ABSTRACT: Cranberry is reported to have health benefits, including prevention of urinary tract infections and other chronic diseases, due to the high content of polyphenols, including flavonols and flavan-3-ols. The aim of this study was to determine the clearance of flavonol glycosides and flavan-3-ols and/or their metabolites in human urine. Ten healthy women volunteers ingested 240 mL of cranberry juice containing flavonol glycosides. Urine samples were collected at 0, 90, 225, and 360 min postingestion. While flavan-3-ols were not detected, five flavonol glycosides common in cranberry were identified. Quercetin-3-galactoside, the most abundant cranberry flavonol, exhibited the highest peak urine concentration (Cmax) of 1315 pg/mg creatinine, followed by quercetin-3-rhamnoside, quercetin-3-arabinoside, myricetin-3-arabinoside, and myricetin-3-galactoside. Quercetin-3-arabinoside showed delayed clearance, Cmax at 237 min (Tmax), relative to other flavonols (90−151 min). Both aglycone and the conjugated sugar moiety structure mediate the flavonol’s bioavailability. Interindividual variation for bioavailability and clearance is also apparent. Metabolites, e.g. glucoronides, were not detected. KEYWORDS: flavonols, glycosides, flavan-3-ols, cranberry juice, human urine, MS-MS

Cranberry has been used traditionally to prevent urinary tract infections (UTIs), primarily among generally healthy women prone to recurrent UTIs. Results from a number of published clinical studies have supported this benefit; however, meta-analyses on cranberry and UTI prevention have reported conflicting conclusions. This article explores the methodological differences that contributed to these disparate findings. Despite similar research questions, the meta-analyses varied in the studies that were included, as well as the data that were extracted. In the 2 most comprehensive systematic reviews, heterogeneity was handled differently, leading to an I2 of 65% in one and 43% in the other. Most notably, the populations influencing the conclusions varied. In one analysis, populations with pathological/physiological conditions contributed 75.6% of the total weight to the summary risk estimate (RR: 0.86; 95% CI: 0.71, 1.04); another weighted the evidence relatively equally across UTI populations (RR: 0.62; 95% CI: 0.49, 0.80); and a third included only women with recurrent UTIs (RR: 0.53; 95% CI: 0.33, 0.83). Because women with recurrent UTIs are the group to whom most recommendations regarding cranberry consumption is directed, inclusion of other groups in the efficacy assessment could influence clinical practice quality. Therefore, conclusions on cranberry and UTIs should consider differences in results across various populations studied when interpreting results from meta-analyses.

PURPOSE: To evaluate the effect of cranberry extract (PAC-A ~ proanthocyanidin-A) on the in vitro bacterial properties of uropathogenic (E. coli) and its efficacy/tolerability in patients with subclinical or uncomplicated recurrent UTI (r-UTI). MATERIALS AND METHODS: After obtaining clearance from the ethics committee and administering a written informed consent, 72 patients with r-UTI were enrolled as per protocol (November 2011 to March 2013) in this prospective study, to randomly receive (PAC-A: group I, 36) or (placebo: group II, 36), for 12 weeks. Any change/reduction in the incidence of r-UTI at 12 weeks was construed to be the primary endpoint of this study. RESULTS: After 12 weeks, bacterial adhesion scoring decreased (0.28)/(2.14) in group I/II (p < 0.001); 32/36 (88.8 %) and 2/36 (5.5 %) in groups I and II, respectively, turned MRHA negative (p < 0.001); biofilm (p < 0.01) and bacterial growth (p < 0.001) decreased in group I; microscopic pyuria score was 0.36/2.0 in group I/II (p < 0.001); r-UTI decreased to 33.33 versus 88.89 % in group I/II (p < 0.001); mean subjective dysuria score was 0.19 versus 1.47 in group I/II (p < 0.001), while mean urine pH was 5.88 versus 6.30 in group I/II (p < 0.001). No in vitro antibacterial activity of cranberry could be demonstrated, and no adverse events were noted. CONCLUSIONS: The overall efficacy and tolerability of standardized cranberry extract containing (PAC-A) as a food supplement were superior to placebo in terms of reduced bacterial adhesion; bacterial MRHA negativity; urine pH reduction; and in preventing r-UTI (dysuria, bacteriuria and pyuria). Larger randomized controlled trials are needed to elucidate the precise role, exact dose and optimal duration of PAC-A therapy in patients at risk of r-UTI.

Urinary tract infections (UTIs) are common in women and many patients with recurrent UTIs do not eradicate the condition albeit being treated with multiple courses of antibiotics. The use of nutritional supplements might reduce the risk of recurrent UTIs. However, the role of supplements taken as single agents appears to be limited. We hypothesized that a combination of cranberries, Lactobacillus rhamnosus, and vitamin C might produce a clinical benefit due to their additive or synergistic effects. We prospectively enrolled 42 consecutive women with recurrent UTIs treated with 120mg cranberries (minimum proanthocyanidin content: 32mg), 1 billion heat-killed L. rhamnosus SGL06, and 750mg vitamin C thrice daily for 20 consecutive d. Patients were advised to stop taking these supplements for 10 d and then to repeat the whole cycle three times. Patients were contacted three mo and six mo following the end of the administration of these supplements and evaluated with a semistructured interview and urinalysis. Responders were defined as the absence of symptoms and negative urinalysis or urine culture. Follow-up data were available for 36 patients. Overall, 26 (72.2%) and 22 patients (61.1%) were responders at the 3-mo and 6-month follow-up. No major side effects were recorded. The administration of cranberries, L. rhamnosus, and vitamin C might represent a safe and effective option in women with recurrent UTIs.

OBJECTIVE: To determine effects of cranberry extract on development of urinary tract infection (UTI) in dogs and on adherence of Escherichia coli to Madin-Darby canine kidney (MDCK) cells. ANIMALS: 12 client-owned dogs (in vivo experiment) and 6 client-owned dogs (in vitro experiment). PROCEDURES: 12 dogs with a history of recurrent UTI received an antimicrobial (n=6) or cranberry extract (6) orally for 6 months. Dogs were monitored for a UTI. For the in vitro experiment, cranberry extract was orally administered to 6 dogs for 60 days. Voided urine samples were collected from each dog before and 30 and 60 days after onset of extract administration. Urine was evaluated by use of a bacteriostasis assay. An antiadhesion assay and microscopic examination were used to determine inhibition of bacterial adherence to MDCK cells. RESULTS: None of the 12 dogs developed a UTI. The bacteriostasis assay revealed no zone of inhibition for any urine samples. Bacterial adhesion was significantly reduced after culture with urine samples obtained at 30 and 60 days, compared with results for urine samples obtained before extract administration. Microscopic examination revealed that bacterial adherence to MDCK cells was significantly reduced after culture with urine samples obtained at 30 and 60 days, compared with results after culture with urine samples obtained before extract administration. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of cranberry extract prevented development of a UTI and prevented E. coli adherence to MDCK cells, which may indicate it has benefit for preventing UTIs in dogs.

Purpose: Urinary tract infections (UTIs) are widespread and affect a large portion of the human population. Cranberry juices and extracts have been used for UTI prevention due to their content of bioactive proanthocyanidins (PACs), particularly of the A type (PAC-A). Controversial clinical results obtained with cranberry are often due to a lack of precise determination and authentication of the PAC-A content. This study used OximacroReg. (Biosfered S.r.l., Turin, Italy), a cranberry extract with a high content of PAC-A, to prevent UTIs in female and male volunteers. Materials and Methods: The OximacroReg. PACs content was assayed using the Brunswick Laboratories 4-dimethylaminocinnamaldehyde (BL-DMAC) method, and the dimer and trimer PACs-A and PACs-B percentages were determined via high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ESI-MS/MS). A balanced group of female (ranging from 19 to over 51 years) and male volunteers (over 51 years) was divided into two groups. The experimental group received 1 capsule containing OximacroReg. (36 mg PACs-A) twice per day (morning and evening) for 7 days, and the placebo group was given the same number of capsules with no PACs. Results: Analysis of OximacroReg. revealed a high total PAC content (372.34 mg/g+or-2.3) and a high percentage of PAC-A dimers and trimers (86.72%+or-1.65). After 7 days of OximacroReg. administration, a significant difference was found between the placebo and OximacroReg. groups for both females (Mann-Whitney U-test=875; P=.001; n=60) and males (Mann-Whitney U-test=24; P=.016; n=10). When the female and male age ranges were analysed separately, the female age range 31-35 showed only slightly significant differences between the placebo and OximacroReg. groups (Mann-Whitney U-test=20.5; P=.095; n=10), whereas all other female age ranges showed highly significant differences between the placebo and OximacroReg. groups (Mann-Whitney U-test=25; P=.008; n=10). Furthermore, colony forming unit/mL counts from the urine cultures showed a significant difference (P<.001) between the experimental and the placebo groups (SD difference=51688; df=34, t=-10.27; Dunn-Sidak Adjusted P<.001, Bonferroni Adjusted P<.001). Conclusion: Careful determination of the total PAC content using the BL-DMAC method and the authentication of PACs-A with mass spectrometry in cranberry extracts are necessary to prepare effective doses for UTI prevention. A dose of 112 mg OximacroReg. containing 36 mg PACs-A was found to be effective in preventing UTIs when used twice per day for 7 days.

Objective: We assessed the effects of the consumption of a cranberry beverage on episodes of clinical UTIs.

Design: In this randomized, double-blind, placebo-controlled, multicenter clinical trial, women with a history of a recent UTI were assigned to consume one 240-mL serving of cranberry beverage/d (n = 185) or a placebo (n = 188) beverage for 24 wk. The primary outcome was the clinical UTI incidence density, which was defined as the total number of clinical UTI events (including multiple events per subject when applicable) per unit of observation time.

Results: The dates of the random assignment of the first subject and the last subject’s final visit were February 2013 and March 2015, respectively. The mean age was 40.9 y, and characteristics were similar in both groups. Compliance with study product consumption was 98%, and 86% of subjects completed the treatment period in both groups. There were 39 investigator-diagnosed episodes of clinical UTI in the cranberry group compared with 67 episodes in the placebo group (antibiotic use–adjusted incidence rate ratio: 0.61; 95% CI: 0.41, 0.91; P = 0.016). Clinical UTI with pyuria was also significantly reduced (incidence rate ratio: 0.63; 95% CI: 0.40, 0.97; P = 0.037). One clinical UTI event was prevented for every 3.2 woman-years (95% CI: 2.0, 13.1 woman-years) of the cranberry intervention. The time to UTI with culture positivity did not differ significantly between groups (HR: 0.97; 95% CI: 0.56, 1.67; P = 0.914).

Conclusion: The consumption of a cranberry juice beverage lowered the number of clinical UTI episodes in women with a recent history of UTI. This study was registered at clinicaltrials.gov as NCT01776021.

Full article: http://ajcn.nutrition.org/content/103/6/1434.full

Most research on American cranberry in the prevention of urinary tract infection (UTI) has used juices. The spectrum of components in juice is limited. This study tested whether whole cranberry fruit powder (proanthocyanidin content 0.56%) could prevent recurrent UTI in 182 women with two or more UTI episodes in the last year. Participants were randomized to a cranberry (n=89) or a placebo group (n=93) and received daily 500mg of cranberry for 6months. The number of UTI diagnoses was counted. The intent-to-treat analyses showed that in the cranberry group, the UTIs were significantly fewer [10.8% vs. 25.8%, p=0.04, with an age-standardized 12-month UTI history (p=0.01)]. The Kaplan-Meier survival curves showed that the cranberry group experienced a longer time to first UTI than the placebo group (p=0.04). Biochemical parameters were normal, and there was no significant difference in urinary phenolics between the groups at baseline or on day180. The results show that cranberry fruit powder (peel, seeds, pulp) may reduce the risk of symptomatic UTI in women with a history of recurrent UTIs.

Research suggests that cranberry (Vaccinium macrocarpon) helps maintain urinary tract health. Bacterial adhesion to the uroepithelium is the initial step in the progression to development of a urinary tract infection. The bacterial anti-adhesion activity of cranberry proanthocyanidins (PACs) has been demonstrated in vitro. Three different cranberry extracts were developed containing a standardized level of 36 mg of PACs. This randomized, double-blind, placebo controlled, ex vivo, acute study was designed to compare the anti-adhesion activity exhibited by human urine following consumption of three different cranberry extracts on uropathogenic P-fimbriated Escherichia coli in healthy men and women. All three cranberry extracts significantly increased anti-adhesion activity in urine. from 6 to 12 hours after intake of a single dose standardized to deliver 36 mg of PACs (as measured by the BL-DMAC method), versus placebo.

OBJECTIVE: To evaluate the existing data regarding the use of cranberry products for the prevention of urinary tract infections (UTIs) in pediatric patients.
DATA SOURCES: A literature search of Medline databases from 1966 to June 2015 was conducted.
STUDY SELECTION AND DATA EXTRACTION: The databases were searched using the terms ""pediatrics,"" ""children,"" ""cranberry,"" ""cranberry juice,"" and ""urinary tract infections."" The identified trials were then searched for additional references applicable to this topic.
DATA SYNTHESIS: A total of 8 clinical trials were identified that examined the use of cranberry products, mostly juice, for the prevention of UTIs in children. Three trials examined the use in otherwise healthy children. Five trials examined the use in pediatric patients with underlying urogenital abnormalities of which 2 compared cranberry to antibiotics. In healthy pediatric patients, cranberry use was associated with a reduction in the overall number of UTIs and a decrease in the number of antibiotic days per year for UTI treatment. In patients with urogenital abnormalities, results were conflicting, with some studies showing no reduction in UTIs compared with placebo, but others demonstrating a significant reduction. However, cranberry products had similar efficacy when compared with both cefaclor and trimethoprim. All studies used a wide variety of doses and frequencies of cranberry, making specific product recommendations difficult.
CONCLUSIONS: Cranberry appears effective for the prevention of UTIs in otherwise healthy children and is at least as effective as antibiotics in children with underlying urogenital abnormalities. However, recommendations for cranberry dosing and frequency cannot be confidently made at this time. Larger, well-designed trials are recommended.