Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-04-21
2001-05-08
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06228843
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a method for treating pulmonary and systemic vascular diseases associated with cardiac hypertrophy, dysfunction, or failure, such method comprising administering effective amounts of a PKC antagonist to a patient suffering from one of such diseases. The methods may also be effective at directly treating airway and interstitial diseases of the lung that lead to the development of pulmonary hypertension. Other embodiments relate to particular formulations of bryostatin compounds formulated for particular diseases, as well as methods of using such compounds to treat patients having such diseases.
BACKGROUND OF THE INVENTION
Adult and neonatal pulmonary and systemic vascular disease is a common clinical problem. These vascular diseases include pulmonary and/or systemic hypertension, atherosclerosis, post-angioplasty re-stenosis, post-transplant vasculopathy, diabetic vasculopathy, peripheral vascular disease, vasculitis, and capillaritis. They are complicated by cardiac hypertrophy, dysfunction, or failure. These clinical problems characteristically include alterations in vascular structure, such as abnormalities in vessel wall thickness and/or vessel formation and/or obliteration, and alterations in vascular tone, such as abnormal contractile response to agonists. Myocardial hypertrophy, dysfunction, or failure are also often observed. These disease processes also cause important vascular cell responses in smooth muscle cells, adventitial fibroblasts, and endothelial cells that contribute to the disease process, including hypertrophy, proliferation, migration, matrix protein synthesis, permeability, and contraction. Inflammatory cell recruitment and activation is also though to be important in the pathogenesis of vascular disease.
Among these diseases is chronic hypoxic pulmonary hypertension (PHTN), which results from structural remodeling and abnormalities of vascular tone (Reeves and Herget, 1984; Haworth, 1993). The alteration in vascular structure results from changes in cellular hypertrophy, proliferation, apoptosis, differentiation, migration, permeability and matrix protein synthesis (Meyrick and Reid, 1979; Rabinovich, et al., 1981; Jones, et al., 1984; Stenmark, et al., 1987). The pulmonary hypertensive process has been observed in several species, including adult mice (Hales, et al., 1983; Klinger, et al., 1993; Steudel, et al., 1998; Fagan, et al., 1999).
The cellular and molecular mechanisms by which the pulmonary hypertensive process occurs are still poorly understood. However, it has been observed that protein kinase C (PKC) is involved in many of the vascular cell responses that contribute to the pulmonary hypertensive process (Komero, et al., 1991; Nishizuka, 1992; Haller, et al., 1994; Ways, et al., 1995). PKC is an important signal transduction pathway involving a family of at least 11 related intracellular kinases. One isozyme in particular, PKC-&agr;, has been implicated in vascular cell responses to hypoxia (Goldberg, et al., 1997; Dempsey, et al., 1997, 1998; Xu, et al., 1997). On the basis of this assertion, as well as earlier studies, the PKC pathway has been presumed to be important in the pathogenesis of chronic hypoxic PHTN (Orton and McMurtry, 1990; Dempsey, et al., 1990, 1991; Xu, et al., 1997). Mechanisms that important here (like PKC) are also thought to play a critical role in other forms of PHTN, systemic vascular diseases, and various lung conditions like asthma, bronchiolitis, interstitial lung disease and lung injury.
It is, therefore, desirable to develop pharmacological strategies to attenuate chronic hypoxic pulmonary hypertension. One such strategy involves the PKC signal transduction pathway. One family of compounds that bind to PKC with high affinity is the bryostatins, a group of macrocyclic lactones isolated from marine bryozoans (Pettit et al., 1982; Kraft et al. 1986). In vitro, it has been found that bryostatin-1 inhibits cell growth and activity of isozymes of PKC, as well as inducing cell differentiation and apoptosis of a variety of transformed cell lines. Its effects on migration and contraction are unknown. Bryostatin-1 induces rapid inactivation and degradation of PKC in a cell-type-and isozyme-specific manner (Lee, et al., 1996, 1997; Blumberg, et al., 1997). In vivo, bryostatin-1 is known to accumulate in the lung in high concentrations. It is currently being tested in NCI-sponsored clinical trials for treatment of several types of malignancies (Zhang, et al., 1996; Caponigro, et al., 1997; Weitman et al., 1999).
SUMMARY OF THE INVENTION
In accordance with the present invention, bryostatin-1 has been tested in vitro in bovine pulmonary artery smooth muscle cells and in vivo in an adult murine model of vascular disease, specifically, chronic hypoxic pulmonary hypertension. The present invention relates to the discovery that bryostatin-1 can attenuate the development of chronic hypoxic pulmonary hypertension in adult ICR mice. The attenuating effects observed here on pulmonary vessels and the right ventricle of the heart are applicable to other types of pulmonary and systemic vascular and related disease. Other bryostatin derivatives could also have attenuating effects on these vascular disorders.
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Sheridan & Ross P.C.
Spivack Phyllis G.
University Technology Corporation
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