Effects of new perio drug focus on moderating the bodys response to infection

Have you heard about or read about the new "perio pill?" Maybe your patients have started to ask questions. In 1994, research on the drug created a flurry of interest outside dentistry, sparked by an editorial by Dr. Harold Löe in the Journal of the American Medical Association and a textbook published by the New York Academy of Sciences.

Trisha E. O`hehir, RDH, BS

Have you heard about or read about the new "perio pill?" Maybe your patients have started to ask questions. In 1994, research on the drug created a flurry of interest outside dentistry, sparked by an editorial by Dr. Harold Löe in the Journal of the American Medical Association and a textbook published by the New York Academy of Sciences.

The patent for a new use of this drug belongs to CollaGenex, a company I didn`t pay too much attention to because I assumed (a bad habit!) that they sold a collagen-grafting material. I was surprised to find their connection to collagen was a systemic drug, controlling collagen breakdown associated with periodontal disease. Quite simply, the perio pill, Periostat®, is a subantimicrobial dose of doxycycline. In a low dose, this drug has potent anticollagenase activity and, therefore, enhances the results achieved with periodontal debridement therapy. Of course, it`s a bit more complex than that, but, with that snapshot, you can explain it to your patients.

A new acronym you will hear in connection with Periostat is MMP or matrix metalloproteinases. MMPs are a family of at least 12 zinc- and calcium-dependent enzymes capable of breaking down collagen. In health, these enzymes facilitate the normal turnover of tissue. However, during periodontal disease, an imbalance occurs which cannot be handled by the body, leading to more tissue breakdown than repair. The MMP you are probably most familiar with is collagenase.

Bacteria are considered to be the cause of periodontal disease. More accurately, bacteria initiate the disease process. Some collagenase is released directly from the bacteria. The destruction of bone and connective tissue leading to tooth loss, however, is due to an excess of destructive enzymes produced by the body in defense.

Endotoxins from the bacterial cell walls enter the periodontal tissues and stimulate immune system cells to release chemical mediators called cytokines. In response, the body sends polymorphonuclear leukocytes (PMNs) to the area as the first line of defense. Their primary objective is to eliminate the bacteria and resolve the infection. As they move through the tissues, PMNs release collagenase and are considered the primary source of MMPs in the periodontal tissues.

It appears that host-derived collagenase is responsible for most of the tissue breakdown associated with periodontal disease. Host-derived collagenase comes from both infiltrating blood cells (PMNs) and from local cells - such as fibroblasts, epithelial cells, endothelial cells, osteoblasts,

and osteoclasts. Cytokines are signaling chemicals which mediate the production of MMPs by both resident cells and infiltrating blood cells.

Our traditional approach to periodontal disease has focused on the bacteria, either through daily plaque control, antimicrobials, mechanical therapy, surgery, or systemic antibiotics. Systemic drugs, such as Periostat, do not eliminate the bacteria. Instead, they attempt to alter the body`s destructive defense mechanism. This approach is termed "host modulation" since it deals with the body`s response rather than the bacteria.

Dr. Lorne Golub, of the State University of New York at Stony Brook, was the first to identify the anticollagenase property of tetracyclines in his 1983 study of diabetic rats. Doxycycline and minocycline were also tested and found to have greater anticollagenase activity than the parent compound of tetracycline.

The first test on periodontal patients was reported in 1990. A two-week regimen of low-dose doxycycline reduced collagenase in the gingival crevicular fluid and was also found to be effective within gingival tissues, as measured in tissue samples.

Research for FDA approval involved patients taking the drug for a total of nine months.

Collagenase activity was reduced, and no side effects from long-term antibiotic activity were seen. Reductions in pocket depths, gains in clinical attachment levels, and a trend toward inhibition of bone loss were demonstrated. Although the exact mechanism is not yet known, osteoblast activity is enhanced, resulting in collagen and bone formation. Not only does doxycycline seem to prevent bone loss, but it may also lead to bone regeneration.

During my work assisting in oral surgery, I was surprised to see that young patients taking tetracycline for acne problems had bright yellow bone, graphically illustrating a link between tetracycline and bone.

Subantimicrobial-dose doxycycline (SDD), which in early research was referred to as low-dose doxycycline (LDD), that is given orally in 20 mg capsules twice daily results in a blood serum level of 0.7 µg/ml compared to 1.0 µg/ml which is required to exert antibiotic effects. Used at 20 mg twice daily, which is below antimicrobial level, no resistant microorganisms have been detected. This low dose of doxycycline does not result in the usual side effects seen with the higher, typical dosages of tetracyclines, such as gastrointestinal distress and photosensitivity.

Since collagen is found in connective tissue, bone, ligament, skin, and cartilage, the discovery of anticollagenase properties of tetracyclines will have implications throughout the body, not just in the mouth. Researchers currently are investigating the potential for other subantimicrobial-dose tetracyclines in the treatment of rheumatoid and osteoarthritis, osteoporosis, skin disorders, complications of diabetes, chronic pain, cancer metastasis, emphysema, cystic fibrosis, and many other disorders.

Periostat received FDA approval in October 1998 and has been available in pharmacies since November. For more information visit the CollaGenex Web site: www.collagenex.com.

Trisha E. O`Hehir, RDH, BS, is a senior consulting editor of RDH. She also is editor of Perio Reports, a newsletter for dental professionals that addresses periodontics. The Web site for Perio Reports is www.perioreports.com. Her e-mail address is trisha @perioreports.com.

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