Anti-infective herbs Cranberry

One of the most useful herbs for the prevention and treatment of urinary tract infections (UTIs), cranberry, lacks any antiseptic or antibiotic properties per se. The sweetened, diluted juice of the American cranberry, Vaccinium macrocarpon Ait. (family Ericaceae)—also known as the trail- ing swamp cranberry—is marketed as cranberry juice cocktail. It was reported in 1923 that the urine of test subjects became more acid after eat-

ing large amounts of cranberries. 38 Because an acid medium hinders bacterial development, it was postulated that the berries might be useful in preventing or curing UTI, a condition especially prevalent among women. At the time, conventional medical treatments were largely ineffective.

In consequence, many women suffering from this condition began to consume quantities of the cocktail and reported good results. Such word- of-mouth recommendations were supplemented occasionally by articles in regional medical journals. One of the latter reported symptomatic relief from chronic kidney inflammation in female patients who drank 6 oz of cranberry juice twice daily. Even though a 1967 study showed that consumption of the commercial cranberry juice cocktail did not appreciably

acidify the urine of consumers, 39 UTI sufferers continued to drink it and to report beneficial results. It is now recognized that the effectiveness of cranberry juice in treat- ing UTI results not from its acidifying properties but, rather, from its abil- ity to prevent the microorganisms from adhering to the epithelial cells that line the urinary tract. 40,41 The most common of the UTI-causing bac-

teria is Escherichia coli. Many Gram-negative bacteria, such as E. coli, have thin, hairlike appendages covering their surface that are called fimbriae or pili. These fimbriae enable the bacteria to adhere to various epithelial surfaces for the purpose of colonization and are therefore referred to as adhesins or colonization factors. E. coli can make at least two types of adhesins. Most strains produce type 1 fimbriae, which adhere to epithelial cell receptors containing d-mannose.

Most uropathogenic E. coli strains that cause urinary tract infections commonly do not have d-mannose-mediated adherence but, rather, have P fimbrial adhesions, which attach to a portion of the P blood group anti- gen and recognize the disaccharide α-d-galactopyranoside-(1→4)-β-d- galactopyranoside (GAL–GAL). As illustrated in Figure 4.1 , the P fimbrial adhesin mediates the adherence of the E. coli to uroepithelial cells that contain the GAL–GAL recognition site. Upon adherence, the bacterial cells multiply rapidly, causing infection. 41,42

E. coli adhesin activity is inhibited by two different constituents of cranberry juice. One of these is the nearly ubiquitous fructose, which is found in all fruit juices and has limited significance in the prevention of

66 Tyler's herbs of choice: The therapeutic use of phytomedicinals

Escherichia coli

Type 1 ﬁmbrial adhesin Fructose

P ﬁmbrial adhesin

(all fruit juices)

Cranberry juice

-Mannose recognition (proanthocyanidins?) site on epithelial cells

α--Galactopyranosyl-(1 4)-β-- galactopyranoside recognition site

on uroepithelial cells Adherence

Adherence

Bacterial colonization Urinary tract colonization

Pathogenic signiﬁcance unknown

Urinary tract infection Figure 4.1 The mechanism of action of cranberry juice in preventing Escherichia

coli urinary tract infection. UTI. Fructose inhibits type 1 fimbrial adhesion, which does not have a

role in the establishment of E. coli UTI. The other constituent is a high- molecular-weight compound that is incompletely identified. It is not found in other fruit juices (with the exception of blueberry juice) and acts spe- cifically to inhibit P fimbrial adhesin that is expressed by uropathogenic strains of E. coli by binding to the bacterial surface, possibly to the adhesin itself (see Figure 4.1). Purification of this high-molecular-weight inhibitor from 1.5 L of cranberry juice cocktail using dialysis and fractionation on polyacrylamide resin resulted in 100 mg of an active fraction comprising

mainly condensed tannins (proanthocyanidins). 43 Other constituents in cranberry include various carbohydrates and fiber, as well as a number of plant acids, including benzoic, citric, malic, and quinic. 44

Recent clinical studies that support the efficacy of cranberry juice in the prevention and treatment of UTIs include a randomized, double- blind, placebo-controlled trial to measure the effect of regular ingestion of cranberry juice on the bacterial flora of older women. The study sample consisted of 153 women who were randomly allocated to an experimental group that drank 300 mL per day of a standard commercially available

Chapter four: Kidney, urinary tract, and prostate problems

67 cranberry beverage containing 26 percent juice. The controls were given

a synthetic placebo drink, which had an identical taste and color but con- tained no cranberry product. Urine samples were collected monthly for six months and tested for the presence of bacteria and white blood cells. It was found that women assigned to the cranberry beverage group had significantly less bacteriuria with pyuria than controls. The pH measure- ments of urines in both groups were nearly identical, indicating that urinary acidification did not explain the findings. 45

In the Netherlands, using a randomized controlled crossover design, one group of patients in a nursing department of a general hospital was given 15 mL of cranberry juice mixed with water twice a day, and the control group received the same volume of water each day. After four weeks, the regimens were changed between groups, and a urine culture was taken after each four-week period. It was found that there were fewer cases of bacteriuria in patients during the period when they were admin- istered cranberry juice. 46

Recommended dosage of cranberry juice cocktail as a UTI preventive is 3 fluid oz (about one-third of which is pure juice); as a UTI treatment, consumption should be increased into the range of 12–32 fluid oz daily. An artificially sweetened product is available if sugar intake is to be limited.

Capsules containing dried cranberry powder are also available; six are said to be equivalent to 3 fluid oz of cocktail. Fresh or frozen cranberries may also be consumed; 1.5 oz is equivalent to 3 fluid oz of cocktail. In practice, this is scarcely feasible because of the high acidity and extremely sour taste of the raw berries.

Caution: Cranberry concentrate tablets available at nutrition stores are promoted for urinary tract health and are popular among women for preventing bladder infections. However, due to cranberry’s high concentration of oxalate, which contributes to the development of kidney stones (nephrolithiasis), cranberry concentrates should be

consumed with caution. In response to a case of acute nephrolithiasis, researchers at Stanford University Medical Center subjected five healthy female volunteers to the manufacturer’s recommended dosage of cranberry tablets for seven days. At the onset of treatment and at the end of the seven-day period, twenty-four-hour urine collec- tions were tested for pH, volume creatinine, oxalate, calcium, phosphate, uric acid sodium, citrate, magnesium and potassium, Urinary oxalate levels in the volunteers were significantly increased (p = 0.01)

by an average of 43.4 percent, and excretion of potential lithogenic ions calcium, phosphate, and sodium also increased. The authors of the study advise that “physicians and manufacturers of cranberry products should make an effort to educate patients at risk for nephro-

lithiasis against ingestion of these dietary supplements.” 47

68 Tyler's herbs of choice: The therapeutic use of phytomedicinals Cranberry–warfarin interaction?

In September 2003, the UK Committee on Safety of Medicines (CSM) issued a warning: “Patients taking warfarin should limit or avoid drink-

ing cranberry juice.” 48 No such warning has emerged in the United States. The UK judgment was based on five case study reports (one involving a death 49 ) and speculated that cranberry juice inhibited the primary cyto- chrome P450 isoenzyme that metabolizes warfarin, CYP 2C9. On December 23, 2003, the Cranberry Institute in the United States issued a press release that considered the UK advisory unwarranted, based on the opinion of experts whom they had engaged to review the evidence, which was viewed as inadequate. Nonetheless, the institute encouraged patients to consult with their physicians, promising to monitor emerging

reports and support further research on warfarin interactions. 50 In early 2004, another case report concerned a patient with a heart valve replace- ment who exhibited elevated INR (international normalized ratio) clotting time and bleeding after commencing to drink cranberry juice cocktail on

a regular basis. 51 In addition to the theory of CYP 2C9 inhibition, other theories advanced to explain a potential warfarin interaction have included direct anticoagulant or antiplatelet effects, inhibition of vitamin K absorption, or inhibiting bacterial adhesion effecting changes to the microbial popula- tion of the large intestine and causing a shift away from bacteria that pro-

duce vitamin K. 52 None of these theories has been established thus far.

Anti-infective herbs Cranberry