Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
1997-08-07
2001-09-11
Weddington, Kevin E. (Department: 1205)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
C514S008100, C514S492000
Reexamination Certificate
active
06287606
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of group IIIa element-containing compounds in biological applications, including those previously indicated for transforming growth factor &bgr; (TGF&bgr;). For example, the present invention includes the use of group IIIa element-containing compounds to enhance tissue and organ repair, healing and augmentation. As used herein, the phrase group IIIa element-containing compounds refers to compounds containing the group IIIa elements boron, aluminum, gallium, indium, or thallium. Group IIIa element-containing compounds mimic the beneficial activities of the natural repair factor, TGF&bgr;. As used herein and in the claims, the word TGF&bgr; refers to a family of endogenous growth factors such as TGF&bgr;-1, TGF&bgr;-2, TGF&bgr;-3 and bone morphogenetic proteins (BMP).
BACKGROUND OF THE INVENTION
Naturally produced substances have been discovered which promote repair, healing and augmentation of tissues and organs. Such substances have been termed “growth factors”. Growth factors, usually proteins, initiate programs of differentiation and/or development within an organism. When referring to tissue repair, the appellation “growth factor” is a misnomer. Confusion in separating the biological processes of growth from the processes involved in repair, healing and augmentation is often caused by the use of the term “growth factors” to describe these proteins. Repair, healing and augmentation, as discussed in detail below, are distinct biological activities and are clearly distinguishable from growth. Growth in the biological sense is defined as progressive development from a lower or simpler to a higher or more complex form of organization. Tissues and organs “grow” from a few similar appearing cells to a complex organized structure, such as a kidney or an eye. For clarity, organs are defined as functional units of the body containing multiple cell types. Examples of organs include, for instance, kidneys, eyes, the liver, the heart, bone, skin and cartilage. Tissues are defined as functional units of the body that are made up of almost an entirely single cell type. For instance, connective and support tissues are derived from and comprised of almost entirely a single cell type, e.g. fibroblast or muscle cell.
Growth factors can stimulate wound healing. The process of wound healing begins immediately following surface lesions or after skin proteins become exposed to radiation, chemical damage or extreme temperatures. Wound healing requires close control of degradative and regenerative processes, involving numerous cell types and complex interactions between multiple biochemical cascades. Growth factors released in the traumatized area stimulate and promote the following: 1) cell migration into the wound area (chemotaxis); 2) proliferation of epithelial cells, muscle cells, endothelial cells, blood cells and fibroblasts (mito-genesis); 3) formation of new blood vessels (angiogenesis); and 4) matrix formation and remodeling of the affected region including re-epithelization by keratinocytes. Studies on animals have shown that exogenously added growth factors can accelerate the normal healing process, and studies on humans have shown that growth factors can heal previously incurable wounds. Factors capable of enhancing wound healing are particularly important in treatment of patients with chronic wounds which may require daily treatment, represent a constant source of pain to the patient, may lead to life threatening infection and are a significant medical expense. Chronic wounds are those which are slow-healing or which do not heal at all and are common to diabetics, cancer patients and those confined to bed for long periods of time. Treatment of chronic wounds may consume up to $4 billion per year in medical expenses in the United States alone. Skerrett, “‘Matrix Algebra’ Heals Life's Wounds”, Science, 252:1064-1066 (1991).
Despite their beneficial effect on bone, cartilage, skin and connective and support tissue, the use of growth factors poses several problems. Growth factors, when systemically administered, affect non-target organs and may therefore elicit a variety of adverse side effects. For instance, one recent article expressed the opinion that TGF&bgr; may contribute to the renal lesions found in glomerulone-phritis, the leading cause of kidney failure in people with diseases such as lupus, diabetes and hypertension. Skerrett (1991). Further problems with growth factors are their instability and tendency to break down once purified and stored for therapeutic use. Moreover, many of the amino acid sequences of growth factors vary between species and are consequently recognized as foreign by dissimilar, or heterologous, species. There is thus the constant danger of eliciting an immune response upon administration of heterologous growth factors. Furthermore, there is no evidence that parenterally administered growth factors target to bone, cartilage, skin and connective and support tissues. Parenteral administration refers to routes such as intravenous, intramuscular, intraperitoneal and subcutaneous.
As proteins, growth factors are not suitable for oral administration, since they are digested and destroyed before entering the blood stream. Growth factors cannot be satisfactorily administered as topical ointments except for skin wounds, because they are only slowly absorbed by the body and subsequently break down rapidly. Because of these and other problems, growth factors are typically administered intravenously. Since naturally occurring growth factors can alter the function of many organs and tissues of the body, intravenous administration of growth factors affects many non-target organs. A therapeutically effective compound that directly targets bone, cartilage, skin and connective and support tissues when parenterally administered or that can be directly applied to the tissues or organs that need to be repaired, healed or augmented is highly preferred to currently available naturally occurring growth factors.
TGF&bgr; belongs to a family of growth factors that produce multiple biological effects, including mitogenesis, growth regulation, regulation of cartilage and bone formation, chemotaxis and induction or inhibition of cell differentiation, depending on the tissue or cell type and the presence or absence of other growth factors. Most of the published work on TGF&bgr; relates to its wound healing capabilities. However, TGF&bgr; plays other physiological roles, as shown by the fact that it is known to be contained and produced within bone. Seyedin et al., “Cartilage-Inducing Factor”, J. Biol. Chem., 261:5693-5695 (1986); and Robey et al., “Factor-Type &bgr; (TGF&bgr;) in vitro”, J. Cell Biol., 105:457-463 (1987). TGF&bgr; will enhance bone formation. Sporn et al., “Some Recent Advances in the Chemistry and Biology of Transforming Growth Factor-&bgr;”, J. Cell Biol., 105:1039-1045 (1987). Other members of the TGF&bgr; family of growth factors, notably BMP, have also been shown to enhance bone formation. Wozney et al., “Novel Regulators of Bone Formation: Molecular Clones and Activities”, Science, 242:1528-1533 (1988).
Recent studies with purified cell membranes have shown that gallium nitrate (Ga(NO
3
)
3
) can block the transport of hydrogen atoms across osteoclast cell membranes. This hydrogen atom transport would otherwise lead to the dissolution of the mineral matrix of bone, thereby releasing calcium ions into the blood. Although TGF&bgr; affects bone repair, healing and augmentation, it has not been shown to block transport of hydrogen atoms across osteoclast cell membranes. In fact, TGF&bgr; has not been demonstrated to be a clinically effective antiresorptive agent capable of preventing accelerated bone breakdown and disordered calcium homeostasis. Indeed, unlike previously shown activity of gallium nitrate, TGF&bgr; inhibits the differentiation and proliferation of osteoclastic cells, leading to decreased osteoclast cell numbers. Chenu et al., “Transforming Growth Factor Beta Inhibits Formation of O
Bockman Richard
Guidon Peter
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