Inhibition of Experimental Gingivitis in Beagle Dogs With Topical Mercaptoalkylguanidines David W. Paquette,* Adam Rosenberg,* Zsolt Lohinai,† Garry J. Southan,‡ Ray C. Williams,* Steven Offenbacher,* and Csaba Szab†‡ *Department of Periodontology, School of Dentistry, Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC.
†Department of Human Physiology and Clinical Experimental Research, Semmelweis University Medical School, Budapest, Hungary.
‡Inotek Pharmaceuticals, Beverly, MA.
Correspondence: Dr. David W. Paquette, Department of Periodontology, School of Dentistry, Comprehensive Center for Inflammatory Disorders, University of North Carolina, Brauer Hall, CB 7450, Chapel Hill, NC 27599-7450. E-mail: david_paquette@dentistry.unc.edu.
Background: Nitric oxide is a free radical produced in host tissues by constitutive and inducible forms of the enzyme nitric oxide synthase. Nitric oxide plays physiological roles, but it is also involved in the pathophysiology of several inflammatory conditions, including arthritis, ulcerative colitis, and circulatory shock. Local increases in inducible nitric oxide synthase (iNOS) and reactive nitrogen products have also been demonstrated in humans and animals with periodontal disease. This masked, randomized, placebo-controlled preclinical investigation examined the effect of two mercaptoalkylguanidines, mercaptoethylguanidine (MEG) and guanidinoethyldisulfide (GED), which are iNOS inhibitors and reactive nitrogen scavenging compounds, on the development of experimental gingivitis in beagle dogs.
Methods: Fifteen female, 1-year-old beagles first completed a 2-week dose-escalation experiment during which a maximum tolerated dose was determined for MEG and GED gels. Thereafter, all animals were brought to optimal gingival health by mechanical scaling, followed by rigorous daily toothbrushing over a 4-week washout period. Experimental gingivitis was then induced, with cessation of plaque control and institution of a soft diet over 8 weeks. Beagles randomly received 0.3% MEG, 0.3% GED, or placebo (vehicle) gels, topically applied twice daily to premolar teeth. Gingival inflammation, bleeding tendency, and supragingival plaque were clinically measured at baseline and at 2, 3, 4, 6, and 8 weeks. Comparisons among groups and between group pairs (active versus placebo) were made using Kruskal-Wallis tests.