UA75587C2 - Use of enoxaparin for treating cerebral ischemia - Google Patents

Abstract

The invention concerns the use of enoxaparin for treating cerebral ischemia.

Description

Description of the invention

The present invention relates to a new therapeutic application of enoxaparin. 2 Enoxaparin (Iomepoheb, Siehape?) is a low-molecular-weight heparin supplied for the prevention of venous thromboembolic diseases in surgery with moderate or high risk, for the prevention of coagulation during extracorporeal circulation during hemodialysis, the treatment of deep vein thrombosis and, in combination with aspirin, for treatment of unstable angina pectoris and myocardial infarctions without an O wave in the acute stage. Enoxaparin can also be used for the prevention and/or treatment of central nervous system injuries (M/098/53833) and cerebral edema (M/098/53834).

Low molecular weight heparins! were tested for the prevention and/or treatment of deep vein thrombosis in patients suffering from cerebral ischemia, but no effect on ischemia was shown (A. EGIAZ ei soi, and

Kemuce de Medesipe Ipiegpe, 17, Tote XI, 95-98 (1990); MN. RKIM5 ei soiI., Naetozviavziv, 19, 245-250 (1989);

Assoc. TOERIE ei soi., TNe I apsei, 523-526 (1987). 19 Currently, enoxaparin has been found to reduce the complications of cerebral ischemia and, thus, can be used for the treatment of cerebral ischemia.

This new therapeutic application was tested in rats according to the following study design:

Male rats of Zrgadie Yuamieu (230-250 Sha Stgedo) were fed and watered with ai IBisht and kept under conditions of a 12-hour light-dark cycle. Surgery was performed under halothane anesthesia (1.495 in a mixture of 7095 Mag2Oz5/3096 02). During anesthesia, normothermia was maintained by keeping the rats under a thermostatic blanket. The left common carotid artery was isolated and a loose ligature was applied. The left middle cerebral artery was exposed using a subtemporal craniotomy and a microclamp was placed on the proximal part of the artery, after which a ligature was immediately placed on the carotid artery. Two hours later, the animals were re-anesthetized and cerebral circulation was restored by removing the clamp from the middle cerebral artery and the ligature from the carotid artery. After that, the rats were placed in cages in a room in which the temperature of 26-2826 was maintained.

48 hours after surgery, a neurological examination was performed on each rat, and the researcher was unaware of the surgery. The used neurological scale is shown in Table 1. m

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After the neurological examination, the animals were euthanized and their brains were extracted. A series of sections with a thickness of 1.5 mm was prepared and stained with 295 2,3,5-triphenyltetrazolium chloride (TS). After 24 hours - post-fixation in a 1095 solution of formaldehyde, the damaged areas (brain infarction) were measured at the level of the cortex and 1 striatum; the volumes were calculated by integrating the damaged surfaces. Are the values expressed in mm? (mean and standard deviation). Statistical analysis was performed using the Mann-Whitney test or t-test

Kruskle-Wallis for non-parametric variance analysis followed by Dunn's test for comparison of groups (ee) 20 (ptre0.05, and re0.01, and re0.001 relative to the control group). -h In study 1, enoxaparin was administered to 12 rats at the rate of 1.5 mg/kg intravenously, 2 hours and 24 hours after the onset of ischemia. Animals from the control group (10 rats) received only an inert carrier (0.996 physiological solution of sodium chloride) according to the same scheme.

Study 2 investigated enoxaparin as an emerging therapeutic option. Treatment was started 5 hours after ischemia with re-administration 24 hours later. The study was conducted in relation to

HF) of the dose-dependent effect of enoxaparin on brain damage. The studied doses were 0.5:1 and 1.5 mg/kg

HF intravenously (9-10 rats in each group). A control group of 11 rats received only an inert vehicle (0.996 sodium chloride physiological solution).

In study C, enoxaparin was administered to 10 rats at 1.5 mg/kg intravenously 5 and 24 hours after the onset of ischemia. A control group of 13 rats received only an inert vehicle (0.990% saline solution of sodium chloride).

Study 4 followed the same scheme as in the other studies, but the left middle cerebral artery was subjected to irreversible cauterization, while the left carotid artery was not occluded. Enoxaparin was administered to 13 rats at 1.5 mg/kg intravenously, 5 and 24 hours after the onset of ischemia. A control group of 13 rats 65 received only an inert vehicle (0.995 sodium chloride saline).

The obtained results are presented in table 2. ;

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These results show that in study 1, enoxaparin significantly improves the neurological index after 48 hours of cerebral ischemia and, in addition, significantly reduces cortical damage by 3095, in study 2, enoxaparin reduces cortical damage by 3095 (2x1mg/kg) and 3690( 2x1.5MG/kg), in study C enoxaparin significantly improves the neurological index and reduces cortical damage by 3490, in study 4 enoxaparin significantly improves the neurological index and reduces cortical damage by 49905. Bleeding was not observed in these studies. Medicinal products consist of enoxaparin in the form of a composition in which it is combined with any other pharmaceutically compatible product, which can be (o) inert or physiologically active. Medicinal products according to the invention can be used, preferably, with intravenous or subcutaneous administration.

Sterile compositions for intravenous or subcutaneous administration are usually aqueous M solutions. These compositions may also contain adjuvants, in particular, wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out by several means, for example (ee) aseptic filtration, introduction of sterilizing agents into the composition, irradiation. They can also be obtained in the form of solid sterile compositions that can be dissolved in sterile water or any other sterile environment suitable for injections at the time of use. IF)

As an example of such a composition, it is possible to dissolve 20 mg of enoxaparin in an amount of distilled water sufficient to obtain 0.2 mL m solution.

Doses depend on the required effect, the duration of treatment and the route of administration used; usually they are from 0.2 to 4 mg/kg per day for subcutaneous administration, i.e. from 14 to 280 mg per day for an adult, with a single dose from 5 to 280 mg. « 20 | As a rule, the doctor determines the appropriate dosage, based on age, body weight and other factors related to the patient's observation. c The present invention also relates to a means of treating human cerebral ischemia, :c" The present invention also relates to a means of treating human cerebral ischemia comprising administering an effective amount of enoxaparin.

The present invention also relates to the use of enoxaparin for the preparation of a medicinal product suitable for the treatment of cerebral ischemia.

Claims (1)

The formula of the invention (ee) 50 1. Use of enoxaparin for the preparation of a medicinal product suitable for the treatment of cerebral ischemia. - h 2. Application according to claim 1 for obtaining a medicinal product containing from 5 to 280 mg of enoxaparin. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 5, 15.05.2006. State Department of Intellectual Property of the Ministry of Education and 59 Science of Ukraine. F) name) 60 b5