Intraoral administration device and system

An intraoral administration device having an elongated, substantially plate-like arcuate oral screen designed to conform to the teeth and intended to be accommodated in the space between the teeth and the lips. The oral screen includes containers for the agent to be administered intraorally, which containers have provision for allowing the free entrance of saliva into the container and its exit therefrom. An administration system using the administration device and an active agent, such as for example an agent against caries or otitis media is also contemplated.

The object of the present invention is an intraoral administration device 
comprising an elongated, substantially plate-like curved oral screen 
designed to conform to the teeth and intended to be positioned in the 
space between the teeth and the lips. The object of the present invention 
is also an administration system, which comprises the administration 
device according to the invention in combination with an active agent. 
By means of the administration system according to the invention it is 
possible to provide a sustained local therapeutic effect in the region of 
the mouth and throat which is adapted to take into account the eruption 
order of the teeth and the location of the salivary glands, while 
simultaneously satisfying the physiological sucking need and craving for 
sweetness of small children, using small dosage levels tolerated by 
children and without causing malocclusions, especially when the sucking 
need of the child continues too long from the orthodontic point of view. 
Various dispensing pacifiers are known (for example U.S. Pat. No. 
4,078,566, GB-patent application 2 181 957A; EP Pat. No. 0 494 904, 
FI-patent application FI-A 921411, U.S. Pat. No. 5,395,392; and the 
commercially available CANNON babysafe Minifeeder). Suhonen (1992) has 
presented the theoretical background for the use of a pacifier like 
administration device which slowly releases fluorides, xylitol, monoclonal 
caries antibodies or lactoperoxidase enzyme components into the mouth, in 
a prophylactic method for the prevention of dental caries. The operability 
of a dispensing pacifier for releasing sodium fluoride, xylitol and 
sorbitol from a tablet has been established in vitro, and the 
administration from a pacifier of passive vaccines against microbes 
causing oral diseases has been suggested (Suhonen at al, 1994). A pacifier 
prototype for dispensing sodium fluoride, xylitol and sorbitol has in our 
field trial with children of the age of 16 months proved to be a 
functioning weans with potential for development for the treatment of 
diseases of the mouth and throat of children in the sucking-age. In our 
follow-up study it also became evident that in the group of children that 
had accepted the test pacifier, there appeared significantly less often 
infection of the middle ear (otitis media, 48% versus 70%) than in the 
comparison group. Recently it has been shown that xylitol also inhibits 
the growth of Streptococcus pneumoniae (pneumococcus) (kontiokari et al 
1995). According to one report (October 1996) the use of a xylitol bubble 
gum several times a day has reduced infection in the middle ear in 
kindergarten children in Oulu. The mouth cavity can thus be an area of 
primary defense in the battle against bacteria aiming for the middle ear. 
In the continuous follow-up of our study cohort, it has been established 
that malocclusions in children using a pacifier become significantly more 
common when the use of the pacifier continues beyond the age of two. For 
this reason, taking into account the individual dentoalveolar jaw 
development, the pacifier should be given up at the stage of eruption of 
the deciduous molars which, on an average, coincides with that age, at 
which stage the sucking-need of a child optimally should already have 
changed into a chewing-need (Laitinen 1995). To prevent malocclusions 
Varrela and Alanen (1995) have presented an extensive pacifier study with 
an aim at finding a pacifier model which broadens the dental arch of the 
upper jaw. Prolonged pacifier sucking has also been alleged to cause 
middle ear infection (Niemela 1984). On the other hand, if the pacifier is 
taken away from a child too early, he easily becomes a thumb-sucker which, 
from the point of view of bite development, is an even worse habit than 
sucking a pacifier. Also deciduous dentition destroyed by early caries 
attack cause displacements and malocclusion of the permanent teeth. 
According to the invention, an administration device of the oral screen 
type has now been developed, by means of which an active agent can be 
slowly released into the mouth of a child, especially after the pacifier 
stage, in a manner preventing deformation of occlusion. 
The invention is based on a so-called oral screen, that is an elongated, 
substantially plate-like device with an arcuate longitudinal 
cross-section, to be inserted in the space between the lips and the teeth. 
The administration device is characterized in that the oral screen 
comprises containers for an intraorally administrable agent which 
containers are provided with means, such as holes or apertures, allowing 
the free entrance of saliva into the containers and its exit therefrom. 
The oral screen (OS) is a device known in orthodantology which is kept in 
the space (vestibulum oris, VO) between the teeth (T) and the lips (L) to 
push backward front teeth protruding in an open bite caused by a pacifier, 
lip-sucking or visceral act of swallowing (FIG. 1). In addition to oral 
screens individually manufactured in a dental laboratory, serially 
produced screens of different size are available, which are provided with 
a ring and are elastic or made from a harder plastics material (the first 
ones were made in 1956, the material being polyamide, Dr. E. Schonherr, 
Radebeul. DDR; presently known manufacturers: Dentaurum, Germany; 
Dentamar, Holland, Myofunctional Research Co., Australia), which are sold 
and used for the main indication of strengthening poorly developed lip 
muscles and for breaking detrimental habits. It is known to provide the 
screen with additional means for guiding the position of the tongue or 
prominences for guiding the bite, such as a cap for the lower front teeth 
to bite into (Prof. R. Hinz, Herne, West-Germany, material "Duralan", year 
1974; DE 3 840 178 A1). In a distal occlusion, the cap facilitates in 
keeping the device in place and accommodates the masticatory muscles so 
that growth is possible in the condyle area, which in favourable 
instances, in addition under the control of the inclined plane or the cap, 
moves the lower jaw permanently forward in an orthognathicly more correct 
position with respect to the skull base. Also a combination of an oral 
screen and a sucking piece of a pacifier is known (CH-patent 662 271 A5). 
There is need for orthodontic prophylaxis (Laitinen 1995, Verrela and 
Alanen 1900). There is, however, one problem with respect to taking an 
oral screen into use, namely pacifier users under the age of 3 and 
thumbsuckers under the age of 4 do not want to keep it in the mouth. When 
training the use of an oral screen, it can in a transitional period, in 
order to facilitate the adaptation process, initially be provided with a 
pacifier-like sucking piece which is acceptable to the child. One should, 
however, relatively soon get rid of the model provided with a sucking 
piece. 
According to our invention, an oral screen of the known type has been 
provided with containers for the agent to be released into the mouth. One 
idea according to our invention is that when a good tasting substance, for 
example non-cariogenic xylitol (X) is placed in the dispensing containers 
in the cheek flanges of the oral screen (OS), and the xylital slowly 
dissolved primarily under the effect of saliva secreted from the glandula 
parotidea (parotid saliva, PS) gives the children a pleasant taste 
sensation (FIG. 2), such a device can be used to wean already a 2-year old 
child from teeth-damaging sucking habits, such as a sweet bottle, pacifier 
and perhaps also thumbsucking. As it, in addition, prevents mouth 
breathing (Darby 1890), the nose cavities are enlarged and remain open 
more easily, reducing simultaneously the risk for middle ear infection. 
Xylitol as such prevents middle ear infection (Uhari et al 1996). In mouth 
breathers, when the mouth is open, the stretched strong cheek muscles 
compress and flatten the upper jaw bone, whereby crossbites are easily 
developed on the sides. The oral screen removes the pressure of the 
muscles on the upper dental arch, allowing the arch to broaden freely, for 
example pushed by the pressure exerted by the tongue when swallowing. The 
taste buds in the tongue tip are sensitive to sweet. When the substance 
containers according to the invention are placed in the back and to the 
sides near the parotid gland duct (FIG. 2), the sweetener dissolved by the 
saliva (Xd) makes the child instinctively move the tip of the tongue. The 
pressure of the tongue resulting therefrom should reduce the risk for 
crossbites at the canine tooth area. 
A suitable sweetening agent for use in the said application would be, for 
example, xylitol, which per se has several beneficial effects on the teeth 
(Arends er al. 1984, Muhlemann et al. 1970, Makinen 1978, Makinen and 
Isokangas 1988, Makinen and Scheinin 1982, Scheinin and Makinen 1975, 
Soderling and Pihlanto-Leppala 1989, Soderling and Scheinin 1991, Touster 
1960). Further possible non-cariogenic sweetening agents for the said use 
are i.a. saccharin, acesulfam-K, cyclamate, aspartame, alitame, 
thaumatins, rebaudocides, glycyrrhizin, sucralose and neohesperidin 
dihydrocalcone, although some of these are restricted in use and for 
others the safety testing and practical experience are still insufficient 
(Granby 1991). 
Xylitol is not able to cause bacterial acid production wherefore it is a 
cariostatic agent (Muhlemann et al. 1970, Scheinin and Makinen 1975). In 
addition to the said cariostatic effect xylitol possesses apparent 
bacterial adhesion and accumulation inhibiting properties, and 
consequently it can reduce caries and middle ear infection in long term 
and frequent administration (Makinen 1978, Isokangas 1994, Kontiokari et 
al 1995, Uhari et al. 1996). Contrary to, for example sorbitol, xylitol 
causes in bacteria a so called "futile xylitol cycle" which uses much 
energy (Soderling and Pihlantoo-Leppala 1989). Many so called xylitol 
products contain more than 30% sorbitol. Such products should not be used 
in our administration system, unless they are used together with further 
effective caries inhibitors, such as sodium fluoride. The Xylitol-Fludent 
fluoride tablet which is in general use in Finland, contains sorbitol 50%. 
Due to its sweet taste, children usually take it eagerly, and due to its 
sodium fluoride content it is suitable for use in the administration 
device according to the invention. By applying the oral screen strategy, 
it is possible to create for hours an oral fluid environment around the 
erupting teeth, which according to our studies have apparent caries 
preventing properties. Care has to be taken that the sweetening or other 
agents used are not cariogenic, i.e. do not cause caries. Preparations, 
wherein the proportion of xylitol as a sweetening agent is over 70%, can 
usually be held as cariostatic and safe for the teeth. A disadvantage of 
xylitol and other polyols is, however, their slow absorption from the 
intestine, especially in small children, whereby large doses can lead to 
osmotic diarrhea. 
It is generally believed that the fluoride ion does not under normal 
conditions affect the colonization or mutans streptococci (Ms) (Kilian et 
al. 1979, van Houte et al. 1978, Zickert and Emilson 1982). According to 
one theory, however, the fluorides, at least at stronger concentrations, 
prevent the bacteria from adhering to the tooth surface by reducing the 
adhering electrostatic forces (Rolla 1977a). Usually the caries-preventing 
effect of fluorides on the teeth is associated with the capacity of the 
fluoride ion to harden the tooth surface and promote remineralization. In 
addition, the fluoride ion disturbs the carbohydrate metabolism of mutans 
streptococci and thus reduces the acid production in plaque (Hamilton 
1977, Harper and Loesche 1986). 
The adhesion of bacteria can be prevented also with substances of the 
lactin type, which have been found species-specifically i.e. in milk and 
in plant seeds (for example Neeser et al. 1988). Further optionally 
applicable agents are non-specifically antibacterial enzymes 
(Lenander-Lumikari 1992). One additional alternative is to add protecting 
agents in an amount sufficient to prevent the accumulation (aggregation) 
of plaque, acid production or other virulence factors, or use 
remineralizing agents which inhibit the damaging symptom of caries, 
demineralization of the tooth, of which agents the effect of the fluorides 
has been known for already half a century. 
Interesting from the point of view of our inventive administration device 
are i.e. the caries antibodies produced in egg yolk (Sun GY, Taiyo Kagaku 
Co., Ltd, Japan) and the monoclonal mouse anti-mutans-streptococci 
antibodies (Ma and Lehner 1990, Ma et al. 1990). One relatively cheap 
method of producing antibodies is the so-called immune milk which method 
has been considered safe for human use. Immune milk can be produced by 
vaccinating a pregnant cow against certain pathogens, whereby the cow 
organism forms antibodies to these diseases, which are transferred to the 
colostrum. The remedying effects of immune milk are long known. Also known 
is a caries preventing cow immune milk product, which contains specific 
antibodies to killed streptococcus mutans--cells (U.S. Pat. No. 
4,324,782). Immune milk has also been prepared against the cariogenic 
MS-species S. sobrinus, and the anti-MS-affect of an immune whey product 
has been studied also in vitro. The efficiency of a corresponding anti-S. 
mutans--whey product has been shown earlier in animal and human tests in 
adults (Michalek et al. 1987, Filler et al. 1991). 
By means of an administration device which releases effective antibodies 
slowly into the mouth, a relatively sustained effect on the microflora of 
the mouth and throat is obtained with small doses. It is thus of 
importance that the used antibodies do not disturb the development of the 
normal flora which is important for the health of the mouth. As regards 
ear pathogenic pneumococci it is expected that an octavalent 
polysaccharide antigen vaccine conjugated to a protein carrier will to a 
large degree remove the problem of middle ear infection due to pneumococci 
(Gleblnk 1994). Thus Heamophilus influenzae (non-type b) and Branhamella 
(Moramxella) catarrhalis remain which are more difficult to treat and 
against which there is no known vaccine. Of these, the former is better 
known to its living habits. It has been shown already a long time ago that 
H. influenzae lives also in the south region, and its uncapsuled form 
(nontype b) is a quite common cause for recurrent middle ear infections in 
under 5 year olds. An IgG-antibody dispensed by the administration device 
against middle ear infection causing bacteria in a prophylactic manner 
could be surprisingly effective, even though the mechanisms are not known 
in detail (Kauppi et al. 1993). 
An immune whey powder obtained from immune milk containing antibodies 
primarily of the IgG-type against middle ear infection contains also 
lactose, which stabilizes proteins and facilitates compressing of the 
powder into tablet form. It is possible to remove the lactose and replace 
the same at least partly with xylitol. An addition of xylitol would be 
beneficial because of the expected additive anti-caries and anti-otitis 
effect, and its protein stabilizing property. 
It is in principle possible to make accurate monoclonal antibodies against 
any virulence factor of a microbe, after it has been identified, using 
known hybridoma and gene manipulation techniques. Perhaps the so far most 
promising anti-cariotic antibody preparation in the monoclonal IgGl-type 
antibody against the adhesive protein antigen SA I/II of the S. mutans 
cell wall (Ma et al. 1990). By treating the teeth with this antibody it 
has been possible to prevent the return of MS in the tooth plaque of adult 
humans (Ma and Lehner 1990). 
Thus, in order to administer the afore mentioned and other active agents, 
an administration device is used according to the invention, which at the 
same time functions as an orthodontic oral screen preventing the 
development of jaw deformities. New in the invention is the fact that the 
active agent in a suitable manner is combined with the oral screen, 
suitably in containers in the oral screen or associated therewith, in 
which containers the agent can be introduced in the form of a tablet, 
lozenge mass or a cellulose, gelatin or nonwoven fabric disc (for example 
Fibrella, Suominen Oy, Nakkila, Finland) "impregnated" with the agent, and 
from which the active agent, for example through holes, is released into 
the oral cavity. The characteristics of the invention are given in the 
appended claims. 
The administration device is preferably provided with a gripping means 
attached to the outer surface of the oral screen, that is to the surface 
facing the lips or the cheeks in use, the gripping means extending outside 
the mouth and which can also be provided with a gripping ring. 
According to one embodiment of the invention, the container is formed by a 
recess made in the oral screen, especially in its end regions, that is in 
the cheek flanges, and a lid which at least partly covers the recess. If 
the oral screen is made from an elastic material, the said lid can be a 
strip-like member forming one piece with the oral screen, which at least 
partly covers the recess. If the oral screen is made from a hard material, 
the lid can be hinged to the oral screen and provided with suitable 
locking means, such as a suitable looking tongue. 
The container can also be a cup-like, cage- or sieve-like construction 
opening outward from the surface of the oral screen, especially from its 
outer surface, and provided with a suitable lid. 
According to a further embodiment, the container can be formed from a 
sheath-like member made from an elastic material and slid over the end 
part of the oral screen in a sealing engagement with the oral screen, 
which advantageously is provided with a loop member to be slid and 
tightened over the gripping means of the oral screen. 
According to another alternative embodiment, the oral screen is in two-part 
form and comprises a so-called casing cover, the dispensing containers 
being arranged in the vicinity of the end regions of the said casing 
cover, which, in its longitudinal direction, is provided with a sliding 
slot extending from the center of the cover towards its end regions, and 
in addition, a sliding plate slidably mounted in a groove or recess in the 
inner surface of the cover, allowing the containers to be opened, to which 
plate gripping means are attached, which are slidably mounted in the 
sliding slot and extending outwards therefrom through the casing cover, as 
well as means for locking the sliding cover and the casing plate to each 
other.

The FIGS. 3 and 4 show an embodiment of an oral screen dispenser according 
to the invention, which is made from an elastic material. In this case the 
whole device with its frame 7, ring 12 and tablet fastening means, which 
in this case is a strip 8 extending over the tablet container 9, is made 
in one part from an elastic plastic, for which purpose a stiff silicone is 
suitable. The strip 8 can be loosened by straightening the arched end part 
16 of the cheek flange. By simultaneously pulling the strip 8 to the side, 
a tablet strictly matching its recess 9 can be placed underneath the strip 
8. When the end part 16 is not bent any longer, it strives at regaining 
its original arched form tightening the tablet in its place so that a 
small child cannot remove the same. The bottom of the tablet container 9 
is provided with one or more holes 5. In the example, there are four boles 
5 placed cylindrically on the outer periphery of the container 9, half 
outside the edge so that the parotid saliva flowing past the side edges of 
the fastening strip 8 into the container 9 can flow freely past the sides 
of the tablet which initially sealingly fills the bottom of the container, 
slowly dissolving the same, to the inner oral cavity. 
The following examples illustrate embodiments made completely or partly 
from a hard plastic (for example an ABS plastic): 
FIGS. 5-7 illustrate an oral screen dispenser, wherein pill casings form 
dispensing containers 9 mounted in the cheek flanges of the oral screen 
and provided with buccally opening hinged lids 6, the hinge part 14 being 
placed distally. In the cross-section through the plane of the middle seam 
15 (FIG. 6), the left hand pill casing is seen with the lid 6 open. In the 
lid 6 and in the frame 7 in the bottom of the container 9, there are holes 
5. A locking tongue 6a functions as a locking means for the lid 6, and the 
lid is opened by gripping and lifting the opening rim 6b. 
The FIGS. 8-9 illustrate an oral screen dispenser formed by a sliding plate 
7' and a caning cover 17. The sliding plate 7' is provided with a shaft 7a 
insertable through a mounting aperture 17a in the casing cover 17, the end 
part or which having recesses 7b into which a ring 12 is fastened. The 
sliding plate 7' is snap-shut into its groove or casing 18 in the casing 
cover, when the ring 12 is pulled in an outward direction. At this stage, 
the right hand tablet casing acting as a dispensing container 9, as seen 
from the direction of the child, and having a cover 6 with holes 5, is 
open for filling purposes. By pushing the shaft 7a of the sliding plate to 
the right hand edge of the sliding slot 17b in the casing cover 17, the 
left hand tablet casing opens for filling. In the center position of the 
shaft 7a, which is the normal position of the device in use, the 
containers 9 in a closed position, the sliding plate 7' is locked into 
place by means of elastic locking tongues 6a situated at the distal ends 
of the casing cover, a locking rim 7c in the shaft 7a preventing the 
sliding plate 7' from detaching from the groove 18 in the casing cover 17, 
if a pushing force were to hit the shaft 7a from the front. For cleaning 
purposes, the sliding plate 7' can be detached from the groove 18 in the 
casing cover by pushing the shaft 7a with rim 7c through the mounting 
aperture 17a inwards. Even in this case the parts do not detach from each 
other completely due to the ring 12. The ring 12 cannot be released from 
its recesses 7b by a child, but needs the force of a grown-up's fingers. 
In the sliding cover there are holes 5 at the tablet containers 9, through 
which the agent to be dispensed and dissolved primarily by the effect of 
the saliva from the glandula parotidea can affect the solar teeth region. 
FIGS. 10 and 11 illustrate an oral screen wherein the frame 7 of the device 
is made from a hard plastics material and the dispensing containers with 
their fastening means are made from an elastic material (silicone, 
rubber). The dispensing container unit is a flat baglike sheath structure 
which forms a container 9 resembling the sucking piece of a pacifier, 
which is pulled, with the tablet 13 to be dispensed inside, over the end 
of the cheek flange 16 of the plate 7 and is tensioned tightly into place 
by stretching the loop 11 in the strap 10 of the container 9 facing the 
cheek, over the ring 12 in back of the shaft 7a. Sheaths are needed one 
for each cheek flange of the oral screen, the tablet recesses in the cheek 
flanges having in this example one smallish hole 5 made in their bottom. 
Saliva can freely flow through the holes 3 in the container 9 and the hole 
5, as well as due to the lateral clearance of the sheath, through the 
container 9, inside and out. 
As alternative solutions, the afore described individual containers 9 can 
be combined either from their loop straps on the cheek facing side, or so, 
that the whole surface of the oral screen facing the teeth is covered with 
a fastening collar means joining the sheaths into one piece having two 
sheaths. 
FIG. 12 illustrates a training oral screen. A child can be trained to use 
an oral screen while being weaned from pacifier use by providing the oral 
screen frame 7, on its inside, with a pacifier-like sucking piece 2, for 
example a dispensing sucking piece. The sucking piece 2 can suitably be 
made in one piece with the oral screen, for example from soft vinyl, and 
it can be provided with holes 3 for the active agent, its opening opening 
up in the container 9. The opening is closed with a plug 24, the 
continuation part or shaft 25 of which joins two closing shafts 26 
arranged substantially in a V-shaped manner with respect to each other and 
extending to the inside periphery 27 of the sides of the ring-shaped 
gripping device 12, 12a. The said construction effectively prevents the 
opening of the plug during use. 
The pacifiers and the oral screens can be boiled. Thus the required 
hygienic level can be reached in domestic circumstances. 
For a person skilled in the art it is evident that the invention is not 
restricted only to the examples shown above, but can vary within the scope 
of the appended patent claims. 
REFERENCES 
Arends J, Christofferssen J, Schuthof J, Smitz M T. Influence of xylitol on 
demineralization of enamel. Caries Res 1984, 18, 296-301 
Darby F B. Appliance to prevent mouth breathing. Dent Cosmos 1890, 32; 214 
Filler S J, Gregory R L, Michalek S M, Katz J, McGhee J R. Effect of immune 
bovine milk on Streptococcus mutans in human dental plaque. Arch Oral Biol 
1991, 36, 41-7 
Giebink G S. Preventing otitis media. Ann Otol Rhinol Laryngol 1994, 103, 
20-3 
Grenby T H. Advances in non-caloric sweeteners with dental health 
advantages over sugars. Proc Finn Dent Soc 1991, 87, 489-99. 
Hamilton I R. Effects of fluoride on enzymatic regulation of bacterial 
carbohydrate metabolism. Caries Res 1977, 11, (suppl 1) 262-91 
Harper D S, Loesche J. Inhibition of acid production from oral bacteria by 
fluoroapatite derived fluoride. J Dent Res 1986, 65, 30-3 
Isokangas P. Ksylitolin kaytto kouluikaisten kariespreventiossa. 
Tieteellinen tausta. Fiksu tapa. Valtakunnallinen terveystapahtuma. 
STAKES, Helsinki 1994, 4-16 
Kauppi M, Saarinen L, Kayhty H. Anti-capsular polysaccharide antibodies 
reduce nasopharyngeal colonization by Haemophilus influenzae type b in 
infant rats. J Infect Dis 1993, 167, 365-71. 
Kilian M, Thylstrup A, Fejerskov O. Predominant plaque flora of Tanzanian 
children exposed to high and low water fluoride concentrations. Caries Res 
1979, 13, 330-43 
Kontiokari T, Uhari M, Koskela M. Effect of xylitol on growth of 
nasopharyngeal bacteria in vitro. Antimikrob Agents Chemother 1995, August 
39(8), 1820-1823. 
Laitinen S. Ristipurennat yleistymassa--missasyy? (Crossbites becoming more 
general--where is the reason?) Suom Hammaslaak L 1995, n:o 16, 896-901 
Lenander-Lumikari M. Salivary peroxidase systems and lysozyme in defence 
against cariogenic microorganisms. Thesis. University of Turku 1992 
Ma JK-C, Lehner T. Prevention of colonization of Streptococcus mutans by 
topical application of monoclonal antibodies in human subjects. Arch Oral 
Biol 1990, 35, Suppl 115S-122S 
Ma J K-C, Hunjan M, Smith R, Kelly C, Lehner T. An investigation into the 
mechanism of protection by local passive immunization with monoclonal 
antibodies against Streptococcus mutans. Infect Immun 1990, 58, 3407-14 
Michalek S M, Gregory R L, Harmon C C, Kak J, Richardsson G J, Hilton T, 
Filler S J, McGhee J R. Protection of gnotobiotic rats against dental 
caries by passive immunization with bovine milk antibodies to 
Streptococcus mutans. Infect Immun 1987, 55, 2341-7 
Muhlemann H, Regolati B, Marthaler T. The effect of rat fissure caries of 
xylitol and sorbitol. Helv Odont Acta 1970, 14, 48-50 
Makinen K K. Biochemical principles of the use of xylitol in medicine and 
nutrition with special consideration of dental caries. Birkhauser Verlag, 
Basel 1978 
Makinen K K, Isokangas P. Relationship between carbohydrate sweeteners and 
oral diseases. Prog Food Nutr Sci 1988, 12, 73-109 
Makinen K K, Scheinin AS. Xylitol and dental caries. Ann Rev Nutr 1982, 2, 
100-20 
Neeser J-R, Chambaz A, Del Vedovo S, Prigent M-J, Guggenheim B. Specific 
and nonspecific inhibition of adhesion of oral Actinomyces and 
Streptococci to erythrocytes and polystyrene by caseinoglycopeptide 
derivates. Infect Immun 1988, 56, 3201-8 
Niemela M. Risk factors and symptoms of acute otitis media in children. 
Dissertation. Acta Universitatis Ouluensis D Medica 324. Oulu University, 
Oulu 1994 
Rolla G. Effects of fluoride on initiation of plaque formation. Caries Res 
1977a, 11 (suppl 1), 243-61 
Scheinin A, Makinen K K. Turku sugar studies I-XXI. Acta Odontol Scand 
(Suppl 70) 1975, 33, 1-351 
Suhonen J. Mutans streptococci and their specific oral target. New 
implications to prevent dental caries? Schweiz Monatsschr Zahnmed 1992, 
102, 286-291 
Suhonen J, Sener B, Bucher W, Luk F. Release of preventive agents from 
pacifiers in vitro. An introduction to a novel preventive measure. Schweiz 
Monatsschhr Zahnmed 1994, 104, 946-51 
Soderling E, Pihlanto-Leppala A. Uptake and expulsion of 
.sup.14 C-xylitol by xylitol-cultured Streptococcus mutans ATCC 25175 in 
vitro. Scand J Dent Res 1989, 97, 511-19 
Soderling E, Scheinin A. Perspectives on xylitol-induced oral effects. Proc 
Finn Dent Soc 1991, 87, 217-30 
Touster O. Essential pentosuria and the glucuronate-xylulose pathway. fed 
proc 1960, 19, 977-83 
Uhari M, Kontiokari T, Koskela M, Niemela M. Br Med J 1996, 313, 1180- 
van Houte J, Aasenden R, Peebles T C. Oral colonization of Streptococcus 
mutans in human subjects with low caries experience given fluoride 
supplements from birth. Arch Oral Biol 1978, 23, 361-6 
Varrela J, Alanen P. Voidaanko hampaiden asentovirheita ehkaista? (Can 
malpositions of the teeth be prevented?) Suom Hammasl L 1995, n:o 17, 
951-4 
Zickert I, Emilson C G. Effect of a fluoride-containing varnish on 
Streptococcus mutans in plaque and saliva. Scand J Dent Res 1982, 90, 
423-8