Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
1998-06-30
2001-04-03
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S442000, C424S420000, C424S283100, C426S443000, C426S601000, C426S615000
Reexamination Certificate
active
06210700
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to therapeutic regimens for immunologically impaired individuals recovering from surgery, infection, burns and other trauma. More specifically, the invention relates to an immunomodulatory diet and immunosuppressive therapy for the enhancement of host defense mechanisms and prolongation of allograft survival.
BACKGROUND OF THE INVENTION
The physiological trauma that besets the human body as a result of surgery, cancer, intensive burns, radiation therapy and the like has a deleterious effect on the health of the individual in more ways than one. It is well known that patients recovering from such trauma and who are being therapeutically treated often have compromised host defense mechanisms. A damaged or reduced immune system can often lead to increased morbidity and eventual death as a result of infection and/or organ failure through rejection.
In a related case U.S. Pat. No 5,231,085 also to Alexander, the present applicants discovered novel immuno- modulatory compositions and methods which enhance host defense mechanisms which have been compromised and are deficient for one reason or another. The immunomodulatory compositions are composed of an amino acid such as arginine or ornithine that are used in the biosynthetic pathways of other polyamines, a nucleobase source and a combination of omega-3- and omega4-polyunsaturated fatty acids. The composition is administered enterally or modified for parenteral administration and is preferably used as a supplement to a complete nutritional diet meeting the complete daily caloric and vitamin requirements of the patient. The administration of these compositions restore damaged or compromised immune systems to their healthy state. The Alexander patent 5,231,085 is hereby incorporated by reference.
The immunomodulatory compositions of Alexander et. al. '085 are believed to decrease the damage caused by the inflammatory response through multiple immune functional pathways. These compositions, when administered to surgery patients during the early post-operative period have been shown to bring about a significant reduction in the length of the average hospital stay as well as a significant reduction in the number of wound complications.
U.S. Pat. No. 5,055,446, to Alexander and Peck, was premised on the realization that sepsis was treatable in part by diet; as was U.S. Pat. No. 4,981,844, also to Alexander and Peck. In the latter patent, linoleic acid was employed to provide 20% to 80% of the calories in a diet ingested for at least 10 days prior to an operative procedure, to provide resistance to infection following the surgery. It was reported that excessive dietary polyunsaturated linoleic acid influenced immunocompetence after burns; this was also shown to reduce the risk of infection after surgery. The U.S. Pat. No. 5,055,446 provided a method to improve immune response and survival during sepsis, also by diet composition, comprising optimizing the protein level in diet to form only about 4 to less than 10% of total calories, while also supplementing the diet with omega 3 and omega 6 fatty acids.
Other related cases include pending U.S. applications, attorney docket 610-7236, Ser. No. 08/611,144, filed Mar. 5, 1996, now abandoned; and attorney docket 610-7218, Ser. No. 08/452,550, filed May 25, 1995, now U.S. Pat. No. 5,612,060. Some of the subject matter in these applications is also disclosed in
Transplantation,
Vol. 60, 812-815, No. 8, Oct. 27, 1995, “Nutritional Immunomodulation Enhances Cardiac Allograft Survival in Rats Treated with Donor-Specific Transfusion and Cyclosporine”, Levy and Alexander.
All of these disclosures are incorporated by reference.
It is also well documented that the administration of lipids such as those found in a number of common fish oils significantly reduce the degree of immune response to solid organ allografts leading to improved survival. In one study, fish oil supplementation reduced the number of rejection episodes of renal allografts during the first year post-operative by 60%. Omega-3-polyunsaturated fatty acids which are found in these fish oils in fact have several properties which suggest that they play a key role in the inflammatory response. They are known to be potent inhibitors of platelet aggregation, thrombus formation and appear to reduce small vessel arteriosclerosis. These effects are presumed to occur in part through the down regulation of TxA-2 production in multiple cell lines.
Catabolic states after major operation or multiple trauma result in weight loss, negative nitrogen balance, and immune dysfunction. Maintaining adequate nutritional support may be of critical importance for the successful recovery of surgical patients. Early postoperative enteral feeding, in particular, helps to ameliorate weight loss and to counteract the nitrogen losses in catabolic states after extensive surgical procedures. Furthermore, an argimine-omega-3 fatty acid and ribonucleic acid (RNA)—supplemented enteral diet has been reported to better overcome postoperative immune dysfunction and to improve clinical outcome after major surgery.
Arginine is essential during growth and may become essential in catabolic states. Supplementation of diet with arginine promoted wound healing and enhanced immune function in animals by decreasing the T-cell dysfunction associated with injury. Animal studies showed that arginine administration resulted in increased thymic size and cellularity, enhanced lymphocyte proliferation to mitogen and alloantigen, augmented macrophage and natural killer cell lysis of tumor targets, and increased lymphocyte interleukin-2(IL-2) production and receptor activity.
Alexander, et al., The Importance of Lipid Type in the Diet After Burn Injury, Ann. Surg. 1986; 204:1-8 demonstrated that administration of increasing doses of omega-3 fatty acids in the diet improved immune function in burned guinea pigs, probably through alteration of prostaglandin synthesis pathways from dienoic to trienoic prostaglandins. In another study, omega-3 fatty acid supplementation improved survival after burn injury, reduced postinjury infectious complications, and diminished immunosuppression secondary to transfusion.
Certain nutrients such as the semi-essential amino acid arginine, RNA, and omega-3 fatty acids may act pharmacologically on the immune system. These nutrients may improve host immune defenses. The specific nutrient substrates seem to act via different mechanisms.
Supplemental dietary arginine has thymotrophic properties and enhances the responsiveness of thymic lymphocytes to mitogens in normal and traumatized animals. Arginine augments cellular immunity, as shown by enhanced skin allograft rejection in normal mice, and improves delayed hypersensitivity responses as well as survival in burn animal model. Arginine supplementation of an enteral diet in postoperative cancer patients has been evaluated, and showed that dietary arginine supplementation improves mitogen-stimulated lymphocyte blastogenesis. Increased IL-2 production and up-regulation of IL-2 receptor activity on T cells have also been described.
SUMMARY OF THE INVENTION
The present invention comprises the use of omega-9 unsaturated fatty acids, especially as found in canola oil, high oleic acid sunflower oil, or olive oil, to inhibit the rejection response associated with organ transplantation. The omega-9 fatty acid is administered in conjunction with an immunomodulatory effective amount of arginine or its salts or metabolic precursors of arginine, in addition to other immunosuppressive treatment regimens for the enhancement of allograft survival and altered host defense mechanisms. Preferably, the person needing the dietary supplement is fed orally with the added omega-9 fatty acid containing oil or the methyl or ethyl ester of the omega-9 fatty acid.This can be combined with a therapeutic dosage form of cyclosporine, with the optional presence of a donor specific transfusion and/or lipids containing omega-3 and omega-6 polyunsaturated fatty acids.
REFERENCES:
Alexander J. Wesley
Greenberg Norman A.
Ogle Cora K.
Valente John F.
Bansal Geetha P.
Novartis Nutrition AG
Pfeiffer Hesna J.
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