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Cranberry juice for prophylaxis of urinary tract infections - conclusions from clinical experience and research.

Abstract

Cranberry juice (Vaccinium macrocarpon) is a widely used and recommended North-American folk remedy for prophylaxis of urinary tract infections (UTI). Clinical trials have documented its efficacy in women with recurrent UTI, but so far not in other groups of patients. The composition of effective cranberry products and its dosage in UTI prophylaxis have not been defined. Intriguing experimental research has identified an anti-adhesive mechanism of cranberry juice that prevents docking of bacteria on host tissues. This efficacy mechanism can be traced in patients' urine following oral intake of cranberry products and appears to be due to proanthocyanidins with an A-type linkage of flavanols. The application of this anti-adhesion mechanism of cranberry-proanthocyandins is currently also investigated in other common diseases of bacterial pathogenesis, for example Helicobacter pylori-associated gastritis and dental caries/periodontal disease. The use of cranberry products appears to be safe and provide additional benefits by anti-oxidant and cholesterol-lowering activity. [c] 2008 Elsevier GmbH. All rights reserved.

Keywords: Cranberry (Vaccinium macrocarpon Aiton); Urinary tract infection; Proanthocyanidines; Anti-adhesion; p-fimbriae; Escherichia coli

Introduction

The first author's interest into cranberry juice as a prophylaxis of urinary tract infections (UTI) goes back to the late 1990s when his attention had been drawn to this strategy by a letter published in the Lancet (Kerr, 1999). Cranberry juice had then been virtually unknown in Germany and attempts to establish it on the German soft-drink market had repeatedly failed.

The status of cranberry research by the end of 1990s was encouraging enough to recommened its use as a prophylactic. Cranberry juice apparently worked by inhibition of bacterial adhesion to host tissue, a unique and hitherto unknown anti-infective mechanism. Because cranberry juice of high quality had not been commercially available in Germany, it had to be self-produced from imported American cranberry juice concentrate. This ensured that patients received the well-investigated juice from Vaccinium macrocarpon rather than lingonberry or blueberry juice of unknown prophylactic values. The self-produced cranberry juice had been controlled for a high content of proanthocyanidins, because these macromolecules appeared to be responsible for the anti-adhesion effect.

Anecdotal efficacy and tolerability

Several hundred patients received this cranberry juice for prophylaxis of UTI, usually two glasses daily (2 x 200 ml). Its taste, efficacy and tolerability were generally described as good. In patients with frequent recurrent UTI, the number and severity of infections could be reduced. There were occasional complaints about gastrointestinal discomfort and the need for an increased insulin dosage in diabetics. Several patients with recurrent severe UTI who had depended on permanent or frequent antibiotic usage before, had become long-term users (> 1 y) of the juice. Three female renal transplant recipients who had suffered from extraordinarily tantalizing UTI before and needed 3-5 courses of antibiotics yearly, responded by a reduction of the yearly episodes to 0-1. Cranberry juice, however, could not eradicate their permanent bacteriuria with different species (E. coli, Proteus, Klebsiella, etc.). Cranberry juice provided an outstanding benefit in some, but not all of our patients with neuropathic bladder dysfunction. However, the juice had caused intolerable irritations of the mucosa in patients with an urostoma.

Patients with recurrent UTI usually have a high level of suffering and tend to accept any promising remedy, especially when it is a "natural" one. Nevertheless, they want to understand the active principle and be informed about potential modifications and alternatives before accepting a long-term prophylaxis. Physicians trying to consult patients in that respect will soon discover many blind spots of the current research evidence, for example with respect to the minimum effective dosage.

Efficacy in clinical trials

Is cranberry juice protecting from recurrent UTI better than placebo? It is conveniently to consult the most recent Cochrane statement (Jepson and Craig, 2008). The Cochrane institution is devoted to evidence-based medicine and assesses the latest published research. Cochrane has continued to cautiously classify cranberry juice as an evidence-based UTI prophylaxis in women since 2003, but their earlier judgements had been reserved (Jepson et al., 2000).

Currently, there are about a dozen published clinical trials on UTI prophylaxis with cranberry products (Table 1) in different populations, some of them with very low numbers of included patients. The larger-scale and better designed trials have contributed to the positive Cochrane assessments.
Table 1. Clinical trials on cranberry products for UTI prophylaxis

Studypopulation/ Result Publication
intervention/design

Populatin: 150 young women After 6 months, of the Kontiokari
(mean age 30 y) with previous 150 women 16% of the et al.
UTI cranberry--lingonberry (2001)
 group, 39% of the
 lactobacillus, and 36%
 of the control group
 had a UTI recurrence.
 Drinking cranberry
 juice reduced the
 cummulative rate of the
 first re-occurrence of
 UTI by 56% versus
 control group and the
 absolute risk for UTI
 was reduced by 20%

Intervention: Randomisation to
drink 50 ml. Europeancranberry/
lingonberry concentrate daily
for 6 months,or to drink or 100
ml of a lactobacillus-drink 5
days per week for 12 months or
no intervention

Design: Open design with first
re-occurrence of symptomatic
UIT as study end-point

Population: 153 elderly In the cranberry group, Avorn
postmenopausal women the odds for infected et al.
(mean age 78.5 y) urine had been 42% of (1994)
 the odds of the control
 group. The difference
 was first detectable
 after 2 months. The
 odds for patients with
 infected urine to remain
 so was 27% fo the control
 group. Patients in the
 cranberry group were
 far more likely to make
 the transition from
 infected to non-infected
 urine. There was no
 acidification of urine
 by cranberry

Intervention: Daily consumption
of 300 ml standard cranberry
beverage or placebo-drink for 6
months

Design: Double-blind,
placebo-controlled trial, no
intent-to-treat design. Study
groups were compared for the
combined soccurrence of
bacteriuria and pyuria
( = infected urine) in 818
urine samples collected at.
baseline and monthly during the
study period

Population: 150 sexually active Both, cranberry juice Stothers
women (aged 21-72 y) with and tablets decreased (2002)
history of UTI the number of patients
 experiencing at least
 1 symptomatic UTI/year
 (to 205 and 18%,
 respectively) compared
 with placebo (to 32%)
 (p < 0.05). The mean
 annual cost was lower
 for tablets than for
 juice

Intervention: Consumption of
American cranberry juice (250
ml 3x/d) or tablest with
cranberry extract (2x/d) for
1 year Design: Double-blind,
placebo- controlled,
intent-to-treat design and
cost effectiveness
analysis. Randomisation to
three groups: placebo juice
+ placebo tablets vs.
placebo juice + cranberry
tablets vs. cranberry juice
+ placebo tablets. Outcome
measures:
> 50% decrease in symptomatic
UTI per year (symptoms + or
> 100 000 organisms/ml) and >
50% decrease of annual
antibiotic consumption

Population: 367 (mean age 81.5 UTI occurred in only McMurdo
y) older patients of both sexes 21/376 (5.5%) et al.
inhospitals without previous participants without (2005)
history of UTI differences between
 the groups (14/189 in
 the placebo group and
 7/187 in the cradberry
 juice group). Infections
 with E. coli were
 significantly reduced
 in the cranberry group
 (13 versus 4) RR 0.31
 [95% CI 0.10-0.94, p =
 0.027]

Intervention: Daily ingestion
of 300ml cranberry juice or
matching placebo beverage for a
mean of 18 days
Desing: Randomised,
placebo-controlled,
double-blind trial.
End-point: symptomatic UTI

Population: 12 Women (25-70y No UTI occuring during Bailey et
old) with at least 6 UTI in intake; 8/12 women al.(2007)
the prrceding year remaining free of
 infection 2 years
 later

Intervention: Twice daily
intake of 200 mg concentated
cranberry extract standardized
to 30% phenolic
Design: Open label pilot study
with 12-week duration of
intervention. Follow-up for
further 2 years. Recurrence of
UTI reported by questionnaire

Population: 40 Children with High drop-out rate, Foda
neuropathic bladder needing only 21 finished trial. et al.
intermittent catheterisation No effect greater than (1995)
 that of water on UTI
 occurrence

Intervention: 15 ml/kg/day
cranberry cocktail or water
Dasign: Randomised single-blind
cross-over study

Population: 15 Children with No change of the high Schlager
neurogenic bladder receiving UTI prevalence of 75% et al.
intermittent catheterisation by cranberry juice (1999)
 consumption. E. coli.
 remained the
 predominant pathogen
 during placebo and
 cranberry periods

Intervention: Cranberry
concentrate or placebo
concentrate
Design: Double-blind,
placebo-controlled cross-
over study for 6 months,
change of intervention
after 3 months. Urine
samples were taken during
weekly visits by
catheterisation, and
infection symptoms recorded

Population: 15 spinal cord Cranberry juice intake Reid
injured patients reduced the biofilm et al.
(mean age 42 y) load compared to (2001)
 baseline (p = 0.01)
 and the adhesion of
 Gram-negative (p =
 0.054) and Gram-
 positive (p = 0.022)
 bacteria to cells.
 Water intake had no
 effect on bacterial
 adhesion or bioflim
 presence

Intervention: Commercial
cranberry juice (3 x 250 ml/d)
Design: Pilot study with open
cross-over design to determine
whether alteration of fluid
intake and use of cranberry
juice affects biofilm
generation. Urine samples were
investigated for bacterial
biofilm load after 7 days
drinking three glasses of
water daily and after further
7 days drinking three glasses
of cranberry juice daily.
Urine samples used to harvest
uroepithelial cells to look for
biofilm coating and to test
for bacterial adhesion

Population: 305 spinal cord Both treatment groups Lee et al.
injured patients with had no longer UTI-free (2007)
neurogenic bladder and periods than placebo
stable bladder management groups (p = 0.70 for
 cranberry; p = 0.75 for
 Methenamine Hippurate)

Intervention: Methenamine
Hippurate I g twice daily or
800 mg cranberry extract twice
daily, both indistinguishable
in taste and appearance
Design: Double-blind randomised
placebo-controlled trial with
6 months follow-up. The main
outcome measure was time to
occurrence of a symptomatic UTI

Population: Persons with spinal No differences or Waites et
cord injury (SCI) with trends detected al.(2004)
neurogenic bladder managed by between participants
intermittent catheterisation or and controls with
external collection device and respect to bacterial
bacteriuria. 26 persons received counts, types and
cranberry extract and 22 numbers of different
persons received placebo bacterial species,
 leukocyturia, urinary
 pH, or episodes of
 symptomatic urinary
 tract infection

Intervention: Daily ingestion
of capsules with 2 g of
concentrated cranberry juice
or placebo for 6 months
Design: Randomised, double-
blind, placebo-controlled study
Baseline urinalysis and
cultures were performed at the
time of the initial clinic visit
and monthly for 6 months

Population: Volunteers No reduction of the Morris and
 amounts of calcium and Stickler
 magnesium recovered (2001)
 from catheters by
 cranberry drinking
 and even more
 encrustation. In this
 in vitro study,
 drinking cranberry
 juice did not produce
 urine that was
 inhibitory to the
 development of
 crystalline catheter-
 blocking P. mirabilis
 biofilms. The important
 factor in preventing
 catheter encrustation
 proved to be a high fluid
 intake

Intervention: Urine tested
after cranberry juice or water
drinking for development of
crystalline Proteus mirabilis
biofilms

Design: Urine from volunteers
who had drunk up to 2 x 500mL
of cranberry juice or water
within an 8-h period. In a
laboratory model of the
catheterized bladder these
samples were inoculated
with P. mirabilis and after
incubation for 24 or 48 h, the
extent of catheter encrustation
was determined by chemical
analysis for calcium and
magnesium and visualized by
scanning electron microscopy


A Finnish trial had found an impressive reduction of the first recurrence of UTI in young women who had consumed a cranberry-lingonberry concentrate for prophylaxis. This trial had received enormous interest from the media and had popularized cranberry-based strategies in Europe (Kontiokari et al., 2001) (Fig. 1).

[FIGURE 1 OMITTED]

Young women (n = 150; mean age 30 y) with a history of UTI caused by E. coli had been randomised to drink either 50 ml of a juice concentrate mixed from lingonberry (Vaccinium vitis-idaea) and European cranberry (V. oxycoccus)) daily for 6 months, or 100 ml of a probiotic Lactobacillus-drink 5 days per week for 12 months, or to receive no intervention. Patients were followed for 12 months to reach the study end-point of first recurrence of symptomatic UTI.

At the end of the 6-month treatment period, of the 150 women 16% of the cranberry--lingonberry group, 39% of the lactobacillus, and 36% of the control group had a UTI recurrence. Even after the cranberry had to be discontinued - because there was a halt in product production the infection rates in this group remained lower than in the two other groups. Drinking cranberry juice reduced the cumulative rate of the first recurrence of UTI by 56% versus control group, and the absolute risk for UTI was reduced by 20%.

This was a landmark study, although it had on open design, and the women knew what they were randomised to. The result is not explained by a placebo effect, since the other intervention had failed and was not different from the group with no intervention.

It needs to be clearly stated and acknowledged by clinicians, scientists and the industry that the impressive outcome of this trial had not been accomplished with American cranberry juice, but with juice from two closely related European species (Nowack, 2003). This information is often suppressed in recommendations about products suitable for UTI prophylaxis. Moreover, it is interesting and possibly of relevance for the putative prophylactic mechanism of the applied juice, that the benefit extended beyond the actual time of consumption.

In a Canadian study the prophylactic value of cranberry juice (250ml three times daily) or cranberry extract in tablets (taken twice daily) for 1 year had been investigated in 150 sexually active women (21-72 years old) (Stothers, 2002). Patients received either placebo juice + placebo tablets or placebo juice + cranberry tablets or cranberry juice+placebo tablets. Both cranberry products reduced the number of patients experiencing at least 1 symptomatic UTI/year (20% (juice) and 18% (tablets), respectively) versus placebo (32%) (p < 0.05). Beyond that benefit, there was a reduction of spent antibiotics in both treatment groups. Cranberry tablets turned out to be twice as cost-effective as juice for UTI prevention.

Another study with an impressive number of included patients failed to find a prophylactic value of cranberry products (McMurdo et al., 2005). A total of 376 older patients in hospitals (mean age 81.5y) had been randomised to drink either 300 ml commercial cranberry juice daily or a matching placebo beverage. There was a rather short period of intervention (18 days) and follow-up (35 days). Time to onset of first UTI had been the primary outcome criteria. Symptomatic UTI occurred in only 21/376 (5.6%) participants and with this low incidence there was no difference between the groups (14/189 in the placebo group and 7/187 in the cranberry juice group). However, in the cranberry group the infections with E. coli were significantly reduced ((13 versus 4) RR 0.31 [95% CI 0.10-0.94, p = 0.027]). It therefore appears, that, despite having included so many patients, the low infection rate within this rather short intervention and observation period rendered the study underpowered to find a benefit for cranberry. The low infection rate is not surprising, since in contrast to other studies, males and participants without previous UTI had been included. These patients are not particularly prone to acquire UTI.

The first major clinical trial on cranberry juice as an UTI prophylactic had been performed in the risk population of elderly women (Avorn et al., 1994) (Fig. 2). The study was placebo-controlled, but not "intent-to treat". Instead, the infection status of monthly collected urine samples had been the primary outcome. Post-menopausal women (n = 153; mean age 78.5y) were randomised to drink either 300ml of cranberry juice daily or a synthetic placebo drink with identical taste, colour and sugar content for 6 months. In the monthly collected urine samples the combined occurrence of significant bacteriuria and pyuria had been classified as infected urine.

[FIGURE 2 OMITTED]

Infected urine samples were reduced in the cranberry group by 42% over the control group (p = 0.004), and there was less need to use antibiotics. However, only 121 patients completed the full 6-month study (60 in experimental group). While bacteriuria (with E. coli or Klebsiella) had been precisely defined, a definition for pyuria was lacking (no information on sample collection and leukocyte count). This shortcoming weakens the interpretation, since bacteriuria without pyuria is a common finding in elderly women and requires no treatment, unless accompanied by clinical symptoms. Symptoms referable to UTI had nevertheless been recorded but could not be correlated to urinary findings. This again casts doubt on the validity of the concept of "infected urine" applied in this study. The randomisation had also been criticised because substantially more of the placebo group (25%) than of the cranberry group (7%) had a history of UTI in the 6 months prior to the study. It is interesting but rarely quoted that the probability of transition was higher inconverting urine from out of the state of bacteriuria with pyuria as compared with the prevention of conversion from non-infected to bacteriuric-pyuric. This result suggests a potential effect of cranberries in active infection. That the reduction of infected urine in the cranberry group set on only after several months of intervention is also rarely mentioned in discussions and reviews, probably, because it is not easily compatible with the favoured anti-adhesion concept as cranberries' main efficacy mechanism.

In synopsis, the better designed clinical trials provide encouraging support for a prophylactic value of cranberry products (both juice and extract) in women with a history of UTI, especially when caused by E. coli. In comparison with other strategies for UTI prophylaxis, for example with vaccination, the evidence is outstanding. However, there is no clinical proof that cranberry prophylaxis works in males.

Since different cranberry products (e.g. commercial cranberry juice, cranberry cocktail, cranberry juice concentrate and dietary cranberry supplements (dried extract), and juice concentrate from European cranberry/1ingonberry) had been employed in clinical trials, a minimum or optimal dosage or composition of effective preparations cannot be specified. The prophylactic value of a less than daily consumption is not supported by clinical trials. Cranberry products had not faced head-to-head comparisons with other prophylactic regimes with the exception of Lactobacillus. Ongoing and future studies intend to better define the relative position of a prophylaxis with cranberries. Two large-scale trials with American cranberry juice products are under way. The NAPRUTI study in the Netherlands tests the non-inferiority of two alternative prophylactic strategies against standard antibiotic prophylaxis with 480 mg Trimethoprim-Sulfamethoxazol daily (Beerepoot et al., 2006). With a planned follow-up for 12 months cranberry capsules will be studied in pre-menopausal women, while a probiotic drink is given to postmenopausal elderly women. In a Canadian study, participants will be randomly assigned to receive varying dosages of either cranberry-containing products or placebo for 1 year. The study intends to find the minimum dosage of cranberry-containing products necessary to achieve a 30% prophylaxis of UTIs in women with recurrent UTI (Stothers, 2008).

Efficacy in patients with complicated UTI

Prophylaxis of recurrent UTI is most urgently needed in patients with defective anatomy and/or function of the urinary tract. Neuropathic bladder-dysfunction following spinal cord injuries predisposes for chronic UTI, often with multi-resistant bacteria. Biofilms, generated along the catheters, are difficult to erase and are sources of bacterial re-infections. For cranberries, there are currently controversial and not really encouraging results. Pilot studies found a reduction of UTI by cranberry juice in patients with neuropathic bladder or impaired generation of biofilms (Foda et al., 1995; Reid et al., 2001), but a recent randomized placebo-controlled trial could not confirm a benefit of daily cranberry juice consumption (Lee et al., 2007). Overall, there are more trials with negative outcomes in these groups of patients (Table 1).

The active principle of cranberry juice--Is it inhibition of bacterial adhesion?

There have been several hypotheses how cranberry juice might prevent UTI. Fresh cranberries taste sour due to their content in organic acids like hippuric and benzoic acid. Cranberry juice had been supposed to lower the urinary pH to an extent that will stop bacterial growth (Blatherwick and Long, 1923; Bodel et al., 1959). However, cranberry juice had not affected patient's urinary pH in clinical trials (Avorn et al., 1994; Monroy-Torres and Macias, 2005; Valentova et al., 2007), and drinking of 21 cranberry juice daily had not acidified urine in volunteers (McLead and Nahata, 1975).

Cranberry products do also not act as natural antibiotics. Significant amounts of bactericidal or bacteriostatic constituents had not been detected in screenings (Leitao et al., 2005; Monroy-Torres and Macias, 2005).

Quite early on, it had been observed that cranberry juice interfered with the adhesion of uropathogenic bacteria to host tissue (Sobota, 1984; Schmidt and Sobota, 1988). It is currently believed and supported by a growing body of data that this might be an active principle of cranberry-based infection prophylaxis. It aims at an early and crucial step in the pathogenesis of bacterial UTI.

Adhesion of uropathogenic E. coli is accomplished by binding of lectins exposed on the surface of fimbriae to complementary carbohydrates on the host tissue (Johnson et al., 2003). Bacteria express various types of fimbriae which differ according to their strength of adherence. Adherence of E. coli by means of the ubiquitous type-1 fimbriae is easily inhibited by fructose (hence mannose-sensible fimbriae). E. coli isolated from patients with pyelonephritis and recurrent UTI owe their enhanced virulence to further types of fimbriae, notably p-fimbriae are associated with the alpha-Gal (1-4) beta-Gal specific lectin and bind to the complementary galabiose-containing structures on the uroepithelial cell-surface (Salminen et al., 2007). This lectin is a marker of bacterial virulence and restricted to bacterial strains causing severe and complicated UTI. The prefix "p" is derived from pyelonephritis, and the binding of p-fimbriated E. coli to glycosphingolipids of the lipid-double-membrane of renal cells precedes renal parenchymal invasion (Rice et al., 2005). P-fimbrial bacterial adhesion to host tissue is not inhibited by fructose or other low-molecular carbohydrates (hence mannose-resistant fimbriae).

Incubation of uropathogenic bacteria with cranberry juice or with urine harvested from humans or experi mental animals after they had ingested cranberry juice reduces their ability to adhere in biologically relevant models (Sobota, 1984; Schmidt and Sobota, 1988; Howell et al., 1998). This anti-adhesion effect of cranberries extends to uropathogenic bacteria of increased virulence, for example p-fimbriated and antibiotic-resistant E. coli strains (DiMartino et al., 2006) (Fig. 3), while adhesion of fecal E. coli isolates is less strongly inhibited (Schmidt and Sobota, 1988). The efficacy of cranberry juice on p-fimbriated E.coli suggests the presence of a further inhibitor of lectin-mediated adherence besides fructose that is intestinally absorbed and filtered or secreted into the urine in active form (Zafriri et al., 1989).

[FIGURE 3 OMITTED]

A-type PAC are the putative active compounds

In a series of experiments the anti-adhesion compounds of cranberries had been identified as three trimeric proanthocyanidins (PAC) and one dimeric A-type procyanidin ( = procyanidin [A.sub.2]) (Howell et al., 1998; Foo et al., 2000a, b). The exact chemical structures possessing A-type interflavanoid linkage are epicatechin-(4[beta]-6)-epicatechin-(4[beta]-8,2[beta][right arrow]O[right arrow]7)-epicatechin (Fig. 4), epicatechin-(4[beta]-8,2[beta][right arrow]O[right arrow]7)-epicatechin-(4[beta]-8)-epicatechin and epicatechin-(4[beta]-8)-epicatechin-(4[beta]-8, 2[beta][right arrow]O[right arrow]7)-epicatechin (Table 2). PAC are stable polyphenolic flavanoles, and those predominating in cranberries are oligomers of catechin and epicatechin also classified as condensed tannins for their denaturing effect on proteins. PAC are generally widely distributed in plants, but those possessing anti-adhesion activity in cranberries are characterized by an A-type linkage of catechin-and epicatechin-oligomers and have a restricted occurrence. A-type PAC contain a second link, a carbon-oxygen connection between at least two of their epicatechin monomer units, while there is only a single C-C link in B-type PAC (Table 2). PAC of B-type inter-flavonoid linkage, present for example in green tea or in chocolate, possess no anti-adhesive activity in experimental models (Ofek et al., 1996; Howell et al., 2005). Sources of B-type PAC are therefore not regarded as promising anti-adhesion agents for UTI prophylaxis. Other constituents which have been additionally isolated from the fruits (Table 2) belong to other structure types. They possess also no anti-adhesion activity, but are known for their antioxidant and chemopreventive potential (Table 2).

[FIGURE 4 OMITTED]

Table 2. Constituents isolated from the fruits of Vaccinium macrocarpon

Trimeric A-Type

Epicatechin-(4[beta]-6)-epicatechin-(4[beta]-8, 2[beta] [right arrow] O [right arrow]7)-epicatechin

Epicatechin- (4[beta]-8,2[beta] [right arrow] O 7)-epicatechin-(4[beta]-8)-epicatechin

Epicatechin-(4[beta]-8)-epicatechin-(4[beta]-8,2[beta] [right arrow] O [right arrow] 7)-epicatechin

Dimeric A-Type

Epicatechin-(4[beta]-8,2[beta] [right arrow] O [right arrow] 7)-epicatechin (procyanidin [A.sub.2])

Dimeric B-Type

Epicatechin-(4[beta]-8)-epicatechin (procyanidin [B.sub.2])

Other constituents

Flavonoids quercetin, quercetin-3-0-glucoside, quercetin-3-0-galactoside, quercetin-3-0-[alpha]-l-arabinofuranoside (He and Liu, 2006)

Resveratrol (Rimando et al., 2004)

Cis(trans)3-0-p-hydroxycinnamoyl ursolic acid (Murphy et al., 2003)

10-trans (p-cis)-coumaroyi-ls-dihydromonotropein

( = coumaroyl iridoid glycoside) (Turner et al., 2007)

What exactly happens to bacteria exposed to cranberry juice, and what causes their loss of adherence? It had been observed that bacteria remained viable but changed their shape (Sobota, 1984; Ahuja et al., 1998). A less than 3-hourly incubation of p-fimbriated E. coli with cranberry juice of neutral pH changed the conformation of surface molecules on p-fimbriae profoundly and results in the loss of adhesion power (Liu et al., 2006) (Table 3). Cranberry juice has even suppressed the development of p-fimbriae in E. coli, when added to culture medium (Ahuja et al. 1998). These observations suggest a substantial effect of cranberry constituents on bacterial integrity rather than only a passive obstruction of binding to complementary structures. Currently, the ensuing consequences of such bacterial transformation are unknown in detail. For an understanding of cranberry juice's long-term consequences on the microbial environment it is desirable to know, if bacteria could still reproduce and sustain their populations.
Table 3. Effects of cranberry-products on becterial adhesion in vitro

Design/test system Results Publication

Product: Cranberry Cranberry juice inhibited Sobota
juice, cranberry juice adherence [greater than or equal (1984)
cocktail and urine of to] 75% in >60% of E. coli
mice and men following isolates. Urine collected from
cranberry juice mice inhibited adherence of E.
ingestion coli to uroepithelial cells
 by 80%. 15/22 volunteers
 showed urinary anti-adherence
 activity 1-3 h after drinking
 15 ounces of cranberry cocktail

Design: Adherence of
77 clinical isolates
of E. coli to
uroepithelial cells
tested with and
without cranberry
juice or urine
following its
consumption. Urine
from mice
investigated after
a period of 14 days
of cranberry
cocktail drinking.
Urine from volunteers
investigated few
hours after drinking
cranberry
cocktail

Product: Cranberry Cranberry juice cocktail; and Schmidt
juice cocktail, and urine and urinary epithelial and Sobota
urine and urinary cells obtained after drinking (1988)
epithelial cells the cocktail all demonstrated
obtained after anti-adherence activity against
drinking the Gram-negative bacteria.
cocktail Anti-adherence activity of
 cranberry had a greater effect
 on bacterial strains isolated
 from urine than on organisms
 isolated from sputum, stool and
 wounds

Design: Testing of
bacterial adherence
to uroepithelial
cells of clinical
isolates of E. coli,
Proteus, Klebsiella,
Enterobacter and
Pseudomonas isolated
from urine, sputum,
wounds and stool

Product: Cranberry Cranberry juice cocktail Zafriri et
cocktail and juice inhibited adherence of urinary al. (1989)
 E. coli with type 1 fimbriae
 (mannose specific) and P
 fimbriae [specific for
 alpha-D-Gal(1-4)-beta-D-Gal],
 but had no effect on a
 diarrheal isolates expressing
 a CFA/I adhesin. The cocktail
 also inhibited yeast
 agglutination by purified type
 1 fimbriae. The inhibitory
 activity for type 1 fimbriated
 E. coli could be ascribed to
 fructose, while the inhibitory
 activity for the P-fimbriated
 bacteria was a higher-molecular
 non-dialyzable compound.
 Cranberry juice, orange juice,
 and pineapple juice also
 inhibited adherence of type 1
 fimbriated E. coli, most likely
 because of their fructose
 content, but were not able to
 inhibit the P-fimbriated
 bacteria. Cranberry juice
 contains at least two inhibitors
 of lectin-mediated adherence
 of uropathogens to eucaryotic
 cells

Design: In vitro
testing of the
adherence of E. coli
expressing surface
lectins of defined
sugar specificity
to yeasts, tissue
culture cells,
erythrocytes, and
mouse peritoneal
macrophages in the
presence of
cranberry
products or other
juices (e.g. orange
and pineapple
juice)

Product: Juices from Only juice from Vaccinium spec. Ofek et al.
blueberry, cranberry, (cranberry, blueberry) (1991)
grapefruit, guava, inhibited E. coli adhesion. The
mango, orange and polymeric compound
pineapple were responsible for this effects was
tested for a polymeric partially purified by
inhibitor of E. coli chromatography from cranberry
adherence, isolated juice and was absent from
before from the other juices. The inhibitory
cranberry juice activity of this compound
 was more pronounced on urinary
 then on non-urinary (fecal)
 E. coli isolates

Design: Single dosages
of juice tested for
inhibition of
hemagglutionation by
urinary and
non-urinary isolates
of E.coli with
mannose-resistant
fimbriae.
Partial purification
of the polymeric
inhibitor from
cranberry juice

Product: Cranberry Cranberry juice inhibited Ahuja et
juice concentrate P-fimbrial agglutination by al. (1998)
 E. coli irreversibly. Fully
 inhibited bacteria had a 100%
 reduction in expression of
 fimbriae and showed cellular
 elongation. Electron
 micrographic evidence
 suggests that cranberry
 juice acts on the cell wall
 preventing proper attachment of
 the fimbrial submits or as a
 genetic control preventing the
 expression of normal fimbrial
 subunits or both

Design: P-fimbriated
E. coli were exposed
to cranberry juice
in growing medium
(Cranberry
concentrate at pH 7.0
added to CFA medium to
a final concentration
of 25%). Cultures
tested for ability to
agglutinate P-receptor
specific beads

Product: Purified Three proanthocyanidin trimers Foo et al.
proanthocyanidins possesing A-type (2000a, b)
from V. macrocarpon interflavanoid linkages
 (epicatechin-(4beta [right
 arrow] 6)-epicatechin-
 (4beta [right arrow] 8, 2beta
 [right arrow] O 7)-epicatechin
 (4), epicatechin-(4beta
 [right arrow] 8, 2beta
 [right arrow] O 7)-epicatechin
 (4beta [right arrow] 8)-
 epicatechin (5), and
 epicatechin-(4beta [right arrow]
 8)-epicatechin-(4beta
 [right arrow] 8, 2beta
 [right arrow] O 7)-epicatechin
 (6)), prevented adherence of
 P-fimbriated E. coli isolates.
 Further less active PAC were
 isolated: (epicatechin-(4beta
 [left arrow]8, 2beta
 [left arrow] 0 [left arrow]7)
 -epicatechin (procyanidin A2)
 (3) and the inactive
 epicatechin-(4beta [left
 arrow]8)-epicatechin
 (procyanidin B2) (2))

Design: In vitro
inhibition of
adherence of P-
fimbriated E. coli
isolates from the
urinary tract to
cellular surfaces
containing alpha-Gal(1
[right arrow]
4)beta-Gal receptor
sequences similar to
those on uroepithelial
cells by different PAC
isolates from ripe
cranberries

Product: Cranberry Isolated A-type PAC from Howell
juice cocktail, cranberry juice cocktail et al. (2005)
isolated A-type elicited in vitro
proanthocyanidins, anti-adhesion activity
isolated B-type PAC, at 60 microg/ml, the B-type
and human urine proanthoyanidins from grapes
after drinking of exhibited minor activity at
cranberry juice and 1200 microg/ml, while other
B-type PAC sources B-type proanthoyanidins were
(green tea, chocolate) not active. Anti-adhesion
 activity in human urine was
 detected following cranberry
 juice cocktail consumption.
 products. The results suggest
 that an A-type linkage of PAC
 is a prerequisite for in vitro
 anti-adhesion activity of foods

Design: Anti-adhesion
activity of A-linked
proanthoyanidins from
cranberry juice
cocktail was grapes,
apple juices, green
tea and dark chocolate
in vitro.
Anti-adhesion activity
was also determined in
human urine following
consumption of single
servings of each
commercial food
product

Product: Unfractioned Cranberry juice affected Liu et al.
cranberry juice bacterial surface polymer and (2006)
 adhesion behaviour after a short
 exposure period ( < 3h)
 and decreased adhsion forces
 between the bacterium and
 tip and by altering the
 conformation of the surface
 macromolecules of P-fimbriae) on
 this bacterium decreased
 length of polymer (P-fimbriae)
 on this bacterium decreased
 from approximately 148 to
 approximatley 48 nm upon
 being exposed to cranberry
 juice. These effects were
 independent of pH lowering

Design: To study the
molecular-scale
effects of cranberry
juice, two E. coli
strains (HB101,
without fimbriae,
and the mutant HB101
pDC1 with P-fimbriae)
were exposed to
cranberry juice.
Bacterial surface
characteristics were
investigated by using
atomic force
microscopy; and in
addition adhesion
foces between a probe
surface (silion
nitride) and the
bacteria were
evaluated

Product: Different No influence on any paramenter Valentova
dosages of dried tested by 400 mg DCJ/day. et al. (2007)
cranberry juice 1200 mg DCJ/day caused a
(DCJ) decrease in serum levels of
 advanced oxidation protein
 products. Urine samples had on
 inhibitory effect on adhesion
 of uropathogenic E. coli.
 Hippuric acid, isomers of
 salicyluric were the
 dihydroxybenzonic and quecetin
 glucuronide were the main
 metablites acids, detected in
 urine, but caused no pH lowering

Design: Influence of 8
weeks consumption of
DCJ in 65 healthy
young women determined
on antioxidant status.
presence of
metabolities in urine,
and urinary x vivo
anti-adherence
activity throughout
the trial

Product: Cranberry Urine obtained after ascorbic Habash
supplements acid or cranberry et al. (1999)
 supplementation reduced the
 initial deposition rates and
 not of Pseudomonas aeruginosa,
 Staphylococus epidermidis,
 or Candida albicans. Only
 ascorbic acid intake
 consistently produced
 acidic urine

Design: Urine
collected from
volunteers following
the consumption to
study uropathogen
adhesion to silicone
rubber in a parallel
plate flow chamber

Product: Low polarity The juice cocktail demonstrated Turner et
fraction of cranberry dose-dependent inhibition al. (2005)
juice cocktaill of E. coli adherence. The active
 fraction contained prunin,
 phlorizin and
 1-0-methylgalactose. This in
 vitro assay might prove
 useful for the standardization
 of cranberry dietary supplements

Design: Adhesion of
P-fimberiated E. coli
to human uroepithelial
cell-line T24 tested
in the presence of
the cranberry product.
Effect was validated
by

Product: Cranberry Cranberry powder decreased mean Gupta et
powder (9mg PAC/mg) adherence of E. coli to al. (2007)
or increasing vaginal epithelial cells from
concentrations of PAC 18.6 to 1.8 bacteria per cell
extract (p < 0.001). Mean adherence of
 E. coli to primary cultured
 bladder epithelian cells was
 decreased by 50 mug/ml
 proanthocyanidin extract from
 6.9 to 1.6 bacteria per cell
 proanthocyandin extract from 6.9
 to 1.6 bacteria per cell
 (p < 0.001). Inhibition of
 adherence of E. coli by PAC
 extract occured in linear, doese
 dependent fashion over a
 PAC concentration range of 75-5
 mug/ml

Design: Effect on
adherence of
p-filmbriated E. coli
on cultured bladder
and vaginal epithelian
cells tested before
and after exposure
to test products

Product: Humane urine Dose-dependent decrease in DiMartino
harvested after bacterial aherence associated et al. (2006)
cranberry juice intake with cranberry consumption.
 Adherence inhibition was
 independent of the presence of
 genes encoding P-fimbriae
 and antibiotic resistance
 phenotypes. The anti-adhesive
 quality was first detectable 2h
 after cranberry ingestion and
 lastest up to 12h (see Fig. 3)

Design: Double-blind,
randomised,
placebo-controlled
cross-over study to
set the in vitro
bacterial
anti-adherence
activity of urine of
healthy volunteers
(10 men; 10 women)
exposed to two
different cranberry
dosages on the
previous day. Six
uropathogenic E. coli
strains (all
expressing type 1
fimbriae; three
positive for the gene
marker fro P-fimbriae
papC and three
negative for papC)
isolated from
patients with UTI
were tested for their
ability to adhere
to the T24 bladder
cell in vitro

Product: Dried A single serving of cranberries Greenberg
cranberries and elicited a bacterial et al. (2005)
raisins anti-adhesion activity of up
 to 50% 2-5h after consumption,
 while raisins failed to do that

Design: The effect of
urine samples 5 women
on adhesion of
E. coli isolates by
using a mannose-
resistent
hemagglutination assay
with human
erythrocytes was
investigated after
consumptions of
a single serving of
cranberries or
raisins

Product: Different Dose-dependent decrease in Lavigne
dosages (108-36 mg) of bacterial adherence in vitro et al. (2008)
cranberry extract after the consumption of 108 and
and placebo 36 mg of cranberry (p < 0.001).
 The in-vivo model confirmed
 E. coli's reduced ability
 to kill C. elegans by
 cranberry extract

Design: Double-blind,
placebo-controlled
cross-over trial in 8
volunteers. Urine
tested 12 h after
cranberry consumption
for inhibition of
bacterial adhesion to
human uropithelial
cells and for the
effect in the
Caenorhabditis elegans
killing model


Instead, the research had concentrated on further characterization of cranberry constituents with antiadhesion activity. In comparative studies with other plants (e.g. ananas, guava, raisins) cranberries had demonstrated superior anti-adhesion power (Ofek et al., 1991, 1996; Greenberg et al., 2005; Johnson-White et al., 2006). However, the selection of plants investigated in such studies is still limited, a fact possibly explained by a bias caused by research funding of the cranberry industry. Even the close cranberry relatives lingonberry and European cranberry have not been studied for their anti-adhesion activity.

Nevertheless, the evidence of a robust in vitro anti-adhesive effect of cranberries largely attributable to their content in A-type PAC has to be acknowledged and has nurtured ideas to use these bioactive constituents, selectively. In vitro, A-type PAC (Fig. 4) from cranber ries inhibit bacterial adhesion in a dose-dependent fashion, for example in hemagglutination models (Foo et al., 2000a, b), whereas fruits devoid of A-type PAC fail to do that (Howell et al., 2005). However, it is still premature, in the authors' opinion, to select and breed a "super" cranberry for a high PAC content or design drugs from isolated PAC. Neither the anti-adhesion activity of cranberries, nor their PAC-content had been related to a reduction of UTI in vivo. In clinical trials, cranberry products had not been standardized with respect to PAC composition or concentration, and the appearance of these phytochemicals in the participants' blood or urine had not been measured. It is also unknown, whether lingonberry and European cranberry, which proved to be successful in a clinical trial, possess anti-adhesion activity or contain A-type PAC. Attributing the clinical benefit of cranberries on anti-adhesion and PAC alone is therefore still unjustified.

It is controversial, moreover, if PAC are sufficiently bioavailable in men. In pharmacokinetic studies, B-type PAC had been poorly intestinally absorbed and had not reached the urinary tract intact (Turner et al., 2007). However, other studies suggest an excellent bioavailability of PAC (Harmand and Blanquet, 1978; Habash et al., 1999; Howell et al., 2001). An ongoing Canadian trial addresses this open question by monitoring of cranberry PAC excreted into participants' urine and relating it to the study's end-points (Stothers, 2008).

Finally, the time course of the anti-adhesion effect does not fit with the pattern of prophylaxis in clinical trials. The anti-adhesion activity has a rapid onset and can be traced in human urine already 2h following cranberry ingestion (Sobota, 1984; DiMartino et al., 2006; Greenberg et al., 2005), while the prophylactic effect in clinical trials had a delayed onset. It is therefore unknown, how far the anti-adhesive effect explains the longer-term UTI protection by cranberry juice.

Anti-adhesion effects of other plants

Cranberries are not the only known sources of anti-adhesion agents of potential medicinal value. Berberis aristata and the goldenseal (Hydrastis canadensis). for example, owe their efficacy against infections to the alkaloide berberine. Berberine reduces the adhesion of uropathogenetic E. coli to uro-epithelia by suppressing the synthesis of fimbriae and flagellae in a fashion reminiscent of the cranberry effects on bacteria (Sun et al., 1988). Many other plants contain macromolecules of anti-adhesion properties. Such molecules are currently investigated for treatment of Helicobacter pylori-associated diseases (Wittschier et al., 2007; Lengsfeld et al., 2004).

Is the use of cranberry juice safe?

The intake of cranberry products on a daily basis as recommended for prophylaxis exposes patients to high concentrations of cranberry constituents for extended periods of time. No serious adverse effects are known from cranberries as a food. However, high drop-out rates in early trials with cranberries as a prophylactic had alerted reviewers and had been criticized in the Cochrane assessments (Jepson et al., 2000). Recently, the safety of cranberry products in pregnancy and lactation has been assessed as excellent (Dugoua et al., (2008). In adults, even high amounts of cranberry juice appear to be non-toxic with the exception of people with a history of nephrolithiasis. Infants and young children should also restrict the consumption to moderate quantities since they may suffer gastrointestinal distress and diarrhoea.

There are very few anecdotal reports about adverse effects, and most of them can be explained by an unreasonable high intake of cranberry juice. Deranged coagulation parameters and bleeding in patients on chronic warfarin treatment had been blamed on cranberry juice (Rindone and Murphy, 2006). It was hypothesized that cranberry ingredients had increased warfarin's bioavailability by interactions with the cytochrome P 450 enzymes. A randomized trial could not confirm changes in prothrombin time of warfarin-treated males by consumption of 250 ml commercial cranberry juice daily (Li et al., 2006).

Another concern is the immunosuppressive treatment of transplant patients, which can be affected by herbal drugs that modify cytochrome P 450 enzymes and drug transporting proteins. Despite the absence of reported incidents, a clinical trial recently addressed the impact of cranberry juice on cyclosporin pharmacokinetics in volunteers and found no clinical interaction (Grenier et al., 2006).

Finally, cranberry juice was discussed to promote the formation of kidney stones (Terris et al., 2001), but the results of studies are inconclusive. In volunteers, and known calcium-oxalate stone formers, cranberry juice had mixed effects on urinary stone forming propensity (Gettman et al., 2005). A randomized cross-over trial from South-Africa even found anti-lithogenic properties of cranberry juice (McHarg et al., 2003).

Potential further applications of cranberries

Dental decay, periodontal disease

Presently, there is a growing interest in anti-adhesion drugs for various applications. Cranberries helped to reduce the microbial contamination of microscope slides in immunoassays by inhibiting bacterial adhesion (Johnson-White et al., 2006). Other tested fruit juices (grape, oranges, and apple) had not been effective, a finding, which again strengthens the unique position of cranberries in that respect.

Cranberry products may be used in prophylactic dentistry. Tooth decay and periodontal disease are caused by pathogenic bacteria resident in the oral cavity that deliver metabolic products attacking teeth. Different bacterial species, specifically those from the Streptococcus mutans group, co-aggregate by adhesion to generate a biofilm on the tooth surface. Within a matrix of salivary proteins these bacteria release enzymes, e.g. glucosyltransferase (GTF) and fructosyltransferase (FTF). and synthesize fructanes and glucanes, which facilitate further bacterial adherence. Metabolic transformations of carbohydrates result in the release of organic acids, which demineralisc the teeth.

A high-molecular constituent isolated from cranberry juice reduced and even reversed bacterial co-aggregation in dental biofilms and reduced the enzymatic activity of GTF and FTF within the biofilm (Weiss et al., 1998). The high-molecular cranberry compounds des-integrated dental plaques by separation of Streptococcus sobrinus from the biofilm, and pre-incubation of Streptococci with cranberry extracts reduced the biofilm generation (Duarte et al., 2006). These promising results with artificial biofilm have been succeeded by an affirmative clinical trial. Two groups of each 30 volunteers were randomized to use either a daily cranberry mouth-wash or a placebo mouth-wash for 6 weeks, which resulted in a significant reduction of salivary bacteria, notably of Streptococcus mutans in the cranberry group (Weiss et al., 2004). Cranberry macro-molecules also improve periodontal disease, for example by halting lipopolysaccharide (LPS) induced bacterial production of pro-inflammatory cytokines and proteolytic enzymes (Bodet et al., 2006).

Helicobacter pylori infection

Gastritis and peptic ulcer disease are strongly associated with the mucosal presence of the bacterium Helicobacter pylori (Hp). Since the discovery of its bacterial aetiology, Hp-positive gastritis or duodenal ulcers have been treated with combinations of antibiotics to eradicate Hp colonisation. Now there is growing problem with resistance of Hp towards antibiotics which has stimulated the research to find novel treatments, for example by utilizing herbal sources of anti-adhesion compounds (Wittschier et al., 2007; Lengsfeld et al., 2004).

High-molecular fractions of cranberries inhibit the adhesion of Hp to gastric mucus and mucosal cells "in vitro" (Burger et al., 2002), also when these bacteria have acquired antibiotic resistance (Chatterjee et al., 2004). A clinical trial performed in an area of endemic Hp infection in China further supports the application of cranberries in this indication. Half of the 189 patients tested positive for Hp infection by 13 C urease breath-test drank 250 ml cranberry juice daily for 90 days, while the others received a placebo drink. After 35 and 90 days, there were fewer patients tested positive for Hp in the cranberry group (Zhang et al., 2005).

More health benefits of cranberry products?

Preliminary research suggests that cranberry constituents have anti-viral effects (Weiss et al., 2005), but these results are still not clinically applicable. Cranberries rank high among fruits with anti-oxidative properties, and they prevent LDL-cholesterol oxidation (Ruel et al., 2005) and the generation of advanced oxidation proteins products (Valentova et al., 2007). The anti-oxidative capacity of cranberries is apparently linked to the same biochemicals that are responsible for infection-prophylaxis, e.g. catechins and PAC (Maatta-Riihinen et al.,2005). Cranberry constituents have also been shown to have anti-proliferative effects on tumour cell lines in vitro, especially when administered as a whole cranberry extract instead of single fractions (Seeram et. al., 2004).

Conclusions

Prophylaxis of UTI is a key application of cranberry products. The evidence for its effectiveness is rather good but needs to be improved with respect to product specifications. The effects should be related to products of well-characterised composition and clearly defined modes of application. There is good evidence that cranberry juice inhibits bacterial adhesion in biologically relevant models and that this effect is due to the content in A-type PAC. It is still not proven that this anti-adhesive effect is relevant for the prophylaxis observed in clinical trials.

Some clinical observations suggest an efficacy of cranberry products also for treatment of active infections, which needs to be explored by future research. There are further potential applications of cranberry products which can currently not be recommended as evidence-based. In the authors' opinion, it would be a greater scientific achievement to expand and intensify the research on cranberry prophylaxis of UTI than to search for further cranberry benefits by broad-scale cursory screenings.

Botanical portrait of the cranberry

American cranberry ( Vaccinium macrocarpon Aiton); Family: Ericaceae

Description: Evergreen trailing shrub with slender stems. Leaves leathery, elliptic-oblong. Flowers in clusters of 2-6, in the axils of a reduced leave. Flowers deeply 4-cleft, the lobes strongly reflexed. Flowering time: June-August. The fruit is a false berry, larger than the leaves of the plant; initially white, but turning a deep red when fully ripe. It is edible, with an acidic taste. Fruits are harvested from October to November.

Distribution: Cranberries grow in bogs of northern North-American from Newfoundland to North-Carolina. Tennessee and Virginia. The American cranberry has been introduced as a neophyte to several European bogs. It is known from the Dutch island Terschelling since 1845, and is now cultivated commercially there. It had probably arrived with a wrecked windjammer that had loaded cranberries.

Related species: Within the genus Vaccinium there are three species constituting the subgenus Oxycoccus (sometimes also classified as a distinct genus) to which the cranberry belongs. Vaccinium oxycoccus (Common Cranberry or Northern Cranberry) is widespread throughout the cool temperate northern hemisphere, including northern Europe, northern Asia and northern North America. It has tiny leaves of 5-10 mm length. The flowers are of dark pink colour, with a purple central spike. The fruits are small pale-pink false berry, with a refreshing acidic flavour. V. macrocarpon and V. oxycoccus have an overlapping distribution in North America. Oxycoccus microcarpus (Small Cranberry) occurs in northern Europe and northern Asia, and differs from V. oxycoccus in the leaves being more triangular, and the flower stems hairless. Some botanists have included it within V oxycoccus. In Europe, the cranberry is often confused with the lingonberry (V. vitis-idaea), which is not as closely related as V. oxycoccus and does not belong to the subgenus Oxycoccus. Further species from the genus Vaccinium are used for nutritional or medicinal purposes, for example the blueberries ((V. myrtillus (Europe), V. corymbosum. V angus (ifolium and others (North-America)).

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Rainer Nowack *, Wilhelm Schmitt

Centers for Nephrologyl Dialysis, Lindau and Weinheim, Germany

* Corresponding author at: Center for Nephrology/Dialysis. Frie-drichshafener Str. 82, D-88131 Lindau, Germany.

Tel.: + 4983822762100; fax: +49 83822762109.

E-mail address: nowack@dialyse-lindau.de (R. Nowack).
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Author:Nowack, Rainer; Schmitt, Wilhelm
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
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Date:Sep 1, 2008
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