Issue:
112
Page: 29-33
Further Evidence for the Clinical Efficacy of Cranberry
A Brief Review of Recent Clinical Trials
by Kerry Bone
HerbalGram.
2016; American Botanical Council
Recent clinical trials* provide further evidence for the
role of cranberry (Vaccinium macrocarpon, Ericaceae) preparations in preventing
urinary tract symptoms in a variety of circumstances, including
radiation-induced cystitis, lower urinary tract infections (UTIs), infections
after ureteral catheter placement, UTIs after gynecological surgery, and lower
urinary tract symptoms (LUTS) in men. A growing body of scientific work
supports the simple strategy of using appropriately manufactured cranberry
preparations for lower urinary tract health.
Acute radiation cystitis (i.e., inflammation of the bladder
caused by radiation therapy) is a common complication in men receiving external
beam radiation for prostate cancer. Although several treatments provide
symptomatic relief, there is no consensus treatment or standard prevention
measure for radiation cystitis.
A New Zealand study aimed to determine the effect of a
standardized cranberry extract encased in coated capsules (Naturo Pharm Ltd.;
Rotorua, New Zealand; each capsule containing 72 mg proanthocyanidins [PACs])
on the incidence and severity of radiation cystitis.1 Forty-one men with
prostate cancer participated in this randomized, double-blinded,
placebo-controlled (RDBPC) clinical trial. Participants took one capsule per
day at breakfast during radiation treatment and for two weeks after treatment
completion. They also were asked to follow a hydration regimen (8 cups [1.9 L]
of water per day), but a low-hydration regimen (4-6 cups [0.9-1.4 L] of water
per day) was added during the course of the trial since some patients, older
men in particular, experienced discomfort with the recommended hydration protocol.
Severity of urinary symptoms was measured using a modified version of the
Expanded Prostate Cancer Index Composite (EPIC). At the end of the study, men
in the cranberry group had lower incidences of cystitis and severe cystitis
(65% and 30%, respectively) compared with those in the placebo group (90% and
45%, respectively), although these differences were not statistically
significant (P = 0.058 and P = 0.30, respectively). Overall, the incidence of
pain/burning was significantly lower in the cranberry group (P = 0.045)
compared with the placebo group. Men on the low-hydration regimen in the
cranberry group had less pain/burning (P = 0.038), stronger urine stream (P =
0.030), and used significantly fewer pads/liners (P = 0.042) compared to the
placebo group. The authors concluded that men receiving radiation therapy for
prostate cancer may benefit from using cranberry supplements, particularly
those on low-hydration regimens or with baseline urinary symptoms.
In two recent clinical studies it was also found that
cranberry may be able to effectively prevent recurrent lower UTIs. The first
study was a small Italian study in which 22 people were offered a standardized
cranberry extract (Anthocran; Indena SpA; Milan, Italy) with lifestyle advice,
and 22 people were offered lifestyle advice without the cranberry extract (the
control group).2 The cranberry group experienced a 73.3% reduction (P <
0.05) in the frequency of UTI episodes during the study period compared with
the two months before the trial, and the control group had a 15.4% reduction in
frequency compared with the same period, a significant difference between
groups (P = 0.012). Seven (31.8%) people in the cranberry group were
symptom-free at the end of the study, but no patients in the control group were
symptom-free, a significant between-group difference (P < 0.05). During the
study period, the mean duration of UTI episodes was 2.5 ± 1.3 days in the
cranberry group, compared with 3.6 ± 1.7 days in the control group, a
significant difference (P < 0.05). Urine evaluation for blood or bacteria
was completely negative in 90.9% of those in the cranberry group and in 50% of
those in the control group (P < 0.005). No adverse events were observed. The
authors asserted that these preliminary results, which were obtained in a
field-practice setting, indicate that a standardized cranberry extract can be
effective and safe in the prevention of recurrent UTIs.
In the second, and much larger, study, 928 older adults
(median age of 84; 703 women) living in nursing home facilities in the
Netherlands took 500-mg cranberry capsules (containing 9 mg of PACs) or placebo
capsules (both supplied by Springfield Nutraceuticals; Oud-Beijerland,
Netherlands) twice daily for 12 months.3 Participants were stratified according
to UTI risk (risk factors included long-term catheterization, diabetes
mellitus, and one or more UTIs in the preceding year). In participants with a
high UTI risk at baseline (n = 516), the incidence of clinically defined UTIs
was significantly lower with cranberry capsules than with placebo (P = 0.04).
The treatment effect was 0.74 (95% confidence interval [CI] = 0.57-0.97),
meaning the treatment reduced the risk of a clinically defined infection by
26%.
UTIs are among the most frequent complications after urinary
tract surgical procedures, mainly when catheter placement is necessary.
Although the use of cranberry has been linked to a reduced risk of UTIs, there
has been no published study, until recently, reporting the value of its
preventive effect against catheter-associated UTIs. A prospective trial of
patients with double J catheters compared the UTI rate (confirmed by positive
urine culture) of patients taking a cranberry extract (Urosens; Laboratorios
Salvat; Barcelona, Spain) (120 mg per day) in addition to their routine
prophylactic therapy (n = 31) to the rate of those receiving only routine
prophylactic therapy (n = 31).4 When the catheters were removed approximately
30 days after the start of the study, the UTI incidence was found to be
significantly lower (P = 0.04) in the cranberry group (12.9%) compared to the
placebo group (38.7%).
UTIs are a common hospital-acquired infection, and the risk
is high after gynecological surgery during which a catheter is placed. Women (N
= 160) undergoing such elective surgery were randomly assigned to take either
TheraCran cranberry capsules (provided by Theralogix, LLC; Rockville, Maryland;
equivalent to 480 mL per day of cranberry juice) or a matched placebo for six
weeks after surgery.5 The occurrence of UTIs during the study period was
significantly lower (P = 0.008) in the cranberry group (19%) compared with the
placebo group (38%) (odds ratio, 0.38; 95% CI = 0.19-0.79). After adjustment
for known confounders, including the frequency of intermittent
self-catheterization in the postoperative period, the protective effect of
cranberry remained (odds ratio, 0.42). There were no significant differences
between groups in terms of adverse events, such as gastrointestinal upset (56%
in the cranberry group and 61% in the placebo group).
Finally, a cranberry powder (Flowens; supplied by
Naturex-DBS LLC; Sagamore, Massachusetts) produced a clinically relevant,
dose-dependent reduction in LUTS in men over 45.6 This six-month, RDBPC study
aimed to evaluate the effect of 250 mg or 500 mg cranberry powder on LUTS and
urinary flow. A total of 124 volunteers with prostate-specific antigen (PSA)
levels less than 2.5 ng/mL of blood and International Prostate Symptom Scores
(IPSSs) of 8 or higher were recruited for the study. The primary outcome
measure was the IPSS, evaluated at three and six months. Secondary outcome
measures included quality of life, bladder volume (Vol), maximum urinary flow
rate (Q max), average urinary flow rate (Q ave), ultrasound-estimated post-void
residual urine volume (PVR), and levels of serum PSA, selenium, interleukin 6,
and C-reactive protein, at six months. At the end of the study, volunteers in
both cranberry groups had significantly lower IPSSs (-3.1 in the 250 mg group [P
= 0.05] and -4.1 in the 500 mg group [P < 0.001]) compared to the placebo
group, and a dose-response effect was observed. There were significant,
favorable differences in Q max, Q ave, PVR, and Vol in the 500 mg cranberry
group versus baseline (P < 0.05). A dose-dependent effect on Vol was
observed, as well as on PVR for participants with a non-zero PVR. There was no
effect on clinical chemistry or hematology markers.
Complex Mechanisms of Action
One of cranberry’s most-studied mechanisms of action for
preventing UTIs involves increasing the capacity of urine to prevent certain
uropathogenic bacteria from adhering to epithelial cell receptors in the
urinary tract. Many pathogenic bacteria contain fimbriae (thread-like
appendages) that allow them to attach to epithelial cells. For example, the
strains of Escherichia coli that cause UTIs can attach to uroepithelial cells.
Cranberry’s ability to prevent the P-fimbriated E. coli bacterium from adhering
to these cells has been attributed to its content of A-type proanthocyanidins
(A-PACs). PACs typically consist of molecules of catechin and epicatechin
joined by carbon-carbon or carbon-oxygen bonds. Hence, catechin and epicatechin
are referred to as monomers, and those polyphenols containing two to four of
these monomers are referred to as oligomeric (meaning “a few”)
proanthocyanidins. In cranberry, they are also called procyanidins because they
release colored cyanidin upon boiling with acid, hence the prefix “pro” (meaning
“forming”). The linkage between the monomers in PACs can be either through one
(B-type) or two covalent bonds (A-type). B-type PACs occur in grape (Vitis
vinifera, Vitaceae) seed and pine (Pinus spp., Pinaceae) bark, whereas A-type
PACs are found in cranberries.
Only the A-type PACs have demonstrated anti-adherence
activity (larger PACs do not get absorbed in the bloodstream and are excreted
in the urine due to their size), and urinary anti-adherence activity is
correlated with a dose-dependent increase in PACs in cranberry products.7
Preliminary studies suggest that larger PACs act in the gut to prevent E. coli
invasion, thereby reducing the resident population capable of causing future
UTIs, and may induce the indirect excretion of anti-adherence molecules into
the urine. Further, the larger A-type PACs may bind to uropathogenic rectal
isolates in the colon, rendering them unable to adhere in the urinary tract if
they were to enter.8
A human study published in 2012 found procyanidin A2 (a
dimer [i.e., a molecule composed of two identical or structurally similar,
bonded monomers]) at 24 ng/mg creatinine in urine 11 hours after ingestion of
cranberry.9 (Concentrations of urinary metabolites are typically expressed per
mg of creatinine due to the variability of a person’s water intake, and hence
excretion.) This was shared in a conference report, and the same group finally
published more details of their findings in 2015, which indicate that other
cranberry phytochemicals, or their metabolites, generally occur at much higher
levels than procyanidin A2 (e.g., protocatechuic acid [a phenolic acid] at 21.1
mcg/mg creatinine is almost 1,000 times greater). However, these metabolites
were not individually tested for anti-adherence activity.10
As studies continue to elucidate the details concerning the
mechanisms of action, the anti-adherence activity of urine after cranberry
consumption is now well-supported by clinical evidence. For example, two recent
clinical studies from the same research group demonstrated a substantial rise
in bacterial anti-adherence activity that peaked around three hours after
cranberry beverage or extract consumption.11,12
Cysticlean (Vita Green Europa; Barcelona, Spain), at a
dosage of 118 mg PACs per day, was found to reduce recurrent UTIs by 93% in a
six-month, observational prospective study in 20 women.13 And yet, 500 mg per
day of cranberry fruit powder supplied by Naturex-DBS LLC, reported to contain
only 2.8 mg A-type PACs per dose, also reduced UTIs in a trial involving 182
women with two or more UTI episodes in the past year.14 Participants were
randomly assigned to the cranberry (n = 89) or placebo group (n = 93) and
received treatment for six months. Intention-to-treat analysis showed that in
the cranberry group UTIs were significantly fewer than in the placebo group
(10.8% vs. 25.8%, P = 0.04) over the course of the study. The cranberry group
also experienced a longer time-to-first-UTI than the placebo group (P = 0.04).
Future Research Directions
The clinical trials summarized above add to the evidence
that cranberry is a viable option for the prevention of UTIs in at-risk
populations, or in those suffering from recurrent infections. The potential of
cranberry for LUTS in older men is worthy of clinical consideration, and has
been demonstrated in previous research.15
There is controversy about label claims for, and measurement
of, A-type PACs found in cranberry. This may explain some of the discrepancies
in the clinical findings, meaning that the PAC contents of tested products may
have been rather different than what was claimed in the studies, depending on
the analytical method(s) used. Evidence of these complexities is provided in a
study in which four products on the Swiss market with labeled PAC levels were
tested by two different analytical techniques.16 Results were provided by a
photometric DMAC method (which uses 4-(dimethylamino)cinnamaldehyde [DMAC] as
the color reagent) and an ultra high-performance liquid chromatography-tandem
mass spectrometry (UHPLC-MS2) assay. Per the DMAC method, PACs ranged from
16-61% of the label claim. The UHPLC-MS2 assay yielded an even more stunning
deviation, with PAC levels found to be 1.4-7.2% of what was declared on the
labels. The discrepancies between the two methods may be explained in part by
the fact that the UHPLC-MS2 method quantified only catechin/epicatechin dimers
and trimers, while the DMAC method included PACs of higher polymerization
degrees as well. However, all results, regardless of the method used, were
still short of the label claims. The DMAC method is appropriate for measuring
total PACs in soluble cranberry products, but results depend on the type of
standard used.17 Standardization of methods used to quantify A-type PACs in
cranberry products of different tissue types (juice or pomace) and accurate
labeling of products by type are essential to reduce consumer confusion and
increase accuracy in reporting A-type PAC contents in clinical trials.
Many questions remain to be answered before the true
mechanisms of action of cranberry in preventing UTIs are properly understood
and corresponding quality/activity markers can be agreed upon with appropriate
methods of analysis. Anti-adherence activity of urine is likely part, or
perhaps even all, of the story, but the specific metabolites that deliver this
activity remain to be unequivocally established.
Kerry Bone is the co-founder of and innovation driver at
MediHerb, where he serves as director of research and development. In 2016,
MediHerb was awarded the American Botanical Council’s (ABC’s) Varro E. Tyler
Award for Excellence in Phytomedicinal Research. As part of his educational
role, Bone is principal of the Australian College of Phytotherapy and also
adjunct professor at New York Chiropractic College, providing input into their
postgraduate applied nutrition program. Bone has co-authored more than 30
scientific papers on herbal research, including original research and
systematic reviews. He has also written or co-written six popular textbooks on
herbal medicine, including his latest with Simon Mills, the long-awaited second
edition of Principles and Practice of Phytotherapy, which was awarded ABC's
2013 James A. Duke Excellence in Botanical Literature Award.
*While this review comprehensively covers most of the
clinical trials on cranberry preparations from 2010 to early 2016, this article
is not meant to be exhaustive; accordingly, some studies have not been
included.
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