MXPA99000772A - Method for treating gastrointestinal damage - Google Patents

Abstract

A method of preventing, countering or reducing chronic gastrointestinal disorders or NSAID-induced gastrointestinal damage in a subject suffering from such ailments. The method comprises hyperimmunizing an egg-producing and/or milk-producing animal and administering an effective amount of hyperimmunized egg product, hyperimmunized milk product or mixtures thereof to the subject.

Description

TITLE METHOD FOR TREATING GASTROINTESTINAL DAMAGE FIELD OF THE INVENTION This invention relates to a method for treating gastrointestinal damage. More particularly, this invention relates to a method for preventing, combating or reducing chronic gastrointestinal disorders as well as gastrointestinal damage induced by anti-inflammatory, non-spheroidal drugs, using a natural food product.

BACKGROUND OF THE INVENTION Anti-inflammatory, non-spheroidal drugs, generally referred to as NSAIDs, have strong anti-inflammatory, antipyretic and analgesic properties, and are an effective treatment for inflammatory diseases, such as arthritis. rheumatoid, osteoarthritis, spondylitis, ankylosing, bursitis and tendonitis. This large class of drugs includes drugs such as: indomethacin, aspirin, naproxen, ibuprofen and diclofenac. • All these compounds give a REF: 29203 major relief to more than 50 million individuals suffering from inflammatory diseases in the United States. In addition to its effectiveness against inflammatory diseases related to joints, NSAIDs can prevent or reduce the risk of other diseases that can be associated with inflammation, such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. However, patients treated with NSAIDs on a long-term basis often experience serious side effects. Up to 50% of patients receiving therapeutic doses, conventional NSAIDs undergo gastrointestinal damage, and approximately 20% should discontinue use due to these side effects. Side effects include anorexia, nausea and abdominal pain in usual doses. At higher doses, side effects include individual or multiple ulcerations of the upper gastrointestinal tract that may result in hemorrhage. In some cases, for example when perforations occur, these side effects can result in fatalities. In the United States, it is believed that 6,000 deaths per year are caused by gastrointestinal damage related to NSAIDs.

In this way, doctors or physicians who prescribe anti-inflammatory, non-spheroidal drugs for their patients face a serious dilemma. They can use NSAIDs to reduce joint pain and increase the mobility of their patients (for example arthritis), but as a result of this type of drug therapy, the risk is that their patients may develop intestinal ulcers. The causes of intestinal ulceration produced by NSAIDs are multifactorial. For example, due to the way in which drugs circulate in the body, they often concentrate in the bile. The high concentrations of NSAIDs in the bile can cause irritation by direct contact and result in damage to the intestinal mucosal surface. Also, changes in inflammatory mediators in the intestinal mucosa and lumen, alterations in blood flow and bacterial development have been implicated. Regimens of therapy that inhibit gastrointestinal damage induced by NSAIDs include antacids (acid neutralization), and cimetidine, ranitidine, and famotidine (inhibition of acid secretion). Although high doses of steroids and antibiotics have provided some protection from the damage of intestinal mucosa NSAIDs, at present there is no screening drug for the prevention of enteritis induced by NSAIDs. Some gastrointestinal disorders not induced by NSAIDs include those that are chronic, such as Inflammatory Bowel Disease. The Inflammatory Bowel Disease is a progressive, serious condition that affects the gastrointestinal tract and causes a significant decrease in the quality of life for those who suffer from this flp disease. This condition presents itself in the forms of Crohn's disease and ulcerative colitis. The symptoms are malabsorption, diarrhea, abdominal pain, anemia, weight loss and injuries in the intestinal wall. These diseases can also lead to the formation of fistula (deep ulcers of the intestine or rectum) and intestinal blockage. In the United States alone, these diseases affect an estimated 50,000 to 1,000,000 patients per year. 20 There are a few drugs or other modes of treatment available that effectively treat or prevent gastrointestinal, chronic disorders. Currently, the medical management of Inflammatory Bowel Disease and related conditions includes a broad spectrum of antibiotics, steroids, and immune modulation therapies such as cyclosporin. In addition, drugs such as aminosalicylates (eg, mesalamine and olsalazine) may be prescribed, but NSAIDs are contraindicated because they exacerbate gastrointestinal inflammation in patients with Inflammatory Bowel Disease. Patients who fail to respond to drug treatment may be candidates for surgery. However, surgery is a dangerous procedure that causes greater discomfort, great cost, and usually an extended stay in the hospital. In addition, surgery always involves the risk of mortality. Unfortunately, for many victims, medical management does not completely eliminate their chronic gastrointestinal disorders. Accordingly, there is a need for a simple, effective treatment that can alleviate and prevent gastrointestinal damage induced by NSAIDs and chronic gastrointestinal disorders, without the complication of side effects.

BRIEF DESCRIPTION OF THE INVENTION The invention is a method for preventing, combating or reducing chronic gastrointestinal disorders or gastrointestinal damage induced by NSAIDs in a subject comprising: A. hyperimmunising an animal that produces eggs or an animal that produces milk; and B. administering to the subject an effective amount of the product of a hyperimmunized egg, the hyperinnated milk product, or combinations thereof.

In another embodiment, the invention is a method for preventing, combating or reducing inflammation in a subject comprising simultaneously administering an effective amount of an NSAID to the subject and an effective amount of a product selected from the group consisting of the product of a hyperimmunized egg, the hyperimmunized milk product, and combinations thereof. In yet another embodiment, the invention is a method of preventing, combating or reducing chronic gastrointestinal disorders or gastrointestinal damage induced by NSAIDs in a subject, comprising separately administering an effective amount of a hyperimmunized egg product and a product. of milk hyperimmunized to the subject.

DESCRIPTION OF THE INVENTION The invention relates to a method for significantly reducing or preventing the formation of ulcerations in the gastrointestinal tract by using a natural food product, i.e., hyperimmunized egg and / or hyperimmunized milk. The following definitions apply in all respects: Definitions The term "hyperimmunized egg product" means a whole egg or products derived therefrom, obtained from animals that produce eggs maintained in a hyperimmune state. The term "hyperimmunized milk product" means milk or products derived therefrom, obtained from milk producing animals maintained in a hyperimmune state. The term "processed hyperimmunized egg product" means a product of. hyperimmunized egg that is in a form acceptable for administration to a subject. The term "processed hyperimmunized milk product" means a hyperimmunized milk product that is in a form acceptable for administration to a subject.

The term "inflammation" means the involvement of a complex series of events that They include dilatation of blood vessels together with increased permeability and blood flow, fluid exudation, including plasma proteins, change in cell mediator levels, and migration of leukocytes into the inflammatory focus. Inflammation of the bowel may also be associated with sloughing of mucous membranes, ulceration, and perforation. The term "chronic" means a long duration, continuous, constant, prolonged or persistent. The term "gastrointestinal disorder" means the alteration or disorder of regular or normal physical function or vitality of the gastrointestinal system. Some examples include Crohn's disease and ulcerative colitis, among others. The term "gastrointestinal damage" means the deterioration or impairment of the normal or normal physical function or vitality of the gastrointestinal system.

Some examples include individual or multiple ulcerations, injuries and hemorrhage, among others. The term "administer" means any method for providing a subject with a substance, which includes orally, intranasally, parenterally (intravenously, intramuscularly or subcutaneously) or rectally. The term "subject" means any living animal that has a gastrointestinal system and is subject to gastrointestinal disorders and / or damage, including humans and other animals. The method particularly relates to the use of a hyperimmunized egg or hyperimmunized milk, each of which are natural food products. Such as, although the risk of allergic reaction is always present, these natural food products can be used to treat chronic gastrointestinal disorders as well as gastrointestinal disorders induced by NSAIDs, without the fear of side effects. For purposes of this invention, the treatment includes prevention, combat and reduction. Some symptoms of gastrointestinal disorders and gastrointestinal damage induced by NSAIDs that can be treated by the method of this invention are: inflammatory foci, ulceration, hemorrhage and perforations. NSAIDs are generally used for the treatment of inflammatory diseases related to joints such as reu atoid arthritis, osteoarthritis, ankylosing spondylitis, bursitis, and tendonitis, and may also be effective in the treatment of other diseases that may be associated with inflammation. , such as Alzheimer's disease, multiple sclerosis and Parkinson's disease. The method of this invention increases the ability of victims of such inflammatory diseases to utilize NSAIDs with less than one relation to the side effects of gastrointestinal damage of this category of the drug. If a subject will be placed on a regimen of treatment with the NSAIDs, that subject can be pretreated by the method of this invention for some time before taking the NSAIDs. In addition, the method of this invention can be undertaken concurrently with treatment with NSAIDs to prevent, combat or reduce the side effects of gastrointestinal damage of such treatment. An added benefit of the use of this method is that those who use the product of a hyperimmunized egg and / or milk are able to be administered or treated, with higher doses of the NSAIDs to produce a greater anti-inflammatory effect.

A subject suffering from disorders induced by NSAIDs and other gastrointestinal disorders and damages can be treated by any of the following procedures: administration of a hyperimmunized egg product alone; administration of a hyperimmunized milk product alone; or administration of both a hyperimmunized egg product and a milk product hyperimmunized to the subject.

Hyperimmunized Egg Product The hyperimmunized egg product can be produced by any animal that produces eggs. It is preferred that the animal be a member of the Aves class. Within the Aves class, domesticated poultry are preferred, but other members of this class, such as turkeys, ducks and geese, are a suitable source of hyperimmunized egg product. When such egg-producing animals are brought to a specific state of immunization by means of, for example, periodic administrations of antigen reinforcement, the animals will produce eggs which, when consumed by a subject, will have beneficial properties in the treatment of induced damage. for NSAIDs and chronic gastrointestinal disorders in that subject.

The beneficial properties of the egg are not produced by all the animals that produce eggs that are simply immunized. Induction of immune sensitivity alone (such as chickens immunized against poultry diseases) is insufficient to cause the beneficial properties mentioned above in eggs. It is only in the hyperimmune state that the eggs produced have the desired effect. This special state is achieved preferentially by administering periodic reinforcements to the animal that produces eggs with doses of sufficiently high antigens. The preferred dose range should be equal to or greater than 50% of the dose needed to cause a primary immune response in the animal that produces eggs. Having knowledge of the requirement for the development and maintenance of a hyperimmune state, it is within the experience of the technique to vary the amount of antigen administered, depending on the gender of the animal that produces eggs and the breed used, in order to keep the animal in the hyperimmune state. Alternate modes of hyperimmunization of animals that produce eggs can be used in place of antigenic vaccines and include the use of genetic vaccines. In particular, any DNA construct (in -general consisting of a promoter region and an antigen coding sequence) will cause the release of antibodies. Genetic vaccines consist of vectors encoding antigens, pure or simple DNA fragments, extracomosomal ring DNA, DNA-RNA antigens, DNA-protein conjugates, DNA-liposome conjugates, DNA and viral DNA expression libraries and bacterial supplied to produce an immune response. Methods of DNA delivery include particle bombardment, direct injection, viral vectors, liposomes and jet injection, among others. When these delivery methods are applied, much smaller quantities are necessary and generally result in more persistent antigen production. When such genetic processes are used, the preferred method for introducing DNA into birds is through the intramuscular injection of DNA into the chest muscle. The following is an example of the procedure used to bring an animal that produces eggs to an increased state of immunity and administer the hyperimmunized egg product to the subject: 1. Select one or more antigens. 2. To produce an immune response in the animal that produces eggs through primary immunization. 3. Administer antigen booster vaccines of appropriate dosage to induce and maintain the hyperimmune state. 4. Collect and process the eggs to produce a hyperimmunized egg product from the egg-producing animal maintained in the hyperimmune state. 5. Administer the product of the hyperimmunized egg to the subject.

Step 1: Any antigen or combination of antigens can be used. The antigens can be bacterial, viral, protozoan, fungal, cellular or other substances to which the immune system of an animal that produces eggs will respond. The critical point in this step is that the antigen (s) must be able to induce immune and hyperinfluent states in the egg-producing animal. A preferred vaccine is a mixture of polyvalent bacterial antigens, referred to as Series 100 vaccine (S-100).

The bacteria included in the S-100 vaccine are listed in Table 1 of Example 1. This vaccine has been previously described in U.S. Patent Nos. 5,106,618 and 5,215,746, both assigned to Stolle Research and Development Corporation. Another preferred vaccine for use is the EB-100E vaccine, the details of which are also described in Example 1.

Step 2: The vaccine can be either a killed or killed vaccine and can be administered by any method that produces an immune response. It is preferred that the immunization be carried out by administering the antigens through intramuscular injection. The preferred muscle for injection in a bird is the chest muscle. The dose is preferably 0.5-5 milligrams of the antigen vaccine (s). Other methods of administration that can be used include intravenous injection, intraperitoneal injection, rectal suppository or oral administration. When DNA techniques are used for the hyperimmunization process, much smaller amounts are required, generally 1-100 micrograms. It can be determined whether the vaccine has elicited an immune response in the animal that produces eggs through a number of methods known to those having experience in the immunology art. Examples of these include enzyme-linked immunosorbent assays (ELISAs), tests for the presence of antibodies for the stimulation of antigens, and tests designed to evaluate the ability of immune cells of the host to respond to the antigen. In general, the appearance of the egg antibodies after immunization with the vaccine is indicative of an immune response. The minimum dose of antigen needed to induce an immune response depends on the vaccination procedure used, including the type of antigen (s) used (s) as well as the type of animal that produces eggs used as the host.

Step 3: The hyperimmune state is preferentially induced and maintained by repeated booster administrations of an appropriate dose at fixed time intervals. The time intervals are preferably two week intervals over a period of six months. However, it is essential that booster administrations do not lead to immune tolerance.

It is possible to use other methods or combination of procedures for maintenance of hyperimmunization, such as, for example, intramuscular injection for primary immunization and intravenous injection for booster injections. Additional methods include simultaneously administering the microencapsulated and liquid antigen, or intramuscular injection for primary immunization, and booster doses by oral administration or parenteral administration by microencapsulation means. Several combinations of primary immunization and hyperimmunization are. known to those skilled in the art.

Step 4: Hyperimmunized eggs can be processed for administration to the subject in a variety of ways. These include the therapeutic administration of the hyperimmunized egg product itself (e.g., capsules) and incorporation of the hyperimmunized egg product into foods. It is preferred that the egg product be incorporated into a food product. A preferred method for preparing the egg to be incorporated into a food product involves drying the egg in an egg powder. Although several methods are known for drying the eggs, spray drying is a preferred method. A temperature below 60 ° C (140 ° F) is preferably used. The samples are monitored for moisture content during the drying process to obtain a final product that has any desired consistency. Dry egg powder can be used in beverages in the form of, for example, protein powders, powder reconstruction beverages, protein supplements and any other nutritional product associated with athletes. In addition, egg powder can be used in baking mixes, powder bars, candies, cookies, etc. Other examples of egg processing include making an omelet or an egg omelette, cooking a lot or watering the egg, baking the egg, or, if desired, the egg can be eaten raw. Finally, it is generally known in the art that the fractions of the yolk and / or the clear contain the agent or agents responsible for the beneficial properties observed and referred to above. Those of ordinary skill in the art would clearly recognize that additional separation could provide more powerful fractions.

Step 5: In the case of the treatment of gastrointestinal, chronic disorders, the hyperimmunized egg product should be administered to the subject in an amount that is immunologically effective in the treatment of the particular disorder. In cases where the subject is taken or prepared to take the NSAIDs for the treatment of inflammation, the procedure is different. For those who have not yet started treatment with NSAIDs, it is preferred that those subjects be previously treated for 6-8 weeks with the hyperimmunized egg product. After treatment with the hyperimmunized egg product, the hyperimmunized egg product must continue to be administered to the subject along with the administration of the NSAID to treat the inflammation. Daily doses are preferred. For those who take the NSAIDs, pretreatment with, or concurrent administration of, the hyperimmunized egg product will reduce the incidence of gastrointestinal damage. As such, higher doses of NSAIDs can be administered without fear of side effects of increased gastrointestinal damage. The duration and intensity of the treatment will depend on the particular condition and the progress of the condition of the subject. The hyperimmunized egg product can be provided in any amount that treats or prevents damage and chronic gastrointestinal disorders or induced by NSAIDs. For example, in some cases, daily amounts of one or more complete hyperimmunized eggs, or hyperimmunized egg products containing the equivalent of one or more complete hyperimmunized eggs, may be administered to the subject, depending on the particular circumstance of the gastrointestinal damage or disorder. The hyperimmunized egg product produced by the hyperimmunization of a bird with certain antigens, is effective in the treatment of chronic gastrointestinal disorders as well as gastrointestinal damage induced by NSAIDs. The preferred antigen mixture injected into the birds does not contain specific antigens that are known to cause gastrointestinal damage. Therefore, it is surprising that treatment with the egg product obtained from birds immunized against a mixed antigen vaccine is effective in reducing and preventing chronic gastrointestinal damage and induced by NSAIDs when administered to a subject.

Hyperimmunized Milk Product The source of milk includes any animal that produces milk. In a preferred embodiment, any bovine animal is used. Dairy cows are preferred, but any other cattle or animals that produce milk in commercially acceptable amounts, such as goats, sheep, buffalo or llamas, can also be used. This hyperimmunized milk product can be used in the prevention, combat or reduction of chronic gastrointestinal disorders and induced by NSAIDs in a subject. When such milk producing animals are brought to a specific state of immunization by means of, for example, periodic booster administrations of antigens, the milk producing animal will produce milk which, when administered to a subject, will have beneficial properties in the treatment of chronic gastrointestinal damage and induced by NSAIDs in that subject. All alternative modes and modes of immunization and administration described for animals that produce eggs in the production of the hyperimmunized egg product can be used in animals that produce milk to produce hyperimmunized milk and deliver hyperimmunized milk to a subject. The following is an example of the procedures used to bring an animal that produces milk to a state of immunity and administer the hyperimmunized milk product to the subject. 1. Select from one or more antigens. 2. Produce an immune response in animal 5 that produces milk by primary immunization. 3. Administer antigen-reinforcing vaccines of appropriate doses to induce and maintain the hyperimmune state. 10 4. Collect and process milk to produce a ^ P hyperimmunized milk product of the animal that produces milk maintained in the hyperimmune state. 5. Administer the hyperimmunized milk to the subject.

Step 1: This step is done in the same way as ^? is described in step 1 above for the hyperimmunized egg. The only difference is that the antigen or combination of antigens must produce a response in an animal that produces milk.

Step 2: The vaccine can be either a killed or killed vaccine and can be administered by any method that produces an immune response. In one method, a vaccine composed of an antigen derived from 1 x 106 to 1 x 1020, preferably 108 to 1010, more preferably 2 x 108, killed bacterial cells is administered by intramuscular injection. However, other methods such as intravenous injection, intraperitoneal injection, rectal suppository or oral administration can be used. In cases where DNA techniques are used for the hyperimmunization process, much smaller amounts are required, preferably 1-100 micrograms. It can be determined if the vaccine has produced an immune response in the animal that produces milk through a number of methods known to those having experience in the immunology art. Examples of these include enzyme-linked immunosorbent assays (ELISA), tests for the presence of antibodies for the stimulation of antigens, and tests designed to evaluate the ability of the host immune cells to respond to the antigen. In general, the appearance of milk antibodies after immunization with the vaccine is indicative of an immune response. The minimum dose of antigen needed to induce an immune response depends on the vaccination procedure used, including the type of antigen (s) used (s) as well as the type of animal that produces milk used as a host.

Step 3: The hyperimmune state is preferentially induced and maintained by repeated booster administrations of an appropriate dose at fixed time intervals. The time intervals are preferably two week intervals over a period of six months. It is essential that booster administrations do not lead to immune tolerance. In "a preferred embodiment, hyperimmunization of the milk producing animals can be achieved by the individual administration of an icroencapsulated vaccine, prepared as described in U.S. Patent No. 5,352,462." The advantage of the controlled release form of hyperimmunization is that constant exposure to the antigen ensures that the animal remains in the hyperimmune state.It is possible to use other procedures for the maintenance of hyperimmunization or a combination of procedures, such as intramuscular injection for primary immunization and intravenous injection for booster injections. Additional methods include simultaneously administering a microencapsulated and liquid antigen, or intramuscular injection for primary immunization, and booster doses by oral administration or parenteral administration by microencapsulation means. Primary immunization and hyperimmunization are known to those skilled in the art.

Step 4: Hyperimmunized milk can be collected by conventional methods, and then pasteurized. After pasteurization, the fat is removed by normal procedures and the milk is spray dried by conventional spray drying procedures known in the art. Fluid milk can also be used as concentrated milk products or a fraction of the milk, such as the fraction of the acid whey, which has the beneficial properties. Fat-free milk can be incorporated into any food product. For example, puddings or yogurt can be prepared with the hyperimmunized milk product. In addition, when the fat-free milk is treated with acid at about room temperature (bringing the pH of the milk to about 4.2-4.6) and the casein is separated after the precipitation thereof, the fraction of the supernatant of the acidic serum It can also be added to syrups, ice cream mixes, sweets, drinks, cattle feed or similar.

Step 5: In the case of the treatment of chronic gastrointestinal disorders, the hyperimmunized milk product should be administered to the subject in an amount that is immunologically effective in the treatment of the particular disorder. In cases where the subject is taken or prepared to take the NSAIDs for the treatment of inflammation, the procedure is different. For those who have not yet started treatment with the NSAIDs, it is preferred that these subjects be previously treated for 6-8 weeks with the hyperimmunized milk product. After pre-treatment with the hyperimmunized milk product, the hyperimmunized milk product should be continued to be administered to the subject along with the administration of the NSAID to treat the inflammation. Daily doses are preferred. For those who take the NSAIDs, prior treatment with, or concurrent administration of, the hyperimmunized milk product will reduce incidents of gastrointestinal damage. As such, it will be possible for higher doses of NSAIDs to be administered without the fear of side effects of increased gastrointestinal damage. The duration and intensity of the treatment will depend on the particular condition and the progress of the condition of the subject. The hyperimmunized milk product can be provided in any amount that treats or prevents the damage and gastrointestinal disorders chronic and induced by the NSAIDs. For example, in some cases, daily amounts of 1 mL to 10 L may be administered to the subject based on the fluid milk depending on the particular circumstance of the gastrointestinal damage or disorder.

Both hyperinlated egg and hyperimmunized milk In another embodiment, the subject can be administered a combination of both a hyperimmunized egg product and a hyperimmunized milk product. The hyperimmunized egg product and the hyperimmunized milk product are prepared by methods such as those described above. In particular, each product is processed in a form suitable for administration in accordance with the methods outlined above.

With respect to the administration of both the hyperimmunized egg product and the hyperimmunized milk product, in one embodiment the hyperimmunized egg product and the hyperimmunized milk product can be administered separately to the subject. In an alternative embodiment, the subject can be administered a composition comprising an effective amount of the hyperimmunized egg product and the hyperimmunized milk product. Administration to the subject should be carried out in an amount that is effective for the treatment of gastrointestinal disorder or gastrointestinal damage induced by the NSAIDs. It is preferred that a quantity of the hyperimmunized egg product processed, or mixed, be administered with an equal amount of the hyperimmunized milk product before administration. However, if, for example, better treatment and prevention is observed when the subject is administered a higher dose of the hyperimmunized egg administered, or mixed, with a lower dose of hyperimmunized milk, or vice versa, then such unequal doses are appropriate for the patient. treatment and prevention, and should be administered in those amounts. In addition, it is believed that there is a possible synergistic effect of the hyperimmunized egg and milk product, combined. As such, the administration should be adjusted accordingly. Those of skill in the art are familiar with the determination of the amounts of doses that would treat and would better prevent the disorder or damage of interest. The hyperimmunized egg product and the hyperimmunized milk product can each be processed in any way, as described above, for administration to the subject. The administration of both hyperimmunized egg and milk products is can provide in any amount that treats or prevents the damage or chronic gastrointestinal disorder or induced by the NSAIDs. The treatment is administered as described above for the hyperimmunized egg alone and the hyperimmunized milk alone. The duration and intensity of the treatment will depend on the particular condition and the progress of the condition of the subject. The advantageous properties of this invention can be observed by reference to the following examples illustrating the invention.

EXAMPLES EXAMPLE 1 This example illustrates the cytoprotective effect of the hyperimmunized egg on the gastrointestinal damage induced by the indomethacin of the NSAID.

Preparation of S-100 Vaccine A bacterial culture containing the spectrum of bacteria shown in Table 1 below, such as that obtained from the American Type Culture Collection, was reconstituted with 15 mL of media and incubated overnight at 37 ° C. . Once a good development was obtained, approximately one-half of the bacterial suspension was used to inoculate one liter of broth with the inoculum that is incubated at 37 ° C. After a good development in the culture was visible, the bacterial cells were collected by centrifugation of the suspension for 20 minutes to remove the media. The obtained bacterial pellet was resuspended in sterile saline and the bacterial sample was centrifuged three times to wash the cell media. After the third wash with sterile saline, the bacterial pellet was resuspended in a small amount of double distilled water.

The media-free bacterial suspension was killed by placing the suspension in a glass flask in a bath with water at 80 ° C overnight. The viability of the broth culture was verified with a small amount of the exterminated bacteria, incubated at 37 ° C for five days and verified daily for development to certify that the bacteria had been exterminated. The killed bacteria were lyophilized until dried. The dried bacteria were then mixed with sterile saline at a concentration of 2.2 x 10 8 bacterial cells / mL of saline (0.1 optical density read at 660 nm). The bacteria contained in the S-100 vaccine are listed in Table 1 below.

TABLE 1 List of bacteria of S-100 Escherichia coli Escherichia coli (Aerobacter) Klebsiella pneumoniae Pseudomonas aeruginosa Salmonella typhimurium Salmonella dysenteriae Salmonella enteriditis Salmonella epidermis Salmonella simulans Streptococcus pyogenes, type 1 Streptococcus pyogenes, type 3 Streptococcus pyogenes, type 5 Streptococcus pyogenes, type 8 Streptococcus pyogenes, type 12 Streptococcus pyogenes, type 14 Streptococcus pyogenes, type 18 Streptococcus pyogenes, type 22 Pseudomonas vulgaris Streptococcus agalactiae Streptococcus mitis • Streptococcus mutans Streptococcus salavarius Streptococcus sanguis Streptococcus pneumoniae Propionibacterium acnes Haemophilis influenzae EB-100E vaccine The EB-100E vaccine is known by the trade name of Scourmune®-CRT, manufactured by Schering- • 5 Plow Animal Health, of Kenilworth, New Jersey, USA. The vaccine consists of Clostridium um perfringens, type C, Escheri chia coli, porcine rotavirus, and transmissible gastroenteritis.

Immunization Procedure for the Hyperimmunized Egg Product An exterminated preparation of pathogens was prepared as described above. For the first vaccination, the bacteria were mixed with complete Freund's adjuvant, and 5.6 mg of the bacterial material was injected into the muscle of a chicken breast. For the remaining vaccines, the bacterial preparation was mixed with incomplete Freund's adjuvant and injected into the chickens at two-week intervals for six months.

Immunization Procedure for the Hyperimmunized Milk Product The use of the hyperimmunized milk product used in this example was obtained from Stolle Research & Development Corporation (Stolle), Cincinnati, Ohio, USA, lots Nos. 247A5 and 289A5. Stolle has prepared the hyperimmunized milk product through the following immunization processes. An exterminated preparation of pathogens was prepared in the manner described above. The sample of polyvalent antigens (S-100) obtained was microencapsulated by a conventional phase separation process to prepare a microparticle product containing polyvalent antigens. In general, the matrix materials formed containing antigens are formed of polymer of biocompatible material, preferably biodegradable or bioerodible materials, preferably polylactic acid, polyglycolic acid, lactic and glycolic acid copolymers, polycaprolactone, copolyoxalates, proteins such as collagen, fatty acid esters of glycerol and cellulose esters. These polymers are well known in the art. The polymeric matrix material used was a biodegradable lactide-glycolide copolymer.

The exterminated pathogens were encapsulated in such matrix materials, preferably as microspheres between 1-500 μm in diameter, preferably 10-250 μm. The encapsulation processes are conventional and comprise phase separation methods, interfacial reactions and physical methods. Many combinations of matrices and many concentrations of mixed antigens can be employed in order to provide optimal rates of release of the bacterial antigens to the host body of the microparticles. These combinations can be determined by those skilled in the art without undue experimentation. The microparticles in the example were less than 250 μm in diameter. Approximately 750 mg 'of microparticles containing 22% (16.5 mg) of polyvalent antigen was then suspended in approximately 3 cc of a vehicle (1% by weight of Tween "20 and 2% by weight of carboxymethyl cellulose in water). Small cattle were selected from a larger herd of cattle, five of those randomly selected cattle were selected as controls Four cows were injected intramuscularly with microparticles containing a polyvalent antigen Microparticle samples were sterilized with 2.0 mRad radiation The antibody titre levels (gG) were determined periodically from the samples of the cow's milk obtained from the inoculated cows, as well as the control cows.

Administration of hyperimmunized egg products and hyperimmunized milk to subjects Seven groups of six female albino rats, weighing approximately 200 grams each, were fed several diets over a period of approximately seven weeks. The diets were as follows: Group 1 - Control - basic diet of certified food. (Certified Rodent Chow 5001, manufactured by Purina Mills). Group 2 - 10% of Hyperimmunized Egg (S-100 vaccine) - in powder form, by weight of the food. Group 3 - 10% of Hyperimmunized Egg (EB-100E vaccine) - in powder form, in food weight. Group 4 - 10% of Hyperimmunized Milk (S-100 vaccine) - in powder form, by weight of the food.

Group 5 - 10% of Hyperimmunized Egg (S-100 vaccine) + 10% of Hyperimmunized Milk (S-100 vaccine) - in powder form, by weight of the food. Group 6 - 10% of Hyperimmunized Egg (EB-100E vaccine) + 10% of Hyperimmunized Milk (S-100 vaccine) - in powder form, by weight of the food.

The rats were allowed free access to food and water and were kept on these diets for approximately seven weeks. Forty-eight hours before slaughter, all rats were dosed with 15 mg / kg indomethacin by priming, prepared as a 1.5% w / v suspension in methyl cellulose solution. At sacrifice, the intestines were removed and recorded for the presence of lesions (Table 2).

TABLE 2 Injury Registration Method The records for the rats are detailed in Table 3. Two independent evaluations of the lesions were made and averaged over an average injury value. These average injury values are recorded in Table 3.

TABLE 3 Injury Record ^ Duncan Multiple Range Test Analysis of HIE Variation = hyperimmunized egg product HIM = hyperimmunized milk product Previous records were based solely on the quantitative nature of the injuries. The lesion records illustrate the cytoprotective effect and the relief of the cytodestructive effect by the hyperimmunized egg product when the rats are fed before they are dosed with indomethacin. These data indicate that prior treatment with the hyperimmunized egg product, the hyperimmunized milk product, or a combination of both, significantly reduces the damage induced by the NSAIDs of the intestine. The data would imply that patients who require treatment with NSAIDs for chronic inflammatory conditions such as arthritis, they could use the hyperimmunized egg product, the hyperimmunized milk product or a combination of the two together with their usual dose of NSAIDs and experience a reduction in gastrointestinal side effects induced by typical NSAIDs. Additionally, the use of hyperimmunized egg and milk products in conjunction with the NSAIDs could allow a. increase in the dose of prescribed NSAID, which would increase its therapeutic effect without increasing the risk of detrimental side effects.

EXAMPLE 2 This example examines and illustrates the severity of the indomethacin-induced lesions and the cytoprotective effect of the hyperimmunized egg and the hyperimmunized milk as prepared in Example 1. The protocol used was the same as in Example 1, except that the rats were fed several diets for approximately ten weeks before these were dosed with indomethacin and subsequently sacrificed. At sacrifice, the intestines were removed and recorded for the presence of lesions as summarized in Table 4 below.

TABLE 4 Injury Registration Method The records for the rats are detailed in table 5. The average injury value is the average record between the groups.

TABLE 5 Injury Registry ^ Duncan Multiple Range Test Analysis of HIE Variation = hyperimmunized egg product HIM = hyperimmunized milk product Previous records were based on a more detailed registration system than that used in Example 1. Both quantitative and qualitative parameters were used (ie the appearance of the lesions and the severity of the injuries). A comparison of Example 2 with Example 1 shows that pretreatment with the hyperimmunized egg product provided a higher level of protection in Example 2 than Example 1. The records illustrate the cytoprotective effect and the relief of the cytodestructor effect by the product of hyperimmunized egg when fed to rats before they are dosed with indomethacin. In particular, the greatest protection of lesion formation occurred when the combination of hyperimmunized egg and hyperimmunized milk was used. Furthermore, the EB-100E vaccine appears to have a greater effect in reducing the cytodestructive effect of indomethacin than the S-100 vaccine. Example 2 confirms that long-term ingestion of the hyperimmunized egg and / or hyperimmunized milk protects against intestinal ulceration induced by indomethacin. The studies support the concept that hyperimmunized egg and milk products have a cytoprotective effect capable of reducing the adverse gastrointestinal effects induced by NSAIDs. Concomitantly, the use of the hyperimmunized egg product, the hyperimmunized milk product or a combination of the two products may allow the therapc use of higher doses of NSAIDs.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following claims is claimed as property.

Claims (19)

1. A method to prevent, combat or reduce chronic gastrointestinal disorders or gastrointestinal damage induced by NSAIDs in a subject, the method is characterized in that it comprises: A. hyperimmunizing an animal that produces egg or an animal that produces milk; and B. administering to the subject an effective amount of the hyperimmunized egg product, the hyperimmunized milk product or combinations thereof.

2. The method according to claim 1, characterized in that the subject is administered an effective amount of the hyperimmunized egg product.

3. The method according to claim 1, characterized in that the subject is administered an effective amount of the hyperimmunized milk product.

4. The method according to claim 1, characterized in that the subject is administered separately an effective amount of the hyperimmunized egg product and the hyperimmunized milk product.

5. The method according to claim 1, characterized in that the subject is administered a composition comprising an effective amount of the hyperimmunized egg product and the hyperimmunized milk product.

6. The method according to claim 1, characterized in that the animal that produces eggs or the animal that produces milk is hyperimmunized with an antigenic and genetic vaccine.

7. The method according to claim 6, characterized in that the antigenic vaccine comprises at least one antigen selected from the group consisting of bacterial, viral, protozoan, fungal and cellular antigens and combinations thereof.

8 The method according to claim 6, characterized in that the antigenic vaccine consists of a mixture of bacterial antigens, the mixture comprises at least one antigen from each of the following bacterial strains: Escherichia coli; Escherichia coli (Aerobacter); Klebsiella pneumoniae; Pseudomonas aeruginosa; Salmonella typhimurium; Salmonella dysenteriae; Salmonella enteriditis; Salmonella epidermis; Salmonella simulans; Streptococcus pyogenes, type 1; Streptococcus pyogenes, type 3; Streptococcus pyogenes, type 5; Streptococcus pyogenes, type 8; Streptococcus pyogenes, type 12; Streptococcus pyogenes, type 14; Streptococcus pyogenes, type 18; Streptococcus pyogenes, type 22; Pseudomonas vulgaris; Streptococcus agalactiae; Streptococcus mitis; Streptococcus mutans; Streptococcus salava ^ ius; Streptococcus sanguis; Streptococcus pneumoniae; Propionibacterium acnes; and Haemophilis influenzae.

9. The method according to claim 6, characterized in that the antigenic vaccine consists of a mixture of antigens, the mixture comprising at least one antigen of each of the following: Clostridum perfringens, type ^ C; Escherichia col i; porcine rotavirus; and transmissible gastroenteritis.

10. The method according to claim 6, characterized in that the genetic vaccine comprises at least one DNA construct encoding antigens selected from the group consisting of pure or simple DNA fragments, extrachromosomal ring DNA, viral DNA, bacterial DNA, libraries of DNA expression, DNA-RNA antigens, DNA-protein conjugates and DNA-liposome conjugates and combinations thereof.

11. The method according to claim 1, characterized in that the animal that produces eggs is a member of the class of birds.

12. The method according to claim 11, characterized in that the animal that produces eggs is selected from the group consisting of poultry, turkey, duck and goose.

13. The method according to claim 1, characterized in that the animal that produces milk is a member of the bovine class.

14. The method according to claim 13, characterized in that the animal that produces milk is selected from the group consisting of cow, goat, sheep, buffalo and llama.

15. The method according to claim 6, characterized in that the antigenic vaccine is an exterminated vaccine.

16. The method according to claim 6, characterized by the antigenic vaccine is an attenuated life vaccine.

17. A method for preventing, combating or reducing chronic gastrointestinal disorders or gastrointestinal damage induced by NSAIDs in a subject, characterized in that it comprises administering an effective amount of the hyperimmunized egg product to the subject.

18. A method according to claim 17, characterized in that it comprises administering an effective amount of hyperimmunized milk product to the subject.

19. A method for preventing, combating or reducing chronic gastrointestinal disorders or gastrointestinal damage induced by NSAIDs in a subject, characterized in that it comprises administering a composition comprising an effective amount of a hyperimmunized egg product and a hyperimmunized milk product to the subject. RES UMEN OF THE INVENTION A method for preventing, combating or reducing chronic gastrointestinal disorders or gastrointestinal damage induced by NSAIDs in a subject suffering from such ailments. The method comprises hyperimmunizing an animal that produces eggs and / or an animal that produces milk and administering an effective amount of the hyperimmunized egg product, the hyperimmunized milk product or mixtures thereof to the subject.