USE OF ETODOLAC FOR LOWERING URIC ACID BLOOD LEVELS

Abstract: A method is disclosed for lowering uric acid blood levels by administering an effective amount of etodolac.

Description: This invention relates to a novel therapeutic use of 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid whose generic name is etodolac. More specifically this invention relates to a method of lowering uric acid blood levels in humans for treatment of gout. The active agent of this invention, 1,8-diethyl-1,3, 4,9-tetrahydropyrano [3,4-b]indole-1-acetic acid or a therapeutically acceptable salt thereof, is disclosed in U.S Patent No. 3,939,178 issued February 17, 1976. This active agent, hereinafter designated by its generic name etodolac, previously has been reported to be useful as an analgesic and anti-inflammatory agent. (See U.S. Patent No. 3,939,178) The applicants have now found unexpectedly that etodolac, either in its free acid form or in its therapeutically acceptable salt form, is useful for lowering uric acid blood levels in humans, and particularly humans suffering from gout. This finding, coupled with the fact that etodolac is a relatively safe drug, renders the method of this invention particularly useful and advantageous. Accordingly this invention provides the use of etodolac or a therapeutically acceptable salt thereof for the preparation of a medicament for lowering uric acid blood levels in humans. According to the present method, etodolac, either in its free acid form or in the therapeutically acceptable salt form, is employed as the active agent. Examples of suitable salt forms are described in U.S.Patent No. 3,939,178 and include the sodium, potassium, magnesium, triethylamine and benzylamine salt forms. A preferred salt form is the sodium salt, i.e. etodolac sodium. Etodolac or a therapeutically acceptable addition salt thereof is administered to humans suffering from elevated uric acid levels (hyperuricemia), either orally or parenterally. For many reasons oral administration is preferred. While etodolac or a therapeutically acceptable salt thereof can be administered alone, e.g. as a sole component of a filled capsule, it is preferred to formulate the compound in various dosage forms for oral or parental administration, e.g. tablets, or sterile solutions. Such formulations are described in U.S.Patent No 3.939,178. When utilizing etodolac or one of its above-noted salts as agents for lowering uric acid blood levels, the total dose of active agent can range from about 50 milligrams to about 1000 milligrams per day with a preferred dosage range of from about 200 to about 600 milligrams per day. However, greater lowering of uric acid can be achieved with about 1000 mg per day. Generally, a parental dose or an oral dose is administered in one to four applications per day, but more commonly twice a day. Such doses are considered to be an effective amount when, following their administration, a decrease in uric acid blood levels is experienced by the patient, or when the subjective symptoms complained of by said human beings are reported as having disappeared, or as being ameliorated or reduced in severity following such treatment. The effectiveness of etodolac or its therapeutically acceptable salts as agents for lowering uric acid blood levels in a human has been demonstrated in human patients. Three 6-week and four 12-week double blind clinical trials were conducted with patients suffering from rheumatoid arthritis or degenerative joint disease. A total of 711 patients received etodolac at a daily dose of 50 to 600 milligrams and 339 patients were receiving placebo. The frequency distribution of daily dose by treatment group, i.e. how many patients received etodolac and in what amount is shown in the following Tables I and II. Frequency Distribution of Prescribed Daily Dose by Treatment Group Etodolac, Milligrams Number of Patients Four 12 Week Studies 1 2 3 4 50 0 0 0 0 100 8 4 0 39 200 8 7 6 80 300 19 12 0 0 400 29 45 27 0 600 0 0 0 0 Frequency Distribution of Prescribed Daily Dose by Treatment Group Prescribed Daily Dose Etodolac, Milligrams Number of Patients Three 6 Week Studies 1 2 3 50 56 0 45 100 55 0 43 200 49 44 44 300 0 0 0 400 0 91 0 600 0 0 0 The Three 6-week and four 12-week double-blind studies were analyzed statistically to compare etodolac and placebo with respect to uric acid levels. The analysis included 688 patients (265 from the 12-week studies) receiving etodolac and the 339 placebo patients (200 from the 12-week studies). The variable of interest was each patient's average uric acid level within each of the following day range: baseline, days 1-27, days 28-55, days 56-83, and days 84-111. Regression analysis revealed that in both the pool of 12-week studies and the pool of all studies, there was a significant difference between the etodolac group and the placebo group in the estimated slope of the relationship between uric acid and day range. In each case, the slope in the etodolac group was negative, indicating a decrease over time in uric acid levels, while the slope in the placebo group was positive. Time-point analyses performed on the pool of all studies revealed that within each day range, there was a significant difference between etodolac and placebo in the mean change from baseline and in the proportion of patients who decreased from baseline. Within each day range, the etodolac group showed a mean decrease from baseline while the placebo group showed a mean increase from baseline; greater proportions in the etodolac group showed decreases. The mean changes in the etodolac group were between -0.05 mg uric acid per 100 milliliter of serum and -0.31 mg uric acid per 100 milliliter of serum; in the placebo group they were between 0.12 mg uric acid per 100 milliliters of serum and 0.23 mg uric acid per 100 milliliters of serum. The results of the analysis of all 7 double-blind protocols were: 1. the etodolac slope was negative, -0.0872, and significantly different from zero,p=.0015, 2. the placebo slope, 0.0478, was not significantly different from zero, p=.1887, and 3. a significant difference between drug groups in slopes as indicated by the drug by day range interaction, p=.0024. The results are shown in Table III The method of this invention is particularly beneficial for lowering uric acid blood levels in a patient suffering from gout. The lowering of the uric acid blood levels was is addition to the usual anti-inflammatory effect exhibited by etodolac. In another study in which patients with rheumatoid arthritis received either 300 or 1000 mg per day etodolac, there was a greater reduction in uric acid blood levels with the higher dose. The 157 patients receiving 300 mg per day etodolac had a mean reduction in uric acid over 6 months of 0.47 mg per 100 milliliter wherein, the 105 patients receiving 1000 mg per day for 6 months had a mean reduction for uric acid levels of 1.47 mg per 100 milliliter.

Claims: The use of etodolac or a therapeutically acceptable salt thereof for the preparation of a medicament for lowering uric acid blood levels in humans. The use of etodolac or a therapeutically acceptable salt thereof as claimed in claim 1 for the preparation of a medicament for lowering uric acid blood levels in humans by the administration of etodolac or a therapeutically acceptable salt thereof in an amount within the range from 50mg to 1000mg per day. The use of etodolac or a therapeutically acceptable salt thereof as claimed in claim 1 for the preparation of a medicament for lowering uric acid blood levels in humans by the administration of etodolac or a therapeutically acceptable salt thereof in an amount within the range of 200mg to 1000mg per day. The use of etodolac or a therapeutically acceptable salt thereof as claimed in any one of claims 1 to 3 for the preparation of a medicament for lowering uric acid blood levels in humans suffering from gout.

Inventors: MULLANE, JOHN FRANCIS
Applicants: AMERICAN HOME PRODUCTS CORPORATION
Application year: 1987
Main classification: A61K31
IPC codes: A61K31, A61P19, C07D491