Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2002-01-08
2004-02-24
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
Reexamination Certificate
active
06696082
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention pertains to the enhancement of the anticarcinogenic, antineoplastic, antiviral, antiatherogenic, and antiaging activities of thioretinaco ozonide by use of specialized liposomal carrier particles containing oxygen, adenosine triphosphate, and glycolipids, phosphatides and sterols in which all carbon—carbon bonds are fully saturated with hydrogen.
2. Description of the Related Art Including Information Disclosed Under 37 CFR 1.97 and 1.98
Homocysteine thiolactone, a metabolite of the essential amino acid, methionine, is metabolized abnormally in malignant cells, as reported in
Cancer Research
36:3198-3202, 1976. Unlike normal cells or cells lacking cystathionine synthase, which rapidly complete this conversion, malignant cells are unable to metabolize homocysteine thiolactone to sulfate ions. Because of this abnormality, homocysteine thiolactone accumulates within malignant cells and reacts with the free amino groups of proteins, nucleic acids, glycosaminoglycans, and other macromolecules. As the result of this reaction, peptide bonds are formed between homocysteine thiolactone and the free amino groups of macromolecules, a process known as homocysteinylation. Extracts of human tumors contain free homocysteine thiolactone, as demonstrated by chromatographic separation and detection by column and thin layer chromatography, as reported in
Research Communications in Chemical Pathology and Pharmacology
59:107-119, 1988. Free homocysteine thiolactone is present in cultured malignant cells, but only trace amounts are found in normal cells and tissues. The formation of homocysteine thiolactone from methionine is catalyzed by methionyl tRNA synthase by an error editing reaction, as reported in
FEBS Letters
317:237-240, 1993.
In addition to the abnormality of conversion of homocysteine thiolactone to sulfate, malignant cells also possess other characteristic abnormalities of methionine metabolism, as described in
Annals of Clinical and Laboratory Science
24:27-59, 1994. Malignant cells grow very slowly in media that are free of methionine when supplemented by homocysteine and a source of methyl groups, such as methyltetrahydrofolate, whereas non-malignant cells grow normally under these conditions. The ratio of adenosyl methionine to adenosyl homocysteine concentrations in malignant cells is decreased because of decreased synthesis of adenosyl methionine and increased formation of adenosyl homocysteine, as compared with normal cells. As a result, an increased concentration of homocysteine is present in the plasma of many human patients with malignant tumors of different types. Cells and tissues from malignant tumors also contain increased transmethylase activity, and the DNA of malignant tumors are characteristically hypomethylated, as compared with the DNA of normal tissues. The carcinogenic effect of the antimetabolite, ethionine, is counteracted by dietary methionine in experimental animals because of decreased formation of adenosyl ethionine from ethionine and increased formation of adenosyl methionine from methionine. Totally synthetic experimental diets that are deficient in choline and other sources of methyl groups are carcinogenic in animals, and dietary methionine counteracts this carcinogenic effect. Increased concentrations of methionine in the culture medium of malignant or transformed cells inhibit aerobic glycolysis and the production of lactic acid in the presence of oxygen, a characteristic metabolic abnormality of malignant cells.
The cause of abnormal homocysteine thiolactone metabolism in malignant cells was hypothesized to result from a deficiency of or failure to synthesize an N-substituted derivative of homocysteine thiolactone, as discussed in
Cancer Research
36:3198-3202, 1976. According to this hypothesis, normal cells contain this chemopreventive derivative that facilitates sulfate formation from homocysteine thiolactone. The concentration of this hypothetical chemopreventive derivative is believed to be diminished during the carcinogenic transformation of normal to malignant cells through the action of carcinogenic chemicals, radiation, viruses or other stimuli. The function of this chemopreventive derivative in normal cells is to prevent accumulation of homocysteine thiolactone by catalyzing its conversion to phosphoadenosine phosphosulfate, sulfate esters of glycosaminoglycans, steroids and other compounds, and sulfate ions. As a result of this chemopreventive derivative in metabolic functions, the characteristic metabolic abnormalities of malignancy, which are attributable to excess accumulation of homocysteine thiolactone, are prevented in normal cells. Thus according to this concept, the increased growth rate, the aggregation of nucleoproteins, the increased expression of developmentally suppressed genes, the degradation of cellular membranes and the abnormalities of oxidative metabolism, such as aerobic glycolysis, are all attributable to increased accumulation of homocysteine thiolactone resulting from depletion of the chemopreventive derivative within malignant cells.
The identity of the N-substituted derivative of homocysteine thiolactone that prevents growth of malignant tumors in animals was elucidated by organic synthesis of antineoplastic compounds containing homocysteine thiolactone. As described in U.S. Pat. No. 4,383,994, N-maleyl homocysteine thiolactone amide, N-maleamide homocysteine thiolactone amide, and rhodium trichloride oxalyl homocysteine thiolactone amide suppress the growth of malignant tumors in animals. Encapsulation of N-maleamide homocysteine thiolactone amide within liposomes greatly enhances its antineoplastic activity, as reported in
Proceedings of the Society for Experimental Biology and Medicine
180:57-61, 1985. Structural analysis of these biologically active derivatives of homocysteine thiolactone suggests that the hypothetical chemopreventive derivative is (1) active in a lipid-soluble form, (2) contains a conjugated double bond system with a carbonyl group adjacent to the nitrogen atom of homocysteine thiolactone, and (3) forms a complex with a transition metal atom that enhances antineoplastic activity.
U.S. Pat. Nos. 4,618,685 and 4,925,931, describe the reaction of homocysteine thiolactone with retinoic acid to form N-homocysteine thiolactonyl retinamide (NHTR), known as thioretinamide, and thioretinamide reacts with cobalamin to form N-homocysteine thiolactonyl retinamido cobalamin (NHTR)
2
Cbl, known as thioretinaco. Both thioretinamide and thioretinaco have anticarcinogenic and antineoplastic activities, as reported in
Carcinogenesis
8: 1559-1562, 1987 and in
Proceedings of the Society for Experimental Biology and Medicine
191:346-351,1989. The method of synthesis of thioretinamide was significantly improved by use of N-ethyl-N′-(3-dimethyl-aminopropyl) carbodiimide in the reaction mixture, discussed in U.S. Pat. No. 6,054,595. This method replaces the conjugation agent, dicyclohexyl carbodiimide, in the reaction mixture of the original method and produces pure thioretinamide in high yield, approximately 72% of theoretical yield. This highly pure thioretinamide and its complex with cobalamin, thioretinaco, have antiatherogenic activity in rats treated with parenteral homocysteine thiolactone, as reported by M. Kazimir in MS Thesis, Baylor University, 1999.
In experiments with cultured malignant and normal cells thioretinamide and thioretinaco were demonstrated to decrease growth without degeneration or detachment of the cells from the culture dish, except at high concentrations, as reported in
Research Communications in Chemical Pathology and Pharmacology
77:125-128, 1992. Intra-tumor administration of thioretinaco decreased the growth of human pancreatic adenocarcinomas in athymic mice, as reported in
Research Communications in Chemical Pathology and Pharmacology
66:117-122, 1989.
In U.S. Pat. No. 5,565,558, the biological activity of thioretinaco is enhanced by ozone in combination with interferon. Ozone is believed t
Breneman & Georges
Breneman, Esq. William D.
Gorges, Esq. Peter J.
Kishore Gollamudi S.
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