MXPA01007008A - Method for reducing blood cholesterol and/or blood triglycerides - Google Patents

Method for reducing blood cholesterol and/or blood triglycerides

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Publication number
MXPA01007008A
MXPA01007008A MXPA/A/2001/007008A MXPA01007008A MXPA01007008A MX PA01007008 A MXPA01007008 A MX PA01007008A MX PA01007008 A MXPA01007008 A MX PA01007008A MX PA01007008 A MXPA01007008 A MX PA01007008A
Authority
MX
Mexico
Prior art keywords
dosage unit
butylhydroquinone
tert
blood
triglycerides
Prior art date
Application number
MXPA/A/2001/007008A
Other languages
Spanish (es)
Inventor
William Lawrence Stone
Andreas M Papas
Original Assignee
Eastman Chemicals Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eastman Chemicals Company filed Critical Eastman Chemicals Company
Publication of MXPA01007008A publication Critical patent/MXPA01007008A/en

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Abstract

Blood cholesterol and/or blood triglycerides are reduced in a mammalian subject by administering an effective amount of tert-butylhydroquinone or a salt thereof. The mammalian subject is preferably human. Additionally, a preparation of tert-butylhydroquinone in dosage unit form is provided to reduce blood cholesterol and/or blood triglycerides. The preparation is advantageously designed for oral administration.

Description

METHOD FOR REDUCING CHOLESTEROL IN BLOOD AND / OR TRIGLYCERIDES IN BLOOD DESCRIPTION OF THE INVENTION The invention relates to the health of the human body, and more particularly to a healthy body by reducing blood cholesterol and / or triglycerides in blood. TBHQ (tert-butylhydroquinone, C? 0H? 4O2, molecular weight 166.22, CAS No. 1948-33-0) is a white to light pale brown crystalline phenolic antioxidant. Other major commercial phenolic antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and propylgalate. TBHQ is approved in the United States for food use in up to 200 mg / kg of fat or oil in the food (21 cfr 172.185). TBHQ works mainly as a food antioxidant by inhibiting the oxidation of fatty acids. Such oxidation leads to the production of objectionable end products such as peroxides, aldehydes and ketones that impart offensive odor and taste to the food. The TBHQ has other uses too. TBHQ is approved for use in cosmetics in up to 0.1% of the product and as a polymerization inhibitor of polyunsaturated polyesters including those in contact with food (Cosmetics Ingredients Review, 1986). In . Stone, et al. , J. National Cancer Inst. , 89: 1006-1014, 1997, phenolic antioxidants have been reported as possibly reducing the risk of some forms of cancer, especially of the digestive system. However, it is suspected that high levels of BHA cause carcinomas in the anterior stomach in rodents and it is suspected that high levels of BHT cause cancers in the liver. TBHQ has not shown such carcinogenicity. Thus, a study was started to determine if TBHQ reduces the risk of colon cancer. The results of this study prompted the discovery of the present invention, which has major health implications. It has been unexpectedly found that tert-butylhydroquinone (TBHQ) reduces blood cholesterol and triglycerides in the blood. The effect of which is to significantly reduce the risk of heart disease. Thus, the present invention is a method for reducing blood cholesterol and / or triglycerides in blood in a mammalian subject. The method comprises the step of administering an effective amount of tert-butylhydroquinone (or a salt thereof) such that the level of blood cholesterol and / or triglycerides in blood is reduced. Another aspect of the present invention is a preparation of THBQ in unit dosage form that can be administered to a subject to obtain a reduction of blood cholesterol and / or blood triglycerides. The preparation has from about 1 mg to about 150 mg of at least one compound selected from the group consisting of tert-butylhydroquinone and pharmacologically acceptable salts thereof, and a pharmaceutical diluent. Preferably, the unit dosage form is adapted for oral administration. In this regard, the unit dosage form may be a tablet, capsule, food or beverage portion, or a liquid. A study was conducted that focused on the question of whether tert-butylhydroquinone (THBQ) reduces the risk of colon cancer. The results of that study prompted the unexpected discovery that TBHQ when administered to a subject at a particular dosage level, has an effect that reduces blood cholesterol and / or triglycerides in the blood in the subject. This unexpected efficiency of reducing blood cholesterol and / or triglycerides in the blood of the present invention has major health implications. The evidence is overwhelming that there is a direct association between high cholesterol and triglyceride levels and a significant increase in the risk of heart disease. In a proposed mechanism, cholesterol and triglycerides play a significant role in heart disease. Low density lipoprotein LDL comprises mainly cholesterol, cholesteryl ester and triglyceride. LDL undergoes oxidation and causes macrophage cells to associate with immune function to absorb it. Excess production of oxidized LDL results in foam cells that are macrophages loaded with oxidized LDL. Foam cells have very low mobility and, with that, tend to accumulate on the wall of the artery and initiate atherogenesis by attracting leukocytes and platelets. This association is further confirmed by a report by G. Levine which indicates that the reduction of blood cholesterol in humans by the use of effective drugs reduces heart disease and mortality significantly (G. Levine, et al., England Journal of Medicine, 332: 512-521, 1995). The present invention provides a method for reducing blood cholesterol and / or triglycerides in blood in a mammalian subject comprising the step of administering an effective amount of tert-butylhydroquinone (or a salt thereof) such that the level of blood cholesterol and / or triglycerides in blood is reduced. The mammalian subject is preferably human. The TBHQ is preferably administered in a unit dosage form having from about 1 mg to about 150 mg of a TBHQ compound or pharmacologically acceptable salts thereof and a pharmaceutical diluent. More preferably, the dosage unit would be from about 3 mg to about 150 mg. Even more preferably, the dosage unit would be from about 15 mg to about 150 mg. For example, the dose of TBHQ of 25.9 mg / kg of diet is equivalent to 25.9 ng / 4490 kcal of diet. Assuming that this is extrapolated directly to humans who consume 3,000 kcal / day, the daily intake would be 17.3 mg / day. Since it is known that there is a broad effective range for compounds that have biological activity, doses up to five times smaller and doses up to five times higher are probably effective. The dosage unit of TBHQ would typically be administered once a day up to 3 times a day. The dosage unit is prepared by combining TBHQ or its salt with non-toxic pharmaceutical diluents, which are well known in the art. The diluents may include solids or liquids, such as corn starch, lactose, sucrose, peanut oil, olive oil, sesame oil and water. The diluent may also include foods fortified with TBHQ such as drinks, snacks or other foods. Other diluents that can be used include lipophilic antioxidants, fish oils, or other edible oils. The concentration of TBHQ in the diluent should exceed 200 ppm by weight per weight. The dosage unit can be incorporated into a number of formulations of different use such as tablets or capsules containing TBHQ; fortified foods to supply TBHQ (drinks, snacks, other foods); and nutritional supplements fortified with TBHQ such as capsules of mineral vitamins, antioxidant capsules, tablets or other formulations (powder, etc.). TBHQ can be used alone or in formulations or in combination with other synthetic and natural antioxidants, such as BHA, BHT, propylgalate, vitamin E, vitamin C, tocopherols, tocotrienols, beta-carotenes, other carotenoids, phytochemicals lipoic acid, isoflavones, Coenzyme Q10, etc. When TBHQ is combined with a different antioxidant, the combined antioxidants can result in an additive or synergistic effect. In a preferred embodiment, the invention is provided as a kit for orally administering a preparation in unit do form to obtain the effect that reduces blood cholesterol and / or triglycerides in blood. The kit comprises a do unit of about 1 mg to about 150 mg of at least one compound selected from the group consisting of tert-butylhydroquinone and pharmacologically acceptable salts thereof, a pharmaceutical diluent; and instructions to orally administer the preparation. A description of the experimental work leading to the determination that TBHQ has an effect that reduces blood cholesterol and / or triglycerides in blood is described below. Experiment 1 was conducted with the purpose of studying the potential influence of TBHQ on oxidative stress in the colon of rats. Experiment 1 unexpectedly found that diet TBHQ reduces plasma levels of cholesterol and triglycerides. Experiment 2 was conducted, therefore, to determine whether: (1) the results of experiment 1, with respect to plasma lipids, was reproducible; (2) TBHQ influences plasma lipids in a dose-dependent manner; and (3) BHT, an antioxidant similar to TBHQ, also decreases plasma lipid levels. Experiment 1 Rats (12 / group) were fed a high-fat semisynthetic diet (containing 15% corn oil stripped of tocopherol plus 1% cholesterol) containing all the necessary nutrients as described by the National Research Council (NRC) , 1978). The treatments evaluated consisted of the semisynthetic diet plus the following test agents: (1) control (without test agent); (2) alpha-tocopherol, 0.156 mmoles / kg of diet equivalent to 100 IU / kg; (3) gamma-tocopherol 0.156 mmoles / kg; (4) TBHQ, 0.156 mmoles / kg equivalent to 25.9 mg / kg of diet. The rats were fed these diet treatments for 12 weeks and then half of the rats in each group were switched to lower diets in fats containing 5% corn oil and no cholesterol. Because the rats consumed 11% more of the low-fat diet to maintain the same caloric intake, the nutrient levels and test agents were adjusted accordingly. Blood samples were collected after 24 weeks of the test in tubes containing sodium EDTA as an anticoagulant. The plasma separated from these blood samples was analyzed by cholesterol and triglycerides using standard commercial equipment obtained from Sigma. Very unexpectedly, this study showed that TBHQ reduces cholesterol and triglycerides in the blood, especially in rats fed a high-fat diet. Specifically, rats fed a high fat control diet without TBHQ had cholesterol levels of 79 mg / 100 ml, while the group fed the same diet but supplemented with TBHQ cholesterol was 44.6 mg / 100 ml. The corresponding triglyceride values were 157.2 mg / 100 ml and 39.1 mg / 100 ml, respectively. The effect of TBHQ was lower or absent in the low-fat diet. This is probably due to the fact that the absorption of TBHQ is improved by fat. In addition, TBHQ can affect the enzymatic action that is stimulated only by high fat in the diet. In this regard, the high fat diet of the rat in this example, contains a caloric percentage derived from fat comparable to that of the typical human diet. As such, the low fat diet of rat has limited relevance to human nutrition and its effects on plasma lipids. Experiment 2 Sixty Fisher-334 inbred rats (12 / diet group) were fed a high-fat, semi-synthetic diet containing 15% corn oil, 1% cholesterol, torula yeast, sucrose, and complete mixture of vitamins and minerals with selenium and methionine supplement (since the torula yeast is low in this amino acid). The rats were divided into diet groups as follows: (1) TBHQ at two doses (25 mg / kg diet or 200 mg / kg diet) (2) BHT at two doses (25 mg / kg diet or 200 mg / kg diet) (3) Control without TBHQ or BHT Plasma cholesterol and plasma triglycerides were measured (using a standard enzymatic test) in triplicate for each rat at two-week intervals. The results are presented in Table 1 below. Table 1 * The entries in the column that have different letters indicate that the entries are statistically different Cp < 0.05). The data in Table 1 support the following conclusions: (1) BHT increases the plasma levels of cholesterol and triglycerides in a rat model; (2) TBHQ does not increase cholesterol or triglycerides in plasma, and has a tendency to decrease the levels of these lipids; and (3) TBHQ appears to be a better synthetic antioxidant than BHT from a cardiovascular disease standpoint. While the study was carried out with rats, the findings are applied to humans because the rat has been shown to be a good model for many conditions related to lipid metabolism and health. See, for example, Stone, et al. , Annals of Nutrition and Metabolism, 30: 94-103, 1986, for a discussion of the use of a rat model to study the influence of dietary factors on plasma composition and alterations in lipoprotein levels. See also Mahley, et al. , PNAS USA, 76: 1746-1750, 1979, where the rat was used as a model in which to study the metabolism of human lipoproteins. Finally, see Mahley et al. , J. Lipid Research, 18: 314-324, 1997, which states that rats are particularly resistant to the development of hypercholesterolemia. In general, the effects of diet or drug factors that influence plasma cholesterol or triglyceride levels are higher in humans than in rats. This suggests that the effects of TBHQ on the decrease of cholesterol and / or triglycerides in plasma would be higher in humans than in rats, because rats are a strict species. The invention has been described in detail with particular reference to the preferred embodiments thereof, but it will be understood that variations and modifications may be made within the spirit and scope of the invention.

Claims (13)

  1. CLAIMS 1. A method for reducing blood cholesterol and / or triglycerides in blood in a mammalian subject characterized in that it comprises the step of: administering an effective amount of tert-butylhydroquinone or a salt thereof such that the blood cholesterol level and / or triglycerides in blood is reduced.
  2. 2. The method according to claim 1, characterized in that the tert-butylhydroquinone or the salt is administered together with synergistic compounds selected from the group consisting of BHA, BHT, propylgalate, vitamin E, vitamin C, tocopherols, tocotrienols, beta- carotenes, other carotenoids, lipoic acid from phytochemicals, isoflavones, coenzyme Q10.
  3. 3. The method of compliance with the claim 1, characterized in that a pharmaceutical diluent is used with tert-butylhydroquinone.
  4. 4. The method according to claim 3, characterized in that the concentration of tert-butylhydroquinone in the diluent exceeds 200 ppm w / w.
  5. 5. The method according to claim 1, characterized in that the amount of tert-butylhydroquinone is from about 1 mg to about 150 mg.
  6. 6. The method according to claim 1, characterized in that the mammalian subject is a human.
  7. 7. The method according to claim 1, characterized in that the form of the tert-butylhydroquinone is one of a tablet, capsule, food, liquid or beverage.
  8. 8. A preparation in the form of dosage unit adapted for administration to obtain an effect that reduces blood cholesterol and / or triglycerides in blood, characterized in that it comprises, per dosage unit, from about 1 mg to about 150 mg of at least one compound selected from the group consisting of tert-butylhydroquinone and pharmacologically acceptable salts thereof, and a pharmaceutical diluent. The preparation according to claim 8, characterized in that the dosage unit includes synergistic compounds selected from the group consisting of BHA, BHT, propylgalate, vitamin E, vitamin C, tocopherols, tocotrienols, beta-carotenes, other carotenoids, acid lipoic of phytochemicals, isoflavones, coenzyme Q10. The preparation according to claim 8, characterized in that the dosage unit form is adapted for oral administration. The preparation according to claim 10, characterized in that the dosage unit form is a tablet. The preparation according to claim 10, characterized in that the dosage unit form is a capsule. The preparation according to claim 10, characterized in that the dosage unit form is a food portion. 1 . The preparation according to claim 10, characterized in that the dosage unit form is a beverage portion. 15. The preparation according to claim 10, characterized in that the dosage unit form is a liquid. 16. The preparation according to claim 8, characterized in that the concentration of tert-butylhydroquinone or its salt in the diluent exceeds 200 ppm w / w. 17. A device for orally administering a preparation in the form of a dosage unit for obtaining an effect that reduces blood cholesterol and / or triglycerides in blood, characterized in that it comprises: a dosage unit of approximately 1 mg to approximately 100 mg of a minus a compound selected from the group consisting of tert-butylhydroquinone and pharmacologically acceptable salts thereof; a pharmaceutical diluent; and instructions to orally administer the preparation. The equipment according to claim 17, characterized in that the dosage unit includes synergistic compounds selected from the group consisting of BHA, BHT, propylgalate, vitamin E, vitamin C, tocopherols, tocotrienols, beta-carotenes, other carotenoids, acid lipoic of phytochemicals, isoflavones, coenzyme Q10. The equipment according to claim 17, characterized in that the dosage unit form is a tablet. 20. The equipment according to claim 17, characterized in that the dosage unit form is a capsule. 21. The equipment in accordance with the claim 17, characterized in that the dosage unit form is a food portion. 22. The equipment according to claim 17, characterized in that the dosage unit form is a portion of a beverage. 23. The equipment according to claim 17, characterized in that the concentration of tert-butylhydroquinone or its salt in the diluent exceeds 200 ppm w / w.
MXPA/A/2001/007008A 1999-01-11 2001-07-10 Method for reducing blood cholesterol and/or blood triglycerides MXPA01007008A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US09228092 1999-01-11

Publications (1)

Publication Number Publication Date
MXPA01007008A true MXPA01007008A (en) 2002-03-05

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