Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-06-05
2003-12-30
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06670327
ABSTRACT:
BACKGROUND OF THE INVENTION
Otitis media is the most frequently diagnosed disease in children in the United States, and most children will have at least one episode. It is most common in children under 6 years of age. The term “otitis media” refers to a spectrum of diseases in which fluid (effusion) is present in the middle ear space. The effusion may be serous, mucoid, purulent or some combination of these. In acute otitis media, signs and symptoms of acute infection and inflammation accompany middle ear effusion.
In otitis media with effusion (OME), there is a middle ear effusion behind an intact tympanic membrane without signs or symptoms of acute infection; synonymous terms include “fluid in the ear,” “glue ear,” and “serous otitis media.” OME is defined as chronic when middle ear effusion has been present for at least three months. OME frequently can cause hearing loss at a critical time in a child's development and can interfere with speech, language, behavioral and cognitive development. In most cases, the effusion may resolve spontaneously, but there remain a significant number of children in whom effusion persists even after the acute infection has resolved. Approximately 15% of children have chronic problems with longer term conductive hearing loss and sometimes lasting changes of the eardrum and middle ear ossicles. The complications and sequelae often persist into the adult years.
Persistent effusion, infection or epithelial damage promotes the release of a number of potent inflammatory mediators which, together with numerous bacterial toxins and enzymes present in the effusion, may be stimuli for metaplasia of the middle ear epithelium into a more secretory (mucus-producing) type of epithelium, similar to that found in the lower respiratory tract. The resulting effusion formed in the tympanic cavity will be removed to the pharynx, provided that the mucociliary clearance system (MCS) is functioning normally. The MCS is composed of ciliated cells, secretory cells and a mucus blanket, and propels mucus towards the eustachian tube by means of beating cilia. Mucociliary function can be impaired not only due to lowered ciliary activity but also due to mucus abnormalities. Increased mucus production and altered mucus consistency may seriously affect ciliary beat and coordination.
The two most important factors preceding the development of OME are a gram-negative bacterial infection and a dysfunction of the eustachian tube. Obstruction of the eustachian tube in germ-carrying rats was reported to result in secretory transformation of the epithelium, a phenomenon not observed in germ-free rats. Kuijpers et al.,
Histochemical J.
16:807-18 (1984).
Endotoxin is the lipopolysaccharide (LPS) outer membrane constituent of gram-negative bacteria and is a strong inducer of inflammation. The lipid A portion of LPS, which accounts for the toxic properties of endotoxin, is structurally similar and serologically cross-reacts among many species of gram-negative bacteria. Endotoxin has been found in human middle ear effusions. DeMaria et al.,
J. Clin. Microbiol.
20(1):15-17 (1984); Ovesen et al.,
Clin. Otolaryngology
17:531-4 (1992); and Dingman et al.,
J. Clin. Microbiol.,
36:3417-19 (1998). Inoculation of endotoxin into the middle ear has been shown to induce morphological changes in the mucociliary transport system, although long term effusion was not observed. [Ohashi et al.,
Ann. Otol. Rhinol. Laryngol.
98:479-84 (1989) and Ohashi et al,
Acta Otolaryngol
(
Stockh
), 486:149-61 (1991).] Moreover, injection of viable or non-viable
H. influenzae
or its endotoxin has been shown to induce some inflammatory changes. [DeMaria et al.,
Ann. Otol. Rhinol. Laryngol
94 (S120):14-6 (1985) and 93:52 (1984).]
Obstruction of the eustachian tube disables the normal clearance system of the middle ear. The normal middle ear mucosa has a mucociliary clearance system which consists of ciliated cells interspersed with secretory cells. Both the ciliary function and the secretory activity in the tympanic orifice of the middle ear are important for the clearance of the middle ear. During OME this clearance system is often impaired. When an obstruction of the eustachian tube is accompanied by inflammatory changes in the middle ear which lead to dysfunction of the mucociliary clearance system (MCS), an accumulation of fluid in the tympanic cavity occurs.
A model for OME has been developed in which a combination of eustachian tube obstruction (ETO) and endotoxin injection is used to produce structural changes to and dysfunction of the mucociliary clearance system which persists for 12 weeks. [Nell et al.,
Eur. Arch. Otorhinolaryngol.,
256:167-172 (1999).]
Although acute otitis media is typically treated with antibiotic therapy, medical treatment of OME is problematic and has been unsatisfactory. The efficacy of treatment with an antihistamine-decongestant combination has been debated; Daley [
Pediatrics in Review,
20:85 (1999)] has reported that this therapy is not recommended because these agents are not effective either separately or together. The use of systemic corticosteroids is common, and benefits of this therapy have been demonstrated in several trials, although the risks and side effects of this type of treatment are significant. Sequentially increasing doses of antimicrobial agents and prolonged courses of antibiotic therapy are common treatments but their efficacy has also been debated. Myringotomy with tube placement (through the tympanic membrane) has been shown to reduce the frequency of recurrence of acute otitis media and to improve hearing while the tubes remain in place, but is a surgical procedure requiring general anesthesia. Adenoidectomy is generally not recommended but may be beneficial in children older than 4 years of age with chronic OME. [Shapiro et al.,
Postgraduate Medicine,
97:73 (1995); Klein,
Clin. Infect. Dis.,
19:823 (1994); Daley, supra.]
A number of other potential therapies, including anti-inflammatory agents, have been tested in various models of otitis media. S-carboxymethylcysteine has been reported to reduce damage to ciliated cells and goblet cell hyperplasia in chinchillas with immune-mediated OME, although it did not inhibit infiltration or prevent release of chemical mediators such as histamine and prostaglandin E2. [Hori et al,
Ann. Otol. Rhinol. Laryngol
103:567-75 (1994). ] Treatment of children with secretory otitis media with hydroxyzine, an anti-histamine, has been reported to reduce the rate of relapse and the amount of histamine present in middle ear effusions. [Theoharides et al.,
Int. Arch. Allergy Immunol.
103:95-101 (1994).] Endotoxin-induced hypertrophic and metaplastic changes of goblet cells in rat nasal respiratory epithelium was reported to be inhibited by intraperitoneal injection of anti-inflammatory drugs. [Takahashi et al.,
Ann. Otol. Rhinol. Laryngol
106:683-7 (1997).] Indomethacin has been reported to inhibit the accumulation of middle ear effusion [Goldie et al., Ann. Otol. Rhinol. LaryngolI 102(12):954-60 (1993)]. In vitro addition of human monoclonal antibody against endotoxin, HA-1A (Centoxin), to medium supplemented with endotoxin has been reported to partially suppress some of the proliferative and morphological effects of endotoxin on cultured rat middle ear epithelium, although the morphology of epithelium cultured in the presence of HA-1A and endotoxin was still altered. [Grote et al.,
Ann. otol. Rhinol. Laryngol
104:226-230 (1995).]
Children with OME are currently treated with recurrent placement of ventilation tubes and/or with antibiotics. However, the insertion of tubes will only temporarily remove the middle ear effusion, and antibiotics can be effective in eradicating the infection yet do not reduce the accumulation of fluid.
Because of the current lack of satisfactory treatment, including the disadvantages of ventilation tubes and the growing resistance of many bacterial species to antibiotics
Grote Jan J.
Nell Maartje J.
Carlson Karen Cochrane
Marshall & Gerstein & Borun LLP
Snedden Sheridan
Xoma (US) LLC
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