МОНОГРАФИИ ВОЗ Т 4

Fructus Macrocarponii

Medicinal uses

Uses supported by clinical data

Orally as adjunct therapy for the prevention and symptomatic treatment of urinary tract infections in adults (8–20). Two clinical trials have assessed the effect of the fruit juice in paediatric populations (17, 21), but the results were negative. Results from clinical trials involving the use of cranberry for the treatment of children with neurogenic bladder were also negative and do not support the use of cranberry products in paediatric populations (22).

Uses described in pharmacopoeias and well established documents

No information was found.

Uses described in traditional medicine

Treatment of asthma, fever, loss of appetite, scurvy and stomach ailments, as well as gallbladder and liver disease and for treatment of wounds (3, 23).

Pharmacology

Experimental pharmacology

Antimicrobial and antiadhesive activity

A concentrated extract of the juice of the crude drug was tested for activity against the following pathogens: Alcaligenes faecalis, Clostridium perfringens, Enterococcus faecalis, Escherichia coli, Mycobacterium phlei, Pseudomonas aeruginosa, Salmonella california, Salmonella enteritidis, Salmonella typhimurium, Shigella sonnei, Staphylococcus aureus and me- thicillin-resistant S. aureus, as well as Candida albicans. The crude drug concentrate did not inhibit the growth of C. albicans, but had variable activity against the bacteria at dilutions of 1:5 and 1:10 (24).

Early investigations of the mechanism of cranberry’s bacteriostatic activity suggested that acidification of the urine may be responsible for its activity. However, more recent studies have demonstrated that urinary acidification is not the mechanism by which cranberry exerts its effects, but it does so through a mechanism that involves the inhibition of bacterial adherence (25–27). In vitro studies have shown that, in the 77 clinical isolates tested, cranberry juice decreased bacterial adherence of E. coli to uroepithelial cells by 60% when compared with saline solution (28). Furthermore, cranberry juice inhibited the adherence of E. coli to human urinary epithelial cells three times more stongly than E. coli isolated from other clinical sources (27, 28). One study demonstrated that cranberry juice dose-dependently inhibited the haemagglutination activity of E. coli urinary isolates expressing type I and P adhesion (27).

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The effect of the fruit on the expression of P-fimbriae of E. coli was assessed by growing P-fimbriated E. coli in solid media containing cranberry juice. Cranberry concentrate at pH 7.0 was added to the medium to achieve a final concentration of 25%. E. coli strains JR1 and DS17 were plated on to this medium, with a plain medium control, and incubated at 37 °C. Cultures were tested for ability to agglutinate P-receptor-specific beads. The results demonstrated that for E. coli strain JR1, P-fimbrial agglutination was inhibited after the third plating and strain DS17 was fully inhibited after the second plating. Fully inhibited bacteria had a 100% reduction in expression of fimbriae (25). Two compounds in cranberry juice inhibited lectin-mediated adherence of E. coli to mucosal cells. One of these compounds was fructose and the other was a nondialysable polymeric compound (25). Further investigations have found that exposure of pathogenic bacteria to the nondialysable polymeric compound in either the gut or bladder produces a bacteriostatic effect by inhibiting the expression of specific adhesins present on the pili on the bacterial surface (26, 28).

The proanthocyanidin fraction, isolated from an ethyl acetate extract of the fruit, was assessed for its ability to prevent adherence of E. coli by measuring the ability to prevent agglutination of both isolated P-receptor resin-coated beads and human erythrocytes. The proanthocyanidin fraction, at a concentration as low as 75.0 mg/ml, exhibited potent antiadherence activity in uropathogenic isolates of P-fimbriated E. coli bacteria to cellular surfaces containing alpha-Gal(1λ4)beta-Gal receptor sequences similar to those on epithelial cells in the urinary tract. The chemical structures of the proanthocyanidins consisted predominantly of epicatechin units containing at least one A-type linkage. The procyanidin A2 was the most common terminating unit, occurring about four times as frequently as the epicatechin monomer (29). Isolated A-type proanthocyanidins isolated from cranberry juice cocktail had anti-adhesive activity at 60 Μg/ml, while the B-type exhibited weak activity at 1.2 mg/ml (30).

A high-molecular-weight constituent of the fruit, named nondialysable material, at concentrations of 100.0 μg/ml, inhibited the adhesion of Helicobacter pylori strain BZMC-25 to human gastric mucosal cells. The inhibition of adhesion by nondialysable material was dose-dependent, and the 50% inhibitory concentration was strain-dependent, the concentrations being 37.0, 125.0 and 305.0 μg/ml for H. pylori strains BZMC-25, EHL-65 and 17874, respectively (31).

In one study, uropathogenic P-fimbriated E. coli isolates were obtained from the urine of women with clinically diagnosed, culture-confirmed urinary tract infections and incubated for 20 minutes in urine collected over a 12-hour period from healthy women before and after consumption

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of 240 ml of commercial cranberry juice cocktail (30% pure juice), and in cranberry proanthocyanidin extract (pH 6.5) (2-fold dilution series). These bacteria were then harvested and screened for ability to adhere to isolated uroepithelial cells and to agglutinate human red blood cells (A1, Rh+), and resin beads coated with isolated P-receptor oligosaccharides. Urine collected from healthy women after consumption of the cranberry juice cocktail (average pH 6.2) prevented adhesion in 31 (80%) of the 39 isolates and 19 (79%) of the 24 antibiotic-resistant isolates in all bioassays, while urine collected prior to the administration of the juice (average pH 6.2) failed to prevent adhesion in any of the samples. Anti-adhesion activity was evident in the urine within 2 hours and persisted for up to 10 hours following ingestion of the cranberry juice cocktail. The extracted proanthocyanidins inhibited adhesion of all isolates at concentrations ranging from 6 to 375.0 μg/ml, demonstrating potent in vitro anti-adhe- sion activity against these bacterial strains (32).

In another study, urine samples were collected from groups of volunteers following the consumption of water, ascorbic acid or cranberry supplements (unspecified) and tested in an anti-adhesion assay. Only intake of ascorbic acid consistently produced acidic urine. Surface tension measurements of the urine collected showed that both water and cranberry supplementation consistently produced urine with a surface tension higher than that in urine from the control group or urine collected following ascorbic acid intake. Urine obtained after supplementation with ascorbic acid or cranberry reduced the initial in vitro deposition rates and numbers of adherent E. coli and Enterococcus faecalis, but not Pseudomonas aeruginosa, Staphylococcus epidermidis, or Candida albicans. Conversely, urine obtained from subjects with increased water intake vastly increased the initial deposition rates and numbers of adherent E. coli and E. faecalis (p < 0.05) (33).

Antioxidant activity

The antioxidant activities of the fruit and its phenolic constituents were measured in vitro. The fruit had an anthocyanin concentration of 0.32 mg/g fresh weight and a total phenolic concentration of 3.15 mg/g fresh weight. In vitro the fruit exhibited antioxidant effects at a concentration of 18.5 μmol/g fresh weight. Chlorogenic acid, peonidin 3-galactoside, cyanidin 3-galactoside and cyanidin 3-galactoside were the most important antioxidants in the fruit (34). Methanol extracts of the fruit were assayed for radical-scavenging activity and cell growth inhibition using seven tumour cell lines. A methanol extract of the fruit caused inhibition of the proliferation of K562 and HT-29 cell lines at concentrations in the range of 16.0–125.0 μg/ml. Radical-scavenging activity was greatest in an extract composed primarily of flavonol glycosides. Seven flavonol mono-

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glycosides: myricetin 3-alpha-arabinofuranoside, quercetin 3-xyloside, 3-methoxyquercetin 3-beta-galactoside (isorhamnetin), myricetin 3-beta- galactoside, quercetin 3-beta-galactoside, quercetin 3-alpha-arabinofura- noside and quercetin 3-alpha-rhamnopyranoside were evaluated for 1,1- diphenyl-2-picrylhydrazyl radical-scavenging activity and ability to inhibit low-density lipoprotein oxidation in vitro. Most of the flavonol glycosides had antioxidant activity comparable to or superior to that of vitamin E. Cyanidin 3-galactoside showed activity superior to that of the flavonoids as well as vitamin E or of a water-soluble vitamin E analogue in both antioxidant assays (35).

In another in vitro study, the antioxidant and anti-inflammatory effects of cranberry anthocyanins and hydroxycinnamic acids were measured against hydrogen peroxideand tumour necrosis factor (TNFΑ)- induced damage to human microvascular endothelial cells. Polyphenols from the crude drug were absorbed into endothelial cells and subsequently reduced the vulnerability of endothelial cells to increased oxidative stress in the membrane and cytosol. Furthermore, the polyphenols also reduced TNFΑ-induced up-regulation of various inflammatory mediators (interleukin-8) involved in the recruitment of leukocytes to sites of damage or inflammation along the endothelium. Maximum inhibition for all treatments was observed at a concentration of 0.1 mg/ml for 2 hours (p < 0.001 in all cases) (36).

Clinical pharmacology

Numerous clinical studies have assessed the effects of the fruit and of fruit juice preparations in humans, but only 18 clinical trials have assessed the effects of cranberry juice on urinary pH and urinary tract infections (8–20, 37). Of these 18 trials assessing the safety and efficacy of cranberry for the prevention and treatment of urinary tract infections (UTIs), only four were controlled and of sufficient scientific quality (8, 14, 16, 19, 38).

A double-blind, placebo-controlled trial involving 376 elderly patients in hospital assessed the prophylactic effects of cranberry juice (30% pure juice, 300 ml per day) against the onset of urinary tract infections (37). Although the results suggested that cranberry supplementation may be protective, these results were not statistically significant.

A randomized placebo-controlled clinical trial compared the effectiveness and cost-effectiveness of concentrated cranberry tablets (1:30 pure dried juice), cranberry juice, and a placebo used as prophylaxis against lower urinary tract infections in adult women. One hundred and fifty sexually active women aged between 21 and 72 years were randomly assigned for one year to one of three groups receiving prophylaxis: placebo juice + placebo tablets; placebo juice + cranberry tablets; or cranberry

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juice + placebo tablets. Tablets were taken twice daily; juice was administered at a dose of 250 ml three times daily. Outcome measures were:

—a > 50% decrease in number of symptomatic UTIs per year (symptoms θ 100 000 single organisms/ml); and

—a > 50% decrease in annual consumption of antibiotics.

Cost-effectiveness was calculated as cost in US dollars per urinary tract infection prevented. Both cranberry juice and cranberry tablets led to a statistically significant decrease in the number of patients experiencing at least one symptomatic UTI per year (to 20% and 18%, respectively) compared with placebo (to 32%) (p < 0.05) (19).

An open, randomized controlled 12-month follow-up trial was performed to determine whether recurrences of urinary tract infection could be prevented with cranberry–lingonberry juice or with a lactobacillus drink. One hundred and fifty women, with UTIs caused by E. coli, were allocated to one of three groups. The first group received 50.0 ml of cran- berry–lingonberry juice concentrate mixed in 200.0 ml water (7.5 g cranberry concentrate and 1.7 g lingonberry concentrate in 50.0 ml water, no sugar added) daily for 6 months; the second, 100 ml of lactobacillus drink 5 days per week for one year; and the third group received no intervention. Outcomes measured included the first recurrence of symptomatic UTI, defined as bacterial growth of θ 105 colony-forming units/ml in a clean voided midstream urine specimen. The cumulative rate of the first recurrence of UTI during the 12-month follow-up period differed significantly between the groups (p = 0.048). After 6 months, eight (16%) women in the group treated with cranberry, 19 (39%) in the lactobacillustreated group, and 18 (36%) in the control group had had at least one recurrence. A 20% reduction in absolute risk in the group given cranberry was observed as compared with the control group (14).

A randomized, double-blind, placebo-controlled parallel trial involving 153 elderly female volunteers (mean age 78.5 years) assessed the effect of a cranberry juice preparation (27% pure juice, saccharin-sweet- ened) on asymptomatic bacteriuria (defined as > 105 colony forming units/ml) and pyuria (38). The subjects were randomly assigned to receive 300 ml/day of cranberry juice or a cranberry-flavoured placebo containing vitamin C for 6 months. Urine samples were collected at monthly intervals. The subjects receiving the cranberry juice had a lower frequency of bacteriuria with pyuria than the subjects in the control group (odds ratio 42% of the control group, p = 0.004), of nearly 50% after 4–8 weeks of cranberry use. There was no evidence of urinary acidification, and the median pH of urine in the cranberry-treated group was 6.0.

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A randomized, double-blind, placebo-controlled trial assessed the effects of capsules containing concentrated cranberry (400.0 mg of cranberry solids) in 19 women with a history of recurring UTI (20). Half of the women were given two capsules of a dried extract of the crude drug daily for 3 months followed by 3 months of treatment with a placebo. The other group received a placebo for the first 3 months then the active treatment for a further 3 months. However nine subjects dropped out due to pregnancy or unrelated infections, or were lost to follow-up. Treatment with cranberry capsules significantly reduced the occurrence of UTIs (p < 0.005). On average, 2.4 UTIs per year were recorded in the cranber- ry-treated group and 6.0 UTIs per year occurred in the placebo-treated group. Treatment was well tolerated and no side-effects were reported.

A pilot study of 15 patients who had spinal cord injuries was performed to determine whether alteration of fluid intake and use of cranberry juice altered the bacterial biofilm load in the bladder. Urine samples were collected on day 0 (start of study), on day 7 – after each patient had drunk one glass of water three times during the day in addition to the normal diet, and on day 15 – after each patient had drunk one glass of cranberry juice three times during the day. The results showed that cranberry juice intake significantly reduced the biofilm load compared to baseline (p = 0.013). This was due to a reduction in adhesion of Gramnegative (p = 0.054) and Gram-positive (p = 0.022) bacteria to cells. Water intake did not significantly reduce the bacterial adhesion or biofilm presence (16).

A randomized, placebo-controlled trial assessed the efficacy of 30 ml of pure cranberry juice for reducing the bacterial concentrations in the urine of elderly subjects with a mean age of 81 years (10). Thirty-eight volunteers were treated with 30 ml of cranberry juice mixed with water or with water alone for 4 weeks, followed by cross-over for a further 4 weeks. Statistically significant results were reported; cranberry treatment decreased the frequency of bacteriuria (p = 0.004). However, 21 patients dropped out before the end of the trial, leaving only 17 patients in the fi- nal evaluation. No side-effects were reported (10).

In an uncontrolled study involving 60 subjects with symptoms of acute UTI such as frequency, dysuria, urgency and nocturia, the effects of cranberry on the numbers of bacteria in the urine was assessed (15). Patients were treated with 16 ounces of cranberry juice daily for 21 days. After 3 weeks, a positive clinical response (no urogenital complaints and fewer than 100 000 bacteria per ml of urine) was noted in 32 patients (53%). Another 12 patients (20%) were “moderately improved” and 16 patients (27%) showed no bacteriological improvement or symptomatic relief (15).

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In an uncontrolled study, 28 patients in a nursing home were treated with 4–6 ounces of cranberry juice (30% juice) daily for 7 weeks (9). Twice-weekly urine samples were examined for leukocytes and/or nitrates as a measure of UTI. At the end of 7 weeks, 10 patients had no leukocytes or nitrates in the urine; nine patients had from a trace to 2+ leukocytes and no nitrates; nine had a trace or greater number of leukocytes. However, this study did not include a non-exposure cohort (control) (9).

A number of uncontrolled observational studies have assessed the effects of cranberry juice (33% juice) on urinary pH (12, 13). In the study by Kinney & Blount (13), 59 patients (40 of whom completed the study) were treated with 450–720 ml of a preparation containing 80% cranberry juice per day for 6 days, followed by 6 days of no juice, and the pH of their urine was measured. A decrease in urine pH was observed, but it was not dose-related. The second study involved four healthy volunteers who were administered from 1.5 to 4.0 l per day of a 33% cranberry juice product (12). Three of the four subjects showed transient changes in urine pH, from 6.6 to 6.33 (p = 0.01) and titratable acidity (12).

A randomized, double-blind, placebo-controlled study was conducted on 48 patients with neurogenic bladder secondary to spinal cord injury (39). Twenty-six of the patients received 2 g of cranberry juice concentrate and 22 received placebo. After 6 months of treatment, bacteriuria and pyuria were not reduced (39).

Paediatric populations

An uncontrolled study assessed the efficacy of cranberry (30% pure juice) in 17 children with spina bifida who were using either an indwelling catheter or intermittent self-catheterization (21). The children received one, two or three glasses of cranberry juice over a 2-week period. The results of this study showed a reduction of white and red blood cell counts in nearly all urine samples; however the urine from most of the children remained positive for E. coli (21).

At least two controlled clinical trials have assessed the effects of cranberry in children with neurogenic bladder. A randomized single-blind, cross-over study assessed the efficacy of 15 ml/kg body weight/day of cranberry cocktail juice (30% concentrate) as prophylaxis for bacterial UTIs in 40 children with neuropathic bladder, managed by intermittent catheterization (8). The subjects were treated for 6 months with either cranberry juice or water as a control. Outcomes measured were a positive or negative urine culture with symptomatic UTI. The results of this study did not support the use of cranberry juice as prophylaxis against UTIs in children with neuropathic bladder. However, 19 subjects dropped out of

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the trial, and the diagnostic criteria for the UTI were much lower than those used in any other trial (103 colony-forming units/l of a pathogenic organism).

The results of this trial were confirmed in a double-blind, placebocontrolled, cross-over study involving 15 paediatric patients with neurogenic bladder receiving clean intermittent catheterization (17). Two ounces of cranberry juice concentrate (equal to 300 ml of cranberry juice cocktail) or a placebo were administered daily for 3 months, followed by a 3-month cross-over (no washout period was described). Weekly home visits were made, during which a sample of bladder urine was obtained by intermittent catheterization. Signs and symptoms of UTI and all medications were recorded, and compliance was assessed. The results of the study demonstrated that during consumption of the cranberry concentrate, the frequency of bacteriuria remained high. Cultures of 75% (114) of the 151 samples obtained during consumption of placebo were positive for a pathogen (θ 104 colony-forming units/ml) compared with 75% (120) of the 160 samples obtained during consumption of cranberry concentrate. Escherichia coli remained the most common pathogen during periods of consumption of placebo and cranberry. Three symptomatic infections occurred during the period of treatment with the placebo and three during the period of treatment with the cranberry juice. No significant difference was observed between the acidification of urine in the placebotreated group and that in the cranberry-treated group (median, 5.5 and 6.0, respectively). Thus, cranberry ingestion did not reduce bacteriuria or symptomatic UTIs in this population (17). Unfortunately the only outcomes measured were bacteriuria and presence of symptoms and no blood cell counts were performed.

A review of these clinical data on cranberry juice and supplements in paediatric populations indicates that these products are not effective for the treatment of UTIs in children with neuropathic bladder (22).

In an uncontrolled trial involving 13 urostomy patients, the effects of cranberry juice on skin complications were assessed (40). Patients were treated with 160 to 320 ml of cranberry juice daily for 6 months. The results of this study showed an improvement of the skin conditions in four urostomy patients with peristomal skin disorders. A decrease in erythema, maceration and pseudoepithelial hyperplasia was observed, but no effects on urine acidity were noted (40).

A study was performed to assess the effects of cranberry on the complications of long-term indwelling bladder catheterization (e.g. encrustation and blockage by crystalline Proteus mirabilis biofilms). Urine was collected from groups of volunteers who had been treated with up to

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1000 ml of cranberry juice or water over an 8-hour period. Laboratory models of the catheterized bladder were supplied with urine from these groups and then inoculated with P. mirabilis. After incubation for 24 or 48 hours, the extent of catheter encrustation was determined by chemical analysis for calcium and magnesium. The amount of calcium and magnesium recovered from catheters incubated in urine pooled from individuals who had drunk 500 ml of cranberry juice did not differ significantly from that on catheters incubated in pooled urine from control subjects who had drunk 500 ml of water. However, there was significantly less encrustation (p = 0.007) on catheters from models incubated in urine from volunteers who had been given 1000 m1 of water than on catheters incubated in models supplied with urine from volunteers who had been given 1000 ml of cranberry juice. The amounts of encrustation on these two groups of catheters were also significantly less than that on catheters incubated in models supplied with urine from volunteers who had not supplemented their normal fluid intake (p < 0.001) (41).

Urolithiasis

The potential influence of cranberry juice on urinary biochemical and physicochemical risk factors associated with the formation of calcium oxalate kidney stones was assessed in a randomized cross-over trial. Urinary variables were assessed in 20 South African men with no previous history of kidney stones. The first group of 10 subjects drank 500 ml of cranberry juice diluted with 1500 ml tap water every day for 2 weeks, while the second group drank 2000 ml of tap water daily for the same period. This was followed by a 2-week washout period before the two groups were crossed over. During the experimental phase, subjects kept a 3-day food diary to assess their dietary and fluid intakes; 24-hour urine samples were collected at baseline and on day 14 of the trial periods, and analysed using modern laboratory techniques. Urine analysis data were used to calculate the relative urinary supersaturations of calcium oxalate, uric acid and calcium phosphate. The results demonstrated that the ingestion of cranberry juice decreased oxalate and phosphate excretion and increased citrate excretion. There was also a decrease in the relative supersaturation of calcium oxalate, which tended to be significantly lower than that induced by water alone (42).

In another study, five healthy volunteers on a normal diet provided 24-hour urine samples for analysis of pH, volume, creatinine, oxalate, calcium, phosphate, uric acid, sodium, citrate, magnesium and potassium. Tablets containing the crude drug were administered to these volunteers at the manufacturer’s recommended dosage (not stated) for 7 days. On the seventh day, a second 24-hour urine sample was obtained from each

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volunteer. The results demonstrate that urinary oxalate levels in the volunteers significantly increased (p = 0.01) by an average of 43.4% during treatment. The excretion of potential lithogenic ions, calcium, phosphate, and sodium also increased. However, inhibitors of stone formation, magnesium and potassium, rose as well (43).

The effect of cranberry juice on risk factors for urinary stones was assessed in a trial involving 12 healthy male subjects. The subjects provided 24-hour urine samples (three samples from each patient during the three loading phases with water only). In each loading phase a neutral mineral water was substituted for 330 ml of the juice. Cranberry juice decreased the urinary pH, whereas the excretion of oxalic acid and the relative supersaturation for uric acid were increased, indicating the potential for the development of urinary stones (44).

Adverse reactions

One rare case of immune-related thrombocytopaenia has been reported in a 68-year-old patient (45).

Nausea and severe vomiting were reported in a 4-month-old infant after administration of 180 ml of cranberry juice (46).

Contraindications

The use of cranberry for the treatment of diseases of the urinary tract in paediatric populations is ineffective and is not recommended (22, 43).

Warnings

Patients with kidney stones or impaired kidney function should use products containing the fruit only after consulting their health care provider (47).

Precautions

A health care professional should be consulted prior to treatment to rule out serious conditions such as pyelonephritis.

People with diabetes should be aware of the high content of sugar in the juice and use sugar-free preparations.

Drug interactions

One case of a fatal internal haemorrhage was reported in a male patient whose international normalized ratio (INR) increased to > 50 after being treated with cefalexin, digoxin, phenytoin and warfarin, as well as cranberry juice for 2 weeks. The subject was also unable to eat during the 2-week period (48). One case report of a possible interaction with warfa-

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