Patent Application: US-201213982005-A

Abstract:
the invention relates to the use of a composition comprising extract of buddleja globosa hope and pharmacologically accepted excipients for the preparation of a phyto - pharmaceutical agent , a drug or a nutraceutical for the prevention of gastrointestinal disorders , particularly those associated with treatment with nitrofurantoin or gastric disorders produced by ulcers , gastric diseases or damage to the gastrointestinal tract . the aforementioned disorders can correspond to abdominal pain , dyspepsia , nausea , vomiting , diarrhea , constipation , inflammation and cephalalgia resulting from treatment with nitrofurantoin and other antimicrobials . in addition , the extract and the compositions thereof can be used to enhance the antibacterial action of nitrofurantoin , particularly against escherichia coli .

Description:
within the plants used with medicinal aims is the buddleja globosa hope ( matico ), for which several agronomic studies already exist , both about its composition and / or its active principles . the extracts , especially from their leaves , are used by the native medicine for healing and as anti - inflammatory . this medicinal plant is a chilean native plant of recognized antioxidant , antiinflammatory and for healing activity [ doll et al , 2003 ; hoffmann et al , 1992 ; mensah et al , 2001 ]. the buddleja genus belongs to the escrofulariales order , which comprises near to 100 species between trees and shrubs of the tropical of america , asia and africa . in chile , two species grow in wild form in hills and gullies , between the region of valparaiso and “ los lagos ”, buddleja suaveolens kunth et bouché and buddleja globosa hope . only the latter is used medicinally [ hoffman et al , 1992 ; muñoz et al , 2001 ]. nevertheless , studies do not exist about the doses to be used . the doses administered to patients are very diverse , thus , they are administered empirically under the popular belief that the natural products are innocuous to the human being . among chemical compounds present in this plant the following component have been reported : flavonoids , escutelarena , phenylpropanoids ( verbascoside , caffeic acids ), terpenes : iridoids , sesquiterpenoids ( buddlejinas a , b , c ), diterpene ( buddlejona ), phenylethanoid glycoside ( angaroside ) and tannins [ muñoz et al , 2001 ; pardo et al , 1993 , pardo et al , 1997 ; houghton y hikino , 1989 ; liao et al , 1999 ; mensah et al , 2000 ; vogel et al , 2002 ]. these compounds arrange in heterogeneous way depending on the different structures of the plant , for example : in leaves : terpenoids , iridoids ( aucubine ), phenylethanoids ( verbascoside and echinacoside ), flavonoids ( linarine , luteoline and 6 - oh - luteoline ) [ houghton and mensah , 1999 ]. in crust : diterpens ( buddlejona and deoxibuddlejona ), bisditerpene ( mayenona ), sesquiterpenes ( buddlejina a and buddlejina b ), phenolic fatty acid esters [ houghton and mensah , 1999 ; mensah et al , 2000 ]. in roots : terpenoids ( dihydrobuddlejina a , buddlejona a and buddlejona b ), buddlejina ( a , b and c ) and zerumbona [ liao et al , 1999 ]. gastroprotective activity : the crude methanol extract of the leaves of b . globosa hope improve the recovery from gastric ulcer injuries induced by acetic acid [ yáñez , 2001 ; stream , 2000 ]. antioxidant activity : in isolated compounds of leaves b . globosa , in hydroalcoholic or propilenglicolic extracts [ mensah et al , 1998 ; mensah et al , 2001 ; holst - schlager y letelier , 2004 ]. analgesic and antiinflammatory activity : lipophilic extract of roots and crust of b . globosa inhibits the activity of cox - 2 and 5 - lipooxygenase [ liao et al , 1999 ]. nevertheless , there are not reported studies that approach dose protocols to use ; it is probably because of the belief that natural active principles are innocuous . the alcoholic extract of leaves of b . globosa ( buddlejaceae ) has a dose - dependent analgesic activity in several models of pain [ backhouse et al , 2008a ; backhouse et al , 2008b ]. finally , using albino mice , administered by topical route , a poaching ( in nacl ) of the matico extract at 100 mg / kg , a rapid decrease in edema was observed in relation to the control group ( diclofenac treated mice ). authors conclude it is viable to recommend their use as topical antiinflammatory [ martinez , 1994 ]. with this fact the use of matico in the chilean folkloric medicine has been validated ( use of matico in treatment of wounds ). activity on the liver : protective effect of flavonoids and phenylpropide glycosides components have been previously shown [ houghton et al , 1989 ]. activity on the skin : water extract of b . globosa increases the proliferation of fibroblasts in cultures ; this activity can accelerate the healing of wounds [ mensah et al , 1998 ; mensah et al , 2001 ]. antimicrobial activity : lipophilic extracts of crust of stem of b . globosa has an antifungal activity against 3 species of dermatophytes fungi ( trichophyton rubrum , tricophyton interdigitale and epidermophyton floccosum ). the compounds in this extract were diterpenes ( buddlejona ), bisditerpen ( mayenona ) and two sesquiterpenes ( buddlejina a and buddlejina b ) [ mensah et al , 2000 ]. in addition , it has been reported that glycosides of b . globosa display bactericidal activity [ pardo et al , 1993 ; pardo et al , 1997 ]. ancestral therapeutic uses : leaves , stems and roots are used traditionally in respiratory affections , contusions , luxation , conjunctivitis , digestive and hemostatic disorders , as carminative , antidiabetic , sedative , antihemorroidal ; in insomnia , eczemas , malaria , as anti - inflammatory for eyes , mouth , skin and mucoses , healing , antiulcerous , also used in hemorrhages , bloody diarrheas , antitusive and expectorant . the toxicity of any compound depends on the administered dose . for example , an increase of 10 times dose of the majority of the allopathic drugs generates severe acute toxicity . in addition , the possible beneficial and / or adverse effects that herbal preparations can cause in the body are alterations of blood homeostasis . in our specific product buddlejinas a , b and c have shown not to be toxic effects after oral administration of the crude extract up to 2 g / kg and intraperitoneal up to 600 mg / kg , in mice [ yañez , 2001 ]. other authors have reported cytotoxicity in concentrations greater than 50 μg / ml [ mensah et al , 2001 ]. antiinflammatory and healing activity : it has been shown in animal models , an inhibitory activity of cox - 2 and 5 - lipooxygenase , in vitro [ konstan , 1998 ]. nevertheless , no mechanisms have been studied . the inventors of the present application have found that , surprisingly , the treatment with a matico extract decrease considerably the gastrointestinal adverse reactions caused by the oral administration of nitrofurantoin to patients with bacterial infections of low urinary tract . in this regard , the analysis of the literature shows a series of documents related to several species of buddleja and their properties . of these reports , the authors have considered as closer documents the inventions of kr20100028202 and kr100644773 referred to a species of buddleja from china which shows other therapeutic properties not related to the field of the present invention . moreover , u . s . pat . no . 4 , 855 , 138 describes a mixture containing an extract ( water - oil ) of dry leaves of matico ( 2 - 35 %) and its use against disorders of the skin ( acne , psoriasis , burns , etc ). the composition contains , in addition to the matico extract , sulfo - derivatives like sulfathiazole ( 2 - 15 %), alcohol amines , oils and a lipophilic base . furthermore , it is possible to add an inert pigment as zinc oxide and a fragrance . the procedure for obtaining the extract is not described , but it is not a hydroalcoholic extract neither is directed to solve the technical problem raised in the present invention . accordingly , the present application directs to the use and the composition of dry extract of leaves of buddleja globose hope ( matico ) for the treatment of the gastrointestinal affections associated to the oral administration of nitrofurantoin ( especially in microcrystal formulations ) in patients with uti . in some embodiments , stems are also included in the composition . in the preferred composition , bg126 capsules are used and each includes 350 mg of extract with a polyphenol concentration not exceeding 18 mg . it should be noted that other pharmaceutical formulations can be prepared including up to a tenfold increase in the polyphenol concentration . such an increase did not show acute toxicity in rats . the following suitable examples according to the invention are preferred but this does not limit the invention in any way . table 1 summarizes the results obtained by means of a procedure of standard hydroalcoholic extraction of buddleja buddleja globosa hope . a capsule of 250 - 550 mg contains 250 - 550 mg of bg - 126 , standardized dry extract of buddleja buddleja globosa hope . the total polyphenols is expressed in mg of catechin by mg extract . the standardized dry extract bg - 126 is obtained by dehydrating the liquid extract with maltodextrin by spraying , and then the dry extract is quantified , giving raise to the raw material of the capsules , without any other additive . the capsule can be administered in the following affections with the following indicated dosage : a . infections of the low urinary tract : 1 capsule every 12 hours the toxicity of the hydroalcoholic extract in male adult rats ( rattus norvegicus ) of the stock sprague dawley was determined . this study consisted in the oral administration of the hydroalcoholic extract of leaves of buddleja globosa ( dose : 12 fold greater than the dose advised for the phytopharmaceutical gug / x ® laboratorios ximena polanco chile s . a .) every 8 hours during 12 days . significant differences in hemogram parameters ( red series and white series ) or in biochemical profiles were not observed ( p & gt ; 0 . 05 ). similarly , statistically significant differences in the macroscopic parameters ( relative weight , longitudinal and cross - sectional axis ) and hematoxylin - eosin dyed histological samples of spleen were not observed ( number of pals and germinal centers ; diameter and area of the germinal centers ). moreover , any evidence of toxic effects was not observed . because the extract does not alter hepatic and renal function of the animals , neither the hemogram or even more , the hepatic metabolism of the active components in the extract were affected , this indicate a low toxicity of the tested extract . thus , the used dose in this test seems not to produce side effects on the animals and would be , for instance , a safe dose . a double blind randomized clinical assay was performed in women who required treatment due to infection of low urinary tract ( positive urocultive , bacterium susceptible to nitrofurantoin ). patients were ambulatory in the urology polyclinical of the clinical hospital of the university of chile ( hcuch ). those that fulfilled the inclusion and exclusion criteria signed an informed consent to participate in the study . patients were distributed randomly in the two following groups : group 1 : 15 patients treated with 100 mg nitrofurantoin ( microcrystals ) and one placebo capsule , every 12 hours , by 10 days . group 2 : 15 patients treated with 100 mg nitrofurantoin ( microcrystals ) and one capsule of dry extract standardized bg - 126 of matico leaves , every 12 hours , by 10 days . during the treatment , under medical and nursery checkup registers of adverse reactions , hemogram , biochemical profile , urocultive and determination of plasma antioxidant capacity were made . all these results can be observed in fig2 to 9 . control of gastrointestinal adverse reactions caused by nitrofurantoin , and nitrofurantoin plus matico extract , showed that combined use of this drug and capsules of matico decrease the frequency and intensity of the analyzed gastrointestinal adverse reactions . significant differences in hemogram , biochemical profile , plasma antioxidant capacity in both groups of patients , were not found , indicating that extract would have preferably local action . additionally , it is necessary to highlight that 2 patients passed away because of the gastrointestinal adverse reactions . these patients received only nitrofurantoin . urocultives done 1 day after finalizing the treatment were negative ; nevertheless , one patient who received only nitrofurantoin was positive . the results of this study allow us to conclude that the concomitant use of nitrofurantoin and matico , represents an alternative treatment for uti , with lower adverse effects of nitrofurantoin which can allow patients to leave the therapy , especially in patients from primary attention . albert k ., sedman a ., wilkinson p ., stoll r ., murray w . and wagner j . 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