Claims for Patent: 6,469,035

Summary for Patent: 6,469,035

Title:	Methods of pretreating hyperlipidemic individuals with a flush inhibiting agent prior to the start of single daily dose nicotinic acid therapy to reduce flushing provoked by nicotinic acid
Abstract:	The present invention relates to pretreating individuals with an effective amount of a flush inhibiting agent for a sufficient period of time prior to the start of single daily dose nicotinic acid therapy to reduce the capacity of nicotinic acid to induce flushing reactions in such individuals during nicotinic acid therapy. In accordance with the present invention, the flush inhibiting agents are administered orally one to four times a day, and preferably one to two times per day, for between about 7 to about 14 days prior to the start of the nicotinic acid therapy. Examples of flush inhibiting agents include nonsteroidal anti-inflammatory agents. Aspirin is a preferred flush inhibiting agent and may be orally administered in daily doses of between about 80 mg to about 1000 mg, and preferably between about 80 mg and about 650 mg, and more preferably between about 80 mg and about 325 mg, during the pretreatment period. Also consistent with the present invention, the pretreatment therapy may be continued during and administered concurrently with the nicotinic acid therapy, in which the nicotinic acid is preferably administered once per day as a single dose during the evening hours or before or at bedtime. The nicotinic acid may be administered alone or in combination with HMG-CoA reductase inhibitors as well as other lipid-altering agents, like cholestyramine and colestipol.
Inventor(s):	Cefali; Eugenio A. (Hollywood, FL)
Assignee:
Application Number:	08/903,755
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,469,035
Patent Claims:	1. A method of reducing the capacity of extended release nicotinic acid to provoke a flushing reaction in an individual when extended release nicotinic acid is orally administered in an effective lipid-altering amount as a single dose once a day during the evening hours or before or at bedtime, comprising orally pretreating the individual with an effective flush inhibiting amount of a flush inhibiting agent for a sufficient period of time prior to initiating the administration of the extended release nicotinic acid in the individual to inhibit or reduce prostaglandin PGD.sub.2 induced by the extended release nicotinic acid; and orally administering the nicotinic acid to the pretreated individual in an effective lipid-altering amount as a single dose once a day during the evening hours or before or at bedtime without causing treatment-limiting hepatotoxicity and elevations in glucose and/or uric acid levels, whereby the capacity of the extended release nicotinic acid to provoke a flushing reaction in the pretreated individual is reduced or prevented. 2. A method of claim 1, wherein said method includes the further step of orally administering to the pretreated individual an HMG-CoA reductase inhibitor in an effective lipid-altering amount without causing treatment-limiting myopathy and rhabdomyolysis. 3. A method of claim 2, wherein said HMG-CoA reductase inhibitor oral administartion is concomitantly with said extended release nicotinic acid oral administration. 4. A method of claim 2, wherein the HMG-CoA reductase inhibitor is an extended release form or in an immediate release form. 5. A method of claim 2, wherein said HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, flavastatin, lovastatin, pravastatin and simvastatin. 6. A method of claim 1, wherein the flush inhibiting agent is a nonsteroidal anti-inflammatory agent. 7. A method of claim 6, wherein the nonsteroidal anti-inflammatory agent is selected from the group consisting of indomethacin, sulindac, etodolac, aspirin, salicylate salts, ibuprofen, fluribprofen, fenoprophen, suprofen, benoxaprofen, ketoprofen, carprofen, naproxen, sodium naproxen, aclofenac, diclofenac, fenclofenac, tolmectin, zomepirac, meclofenamate, mefanamic acid, oxyphenbutazone, phenylbutazone and piroxicam. 8. A method of claim 1, wherein the flush inhibiting agent is aspirin. 9. A method of claim 8, wherein said oral administration of the aspirin comprises orally administering the aspirin in one to four doses per day during said pretreatment. 10. A method of claim 8 wherein said method includes the further step of orally administering the aspirin as the flush inhibiting agent in an amount of between about 80 mg and 1000 mg daily during said pretreatment. 11. A method of claim 2, wherein the flush inhibiting agent is aspirin. 12. A method of claim 11, wherein said oral administration of the aspirin comprises orally administering the aspirin in one to four doses per day during said pretreatment. 13. A method of claim 11, wherein said oral administration of the aspirin comprises orally administering the aspirin in one or two doses per day during said pretreatment. 14. A method of claim 11, wherein said method includes the further step of orally administering the aspirin as the flush inhibiting agent in an amount of between about 80 mg and about 1000 mg daily during said pretreatment. 15. A method of claim 11, wherein said method includes the further step of orally administering the aspirin as the flush inhibiting agent in an amount of between about 80 mg and about 650 mg daily during said pretreatment. 16. A method of claim 11, wherein said method includes the further step of orally administering the aspirin as the flush inhibiting agent in an amount of between about 80 mg and about 325 mg daily during said pretreatment. 17. A method of claim 11, wherein said method includes the further step of orally administering a nicotinic acid compound to the pretreated individual in an effective lipid-altering amount. 18. A method of claim 17, wherein the extended release nicotinic acid compound is selected from the group consisting of nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d, 1-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-2-pyriidine-8-carboxamide, N-methyl-nicotinamide, N-ribosyl-2-pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradilian, sorbinicate, hexanicite, ronitol, and lower alcohol esters of nicotinic acid. 19. A method of claim 11, wherein said method includes the further step of orally administering a cholestyramine to the pretreated individual in an effective lipid-altering amount. 20. A method of claim 11, wherein said method includes the further step of orally administering a colestipol to the pretreated individual in an effective lipid-altering amount. 21. A method of (a) altering serum lipid levels in an individual without causing treatment-limiting hepatotoxicity, myopathy, rhabdomyolysis and elevations in glucose and/or uric acid levels in the individual and (b) reducing the capacity of an extended release nicotinic acid to provoke a flushing reaction in the individual when the extended release nicotinic acid is orally administered in an effective lipid-altering amount as a single dose once a day during the evening hours or before or at bedtime, comprising orally pretreating the individual with an effective flush inhibiting amount of a flush inhibiting agent for a sufficient period of time prior to initiating administration of the extended release nicotinic acid in the individual to inhibit or reduce prostaglandin PGD.sub.2 induced by the extended release nicotinic acid, and orally administering an oral solid dosage form comprised of an effective lipid-altering amount of the extended release nicotinic acid and an effective lipid-altering amount of an immediate release HMG-CoA reductase inhibitor to the pretreated individual as a single dose once a day during the evening hours or before or at bedtime, whereby the capacity of the extended release nicotinic acid to provoke a flushing reaction in the pretreated individual is reduced or prevented and the serum lipid levels in the individual are altered. 22. A method of claim 21, wherein the oral solid dosage form is a tablet. 23. A method of claim 21, wherein the extended release nicotinic acid is coated with the immediate release HMG-CoA reductase inhibitor. 24. A method of claim 23, wherein the oral solid dosage form is a tablet. 25. A method of claim 22, wherein the tablet includes an inner core containing the extended release nicotinic acid and a coating layer containing the immediate release HMG-CoA reductase inhibitor, wherein the inner core is coated with the coating layer. 26. A method of claim 21, wherein the oral solid dosage form contains the extended release nicotinic acid in an amount between about 250 mg and about 1,000 mg and the immediate release HMG-CoA reductase inhibitor in an amount between about 0.05 mg and about 80 mg. 27. A method of claim 22, wherein the oral solid dosage form contains the extended release nicotinic acid in an amount between about 250 mg and about 1,000 mg and the immediate release HMG-CoA reductase inhibitor in an amount between about 0.05 mg and about 80 mg. 28. A method of claim 23, wherein the oral solid dosage form contains the extended release nicotinic acid in an amount between about 250 mg and about 1,000 mg and the immediate release HMG-CoA reductase inhibitor in an amount between about 0.05 mg and about 80 mg. 29. A method of claim 24, wherein the oral solid dosage form contains the extended release nicotinic acid in an amount between about 250 mg and about 1,000 mg and the immediate release HMG-CoA reductase inhibitor in an amount between about 0.05 mg and about 80 mg. 30. A method of claim 25, wherein the oral solid dosage form contains the extended release nicotinic acid in an amount between about 250 mg and about 1,000 mg and the immediate release HMG-CoA reductase inhibitor in an amount between about 0.05 mg and about 80 mg.