Methods and compositions for reducing toxicity associated with leflunomide treatment
First Claim
Patent Images
1. A pharmaceutical composition in unit dosage form for oral administration comprising an effective amount of a leflunomide compound;
- and an orally bioavailable pyrimidine compound, salts thereof or a combination thereof;
together in a pharmaceutically acceptable carrier.
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Accused Products
Abstract
The invention relates to methods and compositions useful in alleviating or reducing toxicity associated with leflunomide administration without reducing its bioactivity, e.g., without reducing its immunosuppressive activity, that is, utilizing a bioavailable pyrimidine compound to ameloriate the toxic effects caused by leflunomide compounds.
23 Citations
25 Claims
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1. A pharmaceutical composition in unit dosage form for oral administration comprising an effective amount of a leflunomide compound;
- and an orally bioavailable pyrimidine compound, salts thereof or a combination thereof;
together in a pharmaceutically acceptable carrier. - View Dependent Claims (2, 3, 4, 5, 6)
- and an orally bioavailable pyrimidine compound, salts thereof or a combination thereof;
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7. A pharmaceutical composition comprising a formulation for oral administration, the formulation comprising a therapeutically effective amount of leflunomide, and orotic acid or a salt thereof, and a pharmaceutically acceptable carrier.
- 8. A method of reducing toxicity associated with administration of a leflunomide compound to a patient in need thereof, comprising administering to the patient a toxicity-reducing amount of a bioavailable pyrimidine compound.
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17. A method of extending the dosage range of a leflunomide compound comprising co-administering to a subject:
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a) an effective amount of a leflunomide compound of formula (II);
wherein R1 and R2 are independently selected from the group consisting of —
CF3, —
H, —
Cl, —
F, —
Br, —
CN, —
COOH, —
OCH3, —
NH—
CO—
CH2Cl and —
NH—
CO—
CH2Br;
or formula (IV);
wherein R1 and R2 are independently selected from the group consisting of —
CF3, —
H, —
Cl, —
F, —
Br, —
CN, —
COOH, —
OCH3, —
NH—
CO—
CH2Cl and —
NH—
CO—
CH2Br; and
R3 is selected from the group consisting of C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-6 cycloalkyl; and
b) a toxicity-reducing amount of an orally bioavailable pyrimidine compound selected from the group consisting of orotic acid, a salt thereof, triacetyl uridine, a salt thereo, cytidine, a salt thereof, an acylated cytidine, a salt thereof, and a combination thereof.
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18. A method of administering a toxic dose of a leflunomide compound to a mammal, comprising administering to the mammal an amount of an orally bioavailable pyrimidine compound sufficient to reduce the toxic effects of the leflunomide compound.
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19. A method of reducing toxicity associated with the administration of a therapeutically effective amount of a leflunomide compound to a mammal, comprising:
- orally administering to the mammal a bioavailable pyrimidine compound selected from orotic acid, a salt thereof, triacetyluridine, a salt thereof, cytidine, a salt thereof, an acylated cytidine, a salt thereof, and a combination thereof, in an amount effective to reduce the toxicity without blocking therapeutic
effect of the leflunomide compound, wherein the leflunomide compound is a compound of formula (II) or formula (IV). - View Dependent Claims (20)
- orally administering to the mammal a bioavailable pyrimidine compound selected from orotic acid, a salt thereof, triacetyluridine, a salt thereof, cytidine, a salt thereof, an acylated cytidine, a salt thereof, and a combination thereof, in an amount effective to reduce the toxicity without blocking therapeutic
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21. A method of treating rejection in a transplant recipient comprising co-administering
a therapeutically effective amount of a leflunomide compound and a toxicity-reducing effective amount of bio-available pyrimidine compound.
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24. A method of achieving an effect in a patient comprising co-administering an effective amount of a leflunomide compound and an effective amount of orotic acid, a salt thereof, triacetyl uridine, a salt thereof, or a combination thereof, wherein the effect is treatment of rejection of a transplant, wherein the transplant is heart, kidney or bone marrow.
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25. A pharmaceutical combination comprising a packaging having a plurality containers, at least one container containing a leflunomide compound, at least one other container containing a bioavailable pyrimidine compound, and an instructions for co-administering the leflunomide compound and the pyrimidine compound to a subject who is a transplant recipient.
Specification