Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
2000-03-17
2003-06-17
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
Reexamination Certificate
active
06579540
ABSTRACT:
The present invention relates to a novel therapeutical use of physiologically acceptable vanadium compounds, salts or complexes. The present invention relates in particular to the use of a physiologically acceptable vanadium compound, salt or complex as active component in the preparation of a pharmaceutical composition for the prophylactic treatment of secondary injury of tissue, said secondary injury being induced by primary injury of mainly surrounding tissue, in particular surrounding tissue, and being the result of a traumatic event. It will be clear to the person skilled in the art that secondary injury of tissue may also occur by toxins secreted by already injured tissue and that said already injured tissue has not necessarily to be located in the direct vicinity of the tissue to be protected from secondary injury. In this description the terms vanadium compound, salt or complex are used interchangeably and refer to an organic, inorganic or organometallic compound containing at least one vanadium atom and/or ion in the usual oxidation states, preferably V(II), V(III), V(IV) and/or V(V), said compound optionally being a cation or an anion and optionally being a component of an ion pair.
The use of vanadium compounds for therapeutic purposes is known. For instance, WO 90/12563 discloses the therapeutic use of compositions comprising vanadium compounds as active substance for healing mammalian tissue, e.g. the skin and organs such as heart and brain, wherein vanadium compounds are repeatedly administered in a selected concentration range over a prolonged period of time. In particular, these compositions are said to be able to prevent wrinkles in skin tissue.
The mechanism by which the vanadium compounds according to WO 90/12563 act is not clear as they may inhibit degenerative processes—reduced rate of cell death—and/or stimulate regenerative processes—increased rate of cell proliferation—wherein the net effect is that cell growth surpasses cell death which ultimately leads to healing of the injured tissue. It is, however, disclosed that the vanadium compounds have a stimulating effect on cell proliferation by inhibiting enzymatic dephosphorylation whereby growth factors such as epidermal growth factor (EGF), insulin and platelet-derived growth factor are active for a prolonged period. It is furthermore suggested that the vanadium compounds would promote the healing of e.g. heart and brain. As however heart and brain are non-proliferative tissue the suggested treatment would be unsuccessful on the basis of the postulated mechanism as set out in said cited document and a person skilled in the art would not contemplate treatment of such tissue with vanadium compounds on the basis of the cited disclosure. In this context non-proliferative tissue is understood as tissue or cells which under normal circumstances hardly proliferate. More particularly, non-proliferative tissue is only able to differentiate and thus direct or primary injury of said non-proliferative tissue, e.g. liver necrosis, can therefore not be healed by the use of a vanadium compound said to stimulate the process of proliferation. For example, the mitotoxic index of liver cells as example of non-proliferative tissue under normal conditions is extremely low and is about 1:10.000 to 1:20.000. No evidence for the promoting effect of vanadium compounds on the healing of heart or brain tissue is presented and, consequently, WO 90/12563 is considered as only disclosing the use of vanadium compounds for the enhancement of cell proliferation which in fact can only be effective in so far proliferative tissue, e.g. the skin, is involved, thereby healing direct or primary injury of said proliferative tissue. No disclosure of treatment of non-proliferative tissue is taught.
Besides the growth factor and insulin mimicking properties of vanadium compounds being known the compounds are further known to be Na/K ATP-ase inhibitors, free radical scavengers, in particular superoxide radical scavengers produced by xanthine-oxidase in injured tissues, e.g. ischaemic tissue, bums and other traumata, and inhibitors of the angiotensin II type 2 receptor.
Superoxide radicals can induce apoptosis in tissue and vanadium compounds are therefore expected to be apoptosis inhibitors by scavenging the superoxide radicals. Additionally, Yamada et al. [T. Yamada, M. Horiuchi and V. J. Dzau, Procl. Natl. Acad. Sci. U.S.A 93, 156-160 (1996)] disclose that the angiotensin II type 2 receptor mediates apoptosis. Said receptor is abundantly present in fetal tissue and immature brain and mediates anti-growth effects on vascular smooth tissue and endothelial tissue, wherein the cellular mechanism appears to involve enhancement of the dephosphorylation of mitogen-activated protein kinase (MAP kinase). It should be understood that in the present description immature brain tissue is considered as proliferative tissue. From in vitro studies they conclude that vanadate attenuated the dephosphorylation of MAP kinases thereby inhibiting the angiotensin II type 2 receptor and preventing apoptosis. Thus the suggestion of apoptosis inhibition in these types of tissue by application of vanadium compounds is provided. No data of such application is, however, provided in vitro or in vivo and no non-proliferative tissue is mentioned.
Buerke et al. [M. Buerke, T. Murohara, C. Skurk, C. Nuss, K. Tomaselli and A. M. Lefer, Proc. Natl. Acad. Sci. U.S.A. 92, 8031-8035 (1995)] disclose the use of insulin-like growth factor (IGF) for preventing reperfusion injury after ischaemia. From in vitro studies they conclude that IGF prevents myocardial injury after reperfusion and that pretreatment with IGF affords cardioprotection. Several mechanisms are present to elucidate these effects of IGF including neutrophil accumulation in the ischaemic-reperfused myocardium, inhibition of polymorphonuclear leucocyte-induced cardiac necrosis and induction of reperfusion induced apoptosis of cardiac myocites. However, stimulation of IGF in vivo to reduce reperfusion damage, i.e. indirect or secondary injury of the myocardium, is not disclosed. In addition, Buerke et al. used IGF intracoronary as it would decompose within a very short period of time if it would be administered intravenously. Furthermore, isolated growth factors such as IGF-I, IGF-II and EGF can be obtained in usable quantities only by recombinant technology and are therefore extremely expensive. Use thereof in medicine is therefore also possible only on a very limited scale.
Olivetti et al. [G. Olivetti, R. Abbi, F. Quaini, J. Kajstura, W. Cheng, J. A. Nitahara, E. Quaini, C. DiLoreto, C. A. Beltrami, S. Krajewski, J. C. Reed and P. Anversa, N. Engl. J. Med. 16, 1131-1141 (1997)] disclose that death of myocyte cells as a result of ischaemia occurs through apoptosis and necrosis. Nothing is suggested or disclosed about indirect or secondary injury caused by reperfusion after ischaemia. Nothing is mentioned concerning treatment of any kind. Nothing is disclosed about vanadium compounds.
U.S. Pat. No. 5,583,242 discloses the use of vanadium compounds to inhibit malignant B lymphocyte proliferation by inducing apoptosis in such cells. This effect could, however, not be observed in human T cell leukaemia cell lines or in human colon carcinoma cells thereby indicating that vanadium compounds cannot induce apoptosis in all kinds of cells. Nothing is mentioned about other cell types. As no correlation between B cell population and injury of heart or epithelial tissue is known and B cell population does not increase in events of injury of myocardial or epithelial tissue, application of vanadium compounds for treatment of myocardial or epithelial tissue is not suggested by this document.
Furthermore, vanadium compounds, salts and complexes can be used as insulin simulators in the treatment of diabetes and for the treatment of hypertension and obesity. Known insulin-simulating vanadium salts are sodium orthovanadate (Na
3
VO
4
), vanadyl sulphate (VOSO
4
.(H
2
O)
x
) and other reaction products of vana
Criares Theodore J.
Gho'st Holding B.V.
Kim Jennifer
Sughrue & Mion, PLLC
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