Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-23
2002-05-21
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S261000, C546S256000, C546S255000, C546S024000, C514S333000, C514S332000, C514S184000
Reexamination Certificate
active
06391895
ABSTRACT:
The present invention relates to nitric oxide releasing compounds and their use in treating a variety of disorders, in particular conditions resulting from the presence of free radicals in the body. In particular, the invention relates to the use of such compounds in the treatment of ischaemia-related diseases, inflammatory conditions, and retroviral diseases, in anti-tumor therapy, and in cytotoxic antimicrobial treatment (e.g. to combat bacteria, parasites, etc.).
Short-lived but highly reactive free radicals have long been believed to be involved in various sorts of tissue damage, especially in ischaemia-related diseases such as stroke, cerebral injury and thrombotic diseases, and during reperfusion of ischaemic tissue such as may occur during transplantation or microsurgery. Tissue-damaging free radicals may also be produced in certain chronic diseases, for example in diabetes, and are also produced as a result of several anti-cancer treatments, such as radiation therapy or treatment with cytotoxic drugs, e.g. anthracyclines or paclitaxel (taxol).
Ischaemia-related diseases, in particular coronary artery diseases, account for the majority of deaths in Western countries. Typically, coronary narrowing is due to the formation of thromboses at the site of atherosclerotic plaques. Acute coronary thrombosis is often treated by agressive thrombolytic treatment with streptokinase or r-tPA with the object of reperfusing the obstructed artery. However, reocclusion occurs in approx. 10% of cases. Severe coronary artery disease can be ameliorated by elective by-pass surgery, with attendant perioperative risks, or in some patients by the mechanical dilation of the blood vessels by angioplasty. However, the latter treatment carries a significant risk (approx. 30-40%) of restenosis within 6 months.
The reintroduction of oxygenated blood into ischaemic cardiac tissue can, in many cases, result in various forms of cardiac dysfunction, including arrhythmias, myocardial “stunning”, arterial spasm and endothelial damage (Kirschner et al. J. Amer. College of Surgeons 179: 103-117, 1994). Several studies now suggest that much of this reoxygenation damage is a result of the production of superoxide which may in turn lead to intracellular reduction of ferritin-bound Fe(III) to Fe(II) and lipid peroxidation (see Ryan & Aust, Crit. Rev. Toxicol. 22: 119, 1992). Furthermore, the production of certain free radicals, e.g. superoxide, can result in reaction with and hence reduced levels of nitric oxide. This is undesirable since nitric oxide is believed to be essential for correct endothelial function (e.g. antithrombotic activity) and for avoiding vasospasm. Nitric oxide is also believed to have cardioprotective effects (see Vegh et al. Brit. J. Pharmacol. 107: 910-911, 1992 and Lefer et al. Circulation 88: 2337-2350, 1993).
A number of anti-tumor agents are associated with adverse side-effects which severely limit their widespread use. Paclitaxel is one such agent which has shown anti-neoplastic action against a variety of malignant tissues, including those of the breast, colon, lung and ovary, as well as in malignant melonoma. However, at the high dosages required to have an anti-neoplastic effect, paclitaxel has a number of adverse side-effects which can include cardiovascular irregularities as well as hematological and gastrointestinal toxicity.
Anthracycline antibiotics, such as doxorubicin (adriamycin), are amongst the most important of the anti-tumor agents. However, their clinical value is also limited by their cardiotoxicity, which manifests itself as congestive heart failure in 15-40% of patients undergoing therapy. The most likely mechanism for their toxicity is believed to be the production of oxygen-derived free radicals in the heart which cause membrane damage and mitochondrial damage in metabolically active tissues such as heart muscle and intestinal mucosa. Whilst there is evidence to suggest that cardiac damage during anthracycline therapy can be reduced by simultaneous administration of the iron chelator, dexrazoxane, this has been found to be toxic and as a result can only be used in relatively low dosages.
It will be appreciated that there exists a continuing need for alternative compounds capable of treating or preventing conditions generally arising from the presence of free radicals in the body, in particular compounds which are able to prevent reperfusion injuries and act as chemoprotectants during anti-cancer therapy.
In particular, there exists a need for an effective chemoprotectant which in reducing the toxic effects of anti-tumor agents, will permit higher, more effective doses of such agents to be administered.
We have now found that chelating agents linked to at least one nitric oxide releasing moiety, and their metal chelates, are particularly effective in relieving symptoms associated with reperfusion of ischaemic tissue, and in reducing the toxicity of anti-tumor agents, e.g. anthracyclines and paclitaxel.
It has also been found that certain chelating agents, e.g. dipyridoxyl and aminopolycarboxylic acid based chelating agents, and their metal chelates, either when linked directly or indirectly to at least one nitric oxide releasing moiety, or when used in combination with nitric oxide or a nitric oxide releasing moiety, are effective in treating a variety of disorders, especially conditions associated with the presence of free radicals in the body.
Thus, viewed from one aspect the invention provides the use of a chelating agent, or a metal chelate or salt thereof, capable of releasing nitric oxide in vivo in the manufacture of a therapeutic agent for use in relieving symptoms associated with reperfusion of ischaemic tissue.
In another aspect the invention provides a method of treatment of the human or non-human animal body to relieve the symptoms associated with reperfusion of ischaemic tissue, said method comprising administering to said body a chelating agent, or a metal chelate or salt thereof, capable of releasing nitric oxide in vivo.
Viewed from a further aspect the invention provides the use of a chelating agent, or a metal chelate or salt thereof, capable of releasing nitric oxide in vivo in the manufacture of a therapeutic agent for use in reducing the cardiotoxicity of an anti-tumor agent, e.g. an anthracycline drug and/or paclitaxel.
In another aspect the invention provides a method of reducing the cardiotoxicity of an anti-tumor agent administered to the human or non-human animal body, e.g. a method of reducing the cardiotoxicity of an anthracycline drug and/or paclitaxel, said method comprising administering to said body an anti-tumor agent and simultaneously, separately or sequentially a chelating agent, or a metal chelate or salt thereof, capable of releasing nitric oxide in vivo.
Viewed from another aspect the invention provides the use of a chelating agent, or a metal chelate or salt thereof, capable of releasing nitric oxide in vivo in the manufacture of a therapeutic agent for use in combating microbial infection, e.g. by virtue of a cytotoxic antimicrobial effect.
Viewed from a still further aspect the invention provides a method of treatment of the human or non-human animal body to combat microbial infection, said method comprising administering to said body a chelating agent, or a metal chelate or salt thereof, capable of releasing nitric oxide in vivo.
Examples of microbial infection suitable for prophylactic, palliative or curative treatment according to the invention include bacterial and parasitic infections, in particular protozoal infections, for example malaria, trypanosomiasis and leichmaniasis, e.g. Chagas' disease.
Viewed from another aspect the invention provides the use of a chelating agent, or a metal chelate or salt thereof, capable of releasing nitric oxide in vivo in the manufacture of a therapeutic agent for use in combating inflammatory conditions and retroviral disease.
Viewed from a still further aspect the invention provides a method of treatment of the human or non-human animal body to combat inflammatory conditions a
Karlsson Jan Olof Gustav
Malmgren Hakan
Towart Robertson
Wistrand Lars Goran
Amersham Health AS
Aulakh Charanjit S.
Ronning, Jr. Royal N.
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