Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
2001-06-21
2002-02-05
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C424S009100, C435S004000, C514S866000
Reexamination Certificate
active
06344181
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention is related to the area of wound healing in diabetes. In particular it is related to assays for the level of nitric oxide in non-healing diabetics.
BACKGROUND OF THE INVENTION
Diabetes affects an estimated 15 million people in the United States. Within the diabetic population are individuals with chronic, non-healing lower extremity ulceration (LEU), which is associated with significant morbidity and treatment costs. Chronic, non-healing LEU precedes about 85 % of the lower extremity amputations (LEA) that over 50,000 diabetics experience annually (G E Reiber, E J Boyko, D G Smith, in Diabetes in America, NIH Publication No. 95-1468, Bethesda, Md., ed. 2, 1995, pp. 409-428). This represents more than half of all individuals receiving LEA in this country. While only 6% of diabetic hospitalizations are associated with LEU, the total government reimbursement for diabetic lower extremity complications in 1992 exceeded $1.5 billion, not including costs for limb amputation and rehabilitation. Clinical pathophysiologic risk factors for LEA include diabetic neuropathy, lower extremity ischemia, and chronic, non-healing diabetic foot ulcers.
The underlying problem in diabetics with LEU is impaired wound healing, which is poorly understood. While the majority of diabetics exhibit “normal” wound healing, those presenting with chronic LEU often demonstrate decreased wound inflammation, recurrent wound infections, decreased cutaneous vascular perfusion, poor wound collagen deposition, and scar maturation. Platelet derived growth factor (PDGF) deficiency is associated with the chronic diabetic ulcer and contributes to impaired healing (H D Beer, M T Longaker, S Werner, J Invest Dermatol 109, 132 (1997)). Clinical trials using Regranex® have shown efficacy in improving chronic foot ulcer healing in only half or less of the patients evaluated (D L Steed, J Vasc Surg, 21, 71 (1995)).
Recent research on the role of nitric oxide (NO) in wound inflammation, tissue repair, and microvascular homeostasis has allowed us to consider NO as a primary regulator of wound healing (D Bruch-Gerharz, T Ruzicka, V Kolb-Bachofen. J Invest Dermatol. 110, 1 (1998); M R Schaffer et al., Surgery 121, 513 (1997)). A systemic deficiency of endothelial-derived NO has been observed in all diabetics (A Veves et al., Diabetes, 47, 457 (1998); M Huszka et al., Thrombosis Res, 86(2), 173 (1997); S B Williams, J A Cusco, M A Roddy, M T Hohnston, M A Creager, J. Am. Col. Cardiol., 27(3), 567 (1996)), suggesting that NO plays a fundamental role in the pathogenesis of chronic, non-healing LEU. Consequently, there is a need to correlate NO production with wound healing ability in diabetics. Such a correlation would allow the development of methods to predict the wound healing ability of diabetics based on their production of NO and would provide a useful clinical indicator which could serve as a basis for choosing appropriate therapy.
SUMMARY OF THE INVENTION
It is an object of the invention to provide a method of determining whether a diabetic subject is a wound healing diabetic or a non-wound healing diabetic. The method comprises the steps of: (a) collecting a specimen from the subject; (b) determining the level of a nitric oxide related product in the specimen; and (c) comparing the level of the nitric oxide related product in the specimen with a threshold value which discriminates between wound healing and non-wound healing diabetics. If the level of the nitric oxide related product is above the threshold value, then the subject is a wound healing diabetic. If the level of the nitric oxide related product is approximately at or below the threshold value, then the subject is a non-wound healing diabetic.
It is also an object of the invention to provide a method of treating a diabetic subject. The method comprises the steps of: (a) collecting a specimen from the subject; (b) determining the level of a nitric oxide related product in the specimen; and (c) comparing the level of the nitric oxide related product in the specimen with a threshold value which discriminates between wound healing and non-wound healing diabetics; and (d) treating the subject according to whether the subject is a wound healing diabetic or a non-wound healing diabetic.
It is a further object of the invention to provide a method of monitoring the effectiveness of treatment of a non-wound healing diabetic patient. The method comprises the steps of: (a) administering to the patient a therapeutic agent designed to raise the level of nitric oxide in the patient; (b) collecting a specimen from the subject; and (c) determining the level of a nitric oxide related product in the specimen as a measure of the effectiveness of the treatment.
It is yet another object of the invention to provide a kit for determining whether a diabetic subject is a wound healing diabetic or a non-wound healing diabetic. The kit comprises reagents for determining the level of a nitric oxide related product in a specimen and instructions for obtaining the specimen, using the reagents, and interpreting the results.
These and other objects of the invention are provided by one or more of the embodiments described below.
REFERENCES:
patent: 5912114 (1999-06-01), Hutchinson et al.
Schaffer, et al. “Nitric Oxide Is Decreased In Diabetic Wound Healing”; English Abstract; Langenbecks Arch Chir Suppl Kongressbd 1997; 114():519-21.
Schaffer, et al. “Nitric Oxide Regulates Wound Healing”; Journal of Surgical Research, 63, 237-240 (1996),Article No. 0254, pp. 237-240.
Veves et al. “Endothelial Dysfunction and the Expression of Endothelial Nitric oxide Synthetase in Diabetic Neuropathy, Vascular Disease, and Foot Ulceration”; Diabetes, vol. 47, pp. 457-463Mar. 1998.
Williams et al. “Impaired Nitric Oxide-Mediated Vasodilation in Patients With Non-Insulin-Dependent Diabetes Mellitus”; JACC, vol. 27, No. 3, Mar. 1, 1996, pp. 567-574.
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Schaffer et al. “Diabetes-Impaired Healing and Reduced Wound Nitric Oxide Synthesis: A Possible Pathophysiologic Correlation”, Surgery, vol. 121, No. 5, May 1997, pp. 513-519.
Catalano, et al. “Basal Nitric Oxide Production Is Not Reduced In Patients With Noninsulin-Dependent Diabetes Mellitus”, Vascular Medicine, 1997, 2, pp. 302-305.
Bulgrin et al. “Nitric Oxide Synthesis is Suppressed in Steroid-Impaired and Diabetic Wounds”; Wounds: A Compendium of Clinical Research and Practice, vol. 7, No. 2, Mar./Apr. 1995, pp. 48-57.
Huszka et al. “The Association of Reduced Endothelium Derived Relaxing Factor—No Production With Endothelial Damage and Increased In Vivo Platelet Activation in Patients With Diabetes Mellitus” Thrombosis Research, vol. 86, No. 2, 1997, pp. 173-180.
Jeffrey P Bulgrin., et al.: “Arginine-free diet suppresses nitric oxide production in wounds”, Journal of Nutritional Biochemistry, vol. 4, 1993, pp. 588-593.
Thomas P. Misko, et al.: “A fluorometric assay for the measurement of nitrite in biological samples”, Analytical Biochemistry, vol. 214, 1993, pp. 11-16.
Mary B. Gillam, et al.: “A spectrophotometric assay for nitrate using NADPH oxidation by Aspergillus nitrate reductase”, Analytical Biochemistry, vol. 212, 1993, pp. 359-365.
E. B. Jude, et al.: “The role of nitric oxxide synthase isoforms and arginase in the pathogenesis of diabetic foot ulcers: Possible modulatory effects by
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