Cdp-choline - prophylactic agent for treatment of cerebral ischemia and method for treatment with its using

FIELD: medicine, biochemistry.

SUBSTANCE: invention proposes applying CDP-choline (cytidinediphosphocholine) or its salt as a prophylactic agent for treatment of cerebral ischemia and a method for such prophylactic treatment. Invention found new and unknown early mechanism of action of CDP-choline or its salt: inhibition of activation of caspase cascade being the effectiveness of this effect is high in prophylactic intake of drug.

EFFECT: valuable medicinal properties of agent.

6 cl, 5 dwg, 4 ex


The technical field to which the invention relates.

This invention relates to the use of CDP-choline for the preventive treatment of cerebral ischemia.

The level of technology.

There are several factors involved in the emergence and development of cerebral ischemic disorders, secondary to local ischemia. These factors include lack of energy and loss of homeostasis of neurotransmitters and cations; induction and unregulated expression of early genes, as well as mobilizing cytokines that alter the function of the blood-brain barrier and are involved in the infiltration of leukocytes; rapid cell death in the Central zones of infarction and delayed deaths, often associated with apoptosis in peripheral and border areas, as well as the induction or expression of trophic factors and their receptors, which contribute to compensatory plastic phenomenon and angiogenesis.

Knowledge of the mechanisms of cell death resulting from ischemia, is a basic aspect, since their control makes it possible vneshneeconomicheskoy intervention. Genetic control of programmed cell death was mainly studied in the nematode Caenorhabditis elegans and is related to genes ced-3, ced-4 and ced-9. Caspase type cysteine-dependent proteases mammals, meet a number of options, the ants gene product ced-3 and are important elements in the development of apoptosis. Caspase different way include a number of models of cell death, and they act on different underlying substrates that determine cell survival, leading to their disintegration. Caspase 1, 2, 3, 6, and 8 are associated with various diseases of the Central nervous system. In the works I.E. Andreoli (see Am. J. Med., 107, 488-506, (1999)) and B.C. Albensi (see Drug News Perspect., 12(8), 453-457, (1999)) describes the phenomenon of apoptosis and the role of caspases.

Currently there is little published data regarding the expression of caspases after damage induced temporary total ischemia or focal ischemia. Modern research has shown that for each caspase characteristic variable expression depending on the duration and types of cells. Applicants discovered that caspase involved in ischemic episode in both cases - as in the brain, and in models of focal ischemia in rats, and that the expression of caspases, as proven, is especially noticeable in the border zone during the first days after a heart attack.

CDP-choline (citizen-diphosphate-choline, Citicoline) is a key precursor in the synthesis of membrane phosphatidylcholine. In experimental models of exogenous introduction of CDP-choline reduces the destruction of cell membranes by inducing increased synthesis of phosphatidylcholine and reduced levels of free fatty KIS is from. It was shown that treatment with CDP-choline is effective in several models of ischemia or hypoxia in animals. Antiapoptotic, neuroprotective and antiamnezicescuu effects of CDP-choline was investigated in experiments on rats in the work HA Alvarez et al. (see Methods and Findings in Experimental and Clinical Pharmacology: 21(8), 535-540, (1999)). Neuroprotective mechanism of CDP-choline completely unknown. Currently consider that this effect is associated with reduced levels of free fatty acids, the formation of free radicals, stabilizing the membranes of nerve cells, reduction of toxicity induced by glutamate, and improved survival of nerve cells. Not yet clear whether the positive effect of CDP-choline in ischemic episodes can be associated with a decrease in the level of cell death due to apoptosis in the border region after focal cerebral ischemia.

It has been unexpectedly found that the introduction of CDP-choline in front of cerebral ischemic episode gives a stronger positive effect in preventing the severity of the consequences of the disease, than the introduction of CDP-choline after the occurrence of the consequences.

The essence of the invention.

This invention relates to the use of CDP-choline or its pharmaceutically acceptable salt for the manufacture of medicinal products for preventive treatment of cerebral ischemia.

Prophylactic treatment of the means, that CDP-choline or its pharmaceutically acceptable salt is administered before the possible development of an ischemic episode. In the case when an ischemic episode occurs, further treatment is preferred. In this case, the treatment can be adapted in accordance with the needs of the patient.

From the point of view of another aspect of the invention relates to a neuroprotective treatment. Neuroprotection means protecting brain tissue from damage, particularly from cerebral infarction.

According to another aspect, the invention concerns the use of CDP-choline or its pharmaceutically acceptable salt for the prevention of the extent of damage to brain tissue.

According to a specific variant implementation of the invention relates to the aforementioned applications, in which damage brain tissue and, in particular, cerebral infarction, associated with cerebral ischemia.

Cerebral ischemia includes cerebral ischemic events. Ischemic event can be defined as a reduction of blood supply to tissue. Cerebral ischemia may be caused by the reduction or even circulatory disorders of the arteries supplying the brain.

CDP-choline has an inhibitory effect on the activation caspases circuit and reduces the level of apoptosis in nerve cells in the boundary of the region.

Thus, in the light of another aspect, this invention relates to the use of CDP-choline or its pharmaceutically acceptable salts for inhibiting activation caspases chain. Because this effect was higher in previously treated subjects, concluded that CDP-choline causes prophylactic neuroprotective effect in cerebral ischemic events. In short, the fact that CDP-choline is more effective when introduced before ischemia, assumes the availability of preventive actions on the severity of ischemic complications. Finally, preventive method corresponding to the invention is significantly more effective than traditional treatment after the event.

Application in accordance with this invention includes a method of preventive treatment of cerebral ischemia, providing an introduction to the needy in this subject an effective amount of CDP-choline or its pharmaceutically acceptable salt.

CDP-choline or its pharmaceutically acceptable salt, or a mixture thereof may be introduced or optional jointly introduced to the needy in the subject, usually a patient person, sequentially or simultaneously with additional therapeutic agents in a pharmaceutically acceptable form, for example, in the form of suitable compounds with pharmaceutical the ski carriers and/or excipients, in effective amounts, preferably in daily doses of lying in the interval from 0.5 to 4 g free CDP-choline, more preferably from 1 to 2 g of free CDP-choline, as orally or parenterally depending on the patient's condition.

List of drawings and other materials.

In Figures 1, 2, 3, 4 and 5 the graphs in the form of columns, reflecting the average measurement of caspases 1, 2, 3, 6, and 8, respectively, in the analysis using immunofluorescence assay. The confidence interval is 95% and statistical significance relative to control equal to *p<0,05, **p<0,025, ***p<0,01.

Information confirming the possibility of carrying out the invention.

Pharmaceutically acceptable salts of CDP-choline include its salts obtained by addition of bases, in particular salts of alkaline or alkaline earth metals, such as salts of sodium, potassium, calcium and magnesium, or salt accession obtained by adding inorganic or organic acids, such as hydrochloric acid, bromatologia acid, sulfuric acid, acetic acid, triperoxonane acid, citric acid, lactic acid, malonic acid, tartaric acid, acrylic acid, methacrylic acid, malic acid, maleic acid, fumaric acid, benzoic acid, salicylic acid, cinnamic acid, methansulfonate acid, benzolsulfonat acid, p-toluensulfonate acid and nicotinic acid.

CDP-choline or its salts can be used in anhydrous or solvated, especially hydrated form.

The introduction may be administered orally in the form of tablets, capsules, powder, granules, wafers, cakes, solution, suspension, emulsion, syrup, gel, etc., or parenterally in the form of a solution, suspension, emulsion, etc. for intravenous or intramuscular injection.

The actors, especially those in need of treatment in accordance with this invention, is represented by:

- Patients who underwent primary surgical intervention, i.e. patients who will be doing, are doing and especially which made the surgery, when are probable or, in particular, which was bleeding, manipulation of the vessels or induced and supported hypotension (neurosurgery, cardiovascular surgery, transplants of organs, the orthopedic implant of the prosthesis and the like). In these cases it is preferable to start treatment for 24-48 hours before surgery, for example, at effective oral doses of 1-2 g/day. Medication continue during surgery in effective doses, components, for example, 1-2 g intravenously during anesth the Ziya and then for 1 week in effective doses, components, for example, 1-2 g/day orally or intravenously depending on the patient's condition.

- Patients with high risk of acute ischemic events such as stroke, due to several known risk factors such as history of previous transient ischemic episodes, arterial hypertension, hypercholesterolemia, Smoking, atrial fibrillation or other cardiac embolic disease. In this case, patients should be treated with effective doses, for example, 1-2 g/day when administered orally, as if the patient has suffered a hypothetical stroke.


The following examples illustrate the preparations of the active ingredient, suitable for use in the method appropriate for the invention. Competent professionals in this field will be able to make any change, provided that a specific way of carrying out the invention is not modified, and therefore the invention is not limited to the specific details of these examples.

EXAMPLE 1: tablets of 500 mg

CDP-choline, sodium salt 522,5 mg

Talc 30.9 mg

Magnesium stearate 3.0 mg

Silicon dioxide 2.5 mg

Na-20.0 mg Croscarmellose

Corn starch 20.0 mg

Microcrystalline cellulose, s.q.* 780,0 mg

*s.q. - sufficient, or as needed.

CDP-choline, sodium salt 26,12 g

70% sorbitol 20,00 g

Methyl ester of p-hydroxybenzoic acid, 0.16 g

Propyl ester of p-hydroxybenzoic acid 0.04 g

Citrate disodium 0,60 g

Saccharin sodium salt 0.02 g

Strawberry essence 0.04 g

Dye Red Punzo 4R 0.50 g

Anhydrous citric acid 0.05 g

Purified water, s.q.* 100,00 ml

*s.q. - sufficient, or as needed.

EXAMPLE 3: Solution for intravenous injection

CDP-choline, sodium salt 522,50 mg

Hydrochloric acid, pH 6,0-6,5, q.s.

Water q.s.* 4,00 ml

*q.s. - (quantum satis) in sufficient quantities or as required.

EXAMPLE 4: a Neuroprotective effect

The effect of CDP-choline on a delayed loss of nerve cells (apoptosis) estimate on the model cortical cerebral ischemia in rats in accordance with the following Protocol of the experiment:

1) Animals:

All tests for cerebral infarction conducted on male rats Sprague-Dawley mass 220-270, Animals are given free access to feed and water in rooms with controlled temperature and humidity cycle of alternation of light and darkness 12/12 hour.

2) - Model occlusion of the middle cerebral artery:

Cerebral ischemia induce by a constant direct blockage of the middle cerebral artery using electrocautery. Under deep anesthesia at Golo is a rat impose clamps and make the cut between the left ear and left eye. Then expose the skull, cutting the temporal muscle. Craniotomy performed using a drill with a diameter of 1-2 mm behind the scaly furrow. Dura bore through to expose the branch of the middle cerebral artery, which always coagulation.

3) - Schema of the treatment:

Rats randomly divided into three groups:

(a) the Group receiving treatment within 30 minutes after ischemia, animals in this group treated with CDP-choline (500 mg/kg) in 0.9% sterile physiological saline (0.1 ml), which is injected intraperitoneally. This group is illustrated in Figures 1-5, as After ischemia".

(b) a Group receiving treatment for 24 hours before ischemia and after 30 minutes of ischemia, the animals of this group receive the same treatment as in group (a). This group is illustrated in Figures 1-5, as Before ischemia".

(c) Animals of this group used as control. After ischemia treated with 0.9% physiological saline (0.1 ml), which is injected intraperitoneally. This group is illustrated in Figures 1-5, as "Control".

4) Obtaining samples for morphological study.

Labelling of fragmented DNA and immunohistochemical analysis of caspase:

Animals allow you to return to a normal state in different periods of time (30 min and 1, 4, 8, 12, 24 and 48 hours) before they are euthanized ethyl ether. the ATEM in their brain immediately injected with PBS (phosphate buffer solution) at 4° With using a cannula introduced into the heart (left ventricle) with the subsequent introduction of a 4% paraformaldehyde. The brain was quickly removed and fixed by immersion in the same fixative for 24 h at 4°C. After cryoprotection using 30% sucrose brain frozen in isopentane cooled with liquid nitrogen and then stored at -70°C. using a cryostat from the brain to make the cuts with a thickness of 50 μm. Brain slices stored at -70°using cryoprotector. These drugs are then used as samples for immunohistochemical analysis, the study of morphology and tagging in situ apoptotic cells. The morphology of a heart attack study on sequential preparations, including the beginning and end of infarction using staining with hematoxylin and eosin and staining on Nissle (NissI) (cresyl purple). Apoptotic cells have been labelled variants of fragmented DNA by the introduction of the label in situ. Immunohistochemical analysis of the expression of caspase carried out using the method with the use of avidin-Biotin-peroxidase with specific primary antibodies against caspase 1, 2, 3, 6, and 8, obtained from company Santa Cruz Biotechnology.

5) - Gel electrophoresis and analysis by the method of Western blotting:

Sample preparation in terms of groups and time periods, similar to the procedure described in RA matter 4). Animals that are in a state of deep anesthesia, decapitat and immediately remove the brain. In each case, to make the cuts in the following areas: (a) gray matter in the field of heart attack; b) white matter in the region of the heart; b) gray matter in the border region and g) of the white matter in the border region. For each case receive the samples from the contralateral and ipsilateral sides. These samples are subsequently used for analysis by the method of Western blotting using antibodies against caspase and antibodies against various substrates of caspases to study their possible degradation after ischemic damage.

6 - Results

To assess the effect of treatment on the expression of caspase 1, 2, 3, 6, and 8 as markers of apoptosis was measured 12 hours after induction of myocardial infarction, the results are in Figures 1, 2, 3, 4 and 5, respectively. Applicants observe significant differences between treated and control animals in terms of expression of these markers. In addition, more importantly, these differences are greater in animals receiving treatment before ischemia than in animals receiving treatment after ischemia. All these experiments make clear that CDP-choline in the introduction before and after induction of myocardial infarction reduces the level of caspase more significantly than the ri introduction only after induction of myocardial infarction.

1. Method of preventive treatment of cerebral ischemia, wherein the subject is administered citizen-diphosphate-choline (CDP-choline) or its pharmaceutically acceptable salt before and after the occurrence of ischemic episodes with daily doses equivalent to free citizen-diphosphate-choline numbers lying in the interval from 1 to 2,

2. The method according to claim 1, characterized in that the pharmaceutically acceptable salt citizen-diphosphate-choline presents its salts of alkali or alkaline earth metals or salts formed with mineral or organic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, acetic acid, triperoxonane acid, citric acid, lactic acid, malonic acid, tartaric acid, acrylic acid, methacrylic acid, malic acid, maleic acid, fumaric acid, benzoic acid, salicylic acid, cinnamic acid, methanesulfonate acid, benzolsulfonat acid, p-toluensulfonate acid and nicotinic acid in anhydrous or hydrated form.

3. The method according to claim 1, characterized in that the preventive treatment of a subject having a risk of acute ischemic events.

4. The method according to claim 1, characterized in that the preventive treatment of the subject, which is versa extensive surgery.

5. The method according to any one of claims 1 to 4, characterized in that the subject is a patient.

6. Application citadin-diphosphate-choline or its pharmaceutically acceptable salts for inhibiting activation caspases circuit for prophylactic treatment of cerebral ischemia.


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