**Acknowledgements**

This study was carried out with the support of the grant in aid for scientific research (A) and (B) of JSPS. The experiments were assisted by Mr. Tsurui and Mr. Sugano who were the graduate students of Kyoto University at that time. We appreciate the financial and technical support.


**Author details**

Roger Saint-Fort

Address all correspondence to<EMAIL_ADDRESS>
Department of Environmental Science, Faculty of Science and Technology, Mount Royal University, Calgary, AB, Canada


**8. Surgical approach**

Obesity is an important factor to consider when determining an appropriate surgical approach to hysterectomy. A systematic review published in 2015 by Blikkendaal et al., found that laparoscopic hysterectomy and vaginal hysterectomy are associated with significantly fewer postoperative complications and shorter lengths of hospital stay [31]. While vaginal hysterectomy is generally the preferred surgical approach and is associated with improved outcomes, it seems to be less favorable in obese patients due to large uterine size, early-stage endometrial cancer, or lack of vaginal access and exposure secondary to the patient's body habitus [31]. In patients who are not good candidates for vaginal surgery, conventional laparoscopic hysterectomy and robotic hysterectomy are alternative approaches that are shown to be safe and feasible in this patient population [31, 32].

The benefits of minimally invasive surgery are well studied. Compared to laparotomy, laparoscopic hysterectomy results in fewer postoperative complications, decreased blood loss, less time in the hospital, and faster recovery [31, 33]. One study showed that obese patients who underwent laparoscopic hysterectomy compared with laparotomy had fewer incidences of postoperative ileus (0% vs. 13.3%), less postoperative fevers (5.5% vs. 31.1%), and a decrease in wound infections (9% vs. 22%) [15]. Additionally, obese women undergoing laparoscopic hysterectomies, bilateral salpingo-oophorectomy, and lymph node dissection for stage I endometrial carcinoma were found to have shorter hospital stays (2.5 vs. 5.6 days), less pain (32.2 vs. 124.1 mg of pain medication), and earlier return to normal activity [15].

Despite the clear benefits of minimally invasive techniques, research evaluating surgeons' surgical preference shows that the rate of abdominal hysterectomy increases as BMI increases [31]. In fact, in the past obesity was considered a relative contraindication to laparoscopic surgery. This is due to associated difficulties with Verees needle placement, accumulation of fat in the omentum obstructing the operative field and manipulation of laparoscopic instruments [15]. However, more recent studies have shown that minimally invasive approaches including robotics and conventional laparoscopic techniques can be successful in obese patients with proper planning and appropriate laparoscopic surgical experience.

Robotic surgery may help overcome some of the inherent challenges of minimally invasive surgery in obese patients. Robotic surgery offers greater flexibility, articulation, and control of the instruments with reduced hand tremors. Improved ergonomics and the 3D-HD view allow for surgeons to more easily operate within the confined space of an obese abdomen and reduce surgeon fatigue [33]. This is especially relevant in obese patients with endometrial cancer when lymphadenectomy is required [34]. The advantages of robotic surgery may help facilitate the completion of hysterectomy using a minimally invasive approach, however, the cost is significant. Each robotic console has a direct cost of \$2.6 million USD and about \$2000 per surgical case [34].

While most studies comparing robotic surgery to laparoscopic surgery have not been able to show an improvement in safety or efficacy compared with conventional laparoscopy, there is evidence that robotic surgery may provide clinical benefits in specific populations like the morbidly obese [34–36]. In fact, there is evidence of cost neutralization with robotic procedures when the rate of conversion to laparotomy is decreased [34]. A recent systematic review and meta-analysis comparing laparoscopic and robotic hysterectomy in endometrial cancer patients with obesity found similar perioperative complication rates but a decrease in conversion to laparotomy in robotic procedures performed on patients with BMI > 40 kg/m2 (7.0% vs. 3.8%) [34]. Additionally, the qualitative reasons for conversion were different in robotic hysterectomy and conventional laparoscopic hysterectomy. Conversion to laparotomy from conventional laparoscopy was more often due to obesity-related anesthetic concerns (30% vs. 6%) while conversion from robotic assisted laparoscopy was attributed more frequently to increased uterine size [34].


**Present and Future Non-Surgical Therapeutic Strategies for the Management of Periodontal Diseases**

Renata S. Leite1,3 and Keith L. Kirkwood2,3 *1Department of Stomatology and 2Craniofacial Biology, College of Dental Medicine, 3Center for Oral Health Research, Medical University of South Carolina, Charleston, SC, USA*

## **1. Introduction**

Periodontal disease is a chronic bacterial infection of the periodontium affecting the tissues surrounding and supporting the teeth. Periodontal disease progression is associated with subgingival bacterial colonization and biofilm formation principal to chronic inflammation of soft tissues, degradation of collagen fibers supporting the tooth to the gingiva and alveolar bone, as well as resorption of the alveolar bone itself. Since the fundamental role of microorganisms in its etiology was systematically demonstrated some forty years ago, research efforts have long focused on identifying the pathogenic microorganisms and their virulence factors (Socransky and Haffajee, 1994). The search for these putative microorganisms was driven, in part, by knowledge indicating that colonization of the oral cavity and presence of dental biofilm is normally associated with health, similarly to the colonization of the colon. To treat periodontal diseases as an infectious disease, numerous therapeutic strategies aimed at eradication of periodontal pathogens have been studied over the years, including local and systemic delivery of antimicrobial and antibiotic agents. This review will cover an update on chemotherapeutic agents used adjunctively to treat and manage periodontal diseases.

In the current paradigm of periodontal disease, specific periodontal pathogens are necessary for disease initiation; however, the extent and severity of tissue destruction are largely dependent on the nature of the host-microbial interactions. These interactions are dynamic, since both the microbial composition of the dental biofilm and the competency of host immune responses can vary, in the same individual, over time. This concept was developed in parallel to the advances on the understanding of the immune response, and research on periodontal disease has been emphasizing mechanisms of host-microbial interactions to understand the disease process, as well as for the development of novel therapeutic strategies. For the past two decades, the host response to the bacterial challenge originating from the dental biofilm has been considered to play a major role on both initiation of the disease and on the tissue destruction associated with its progress (Kirkwood, et al., 2007). The importance of host-microbial interactions is reinforced by epidemiological data indicating different susceptibilities to periodontal disease among individuals, in spite of the

Present and Future Non-Surgical Therapeutic

compared to placebo (Ng and Bissada, 1998).

Macrolide Azithromycin

Table 1. Systemic antibiotic choices.

**Combination Therapy**

Table 2. Systemic antibiotic dosing regimens.

**Class Agent Effect Target**

Penicillin Amoxicillin Bacteriocidal Gram + and

Augmentin Bacteriocidal

Minocycline Bacteriostatic Gram + >

Doxycycline Bacteriostatic Gram + >

Bacteriostatic

Bacteriocidal depending on concentration

to Gram -

Metronidazole + Amoxicillin 250 mg of each Three times daily X 8 days Metronidazole + Ciprofloxacin 500 mg of each Twice daily X 8 days

**Single Agent Regimen Dosage/Duration**  Amoxicillin 500 mg Three times per day X 8 days Azithromycin 500 mg Once daily X 4-7 days Ciprofloxacin 500 mg Twice daily X 8 days Clindamycin 300 mg Three times daily X 10 days Doxycycline or Minocycline 100-200 mg Once daily X 21 days Metronidazole 500 mg Three times daily X 8 days

OR

Quinolone Ciprofloxacin Bacteriocidal Gram - rods Nausea, GI discomfort

Tetracycline Tetracycline Bacteriostatic Gram + >

Lincomycin Clindamycin Bacteriocidal Anaerobic

Nitroimidazole Metronidazole Bacteriocidal

**Antibiotic**

Strategies for the Management of Periodontal Diseases 299

on supragingival plaque accumulation with a possible exception in one study where doxycycline significantly decreased plaque accumulation at a twelve-week evaluation

Gram -

Gram -

Gram -

bacteria

Gram -; esp. *P. gingivalis* and

*P. intermedia*

Narrower spectrum than Amoxicillin

**Organisms Limitation**

Patient

Gram - Bacterial resistance

Penicillinase sensitive

More expensive than

Not good choice for *A. Actinomycetemcomitans*

infections

hypersensitivity

Amoxicillin

long-term presence of oral biofilm (Baelum and Fejerskov, 1986, Baelum, et al., 1988, Loe, et al., 1986). Other studies demonstrating increased susceptibility and greater severity of periodontal disease in individuals with impaired immune response due to systemic conditions also indicate the significance of the host response to the bacterial challenge (Feller and Lemmer, 2008, Mealey, 1998). Both past and future directions of host-modulatory agents will be addressed here to provide the dental practitioner with a broader prospective of chemotherapeutic agents used to manage periodontal diseases.

## **2. Antibiotics**

Contemporary periodontal therapies aim at mechanical removal of bacterial deposits to maintain a healthy sulcus or produce an environment suitable for new attachment. The inability of mechanical treatment to produce a desirable root surface in all cases coupled with the nature and complexity of the subgingival biofilm has fueled the search for adjunctive treatment regimens that increase the likelihood to successfully manage periodontal diseases.

While more than 700 bacterial species may be present in the gingival sulcus, it is clear that only a subset of bacterial species are consistently found to be associated with diseased sites. These findings make the prospect of targeted antibiotic therapy an attractive goal. The literature on antimicrobial periodontal therapy has been thoroughly reviewed (Ellen and McCulloch, 1996, Goodson, 1994, van Winkelhoff, et al., 1996).

## **2.1 Systemic antibiotics**

Adjunctive systemic antibiotic therapies have indicated beneficial effects for patients with periodontal diseases., The optimal timing of antimicrobial drug administration is still a subject of discussion, as the literature is controversial whether it should be administered during the initial non-surgical phase (Loesche, et al., 1992), or during a subsequent surgical phase (Herrera, et al., 2008). Although not directly confirmed yet by a clinical trial, it seems preferable, from a general health point of view, to let patients benefit early from the positive systemic effects of successful periodontal therapy. Table 1 provides an overview of some orally active systemic antibiotics commonly used in clinical periodontics.

Caution should be noted that none of these antibiotics is to be used as a monotherapy to treat periodontal diseases. Systemic antibiotics reach the periodontal tissues by transudation from the serum then cross the crevicular and junctional epithelia to enter the gingival sulcus. The concentration of the antibiotic in this site may be inadequate for the desired antimicrobial effect without mechanical disruption of the plaque biofilm. In addition to any effect produced in the sulcus, a systemically administered antibiotic will produce antimicrobial effects in other areas of the oral cavity. This additional effect will reduce bacterial counts on the tongue and other mucosal surfaces, thus potentially aiding to delay re-colonization of subgingival sites. Research however, indicates that antibiotics are detectable in the sulcus and the range of their concentrations in the gingival crevicular fluid is known to be in therapeutic range treatment efficacy. Table 2 provides information to facilitate the clinician's decision to the most reasonable choice of antibiotic, dose and duration of administration.

Many studies have been completed and published describing the effect of systemic antibiotic therapy on periodontal disease. Several different treatment regimens have been employed successfully to manage periodontal diseases (Slots and Ting, 2002). Considering a number of studies, it can be stated generally that systemic antibiotic therapy has little effect

long-term presence of oral biofilm (Baelum and Fejerskov, 1986, Baelum, et al., 1988, Loe, et al., 1986). Other studies demonstrating increased susceptibility and greater severity of periodontal disease in individuals with impaired immune response due to systemic conditions also indicate the significance of the host response to the bacterial challenge (Feller and Lemmer, 2008, Mealey, 1998). Both past and future directions of host-modulatory agents will be addressed here to provide the dental practitioner with a broader prospective

Contemporary periodontal therapies aim at mechanical removal of bacterial deposits to maintain a healthy sulcus or produce an environment suitable for new attachment. The inability of mechanical treatment to produce a desirable root surface in all cases coupled with the nature and complexity of the subgingival biofilm has fueled the search for adjunctive treatment regimens that increase the likelihood to successfully manage

While more than 700 bacterial species may be present in the gingival sulcus, it is clear that only a subset of bacterial species are consistently found to be associated with diseased sites. These findings make the prospect of targeted antibiotic therapy an attractive goal. The literature on antimicrobial periodontal therapy has been thoroughly reviewed (Ellen and

Adjunctive systemic antibiotic therapies have indicated beneficial effects for patients with periodontal diseases., The optimal timing of antimicrobial drug administration is still a subject of discussion, as the literature is controversial whether it should be administered during the initial non-surgical phase (Loesche, et al., 1992), or during a subsequent surgical phase (Herrera, et al., 2008). Although not directly confirmed yet by a clinical trial, it seems preferable, from a general health point of view, to let patients benefit early from the positive systemic effects of successful periodontal therapy. Table 1 provides an overview of some

Caution should be noted that none of these antibiotics is to be used as a monotherapy to treat periodontal diseases. Systemic antibiotics reach the periodontal tissues by transudation from the serum then cross the crevicular and junctional epithelia to enter the gingival sulcus. The concentration of the antibiotic in this site may be inadequate for the desired antimicrobial effect without mechanical disruption of the plaque biofilm. In addition to any effect produced in the sulcus, a systemically administered antibiotic will produce antimicrobial effects in other areas of the oral cavity. This additional effect will reduce bacterial counts on the tongue and other mucosal surfaces, thus potentially aiding to delay re-colonization of subgingival sites. Research however, indicates that antibiotics are detectable in the sulcus and the range of their concentrations in the gingival crevicular fluid is known to be in therapeutic range treatment efficacy. Table 2 provides information to facilitate the clinician's decision to the most

Many studies have been completed and published describing the effect of systemic antibiotic therapy on periodontal disease. Several different treatment regimens have been employed successfully to manage periodontal diseases (Slots and Ting, 2002). Considering a number of studies, it can be stated generally that systemic antibiotic therapy has little effect

of chemotherapeutic agents used to manage periodontal diseases.

McCulloch, 1996, Goodson, 1994, van Winkelhoff, et al., 1996).

orally active systemic antibiotics commonly used in clinical periodontics.

reasonable choice of antibiotic, dose and duration of administration.

**2. Antibiotics**

periodontal diseases.

**2.1 Systemic antibiotics**

on supragingival plaque accumulation with a possible exception in one study where doxycycline significantly decreased plaque accumulation at a twelve-week evaluation compared to placebo (Ng and Bissada, 1998).

Table 1. Systemic antibiotic choices.

Table 2. Systemic antibiotic dosing regimens.

Present and Future Non-Surgical Therapeutic

**Delivery**

Hollow fibers

Fluid; multi-

depending on volume of site; in syringe

Solid; in unit doses applied with syringe

Table 3. Local antibiotic delivery systems.

gel it is still better than the solid Actisite™ fibers.

that is applied as a gel using a syringe method.

site

Fluid; multi-site depending on volume of site; in syringe

absorbable system (Table 3).

**Antimicrobial Agent**

Tetracycline 12.7 mg per 9 inches of fiber

Doxycycline

Metronidazole

Minocycline Spheres

10%

25%

Gel

2%

Strategies for the Management of Periodontal Diseases 301

shrinkage and pocket reduction and reduction of the inflammatory response were commonly seen. The Actisite™ system, while very effective, was tedious to use and required the second visit for removal of the fiber. These issues fueled the development of an

**Concentration**

>1300 ug/ml for 10 days

250 ug/ml still noted at 7 days

More than 120 mg/ml of sulcus fluid in the first few hours

Therapeutic drug levels for 14 days

The first resorbable local antibiotic system was Atridox™(Atrix Laboratories). In this system, longer half-lived doxycycline replaced tetracycline supplied at a concentration of 42.5 mg per unit of material. Atridox™ improved the local antibiotic routines by allowing placement of the material to the depth of most pockets and in a manner that allowed it to conform to the shape of the pocket unlike the solid fibers of Actisite™. Depending on the size of the

Further development of absorbable local antibiotic systems led to Arestin™ (OraPharma) that uses minocycline in a microsphere configuration, each sphere measuring 20-60 microns in diameter. The antibiotic maintains therapeutic drug levels and remains in the pocket for 14 days. This configuration of the material allows placement to the depths of most pockets and while the material cannot conform to the shape of the pocket as well as the Atridox™

Another material, not available in the United States, is Elyzol™(Colgate), a metronidazole gel system. This material is supplied as 25% metronidazole in a glyceryl mono-oleate and sesame oil base. The concentration of Metronidazole in this system is 250 mg/g of material

**Time to**

Not absorbable

**Absorption Brand Name**

21 days Atridox

14 days Arestin

Concentration decreases rapidly after the first few hours (Knoll-Kohler, 1999)

Actisite No longer commercially available

Elyzol

**Form Drawback GCF**

2nd procedure for fiber removal

Often pulls out when removing syringe

May require multiple applications for desirable results

Unit doses may not be sufficient for every site volume

pocket, more than one site could be treated with a single unit of Atridox™.

Except for the combination of metronidazole with amoxicillin, systemic antibiotic treatment produces no clinically significant effects on periodontal pocket depth reduction compared with controls (Winkel, et al., 2001) ((Cionca, et al., 2009). A seven-day regimen of systemic metronidazole significantly reduced the percentage of sites with bleeding compared to controls (Watts, et al., 1986). Others have reported a 12-month reduction in bleeding after treatment with a metronidazole-amoxicillin combination compared to a placebo treatment (Lopez, et al., 2000). With respect to clinical attachment levels, systemic metronidazole and combinations of metronidazole with other antibiotics has shown improvement in several studies. Several investigators found significant improvement of attachment levels at sites initially 4-6 mm in depth with a seven-day treatment with metronidazole (Elter, et al., 1997, Loesche, et al., 1992, Loesche, et al., 1984). Winkel et al. showed that the combination of metronidazole and amoxicillin for 7 to 14 days produced a significant increase in the percentage of sites showing improved attachment levels compared to control sites (Winkel, et al., 2001). A combination of metronidazole and clindamycin for three weeks also produced improved attachment levels. (Gomi, et al., 2007, Sigusch, et al., 2001).

Some data to date supports a clinical benefit from the use of azithromycin as a systemic approach in combination with mechanical routines. In one limited study, seventeen subjects receiving azithromycin (500 mg), three days before full-mouth scaling and root planing produced greater clinical improvement than in seventeen subjects treated with full-mouth scaling and root planing alone (Gomi, et al., 2007). Dastoor et al. studied thirty patients who reported smoking more than one pack per day and presented with periodontitis. A comparison was made between the response to treatment with periodontal surgery and 500 mg Azithromycin per day for three days and treatment with periodontal surgery only. The addition of Azithromycin did not enhance improvements seen in both groups for attachment gain, depth reduction and reduction of bleeding on probing. However, the adjunctive use of Azithromycin was associated with a lower gingival index at two weeks and what the authors saw as more rapid wound healing. The addition of Azithromycin also produced reductions of red-complex bacteria that were maintained to three months (Dastoor, et al., 2007).

It is important to remember that the systemic antibiotic therapy is not intended as a monotherapy but is always best as an adjunctive therapy combined with traditional mechanical therapy and patient plaque control.

#### **2.2 Local antibiotic therapy**

After considering the risk to benefit ratio of systemic antibiotic administration as an adjunct treatment of periodontal diseases, interest in antibiotic therapy applied locally was developed. Historically, the first such local antibiotic therapy for periodontal disease was the Actisite™(no longer commercially available) fiber system. Actisite™ was supplied as hollow, nonabsorbable fibers filled with tetracycline (12.7 mg/9 inch fiber). The fiber was inserted into the pocket, wrapped repeatedly circumferentially around the tooth keeping the fiber in the pocket. Often a periodontal dressing was placed to aid maintaining the fiber in the pocket. The fiber was retained for ten days until operator removal. During this ten-day period drug concentrations of more than 1300 μg/ml of tetracycline were achieved and maintained. When the fiber was removed the soft tissue was often distended allowing temporary improved access and visibility of the root surfaces for any additional root planing or calculus removal. Following removal of the fiber the soft tissues generally showed

Except for the combination of metronidazole with amoxicillin, systemic antibiotic treatment produces no clinically significant effects on periodontal pocket depth reduction compared with controls (Winkel, et al., 2001) ((Cionca, et al., 2009). A seven-day regimen of systemic metronidazole significantly reduced the percentage of sites with bleeding compared to controls (Watts, et al., 1986). Others have reported a 12-month reduction in bleeding after treatment with a metronidazole-amoxicillin combination compared to a placebo treatment (Lopez, et al., 2000). With respect to clinical attachment levels, systemic metronidazole and combinations of metronidazole with other antibiotics has shown improvement in several studies. Several investigators found significant improvement of attachment levels at sites initially 4-6 mm in depth with a seven-day treatment with metronidazole (Elter, et al., 1997, Loesche, et al., 1992, Loesche, et al., 1984). Winkel et al. showed that the combination of metronidazole and amoxicillin for 7 to 14 days produced a significant increase in the percentage of sites showing improved attachment levels compared to control sites (Winkel, et al., 2001). A combination of metronidazole and clindamycin for three weeks also

produced improved attachment levels. (Gomi, et al., 2007, Sigusch, et al., 2001).

(Dastoor, et al., 2007).

**2.2 Local antibiotic therapy**

mechanical therapy and patient plaque control.

Some data to date supports a clinical benefit from the use of azithromycin as a systemic approach in combination with mechanical routines. In one limited study, seventeen subjects receiving azithromycin (500 mg), three days before full-mouth scaling and root planing produced greater clinical improvement than in seventeen subjects treated with full-mouth scaling and root planing alone (Gomi, et al., 2007). Dastoor et al. studied thirty patients who reported smoking more than one pack per day and presented with periodontitis. A comparison was made between the response to treatment with periodontal surgery and 500 mg Azithromycin per day for three days and treatment with periodontal surgery only. The addition of Azithromycin did not enhance improvements seen in both groups for attachment gain, depth reduction and reduction of bleeding on probing. However, the adjunctive use of Azithromycin was associated with a lower gingival index at two weeks and what the authors saw as more rapid wound healing. The addition of Azithromycin also produced reductions of red-complex bacteria that were maintained to three months

It is important to remember that the systemic antibiotic therapy is not intended as a monotherapy but is always best as an adjunctive therapy combined with traditional

After considering the risk to benefit ratio of systemic antibiotic administration as an adjunct treatment of periodontal diseases, interest in antibiotic therapy applied locally was developed. Historically, the first such local antibiotic therapy for periodontal disease was the Actisite™(no longer commercially available) fiber system. Actisite™ was supplied as hollow, nonabsorbable fibers filled with tetracycline (12.7 mg/9 inch fiber). The fiber was inserted into the pocket, wrapped repeatedly circumferentially around the tooth keeping the fiber in the pocket. Often a periodontal dressing was placed to aid maintaining the fiber in the pocket. The fiber was retained for ten days until operator removal. During this ten-day period drug concentrations of more than 1300 μg/ml of tetracycline were achieved and maintained. When the fiber was removed the soft tissue was often distended allowing temporary improved access and visibility of the root surfaces for any additional root planing or calculus removal. Following removal of the fiber the soft tissues generally showed shrinkage and pocket reduction and reduction of the inflammatory response were commonly seen. The Actisite™ system, while very effective, was tedious to use and required the second visit for removal of the fiber. These issues fueled the development of an absorbable system (Table 3).

Table 3. Local antibiotic delivery systems.

The first resorbable local antibiotic system was Atridox™(Atrix Laboratories). In this system, longer half-lived doxycycline replaced tetracycline supplied at a concentration of 42.5 mg per unit of material. Atridox™ improved the local antibiotic routines by allowing placement of the material to the depth of most pockets and in a manner that allowed it to conform to the shape of the pocket unlike the solid fibers of Actisite™. Depending on the size of the pocket, more than one site could be treated with a single unit of Atridox™.

Further development of absorbable local antibiotic systems led to Arestin™ (OraPharma) that uses minocycline in a microsphere configuration, each sphere measuring 20-60 microns in diameter. The antibiotic maintains therapeutic drug levels and remains in the pocket for 14 days. This configuration of the material allows placement to the depths of most pockets and while the material cannot conform to the shape of the pocket as well as the Atridox™ gel it is still better than the solid Actisite™ fibers.

Another material, not available in the United States, is Elyzol™(Colgate), a metronidazole gel system. This material is supplied as 25% metronidazole in a glyceryl mono-oleate and sesame oil base. The concentration of Metronidazole in this system is 250 mg/g of material that is applied as a gel using a syringe method.

Present and Future Non-Surgical Therapeutic

action is related to plaque reduction.

**Commercial Name**

Listerine (Johnson & Johnson)

(Colgate) No

Cepacol and Scope (Procter & Gamble)

Table 5. First generation antimicrobials.

No

**ADA Seal of Acceptance**

Yes

**Antimicrobial**

Phenolic Compounds

Sanguinarine Viadent

Quaternary Ammonium Compounds

Strategies for the Management of Periodontal Diseases 303

(http://www.ada.org/ada/seal/index.asp). These guidelines describe the clinical, biological, and laboratory studies necessary to evaluate safety and effectiveness and are subject to revision at any time. Importantly, they do not describe criteria for evaluating the management of periodontitis or other periodontal diseases. All claims of efficacy, including all health benefit claims, (e.g. gingivitis reduction), and all claims which imply a health benefit (e.g. plaque reduction) must be documented. There will be two Seal statements to be used with an Accepted product, depending on whether or not the product's mechanism of

Oral antiseptics have evolved from short-lived effects (soon after rinsing) as with the first generation antimicrobials (Table 5) to the second generation, which have the antimicrobial effect that lasts for a time period after the mouthrinse has been expectorated (Table 6).

> **Alcohol content**

26.9%

5.5%

Cepacol 14%

Scope 18.9% **Mechanism of Action**

Appears to be related to alteration of the bacterial cell wall

Alteration of bacterial cell surfaces so that aggregation and attachment is reduced

Related to increased bacterial cell wall permeability, which favors lysis, decreased cell metabolism and a decreased ability for bacteria to attach to tooth surfaces.

**Efficacy published by the manufacturer**

52% plaque reduction 36% gingivitis reduction

28% plaque reduction 24% gingivitis reduction

Care-Oral-Rinse/details)

15.8% plaque reduction 15.4% gingivitis reduction

h.asp) and

(www.listerine.com)

(www.colgateprofes sional.com/products /Viadent-Advanced-

(www.cepacol.com/ products/mouthwas

(www.pg.com/prod uct\_card/prod\_card \_main\_scope.html)

**Active ingredients**

Essential oils: Thymol (0.06%) Eucalyptol (0.09%) Methyl salicylate (0.06%) Menthol (0.04%)

0.03% Sanguinarin e extract

Cepacol: 0.05% CPC

Scope: 0.045% CPC + 0.005% domiphen bromide

Overall efficacy of local antibiotic therapies has been evaluated using meta-analysis of fifty articles, each reporting studies of at least six months follow-up (Bonito, et al., 2005). The meta-analysis considered studies of the addition of local adjuncts and found such additions provide generally favorable but minimal differences. The clinical effects of these various systems have been reported in several publications. Table 4 summarizes several studies of various local adjunctive materials. The overall treatment effect is somewhat variable and while found to be statistically significant has led many to be suspect of the general clinical benefit.

Table 4. Local Antibiotic System Studies.

## **3. Antiseptics**

The use of chemical agents with anti-plaque or anti-gingivitis action as adjuncts to oral hygiene seems to be of limited value, since mouthrinses do not appreciably penetrate into the gingival crevice, but they are of specific benefit when used as adjuncts to control gingival inflammation, especially in acute situations and during periods of interrupted hygiene (Ciancio, 1989). The challenge with chemical plaque control is to develop an active anti-plaque agent that does not disturb the natural flora of the oral cavity. The American Dental Association (ADA) Seal of Acceptance is seen as a standard for oral health care products. The ADA Seal Program ensures that professional and consumer dental products meet rigorous ADA criteria for safety and effectiveness. Guidelines have been established for the control of gingivitis and supragingival plaque

Overall efficacy of local antibiotic therapies has been evaluated using meta-analysis of fifty articles, each reporting studies of at least six months follow-up (Bonito, et al., 2005). The meta-analysis considered studies of the addition of local adjuncts and found such additions provide generally favorable but minimal differences. The clinical effects of these various systems have been reported in several publications. Table 4 summarizes several studies of various local adjunctive materials. The overall treatment effect is somewhat variable and while found to be statistically significant has led many to be suspect of the general clinical

> **Depth Change with S/RP + Agent**

(fiber only) Not reported

(drug only) 38% (drug only)

only

(drug only) Not reported

**Sites With At Least 2 mm Attachment Gain with S/RP + Agent**

Not reported; reports attachment gain of 1.16 with agent, 0.8 S/RP

gain at all time points with agent

**Depth Change with S/RP Only**

105 1.3 1.5 52%

(Machion, et al., 2006) 48 1.5 - 2.19 1.63-2.29 34.4% vs. 18.1% S/RP only

(Pradeep, et al., 2008) 80 2.13 2.53 Not reported; reports greater

The use of chemical agents with anti-plaque or anti-gingivitis action as adjuncts to oral hygiene seems to be of limited value, since mouthrinses do not appreciably penetrate into the gingival crevice, but they are of specific benefit when used as adjuncts to control gingival inflammation, especially in acute situations and during periods of interrupted hygiene (Ciancio, 1989). The challenge with chemical plaque control is to develop an active anti-plaque agent that does not disturb the natural flora of the oral cavity. The American Dental Association (ADA) Seal of Acceptance is seen as a standard for oral health care products. The ADA Seal Program ensures that professional and consumer dental products meet rigorous ADA criteria for safety and effectiveness. Guidelines have been established for the control of gingivitis and supragingival plaque

benefit.

Tetracycline Fibers

Doxycycline gel

Doxycycline gel (Wennstrom, et al.,

Doxycycline gel

Minocycline spheres

Minocycline spheres

Metronidazole gel

Azithromycin gel

**3. Antiseptics**

2001)

**Agent Subjects**

(Goodson, et al., 1991) 107 0.67 1.02

(Garrett, et al., 1999) 411 1.08 1.30

(Goodson, et al., 2007) 127 1.01 1.38

(Ainamo, et al., 1992) 206 1.3 1.5

Table 4. Local Antibiotic System Studies.

(Williams, et al., 2001) 728 1.08 1.32 42%

(http://www.ada.org/ada/seal/index.asp). These guidelines describe the clinical, biological, and laboratory studies necessary to evaluate safety and effectiveness and are subject to revision at any time. Importantly, they do not describe criteria for evaluating the management of periodontitis or other periodontal diseases. All claims of efficacy, including all health benefit claims, (e.g. gingivitis reduction), and all claims which imply a health benefit (e.g. plaque reduction) must be documented. There will be two Seal statements to be used with an Accepted product, depending on whether or not the product's mechanism of action is related to plaque reduction.

Oral antiseptics have evolved from short-lived effects (soon after rinsing) as with the first generation antimicrobials (Table 5) to the second generation, which have the antimicrobial effect that lasts for a time period after the mouthrinse has been expectorated (Table 6).

Table 5. First generation antimicrobials.

Present and Future Non-Surgical Therapeutic

(Flotra, et al., 1972, Overholser, et al., 1990).

**3.2 Chlorhexidine**

**Short-term indication (less than 2 months)**

Following periodontal and oral surgery

During initial periodontal therapy

Treatment of candidiasis

Gingivitis Gingivitis

Strategies for the Management of Periodontal Diseases 305

35.9% (DePaola, et al., 1989, Gordon, et al., 1985). Possible adverse effects reported in the

Chlorhexidine gluconate (0.12%), such as Peridex® and Periogard®, is sold in the United States by prescription only. It was the first antimicrobial shown to inhibit plaque formation and the development of chronic gingivitis (Loe and Schiott, 1970). Chlorhexidine is effective against gram-positive and negative bacteria and yeast. It has very low toxicity, since it is poorly absorbed from the GI tract and 90% is excreted in the feces. Chlorhexidine 0.12% is indicated for short-term (less than 2 months), intermittent short-term (alternating on and off every 1 to 2 months) and long-term (greater than 3 months to indefinitely) use (Table 7). Of all the products included here, chlorhexidine appears to be the most effective agent for reduction of both plaque and gingivitis with short-term reductions averaging 60% (Flotra, et al., 1972). Long-term reductions in plaque averaged between 45-61% and in gingivitis, 27- 67% (Ciancio, 1989). Adverse effects reported may include staining of teeth, reversible desquamation, poor taste and alteration of taste and an increase in supragingival calculus

> **Long-term indications (greater then 3 months to indefinitely)**

Patients with reduced resistance to bacterial plaque: AIDS, leukemia, kidney disease, bone marrow transplants, agranulocytosis, thrombocytopenia

Physically handicapped patients: rheumatoid arthritis, scleroderma, disturbance of muscles and/or motor

Patients treated with: cytotoxic drugs, immunosuppressive drugs, and

capacity and coordination

radiation therapy.

literature include a burning sensation, bitter taste and possible staining of teeth.

**Intermittent short-term indications (alternating on and off every 1 to 2 months)**

Periodontal maintenance

Physically and /or mentally

Several other agents have been evaluated for their effect on bacterial plaque and gingivitis, but results are inferior to those of chlorhexidine and phenolic compounds (see Table 8). Pires et al. (Pires, et al., 2007) have concluded that a mouthwash containing a combination of Triclosan/Gatrez and sodium bicarbonate has an *in-vitro* antimicrobial activity superior to

handicapped

Table 7. Chlorhexidine 0.12% Indications.

**3.3 Other antimicrobial mouthrinses**

Extensive prosthetic reconstruction

that of a placebo, but still inferior to that of chlorhexidine.

On the downside, it is also recognized that oral hygiene products may have the potential for producing harm in the mouth, some of which are more serious and long lasting than others. These types of harm range from production of a cosmetic nuisance, such as staining occurring as a result of the use of cationic antiseptics like chlorhexidine and cetylpyridinium chloride, to more permanent damage to the dental hard tissues through possible erosive and abrasive effects of low-pH mouthrinses and toothpastes respectively. Of serious concern is controversially the ability to produce carcinogenic changes to the oral mucosa through the use of alcoholic mouthrinses. Recently, the potential harm of oral hygiene products to oral and systemic health was fully reviewed with reference to present-day evidence (Addy, 2008).

Table 6. Second generation antimicrobials.

## **3.1 Phenolic compounds**

Among the first generation antimicrobials, the phenolic compounds, such as Listerine® and its clones, are the only ones that have the ADA Seal of Acceptance to prevent and reduce supragingival plaque accumulation and gingivitis. Short-term studies have shown plaque and gingivitis reduction averaging 35% (Fornell, et al., 1975) and long-term studies have shown plaque reduction between 13.8 and 56.3% and gingivitis reduction between 14 and 35.9% (DePaola, et al., 1989, Gordon, et al., 1985). Possible adverse effects reported in the literature include a burning sensation, bitter taste and possible staining of teeth.

## **3.2 Chlorhexidine**

304 Periodontal Diseases - A Clinician's Guide

On the downside, it is also recognized that oral hygiene products may have the potential for producing harm in the mouth, some of which are more serious and long lasting than others. These types of harm range from production of a cosmetic nuisance, such as staining occurring as a result of the use of cationic antiseptics like chlorhexidine and cetylpyridinium chloride, to more permanent damage to the dental hard tissues through possible erosive and abrasive effects of low-pH mouthrinses and toothpastes respectively. Of serious concern is controversially the ability to produce carcinogenic changes to the oral mucosa through the use of alcoholic mouthrinses. Recently, the potential harm of oral hygiene products to oral and systemic health was fully reviewed with reference to present-day evidence (Addy,

**chloride Chlorhexidine**

Peridex (3M Espe) Periogard (Colgate)

0.12% Chlorhexidine gluconate

ate-Periogard-Rinse-Rx-only/details)

Certain aerobic and anaerobic bacteria

ate-Periogard-Rinse-Rx-only/details)

reduction from 54 - 97% through six months use (solutions.3m.com/wps/portal/3M/en\_US/pr eventive-care/home/products/home-care-

(www.colgateprofessional.com/products/Colg

therapies/peridex/) and

therapies/peridex/) - 29% gingivitis reduction - 54% plaque reduction

Among the first generation antimicrobials, the phenolic compounds, such as Listerine® and its clones, are the only ones that have the ADA Seal of Acceptance to prevent and reduce supragingival plaque accumulation and gingivitis. Short-term studies have shown plaque and gingivitis reduction averaging 35% (Fornell, et al., 1975) and long-term studies have shown plaque reduction between 13.8 and 56.3% and gingivitis reduction between 14 and

(solutions.3m.com/wps/portal/3M/en\_US/pr eventive-care/home/products/home-care-

(www.colgateprofessional.com/products/Colg

Positively charged chlorhexidine molecule binds to negatively charged microbial cell wall, altering osmotic equilibrium, causing potassium and phosphorous leakage, precipitation of cytoplasmic contents and consequent cell death.

2008).

Commercial Name

ADA Seal of

Mechanism of Action

Efficacy published by

manufacturer

the

ingredients 0.07% CPC

Active

**Antimicrobial Cetylpyridinium**

Crest Pro-Health (Procter & Gamble)

Acceptance No Yes

Bactericidal agent

kills the bacteria.

Similar to Listerine (www.dentalcare.com/so ap/products/index.htm)

Table 6. Second generation antimicrobials.

**3.1 Phenolic compounds**

interacts with the bacterial membrane. The cellular pressure disrupts the cell membrane and effectively

Chlorhexidine gluconate (0.12%), such as Peridex® and Periogard®, is sold in the United States by prescription only. It was the first antimicrobial shown to inhibit plaque formation and the development of chronic gingivitis (Loe and Schiott, 1970). Chlorhexidine is effective against gram-positive and negative bacteria and yeast. It has very low toxicity, since it is poorly absorbed from the GI tract and 90% is excreted in the feces. Chlorhexidine 0.12% is indicated for short-term (less than 2 months), intermittent short-term (alternating on and off every 1 to 2 months) and long-term (greater than 3 months to indefinitely) use (Table 7). Of all the products included here, chlorhexidine appears to be the most effective agent for reduction of both plaque and gingivitis with short-term reductions averaging 60% (Flotra, et al., 1972). Long-term reductions in plaque averaged between 45-61% and in gingivitis, 27- 67% (Ciancio, 1989). Adverse effects reported may include staining of teeth, reversible desquamation, poor taste and alteration of taste and an increase in supragingival calculus (Flotra, et al., 1972, Overholser, et al., 1990).

Table 7. Chlorhexidine 0.12% Indications.

## **3.3 Other antimicrobial mouthrinses**

Several other agents have been evaluated for their effect on bacterial plaque and gingivitis, but results are inferior to those of chlorhexidine and phenolic compounds (see Table 8). Pires et al. (Pires, et al., 2007) have concluded that a mouthwash containing a combination of Triclosan/Gatrez and sodium bicarbonate has an *in-vitro* antimicrobial activity superior to that of a placebo, but still inferior to that of chlorhexidine.

Present and Future Non-Surgical Therapeutic

inflammatory agents, and anti-resorptive agents.

**4.2 Non-steroid anti-inflammatory drugs**

**4.1 MMP Inhibitors**

1990).

studies.

**4. Anti-inflammatory strategies**

Strategies for the Management of Periodontal Diseases 307

It is well established that periodontal disease is an infectious disease and that the host immune and inflammatory response to the microbial challenge mediates tissue destruction (Offenbacher, 1996). Considering that the primary etiology of the disease are bacteria in the plaque and their products, mechanical and chemical approaches to reduce the presence of periodontopathogens in the plaque have been largely used in the treatment of periodontal patients over the years (Greenwell, 2001). Most recently, the better understanding of the participation of host immune-inflammatory mediators in the disease progression has increased the investigation of the use of modulating agents as an adjunctive therapy to the periodontal treatment. Inhibition or blockade of proteolytic enzymes, pro-inflammatory mediators and of osteoclast activity has been the focus of these agents which has lead to encouraging results in pre-clinical and clinical studies (Reddy, et al., 2003). More specifically, three types of host-modulatory agents have been investigated for the management of periodontitis including anti-proteinases (MMP inhibitors), anti-

One important group of proteolytic enzymes present in the periodontal tissues is formed by the matrix metalloproteinases (MMPs), which include collagenases, gelatinases and metalloelastases. MMPs are produced by many periodontal tissues and are responsible for remodeling the extracellular matrix (Birkedal-Hansen, 1993). In 1985, tetracyclines were found to have anti-collagenolytic activity and proposed as a host modulating agent for periodontal treatment (Golub, et al., 1985). Initial studies demonstrated that doxycycline was the most potent tetracycline in inhibition of collagenolytic activities (Burns, et al., 1989). This property of doxycycline provided the pharmacological rationale for the use of a low or subantimicrobial dose of doxycycline (SDD) that was shown to be efficient in inhibiting mammalian collagenase activity without developing antibiotic resistance (Golub, et al.,

Several clinical studies have been conducted assessing the benefits of the SDD as an adjunctive therapy to scaling and root planing (SRP) in the treatment of the periodontal disease. Reddy et al. recently presented a meta-analysis (Reddy, et al., 2003) of 6 selected clinical studies comparing long-term systemic SDD (20mg bid doxycycline) to placebo control in periodontal patients. A statistically significant adjunctive benefit on clinical attachment levels (CAL) and probing depth was found when SDD was used in combination with SRP, in both 4 to 6mm and ≥ 7mm pocket depth categories. Bleeding on probing (BOP) was not assessed in the meta-analysis but, in general, SDD did not improve this parameter when compared to placebo. No significant adverse effects were reported in any of the

The non-steroidal anti-inflammatory drugs (NSAIDs) represent the next major pharmacological class of agents that has been well studied as inhibitors of the host response in periodontal disease. These agents are well known for the ability to prevent prostanoid formation. In this process, arachidonic acid liberated from membrane phospholipids of cells after tissue damage or stimulus is metabolically transformed via cyclooxygenase or

Table 8. Other antimicrobial mouthrinses.

Table 9. Comparison studies.

## **4. Anti-inflammatory strategies**

306 Periodontal Diseases - A Clinician's Guide

**ingredients Mechanism of Action Efficacy**

Stable, free radical and an oxidant with algicidal, bactericidal, cysticidal, fungicidal, sporicidal, and viricidal properties.

Zinc has an affinity to sulfur and odorizes sulphydryl groups with zinc ions forming stable mercaptides with the substrate, the precursors, and/or the volatile sulfur compounds directly.

A low toxicity, non-ionic phenolic derivative with a wide spectrum of antimicrobial and antiinflammatory activities (Kim, et al., 2005).

Peridex was superior in its ability to maintain optimal gingival health during the entire time of mouthrinse use.

Both Listerine and Peridex significantly inhibited

development of plaque by 36.1% and 50.3%, respectively, and the development of gingivitis by 35.9% and 3.0.5% respectively, compared to placebo.

The chlorhexidine group showed 95% reduction in gingivitis incidence, 100% reduction in BOP, and 80% reduction in plaque scores compared to placebo.

Long-term studies do

not support effectiveness. Short-term studies offer contradictory

findings.

Minimal plaque reduction, but has shown decreases involatile sulfur compounds and halitosis.

BreathRx is a scientific bad breath treatment specially designed to help treat both the causes of bad breath and the

symptoms.

*In vitro* studies show antimicrobial activity superior to that of a placebo, but inferior to that of chlorhexidine (Pires, et al., 2007)

> Siegrist et al. (Siegrist, et al.,

Overholser et al. (Overholser, et al., 1990)

Gusberti et al. (Gusberti, et al.,

1988)

1986)

Anti-inflammatory properties reduce bleeding on probing, a major sign of inflammation; bacterial load is not necessarily reduced; bubbling action cleans and alleviates discomfort to promote healing.

**Active**

Peroxyde

No 1% chlorine dioxide

> -Zinc chloride -Phenolic oils (Thymol and Eucalyptus oil)

**compared Methodology Results References**

**Antimicrobial**

Oxygenating agents

Chlorine Dioxide

Zinc

**Commercial Name**

Peroxyl

RetarDEX (Periproducts)

Oxyfresh

Chloride Breath Rx No

Triclosan Not available

**Antiseptics**

Listerine Viadent Peridex Placebo

Listerine Peridex Placebo

Chlorhexidine 0.12% Hydrogen Peroxide 1% Placebo

**ADA Seal of Acceptance**

(Colgate) No Hydrogen

in the US N/A Triclosan

31 volunteers with healthy gingiva ceased all oral hygiene procedures but rinsing with the designated mouthrinse for 21 days

Double blind, controlled clinical trial. After a baseline complete dental prophylaxis,124 healthy adults used the mouthrinse as a supplement to regular oral hygiene

32 subjects ceased oral hygiene procedures, but rinsed, twice a day, with the designated mouthrinse for

Table 8. Other antimicrobial mouthrinses.

for 6 months.

21 days.

Table 9. Comparison studies.

It is well established that periodontal disease is an infectious disease and that the host immune and inflammatory response to the microbial challenge mediates tissue destruction (Offenbacher, 1996). Considering that the primary etiology of the disease are bacteria in the plaque and their products, mechanical and chemical approaches to reduce the presence of periodontopathogens in the plaque have been largely used in the treatment of periodontal patients over the years (Greenwell, 2001). Most recently, the better understanding of the participation of host immune-inflammatory mediators in the disease progression has increased the investigation of the use of modulating agents as an adjunctive therapy to the periodontal treatment. Inhibition or blockade of proteolytic enzymes, pro-inflammatory mediators and of osteoclast activity has been the focus of these agents which has lead to encouraging results in pre-clinical and clinical studies (Reddy, et al., 2003). More specifically, three types of host-modulatory agents have been investigated for the management of periodontitis including anti-proteinases (MMP inhibitors), antiinflammatory agents, and anti-resorptive agents.

## **4.1 MMP Inhibitors**

One important group of proteolytic enzymes present in the periodontal tissues is formed by the matrix metalloproteinases (MMPs), which include collagenases, gelatinases and metalloelastases. MMPs are produced by many periodontal tissues and are responsible for remodeling the extracellular matrix (Birkedal-Hansen, 1993). In 1985, tetracyclines were found to have anti-collagenolytic activity and proposed as a host modulating agent for periodontal treatment (Golub, et al., 1985). Initial studies demonstrated that doxycycline was the most potent tetracycline in inhibition of collagenolytic activities (Burns, et al., 1989). This property of doxycycline provided the pharmacological rationale for the use of a low or subantimicrobial dose of doxycycline (SDD) that was shown to be efficient in inhibiting mammalian collagenase activity without developing antibiotic resistance (Golub, et al., 1990).

Several clinical studies have been conducted assessing the benefits of the SDD as an adjunctive therapy to scaling and root planing (SRP) in the treatment of the periodontal disease. Reddy et al. recently presented a meta-analysis (Reddy, et al., 2003) of 6 selected clinical studies comparing long-term systemic SDD (20mg bid doxycycline) to placebo control in periodontal patients. A statistically significant adjunctive benefit on clinical attachment levels (CAL) and probing depth was found when SDD was used in combination with SRP, in both 4 to 6mm and ≥ 7mm pocket depth categories. Bleeding on probing (BOP) was not assessed in the meta-analysis but, in general, SDD did not improve this parameter when compared to placebo. No significant adverse effects were reported in any of the studies.

## **4.2 Non-steroid anti-inflammatory drugs**

The non-steroidal anti-inflammatory drugs (NSAIDs) represent the next major pharmacological class of agents that has been well studied as inhibitors of the host response in periodontal disease. These agents are well known for the ability to prevent prostanoid formation. In this process, arachidonic acid liberated from membrane phospholipids of cells after tissue damage or stimulus is metabolically transformed via cyclooxygenase or

Present and Future Non-Surgical Therapeutic

be implemented to confirm the benefits of these drugs.

**5. Future host modulatory approaches**

**5.1 Novel host modulators**

determine the relative risk-benefit ratio of bisphosphonate therapy.

upon molecular interactions in the periodontal environment.

Strategies for the Management of Periodontal Diseases 309

bisphosphonates as an adjunctive agent to periodontal therapy. Additional studies need to

However, there can be significant dental related adverse effects associated with the use of bisphosphonates therapeutics. High-dose, long-term use of bisphosphonates has been reported to be associated with osteonecrosis of the jaw (ONJ) (Marx, 2003, Ruggiero, et al., 2004). Data from multiple sources indicates that patients with prior dental problems may have a higher risk of ONJ. However, as more data is being reported, it still remains controversial that bisphosphonates indeed are causative for ONJ. Since bisphosphonates are potent osteoclast inhibitors, their long-term use may suppress bone turnover and compromise healing of even physiologic micro-injuries within bone (Odvina, et al., 2005). Despite the encouraging therapeutic results, further long-term studies are warranted to

A variety of treatment strategies have been developed to target the host response to LPSmediated tissue destruction. MMP inhibitors such as low dose formulations of doxycycline have been used in combination with scaling and root planing (Caton, et al., 2001) or surgical therapy (Gapski, et al., 2004). In addition, high-risk patient populations such as diabetics or patients with recurrent periodontal disease have benefited from systemic MMP administration (Chang, et al., 1996, Golub, et al., 2001, Novak, et al., 2002). Encouraging results have been shown using soluble antagonists of TNF and IL-1 delivered locally to

periodontal tissues in nonhuman primates (Assuma, et al., 1998, Graves, et al., 1998).

Host response modulation is key therapeutic target used to control periodontal inflammation leading to tissue and bone destruction. Bone loss as a consequence of bacterial-induced inflammation due to subgingival plaque in the periodontal pocket is controlled by the expression of cytokines that direct the biological process of osteoclast differentiation. Several inflammatory cytokines, including interleukin (IL)-1, IL-6 and other cytokines enhance the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) which induced osteoclast formation and leads to bone resorption. RANK is the receptor located on osteoclast precursor cells that respond to RANKL to initiate formation of mature osteoclasts. To balance the effects of RANKL, osteoprotegerin (OPG) acts as a decoy receptor to bind RANKL and inhibits osteoclast development. In periodontal disease, the roles of RANKL, RANK, and OPG in the alveolar bone resorption have been extensively investigated. Based on pre-clinical animal studies and on preliminary human clinical studies, the OPG/RANKL/RANK axis is a new target for the treatment of destructive periodontal disease and other bone resorption related diseases (Cochran, 2008). However, further studies are necessary to determine the most efficacious therapeutic approach based

All immune cells within periodontal tissues generate innate immune cytokines require intracellular signaling to transduce extracellular cues into biochemical information required for inflammatory cytokine gene expression. Cytokines and bacterial components activate many signal transduction pathways. With this concept in mind, new strategies for preventing cell activation via targeting signal transduction pathways could abolish both cell

lipoxygenase pathways in compounds with potent biological activities (Offenbacher, 1996). The cyclooxygenase enzymes are recognized to have two isoforms: cyclooxygenase 1 (COX1) which is a constitutive enzyme present in most of cells and cyclooxygenase 2 (COX2) which is inducible and is present in cells involved in inflammatory processes (DeWitt, et al., 1993). The cyclooxygenase pathway produces prostaglandins, prostacyclin and thromboxane, called prostanoids. Some prostanoids have proinflammatory properties and have been associated with destructive process in inflammatory diseases. In periodontal diseases, Prostaglandin E2 (PGE2) has been extensively correlated to inflammation and bone resorption (Offenbacher, 1996). Its levels in gingival tissues and in the gingival crevicular fluid (GCF) have been shown to be significantly elevated in periodontally diseased patients compared to healthy patients (Dewhirst, et al., 1983, Offenbacher, et al., 1981).

Selective NSAIDs are capable of inhibiting COX-2 without affecting constitutive isoform COX-1. Some studies have indicated that COX-2 inhibitors retain bone sparing effects (Bezerra, et al., 2000, Holzhausen, et al., 2002, Holzhausen, et al., 2005, Shimizu, et al., 1998) without inducing adverse effects associated with COX-1 suppression, such as gastroduodenal problems and renal toxicity (Hawkey, 1993, Lindsley and Warady, 1990). Several adjunctive periodontal clinical trials have been conducted with NSAIDs. In a systematic review (Reddy, et al., 2003), ten clinical studies in which therapeutic outcomes of NSAIDs were expressed in clinical attachment level (CAL) or alveolar crestal height as measured by subtraction radiography were selected. In these studies a variety of different NSAIDs were systemically or locally administered, including flurbiprofen, meclofenamate, ibuprofen, ketorolac, naproxen and aspirin. Although the heterogeneity of data did not permit a metaanalysis, limited quantitative analysis tended to show a significant benefit related to alveolar bone maintenance when NSAIDs were combined with conventional therapy. Notably, none of these studies found significantly less attachment loss after NSAIDs adjunctive therapy when compared to SRP alone.

#### **4.3 Anti-bone resorptive therapeutics**

Alveolar bone destruction is the hallmark feature of periodontal disease. The use of bonesparing drugs that inhibit alveolar bone resorption is another field in host-modulation therapy. Bisphosphonates are a class of agents that binds to hydoxyapatite in bone matrix to prevent matrix dissolution by interfering with osteoclast function through a variety of direct and indirect mechanisms (Rogers, et al., 2000). The principal therapeutic purpose of bisphosphonates is in the prevention and treatment of osteoporosis and also in treatment of Paget's disease and metastatic bone disease (Fleisch, 1997). In periodontics, their use was proposed initially for diagnostic and therapeutic use. As therapeutic agents, bisphosphonates were shown to reduce alveolar bone loss and increase mineral density but not to improve clinical conditions in animal periodontitis models (Brunsvold, et al., 1992, Reddy, et al., 1995). Five studies that assessed the effect of bisphosphonates as an adjunctive agent to SRP in human periodontal treatment were found to date (El-Shinnawi and El-Tantawy, 2003, Jeffcoat, et al., 2007, Lane, et al., 2005, Rocha, et al., 2004, Rocha, et al., 2001). Alendronate was the bisphosphonate used in four studies during a period of 6 months. One study used risedronate during 12 months (El-Shinnawi and El-Tantawy, 2003). All the studies presented significant clinical improvement when compared to placebo, including: probing depth reduction, clinical attachement gain, bleeding on probing reduction, alveolar bone gain and increase in bone mineral density. These results encourage the use of

lipoxygenase pathways in compounds with potent biological activities (Offenbacher, 1996). The cyclooxygenase enzymes are recognized to have two isoforms: cyclooxygenase 1 (COX1) which is a constitutive enzyme present in most of cells and cyclooxygenase 2 (COX2) which is inducible and is present in cells involved in inflammatory processes (DeWitt, et al., 1993). The cyclooxygenase pathway produces prostaglandins, prostacyclin and thromboxane, called prostanoids. Some prostanoids have proinflammatory properties and have been associated with destructive process in inflammatory diseases. In periodontal diseases, Prostaglandin E2 (PGE2) has been extensively correlated to inflammation and bone resorption (Offenbacher, 1996). Its levels in gingival tissues and in the gingival crevicular fluid (GCF) have been shown to be significantly elevated in periodontally diseased patients

Selective NSAIDs are capable of inhibiting COX-2 without affecting constitutive isoform COX-1. Some studies have indicated that COX-2 inhibitors retain bone sparing effects (Bezerra, et al., 2000, Holzhausen, et al., 2002, Holzhausen, et al., 2005, Shimizu, et al., 1998) without inducing adverse effects associated with COX-1 suppression, such as gastroduodenal problems and renal toxicity (Hawkey, 1993, Lindsley and Warady, 1990). Several adjunctive periodontal clinical trials have been conducted with NSAIDs. In a systematic review (Reddy, et al., 2003), ten clinical studies in which therapeutic outcomes of NSAIDs were expressed in clinical attachment level (CAL) or alveolar crestal height as measured by subtraction radiography were selected. In these studies a variety of different NSAIDs were systemically or locally administered, including flurbiprofen, meclofenamate, ibuprofen, ketorolac, naproxen and aspirin. Although the heterogeneity of data did not permit a metaanalysis, limited quantitative analysis tended to show a significant benefit related to alveolar bone maintenance when NSAIDs were combined with conventional therapy. Notably, none of these studies found significantly less attachment loss after NSAIDs adjunctive therapy

Alveolar bone destruction is the hallmark feature of periodontal disease. The use of bonesparing drugs that inhibit alveolar bone resorption is another field in host-modulation therapy. Bisphosphonates are a class of agents that binds to hydoxyapatite in bone matrix to prevent matrix dissolution by interfering with osteoclast function through a variety of direct and indirect mechanisms (Rogers, et al., 2000). The principal therapeutic purpose of bisphosphonates is in the prevention and treatment of osteoporosis and also in treatment of Paget's disease and metastatic bone disease (Fleisch, 1997). In periodontics, their use was proposed initially for diagnostic and therapeutic use. As therapeutic agents, bisphosphonates were shown to reduce alveolar bone loss and increase mineral density but not to improve clinical conditions in animal periodontitis models (Brunsvold, et al., 1992, Reddy, et al., 1995). Five studies that assessed the effect of bisphosphonates as an adjunctive agent to SRP in human periodontal treatment were found to date (El-Shinnawi and El-Tantawy, 2003, Jeffcoat, et al., 2007, Lane, et al., 2005, Rocha, et al., 2004, Rocha, et al., 2001). Alendronate was the bisphosphonate used in four studies during a period of 6 months. One study used risedronate during 12 months (El-Shinnawi and El-Tantawy, 2003). All the studies presented significant clinical improvement when compared to placebo, including: probing depth reduction, clinical attachement gain, bleeding on probing reduction, alveolar bone gain and increase in bone mineral density. These results encourage the use of

compared to healthy patients (Dewhirst, et al., 1983, Offenbacher, et al., 1981).

when compared to SRP alone.

**4.3 Anti-bone resorptive therapeutics**

bisphosphonates as an adjunctive agent to periodontal therapy. Additional studies need to be implemented to confirm the benefits of these drugs.

However, there can be significant dental related adverse effects associated with the use of bisphosphonates therapeutics. High-dose, long-term use of bisphosphonates has been reported to be associated with osteonecrosis of the jaw (ONJ) (Marx, 2003, Ruggiero, et al., 2004). Data from multiple sources indicates that patients with prior dental problems may have a higher risk of ONJ. However, as more data is being reported, it still remains controversial that bisphosphonates indeed are causative for ONJ. Since bisphosphonates are potent osteoclast inhibitors, their long-term use may suppress bone turnover and compromise healing of even physiologic micro-injuries within bone (Odvina, et al., 2005). Despite the encouraging therapeutic results, further long-term studies are warranted to determine the relative risk-benefit ratio of bisphosphonate therapy.

## **5. Future host modulatory approaches**

A variety of treatment strategies have been developed to target the host response to LPSmediated tissue destruction. MMP inhibitors such as low dose formulations of doxycycline have been used in combination with scaling and root planing (Caton, et al., 2001) or surgical therapy (Gapski, et al., 2004). In addition, high-risk patient populations such as diabetics or patients with recurrent periodontal disease have benefited from systemic MMP administration (Chang, et al., 1996, Golub, et al., 2001, Novak, et al., 2002). Encouraging results have been shown using soluble antagonists of TNF and IL-1 delivered locally to periodontal tissues in nonhuman primates (Assuma, et al., 1998, Graves, et al., 1998).

## **5.1 Novel host modulators**

Host response modulation is key therapeutic target used to control periodontal inflammation leading to tissue and bone destruction. Bone loss as a consequence of bacterial-induced inflammation due to subgingival plaque in the periodontal pocket is controlled by the expression of cytokines that direct the biological process of osteoclast differentiation. Several inflammatory cytokines, including interleukin (IL)-1, IL-6 and other cytokines enhance the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) which induced osteoclast formation and leads to bone resorption. RANK is the receptor located on osteoclast precursor cells that respond to RANKL to initiate formation of mature osteoclasts. To balance the effects of RANKL, osteoprotegerin (OPG) acts as a decoy receptor to bind RANKL and inhibits osteoclast development. In periodontal disease, the roles of RANKL, RANK, and OPG in the alveolar bone resorption have been extensively investigated. Based on pre-clinical animal studies and on preliminary human clinical studies, the OPG/RANKL/RANK axis is a new target for the treatment of destructive periodontal disease and other bone resorption related diseases (Cochran, 2008). However, further studies are necessary to determine the most efficacious therapeutic approach based upon molecular interactions in the periodontal environment.

All immune cells within periodontal tissues generate innate immune cytokines require intracellular signaling to transduce extracellular cues into biochemical information required for inflammatory cytokine gene expression. Cytokines and bacterial components activate many signal transduction pathways. With this concept in mind, new strategies for preventing cell activation via targeting signal transduction pathways could abolish both cell

Present and Future Non-Surgical Therapeutic

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No. 10, 825-30, 1992.

28, No. 8, 782-9, 2001.

*Pharmacol* Vol. 91, No. 3, 303-18, 1996.

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*Periodontol* Vol. 80, No. 3, 364-71, 2009.

No. 8 Suppl, 1569-76, 2008.

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2A, 40S-44S, 1993.

Strategies for the Management of Periodontal Diseases 311

Baelum, V., L. Wen-Min, O. Fejerskov, and C. Xia. 'Tooth Mortality and Periodontal

Bezerra, M. M., V. de Lima, V. B. Alencar, I. B. Vieira, G. A. Brito, R. A. Ribeiro, and F. A.

Bonito, A. J., L. Lux, and K. N. Lohr. 'Impact of Local Adjuncts to Scaling and Root Planing

Brunsvold, M. A., E. S. Chaves, K. S. Kornman, T. B. Aufdemorte, and R. Wood. 'Effects of a

Burns, F. R., M. S. Stack, R. D. Gray, and C. A. Paterson. 'Inhibition of Purified Collagenase

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Chang, K. M., M. E. Ryan, L. M. Golub, N. S. Ramamurthy, and T. F. McNamara. 'Local and

Ciancio, Sebastian. 'Non-Surgical Periodontal Treatment', *Procedings of the World Workshop in*

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Cochran, D. L. 'Inflammation and Bone Loss in Periodontal Disease', *J Periodontol* Vol. 79,

Dastoor, S. F., S. Travan, R. F. Neiva, L. A. Rayburn, W. V. Giannobile, and H. L. Wang.

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activation by cytokines or other stimuli and production of proinflammatory cytokines. Signal transduction pathways closely involved in inflammation include the mitogenactivated protein kinase (MAPK) pathway, phosphatidylinositol-3 protein (PI3-kinase) pathway, janus kinase-signal transducer and activator of transcription (Jak-STAT), and nuclear factor kappa B (NF-kB). Thus, small molecule inhibitor compounds have emerged as the new therapeutic strategies that are being explored are aimed at inhibiting signal transduction pathways involved in inflammation. Pharmacological inhibitors of NF-kB and p38 mitogen activating protein (MAP) kinase pathways are actively being developed to manage inflammatory bone diseases (Adams, et al., 2001, Kumar, et al., 2001). p38 inhibitors have already shown promise in preclinical models of periodontal diseases (Kirkwood, et al., 2007, Rogers, et al., 2007). Using this novel strategy, inflammatory mediators including proinflammatory cytokines (IL-1, TNF, IL-6), MMPs and others would be inhibited at the level of cell signaling pathways required for transcription factor activation necessary for inflammatory gene expression or mRNA stability. These therapies may provide the next wave of adjuvant chemotherapeutics that may be used to manage chronic periodontitis.

## **6. Future directions**

Most therapeutics has relied on systemic delivery. Thus, it may be difficult to potentially use systemic therapeutics for periodontal disease due to the long-term chronic nature of the periodontal inflammation and destruction. The future may be the adjunctive use of locally delivered therapeutics, and the need for new targets of therapeutics for periodontal disease. Also, the need for new in situ delivery systems with the ability to locally deliver therapeutics to the periodontal lesion bypassing systemic issues of toxicity.

## **7. Acknowledgment**

This work was supported by P20RR017696 and R01DE018290 from the National Institutes of Health.

#### **8. References**

activation by cytokines or other stimuli and production of proinflammatory cytokines. Signal transduction pathways closely involved in inflammation include the mitogenactivated protein kinase (MAPK) pathway, phosphatidylinositol-3 protein (PI3-kinase) pathway, janus kinase-signal transducer and activator of transcription (Jak-STAT), and nuclear factor kappa B (NF-kB). Thus, small molecule inhibitor compounds have emerged as the new therapeutic strategies that are being explored are aimed at inhibiting signal transduction pathways involved in inflammation. Pharmacological inhibitors of NF-kB and p38 mitogen activating protein (MAP) kinase pathways are actively being developed to manage inflammatory bone diseases (Adams, et al., 2001, Kumar, et al., 2001). p38 inhibitors have already shown promise in preclinical models of periodontal diseases (Kirkwood, et al., 2007, Rogers, et al., 2007). Using this novel strategy, inflammatory mediators including proinflammatory cytokines (IL-1, TNF, IL-6), MMPs and others would be inhibited at the level of cell signaling pathways required for transcription factor activation necessary for inflammatory gene expression or mRNA stability. These therapies may provide the next wave of adjuvant chemotherapeutics that may be used to manage chronic periodontitis.

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This work was supported by P20RR017696 and R01DE018290 from the National Institutes of

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**15**

*Spain*

**Laser Radiation as an Adjunct to Nonsurgical**

It is well known that biofilm and calculus responsible for periodontal disease can be of different nature depending on their supra or subgingival location, and that the physical or chemical methods used for their elimination, achieve different results in both places (Davies et al., 1998). Since the use of laser confocal microscope and the study of biofilms in their natural state, it has been observed that the behaviour of bacteria is quite different to the observed in traditional cultures. In their natural state, the bacterial colonies are constituted by several microcolonies included in a matrix, which has canals through which flow fluids transporting nutrients, metabolic wastes, enzymes, oxygen and other products enabling the

The biofilms adhered on the internal and external walls of the periodontal pocket, the free biofilm and the possibility of a bacterial penetration through the epithelium to the underlying connective tissue can cause a gingival inflammatory reaction. This inflammation may progress with vasodilation, cellular migration and release of mediators, thus increasing the inflammatory response and perpetuating the disease. This situation makes microorganisms more resistant to drugs, which frequently are unable to reach the colonies protected by the matrix and by the presence of resistent bacteria (Donlan & Costerton, 2002). The inflammatory phenomena triggered by the bacteria and their waste products attracts macrophages that produce, among others, interleukin 1 (IL-1) and tumor necrosis factor alfa (TNF-α), which have the ability to activate osteoclasts and produce bone resorption. TNF-α activates the adhesion molecules of the endothelial cells of the vessels, favouring the adhesion of monocytes and diapedesis. It also stimulates the arrival of T lymphocytes, which contribute with receptor activator of nuclear factor kappa B ligand (RANKL) to the bone, consequently favouring the bone loss (Kong et al., 1999). But this process is more complex as it needs some proteins such as nuclear factor kappa B (NF-kB), receptor activator of nuclear factor kappa B (RANK), RANKL and osteoprotegerin (OPG), among others, which may change the answer of the osteoclast precursors and therefore modify the osseous destruction. The NF-kB plays a basic role as activator of immunoglobulins during the infectious process (Gilmore, 2006). So, as IL-1 and TNF-α favour the synthesis of RANK-L

presence of different environments (Costerton et al. 1987).

**1. Introduction**

**Treatment of Periodontal Disease**

Juan Antonio García Núñez1, Alicia Herrero Sánchez1, Ana Isabel García Kass1 and Clara Gómez Hernández2 *1Faculty of Odontology, Universidad Complutense of Madrid (UCM),*

*Consejo Superior de Investigaciones Científicas (CSIC), Madrid,*

*2Instituto Fisica-Quimica Rocasolano,*


**4. Exercise progressions for restoration of musculoskeletal balance**

Exercises, termed "nonmanual techniques" in PRI, are powerful tools for proprioception and physiological transformation for patients with scoliosis of all ages. Based on the model of rightside dominance due to human asymmetry, and taking into consideration the patient's unique configuration and function revealed by the evaluation tests, exercises are carefully chosen to most appropriately meet the tri-planar needs of that patient. Some of the greatest similarities between the methodology of Schroth Barcelona and PRI are in the application of exercises. Both place emphasis on exercise position, breath, and stabilization in the corrected tri-planar position [8, 9].

Exercise progression begins in fully supported positions to isolate and recruit underused or misused muscles. Supported positions are also favored for the introduction of multimuscle integration. When the patient demonstrates competence in activating correct muscle chain activity while supported, challenge is intensified by progression to more upright activities. Repetition of challenging positions, held through multiple breathing cycles, promotes proprioceptive familiarity with new alignment and stabilization in new muscle patterns. Increased self-awareness and more precise muscle and breath control enable the patient to self-correct in activities of daily living. Achieving true alternating, reciprocal movement, as required in gait, is a final challenge.