WO2013041205A1 - Nouveaux concepts thérapeutiques pour le traitement de maladies vasculaires - Google Patents

Nouveaux concepts thérapeutiques pour le traitement de maladies vasculaires Download PDF

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WO2013041205A1
WO2013041205A1 PCT/EP2012/003888 EP2012003888W WO2013041205A1 WO 2013041205 A1 WO2013041205 A1 WO 2013041205A1 EP 2012003888 W EP2012003888 W EP 2012003888W WO 2013041205 A1 WO2013041205 A1 WO 2013041205A1
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pharmaceutical
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Roland RUTSCHMANN
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Pyxirion Pharma Gmbh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the field of treatment of vascular disorders or of vascular changes, in particular the field of treatment of arteriosclerosis or vascular calcification and / or atherosclerosis.
  • the present invention generally relates equally to the treatment of vascular changes in renal impairment or especially terminal renal insufficiency and / or diabetes mellitus.
  • the present invention relates to the field of treatment of atherosclerosis, especially in patients with renal insufficiency, such as renal insufficiency or end stage renal failure.
  • the present invention relates to a pharmaceutical active substance and its use in the field of human and veterinary medicine. Furthermore, the present invention relates to a pharmaceutical preparation containing the pharmaceutical active substance.
  • the present invention relates to the general influence of mycophenolic acid as a pharmaceutical agent on the progression of arteriosclerosis or on the vascular calcification as the basis for arteriosclerosis.
  • CONFIRMATION COPY Vascular changes that occur in the context of pathological processes or are also the result of aging processes.
  • a (blood) vessel has a vessel wall, wherein the vessel wall comprises the following structures, which may be affected by pathological changes to different degrees and depending on the underlying disease: intima (inner lining), media (middle layer or Muscle layer, synonymously also called Tunica media) and adventitia (connective tissue integration).
  • Atherosclerosis in which, in contrast to atherosclerosis, there is a change in the vessel, in particular due to the accumulation of cholesterols beneath the inner lining of the vessel (endothelium), is characterized by atherosclerosis, in which there is a change in the middle vascular muscle layer (media or medial) Tunica media) of the vessels with conversion into bone-like structures, differentiated.
  • Coronary events are usually a consequence of atherosclerosis, which is already accelerated, especially if renal function is impaired.
  • the incidence of heart failure is also disproportionately high in patients with ESRD, with cardiac overload typically being the result of massively accelerated arteriosclerosis, as is commonly seen in renal insufficiency.
  • the massive arteriosclerosis in patients with impaired and end-stage renal failure is mainly observed in patients with long-standing diabetes mellitus and in advanced age.
  • the factors responsible for the pathogenesis of atherosclerosis are very well known as traditional risk factors (nicotine consumption, obesity, hypertension, age or even lipid metabolism disorder).
  • the factors for atherosclerosis are only partially understood. Nicotine consumption and a poor hypertension have also played an important role here. In particular, pure aging also seems to be an important mechanism.
  • atherosclerosis does not play a role in aging mechanisms according to current knowledge.
  • the factors for the accelerated Arteriosclerosis understood in part, with what also called uremic toxins a not to be underestimated role.
  • Arteriosclerosis represents a functional change in the arterial vessels that leads to an increase in arterial vascular stiffness or reciprocally to a decrease in vascular elasticity. Due to the ability of the aorta to stretch reversibly, the aorta in the non-pathological state can buffer the increase in blood pressure caused by the left ventricular ejection (blood ejection of the main ventricle). This leads to a transformation of a cyclic-pulsatile blood flow into a continuous-phasic flow, which is generally referred to as the "wind-bowl function".
  • the classic cardiovascular risk factors already mentioned - there is an increase in arterial vascular stiffness or a loss of vascular elasticity.
  • the most important structural degenerations include progressive vascular calcification, which mainly affects the tunica media, fragmentation of the elastic lamellae in the tunica media (middle muscle layer of the vessel wall) and the increase of collagen fibers in the tunica adventitia of the large arteries of the elastic type.
  • progressive vascular calcification which mainly affects the tunica media
  • fragmentation of the elastic lamellae in the tunica media fragmentation of the elastic lamellae in the tunica media (middle muscle layer of the vessel wall)
  • the increase of collagen fibers in the tunica adventitia of the large arteries of the elastic type In the area of the muscular-arteriolar vessels, the loss of endothelial function represents a substantial functional impairment of the arterial pathway.
  • the increase in vascular stiffness leads to characteristic changes in the hemodynamics: As the aortic vesicular function decreases, the systolic blood pressure increases. At the same time, diastolic blood pressure decreases as a result of decreased aortic retraction force and increased heart failure. These changes are amplified by the shift of the reflected pulse wave from the diastole to the systole, which occurs earlier due to the faster pulse wave velocity. In addition, the underlying changes can be observed physiologically, especially in the context of the aging process. The pulse pressure, as the difference between the systolic and diastolic blood pressure, consecutively shows an age-related exponential increase and is closely associated with vascular stiffness.
  • hemodynamic changes associated with increased vascular stiffness as a result of arteriosclerosis increased the risk of stroke, increased cardiac afterload with increased myocardial oxygen consumption in left ventricular hypertension, and decreased coronary perfusion. These hemodynamic changes contribute to increasing cardiovascular morbidity and mortality.
  • Arteriosclerosis is therefore a major clinical problem.
  • risk factors are already known that can lead to increased arteriosclerosis. These are, in particular, arterial hypertension, diabetes mellitus and an age over 70 years.
  • the presence of renal insufficiency is a very significant risk factor for the formation of vascular calcifications and thus for the development of arteriosclerosis, the risk increasing with the degree of renal insufficiency.
  • computed tomography studies show an increased calcium deposition in coronary vessels of patients with only low renal dysfunction, which indicates a very early remodeling or influence of a renal failure on the development of arteriosclerosis.
  • hypophosphatemia is often accompanied by hypercalcaemia, ie an increase in the calcium concentration or the calcium level in the blood.
  • hypercalcaemia ie an increase in the calcium concentration or the calcium level in the blood.
  • the related interrelations can be seen in the fact that the hormone cycle regulating the phosphate or calcium concentration in the blood is disturbed.
  • the parathyroid hormone (PTH) which is commonly found in the parathyroid gland, is responsible for the regulation of phosphate and calcium in the blood by regulating the excretion of phosphate or calcium through changes in kidney function.
  • PTH parathyroid hormone
  • an adequate excretion of phosphate can not be accomplished to a sufficient extent, and also in the context of dialysis, the phosphate removal from the blood is sometimes limited.
  • the main mechanisms which can lead to a vascular ratification that forms the basis of arteriosclerosis are, on the one hand, the induction of osteogenesis (formation of bony structures in the muscular vascular layer or the tunica media) and, on the other hand, the loss of inhibitors of mineralization.
  • the normal balance between induction on the one hand and inhibition on the other is dysregulated in chronic renal failure, diabetes mellitus and in old age. Also, oxidative stress is said to exert some influence on the development or development of arteriosclerosis.
  • arteriosclerosis A special form of arteriosclerosis or atherosclerosis is the so-called mediasclerosis, in which the muscle layer or the media of the affected arteries calcified very strongly or ossified. Common causes of medial sclerosis are diabetes and high grade and chronic kidney damage.
  • arteriosclerosis synonymously or colloquially also referred to as arteriosclerosis or arterial hardening, is generally understood as a systemic disease of the arteries, which is to be differentiated from atherosclerosis and which involves the deposition of blood lipids, thrombi, connective tissue and, crucially, lime in the vessel walls accompanied.
  • Arteriosclerosis is thus in particular a connective tissue-specific hardening.
  • Arteriosclerosis is generally medically distinct from atherosclerosis.
  • Atherosclerosis focuses on histological changes insofar as it also includes changes in the cells of the inner vessel wall or intima, which are also referred to as plaques.
  • plaques changes in the cells of the inner vessel wall or intima, which are also referred to as plaques.
  • atherosclerosis As a result of atherosclerosis, bottlenecks and occlusions may form on the affected vessel segments.
  • the vessel wall can also be weakened as a result of the A-sclerosis so that an expansion and thus an aneurysm can result.
  • Atherosclerosis Common and significant consequences of atherosclerosis are stroke, especially when the large cervical arteries (common carotid artery, internal carotid artery) are hit, the myocardial infarction, when coronary vessels clog, the abdominal aortic vein (aortic aneurysm) and the arterial occlusive disease of the legs.
  • cervical arteries common carotid artery, internal carotid artery
  • myocardial infarction when coronary vessels clog, the abdominal aortic vein (aortic aneurysm) and the arterial occlusive disease of the legs.
  • Arteriosclerosis focuses on a physiological aging process of an artery, while atherosclerosis emphasizes the formation of a pathological atheroma, which can sometimes cause a stenosis.
  • arteriosclerosis with vascular calcification has been considered a major contributor to passive disorder.
  • Disorders of the calcium phosphate balance which regularly occur in patients with impaired renal function, were among other factors considered crucial as a cause.
  • increased phosphate retention in patients with renal insufficiency has been causally linked to vascular calcification. Therefore, only drug therapies that have an impact on the calcium / phosphate balance have been tested so far.
  • the uptake of phosphate from the diet by so-called phosphate uptake inhibitors was tested and the success on the cardiovascular survival of the patients was examined.
  • only marginal effects on cardiovascular survival was considered a major contributor to passive disorder.
  • WO 2007/047969 AI relates to the influence of an inflammatory cytokine, namely interleukin-1 (IL-1), using specific inhibitors.
  • IL-1 interleukin-1
  • specific inhibitors for example, special receptor antagonists, antibodies and the like are to be used, whereby the vascular calcification should be reduced.
  • the listed substances are firstly only be produced using cost-intensive methods.
  • the application of the substances in question is not always unproblematic, especially with regard to possible side effects, especially as interleukin-1 is not specific for the presence of vascular calcification
  • WO 2006/102061 A2 relates to the use of calcimimetic compositions for the treatment of vascular calcification, in which context special substances are to be used which interact with receptors specific for calcium. Even such a therapeutic approach does not always lead to optimal treatment success.
  • WO 97/38689 A1 relates to a pharmaceutical composition based on enteric coated mycophenolate salt.
  • the composition in question is to be used for the treatment of autoimmune diseases or in the context of organ transplants.
  • EP 0 281 713 A1 relates to morpholinoethyl esters of mycophenolic acid, the use being directed in this connection to the treatment of autoimmune diseases, tumors, rheumatoid arthritis and the like.
  • Mycophenolic acid or representatives of the underlying substance class are used in therapy so far only after solid organ transplantation in the context of immunosuppressive therapy.
  • Mycophenolic acid is also used in therapy in some autoimmune diseases.
  • a specific use of mycophenolic acid or its salts or esters for the very special medical field of vascular diseases has hitherto not been recognized or described in the prior art.
  • the present invention is therefore based on the object of providing a pharmaceutical active substance or a pharmaceutical composition which is or is suitable for the curative or prophylactic treatment of vascular diseases and which or at least largely avoids the disadvantages of the prior art described above or but at least weakens, with the pharmaceutical active substance or the pharmaceutical preparation should be easy to apply with good efficacy and in addition, a good compatibility should be guaranteed.
  • the object of the present invention is to provide an efficient pharmaceutical active ingredient or an efficient pharmaceutical preparation which, while having good compatibility, has a high activity with respect to vascular diseases based on arteriosclerosis, atherosclerosis and vascular calcification, in particular atherosclerosis.
  • the tolerability of the pharmaceutical active ingredient or of the pharmaceutical preparation in question should also be high with regard to possible comorbidities or diseases causing the vascular disease, such as, for example, renal insufficiency or the like, so that the occasionally present underlying disease is not negatively affected or enhanced by the application of the invention.
  • the present invention proposes - according to a first aspect of the invention - a pharmaceutical agent for curative or prophylactic treatment of vascular diseases or for use in the curative and / or prophylactic treatment of vascular disease according to claim 1, wherein it the active pharmaceutical ingredient is mycophenolic acid or its pharmacologically active and / or physiologically tolerable salts or esters and mixtures or combinations thereof;
  • the active pharmaceutical ingredient is mycophenolic acid or its pharmacologically active and / or physiologically tolerable salts or esters and mixtures or combinations thereof;
  • Another object of the present invention - according to a second aspect of the present invention - is a use of the pharmaceutical active substance in the form of mycophenolic acid or its pharmacologically active or physiologically acceptable salts or esters and their mixtures or combinations for curative or prophylactic treatment of vascular diseases or for the preparation of a pharmaceutical preparation according to claim 15. Further, particularly preferred and / or advantageous embodiments of this aspect of the invention are the subject of the relevant subclaims.
  • pharmaceutical preparation synonymously sometimes also referred to as “pharmaceutical composition”, “pharmaceutical formulation”, etc. - is to be understood very broadly in the context of the present invention and includes any type of possible pharmaceutical preparation, composition or combination, in particular pharmaceutical or Pharmaceuticals as such, but also so-called medical devices, homeopathic remedies or the like.
  • mycophenolic acid MPA or (E) -6- (4-hydroxy-6-) Methoxy-7-methyl-3-oxo-l, 3-dihydroisobenzofuran-5-yl) -4-methylhex-4-enoic acid
  • their pharmacologically active and / or physiologically acceptable salts or esters and mixtures or combinations thereof as
  • their pharmacologically active and / or physiologically acceptable salts or esters and mixtures or combinations thereof for the curative and
  • the present invention is associated with a variety of advantages, improvements and particularities which distinguish the present invention from the prior art:
  • mycophenolic acid or its pharmacologically active and physiologically tolerable salts or esters have outstanding prophylactic or curative activity with regard to the treatment of vascular diseases, in which case vascular diseases in particular are involved with excessive calcification of the vessel wall, such.
  • vascular diseases in which case vascular diseases in particular are involved with excessive calcification of the vessel wall, such.
  • arteriosclerosis or the Mediasclerosis and this in particular in connection with renal underlying diseases, such as renal insufficiency
  • mycophenolic acid or the salts or esters in question can reduce the vascular calcification or prevent or delay the occurrence of such a vascular calcification.
  • mycophenolic acid or the salts or esters in question also have an inhibiting effect on the progression of vascular diseases.
  • mycophenolic acid or the corresponding salts or esters also has an inhibitory effect on the progression or formation of atherosclerosis.
  • the applicant has discovered, not least because of their intensive research and development work in a completely surprising way that - without wishing to be limited to this theory - mycophenolic acid or the salts or esters in question sometimes the transformation or differentiation of vascular smooth muscle cells into an osteoblast-like (cell) type, which has a positive influence on the reduction of the calcification of the affected vessel wall.
  • the mycophenolic acid thus starts at a central point of the formation of vascular diseases, which is associated with good efficacy.
  • mycophenolic acid can be attributed a positive effect with regard to the reduction of oxidative stress insofar as mycophenolic acid is able to prevent the underlying oxidative stress, in particular sometimes by inhibiting a membrane-bound LADPH oxidase.
  • the targeted use of mycophenolic acid for the treatment of vascular diseases can be attributed to a degree of dual effectiveness, namely influence on the formation osteoblast-like cell types on the one hand and reducing oxidative stress on the other hand, which leads to an overall excellent efficacy in the context of the inventive use ,
  • the inventive use of the pharmaceutical active substance based on mycophenolic acid also characterized by the fact that any underlying diseases of the vascular disease, such as renal diseases, especially renal failure, are not adversely affected by administration or application of the active substance, so it in this regard no deterioration of the underlying clinical picture comes.
  • the active ingredient based on mycophenolic acid used in the context of the present invention generally has a good or acceptable tolerability, which is associated with a low level of side effects.
  • the pharmaceutical active ingredient based on mycophenolic acid used according to the invention is outstandingly suitable for a prophylactic or prolonged treatment use in the presence of a chronic disease.
  • the mycophenolic acid used according to the invention is a compound of the following formula (I):
  • the active pharmaceutical ingredient may generally be a salt, in particular an alkali or alkaline earth salt, preferably the sodium salt, mycophenolic acid.
  • the pharmaceutical agent according to the invention or used in the invention pharmaceutical composition or formulation example on the basis of market product Myfortic ® from. Novartis Pharma can be provided or administered.
  • mycophenolate mofetil MMF or (E) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1, 3-dihydroisobenzofuran-5-yl) -4-methylhex-4-enoic acid 2-morpholinoethyl ester.
  • the pharmaceutical agent according to the invention or used in the invention pharmaceutical composition or formulation for example, on the basis of market product Cellcept ® from can. Roche Registration Ltd. be provided or administered. Further market products which can be used according to the invention are obtainable from the company Sandoz Pharmaceuticals or from the company Teva Pharma.
  • ester of mycophenolic acid used according to the invention is a compound of the following formula (II):
  • the underlying vascular disease may be selected from the group of arteriosclerosis, atherosclerosis and vascular calcification, preferably arteriosclerosis, in particular mediasclerosis.
  • the underlying calcification may in particular be an atherosclerotic and / or arteriosclerotic calcification, in particular arteriosclerotic calcification.
  • the underlying vascular calcification can refer in particular to the middle vascular muscle layer or the so-called media. Therefore, the underlying vascular calcification is in particular a medial calcification or mediasclerosis, i. H. a calcification or ossification concerning the media of the underlying vessel.
  • the disease to be treated can thus also be a mediasclerosis, preferably a mediasclerosis associated with kidney damage or renal insufficiency and / or diabetes.
  • the vascular disease may also be related to renal insufficiency, in particular chronic, impaired or terminal renal insufficiency, uremia, diabetes mellitus, in particular diabetes mellitus type I or type II, or a cardiovascular disease.
  • the vascular disease is associated with renal insufficiency, such as chronic, impaired or terminal renal insufficiency, preferably chronic and / or terminal renal insufficiency. Because the presence of renal insufficiency is a major risk factor for the development of a vascular disease, especially on the basis of excessive vascular alzador, especially since in such a basic disease often the calcium / phosphate household is disturbed lasting.
  • the active substance according to the invention or the active compound according to the invention can be used for the prophylaxis and / or therapy of vascular calcification in predialysis and / or dialysis patients, in particular with terminal kidney failure.
  • the present invention relates equally to a pharmaceutical agent for the treatment of vascular disorders in persons and or patients with renal insufficiency, in particular chronic, impaired or terminal renal insufficiency, with uremia, with diabetes mellitus, in particular diabetes mellitus type I or type II, or with a cardiovascular disease.
  • the active pharmaceutical ingredient is an ester of mycophenolic acid, in particular mycophenolate mofetil, wherein the vascular disease is arteriosclerosis, in particular arteriosclerosis associated with renal insufficiency, in particular mediasclerosis.
  • the active pharmaceutical ingredient of the invention may in particular on the basis of market product Cellcept ® from. Roche Registration Ltd. or based on corresponding market products from the company Sandoz Pharmaceuticals or the company Teva Pharma.
  • the pharmaceutical active substance should be administered in effective, especially pharmaceutically effective, amounts.
  • the active pharmaceutical ingredient should be administered be prepared in effective, in particular pharmaceutically effective, amounts.
  • the pharmaceutical active ingredient in daily doses of 10 mg / day to 5,000 mg daily, especially 50 mg day to 3,000 mg / day, preferably 100 mg / day to 2,500 mg / day, preferably 250 mg / Day to 2,000 mg / day, more preferably 500 mg / day to 1,750 mg / day, most preferably 800 mg day to 1,600 mg / day.
  • the pharmaceutical active ingredient for administration in daily doses of 10 mg day to 5,000 mg / day, in particular 50 mg / day to 3,000 mg / day, preferably 100 mg / day to 2,500 mg / day , preferably 250 mg day to 2,000 mg / day, more preferably 500 mg / day to 1,750 mg / day, most preferably 800 mg / day to 1,600 mg / day, prepared.
  • the above amounts are absolute amounts per day, which are therefore independent of body weight.
  • the pharmaceutical active ingredient in daily body weight doses of 0.1 to 100 mg of active ingredient per kg of body weight and day, in particular 0, 5 to 75 mg of active ingredient per kg of body weight and day, preferably 1 to 50 mg of active ingredient per kg of body weight and day, preferably 3 to 30 mg of active ingredient per kg of body weight and day administered.
  • the pharmaceutical active ingredient can be administered and / or administered over one to five daily doses, in particular one to three daily doses, preferably one or two daily doses.
  • the phar- maceutical agent for administration and / or application over one to five daily doses, in particular one to three daily doses, preferably one or two daily doses prepared.
  • the pharmaceutical agent can be administered systemically, especially perorally, intravenously or subcutaneously, preferably perorally.
  • the pharmaceutical active substance according to the invention is prepared for systemic, in particular peroral, intravenous or subcutaneous, preferably peroral, administration.
  • the pharmaceutical active substance according to the invention in the form of a systemic, especially peroral, intravenous or subcutaneous application unit, preferably in the form of in particular enteric-coated tablets, dragees, pills, comprets, capsules, Powders, granules or the like or in the form of infusions.
  • the pharmaceutical active ingredient is administered in the form of a systemic, in particular peroral, intravenous or subcutaneous, administration unit, preferably in the form of in particular enteric-coated tablets, dragees, pills, comprints, capsules or the like or in the form of Infusions, prepared.
  • the pharmaceutical active ingredient is administered in combination and / or together with at least one further pharmaceutical active substance.
  • the pharmaceutical active ingredient is prepared for administration in combination and / or together with at least one further pharmaceutical active substance.
  • the further active ingredient may be selected from the group of cardiovascular active substances; Substances with an influence on the physiological logical calcium balance, in particular calcium phosphate balance, preferably calcimimetics and phosphate binders; Interleukin inhibitors, in particular IL-1 inhibitors; antidiabetics; as well as their combinations.
  • the further active substances which can be combined or administered together with the pharmaceutical active substance according to the present invention are generally known to the person skilled in the art, and the person skilled in the art is always in a position to select the further active substances in question and to match them quantitatively with the pharmaceutical active substance.
  • vascular smooth vascular muscle cells Several factors can lead to osteochondrocytic transdifferentiation of vascular smooth vascular muscle cells (VSMCs) in the vascular wall, which can result in elastin fragmentation and ectopic calcification.
  • VSMCs vascular smooth vascular muscle cells
  • vascular calcification is based on active and excessive bone formation in situ by osteoblast-like cells.
  • osteoblast-like cells can either stem cells or on the other hand by dedifferentiation of existing or differentiated cells, such.
  • vascular smooth muscle cells (VSMCs) or pericytes a cell that has a proliferative, synthetic phenotype.
  • ECM extracellular matrix
  • BMP bone morphogenetic proteins
  • CVC calcifying vascular cells
  • AP alkaline phosphatase activity
  • OCN osteocalcin
  • OPN osteonectin
  • OPN osteopontin
  • pericytes share various phenotypic markers with CVCs, and it is believed that this cell type represents mesenchymal progenitor cells that can develop in osteoblasts and chondrocytes. Like CVCs, pericytes also produce the aforementioned nodules containing type I collagen, OPN, matrix ⁇ -carboxyglutamic acid glutamine (MGP), and OCN when kept in culture for a long time. Activation of these cells in arteriosclerotic lesions could thus also be a source of osteogenic progenitor cells in the vessel wall. Osteoblast differentiation requires the formation of extracellular matrix (ECM). This also explains the need for ascorbic acid (vitamin C) in osteoblast differentiation as this is an important cofactor for the secretion of collagen-containing ECM.
  • ECM extracellular matrix
  • a lack of inhibitors of mineralization may also contribute to the differentiation, such as MGP, fetuin, osteoprotegerin (OPG) and OPN.
  • Smad6 an inhibitory protein of the BMP receptor type II, can also antagonize the osteogenic BMP2 / 4 signaling pathway.
  • the transcription factor core binding factor al belongs to the family of genes with an rwwi domain. So far, three cbfa genes are known in mammals: cbfal, cbfa2 and cbfa3. Northern blot studies show that only Cbfal is expressed exclusively in osteoblasts and thus the cbfal gene is the only osteoblast-specific transcription factor-encoding gene so far. Cbfal binding sites are present in the promoter region of most genes expressed in osteoblasts. Transient transfection of primary fibroblasts with Cbfal results in expression of osteoblast-specific genes such as OCN and / or bone sialoprotein (BSP) in these non-osteoblastic cells.
  • BSP bone sialoprotein
  • Another important transcription factor for the differentiation of osteoblasts is Osterix (Osx).
  • the cbfal expression and function is controlled. Regulation can take place at three different levels: first, the transcriptional activity of Cbfal can be regulated by other transcription factors. Furthermore, the Cbfal molecule may have post-translational modifications activated or temporarily repressed. Finally, it is also possible to modulate the Cbfal affinity for DNA or transcriptional efficiency using different cofactors.
  • the cb / a / promoter has functional Cbfal binding sites and is therefore subject to autoregulation.
  • Other possible regulators of expression are Msx2, Bapxl and IHH as activators and Hoxa2 as inhibitor.
  • Smad proteins, mediators of the BMP / TGF- ⁇ signaling pathway can stimulate Cbfal activity, in particular, by post translational mechanisms.
  • Post-translational modifications of transcription factors may e.g. be necessary for the activity or translocation into the nucleus and binding properties with cofactors.
  • the transcriptional activity of Cbfal depends on its phosphorylation, with a likelihood of being under the control of the MAPK signaling pathway.
  • Studies with various truncated protein variants of Cbfal have revealed that the C-terminal PST domain, i. H. a region rich in proline, serine and threonine necessary for MAPK binding and phosphorylation of Cbfal.
  • phosphorylation of Cbfal could be detected by the protein kinase C5 (PKC5).
  • integrins are also important mediators, which provide information about the extracellular matrix (ECM) and thus can also influence the differentiation of cells. In addition, they provide an important link between the ECM and the actin cytoskeleton because integrins are important signal transduction molecules that can activate the so-called Ras Erk signaling pathway, as well as the p38 signaling pathway, calcium channels, and mechanosensors.
  • a pharmaceutical active ingredient based on mycophenolic acid is provided for the first time, which can be used in a targeted manner for the prophylactic or curative treatment of vascular diseases of the aforementioned type.
  • Another object of the present invention - according to a third aspect of the present invention - is also a pharmaceutical preparation, in particular pharmaceutical composition or formulation, for the curative and / or prophylactic treatment of vascular diseases or for use in the curative and / or prophylactic treatment of vascular diseases
  • the pharmaceutical preparation according to the invention may contain the pharmaceutical active substance in amounts of 5 mg to 2,000 mg, in particular 10 mg to 1,500 mg, preferably 20 mg to 1,000 mg, preferably 50 mg to 750 mg, particularly preferably 100 mg to 500 mg. in particular per application and / or dosing unit included.
  • the pharmaceutical preparation may contain the active pharmaceutical ingredient in amounts of 1% to 99%, especially 5% to 90%, preferably 10% to 80%, by weight 20 wt .-% to 70 wt .-%, particularly preferably 30 wt .-% to 60 wt .-%, based on the composition.
  • the pharmaceutical preparation according to the invention may additionally comprise at least one further ingredient, in particular from the group of pH adjusters, pH buffer substances, lubricants, colorants, flavorings and flavorings, flavoring agents, stabilizers, preservatives, consistency control agents, disintegrants, thickeners and mixtures thereof ,
  • the composition may contain conventional excipients or carriers.
  • FIG. 1 shows a microscopic illustration of vascular muscle cells derived from rats under different conditions for alcification and the effect of mycophenolic acid on calcification in this respect;
  • Figure 2 is a graph in the form of a bar graph showing the effect of mycophenolic acid on the inhibition of calcification in aortic vessels of rats;
  • Fig. 3 is a graph in the form of a bar graph showing the influence of mycophenolic acid on the activity of alkaline phosphatase as an indicator of osteoblast-like cells.
  • CM mycophenolic acid
  • CM calcifying medium
  • MPA myocopheric acid
  • Dex dexamethasone
  • the next step was to quantify directly how strong the calcification is. This can be done by means of a calcium C test.
  • the vascular smooth muscle cells were first incubated as in the first experiment. Subsequently, the cells were decalcified with 0.6 mol / l HCl for 24 h. The liberated calcium was then measured photometrically at 570 nm in the supernatants by binding to O-cresolphthalein.
  • a commercial kit from Wako Chemicals, Neuss, Germany was used. The content of calcium in the cells was normalized to the protein content of the cells.
  • the presence of MPA in the CM medium results in a reduction of the calcium content to 0.096 ⁇ g / ⁇ g.
  • MPA significantly inhibits the effect of CM and dexamethasone on calcification.
  • MPA significantly inhibits CM or dexamethasone-induced calcification. It follows immediately that MPA has an inhibitory effect on a typical or established model in the field of vascular calcification.
  • aortae were isolated from untreated rats. The aortae were divided into aortic rings and incubated in the presence of CM and / or MPA for a period of 14 days. Subsequently, the aortic rings were embedded in paraffin and stained with van-Ossa stain for histological examination. To quantify the proportion of calcification, a calcium determination (calcium C test) was carried out, as already described above.
  • Fig. 2 shows that a control experiment with the sole treatment based on MPA (10 ⁇ / ⁇ ) leads to no inhibition or stimulation of calcification in the rat aorta.
  • CM medium significantly stimulated calcification in the aortae (157% of control calcification).
  • the simultaneous presence of MPA causes the calcification to decrease significantly (p ⁇ 0.05) to 132%.
  • MPA mycophenolic acid
  • CM calcifying medium.
  • MPA actually blocks the transformation or differentiation of vascular smooth muscle cells into an osteoblast-like phenotype or cell type and that the observed effect is not caused by a toxic effect of MPA.
  • ALP alkaline phosphatase
  • CM calcifying medium
  • DEX dexamethasone
  • MPA mycophenolic acid
  • ALP alkaline phosphatase
  • d days.
  • the induction of renal insufficiency of the DBA / 2 mice was carried out according to a nephrectomy model with subsequent phosphate-containing diet of the animals. All animals (age of the animals: 18 weeks) were initially kept at normal diet during a two-week adjustment period. Then the operations started. For this purpose, the control group was controlled, while the uraemic groups (animals with renal insufficiency) were nephrectomized to 7/8, whereby initially 75% of the right kidney was obliterated. After a recovery period of two weeks, the second operation step was performed, in which the animals of the uremic groups, the left kidney was removed.
  • each animal received at the same time an ALZET mini Pump (Model 2006, Charles River, Wilmington) implanted.
  • the implantation took place by a cut into the neck fold, the insertion of the pump and by subsequent sewing.
  • HP high phosphate diet
  • the diet of all animals was switched to a so-called high phosphate diet (HP), after which the diet contained 0.9% phosphate.
  • HP high phosphate diet
  • the pumps in the animals were replaced, since the pump reservoir is only sufficient for 6 weeks. For this purpose, the animals were placed under anesthesia again, and over a small section, the subcutaneously implanted empty pumps were replaced with newly filled pumps.
  • the large conduction vessels (aortae) were then examined for calcification in the respective groups.
  • the induction of uraemia and the simultaneous high-dose administration of phosphate showed a marked induction of calcification, which was reduced by approximately 35% and 45%, respectively, in the low-dose and high-dose MPA groups by administration of MPA.
  • MPA has an inhibitory effect on vascular calcification.
  • the course of arteriosclerosis can be favorably influenced by MPA or delayed and / or prevented in the event of preventive use of MPA.
  • mycophenolic acid has an inhibitory effect on arteriosclerosis progression.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Medicinal Chemistry (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne l'utilisation d'acide mycophénolique [encore désigné par "MPA" ou, selon la nomenclature de l'IUPAC, par "acide (E)-6-(4-hydroxy-6-méthoxy-7-méthyl-3-oxo-l,3-dihydroisobenzofliran-5-yl)-4-méthyl-hex-4-anoïque"] ou de ses sels ou esters acceptables sur le plan pharmaceutique et sur le plan physiologique, pour le traitement curatif et/ou prophylactique de maladies vasculaires.
PCT/EP2012/003888 2011-09-19 2012-09-18 Nouveaux concepts thérapeutiques pour le traitement de maladies vasculaires WO2013041205A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0281713A1 (fr) 1987-01-30 1988-09-14 Syntex (U.S.A.) Inc. Morpholinoéthylesters d'acide mycophénolique et leurs dérivés, leur préparation et leur utilisation dans des compositions pharmaceutiques
US5283257A (en) * 1992-07-10 1994-02-01 The Board Of Trustees Of The Leland Stanford Junior University Method of treating hyperproliferative vascular disease
WO1994012184A1 (fr) * 1992-11-24 1994-06-09 Syntex (U.S.A.) Inc. Utilisation d'acide mycophenolique, de mofetile de mycophenolate ou d'un derive de ceux-ci pour inhiber la stenose
WO1997038689A2 (fr) 1996-04-12 1997-10-23 Novartis Ag Compositions pharmaceutiques a delitage enterique et a base de mycophenolate
WO2006102061A2 (fr) 2005-03-17 2006-09-28 Amgen Inc. Methode de reduction de la calcification
WO2007047969A2 (fr) 2005-10-21 2007-04-26 Amgen Inc. Methodes de reduction de la calcification vasculaire a l'aide d'inhibiteurs de l'il-1

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0281713A1 (fr) 1987-01-30 1988-09-14 Syntex (U.S.A.) Inc. Morpholinoéthylesters d'acide mycophénolique et leurs dérivés, leur préparation et leur utilisation dans des compositions pharmaceutiques
US5283257A (en) * 1992-07-10 1994-02-01 The Board Of Trustees Of The Leland Stanford Junior University Method of treating hyperproliferative vascular disease
WO1994012184A1 (fr) * 1992-11-24 1994-06-09 Syntex (U.S.A.) Inc. Utilisation d'acide mycophenolique, de mofetile de mycophenolate ou d'un derive de ceux-ci pour inhiber la stenose
WO1997038689A2 (fr) 1996-04-12 1997-10-23 Novartis Ag Compositions pharmaceutiques a delitage enterique et a base de mycophenolate
WO2006102061A2 (fr) 2005-03-17 2006-09-28 Amgen Inc. Methode de reduction de la calcification
WO2007047969A2 (fr) 2005-10-21 2007-04-26 Amgen Inc. Methodes de reduction de la calcification vasculaire a l'aide d'inhibiteurs de l'il-1

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Title
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ROMERO F ET AL: "Mycophenolate mofetil treatment reduces cholesterol-induced atherosclerosis in the rabbit", ATHEROSCLEROSIS, ELSEVIER IRELAND LTD, IE, vol. 152, no. 1, 1 September 2000 (2000-09-01), pages 127 - 133, XP002387663, ISSN: 0021-9150, DOI: 10.1016/S0021-9150(99)00458-X *
SIBYLLE VON VIETINGHOFF ET AL: "Mycophenolate Mofetil Decreases Atherosclerotic Lesion Size by Depression of Aortic T-Lymphocyte and Interleukin-17 Mediated Macrophage Accumulation", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, ELSEVIER, NEW YORK, NY, US, vol. 57, no. 21, 15 December 2010 (2010-12-15), pages 2194 - 2204, XP028210496, ISSN: 0735-1097, [retrieved on 20110413], DOI: 10.1016/J.JACC.2010.12.030 *
TENG D ET AL: "Conversion From Cyclosporine to Mycophenolate Mofetil Improves Expression of A20 in the Rat Kidney Allografts Undergoing Chronic Rejection", TRANSPLANTATION PROCEEDINGS, ELSEVIER INC, ORLANDO, FL; US, vol. 38, no. 7, 1 September 2006 (2006-09-01), pages 2164 - 2167, XP025008452, ISSN: 0041-1345, [retrieved on 20060901], DOI: 10.1016/J.TRANSPROCEED.2006.06.007 *
VAN LEUVEN S I ET AL: "Mycophenolate mofetil attenuates plaque inflammation in patients with symptomatic carotid artery stenosis", ATHEROSCLEROSIS, ELSEVIER IRELAND LTD, IE, vol. 211, no. 1, 1 July 2010 (2010-07-01), pages 231 - 236, XP027353061, ISSN: 0021-9150, [retrieved on 20100206] *

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