Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-04-04
2003-12-02
Jones, Dwayne C. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S061000, C514S474000, C424S055000, C424S435000, C424S464000, C424S465000
Reexamination Certificate
active
06656920
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for treating xerostomia. More particularly, the invention is directed to the use of disaccharides, preferably in lozenge dosage form, for improving production of unstimulated whole saliva in patients in need of such function.
BACKGROUND AND SUMMARY OF THE INVENTION
Sjögren's syndrome is an idiopathic autoimmune disorder characterized by lymphocytic infiltration of multiple organs and tissues, as well as by the presence of autoantibodies, hypergammaglobulinemia, and immunoregulatory abnormalities. Sjögren's syndrome is primarily a disease of women, with nearly 90% of all patients being female. The disease has a typical onset during the fourth or fifth decade of life, and it may be as prevalent as 1 out of every 2,500 females.
Clinically, Sjögren's syndrome presents in either primary or secondary forms. Primary Sjögren's syndrome is characterized by xerostomia (dry mouth) and xerophthalmia (dry eyes) which are the result of a progressive loss of salivary and lacrimal function. Secondary Sjögren's syndrome includes involvement of one or both of these exocrine sites in the presence of another connective tissue disease such as rheumatoid arthritis, systemic sclerosis, or systemic lupus erythematosus. In both primary and secondary forms, there are commonly multiple extraglandular manifestations and serologic evidence of autoimmmunity.
The presence of a focal, periductal mononuclear cell infiltrate is the characteristic histopathologic finding in salivary glands in Sjögren's syndrome. Lymphocytic infiltrates of exocrine glands increase as the inflammatory disease progresses, ultimately producing acinar gland degeneration, necrosis, and atrophy.
Management of the dry eyes and mouth in subjects with Sjögren's syndrome is a daily problem. Dry eyes are treated by protective measures, frequent ophthalmologic evaluations, and wetting agents to sustain a normal ocular surface. The treatment of xerostomia is more difficult. Preventive measures such as supplemental fluoride, avoiding sugar or medications known to cause a dry mouth, and frequent dental checkups are recommended. Artificial saliva or frequent ingestion of non-sugared liquids may provide symptomatic benefit for some subjects. Pharmacologic agents designed to increase salivary flow (secretogogues), including bromhexine, anetholetrithione, pilocarpine, and cevimeline have been tested in subjects with Sjögren's syndrome. They have been shown to increase salivary output transiently, however, none have demonstrated sustained benefit in controlled clinical trials.
Interferons (IFN) have potent antiviral and immunomodulating effects, and five distinct classes of IFN have been designated; alpha (&agr;), beta, gamma, omega, and tau. IFN have been shown to enhance phagocytic antigen processing and immune regulatory activity of macrophages, regulate specific cytotoxicity of lymphocytes for target cells, and enhance natural killer cell activity.
The therapeutic utility of IFN-&agr; by the parenteral route has been well established. One natural and two recombinant forms of human IFN are approved for clinical use in the United States in doses ranging from 0.25×10
6
IU/lesion administered twice weekly in condyloma acuminata up to 36×10
6
IU given daily in AIDS-related Kaposi's sarcoma. Other approved indications for IFN treatment include hairy cell leukemia, chronic hepatitis B, and chronic hepatitis C. The adverse experiences associated with parenteral IFN appear to be dose related, with the majority of subjects developing one or multiple flu-like symptoms at doses greater than 1×10
6
IU/day.
The use of high-dose injectable IFN-&agr; for subjects with Sjögren's syndrome was first described in 1993. Shiozawa et al. reported that weekly intramuscular (i.m.) injections of IFN (1×10
6
IU/dose) resulted in a significant increase of saliva secretion in subjects with primary Sjögren's syndrome. Ferraccioli et al. successfully treated Sjögren's syndrome subjects with 3×10
6
IU IFN parenterally three times weekly. These investigators reported significant increases in lacrimal and salivary function with IFN compared to subjects treated with hydroxychloroquine. They also noted improvement in minor salivary gland histopathology on repeat biopsy in 3 of the IFN-treated subjects. Although few subjects experienced adverse effects at these high doses, it is well established that higher doses can cause a consistent and high percent of untoward effects.
Shiozawa and colleagues subsequently examined the potential benefit of natural human IFN-&agr; in low-dose lozenges in two open-label studies. Using 150 IU IFN lozenges three times daily, 5 of 7 subjects and 13 of 24 subjects with Sjögren's syndrome had >30% increase in stimulated whole saliva output after treatment between 9 and 37 weeks (mean duration =22 weeks). Recently, these investigators reported the effectiveness of 150 IU IFN lozenges given TID in 30 subjects with Sjögren's syndrome (28 with the primary form). At 24 weeks, 15 (50%) of 30 subjects treated with 150 IU IFN lozenges TID had a ≧100% increase from baseline in stimulated whole salivary flow, compared to only 1 (3%) of 30 control subjects given sucralfate (p<0.001). No clinically significant adverse experiences were reported in this clinical trial. Additionally, the investigators examined minor salivary glands at the completion of the trial in 9 subjects who had responded to treatment with at least a two-fold increase in saliva output. A significant improvement in pathologic changes, including reduced mononuclear infiltration and increased histologically normal epithelial tissue, was found compared to pretherapy biopsies.
Therefore, it appears that low-dose IFN-&agr; administered via the oral-mucosal route may significantly increase salivary secretions in subjects with Sjögren's syndrome without causing the troublesome adverse effects associated with high dose parenteral IFN administration. The purposes of our investigations were to examine the safety and efficacy of four different dosages of IFN lozenges compared to placebo in subjects with primary Sjögren's syndrome over a 12-week period in a Phase 2 trial, and to examine the best dose from our Phase 2 trial in a 24-week Phase 3 trial.
The primary endpoints of our Phase 2 and Phase 3 trials were measurements of unstimulated saliva and stimulated saliva and subjective assessments of dry mouth.
Adequate salivary gland function is critical for protection of the oral cavity and support of oral functions. In humans, saliva is provided by the 3 paired major salivary glands, (parotid, submandibular and sublingual), and thousands of minor salivary glands which are situated throughout the oral cavity and named based on location (buccal, palatal, labial, etc.). Approximately 90% of the day, salivary flow is maintained at a low level of output by endogenous physiologic mechanisms. This is termed unstimulated, or resting, saliva and is essential for general oral comfort and for defense of the oral cavity. The unstimulated saliva is high in antimicrobial and mucoprotective factors. Contrasting with this unstimulated function is the response of the salivary glands to masticatory and gustatory stimuli. During meals, with the stimulation provided by chewing and food flavors, there is a marked increase in salivary output. This stimulated output provides support for swallowing, chewing and buffering of microbial acids, and quickly diminishes when active stimulation ceases.
Since individuals experience their unstimulated saliva flow the great majority of the time, this represents the most important functional state. It also is reflective of the underlying gland health. Generally, an improvement in unstimulated salivary function will be associated with an increase in stimulated salivary capability. Importantly, an increase in unstimulated saliva function provides benefit without any additional action on the part of the
Cummins Joseph M.
Cummins Martin J.
Fox Philip C.
Amarillo Biosciences, Inc.
Barnes & Thornburg
Jones Dwayne C.
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