Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-03
2004-02-24
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S457000, C514S690000, C514S725000
Reexamination Certificate
active
06696483
ABSTRACT:
TECHNICAL FIELD
This invention relates to formulations containing pharmacologically active agents, solvents, carriers, and the like. More particularly, the invention relates to compounds and formulations that have anti-angiogenic effects.
BACKGROUND
The circulatory system serves an important role in the transport of nutrients, proteins, hormones, and other vital molecules that are necessary to maintain life. Blood vessels, which form an intricate network of pathways, represent an integral component of the circulatory system. In mammalian species, the internal surface of a blood vessel lumen is comprised of endothelial cells. These endothelial cells impart a smooth and low resistance quality to the lumenal surface. Critical to the free flow and transport of blood and blood constituents, the smooth and nonadhesive internal surface of the blood vessel increases the ease with which fluid flows. Without a smooth internal surface, blood vessels would become obstructed due to the formation of thrombi or other blockages at “sticky” locations on the internal walls. Complete or even partial blood vessel blockage would cause restriction of blood flow, thereby compromising the viability of living tissue served by the vessel. Thus, endothelial cells represent an important structural component of blood vessels and also provide blood vessels with a smooth internal surface.
The formation of blood vessels in vivo takes place in response to stimuli, which are provided in the form of specialized growth factors. These growth factors induce mitosis in cells already present in blood vessels. The new cells may replace nearby damaged cells, or the new cells may arrange themselves such that new blood vessels are formed. The process of growing blood vessels from endothelial cells is termed “angiogenesis,” which results in, among other characteristics, the vascularization of tissue.
Angiogenesis has become a central theme in promoting our understanding of how tissue grows. As indicated above, endothelial cell proliferation is not only desirable, but also necessary to carry out a number of physiological processes, for example the in utero formation of tissues and organs. In other contexts, however, angiogenesis may be harmful to the overall health of an organism. For example, continuous or uncontrolled angiogenesis can cause or exacerbate diseases such as rheumatoid arthritis, psoriasis, and certain retinopathies, e.g., diabetic retinopathy. Furthermore, angiogenesis makes tumor growth and metastasis possible by vascularizing the tumor, thereby supplying the tumor with blood and nutrients that are necessary to sustain the tumor's growth, as well as providing routes by which tumor cells can migrate to distant parts of the body. Folkman (1986)
Cancer Res.
46(2):467-473. Clearly then, the prevention or reduction of angiogenesis may be a desirable goal in treating some disorders and diseases. Compounds have been tested for their ability to inhibit or reduce angiogenesis. Inhibitors of vascular endothelial growth factor (VEGF), a protein that selectively induces mitosis of vascular endothelial cells, have been investigated. For example, U.S. Pat. No. 6,284,751 to Aiello et al. describes using inhibitors of the &bgr; isozyme of protein kinase C to counteract the effects of VEGF. Antibiotics such as minocycline have also been reported to inhibit angiogenesis. Some investigators have reported inhibition of tumor growth as well as reduction in the number of metastatic tumors following administration of minocycline in combination with radiation or chemotherapy. See Tamargo et al. (1991)
Cancer Res.
51(2):672-675, and Teicher (1992)
Cancer Res.
52(23):6702-6704. U.S. Pat. No. 5,843,925 to Backer et al. describes inhibition of angiogenesis upon administration of certain deoxytetracylines. Many of these angiogenesis-inhibiting compounds, however, have only been tested in vitro for their antiproliferative activity.
Thus, there remains a need to identify additional angiogenesis-inhibiting compounds that have demonstrated in vivo efficacy.
Brefeldin A (BFA) is a macrocyclic lactone first described by Haerri et al. See Haerri et al. (1963)
Chem. Abs.
59:5726 h. Brefeldin A was also reported to have anti-viral properties, according to Tamura et al. (1968)
J. Antibiotics
21:161-166. In recent years, brefeldin A has been studied extensively as a protein transport inhibitor. It is believed that brefeldin A can reversibly disrupt the Golgi apparatus, thereby affecting protein transport through the cytoplasm. Domes et al. (1989)
J. Cell Biol.
109:61-72; Lippincott-Schwartz et al. (1991)
J. Cell Biol.
112:567-577. It is now known that brefeldin A induces retrograde membrane transport from the Golgi apparatus to the endoplasmic reticulum (ER). Dinter et al. (1998)
Histochem. Cell Biol.
109:571-590. Currently, brefeldin A is used by researchers primarily as a tool by which to interfere with the processing and sorting of finished proteins in order to more fully understand protein trafficking.
Due to its perceived lack of solubility as well as its resultant toxicity, brefeldin A has not yet been used clinically as an active agent in a pharmaceutical formulation. U.S. Pat. No. 4,608,078 to Acker et al. reported preparation of derivatives of brefeldin A with enhanced solubility, but these derivative compounds still exhibited toxicity due to inadequate solubility. In 1997, the preparation and antitumor activity of water-soluble derivatives of brefeldin A were disclosed in U.S. Pat. No. 5,696,154 to Malspeis et al. These derivatives were claimed to be suitable for intravenous delivery to animals and humans. However, these analogs have only been tested in vitro using minute quantities, which may be insufficient to produce desired therapeutic effects in vivo. U.S. Pat. No. 6,287,602 to Singh describes formulations comprising a Golgi apparatus disturbing agent as the active agent; a biocompatible carrier to increase the effective solubility of the active agent in the formulation and/or to provide a desired sustained release profile of the active agent; and a solvent. Formulations that lack a biocompatible carrier as well as those that are effective in inhibiting angiogenesis, however, are not disclosed.
Thus, there is a need to identify additional compounds as inhibitors of angiogenesis. Furthermore, there remains a need for additional formulations comprising Golgi apparatus disturbing agents for the treatment of disease. The current invention is directed to address these and other needs in the art by providing, inter alia, brefeldin A and related compounds as active agents in methods and formulations for inhibiting angiogenesis.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the invention to provide a method for inhibiting angiogenesis in a patient by administering an effective angiogenesis-inhibiting amount of a Golgi apparatus disturbing agent to the patient.
It is yet another object of the invention to provide such a method wherein the Golgi apparatus disturbing agent is administered to a patient in need of anti-angiogenic therapy.
It is still another object of the invention to provide such a method wherein the Golgi apparatus disturbing agent is administered via injection, either systemically or locally.
It is a further object of the invention to provide a pharmaceutical formulation to treat a patient in need of anti-angiogenic therapy, wherein the formulation is comprised of a solvent, a pharmaceutically acceptable carrier, and a Golgi apparatus disturbing agent in a substantially noncytotoxic quantity effective to inhibit angiogenesis.
Additional objects, advantages, and novel features of the invention will be set forth in part in the description that follows, and in part, will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In a first embodiment, then, a pharmaceutical formulation is provided comprising: a Golgi apparatus disturbing agent in a substantially noncytotoxic amount effective to inhibit angiogenesis in a
Canaan Karen
OncoPharmaceutical, Inc.
Reamer James H.
Reed & Eberle LLP
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