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(12) United States Patent (10) Patent No.: US 6,537,992 B2 Parker (45) Date of Patent: Mar

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(12) United States Patent (10) Patent No.: US 6,537,992 B2 Parker (45) Date of Patent: Mar USOO6537992B2 (12) United States Patent (10) Patent No.: US 6,537,992 B2 Parker (45) Date of Patent: Mar. 25, 2003 (54) REGULATION OF ORGANIC NITRATE Erik Stroes, et al., “Tetrahydrobiopterin Restores Endothe TOLERANCE lial Function in Hypercholesterolemia', J. Clin. Invest., vol. 99, No. 1, Jan., 1997, pp. 41–46. (75) Inventor: John D. Parker, 15 Oakly Place, Jørn Bech Laursen, et al., “Nitrate Tolerance Impairs Nitric Toronto, Ontario (CA), M2P 2G3 Oxide-Mediated Vasodilation in Vivo”, Cardiovascular Research, vol. 31, (1996) pp. 814-819. (73) Assignee: John D. Parker (CA) Chao Han, et al., “Pharmacokinetics of Nitroglycerin and Its * Y NotOtice: Subjubject to anyy disclaimer,disclai theh term off thisthi Four Metabolites During Nitroglycerin Transdermal Admin patent is extended or adjusted under 35 istration', Biopharmaceutics & Drug Disposition, Vol. 15, U.S.C. 154(b) by 0 days. (1994) pp. 179–183. Georgette M. Buga, et al., “Negative Feedback Regulation of Endothelial Cell Function by Nitric Oxide', Circulation (21) Appl. No.: 09/754,196 Research, vol. 73, No. 5, Nov., 1993, pp. 808–812. (22) Filed: Jan. 5, 2001 Frank W. Lee, et al., “Pharmacokinetics and Pharmacody namics of Nitroglycerin and Its Dinitrate Metabolites in (65) Prior Publication Data Conscious Dogs: Intravenous Infusion Studies”, J. of Pharm. US 2002/009 1126 A1 Jul. 11, 2002 and Biopharm., vol. 21, No. 5, (1993) pp. 533–550. Walter E. Haefeli, et al., “Comparison of Vasodilatory (51) Int. Cl." .............................................. A61K 31f495 Responses to Nitroglycerin and its Dinitrate Metabolites in (52) U.S. Cl. ....................................................... 514/249 Human Veins”, Clin. Pharmacol. Ther., vol. 52, No. 6, Dec., (58) Field of Search .......................................... 514/252 1992, pp. 590–596. (56) References Cited M. Gumbleton, et al., “Pharmacological Activity of the Dinitrate Metabolites of Nitroglycerin Following their Oral U.S. PATENT DOCUMENTS Administration to Healthy Volunteers”, Br. J. Clin. Pharma 5,922,713 A * 7/1999 Warner ....................... 514/249 col., vol. 31, (1991) pp. 211-213. 5.945.452 A * 8/1999 Cooke et al. ........ ... 514/564 Dale K. Yu, et al., “Pharmacokinetics of Nitroglycerin and Metabolites in Humans Following Oral Dosing”, Biophar 6,117.872 A * 9/2000 Maxwell et al. ..... ... 514/252 6,127,370 A * 10/2000 Smith et al. ......... ... 514/252 maceutics & Drug Disposition, vol. 9, (1988) pp. 557–565. 2002/0052374. A1 5/2002 Rabelink et al. ............ 514/250 B. Mayer, et al.: “Biosynthesis and action of nitric acid oxide FOREIGN PATENT DOCUMENTS in mammalian cells”, TIBS 22–Dec. 1997, pp. 477–481. E. Stroes, et al.: “Origin of Superoxide production by endot DE 199 20 775 11/2000 .......... A61Kf45/OO helial nitric oxide synthase”, FEBS Letters 438 (1998), pp. OTHER PUBLICATIONS 161-164. Adak et al., J. Biological Chem., vol. 275, No. 43, pp. Database Biosis. Online, BioSciences Information Service, 33554-33561 (Oct. 2000).* W. Kaesemeyer, et al., Endothelial nitric oxide Synthase is a Bune et al, Biochemical & Biophysical Res. Comm., vol. Site of Superoxide Synthesis in endothelial cells treated wit 220, pp. 13–19 (1996).* glyceryl trinitrate. Seiji Ueda, et al., “Tetrahydrobiopterin Restores Endothelial R.M.F. Weaver, et al.: “Tetrahydrobiopterin regulates Super Function in Long-Term Smokers”, J. of the American oxide and nitric oxide generation by recombinant endothe College of Cardiology, vol. 35, No. 1, Jan., 2000, pp.71-75. lial nitric oxide synthase”, Biochemical And Biophysical Hanneke W. Wilmink, et al., “Influence of Folic Acid on Research Communications 237 (1997), pp. 340-344. Postprandial Endothelial Dysfunction”, Arterioscler. Thromb. Vasc. Biol., vol. 20, Jan., 2000, pp. 185-188. * cited by examiner Stephen D. Milone, et al., “Biochemical, Hemodynamic, and Vascular Evidence Concerning the Free Radical Hypothesis Primary Examiner James H. Reamer of Nitrate Tolerance”, J. of Cardiovascular Pharmacology, (74) Attorney, Agent, or Firm- Katten Muchin Zavis vol. 33, No. 5, (1999) pp. 685–690. Rosenman Sabine Kurz, et al., “Evidence for Casual Role of the (57) ABSTRACT Renin-Angiotensin System in Nitrate Tolerance”, Circula tion, vol. 99, (1999) pp. 3181-3187. There is disclosed pharmaceutical compositions and meth John D. Parker, et al., “Nitrate Therapy for Stable Angina ods useful in obviating or mitigating tolerance during Pectoris", The New Eng.J. of Med., vol. 338, No. 8, Feb. 19, organic nitrate therapy. The compositions and methods 1998, pp. 520–531. comprise compounds Selected from the group comprising a Marianne C. Verhaar, et al., “5-Methyltetrahydrofolate, the folate compound, a folate derivative compound, tetrahydro Active Form of Folic Acid, Restores Endothelial Function in biopterin and mixtures thereof. Familial Hypercholesterolemia', Circulation, vol. 97, (1998) pp. 237-241. 20 Claims, No Drawings US 6,537,992 B2 1 2 REGULATION OF ORGANIC NITRATE (i) a first active ingredient comprising an organic nitrate; TOLERANCE (ii) a second active ingredient comprising a folate compound, a folate derivative compound, tetrahydro biopterin and mixtures thereof, and BACKGROUND OF THE INVENTION (iii) a pharmaceutically acceptable carrier therefor. 1. Field of the Invention In yet another of its aspects, the present invention pro In one of its aspects, the present invention relates to a vides a kit for use in organic nitrate therapy, the kit com pharmaceutical composition for regulation of organic nitrate prising: tolerance. In another of its aspects, the present invention 1O (i) a first pharmaceutical composition comprising an relates to a method for regulating organic nitrate tolerance. organic nitrate, together a pharmaceutically acceptable 2. Description of the Prior Art carrier therefor; Organic nitrates Such as glyceryl trinitrate, isosorbide (ii) a Second pharmaceutical composition comprising a dinitrate, isosorbide-5-mononitrate, and the like are recog folate compound, a folate derivative compound, tet nized as important pharmacologic agents used in the treat 15 rahydrobiopterin and mixtures thereof, together with a ment of coronary artery disease and congestive heart pharmaceutically acceptable carrier therefor. failure-see Parker J. Nitrate Therapy for Stable Angina In yet another of its aspects, the present invention pro Pectoris. N Engl J Med 1998:338:520–531. Despite suc vides a method for regulating tolerance during organic cessful application, the use of nitroglycerin is limited by a nitrate therapy, the method comprising the Step of adminis number of its pharmacologic characteristics. One of the tering to a patient: important limitations is loSS of efficacy during continuous (i) a first pharmaceutical composition comprising an therapy, a phenomenon known as “tolerance'. The etiology organic nitrate, together a pharmaceutically acceptable of tolerance is not clearly understood, however recent carrier therefor; and experimental data have improved the understanding of the (ii) a Second pharmaceutical composition comprising a mechanism(s) involved-see one or more of: 25 folate compound, a folate derivative compound, tet a. Minzel T, Sayegh H, Freeman BA et al. Evidence for rahydrobiopterin and mixtures thereof, together with a enhanced vascular Superoxide anion production in pharmaceutically acceptable carrier therefor. nitrate tolerance. A novel mechanism underlying toler In yet another of its aspects, the present invention pro ance and cross-tolerance. J Clin Invest 1995; 95 vides for the use of a compound Selected from the group (1):187–94; comprising a folate compound, a folate derivative b. Münzel T, Li H, Mollnau H, Hink U et al. Effects of compound, tetrahydrobiopterin and mixtures thereof for the long-term nitroglycerin treatment on endothelial nitric production of a pharmaceutical composition useful in regu oxide synthase (NOS III) gene expression, NOS III lated tolerance to organic nitrate therapy. mediated Superoxide production, and vascular NO bio 35 DETAILED DESCRIPTION OF THE availability. Circ Res 2000; 86 (1): E7–E12; and PREFERRED EMBODIMENTS c. Minzel T, Mollnau H, Hartmann M et al. Effects of a Thus, I have Surprisingly and unexpectedly discovered nitrate-free interval on tolerance, vasoconstrictor Sen that Selected compounds are useful in obviating or mitigat Sitivity and vascular Superoxide production. JAm Coll ing tolerance during organic nitrate therapy. Cardiol 2000; 36 (2): 628–34. 40 Thus it would desirable to have a pharmaceutical com The compounds may be selected from the group com position which obviates or mitigates tolerance to organic prising a folate compound, a folate derivative compound, nitrate therapy. tetrahydrobiopterin and mixtures thereof. The term “folate derivative compound” will be readily understood by those of SUMMARY OF THE INVENTION 45 skill in the art to encompass compounds having a folate “backbone” which has been derivatized. Non-limiting It is an object of the present invention to provide a novel examples of Suitable Such compounds may be Selected from composition which is useful to obviate or mitigate tolerance the group comprising tetrahydrofolate, to organic nitrate therapy. 5-methyltetrahydrofolate and mixtures thereof. It is another object of the present invention to provide a 50 The dosage administered of the folate compound, the novel method for regulating tolerance to organic nitrate folate derivative compound or the tetrahydrobiopterin will therapy. vary depending on the use and known factorS
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