SUPPLEMENT MONOGRAPHS XYLITOL / 721

with activities of other hop constituents and xanthohumolmetabolites.Mol Nutr Food Res. 2005;49(9):827-831.

Goto K, Asai T, Hara S, et al. Enhanced antitumor activity ofxanthohumol, a diacylglycerol acyltransferase inhibitor, underhypoxia. Cancer Leu. 2005;219(2):215-222.

Herath W, Ferreira 0, Khan SI, et al. Identification andbiological activity of microbial metabolites of xanthohumol.Chem Pharm Bull (Tokyo). 2003;51(11):1237-1240.

Herath WH, Ferreira 0, Khan IA. Microbial transformation ofxanthohumol. Phytochemistry. 2003;62(5):673-677.

Kac J, Plazar J, Mlinaric A, et al. Antimutagenicity of hops(Humulus lupulus L.): bioassay-directed fractionation andisolation of xanthohumol. Phytomedicine. 2008;15(3):216-220.

Kim HJ, Lee IS. Microbial metabolism of the prenylatedchalcone xanthohumol. J Nat Prod. 2006;69(10):1522-1524.

Koo JH, Kim HT, Yoon HY, et al. Effect of xanthohumol onmelanogenesis in B16 melanoma cells. Exp Mol Med.2008;40(3):313-319.

Lee SH, Kim HJ, Lee JS, et al. Inhibition of topoisomerase Iactivity and efflux drug transporters' expression byxanthohumol. from hops. Arch Pharm Res. 2007;30( I I): 1435-1439.

Meissner 0, Haberlein H. Influence of xanthohumol on thebinding behavior of GABAA receptors and their lateral mobilityat hippocampal neurons. Planta Med. 2006;72(7):656-658.

Monteiro R, Calhau C, Silva AO, et al. Xanthohumol inhibitsinflammatory factor production and angiogenesis in breastcancer xenografts. J Cell Biochem. 2008;104(5):1699-1707.

Nikolic 0, Li Y, Chadwick LR, et al. Metabolism ofxanthohumol and isoxanthohumol; prenylated flavonoids fromhops (Humulus lupulus L.), by human liver microsomes. JMass Spectrom. 2005;40(3):289-299.

Nozawa H. Xanthohumol, the chalcone from beer hops(Humulus lupulus L.), is the ligand for famesoid X receptorand ameliorates lipid and glucose metabolism in KK-A(y) mice.Biochem Biophys Res Commul1. 2005;336(3):754-761.

Pan L, Becker H, Gerhauser C. Xanthohumol induces apoptosisin cultured 40-16 human colon cancer cells by activation of thedeath receptor- and mitochondrialpathway. Mol Nutr Food Res.2005;49(9):837-843.

Plazar J, Filipic M, Groothuis GM. Antigenotoxic effect ofXanthohumol in rat liver slices. Toxicol In Vitro.2008;22(2):318-327.

Plazar J, Zegura B, Lah IT, et al. Protective effects ofxanthohumol against the genotoxicity of benzo(a)pyrene (BaP),2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and tert-butylhydroperoxide (t-BOOH) in HepG2 human hepatoma cells.Mutat Res. 2007;632(1-2): 1-8.

Possemiers S, Bolca S, Grootaert C, et al. The prenylflavonoidisoxanthohumol from hops (Humulus lupulus L.) is activatedinto the potent phytoestrogen 8-prenylnaringenin in vitro and inthe human intestine. J NWr. 2006;136(7):1862-1867.

Radovi B, Schmutzler C, Kohrle 1. Xanthohumol stimulatesiodide uptake in rat thyroid-derived FRTL-5 cells. Mol NutrFood Res. 2005;49(9):832-836.

Ruefer CE, Gerhauser C, Frank N, et al. In vitro phase IImetabolism of xanthohumol by human UDP-glucuronosyltransferasesand sulfotransferases.Mol Nutr FoodRes. 2005;49(9):851-856.

Vogel S, Ohmayer S, Brunner G, et al. Natural and non-naturalprenylated chalcones: synthesis, cytotoxicity and anti-oxidativeactivity. Bioorg Med Chem. 2008;16(8):4286-4293.

Wang Q, Ding ZH, ~iu JK, et al. Xanthohumol, a novel anti-HIV-I agent purified}rom Hops Humulus lupulus. AntiviralRes. 2004;64(3):189-194.

Yang JY, Della-Fera MA, Rayalam S, et al. Enhanced effectsof xanthohumol plus honokiol on apoptosis in 3T3-Lladipocytes. Ohesity (Silver Spring). 2008; 16(6): 1232-1238.

Yang JY, Della-Fera MA, Rayalam S, et al. Effect ofxanthohumol and isoxanthohumol on 3T3-Ll cell apoptosis andadipogenesis. Apoptosis. 2007; 12(11): 1953-1963.

Yilmazer M, Stevens JF, Buhler DR. In vitro glucuronidation ofxanthohumol, a flavonoid in hop and beer, by rat and humanliver microsomes. FEBS Leu. 200 1;491(3):252-256.

Yilmazer M, Stevens JF, Deinzer ML, et al. In vitrobiotransformation of xanthohumol, a flavonoid from hops(Humulus lupulus), by rat liver microsomes. Drug MetabDispos. 200 1;29(3):223-231.

Zanoli P, Zavatti M. Pharmacognostic and pharmacologicalprofile of Humulus lupulus L. J Ethnopharmacol.2008; 116(3):383-396.

XylitolDESCRIPTION

Xylitol is classified as a "sugar alcohol." It has similarsweetness to sucrose, but in a strict chemical sense it is notreally a sugar; it is a polyhydroxy alcohol. A sugar is definedchemically as a polyhydroxy aldehyde (eg, glucose) or apolyhydroxy ket~ne (eg, fructose). However, since "sugaralcohol" is the term commonly used, including by the FDA,for xylitol and other polyhydroxy alcohols, that is the termthat will be used in this monograph. Xylitol is a five-carbonacyclic polyhydroxy alcohol, or polyol (pentilol), named forits corresponding aldose, the sugar xylose. Xylitol is foundnaturally in small quantities in fruits and vegetables,including plums, strawberries, raspberries and rowan berries.It is also found in com husks, mushrooms and oats. Xylitolwas first derived from the complex carbohydrate xylan frombirch trees in Finland, where it was called birch sugar, orkoivusokeri. About 5 to 10 grams of xylitol are made daily inthe human body, from its corresponding aldose xylose andfrom its corresponding ketose xylulose.

722/ XYLITOL PDR FOR NUTRITIONAL SUPPLEMENTS

Xylitol was first popularized in Europe as a safe sweetenerfor diabetics. It is now widely used as a low-caloriesweetener and for several health conditions. These includecaries, middle ear infections (otitis media), and sinusinfections, among other health concerns. Currently, most ofthe world supply of xylitol is derived from com sources andreportedly comes mainly from China.

Xylitol is also known as xylo-pentane-I,2,3,4,5-pentol,(2R,3R,4S)-pentane-I,2,3,4,5-pentanol, 1,2,3,4,5-pentahy-droxypentane, xylite, and birch sugar (see above). Itsmolecular formula is CsH 120S' its molecular weight is152.15, and its CAS registration number is 87-99-0. Xylitolis written without an L or a D prefix owing to the symmetryof the molecule. Xylitol is represented by the followingchemical structure.

H!CH~~H

HO H

H OH

CH20H

Xylitol

When chewed in the form of gum, xylitol has a coolingeffect in the mouth, which is accounted for by theendothermic reaction that occurs when xylitol is dissolved.Sportswear is available that uses xylitol infused into thefabric in order to absorb the heat coming from perspiration.The energy content of xylitol is 2.4 kcal per gram. Incomparison, the energy content of sucrose is 4 kcal per gram.

The FDA allows the claim to be made that the noncariogeniccarbohydrate sweetener xylitol present in the food does notpromote tooth decay, and may reduce the risk of tooth decay.Other "sugar alcohols" considered noncariogenic includesorbitol, mannitol, lactilol, isomalt (a disaccharide composedof the sugar glucose and the sugar alcohol mannitol),erythritol, and hydrogenated starch hydrolysates (a mixtureof several sugar alcohols). Also, the claim is allowed for thesugars tagatose (a monosaccharide) and isomaltulose (adisaccharide that is a natural constituent of honey). This isbecause the FDA was convinced that isoma!tulose andtagatose were ~ot fermented by oral bacteria to an extentsufficient to lower dental plaque pH to levels that wouldcontribute to the erosion of dental enamel.

ACTIONS AND PHARMACOLOGY

ACTIONS

Xylitol is a low-calorie sweetener, suitable for use bydiabetics. Xylitol has anticariogenic activity and may haveantimicrobial activity against middle ear infections (otitismedia), nasal and sinus infections, and pulmonary infections.It also may have antiosteoporotic activity. Xylitol may have

some benefits for the treatment of the inborn errors ofmetabolism, such as myoadenylate deaminase deficiency andglucose-6-phosphate dehydrogenase deficiency.

MECHANISM OF ACTION

Anticariogenic activity: Dental caries are the localizeddestruction of susceptible dental hard tissues by acidic by-products from bacterial fermentation of dietary carbohy-drates. The disease process starts within the bacterial biofilmalso known as dental plaque. The bacteria that comprise thebiofilm are mainly Streptococcus mutans, Streptococcussobrinus and Lactobacillus spp.

These bacteria ferment sugars such as sucrose, producinglactic acid. Lactic acid causes local pH to fall, resulting inthe demineralization of tooth tissues. If the diffusion ofcalcium, carbonate and phosphate out of the tooth is allowedto continue, caries will eventually form. This process can bereversed in its early stages through uptake of calcium,phosphate and fluoride. Fluoride works by causing diffusionof calcium and phosphate into the tooth, which remineralizesthe crystalline structure of the lesion. The rebuilt crystallinesurfaces are composed of fluoridated hydroxyapatite andfluorapatite, which is much more resistant to acid attack thanis the original structure.

Administration of xylitol is another way of preventing dentaldecay. There are now many human studies, beginning in1970 in Finland, testing the effect of xylitol on the growth ofdental plaque and the formation of dental caries. In the earlystudies, diets containing xylitol were compared with dietscontaining sucrose or fructose. In later studies, xylitol waspresented to the subjects in the form of chewing gum. Inmost cases, xylitol was demonstrated to decrease theformation of dental caries. Streptococcus mutans, the majorcariogenic bacterium in the mouth, is able to transport xylitolinto the cell. It does this via the fructose phosphotransferasesystem. Once inside, xylitol is phosphorylated to xylitol-5-phosphate. S. mutans cannot ferment the five carbonstructure of xylitol to form lactic acid as it can six- and 12carbon sugars. S. mutans has to expel xylitol-5-phosphate inorder to survive. This futile energy-consuming xylitol cycleis thought to be responsible for the inhibition of the growthof the cariogenic bacteria, both in vitro and in vivo. Xylitolwas also thought to prevent the adhesion of the biofilm to theteeth.

Antiosteoporotic: Animal studies found that xylitol preventsexperimental osteoporosis and improves the properties ofbones and collagen. The mechanism of these effects isunclear, and more research is warranted. There is someevidence that xylitol increases calcium absorption indepen-dent of the effect of vitamin D.

SUPPLEMENT MONOGRAPHS XYLITOL 1723

Low-calorie sweetener: The energy content of xylitol is 2.4kcal per gram. In comparison, the energy content of sucroseis 4 kcal per gram. Xylitol and sucrose have equal levels ofsweetness and there is no after taste with xylitol, which is tosay that, in addition to its reduced calories, xylitol hasexcellent organoleptic ("mouth fee!':) qualities for a sugarsubstitute. Xylitol has been an excellent sugar substitute fordiabetics. Following its ingestion, there is little change inplasma glucose and insulin levels.

Nasal and sinus infections: Preliminary studies with xylitolsuggest that it also may have some utility against nasal andsinus infections. More research is required to establish thiseffect. The mechanism of action of such an effect should besimilar to that described for xylitol and otitis media (seebelow).

Otitis media: Xylitol has been found to be effective inpreventing acute otitis media (middle ear infection) by up to42% when administered either in the form of chewing gumor as a syrup. Otitis media develops when bacteria from thenasopharynx-usually Streptococcus pneumoniae, whosegrowth is known to be inhibited by xylitol-enter the middleear through the Eustachian tube. The mechanism of theinhibitory effect is not completely known.' Possibilitiesinclude: Xylitol is known to have anti-adhesive effects onboth S. pneumoniae and Haemophilus influenzae, which aremediated by its effect on the cell wall of the bacteria; xylitolis an unsuitable source of energy for these bacteria (see:Anticariogenic activity, above); xylitol causes a markedreduction in the intracellular redox state due to the rapidproduction of NADH and NADPH in the polyoI dehydroge-nase reaction. This could improve the oxidative burst inpolymorphonuclear leukocytes with consequent bacterialkilling via reactive oxygen species.

Pulmonary infections: A study reported in the Proceedingsof the National Academy of Sciences (PNAS) has introducedstill another way of accounting for the antimicrobial effect ofxylitol. It appears that the surface of the airways is coveredby a thin layer of liquid. This liquid contains a number ofantimicrobial substances, including lysozyme, lactoferrin,secretory leukoproteinase inhibitor, human beta defensins Iand 2, secretory phospholipase A2 and cathelicidin LL-37.These substances form part of the pulmonary defensesystem, killing the small numbers of bacteria that areconstantly being deposited on the pulmonary airway surface.Importantly, the antibacterial activity of most of thesesubstances is salt sensitive. An increase of the salt concentra-tion in the liquid layer inhibits the antibacterial activity ofmost of the above agents. The study suggested that xylitoldelivered to the airway surface appears to lower the saltconcentration, thus enhancing the innate antibacterial de-

fense system. Further study is needed to test this interestinghypothesis.

Xylitol and myoadenylate deaminase deficiency: Myoadeny-late deaminase (muscle AMP deaminase) deficiency is aninborn error of metabolism disorder that is manifested bymuscle weakness and cramping after exercise, decreasedmuscle mass, hypotonia and generalized weakness in somecases. The diagnostic test is based on the lack of anexertional increase in plasma ammonia in patients and wasbased on the fact that AMP (adenosine phosphate) deami-nase is the major ammonia-producing enzyme in skeletalmuscles. AMP is comprised of adenine, ribose and phos-phate. Ribose is essential in the synthesis of DNA, RNA andATP, among many other important biological molecules. Inmyoadenylate deaminase deficiency, some ribose is effec-tively lost from the metabolic pool and may create a storagedeficiency of this crucial metabolite. It was reported thatwhen oral ribose was administered before and after exerciseto a patient with this disorder, exercise-related symptomsdiminished.

Xylitol can be converted metabolically to ribose, and there isa report that xylitol was beneficial to one patient whenadministered orally at 15 grams to 20 grams daily.

Xylitol and glucose-6-phosphate dehydrogenase deficiency:Red blood cell glucose-6-phosphate dehydrogenase deficien-cy (G6PD) is a widespread genetic disorder. Hemolyticanemia is the most serious feature of this disease. Thedisease is characterized biochemically by a low or almostabsent G6PD and an abnormally low red blood cell reducedglutathione (GSH) level. This is because a normal glucose-6-phosphate dehydrogenase is necessary for the production ofNADPH, which in turn maintains glutathione in its reducedstate. GSH is the major intracellular buffer against oxidativestress, and a d~ficiency of red blood cell GSH makes the cellvery vulnerable to any oxidative threat. In G6PD, theproduction of NADPH is impaired.

It turns out that the NADP-linked xylitol dehydrogenase isfound in red blood cells and that its enzyme activity isnormal in most G6PD-deficient red blood cells. Xylitol wasdemonstrated to preserve GSH levels in vitro (rabbit redblood cells) and in vivo (rabbits with deficient GSH) and toprevent hemolysis of the red blood cells. Further research inthis promising area is certainly warranted.

PHARMACOKINETICS

Many details of the pharmacokinetics of xylitol are stillmissing. After ingestion, xylitol is absorbed slowly from thesmall intestine and a portion passes into the large intestinewhere it is fermented by the microfIora of the gut to theshort-chain fatty acids, acetate, propionate and butyrate, andthe gases hydrogen, hydrogen sulfide, carbon dioxide and

724 I XYLITOL PDR FOR NUTRITIONAL SUPPLEMENTS

methane. The portion that is absorbed from the smallintestine is distributed to several tissues in the body, butmainly to the liver. In the liver, xylitol is converted toxylitol-5-phospate. Xylitol-5-phosphate is converted to xylu-lose-5-phosphate via a polyol dehydrogenase reaction; thismetabolite enters the pentose phosphate cycle to be furthermetabolized.

INDICATIONS AND USAGE

Some, though not all, studies indicate that xylitol, a sugaralcohol found in a number of fruits and vegetables, is aneffective anticaries agent. There is some support for claimsthat xylitol has significant antimicrobial effects and may beuseful in treating and preventing otitis media and some lungand nasopharyngeal infections. Scant preliminary in vitroand animal data suggest possible contributions to bone, skinand colon health.

RESEARCH SUMMARY

Xylitol has been promoted for some time as an effectiveanticaries agent and is sold in the form of gum and otherproducts advertised to protect dental health. Evidence thatxylitol gums are any better than gums sweetened withsorbitol or other sugar alcohol is inconsistently demonstratedin clinical trials that have sought to assess the effects of thesegums on tooth decay. One review of the literature found thatthe claimed superiority of xylitol was not demonstrated intwo out of four clinical trials comparing the anticariespotential of xylitol with that of sorbitol-sweetened gums.These reviewers, in fa~t, concluded that, to the extent anypositive effect was observed, it was more likely due to thestimulation of salivary flow, which was roughly equalirrespective of the type of gum chewed. They did not,

. however, entirely rule out the possibility of a relevantxylitol-related antimicrobial effect. So,?e studies have foundthat xylitol does, indeed, significantly suppress some oralbacteria, specifically Streptococcus mutans, but it has notbeen conclusively demonstrated that this effect significantlyimpedes the formation of dental caries. One can say,however, that xylitol is highly unlikely to promote caries, ascertain sugars are known to do. More research will berequired to definitively determine whether xylitol is superiorto sorbitol as an anticaries agent.

A number of recent studies suggest that xylitol may havesignificant antimicrobial effects that could be' clinicallybeneficial in a number of circumstances. One of thesestudies, performed double-blind and placebo-controlled,demonstrated that xylitol, whether administered in a gum orin a syrup, was significantly superior to xylitol-devoidchewing gum and xylitol-devoid syrup in preventing acuteotitis media (AOM) in healthy children. The study continuedfor three months, during which time the experimentalsubjects received 8.4 to 10 grams of xylitol daily. Whereas

41% of the children who received control syrup experiencedat least one incident of AOM, only 29% of those receivingxylitol syrup were similarly affected. Occurrence of AOMdecreased by even more among those taking the xylitol gumversus those using the non-xylitol gum. Given the apparentefficacy of xylitol in this study and the high economic costsof AOM, further research is needed and warranted.

Numerous animal studies have demonstrated additionalantimicrobial effects. In a recent trial, xylitol-supplementednutrition was found to enhance bacterial killing and prolongsurvival of rats in experimental pneumococcal sepsis. Afinding of the study was enhanced neutrophilic leukocytefunction. A previous report had demonstrated that parenteraladministration of xylitol could significantly improve survivalof rats suffering intestinal sepsis. A study in which xylitolwas shown to enhance bacterial killing in the rabbitmaxillary sinus led the researchers to conclude that xylitoImight be useful in some cases of human sinusitis. Far morestudy will be required to establish this.

In one double-blind, placebo-controlled clinical trial, xylitolwas sprayed for four days into each nostril of volunteers.Compared with saline-administered controls, the experimen-tal subjects receiving the xylitol spray exhibited significantlydecreased numbers of nasal coagulase-negative Staphylococ-cus. This research further revealed some evidence suggestingthat xylitol might be of benefit in cystic fibrosis throughpositive effects in the human airway. Again, more research isneeded and warranted.

In a study utilizing an in vitro colon simulator, another groupof researchers reported positive effects of xylitol on themetabolic activity and patterns of colon microbes, suggestingthat the sugar alcohol might have some benefit on colonichealth. Other, similarly very preliminary in vitro and animalresearch has pointed toward possible positive effects ofxylitol on bone and skin. One study showed that dietaryxylitol helped protect against weakening of bone biomechan-ical properties in an experimental model of postmenopausalosteoporosis. The same group subsequently demonstratedimproved bone biomechanical properties in xylitol-fed, agedmale rats. Clinical trials are needed to see whether xylitolcan have any bone-strengthening effects in humans. Similar-ly, a finding that long-term dietary xylitol supplementationincreases the synthesis of collagen in the skin of aging ratsneeds further exploration and extension into clinical inquiry.

CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS

CONTRAINDICA TIONS

Xylitol is contraindicated in those who are hypersensitive toany component ofaxylitol-containing product.

SUPPLEMENT MONOGRAPHS XYLITOL /725

PRECAUTIONS

Those who develop gastrointestinal symptoms (flatus, bloat-ing, diarrhea) with the use of xylitol should start with lowerdoses and slowly go up in dose. Those receiving whole bodyradiation or radiation to the gastrointestinal tract shouldavoid xylitol until they have completed their course ofradiation. Those with diarrhea-prominent irritable bowelsyndrome should begin the use of xylitol at low doses andincrease the dose as tolerated.

ADVERSE REACTIONS

Doses of xylitol up to 30 to 60 grams daily are usually welltolerated. Higher doses may cause gastrointestinal symp-toms, such as flatulence, bloating and diarrhea, in anunadapted user. Adapted users have gone up to 400 gramsdaily without any side effects. The most common side effectis flatulence. Some may have side effects at lower doses, eg,a person with diarrhea-prominent irritable bowel syndrome.

There are a couple of reports of dogs having serious adverseevents after ingesting xylitol. In one report, eight adult dogswere evaluated for treatment of lethargy, vomiting, wide-spread petechial, ecchymotic, or gastrointestinal hemor-rhages, hyperglycemia, hyperbirubinemia and thrombo-cytopenia. Three dogs were euthanized, two dogs died, twodogs made a complete recovery, and one dog was recover-ing, but was lost to follow-up. In another report, a 9-monthold Labrador retriever developed hypoglycemia nad seizuresafter ingesting a large quantity of gum swetened with xylitol.There have been other reports of dogs becoming hypoglyce-mic after consuming xylitol. There are no such reports forhumans.

INTERACTIONS

DRUGSNo known interactions.

FOODS

No known interactions.

NUTRITIONAL SUPPLEMENTS

Arginine-containing mints have been found to have anticar-iogenic activity secondary to their ability to buffer the acidproduced by cariogenic bacteria. Mints containing a combi-nation of xylitol and arginine may give better anticariogeniceffects that the use of either alone.

OTHER

The combination of xylitol and the use of fluoride tooth-pastes may give better anticariogenic effects than the use ofeither alone.

OVERDOSAGE

No reports.

DOSAGE AND ADMINISTRATION

Xylitol is available as chewing gum, as a nasal wash, in bulkas a sugar substitute and as mints. For dental benefits, 4 to 12grams of xylitol daily are used. The chewing gum and mintstypically contain about 1 gram of xylitol in each piece. Onecan start by chewing one piece four times a day for a total of4 grams and work up from there to a total of 12 to 15 gramsdaily. For prevention of otitis media, 8.5 to 10 grams ofchewing gum or syrup was used taken in five divided dosesover a course of two months a study.

LITERATURE

Alanen P. Does chewing explain- the caries-preventive results

with xylitol? J Dent Res. 2001;80(7):1600-1601.

Amaechi BT, Higham SM, Edgar WM. Caries inhibiting and

remineralizing effect of xylitol in vitro. J Oral Sci.1999;41 (2):71-76.

Brown CL, Graham SM, Cable BB, et al. Xylitol enhancesbacterial killing in the rabbit maxillary sinus. Laryngoscope.2004; 114(11):2021-2024.

Caglar E, Kavaloglu SC, Kuscu 00, et al. Effect of chewinggums containing xylitol or probiotic bacteria on salivary mutansstreptococciand lactobacilli. Clin Oral Investig. 2007;II (4):425-429.

Chunmuang S, Jitpukdeebodintra S, Chuenarrom C, et al. Effectof xylitol and fluoride on enamel erosion in vitro. J Oral Sci.2007;49(4):293-297.

Granstrom TB, Izumori K, Leisola M. A rare sugar xylitol. Part

II: biotechnological production and future applications of xylitol.Appl Microbiol Biotechnol. 2007;74(2):273-276.

Granstrom TB, Izumori K, Leisola M. A rare sugar xylitol. Part

I: the biochemistry and biosynthesis of xylitol. Appl MicrobiolBiotechnol. 2007;74(2):277-281.

Grillaud M, Bandon 0, Nancy J, et al. [The polyols inpediatric dentistry: advantages of xylitol] [Article in French.]Arch Pediatr. 2005; 12(7): 1180-1186.

Hildebrandt GH, Sparks BS. Maintaining mutans streptococcisuppression with xylitol chewing gum. J Am Dent Assoc.2000; 131(7):909-916.

Kontiokari T, Uhari M, Koskela M. Effect of xylitol on growthof nasopharyngeal bacteria in vitro. Antimicrob AgentsChemother. 1995;39(8): 1820-1823.

Maguire A, Rugg-Gunn AJ. Xylitol and caries prevention-is ita magic bullet? Br Dent J. 2003; 194(8):429-436.

Makinen KK. Xylitol: the sugar that does not cause toothdecay. Refuat Hapeh Vehashinayim. 1978;27(2):36-37.

Makinen KK. Xylitol-a therapeutic and caries inhibitorynatural carbohydrate. N M Dent J. 1976;26(4):13,20-21.

Mattila P, Knuuttila M, Kovanen V, et al. Improved bonebiomechanical properties in rats after oral xylitol administration.Calcif Tissue Int. 1999;64(4):340-344.

726 I X YLITOL PDR FOR NUTRITIONAL SUPPLEMENTS

Mattila PT, Knuuttila ML, Svanberg MJ. Dietary xylitolsupplementation prevents osteoporotic changes. in streptozotocin-diabetic rats. Metabolism. 1998;47(5):578-583.

Mattila P, Svanberg M, Knuuttila M. Diminished boneresorption in rats after oral xylitol administration: a dose-response study. Calclf Tissue Int. 1995;56(3):232-235.

Mattila PT, Svanberg MJ: Jamsa T, et al. Improved bonebiomechanical properties in xylitol-fed aged rats. Metabolism.2002;51 (I ):92-96.

Mattila PT, Svanberg MJ, Knuuttila ML. Increased bonevolume and bone mineral content in xylitol-fed aged rats.Gerontology. 200 1;47(6):300-305.

Mattila PT, Svanberg MJ, Pokka P, et al. Dietary xylitolprotects against weakening of bone biomechanical properties inovariectomized rats. J Nutr. 1998; 128(10):1811-1814.

Mattila PT, Pelkonen P, Knuuttila ML. Effects of a long-termdietary xylitol supplementation on collagen content andfluorescence of the skin in aged rats. Gerontology.2005;51(3): 166-169.

Renko M, Valkonen P, Tapiainen T, et al. Xylitol-supplementednutrition enhances bacterial killing and prolongs survival of ratsin experimental pneumococcal sepsis. BMC Microbiol.2008;8:45.

Tapiainen T, Kontiokari T, Sammalkivi L, et al. Effect ofxylitol on growth of Streptococcus pneumoniae in the presenceof fructose and sorbitol. Antimicrob Agents Chemother.200 I;45( I): 166-169.

Uhari M, Kontiokari T, Koskela M, et al. Xylitol chewing gumin prevention of acute otitis media: double blind randomisedtrial. BMJ. 1996;313(7066): 1180-1184.

Uhari M, Kontiokari T, Niemela M. A novel use of xylitolsugar in preventing acute otitis media. Pediatrics. 1998;102(4 Pt1):879-884.

Uhari M, Tapiainen T, Kontiokari T. Xylitol in preventingacute otitis media. Vaccine. 2000;19 Suppl I:SI44-147.

Van Loveren C. Sugar alcohols: what is the evidence forcaries-preventive and caries-therapeutic effects? Caries Res.2004;38(3):286-293.

Yeast Beta-D-GlucanDESCRIPTION

Beta-D-glucans are nondigestible polysaccharides widelyfound in nature in such sources as cereal grains, includingoats and barley, as well as in yeast, bacteria, algae andmushrooms. Beta-D-glucans are primarily located in the cellwalls. Yeast beta-D-giucan is marketed as a nutritionalsupplement. The yeast beta-D-glucan in the supplement is apolyglucose polysaccharide derived from the cell walls ofbaker's yeast or Saccharomyces cerevisiae.

Yeast beta-D-glucan, usually referred to as yeast beta-glucan, consists of straight-chain and branched polymers.The straight-chain structures are (l/3)-beta-D-linked glucosepolymers and (1/6)-beta-D-linked glucose polymers. Thebranched polymers consist of a (1/3)-beta-D-linked back-bone containing varying degrees of (l-6)-beta branches.Yeast beta-glucan is sometimes designated as beta I, 3/1, 6glucan. .

Yeast beta-glucan appears to have immunomodulatoryproperties. It can bind to various cells of the non-specificimmune system, such as macrophages and neutrophils. PGG-glucan or poly- [I, 6]-beta-D-glucopyranosyl- [1,3]-beta-D-glucopyranose is a genetically modified Saccharomycescerevisiae beta-glucan. It is being evaluated in clinicalstudies as an immunomodulatory agent and a biologicalresponse modifier.

Zymosan is the name of a cell wall preparation derived fromSaccharomyces cerevisiae, which contains beta (1/3)-glucan,beta (I /6)-glucan and other components of the cell wall, suchas chitin and mannoprotein. Zymosan's immunologicaleffects are mainly attributed to the beta-glucans.

ACTIONS AND PHARMACOLOGY

ACTIONS

Yeast beta-glucan may have immunomodulatory and lipid-lowering activity.

MECHANISM OF ACTION

Most of the studies done with yeast beta-glucan have beenperformed in tissue culture, in animals and with PGG-glucan, which is administered parenterally. Yeast beta-glu-can can bind to a beta-glucan receptor in macrophages andstimulate the production of such cytokines as TNF (tumornecrosis factor)-alpha and IL (interleukin)-I beta. Binding tothe beta-glucan receptor may also induce the release of suchreactive oxygen species as superoxide anions and hydrogenperoxide. Yeast beta-glucan may also stimulate such cells asneutrophils NK (natural killer cells) and LAK (lymphokine-activated killer) cells. All of the above stimulation effectsmay result in antimicrobial and tumoricidal activities.

Research on PGG-glucan indicates that it interacts withreceptors on monocytes and neutrophils. It is thought thatthis interaction primes these cells for production of cytokinesand other immune-modulating substances when they areneeded. In this sense, yeast beta-glucan may be consideredan immune system primer.

The possible immunomodulatory effects of oral yeast beta-glucan remain unclear. Yeast beta-glucan is an indigestiblepolysaccharide and very little hydrolysis of it takes place inthe stomach or small intestine. There is some digestion ofyeast beta-glucan that does take place in the large intestine