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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