Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ether doai
Reexamination Certificate
1998-08-27
2001-01-23
Cintins, Marianne M. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ether doai
C514S715000, C514S723000
Reexamination Certificate
active
06177476
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to nutritional supplements and methods of using them. More particularly, the invention relates to nutritional supplements which aid in the replenishment of plasmalogens.
1. Bibliography
Complete bibliographic citation for the references cited below are included in the “Bibliography” section, immediately preceding the claims. All of the references cited below are incorporated herein by reference in their entirety.
2. Description of the Prior Art
Glycerophospholipids and related glycerol-derived lipid analogs are ubiquitous compounds which are major constituents in mammalian cellular membranes. For instance, they are present in relatively large amounts in skin fibroblasts. As a class of compounds, these lipids share the common feature of a 3-carbon glycerol backbone. A wide range of physiologically important compounds, such as phosphatidic acid analogs, fatty acid and aldehyde glycerols, ether glycerol phospholipids, plasmalogens, and the like, are defined by the chemical side chains attached to the glycerol backbone. The side chains are linked to the glycerol backbone via several different types of bonds, including ester linkages, ether linkages, phosphoester linkages, and alk-1′-enylether linkages.
Ether glycerophospholipids bearing an alk-1′-enylether-linked substituent are given the trivial class name plasmalogens. Plasmalogens are generally thought to play an important, albeit undefined, role in cellular growth, maintenance, and apoptosis. For instance, it is thought that plasmalogens function as antioxidants in vivo . Reiss et al. (1997) showed in an in vitro model that the peroxidation of lipids is delayed in the presence of plasmalogens. The uncertainty of the role played by reactive oxygen intermediates, if any, in programmed cell death is summed up by Nunez and Clarke (1994), who note that “it is unclear whether reactive intermediates are required for apoptosis.”
For an excellent review of the present scientific knowledge regarding ether phospholipids in biomembranes, see Paltauf (1994).
Decreased antioxidant status has been implicated in the aging process. Not only are dietary antioxidants, such as Vitamnin C and Vitamin E, decreased, but enzymes normally present to neutralize these oxygen radicals appear to be deficient as well. Enzymes such as superoxide dismutase, catalase and glutathione peroxidase appear to be produced in lesser quantities as the body ages. Most importantly, the levels of plasmalogens are significantly decreased with age.
Particularly helpful in understanding the general field to which the invention pertains is Paltauf's discussion of ether lipid biosynthesis and metabolism in mammalian cells. An interesting feature of the biosynthetic pathway is that two of the enzymes involved in the formation of an alkyl ether bond to the glycerol backbone, namely dihydroxyacetone phosphate acyltransferase (DHAP-AT) and alkyldihydroxyacetone phosphate synthase (alk-DHAP synthase) are located solely in the peroxisomes. Consequently, the biosynthetic pathway leading from dihydroxyacetone phosphate (DHAP) to glycerophospholipids is divided between cytosolic reactions (at both the initial and final stages of synthesis) and peroxisome-located reactions.
The metabolic pathway leading from DHAP to various glycerophospholipids, as described by Paltauf (1994), is summarized below.
DHAP from the cytoplasm is first imported into the peroxisome, where it then reacts with acyl CoA to yield a 1-acyl-3-hydroxyacetone phosphate. This first reaction is catalyzed by DHAP-AT. Enzymatic reaction with a primary alcohol (catalyzed by alkyl-DHAP-synthase) then yields the 1-alkylether-3-hydroxyacetone phosphate analog. Further reaction with NADPH causes reduction of the 2-position carbonyl into an alcohol. At this point, the 1-alkylether-2-hydroxyglycerol-3-phosphate intermediate is transported out of the peroxisome for further biosynthetic reactions in the cytoplasm or endoplasmic reticulum (ER). The biosynthetic reactions which occur solely within the peroxisome are summarized as follows:
Outside of the peroxisome, plasmalogens are formed by the step-wise acylation of the 2-position carbonyl, amine functionalization of the 3-position orthophosphate (as with choline or ethanolamine), followed by enzymatic dehydrogenation of the 1-position alkylether side chain.
Paltauf notes that in peroxisomal disorders such as Zellweger's syndrome and rhizomelic chondrodysplasia punctata (RHCP), the impediment to the peroxisomal enzymatic reactions may be circumvented by providing to the either lipid-deficient cells a suitable precursor which can be used for plasmalogen synthesis in the ER. For instance, Paltauf notes that fibroblasts from healthy donors contain approximately 15% ethanolamine plasmalogen. However, supplying exogenous alkylglycerol to these normal cells has no effect on the plasmalogen content of the cells. In contrast, the reduced plasmalogen levels found in cultured fibroblasts of Zellweger's or RHCP patients can be elevated to almost normal levels if the cells are cultured in the presence of an alkylglycerol. (See also, Hennetter and Paltauf (1995).)
It must be noted, however, that very little is known about the ether lipid content of other tissues in patients suffering from peroxisomal disorders. See, for instance, Das et al. (1992). Das et al. note that chronic feeding of 1-O-octadecyl-sn-glycerol (batyl alcohol) to human patients suffering from peroxisomal disorders which result in a low tissue content of ether glycerolipids, results in increased plasmalogen content within their red blood cells (erythrocytes). Das et al. were interested in whether the oral administration of ether lipids to patients with peroxisomal disorders might increase the concentration of tissue ether lipids. Das et al. convincingly show that chronic oral administration of batyl alcohol to patients suffering from certain peroxisome dysfunction disorders results in a significant increase in red blood cell ethanolamine plasmalogen concentration. This leads Das et al. to conclude that the administration of oral ether lipids represents a “potential” treatment for patients with peroxisomal disorders.
This conclusion, however, must be treated with caution in that while Das et al. noted that the infant subjects described therein showed improved nutritional status, liver function, retinal pigmentation, and replenishment of deficient erythrocyte ethanolamine plasmalogen level by the feeding of ether lipids, Das et al. also conclude that it is not possible to separate these changes from the natural history of the untreated disease. For instance, Wander et al. (1986) have documented that plasmalogen levels in Zellweger's syndrome patients increase naturally as a function of age. It is hypothesized that this may be due to the intake of natural alkylglycerols present in food. Alkylglycerols and their mono- and diesters are found in fish oils, such as shark oil, and other foods. Horrocks (1972) estimates that the average adult consumes from 10-100 milligrams of batyl alcohol per day.
Das et al. also investigated the extent of incorporation of dietary ether lipids into tissue lipids by administering different precursors of the ether lipids, such as heptadecanoic acid, heptadecanol, 1-O-heptadecyl-sn-glycerol, and 3-O-heptadecyl-sn-glycerol, to young rats. Das et al. 's data indicate that natural glycerols are incorporated more readily than unnatural optical isomers. While the precursors were incorporated into various plasmalogens, the total plasmalogen content of the tissues tested did not increase. The relative incorporation rates of the various ether lipid precursors is reported by Das et al. to be as follows: 1-O-heptadecyl-sn-glycerol> heptadecanol>heptadecanoic acid>3-O-heptadecyl-sn-glycerol. This leads Das et al. to conclude that while most exogenous long chain either lipids are eventually incorporated into alkylglycerol ether lipids, the subsequent conversion of the alkylglycerol ether lipids into plasmalogens occurs on
Peterson Andrew C.
Pruss Thaddeus P.
Cintins Marianne M.
Clarion Pharmaceuticals Inc.
Conte, Esq. Salvatore R.
Delacroix-Muirheid C.
Leone, Esq. Joseph T.
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