aDENTSPLY International, Inc., Susquehanna Commerce Center,
221 West Philadelphia Street, York, PA 17405-0872, USA
bBaltimore College of Dental Surgery, University of Maryland,
Aesthetics of the teeth is of great importance to many patients. Public de-
mand for aesthetic dentistry, including tooth whitening, has increased in re-cent years. Patient interest in whitening and articles on whitening in popularmagazines suggest that tooth color is a signiﬁcant factor in the attractivenessof a smile. An attractive smile plays a major role in the overall perception ofphysical attractiveness . Studies conﬁrm the importance of attractivenesson perceived success and self-esteem Compared with restorative treat-ment modalities, whitening, also referred to as bleaching, is the most conser-vative treatment for discolored teeth. This public demand for a whiter smileand improved aesthetics has made tooth whitening a popular and often-requested dental procedure, since it oﬀers a conservative treatment optionfor discolored teeth. Whitening often enhances the treatment and encour-ages patients to seek further aesthetic treatment
Successful whitening treatment depends on the correct diagnosis by the
practitioner of the type, intensity, and location of the tooth discoloration. It is imperative to determine if the discoloration is extrinsic, which is asso-ciated with the absorption of such materials as tea, red wine, some medica-tions, iron salts, tobacco, and foods, onto the surface of the enamel and, inparticular, the pellicle coating or intrinsic, where the tooth color isassociated with the light-scattering and -absorption properties of the enameland dentin as seen in tetracycline staining, amelogenesis and dentinoge-nisis imperfecta, hypoplasia, erythroblastosis fetalis, and porphyria. Addi-tionally, discoloration results from the aging process. As teeth age, moresecondary dentin is formed and the more translucent enamel layer thins. The combination of less enamel and darker, opaque dentin creates anolder-looking, darker tooth The practitioner must identify the type of
* 932 Castle Pond Drive, York, PA 17402. E-mail address:
0011-8532/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cden.2006.12.001
discoloration, diagnose the cause, and then deﬁne the appropriate treatmentplan.
Tooth bleaching is not a new technique in dentistry. It was reported more
than a century ago . In 1916, Adams reported the use of hypo-chloric acid to treat ﬂuorosis. In 1937, Ames reported a technique us-ing a mixture of hydrogen peroxide and ethyl ether on cotton, heated witha metal instrument for 30 minutes, and applied over 5 to 25 visits to treatmottled enamel. Younger used this technique in 1942 in 40 children withdental ﬂuorosis. This and similar techniques using concentrated hydrogenperoxide and heat have been accepted treatment since the 1930s In1966, the combined use of hydrochloric acid and hydrogen peroxide waspromoted to remove brown stain from mottled teeth In 1970, Cohenand Parkins published a method for whitening tetracycline-discoloreddentin of the teeth of young adults treated for cystic ﬁbrosis. This was theﬁrst publication indicating that there is chemical penetration of hydrogenperoxide to the dentin to whiten teeth. Previous study concentrated entirelyon the removal of extrinsic staining only. In 1976, Nutting and Poe in-troduced the walking bleach technique, which uses 35% hydrogen peroxideand sodium perborate for whitening nonvital teeth. In 1968, Klusmeier described a technique using Gly-Oxide (Marion Merrel Dow, Inc., KansasCity, Missouri), a 10% carbamide peroxide oral antiseptic, which he placedin the orthodontic positioners of some patients to improve gingival health. He noted whitened teeth as well as tissue improvement as a result. Heswitched to Proxigel, which also contained 10% carbamide peroxide, ina custom-ﬁtted night guard in 1972 because the viscosity of the Proxigelallowed it to stay in the tray
The ﬁrst commercially available 10% carbamide peroxide was developed
and subsequently marketed by Omni International in 1989 based on theﬁndings of Munro who used a 10% carbamide peroxide solution tocontrol inﬂammation after root planing in a vacuum-formed plastic splint. He noted whitened teeth. Haywood and Heymann published the ﬁrst clini-cal study on tooth whitening using Proxigel in vacuum-formed custom trays. This is the technique known as ‘‘night guard vital bleaching’’ in common usetoday. Haywood and Heymann conducted laboratory and clinical in-vestigations of this technique and reported it in the literature in 1989. They reported on night guard vital bleaching using 10% carbamide perox-ide. The night guard was custom fabricated to hold the whitening gel in con-tact with the enamel surface.
The dental profession rapidly recognized the beneﬁts of an at-home bleach-
ing agent and it has become a popular method of lightening teeth Theacceptance of this procedure, according to a 1991 use-survey, found 78% of
general practitioners perform tooth-whitening procedures with 59% recom-mending the doctor-prescribed at-home method In another survey,9,846 dentists stated using at-home whitening techniques and 79% of thoserecognized the technique’s usefulness and overall clinical success Ninety-one percent of 8,143 dentists responding to a 1995 Clinical ResearchAssociates (CRA) questionnaire stated that they had used vital tooth bleach-ing with 79% reporting success and 12% reporting that they were not satisﬁedwith the concept .
Many companies followed Omni International’s lead, marketing carbam-
ide-peroxide–containing agents directly to consumers. In response to this di-rect marketing, the Food and Drug Administration issued a statement tomanufacturers requiring appropriate safety and eﬃcacy documentation in1991 and the American Dental Association subsequently developedguidelines for acceptance . Currently available peroxide-containingtooth-whitening materials include professionally dispensed and supervisedproducts for use by patients at home, professional-use in-oﬃce products,and over-the-counter products for sale directly to consumers.
The mechanism of whitening by hydrogen peroxide is not well under-
stood. Hydrogen peroxide whitening generally proceeds via the perhydroxylanion (HO À
2 ). Other conditions can give rise to free radical formation, for
example, by hemolytic cleavage of either an O–H bond or O–O bond in hy-drogen peroxide to give H þ OOH and 2OH (hydroxyl radical), respectivelyUnder photochemically initiated reactions using light or lasers, the for-mation of hydroxyl radicals from hydrogen peroxide has been shown to in-crease Available literature indicates that teeth are whitened by suchmaterials as hydrogen peroxide and carbamide peroxide by the initial diﬀu-sion into and through the enamel to the dentin . Hydrogen peroxideis an oxidizing agent that, as it diﬀuses into the tooth, breaks down to pro-duce unstable free radicals. These unstable free radicals attack organic pig-mented molecules in the spaces between the inorganic salts in tooth enamelresulting in smaller, less heavily pigmented constituents. These smallermolecules reﬂect less light, thus creating a ‘‘whitening eﬀect.’’ McCaslinand colleagues demonstrated in vitro that, following external whiteningwith carbamide peroxide, color change occurred throughout the dentin. Ad-ditional studies where dentin specimens were treated using 10% carbamideperoxide, 5.3% hydrogen peroxide and 6% hydrogen peroxide have shownsigniﬁcant reduction in the yellowness of the dentin and an increase in white-ness Sulieman and colleagues showed that signiﬁcant bleachingof extracted teeth internally stained by black tea was achieved when a 35%hydrogen peroxide gel had been applied.
The color seen in tetracycline-stained teeth is derived from photo-oxida-
tion of tetracycline molecules found within the tooth structures The
mechanism in this case is thought to be by chemical degradation of the un-saturated quinone-type structures found in tetracycline leading to less col-ored molecules In some cases, long-term night guard vital bleachingcan improve the color of tetracycline-stained teeth .
Numerous studies assessing the safety of hydrogen peroxide and carbam-
ide peroxide for tooth whitening indicate that 10% carbamide peroxide,which is equivalent to 3.6% hydrogen peroxide, is safe when applied inthe night guard vital bleaching techniques Trayless systemsin the form of whitening strips, containing 5.3% hydrogen peroxide, andin the form of a paint-on whitening gel, containing 18% carbamide perox-ide, are available for use by patients. The concentration is higher thanwhat has been studied to be safe in the previously mentioned studies, butthe total contact time is signiﬁcantly reduced. It is believed that the peroxidedose is no greater than that delivered by tray systems An in vitro tox-icologic study of whitening agents by Li showed fewer or comparableside eﬀects than those with commonly used dental materials, such as euge-nol, dentifrices, mouthwashes, and composites. The same study reportedthat the average amount of tooth-whitening agent used per application is502 mg. All of this amount swallowed would not exceed 8.37 mg/kg ,which is below the 10 mg/kg associated with acute toxicity in rats . Per-oxides are mutagens and there has been some thought that bleaching shouldnot be recommended to patients who are smokers or heavy drinkers. How-ever, to date, no studies in animals or humans link tooth whitening to oralcancer. The products are regulated by the Food and Drug Administration ascosmetics, not medical devices, and are therefore not subject to MedicalDevice Reporting requirements. Evidence to date indicates that the safetyfactor of whitening agents is quite high.
The most commonly reported side eﬀects are gingival or mucosal irrita-
tion and tooth sensitivity. Other reported side eﬀects include sore throat,temporomandibular dysfunction secondary to long-term tray use, and mi-nor orthodontic tooth movement Typically, the gingival or mucosal ir-ritation is related to improperly ﬁtted trays, improper or excess applicationof the gel, and the use of the gel longer than prescribed. The soft tissue ir-ritation noted is usually mild and transient and is resolved shortly afterthe treatment has ended Mitigation for soft tissue and throat irritationmay require an adjustment of the tray or a reduction of the application pe-riod Mitigation for temporomandibular dysfunction and tooth move-ment requires use of a thin tray material (0.40 in) for tray fabrication.
Tooth sensitivity is by far the most common side eﬀect reported. Studies
have reported that sensitivity occurs in 55% to 75% of the treatmentgroups. The sensitivity is believed to be the result of the freely diﬀusible na-ture of the materials used Carbamide peroxide decomposes to hydro-gen peroxide and urea. Hydrogen peroxide further decomposes to waterand oxygen and the urea breaks down to ammonia and carbon dioxide. Some of the by-products pass through the dentinal tubules reaching thepulp, thus causing reversible pulpitis , resulting in tooth sensitivity. The carrier for many whitening products is glycerin, which absorbs waterand causes dehydration during the whitening treatment. This dehydrationcauses tooth sensitivity . The sensitivity related to tooth whiteningis generally mild and transient, occurs early in the treatment, and generallydecreases as treatment continues with cessation shortly after the treatmentends. Mitigation includes treatment with ﬂuoride gel or a potassium nitratetoothpaste in the tray for 10 to 30 minutes before use of the whitening agent,treatment of the teeth with a desensitizing agent after treatment, and reduc-tion of the number of applications by requiring fewer per day or by requir-ing applications only every other day. Additionally, use of a potassiumnitrate plus ﬂuoride toothpaste 2 weeks before whitening and during thewhitening treatment has been suggested as an adjunct therapy for sensitivitymanagement. Although whitening procedures have been reported to inducesensitivity in 55% to 75% of treatment groups, the procedure is welltolerated.
Another consideration with tooth whitening is the eﬀect it has on enamel
and dentin. One study found that whitening agents were capable of remov-ing the smear layer from dentin, but produced little or no change in enamelAdditional studies concluded the same result in enamel butothers have shown changes in porosity and surface morphology of enamel. Another study evaluated the eﬀects of take-home whitening systemson enamel surfaces, and suggested that a period of 4 days must elapse beforebonding to the enamel of a tooth treated with a peroxide containing whiten-ing agent. However, no delay is necessary if the agent does not contain per-oxide . Since the data have produced equivocal results, the currentpractice is to wait before performing bonding procedures after toothwhitening.
Studies evaluating the eﬀects of home bleaching products on restorative
materials have also produced equivocal results. One study found thata home whitening gel signiﬁcantly reduced the hardness of a hybrid resincomposite over a 4-week treatment period. Scanning electron photomicro-graphs also revealed surface cracking . Whitening agents have beenfound to adversely aﬀect the color of various restorative materials, withglass ionomers exhibiting the greatest color change Another investiga-tion found that the shades of two hybrid and one microﬁll composite wereunaﬀected by two home whitening products . Still another report foundno adverse eﬀects from whitening solutions on either the surface texture or
color of porcelain, resin composite, amalgam, or gold restorations . Some researchers believe that the tendency for whitening agents to adverselyaﬀect restorative materials is related to their pH because greater eﬀects havebeen noted for products with pH values !5.5. In many instances, restora-tions are replaced after the whitening treatment at the patient’s request orthe clinician’s recommendation for an improved aesthetic result.
A number of methods and approaches for whitening have been described
in the literature. There are methods using diﬀerent whitening agents, con-centrations, times of application, product formats, application modes, andlight activation methods . However, three fundamental bleachingapproaches existddentist-supervised night guard bleaching, in-oﬃce orpower bleaching, and bleaching with over-the-counter bleaching products. Night guard bleaching typically uses a low level of whitening agent ap-plied to the teeth via a custom-fabricated mouth guard worn at night for atleast 2 weeks . In-oﬃce bleaching generally uses high levels of whit-ening agents (eg, 25%–35% hydrogen-peroxide–containing products) forshorter periods. The whitening gel is applied to the teeth after protectionof the soft tissues and the peroxide may be further activated by heat or lightThe in-oﬃce treatment can result in signiﬁcant whitening after onlyone treatment visit but may require multiple treatment appointmentsfor optimum whitening . Over-the-counter products typically containlow levels of whitening agent (eg, 3%–6% hydrogen peroxide), which areself-applied to the teeth via gum shields, strips, or paint-on product formats. These typically require twice-per-day application for up to 2 weeks .
Professionally dispensed and supervised productsfor at-home use (take-home systems)
The regimen for take-home systems involves the fabrication of a soft
plastic night guard, which may or may not contain reservoirs, to hold thewhitening gel in contact with the teeth. The night guard is made from a modelof the patient’s teeth. Instructions typically call for twice daily treatments offrom 30 minutes to 2 hours a day for 2 to 6 weeks, depending on the color ofthe teeth at the start of treatment . Most of the products also provide thealternative of overnight applications, leaving use up to patient preference. Products are available containing as little as 5% and as much as 36% car-bamide peroxide; as well as 6%, 7.5%, 9.5%, 14%, or 15% hydrogen perox-ide. Using stronger concentrations of whitening agents will whiten teethsomewhat faster. For example, a quicker two-tab color change has beennoted for 10% and 16% carbamide peroxide compared with 5% carbamideperoxide at days 8 and 15 of treatment. However, continuation of the 5%treatment to 3 weeks results in shades that are equivalent to shades achieved
after 2-week use of the 10% and 16% treatment regimens. Advantages in-clude lower cost to patient and minimal in-oﬃce chair time. Additionally,this technique has the most research and scientiﬁc evidence supporting itseﬀectiveness. The major disadvantage is that signiﬁcant patient complianceis necessary for optimal results. Examples of products for nighttime useinclude:
Opalescence PF (Ultradent Products), containing 10%, 15%, and 20%
Nupro White Gold (DENTSPLY Professional), containing 10% and
Nite White Turbo (Discus Dental), containing 6% hydrogen peroxidePolaNight (Southern Dental Industries), containing 10%, 16%, and 22%
Examples of products for daytime use include:
Opalescence PF (Ultradent Products), containing 10%, 15%, and 20%
Treswhite (Ultradent Products), containing 9% hydrogen peroxideRembrandt XTRA-Comfort (Johnson & Johnson), containing 16%,
Natural Elegance (Henry Schein), containing 10%, 15%, and 22% car-
JustSmile (JustSmile Whitening Systems), containing 2% to 10% hydro-
Perfecta Bravo (Premier Dental Products), containing 9% hydrogen
PolaDay (Southern Dental Industries), containing 3%, 7.5%, and 9%
In-oﬃce systems typically use a 15%, 30%, or 35% hydrogen peroxide
whitening agent, either heated or nonheated, and the recommended use ofgingival isolation, either by means of a gingival dam or a gingival paint-onbarrier product. The product is applied in the oﬃce. Advantages include min-imal dependence on patient compliance and immediate visible results, whichsatisfy patients who want to see quick results. The disadvantages are higherpatient cost, the use of chair time, and the requirement of multiple in-oﬃcevisits to get optimal results and retain them. Examples of products include:
Illumine (DENTSPLY Professional), containing 15% hydrogen peroxideOﬃceWhite (Life-Like Cosmetic Solutions), containing 40% hydrogen
Perfection White (Premier Dental Products), containing 35% hydrogen
Niveous (Shofu Dental), containing 25% hydrogen peroxideOpalescence Xtra Boost (Ultradent Products), containing 35% hydrogen
Combination treatment involves application in the oﬃce of a high-con-
centration hydrogen-peroxide agent followed by a professionally dispensedand supervised product for at-home use for 5 days, often followed by an ad-ditional chairside application Compared with in-oﬃce stand-alonetreatment, combination treatments take less time, require fewer oﬃce visits,and cost patients less . The major disadvantage is the need for in-oﬃcechair time. Also, combination treatment is not a one-time treatment, whichpatients prefer.
Light-activated treatment involves application in the oﬃce of a high-con-
centration hydrogen-peroxide agent, which is then ‘‘activated’’ by plasma-arc, light-emitting diodes, argon lasers, and metal halide and xenon-halogenlight sources. The theory behind the treatment is that light or heat will speedthe breakdown of the hydrogen peroxide and thus lighten the teeth morerapidly. The assumed beneﬁt is that the procedure is less time-consumingwhile producing faster results. Current studies have produced equivocal re-sults with some touting the beneﬁts while others conclude there is nobeneﬁt . Examples of products include
LaserSmile (Biolase Technology), containing 37% hydrogen peroxideArcBrite (Biotrol), containing 30% hydrogen peroxideBriteSmile (BriteSmile), containing 15% hydrogen peroxideRembrandt Lightening Plus (Johnson & Johnson), containing 35%
Zoom (Discus Dental), containing 20% hydrogen peroxideLumaWhite Plus (LumaLite), containing 35% hydrogen peroxide
Over-the-counter treatments include dentifrices, whitening strips, paint-
on brush applications, and whitening kits complete with a preformed orsemimolded tray. The toothpastes marketed as whitening products typicallycontain a mild abrasive to remove surface stains and some contain a minimalamount of peroxide. The exposure time to the toothpaste is minimal. There-fore any potential whitening in minimal . Whitening strips use 6.5% hy-drogen peroxide and the paint-on brush application uses 18% carbamideperoxide as the whitening agent. Contact time is signiﬁcantly reduced as
compared with professionally prescribed products. Therefore, whiteningstrips and paint-on brush applications must be used longer to obtain similarresults to those from the professionally prescribed products. Minimal re-search exists on these products and, because they can be bought and usedindiscriminately by patients, the risk of inappropriate use is high. Long-term risks have yet to be determined These methods are excellent formaintaining already whitened teeth and are a good option for patientswho cannot aﬀord the professionally prescribed products or who do nothave time for multiple oﬃce visits
The whitening kits with supplied tray and whitening agent present patient
problems in that the trays are not custom ﬁtted and the formulations may bevariable as compared with the products for sale to dentists Results ob-tained from these products vary. Examples of products include Crest White-strips (Proctor & Gamble), containing 6.5% hydrogen peroxide; andSimply-White Whitening Gel (Colgate), containing 5.9% hydrogenperoxide.
Vital night guard whitening using 10% carbamide peroxide has been in
use for close to 20 years and has been the most extensively researchedmethod for tooth whitening. It has been shown to be eﬀective for lighteningprimary teeth discolored by trauma lightening tetracycline-stained teethremoving brown stain, including ﬂuorosis stain and lighteningteeth stained by nicotine. It will not, however, change the color of rootsof teeth, and this must be taken into consideration in the patient’s treatmentplan. The teeth get lighter through the process and reach a maximum light-ness regardless of the concentration of the agent or contact time used. Oncetreatment is completed, the teeth will rebound by approximately a halfshade, probably due to the complete rehydration of the teeth. There is min-imal information regarding retention. Retention studies reported satis-factory shade retention in 82% of the cases treated at 47 monthsposttreatment and long-term retention of the shade change at a satis-factory level without re-treatment for 10 years posttreatment in at least 43%of the cases
Areas of further research with regard to whitening include elucidation of
the true mechanism of action, the nature and composition of colored mate-rials naturally found within the dental hard tissues, and the mechanistic ef-fects of peroxide on these structures. Joiner believes this is necessaryresearch if the chemical mechanistic aspects of tooth bleaching are to be re-solved. There is much research around whitening, but most is reported on
use of the 10% carbamide peroxide products. Therefore further research ofthe eﬀects and dose on outcomes of the higher-concentration products iswarranted. Further information is required regarding how long the whiten-ing eﬀect lasts, at what point and what patient factors lead to rebound, andwhat is an appropriate recommendation for the maintenance of whitening. There are a number of approaches to measuring color change and researchfor standardization to measure color change would remove the human vari-able and provide more reliable results for comparison of products. Currentinformation regarding the eﬀects on enamel and dentin is controversial andadditional information is needed on the eﬀects to provide good recommen-dations to practitioners regarding placement of composite resins after whit-ening. Current information regarding whether the use of light and heat toactivate the whitening is necessary is also controversial and further researchis needed in this area to elucidate if this is really beneﬁcial to the whiteningprocess and patients or just a marketing ploy. Lastly, more research isneeded to provide better and more consistent management of tooth sensitiv-ity, which can be quite signiﬁcant, or to ﬁnd products or additives to prod-ucts to mitigate the sensitivity during treatment.
The typical result of treatment is a whiter appearance of the teeth, which
reduces the aged look patients may have as a result of more yellow, darkerteeth. This whiter appearance often leads to a heightened awareness of otherproblems with dentition and a desire for further treatment. The dentist canplay an active role in encouraging patients and educating them aboutchoices for tooth whitening and in providing them the best treatment op-tion. To that end, dentists who provide this service need to educate them-selves to be able to eﬀectively inform their patients of the beneﬁts andrisks of the diﬀerent options for whitening based on as much scientiﬁc evi-dence as possible, of additional treatment that may be necessary after whit-ening, and of the cost/beneﬁt ratio of the treatment. Vital tooth whitening,when administered correctly, is by all accounts one of the safest, most con-servative, least expensive, and most eﬀective aesthetic procedures currentlyavailable to patients.
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RESUMEN DEL PROTOCOLO DEL ESTUDIODE BIOEQUIVALENCIA Y CONCLUSIONES T’tulo del estudio: Estudio comparativo de bioequivalencia en voluntarios sanos de Aciclovir comprimidos 800mgfrente a comprimidos 800mg de aciclovir de referencia (Zovirax¨, Glaxo Wellcome) Investigador: Pavia UniversityPharmacology Department. Piazza Botta, 10. Pav’a (Italy) Objetivos: Determinar si dos formulacione
Nonmyeloablative Hematopoietic Stem Cell Transplantation for Systemic Lupus Erythematosus Richard K. Burt, MD Context Manifestations of systemic lupus erythematosus (SLE) may in most pa- tients be ameliorated with medications that suppress the immune system. Neverthe-less, there remains a subset of SLE patients for whom current strategies are insuffi-cient to control disease. Objective T