Cranberry

Scientific Name(s): Vaccinium macrocarpon Aiton. Family: Ericaceae (heath family)

Common Name(s): Cranberry , American cranberry , arandano Americano , arandano rtepador , grosse moosbeere , kranbeere , tsuru-kokemomo , vaccinium

Uses

Some evidence exists for the use of cranberry in preventing, but not treating, urinary tract infections. Other possible roles for cranberry, with limited evidence include reduction of the risk of cardiovascular disease and cancer treatment.

Dosing

A lack of consistency in clinical trials makes dosage guidance difficult.

Contraindications

Predisposition to nephrolithiasis.

Pregnancy/Lactation

Information is limited; however, at normal consumption dosages as food, cranberry is considered relatively safe in pregnancy. Safety during lactation is unknown.

Interactions

An interaction between cranberry and warfarin has been suggested in case reports; however, evidence of a causal relationship is lacking.

Adverse Reactions

The berries and juice have few adverse reactions associated with their consumption. Large doses (more than 3 to 4 L per day) may produce GI symptoms such as diarrhea. Concentrated cranberry tablets may predispose patients to calcium oxalate stone formation.

Toxicology

Information is lacking.

Botany

The cranberry plant is native to eastern North America. 1 , 2 Some research on the plant can be found under the older name Oxycoccus macrocarpus (Aiton) Pursh. A number of related cranberries are found in areas ranging from damp bogs to mountain forests. These plants grow from Alaska to Tennessee as small, trailing evergreen shrubs. Their flowers vary from pink to purple and bloom from May to August depending on the species. The genus Vaccinium also includes the blueberry ( V. angustifolium Ait.), deerberry ( V. stamineum L.), the bilberry ( V. myrtillus ), and the cowberry ( V. vitis-idaea L.). 1 They should not to be confused with another highbush cranberry, Viburnum opulus L. (family: Caprifoliaceae). 3

History

The cranberry was primarily used as a traditional medicine for the treatment of bladder and kidney ailments among American Indians. 2 The berries were also used as a fabric and food dye, and as a poultice to treat wounds and blood poisoning. 4 Sailors used the berries as a scurvy preventative. Despite a general lack of scientific evidence to indicate that cranberries or their juice are effective urinary acidifiers, interest persists among the public in the medicinal use of cranberries. Cranberries are used in eastern European cultures because of their folkloric role in the treatment of cancers and to reduce fever.

Chemistry

The berries contain about 88% water. 5 Cranberries are a rich source of phenolic phytochemicals including phenolic acids (benzoic, hydroxycinnamic, sinapic, caffeic, and ferulic acids) and flavonoids (quercetin, myericetin, cyanidin, and peonidin). 4 , 6 Cranberries also contain anthocyanins and proanthocyanins, catechin, triterpenoids, lutein and zeaxanthin, and small amounts of protein, fiber, sodium potassium, selenium, and vitamins A, C, and E (2 to 10 mg). 4 , 7 Dried berries contain little sodium or fat. 4 The major organic acids are citric, malic, 8 and quinic acids, with small amounts of oxalate, and benzoic and glucuronic acids. The glycoside leptosine and several related compounds have been isolated, 9 along with small amounts of alkaloids. 10 The peel contains substantial amounts of triterpenoid ursolic acid. 6

Uses and Pharmacology

The widespread consumption of cranberries makes the results of animal trials largely irrelevant.

Urinary tract infections

Two main mechanisms of action have been postulated. A change in the pH of urine by the conversion of benzoic acid to hippuric acid has been suggested. Consequent acidification of the urine was demonstrated in some studies. 11 , 12 Hippuric acid is also considered to be bacteriostatic, but the amount of benzoic acid in the fruit rarely results in the production of sufficient hippuric acid to be effective as a urinary bacteriostatic agent. 12 The other mechanism by which cranberry may act is via properties that inhibit the adhesion of the pathogen ( E. coli ) to urinary epithelial cells. 13 , 14 , 15 Preliminary data suggest that concentrated cranberry juice has some antibacterial activity, but whether sufficient urinary concentrations of the active ingredients can be achieved needs further investigation. 12 , 16

Treatment

A systematic review found no well-designed trials assessing evidence for effect in the treatment of urinary tract infections. Methodological issues include study design, measurement of outcomes and dosage, and duration of treatment. The use of cranberries for the treatment of urinary tract infections remains unsupported. 12 , 17 , 18 , 19

Prevention

A systematic review found a reduction in the incidence of urinary tract infections at 12 months compared with placebo (relative risk [RR] 0.65; 95% confidence interval [CI], 0.46 to 0.90). 20 A greater effect was found for reducing the incidence of recurrent urinary tract infections in women, than among elderly men and women, or people requiring catheterization. 20 , 21 , 22 , 23 A large number among the participants dropped out of the studies, and optimal dosage was unclear.

Among patients with spinal cord injury, no preventative effect was found for cranberry consumption in treating neurogenic bladders in 2 small trials. 24 , 25

Other effects
Cancer

Cranberry phytochemicals, especially proanthocyanidins, quercetin, and ursolic acid, are being investigated for a role in cancer treatment. Induction of apoptosis and inhibition of tumor proliferation have been suggested. Clinical studies are limited. 6 , 26

Cardiovascular

Reviews suggest that the high polyphenolic content of cranberry may contribute to a reduction in the risk of cardiovascular disease. Suggested mechanisms, based mainly on animal studies, include increased resistance of LDL to oxidation, inhibition of platelet aggregation, and reduced blood pressure. 4 , 26 , 27

Diabetes

A small trial investigated the effect of daily cranberry consumption among patients with type 2 diabetes. Lower insulin levels compared with placebo were found in the experiment arm at 12 weeks. 4 , 28

Gastrointestinal/antibacterial

Trials investigating the efficacy of cranberry in H. pylori eradication have been of varying methodological quality. 29 , 30 In vitro studies evaluated the effect of cranberry on GI bacteria, as well as on nasopharyngeal bacteria. 31 , 32

Dosage

A lack of consistency in clinical trials makes dosage guidance difficult.

Cranberry juice, juice concentrate, and dried extract have been extensively studied in urinary tract infections. Doses of juice studied have ranged from 120 to 4,000 mL/day. Concentrated cranberry extract in the form of tablets is available.

A trial in children used 5 mL/kg (up to 300 mL) daily in divided doses. 32

Pregnancy/Lactation

No direct evidence of safety or harm to the mother or fetus has been found. Indirect evidence suggests minimal risk in pregnancy. There were insufficient data to evaluate risk during lactation. Because of its common use, when ingested at normal food consumption amounts, cranberries are considered safe during pregnancy. 2

Interactions

Cranberry is reported to interact with warfarin, based on a number of case reports. The Committee on Safety of Medicines issued a warning in 2004 against the consumption of cranberry products and juice in patients taking warfarin. 33 However, a systematic literature review found no available data to suggest a clinically relevant interaction, also noting that the case reports failed to identify cranberry as the sole cause of international normalized ratio (INR) elevations. 34 A number of trials have been conducted to establish the effect of cranberry on CYP-450 2C9, the enzyme responsible for the metabolism of the active S -enantiomer of warfarin. Among healthy participants, no pharmacokinetic effect on CYP2C9 was established. 35 In patients with atrial fibrillation taking warfarin for 3 months, no difference in INR was found with daily intake of 250 mL cranberry juice. 36 A theoretical antithrombotic effect may be possible because of flavonoid action on platelet function, but this has not been demonstrated. 34

Adverse Reactions

The ingestion of large amounts (more than 3 to 4 L per day) of cranberry juice may result in diarrhea and other GI symptoms; however, trials record few adverse reactions. 17

Controversy exists over cranberry as a risk factor for the formation of calcium oxalate kidney stones. A case report suggested that concentrated cranberry tablets caused urinary tract stones in a man with a history of nephrolithiasis. 37 However, a randomized, crossover trial conducted among healthy adults found reduced oxalate and phosphate excretion, and increased urinary citrate excretion conditions unfavorable for calcium oxalate stone formation. 38 The amount of oxalate ingested daily from cranberry juice was approximately equivalent to 86 mg/L in the crossover trial, compared with delivery of approximately 363 mg from the concentrated cranberry tablet. 38 , 39 Bioavailability of oxalate from the food source may be limited. 38 , 39

Toxicology

Information is lacking.

Bibliography

1. Vaccinium macrocarpon Aiton. USDA, NRCS. 2008. The PLANTS Database ( http://plants.usda.gov , 9 September 2008). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Dugoua JJ, Seely D, Perri D, Millis E, Koren G. Safety and efficacy of cranberry ( vaccinium macrocarpon ) during pregnancy and lactation. Can Clin Pharmacol . 2008;15(1):e80-86.
3. Dobelis I. Magic and Medicine of Plants . Pleasantville, NY: Reader's Digest Association; 1986.
4. McKay DL, Blumberg J.: Cranberries ( vaccinium macrocarpon ) and cardiovascular disease risk factors. Nutr Rev . 2007;65(11):490-502.
5. Lentner C, ed. Geigy Scientific Tables . 8th ed. West Caldwell, NJ: CIBA-Geigy; 1991.
6. Neto CC. Cranberry and its phytochemicals: a review of in vitro anticancer studies. J Nutr . 2007;137(1 Suppl):186S-193S.
7. Melgalve I. Quantity of vitamin C in cranberries. Latv Lauksaimn Akad Raksti . 1976;107:28. Chem Abs . 86:1542:12.
8. Borukh IF, Kirbaba VI, Senchuk GV. Antimicrobial properties of cranberry [in Russian]. Vopr Pitan . 1972;31(5):82.
9. Jankowski K, et al. Trace glycoside from cranberries ( vaccinium oxicoccos ). J Nat Prod . 1983;46:190.
10. Jankowski K. Alkaloids of cranberries V. Experientia . 1973;29(11):1334-1335.
11. Blatherwick N, et al. Studies of urinary acidity II: The increased acidity produced by eating prunes and cranberries. J Biol Chem . 1923;57:815.
12. Raz R, Chazan B, Dan M. Cranberry juice and urinary tract infection. Clin Infect Dis . 2004;38(10):1413-9.
13. Howell AB, Vorsa N, Der Marderosian A, Foo LY. Inhibition of the adherence of p-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries. N Engl J Med . 1998;339(19):1085-1086.
14. Ofek I, Goldhar J, Zafriri D, Lis H, Adar R, Sharon N. Anti-Escherichia coli adhesin activity of cranberry and blueberry juices. N Engl J Med . 1991;324(22):1599.
15. Ahuja S, Kaack B, Roberts J. Loss of fimbrial adhesion with the addition of Vaccinium macrocarpon to the growth medium of P-fimbriated Escherichia coli. J Urol . 1998;159(2):559-662.
16. Lee YL, Owens J, Thrupp L, Cesario TC. Does cranberry juice have antibacterial activity? JAMA . 2000;283(13):1691.
17. Jepson RG, Mihaljevic L, Craig J. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2004;(2): CD001321.
18. Tong H, Heong S, Chang S. Effect of ingesting cranberry juice on bacterial growth in urine. Am J Health Syst Pharm . 2006;63(15):1417-1419.
19. Waites KB, Canupp KC, Armstrong S, DeVivo MJ. Effect of cranberry extract on bacteriuria and pyuria in persons with neurogenic bladder secondary to spinal cord injury. J Spinal Cord Med . 2004;27(1):35-40.
20. Jepson RG, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database of Systematic Reviews 2008, (1): CD001321.
21. Recurrent cystitis in non-pregnant women. Clin Evid . 2003;(9):2152-2160.
22. Franco AV. Recurrent urinary tract infections. Best practice & research. Clinical obstetrics & gynaecology . 2005;19(6):861-873.
23. Donabedian H. Nutritional therapy and infectious diseases: a two-edged sword. Nutr J . 2006;5:21.
24. Lee BB, Haran MJ, Hunt LM, et al. Spinal-injured neuropathic bladder antisepsis (SINBA) trial. Spinal Cord . 2007;45(8):542-550.
25. Linsenmeyer TA, Harrison B, Oakley A, et al. Evaluation of cranberry supplement for reduction of urinary tract infections in individuals with neurogenic bladders secondary to spinal cord injury. A prospective, double-blinded, placebo-controlled, crossover study. J Spinal Cord Med . 2004;27(1):29-34.
26. Duthie SJ, Jenkinson AM, Crozier A, et al. The effects of cranberry juice consumption on antioxidant status and biomarkers relating to heart disease and cancer in healthy human volunteers. Euro J Nutr . 2006;45(2):113-122.
27. Neto CC. Cranberry and blueberry: evidence for protective effects against cancer and vascular diseases. Mol Nutr Food Res . 2007;51(6):652-664.
28. Chambers BK, Camire ME. Can cranberry supplementation benefit adults with type 2 diabetes? Diabetes Care . 2003;26(9):2695-2696.
29. Shmuely H, Yahav J, Samra Z, et al. Effect of cranberry juice on eradication of Helicobacter pylori in patients treated with antibiotics and a proton pump inhibitor. Mol Nutr Food Res . 2007;51(6):746-751.
30. Zhang L, Ma J, Pan K, Go VL, Chen J, You WC. Efficacy of cranberry juice on Helicobacter pylori infection: a double-blind, randomized placebo-controlled trial. Helicobacter . 2005;10(2):139-145.
31. Puupponen-Pimia R, Nohynek L, Alakomi HL, Oksman-Caldentey KM. The action of berry phenolics against human intestinal pathogens. BioFactors . 2005;23(4):243-251.
32. Kontiokari T, Salo J, Eerola E, Uhari M. Cranberry juice and bacterial colonization in children--a placebo-controlled randomized trial. Clin Nutr . 2005;24(6):1065-1072.
33. Committee on Safety of Medicines, Medicines and Healthcare Products Regulatory Agency. Interaction between warfarin and cranberry juice: new advice. Curr Probl Pharmacovigil . 2004;30:10.
34. Pham DQ, Pham AQ. Interaction potential between cranberry juice and warfarin. Am J Health Syst Pharm . 2007;64(5):490-494.
35. Greenblatt DJ, von Moltke LL, Perloff ES, et al. Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies. Clin Pharmacol Ther . 2006;79(1):125-133.
36. Li Z, Seeram NP, Carpenter CL, et al. Cranberry does not affect prothrombin time in male subjects on warfarin. Journal of the American Dietetic Association . 2006;106(12):2057-2061.
37. Terris MK, Issa MM, Tacker JR.. Dietary supplementation with cranberry concentrate tablets may increase the risk of nephrolithiasis. Urology . 2001;57(1):26-29.
38. McHarg T, Rodgers A, Charlton K. Influence of cranberry juice on the urinary risk factors for calcium oxalate kidney stone formation. BJU Int . 2003;92(7):765-768.
39. Brinkley L, McGuire J, Gregory J, Pak CY. Bioavailability of oxalate in foods. Urology . 1981;17(6):534-538.

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