CRANBERRY CLAIMS Reduce the risk of urinary tract infection Exhibit bacterial anti adhesion activity Reduces the incidence of E. coli infections Reduces the incidence of recurrent urinary bladder infections CERTIFICATIONS Oceanspray's is a patent brand cranberry extract enriched with proanthocyanidins Kosher certified Halal certified
Introduction Cranberry is a term derived from the contraction of crane berry. This name is derived from the nickname of the bilberry flower, which, when it withers, is similar in appearance to the head and neck of the sand crane, a bird that often feeds on the berries of this plant (1). The cranberry is part of the Ericaceae family and naturally grows in acidic swamps full of peat moss in humid forests (2). The American cranberry (Vaccinium macrocarpon) was historically used by North American Indians to treat UTIs (10). There are other relatives of the cranberry family (European cranberry V. oxycoccus; lingonberry V. vitis-idaea; blueberry V. myrtillus) that share some of the cranberry's basic components, but research evidence for a role in prevention is limited (3,4). Cranberries are composed of water (88%), organic acids (including salicylate), fructose, vitamin C (high levels, i.e., 200 mg/kg of fresh berries), flavonoids, anthocyanidins, catechins, and triterpinoids (10). The chemical constituents responsible for their taste are the iridoid glycosides. The anthocyanidins and proanthocyanidins (PAC) are tannins (stable polyphenols) found only in vaccinium berries and function as a natural plant defense system against microbes (1,5). to the host tissue; these proteins can be either mannose-resistant or mannose-sensitive. The mannose-sensitive pili, called type 1 pili, permit bacterial adhesion to the urothelium; the fimbriae are inhibited by fructose (present in grapes, oranges, and cranberries). The more virulent strains of E. coli, isolated from patients with pyelonephritis and recurrent UTIs, have other types of fimbriae, notably p-fimbriae (pyelonephritis fimbriae). These fimbriae bind to glycosphingolipids of the lipid double membrane of renal cells, which precedes renal parenchymal invasion (7) Symptoms of urinary tract infections may include: UTI Infection One important property of E. coli is its adherence to the host tissue. The main protein structure related to this phenomenon is the adhesin protein, and its name is based on its shape: pili or fimbriae (6). Bacterial adhesion is accomplished by the binding of lectins exposed on the cell surfaces of these fimbriae to complementary carbohydrates on the host tissues. Pili are small filaments that enable bacteria to adhere Strong urge to urinate frequently, even immediately after the bladder is emptied Painful burning sensation when urinating Discomfort, pressure, or bloating in the lower abdomen Pain in the pelvic area or back Cloudy or bloody urine, which may have a strong smell
Chemical Profile Characterization of the AC-PACs fraction was made b y 1 3 C - N M R. A s s h o w n i n F i g u re 1, t h e proanthocyanidin molecules consist of epicatechin units presenting mainly a degree of polymerization (DP) of 4 and 5 and containing at least one A-type linkage, as previously reported [8]. The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli in vitro [8]. Pharmacology The current hypothesis is that cranberries work principally by preventing the adhesion of type 1 and p-fimbriae strains (particularly from E. coli) to the urothelium (10-13). Without adhesion, the bacteria cannot infect the mucosal surface. In vitro, this adhesion is mediated by two components of cranberries: fructose, which inhibits the adherence of type 1 fimbriae (11,8) and PAC, which inhibits the adherence of p-fimbriae (14,15). The binding of the proteinaceous bacterial fimbrial tips to mucosal surfaces on the uroepithelium occurs as a specific receptor ligand association favored by hydrophobic interactions. One possible mechanism is that the cranberry compounds, acting as receptor analogs, competitively inhibit the adhesion of E. coli to host cells by binding to the fimbrial tips. The in vitro antiadherence effect of cranberries is dose-dependent (9,12,16,17). Another mechanism of cranberry activity is the in vitro reduction in the expression of p-fimbriae in E. coli by changing the conformation of surface molecules (12,18). Lavigne et al. (16) demonstrated that cranberries can decrease the virulence of E. coli strains. Furthermore, they described a reduction in adherence activity even in strains with no expression of type 1 fimbriae or p-fimbriae, which adhere via an adhesin, suggesting that cranberry extracts affect a variety of fimbriae. In a recent study, ph-neutralized cranberry juice induced conformational changes in the surface macromolecules of p-fimbriated E. coli by specifically reducing fimbrial length and density (18). Most studies have focused on uropathogenic E. coli type 1 and p-fimbriated E. coli, but there are many in vitro studies showing an inhibition of adherence for Proteus spp., P. aeruginosa, E. faecalis, S. aureus, S. typhimurium and K. pneumoniae (19,20). Even multidrug resistant strains of E.coli exhibited inhibition of adherence to uroepithelial cells in the presence of proanthocyanidin (21).Tao et al. (22) demonstrated that cranberry juice could decrease E. coli adhesion up to 8 hours after consumption. UTI refers to the presence of bacteria in the urinary tract. Symptomatic UTI are usually accompanied by bacteriuria at levels of 105 /ml urine (WHO, 2006). Uropathogenic strains of E. coli bacteria cause up to 95 % of UTIs (Ronald 2003; WHO, 2006). Bacterial adherence to mucosal surfaces is generally considered to be an important prerequisite for colonisation and infection with bacteriuria (Harber and Asscher, 1985). Adherence is facilitated by fimbriae which are proteinaceous fibers on the bacterial cell wall (Beachey et al., 1981; Duguid et al., 1955). Preventing adhesion facilitates urinary
flushing of the causative bacteria, preventing bacterial colonisation of the urinary tract (Foo et al., 2000a). The Panel notes that bacterial adherence precedes an infection and therefore inhibition of bacterial adhesion might result in a reduction for the risk of symptomatic UTI with bacteriuria 105 cfu/ml. Mechanism of action Cranberry contains fl avonoids, anthocyanins, catechin,terpenoids, and organic acids (citric, malic, quinic,benzoic, and glucuronic).(23) Benzoic acid is excreted in the urine as hippuric acid, and the therapeutic effect of cranberry juice has long been attributed to hippuric acid inhibiting the growth of bacteria.(23) However, an acid medium is required for bacteriostatic activity of hippuric acid, and it has been shown that, owing to the low level of benzoic acid in cranberry (< 0.1%), ingestion of more than 4 L of cranberry juice a day is required to acidify the urine and increase hippuric acid excretion.(24) Another mechanism of action is the inhibition of adhesion of type I and P-fi mbriated uropathogens (such as Escherichia coli) to the uroepithelium, prohibiting colonization and infection (25,26).The E coli fi mbriae produce 2 adhesins, one of which is mannose sensitive and the other of which is mannose resistant(27). Cranberry juice contains proanthocyanidin, which has been found to block the attachment of bacterial fi mbriae to the urothelial mucosa owing to strong inhibitory activity against mannose-resistant adhesins of urinary E coli(28). Clinical Studies a) Anti adherence activity The claimed effect is helps reduce the risk of urinary tract infection in women by inhibiting the adhesion of certain bacteria in the urinary tract. The target population is healthy women from the age of 16 years. Urinary tract infection (UTI) refers to the presence of bacteria in the urinary tract. Symptomatic UTI are usually accompanied by bacteriuria at levels of 105 cfu/ml urine. Uropathogenic strains of E. coli bacteria cause up to 95 % of UTIs. Bacterial adherence to mucosal surfaces is generally considered to be an important prerequisite for colonisation and infection with bacteriuria. The Panel notes that bacterial adherence precedes an infection and therefore inhibition of bacterial adhesion might result in a reduction for the risk of symptomatic UTI with bacteriuria 105 cfu/ml. The Panel considers that the claimed effect helps reduce the risk of urinary tract infection in women by inhibiting the adhesion of certain bacteria in the urinary tract is beneficial to human health. Fimbria Cranberry active compounds Escherichia Coli Bacteria adhesion Escherichia Coli Urinary Tract Cell Fig 1 : Anti adherence activity of Oceanspray' s Cranberries Urinary elimina on To determine the effects of cranberry in the antiadherence of uropathogenic organisms, the applicant indicates 8 studies where urine from human female volunteers ex vivo was subsequently assayed in vitro for bacterial anti-adhesion to uroepithelial cells. In these studies urine from female subjects (number of subjects ranged from 4 to 39) having consumed cranberry drink, cranberry concentrate, cranberries, or dried cranberries in a single dose or during a few days was found to contain bacterial anti-adhesion activity (29). All of these studies were performed with foods provided by the applicant.
100 cells. The cranberry preparations administered were based on a proprietary formula of Ocean Spray Cranberry Inc., USA. Anti-adherence activity on uropathogenic E. coli strains was also detected in urine samples in a study with 65 healthy women, aged 19 to 28 years, after consumption of 1200 mg (but not after 400 mg) dried cranberry juice in capsule form for 8 weeks (31). Fig. 2. Detection of bacterial anti-adhesion activity of human urine pre- and post-consumption of single servings of proanthocyanidincontaining juice and food products. Average percent inhibition of antiadhesion activity was recorded over an 8-h period for each set of urine samples tested. Urine collected during each 2-h time period was pooled for each participant prior to testing for anti-adhesion activity. Detection of the activity continuously increased in a regular progression, peaking at 4 h postconsumption and persisting in the urine for at least 8 h, suggesting potential protection against bacterial attachment in the uroepithelium during this period. No activity was detected at any time period in the urines of volunteers that consumed the commercial apple juice (0.27 mg PAC/240 ml serving), purple grape juice (39.1 mg PAC/240 ml serving), green tea (4.4 mg/2g serving) or dark chocolate (106 mg/40 g serving) products, suggesting that the B-linked proanthocyanidins and/or their metabolites either do not have bacterial anti-adhesion activity or the compounds are not bioavailable. No anti-adhesion activity was detected in urines prior to consumption of products (30). The cranberry preparations administered were based on a proprietary formula of Ocean Spray Cranberry Inc., USA.The decrease of the adhesion activity was measured by counting the average number of bacteria per cell determined by examining Effect on Elder women A randomised, double-blind, placebo controlled trial was carried out in a nursing home population of women with a mean age of 78.5 years over a period of 6 months (Avorn et al. 1994; proprietary data). Urine samples from 153 out of originally 192 recruited women with a daily consumption of either 300 ml of a low-calorie cranberry juice drink (provided by Ocean Spray Inc., 100 mg PAC/day, est) or of a placebo drink were analysed monthly for bacteriuria ( 105 organisms/ml urine) and pyuria. A total of 121 subjects completed the 6 months of study (60 in the cranberry group, 61 in placebo). In total 818 urine samples were collected and investigated. Bacteriuria with pyuria was found in 28 % of urine samples of the placebo group versus 15 % of the cranberry juice group. b) Recurrent UTI Infection Fig. 3. Cumulative rate of first recurrence of urinary tract infection during 12 month follow up in women
receiving cranberry juice for six months, Lactobacillus GG drink for 12 months, or no intervention. Occurrence of urinary tract infection was significantly lower in cranberry group than in control group. In an open labelled intervention pilot study, Bailey et al. (2007) investigated the ability of cranberry to prevent UTI for three months in 12 women (25-70 years) with a history of recurrent UTI (patients with 6 occurrences in the previous 12 months). The intervention was 2 x 200 mg capsules of dried cranberry extract standardised to 30 % phenols ( 25 % minimum proanthocyanidins) equivalent to a daily intake of approximately 100 mg cranberry proanthocyanidins. Outcome measures were monthly urine analysis by microscopy to detect bacteriuria and pyuria and symptoms of UTI as assessed by questionnaire. At the start of the study all subjects were free of symptomatic and asymptomatic UTI. None of the subjects developed a symptomatic UTI during the study compared to 24 UTI occurrences predicted on the basis of the previous 12-months history of the study population. Comparison between antibiotic prophylaxis & Cranberry based supplement Two studies in women with recurrent UTI (32) and one study in children (Uberos 2010), compared cranberry product with antibiotic prophylaxis. All three studies used either cranberry capsules or syrup, rather than cranberry juice. Analysis of the two studies in women showed that cranberry product compared to antibiotic were equally as effective in reducing the risk of repeat UTI in women ( Analysis 2.1.1: RR 1.31, 95% CI 0.85 to 2.02) The study in children also showed that the cranberry product were equally as effective in reducing the risk of repeat symptomatic UTI compared to antibiotics (Analysis 2.1.2: RR 0.69, 95% CI 0.32 to 1.51). Conclusion However, processing of cranberries into various products such as tablets or capsules can impact on the PAC composition (Howell 2010) which may result in products which contain little or no PAC - the 'active' anti-adhesion ingredient. In addition, the complexities of the PAC structures and A-type linkages means that measurement of PAC content can often be erroneous and may not be reproducible (Prior 2010). Howell 2010 suggested that at least 36 mg of cranberry PAC equivalents/d is required to be effective, divided into two doses, one in the morning and one at night. Only three studies measured PAC content in non-juice products. The PAC content reported in NAPRUTI Study 2011 was 9.1 mg/g; 1.5% in Sengupta 2011; and in Uberos 2010 (of children) 5 ml of the syrup contained 36 mg. The other studies of non-juice products did not report the PAC content, and thus it is not possible to ascertain whether the products used contained enough PAC content to be effective. There are currently three studies (33) evaluating cranberry tablets or capsules which have not reported enough data to be included in this review update. More studies of cranberry capsules or tablets containing PAC amounting at least 36 mg/d, quantified using a standard measure, and taken twice daily may be warranted but potentially only for women with recurrent UTIs. The cranberry proanthocyanidin (PAC) content at typically 80 mg per serving in Ocean Spray products possibly together with other factors present in cranberry, have properties that inhibit the adhesion of p-fimbriated E. coli bacteria to uroepithelial cells, acting to reduce a risk factor for urinary tract infection. Cranberry PAC have been shown to have a relatively rare A-type linkage that is important in this anti-adhesion phenomenon.
Side-Effect and Toxicity References Cranberry is known to have a negative effect on certain drugs like Warfarin. There may be interference with the effectiveness of the drug. Antacids: Theoretically, cranberry juice may counteract antacids due to its acidic ph. Gastrointestinal agents, miscellaneous: Doses greater than 3L daily will likely cause gastrointestinal distress and diarrhea. Gastrointestinal upset has also been reported in patients consuming cranberry juice daily. Proton pump inhibitors (PPIs): Cranberry juice has been noted to increase absorption of vitamin B12 in patients using proton pump inhibitors. Salicylates: Based on a study of healthy women who were not taking salicylate drugs, consumption of cranberry juice may be associated with an increase of salicyluric in urine and salicylic acids and plasma. Recommended Usage Benefits: Reduce the risk of urinary tract infection Exhibit bacterial anti adhesion activity Reduces the incidence of E. coli infections Reduces the incidence of recurrent urinary bladder infections Target age group : for women 16yrs and above. Dosage : Regular consumption of 2 servings per day of an Ocean Spray product each containing typically 80 mg cranberry proanthocyanidins helps reduce the risk of urinary tract infection in women by inhibiting the adhesion of certain bacteria in the urinary tract. 1. Guay D.R. (2009). Cranberry and urinary tract infections. Drugs,69(7), 775 07. 2. Bruyere F. (2006). Use of cranberry in chronic urinary t r a c t i n f e c t i o n s. M é d e c i n e e t M a l a d i e s Infectieuses,36(7), 358 3. 3. Kontiokari T., Sundqvist K., Nuutinen M., et al. (2001). Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. British Medical Jornal,322(7302), 1571. 4. Jepson R.G. and Craig J.C. (2007). A systematic review of the evidence for cranberries and blueberries in UTI p r e v e n t i o n. M o l e c u l a r N u t r i t i o n & F o o d Research,51(6), 738 5. 5. Cimolai N. and Cimolai T. (2007). The cranberry and the urinary tract. European Journal of Clinical Microbiology & Infectious Disease,26(11), 767 6. 6. Hooton T.M. (1997). Recurrent urinary tract infection in women. International Journal of Antimicrobial Agents,17(4), 259 8. 7. Svanborg C. and Godaly G. (1997). Bacterial virulence in urinary tract infection. Infectious Disease Clinics of North America,11(3), 513 9. 8. Foo, L.Y., Lu, Y., Howell, A.B., et. al. (2000). The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli in vitro. Phytochemistry,54, 173 81. 9. Gupta K., Chou M.Y., Howell A., et. al. (2007). Cranberry products inhibit adherence of p-fimbriated Escherichia coli to primary cultured bladder and vaginal epithelial cells. Journal of Urology,177(6), 2357 0. 10. Schmidt D.R. and Sobota A.E. (1988). An examination of the anti-adherence activity of cranberry juice on urinary and nonurinary bacterial isolates. Microbios,55(224 225),173 1. 11. Zafriri D., Ofek I., Adar R., et al. (1989). Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells. Antimicrobial Agents and Chemotherapy,33(1), 92.
12. Pinzon-Arango P.A., Liu Y., Camesano T.A. (2009). Role of cranberry on bacterial adhesion forces and implications for Escherichia coli-uroepithelial cell attachment. Journal of Medicinal Food,12(2), 259 0. 13. Ofek I., Mirelman D. and Sharon N. (1977). Adherence of Escherichia coli to human mucosal cells mediated by mannose receptors. Nature,265(5595),623. 15. Howell A.B., Vorsa N., Der Marderosian A., et.al. (1998). Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries.the New England Journal of Medicine,339(15), 1085. 16. Foo L.Y., Lu Y., Howell A.B., et. al. (2000). A-Type proanthocyanidin trimers from cranberry that inhibit adherence of uropathogenic P-fimbriated Escherichia coli. Journal of Natural Products,63(9),1225. 17. Lavigne J.P., Bourg G., Combescure C., et. al. (2008). In-vitro and in-vivo evidence of dose-dependent decrease of uropathogenic Escherichia coli virulence after consumption of commercial Vaccinium macrocarpon (cranberry) capsules. Clinical Microbiology and Infection,14(4),350. 18. Howell A.B., Botto H., Combescure C., et. al. (2010). Dosage effect on uropathogenic Escherichia coli antiadhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infectous Disease,10, 94. 19. Liu Y., Gallardo-Moreno A.M., Pinzon-Arango P.A., et. al. (2008). Cranberry changes the physicochemical surface properties of E. coli and adhesion with uroepithelial cells. Colloids and Surfaces. B Biointerfaces,65(1), 35 2. 20. Lee Y.L., Owens J., Thrupp L., et al. (2000). Does cranberry juice have antibacterial activity. Journal of American Medicine Association,283(13),1691. 21. Lee Y.L., Najm W.I., Owens J., et. al. (2010). Antimicrobial activity of urine after ingestion of Cranberry: A Pilot Study. Evidence-Based Complementary and Alternative Medicine,7(2), 227 2. 22. Gupta A., Dwivedi M., Mahdi A.A., et.al. (2011). Inhibition of adherence of multi-drug resistant E. coli by proanthocyanidin. Urological Research,40(2), 143 50. 23. Tao Y., Pinzon-Arango P.A., Howell A.B., et al. (2011). Oral Consumption of Cranberry Juice Cocktail Inhibits Molecular-Scale Adhesion of Clinical Uropathogenic Escherichia coli. Journal of Medicinal Food,14(7 8), 739 45. 24. Raz R., Chazan B., Dan M. (2004). Cranberry juice and urinary tract infection. Clinical Infectious Disease,38(10), 1413 9. 25. Avorn J., Monane M., Gurwitz J.H., et. al. (1994). Reduction of bacteriuria and pyuria after ingestion of cranberry juice. Journal of American Medicinal Association,271(10),751 4. 26. Lowe F.C. and Fagelman E. (2001). Cranberry juice and urinary tract infections: what is the evidence? Urology,57(3),407 13. 27. Guay D.R. (2009). Cranberry and urinary tract infections. Drugs,69(7), 775 807. 28. Duguid J.P. and Old D.C. (1980). Adhesive properties of Enterobacteriaceae. In: Beachey EH, (ed). Bacterial adherence: receptors and recognition. Series B. Vol. 6. London, Engl: Chapman and Hall, pp. 185 217. 29. Di Martino et al., 2006; Greenberg et al., 2005; Howell and Foxman, 2002b; Howell et al., 2005; Schmidt and Sobota, 1988; Sobota 1984. 30. Howell A.B., Vorsa N., Der Marderosian A.D., et. al. (1998). Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries. The New England Journal of Medicine,339(15), 1085 6. 31. Valentova et al. 2007 32. McMurdo 2009; NAPRUTI Study 2011 33. Bonetta 2011; NCT00280592; NCT01033383 Disclaimer: The products and information are not intended to diagnose, treat, cure, or prevent any disease. Actual results may vary. Information on this site have not been evaluated by the Food and Drug Administration. Consult with your physician before using any dietary supplement. No liability is assumed by My Wish Hub Limited, London, UK., for any information contained herein.
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