COLA ----

RASPBERRY ---

POPLAR ---

HAWTHORN ----

PARSLEY --

PLANTAIN ---

FIGWORT ---

CRANBERRY --- Vaccinium macrocarpon Aiton (Ericaceae) +++

 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.