Host Modulation Therapy
Question 1. Write short answer on host modulation agent.
Answer. A variety of drug classes have been evaluated as host modulation agents, including NSAIDs, bisphosphonates, tetracyclines, enamel matrix proteins, growth factors, and bone morphogenetic proteins.
Drugs which can cause host modulation are:
- Systemically: NSAIDs, sub antimicrobial-dose doxycycline and bisphosphonates.
- Locally administered agents i.e. NSAIDs, enamel matrix proteins, growth factors and bone morphogenetic proteins
- NSAIDs: Strong evidence suggests that products of cyclooxygenase pathway can be important mediators in disease process of periodontium. Hence, NSAIDs play an important role in treatment of periodontal disease. Mechanism of action is decreased PMNL migration; decrease in vascular permeability; and decreased platelet aggregation. Various drugs which are studied consist of ibuprofen, mefenamic acid and naproxen.
- Bisphosphonates: They inhibit bone resorption by disrupting osteoclastic activity e.g. alendronate.
- Tetracyclines (subantimicrobial dose doxycycline): A 20 mg dose of doxycycline is indicated as an adjunct to scaling and root planing. It has anti – collagenase effect. It is taken upto maximum 9 months. It is marketed as Periostat.
- Growth factors, Bone morphogenic proteins and enamel matrix proteins: These are currently approved by FDA for adjunctive use during surgery. Most commonly marketed brand is Emdogain.
Read And Learn More: Periodontics Question And Answers
Various host modulation therapies are developed to block the pathways which causes breakdown of periodontal tissues is:
- Inhibition of matrix metalloproteinases (MMPs) via chemically-modified tetracyclines (CMTs).
- Inhibition of arachidonic acid (AA) metabolites via nonsteroidal anti-inflammatory drugs (NSAIDs)
- Modulation of bone metabolism
- Regulation of immune and inflammatory responses
Inhibition of Matrix Metalloproteinases (MMPs) via Chemically Modified Tetracyclines (CMTs).
Chemically modified tetracyclines usually lack dimethylamino group on the 4th carbon atom. They inhibit or chelates the calcium atoms and subsequently inhibit the action of MMPs due to lack of calcium. It inhibits already active MMPs; downregulate MMPs expression; act as reactive oxygen species scavengers and modulates the osteoclastic functions.
Inhibition of Arachidonic Acid (AA) Metabolism
As a consequence of the periodontal diseases, prostaglandins are synthesized and released within the periodontal tissues along with the other AA metabolites. AA is usually metabolized through the cyclooxygenase (COX) or lipoxygenase (LOX) pathways. In such cases, modulation of the host response can be possible with the inhibition of the enzymes that are responsible for the release of these destructive products.
Systemically Administered Agents NSAIDs
These drugs are propionic acid derivatives, which act by inhibiting the COX pathway of arachidonic acid metabolism, thereby reducing prostaglandin formation. Prostaglandins, including prostaglandin E2 (PGE2), are produced by gingival epithelial cells, neutrophils, macrophages and fibroblast through COX pathway. Prostaglandins are released in response to the lipopolysaccharide (LPS) that is present in the cell wall of the Gram-negative bacteria. PGE2 induces bone loss; thus NSAIDs control the alveolar bone loss.
Locally Administered Agents NSAIDs
Alternative to systemic administration, NSAIDs can be applied topically in affected areas. Generally, topical application of NSAlDs is effective due to its lipophilic nature and absorbance into gingival tissues. Ketorolac tromethamine rinse and S-ketoprofen dentifrice are the NSAIDs that have also been evaluated for the topical administration.
Modulation of Bone Metabolism
Following are the two molecules that are involved in regulation of osteoclast formation and process of bone resorption.
- Receptor activator of nuclear factor-kappa B ligand (RANKL).
- Osteoprotegerin (OPG).
Osteoprotegerin blocks the process of osteoclast differentiation and activation induced by RANKL by acting as a decoy receptor for RANKL.
As bone loss is a cardinal feature of periodontitis, the use of bisphosphonates seem to be a viable option. Bisphosphonates are shown the ability to inhibit osteoclastogenesis, affect osteoclast differentiation and regulate their resorption of mineralized tissues. Bisphosphonates have been classified into various generations depending on their chemical structure and it has been postulated that the second generation bisphosphonates exhibit comparatively fewer adverse effects when compared to the other generations. Bisphosphonates have been widely used in the treatment of rheumatoid arthritis, but their use in periodontal disease has been limited to experimental stages. The potential for complications such as avascular necrosis and malignancies has limited their mode wide spread use.
Regulation of Immune and Inflammatory Response
Nitric oxide is a short-lived molecule having an integral role in biological processes. It is produced by the epithelial and the inflammatory cells in response to the cytokines. It shows cytotoxic effects towards the host cells only when its concentration is elevated as in periodontitis. It is a highly reactive free radical molecule which reacts with metal and also the thiol residues, leading to the lipid peroxidation, destruction of protein and deoxyribonucleic acid (DNA) and the stimulation of cytokine release. Nitric oxide synthase (NOS) are enzymes that generate NO in tissues.
Modulation of Nitric Oxide Activity
Inhibitors of nitrous oxide synthetase and nitrous oxide: Mercaptoethyl guanidine inhibits inducible nitrous oxide synthetase; and also scavenges peroxynitrite which is the product of nitrous oxide and superoxide radical. Nitrous inhibitor inhibits bone resorption.
Inhibitors of downstream mediator: Nuclear poly (ADP-ribose) polymerase-1 (PARP) enzyme is a mediator of downstream NO toxicity. Inhibition of PARP enzyme reduces alveolar bone resorption.
Cytokines
- They are the regulatory proteins controlling the survival, growth, differentiation and functions of cells. The process of bone resorption is stimulated by IL-1 and TNF-α, through PGE2 and MMPs release from fibroblasts and monocytes. TNF-α is an inflammatory cytokine which is released by activated macrophages, T lymphocytes. TNF- α stimulates osteoclast formation thus, blocking it inhibits osteoclast formation.
- Suppressing proinflammatory cytokines: Cytokine antagonists, such as IL-1 receptor antagonist (IL-1Ra) and TNF-α receptors antagonist inhibit the progression of inflammatory cell infiltrate and recruitment of osteoclasts. IL-4 stimulates the production of IL-1Ra.
- Anti-cytokine agents: Anakinra (recombinant human IL 1Ra); AMG 714 (human monoclonal antibody against IL-l5); recombinant human IL-11 inhibits production of TNF-α and IL-1.
- Other locally administered agents: Various locally acting host modulation agents have been tested in order to use as an adjunct to surgical procedures. Growth factors and bone morphogenetic proteins are an example of enamel matrix proteins. They improve wound healing process and stimulate the regeneration of cementum, lost bone and periodontal ligament. These properties help to restore the complete periodontal attachment apparatus. Currently, Food and Drug administration (FDA) approved only one local host modulation agent Emdogain to use as an adjunctive during surgery.
Probiotics
Probiotics interacts with and strengthen the immune system and helps to prevent periodontal disease in the following manner: induces expression of cytoprotective proteins on host cell surfaces; prevents cytokine-induced apoptosis and modulates pro—inflammatory pathways induced by pathogens.
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