WO2003055476A1

WO2003055476A1 - Use of succinic acid and salts thereof for inhibiting platelet aggregation

Info

Publication number: WO2003055476A1
Application number: PCT/RU2001/000566
Authority: WO
Inventors: Igor A. Pomytkin; Pavel V. Verteletsky
Original assignee: Individual
Current assignee: Individual
Priority date: 2001-12-25
Filing date: 2001-12-25
Publication date: 2003-07-10
Anticipated expiration: 2004-06-25
Also published as: AU2002243120A1

Abstract

This invention relates to the use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of medicaments or nutritional supplements useful for inhibiting platelet aggregation in a mammal and for the treatment or prophylaxis of thrombosis. Further, this invention relates to methods for inhibiting platelet aggregation in mammals in need thereof, which methods comprise administering to said mammals an effective amounts of succinic acid or a pharmaceutically acceptable salt thereof.

Description

USE OF SUCCINIC ACID AND SALTS THEREOF FOR INHIBITING PLATELET AGGREGATION

FIELD OF THE INVENTION

The present invention relates to medicaments and nutritional supplements for the treatment or prophylaxis of thrombosis. More particularly, the invention provides methods for inhibiting platelet aggregation in mammals in need thereof.

BACKGROUND OF THE INVENTION

Succinic acid is the physiologically occurring substrate of succinate dehydrogenase in mammals that play a role in cellular respiration and energy metabolism.

The importance of platelets in the pathophysiology of cardiovascular diseases (CVD) is well established. Thrombus formation involves a complex interaction of aggregated platelets and activated coagulation factors with the damaged vessel wall. Circulating platelets are nonadherent to normal endothelium or to each other, but when the endothelum of a vessel is broken, the platelets adhere to exposed subendothelial collagen, secret the platelet contents, and aggregate to form a thrombus in response to stimuli generated in endothelia of damaged blood vessels. These proaggregatory stimuli include thrombin, collagen, and agents such as ADP, which is secreted from platelet storage granules, and thromboxane A2 (TxA2 ), which is synthesized by the platelets during activation. Increased platelet activity and an increased tendency for thrombus formation occur in atherosclerosis, heart disease, hypertension, and diabetes.

Therapeutic treatments to alter thrombus formation have focused mainly on inhibition of the platelet aggregation. The most widely accepted agent for this purpose is acetylsalicylic acid (ASA), or aspirin.

The finding that succinic acid and salts thereof are suitable for inhibiting platelet aggregation is new and unexpected and not inferable by those skilled in the art. Our own experiments have shown that platelet aggregation was inhibited in animals treated by succinic acid. Preferably, succinic acid proves to be suitable for inhibiting platelet aggregation induced by platelet integrin receptor agonists such as collagen.

It is an object of the present invention to provide the use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of medicament or nutritional supplement useful for inhibiting platelet aggregation in a mammal.

It is an object of the present invention to provide a method of inhibiting platelet aggregation in a mammal, comprising administering to the mammal in need thereof an effective amount of succinic acid or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method of inhibiting platelet aggregation in a mammal, which comprises administering to a mammal in need thereof an effective amount of succinic acid or a pharmaceutically acceptable salt thereof. Succinic acid has the chemical formula given below:

HOOCCH₂CH₂COOH

The pharmaceutically acceptable salt of the succinic acid is prepared by known methods from organic and inorganic bases. Such bases include, but are not limited to, nontoxic alkali metal and akaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide and nontoxic organic bases, such as triethylamine, butylamine, diethanolamine, triethanolamine, and choline base. The succinic acid or a pharmaceutically acceptable salt thereof is preferably administered orally in the method of this invention. The succinic acid or a pharmaceutically acceptable salt thereof may also be administered by a variety of other routes such as parenterally (e.g. intravenously, subcutaneously, intramuscularly), topically or rectally. Preferably, the succinic acid or pharmaceutically acceptable salt thereof is administered for a period of 1 day or longer; more preferably for a period of 3 to 7 days. The effective amount of succinic acid or a pharmaceutically acceptable salt thereof for use in the method of this invention is preferably from 1 milligram to 150 milligrams per day per kilogram of body weight of the mammalian subject.

Also, the present invention relates to use succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament or a nutritional supplement useful for inhibiting platelet aggregation in a mammal. Preferably, the mammal is a human. The medicaments or nutritional supplements of the invention are prepared by known procedures using well-known ingredients. In making the medicaments or nutritional supplements, the active ingredients will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, tablet, paper or other container. When the carrier serves as a diluent, it may be a solid, semisolid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The nutritional supplements can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules. The medicaments can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, aerosoles, suppositories, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable carriers, diluents, and excipients include lactose, dextrose, sorbitol, mannitol, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, stearic acid, and mineral oil. The medicaments or nutritional supplements can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Preferably the medicament or nutritional supplement of the invention is in a dosage form and can be administrated orally, parenterally, topically, or rectally.

The medicament or nutritional supplement of the invention can also be used advantageously in combination with other platelet aggregation inhibitors, particularly with aspirin.

The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.

EXAMPLE 1

This example shows that disodium succinate inhibits ADP-induced platelet aggregation in rats.

Animals. Male Wistar rats 8-10 weeks of age 220-250 g of body weight were used. The rats were housed at the temperature of 18 ± 21°C. The rats were fed on a stock laboratory diet and allowed water ad libitum.

Platelet aggregation test.

As used in the following examples, platelet aggregations were performed on a PICA platelet aggregometer (Chrono-Log, Havertown P.A. USA) with platelet rich plasma (PRP) prepared from rat venous blood anticoagulated with 3.8% sodium citrate according to the turbidometric method of Born, G.N.R., "Aggregation of

Blood Platelets by Adenosine Diphosphate and Its Reversal," Nature 194:927-929,

1962. The platelet count in PRP was 5 x 10 ⁸ /ml. The aggregating agents were ADP (Sigma) and collagen reagent (Sigma). The change in aggregation response was assessed by degree of inhibition as represented by alteration of the aggregation curve.

Treatment.

Rats were divided into three groups and treated for the 14 days with daily i.p. injections of saline (control, n=10), disodium succinate (30 mg/kg body weight, n=10), or disodium succinate (45 mg/kg body weight, n=10). Platelet aggregation with ADP (10 μmol/L final concentration) as an inductor was measured at the 15th day since treating beginning. Data are presented in Table 1 in % as mean ±SD (n=10).

Table 1. Platelet aggregation with ADP as an inductor.

*Differs significantly from control (P<0.01 )

EXAMPLE 2 This example shows that disodium succinate inhibits collagen-induced platelet aggregation in rats.

Animals.

Rats were used as described in Example 1 of the invention.

Platelet aggregation test.

Platelet aggregation was tested as described in Example 1 of the invention Treatment.

Rats were divided into three groups and treated for the 7 days with daily i.p. injections of saline (control, n=10), disodium succinate (22 mg/kg body weight, n=10), disodium succinate (36 mg/kg body weight, n=10),or disodium succinate (72 mg/kg body weight, n=10). Platelet aggregation with collagen (4 μg/ml final concentration) as an inductor was measured at the 8th day since treating beginning. Data are presented in Table 2 in % as mean ±SD (n=10). Table 2. Platelet aggregation with collagen as an inductor.

*Differs significantly from control (P<0.01)

EXAMPLE 3 Tablets with 100 mg of succinic acid.

Succinic acid (250 g) is triturated uniformly with 750 g of microcrystalline cellulose. After the mixture is screened, 250 g of starch (Starch 1500/Colorcon), 732.5 g of lactose, 15 g of magnesium stearate and 2.5 g of highly dispersed silica are admixed and the mixture is pressed into tablets weighing 800.0 mg. One tablets contains 100 mg of succinic acid.

Claims

WE CLAIM:

1. The use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for inhibiting platelet aggregation in a mammal.

2. The use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of a nutritional supplement useful for inhibiting platelet aggregation in a mammal.

3. A method of inhibiting platelet aggregation, which comprises administering to a mammal in need thereof an effective amount of succinic acid or a pharmaceutically acceptable salt thereof.

4. The method as claimed in Claim 3 wherein the effective amount is 1 mg to 150 mg per kilogram of body weight per day.