Non-antibacterial tetracycline formulations: clinical applications in dentistry and medicine

Abstract

In 1983, it was first reported that tetracyclines (TCs) can modulate the host response, including (but not limited to) inhibition of pathologic matrix metalloproteinase (MMP) activity, and by mechanisms unrelated to the antibacterial properties of these drugs. Soon thereafter, strategies were developed to generate non-antibacterial formulations (subantimicrobial-dose doxycycline; SDD) and compositions (chemically modified tetracyclines; CMTs) of TCs as host-modulating drugs to treat periodontal and other inflammatory diseases. This review focuses on the history and rationale for the development of: (a) SDD which led to two government-approved medications, one for periodontitis and the other for acne/rosacea and (b) CMTs, which led to the identification of the active site of the drugs responsible for MMP inhibition and to studies demonstrating evidence of efficacy of the most potent of these, CMT-3, as an anti-angiogenesis agent in patients with the cancer, Kaposi's sarcoma, and as a potential treatment for a fatal lung disease (acute respiratory distress syndrome; ARDS). In addition, this review discusses a number of clinical studies, some up to 2 years’ duration, demonstrating evidence of safety and efficacy of SDD formulations in humans with oral inflammatory diseases (periodontitis, pemphigoid) as well as medical diseases, including rheumatoid arthritis, post-menopausal osteopenia, type II diabetes, cardiovascular diseases, and a rare and fatal lung disease, lymphangioleiomyomatosis.

Systematic review and meta-analysis on the nonsurgical treatment of chronic periodontitis by means of scaling and root planing with or without adjuncts

“…Specifically, it inhibits host collagen-degrading enzymes. 29,30 Eleven studies 31-42 in 12 publications met the inclusion criteria for reporting the effect of SRP plus SDD versus SRP alone. All were parallel-group trials.…”

Matrix metalloproteinase-9 in the pathophysiology and diagnosis of dry eye syndrome

“…Oral doxycycline has also been used off-label to treat recurrent corneal erosions, ocular rosacea and MGD, [99][100][101][102] as well as other inflammatory diseases where MMPs are implicated, including rheumatoid arthritis, and atherosclerotic cardiovascular disease. 103 It is FDA approved to treat periodontitis, a disease of the gums where increased levels of MMPs are found. However, side effects of oral administration, such as gastrointestinal upset, photosensitivity and vaginal candidiasis, can occur.…”

The Effect of Bisphosphonates and Low-Dose Doxcycline Therapy in Diabetics With Periodontitis: A Review

“…112 Tetracycline administration normalizes the structure and acid phosphatase activity of osteoclasts 130 and restores osteoblast structure and function in the diabetic rats. 131 Golub et al 111 determined that doxycycline prevented the development of the bone deficiency disease without affecting the severity of hyperglycemia in the rat with diabetesinduced osteopenia.…”

“…112,115 Several studies have shown that use of LDD as adjunctive therapy to SRP could provide additional benefits in the management of chronic periodontitis compared to non-surgical periodontal treatment alone. 99,101,110,112,116 Golub et al 99 determined that LDD regimen administered to patients with adult periodontitis can reduce pathologic elevations in gingival crevicular fluid (GCF) collagenase activity and improve attachment level measurements. Mavragani et al 100 demonstrated that systemic administration of LDD inhibited root resorption, alveolar bone loss, increased the alveolar bone mass and decreased number of osteoclast in the rat with experimental orthodontic tooth movement.…”