WO1992020351A1

WO1992020351A1 - Use of the cation-exchanger resins resonium a and sobisterite for controlling circulatory disorders

Info

Publication number: WO1992020351A1
Application number: PCT/EP1992/001159
Authority: WO
Inventors: Elfriede Leniger-Follert
Original assignee: Leniger Follert Elfriede
Priority date: 1991-05-23
Filing date: 1992-05-22
Publication date: 1992-11-26
Also published as: DE4116889A1

Abstract

A cation-exchanger resin capable of absorbing potassium ions at physiological pH values, such as for example a polystyrol-divinylbenzol sulfonic acid salt in the Na+ and/or Ca2+ form (resonium A R, sorbisterite R), is used as the active substance in a medicament for controlling circulatory disorders.

Description

USE OF RESONIUM A AND SORBISTERITE CATION EXCHANGER RESIN FOR CONTROLLING BLOOD DISEASES

Description

The invention relates to the use of ion exchange resins to combat circulatory disorders.

Circulatory disorders are caused by various causes. For example, they can be purely mechanical, e.g. Thrombus or embolus or caused by a vascular stenosis in the event of changes in the wall of the vessel or by a drop in cardiac and circulatory blood pressure below a critical lower perfusion pressure. Furthermore, disorders of the blood composition can lead to circulatory disorders. The blood flow in an organ or in the overall organism can only be reduced or completely abolished compared to the normal state. As a result of the circulatory disorder, there is a lack of oxygen and substrate, less removal of the metabolic end products and damage to the cell membranes in the affected organ or in the whole organism.

Depending on the extent of the reduced blood flow, this leads to serious consequences in the affected areas and therefore to serious clinical pictures, which can even lead to death.

From a pathophysiological point of view, in the event of a disorder, calcium ions first flow into the cell from the extracellular space and, in return, potassium ions flow out of the cells into the extra-cellular space. In addition, increased lactate formation leads to intracellular and extracellular acidosis. The increase in the potassium concentration in the extracellular space initially causes the arterial blood vessels to expand in the range from 3 to 20 mmol / l by hyperpolarization of the smooth vascular muscle cell membrane. Above 20 mmol / 1, a further increase in the K ⁺ concentration in the extracellular space leads to a narrowing of the blood vessels, caused by a K ⁺ -Depola- rization of the smooth vascular muscle cell membrane. The ^ concentration can rise up to a maximum of 100 mmol / l and lead to a complete occlusion of the arterial blood vessels. An increase in the extracellular K ⁺ concentration, which has a narrowing effect on the vessels, can also be caused by the release of potassium ions from erythrocytes after bleeding into the tissue, for example after subarachnoid hemorrhage in aneurysms of the brain arteries.

The narrowing of the vessels due to the increased potassium concentration in the extracellular space has very serious consequences for the organs or tissues concerned. It is the actual reason why the blood flow can no longer be started after a primary disruption. This then leads to a final destruction of cells and parts of the tissue, so that, particularly in the cerebral and coronary areas, clinical pictures arise which can even lead to death.

Cerebral and coronary circulatory disorders are common in the population. There is therefore a need to provide a drug for the treatment of this disease.

The aim of the invention was therefore to provide a medicament which is suitable for the treatment of circulatory disorders, in particular in the cerebral and coronary area.

This goal is achieved by using a cation exchange resin as an active ingredient for a medicament for combating circulatory disorders, which is characterized in that it can trap potassium ions at physiological pH values. If appropriate, the medicament can contain the ion exchange resin together with conventional physiological additives, solvents and / or diluents. Resonium A® is preferably used as the ion exchange resin. Resonium A® is a polystyrene sulfonic acid salt that is cross-linked with divinyl benzene sulfonic acid. Its theoretical exchange capacity is 135 mg potassium / g resin. Under practical conditions of use, however, only about 1/3 of this theoretical capacity can be occupied by potassium ions. Also preferred is the Sorbisterit® ion exchange resin, which is an ion exchange resin in the form of a Ca ²⁺ salt.

Resonium A® is known as a medicament for use in the case of potassium poisoning, in particular hyperkalaemia in dialysis patients. The present invention therefore represents a new indication. The resin and similar resins from other manufacturers are normally used in the form of the sodium or calcium salt.

Surprisingly, it has been shown that it is possible to treat circulatory disorders with an ion exchange resin which can trap potassium ions in the extracellular region. With the help of this new drug, the narrowing of the arterial blood vessels in the brain and organs, which is due to an increase in K ⁺ concentration, is eliminated and the vessels are enlarged so that blood can flow again.

Even an expansion of the vessels compared to the original diameter is found without the addition of potassium ions in the case of treatment with ion exchangers.

The ion exchanger resin which traps potassium ions is preferably used together with conventional physiological additives, solvents and / or diluents. These means are known to the person skilled in the art. Conventional additives can also be added to the ion exchange resin. In particular, physiologically suitable buffer substances come into consideration. Tris buffer, bicarbonate or phosphate buffer are used in particular as buffer substances. In a preferred embodiment, a thrombolytic additive is also added to the medicament. This is particularly useful if the circulatory disorder to be treated was triggered by a vascular blockage, for example in the event of an infarction, by a thrombus. Anti-edematous agents can also be added to the drug.

In particular in the case of coronary circulatory disorders, it is further preferred to add a compound to the ion exchange resin which acts as a calcium antagonist, in which case the ion exchange resin must not be present as a calcium salt.

The medicament according to the invention is suitable for the treatment of all types of circulatory disorders. It can be used to treat circulatory disorders in all organs and in the whole organism. The remedy is suitable for generalized and local circulatory disorders. It is particularly preferred in the treatment of cerebral and coronary circulatory disorders in the newborn infant.

The agent can be applied systemically. The agent can be administered in the form of injections and infusions. The injection is preferably carried out intra-arterially. However, it is also possible to administer the agent intravenously. As an infusion, the medicament is preferably contained in a rheologically effective infusion for haodilution of the blood. In addition, the agent can also be administered orally in the form of drops or tablets. In a further preferred embodiment, the agent is used directly in the treatment of circulatory disorders in individual organs injected the affected organ. For example, in the case of a cerebral infarction, the agent is injected directly into a cerebral artery, and in the case of a heart attack, the agent is injected directly into the heart. In particular, if the heart is affected, it is also preferable to place a catheter and introduce the agent through this catheter.

Furthermore, the agent can also be applied locally from the outside to the affected organ. For example, after bleeding in the area of the pial brain arteries, the agent can be applied to the brain through a borehole or during neurosurgical surgery in order to eliminate the localized or generalized spasms caused by the K ⁺ release after bleeding.

The dose of the drug depends on the type and location of the circulatory disorder. The agent can be dosed precisely depending on the potassium concentration at the site of the circulatory disorder. The drug is preferably used in a concentration such that the potassium ion concentration is adjusted to a range from 3 to 20 mmol, particularly preferably 3 to 10 mmol.

Circulatory disorders and vascular occlusions can be treated with the medicament according to the invention. With the remedy, the vascular constriction is removed and the ischemia is eliminated. Surprisingly, it is thus possible to prevent or at least reduce damage caused by ischemia.

The invention is illustrated by the following example: example 1

The effect of the ion exchanger Resonium A (poly (styrene, divinylbenzene) sulfonic acid sodium salt) on the diameter of the arterial or arteriolar vessels on the exposed brain surface of an anesthetized rat was examined. The physiological blood parameters such as blood pressure, blood gases and pH as well as the ion concentration of the blood were all within the normal range. By means of an appropriate light microscope, the vascular responses were observed with an attached to the microscope camera Aus¬ cut from the brain surface with the vessels before and photographed after ^'application of the corresponding substance.

Three vessels were marked in the observation section of the microscope in the control state under initial conditions by means of a microscope marker and photographed. A 1 M KCl solution was then dripped onto the surface of the brain with a pipette and the reaction of the marked vessels was observed. The vessel diameters narrowed within seconds. After about 2 minutes, the vessels were photographed again. Then Resonium A was applied to the brain surface in an emulsion and the vessels were photographed again after 2 minutes and 10 minutes after application of Resonium A. After the end of the experiment, the diameters of the three marked vessels were measured with a suitable enlargement of the developed images. The diameter of the three vessels under control conditions was set to 100% and the percentage change in the vessel diameter after KCl and after Resonium A application was determined (Table 1). Table 1

Conditions vessel diameter (%)

Vessel 1 2

Check 100 100 100

KC1 68.4 86.3 82.6

Resonium A (2 min) 89.5 113.3 87.0

Resonium A (10 min) 94.7 106.7 118.3

The flow changes were calculated from the percentage changes in the vessel diameter in accordance with the Hagen-Poiseuille law. The output flow was set as 100% in the control state (Table 2).

Table 2

River conditions (%)

Vessel 2

Check 100 100 100

KC1 21.4 56.2 46.6

Resonium A (2 min) 64.2 164.8 57.3

Resonium A (10 min) 80.4 129.6 118.3

As the test results show, reduced blood flow caused by potassium ions is reversed by the applied ion exchanger.

Claims

Patent claims

1. Use of a cation exchange resin as an active ingredient for a medicament for combating circulatory disorders, since the cation exchange resin can trap potassium ions at physiological pH values.

2. Use according to claim 1, characterized in that the cation exchange resin is a (polystyrene-divinyl-benzene) sulfonic acid salt in Na ⁺ - and / or Ca ²⁺ form.

3. Use according to claim 1 or 2, d a d u r c h g e k e n n z e i c h n e t that the cation exchange resin is Resonium A® or Sorbistit®.

4- Use of a cation exchange resin for the production of a medicament for combating circulatory disorders, since the cation exchange resin can trap potassium ions at physiological pH values.

5. Use according to claim 4, characterized in that the cation exchange resin is a (polystyrene-divinyl-benzene) sulfonic acid salt in Na ⁺ - and / or Ca ²⁺ form.

6. Use according to claim 4 or 5, d a d u r c h g e k e n n z e i c h n e t that the cation exchange resin is Resonium A® or Sorbisterite®.