Gamma-linolenic acid for the preparation of a medicament for preventing reocclusion of arteries

Abstract: Gamma-linolenic acid and/or dihomo-gamma-linolenic acid is used in the preparation of a medicament for inhibiting reocclusion of an artery from which an occlusion or other blockage has been removed, or for preventing occlusion of peripheral or coronary arteries. The medicament may also comprise eicosapentaenoic acid.

Description: The present invention relates to inhibiting reocclusion of arteries, and in particular to the use of GLA and/or DGLA for the preparation of a medicament for use therein. Arteries frequently become partially or totally occluded by atherosclerosis. Over the past twenty years, many methods have been developed aimed at clearing obstructions and allowing the free flow of blood. Such methods have included direct surgical techniques, the introduction of balloons, or other devices, attached to catheters which, when expanded at an appropriate site, partially or completely clear the blockage, and the use of lasers to blast away the occlusion. Unfortunately, however, the artery does not always remain open. Sometimes it becomes blocked again very quickly because of a thrombosis. More frequently it closes after weeks, months or even years as a result of the redevelopment of the atherosclerosis. These closures are known as reocclusions. Depending on various factors, such as the technique used, may arteries are found to reocclude. Typically, 20 - 40% of opened arteries close again. Thus, it would be highly advantageous if reocclusion could be prevented. The benefits to patients and the saving of costs would be considerable. Many drugs have been tested for the prevention of reocclusion, but the results have thus far been largely disappointing. Fish oils, containing the fatty acids eicosapentaenoic acid and docosahexaenoic acid have been tested and occasionally been found to be beneficial, but even the positive effects have been small. There is therefore a great need for new agents in this field. In published material, Lovquist et al J. Internal Medicine 1993 223 215-226 have reviewed problems in restenosis, showing that prediction of favourable effects on restenosis from generally favourable cardiovascular properties of drugs is problematic. Reports of effects of essential fatty acids include Japanese published abstract 60-132916 (Nisshin, linoleic acid and eicosapentaenoic acid, platelet aggregation); U.S. Patent 4,526,902 (linoleic acid etc., platelet aggregation and inhibition of cholesterol and collagen synthesis, thromboembloic and atherosclerotic conditions generally); Lechleitner et al Wien. Med. Wochenschr. 1990 140 (10-11) 277-8 (n-3 essential fatty acids in therapy, value not established, against occlusion of coronary by-pass grafts). The essential fatty acid γ-linolenic acid is known to be converted within the body to dihomo-γ-linolenic acid, a precursor of the prostaglandin PGE₁, which is a powerful anti-aggregatory agent which inhibits platelet aggregation. However, inhibition of the aggregation of platelets alone is unlikely to be effective. EPA, which has a similar effect on platelet aggregation to GLA, has given equivocal and inconsistent results in tests of its ability to prevent reocclusion. GLA has additional cardiovascular benefits in that it, probably through its conversion to PGE₁, lowers cholesterol levels and causes dilation of small blood vessels. Surprisingly, it has been found that administration of γ-linolenic acid to patients after they have undergone angioplasty, or any other equivalent method of reopening blood vessels, results in an impressive reduction of the rate of reocclusion in these patients. Although DGLA has not been tested directly, it is believed as efficacious as GLA, given that the administration of GLA to humans is rapidly followed by an elevation of DGLA levels because of rapid conversion of the GLA. The γ-linolenic acid or dihomo-γ-linolenic acid may be administered in the form of any appropriate derivative such as the free acid, the potassium, lithium or other alkali metal salt, a salt of another metal, eg. zinc, calcium or magnesium, the mono-, di- or triglyceride, ethyl or any other appropriate esters, phospholipids, amides or any other derivative which will lead to elevation of γ-linolenic acid or dihomo-γ-linolenic acid and/or its metabolites in the body. The invention thus lies in use of γ-linolenic acid or dihomo-γ-linolenic acid for the manufacture of a medicament for the inhibition of reocclusion of an artery from which an occlusion or other blockage has been removed. The invention also embraces arteries generally, whether peripheral or coronary. Furthermore, it has been found that additional use of the fatty acid eicosapentaenoic acid (which has been shown to have little effect in the prevention of reocclusion when administered on its own), is particularly effective in preventing reocclusion. Administration of capsules containing γ-linolenic acid in combination with eicosapentaenoic acid, over a period of up to 1 year, to patients who have had an occlusion of the femoral artery removed by balloon angioplasty, has been found to result in a significant reduction of the reocclusion rate. There is every reason to believe that such reductions in the reocclusion rate will also be observed on administration following coronary angioplasty, as well as methods of reopening blood vessels other than angioplasty. Since GLA, optionally with EPA is able to prevent reocclusion, it is also likely to be able to prevent occlusion in the first place and such prevention of occlusion of peripheral or coronary arteries is within the scope of this invention. It is preferred that γ-linolenic acid or dihomo-g-linolenic acid is administered in a dose of from 1 mg to 10 g/day, preferably 100 mg to 4 g/day, particularly 500 mg to 2 g/day. When eicosapentaenoic acid is administered in addition, the amount is preferably 1 mg to 10 g/day, preferably 100 mg to 4 g/day, particularly 500 mg to 2 g/day. It is particularly preferred that the amount of eicosapentaenoic acid is relatively smaller compared to the amount of γ-linolenic acid or dihomo-γ-linolenic acid. The ratio of g-linolenic acid:eicosapentaenoic acid is typically from 20:1 to 3:1. The γ-linolenic acid or dihomo-γ-linolenic acid, either singly or in combination, further optionally in combination with eicosapentaenoic acid, may be administered orally in any appropriate dosage form, such as soft or hard gelatin capsules, which may or may not be enteric-coated, tablets, whips, liquids, internal formulations or any other appropriate formulation known to those skilled in the art. The medicaments may also be administered topically, parenterally by injection (intravenous, intradermal or subcutaneous), infusion or any other appropriate route, rectally or vaginally. Soft or hard gel gelatin capsules, enteric coated or not, for example, may contain 100, 200, 300 or 600 mg of γ-linolenic acid in any appropriate form, optionally with an appropriate amount of eicosapentaenoic acid in any appropriate form. Further examples include an emulsion for intravenous administration which may contain 100 mg of γ-linolenic acid/ml optionally with 5 - 30 mg of eicosapentaenoic acid/ml, a cream for topical administration which may contain 1 - 20% of triglyceride γ-linolenic acid, while a suppository for rectal administration or a pessary for vaginal administration may contain 1 g of γ-linolenic acid in an appropriate formulation. The invention is further illustrated by the following, non-limiting example. Example Patients with occlusion of the femoral artery were entered into the study. The occlusion was treated by balloon angioplasty. One week prior to the angioplasty patients commenced treatment with either 6 capsules/day of placebo or 6 capsules/day of 270 mg of γ-linolenic acid and 45 mg of eicosapentaenoic acid. Treatment with active drug or placebo then continued for one year after angioplasty. Blood flow in the femoral artery was monitored before angioplasty, 1 - 2 days after angioplasty and at 6 months and 12 months using Doppler flowmetry. If symptoms suggesting reocclusion developed at any time during the study, Doppler flowmetry was performed and if occlusion was suspected this was confirmed by performing an angiogram. 60 patients entered the study and 46 have completed one year. 30 patients received active and 30 placebo treatment. Of the 46 patients who have completed one years treatment at the time of writing, 23 were assigned to active treatment, and 23 to placebo. In the patients in the active group, the arteries of 19 patients have remained open, while 4 have reoccluded. In the placebo group, the arteries of 12 patients have remained open, while 11 have reoccluded. This is a significant reduction of the reocculsion rate, showing that linolenic acid in combination with eicosapentaenoic acid is highly effective in preventing reocclusion after femoral angioplasty.

Claims: Use of an effective, non-toxic amount of γ-linolenic acid and/or dihomo-γ -linolenic acid for the preparation of a medicament for inhibiting reocclusion of an artery from which an occlusion or other blockage has been removed. A use according to claim 1, the medicament being suited to the administration of the γ-linolenic acid and/or dihomo-γ-linolenic acid in a dose range of from 1 mg to 10g/day, preferably from 100mg to 4g/day, and more preferably from 500mg to 2g/day. A use according to claims 1 or 2, wherein the medicament further comprises eicosapentaenoic acid. A use according to claim 3, the medicament being suited to the administration of the eicosapentaenoic acid in an amount of from 1mg to 10g/day, preferably from 100mg to 4g/day, and more preferably from 500mg to 2g/day. A use according to claim 3, wherein the medicament comprises a relatively smaller amount of eicosapentaenoic acid than of γ-linolenic acid and/or dihomo-γ-linolenic acid. A use according to claim 5, wherein the medicament comprises a ratio of γ-linolenic acid and/or dihomo-γ-linolenic acid to eicosapentaenoic acid of from 20:1 to 3:1.

Inventors: HORROBIN DAVID FREDERICK, STEWART JOHN CHARLES, HORROBIN, DAVID FREDERICK,, STEWART, JOHN CHARLES
Applicants: SCOTIA HOLDINGS PLC
Application year: 1992
Main classification: A61K31
IPC codes: A61P9, C07C57, A61K31