Study Shows Sub-Antimicrobial Dose Doxycycline Lowers C-Reactive Protein In Patients Suffering From Acute Coronary Syndromes
Marketed under the brand name Periostat (doxycycline hyclate) by CollaGenex Pharmaceuticals (NASDAQ: CGPI), the 20 mg tablet, which is taken twice daily, provides a sub-antimicrobial dose of a commonly used antibiotic. In the MIDAS (Metalloproteinase Inhibition with Low-Dose Doxycycline to Prevent Acute Coronary Syndromes) pilot trial, Periostat not only lowered levels of CRP, but also reduced levels of the inflammatory cytokine interleukin (IL)-6, which is implicated in CRP production and the occurrence of acute coronary events.
"In this small study, sub-antimicrobial dose doxycycline produced striking reductions in CRP that mandate a larger study to further explore its utility in modulating inflammation in ACS," said David L. Brown, MD, Director of Interventional Cardiology and Cardiac Catheterization Laboratories of Beth Israel Medical Center, New York, and MIDAS lead investigator. "This is a compelling finding, as we are learning that CRP is not only a key indicator of inflammation leading to acute cardiac events, but that it may itself play an important, pathological role in the initiation and progression of atherosclerosis. Finding potent methods for inhibiting its effects could have important implications for ACS patients."
MIDAS was a prospective, randomized pilot study of 50 patients with recent acute coronary syndromes who were randomized into two groups and administered placebo or
sub-antimicrobial dose doxycycline (Periostat). Blood samples were taken at study entry and after six months of therapy and then analyzed, using state-of-the-art techniques, for CRP, IL-6 and two matrix metalloproteinases, MMP-2 and MMP-9, enzymes associated with atherosclerotic plaque rupture. While the small study was of insufficient length to assess a significant difference in its primary objective, a reduction in coronary events at six months, Brown and colleagues found that not only did sub-antimicrobial dose doxycline lower CRP by a statistically significant 46 percent compared to baseline levels, it also reduced IL-6 and MMP-9 activity by 34 percent and 50 percent, respectively (p£ .05). A 38 percent reduction in MMP-2 activity among treated patients did not reach statistical significance.
In the blood sample analyses performed by Lorne M. Golub, DMD, MSC, honorary MD, professor in Oral Biology and Pathology, State University of New York (SUNY) at Stony Brook, and colleagues, researchers found that not only did Periostat lower levels of MMP-9 protein, but it also inhibited its activity. "This is an important finding as it facilitates our understanding of Periostat's mechanism of action in reducing the activity of MMPs, which are associated with the destabilization of atherosclerotic plaque," said Dr. Golub. "While we have long known Periostat's local effects on the periodontium in gum disease, the MIDAS study demonstrates a similar effect on the vasculature, which may have implications for other systemic diseases as well." Dr. Golub and his team were the first to discover that tetracyclines, such as doxycycline, could inhibit MMPs, that their mechanism of action was unrelated to their antibiotic activity, and that this previously unrecognized property of these drugs had therapeutic potential for a variety of diseases.
The Role of C-Reactive Protein
CRP is an acute-phase inflammatory protein that is produced as part of the body's response to infection and injury. It has been shown to be a sensitive indicator of these acute pathological events, because blood levels of CRP temporarily soar as the immune system jumps into action. One of the triggers of this overproduction of CRP is inflammation caused by heart disease, specifically acute cardiac events such as unstable angina and myocardial infarction. New research is showing that CRP may be more than just a marker for cardiovascular events; it may trigger the cascade of events leading to the initiation and progression of atherosclerosis.
In patients with stable premature coronary artery disease, CRP levels in the presently accepted upper normal range or higher are accompanied by an increased long-term risk for development of cardiovascular events, such as cardiac death, AMI or the need for revascularization. Studies have found that those with high levels of CRP have twice the risk of an acute event compared with people who have only elevated cholesterol.
The Role of Periostat
Periostat is indicated as an adjunct to scaling and root planing to promote the attachment of gums to teeth and reduce the depth of the pocket that forms between teeth and gums in patients with adult periodontitis (AP), or advanced gum disease. Research has shown that the drug works in gum tissue by suppressing the pathologically elevated levels of inflammatory cytokine activity and tissue-destroying enzymes, which ultimately cause the clinical signs and symptoms of the periodontitis. Periostat is the only treatment for AP specifically designed to suppress tissue-destroying enzymes and prevent tooth loss by
restoring the balance of enzymes, cytokines and their natural inhibitors in favor of the preservation of connective tissue. It is these same cytokines and enzymes that are believed to contribute to increased risk of heart disease.
Independent research has shown that patients suffering from periodontitis also may be at an increased risk of developing heart disease. One explanation for this link is that the inflammatory response characteristic of periodontal disease, which is marked by high levels of inflammatory mediators, intensifies the process of developing atherosclerosis. Therefore, it is plausible that a drug such as Periostat, which is designed to reduce these mediators in periodontitis, may also help reduce the risk of cardiovascular disease.
While the active ingredient in Periostat is doxycycline, the dose administered (20 mg twice a day) has been demonstrated through exhaustive clinical studies not to cause any detrimental effect on the normal and pathological microflora of the human body. Specifically, in clinical studies, administration of Periostat for periods of up to 18 months has demonstrated no antibacterial effect in the microflora of the oral cavity, the gastrointestinal and genitourinary tract, nor the skin. Furthermore, the side effects typically associated with the long-term administration of higher doses of tetracycline antibiotics have not been seen with Periostat. Side effects with Periostat are reported to be comparable in nature and incidence to those of placebo.
Periostat is also being tested in new drug application (NDA)-focused clinical trials for the treatment of acne and rosacea, two dermatological conditions that are also associated with a local inflammatory response and elevated levels of cytokines and tissue-destroying enzymes. Early stage clinical research is also underway studying the impact of Periostat in patients with meibomianitis (cause of dry eye), diabetes and post-menopausal osteoporosis.
Source: MCS