Claims
- 1. A method for measuring a thermodynamic change in an area of interest in a patient comprising:
(i) measuring the baseline temperature of the area of interest using infrared thermography, (ii) administering to the patient a composition comprising at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, or a pharmaceutically acceptable salt thereof and/or at least one vasoactive agent or a pharmaceutically acceptable salt thereof, (iii) measuring the temperature of the area of interest using infrared themography, (iv) comparing the temperature obtained in step (i) with the temperature obtained in step (iii), wherein the baseline temperature can be taken before and/or after steps (ii) and (iii), and wherein a difference in temperature between that obtained in step (i) and that obtained in step (iii) indicates that the compound causes a thermodynamic change
- 2. The method of claim 1, wherein the composition in step (ii) further comprises a pharmaceutically acceptable carrier.
- 3. The method of claim 1, wherein the infrared thermography is infrared imaging thermography.
- 4. The method of claim 1, wherein said measuring of step (i) and step (iii) is effected using infrared thermography at a specific wavelength or within a specific band of wavelengths.
- 5. The method of claim 1, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is an S-nitrosothiol.
- 6. The method of claim 5, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso—N-acetylpenicillamine, S-nitroso-homocysteine, S-nitrosocysteine, S-nitroso-glutathione or S-nitroso-cysteinyl-glycine.
- 7. The method of claim 6, wherein the S-nitrosothiol is S-nitroso-glutathione.
- 8. The method of claim 5, wherein the S-nitrosothiol is:
(i) HS(C(Re) (Rf))mSNO; (ii) ONS(C(Re) (Rf))mRe; and (iii) H2N—CH(CO2H)—(CH2)m—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein m is an integer from 2 to 20; Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cycloalkylthio, a cycloalkenyl, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, a carbamate, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a sulfonic ester, a urea, a phosphoryl, a nitro, —T—Q , or —(C(Re) (Rf))k—T—Q or Re and Rf taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO2; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O)O— or —N(Ra)Ri—, wherein o is an integer from 0 to 2, Ra is a lone pair of electrons, a hydrogen or an alkyl group; Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, —CH2—C(T—Q) (Re) (Rf) or —(N2O2—)&Circlesolid;M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is —CH2—C(T—Q) (Re) (Rf) or —(N2O2—)&Circlesolid;M+; then “—T—Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
- 9. The method of claim 1, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is:
(i) a compound that comprises at least one ON—O—, ON—N— or ON—C— group; (ii) a compound that comprises at least one O2N—O—, O2N—N—, O2N—S— or —O2N—C— group; (iii) a N-oxo-N-nitrosoamine having the formula: R1R2—N(O-M+)—NO, wherein R1 and R2 are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M+ is an organic or inorganic cation.
- 10. The method of claim 9, wherein the compound comprising at least one ON—O—, ON—N— or ON—C— group is an ON—O— polypeptide, an ON—N-polypepetide, an ON—C-polypeptide, an ON—O— amino acid, an ON—N-amino acid, an ON—C-amino acid, an ON—O— sugar, an ON—N-sugar, an ON—C-sugar, an ON—O— oligonucleotide, an ON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O— hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—C-hydrocarbon, an ON—O— heterocyclic compound, an ON—N-heterocyclic compound or a ON—C-heterocyclic compound.
- 11. The method of claim 9, wherein compound comprising at least one O2N—O—, O2N—N—, O2N—S— or O2N—C— group is an O2N—O-polypeptide, an O2N—N-polypeptide, an O2N—S-polypeptide, an O2N—C-polypeptide, an O2N—O— amino acid, O2N—N-amino acid, O2N—S— amino acid, an O2N—C-amino acid, an O2N—O-sugar, an O2N—N-sugar, O2N—S-sugar, an O2N—C-sugar, an O2N—O— oligonucleotide, an O2N—N-oligonucleotide, an O2N—S— oligonucleotide, an O2N—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—O— hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—S— hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—C-hydrocarbon, an O2N—O— heterocyclic compound, an O2N—N-heterocyclic compound, an O2N—S-heterocyclic compound or an O2N—C-heterocyclic compound.
- 12. The method of claim 1, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is Larginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, omithine, glutamine, lysine, polypeptides comprising at least one of these amino acids or inhibitors of the enzyme arginase.
- 13. The method of claim 1, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is a NONOate.
- 14. The method of claim 1, wherein the vasoactive agent is a potassium channel activator, a calcium channel blocker, an α-adrenergic receptor antagonist, a β-blocker, a phosphodiesterase inhibitor, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a prostaglandin, a dopamine agonist, an opioid antagonist, an endothelin antagonist, a thromboxane inhibitor or a mixture thereof.
- 15. The method of claim 1, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent is administered orally, bucally, topically, by injection, by inhalation or by transurethral application.
- 16. The method of claim 15, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent is administered orally as a solid or liquid dose.
- 17. The method of claim 13, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent is administered topically as a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 18. The method of claim 1, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and the at least one vasoactive agent are administered separately.
- 19. The method of claim 1, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and the at least one vasoactive agent are in the form of a composition.
- 20. The method of claim 1, wherein the difference in temperature between that obtained in step (i) and that obtained in step (iii) is a positive number.
- 21. The method of claim 1, wherein the difference in temperature between that obtained in step (i) and that obtained in step (iii) is a negative number.
- 22. The method of claim 20 or 21, wherein the difference in temperature obtained in step (i) and that obtained in step (iii) is at least 0.2° C.
- 23. A method for monitoring the effectiveness of a compound for treating a sexual dysfunction in a patient comprising:
(i) measuring the baseline temperature of the genitalia of the patient using infrared thermography, (ii) administering to the patient a composition comprising at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, or a pharmaceutically acceptable salt thereof and/or at least one vasoactive agent or a pharmaceutically acceptable salt thereof, (iii) measuring the temperature of the genitalia of the patient using infrared themography, (iv) comparing the temperature obtained in step (i) with the temperature obtained in step (iii), wherein the baseline temperature can be taken before and/or after steps (ii) and (iii), and wherein an increase in temperature between that obtained in step (i) and that obtained in step (iii) indicates that the compound is effective for treating the sexual dysfunction.
- 24. The method of claim 23, wherein the increase in temperature between that obtained in step (i) and that obtained in step (iii) is at least 0.2° C.
- 25. The method of claim 23, wherein the patient is female.
- 26. The method of claim 23, wherein the patient is male.
- 27. The method of claim 23, wherein the composition in step (ii) further comprises a pharmaceutically acceptable carrier.
- 28. The method of claim 23, wherein the infrared thermography is infrared imaging thermography.
- 29. The method of claim 23, wherein said measuring of step (i) and step (iii) is effected using infrared thermography at a specific wavelength or within a specific band of wavelengths.
- 30. The method of claim 23, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is an S-nitrosothiol.
- 31. The method of claim 30, wherein the S-nitrosothiol is S-nitroso—N-acetylcysteine, S-nitroso-captopril, S-nitroso—N-acetylpenicillamine, S-nitroso-homocysteine, S-nitrosocysteine, S-nitroso-glutathione or S-nitroso-cysteinyl-glycine.
- 32. The method of claim 31, wherein the S-nitrosothiol is S-nitroso-glutathione.
- 33. The method of claim 31, wherein the S-nitrosothiol is:
(i) HS(C(Re) (Rf))mSNO; (ii) ONS(C(Re) (Rf))mRe; and (iii) H2N—CH(CO2H)—(CH2)m—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein m is an integer from 2 to 20; Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cycloalkylthio, a cycloalkenyl, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, a carbamate, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a sulfonic ester, a urea, a phosphoryl, a nitro, —T—Q , or —(C(Re) (Rf))k—T—Q, or Re and Rf taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO2; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O)o— or —N(Ra)Ri—, wherein o is an integer from 0 to 2, Ra is a lone pair of electrons, a hydrogen or an alkyl group; Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, —CH2—C(T—Q) (Re) (Rf), or —(N2O2—)&Circlesolid;M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is —CH2—C(T—Q) (Re) (Rf) or —(N2O213 )&Circlesolid;M+; then “—T—Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
- 34. The method of claim 23, wherein at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is:
(i) a compound that comprises at least one ON—O—, ON—N— or ON—C— group; (ii) a compound that comprises at least one O2N—O—, O2N—N—, O2N—S— or —O2N—C— group; (iii) a N-oxo-N-nitrosoamine having the formula: R1R2—N(O—M+)—NO, wherein R1 and R2 are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M+ is an organic or inorganic cation.
- 35. The method of claim 34, wherein the compound comprising at least one ON—O—, ON—N— or ON—C— group is an ON—O-polypeptide, an ON—N-polypepetide, an ON—C-polypeptide, an ON—O— amino acid, an ON—N-amino acid, an ON—C-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—C-sugar, an ON—O— oligonucleotide, an ON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O— hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—C-hydrocarbon, an ON—O— heterocyclic compound, an ON—N-heterocyclic compound or a ON—C-heterocyclic compound.
- 36. The method of claim 34, wherein compound comprising at least one O2N—O—, O2N—N—, O2N—S— or O2N—C— group is an O2N—O-polypeptide, an O2N—N-polypeptide, an O2N—S-polypeptide, an O2N—C-polypeptide, an O2N—O— amino acid, O2N—N-amino acid, O2N—S— amino acid, an O2N—C-amino acid, an O2N—O-sugar, an O2N—N-sugar, O2N—S-sugar, an O2N—C-sugar, an O2N—O— oligonucleotide, an O2N—N-oligonucleotide, an O2N—S— oligonucleotide, an O2N—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—O— hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—S— hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—C-hydrocarbon, an O2N—O— heterocyclic compound, an O2N—N-heterocyclic compound, an O2N—S-heterocyclic compound or an O2N—C-heterocyclic compound.
- 37. The method of claim 23, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, omithine, glutamine, lysine, polypeptides comprising at least one of these amino acids or inhibitors of the enzyme arginase.
- 38. The method of claim 23, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is a NONOate.
- 39. The method of claim 23, wherein the vasoactive agent is a potassium channel activator, a calcium channel blocker, an α-adrenergic receptor antagonist, a β-blocker, a phosphodiesterase inhibitor, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a prostaglandin, a dopamine agonist, an opioid antagonist, an endothelin antagonist, a thromboxane inhibitor or a mixture thereof.
- 40. The method of claim 23, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent is administered orally, bucally, topically, by injection, by inhalation or by transurethral application.
- 41. The method of claim 40, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent is administered orally as a solid or liquid dose.
- 42. The method of claim 40, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent is administered topically as a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 43. The method of claim 23, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and the at least one vasoactive agent are administered separately.
- 44. The method of claim 23, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and the at least one vasoactive agent are in the form of a composition.
- 45. A method for measuring the effectiveness of a compound in treating a disease or disorder resulting from vasodilation or changes in blood flow comprising:
(i) measuring the baseline temperature of the area of interest using infrared thermography, (ii) administering to the patient a composition comprising at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, or a pharmaceutically acceptable salt thereof and/or at least one vasoactive agent or a pharmaceutically acceptable salt thereof, (iii) measuring the temperature of the area of interest using infrared themography, (iv) comparing the temperature obtained in step (i) with the temperature obtained in step (iii), wherein the baseline temperature can be taken before and/or after steps (ii) and (iii), and wherein an increase in temperature between that obtained in step (i) and that obtained in step (iii) indicates that the compound is effective in treating a disease or disorder resulting from vasodilation or changes in blood flow.
- 46. The method of claim 45, wherein the disease or disorder resulting from vasodilation or changes in blood flow is Raynaud's syndrome, inflammation, hypertension, a gastrointestinal disorder or a central nervous system disorder.
- 47. The method of claim 45, wherein the composition in step (ii) further comprises a pharmaceutically acceptable carrier.
- 48. The method of claim 45, wherein the infrared thermography is infrared imaging thermography.
- 49. The method of claim 45, wherein said measuring of step (i) and step (iii) is effected using infrared thermography at a specific wavelength or within a specific band of wavelengths.
- 50. The method of claim 45, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is an S-nitrosothiol.
- 51. The method of claim 46, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitrosocysteine, S-nitroso-glutathione or S-nitroso-cysteinyl-glycine.
- 52. The method of claim 51, wherein the S-nitrosothiol is S-nitroso-glutathione.
- 53. The method of claim 50, wherein the S-nitrosothiol is:
(i) HS(C(Re) (Rf))mSNO; (ii) ONS(C(Re) (Rf))mR; and (iii) H2N—CH(CO2H)—(CH2)m—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein m is an integer from 2 to 20; Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cycloalkylthio, a cycloalkenyl, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, a carbamate, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a sulfonic ester, a urea, a phosphoryl, a nitro, —T—Q , or —(C(Re) (Rf))k—T—Q, or Re and Rf taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO2; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O)O— or —N(Ra)Ri—, wherein o is an integer from 0 to 2, Ra is a lone pair of electrons, a hydrogen or an alkyl group; Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, —CH2—C(T—Q) (Re) (Rf), or —(N2O2—)&Circlesolid;M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is —CH2—C(T—Q) (Re) (Rf) or —(N2O2—)&Circlesolid;M+; then “—T—Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
- 54. The method of claim 45, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is:
(i) a compound that comprises at least one ON—O—, ON—N— or ON—C— group; (ii) a compound that comprises at least one O2N—O—, O2N—N—, O2N—S— or —O2N—C— group; (iii) a N-oxo-N-nitrosoamine having the formula: R1R2—N(O—M+)—NO, wherein R1 and R2 are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M+ is an organic or inorganic cation.
- 55. The method of claim 54, wherein the compound comprising at least one ON—O—, ON—N— or ON—C— group is an ON—O-polypeptide, an ON—N-polypepetide, an ON—C-polypeptide, an ON—O— amino acid, an ON—N-amino acid, an ON—C-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—C-sugar, an ON—O— oligonucleotide, an ON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O— hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—C-hydrocarbon, an ON—O— heterocyclic compound, an ON—N-heterocyclic compound or a ON—C-heterocyclic compound.
- 56. The method of claim 54, wherein compound comprising at least one O2N—O—, O2N—N—, O2N—S— or O2N—C— group is an O2N—O-polypeptide, an O2N—N-polypeptide, an O2N—S-polypeptide, an O2N—C-polypeptide, an O2N—O— amino acid, O2N—N-amino acid, O2N—S— amino acid, an O2N—C-amino acid, an O2N—O-sugar, an O2N—N-sugar, O2N—S-sugar, an O2N—C-sugar, an O2N—O— oligonucleotide, an O2N—N-oligonucleotide, an O2N—S— oligonucleotide, an O2N—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—O— hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—S— hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—C-hydrocarbon, an O2N—O— heterocyclic compound, an O2N—N-heterocyclic compound, an O2N—S-heterocyclic compound or an O2N—C-heterocyclic compound.
- 57. The method of claim 45, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated Larginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, omithine, glutamine, lysine, polypeptides comprising at least one of these amino acids or inhibitors of the enzyme arginase.
- 58. The method of claim 45, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is a NONOate.
- 59. The method of claim 45, wherein the vasoactive agent is a potassium channel activator, a calcium channel blocker, an (x-adrenergic receptor antagonist, a β-blocker, a phosphodiesterase inhibitor, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a prostaglandin, a dopamine agonist, an opioid antagonist, an endothelin antagonist, a thromboxane inhibitor or a mixture thereof.
- 60. The method of claim 45, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent is administered orally, bucally, topically, by injection, by inhalation or by transurethral application.
- 61. The method of claim 60, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent is administered orally as a solid or liquid dose.
- 62. The method of claim 60, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent is administered topically as a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 63. The method of claim 45, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and the at least one vasoactive agent are administered separately.
- 64. The method of claim 45, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and the at least one vasoactive agent are in the form of a composition.
- 65. A method for identifying a compound that produces vasodilation or changes in blood flow comprising:
(i) measuring the baseline temperature of an area of interest using infrared thermography, (ii) administering to the patient a test compound, (iii) measuring the temperature of the area of interest using infrared themography, (iv) comparing the temperature obtained in step (i) with the temperature obtained in step (iii), wherein the baseline temperature can be taken before and/or after steps (ii) and (iii), and wherein an increase in temperature between that obtained in step (i) and that obtained in step (iii) indicates that the compound is effective in producing vasodilation or changes in blood flow.
- 66. The method of claim 65, wherein the infrared thermography is infrared imaging thermography.
- 67. The method of claim 65, wherein said measuring of step (i) and step (iii) is effected using infrared thermography at a specific wavelength or within a specific band of wavelengths.
- 68. The method of claim 65, wherein the at least one compound is administered orally, bucally, topically, by injection, by inhalation or by transurethral application.
- 69. The method of claim 68, wherein the at least one compound is administered orally as of a solid or liquid dose.
- 70. The method of claim 65, wherein the at least one compound is administered topically as a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 71. The method of claim 65, further comprising comparing the difference in temperature between that obtained in step (i) and that obtained in step (iii) for a first test compound with the difference in temperature between that obtained in step (i) and that obtained in step (iii) for a second test compound, wherein the test compound that produces a greater increase in temperature between step (i) and step (iii) is therapeutically more effective.
- 72. The method of claim 71, the difference in temperature between that obtained in step (i) and that obtained in step (iii) is at least 0.2° C.
- 73. A composition comprising at least one S-nitrosothiol compound or a pharmaceutically acceptable salt thereof, and at least one penetration enhancer.
- 74. The composition of claim 73, further comprising a pharmaceutically acceptable carrier.
- 75. The composition of claim 73, wherein the S-nitrosothiol compound is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione or S-nitroso-cysteinyl-glycine.
- 76. The composition of claim 75, wherein the S-nitrosothiol compound is S-nitroso-glutathione.
- 77. The composition of claim 73, wherein the S-nitrosothiol compound is:
(i) HS(C(Re) (Rf))mSNO; (ii) ONS(C(Re) (Rf))mRe; and (iii) H2N—CH(CO2H)—(CH2)m—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein m is an integer from 2 to 20; Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cycloalkylthio, a cycloalkenyl, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, a carbamate, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a sulfonic ester, a urea, a phosphoryl, a nitro, —T—Q , or —(C(Re) (Rf))k—T—Q, or Re and Rf taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO2; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O)o— or —N(Ra)Ri—, wherein o is an integer from 0 to 2, Ra is a lone pair of electrons, a hydrogen or an alkyl group; Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, —CH2—C(T—Q) (Re) (Rf), or —(N2O2—)&Circlesolid;M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is —CH2—C(T—Q) (Re) (Rf) or —(N2O2—)&Circlesolid;M+; then “—T—Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
- 78. The composition of claim 73, wherein the penetration enhancer is dimethylsulfoxide, dimethyl formamide, N,N-dimethylacetamide, decylmethylsulfoxide, polyethylene glycol monolaurate, polyethyleneglycol, glycerol monolaurate, lecithin, a 1-substituted azacycloheptan-2-one, a lower alkanol, a C6 to C20-hydrocarbyl substituted 1,3-dioxane, a C6 to C20-hydrocarbyl substituted 1,3-dioxolane or a C6 to C20-hydrocarbyl substituted acetal, an alkonate, a glyceride, a surfactant, or a mixture thereof.
- 79. The composition of claim 78, wherein the glyceride is a mono glyceride, a diglyceride, a triglycerides, a polyglycolyzed glyceride or a mixture thereof.
- 80. The composition of claim 79, wherein the glyceride is MIGLYOL, LABRASOL, LABRAFIL or a mixture thereof.
- 81. The composition of claim 73, further comprising a vasoactive agent.
- 82. The composition of claim 81, wherein the vasoactive agent is a potassium channel activator, a calcium channel blocker, an α-adrenergic receptor antagonist, a β-blocker, a phosphodiesterase inhibitor, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a prostaglandin, a dopamine agonist, an opioid antagonist, an endothelin antagonist, a thromboxane inhibitor or a mixture thereof.
- 83. The composition of claim 73, wherein the composition is administered topically.
- 84. The composition of claim 83, wherein the composition is administered topically as a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 85. The composition of claim 73, further comprising at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase.
- 86. The composition of claim 85, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is:
(i) a compound that comprises at least one ON—O—, ON—N— or ON—C— group; (ii) a compound that comprises at least one O2N—O—, O2N—N—, O2N—S— or —O2N—C— group; (iii) a N-oxo-N-nitrosoamine having the formula: R1R2—N(O-M+ )—NO, wherein R1 and R2 are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M+ is an organic or inorganic cation.
- 87. The composition of claim 86, wherein the compound comprising at least one ON—O—, ON—N— or ON—C— group is an ON—O-polypeptide, an ON—N-polypepetide, an ON—C-polypeptide, an ON—O— amino acid, an ON—N-amino acid, an ON—C-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—C-sugar, an ON—O— oligonucleotide, an ON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O— hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—C-hydrocarbon, an ON—O— heterocyclic compound, an ON—N-heterocyclic compound or a ON—C-heterocyclic compound.
- 88. The composition of claim 86, wherein compound comprising at least one O2N—O—, O2N—N—, O2N—S— or O2N—C— group is an O2N—O-polypeptide, an O2N—N-polypeptide, an O2N—S-polypeptide, an O2N—C-polypeptide, an O2N—O— amino acid, O2N—N-amino acid, O2N—S— amino acid, an O2N—C-amino acid, an O2N—O-sugar, an O2N—N-sugar, O2N—S-sugar, an O2N—C-sugar, an O2N—O— oligonucleotide, an O2N—N-oligonucleotide, an O2N—S— oligonucleotide, an O2N—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—O— hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—S— hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—C-hydrocarbon, an O2N—O— heterocyclic compound, an O2N—N-heterocyclic compound, an O2N—S-heterocyclic compound or an O2N—C-heterocyclic compound.
- 89. The composition of claim 85, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated Larginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, omithine, glutamine, lysine, polypeptides comprising at least one of these amino acids or inhibitors of the enzyme arginase.
- 90. The composition of claim 85, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is a NONOate.
- 91. A method for measuring a thermodynamic change in an area of interest in a patient comprising:
(i) measuring the baseline temperature of the area of interest using infrared thermography, (ii) administering to the patient a composition of claim 73, (iii) measuring the temperature of the area of interest using infrared themography, (iv) comparing the temperature obtained in step (i) with the temperature obtained in step (iii), wherein the baseline temperature can be taken before and/or after steps (ii) and (iii), and wherein a difference in temperature between that obtained in step (i) and that obtained in step (iii) indicates that the composition of claim 73 causes a thermodynamic change.
- 92. A method for monitoring the effectiveness of the composition of claim 73 for treating a sexual dysfunction in a patient comprising:
(i) measuring the baseline temperature of the genitalia of the patient using infrared thermography, (ii) administering to the patient the composition of claim 73, (iii) measuring the temperature of the genitalia of the patient using infrared themography, (iv) comparing the temperature obtained in step (i) with the temperature obtained in step (iii), wherein the baseline temperature can be taken before and/or after steps (ii) and (iii), and wherein an increase in temperature between that obtained in step (i) and that obtained in step (iii) indicates that the composition of claim 73 is effective for treating the sexual dysfunction.
- 93. A method for measuring the effectiveness of the composition of claim 73 in treating a disease or disorder resulting from vasodilation or changes in blood flow comprising:
(i) measuring the baseline temperature of an area of interest using infrared thermography, (ii) administering to the patient the composition of claim 73, (iii) measuring the temperature of the area of interest using infrared themography, (iv) comparing the temperature obtained in step (i) with the temperature obtained in step (iii), wherein the baseline temperature can be taken before and/or after steps (ii) and (iii), and wherein an increase in temperature between that obtained in step (i) and that obtained in step (iii) indicates that the composition of claim 73 is effective in treating a disease or disorder resulting from vasodilation or changes in blood flow.
- 94. The method of claim 93, wherein the disease or disorder resulting from vasodilation or changes in blood flow is Raynaud's syndrome, inflammation, hypertension, a gastrointestinal disorder or a central nervous system disorder.
- 95. A method for treating a female sexual dysfunction in a patient in need thereof comprising administration to the patient the composition of claim 73.
- 96. The method of claim 95, wherein the composition is administered topically.
- 97. The method of claim 96, wherein the composition is administered topically as a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 98. The method of claim 95, further comprising at least one vasoactive agent.
- 99. The method of claim 98, wherein the vasoactive agent is a potassium channel activator, a calcium channel blocker, an α-adrenergic receptor antagonist, a β-blocker, a phosphodiesterase inhibitor, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a prostaglandin, a dopamine agonist, an opioid antagonist, an endothelin antagonist, a thromboxane inhibitor or a mixture thereof.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 60/202,935 filed May 9, 2000.
Provisional Applications (1)
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Number |
Date |
Country |
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60202935 |
May 2000 |
US |
Patent Application
20010046471
