Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-28
2001-01-09
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06172106
ABSTRACT:
BACKGROUND OF THE INVENTION
Dietary polyunsaturated fatty acids (PUFA) play a major role in the regulation of immune responses during infection and inflammation. Linoleic acid (LA:18:2&ohgr;6) is the precursor for the formation of arachidonic acid which is metabolized to proinflammatory mediators such as prostaglandins (PG)E
2
and thromboxane (Tx)A
2
. Other polyunsaturated fatty acids such as &agr;-linolenic acid (18:3&ohgr;6) and &ggr;linolenic acid (18:3&ohgr;6) are precursors for the formation of eicosapentaenoic acid (EPA: 20:5&ohgr;3) and dihomo-&ggr;-linolenic acid (DGLA: 20:3&ohgr;6), respectively, both of which displace arachidonic acid (20:4&ohgr;6), reduce the production of PGE
2
and also form mediators such as PGE
3
and PGE
1
which are less inflammatory. Thus, dietary fats rich in &ggr;-linolenic acid, &agr;-linolenic acid, or EPA have been employed to modulate some of the inflammatory responses in experimental animal models (Carrick et al.,
Shock
2:421-426 (1994); Yacoob and Calder,
Cell Immunol
163:120-128 (1995)) and in clinical trials (Espersen et al.,
Clin Rheumatol ll
:393-395 (1992); Engler et al.,
J Hyperien
10(1):197-204 (1992); Harrobin,
Rev Contem Pharmacol. Ther.
1:1-45 (1990)).
Recently, it has been demonstrated that in animals fed sesame seed oil (SSO), an increased survival in mice exposed to a lethal dose of LPS is associated with a substantial increase in the accumulation of dihomo-&ggr;-linolenic acid (Chavali et al.,
Int Arch Allergy Immunol
114:153-160 (1997)). Moreover, the experimental data suggest that these beneficial effects are attributed to the lignans in the non-fat portion of the oil. These lignans, including sesamin, episesamin, sesaminol and sesamolin but not sesamol, inhibit the activity of &Dgr;-5 desaturase enzyme in vitro (Shimizu et al.,
Lipids
26:512-516 (1991)). Unlike sesamol (3,4-methylenedioxyphenol), the other lignans are dimeric compounds and have in common a methylene-bridged 3,4-dihydroxyphenol moiety (FIGS.
1
A and
1
B). Further, data (Shimizu et al.,
Lipids
26:512-516 (1991); Fujiyama et al.,
J Nutr Sci Vitaminol
41:217-225 (1995)) suggest that sesamin inhibits the &Dgr;-5 desaturase activity of &ohgr;6 polyunsaturated fatty acids, resulting in an accumulation of dihomo-&ggr;-linolenic acid. In mice fed sesamin, the LPS-induced production of PGE
2
, IL-10 and IL-6 was lower and that of TNF-&agr; was higher, while these levels are unaffected in SSO fed animals (Chavali et al.,
Int Arch Allergy Immunol
114:153-160 (1997)).
SUMMARY OF THE INVENTION
As described herein, the effects of consumption of sesamol-supplemented safflower oil (SO) diet (providing linoleic acid, an essential fatty acid) on the fatty acid composition and the endotoxin-induced production of eicosanoids as well as cytokines in mice, were investigated. The fatty acid composition (mean±s.d. mol. %) of liver membrane phospholipids and the levels of endotoxin-induced prostaglandin (PG) E
2
, interleukin (IL)-6, IL-10, IL-12 and tumor necrosis factor (TNF)-&agr; were determined in mice fed diets supplemented with safflower oil (5%) and sesamol (1%). The levels of dihomo-&ggr;-linolenic acid (DGLA; 20:3&ohgr;6) were markedly higher (p<0.05) in the livers from mice fed sesamol supplemented SO diets (1.6±0.1) compared to the controls (1.4±0.1). In contrast, the levels of docosapentaenoic acid (22:5&ohgr;6) were significantly lower in animals fed sesamol (1.4±0.1) compared to the controls (2.5±0.4). These data suggest that sesamol or its metabolite can inhibit the in vivo &Dgr;-5 desaturation of &ohgr;6 fatty acids.
Further, in animals fed sesamol-supplemented SO diets, the levels of PGE
2
(228±41 pg/ml) were markedly lower (p<0.05) compared to those fed SO diet alone (1,355±188 pg/ml). In the group of animals maintained on sesamol supplemented diets, the plasma levels of IL-6 (63±11 ng/ml) were significantly lower compared to those fed SO diet alone (143±22 ng/ml). The concentrations of TNF-&agr; and IL-10 did not differ significantly between the two dietary groups. In mice fed sesamol-supplemented diets, even in the absence of any differences in the amounts of arachidonic acid, a marked reduction of PGE
2
levels suggest that the observed anti-inflammatory effects could result from the ability of sesamol to inhibit or decrease the activity of phospholipase A
2
(PLA
2
) responsible for the release of arachidonic acid from membrane phospholipids.
The invention pertains to compositions comprising sesamol in an amount effective to treat inflammation. In particular embodiments, the composition is a dietary supplement or nutritional solution, such as a dietary supplement or nutritional solution suitable for enteral or parenteral administration. In one embodiment of the invention, the sesamol of the composition is essentially purified. In other embodiments, the composition further comprises essential fatty acids and/or essential vitamins and minerals.
The invention further relates to a dietary supplement or medical food comprising an effective amount of sesamol. For example, the dietary supplement or medical food can be selected from the group consisting of nutritional beverage, baked good (cookie, brownie, fudge, cake, bread, biscuit and cracker), pudding, confection, snack food, ice cream, frozen confection, and non-baked, extruded food product such as a bar.
The invention also pertains to a method of inhibiting inflammation in a mammal comprising administering a composition comprising an effective amount of sesamol to a mammal in need thereof. In one embodiment, the composition to be administered is a dietary supplement or nutritional solution, such as one which is suitable for enteral or parenteral administration. In another embodiment, the composition further comprises essential fatty acids and/or essential vitamins and minerals. The composition can be administered enterally or parenterally.
The invention also pertains to a method of inhibiting inflammation in a mammal comprising administering a composition comprising an effective amount of a sesamol metabolite to a mammal in need thereof, as well as to compositions comprising a sesamol metabolite in an amount effective to treat inflammation.
The invention also pertains to a method of inhibiting &Dgr;-5-desaturase activity in a mammal comprising administering to the mammal a composition comprising an effective amount of sesamol or a sesamol metabolite.
The invention further relates to a method of inhibiting arachidonic acid metabolism in a mammal comprising administering to the mammal a composition comprising an effective amount of sesamol or a sesamol metabolite. Inhibition of arachidonic acid metabolism results in inhibition of the formation of arachidonic acid metabolites, such as PGE
2
and thromboxane (Tx)A
2
.
The invention further relates to a method of inhibiting the level of PGE
2
and TxA
2
in a mammal comprising administering to the mammal a composition comprising an effective amount of sesamol or a sesamol metabolite.
The invention also relates to a method of inhibiting the activity of PLA
2
in a mammal comprising administering to the mammal a composition comprising an effective amount of sesamol or a sesamol metabolite.
Sesamol has several benefits and advantages for the health of mammals to which it is administered. In general, consumption of sesamol-supplemented diets could improve the functions of vital organs such as heart, lungs, liver and kidneys. The levels of TNF, a proinflammatory mediator, are not elevated in mice fed sesamol in contrast to TNF levels with other anti-inflammatory drugs; therefore, use of sesamol as an anti-inflammatory agent does not induce the undesirable side effects induced by many other anti-inflammatory agents. Further, because it is available naturally in sesame oil, sesamol can be used as a dietary supplement providing beneficial effects to the host. Proinflammatory mediators such as PGE
2
and IL-6 are also associated with increased mortality of patients with cancer/
Chavali Sambasiva R.
Forse R. Armour
Hamilton Brook Smith & Reynolds P.C.
Spivack Phyllis G.
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