SK9612002A3 - Novel therapeutic use of enoxaparin - Google Patents

Abstract

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

Description

Technical field

The invention relates to a new therapeutic use of enoxaparin.

BACKGROUND OF THE INVENTION

Enoxaparin (Lovenox ^R , Clexane ^R ) is a low molecular weight heparin that is commercially available as an agent for the prophylactic treatment of thromboembolic disease in moderate or high risk surgery, to prevent coagulation in the extracorporeal circulatory cycle during hemodialysis, to treat deep vein and deep vein therapy. aspirin for the treatment of unstable angina pectoris and myocardial infarction without Q wave in the acute phase. Enoxaparin is also useful in the prevention and / or treatment of central nervous system injuries (WO98 / 53833) or brain edema (WO98 / 53834).

Low molecular weight heparins have been tested to prevent and / or treat venous thrombosis in patients suffering from cerebral ischemia, but no effect on ischemia has been demonstrated (A. Eíias et al., La Revue de Médicine Interne, 1, vol. XI) 95-98 (1990); Mh Prins et al., Haemostasis, 19, 245-250 (1989); Agg. Turpie et al., The Lancet, 523-526).

It has now been found that enoxaparin makes it possible to limit the consequences of cerebral ischemia and can thus be used to treat cerebral ischemia.

This new therapeutic use was demonstrated in rats according to the following protocol.

Male Sprague Dawley rats (230-250 g, Iffa Credo) are maintained in ad libitum food and fluid mode over a 12 hour light-dark cycle. Surgery was performed using halothane (1.4% in 70% N ₂ O / 30% O ₂ ). During anesthesia, a normal temperature regime was maintained by placing the rats under a thermostatic blanket. The left carotid artery is isolated for free ligation. Immediately after ligation of the carotid artery, the middle left cerebral artery is exposed by craniotomy in the area under sleep and a microclip is applied to the proximal artery. After two hours, the test animals are re-anesthetized and the cerebral circulation is restored by removing the micro-clamp from the cerebral artery and removing the ligated carotid artery. The rats are then placed in a cage housed in a room thermostated at 26-28 ° C.

hours after said surgery, each rat is subjected to a neurological test, and the person performing the test was not familiar with the treatment. The neurological scale used is described in Table 1 below.

Table 1

normal deficit engagement Right front 1 0 reflex paw

Storage reactions

Loss of support 'Right front paw 1 1 ) f 0 Right hind paw 1 0 erection reflex rotation right side 1 0 left side 1 0

Abnormal posture absent present

Flexia pravej front paws 1 0 Body torsion 1 0 Overall 7 0 neurologic 1 score

After performing the neurological test, the rats are sacrificed and their brains removed. A series of 1.5 mm sections are prepared and stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC). After 24 hours post-fixation in a 10% formaldehyde solution, lesion areas (cerebral infarction) are measured at the cortical and striatal levels; volumes are calculated by integrating lesion surfaces.

These values are expressed in mm ³ (mean +/- standard deviation).

Statistical analysis is performed with the Mann-Whitnex test or the Kruskal-Wallise test for nonparametric variation analysis followed by Dunn's test for comparison between groups (*: p <0.05, **: p <0.01, ***: p <0.001 versus control group).

In Study 1, enoxaparin is administered to 12 rats in an amount

1.5 mg / kg i. in. 2 hours and 24 hours of onset of ischemia. A control group of 10 rats received only vehicle (saline 0.9% sodium chloride) according to the same protocol.

Study 2 investigates the appropriate therapeutic range of enoxaparin. Treatment begins 5 hours after ischemia and is followed by a second administration at 24 hours. This study consisted of determining the dose-dependency of enoxaparin's activity on cerebral lesions. The doses studied are 0.5, 1 and 1.5 mg / kg i.v. (9 to 10 rats per group). A control group of 11 rats received only vehicle (saline consisting of 0.9% sodium chloride solution).

In Study 3, enoxaparin is administered to 10 rats in an amount

1.5 mg / kg i.v. 5 and 24 hours after the onset of ischemia. A control group of 13 rats received only vehicle (saline 0.9% sodium chloride).

In Study 4, the protocol is the same as in the other studies, except that the middle left c'erebral artery

is permanently cauterized and no left occlusion of the carotid artery. Enoxaparin is administered to 13 rats in an amount 1.5 mg / kg i.v. 5 and 24 hours after the onset of ischemia. inspection

Group 13 rats received only vehicle (saline 0.9% sodium chloride).

The results obtained are shown in Table 2 below.

Table 2

study Cortical lesion (mm ³ ) Neurological score (7 degree scale) Study 1 Control group 186 +/- 18 1.7 +/- 0.3 Enoxaparin group 2x1.5 mg / kg, i.v. 131 +/- 13 * 3.1 +/- 0.2 ** Study 2 Control group 203 +/- 12 Enoxaparin group 2x0.5 mg / kg, i.v. 164 +/- 15 2x1 mg / kg, i.v. 142 +/- 24 * 2x1.5 mg / kg, i.v. 129 +/- 17 * Study 3 control group 195 +/- 12 1.8 +/- 0.3

Enoxaparin group 2x1.5 mg / kg, i.v. 129 +/- 16 ** 3.4 +/- 0.3 *** Study 4. Control group 137 +/- 23 1.7 +/- 0.2 Enoxaparin group 2x1.5 mg / kg, i.v. 71 +/- 13 * 2.9 +/- 0.3 **

The results shown above show that:.

- in study 1, enoxaparin significantly improves the neurological score of hours after cerebral ischemia and in addition significantly reduces cortical lesion by 30%.

enoxaparin α 36% in study 2 30% (2x1 mg / kg) in study 3 enoxaparin reduced cortical lesion in study 4 enoxaparin reduced cortical lesion reduced (2x1.5 mg / kg);

significantly improves by 34%;

significantly improves by 49%.

cerebral neurological neurological lesion score score

No bleeding was observed in these studies.

Said medicaments are formed by enoxaparin in the form of a composition in which enoxaparin is in combination with any pharmaceutically compatible product which may be inert or physiologically active. The medicaments according to the invention can preferably be used intravenously or subcutaneously.

Sterile compositions for intravenous or subcutaneous administration are generally aqueous solutions. These compositions may also contain additives, in particular wetting agents, isotonizing agents, emulsifying agents, dispersing agents and stabilizing agents. Sterilization may be performed. in various ways, for example by aseptic filtration, incorporation of sterilizing agents into the composition, or by irradiation. These compositions may be prepared in the form of solid sterile compositions which, at the time of use, may be dissolved in sterile water or any other injectable sterile medium.

An example of said composition is a composition obtained by dissolving 20 mg. enoxaparin in distilled water in an amount sufficient to prepare a 0.2 ml solution.

The doses administered depend on the desired effect, the time of treatment and the route of administration used; these doses generally range from 0.2 to 4 mg / kg / day for subcutaneous administration, which is 14 to 280 mg / day for an adult patient using unit doses of 5 to 280 mg.

In general, it is the attending physician who will determine the appropriate dosage according to the age, weight and any other individual factors of the patient being treated.

The invention also relates to a method of treating cerebral ischemia in a human by administering an effective amount of enoxaparin.

The invention also relates to the use of enoxaparin for the preparation of a medicament for the treatment of cerebral ischemia.

Claims (2)

PATENT CLAIMS Use of enoxaparin for the preparation of a medicament for the treatment of cerebral ischemia. I Use according to claim 1 for the preparation of medicaments containing 5 to 280 mg enoxaparin.