Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1997-06-20
2001-07-03
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06255347
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of chemotherapeutic treatments. More particularly, it concerns the use of ibuprofen, a non-steroid anti-inflammatory drug, in the treatments of malignancies such as cancer. In other embodiments, the present invention relates to the therapeutic uses of ibuprofen in the treatments of Alzheimer's and Alzheimer's-related diseases.
2. Description of Related Art
Neoplastic diseases are conditions in which the abnormal proliferation of cells results in a cancerous mass of cells. These cancers are responsible for hundreds of thousands of deaths in the U.S. alone each year. Unfortunately, neoplasia possess a wide variety of abnormalities in structure and function that render them difficult to attack. Thus, new and effective treatments of neoplastic diseases are valuable for the prevention and/or cure of cancer.
Alzheimer's Disease is a complex pathology that affects 5 to 11% of the population over 65 years, and as much as 47% of the population over the age of 85 in developed countries. The health care cost per patient for this disease are staggering, given the severe physical and mental debilitation of the patients. If preventive measures are not found, the numbers can be expected to increase dramatically as the aging population increases (Flier and Underhill, 1991), further escalating costs.
A class of compounds with a potential therapeutic value in both of the aforementioned afflictions is non-steroidal anti-inflammatory drugs (NSAID). NSAIDs are commonly used as anti-inflammatory agents and as analgesics. Physiologically, these compounds are known to inhibit the biosynthesis of prostaglandins by inhibition of the cyclooxygenase enzyme (Buckley et al., 1990).
Ibuprofen is an NSAID that acts by inhibiting cyclooxygenase and omithine decarboxylase activities. However, it appears that this effect also is associated with a number of undesirable effects, including toxicity, because the inhibition of prostaglandin synthesis leads to gastrointestinal distress, possible renal and hepatic toxicities, and other malfunctions including thrombocytopenia and leukopenia (leading to subsequent agranulocytosis). Agranulocytosis is a life threatening condition that develops rapidly and is difficult to detect, and has been described for several NSAIDs including indomethacin, ketoprofen and ibuprofen. Thus, NSAIDs are contraindicated in patients whose immune systems are compromised by HIV infection, chemotherapy, ionizing irradiation, corticosteroids, immunosuppressives and the like and also in conditions such as emphysema, bronchiectasis, diabetes mellitus, leukemia and the like (Broda et al., 1992).
Ibuprofen, like many other NSAIDs, exhibits molecular chirality, and thus can be found in R- and S-enantiomeric forms. Such compounds typically are produced in enantiomeric mixtures which subsequently can be separated into the individual enantiomers (Yamaguchi et al., 1987). It is generally alleged that the S-enantiomer has the higher prostaglandin synthesis activity of the two enantiomers (Yamaguchi et al., 1987). Indeed Caldwell et al. (1988) have suggested that the R-isomer functions, at best, as prodrugs for the therapeutically active S-forms when the racemic drug is administered. Further, Caldwell et al. suggest that at worst the R-enantiomers of NSAIDs are undesirable impurities in an active drug causing difficulties due to non-stereoselective toxicity.
NSAIDs previously have been shown to be therapeutically effective against a variety of cancers (Heath et al., 1994). However, the toxicity and side effects of S-enantiomers, as described above, make NSAIDs unfavorable for use in human treatment. Indeed, many NSAIDs have been removed from common usage even as analgesics. It would be a fruitful endeavor to identify formulations of NSAIDs for use as treatments of cancers and other diseases, but without the aforementioned disadvantages of the S-enantiomeric compositions.
SUMMARY OF THE INVENTION
The present invention is directed to the provision of novel compositions and uses of ibuprofen. In particular, it has been discovered that the R-enantiomer of ibuprofen, previously thought to be inactive, may be used as a prophylactic and therapeutic agent in the treatment of diseases such as cancers, Alzheimer's and Alzheimer's related diseases.”
Thus, in one embodiment, there is provided a method of inhibiting neoplastic transformation of a cell, comprising contacting the cell with an amount of an R-ibuprofen composition effective to inhibit neoplastic transformation of the cell. In particular embodiments, the tumor cell may be selected from the group consisting of cecum, colon, rectum, jejunum, duodenum, esophagus, stomach, pancreas, liver, bile duct, gall bladder, prostate gland, breast, kidney, pituitary gland, adrenal gland, thyroid gland, ovary, testicle, lung, brain, bone, blood and bone marrow cell.
In certain other embodiments, the cell further is exposed to a chemo- or radiotherapy. It is envisioned that the R-ibuprofen composition may be dispersed in a pharmaceutically acceptable excipient. In particular aspects, it is envisioned that the R-ibuprofen pharmaceutical composition is administered orally. An “R-ibuprofen composition” as used herein is a composition comprising enantiomerically enriched R-ibuprofen, R-ibuprofen substantially free from S-ibuprofen, or a substantially pure R-ibuprofen isomer.
In other embodiments, the cell is located within an animal. In preferred embodiments, the animal is a human subject. In particular embodiments, the animal has colorectal cancer. In yet other embodiments, the animal has an adenoma-based cancer. In preferred embodiments, the cancer may be cecum, colon, rectum, jejunum, duodenum, esophagus, stomach, pancreas, liver, bile duct, gall bladder, prostate gland, breast, kidney, pituitary gland, adrenal gland, thyroid gland, ovary, testicle, lung, brain, bone, blood or bone marrow cell cancer.
In other aspects of the present invention, there is provided a method of preventing cancer growth, comprising administering to an animal at risk for, or having cancer, an amount of an R-ibuprofen pharmaceutical composition effective to inhibit cancer growth in the animal. In particular aspects, the R-ibuprofen composition is for use in the preparation of a prophylactic formulation for administration to a patient at risk for developing cancer. In other embodiments the R-ibuprofen composition may be used for the preparation of a medicament for treating cancer. The R-ibuprofen may have a reduced toxicity and gastropathy as compared with a racemic mixture of R- and S-ibuprofen, or an enantiomerically pure S-ibuprofen composition.
The present invention further contemplates a method of treating cancer comprising administering to an animal with cancer a therapeutically effective amount of an R-ibuprofen pharmaceutical composition. In particular aspects, the method further comprises administering to the animal a therapeutically effective amount of at least a first selected anti-cancer agent In certain preferred embodiments, the anti-cancer agent is taxol, tamoxifen, cyclophosphamide, doxorubicin, 5-fluorouracil, tretinoin, all-trans retinoic acid, methotrexate, 5-azacytidine, daunarubicin, vinblastine, vincristine, ifosfamide, carboplatin, cisplatin, semustine, adriamycin, finasteride, raloxifene, melphalan, buthionine, cyclopentylcytosine, tiazofurin, cytarabine, carmustine, aspirin, flurbiprofen, piroxicam, sulindac, paclitaxel, glycerrhetinic acid, lonidamine, mitoguazone, homoharringtonine, topotecan, edatrexate or aminocampothecin.
Also provided by the present invention, is a composition comprising a combined effective amount of R-ibuprofen and a chemotherapeutic agent. The composition may be dispersed in a pharmaceutically acceptable excipient.
Another aspect of the invention provides a kit comprising, in suitable container means, R-ibuprofen and a chemotherapeutic agent.
In yet a further aspect, the present invention provides a method of inhibiti
Hall Stephen D.
Xiaotao Qian
Advanced Research and Technology Institute
Fulbright & Jaworski
Goldberg Jerome D.
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