This manuscript discusses the mechanisms through which D-mannose acts to highlight the regulatory aspects relevant for determining the administrative category of healthcare products placed on the market. The existing literature permits to conclude that the anti-adhesive effect of D-mannose cannot be considered as a pharmacological effect and, therefore, D-mannose-based products should be classified as medical devices composed of substances.
Urinary tract infections UTIs are very common disorders affecting adult women. Their incidence is between and million cases worldwide per year. The majority of UTIs seems to be due to uropathogenic Escherichia coli UPEC , which is able to colonize urothelium, invade epithelial cells and form quiescent biofilms Sarshar et al. This bacterial reservoir may provide a source for bacterial persistence and UTIs recurrence Berry et al.
Besides, recurrent UTIs may be also caused by the periodic translocation of other bacteria which originate from the gastrointestinal tract or reinfections due to external sources e. Recurrences of UTIs are often treated with antibiotics.
Considering the inexorable rise of antimicrobial resistance worldwide, great efforts have been made by the European Commission to reduce the improper and free use of antibiotics by patients European Commission, b. In this context, there is a need for alternative approaches, which can reduce the consumption of antibiotics counteracting the emergence of resistance Loubet et al.
A promising therapeutic approach is the use of anti-adhesive agents, like D-mannose Kyriakides et al. It is an inert monosaccharide that is excreted not metabolized in urine after oral absorption and inhibits the bacterial adhesion to the urothelium Wellens et al.
The purpose of this manuscript is to analyze the mechanisms through which D-mannose acts to prevent UPEC colonization of the urinary tract and highlight the regulatory aspects relevant for determining the administrative category of healthcare products placed on the market. Such aspect is particularly relevant also for the identification of the proper administrative classification of other healthcare products containing therapeutic substances.
Indeed, based on their mechanism of action they must fulfill the regulatory framework on medicinal products or on medical devices containing substances to be placed on the market. D-Mannose is a natural aldohexose sugar differing from glucose by inversion of one of the four chiral centers of the molecule, precisely that on the carbon atom in the second position Figure 1.
This sugar is physiologically present in the human body and it is involved in the immunoregulation Zhang et al. However, the D-mannose used in the N-glycosylation and glycerophospholipid anchor synthesis seems to derive from enzymatic stereospecific interconversion of glucose, not from diet intake.
Indeed, although D-mannose is a simple sugar, it is not metabolized in humans Herman, ; Alton et al. Its plasma half-time ranges from 30 min to some hours. The large amount is excreted unconverted into the urine within 30—60 min; the remainder is excreted within the following 8 h Alton et al. No significant increase in glucose blood levels occurs during this time, and D-mannose is detectable in the tissues only in trace level. The rationale to the use of D-mannose in UTIs prophylaxis is based on its competitive inhibition of bacterial adherence to urothelial cells due to its similar structure to the binding site of type 1 fimbriae expressed on the bacteria Schaeffer et al.
Indeed, UPEC can adhere and, therefore, colonize the urothelium taking advantage from the interaction between type 1 fimbriae and the glycoproteins expressed by epithelial cells Zhou et al. Type 1 fimbriae have a strong affinity for the terminal mannose epitopes of uroplakin Ia UPIa , a highly mannosylated membrane protein that coats superficial epithelial umbrella cells of the urinary tract Sauer et al.
A similar adhesion mechanism has been suggested between other types of microorganisms Pak et al. For example, type 1 fimbriae have been documented on other members of the Enterobacteriaceae family, including Klebsiella pneumoniae , Shigella flexneri , Salmonella typhimurium , Serratia marcescens , and Enterobacter cloacae Jones et al. Many of these are also uropathogens of recurrent UTIs. Moreover, it has been demonstrated that fimbriae play a key role also in extraintestinal pathogenic E.
The anti-adhesive effect of other sugars e. However, the anti-adhesive effect of D-mannose is not a consequence of a pharmacological effect on either the host body or the microorganism. It has been demonstrated that, when D-mannose is pre-incubated with human epithelial cells, it does not significantly affect bacteria adhesive capabilities Schaeffer et al.
Moreover, D-mannose binds the fimbriae, which are not receptors since they are not able to recognize or respond to endogenous chemical signals Madison et al. Although D-mannose shows a concentration-dependent effect, its interaction with the FimH adhesin neither causes nor blocks signal transduction, and a subsequent biochemical reaction Scribano et al.
Indeed, if urine contains sufficiently high levels of free D-mannose to saturate the FimH adhesin of UPEC, bacteria are unable to grapple onto the epithelial cells and are flushed away by shear forces due to the urinary flow Ofek et al.
Starting from such scientific evidence, D-mannose and its derivatives e. Moreover, due to this physical mechanism of action, D-mannose has a negligible risk of developing bacterial resistance, unlike antibiotics Sarshar et al.
D-mannose is contained both in the EU and the United States in different types of healthcare products, such as food supplements Altarac and Papes, , and class IIa medical devices. The rational of such healthcare products has its bases on several clinical studies demonstrating the efficacy of D-mannose for the prophylaxis of UTIs Kranjcec et al.
Therefore, the higher the risks for the consumers, the more restrictive the provisions of the regulatory framework required for placing that product on the market. For example, a product developed for supplementing the normal diet food supplement is considered, from a regulatory point of view, less critical than a product developed for a specific therapeutic indication, such as preventing or treating a bacterial infection i.
EU directives and regulations classify the different types of healthcare products based on their intended use. Consequently, the requirements for medicinal products and medical devices are more stringent than those for food supplements, since they are developed with the aim to diagnose, prevent, or treat human diseases. In this context, D-mannose containing products intended to be used for UTIs prophylaxis cannot be marketed as food supplements due to the claimed therapeutic indication, but they fall in the class of medical devices or in that of medicinal products.
From both definitions, the medical application of medicinal products and medical devices is evident. Moreover, the EU jurisprudence clarified that, for having a therapeutic activity, a healthcare product should act not only on the human body, but also on microorganisms e. As an example, in the judgment on the case of chlorhexidine containing mouthwash, the EU Court states that such a product shall not be considered as a cosmetic one since the mechanism of action of chlorhexidine is pharmacological European Union Court, Indeed, even if such substance has not a direct pharmacological interaction with a human cellular constituent e.
The difference between medicinal products and medical devices resides, therefore, in the mechanism of action. However, in some cases, a clear distinction between the two is difficult e. The contact between the substance and a cellular constituent is expected for both products, and therefore a key point for distinguishing them resides into the nature of such a contact. The mechanism of action is pharmacological if such a contact induces a response in the cellular constituents e.
Indeed, from a scientific point of view, pharmacology can be defined as the study of substances that interact with living systems through chemical processes Katzung, Such concepts have been translated into the current regulatory framework of medical devices. Therefore, from both a scientific and a regulatory point of view, a pharmacological action can be established based on three criteria: 1 the existence of an interaction between the molecule and a cellular constituent of an organism, 2 such interaction induces a direct response, activating or inhibiting normal processes in the organism, and 3 the induced response should restore, correct, or modify the physiological functions in the human beings.
Borderline situations, like D-mannose, are particularly frequent in the case of medical devices in which substances are responsible for the therapeutic action, but for which robust scientific evidence on the exact nature of the mechanism of action is lacking. In this context, manuals and guidelines issued from the EU authorities support manufacturers in the correct classification of the healthcare product European Commission, a ; European Commission, b ; European Commission, The case-studies reported in such regulatory guidelines can be grouped in three classes based on the relevant data to determine the nature of their therapeutic action: 1 scientific evidence demonstrates that the mechanism of action is pharmacological, immunological, or metabolic and, therefore, the product must be classified as medicinal product; 2 scientific evidence suggests that the substance may have more than one mechanism of action.
Most of the borderline products reported in the manual and guidelines fall in the first class since the pharmacological mechanism of action is clearly demonstrated in the literature European Commission, b ; European Commission, For example, mustard packs, which are marketed to alleviate the symptoms of common colds and other respiratory diseases, act pharmacologically since their heating and analgesic effect is due to a direct cellular and tissue response e.
A classic example of the second scenario is provided by healthcare products containing derivatives of hyaluronic acid. Since , they have been marketed as synovial fluid replacements for viscosupplementation and to restore the physiological and rheological states of the arthritic joint tissue Richards et al. However, hyaluronic acid can suppress the production of pro-inflammatory mediators and proteases, the function of immune cells involved in the arthritic process Carrington Reid, For low-molecular-weight hylans, this pharmacological action cannot be considered ancillary to the rheological effects on synovial fluids and, therefore, the products should be classified as medicinal products European Parliament and Council, As an example, the polysaccharide-resin-honey complex has been marketed as a medical device to treat acute cough because it forms a physical and protective coating on the oral and pharyngeal mucosa Cohen et al.
The case of D-mannose is particularly debated in the scientific community, especially since it was included in the version 1. It classifies the D-mannose mechanism of action as pharmacological, observing that interactions between such sugar and FimH adhesin can inhibit the adhesion and colonization of UPEC on the urothelium.
On the contrary, literature data suggests that the interaction between D-mannose and FimH adhesin does not produce any activation or inhibition response either to the bacteria or to the epithelial cells of urothelium Schaeffer et al. The D-mannose inhibition of bacteria adhesion seems, therefore, based on inert physical interactions, which are comparable to those between the platelets and calcium alginate or oxidized cellulose.
D-mannose is absorbed, but not metabolized by the human body and it is excreted intact in urine. With growing awareness of antibiotic-resistant bacteria, you…. Does drinking cranberry juice actually help treat UTIs or reduce your risk of getting one? This article separates the myths from the science. Apple cider vinegar is a popular home remedy for poison ivy rash. But does it actually help and is it safe?
We review pros and cons, materials, and what customers have to say about the two Molecule mattress options. Health Conditions Discover Plan Connect. Medically reviewed by Alan Carter, Pharm. Several fruits and vegetables contain D-mannose, including: cranberries and cranberry juice apples oranges peaches broccoli green beans This sugar is also found in certain nutritional supplements, available as capsules or powders.
Some contain D-mannose by itself, while others include additional ingredients, such as: cranberry dandelion extract hibiscus rose hips probiotics Many people take D-mannose for treating and preventing urinary tract infections UTIs.
What the science says. How to use D-mannose. Side effects of taking D-mannose. Stick with the proven methods. Read this next. Medically reviewed by Debra Rose Wilson, Ph. Medically reviewed by Judith Marcin, M. Urine Culture. During the six-month period, the rate of recurrent UTIs was significantly higher in women who took nothing compared to those who took D-mannose or nitrofurantoin. Fewer side effects were reported with D-mannose compared to the antibiotic.
A small pilot study of 43 women published in found that D-mannose administered twice daily for three days followed by once a day for 10 days resulted in a significant improvement in symptoms, UTI resolution, and quality of life. Those who received D-mannose for six months following treatment had a lower rate of recurrence than those who took nothing.
Although D-mannose shows promise, a review of studies published in concluded that D-mannose and other non-pharmaceutical remedies like cranberry juice and vitamin C are ill-suited to replace antibiotics in treating UTIs. Common side effects of D-mannose include bloating, loose stools, and diarrhea. As D-mannose is excreted from the body in urine, there is also some concern that high doses may injure or impair the kidneys.
Since D-mannose can alter your blood sugar levels, it's crucial for people with diabetes to take caution when using D-mannose supplements. Not enough is known about the safety of the supplement during pregnancy or breastfeeding, so it should be avoided.
Children shouldn't take D-mannose as well. As a rule, self-treating a UTI with D-mannose, or avoiding or delaying standard care, is unadvised as it can lead to serious complications, including a kidney infection pyelonephritis and even permanent kidney damage. Little is known about the long-term safety of D-mannose or at what dose the supplement may be considered harmful or toxic. While D-mannose is typically considered safe because it occurs naturally in many foods, doses higher than what is consumed through normal diets may pose unknown health problems; it's simply not known at this stage.
It's important to keep in mind that dietary supplements haven't been tested for safety and are largely unregulated. When shopping for supplements, look for products that have been certified by ConsumerLabs, The U. These organizations don't guarantee a product is safe or effective, but they indicate that it's undergone testing for quality. If you're still thinking of trying D-mannose to treat a UTI or are considering it for preventative purposes , talk with your healthcare provider first to weigh the pros and cons and decide whether it's the best option for you.
Sign up for our Health Tip of the Day newsletter, and receive daily tips that will help you live your healthiest life. Long-term antibiotics for prevention of recurrent urinary tract infection in older adults: systematic review and meta-analysis of randomised trials.
BMJ Open. Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH-oligomannose-3 complex. PLoS One. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. D-mannose: a promising support for acute urinary tract infections in women.
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