growing obesity - related health concerns in the united states and is characterized by a cluster of health problems including obesity , hypertension , abnormal lipid levels , and high blood sugar . according to the centers for disease control and prevention ( cdc ), the metabolic syndrome affects almost one quarter ( 22 percent ) of the american population — an estimated 47 million people . the assemblage of problems characterized as comprising the metabolic syndrome can increase a patient &# 39 ; s risk for developing more serious health problems , such as diabetes , heart disease , and stroke . overweight and obese people have an increased incidence of heart disease , and thus fall victim to heart attack , congestive heart failure , sudden cardiac death , angina , and abnormal heart rhythm more often than those that maintain a healthy body mass index . obesity often increases the risk of heart disease because of its negative effect on blood lipid levels , which increase in obese patients and then , in turn , increase triglyceride levels and decrease high - density lipoprotein — which is also known as hdl . people with an excessive amount of body fat have higher levels of triglycerides and low - density lipoprotein — which is also known as ldl or “ bad cholesterol ”— as well as lower levels of hdl cholesterol in the blood . this combination creates optimal conditions for developing atherosclerotic heart disease . being overweight or obese increases the risk of developing high blood pressure . hypertension , or high blood pressure , greatly raises the risk of heart attack , stroke , and kidney failure . in fact , blood pressure rises as body weight increases . losing even 10 pounds can lower blood pressure — and losing weight has the biggest effect on those who are overweight and already have hypertension . obesity is associated with the development of diabetes . more than 80 percent of people with type 2 diabetes , the most common form of the disease , are obese or overweight . type 2 diabetes develops when either there is impaired insulin production by the pancreas in the setting of insulin resistance in the tissues and organs in the body . as obesity diminishes insulin &# 39 ; s ability to control blood sugar ( glucose ), there is an increased risk of developing diabetes because the body begins overproducing insulin to regulate blood sugar levels . over time , the body is no longer able to keep blood sugar levels in the normal range . eventually the inability to achieve healthy blood sugar balance results in the development of type 2 diabetes . furthermore , obesity complicates the management and treatment of type 2 diabetes by increasing insulin resistance and glucose intolerance , which makes drug treatment for the disease less effective . in many cases , a reduction of body weight to a normal range normalizes blood glucose and restores insulin sensitivity . childhood obesity is also a major public health problem , particularly in western countries . children 2 - 18 years of age are considered obese if the bmi is greater than the 95th percentile . despite policies targeted at reducing its prevalence , childhood obesity has more than doubled in children and tripled in adolescents in the past 30 years . as with adults , obesity in childhood causes hypertension , dyslipidaemia , chronic inflammation , increased blood clotting tendency , endothelial dysfunction , and hyperinsulinemia . this clustering of cardiovascular disease risk factors has been identified in children as young as 5 years of age . thus there is an urgent need for safe effective interventions , including nutritional interventions , to combat the epidemic of obesity in children as well as in adults . the present compositions , medicaments , therapeutics , systems , methods , etc ., are directed to the prevention , inhibition and treatment of obesity and obesity - related conditions . said obesity - related conditions are selected from the group consisting of insulin resistance , hyperglycemia , diabetes , hypertriglyceridemia , atherosclerosis , angina pectoris , myocardial infarction and / or stroke . “ probiotics ” within the context of the present invention is used in accord with its usual meaning , for example as selected , viable microbial dietary supplements that , when introduced in sufficient quantities , beneficially affect the human organism via their effects in the gastrointestinal tract ( holzapfel et al ., 2001 ; holzapfel & amp ; schillinger , 2002 ). the fao / who has adopted the definition of probiotics as “ live microorganisms which when administered in adequate amounts confer a health benefit on the host ” ( fao / who guidelines , 2002 ). these beneficial bacteria may be found for example in milk or in milk processing factories , living or decaying plants , and also in the intestines of man and animals . currently , the best - studied probiotics are the lactic acid bacteria , particularly lactobacillus spp . and bifidobacterium spp . lactobacillus is a genus of gram - positive facultative anaerobic bacteria . the genus lactobacillus currently comprises over 100 species and encompasses a wide variety of organisms . they are common and usually benign . in humans they are present in the vagina and the gastrointestinal tract , where they are symbiotic and make up a small portion of the gut flora ( tannock , 1999 ). lactobacilli that have been used in humans include l . acidophilus , l . salivarius , l . johnsonii , l . casei , l . lactis , l . reuteri , l . plantarum , l . rhamnosus , l . brevis , l . gasseri , and other species and subspecies . the use of lactobacillus species in humans has been extensively reviewed in the scientific literature , including the references provided herein . these ingredients are readily available from commercial suppliers , including danisco - dupont ( us ); chr . hansen ( denmark ); institut rosell lallemand ( montreal , canada ); and others . exemplary species and strains of lactobacillus for the present invention include the following well - known strains : l . acidophilus ncfm , l . acidophilus la - 14 , l . bulgaricus lb - 64 , l . brevis lbr - 35 , l . casei lc - 11 , l . lactis l1 - 23 , l . plantarum lp - 115 , l . paracasei lpc - 37 , l . rhamnosus lr - 32 and l . salivarius ls - 33 , which are well known to those skilled in the art . bifidobacterium is a genus of gram - positive anaerobic bacteria , currently comprised of 31 characterized species , 11 of which have been detected in human feces ( tannock , 1999 ). bifidobacteria are gram - positive , irregular or branched rod - shaped bacteria that are commonly found in the intestines of humans and most animals and insects . probiotic bifidobacterium strains that are useful for the present invention include but are not limited to the following strains which are well known to those skilled in the art : b . breve bb - 03 , b . lactis bi - 07 and bi - 04 , b . longum bi - 05 . leuconostoc is a genus of gram - positive bacteria , placed within the family of leuconostocaceae . all species within this genus are heterofermentative . leuconostoc , along with other lactic acid bacteria such as pediococcus and lactobacillus , is responsible for the fermentation of cabbage making sauerkraut . for the purposes of the present invention , one exemplary strain of leuconostoc is l . mesenteroides atcc 13146 . lactic acid bacteria ( lab ) are capable of generating energy by homo - or heterofermentative metabolism of sugars . during anaerobic growth of obligately homofermentative lab in the presence of excess substrate , energy sources like glucose are converted into pyruvate via the embden - meyerhoff - parnas pathway , and the pyruvate is further metabolized to lactate ( see fig1 ). homofermentative lab include most species of enterococci , lactococci , pediococci , streptococci , tetragenococci , and vagococci . early work demonstrated that fructose 1 , 6 bisphosphate aldolase ( ec 4 . 1 . 2 . 13 ) and isomerase enzymes were absent in heterofermentative organisms , suggesting that the pathway does not follow the usual embden - meyerhof pattern of glycolysis ( demoss et al ., 1951 ). as more research was conducted , it was realized that these organisms utilize a different pathway , named the phosphoketolase pathway ( pkp ; ec 4 . 1 . 2 . 9 ), which produces equimolar amounts of co 2 , lactate , and acetate - ethanol ( fig2 ). heterofermentative lab can be divided into obligately heterofermentative species , in which both hexoses and pentoses are fermented via the pkp , and facultatively heterofermentative organisms , which degrade hexoses via the embden - meyerhoff - parnas pathway and pentoses via the pkp . many of the enzymes used in the latter pathway are shared with the pentose phosphate pathway . xylulose 5 - phosphate phosphoketolase ( xpk ; ec 4 . 1 . 2 . 9 ) is the central enzyme of the pkp of heterofermentative and facultative homofermentative lactic acid bacteria . xpk prefers xylulose 5 - phosphate to fructose 6 - phosphate . in the presence of inorganic phospate this enzyme converts xylulose 5 - phosphate ( x5p ) into glyceraldehyde 3 - phosphate and acetylphosphate . some taxa known to possess the pkp pathway include lactobacillus brevis , lactobacillus buchneri , lactobacillus casei , lactobacillus fermentum , lactobacillus reuteri , leuconostoc lactis , leuconostoc mesenteroides , leuconostoc mesenteroides ssp . cremoris , and some species of weissella . 1 ) obligately homofermentative ( group i ) including : l . acidophilus , l . delbrueckii , l . helveticus , l . salivarius 2 ) facultatively heterofermentative ( group ii ) including : l . casei , l . curvatus , l . plantarum , l . sakei 3 ) obligately heterofermentative ( group iii ) including : l . brevis , l . buchneri , l . fermentum , l . reuteri bifidobacteria are considered key commensals in human - microbe interactions and they contribute to the degradation of undigested polysaccharides in the human colon ( suzuki et al ., 2010 ). bifidobacteria utilize a unique pathway of hexose catabolism which produces primarily acetate and lactate ( de vries and stouthamer , 1967 ). this fermentation pathway , which is known as the “ bifid shunt ” or the “ fructose - 6 - phosphate pathway ” yields 3 mols of acetate and 2 mols of lactate for 2 mols of glucose , with production of 5 mols of atp . the key enzyme in the pathway is xylulose - 5 - phosphate phosphoketolase / fructose - 6 - phosphate phosphoketolase ( xfp ; ec 4 . 1 . 2 . 22 ), which catalyzes two important steps : splitting d - fructose 6 - phosphate into d - erythrose 4 - phosphate and acetylphosphate , and splitting d - xylulose 5 - phosphate into d - glyceraldehyde 3 - phosphate and acetylphosphate . this enzyme has often been used as a tool in the identification of bifidobacteria . more recently , such dual substrate - specificity enzymes have been found in other organisms including leuconostoc mesenteroides and lactobacillus paraplantarum ( lee et al . 2005 ; jeong et al ., 2007 ). in addition , bifidobacterium longum , which metabolizes intracellular fructose via the fructose - 6 - p phosphoketolase pathway , contains a fructokinase ( frk ; ec 2 . 7 . 1 . 4 ) ( caescu et al . 2004 ). fructokinases have also been found in leuconostoc mesenteroides , leuconostoc pseudomesenteroides , lactobacillus plantarum , and lactococcus lactis . the presence of fructokinase enables these organisms to grow using fructose as a unique carbon source . furthermore , a number of heterofermentative lactic acid bacteria ( lab ), yeasts , and filamentous fungi also are known to convert fructose into mannitol in significant quantities , including leuconostoc mesenteroides . the reduction of fructose to mannitol in heterofermentative lactic acid bacteria is catalyzed by an nadh - linked mannitol dehydrogenase ( ec 1 . 1 . 1 . 67 ) ( wisselink et al ., 2002 ; saha & amp ; racine , 2011 ). in clinical practice we have discovered that certain combinations of lactic acid bacteria , if given together , are far more effective than if either species is given alone . the basis of the present invention is the observation that compositions comprising two or more probiotic organisms , with distinct pathways of carbohydrate metabolism , produce synergistic results with respect to weight loss and diabetes . specifically , we have discovered that combination products containing at least one species of lactobacillus and at least one species of bifidobacterium or leuconostoc are effective in the treatment of obesity , diabetes , and obesity - related conditions . no one has previously recognized that distinct carbohydrate metabolic pathways can be used to design synergistic compositions for the treatment of obesity . without being bound by theory , we propose that the beneficial effects of our compositions may result from the efficient metabolism of carbohydrates by the combined action of these particular species ; from the combination of short - chain fatty acids or other metabolites produced by the complementary species ; or by another mechanism . a 47 year - old man presents for evaluation of obesity . he has been gaining weight since his early 40s . he weighs 280 pounds and is 5 foot 11 inches tall with a body mass index ( bmi ) of 39 . his blood pressure is 140 / 90 . laboratory testing is remarkable for a fasting blood glucose of 136 mg / dl and triglycerides of 220 mg / dl . a diet is recommended consisting of high protein , reduced refined carbohydrates , and 2200 calories per day . a 4 - day - per - week minimum program of aerobic exercise is prescribed . the patient is given a multispecies bifidobacterium / lactobacillus probiotic formula , ( composition 1 ; see table 1 ) in the amount of two capsules per day to be taken with meals . when the patient is seen in follow up after 3 months , his weight is 232 with a bmi of 32 . 4 . his blood pressure is now 130 / 84 and his glucose and triglycerides are normal . he is advised to continue his diet , exercise and probiotics . when he is seen again in 6 months , he weighs 189 pounds with a bmi of 26 . 8 . a 62 - year old woman presents for evaluation of obesity . she weighs 191 pounds and is 5 foot 6 inches tall with a body mass index ( bmi ) of 31 . she reports consuming a diet consisting of approximately 2200 calories per day and walking for 30 minutes three to four days per week . for the past three months she has been consuming 3 billion cfu / day of a commercial lactobacillus acidophilus supplement ; however , she has been unable to lose weight . the patient is given a multispecies probiotic formula containing bifidobacterium and leuconostoc in addition to lactobacillus ( composition 4 ; see table 1 ) in the amount of one capsule per day to be taken with a meal . when the patient is seen at followup in 3 months her weight is 175 pounds with a bmi of 28 . a 30 - year - old pregnant woman presents for evaluation of excessive weight gain and gestational diabetes in her 28 th week of pregnancy . she is 5 ′ 4 ″ tall and weighs 163 pounds , having gained 40 pounds during her pregnancy . an oral glucose tolerance test reveals a plasma glucose level of 12 mmol / l when measured 2 hours after the challenge , suggesting overt diabetes . the patient is advised to avoid high - sugar foods , like sweets and desserts ; to increase her daily intake of dietary fiber and protein ; and to incorporate at least 40 minutes per day of gentle exercise in her routine . in addition , the patient is given a lactobacillus / bifidobacterium probiotic formula , consisting of l . acidophilus , l . rhamnosus , b . bifidum , and b . lactis ( composition 3 ; see table 1 ) and advised to take one capsule per day with a meal . when the patient is seen at followup in 2 weeks her weight has stabilized at 163 pounds and her plasma glucose level has decreased to 10 . 5 mmol / l when measured 2 hours after a glucose challenge . a 10 - year - old female child is seen at a pediatric clinic for evaluation of obesity . at birth , she weighed 9 pounds and was 20 inches in length . even in infancy the child had risk factors for obesity as a result of a family history of the disease . also , the patient &# 39 ; s mother had gestational diabetes , which can predispose a child to overweight / obesity . children 2 - 18 years of age are considered obese if the bmi is greater than the 95th percentile . during early childhood , the patient &# 39 ; s weight was maintained in the 90 th to 95 th percentile . however , she continued to grow , and by her 10 th birthday she was considered overweight with a height of 50 inches , weight of 85 pounds , and bmi of 24 which is in the 96 th percentile according to cdc guidelines ( centers for disease control ). a dietitian advises the mother to modify the child &# 39 ; s diet by limiting snack foods and providing fresh fruit for dessert instead of cookies . the dietitian also advises a probiotic supplement , ( composition 2 ; see table 1 ), which contains a mixture of lactobacillus and bifidobacterium , in the amount of one capsule per day to be consumed with a meal . when seen at follow - up 6 months later the patient &# 39 ; s height is 52 inches and her weight is 74 pounds , which represents a weight loss of 11 pounds . the patient &# 39 ; s bmi is now 19 . 2 , placing the bmi - for - age at the 76th percentile . the patient &# 39 ; s mother is advised to continue the diet and probiotic regimen and to encourage the child to participate in a sports , dance or an exercise program . the entire contents including the references cited therein and the following patents , published applications including all their foreign equivalents and journal publications are incorporated by reference in their entirety for all purposes to the same extent as if each individual patent , patent application or publication were so individually denoted . arora t , anastasovska j , gibson g , tuohy k , sharma r k , bell j , frost g . effect of lactobacillus acidophilus ncdc 13 supplementation on the progression of obesity in diet - induced obese mice . brit j nutr 2012 ; 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