Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-02-06
2002-04-02
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S468000
Reexamination Certificate
active
06365627
ABSTRACT:
BACKGROUND OF THE INVENTION
Virtually all of the many antineoplastic drugs that are currently used in the treatment of cancer have very serious and harmful side effects. This is because cancer is generally treated with medications that interfere with the growth of rapidly dividing cells. Such medications can inhibit the growth of the cancer cells, but they almost always also inhibit the growth of normal cells that divide rapidly in the body. Some of the normal tissues that divide very rapidly include bone marrow (which produces blood cells), hair follicles, and intestinal epithelium. The usefulness of virtually all antineoplastic drugs is severely limited by the damage they cause to these normal tissues.
This invention relates to methods for treating neoplasia using both a paclitaxel derivative (a common chemotherapeutic) and a cyclic GMP (cGMP)-specific phosphodiesterase (PDE) inhibitor to reduce the side effects or increase the efficacy of paclitaxel treatment. Paclitaxel derivatives (e.g., taxol) have been used to treat certain cancers, particularly ovarian and breast cancers in patients where at least first-line chemotherapy has failed. Under current practice, taxol therapy is typically used after first-line failure because taxol is so toxic and its side effects are so bad that the risks of the therapy outweigh the benefits until other chemotherapeutic options commonly have been exhausted.
The side effects of taxol include anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension, angiodemia, and generalized urticaria. Side effects also include nausea and vomiting. However, the dose-limiting side effect of taxol is bone marrow suppression. Bone marrow produces blood cells. Taxol can lower the number of white blood cells that guard against infections, and lower the number of platelets that prevent bleeding. Still other side effects include neuropathy, joint and muscle pain or weakness, alopecia (or complete hair loss, which almost always occurs with taxol).
Investigators have reported that some of its side effects can be attenuated by the pre-medication of the cancer patient with a medication that eliminates or reduces hypersensitivity. For example, in U.S. Pat. No. 5,670,537, the applicants reported that if a cancer patient is pretreated with a steroid or the like, the dose of taxol between 135 and 175 mg/m
2
can be administered in about three hours. However, the Physicians' Desk Reference warns that even in this mode of administration, taxol still causes side effects severe enough to warrant its discontinuation in some patients—patients who already failed to respond to first-line therapy, of course. In other words, taxol is not recommended for first stage cancer therapy given its side effects.
Efforts have been made to improve paclitaxel, but those efforts have concentrated mainly in improving its administrability (e.g., developing more water-soluble forms of the medication). However, few, if any, investigators have reported a significantly better way to reduce the side effect of paclitaxel while maintaining its therapeutic effect, or to increase its therapeutic effect while not increasing the side effects.
SUMMARY OF THE INVENTION
This invention relates to an improved method of cancer therapy that involves treating a patient with both a paclitaxel derivative (e.g., taxol) and a cyclic GMP-specific phosphodiesterase (PDE) inhibitor. The specific PDE inhibitors useful for this invention are compounds that inhibit both PDE5 and the new cGMP-specific PDE described below. The novel cGMP-PDE is fully described by Liu, et al., in the copending U.S. patent application Ser. No. 09/173,375, now U.S. Pat. No. 6,200,771, A Novel Cyclic GMP-Specific Phosphodiesterase And Methods For Using Same In Pharmaceutical Screening For Identifying Compounds For Inhibition Of Neoplastic Lesions. (For general PDE background, see, Beavo, J. A. (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiological Reviews 75:725-747; web site <http://weber.u.washington.edu/~pde/pde.html>(November 1998)).
In this invention, the cGMP-specific PDE inhibitor can be used in combination with paclitaxel in two ways. The first is a lower dosage methodology in which the traditionally recommended dose range of paclitaxel is decreased while its therapeutic effects are maintained and its side effects are attenuated. The second is a higher dosage methodology that utilizes the traditionally recommended dose range for paclitaxel and improves its activity without increasing its side effects.
With either methodology, paclitaxel is administered simultaneously or in succession with a cGMP-specific phosphodiesterase inhibitor, preferably an inhibitor of cGMP-specific phosphodiesterases (“PDE”) found in neoplastic cells, of which there are several. It is even more preferred that such an inhibitor have an inhibiting effect on at least several such PDEs, specifically PDE5 and a new cGMP specific phosphodiesterase found in neoplastic cells, which is described below.
In the low dose regime, paclitaxel is administered at doses less than 135 mg/m
2
over a period of less than six hours. In the high dose regime, paclitaxel is administered at doses between about 135 and 175 mg/m
2
over a period of less than six hours.
REFERENCES:
patent: 5670537 (1997-09-01), Canetta et al.
Menander Kerstin B.
Pamukcu Rifat
Cell Pathways Inc.
Jones Dwayne C.
Stevenson Robert W.
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