JP4079453B2 - Complex linoleic acid to attenuate allergic responses - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates generally to methods for treating animals, including humans; in particular, to methods for treating animals to attenuate the allergic response of said animals. It is known that attenuating an animal's allergic response can be useful for various conditions such as asthma.
Background of the invention Allergy is a term commonly used to describe several types of hypersensitivity. Hypersensitivity is usually classified into four types by Roman numerals I-IV. Type I-III hypersensitivity is thought to be mediated by antibodies and type IV is thought to be mediated by lymphocytes.
Asthma, hay fever and eczema are thought to be type I hypersensitivity mediated by IgE antibodies and are present in a significant percentage of humans. There is general consensus that asthma mortality has increased over the last 10-15 years in many developed countries. This increase occurred despite an improved information base on diagnostic and therapeutic techniques and the development of new and more effective treatment modalities. Regarding this increase, statistical misinformation based on changes in asthma descriptions in international disease classifications ver. 8 to ver. 9, worsened environmental pollution, delayed medical assistance surveys, habit changes, patients and primary care Several interpretations have been proposed, including a lack of asthma education for both providers, beta agonist toxicity and drug therapy disapproval. It has been suggested that changes in our dietary habits contribute as well. The emphasis on reducing the intake of saturated fat and cholesterol has resulted in greater consumption of polyunsaturated fat, resulting in a doubling of the percentage of polyunsaturated linoleic acid in body fat. The only published results of investigating the effects of food ingredients on asthma show that dietary fish oil has a positive impact on asthma and other inflammatory diseases.
IgE-mediated hypersensitivity or type I hypersensitivity is also sometimes referred to as “fast-acting hypersensitivity” because it is recognized that the effect on antigen re-attack is within minutes. Depends on IgE antibody binding to receptors on mast cells and basophils. Cross-linking of bound antibody with antigen leads to degranulation of mast cells and basophils and together with mediators such as histamine that can cause harmful types of inflammatory reactions released from the granules. Suitable for the synthesis of biologically active substances.
It is not known with certainty what activates mast cells and basophils and degranulates and releases mediators from the granules. However, degranulation or activation results in the release of prostaglandins and leukotrienes that are thought to be responsible for clinical signs of allergic reactions. Some of the mediators act on other cells such as eosinophils, neutrophils, monocytes, and lymphocytes to produce other materials that attack or are toxic to the tissue, further May lead to clinical signs. Whatever the mechanism, the end result of a Type I hypersensitivity attack is very serious and can even be fatal.
Any method of attenuating an allergic response by preventing or inhibiting the adverse effects of type I hypersensitivity in an animal body and methods of treating or reducing such adverse effects will clearly be useful.
BRIEF SUMMARY OF THE INVENTION One of the objects of the present invention is to disclose a method for preventing or inhibiting type I or IgE mediated hypersensitivity effects in an animal body.
It is also an object of the present invention to disclose a method for treating or reducing the adverse effects caused by type I or IgE-mediated hypersensitivity in animals, including humans.
It is also an object of the present invention to disclose a method for preserving leukocytes using complex linoleic acid (CLA).
We administer safe and effective amounts of complex linoleic acid (CLA) 9,11-octadecanedioic acid and 10,12-octadecanedioic acid (CLA) or substances that are converted to CLA in the animal body. It has been found that the adverse effects of type I or IgE-mediated hypersensitivity can be suppressed or prevented in the animal body.
We have also found that these adverse effects can be beneficially treated or reduced by methods that include administering CLA to animals experiencing type I or IgE-mediated hypersensitivity adverse effects.
Finally, we have also found a way to preserve leukocytes using CLA.
It will be apparent to those skilled in the art that the above objects and other advantages can be achieved by carrying out the invention.
[Brief description of the drawings]
FIG. 1 shows a graph of CLA challenge response curve versus control.
FIG. 2 shows a graph of prostaglandin E2 release from guinea pig trachea treated with CLA and control.
Description of preferred embodiments In a preferred method of the invention for inhibiting or preventing adverse effects of type I or IgE mediated hypersensitivity in an animal, a safe and effective amount of complex linoleic acid (CLA) or Substances that are converted to CLA in the animal body are administered to animals including humans to suppress or prevent the onset of these adverse effects.
In a preferred method of the invention for beneficially treating or reducing the adverse effects of type I or IgE hypersensitivity in an animal body, a safe and effective amount of complex linoleic acid (CLA) or CLA converted in the animal body. Are administered to animals, including humans, experiencing such adverse effects.
It is not known by what mechanism type I hypersensitivity causes adverse effects in animals. However, it is conceivable that viral infection causes type I hypersensitivity or animals are susceptible to them, and that CLA is somehow interfered with the viral initiation response.
Since CLA is a natural food material and is relatively toxic, the amount that can be administered in the methods of the present invention is not critical as long as it is sufficiently effective. However, due to differences in size and sensitivity of animals, including humans, safe and effective amounts can vary considerably.
In a preferred method for preserving leukocytes, a safe and effective amount of CLA and leukocytes to be preserved are mixed. The amount of CLA used is usually about 0.1 to about 1% by weight of leukocytes.
In this specification, the term CLA refers to free complex linoleic acids such as 9,11-octadecanedioic acid and 10,12-octadecanedioic acid; active isomers of CLA; their non-toxic salts; their active esters and others Active chemical derivatives thereof; and mixtures thereof.
Free complex linoleic acid (CLA) was previously isolated from fried meat, according to YLHa, NK Grimm and MW Pariza, Carcinogenesis Vol. 8, No. 12, pp. 1881-1887 (1987) It is described as an anticancer substance. Since that time it has been found in several processed cheese products (YL Ha, NK Grimm and MW Pariza, J. Agric. Food Chem., Vol. 37, No. 1, pp. 75-81 (1987).
Free amino acid CLA can be produced by isomerizing linoleic acid. A non-toxic salt of free CLA acid can be produced by reacting free CLA acid with a non-toxic base. Natural CLA can also be produced from linoleic acid by the action of W ¹² -cis, W ¹¹ -trans isomerase from harmless microorganisms such as the rumen bacterium Butyrivibrio fibrisolvents . Harmless microorganisms in the intestinal tract of rats and other monogastric animals can also convert linoleic acid to CLA (SF Chin, W. Liu, K. Albright and MWPariza, 1992, FASEB J. 6: Abstract # 2665).
CLA can also be produced by using bacteria that synthesize CLA from linoleic acid. The resulting CLA is stably and easily extracted from the fermentation broth.
Another convenient way to supply CLA is by using milk that is originally rich in CLA. Milk can be produced by adding a free linoleic acid source and harmless bacteria to the milk and incubating the mixture at 37 ° C. for about 1 hour or until linoleic acid is converted to CLA.
CLA obtained by carrying out the described production process comprises one or more of 9,11-octadecanedioic acid and / or 10,12-octadecanedioic acid and their active isomers. It may be free or chemically bonded through an ester bond. CLA is heat stable and can be used as is or dried and powdered. CLA is easily converted to a non-toxic salt such as sodium or potassium salt by reacting chemically equivalent free acid with alkali hydroxide at a pH of about 8-9.
Theoretically, eight possible geometric isomers of 9,11- and 10,12-octadecanedioic acid (c9, c11; c9, t11; t9, c11; t9, t11; c10, c12; c10, t12; t10, c12 and t10, t12) are produced from the isomerization of c9, c12-octadecanedioic acid. As a result of isomerization, only four sets of isomers (c9, c11; c9, t11; t10, c12 and c10, c12) are expected. However, of the four isomers, during the autooxidation or alkaline isomerization of c9, c12-linoleic acid due to the coplanar properties of five atoms around the conjugated double bond and the spatial collision of the resonance groups In addition, the c9, t11- and t10, c12- isomers are preferentially produced. The contributions of the remaining two sets of c, c-isomers are small.
The relatively large distribution of the t, t-isomer of 9,11-octadecanedioic acid or 10,12-octadecanedioic acid is favored thermodynamically during extended processing times or long aging times. , T11- or t10, c12-apparently due to further stabilization of the geometric isomer. Also, 9,11- or 10,12-octadecanedioic acid formed preferentially during the isomerization of linoleic acid geometric isomers (t9, t12-, c9, t12- and t9, c12-octadecanedioic acid) The t, t-isomer of can affect the final isomer ratio or final CLA content in the sample.
Linoleic acid geometric isomers also affect the distribution of minor contribution isomers (9,11- and 10,12-c, c-isomers, t9, c11- and c11, t12-octadecanedioic acid). give. The 11,13-isomer can be prepared from c9, c12-octadecanedioic acid or as a minor product from its isomeric form during processing.
The method of the present invention can take several aspects. In one embodiment, the administered CLA is simply added to the animal or human food. In another embodiment, CLA can be administered to an animal in a pharmaceutical or veterinary form containing a safe and effective amount of CLA. In a third embodiment, the animal can be given a safe amount of a substance such as free linoleic acid that can be formed in situ into CLA in the animal or human body.
CLA and its non-toxic derivatives, such as non-toxic salts, are added to animal food or formed in situ, as well as pharmaceutical or veterinary medicines such as tablets, capsules, solutions or emulsions Can be administered to animals or humans in the form of a pharmaceutical composition. The exact amount to be administered will, of course, depend on the form of CLA used, the method of administration and the nature of the animal or human condition. Generally, the amount of CLA and its non-toxic salts used as pharmaceuticals ranges from about 1 ppm to about 10,000 ppm of CLA in animal or human food. However, since CLA is relatively non-toxic and is a common component of human food (including human milk), the upper limit of the amount used is not important. As an additive, the amount added to a conventional animal diet or human food can range from 0.01 to 2.0% by weight or more of the animal or human food.
Preferred pharmaceutical and veterinary compositions of CLA contain a non-toxic sodium or potassium salt of CLA in combination with a pharmaceutical diluent. When the composition is a solution or suspension intended for external or oral administration, the diluent is one or more liquid diluents. When the product is a tablet or capsule, conventional diluents can be used. When the composition is a solution or suspension intended for parenteral administration, the preferred diluent is sterile injectable water USP.
The following examples further illustrate the invention.
Example 1
Guinea pigs have been found to be a useful model for preclinical studies of substances used in the treatment of asthma (MG Compos and MK Church, Clinical and Experimental Allergy, 1992, Volume 22, pages 665-666). Therefore, the effect of dietary CLA (complex linoleic acid) on allergic responses was measured using a guinea pig model.
Guinea pigs were given 0.25% CLA or control food for 2 weeks and immunized with ovalbumin in the second and third weeks for hyperimmunization. We examined how guinea pigs were euthanized, trachea collected and used in a perfusion model system, and when CLA was given, allergen-induced tracheal contraction. (The perfusion model system consists of connecting the excised tissue to a polygraph and measuring the contraction due to the offset of the polygraph.) The guinea pig trachea fed the CLA is more in the perfusion system than the guinea pig trachea fed the control food. Was also found to be stable (ie, there was less need for correction to return the tissue to baseline stress during equilibration). When allergens were injected into the guinea pig trachea, less than 1 hour after equilibration, less tracheal contraction was observed in the tissues of animals that received CLA. Reduced tracheal contraction corresponds to increased prostaglandin E2 release as measured by enzyme-linked immunosorbent assay. These results are shown in FIGS. Histamine release was not affected by food.
Example 2
The number of white blood cells (WBC) in animals given CLA was 3.5 × 10 ⁶ / ml ±, compared to 2.4 × 10 ⁶ /ml±0.3 (mean +/− SEM) in control animals. Increased to 0.6. Thus, providing CLA can be used as a method to increase the number of WBCs in mammals.
Example 3
CLA (1 wt%) was added to isolated human leukocytes stored at 39 ° C. It was found that the viability of white blood cells, which lasts normally for about 12 hours, was increased to 24 hours by adding CLA. This beneficial life of white blood cells helps to avoid the waste of white blood cells.
It will be readily apparent to those skilled in the art that many modifications and variations can be made without departing from the spirit and scope of the invention. Therefore, the present invention is limited only by the claims.

Claims (5)

A preventive or therapeutic agent for type I or IgE-mediated hypersensitivity and its adverse effects , comprising : c9, c11-octadecanedioic acid, c9, t11-octadecanedioic acid, t9, c11-octadecanedioic acid, t9, t11-octadecane Containing conjugated linoleic acid (CLA) selected from the group consisting of diacid, c10, c12-octadecanedioic acid, c10, t12-octadecanedioic acid, t10, c12-octadecanedioic acid and t10, t12-octadecanedioic acid , the hypersensitivity, asthma, hay fever, der Ru said prophylactic or therapeutic agents that are caused by eczema or viral infection. The prophylactic or therapeutic agent according to claim 1 , wherein the hypersensitivity is caused by asthma . A preventive or therapeutic agent for adverse effects of type I or IgE-mediated hypersensitivity caused by asthma, comprising c9, c11-octadecanedioic acid, c9, t11-octadecanedioic acid, t9, c11-octadecanedioic acid, t9 , T11-octadecanedioic acid, c10, c12-octadecanedioic acid, c10, t12-octadecanedioic acid, t10, c12-octadecanedioic acid and conjugated linoleic acid selected from the group consisting of t10, t12-octadecanedioic acid The preventive or therapeutic agent, wherein the adverse effect is mediated by activation of mast cells and basophils . A method for preserving leukocytes, wherein 0.1 to about 1% by weight of c9, c11-octadecanedioic acid, c9, t11-octadecanedioic acid, t9, c11-octadecanedioic acid, t9, t11-octadecanedi is added to the leukocytes. CLA, selected from the group consisting of acid, c10, c12-octadecanedioic acid, c10, t12-octadecanedioic acid, t10, c12-octadecanedioic acid and t10, t12-octadecanedioic acid is added. . c9, c11-octadecanedioic acid, c9, t11-octadecanedioic acid, t9, c11-octadecanedioic acid, t9, t11-octadecanedioic acid, c10, c12-octadecanedioic acid, c10, t12-octadecanedioic acid, t10, A drug for increasing the number of leukocytes in a mammal containing conjugated linoleic acid selected from the group consisting of c12-octadecanedioic acid and t10, t12-octadecanedioic acid .

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