Cranberry

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Vaccinium macrocarpon Aiton

[Fam. Ericaceae]

Overview

Cranberry, a fruit native to North America, is used by the Iroquois and the Cherokee Indians as a symbol of peace and friendship (Eck, 1990). Almost 98% of the world’s supply is cultivated in natural and artificial bogs in the northern United States and Canada (Vandenberg and Parent, 1999). Both indigenous Americans and colonists valued cranberry, native to Massachusetts, for its medicinal and nutritional properties. Indigenous Americans used cranberries in poultices for treating wounds and blood poisoning. American sailors and colonists used cranberries to prevent scurvy, similar to the use of citrus by the British. They also used cranberries and their leaves for various conditions including blood disorders, stomach ailments, liver problems, fever, “cancers,” swollen glands, and mumps. Cranberry has also been used traditionally to treat urinary tract infections (UTIs) (Avorn et al., 1994). Cranberries are a high-value crop, ranking 40th in sales of all cash crops monitored by the U.S. Department of Agriculture’s National Agricultural Statistical Service (USDA, 1999). Sales of cranberry dietary supplements ranked 10th in 1999 in total herb sales in food, drug, and mass-market retail outlets in the U.S., but dropped off the list of 20 leading herbs in 2001 (Blumenthal, 1999, 2001). This figure reflects sales in supplement (usually capsule) form only, and does not include supplement sales in other retail channels (natural food, multilevel, mail order, professional). It also does not reflect sales in the mainstream market for cranberry juice, which may be increasing due to consumers’ growing recognition of cranberry’s health benefits for the urinary tract system.

Description

Cranberry preparations consist of the ripe fruit of Vaccinium macrocarpon Aiton [Fam. Ericaceae]. U.S. Pharmacopeial-grade Cranberry Liquid Preparation is a bright red juice derived from the fruits of V. macrocarpon or V. oxycoccos, containing no added substances. Its pH is 2.5 ±0.1, with no more than 0.05% sorbitol, or 0.05% sucrose and, not less than 2.4% dextrose, 0.7% fructose, 0.9% quinic acid, 0.9% citric acid and 0.7% malic acid. The ratio of quinic acid to malic acid is not less than 1 (USP, 2002). The Brix level (measurement of sugar content of a solution) of single strength cranberry juice is a minimum 7.5% (US FDA, 1999).

Primary Uses

Urinary tract infection (UTI)

Reduction in UTI occurrence (Walker et al., 1997; Haverkorn and Mandigers, 1994; Gibson et al., 1991)

Nephrolithiasis

Management of kidney stones (Leaver, 1996; Light et al., 1973; Sternlieb, 1963; Zinsser et al., 1968)

Other Potential Uses

Treatment of UTI (Leaver, 1996; Avorn et al., 1994; Papas et al., 1966; Sternlieb, 1963)

Note: Cranberry juice may reduce the need for repeated antibiotic use in the treatment of recurrent UTIs and, therefore, reduce side effects, such as vulvovaginal candidiasis. However, recurrent UTIs require proper medical diagnosis and cranberry is not a substitute for antibiotics (Brown, 2000).

Combination Preparations

Clinical and research experience has demonstrated positive results with cranberry in combination with herbs that have antibacterial activity (e.g., Chinese goldthread rhizome [Coptis chinensis] or goldenseal root [Hydrastis canadensis]) (Barney, 1996). Cranberry juice with bacteriostatic agents is recommended for long-term suppressive therapy of urinary infections in children suffering from recurrent bacterial infections. Cranberry is combined with buchu leaf (Agathosma betulina), three–leaved caper stem bark (Crateva nurvala), and/or uva ursi leaf (Arctostaphylos uva-ursi) for urinary antiseptic, anti-inflammatory, astringent, antilithic, bladder tonic, and diuretic actions (Bone and Morgan, 1999). There appears to be little need for concern about interactions with uva ursi leaf because therapeutic doses of cranberry are not high enough to acidify the urine (Yarnell, 1997). Taking cranberry juice along with beneficial intestinal bacteria, such as Lactobacillus acidophilus, may alleviate the discomfort caused by uropathogens while restoring normal microbial balance in the gut and in vaginal mucosal surfaces (Anon, 1991).

Dosage

Internal

Crude preparations

Note: The following juice doses are based on sweetened preparations unless otherwise noted. At least 10 clinical studies conducted on sweetened cranberry juice cocktail strongly suggest the safety and efficacy of this type of preparation (Jackson and Hicks, 1997; Foda et al., 1995; Avorn et al., 1994; Haverkorn and Mandigers, 1994; Tsukada et al., 1994; Gibson et al., 1991; Kinney and Blount, 1979; Kahn et al., 1967; Papas et al., 1966; Bodel et al., 1959). Some naturopathic authors suggest that sweeteners in the juice should be avoided or minimized, stating that consumers should not rely on sweetened cranberry juice cocktail, which contains only one-third juice mixed with water and sugar (Brown, 2000; Pizzorno and Murray, 1999; Yarnell, 1997). Capsules offer an alternative to unsweetened juice, which can be unpalatable (Brown, 2000; Yarnell, 1997). Additionally, some authors suggest patients drink plenty of fluids (at least
2 liters daily) throughout the day (Brown, 2000; Pizzorno and Murray, 1999).

Juice

Treatment of UTI: 16–32 fl. oz. daily (Leaver, 1996; Papas et al., 1966; Sternlieb, 1963); at least 0.5 liters (approx 18 fl. oz.) of unsweetened juice daily (Pizzorno and Murray, 1999).

Prevention of UTI: 4–32 fl. oz. daily (Leaver, 1996; Avorn et al., 1994; Gibson et al., 1991; Simons et al., 1992; Sternlieb, 1963).

Renal Stones: 16–32 fl. oz. daily for treatment and prevention of renal stones that are more soluble in an acid environment (Leaver, 1996; Light, 1973; Sternlieb, 1963).

Concentrated Juice Extract

Prevention and treatment of UTI: 300–400+ mg, 2–3 times daily (Brown 2000; Yarnell, 1997).

Duration of Administration

Internal

Crude Preparations

Since cranberry is a common food, there is no known limit on the duration of use. Clinical studies have lasted from 6–12 months, with one retrospective study lasting 28 months (Dignan et al., 1998). The minimum time necessary to produce lowered pH for the treatment of UTI is 2–5 days (Kahn et al., 1967; Fellers et al., 1933), with studies showing optimal effect after 12–15 days (Rogers, 1991; Kinney and Blount, 1979; Nickey, 1975). Cranberry juice did not reduce the occurrence of bacteriuria with pyuria in elderly women until after 4–8 weeks of treatment (Avorn et al., 1994).

Chemistry

Cranberry fruit contains six known anthocyanins: cyanidin-3-galactoside, cyanidin-3-glucoside, cyanidin-3-arabinose, peonidin-3-galactoside, peonidin-3-glucoside, and peonidin-3-arabinose (Hong and Wrolstad, 1986; Sapers and Hargrave, 1987); tannins, catechins, flavonol glycosides, proanthocyanidins, organic acids such as quinic, malic, and citric acids, and sugars such as dextrose and fructose (Bone and Morgan, 1999; Coppola et al., 1995; Leung and Foster, 1996). Cranberries also contain proanthocyanidins with A-type, double linkages (Foo et al., 2000a, 2000b). The principle characteristics of an authentic single-strength cranberry juice are reported to be: total organic acids, 2.2–3.3 g/100 g; relative percentages of organic acids, 39% quinic, 32% citric, and 27% malic; total anthocyanins by pH differential, 19.0–53.3 mg/100 g; relative percentages of
anthocyanidins, 57% cyanidin, 43% peonidin; total sugars, 3.6–5.0 g/100 g; relative percentages of sugars, 79% glucose, 21% fructose (Hong and Wrolstad, 1986).

Pharmacological Actions

Human

At normal consumption levels (10 fluid ounces or 300 ml per day), cranberry inhibits bacterial adherence to the lining of the bladder and urethra (Avorn et al., 1994; Yarnell, 1997). At high levels of consumption (50 to 133 fluid ounces or 1,500 to 4,000 ml per day) cranberry may act as a urinary antiseptic (Blatherwick, 1914; Blatherwick and Long, 1923; Fellers et al., 1933; Nickey, 1975; Kinney and Blount, 1979; Bodel et al., 1959; Bone and Morgan, 1999).

In vitro

Urinary tract effects

Inhibited adherence of Escherichia coli to uroepithelial cells (Sobota, 1984); inhibited adherence for gram-negative rods (Schmidt and Sobota, 1988); inhibited adherence of urinary E. coli isolates expressing type I fimbriae and type P fimbriae (Zafriri et al., 1989); juice fraction selectively inhibited mannose-resistant adhesions produced by urinary isolates of E. coli (Ofek et al., 1996); purified cranberry proanthocyanidins inhibited adherence of uropathogenic strains of P-fimbriated E. coli to isolated uroepithelial cells (Howell et al., 1998); inhibits expression of P-fimbriae of E. coli (Ahuja et al., 1998); inhibited adherence and colonization of some uropathogens including E. coli and Enterococcus faecalis (Habash et al., 1999); oligomeric proanthocyanins and flavone-glycosides inhibited adherence of E. coli to human bladder cells (Walker et al., 1999); cranberry proanthocyanidins with A-type linkages inhibited adhesion of uropathogenic strains of P-fimbriated E. coli to mannose-resistant adhesion (Foo et al., 2000a and 2000b).

Cardiovascular effects

Cranberry inhibits oxidation of human low density lipoproteins (LDL) (Wilson et al., 1999); cranberry juice vasodilates rat aortae in vitro (Maher et al., 2000); consumption of cranberry juice increases ex vivo antioxidant capacity (Pedersen et al., 2000); oligomeric and polymeric proanthocyanidins inhibit copper-induced oxidation of human LDL (Krueger et al., 2000).

Cancer

Proanthocyanidin fractions have potential anticarcinogenic
activity (Bomser et al., 1996); cranberry products inhibited proliferation of MDA-MB-435 estrogen receptor-negative and MCF-7 estrogen receptor-positive human breast cancer cells in a dose-dependent manner (Guthrie, 2000).

Other antiadhesion effects

Anticoaggregates subgingival microbiota (Weiss et al., 1998); inhibited adherence of Helicobacter pylori bacteria to human gastric mucus and underlying epithelial cells (Burger et al., 2000).

Antimicrobial

Antimicrobial against Saccharomyces bayanus and Pseudomonas fluorescens (Marwan and Nagel, 1986); a 5x concentrate of cranberry juice adjusted to pH 7 inhibited growth of certain bacteria (E. coli, Staphylococcus aureus, Pseudomonas aeruginosa) (Lee et al., 2000); inactivated polio virus type 1 (Konowalchuck and Speirs, 1978).

Mechanism of Action

Bacterial adherence to mucosal surfaces is generally considered to be the initial event in the pathogenesis of most infectious diseases due to bacteria in humans (Beachey, 1981; Sobota, 1984). UTIs occur most frequently because of adherence of E. coli via P-fimbriae. The usual initiating mechanism involves bacterial adhesion to specific molecules on cell surfaces, followed by invasive disease. The tip proteins of E. coli lead to the initiation of UTI (Roberts, 1996).

Cranberry’s actions occur through the following mechanisms:

Inhibits adherence of E. coli to the lining of the bladder and urethra (Marwan and Nagel, 1986; Ofek, 1991; Schmidt and Sobota, 1988; Sobota, 1984; Zafriri, 1989) through preventing colonization of these sites (Ofek et al., 1991).

Interrupts the binding of type 1 and P fimbriae in the gut and the bladder (Zafriri, 1989).

A bioassay, based upon inhibition of adherence of E. coli to human bladder cells, human erythrocytes, and guinea pig erythrocytes, determined that the main anti-adherence components in cranberry preparations are the oligomeric proanthocyanins (OPCs) and, to a lesser extent, a secondary group of lower-molecular-weight polyphenolic substances, including flavone-glycosides (Walker et al., 1999; Howell et al., 1998).

Proanthocyanidins may be metabolized before reaching the bladder, suggesting that other constituents could be responsible for reducing the risk of E. coli infection (Reid, 1999). No studies have yet been conducted on the absorption and metabolism of cranberry proanthocyanidins, yet there is evidence of absorption of grape procyanidins (Koga et al., 1999, Harmand and Blanquet, 1978).

Contraindications

Some authors have noted the potential contraindications of cranberry with renal insufficiency and in persons with the potential for developing uric acid or calcium oxalate stones (Rogers, 1991; Bone and Morgan, 1999). However, Brinkley et al. (1981) found that cranberry juice contained very low amounts of oxalate and was safe for individuals with calcium stones. Two small studies found that ingestion of large quantities of cranberry juice reduced incidence in stone formation or reduced urinary ionized calcium associated with calcium-containing renal stones (Zinsser et al., 1968; Light et al., 1973).

Pregnancy and Lactation: No known restrictions during pregnancy or lactation (Brown, 2000; Yarnell, 1997).

Adverse Effects

None known at therapeutic dosage levels. At high dosage (more than 3–4 liters daily), diarrhea or mild gastrointestinal upset (Olin et al., 1994; Yarnell, 1997).

Drug Interactions

No known interactions with antibiotics. Cranberry may enhance vitamin B12 absorption, which is useful for patients taking omeprazole, a drug used to treat ulcers (Brown, 2000).

American Herbal Products Association (AHPA) Safety Rating

Not rated (McGuffin et al., 1997).

Regulatory Status

Canada: Food (CFIA, 2000) or Natural Health Product (NHP) depending on label claim statement. In Canada, NHPs, also referred to as complementary medicines or traditional remedies, are subject to the Food and Drug Act and Regulations (Health Canada, 2000).

France: Food. No monograph in the French Pharmacopoeia.

Germany: Food. No German Commission E monograph (Blumenthal et al., 1998). No monograph in the German Pharmacopoeia (DAB).

Sweden: Food. No products containing cranberry are listed in the Medical Products Agency (MPA) “Authorised Natural Remedies” (MPA, 2001).

Switzerland: Food. No monograph in the Swiss Pharmacopoeia.

U.K.: Food. Not listed in the General Sale List (GSL). No monograph in the British Pharmacopoeia.

U.S.: Food (USDA, 1997) or dietary supplement depending on label claim statement (USC, 1994). Cranberry Liquid Preparation, for manufacturing purposes only, is official in the 20th edition of the National Formulary (NF) (USP, 2002).

Clinical Review

Nineteen studies, mostly uncontrolled, are outlined in the table, “Clinical Studies on Cranberry,” including a total of 1,149 participants. All but two studies (Schlager et al., 1999; Foda et al., 1995), demonstrate some positive effect primarily for urinary tract health. All studies investigated effects on the urinary tract system with the exception of one study on 13 patients with skin damage (Tsukada et al., 1994). Of three double-blind placebo-controlled (DB, PC) studies performed on a total of 178 participants (Schlager et al., 1999; Avorn et al., 1994; Walker et al., 1997), two were conducted with statistically significant positive outcomes in favor of cranberry prophylaxis or treatment. One used a dry cranberry extract for reducing the occurrence of UTIs in women (Walker et al., 1997) while the other addressed treatment of bacteriuria and pyuria in elderly women (Avorn et al., 1994). A subsequent randomized, PC, crossover study on 17 elderly patients, confirmed the findings of Avorn (Haverkorn and Mandigers, 1994). The third DB, PC study did not find cranberry juice concentrate to be effective in preventing UTI in 15 children (ages 2–18) with neurogenic bladder (Schlager et al., 1999), nor did another single-blind, randomized, cross-over study performed on 21 participants, investigating ingestion of cranberry juice cocktail vs. water for antibacterial prophylaxis in pediatric neuropathic bladders (Foda et al., 1995). This study also did not find cranberry juice concentrate to be effective in preventing UTIs. A Cochrane Collaboration review evaluated randomized, controlled trials of cranberry juice in preventing urinary tract infections and found that the trials were generally of poor quality and included a large number of dropouts. The reviewers recommended that other cranberry products, such as capsules, may prevent dropouts and that further well-designed trials are necessary (Jepson et al., 2001).

Branded Products

Azo-Cranberry^® Capsules: PolyMedica Corporation / 11 State Street / Woburn, Massachusetts 01801/ U.S.A. / Tel: 781-933-2021 / www.polymedica.com. Capsules contain 450 mg dried cranberry extracted solids.

Ocean Spray^® Cranberry Juice Cocktail: Ocean Spray Cranberries Inc./ One Ocean Spray Drive / Lakeville-Middleboro, MA 02349 / U.S.A. / Tel: (800) 662-3263 / www.oceanspray.com. Cocktail contains: filtered water, cranberry juice (cranberry juice and cranberry juice from concentrate), high fructose corn syrup, ascorbic acid (vitamin C).

Solaray^®CranActin^®: Nutraceutical Corporation / 1400 Kearns Blvd / Park City, Utah 84060 / U.S. / Tel.: (800) 669-8877 / www.neutraceutical.com. Capsules contain 400 mg dried cranberry extracted solids.

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