EP1480628A1

EP1480628A1 - Use of sodium/hydrogen exchange inhibitors for the treatment of thrombotic and inflammatory diseases

Info

Publication number: EP1480628A1
Application number: EP03706415A
Authority: EP
Inventors: Hans-Jochen Lang; Stefan Werner Schneider; Hans Oberleithner; André NIEMEYER
Original assignee: Aventis Pharma Deutschland GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 2002-02-14
Filing date: 2003-02-03
Publication date: 2004-12-01
Also published as: MXPA04007387A; AU2003208368A1; DE10206358A1; WO2003068212A1; BR0307618A; JP2005525336A; TW200403988A; AR038502A1; CA2476446A1

Abstract

Inhibitors of cellular sodium/hydrogen exchangers display an inhibiting effect on the secretion of von-Willebrand factor and/or increased expression of P-selektin. Said inhibitors can thus be used for the treatment of thrombotic and inflammatory diseases.

Description

Use of inhibitors of the sodium-hydrogen exchanger for the treatment of thrombotic and inflammatory diseases

The invention relates to the use of inhibitors of the cellular sodium-hydrogen exchanger in human and veterinary medicine for the prevention and treatment of acute or chronic diseases which are caused by elevated blood levels of the von Willebrand factor. The inhibitors can therefore be used to treat thrombotic and inflammatory diseases.

In numerous preclinical studies, inhibitors of the sodium hydrogen exchanger (NHE) have been characterized in recent years as substances which are superior in protecting the heart tissue, which is at risk from the acute onset of the ischemia event, from deterioration when the heart is not adequately supplied with blood. The protection of the heart tissue with NHE inhibitors includes everyone

Expressions of the damage caused by insufficient blood flow, starting with cardiac arrhythmia, hypercontracture of the heart muscle and temporary loss of function up to the death of the heart tissue and the associated permanent damage.

The important mechanism of action of the NHE inhibitors in acute ischemia is that they reduce the increased sodium ion influx which arises in acutely deficient tissue through activation of the NHE due to intracellular acidification. This will make the situation of sodium overload of the tissue _. delayed. Since sodium and calcium ion transport are coupled to each other in the heart tissue, this prevents the life-threatening calcium overload of the heart cells.

Furthermore, it is known that the inhibitors of the NHE bring about protection of the central nervous system (CNS), such active substances protecting the CNS, similar to the heart, against acute ischemic conditions. These conditions are caused by an acute lack of blood circulation and thus by an Lack of supply with nutrients, oxygen or minerals. Such ischemic damage to the CNS is particularly pronounced in central infarcts, such as a stroke. With normal, healthy blood flow, therefore, as expected, no protective effects of NHE inhibitors were also possible. against these acute events, since no acute ischemic tissue damage to the heart or the CNS occurred.

The prior art describes numerous classes of substances which intervene in the interaction of the coagulation factors and thus bring the coagulation cascade to a standstill. Also numerous

Active principles developed that do not suppress thrombus formation, but cause the dissolution (lysis) of thrombi already formed. Some of these principles of action, which intervene at various switching points in the cascade mentioned, were introduced into therapy for preventing thrombogenesis, such as derivatives of the vitamin K group (phylloquinones), factor VIII and factor IX

Preparations, platelet aggregation inhibitors such as acetylsalicylic acid, dipyridamole and ticlopidine, anticoagulants such as heparins or heparinoids.

The blood coagulation cascade can be mechanistically divided into two paths, as shown in the following scheme, namely an intrinsic and an extrinsic course, both of which ultimately result in the activation of factor X and the resulting generation of thrombin and subsequently fibrin:

Intrinsic Extrinsic

aggregation

Fibrinogen fibrin

Scheme 1: Blood coagulation cascade

In the therapeutic use of such blood coagulation inhibitors, it is important that no excessive or complete anticoagulation is achieved which would inhibit the vital formation of microthrombi and microcoagulations, which must take place on the continuously occurring micro-injuries. The degree of anticoagulation can only be set inaccurately due to the different responsiveness of the individual at the time and must be monitored as far as possible. If these many small, permanent coagulation processes are inhibited, there is a high risk of massive bleeding (hemophilia).

A disadvantage of the known therapeutic agents on the market that intervene in the coagulation process as inhibitors is therefore the high risk of bleeding complications. Especially during high dose thrombolysis therapy, e.g. B. as part of the therapy of acute myocardial infarction or pulmonary embolism, there is a risk of life-threatening bleeding. Therefore there is an urgent one Need for therapeutic agents that, despite overdosing, carry no risk of increased bleeding tendency.

Many of the known anticoagulant substances act by attacking the platelets, the platelets, and inhibiting their function or inhibiting their activation. The endothelium obviously also plays a central role in coagulation. For example, the von Willebrand factor (vWF) required for coagulation is largely formed in the endothelial cells and from there is permanently (constitutively) secreted into the circulating blood to ensure the necessary coagulation processes in the blood. A considerable part of the vWF formed is stored in cytoplasmic granules, the so-called Weibel-Palade bodies, and released when necessary by stimulating the endothelial cells. If endothelial cells are not able to form the vWF and release it into the blood, then the known hereditary vWF-dependent von Willebrand-Jürgens syndrome occurs, which is characterized by its bleeding that cannot be chewed. Only a few years ago, diseases have been known which are caused by increased concentrations of vWF in the blood and which, for example, trigger an increased tendency to clot and inflammatory processes. For example, Kamphuisen et al. in their publication "Elevated factor VIII levels and the risk of thrombosis" [Arterioscler. Thromb. Vase. Biol. 21 (5): 731-738 (2001)] based on numerous studies that a significant connection between increased blood levels in vWF and Factor VIII forms a complex with vWF as a necessary prerequisite for blood coagulation, and it was found that high blood levels of von Willebrand factor (vWF) and of factor VIII bound by vWF are a clear risk factor for thrombosis However, antithrombotic agents that antagonize the stabilizing binding of the vWF to factor VIII can also be disadvantageous because in the event of an overdose, extensive inhibition of blood coagulation and dangerous bleeding tendencies must be expected. In an effort to find effective compounds for the treatment of acute or chronic diseases which are caused by elevated blood levels of the von Willebrand factor, it has now been found that the compounds used according to the invention inhibit the release of the von Willebrand factor from the endothelial cells. The compounds according to the invention inhibit the massive pH-dependent release of the vWF accumulated in ischemia.

While the secretion at normal blood pH is known to be regular, constitutive around 7.4 and part of the vWF is stored in Weibel-Palade bodies, it has now been found that the release of the vWF is delayed and reduced with decreasing pH. The exocytosis of the Weibel-Palade bodies in which the vWF is packaged is increasingly inhibited as the pH drops. Under acidotic conditions, there is a significant increase in Weibel-Palade bodies and thus a massive accumulation of VWF in the endothelial cell and a reduced constitutive and stimulated vWF secretion. This can be made visible by staining measures and proven in the supernatant by quantitative vWF measurements. Such acidic states with significant pH drops below 7 occur, for example, in cases of tissue ischemia. At the moment of realcalinization and endothelial cell stimulation, which corresponds to the state of reperfusion, exocytosis occurs within seconds and thus the Weibel-Palade bodies (WPK) are emptied, thus leading to a massive release of the prothrombotic risk factor.

In addition to the vWF, the transmembrane protein P-selectin is also stored in the Weibel-Palade bodies (Wagner, DD 1993, Thromb. Haemost, 70: 105-110). The P-selectin is located in the vesicle membrane and is after the vesicle fusion (exocytosis ) built into the plasma membrane of the endothelial cell. Every Weibel-Palade body exocytosis thus leads not only to an increased release of vWF, but also to an increased P-selectin expression in the endothelial cell membrane. In the examples, the vWF secretion (quantitative measurement by means of ELISA) is shown under acidosis, as well as during a subsequent reperfusion. In parallel, these quantitative measurements are made with Immunofluorescence data from the Weibel-Palade bodies confirmed. The measured vWF is not only a marker for increased (increase in WF secretion) or decreased (decrease in vWF secretion) tendency to thrombosis (via the increase in aggregation of the platelets), but also a direct marker for an increased or decreased P-selectin expression in the endothelial cell membrane. P-selectin serves as an anchor for leukocytes and thus the initial inflammatory reaction (Vestweber, D., Blanks, JE 1999, Physiol. Rev., 79: 181-213; Issekutz, AC, Issekutz, TB 2002, J. Immunol., 168 : 1934 to 1939). The pathophysiological significance is diverse and is evidence of ischemia / reperfusion disorders, thrombosis and arteriosclerosis (Massberg, S., et al., 1998, Blood, 92: 507-515;

Kita, T., et al., 2001, Ann. N. Y. Acad. Sci., 947: 199-205). In addition to the importance of P-selectin as an inflammation marker and initiator of inflammation, it plays an essential role in the process of cancer spreading (Varki, A., Varki, NM 2001, Braz. J. Med. Biol. Res. 34: 711-717) , as well as during different joint inflammations (arthritis) (Veihelmann, A. et al, 1999, Microcirculation, 6: 281-290; Mclnnes, LB., et al., 2001, J. Immunol., 167: 4075-4082). The mode of action of the substances described here can therefore also be used as a therapeutic agent for all of the above-mentioned P-selectin-associated diseases.

The invention therefore relates to the use of inhibitors of sodium

Hydrogen exchanger for the manufacture of medicines for the prophylaxis and therapy of acute or chronic diseases caused by elevated blood levels of the von Willebrand factor.

The invention further relates to the use of at least one of the following compounds

H

and / or all stereoisomeric forms of the above-mentioned compounds and / or mixtures of these forms in any ratio, and / or the physiologically tolerable salts of the above-mentioned compounds for the manufacture of a medicament for the prophylaxis and therapy of acute or chronic diseases caused by increased blood levels of von Willebrand Factor and / or increased expression of the P-selectin can be caused.

Another object of the invention is the use of cariporides

for the manufacture of a medicament for the prophylaxis and therapy of acute or chronic diseases caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin.

The above-mentioned compounds are known and can be, for example, as in

EP 0 416 499, EP 0 556 673, EP 0 589 336, EP 0 622 356, EP 0 699 666,

EP 0 708 088, EP 0 719 766, EP 0 726 254, EP 0 787 728, EP 0 972 767,

DE 19529612, DE 19601303, WO 99 00379; or T. Kawamoto, et al., Potent and selective Inhibition of the human Na + / H + exchanger isoform NHEI by a novel aminoguanidine derivative T-162559, Eur.J. Pharmacol. 420 (2001), 1-8.

If the above-mentioned compounds permit diastereoisomeric or enantiomeric forms and are obtained as their mixtures in the selected synthesis, the separation into the pure stereoisomers is possible either by chromatography on an optionally chiral support material or, if the racemic compounds mentioned above are capable of salt formation, by fractional crystallization the diastereomeric salts formed with an optically active base or acid as auxiliary. Modified silica supports (so-called Pirkle phases) and high-molecular carbohydrates such as triacetyl cellulose are suitable as chiral stationary phases for the separation of enantiomers by thin-layer or column chromatography. After corresponding derivatization known to the person skilled in the art, gas chromatographic methods on chiral stationary phases can also be used for analytical purposes. To separate the enantiomers of the racemic carboxylic acids, the optically active, usually commercially available base such as (-) - nicotine, (+) - and (-) - phenylethylamine, quinine bases, L-lysine or L- and D-arginine are used to dissolve the differently soluble diastereomeric salts formed, the less soluble component isolated as a solid, the more soluble diastereomer separated from the mother liquor, and the pure enantiomers obtained from the diastereomeric salts thus obtained. In principle, the racemic compounds of the formula I, which contain a basic group such as an amino group, can be treated with optically active acids, such as (+) - camphor-10-suifonic acid, D- and L-tartaric acid, D- and L- Convert lactic acid and (+) and (-) - mandelic acid into the pure enantiomers. It is also possible to use chiral compounds which contain alcohol or amine functions with correspondingly activated or optionally N-protected enantiomerically pure amino acids in the corresponding esters or amides, or conversely chiral carboxylic acids with carboxy-protected enantiomerically pure amino acids in the amides or with enantiomerically pure hydroxycarboxylic acids such as lactic acid transfer the corresponding chiral ester. Then the chirality of the amino acid or alcohol residue introduced in enantiomerically pure form can be used to separate the isomers by separating the diastereomers now present by crystallization or chromatography on suitable stationary phases and then cleaving off the chiral part of the molecule carried along using suitable methods.

Acidic or basic products of the above-mentioned compounds can be in the form of their salts or in free form. Preferred are pharmacologically acceptable salts, e.g. B. alkali or alkaline earth metal salts or hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates and salts of amino acids, natural bases or carboxylic acids. The production of physiologically compatible salts from the abovementioned compounds capable of salt formation, including their stereoisomeric forms, is carried out in a manner known per se. The carboxylic acids and hydroxamic acids form with alkaline reagents such as hydroxides, carbonates, hydrogen carbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine or triethanolamine or also basic amino acids, such as lysine, ornithine or arginine, stable alkali metal, alkaline earth metal or, if appropriate substituted ammonium salts. If the above-mentioned compounds have basic groups, stable acid addition salts can also be prepared with strong acids. Both inorganic and organic acids, such as hydrogen chloride, hydrogen bromide, sulfur, phosphorus, methanesulfone, benzenesulfone, p-toluenesulfone, 4-bromobenzene sulfone, cyclohexylamidosulfone, trifluoromethylsulfone, vinegar and oxal come for this -, Tartaric, succinic or trifluoroacetic acid in question. Methanesulfonic acid salts of the abovementioned compounds are particularly preferred.

Because of the pharmacological properties, the above-mentioned compounds are suitable for the prophylaxis and therapy of acute or chronic diseases which are caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin.

These include thrombotic diseases that are provoked by ischemic conditions with subsequent reperfusion; such as thrombosis in acute myocardial, mesenteric or even cerebral infarction; thrombotic diseases that occur during or after surgery; pulmonary emboli; deep venous

Thromboses, such as those that occur after a prolonged restriction of the blood circulation, in particular of the lower extremities, for example after lying or sitting for a long time, and inflammatory diseases, such as those during ischemia and subsequent reperfusion, during vasculitis (e.g. as part of an autoimmune disease or collagenosis) , occur.

This also includes diseases that are caused by an increased expression of the P-selectin, such as the beginning of inflammatory reactions; but also Prophylaxis and treatment of arteriosclerosis; as well as prophylaxis and treatment of cancer; as well as joint inflammation and arthritic diseases such as rheumatoid arthritis.

The medicaments according to the invention can be administered by oral, inhalative, rectal or transdermal application or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Oral application is preferred.

The invention also relates to a method for producing a medicament, which is characterized in that at least one of the above

Connects compounds with a pharmaceutically suitable and physiologically compatible carrier and, if appropriate, further suitable active ingredients, additives or auxiliaries into a suitable dosage form.

The above-mentioned compounds are mixed with the suitable additives such as carriers, stabilizers or inert diluents and brought into suitable dosage forms by the customary methods, such as tablets, dragées, push-fit capsules, aqueous, alcoholic or oily suspensions or aqueous or oily solutions. As inert carriers such. As gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used. The preparation can take place both as dry and as moist granules. Vegetable or animal oils, such as sunflower oil or cod liver oil, are suitable as oily carriers or solvents.

For subcutaneous, intraperitoneal or intravenous administration, the active compounds are, if desired, brought into solution, suspension or emulsion with the suitable substances, such as solubilizers, emulsifiers or other auxiliaries. As solvents such. B. in question physiological saline or alcohols, e.g. As ethanol, propanol, glycerin, in addition

Sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned. Furthermore, customary auxiliaries, such as carriers, disintegrants, binders, coatings, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers, are used. Magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as sterile are common additives Water and monohydric or polyhydric alcohols such as glycerin.

The above-mentioned compounds are preferably prepared and administered as pharmaceutical preparations in dosage units, each unit containing as active ingredient a certain dose of the compound of the formula I. For this purpose you can take orally in doses of 0.01 mg / kg / day to 25.0 mg / kg / day, preferably 0.01 mg / kg / day to 5.0 mg / kg / day or parenterally in doses of 0.001 mg / kg / day to 5 mg / kg / day, preferably 0.001 mg / kg / day to 2.5 mg / kg / day. The dosage can also be increased in severe cases. In many cases, however, lower doses are sufficient. These figures refer to an adult weighing approximately 75 kg.

The above-mentioned compounds can be used alone or in combination with anticoagulant, platelet aggregation-inhibiting or fibrinolytic active substances. The co-application can take place, for example, with factor Xa inhibitors, standard heparin, low molecular weight heparins such as enoxaparin, dalteparin, certroparin, parnaparin or tinzaparin, direct thrombin inhibitors such as hirudin, aspirin, fibrinogen receptor antagonists, streptokinase, urokinase and / or activator plasmin and / or activator plasmin ,

It is known that the inhibitors of the sodium-hydrogen exchanger act on the aggregation of the platelets and have an adhesion-inhibiting effect (see Rosskopf, Dieter, J. Thromb. Thrombolysis (1999), 8 (1), 15-23 .; or Nieuwland, Rienk; Akkerman, Jan-Willem Nicolaas, Adv. Mol. Cell Biol. (1997), 18 (Platelet), 353-366). In contrast to the effects already described on platelet aggregation, the abovementioned compounds also show an inhibition of the excessive release of the von Willebrand factor. This novel antithrombotic active principle differs from the previously known antithrombotic active principles in a decisive and advantageous manner in that

a) it only works in the ischemic tissue in the subsequent reperfusion phase, while other (pre-ischemic) cells not affected by ischemia remain completely unaffected, and b) none of the dangerous bleeding complications during lysis therapy have to be feared.

The invention is explained in more detail below with the aid of examples.

In the following examples, the effects of extracellular acidosis (pH _ex = 6.4), as well as the effects of the above-mentioned compounds according to the invention on the intracellular pH (pHi) and the release of the von Willebrand factor (vWF) were shown. All examples were performed with human umbilical vein endothelial cells (HUVEC). These were primary cell cultures isolated from the umbilical vein.

For the following examples, the cells were cultured either on gelatinized glass plates (measurement of the intracellular proton concentration) or on cell culture plates (12-well culture plates, Falcon, New Jersey, USA; measurement of the vWF release) after the first passage. Example 1 :

Measurement of the intracellular pH

To measure the intracellular proton concentration (pHj), HUVECs were loaded with the pH-sensitive fluorescent dye BCECF-AM (2 ', 7'-bis (carboxyethyl) - 5 (6) -carboxyfluorescein). A Deltascan Spectrofluorometer (PTI, Hamburg) was used for the subsequent measurement of the fluorescence. This measuring system essentially consists of a UV light source, a monochromator, a photon detector and the software packages Felix and Oscar (PTI, Hamburg) for controlling the system via a computer. After alternating excitation with the wavelengths 439.5 nm (pH-independent) and 490 nm (pH-sensitive), the ratio of the measured emissions of the BCECF (ratio) was recorded and the pH value was determined after calibration. The measuring chamber is constructed in such a way that the parameters of temperature and the carbon dioxide partial pressure of the system are checked with continuous perfusion. For the reperfusion simulation, the test conditions were set to 37 ° C. and a carbon dioxide partial pressure of 5% or 10% by gassing the system and perfusate.

In the experiment, it was first pre-incubated for 60 minutes with sodium bicarbonate buffer pH _ex 6.4 in order to simulate respiratory-metabolic acidosis. Then the perfusion initiated was changed to sodium bicarbonate buffer pH 7.4 with 10 μM histamine as a reperfusion simulation.

In comparison to these control experiments, the test was carried out

Reperfusion buffer of the NHE inhibitor cariporide was added in a concentration of 10 μM.

The results of several tests were summarized in Tables 1 and 2. Table 1: Intracellular pH during an extracellular acidosis (pHj (acidosis)) of at least 15 minutes or under control conditions (Co).

Table 1 :

SEM is the standard deviation from the mean

Extracellular acidosis resulted in intracellular acidification that persisted throughout the duration of the acidosis. The intracellular, acidotic pH value is almost identical to the extracellular pH (extracellular acidosis pH _ex = 6.4).

Table 2: Reperfusion with test buffer containing cariporide (HOE) and control buffer (Co). The initial rate of increase of the pH values was determined after 60 minutes of acidosis from the measured values within the first 30 seconds after reperfusion.

Table 2: pH rate of increase [Δ pH / min]

When the extracellular pH changed from 6.4 to 7.4, the rate of increase of the intracellular pH was reduced by a factor of 3.6 compared to the control. The use of Cariporide during reperfusion thus significantly reduced the rate of realcalinization.

Example 2

Measurement of vWF release after reperfusion

The measurements were carried out in a Heraeus Heracell incubator. This made it possible to cultivate the umbilical vein endothelial cells under controlled physiological conditions (temperature 37 ° C, relative humidity 100%, pCO ₂ constant 5%), and to ensure a rapid change of different cell culture media.

The cells mentioned were first washed with acidic medium (pH 6.4 from the components: medium M199 w / Earle ^'s & Amino Acids, w / L-glutamine, w / o NaHCO ₃ , w / o Hepes + 0.084 g NaHCO ₃ / 1) or pH standard medium (pH 7.4 from the constituents: medium M199 w / ^Earle's & amino Acids, w / L-glutamine, w / o _NaHCO3, w / o Hepes + 2,200g NaHCO _3/1) incubated for one, three or 48 hours. Before the reperfusion started, supernatant samples were taken to determine the vWF concentration under acidotic conditions (vWF _a2 idose) and control conditions (vWF _C0 ). To simulate the reperfusion, a change was made to a medium with a pH of 7.4 (components: medium M199 w / Earle's & Amino Acids, w / L-glutamine, w / o NaHCO ₃ , w / o Hepes + 2,200 g NaHCO _3/1 + 10 .mu.M histamine), which the NHE inhibitor cariporide was added at a concentration of 10 .mu.M. The change to the same medium without a corresponding inhibitor addition served as a control.

The samples taken from the supernatant were used to determine the vWF concentration. An ELISA procedure (enzyme-linked immunosorbent assay) was used for this purpose using specific antibodies. The vWF content of Standard Human Plasma (Behring, Marburg) is based on an international Standards (2 ^nd International Standard 87/718; National Institute for Biological

Standards and Control, London).

Table 3: vWF concentration in the cell supernatant under acidotic (vWF _az i _dose ) and under control conditions (vWF _C0 ) measured after a 15 minute incubation period. The vWF concentration under control conditions is set to 100%.

Table 3:

Acidosis led to a significant decrease in vWF secretion, both the constitutive secretion and the stimulated Weibel palade body secretion. The vWF secretion was reduced by a factor of 2 compared to control cells during acidosis (pH _ex = 6.4).

Table 4: vWF secretion was measured during a 10 minute reperfusion period with stimulation. The vWF secretion of the control cells (vWF _c0 ) was set to 100%. The vWF concentration during reperfusion of preacidotic cells (vWFacidosis) and the vWF concentration during reperfusion of preacidotic cells in the presence of 10 μM cariporide (VWFH _O E) were given as relative values to the control values. Control cells were incubated with Cariporide

(vWF _C o + HOE) Table 4:

During reperfusion there was a massive increase in vWF secretion by a factor of 2. Blocking the NHE with Cariporide reduced the vWF excess secretion by almost 60% and thus approached the control values. Control cells incubated with Cariporide (10 μM) showed no increased or decreased secretion of the vWF.

In the examples it was shown that extracellular acidosis, such as was present during ischemia, led to intracellular acidosis with the consequence of a reduced (constitutive and stimulated) vWF secretion and a reduced P-selectin expression. The subsequent reperfusion and stimulation of the endothelial cells brought about rapid intracellular realcalinization. Simultaneously, there was a massive increase in vWF multiple secretion and increased P-selectin expression. Delaying realcalinization with Cariporide reduced vWF secretion and P-selectin exposure and thus the possible thrombosis and inflammatory reactions. The examples showed that the intracellular pH is determined by the extracellular pH. The secretion rate of the endothelial cells is in turn determined by the intracellular pH. This allows the well-known in the reperfusion phase

Reduce endothelial cell activation and the associated dreaded rethrombosis (vWF secretion) and inflammation by inhibiting realcalinization. Incubation of healthy, non-acidotic control cells with Cariporide had no effect. This indicates a low potential for side effects and prevents excessive bleeding. The active substance only works where there is ischemia.

Claims

claims

1. Use of inhibitors of the sodium-hydrogen exchanger for the production of medicaments for the prophylaxis and therapy of acute or chronic diseases which are caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin.

2. Use according to claim 1, characterized in that at least one of the following compounds as an inhibitor of the sodium hydrogen exchanger

and / or a stereoisomeric form of the abovementioned compounds and / or mixtures of these forms in any ratio, and / or the physiologically tolerable salts of the abovementioned compounds.

3. Use according to claims 1 or 2, characterized in that Cariporide is used as an inhibitor of the sodium hydrogen exchanger.

4. Use according to one or more of claims 1 to 3, characterized in that the disease is a thrombotic disease which is provoked by ischemic conditions with subsequent reperfusion; such as thrombosis in acute myocardial, mesenteric or even cerebral infarction; thrombotic diseases that occur during or after surgery; pulmonary emboli; deep venous thrombosis, such as that which occurs after a prolonged restriction of the blood circulation, in particular of the lower extremities, for example after lying or sitting for a long time, as well as inflammatory diseases, as occur during ischemia and subsequent reperfusion, during vasculitis as part of an autoimmune disease or collagenosis, or is an onset of an inflammatory reaction, prophylaxis and treatment of arteriosclerosis, prophylaxis and treatment of cancer or treatment of joint inflammation and arthritic diseases such as rheumatoid arthritis.

5. Use according to one or more of claims 1 to 4, characterized in that the compounds mentioned in claims 1 to 3 are used in combination with anticoagulant, platelet aggregation-inhibiting or fibrinolytic active substances.

6. Use according to claim 5, characterized in that the additional active ingredients are selected from the group of factor Xa inhibitors, standard heparin, low molecular weight heparins such as enoxaparin, dalteparin, certroparin, parnapärin or tinzaparin, direct thrombin inhibitors such as hirudin, aspirin, fibrinogen receptor Antagonists, streptokinase, urokinase and / or tissue plasminogen activator.

7. Use according to one or more of claims 1 to 6, characterized in that the active ingredients are administered by oral, inhalative, rectal or transdermal administration or by subcutaneous, intra-articular, intraperitoneal or intravenous injection.