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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.
5.
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.
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
20.
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.