Oximacro®, a natural cranberry extract with a very high content of proanthocyanidin A

Oximacro®, a natural cranberry extract with a very high content of proanthocyanidin A

Prevention of urinary tract infections and antiviral activity


Urinary tract infections (UTIs) are widespread and affect a large portion of the human population. About 150 million people worldwide develop UTIs each year, with high societal costs, and an estimated 40% of women develop at least one UTI during their lifetimes. UTIs refer to the presence of a certain threshold number of bacteria in the urine (usually >105/ml) and consist of cystitis (or lower UTIs, with bacteria in the bladder), urethral syndrome and pyelonephritis (or upper UTIs, with infection of the kidneys). Bacterial cystitis (also called acute cystitis) can occur in women and men, and some people also develop recurrent UTIs with an average of two to three episodes per year. Herpes simplex virus (HSV) infection is lifelong and its spectrum of clinical manifestations is wide, ranging from asymptomatic infection or mild mucocutaneous lesions on the lips, cornea, genitals or skin, up to more severe, and even life-threatening, infections, including encephalitis, neonatal infections, and progressive or visceral disease in immunocompromised hosts. Products extracted from the fruit of American cranberry (Vaccinium macrocarpon Ait., Ericaceae), in different formulations, are rich in compounds that are thought to exert numerous health benefits, such as the prevention of microbial infections and beneficial activity against inflammation [1]. Indeed, the berries of cranberry (Vaccinium macrocarpon Aiton) have been used for hundreds of years as a remedy for diseases of the urinary tract and have attracted attention due to their potential health benefits [2, 3]. The beneficial mechanism of cranberry was historically thought to be due to the fruit’s acids causing a bacteriostatic effect in the urine. However, recently, a group of proanthocyanidins (PACs) with A-type linkages (PAC-A) was isolated from cranberries and shown to exhibit bacterial anti-adhesion activity against both antibiotic-susceptible and antibiotic-resistant strains of uropathogenic P-fimbriated Escherichia coli bacteria, including multidrug-resistant E. coli [4–8]. Central to the efficacy of cranberry extract/juice is the determination of the optimum dose of PAC-A, which is an essential requirement in establishing botanical supplements as viable supports to conventional therapies [9]. Oximacro® is a cranberry extract produced by Biosfered (Turin, Italy) that possesses the highest content of PACs and the highest percentages of PAC-A dimers and trimers available on the market. Oximacro® has been shown to exert both antiviral and UTI prevention capability in in vitro and in preclinical studies.

Composition and technical specifications

Schermata 2017-01-13 alle 09.16.08Oximacro® is produced by Biosfered with a proprietary method of extraction. It is characterized by a high content of PACs (>36% according to the BL-DMAC method; >80% according to the Bates-Smith method; >99% according to the European Pharmacopoeia) and the highest percentages of PAC-A dimers and trimers available on the market (>85%, analysed by HPLC coupled to ESI-tandem mass spectrometry). Oximacro® fractionation (Fig. 1) shows that the extract consists of five main fractions: fraction 1 is mainly composed of delphinidin and cyanidin glycosides, and rutin; fraction 2 contains quercetin and isorhamnetin; fractions 3 and 4 are dominated by several isomers of PAC-A dimers and trimers; and fraction 5 shows no detectable compounds (Fig. 1). In vitro tests show that only the fractions containing PACs possess biological activity [10]. Oximacro® is available as both a powder extract and a fluid extract (Oximacro®-FL). The latter is standardized and titrated to provide 36 mg PAC-A per gram of product. Stress tests with increasing temperature from 22°C to 55°C show that Oximacro® is stable and that the content of PACs is not affected by temperature. The technical specifications of Oximacro® and Oximacro®-FL are reported in Table 1.

Schermata 2017-01-13 alle 09.17.20Efficacy In vitro studies and mechanism of action

We recently reported on the ability of Oximacro® to inhibit herpes simplex type 1 (HSV-1) and type 2 (HSV-2) replication in vitro [9]. Analysis of the mode of action revealed that Oximacro® prevents adsorption of HSV-1 and HSV-2 to target cells. Further mechanistic studies confirmed that Oximacro® and its PACs-A target the viral envelope glycoproteins gD and gB (Fig. 2), thus resulting in the loss of infectivity of HSV particles. Moreover, Oximacro® completely retains its anti-HSV activity even at acidic pHs (3.0 and 4.0) and in the presence of 10% human serum proteins, conditions that mimic the physiological properties of the vagina (a potential therapeutic location for Oximacro®). Figure 2 shows the interaction between the A-type PACs present in Oximacro® and HSV envelope glycoproteins.

Clinical studies

Oximacro® was shown to be effective in the prevention of UTIs and support for patients with UTIs. A balanced group of female (ranging from 19 to over 51 years of age) and male volunteers (over 51 years of age) was divided into two groups. The experimental group received one capsule containing Oximacro® (36 mg PACs-A) twice per day (morning and evening) for 7 days, while the placebo group was given the same number of capsules with no PACs. After 7 days of administration, a significant difference was found between the placebo and Oximacro® groups for both females (p<0.001; N=60) and males (p=0.016; N=10) concerning reduction of UTI symptoms (e.g., dysuria, frequency, cloudy urine and occasionally haematuria). Furthermore, CFU/ml counts from the urocultures were almost cleared and showed a highly significant difference between the experimental and the placebo groups (p<0.001) [10].


Oximacro® is produced according to strict procedures and the safety of the product is guaranteed through the use of top technology detection systems (microbiological, chemical and molecular). The product has been recently approved by the US FDA as a New Dietary Ingredient and is Generally Recognized as Safe (GRAS).

Application and use

Careful determination of the total PAC content using the BL-DMAC method and the authentication of PACs-A with mass spectrometry of Oximacro® are necessary to prepare effective doses for antiviral efficacy and UTI prevention. Our published findings indicate Oximacro® is an attractive candidate for the development of novel microbicides of natural origin for the prevention of HSV infections and UTIs and for active support for patients with UTIs. The recommended dosage of Oximacro® is 120 mg/dose, which corresponds to 36 mg PAC-A. This dosage has been demonstrated to be effective when administered twice a day for at least 7 days.


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2. Jass J, Reid G (2009) Effect of cranberry drink on bacterial adhesion in vitro and vaginal microbiota in healthy females. Can J Urol 16:4901–4907

3. Jepson RG, Williams G, Craig JC (2013) Cranberries for preventing urinary tract infections. Sao Paulo Med J 131:363

4. Gupta K, Chou M, Howell A, Wobbe C, Grady R, Stapleton A (2007) Cranberry products inhibit adherence of P-fimbriated Escherichia coli to primary cultured bladder and vaginal epithelial cells. J Urol 177:2357–2360

5. Stapleton AE, Dziura J, Hooton TM, Cox ME, Yarova-Yarovaya Y, Chen S, Gupta K (2012) Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Mayo Clinic Proc 87:143–150

6. Howell AB, Reed JD, Krueger CG, Winterbottom R, Cunningham DG, Leahy M (2005) A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry 66:2281–2291

7. Howell AB, Botto H, Combescure C, Blanc-Potard AB, Gausa L, Matsumoto T, Tenke P, Sotto A, Lavigne JP (2010) 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 10:94

8. Gurley BJ (2011) Cranberries as antibiotics? Arch Int Med 171:1279–1280

9. Terlizzi ME, Occhipinti A, Luganini A, Maffei ME, Gribaudo G (2016) Inhibition of herpes simplex type 1 and type 2 infections by Oximacro®, a cranberry extract with a high content of A-type proanthocyanidins (PACs-A). Antiviral Res 132:154–164

10. Occhipinti A, Germano A, Maffei ME (2016) Prevention of urinary tract infections with Oximacro®, a cranberry extract with a high content of type-A proanthocyanidins (PACs-A): a pre-clinical double-blind controlled study. Urol J 13:2640–2649

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by Cec Editore