Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-01
2002-06-04
Goldberg, Jerome D. (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
06399649
ABSTRACT:
FIELD OF THE INVENTION
The present invention pertains to the treatment of patients with chronic lymphocytic leukemia (CLL) with pharmaceutical compositions comprising Type 4 cyclic adenosine monophosphate phosphodiesterase inhibitors, and more particularly, with an inhibitor that specifically inhibits Type 4 cyclic adenosine monophosphate phosphodiesterase.
BACKGROUND
Leukemias are malignant neoplasms of hematopoietic tissues. These neoplasms are categorized into two predominant forms: chronic and acute. While acute leukemias are characterized by undifferentiated cell populations, chronic leukemias usually present a more mature morphology. Notwithstandmg these classifications, however, the pathological impairment of normal hematopoiesis is the hallmark of all leukemias.
Chronic lymphocytic leukemia (CLL) is a neoplasm in which a clonal expansion of small lymphocytes accumulate in the marrow, lymph nodes, blood, spleen liver, and sometime other organs. The CLL cell is the neoplastic counterpart of an immunologically immature, incompetent lymphocyte. In over 95 percent of the cases, the clonal expansion is of a B-cell lineage.
See Cancer: Principles
&
Practice of Oncology
(3rd Edition) (1989) (pp. 1843-1847). In less than 5 percent of cases the tumor cells have a T-cell phenotype.
CLL, while accounting for only about 0.8 percent of all cancers in the United States, is the most prevalent leukemia afflicting adults in modern. countries, accounting for 30 percent of all leukemias. A majority of patients are over 60 years at the time of disease and 90 percent are over age 50.
Most patients are diagnosed following a routine physical examination or a blood count. The earliest and most frequent symptoms are fatigue and malaise. Later symptoms include lymphadenopathy and splenomegaly. Anemia and thrombocytopenia is found in approximately 15 percent of patients.
The general goal of leukemia therapy is to arrest the proliferation of abnormal morphologies and restore “normal” hematopoiesis in the bone marrow. Treatment regimens include chemotherapy. Unfortunately, chemotherapy is not always successful. Indeed, while CLL patients may have initial clinical responses to alkylating agents such as chlorambucil or adenosine analogs such as fludarabine, many ultimately become refractory to therapy. Consequently, there is a pressing need for the identification of novel approaches to this disease.
SUMMARY OF THE INVENTION
The present invention pertains to the treatment of patients with chronic lymphocytic leukemia with pharmaceutical compositions comprising Type 4 cyclic adenosine monophosphate phosphodiesterase inhibitors, and more particularly, with an inhibitor that specifically inhibits Type 4 cyclic adenosine monophosphate phosphodiesterase. One embodiment of the present invention contemplates a method comprising: a) providing: i) a patient having symptoms of chronic lymphocytic leukemia, and ii) a formulation comprising an inhibitor that specifically inhibits Type 4 cyclic adenosine monophosphate phosphodiesterases; and b) administration of a therapeutically effective dose of said formulation to said patient under conditions such that said symptoms are reduced.
The present invention is not limited by the method of administration. In one embodiment, the administration is enteral administration. In another embodiment, said enteral administration is oral administration. In still another embodiment, said administration is parenteral administration. In these embodiments, said parenteral administration can be topical administration or by a transdermal patch. In another embodiment, said parenteral administration is subcutaneous administration. While in still another embodiment, said parenteral administration utilizes an aerosol.
The present invention is not limited by the nature of the patient. In one embodiment, said patient is a naive patient (e.g., has not undergone prior treatment for CLL), while in other embodiments said patient is unresponsive or refractory to standard chemotherapy (e.g., alkylating agents). In still another embodiment, said patient is immunocompromised. In one embodiment, said patient is over fifty years of age.
The present invention is also not limited by the method of determining response to treatment. In one embodiment, said symptoms comprise lymphadenopathy and splenomegaly. In a yet another embodiment, said symptoms comprise the histology of a lymph node that is consistent with CLL.
The present invention contemplates usage of a variety of specific inhibitors. A preferred inhibitor is rolipram. While it is not intended that the present invention be limited to a specific mechanism by which the inhibitors of the present invention achieve therapeutic success, it has been empirically found (as the data herein shows) that the specific inhibitors of the present invention (e.g., rolipram) augment apoptosis induced by commonly used drugs (e.g., doxorubicin, chlorambucil and fludarabine). Consequently, the present invention specifically contemplates the use of the inhibitors in combination with other drugs, including but not limited to cytotoxic drugs.
Definitions
As used herein, the term “enteral administration” means the introduction of a composition to a patient such that it is absorbed in the intestinal tract of the patient (e.g., pill, tablet, elixir, etc.)
As used herein, the term “oral administration” means the introduction of a composition to a patient through the oral cavity (i.e., in the mouth).
As used herein, the term “parenteral administration” means administration of a composition other than enteral (e.g., injection, transdermal, aerosol, etc.).
As used herein, the term “topical administration” means the introduction of a composition to a patient by application to the surface of the skin.
As used herein, the term, “subcutaneous administration” means introduction of a composition to a patient under the surface of the skin (e.g., injection with a hypodermic needle).
As used herein, the phrase “naive patient” refers to a patient that has not undergone prior treatment for chronic lymphocytic leukemia.
As used herein, the phrase “an inhibitor that specifically inhibits Type 4 cyclic adenosine monophosphate phosphodiesterase” refers to a compound that inhibits Type 4 but not Type 1 or 3 phosphodiesterases. Of course, background level inhibition of Type 1 or 3 phosphodiesterases is permitted within the definition. Where the inhibitor inhibits Type 4 as well as Type 1 and/or 3, but inhibits Type 4 to a greater extent (the amounts being subject to quantitative determination by assays described herein), the phrase “preferentially inhibits Type 4 phosphodiesterases” is used herein (as distinct from “Type 4 specific.”
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Boston Medical Center Corporation
Goldberg Jerome D.
Nixon & Peabody LLP
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