Immunosupportive drug sparing diet

Details Immunosupportive drug sparing diet Immunosupportive drug sparing diet

1998-07-15

2004-03-16

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S269000, C435S004000

Reexamination Certificate

active

06706691

ABSTRACT:

1.0 BACKGROUND OF THE INVENTION
1.1 Field of the Invention
The present invention is generally directed to the field of nutritional medicine. The present invention is directed to an immunosupportive, drug sparing diet and methods of treating patients employing a nucleotide-free diet. The invention is also related to diet-induced alteration of P450 metabolism via a unique diet that has the potential to restore immunity in patients and decrease pharmaceutical costs associated with treatment. More specifically, the present invention is directed to the use of a nucleotide-free diet that can enhance the immunosuppressive potency of a subtherapeutic dose of drugs metabolized by gut P450 isozymes, such as cyclosporine.
1.2 Description of Related Art
1.2.1 Dietary RNA and the Immune Response
Dietary ribonucleic acid (RNA) is required both for maintenance of normal immune responsiveness and for restoration of lost immune response due to protein deprivation (Van Buren et al., 1990). One of the principal targets is the T-lymphocyte, whose maturation and production of viral cytokines is delayed or suppressed by restriction of dietary nucleotides (Van Buren et al., 1985). Response to pathogens requiring normal T-cell function is suppressed by a nucleotide free diet (NFD). RNA or dietary pyrimidines (uracil) can correct this deficient response while dietary purines (adenine) fail to restore immune responsiveness. Specific immune responses as well as nonspecific immune responses can be influenced by dietary nucleotides (Kulkarni et al., 1986). An LD 50 dose of intravenously injected
Staphylococcus aureus
is uniformly lethal in mice on a nucleotide free diet. Adenine supplemented diets do not restore host defenses to this bacterial pathogen while a pyrimidine (uracil) supplemented diet is comparable to an RNA supplemented diet in maintaining host immunity against this bacterium. Uniquely, RNA can maintain normal immune responsiveness even during protein starvation and negative nitrogen balance (Pizzi et al., 1990).
Dietary nucleotides are additive to omega-3 fatty acids and arginine in maintaining immune responses to antigenic challenge. These observations resulted in the development of a commercial diet, which in several randomized studies has reduced length of patient hospital stay by over 20% (Bower et al., 1995).
1.2.2 Drug Bioavailability
A pharmaceutical compound (drug), when ingested orally, is absorbed through the various mucosal surfaces, distributed to various tissues through the blood, inactivated by the liver and other tissues, active at the target site, and eliminated in the urine or bile. Factors that affect steps involved with these processes, among others, determine the bioavailability of the drug. For example, if a drug is not efficiently absorbed by the digestive system, this will decrease the percentage of the oral dose that will reach the target tissue. Similarly, if a percentage of the drug is metabolized before it can act on the target tissue, this also decreases the bioavailability of the drug. To compensate for factors that decrease the bioavailability of drugs, higher oral doses are required to elicit the desired effect.
Traditional approaches to increasing the bioavailability of drugs have focused on increasing the solubility of drugs and mucosal membrane permeability. Approaches that have targeted drug metabolism have generally focused on affecting biotransformation in the liver. These methods are inadequate because they affect general liver metabolism and often produce nonspecific systemic effects.
More recently, approaches for increasing bioavailability have targeted drug metabolism in the gut. The cytochrome P450 is responsible for a majority of the biotransformation of drugs in the gut. U.S. Pat. No. 5,716,928 discloses a method of screening compounds that inhibit cytochrome P450 drug metabolism, particularly cytochrome P450 3A in the gut. Through this method, a number of essential oils were shown to inhibit cytochrome P450 activity and thereby potentially increase the bioavailability of drugs coadministered with the oils.
1.2.3 Deficiencies in the Related Art
Dietary RNA is required to maintain or restore the immune system, particularly T-cell function. As RNA is made up of four subunits (adenine, cytosine, guanine, and uracil) and susceptible to degradation, perhaps certain subunits are responsible for the immunosupportive role of dietary RNA while others are not. Indeed, the inventors have determined that pyrimidines, particularly uracil, are responsible for the maintenance and restoration of immune responsiveness (Van Buren et al., 1994).
The immunosuppressive effect of an NFD has been utilized in situations in which an immune response is not wanted. For example, the inventors have shown that mice fed NFD had improved cardiac allograft survival (Van Buren et al., 1983b). Interestingly, in the same study, the inventors found that the NFD and cyclosporine had a synergistic effect. A similar effect was observed by Yau et al. (1991) in their study of the effect of different doses of immunosuppressive drugs on acute graft-vs.-host disease prophylaxis. This group found that drugs given to patients on an NFD had increased efficacy and decreased toxicity. Although NFDs are effective at increasing the efficacy of drugs for purposes of immunosuppression, the lack of nucleotides makes the diets inappropriate in circumstances in which maintaining immune responsiveness is desired. Thus, there is a need for a diet that is immune supportive and drug sparing, that is able to alter drug metabolism to increase the effectiveness/availability of the drug.
2.0 SUMMARY OF THE INVENTION
It is, therefore, a goal of the present invention to provide an immunosupportive, drug sparing diet. The present invention discloses an immunosupportive, drug sparing diet and methods of treating patients employing an immunosupportive, drug sparing diet. Surprisingly and unexpectedly, the inventors have found that the use of a nucleotide-free diet can synergistically enhance the immunosuppressive potency of a subtherapeutic dose of drugs metabolized by gut P450 isozymes, such as cyclosporine.
Specifically, the inventors have demonstrated that a nucleotide-free diet supplemented with uracil (NFU), or other pyrimidines, fails to stimulate gut P450 enzyme levels and leads to an increase in the bioavailability of drugs metabolized by this enzyme. However, a nucleotide free diet supplemented with adenine (NFA) stimulated expression of P450 in the gut. Therefore, the diets of the present invention are immunosupportive, because they contain compounds (i.e., uracil) that maintain the immune system, yet are drug sparing because they lack compounds (i.e., adenine) that stimulate expression of P450 in the gut. As a result, one can use a diet of the present invention to maintain immune responsiveness and obtain a synergistic potentiation of the activity of drugs metabolized by gut P450. By decreasing drug metabolism, one can reduce pharmacy costs. Additionally, the invented diet at the same time will enhance immune response by the addition of a critical nucleobase.
The present invention encompasses an immunosupportive, drug sparing diet. Another name for diet is a nutritional composition. As used herein, the phrase “drug sparing” refers to the ability of a diet to enhance the bioavailability of an orally administered drug. The drug sparing ability of the diet disclosed herein has been documented by the finding of the inventors of the virtual absence of the p450 enzyme in the gut of mice fed this diet.
To be drug sparing, a diet of the present invention should lack compounds that stimulate the expression of a P450 isozyme in the intestinal tract of an animal receiving the diet. From here on, “P450 expression” or “expression of P450” refers to the expression of P450 isozyme in the intestinal tract of an animal. Disclosed herein are methods of identifying compounds that stimulate the expression of P450. Although in preferred embodiments a diet of the present invention is devoid of any compound that substantiall

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