This invention relates to a method of treating hypertension and reducing serum lipase activity by dietary supplementation with conjugated linoleic acid. The method comprises administering a safe and effective amount of conjugated linoleic acid to a human. The conjugated linoleic acid may be provided in the form of a free fatty acid or chemical derivatives thereof in a pill, or as a component of a prepared food product.

Description of the Invention

FIELD OF THE INVENTION

This invention relates to a method of treating hypertension and reducing serum lipase activity by dietary supplementation with conjugated linoleic acid.

BACKGROUND

1. Hypertension

Antihypertensive therapy has been available for more than 40 years to reduce blood pressure and to prevent morbidity and mortality related to the hypertensive state. Hypertension is generally defined as an abnormally increased blood pressure. It is clinically recognized as an elevation of systolic arterial blood pressure of 150 mm Hg or greater and/or an elevation of diastolic arterial blood pressure of 90 mm Hg or higher. Certain risk factors (e.g., hypercholesterolemia, diabetes, smoking, and a familial history of vascular disease) in conjunction with hypertension may predispose individuals to arteriosclerosis and consequent cardiovascular morbidity and morality.

Data which demonstrates that there is a linear relationship between elevated blood pressure and adverse cardiovascular events has led to the identification of an at risk group with "mild" or stage 1 hypertension. Mild hypertension is defined as a systolic blood pressure of 140-159 mmHg or diastolic blood pressure of 90-99 mmHg. These levels move the definition of hypertension towards the populations mean, effectively doubling the prevalence of hypertension in the U.S. Langer, Clin. and Exper. Hypertension, 17(7):1127-44 (1995). Of the 25% of the U.S. population affected by hypertension under this definition, greater than 60% have mild hypertension.

Prospective observational studies indicate that a prolonged difference of 5-6 mmHg in usual diastolic blood pressure (DBP) is related to differences of approximately 35-40% in the risk of stroke and 20-25% in the risk of cardiovascular disease. Hennekens, Am. J. Medicine, 104(6A):50S-53S (1998). Therefore, it appears that treatment of mild hypertension with drugs would be indicated in a majority of cases. However, the literature indicates that doubt remains as to whether the benefits of utilizing expensive diuretics and n-blockers to treat mild hypertension outweighs the risk, and whether lifestyle changes in physical activity and diet are as effective as drugs and potentially safer. Black, JAMA, 270(6):757-59 (1993). These differences are highlighted by the fact that the Joint National Committee guidelines advises routine treatment of patients with a sustained elevated blood pressure of over 140/90 mmHg, while the British Hypertension Society guidelines advise treatment at 160/100 mmHg. Ransay et al., Am. J. Hypertension 11(6 pt 2):79S-88S (1998). Such concerns may contribute to a hesitancy on the part of some physicians to prescribe drugs to treat mild hypertension.

Several types of anti-hypertensive drugs are known. .beta.-blockers are antagonists of the .beta.-adrenoreceptor and include such drugs as acebutalol, propranolol and timolol. Calcium antagonists including phenylalkylamines, benzothiazepines and dihydropyridines have been shown to reduce blood pressure. Angiotensin Converting Enzyme (ACE) inhibitors which have been used to treat hypertension include captopril and enalapril. Diuretic agents have also become a mainstay in anti-hypertensive therapy, and include thiazides and closely related phthalimidine derivatives (e.g., chlorthalidone).

In general, however, drug therapy for hypertension is reserved for those individuals whose blood pressure cannot be maintained in an acceptable range by non-pharmacological means. Each of the above described methods depends on prescription medications. Of the non-pharmacological treatments for hypertension, weight reduction and salt (sodium chloride) restriction have been considered to be the most successful. Restricting dietary salt, although of somewhat limited and unpredictable effect, can in some cases reduce diastolic blood pressure to an extent comparable to that achieved by treatment with some of the pharmacologic agents.

2. Serum Lipase Activity

Serum lipase is mainly derived from the pancreatic acinar cells, where it is synthesized and stored in granules. The majority of lipase is secreted into the ductal system of the pancreas, with less than 1% diffusing from the acinar cells into the lymphatics and capillaries where it reached the general circulation system. High levels of serum lipase activity are used as a clinical indicator of pancreatitis as described in Tietz et al., Clin. Chem. 39(5):746-56 (1993), incorporated herein by reference. Reduction of lipase activity may be of use in treating the disease hyperlipidaemia, which is reviewed in Thompson, Brit. Med. Bull. 46(4):986-1004 (1994), incorporated herein by reference. Inhibition of pancreatic lipase prevents hydrolysis of triglycerides, thereby reducing triglyceride absorption and the amount of free fatty acids and monoglycerides in the intestine. Tonstad et al., Eur. J. Clin. Pharmacol. 46:405-10 (1994), incorporated herein by reference.

What is needed is a safe, cheap and effective substance for reducing blood pressure in patients with mild hypertension and for reducing serum lipase activity. Preferably the substance should be naturally occurring and should be able to be made part of a healthy every day diet.

SUMMARY OF THE INVENTION

An important challenge in modern medicine is to devise safe and effective methods of treating mild hypertension. This invention relates to methods of treating hypertension and reducing serum lipase activity by dietary supplementation with conjugated linoleic acid.

In some embodiments of the present invention, a method of treating hypertension in a subject is provided, comprising a) providing a subject and a composition comprising a safe and effective amount conjugated linoleic acid; and b) administering the conjugated linoleic acid composition to the subject under conditions such that blood pressure of the subject is reduced. The present invention is not limited to any particular conjugated linoleic acid composition. Indeed, a variety of conjugated linoleic acid compositions are contemplated including, but not limited to, pills, capsules, tablets, food products, esters (e.g., methyl and ethyl esters), and triglycerides. In other embodiments, the CLA composition includes a mixture of the eight possible isomers cis-9, trans-11; cis-9, cis-11; trans-9, cis-11; trans-9, trans-11; cis-10, cis-12; cis-10, trans-12; trans-10, cis-12, and trans-10, trans-12 octadecadienoic acids. In other embodiments, the mixture is a more purified mixture consisting of predominantly the cis-9, trans-11 and trans-10, cis-12 isomers, or simply the cis-9, trans-11 or trans-10, cis-12 isomer alone.

The present invention is not limited to any particular dose of CLA. Indeed, the administration of a variety of amounts of CLA is contemplated. In some embodiments, a safe and effective amount of CLA is administered. In other embodiments, a daily dosage of between 0.1 and 12 grams, preferably about 4.5 grams is administered. In some embodiments, the CLA is administered in a single dose. In other embodiments, the CLA is administered in 2, 3, 4, or more doses throughout a 24 hour period.

The present invention is not limited to any particular subject. Indeed a variety of subjects are contemplated, including, but not limited to, animals, mammals, humans, cows, pigs, goats, horses, dogs, cats, and sheep. In some embodiments, the subject is diagnosed as suffering from hypertension. In other embodiments, the subject suffers from mild hypertension. In still further embodiments, the CLA composition is administered prophylactically to a subject with one or more of the following risk factors for developing hypertension (e.g., hypercholesterolemia, diabetes, smoking, family history of diabetes).

In still further embodiments of the present invention, a method of reducing serum lipase activity in a subject is provided, comprising a) providing a subject and a composition comprising a safe and effective amount conjugated linoleic acid; and b) administering the conjugated linoleic acid composition to the subject under conditions such that serum lipase activity of the subject is reduced. The present invention is not limited to any particular conjugated linoleic acid composition. Indeed, a variety of conjugated linoleic acid compositions are contemplated including, but not limited to, pills, capsules, tablets, food products, esters (e.g., methyl and ethyl esters), and triglycerides. In other embodiments, the CLA composition includes a mixture of the eight possible isomers cis-9, trans-11; cis-9, cis-11; trans-9, cis-11; trans-9, trans-11; cis-10, cis-12; cis-10, trans-12; trans-10, cis-12, and trans-10, trans-12 octadecadienoic acids. In other embodiments, the mixture is a more purified mixture consisting of predominantly the cis-9, trans-11 and trans-10, cis-12 isomers, or simply the cis-9, trans-11 or trans-10, cis-12 isomer alone.

The present invention is not limited to any particular dose of CLA. Indeed, the administration of a variety of amounts of CLA is contemplated. In some embodiments, a safe and effective amount of CLA is administered. In other embodiments, a daily dosage of between 0.1 and 12 grams, preferably about 4.5 grams is administered. In some embodiments, the CLA is administered in a single dose. In other embodiments, the CLA is administered in 2, 3, 4, or more doses throughout a 24 hour period.

The present invention is not limited to any particular subject. Indeed a variety of subjects are contemplated, including, but not limited to, animals, mammals, humans, cows, pigs, goats, horses, dogs, cats, and sheep. In some embodiments, the subject is diagnosed as having elevated serum lipase activity as compared to population norms or as having pancreatitis. In other embodiments, the CLA composition is administered prophylactically to a subject at risk of developing hyperlipidemia.

Dietary supplementation with CLA presents an effective treatment for hypertension or the reduction of serum lipase activity, and may be used alone or in combination with other treatment regimes.

DESCRIPTION OF THE INVENTION

Conjugated linoleic acid (CLA, also known as octadecadienoic acid), has been identified in meat and dairy products by Chin et al., J. Food Comp. Anal. 5: 185-197 (1992). CLA is a collective term for positional and geometric isomers of linoleic acid with conjugated double bonds at carbon atoms 10 and 12 or 9 and 11 in the various cis-trans conformations. CLA differs from ordinary linoleic acid which has double bonds at carbon atoms 9 and 12.

CLA has several unique properties when used as a food additive or dietary supplement. U.S. Pat. No. 5,554,646 (herein incorporated by reference) discloses the use of CLA to reduce the percentage of fat in relation to total body mass. U.S. Pat. No. 5,428,072 (herein incorporated by reference) discloses the use of CLA for increasing the efficiency of feed conversion in animals, which results in more non-fat tissue being formed in relation to weight gain. U.S. Pat. Nos. 5,430,066 and 5,585,400 (herein incorporated by reference) disclose the use of CLA to prevent weight loss due to immune stimulation and to treat immune hypersensitivity. CLA also has anticarcinogenic activity, as shown in Belury, Nut. Rev. 53(4): 83-9 (1995). Therefore, CLA may be used for increasing or maintaining weight gain in animals.

The mechanism by which CLA mediates these effects is not known, although some biochemical models involving fat partitioning and shifts in fatty acid precursor mediated synthesis of end product prostaglandins and leukotrienes have been proposed. It is known that CLA is taken up in triglycerides and phospholipids, and deposited in fat stores. The precise structure and distribution of these lipids is not known. Nor is it known whether there is a competitive incorporation amongst two or more isomers, or a preferential deposition of certain isomers in some lipid species over others.

The CLA of the present invention is preferably a mixture of one or all of the isomers of octadecadienoic acid including the cis-9, trans-11; cis-9, cis-11; trans-9, cis-11; trans-9, trans-11; cis-10, cis-12; cis-10, trans-12; trans-10, cis-12; and trans-10, trans-12 isomers. The rearrangement of the double bonds of linoleic acid to conjugated positions has been shown to occur during treatment with catalysts such as nickel or alkali at high temperatures, and during auto oxidation. Theoretically, eight possible geometric isomers of 9,11 and 10,12 octadecadienoic acid (c9,c11; c9,t11; t9,c11; t9,t11; c10,c12; c10,t12; t10,c12 and t10,t12) would form from the isomerization of c9,c12-octadecadienoic acid.

A general mechanism for the isomerization of linoleic acid was described by J. C. Cowan in JAOCS 72:492-99 (1950). It is believed that the double bond is polarized by the result of a collision with an activating catalyst. The polarized carbon atom and its adjoining carbon are then free to rotate and the forces are such as to make the deficient carbon atom essentially planar. When the system then moves to relieve these forces set up as a result of the collision, both cis and trans isomers are formed. The formation of certain isomers of CLA is thermodynamically favored. This is due to the co-planar characteristics of the five carbon atoms around the conjugated double bond and a spatial conflict of the resonance radical.

The relatively higher distribution of 9,11 and 10,12 isomers apparently results from the further stabilization of the c9, t11 or t10, c12 geometric isomers. The present invention is not limited to any particular mechanism of action. Indeed, an understanding of the mechanism of action is not needed in order to practice the present invention. However, it is contemplated that the cis-9,trans-11 and trans-10, cis-12 isomers are thought to have the most biological activity. Therefore, these isomers may be used in a purified form or CLA compositions which contain high ratios of these isomers may be utilized. Most preferably, the CLA composition used in the present method is CLA 80 and is available from Natural Nutrition, Norway. Methods for manufacturing CLA useful in the present invention are provided in Example 2 (low temperature nonaqueous alkali isomerization) and an alternative method of manufacturing another preferred CLA composition is provided in Example 3 (isomerization with alkali alcoholate in the presence of a monohydric low molecular weight alcohol). Both methods provide for the production of CLA predominantly comprising the c9,t11- and t10,c12- isomers, with low levels of 8,10-,11,13- and trans-trans isomers.

In the preferred embodiment of the present invention, a safe and effective amount of CLA is orally administered to a human to treat mild hypertension (e.g., reduce blood pressure) or to reduce serum lipase activity. The use of CLA for these indications is desirable because CLA is a non-toxic, naturally occurring food ingredient. CLA is not a drug and may be consumed as a part of a normal diet and finds use as a part of everyday nutrition.

The data described below in Example 1 indicates that dietary supplementation with CLA results in a decrease in both systolic and diastolic blood pressure in humans with borderline mild hypertension. Studies have shown that decreases of from 5-6 mmHg in diastolic blood pressure are related to differences of approximately 35-40% in the risk of stroke and 20-25% in the risk of cardiovascular disease. Hennekens, Am. J. Medicine, 104(6A):50S-53S (1998). The effect of reducing blood pressure is known to be linear. Langer, Clin. and Exper. Hypertension, 17(7):1127-44 (1995). Therefore, the reduction of blood pressure due to the dietary administration of CLA will have a positive impact in the reduction of stroke and cardiovascular disease.

The safe and effective amount of CLA is also sufficient to cause a decrease in serum lipase activity as compared to the controls (See, Example 2). This will positively effect overall lipid metabolism, resulting in decreased triglyceride adsorption and a decrease in the amount of free fatty acids and monoglycerides in the intestine. This effect will also be useful in the treatment of hyperlipidaemia in overweight patients, and in the reduction of metabolized plasmid lipids such as free fatty acids and monoglycerides in otherwise healthy patients, leading to improved cardiovascular health. The present invention is not limited to any particular mechanism. Indeed, an understanding of the mechanism is not required to practice the present invention. However, it is contemplated that triglycerides containing CLA isomers will be especially desirable for regulating serum lipase activity. The lipase will hydrolyze the triglyceride to release the CLA isomers as free fatty acids, which results in down regulation of lipase activity by a feed-back loop mechanism. As the free CLA isomers are further metabolized, thereby reducing their effective concentration, lipase activity will increase, causing the release of more CLA isomers from the triglyceride.

A safe and effective amount is that amount CLA that, when ingested in purified form or as food supplement results in a reduction blood pressure or serum lipase activity without impairing or interfering with proper nutrition. About 0.1 to 20 grams of CLA may be administered per day, preferably about 1 to 10 grams per day may be administered and most preferably about 4.5 grams per day may be administered. In general, the amount of CLA administered is not critical as long as it is enough to be therapeutically effective. The amounts of CLA deemed therapeutically effective are those which result in a measurable decrease in blood pressure or serum lipase activity when administered over a three month period or longer.

In a typical regimen, an individual will begin the hypertension treatment program or serum lipase activity reduction program by ingesting up to several grams (e.g., 0.1 to 5 grams) of CLA with each meal, and monitoring blood pressure over a period of several months. The CLA may be provided in the form of a pill or as a component of a prepared food product. Once the desired blood pressure or serum lipase activity has been attained, a proper maintenance level can be found by gradually reducing the dose and continuing to monitor blood pressure to assure there is no increase.

It is anticipated that there will be some variation in effectiveness because of differences among individuals in parameters such as body weight, basal metabolism, exercise, and other aspects of the diet. The individual should begin with the preferred 4.5 gram dose for an initial two month period, and then, if no reduction in blood pressure or serum lipase activity is experienced, gradually increase the CLA dose up to about 10-20 grams per day.

Derivatives of CLA may also be utilized in the present invention. The CLA may be free or bound through ester linkages. For example, the CLA may be provided in the form of an oil containing CLA triglycerides (See, e.g., U.S. application Ser. Nos. 09/160,416 and 09/270,941, each incorporated herein by reference). The triglycerides may be partially or wholly comprised of CLA attached to a glycerol backbone. Furthermore, the CLA may be in the form of a non-toxic salt, such as a potassium or sodium salt, which is formed by reacting chemically equivalent amounts of the free acids with an alkali hydroxide at a pH of about 8 to 9. The CLA may also be used in liquid, gel or powdered forms.

The preferred method of administration is oral. The CLA may be formulated with suitable carriers such as starch, sucrose or lactose in tablets, capsules, solutions and emulsions. The tablet or capsule of the present invention may be coated with an enteric coating which dissolves at a pH of about 6.0 to 7.0. A suitable enteric coating which dissolves in the small intestine but not in the stomach is cellulose acetate phthalate.

A safe and effective amount of CLA may also be provided as a supplement in various prepared food products. For the purposes of this application, prepared food product means any natural, processed, diet or non-diet food product to which CLA has been added. The CLA may be added in the form of free fatty acids or as an oil containing partial or whole triglycerides of CLA. Therefore, CLA may be directly incorporated into many prepared diet food products, including, but not limited to diet drinks, diet bars and prepared frozen meals. Furthermore, CLA may be incorporated into many prepared non-diet products, including, but not limited to candy, snack products such as chips, prepared meat products, milk, cheese, yogurt and any other fat or oil containing foods.

CLA is also susceptible to oxidation. Therefore it is desirable to package CLA for human use with suitable antioxidants such as lecithin, tocopherols, ascorbate, ascorbyl palmitate, or spice extracts such as rosemary extract.
 

Claim 1 of 5 Claims

1. A method of treating hypertension in humans comprising: a) providing a hypertensive human patient in need of hypertension treatment and a composition comprising a safe and effective amount conjugated linoleic acid for treating hypertension; and b) administering said conjugated linoleic acid composition to said human patient so that blood pressure of said human patient is reduced.
 

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