HERBAL
MEDICINAL
PLANT
CRANBERRY
Vaccinium macrocarpon Aiton (Ericaceae) +++
BY
RETTODWIKART THENU
CRANBERRY
(kran’beh-ree)
Vaccinium
macrocarpon Aiton (Ericaceae) +++
SUMMARY AND PHARMACEUTICAL COMMENT
Native American Indians used cranberries as both a food and a
treatment for bladder and kidney diseases. In the mid 1800s, German scientists
suggested that cranberry juice had antibacterial activity, supporting its use
as a treatment for bladder infections. Recent investigation has confirmed its
usefulness in the prevention of urinary tract infections.
Limited chemical information is available for cranberry.
Documented in vitro and
animal studies provide supporting evidence for a mechanism of action for
cranberry in preventing urinary tract infections. However, little is known
about the specific active constituent(s); proanthocyanidins have been reported
to be important.
A Cochrane systematic review of cranberry for the prevention of
urinary tract infections found that there is some evidence to support the
efficacy of cranberry juice for the prevention of urinary tract infections in
women with symptomatic urinary tract infections. However, there is no clear
evidence as to the quantity and concentration of cranberry juice that should be
consumed, or as to the duration of treatment. Rigorous randomised controlled
trials using appropriate outcome measures are required to determine the
efficacy of cranberry juice in other populations, including children and older
men and women. Prevention trials should be of at least six-months’ duration in
order to take into account the natural course of the illness. Another Cochrane
systematic review found that there is no reliable evidence to support the
efficacy of cranberry juice in the treatment of urinary tract infections.
Patients wishing to use cranberry for urinary tract infections
should be advised to consult a pharmacist, doctor or other suitably trained
health care professional for advice.
There are several reports of an interaction between cranberry
juice and warfarin. Most reports have involved increases in patients’
international normalised ratios (INR) and/or bleeding episodes. It is not
possible to indicate a safe quantity or preparation of cranberry juice, and it
is not known whether or not other cranberry products might also interact with
warfarin. Patients taking warfarin should be advised to avoid taking cranberry
juice and other cranberry products unless the health benefits are considered to
outweigh the risks. In view of the lack of conclusive evidence for the efficacy
of cranberry, and the serious nature of the potential harm, it is extremely
unlikely that the benefit–harm balance would be in favour of such patients
using cranberry.
Doses of cranberry greatly exceeding the amounts used in foods
should not be taken during pregnancy and lactation.
TRADE NAMES
Cranberry
OTHER COMMON NAMES
Kronsbeere,
Marsh Apple, Moosbeere, Preisselbeere
Bog Cranberry, Isokarpalo, Mountain
Cranberry, Pikkukarpalo
DESCRIPTION
Cranberry is a small shrub with
relatively short trailing branches that measure approximately 20 cm in length.
The clustered, white flowers of this
plant are small and have reflexed petals.
The stem is robust having several, thick, ovate leaves along its length. Cranberry bears conspicuous,
round, red berries when in fruit.
FLOWERS:
The flowers of
the cranberry are small, measuring 1.5 cm. in width. Each bloom has four thin
white petals that are acutely reflexed, exposing a dark, elongated central cone
of 8-10 fused stamens. Flowers are sparsely arranged in nodding, rounded
clusters along the length of the branches.
FRUIT: The
berry-fruit of the cranberry are round, medium-sized, and bright-red.
LEAVES: The robust
leaves of this wildflowers measure 5-16 mm. in length and are ovate in shape.
They are several and are arranged along the length of the branches and stem.
The upper surface of each leaf is bright glossy green and the underside is a
dull, powdery-white.
HABITAT: Cranberry
grows best in open bogs, swamps, and along lakesides.
FUN FACTS: Cranberry is a popular, commercially harvested crop that is largely produced in Cape Cod. This aquatic wildflower was originally called “craneberry” because the nodding, elongated bloom resembled the head of the crane (http://www.bio.brandeis.edu/. Agustus, 2020)
SPECIES (FAMILY)
Vaccinium
macrocarpon (Aiton) Pers., †Vaccinium oxycoccus L., Vaccinium Erythrocarpum
SYNONYM(S)
*Large Cranberry Oxycoccus
macrocarpus (Aiton) Pursh. is the species
grown for commercial purposes.(1)
†European Cranberry, Mossberry, Oxycoccus palustris
Pursh.
ORIGIN
Cranberry is a small shrub
found in the United States, from Tennessee to Alaska.
PHARMACOPODIAL AND OTHER MONOGRAPHS
AHP(G1)
Martindale 35th edition(G85)
USP29/NF24(G86)
LEGAL CATEGORY (LICENSED PRODUCTS)
Cranberry is not included in the GSL.(G37)
CONSTITUENTS
Acids
Citric, malic, quinic and benzoic acids are present.(2)
Carbohydrates
Fructose and oligosaccharides.
Phenolics
Anthocyanins and proanthocyanidins.
Other Constituents Trace glycoside has been
isolated from V. oxycoccus.(3) Cranberries are also a good source of fibre. Cranberry
juice cocktail contains more carbohydrate than do products (i.e. soft or hard
gelatin capsules) based on cranberry powder (prepared from rapidly dried
fruits), whereas the latter contain more fibre.(2) Alkaloids (N-methylazatricyclo
type) have been isolated from the leaves.(4)
CHEMICAL COMPONENTS
Catechin,
flavone glycosides, fructose, organic acids, proanthocyanidins, vitamin C. Cranberry
has a high flavonol content (100–263 mg/kg) (Hakkinen et al 1999) —
higher than commonly consumed fruits and vegetables.
USES
USES
Cranberry is used to prevent (but not to treat) urinary
tract infections. It may be used to treat kidney stones.
FOOD USE
Cranberries
are commonly used in foods;(5) cranberry juice cocktail (containing
approximately 25% cranberry juice) is widely available.(2, 5) Cranberry is
listed by the Council of Europe as a natural source of food flavouring (fruit:
category N1) (see Appendix 3).(G17)
HERBAL USE
Cranberry
juice and crushed cranberries have a long history of use in the treatment and
prevention of urinary tract infections.(1) Traditionally, cranberries have also
been used for blood disorders, stomach ailments, liver problems, vomiting, loss
of appetite, scurvy and in the preparation of wound dressings.(5)
CLINICAL USE
Prevention of
UTI
Controlled
clinical trials support the use of cranberry products (solid-dose form and
juice) in the prevention of UTI in women experiencing recurrent infections. A
2008 systematic review evaluated data from 10 randomised controlled trials
(RCTs) or quasi- RCTs of cranberry products for the prevention of UTIs in all
populations (n = 1049) (Jepson &
Craig 2008).
The effects of cranberry/cranberry-lingonberry juice
versus placebo, juice or water were evaluated
in seven studies, and cranberry tablets versus
placebo in four studies (one study evaluated both
juice and tablets). Overall, cranberry products significantly
reduced the incidence of UTIs at 12 months
compared with placebo/control. Cranberry products were more effective in women with
recurrent UTIs than in the elderly or people requiring
catheterisation. Only one study reported a significant result for the outcome
of symptomatic UTIs. Side effects were common
in all studies, and dropouts/withdrawals in several of the studies were high (Jepson & Craig
2008).
Previously,
a 2004 Cochrane systematic review considered results from seven randomised
clinical trials ultimately using data from two good-quality studies to
undertake a meta-analysis (Jepson et al 2004,
Kontiokari et al 2001, Stothers 2002). Once again, cranberry
products were found to significantly reduce the incidence of UTI at 12 months compared
with placebo/control in women, and there was no significant difference in the
incidence of UTI between cranberry juice and cranberry capsules. One trial used
7.5 g of cranberry concentrate daily (in 50 mL), whereas the other trial used a
1:30 concentrate given either in 250 mL juice or in tablet form. Additionally,
Stothers showed that cranberry tablets provided the most cost-effective prevention
for UTI when compared with organic cranberry juice (Stothers
2002).
Spinal Cord Injuries
Patients with spinal cord
injuries are a high-risk group for catheter-associated UTIs, so cranberry products
are popular in this group. One doubleblind, factorial design, randomised
controlled trial of 305 people with spinal cord injuries showed no significant
UTI-free period compared to placebo when taking 800 mg of cranberry tablets
twice daily (Lee et al 2007), whilst another randomised, double-blind,
placebo-controlled, crossover trial in 47 patients with spinal cord injury
demonstrated a significant reduction in the frequency of UTIs (Hess
et al 2008). An open, pilot study involving 15 volunteers with
spinal cord injuries showed that three glasses
of cranberry juice daily significantly reduced the
adhesion of gram-negative and gram-positive bacteria
to uroepithelial cells (Reid 2002). Treatment using catheter device with proanthocyanidin solutions
has also been shown to inhibit adhesion of bacteria to non-biological particles
such as PVC (Eydelnant & Tufenkji 2008).
Children
Cranberry use is popular for
children with renal disease. An anonymous survey of 117 parents of children seen
in a hospital paediatric nephrology clinic identified that 29% gave cranberry
products to their children, to treat as well as prevent diverse renal problems (Super
et al 2005). Most parents felt that it was beneficial and only one reported
a side effect (nausea). Two studies conducted with children managed by clean
intermittent catheterisation found no clinical or statistical difference in the
number of symptomatic UTI observed in either the cranberry or placebo groups (Foda
et al 1995, Schlager et al 1999). Foda et al used a dose of 5 mL/kg/day
of cranberry cocktail for 6 months and the dose used by Schlager was 2 ounces (≈55 g) of cranberry concentrate.
Treatment
of UTI
Although
cranberry may be a viable adjunctive treatment in UTI when antibiotic
resistance is encountered, there is no reliable evidence that it is an
effective sole treatment in diagnosed UTI (Ulbricht & Basch 2005).
One study of pregnant women demonstrated comparable effects of daily cranberry
juice cocktail to those of placebo for asymptomatic bacteriuria and symptomatic
UTIs; however, the results were not statistically significant and more than one-third
of participants withdrew from the study because of gastrointestinal upset (Wing
et al 2008). In another study, cranberry exhibited only weak antimicrobial
activity in urine specimens of symptom-free subjects after ingestion of a
single dose (Lee et al 2008b).
Nephroprotection
Cranberries
have an anti-inflammatory effect through their antioxidant function and might
prevent infection-induced oxidative renal damage. Animal studies suggest that
cranberries might be used clinically as a beneficial adjuvant treatment to prevent
damage due to pyelonephritis in children with vesico-ureteric reflux (Han
et al 2007).
Urinary
Deodorising Activity
Cranberry
juice and solid-dose forms are popular in nursing homes as urinary deodorising
agents in older adults with incontinence. Although no clinical study is
available to confirm efficacy, numerous anecdotal reports suggest that it is
useful when used on a regular basis.
OTHER USES
Gout
Cranberry
juice has been used to treat gout. Evidence of increased uric acid excretion in
humans provides a theoretical basis for the indication, although studies in
patients with gout are not available to confirm effectiveness (Kessler
et al 2002).
Oral
Hygiene
The
antiadhesion effect of cranberry on oral microbial flora has been demonstrated
in vitro (Bodet et al 2008, Koo et al 2006, Yamanaka et al 2007). More
specifically, cranberry polyphenol fraction significantly decreased the
hydrophobicity of oral streptococci in a dose-dependent manner suggesting that
it may reduce bacterial adherence to the tooth surface (Yamanaka-Okada
et al 2008).
Prevention
and Treatment of Helicobacter Infection
Cranberry
inhibits the adhesion of H. pylori to human gastrointestinal
cells in vitro (Matsushima et al 2008);
however, very little clinical evidences are available to confirm significance
in humans (Burger et al 2002). A multicentric, randomised controlled, double-blind
trial found that regular intake of cranberry juice or a probiotic
inhibited H. pylori in a trial of 295 children (Gotteland
et al 2008). Another double-blind, randomised clinical study was
carried out in 177 patients with H. pylori infection to
investigate possible additive effect of cranberry juice to triple
therapy with omeprazole, amoxicillin and clarithromycin (OAC). Overall,
there was no statistically significant difference; however, analysis by
gender showed that the eradication rate was higher in females taking
cranberry, but not in males (Shmuely et al 2007).
Chemoprotection
Studies
employing mainly in vitro tumour models show that cranberry extracts and
compounds inhibit the growth and proliferation of several types of tumour,
including lymphoma, bladder, breast, colon, prostate, ovaries, oesophageal,
lung and oral squamous cell carcinoma (Chatelain et al 2008,
Ferguson et al 2006, Hochman et al 2008, Kresty et al 2008, Prasain et al 2008,
Singh et al 2009, Sun & Hai Liu 2006).
The flavonoid components may act in a complementary fashion to limit
carcinogenesis by inducing apoptosis in tumour cells (Neto
et al 2008).
Cardioprotection
Consumption
of 250 mL cranberry juice daily is associated with decreasing markers of
oxidative stress (Ruel et al 2008) and a significant increase in plasma HDL
cholesterol concentration (Ruel et al 2006). In
addition, cranberry extract increases cholesterol uptake and the synthesis of
LDL receptors (Chu & Liu 2005), suggesting that
accelerated cholesterol excretion may occur in vivo (McKay
& Blumberg 2007).
Type
2 Diabetes
Some
studies have suggested that consumption of a low-calorie cranberry juice is
associated with a favourable glycaemic response (Wilson et al 2008a,
2008b); however, a randomised, placebo-controlled, doubleblind study
demonstrated that cranberry had a neutral effect on glycaemic control in type 2
diabetics. This same study found, however, that cranberry supplements are
effective in reducing atherosclerotic cholesterol profiles, including LDL
cholesterol and total cholesterol levels, as well as total:HDL cholesterol ratio
in people with type 2 diabetes (Lee et al 2008a).
Figure 1. Cranberry (Vaccinium
macrocarpon) Fruit (whole Berries)
ACTIONS
Urinary Tract
Action
Studies
abound on the urinary tract action of cranberry. It is well known that
cranberry juice is useful for the prevention of urinary tract infections
(Jackson et al, 1997; Jepson et al, 2000; Lavigne et al, 2007). The increase in
urine acidity causes a decrease in organism growth. However, cranberry juice is
not effective for the treatment of urinary tract infections. Cranberry does
decrease ionized calcium in urine by 50% and therefore may be used to treat recurrent
kidney stones (Murray, Pizzorno, 1998).
Antioxidant
Action
One
study evaluated the antioxidant properties of blueberry and cranberry juice. Consumption
of cranberry juice increased the ability of plasma to increase antioxidants. Blueberry
juice did not exert this effect (Pedersen et al, 2000). However, this was a
small study with only nine participants.
Cardiovascular
Action
There
is a growing body of evidence that the phenolic acids (benzoic,
hydroxycinnamic, ellagic) in cranberries may contribute to reducing
cardiovascular risk, including decreased platelet aggregation, reducing blood
pressure, and increasing resistance of LDL to oxidation (McKay et al, 2007).
Oral Antiplaque
Action
One
study using a high-molecular-weight cranberry constituent found that the substance
altered subgingival microbes and therefore would be able to control periodontal
disease (Weiss et al, 1998).
PHARMACOLOGICAL ACTIONS
Documented activity for cranberry is mainly of its use in the prevention
and treatment of urinary tract infections.(1) Initially it was thought that the
antibacterial effect of cranberry juice was due to its ability to acidify urine
and, therefore, to inhibit bacterial growth. However, recent work has focused
on the effects of cranberry in inhibiting bacterial adherence and on determining
anti-adhesion agents in cranberry juice. Bacterial adherence to mucosal
surfaces is considered to be an important step in the development of urinary
tract infections;(7) it is facilitated by fimbriae (proteinaceous fibres on the
bacterial cell wall) which produce adhesins that attach to specific receptors
on uroepithelial cells.(8)
IN VITRO AND ANIMAL STUDIES
In in vitro studies using human urinary tract isolates of Escherichia coli, cranberry cocktail
(which contains fructose and vitamin C in addition to cranberry juice)
inhibited bacterial adherence to uroepithelial cells by 75% or more in over 60%
of the clinical isolates.(9) In addition, urine from mice fed cranberry juice
significantly inhibited E. coli adherence to uroepithelial cells when compared
with urine from control mice.(9) However, these studies did not define the
bacteria tested in terms of the type of fimbriae they might have expressed
(specific fimbriae mediate bacterial adherence to cells).
Irreversible inhibition of adherence of urinary isolates of E.
coli expressing type 1 and type P fimbriae has been demonstrated with cranberry
juice cocktail.(10) It was thought that fructose might be responsible for the
inhibition of type 1 fimbriae(10) and an unidentified high molecular weight
substance responsible for type P fimbriae inhibition.(11) Further in vitro
studies in which cranberry juice was added to the growth medium of P-fimbriated
E. coli duplicated immediate inhibition of adherence, but also showed the loss
of fimbriae with cellular elongation after longterm exposure; such changed
bacteria are unable to adhere to urothelium.(12)
Proanthocyanidins extracted from cranberries have been shown to
inhibit the adherence of P-fimbriated E. coli to uroepithelial cell surfaces at
concentrations of 10–50 mg/mL, suggesting that proanthocyanidins may be
important for the stated effects of cranberry in urinary tract infections.(13)
The effects of a high molecular weight constituent of cranberry juice
on adhesion of bacterial strains found in the human gingival crevice have also
been investigated.(14) A non-dialysable material derived from cranberry juice
concentrate used at concentrations of 0.6–2.5 mg/mL reversed the interspecies
adhesion of 58% of 84 bacterial pairs. Gram- negative dental plaque bacteria
appeared to be more sensitive to the inhibitory effects of the cranberry constituent
on adhesion.(14)
Crude extracts of cranberry have been reported to exhibit potential
anticarcinogenic activity in vitro as demonstrated by inhibition of the
induction of ornithine decarboxylase (ODC) by the tumour promoter phorbol
12-myristate 13-acetate (TPA).(15) The greatest activity appeared to be in the polymeric
proanthocyanidin fraction which had an IC50 for ODC activity of 6.0 mg. The
anthocyanidin fraction and the ethyl acetate extract were either inactive or
relatively weak inhibitors of ODC activity. A cranberry extract with a polyphenolic
content of 1548 mg gallic acid equivalents per litre inhibited low-density
lipoprotein (LDL) oxidation in vitro.(16)
Cranberry juice has demonstrated marked in vitro antifungal activity
against Epidermophyton floccosum and against several Microsporum and Trichophyton
species, but had no effect against Candida albicans.(17) Benzoic acid and/or
other low molecular weight constituents of cranberry juice were reported to be responsible
for the fungistatic action.
CLINICAL STUDIES
Clinical
trials investigating the use of cranberries for the prevention and treatment of
urinary tract infections have been subject to Cochrane systematic reviews; both
of these systematic reviews sought to include all randomised or quasi randomised
controlled trials.(18, 19)
Prevention of urinary tract infections Seven
trials were included in a Cochrane systematic review of cranberries for
prevention of urinary tract infections; six trials compared the effectiveness
of cranberry juice (or cranberry–lingonberry juice) versus placebo or water and
two trials compared cranberry tablets or capsules with placebo.(18) Studies
differed in the formulations of cranberry, doses and treatment periods used. In
the two trials assessed as being of good methodological quality, use of
cranberry was associated with a statistically significant reduction in the
incidence of urinary tract infections after 12 months (relative risk (95%
confidence interval): 0.61 (0.40–0.91)). One of these trials involved the
administration of cranberry concentrate 7.5 g daily (in 50 mL) and the other assessed
the effects of cranberry concentrate (1 : 30) in tablet form or in 250mL juice.
Apart from these two trials, the methodological quality of the trials was found
to be poor and the reliability of their results questionable. The conclusions
of the review were that there was some evidence to support the efficacy of
cranberry juice for the prevention of urinary tract infections in women with
symptomatic urinary tract infections. However, there was no clear evidence as
to the quantity and concentration of cranberry juice that should be consumed,
or as to the duration of treatment.(18) In addition, rigorous randomised controlled
trials are required to determine the efficacy of cranberry juice in other populations,
including children and older men and women. The largest study of cranberry
juice for the prevention of urinary tract infections was a double-blind,
placebo-controlled trial involving 153 women (mean age 78.5 years) randomised
to receive 300mL cranberry juice cocktail (n = 72) or an indistinguishable
placebo (n = 81) daily for six months.(6) The odds of experiencing bacteriuria
with pyuria were significantly lower in cranberry-treated subjects than in
those who received a placebo beverage (p = 0.004). The validity of the results
of this trial have been questioned because of methodological shortcomings in
the study design, particularly the method of randomisation.(20, 21)
Several
of the other studies included in the review are summarised below. These also have
methodological limitations, for example, several controlled studies claiming to
involve random assignment to treatment(22–24) either did not employ true randomisation(23)
or the method of randomisation was not stated.(22, 24)
A
randomised, controlled, crossover study was conducted involving 38 persons
(mean age 81 years) who had had hospital treatment and were waiting to be
transferred to a nursing home.(23) Subjects received cranberry juice (15 mL)
mixed with water or water alone twice daily for four weeks before crossing over
to the alternative regimen. Seventeen participants completed the study and, of
the seven from whom data were suitable for comparison, there were fewer occurrences
of bacteriuria during the period of treatment with cranberry juice.(23)
The
role of cranberry in the prevention of urinary tract infections in younger
women has been explored in a randomised, double-blind, placebo-controlled,
crossover trial involving 19 nonpregnant, sexually active women aged 18–45
years.(24) Participants received capsules containing 400 mg cranberry solids
daily (exact dose not stated) or placebo for three months before crossing over to
the alternative regimen. Ten subjects completed the six-month study period. Of
the 21 incidents of urinary tract infection recorded among these participants,
significantly fewer occurred during periods of treatment with cranberry than
with placebo (p < 0.005).(24) A
randomised, physician-blind, crossover study investigated the efficacy of cranberry
cocktail (30% cranberry concentrate) (15 mL/kg/day) for six months in 40
children (age range 1.4–18 years, mean age 9.35 years) with neuropathic bladder
and managed by clean intermittent catheterisation; water was used as a
control.(22)
No
benefit was reported for cranberry compared with control. A randomised,
double-blind, placebo-controlled, crossover trial of the effects of consumption
of cranberry concentrate on the prevention of bacteriuria and symptomatic
urinary tract infection has been carried out in children (n = 15) with
neurogenic bladder receiving clean intermittent catheterisation.(25) Children
drank 2 oz of cranberry concentrate or placebo daily for three months before
changing to the alternative regimen. At the end of the study, the number of
urinary tract infections occurring under each regimen was identical (n = 3).
There was no significant difference between cranberry treatment and placebo
with regard to the number of collected urine samples testing positively for a pathogen
(75% of samples for both cranberry and placebo) (p = 0.97). It was concluded
that cranberry concentrate had no effect on the prevention of bacteriuria in
the population studied.(25)
Treatment of urinary tract infections Although
several trials investigating the effectiveness of cranberry juice and cranberry
products for treating urinary tract infections were found, none of these trials
met all the inclusion criteria for systematic review.(19) Two of the studies
identified(26, 27) did report a beneficial effect with cranberry products,
although both contained methodological flaws and no firm conclusions can be
drawn from these studies.(19) Thus, it was stated that there was no evidence to
suggest that cranberry juice or other cranberry products are effective in treating
urinary tract infections.(19)
Other studies
Early studies involving the administration of large amounts of cranberry juice
to human subjects reported reductions in mean urinary pH values.(28, 29) A crossover
study involving eight subjects with multiple sclerosis reported that
administration of cranberry juice and ascorbic acid was more effective than
orange juice and ascorbic acid in acidifying the urine. However, neither treatment
consistently maintained a urinary pH lower than 5.5, the pH previously determined
as necessary for maintaining bacteriostatic urine.(30) Inhibition of bacterial
adherence (see
Pharmacological Actions,
In vitro and animal studies) has been observed with urine from 22 human
subjects who had ingested cranberry cocktail 1–3 hours previously.(9) Protection
against bacterial adhesion has also been reported in a study involving urine
collected from ten healthy male volunteers who had ingested water, ascorbic
acid (500 mg twice daily for 2.5 days) or cranberry (400 mg three times daily
for 2.5 days) supplements.(31) Urine samples were used to determine uropathogen
adhesion to silicone rubber in a parallel plate flow chamber; urine obtained
after ascorbic acid or cranberry supplementation reduced the initial deposition
rates and numbers of adherent E. coli
and Enterococcus faecalis, but not Pseudomonas
aeruginosa, Staphylococcus epidermidis or C. albicans. Other preliminary studies have explored the use of
cranberry juice in reducing urine odours,(32) in improving peristomal skin conditions
in urostomy patients(33) and in reducing mucus production in patients who have
undergone entero-uroplasty.(34)
The
ingestion of cranberry juice by subjects with hypochlorhydria due to omeprazole
treatment or atrophic gastritis has been shown to result in increased
protein-bound vitamin B12 absorption, although the clinical benefit of
ingesting cranberry juice along with a meal (i.e. with the buffering action of
food) remains to be determined.(35) Possible mechanisms by which the ingestion of
an acidic drink such as cranberry juice could result in improved protein-bound
vitamin B12 absorption include increased release of vitamin B12 from protein by
direct action of acid on the vitamin B12–protein bond and a pH-sensitive
bacterial binding activity of vitamin B12 that is altered in an acidic
environment.(35)
MAIN ACTIONS
Bacteriostatic
The
adhesion of pathogenic organisms to a tissue surface is required to initiate
most infectious diseases (Sharon & Ofek 2002).
The proanthocyanidins in cranberry are potent inhibitors of Escherichia coli
adhesion, thereby influencing the initiation of disease without exerting
bactericidal activity. One in vitro study found that cranberry juice inhibited adhesion
of 46 different E. coli isolates by 75% (Sobota 1984): when
administered to mice for 14 days, adherence of E. coli to uroepithelial
cells was inhibited by 80%. Significant inhibition of adherence was also observed
in samples of human urine 1–3 hours after subjects drank a cranberry drink. The
morphology of E. coli is changed when grown in the presence of cranberry
juice or extract (Johnson et al 2008). It appears that the
antiadhesion effects are a result of irreversible inhibition of the expression
of P-fimbriae of E. coli (Ahuja et al 1998).
Electron micrographic evidence suggests that cranberry juice acts either on the
cell wall, preventing proper attachment of the fimbrial subunits, or as a
genetic control preventing the expression of normal fimbrial subunits, or both
(Gupta et al 2007).
Furthermore,
cranberry juice has been shown to disrupt bacterial ligand-uroepithelial cell
receptor binding (Liu et al 2008). This inhibitory effect has been seen
with Staphylococcus aureus (Magarinos et al 2008), E.
coli and uroepithelial tissues, but also in the adhesion of Helicobacter
pylori to human gastrointestinal cells (Burger et al 2002)
and in the co-aggregation of oral bacteria and Streptococcus mutans counts
in saliva (Sharon & Ofek 2002, Weiss et al 1998).
Antioxidant
Cranberries
consistently rank highly among common fruits with antioxidant activity. In
particular, the polyphenolic compounds in cranberry display substantial
antioxidant capacity. In vitro tests with whole fruit and isolated flavonol
glycosides found in cranberry showed free radical scavenging activity comparable
or superior to that of vitamin E (Yan et al 2002).
In vivo studies demonstrate that cranberry juice increases plasma antioxidant
status (Villarreal et al 2007). A small human trial demonstrated that a single 240-mL serving
of cranberry juice increased plasma antioxidant capacity significantly greater than
controls receiving an equivalent amount of vitamin C in solution (Vinson
et al 2008).
Increases
excretion of oxalic acid and uric acid
According
to an open study, a dose of 330 mL cranberry juice can increase the excretion
of oxalic acid and uric acid (Kessler et al 2002).
Alterations
to urinary pH
Earlier
hypotheses that cranberry juice prevents UTI by acidification of urine or by
its hippuric acid content have not been substantiated. Results from human
studies are contradictory, but overall suggest no significant change to urinary
pH at doses less than 330 mL daily. A crossover study of 27 patients with
indwelling urinary catheters and chronic bacteriuria showed no change in
urinary pH (Nahata et al 1982), as did a double-blind
study of 153 women (Avorn et al 1994). One small, open study involving 12
healthy subjects found that 330 mL of cranberry juice reduced the urinary pH (Kessler et
al 2002).
OTHER ACTIONS
In
vitro tests using four different Vaccinium spp. found that the proanthocyanidin
fraction of cranberry exhibits potential anticarcinogenic activity (Bomser
et al 1996). A non-specific antiviral effect has been demonstrated in vitro
for a commercially produced cranberry fruit juice drink (Lipson et
al 2007).
ACTIVITIES
Antiaggregant
(1; JNU); Antibacterial (1; FNF; SKY); Antioxidant (1; JNU); Antiscorbutic (1;
CEB); Antiseptic (1; FAD; PED); Bitter (PED); Diuretic (f; CEB; PED); Hypoglycemic
(1; LEL); Laxative (f; CEB); Urinary Antiseptic (1; FAD).
INDICATIONS
Adenopathy
(f; FEL); Bacteria (1; FNF; SKY); Bladder Infection (2; SKY); Boil (f; FEL);
Cancer (f; CEB; JLH); Cancer, breast (f; JLH); Cancer, cheek (f; JLH); Cancer,
skin (f; JLH); Cardiopathy (1; JNU); Caries (1; JNU); Constipation (f; CEB);
Cystosis (2; SKY); Dermatosis (f; FEL); Diabetes (1; LEL); Diarrhea (f; CEB);
Dropsy (f; CEB); Dysentery (f; CEB); Erysipelas (f; CEB; FEL); Escherichia (1;
JNU); Fever (f; CEB); Gout (f; JAD); Helicobacter (1; JNU); High Cholesterol
(1; JNU); Hyperglycemia (1; LEL); Infection (1; JNU); Inflammation (f; CEB;
FEL); Mastosis (f; JLH); Nausea (f; CEB); Nephrosis (2; PED; SKY); Pleurisy (f;
CEB; DEM); Pulmonosis (f; DEM); Pyelonephrosis (f; APA); Salmonella (1; JNU); Scarlatina
(f; FEL); Sore (f; FEL); Sore Throat (f; FEL); Staphylococcus (1; JNU);
Swelling (f; FEL); Tonsilosis (f; FEL); Urethrosis (2; SKY); UTI (2; FAD; JNU);
Water Retention (f; CEB; PED); Wound (f; CEB).
PRODUCT AVAILABILITY
Capsules, Fresh Berries, Juice
PLANT PART USED: Fruit
(Whole Berries)
DOSAGES
DOSAGES
·
Adult PO capsules: 9-15 capsules/day
(400-500 mg each) (McCaleb et al, 2000)
·
Adult PO capsules (powdered
concentrate): 2 capsules daily
·
Adult PO juice: 1-2 cups daily
(Murray, Pizzorno, 1998)
DOSAGES
The
doses used in clinical trials of cranberry for prevention of urinary tract infections
have been variable. One study used 300 mL cranberry juice cocktail (containing
30% cranberry concentrate) daily for six months.(6)
DOSAGES
·
3 fluid oz (90 mL) fruit juice/day (APA preventative); 12–32
fluid oz fruit juice/day (APA curative);
·
1 oz cranberry juice cocktail = 2 capsules (APA); 5–20 oz/day; 800 mg capsules; 2–4 (505 mg)
capsules 3 ×/day;
·
2–3 (505 mg) capsules StX with meals (APA); 1/2 cup fresh fruit
(PED); 1 tbsp dry fruit (PED);
·
15 g dry fruit:20 mL alcohol/130 mL water (PED).
DOSAGES
Preventing UTI
• According to
clinical studies:
·
Adults: 30–300 mL
daily or 400 mg capsule daily.
·
Children: 15 mL/kg or up
to 300 mL daily.
In practice,
much higher doses are being used in an attempt to achieve quicker results (e.g.
cranberry capsules or tablets 10,000 mg/day for prevention).
ADVERSE REACTIONS
At
high doses (3 L or greater), gastrointestinal discomfort and diarrhoea can
occur (Ulbricht & Basch 2005).
CONTRAINDICATIONS, INTERACTIONS, AND SIDE EFFECTS
STRANGELY
(AHP) omitted this from their Botanical Safety Handbook, but I suppose
they would call it CLASS 1. The
Commission E and herbal PDR apparently also ignored this excellent food
farmaceutical too (KOM; PHR). Ingestion of ridiculous amounts (3–4 liters a
day) may cause diarrhea and other GI disorders (LRNP, Aug. 1987). Lininger et
al. (1998) say it is safe for use during pregnancy and lactation. Should not be
used as an antibiotic substitute during acute UTI (SKY).
CONTRAINDICATIONS AND PRECAUTIONS
People with diabetes should take care when using commercially
prepared cranberry juices because of the high sugar content.
If symptoms of UTI become more severe while cranberry
is being administered, other treatments may be required and medical advice is
recommended. People with a history of oxalate kidney stones should limit their
intake of cranberry juice.
PREGNANCY USE
Women experience UTIs with greater frequency during pregnancy. A
systematic review of the literature for evidence on the use, safety and
pharmacology of cranberry, focusing on issues pertaining to pregnancy and
lactation found that there is no direct evidence of safety or harm to the
mother or fetus as a result of consuming cranberry during pregnancy.
Indirectly, there is good scientific evidence that cranberry may be of minimal
risk, where a survey of 400 pregnant women did not uncover any adverse events
when cranberry was regularly consumed. In lactation, the safety or harm of
cranberry is unknown. Given the evidence to support the use of cranberry for
urinary tract infections and its safety profile, cranberry supplementation as
fruit or fruit juice is an appropriate and valuable therapeutic choice in the
treatment of UTIs during pregnancy (Dugoua et al 2008).
CONTRA-INDICATIONS,
WARNINGS
The
calorific content of cranberry juice should be borne in mind. Patients with
diabetes who wish to use cranberry juice should be advised to use sugar-free
preparations. Patients using cranberry juice should be advised to drink
sufficient fluids in order to ensure adequate urine flow.(G31) Although a
constituent of cranberry juice has been reported to have potential for altering
the subgingival microbiota, some commercially available cranberry juice
cocktails may not be suitable for oral hygiene purposes because of their high dextrose
and fructose content.(14)
Drug Interactions There
are several reports of an interaction between cranberry juice and warfarin. By
October 2004, the UK Committee on Safety of Medicines had received 12 such
reports, of which eight involved increases in patients' international
normalised ratios (INR) and/or bleeding episodes, three involved unstable INR
and one a decrease in INR.(37) These reports include a death in a man whose INR
rose to over 50 six weeks after starting to drink cranberry juice. The man experienced
gastrointestinal and pericardial haemorrhage and died.(38) It is not possible
to indicate a safe quantity or preparation of cranberry juice, and it is not known
whether or not other cranberry products might also interact with warfarin.
Against this background,
patients taking warfarin should be advised to avoid taking cranberry juice and
other cranberry products unless the health benefits are considered to outweigh
the risks.(39) In view of the lack of conclusive evidence for the efficacy of
cranberry, and the serious nature of the potential harm, it is extremely
unlikely that the benefit–harm balance would be in favour of such patients
using cranberry.
The mechanism for the
interaction between cranberry constituents and warfarin is not known. The
suggestion that it may involve inhibition of the cytochrome P450 enzyme CYP2C9
(by which warfarin is predominantly metabolised),(38) requires investigation.
While not a drug
interaction, it is reasonable to provide the following information here.
Interference with dipstick tests for glucose and haemoglobin in urine has been
reported in a study involving 28 patients who had drunk 100 or 150 mL of
low-sugar or regular cranberry juice daily for seven weeks;(40) ascorbic acid in
cranberry juice was reported to be the component responsible for interference
resulting in negative test results.
Pregnancy and Lactation There
are no known problems with the use of cranberry during pregnancy. Doses of
cranberry greatly exceeding the amounts used in foods should not be taken during
pregnancy and lactation.
CONTRAINDICATIONS
Pregnancy category is 1;
breastfeeding category is 2A.
Cranberry should not be used by persons with oliguria,
anuria, or hypersensitivity to this herb.
SIDE EFFECTS/ADVERSE REACTIONS
GI: Diarrhea
(large doses)
INTEG: Hypersensitivity
reactions
INTERACTIONS
Drug
Cytochrome P45 2C9 substrates: Cranberry may inhibit cytochrome P45 2C9 enzymes.
Warfarin: Cranberry,
when given with warfarin, may increase the international normalized ratio and
increase the risk for bleeding.
Lab Test
Urine pH: Cranberry
decreases urine pH.
SIGNIFICANT INTERACTIONS
Proton
Pump Inhibitors
The composition of bioactive components of cranberry juice can
vary substantially and there is potential for drug interaction (Ngo
et al 2009). Cranberry sjuice increases the absorption of vitamin B12 when
used concurrently with PPI medicines (Saltzman et al 1994) —
beneficial interaction.
Warfarin
There are a number of case reports suggesting that cranberry juice
may increase the INR in patients taking warfarin; however, two case reports did
not clearly identify cranberry juice as the sole cause of INR elevation, whereas
one case report appeared to show a correlation between the effects of cranberry
juice and warfarin metabolism (Pham & Pham 2007).
In contrast, results from two clinical pharmacokinetic studies indicate no
clinically relevant pharmacokinetic interaction between cranberry juice and
warfarin (Pham & Pham 2007). One clinical study found
that cranberry juice did not change the anticoagulant effect of warfarin and
daily ingestion of cranberry juice did not inhibit the activities of CYP2C9,
CYP1A2 or CYP3A4 (Lilja et al 2007). A more recent study suggests that a
pharmacodynamic interaction is more likely (Mohammed Abdul et al 2008).
Until the interaction can be better understood, patients taking
warfarin with cranberry juice should be cautioned about a potential interaction
and monitored closely for INR changes and signs and symptoms of bleeding.
SIDE-EFFECTS, TOXICITY
CLINICAL DATA
A Cochrane systematic review of cranberry products for the prevention
of urinary tract infections reported that the drop-out rates in the seven
studies included were high (20–55%).(18) In one of these studies, of 17
withdrawals during cranberry treatment (a further two occurred during the control
period), nine participants gave the taste of cranberry as the reason for
withdrawal.(22)
It has been claimed that ingesting large amounts of cranberry juice
may result in the formation of uric acid or oxalate stones secondary to a
constantly acidic urine and because of the high oxalate content of cranberry
juice.(1) However, it has also been stated that the role of cranberry juice as
a urinary acidifier has not been well established.(36) The use of cranberry
juice in preventing the formation of stones which develop in alkaline urine,
such as those comprising magnesium ammonium phosphate and calcium carbonate,
has been described.(28)
CLIENT CONSIDERATIONS
ASSESS
·
Assess for hypersensitivity
reactions. If present, discontinue use of cranberry and administer an
antihistamine or other appropriate therapy.
·
Assess the client’s
genitourinary status: urinary frequency, hesitancy, pain, or burning.
If a urinary tract infection is
present, refer the client for antibiotic therapy.
ADMINISTER
·
Instruct the client to store
cranberry products away from light and moisture.
TEACH CLIENT/FAMILY
·
Inform the client that
pregnancy category is 1 and breastfeeding category is 2A.
·
Caution the client not to use
cranberry in place of antibiotic therapy if urinary frequency, hesitancy, pain,
or burning are present.
·
Advise the client that
cranberry is effective for preventing urinary tract infections but not for
treating them.
PATIENTS’ FAQs
What will this
herb do for me?
Cranberry
products appear to reduce the risk of developing UTI.
When will it
start to work?
Studies
using 1–2 glasses of cranberry juice suggest that 4–8 weeks’ continual use is
required; however, faster effects using concentrated tablets or capsules have
been reported.
Are there any safety
issues?
If
fever or pain exists or symptoms of UTI become more severe, seek medical
advice. People taking warfarin together with cranberry should monitor their INR
for changes.
PRACTICE POINTS/PATIENT COUNSELLING
·
Cranberry
preparations are widely used to prevent and treat minor UTI.
·
Overall,
clinical testing suggests that the juice and solid-dose forms may have
significant beneficial effects for UTI management.
·
Cranberry
exerts bacteriostatic effects by reducing bacterial adhesion to host tissues.
·
Overall,
evidence suggests no significant alteration to urinary pH at doses less than
330 mL daily.
·
Cranberry
products have also been used to treat gout and to deodorise urine in people with
incontinence.
·
Preliminary
research suggests a possible role in preventing conditions such as Helicobacter
pylori infection and dental plaque formation.
·
Patients
taking warfarin and regular cranberry intake should have their INR monitored.
PREPARATIONS
PROPRIETARY
SINGLE-INGREDIENT PREPARATIONS
Australia: Uricleanse. Canada: Cran Max. France: Gyndelta. UK:
Seven Seas Cranberry Forte.
PROPRIETARY
MULTI-INGREDIENT PREPARATIONS
Australia: Bioglan Cranbiotic Super; Cranberry Complex; Cranberry
Complex; Extralife Uri-Care. Canada: Cran-C; Prostease. Hong Kong: Prostease.
USA: CranAssure; Cranberry; Cran Support; Calcium with Magnesium; My Defense.
EXTRACTS
Anthocyanins and polyphenols in berries of several Ribes, Rubus, and Vaccinium spp have in vitro antiradical
activity on chemically generated superoxide radicals. The extracts also
inhibitory xanthine oxidase. All crude extracts were highly active toward
chemically generated superoxide radicals. Ribes nigrum extracts
exhibited most activity, being the richest in both anthocyanins and
polyphenols. But Ribes rubrum extrac ts seem to contain more active substances (X1332092).
REFERENCE
Barnes, J., Anderson, L. A., and Phillipson, J. D. 2007. Herbal
Medicines Third Edition. Pharmaceutical Press. Auckland and
London.
Braun, L and Cohen, M. 2010. Herbs & Natural Supplements – An
Evidence Based Guide 3rd Edition. Elsevier Australia. Australia
Duke, J. A. with Mary Jo Bogenschutz-Godwin, Judi duCellier, Peggy-Ann K.
Duke. 2002. Handbook of Medicinal Herbs 2nd Ed. CRC Press
LLC. USA.
Linda S-Roth. 2010. Mosby’s Handbook Of Herbs & Natural
Supplements, Fourth Edition. Mosby Elsevier. USA.
Website
:
Cranberry
(Vaccinium macrocarpon) F. Ericaceae -
General Description http://www.bio.brandeis.edu/fieldbio/Wildflowers_Kimonis_Kramer/PAGES/CRANBERRY_PAGE_FINAL.html#:~:text=General%20Description%3A,approximately%2020%20cm%20in%20length.&text=The%20stem%20is%20robust%20having,red%20berries%20when%20in%20fruit.
09 Agust 2020.
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