A-Type PACs: the key to Cranberry’s UTH benefits.

Few botanical products are as widely viewed by consumers as having specific health benefits as cranberries. While cranberries are beneficial for heart and digestive health, and known to be a significant source of antioxidants, most people think first of urinary tract health (UTH). While the link between cranberries and UTH is common knowledge, most consumers don’t know how to evaluate their many product options. The fact is, only an extract high in A-Type proanthocyanidins (PACs), will deliver that much-needed health benefit. Cranberex from Ethical Naturals Inc, is a clinically studied leader in this field.

Demand for natural products that confer real benefits to combat UTIs

Urinary tract infections (UTIs) are the most common outpatient infections in the US, causing an estimated 10.5 million doctor’s office visits each year with a cost estimated at $3.5 billion/yr[1]. Other studies show that this number increases significantly every year.[2] As people age, the severity escalates.

As most UTI cases are caused by bacteria, they are treated with lengthy or repeated antibiotic cycles, contributing to the growing problem of antibiotic resistance and other negative outcomes from long-term antibiotic use. The A-Type PACs however are effective through a different type of action: they prevent bacteria from adhering to the walls of the urinary tract through Anti-Adhesion Activity (AAA). Thus, there is no resistance build-up in the bacteria. This effective, scientifically supported approach to UTH from natural or non-antibiotic sources is consistently growing in demand.

Cranberry for Women’s health

As more focus is brought on women’s health generally and menopause specifically, cranberry plays a major role. Women over 65 experience double the rate of of UTIs than the population as a whole[3]. Because of the growing problem of antibiotic-resistant UTI strains, many women are turning to the use of cranberry extract products as a natural alternative. 

History of Use

The historical use of cranberries, and how medical researchers identified the constituent in cranberry that provides health benefits and its mechanism of action, is an interesting story, that could be a powerful marketing message for brands selling cranberry supplements.

The therapeutic use of cranberries dates back centuries, primarily among Indigenous peoples in North America. Native American tribes, such as the Algonquin and Wampanoag, used cranberries for both food and medicine. After learning of their health benefits, cranberries quickly became popular with settlers from Europe.

Evolution of Cranberry Research

In one of the earliest records of its medicinal use, dating back to 1672, John Josselyn described cranberries as being excellent protection against scurvy on long sea voyages[4] By 1789 the fruit was so in demand that the New Jersey legislature restricted the harvesting of berries to protect future supply.

In the early 1900s research was undertaken to learn more about cranberry support of UTH, with the first papers on this subject published in 1914 noting that cranberry increased the excretion of hippuric acid in urine[5]. It was therefore assumed that the observed benefits of cranberry were due to hippuric acid (a bacteriostatic agent).

It took another 60 years of research to finally establish that the benefits of cranberry weren’t due to high acidity levels after all. The first study establishing that cranberry’s activity in supporting UTH was due its ability to inhibit bacterial adherence to the urinary tract was published in 1984[6]. Instead of killing the bacteria, cranberries were found to interfere with their ability to stick to the urinary tract lining, through their Anti-Adhesion Activity. This reduces the likelihood of infection and made sense to consumers, establishing cranberry as a natural approach to urinary tract health.

While this was useful information, cranberry still was not well understood, so the search for the active constituents in cranberry continued. A research breakthrough was made in 1998 when Amy Howell et al published an article in the NEJM identifying proanthocyanidins (PACs) as being the compounds responsible for the process of bacterial anti-adhesion activity (AAA)[7].

A key question remained however:  PACs are a very large group of compounds that are present in almost all dark colored fruits and berries. Why do the PACs from cranberry result in AAA when those from other berries don’t have this action?

Two other studies, authored by Amy Howell and LY Foo resolved this question. They showed that cranberry is unique in that it contains A-Type PACs not found in other berries or fruits, and that these are responsible for their anti-adhesion activity[8],[9]. This information led to work identifying which cranberries would impart the most health benefits, essential to consistently delivering products that give consumer the results they seek.

DMAC test method and dosage for AAA confirmed using ENI’s Cranberex

In the early 2000’s the DMAC method was developed as a sensitive, specific assay for quantifying A-Type proanthocyanidins (PACs) in high-grade cranberry extracts[10]. DMAC is now the method endorsed by a number of labs and associations including USDA, The Cranberry Institute, American Herbal Pharmacopoeia (AHP), European Food Safety Authority (EFSA), and Rutgers University. Other methods that measure total PACs may give higher potency results, but these don’t identify the percentage of the active, A-Type PACs that are the source of AAA and therefore the desired benefits.

Further progress was made in establishing effective dosage levels for optimal AAA. A key published study confirmed that dosage levels at 72mg A-Type PACs (by DMAC method) provided effective AAA over a 24-hour period[11].

Another multicentric, randomized, double blind clinical trial conducted by Amy Howell at Rutgers University in 2017, using Cranberex brand cranberry extract from Ethical Naturals Inc. (ENI) clearly affirmed a bacterial anti-adhesion effect in urine based upon a 36mg dosage of cranberry A-Type PAC (tested by DMAC method). It also found that effectiveness was dose-dependent, prolonged up to 24 hours with 72 mg of PAC[12].

The power of nature and science behind Cranberex, 15% A-Type PACs

A-Type PACs are found primarily in the skin of cranberry fruit, at very low percentages of total weight. Published data from American Herbal Pharmacopoeia (AHP) showed A-Type PACs from different cranberry growing areas as: Oregon (70mg/100g), Massachusetts (42mg/100g) and Wisconsin (37mg/100g). Content in the juice and pulp of the fruit is even lower[13].

To achieve a therapeutic dosage of up to 15% A-Type PACs requires a high-level of concentration (up to 200X).  These levels of concentration, plus the complex test method required to assure real percentage of A-Type PACs are why so many cranberry products fail to achieve effective levels, and impart the benefits the consumer expects. Many are based upon simple concentrations, powdered juices or other methods. The graphs below show levels of ex vivo testing that compares AAA of Cranberex with five leading brands of cranberry extract:

From Field to Finished Product: The journey of Cranberex begins every fall on the Oregon Coast

The journey for the premium Cranberex extract begins every fall on the Oregon Coast, where family farms produce some of the highest-grade cranberries in the world.

The fruit then goes through a complex extraction process designed to maximize levels of A-Type PACs, verified by DMAC testing.  Cranberex is the culmination of the quest to identify and confirm the material that delivers the health benefits consumers are seeking, and will rely upon. The final extract is supplied to the US, EU and Asia-Pacific markets through ENI’s world-class NSF certified manufacturing and distribution facility in Redwood City, California: Cranberex – The Power of Oregon Cranberry.

[1] Medina M, Castillo-Pino E. An introduction to the epidemiology and burden of urinary tract infections. Ther Adv Urol. 2019 May 2;11:1756287219832172. doi: 10.1177/1756287219832172. PMID: 31105774; PMCID: PMC6502976.

[2] Simmering JE, Tang F, Cavanaugh JE, Polgreen LA, Polgreen PM. The Increase in Hospitalizations for Urinary Tract Infections and the Associated Costs in the United States, 1998-2011. Open Forum Infect Dis. 2017 Feb 24;4(1):ofw281. doi: 10.1093/ofid/ofw281. PMID: 28480273; PMCID: PMC5414046.

[3] An introduction to the epidemiology and burden of urinary tract infections

Martha Medina, Edgardo Castillo-Pinojavascript:popRef(‘corresp1-1756287219832172’)

First Published May 2, 2019, Therapeutic Advances in Urology

An introduction to the epidemiology and burden of urinary tract infections

Martha Medina, Edgardo Castillo-Pinojavascript:popRef(‘corresp1-1756287219832172’)

First Published May 2, 2019, Therapeutic Advances in Urology

[4] American Herbal Pharmacopoeia, Cranberry Fruit, Roy Upton et al, 2016

[5] Blatherwick NR. Arch Intern Med 1914; 14:409–50

[6] Sobota AE. Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infections. J Urol. 1984 May;131(5):1013-6. doi: 10.1016/s0022-5347(17)50751-x. PMID: 6368872.

[7] Howell AB et al Inhibition of the Adherence of P-Fimbriated Escherichia coli to Uroepithelial-Cell Surfaces by Proanthocyanidin Extracts from Cranberries New Engl J Med 1998; 339:1085-1086

[8] Foo LY, Howell AB, Vorsa N, The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli in vitro. Journal of Natural Products 2000, 63, 9, 1185-7

[9] Foo LY, Howell AB, Vorsa N, The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli in vitro. Journal of Natural Products 2000, 63, 9, 1185-7

[10] Prior RL, Fan E, Ji H, Howell A, Nio C, Payne MJ, Reed J. Multi-laboratory validation of a standard method for quantifying proanthocyanidins in cranberry powders. J Sci Food Agric. 2010 Jul;90(9):1473-8. doi: 10.1002/jsfa.3966. PMID: 20549799.

[11] Howell AB, Botto H, Combescure C, Blanc-Potard AB, Gausa L, Matsumoto T, Tenke P, Sotto A, Lavigne JP. Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infect Dis. 2010 Apr 14;10:94. doi: 10.1186/1471-2334-10-94. PMID: 20398248; PMCID: PMC2873556.

[12] Howell AB, Rutgers University, Feb 2017, Bacterial Anti-Adhesion Activity of Human Urine: Cranberex® (Ethical Naturals)

[13] American Herbal Pharmacopoeia and Therapeutic Compendium (2016). Cranberry Fruit, Vaccinium macrocarpon Aiton, Revision. Page 15