Lysine decarboxylase inhibitors for the prevention and...

Drug – bio-affecting and body treating compositions – Dentifrices – Ammonia – amine – or derivative thereof

Reexamination Certificate

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C424S049000

Reexamination Certificate

active

06187296

ABSTRACT:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
BACKGROUND
Adult periodontal disease is a widespread medical problem that is difficult to treat, especially in the middle-aged and elderly. It develops when bacteria indigenous to the oral cavity colonize gingival sulci, forming bacterial plaques in the absence of oral hygiene. Inflammation (gingivitis) develops and eventually spreads, causing tooth attachment loss (periodontitis). The diversity of the oral flora, the chronic nature of the disease, and the absence of a generally accepted animal or in vitro model, have made the molecular pathogenesis of this disease by bacteria difficult to study [1]. Therapies for this disease have also been hampered by ignorance of the bacterial induction process [2]. Current therapy requires that the dentist improve oral hygiene by debridement (scaling and root-planing) and repair tissue architecture using periodontal surgery as necessary [3]. The patient must undertake regular toothbrushing and flossing [4,5]. This therapy is expensive, time-consuming and unpredictable in its outcome [6].
Gingivitis is detected when the gingival sulcus, a shallow crevice between the teeth and gingiva, bleeds on gentle probing [7]. Bacterial plaques extend into this sulcus by an orderly process of colonization and coaggregation in the absence of oral hygiene [8-10]. The initial plaque is mostly composed of actinomyces and viridans streptococci, but it is soon overgrown by Gram-negative bacteria and spirochetes [8,11]. One of the earliest bacterial complexes that overgrow the initial flora in gingival sulci consists of
E. corrodens
and Capnocytophaga spp. These Gram-negative bacteria are found equally in sulci that are both healthy and inflamed, whereas different bacterial complexes are found exclusively at inflamed sulci and in association with uncontrolled periodontitis [12]. Many of these disease-associated bacteria are thought to induce inflammation by making short-chain fatty acids that inhibit cell growth in culture [13,14]. A key observation is that the colonization by indigenous bacteria is required before the disease-associated flora appears in a sulcus. The number of inflamed sulci increases until, by 21 days of no oral hygiene, gingivitis is apparent throughout the mouth [11]. Eventually, the tooth attachment recedes beneath the cemental-enamel junction, forming periodontal pockets or causing gingival recession [15].
A gingival sulcus is formed where the oral epithelium meets the teeth. At the base of a sulcus, the oral epithelium differentiates into a junctional epithelium that mediates the epithelial attachment by further differentiating into dentally attached cells (DAT cells) at the enamel surface (FIG.
1
A). The DAT cells are epithelial basal cells and undergo mitosis in vivo or when cultured in vitro [16]. A key observation is that the coronal DAT cells are distant from underlying capillaries (
FIG. 1A
) and grow on an interstitial fluid transudate across the base of healthy sulci [17]. The bacterial complexes lie about 0.5 mm above the most coronal DAT cells in a sulcus. In gingivitis, these cells disappear and the junctional epithelium becomes filled with neutrophilic granulocytes traversing from the underlying blood vessels (
FIG. 1B
) until it is no longer viable and periodontitis has developed [18,19]. The bacteria target the proliferative capacity of junctional epithelial DAT cells initially and the remainder of the epithelial attachment subsequently.
Saline extracts of bacterial plaques contain toxic proteins and short chain fatty acids that inhibit mammalian cell growth in culture [20-22]. The short chain fatty acid content indicates the presence of disease-associated bacteria in the samples. The toxic proteins were identified with plaque toxin-neutralizing monoclonal antibodies [23] and found to cross-react with a toxic 80 kilodalton protein (p80) from
E. corrodens
[24]. This protein is homologous to lysine decarboxylases from enteric bacteria [25], enzymes that metabolize extracellular lysine into cadaverine and carbon dioxide [26]. The inventor has found that this enzyme inhibits mammalian cell growth by depleting the culture medium of lysine, an amino acid which is not synthesized de novo by mammalian cells.


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