Methods for increasing uridine levels with L-nucleosides
AssigneeThe UAB Research Foundation
InventorsJean-Pierre Sommadossi, Mahmoud H. el Kouni
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Abstract
A method of increasing intracellular and plasma uridine levels comprising the coadministration or sequential administration of a compound from at least two of the following groups: 1) uridine phosphorylase inhibitors, uridine, cytidine, prodrugs of uridine, and prodrugs of cytidine; 2) a uridine secretion inhibiting compound such as dilazep or hexobendine; and 3) a compound which competes with uridine in renal transport mechanisms such as L-uridine, L-2',3'-dideoxyuridine, and D-2', 3'-dideoxyuridine. The elevation of plasma and intracellular levels of uridine reduces the toxicity of pyrimidine nucleoside chemotherapeutic agents.
Claims12
A method of increasing intracellular and plasma uridine levels in a subject by coadministering or sequentially administering to the subject:
- (a) one or more compounds selected from the group consisting of uridine phosphorylase inhibitors, uridine, cytidine, prodrugs of uridine, prodrugs of cytidine;
- and
- (b) an effective amount of a uridine secretion inhibiting compound represented by the following formula or a pharmaceutically acceptable salt thereof ##STR7## where:
- R.sub.1 and R.sub.3 are lower alkoxy groups having from 1 to 3 carbon atoms, and may be the same or different, n is an integer from 1 to 3, m is 2 or 3, R.sub.2 is ##STR8## where R.sub.4 and R.sub.6 are methyl, ethyl or propyl, and may be the same or different, and R.sub.5 is methyl, ethyl, propyl or butyl;
- or where R.sub.2 is ##STR9## where x is an integer from 2 to 4 and y is 2 or 3, and the sum of x and y is from 5 to 7.
A method of treating a subject infected with a retrovirus comprising the steps of:
- administering a pyrimidine nucleoside compound in an amount effective to disrupt viral replication in infected cells;
- and
- coadministering or sequentially administering to the subject a uridine secretion inhibiting compound that competes with uridine in the renal transport mechanism of uridine and is selected from the group consisting of L-uridine, L-2,3'-dideoxyuridine, and D-2',3'-dideoxyuridine in an amount effective to increase intracellular and plasma uridine levels.
A method of increasing intracellular and plasma uridine levels in a subject by coadministering or sequentially administering to the subject:
- (a) one or more compounds which compete with uridine in the renal transport mechanisms of uridine, selected from the group consisting of L-uridine, L-2',3'-dideoxyuridine, and D-2',3'-dideoxyuridine, wherein the compound is administered at a dosage of about 5 to 50 mg per Kg of body weight two to three times per day;
- and
- (b) an effective amount of a uridine secretion inhibiting compound represented by the following formula or a pharmaceutically acceptable salt thereof ##STR10## where:
- R.sub.1 and R.sub.3 are lower alkoxy groups having from 1 to 3 carbon atoms, and may be the same or different, n is an integer from 1 to 3, m is 2 or 3, R.sub.2 is ##STR11## where R.sub.4 and R.sub.6 are methyl, ethyl or propyl, and may be the same or different, and R.sub.5 is methyl, ethyl, propyl or butyl;
- or where R.sub.2 is ##STR12## where x is an integer from 2 to 4 and y is 2 or 3, and the sum of x and y is from 5 to 7.
A method of treating a retroviral infection, comprising the steps of
- administering a pyrimidine nucleoside compound in an amount effective to disrupt viral replication in retrovirus-infected cells;
- administering and an effective amount of uridine to reduce nucleoside toxicity in said uninfected cells;
- and
- administering an amount of a uridine secretion inhibitor effective to increase intracellular and plasma uridine levels, the uridine secretion inhibitor being selected from the group consisting of dilazep, hexobendine, L-uridine, L-2',3'-dideoxyuridine, and D-2',3'-dideoxyuridine.
Dependencies are inferred from the claim text.