The assignee for this patent, patent number 8629110, is Hospital Clinic I Provincial de
Reporters obtained the following quote from the background information supplied by the inventors: "The wall of blood vessels is made up of three concentric strata or tunicae (the tunica intima, media and adventitia) with well distinguished structure and composition. The tunica intima is made up of a single layer of endothelial cells supported on a basement membrane rich in collagen and proteoglycans and separated from the media by the internal elastic lamina. The tunica media is formed by vascular smooth muscle cells (VSMCs) and extracellular matrix, and the adventitia, the outermost layer, is essentially made up of connective tissue and fibroblasts.
"The VSMCs are physiologically located in the tunica media. However, VSMCs can be found in the intimal layer as a result of a lack of organization of the structure of the vascular wall due to vascular pathologies or lesions such as atherosclerosis, hyperplasia of the tunica intima.
"Intimal hyperplasia is a change in the vascular structure which occurs as a result of the biological repair mechanisms after a vascular lesion, either mechanical, surgical, inflammatory or immunological. The most characteristic finding of this structural change is the thickening of the intimal layer, due both to an increase in the number of cells and to an increase in the synthesis of extracellular matrix in which these cells are found (Davies M G, Hagen P O. Pathobiology of intimal hyperplasia.
"There are various pathological situations associated with intimal hyperplasia and the triggering factors can generally be grouped together as physical lesions (in many cases iatrogenic lesions due to vascular surgery), inflammatory lesions (as in atherosclerotic lesions) or due to an increase of the tension of the wall (as in the case of pulmonary hypertension or the use of vein grafts in by-pass surgery). Some of the diseases associated with intimal hyperplasia include:
"Late By-Pass Occlusion:
"Revascularization with vein grafts is the standard treatment for occlusive arterial diseases when the occluded segment is large and an endarterectomy cannot be performed. The most used technique is the autogenic transplant of a segment of the saphenous vein, and it is used both in coronary surgery and in peripheral vascular surgery (intermittent claudication, thromboangiitis obliterans of the tibial artery, etc.). Although the procedure has a very good immediate result, in the long term, the vein graft suffers chronic maladaptive response to an arterial environment in which the primary component is the uncontrolled proliferation of vascular smooth muscle cells, giving rise to intimal hyperplasia which can later become complicated due to the development of atherosclerosis and thrombosis (Murphy G J,
"Post-Transplant Coronary Vasculopathy:
"Post-transplant coronary vasculopathy is the main factor limiting long-term survival after a heart transplant. It manifests as an especially aggressive form of coronary artery disease that is different from conventional arteriosclerosis, which is caused by the combination of physical, chemical and immunological factors causing an endothelial lesion which in turn triggers the proliferation of vascular smooth muscle cells and intimal hyperplasia The pathological analysis of the lesions shows a thickening of the intima in which undifferentiated cells of the smooth muscle and macrophages and lymphocytes participate. This thickening of the intima leads to the obstruction of the coronary arteries, which ultimately leads to graft failure (Aranda and Hill, Chest 2000, 118(6): 1792-1800; Schmauss and Weis, Circulation (2008) 117(16):2131-41M:
"An important aspect of the pathogenesis of vasculopathy is the interaction of immunological and non-immunological factors. In fact, for many years it was believed that intimal hyperplasia was due exclusively to immunological factors. However, immunosuppressant therapies have not been proven to be capable of reducing its incidence. On the contrary, an increase of hyperplasia after the introduction of treatments based on the use of immunosuppressants, such as cyclosporine, has been observed. In studies conducted with experimental animal models, promising results have been obtained when these immunosuppressant agents are combined with drugs such as MMF (mycophenolate mofetil) which inhibits DNA synthesis and therefore has a generalized antiproliferative effect that extends beyond the immune cells. Although revascularization procedures (percutaneous coronary angioplasty, coronary atherectomy, coronary bypass surgery or stent implantation) can be used in patients presenting localized stenoses, the diffuse character of arteriopathy makes the use of these therapies limited; therefore the development of new pharmacological therapies targeted at controlling the factors which determine intimal hyperplasia in this vasculopathy is necessary.
"Post-Transplant Chronic Nephropathy:
"The factors triggering coronary vasculopathy are also present in other post-transplant vasculopathies, as is the case of post-transplant nephropathy, which again represents the most frequent cause of renal transplant failure.
"In addition to those mentioned, there are other diseases resulting from intimal hyperplasia. In order to identify when a disease is due to intimal hyperplasia, the person skilled in the art will use imaging techniques. Specifically, coronary angiography is used in the coronary tree, injecting contrasting fluid into the ostium of said arteries. Likewise, the 64-slice multislice CT and cardiac resonance angiography are also able to display atherosclerotic lesions in the coronary circulation.
"Angiographic techniques are complemented with ultrasound techniques, such as intravascular ultrasound, which allow displaying the thickness of the arterial intimal layer, and determining if there is an atherosclerotic lesion and its characteristics. In normal conditions, the thickness of the intima cannot be measured microscopically because it is a single layer of cells. However, any measurable thickness (which is greater than a single cell layer) is pathological (FIG. 1).
"There are other techniques, such as virtual histology, which allows determining the presence of lipids, calcium, a clot, fibrous tissue and hyperplasia, and OCT (optical coherence tomography), which uses laser technology to determine the entire thickness of the vascular wall and thus identifying the areas of intimal hyperplasia (see FIG. 2). Both in human arterial specimens and in experimental samples of animal models, morphometry is used for the histological analysis of the thickness of the various layers of the arterial wall. After the suitable treatment period, the animal will be euthanized and the studied vessels extracted and fixed for their subsequent analysis. Histological slices will be obtained and stained with hematoxylin-eosin. The internal elastic lamina will be identified and the areas of the various vascular layers evaluated (
"Given the incidence and severity of these pathologies, there is a need to develop a tool which limits or prevents intimal hyperplasia and the pathological situations resulting from it, especially after surgical interventions or transplant surgery.
"The inventors have surprisingly found that the 1.3 voltage-activated potassium channel (Kv1.3) blockers significantly limit intimal hyperplasia.
"Traditionally, inhibitors of Kv1.3 have been used in therapies against immunological diseases, such as encephalomyelitis or multiple sclerosis (Wulff, H. et al., 2003. Curr.
"Document WO2008088422 discloses the use of peptide inhibitors of Kv1.3 for the treatment of autoimmune diseases, allergies, diabetes and obesity and describes the manufacture and purification of derivatives of the toxins ShK, MgTx.sub.1, MTX.sub.1, HsTxl, wGVIA, HaTxl, etc. According to the data shown, the peptide derivatives of ShK are able to inhibit the human Kv1.3 current with an IC of -150 pM. ShK is, furthermore, a potent inhibitor of the proliferation of T-cells so their use in therapies for the treatment of immunological diseases such as multiple sclerosis, rheumatoid arthritis, dermatitis, diabetes type I, etc., is proposed.
"K.sup.+ Channels in the Vascular Smooth Muscle
"Potassium channels also play a very relevant role in the immediate and long-term regulation of the function of the vascular smooth muscle cells. The VSMCs of the walls of the vessels are cells which express a unique repertoire of contractile proteins, ion channels and signaling molecules aimed at maintaining vascular tone. At least four types of K.sup.+ channels have been identified in VSMCs: voltage-dependent K.sup.+ channels (Kv), such as Kv1.2, Kv1.3, Kv1.5, Kv1.6 and Kv2.1, calcium-activated K.sup.+ channels (such as the maxiK or BK channels), of inward-rectifying K.sup.+ channels (such as the K.sub.IR channels and K.sub.ATP channels) and two-pore K.sup.+ channels, which are responsible for the background currents and the TASK and TWIK channels (reviewed in Jackson W F, Microcirculation 12, 113-127, 2005). Furthermore, the existence of regulating subunits of these channels together with the variation in their expression depending on the vascular bed, contributes to the fine regulation of the smooth muscle physiology. Thus, the pathological processes can be associated with the deregulation of multiple control mechanisms acting in parallel or in combination. Determining which mechanism leads to a specific vascular disease is an arduous scientific experiment task.
"According to the foregoing, and due to the diffuse and distal location of hyperplastic lesions, the field of the art cannot provide effective therapies for the treatment of intimal hyperplasia. It would therefore be convenient to develop a therapeutic tool aimed at controlling the factors determining hyperplasia of the tunica intima and which is able to stop the migration and proliferation of the VSMCs therein, as well as the secretion of components of the cell matrix."
In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "According to the need to develop a tool for an effective therapy against hyperplasia of the vascular tunica intima, the inventors propose the use of Kv1.3 channel blocking substances in the manufacture of a pharmacological tool for the treatment of diseases relating to intimal hyperplasia.
"An advantage of the present invention is the selective blocking of the Kv1.3 channels of the VSMCs by means of the use of blocking substances belonging to the group of margatoxin, ShK toxin, psoralen, kaliotoxin, correolide, J123, and the derivatives and combinations thereof, for the manufacture of a pharmacological tool for the treatment of diseases relating to hyperplasia of the vascular tunica intima. According to this, a possible embodiment of the present invention is the use of Kv1.3 blockers in the manufacture of a pharmacological tool for the treatment of vascular diseases which cause restenosis and comprise post-transplant chronic nephropathy, late by-pass occlusion and post-transplant coronary vasculopathy, and the equivalents and combinations thereof. In particular, the present invention comprises the use of Shk-L5, PAP-1 or both, in the manufacture of a pharmacological tool for the treatment of said vascular diseases. An advantageous embodiment of the present invention is the use of said blocking substances in the manufacture of a pharmacological tool for the treatment and/or prevention of restenosis.
"Clinical practice would benefit from the application of a preventive and/or therapeutic protocol against hyperplasia of the tunica intima. Accordingly, a possible embodiment of the present invention consists of a method for the prevention or treatment of intimal hyperplasia, comprising the administration of a Kv1.3 blocking substance. Advantageously, this method is used for the selective blocking of the Kv1.3 channels of the VSMCs by means of the use of pharmacological tools manufactured with blocking substances belonging to the group of margatoxin, ShK toxin, psoralen, kaliotoxin, correolide, J123, and the derivatives and combinations thereof, preferably Shk-L5, PAP-1 or both. In particular, this method can be applied in the treatment of diseases which cause restenosis, such as post-transplant chronic nephropathy, late by-pass occlusion and post-transplant coronary vasculopathy, and the equivalents and combinations thereof.
"Cardiovascular pharmacology lacks effective tools designed for the treatment of diseases resulting from hyperplasia of the tunica intima. For the purpose of solving this lack, a possible embodiment of the present invention consists of a metering apparatus for implanting in an arterial vessel of an animal, which can be a human, comprising a containing system for containing a Kv1.3 blocking substance. An advantage of this apparatus is that the active ingredient it meters is a selective Kv1.3 channel blocker of the VSMCs belonging to the group of margatoxin, ShK toxin, psoralen, kaliotoxin, correolide, J123, and the derivatives and combinations thereof. The present invention preferably comprises the substances Shk-L5, PAP-1 or both. In particular, this apparatus can be applied in the treatment of diseases which cause restenosis, such as post-transplant chronic nephropathy, late by-pass occlusion and post-transplant coronary vasculopathy."
For more information, see this patent: Heras Fortuny, M' Magdalena;
Keywords for this news article include: Biotechnology, Surgery, Angiology, Treatment, Cardiology, Immunology, Nephrology, Restenosis, Hyperplasia, Nephropathy, Gene Therapy, Legal Issues, Muscle Cells, Pharmacology, Therapeutics, Heart Disease, Bioengineering, Cardiovascular, Atherosclerosis, Risk and Prevention, Surgical Technology.
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