Chemically modified tetracycline
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This document discusses chemically modified tetracyclines (CMTs), a group of drugs developed from tetracyclines that lack antimicrobial properties but retain anti-collagenase activity. CMTs have several potential benefits, including inhibiting matrix metalloproteinases (MMPs), reducing proinflammatory mediators, inhibiting bone resorption, and scavenging reactive oxygen species. While CMTs show promise for treating conditions like periodontitis, they have not been fully approved for human use due concerns around excessive MMP suppression and other side effects.
Chemically modified tetracycline
- 1. Guided by Dr. Gowtham MDS., Department of Periodontics and Implantology. Done by Amritha James, Final year.
- 2. INTRODUCTION Tetracyclines were first discovered by Dr. Benjamin Dugger in the mid 1940s. Tetracyclines (TCs) are a class of antibiotics able to inhibit protein synthesis in gram positive and gram negative bacteria by preventing the attachment of aminoacyl-tRNA to the ribosomal acceptor (A) site.
- 3. Currently, 3 groups of tetracyclines are available: tetracycline natural products, tetracycline semi synthetic compounds and chemically modified tetracyclines. Chemically modified tetracyclines are one such group of drugs which have been viewed as potential host modulating agents.
- 4. Structure of CMTs Golub et al discovered that the carbon 4 position side chain was responsible for the antimicrobial activity of tetracyclines. CMTs were produced by removing the dimethylamino group from the carbon-4 position of the A ring of the four ringed (A,B,C,D) structure. The resulting compound, 4-dedimethyl amino tetracycline (CMT-1) did not have antimicrobial property but the anticollagenase activity was retained both in vitro and in vivo.
- 6. Types of CMTs Currently about eight CMTs have been developed. CMT-1(4- dedimethylaminotetracycline), CMT-2(tetracyclinonitrite), CMT-3(6-deoxy-6-demethyl-4-dedimethyl amino tetra cycline), CMT-4(7-chloro-4-de- dimethyl amino tetra cycline), CMT-5(tetracycline pyrazole), CMT-6(4-dedimethylamino.4-hydroxytetracycline), CMT-7(12-deoxy- 4-de-dimethyamino tetracycline) and CMT-8(4-dedimethylaminodoxycycline).
- 7. Inhibits collagenase activity Inhibits neutrophil chemotaxis Increases fibroblast attachment to the root surface Anti-inflammatory effects due to the inhibition of prostaglandin synthesis Inhibits bone resorptionEnhances collagen synthesis Longer half life in serum Inhibits MMPs and iNOS (inducer nitric oxide synthase).
- 8. Advantages of CMTs It lacks antimicrobial activity and hence there is no development of antibiotic resistant microbial flora in vivo in long term therapy. Long term systemic administration does not cause gastrointestinal toxicity. Higher plasma concentrations can be obtained with less frequent administration regimens.
- 9. Limitations of CMTs Photosensitizing property Systemic lupus erythematosis (SLE) is an unexpected side effect of CMT-3, Elevated liver function tests and neurotoxicities. Non-dose related toxicities like anemia, anorexia, constipation, dizziness, fatigue, fever, headache, heartburn, nausea, vomiting, CMTs have shown irregular absorption rates, cytotoxic effects (at higher concentrations). May cause the excessive suppression of MMPs, which can hamper the normal physiologic turnover of collagen.
- 10. Uses of CMTs 1. In host modulation therapy, in management of periodontitis by inhibition of MMPs. 2. Anti-inflammatory actions: a) Inhibits inducible nitric oxide synthase(iNOS) and COX-2 mediated PGE2 production. b) Inhibits Bone Resorption c) Inhibits proinflammatory mediators like IL-1β, IL-6, IL-8, TNF- α and PGE2.
- 11. Microbial challenge Host immune inflammatory response Breakdown of connective tissue Bone resorption Antibody PMNs LPS Antigens Other virulence factors Cytokines Prostanoids MMPs Host modulation CMTs
- 12. The anti-MMP actions of CMTs can be summarized as follows: • Direct inhibition of the active MMPs by the virtue of Ca 2+ and Zn 2+ binding sites. • Inhibition of ROS mediated activation of Pro- MMPs. • Proteolysis of Pro-MMPs into enzymatically inactive fragments. • Protection of α-1 proteinsase inhibitor from MMPs. • Reduction in the activity of serine proteinases.
- 13. This helps in the reduction of pathologic concentrations of collagenases without affecting the normal collagen turnover required to maintain the tissue integrity. Polymorphonuclear leucocytes (PMNs) collagenases connective tissue breakdown Fibroblasts collagenases connective tissue remodeling in normal gingiva CMTs
- 14. Scavenging reactive oxygen species (ROS) and reactive nitrogen species (RNS) • CMTs may decrease the ROS burden by inhibiting PMN-derived reactive oxygen metabolites, by directly scavenging free radicals and inhibiting reactions that lead to free radical generation. The reactive oxygen species include oxygen-derived free radicals (e.g., superoxides, hydroxyl) and non-radical compounds (e.g., hypochlorus acid, hydrogen peroxide). • CMTs inhibit the expression of inducible nitric oxide synthase (iNOS) which is required for the production of peroxynitrite from NO thereby preventing the protein denaturation Reactive nitrogen species include nitric oxide (NO), nitrogen dioxide radicals, and products arising from the reaction of NO with oxygen-free radicals such as peroxynitrite.
- 15. Inhibition of bone resorption CMTs inhibit bone resorption by various mechanisms which include: • reduction in number of osteoclasts by inhibiting their development and inducing apoptosis, • by altering the ruffled border and increasing the size of clear zone, • by decreasing the production of osteoclastic enzymes like TRAP and Cathepsin-L which degrade organic components of bone, • inhibits osteoclastogenesis, • elevates intracellular calcium levels which makes the osteoclasts to detach from bone resorbing site, • inhibits osteoclasts collagenase production and also decreases acid production, thereby inhibiting bone resorption, thus preventing the progression of periodontal disease.
- 16. CMTs suppress phosphorylation of the nuclear factor κ-B cell signalling pathway inhibit release of IL-1β, IL-6, IL- 8, TNF-α and PGE2 from LPS stimulated host immune cells inhibits protein kinase - C production increases the IL-10 levels produce an anti-inflammatory effect Inhibition of proinflammatory mediators
- 17. Other Uses Inhibition of intimal thickening: Smooth muscle cell (SMC) proliferation, migration, and matrix synthesis contribute to the neointimal thickening observed in atherosclerosis, restenosis. CMT-3 significantly reduced smooth muscle cell (smc) proliferation. Antifungal agents: CMT-3 may exert its fungicidal activity. Reaction of CMT-3 with organelles may disturb intracellular membranes, resulting in inhibition of some metabolic steps, such as oxidative phosphorylation or protein synthesis in fungal cells.
- 18. Inhibition of orthodontic tooth displacement: A study done by Bildt et al. reported CMT-3 inhibits tooth movement in the rat, probably by reducing the number of osteoclasts at the compression side. CMTs against advanced cancers: Matrix metalloproteinases (MMPs) make up the majority of ECM degrading enzymes implicated in cancer metastasis. Some of these CMTs, notably, CMT-3 and CMT- 308 significantly inhibited invasive potential and MMP activity
- 19. Diabetes Mellitus: Experiments in diabetic rats have shown that daily oral administration of CMT for 21-37 days reduced the levels of pathologically excessive collagenase in gingival tissues Acne and Acute Respiratory Distress Syndrome: Lower oral doses of CMT-3 are effective in decreasing the severity of acne. They have also been used in the treatment of life threatening conditions like epidermolysis bullosa and acute respiratory distress syndrome associated with excessive collagenase activity
- 21. CMTs and Bisphosphonates A combination of suboptimal CMT-8 and clodronate "normalized" the pathologically elevated levels of MMPs, elastase, and alveolar bone loss, indicating synergistic inhibition of tissue breakdown in animal models of periodontitis. Combination of a CMT and a bisphosphonate may be a useful treatment to optimally suppress periodontal destruction and tooth loss and in other tissue-destructive inflammatory diseases such as arthritis
- 22. Conclusion CMTs are still in their infancy with regard to use in humans as they have not been approved due to concerns like excessive suppression of MMPs which may hinder the normal physiologic turnover of collagen. CMTs have shown to have beneficial effects in the treatment of chronic periodontal disease. However, the gold standard in the treatment of periodontal disease is still mechanical debridement.