Modulation of the nitric oxide synthase pathway for oral health

Abstract

Pharmaceutical compositions and methods of treatment or prevention of diseases and conditions associated with or characterized by at least one of xerostomia and periodontal disease by modulation of the nitric oxide synthase pathway are provided, as are animal models and drug screening methods. Such modulation may be achieved by the administration of tetrahydrobiopterin (BH4) or its prodrugs and/or salts. Treating and preventing xerostomia can have the downstream effect of also preventing periodontitis, dental caries, parotid gland enlargement, inflammation and fissuring of the lips (chelitis), inflammation or ulcers of the tongue and buccal mucosa, oral candidiasis, salivary gland infection (sialadenitis), halitosis, and cracking and fissuring of oral mucosa.

We claim: 
     
         1 . A method of treatment or prevention of a disease state or condition associated with or characterized by at least one of xerostomia and periodontal disease in a subject in need thereof, the method comprising administering an agent selected from tetrahydrobiopterin (BH 4 ), a prodrug of BH 4 , or a pharmaceutically acceptable salt of any of the foregoing to the subject in a therapeutically effective amount. 
     
     
         2 . The method of  claim 1 , wherein the prodrug of BH 4  is sepiapterin. 
     
     
         3 . The method of  claim 1 , comprising delivering the BH 4  to a salivary gland of the subject. 
     
     
         4 . The method of  claim 1 , comprising administering the agent locally to the subject's mouth. 
     
     
         5 . The method of  claim 1 , in which the agent is administered in a dentifrice, film, oral spray, lozenge, or a gum. 
     
     
         6 . The method of  claim 1 , in which the agent is administered in an oral rinse, a paste, a gel, or a varnish. 
     
     
         7 . The method of  claim 1 , further comprising treating the subject for at least one of: head and neck cancer, Sjogren's syndrome, diabetes mellitus, dental caries, parotid gland enlargement, inflammation and fissuring of the lips (chelitis), inflammation or ulcers of the tongue and buccal mucosa, oral candidiasis, salivary gland infection (sialadenitis), halitosis and cracking and fissuring of oral mucosa. 
     
     
         8 . The method of  claim 1 , wherein the amount is about 3.18-635 μmol agent per kg weight of the subject. 
     
     
         9 . The method of  claim 1 , wherein the amount is about 15.9-127 μmol agent per kg weight of the subject. 
     
     
         10 . The method of  claim 1 , wherein the amount is about 31.8-63.5 μmol agent per kg weight of the subject. 
     
     
         11 . The method of  claim 1 , wherein the amount is selected from about 31.8 and about 63.5 μmol agent per kg weight of the subject. 
     
     
         12 . The method of  claim 1 , wherein the amount is about 3.2-3200 μmol. 
     
     
         13 . The method of  claim 1 , wherein the amount is about 180-640 μmol. 
     
     
         14 . The method of  claim 1 , wherein the amount is about 320 μmol. 
     
     
         15 . The method of  claim 1 , wherein the amount is effective to achieve a concentration of 10-1000 μM BH 4  at a salivary gland of the subject. 
     
     
         16 . The method of  claim 1 , wherein the amount is effective to achieve a concentration of 50-200 μM BH 4  at the salivary gland of the subject. 
     
     
         17 . The method of  claim 1 , wherein the amount is effective to achieve a concentration of 100 μM BH 4  at the salivary gland of the subject. 
     
     
         18 . A pharmaceutical composition for the treatment or prevention of a disease state or condition associated with or characterized by at least one of xerostomia and periodontal disease, comprising a dentifrice, gum, film, spray, or lozenge; an agent selected from tetrahydrobiopterin (BH 4 ), a prodrug of BH 4 , or a pharmaceutically acceptable salt of any of the foregoing, in a therapeutically effective amount; and a pharmaceutically acceptable carrier. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the prodrug of BH 4  is sepiapterin. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein the dentifrice is selected from the group consisting of a paste, a gel, a mouthwash, a powder, and a tooth soap. 
     
     
         21 . The pharmaceutical composition of  claim 18 , wherein the dentifrice is a paste or gel comprising an abrasive, a surfactant, a humectant, and a thickener. 
     
     
         22 . The pharmaceutical composition of  claim 18 , wherein the dentifrice is a mouthwash comprising one or more of water and an alcohol. 
     
     
         23 . The pharmaceutical composition of  claim 18 , wherein the dentifrice is a powder comprising an abrasive. 
     
     
         24 . The pharmaceutical composition of  claim 18 , wherein the dentifrice is a tooth soap comprising one or more of oil and water. 
     
     
         25 . The pharmaceutical composition of  claim 18 , wherein the amount is about 3.18-635 μmol agent per kg weight of the subject. 
     
     
         26 . The pharmaceutical composition of  claim 18 , wherein the amount is about 15.9-127 μmol agent per kg weight of the subject. 
     
     
         27 . The pharmaceutical composition of  claim 18 , wherein the amount is about 31.8-63.5 μmol agent per kg weight of the subject. 
     
     
         28 . The pharmaceutical composition of  claim 18 , wherein the amount is selected from about 31.8 and about 63.5 μmol agent per kg weight of the subject. 
     
     
         29 . The pharmaceutical composition of  claim 18 , wherein the amount is about 3.2-3200 μmol. 
     
     
         30 . The pharmaceutical composition of  claim 18 , wherein the amount is about 180-640 μmol. 
     
     
         31 . The pharmaceutical composition of  claim 18 , wherein the amount is about 320 μmol. 
     
     
         32 . The pharmaceutical composition of  claim 18 , wherein the amount is effective to achieve a concentration of 10-1000 μM BH 4  at a salivary gland of the subject. 
     
     
         33 . The pharmaceutical composition of  claim 18 , wherein the amount is effective to achieve a concentration of 50-200 μM BH 4  at the salivary gland of the subject. 
     
     
         34 . The pharmaceutical composition of  claim 18 , wherein the amount is effective to achieve a concentration of 100 μM BH 4  at the salivary gland of the subject. 
     
     
         35 . A method of treatment or prevention of xerostomia, the method comprising administering the pharmaceutical composition of any one of  claims 18 - 34  to a subject in need thereof. 
     
     
         36 . A method of making an animal model of xerostomia, the method comprising administering Streptozotocin to a mammalian subject to induce diabetes mellitus in the subject, and confirming the presence of xerostomia. 
     
     
         37 . The method of  claim 36 , comprising confirming the presence of xerostomia by measuring at least one of: a salivary flow rate and a water consumption rate of the subject. 
     
     
         38 . A method of screening a candidate drug for a beneficial effect on xerostomia, comprising administering the candidate drug to a diabetic subject. 
     
     
         39 . A method of screening a candidate drug for a beneficial effect on xerostomia, comprising administering the candidate drug to the animal model that is the product of the method of  claim 38 . 
     
     
         40 . A use of an agent selected from tetrahydrobiopterin (BH 4 ), a prodrug of BH 4 , or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for the treatment or prevention of a disease state or condition associated with or characterized by at least one of xerostomia and periodontal disease. 
     
     
         41 . The use of  claim 40 , wherein the prodrug of BH 4  is sepiapterin. 
     
     
         42 . The use of  claim 40 , wherein the medicament is in the form of a dentifrice, gum, film, spray, or lozenge. 
     
     
         43 . The use of  claim 42 , wherein the dentifrice is selected from the group consisting of a paste, a gel, a mouthwash, a powder, and a tooth soap. 
     
     
         44 . The use of  claim 42 , wherein the dentifrice is a paste or gel comprising an abrasive, a surfactant, a humectant, and a thickener. 
     
     
         45 . The use of  claim 42 , wherein the dentifrice is a mouthwash comprising one or more of water and an alcohol. 
     
     
         46 . The use of  claim 42 , wherein the dentifrice is a powder comprising an abrasive. 
     
     
         47 . The use of  claim 42 , wherein the dentifrice is a tooth soap comprising one or more of oil and water. 
     
     
         48 . The use of  claim 40 , wherein the agent is present in the medicament in a therapeutically effective amount to treat or prevent the disease state or condition. 
     
     
         49 . The use of  claim 48 , wherein the therapeutically effective amount is about 3.18-635 μmol agent per kg weight of the subject. 
     
     
         50 . The use of  claim 48 , wherein the therapeutically effective amount is about 15.9-127 μmol agent per kg weight of the subject. 
     
     
         51 . The use of  claim 48 , wherein the therapeutically effective amount is about 31.8-63.5 μmol agent per kg weight of the subject. 
     
     
         52 . The use of  claim 48 , wherein the therapeutically effective amount is selected from about 31.8 and about 63.5 μmol agent per kg weight of the subject. 
     
     
         53 . The use of  claim 48 , wherein the therapeutically effective amount is about 3.2-3200 μmol. 
     
     
         54 . The use of  claim 48 , wherein the therapeutically effective amount is about 180-640 μmol. 
     
     
         55 . The use of  claim 48 , wherein the therapeutically effective amount is about 320 μmol. 
     
     
         56 . The use of  claim 48 , wherein the therapeutically effective amount is effective to achieve a concentration of 10-1000 μM BH 4  at a salivary gland of the subject. 
     
     
         57 . The use of  claim 48 , wherein the therapeutically effective amount is effective to achieve a concentration of 50-200 μM BH 4  at the salivary gland of the subject. 
     
     
         58 . The use of  claim 48 , wherein the therapeutically effective amount is effective to achieve a concentration of 100 μM BH 4  at the salivary gland of the subject. 
     
     
         59 . Any one of  claims 1 ,  18 , and  40 , wherein the disease state or condition is xerostomia. 
     
     
         60 . Any one of  claims 1 ,  18 , and  40 , wherein the disease state or condition is periodontitis. 
     
     
         61 . Any one of  claims 1 ,  18 , and  40 , wherein the disease state or condition is selected from the group consisting of: dental caries, parotid gland enlargement, inflammation and fissuring of the lips (chelitis), inflammation or ulcers of the tongue and buccal mucosa, oral candidiasis, salivary gland infection (sialadenitis), halitosis and cracking and fissuring of oral mucosa.