Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
2002-05-31
2004-12-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S009362, C424S009420, C424S009500, C424S009610, C514S185000, C540S145000
Reexamination Certificate
active
06827926
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to metallotetrapyrrolic compounds having phototherapeutic properties utilizable in photodynamic therapy for photodetection and phototherapy of target tissues.
BACKGROUND OF THE INVENTION
Photodynamic therapy (“PDT”) is a new modality for the treatment of malignancies, diseased tissue, hyperproliferating tissues, normal tissues or pathogens. PDT involves a localized or systemic administration of a photosensitizing compound followed by exposure of target tissue to photoactivating light. The photoactivating light excites the photosensitizer which, in turn, interacts with singlet oxygen causing the production of cytotoxic oxygen species. The interaction of the cytotoxic oxygen species with tissues in which the photosensitizer is localized causes a modification of the tissue, resulting in a desired clinical effect. The tissue specificity of the resultant phototoxic damage is determined largely, although not entirely, by the relative concentrations of the photosensitizer in each tissue at the time of exposure to the photoactivating light. The method of light delivery is also an important therapeutic factor.
Following systemic administration, many photosensitizers accumulate to varying degrees within tissues depending on the pharmacokinetic and distribution profile of the photosensitizing compound and the cell types comprising the tissues. The chemical factors that enable certain photosensitizers to accumulate at a target site to a greater degree than other photosensitizers is not well understood. In addition, the biological factors that result in the preferential uptake of some photosensitizers in certain tissue types compared to others is not well understood either. It is clear, however, that each photosensitizer has its own distribution and pharmacokinetic properties within different tissues and these properties determine the relative usefulness of the drug for the desired therapy. Currently, rigorous screening and biological evaluation in appropriate model systems is required to identify suitable photosensitizers that display the characteristics necessary within the diseased or target tissues for an effective therapy.
An emerging clinical role for photodynamic therapy is in the treatment of proliferative cardiovascular diseases such as atherosclerosis, restenosis and vein graft disease. Atherosclerosis is a disease that causes thickening and hardening of the arteries, particularly the larger artery walls. It is characterized by lesions of raised fibrous plaque that form within the vessel lumen. The plaques are most prevalent in, but not limited to, abdominal aorta, coronary arteries and carotid arteries and increase progressively with age. Intravascular ultrasound in man has shown that the plaque has a dome-shaped, opaque, glistening surface that protrudes into the lumen of the vessel. A lesion will typically consist of a central core of lipid and necrotic cell debris, capped by a collagen fibromuscular layer. Complicated lesions will also include calcified deposits, necrotic tissue, thrombosis and fibrin. The occlusion of vessel lumen caused by the plaque leads to reduced blood flow, higher blood pressure and ultimately ischemic heart disease, if untreated.
The treatment of coronary atherosclerosis presently consists of pharmacological drug therapy, bypass surgery, percutaneous angioplasty and/or stent deployment. Drug therapy is primarily directed towards the control of hypertension (with vasodilators, diuretics, anti-adrenergic agents, angiotensin converting enzyme inhibitors etc) or stabilization of the plaque by lowering circulating lipid levels (with statins). The goal of the drug therapy is to return the patient's arterial blood pressure and circulating cholesterol to normal levels and thereby reduce the stress on the patient's heart, kidneys and other organs. Unfortunately, in some cases drug therapy can have side effects and does not control progressive or acute atherosclerosis.
In the more serious instances of coronary atherosclerosis, a thoracic bypass surgery may be performed, where a vein, usually from the patient's leg, is used to bypass the occluded coronary artery. One end of the vein is attached to the aorta, and the other end is attached to the occluded vessel just beyond the obstruction. Although bypass surgery has become an accepted surgical procedure, it can present substantial morbidity risks, is expensive and generally requires extended hospital care. Moreover, the procedure is often limited to proximal vessels to the heart and the long-term prognosis is less than satisfactory. Roughly five percent of bypass grafts can be expected to occlude each year following the operation and the native vessel can also re-occlude as well, necessitating repeat procedures.
Percutaneous transluminal angioplasty (PTA) consists of balloon expansion of vessels to dilate areas of obstruction and has been used since the late 1980's in the treatment of atherosclerotic coronary and peripheral vascular occlusive disease. Advances in catheter design have allowed more complex and distal stenoses and occlusions of coronary vessels to be treated with PTA. While this endovascular procedure displays excellent immediate revascularization of treated vessels and has gained acceptance as a less invasive alternative to bypass surgery, balloon angioplasty simply redistributes the atherosclerotic stenoses. It has also been determined that in some cases acute closure of the vessel after PTA and accelerated arteriosclerosis, or restenosis (re-occlusion) occurred as often as 40% within 6 months post-procedure. These re-occlusions further increase both as a function of the number of lesions treated and the time post-angioplasty.
Restenosis is the vessel's natural healing response that typically occurs in direct proportion to the magnitude of the balloon angioplasty injury. The exact mechanisms responsible for the restenotic process are not fully understood and thus it is not surprising that at present there are no proven clinical therapies to prevent it. Nevertheless, recent studies in man and animals have shown that two events, intimal thickening and abnormal geometric remodeling, occur following PTA. Indeed, intravascular ultrasound and pathologic studies suggest that, in man, intimal thickening and vessel remodeling are responsible for approximately one-third and two-thirds of the total lumen loss, respectively. Intimal thickening involves the recruitment of vascular smooth muscle cells (VSMC) and perhaps advential myofibroblasts to the intima, where they proliferate and secrete an extracellular matrix. Stent deployment (metal scaffolding used to open vessels) is the only intervention that helps to reduce the effects of the vessel remodelling component of restenosis. However, while stents hold an artery open and significantly reduce acute closure—restenosis rates have been reduced with stents from 40% to 20-35%—it is clear that stents have not eliminated the problem.
Neointimal hyperplasia, i.e., new tissue growth through the sides of the stents, has created a new problem, in-stent restenosis. Interventional cardiologists have tried to remove this proliferative tissue with rotational and directional atherectomy, cutting balloons, eximer lasers, and deployment of another stent (stent sandwich), but none of these has shown to be effective. It is estimated that 1.8 million coronary interventions alone (0.36 million PTA and 1.45 million stent procedures) are performed worldwide each year, so a method of reducing neointima formation remains an important goal. Anti-restenosis treatments have focused on arresting the cell replication cycle and the proliferation of VSMC. A number of gene therapy approaches have been used unsuccessfully to interfere with VSMC proliferation including the use of antisense involved in cell proliferation (e.g. c-myc), and the use of adenovirus to increase nitric oxide synthase and thereby increase nitric oxide, an inhibitor of VSMC proliferation. Poor delivery of the gene therapy to the target vessel and
Greene Stephanie
Leitch Ian M.
Robinson Byron C.
Rychnovsky Steve
Finnegan Henderson Farabow Garrett & Dunner LLP
Miravant Pharmaceuticals, Inc.
Raymond Richard L.
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