|Year : 2017 | Volume
| Issue : 5 | Page : 44-48
Charul Preet Kaur, Vikas Jindal, Ranjan Malhotra, Divya Jaggi, Amit Goel, Rupinder Kaur
Department of Periodontics, Himachal Dental College, Mandi, Himachal Pradesh, India
|Date of Web Publication||15-Sep-2017|
Department of Periodontics, Himachal Dental College, Sundernagar, Mandi, Himachal Pradesh
Source of Support: None, Conflict of Interest: None
Perioceutics or use of the pharmacological agents specifically developed to manage periodontitis is an interesting and emerging aids in the development of periodontal disease along with the mechanical debridement. The purpose of host modulatory agent which is a imperative part of perioceutic, is to restore balance between, on the one hand, pro inflammatory mediators and destructive enzymes, and on the other hand, anti-inflammatory mediators and enzyme. Host modulatory therapy (HMT) is a treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or down regulating destructive aspects of the host response and up regulating protective or regenerative responses. This paper review the Host Modulatory Therapy which in future will be the effective tool dental practitioners when used as adjunct to mechanical therapy in treating periodontal diseases.
Keywords: Bisphosphonates, host modulation, nonsteroidal inflammatory drugs, perioceutics, periodontal disease, subantimicrobial dose doxycycline
|How to cite this article:|
Kaur CP, Jindal V, Malhotra R, Jaggi D, Goel A, Kaur R. Perioceutics-A review. Indian J Dent Sci 2017;9, Suppl S1:44-8
|How to cite this URL:|
Kaur CP, Jindal V, Malhotra R, Jaggi D, Goel A, Kaur R. Perioceutics-A review. Indian J Dent Sci [serial online] 2017 [cited 2021 Mar 2];9, Suppl S1:44-8. Available from: http://www.ijds.in/text.asp?2017/9/5/44/214938
| Introduction|| |
Periodontal diseases, which cause the destruction of the supporting structures of the dentition, are common chronic infectious diseases of the oral cavity and are initiated by Gram-negative tooth-associated pathogens organized as a biofilm, whose presence elicits a host inflammatory response. The interaction of microorganisms with the host determines the course and extent of the resulting diseases. Microorganisms may exert pathogenic effects directly by causing tissue destruction or indirectly by stimulating and modulating host responses. The host response is mediated by microbial interaction and inherent characteristics of the host, including genetic factors that vary among individuals. In general, the host response functions in protective capacity by preventing local infection from further progression. A major focus of periodontal research has been directed toward the reduction and/or elimination of these pathogenic bacteria that are thought to cause periodontitis. This has been accomplished in large part by the use of mechanical treatment approaches including the use of scaling and root planning, the use of home care measures, and finally, surgical interventions. In later years, other adjunctive approaches that aim to eradicate or drastically reduce the bacteria have included pharmacological measures, which require the use of systemic as well as topical antimicrobial medications. However, recent research into the pathogenesis of periodontal diseases has led to an important paradigm shift, in the way we view periodontal disease progression. The importance of the host inflammatory response in periodontal pathogenesis presents the opportunity for exploiting new treatment strategies for periodontitis. The host immune-inflammatory response against bacterial plaque can thus be viewed as a “dual-edged sword,” i.e., the response is protective by intent, yet in susceptible patients who exhibit an exaggerated inflammatory response to plaque, it ultimately is responsible for perpetuating the destruction of the periodontium. This shift in paradigms, with emphasis on host response, has led to the development of host modulatory therapies (HMTs) which can improve therapeutic outcomes, slow the progression of a disease, allow for more predictable management of patients, and possibly even work as preventive agents against the development of periodontitis. “Perioceutics” or the use of the pharmacological agents specifically developed to manage periodontitis is an interesting and emerging aid in the management of periodontal diseases along with mechanical debridement. Compared to other therapeutic modalities employed against infection, host response modulation potentially is noninvasive, has fewer side effects, and does not require complicated application method. There are various host modulatory therapeutic agents for the treatment and management of periodontal diseases, which are an indispensable part of perioceutics and are used as an adjunct to the traditional periodontal therapies.
| Host-modulating Agents|| |
There are various HMT agents which have been developed to block or modify the pathways of periodontitis.
- Inhibition of arachidonic acid (AA) metabolite: through Nonsteroids anti-inflammatory drugs
- Cyclooxygenase (COX)-1 inhibitors: indomethacin, flurbiprofen, and naproxen
- COX-2 inhibitors: rofecoxib
- COX and lipoxygenase (LOX) inhibitors: triclosan and topical ketoprofen
- LOX inhibitors: lipoxins.
- Modulation of matrix metalloproteinases (MMPS)
- Recombinant tissue inhibitor of metalloproteinase
- Subantimicrobial dose of doxycycline
- Hydroxamic acid peptides such as galardin
- Chemically modified tetracyclines (CMTs).
- Modulation of bone remodeling: therapeutic approach to treat pathologic bone defect
- Conventional therapy
- Tumor necrosis factor (TNF)-alpha
- Anticytokine drugs
- Antiresorptive therapies
- Hormone replacement therapy
- Disruptive of the receptor activator of nuclear factor-κB ligand/receptor activator of nuclear factor-κB/osteoprotegerin interactions
- Vitamin D
- Regulation of immune and inflammatory response:
- Suppressing proinflammatory cytokines: interleukin 1 (IL1) and TNF-α receptor antagonist
- Modulation of nitric oxide (NO) activity
- Inhibition with mercapto alkyl guanidines
- Inhibition of nuclear poly (ADP-ribose) polymerase (PARP) enzyme.
- Generation of protective antibodies through vaccination (periodontal vaccines)
- Infusion/supplementary anti-inflammatory cytokines: IL-4 and IL-10
- Antagonist for endothelial cell adhesion molecules.
Inhibition of arachidonic acid metabolism
Mechanism of action of nonsteroidal anti-inflammatory drugs
It is explained in [Figure 1].
Systemically administered agents nonsteroidal anti-inflammatory drugs
These drugs are propionic acid derivatives, which act by inhibiting the COX pathway of AA metabolism; thereby reducing prostaglandin (PG) formation. PGs, including PGE2, are produced by neutrophils, macrophages, fibroblast, and gingival epithelial cells in response to the presence of lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria. PGE2 induces bone loss thus nonsteroidal anti-inflammatory drugs (NSAIDs) control the alveolar bone loss.
Topically administered agents nonsteroidal anti-inflammatory drugs
The topical administration of NSAIDs is an alternative method to deliver these agents. In general, topical application of NSAIDs is possible because these drugs are lipophilic and are absorbed into gingival tissues. NSAIDs that have been evaluated for topical administration include ketorolac tromethamine rinse and S-ketoprofen dentifrice.
- A compound which has received interest as both an antibacterial and anti-inflammatory agent is triclosan. Triclosan (2, 4, 4-trichloro-2-hydroxydiphenyl ether) is a nonionic antibacterial agent. Triclosan also inhibits COX and LOX and thus may interfere with the production of AA metabolites.
Inhibition of matrix metalloproteinases
Chemically modified tetracyclines
CMTs are those which lack dimethylamino group on the 4th carbon atom.
Mechanism of action of CMTs is explained in [Figure 2].
Subantimicrobial dose doxycycline
A new approach to nonantibacterial periodontal therapy is the administration of specially prepared low-dose capsules containing as low as 20 mg of doxycycline. Doxycycline is the most potent collagenase inhibitor of commercially available tetracyclines (TCs). Collagenase activity was inhibited by 70% in the presence of doxycycline, 45% with minocycline, and 23% with TC. Kornman and Karl demonstrated that the long-term administration of doxycycline might be associated with the development of antibiotic resistance. When antibiotic doses of TC (250 mg daily for 2–7 years) had previously been given to patients with refractory periodontitis, up to 77% of the patients' cultivable subgingival microflora exhibited TC resistance. In light of this concern, a low, subantimicrobial dose doxycycline (SDD) preparation was introduced, containing 20 mg doxycycline, as opposed to the 50 or 100 mg dose that is available for antibiotic purposes.
To date, this is one approved, systemic therapy that is prescribed as a host response modifier in the treatment of periodontal disease, and that is adjunctive SDD.
Mechanism of action of subantimicrobial dose doxycycline
It is explained in [Figure 3].
Subantimicrobial dose doxycycline as an adjunctive treatment for periodontitis
One of the preliminary experiments to be conducted with this new formulation demonstrated clearly that SDD (20 mg twice daily) administered for just 2 weeks inhibited collagenase activity by 60%–80% in the gingival tissues of patients with chronic periodontitis. Collagenase activity was also significantly reduced in gingival crevicular fluid (GCF) collected from these patients. Subsequent studies of relatively short duration (1–3 months) indicated that this dosing regimen could prevent periodontitis progression without the emergence of doxycycline-resistant microorganisms or other typical antibiotic side effects. Thus, the concept was born that SDD (20 mg twice daily) could be used as an adjunct for the treatment of chronic periodontitis.
In a key study by Golub et al., SDD was given to 12 patients with chronic periodontitis for 2 months following a course of subgingival instrumentation. Six patients were prescribed the placebo. At baseline month 1st and 2nd month; GCF samples were collected and analyzed for MMP-8, MMP-13, and ICTP (carboxy-terminal peptide, a pyridinoline-containing fragment of Type-l collagen). The 2-month regime of SDD resulted in statistically significant reductions in GCF concentrations of ICTP, MMP-8, and MMP-13 compared with placebo.
Thus far, one approved HMT prescribed as systemic SDD (Periostat ®, CollaGenex Pharmaceuticals Inc., Newtown, PA, USA) in conjunction with mechanical periodontal therapy is available in some countries.
Modulation of bone metabolism
These are nonbiodegradable analogs of pyrophosphate that have a high affinity for calcium phosphate crystals and that inhibit osteoclast activity. These compounds also appear to inhibit MMP activity through a mechanism that involves chelation of cations. Alkyl side chains (e.g., etidronate) characterize first-generation bisphosphonates. Second-generation bisphosphonates include amino bisphosphonates with an amino-terminal group (e.g., alendronate and pamidronate). Third-generation bisphosphonates have cyclic side chains (e.g., risedronate). The antiresorptive properties of bisphosphonates increase approximately 10-fold between drug generations. Mechanism of action of bisphosphonates is shown in [Figure 4].
The contraindications for bisphosphonates use are the sensitivity to phosphonates and gastrointestinal upset.
Regulation of immune and inflammatory responses
Modulation of nitric oxide activity
NO is a short-lived molecule implicated in a wide range of biological processes. NO is a highly reactive free radical reacting with metal and thiol residues leading to lipid peroxidation, protein and DNA damages, and stimulation of cytokine release. Nuclear PARP enzyme downstream NO toxicity.
Suppressing proinflammatory cytokines
Cytokines are defined as regulatory proteins controlling the survival, growth, differentiation, and functions of cells. Cytokines function as a network and are produced by different cell types and share overlapping features. This phenomenon is called biological redundancy. To counteract tissue destruction and maintain homeostasis, cytokine antagonists such as IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptors can competitively inhibit receptor-mediated signal transduction.
Other locally administered agents
A number of local host modulation agents, i.e., enamel matrix proteins, growth factors, and bone morphogenetic proteins have been investigated for potential use as adjuncts to surgical procedures, not only to improve wound healing but also to stimulate regeneration of lost bone, periodontal ligament, and cementum and thus restoring the complete periodontal attachment apparatus. The only local host modulation agent currently approved by the Food and Drug Administration (FDA) for adjunctive use during surgery is Emdogain.
| New Emerging Host-modulating Agent|| |
Azithromycin's immunomodulatory properties
It is rapidly taken up by neutrophils, macrophages, and fibroblasts with a high degree of retention. It is carried efficiently into inflamed tissues by neutrophils through chemotaxis while maintaining its activity. When azithromycin (500 mg once daily for 3 days) was taken by healthy volunteers, it persisted in neutrophils for 28 days after the last dose, presumably as a result of accumulation in neutrophil precursor cells. Azithromycin exerted acute effects on the release of neutrophil granular enzymes, on oxidative burst and oxidative protective mechanisms; there was a prolonged degranulation of circulating neutrophils, which could represent a potential anti-inflammatory effect in the treatment of subacute, noninfective inflammatory responses.
Azithromycin, when given as a single course of three, 500 mg tablets, could well play a triple role in the treatment of moderate to advanced periodontitis. Its effectiveness against Gram-negative bacteria, the ability to penetrate biofilm, and a long antibacterial half-life and short course make it an attractive antibiotic option as an adjunct to the management of advanced inflammatory periodontitis. The Intake of azithromycin by neutrophils and macrophages allows it to target and be concentrated at sites of periodontal inflammation and exert its anti-inflammatory properties. As hyperresponsive macrophages are considered to be determinants of susceptibility to periodontitis by producing large quantities of proinflammatory cytokines in response to LPS and bacterial products, a possible beneficial role of azithromycin is to downregulate proinflammatory cytokine production. Azithromycin appears to exert a long-term healing influence on the periodontal tissues. This property may be related to its effect on changing the macrophage phenotype (to M2), thus increasing the production of anti-inflammatory cytokines and favoring healing. If an agent was being specifically designed to treat inflammatory forms of periodontitis, it would have these distinct and temporally overlapping activities. The strategic use of azithromycin may become useful in primary periodontal therapy of patients with a poor treatment response, with respect to both its antibacterial and immunomodulating action.
Azithromycin may prove to be a more effective host modulator in the treatment of periodontitis than low-dose doxycycline (which requires patients to take two tablets a day for 3 months or longer and is accompanied by side effects). It may be possible to develop a subantimicrobial azithromycin-dosing regimen that avoids potential bacterial resistance.
Mechanism of action
Teriparatide and parathyroid hormone (PTH) mediate their biological effects through specific, G-protein-dependent, high-affinity membrane cell-surface receptors which are expressed on osteoblasts and renal tubular cells; both these molecules bind to the receptors with the same affinity and exert the same physiological effects on bone and kidney. It has been suggested that ligand binding induces a cascade that activates protein kinase-1, cyclic adenosine monophosphate, protein kinase C, and phospholipase C. The activation of these pathways results in an increase in the number of active osteoblasts, a decrease in osteoblast apoptosis, and probably, recruitment of bone lining cells as newly formed osteoblasts, thereby increasing bone strength, mass and diameter, and bone structural integrity, as well as increasing serum and urinary levels of markers of bone formation and resorption.
Other factors may also play a role in the anabolic effect of teriparatide. Basic fibroblast growth factor 2 (bFGF-2) is also upregulated in teriparatide-treated individuals. Since bFGF-2 regulates the proliferation and differentiation of osteoblast progenitors, this cytokine could play an important role in the bone formative response to teriparatide therapy. Furthermore, the osteocytic sclerostin gene may be transcriptionally suppressed by PTH. As a result, reductions in sclerostin, a potent inhibitor of bone formation, could account for part of the anabolic response to PTH.
| Conclusion|| |
The recognized importance of the host inflammatory response in the pathogenesis of periodontal diseases presents the opportunity to explore new treatment strategies. A variety of treatment strategies has been developed to target the host response to periodontal infection. This review has sought to provide mechanistic overviews and clinical applications on the use of host modulatory therapeutic regimens for periodontal disease management.
The improved understanding of the host-bacterial interactions and host immune-inflammatory response leading to periodontal tissue destruction has led to the development of HMT. Although the efficacy and usefulness of host-modulating agents have been demonstrated by many clinical trials and have been approved by FDA for the management of periodontitis, the risk/benefit ratio relating to the use of these drugs has yet to be established. Multicenter clinical trials are necessary to fully evaluate the benefits of these agents and to weigh their usefulness against the risks associated with their long-term administration. Furthermore, continuous research in this field would also enable fabrication of individualized treatment for periodontal disease targeting inflammatory host response.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]