JPH0827009A - Beta-(1,3)-glucan used for suppressing destroy of oral cavity tissue caused by infectious irritation - Google Patents

Abstract

PURPOSE: To treat or prevent rupture of oral tissue by infectious irritation by administering β(1,3)-glucan of an amount effective for stimulating phagocytosis or germicidal action of neutrophil and monocyte to mammals without stimulating the production of cytokine. CONSTITUTION: This medicine for treating and preventing oral tissue rupture by infections irritation in mammals contains β(1,3)-glucan such as poly-β(1-6)- glucopyranoseglucan. The administration of therapeutically effective amount of the β(1,3)-glucan facilitates the treatment or the prevention of the oral tissue rupture of the mammals such as necrosis, rupture or failure of soft tissue of oral cavity, and rupture, absorption or failure of bone in addition to treatment or prevention of gingivitis. The medicine is administered in either form of subcutaneous administration, intravenous administration, intramuscular administration, oral administration, spray administration, topical injection, topical coating, oral irrigation, or administration by using a sustained release compound or storage.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to suppression of oral tissue destruction due to infection stimulus.

[0002]

2. Description of the Related Art Dental pulp and periodontal diseases are bacterial infections that cause destruction of local connective tissues and bones. Microorganisms that are considered to be the pathogens of these diseases are mainly Gram-negative anaerobes, and Actino
bacillus actinomycetemcomitans, Porphyromonas ging
ivalis, Prevotella intermedia and Campylobacter
recta (Dzink, JL et al., J. Clin. Perio
dontol. 15 : 316-323 (1988)). Infection with these bacteria is mediated by specific host responses mediated by T and B cells (Ebersole, JL, et al.,
J. Periodont. Res. 22: 184-186 (1987); Stashenko, P. et al., J. Periodont. Res. 18 : 587
-600 (1983)) and non-specific host responses (neutrophils, monocytes and cytokines), but especially in neutrophils and other dietary responses in the host defense response to these microorganisms. Most data support the important role of non-specific mechanisms involved in cells (genco).
(Genco, RJ), J. Periodontol. 63: 338-355 (1992);
Van Dyke, TE and Hoop (GA Hoo
p), Crit. Rev. Oral Biol. Med. 1 : 117-133 (1990)).
This means chronic granulomatous disease, periodic neutropenia,
Papillon-Lefevre synd
rome), leukocyte adhesion deficien
cies), Chediak-East syndrome, etc., is also shown by the finding that periodontal tissue destruction is found at a high frequency and extent (Barrett, AP, et al., O.
ral Surg. Oral Med. Oral Path. 69: 174-176 (1990);
Bauer, WH, J. Dent. Res. 25: 501-508
(1946); Cohen et al. (Cohen, MB, et al.), J. Periodon .
tol. 56 : 611-617 (1985); Cohen and D. Morris.
W., and AL Morris), J. Periodontol. 32: 159-168
(1961); Tempel et al. ( Tempel.TT , et al.), J. Perio
dont. Res. 7 (Suppl 10): 26-27 (1972); Van Dyke (Van
Dyke, TE, et al.), Clin. Immunol. Immunopathos.
31P : 419-429 (1984)).

At the heart of recent treatments for periodontal disease in humans are debridement and surgery, which reduce the microbial load in the affected area and the patient's ability to maintain tissue at the site of infection. To strengthen. Antimicrobial agents are also widely used as adjunctive therapies because it is now recognized that periodontal disease is an infection with a limited range of pathogens (Slots, J., and TE. RAM
s), J. Clin. Periodontol. 17 : 479-493 (1990)). The need for safe and effective treatments for periodontal disease remains high.

[0004]

Accordingly, the gist of the present invention comprises (1) β (1,3) -glucan,
A drug for treating or preventing oral tissue destruction due to infection stimulus in a mammal, (2) The drug according to (1) above, wherein the oral tissue is bone or gingival tissue, (3) β (1,
3) -A drug comprising glucan, which suppresses or prevents periodontal soft tissue destruction due to infection stimulus in mammals,
(4) An agent for suppressing or preventing periodontal bone destruction due to infection stimulation in a mammal, which comprises β (1,3) -glucan, (5) a mammal comprising β (1,3) -glucan (6) A drug for suppressing or preventing gingivitis in an animal, which is used so that a therapeutically effective amount of β (1,3) -glucan is continuously administered.
(7) The drug according to any one of (5), (7) The above-mentioned (1) to (5), which is used such that a therapeutically effective amount of β (1,3) -glucan is administered once. (8) The drug according to any one of (1) to (5) above, wherein the therapeutically effective dose of β (1,3) -glucan is 0.02 to 200 mg / kg. The drug described in (9) β
The drug according to any one of (1) to (8) above, wherein (1,3) -glucan is used together with a pharmaceutically acceptable carrier, (10) subcutaneous administration, intravenous administration, intramuscular administration, Administered by a method selected from the group consisting of oral administration, spray administration, topical infusion (eg, gingival injection), topical application, mouthwash, administration via sustained release compound, and administration via reservoir. (1) to (9)
(11) The drug according to any one of (1) to (10) above, wherein the mammal is a human.
(12) The drug according to any of (1) to (11) above, wherein the β (1,3) -glucan is used together with an antibiotic, (13) the β (1,3) -The glucan is PGG-glucan, (1) to (1) above.
The drug according to any one of 2).

The present invention provides poly-β (1-6) -glucotriosyl-β (1-3) -glucopyranose glucan (PGG-glucan, poly-β (1-6) -glucotriosyl-β (1- 3) -glucopyr
administration of β (1,3) -glucan such as anose glucan) to treat or prevent gingivitis, as well as necrosis, destruction or loss of oral soft tissue, bone destruction, absorption Or, it relates to a drug for treating or preventing the destruction of the oral tissue of a mammal caused by an infection stimulus such as a defect. β (1,3) -glucan is a biological response regulator (biologi) that enhances phagocytosis and bactericidal activity of neutrophils and monocytes.
cal response modifiers). Oral tissue destruction is treated and minimized by administering a therapeutically effective amount of β (1,3) -glucan to a mammal once or continuously at daily or weekly intervals. Limited or suppressed or prevented. Beta (1,3) -glucan is supplemented with pharmaceutically acceptable vehicles.
ly) can also be administered.

Biological response modifiers such as β (1,3) -glucan provide a new therapeutic method for the prevention and treatment of oral bacterial infections by enhancing the defense mechanism against bacteria of the host. This host-oriented method may be particularly timely given the growing concern about bacterial resistance to antibiotics that accompanies the widespread use of antibiotics. Furthermore, specific β (1,3) -glucans, which selectively stimulate the anti-infective function of neutrophils and monocytes without stimulating the production of cytokines such as PGG-glucan, are pro-inflammatory cytokine-induced bone. Since absorption can be prevented from occurring, it is considered to be an ideal drug for the treatment of oral infections such as periodontal disease.

The present invention is directed to oral tissue defects (i
biological response malignant agent as a prophylactic or therapeutic agent for nfection-stimulated oral tissue loss.
odifiers). Poly-β (1-6) -glucotriosyl-β (1-3)-, a biological response modifier that enhances phagocytosis and bactricidal activity of neutrophils and monocytes
Glucopyranose glucan (PGG-glucan) limits or prevents infection-induced alveolar bone resorption in an in vivo model. The basic structure of PGG-glucan is β
The glucopyranosyl skeleton to which -D- (1-3)-is bound has β-D- (1-
6)-has a side chain attached to it and has a molecular weight of about 100 kD (Jamas et al. (Jamas, S., et al.), Abstr. I
nt. Congr. Infect. Dis. 698 : 143 (1990)). PGG-
For details of glucan, refer to US Patent Application No. 07 / 934,015 filed on Aug. 21, 1992 (JP-A-6-107702). PGG-glucan increases neutrophil production and promotes phagocytosis and bactericidal activity in vivo (Shah, PM, et al., Abstr. Int. Co.
ng. Infect. Dis. (1990); Mackin, W. et a
l.), FASEB J. 8 : A488 (1994)). The important thing is PGG
-Glucans are pro-inflammatories such as interleukin-1 (IL-1) and tumor necrosis factor (TNF).
ry) By not inducing cytokines, this minimizes the inflammatory side effects that can injure (Dinarello, CA) , Abstr . Int. Cong. I
nfect. Dis ( 1990)). To date, there have been very few reports of toxicity associated with the use of this substance in animals and humans.

As will be described below, by exposing the pulp by surgery and causing infection under the oral environment, Spra
Induction of periapical bone resorption was induced in gue-Dawley rats. On the day before (1 day) the day of demyelination treatment (Day 0) and on the days 2, 4, 6, 9, 11, 13, 16 and 18 after the treatment of demyelination,
Animals were subcutaneously administered PGG-glucan (0.5 mg / kg) or saline (control). PGG-glucan increased the number of circulating neutrophils and monocytes and increased their phagocytic activity approximately 2-fold. Periapical bone resorption due to infection stimuli was significantly lower in PGG-glucan-treated animals compared to control animals (-40.8% and -42.4% for first and second molars, respectively). ; p <0.01). There was also less soft tissue destruction in PGG-glucan treated animals as indicated by a reduced degree of pulpal necrosis. Of the animals treated with PGG-glucan, the first molar pulp showing complete necrosis was 4 in the control group.
Only 3.3% compared to 0.6%. These findings are
We have shown that biological response modifiers that enhance the endogenous anti-bacterial mechanism of neutrophils can reduce the alveolar bone and soft tissue destruction by infectious stimuli in vivo.

[0009] Based on these findings, a method for treating or preventing the destruction of oral tissues due to the stimulation of infection in mammals including humans has been developed. The term “oral tissue” as used herein includes soft tissues such as bone and gum. As used herein, the term “tissue destruction” includes bone destruction, absorption or loss in addition to soft tissue necrosis, destruction or loss. Methods have also been developed to treat or prevent gingivitis. As used herein, the terms "treat" and "treatment" include bone resorption, bone destruction, as well as treating existing bone resorption, bone destruction or defect, soft tissue necrosis, destruction or defect or gingival inflammation. It also includes minimizing destruction or loss, necrosis of soft tissue, destruction or loss, or development of gingival inflammation. "Prevent"
And the term "prevention" includes the inhibition and / or prevention of bone or soft tissue absorption or destruction or gingival inflammation. A β (1,3) -glucan such as PGG-glucan is administered to a mammal in a therapeutically effective amount to treat or prevent the destruction of oral tissues or gingivitis. β
The (1,3) -glucan can be water-soluble or water-insoluble, and can be chemically modified. A therapeutically effective amount of β (1,3) -glucan is the dose of β (1,3) -glucan required to prevent, reduce or eliminate oral tissue destruction or gingivitis. β (1,3) -glucan is
It can also be administered by continuous administration at daily or weekly intervals. As used herein, the term "single dose" includes single dose and administration of sustained-release preparation. β (1,3) -glucan is subcutaneously, intravenously, intramuscularly, orally, spraying, locally injecting (that is, injecting into the gingiva), locally applying, rinsing the mouth, and as a sustained release compound. Alternatively, it can be administered by a reservoir in a dosage form containing a usual physiologically acceptable carrier or vehicle. The dosage form of PGG-glucan depends, at least in part, on the route of administration.

[0010] The desired therapeutically effective amount is, for embodiments in which the dosage in mg / kg can be determined, approximately
0.02 to 200 mg / kg / dose of β (1,3) -glucan. In other aspects, such as a method of administration by mouthwash,
A therapeutically effective amount is a suitable concentration of β (1,3) -glucan. The therapeutically effective amount is determined on an individual basis and depends, at least in part, on the severity of the tissue destruction or gingivitis to be treated and prevented, the mode of administration and the β (1,
3) -In addition to glucan, it is determined in consideration of the size of an individual. A suitable therapeutically effective amount of PGG-glucan for humans is US patent application Ser. No. 07/21, filed Aug. 21, 1992, the entire disclosure of which is hereby incorporated by reference.
It has been established by clinical tests as described in Japanese Patent Laid-Open No. 6-107702.

Β (1,3) -glucan can be administered alone or together with other agents such as antibiotics. Suitable antibiotics include anti-infective agents such as fungicides or bacteriostats.

[0012]

The present invention will be described in more detail by the following examples. Suppression of Alveolar Bone Defects by In Vivo Infection Stimulation To investigate whether PGG-glucan can be applied to oral infections, a rat model inducing alveolar bone defects was used (Yu and Staschenko (Yu, SM, and P.Sta
shenko), J. Endondon 13:. 535-540 (1987)). In this model, surgical demyelination and infection in the oral environment induce periapical resorption. Bone resorption around the apical root is 2 from 7th day after demyelination
During day 0 it is rapid (active phase) and thereafter absorption is slow (chronic phase). Infiltration with mixed inflammatory cells centering on neutrophils and T lymphocytes is seen. There is a high level of bone resorption activity in the periapical tissues of the active stage (Wang, C.-Y., and P.Stashenko) J.Dent.R
es.70: 1362-1366 (1991)), which is mediated primarily by interleukin-1α (Wan and Stashenko (Wa
ng, C.-Y., and P.Stashenko), Oral Microbiol. Immuno
l. 8: 50-56 (1993)). This model mimics periodontitis in microbiology, immunology and etiology (Tani-Ishii, N., et al.), Oral Microbiol . Immun.
ol ., Printing (1994); Yu, SM, and
P.Stashenko), J. Endondon . 13 : 535-540 (1987)).
However, taking into account the aggressive nature of periapical lesions, this model provides a more stringent way to test the effects of neutrophil biologic response modifiers in combating oral infections that cause periodontal disease.

Embodiment 1. Induction of Periapical Lesions A total of 32 male Sprague-Dawley CD rats weighing 300-325 g were used. To induce periapical lesions (Yu, SM, and P. Stashenko,
) J. Endondon . 13 : 535-540 (1987)), on day 0, ketamine (80 mg / kg) and xylazine (xylazine).
(10 mg / kg) was dissolved in sterile phosphate buffer solution (PBS) and injected intraperitoneally to anesthetize the rat, and the rat was placed on a jaw retraction board. Portable Variable Speed Electric Handpiece (Okada Elec
The pulp was exposed using Tric Co., Los Angeles, Calif.). The demyelination procedure has a bifurcation (furcal
1 of bar drill (bur)
The size was / 4 and the depth was the diameter of the bar drill. The exposed teeth were placed in the oral environment. In all animals, surgical procedures were performed on the mandibular first and second molars (4 teeth / animal).

Example 2. Glucan-treated animals were randomly divided into 16 animals per group and neutrophil biological response modifier PGG-glucan (BETAFECTIN®, Alpha-Beta Technology, Inc., Worcester, Mass.) Or sterile as a control 1 saline solution
0.5 mg / kg was administered. On the day before exposing the pulp of the first and second molars of the lower jaw,
G-glucan or physiological saline was administered. The day when the pulp was exposed was designated as the 0th day. After that, 2, 4, 6,
PGG-glucan or saline was administered on days 9, 11, 13, 16 and 18. Treatment was by subcutaneous injection with a total volume of 0.5 ml.

Example 3. White blood cell count The effect of PGG-glucan treatment was the same as that reported previously (Onderdonk, AB, et al., Infect . Immun .
60 : 1642-1647 (1992)), and evaluated by the change in white blood cell count from the baseline. On days 1 and 10 heparinized blood samples were obtained from the retroorbital sinus,
The effect of PGG-glucan on peripheral leukocyte count was examined. The sample was diluted with 2% acetic acid and the total white blood cell count was counted using a hemocytometer. Blood smear was stained with Wright / Giemsa and leukocyte fractionation (diff
erential counts) were measured. Differences in peripheral leukocyte counts between treated and control groups were analyzed and examined for statistical significance by Student's t-test. The results are shown in Table 1.

[0016]

[Table 1]

As shown in Table 1, in the PGG-glucan-treated animals, total leukocytes in the circulating blood increased by about 25% at 10 days after demyelination (p <0.
01). On the other hand, in control animals that received saline,
Although an increasing tendency was observed on the 10th day, a significant increase in the total white blood cell count was not observed. This slight increase in white blood cells is due to an increase in the number of neutrophils and is thought to be due to dental pulp infection.

By counting leukocyte fractions, the increase in leukocyte numbers in PGG-glucan treated animals was all due to an increase in circulating neutrophils, compared to both control animals and pretreatment levels. It was revealed that the number increased about 2-fold (Table 1). On the other hand, the absolute number of lymphocytes remained constant during the experimental period, although its relative proportion decreased. These data show that administration of β (1,3) -glucan increases neutrophilia and monocytes.
ia), which is in agreement with previous reports of the action of this biological response modifier in vivo (Onderdonk, AB, et al.
al.), Infect. Immun. 60 : 1642-1647 (1992)).

Example 4. Phagocytosis test The ability of PGG-glucan to regulate the antimicrobial activity of neutrophils was measured. Neutrophils were collected from control and PGG-glucan treated animals and tested for phagocytic capacity against opsonized E. coli. Control or PG before killing animals on day 20
Blood was drawn from G-glucan-treated rats by cardiac puncture and collected in test tubes containing EDTA. Discontinuous neutrophils
Separation from whole blood using a coll-Hypaque gradient. Isolate the neutrophil layer and remove the contaminating red blood cells from the double distilled water (doubl
It was dissolved by short-term (30 seconds) exposure to e-distilled water). Neutrophils are treated with Hanks balanced salt solution (Ca
⁺² , Mg ⁺² free) 3 times, final concentration 2
Resuspend at 10 ⁶ / ml. For phagocytosis, opsonized Texas Red-labeled (Texas Red-l
abelled) Escherichia coli (2 × 10 ⁷ / ml; Molecular Pro
bes, Eugene, OR) were incubated with neutrophils for 30 minutes at 37 ° C. with constant agitation. The neutrophil-bacterial mixture was fixed, mounted on a microscope table and observed using a fluorescence microscope (Nikon Diaphot). The number of neutrophils and the number of digested bacteria per cell were measured. The data obtained from a representative experiment are shown in FIG.

Overall, the number of bacteria digested per cell increased approximately 2-fold in PGG-glucan treated animals.
(8.3 ± 5.3 vs 4.5 ± 3.5 bacteria / cell). In addition, E.coli
The proportion of neutrophils containing P was higher in neutrophils isolated from PGG-glucan treated rats (24.8%) than in control rats (16.2%). PGG-
These data demonstrate that neutrophils taken from glucan-treated animals show both increased numbers and enhanced phagocytic activity.

Example 5. Radiography and histomorphometry to measure pulp necrosis To investigate the mechanism of inhibition of bone resorption in PGG-glucan treated animals, the effect on soft tissue pulp destruction was measured. The animals on day 20 of the pulp exposure treatment were killed by asphyxiation in _two boxes CO. The lower jaw is dissected free of tissue and a "soft" X-ray machine (Hewlitt-Packard FAXITRON Model 43855A) and high-speed, high-resolution holographic film (Kodak SO-
253) was used to take radiographs. The radiograph was developed using an A / T 2000 automatic developing device and examined for the presence of radiolucencies around the apical surface of the tooth root. For histomorphometry, the lower jaw was fixed, decalcified in EDTA, embedded in paraffin and sectioned. Every 10 sections were stained with hematoxylin and eosin. Sections selected for analysis were radicul
ar pulp), apical foramen, and the most extensively absorbed periapical region. The size of the absorbed area around the tip of the tooth was previously calibrated in millimeters to the Optimus Bioscan system (O
ptimas Bioscan system). The results showed resorbed bone in mm ² . The extent of pulp necrosis was expressed as the ratio of the length of necrotic root pulp, defined by the loss of histological content of cells and nuclei, divided by the distance from the enamel cement border to the apex. The difference in pulp necrosis between the two groups was determined by the Chi-Square analysis.

As shown in FIG. 2, in the PGG-glucan-treated animals, a significant reduction in the degree of root myelination of the first molar was observed as compared with the control animals. In the PGG-glucan treated group only 1 out of 30 teeth (3.3%) showed complete pulp necrosis, whereas in the control group 13 out of 32 teeth (40.6%) showed complete necrosis ( p <0.001). Similar results were seen with the second molars (complete necrosis: 13 out of 30 in PGG-glucan treated animals and 22 out of 32 in control animals).
Book) . In PGG-glucan-treated animals, the area of infection and necrosis was typically confined to approximately 60% of the root pulp (data not shown), with only marginal periapical bone resorption observed. there were. Extreme infiltration of inflammatory cells was found at the border of necrotic and live tissue. In contrast, control animals often had complete necrosis and mild periapical destruction (data not shown). These data suggest that the observed inhibition of bone resorption may be due to a slower rate of bacterial infection invading the pulp tissue and progressing to the periapical region.

Example 6. Bone resorption test Since the final action of PGG-glucan was the inhibition of bone destruction around the apical tooth, this substance showed osteoclast resorption (osteoc).
It was investigated whether it had a direct regulatory effect on lastic resorption). To this end, the fetal rat long bone test, which is widely used to assess the bone resorption activity of putative agonists, was utilized. The fetal rat long bone test was performed as described using an unpaired format (Wang, C.-Y., an.
d P. Stashenko), J. Dent. Res. 70 : 1362-1366 (199
1)). Briefly, pregnant Holzman rats were treated on day 18 of gestation with 100 μCI of ⁴⁵ Ca (New England Nuclear,
Fetal bones were labeled by injecting (Boston, MA). Radial and ulnar shafts were obtained from fetuses with a 19-year-old fetus by microdissection. Bone was pre-incubated with 0.5 ml BGJb medium for 1 day to reduce exchangeable Ca ⁴⁵ . The radius and ulna were then randomly cultured in humidified 95% air / 5% CO ₂ for 5 days at 37 ° C. After 2 days of culture, the medium was changed once. Unless otherwise noted, the test groups consisted of 5 bones in each group, while the control group (medium only) consisted of 15-20 bones. The percentage of ⁴⁵ Ca released from each bone was determined by measuring the radioactivity of residual bone dissolved in 0-2 day medium, 2-5 day medium and trichloroacetic acid using a liquid scintillation counter. . Mean values and standard deviations were calculated for each group of bones. Significant differences between stimulated ⁴⁵ Ca release compared to controls were examined using Student's t test. The results are shown in Table 2 below.

[0024]

[Table 2]

As shown in Table 2, parathyroid hormone (PTH; 65 ± 5.0%) and interleukin 1β (IL-
β; 49.7 ± 16.5%), compared with the control (19.6 ± 1.4%), osteoclastic bone resorpt
ion). PGG-glucan had no significant effect on basal ⁴⁵ Ca release at concentrations of 0.05-5 μg / ml, and
Bone resorption upon stimulation of H and IL-1 was also unchanged.
These data demonstrate that PGG-glucan does not directly regulate bone resorption in vitro, and its interpretation is that the major action of PGG-glucan is to enhance neutrophil function. I support you.

Example 7. Radiographic analysis of bone resorption and histomorphometry The effect of PGG-glucan on periapical resorption was evaluated by high resolution radiography. Radiographic analysis was performed only on the distal root of the first molar, which is the most radiographically accessible for anatomical reasons.
As shown in Table 3, there was a 48% reduction in the area of the periapical radiolucent area in PGG-glucan treated animals on day 20 of exposure.

[0027]

[Table 3]

Radiography often makes a serious underestimation of periapical bone resorption (Bender, IB, and S. Seltzer, J. A.
m. Dent. Assoc. 62 (Part I): 153-160 (1961)). The mandible was processed for histomorphometry to more reliably measure periapical fracture. The results are shown in Table 4 and FIG.

[0029]

[Table 4]

As shown in Table 4 and FIG. 3, by direct measurement of histological sections, PGG-glucan-treated rats had centrifugal roots of both the first and second molars compared to control rats. Of periapical bone resorption was significantly lower in the surroundings (-40.8% and -42.4%, p <0.0, respectively).
1). In both control and PGG-glucan treated animals, the extent of resorption for the second molar was greater than that around the first molar. This is believed to reflect the fact that infection is more rapid in the periapical region due to the short distal root of the second molar.

Example 8. The relationship between pulp necrosis and resorption The relationship between pulp necrosis and bone resorption was plotted using a scatter plot
Further investigation by plots) and regression analysis. As shown in FIG. 4, in PGG-glucan treated animals, a highly significant correlation was observed between the percentage of necrotic root pulp tissue and the size of periapical lesions that developed (r = 0.52, p <. 0.0
1). Both values were measured by histomorphometry. This relationship was also true in control rats (no data presented; r = 0.75, p <0.001) and similar results were obtained with the second molars (no data presented; control group and PGG-glucan treatment). P <0.001 for both groups. Thus, these findings indicate that PGG-glucan significantly reduces the rate at which bacterial infections invade and destroy soft tissue, limiting the progression of infection around the periapical area, where bone resorption is stimulated by the infection. It proves to be done. The data further suggests that periapical bone resorption correlates with the extent of pulp necrosis in this model.

One of ordinary skill in the art would be able to recognize or ascertain the many equivalents to the particular embodiments discussed in this application using only routine experimentation. Such equivalents are intended to be within the scope of the following claims.

[0033]

EFFECT OF THE INVENTION β (1,3) -such as PGG-glucan
Glucan enhances phagocytosis and bactericidal activity of neutrophils and monocytes without stimulating the production of cytokines, and by administering a therapeutically effective amount of β (1,3) -glucan to mammals. , It is possible to treat or prevent the tissue destruction of the oral cavity due to infection stimulus.

[Brief description of drawings]

FIG. 1 shows P on rat neutrophil phagocytic activity.
The action of GG-glucan is shown. Neutrophils were obtained from the peripheral blood of rats treated with PGG-glucan (●) or saline (■) as a control. The phagocytic capacity of neutrophils against opsonized Texas Red labeled Escherichia coli
It was quantified by a fluorescence microscope. The X-axis represents the number of bacteria that have undergone phagocytosis per cell, and the Y-axis represents the proportion of cells containing phagocytosed bacteria.

FIG. 2 shows the effect of PGG-glucan on pulp necrosis. The degree of necrosis depends on the distal root (t
His distal root of mandibular first molars) was measured by histomorphometry. Data are from 16 animals (2 teeth / animal) in the PGG-glucan and control groups. It is noted that a significant number of teeth in the control group show complete necrosis. Horizontal bars indicate average values.

[Fig. 3] Fig. 3 shows PGG- for bone resorption around the root apex.
It shows the action of glucan. The data are absorption areas (mm ² ) measured by histomorphometry around the distal root of the lower first molar. Data are from 16 animals (2 teeth / animal) in the PGG-glucan group and control group. Horizontal bars indicate average values.

FIG. 4 shows the relationship between pulp necrosis and periapical bone resorption. The X-axis represents the proportion of necrotic pulp, centrifugal roots, and first molars, and the Y-axis represents the absorption area (mm ² ) around the apical root.

Claims (13)

[Claims] 1. A method comprising β (1,3) -glucan,
A drug for treating or preventing oral tissue destruction due to infection stimulus in mammals. 2. The drug according to claim 1, wherein the oral tissue is bone or gingival tissue. 3. A method comprising β (1,3) -glucan,
A drug that suppresses or prevents periodontal soft tissue destruction due to infection stimulus in mammals. 4. A method comprising β (1,3) -glucan,
A drug which suppresses or prevents periodontal bone destruction due to infection stimulation in mammals. 5. A method comprising β (1,3) -glucan,
An agent for suppressing or preventing gingivitis in a mammal. 6. A therapeutically effective amount of β (1,3) -glucan used to be continuously administered.
The drug according to any one of 1. 7. A therapeutically effective amount of β (1,3) -glucan used to be administered as a single dose.
The drug according to any one of 1. 8. The agent according to any one of claims 1 to 5, wherein a single dose of therapeutically effective β (1,3) -glucan is 0.02 to 200 mg / kg. 9. The agent according to claim 1, wherein β (1,3) -glucan is used together with a pharmaceutically acceptable carrier. 10. Subcutaneous administration, intravenous administration, intramuscular administration,
Oral administration, spray administration, local infusion (eg gingival injection),
The agent according to any one of claims 1 to 9, which is administered by a method selected from the group consisting of topical application, mouthwash, administration via sustained release compound, and administration via reservoir. 11. The method according to claim 1, wherein the mammal is a human.
0. The drug according to 0. 12. The agent according to any one of claims 1 to 11, wherein β (1,3) -glucan is used for administration with an antibiotic. 13. The β (1,3) -glucan is PGG-
The drug according to any one of claims 1 to 12, which is a glucan.