Method of treating ischemic stroke

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to neurology, and deals with the treatment of ischemic stroke. For this purpose the introduction of ubidecarenone by injection, mainly intravenous, is carried out.

EFFECT: introduction of the medication provides the reduction of the zone of brain tissue injury and reduction of neurologic deficiency expression due to the accumulation of ubidecarenone, possessing an expressed neuroprotective action, in brain tissues.

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The technical field to which the invention relates

The invention relates to medicine, specifically to the treatment of disorders of the Central nervous system caused by ischemic lesions, namely ischemic stroke.

The level of technology

Ischemic stroke occupies a significant place in the structure of mortality of the population, leading to frequent disability of the working population. One of the promising directions in neurology and clinical pharmacology is the study of drugs, possessing neuroprotective activity aimed at improving the survival of neurons and normalization of neurometabolic processes during cerebral ischemia. For example, many drugs, possessing neuroprotective properties (noopept, gliatilin), presented in the form for oral administration. However, the use of neuroprotective funds in forms for oral administration is ineffective in acute conditions. Injecting the maximum consistent with the purposes and conditions of the emergency treatment of acute severe lesions of the CNS, such as stroke. The most widespread in medical practice has received injectable peptide neuroprotective drugs - Cortexin, Cerebrolysin, known injectable form of the drug noopept (patent RF №2330680, 09.12.2005). In addition to t�, ischemic stroke is justified and illustrates the application of antihypoxants and antioxidants drugs that improve the utilization of circulating in the body of oxygen, inhibiting the processes of free-radical damage to the cells and thereby enhances resistance to hypoxia. The antihypoxic agent applied to the clinic for the treatment of acute stroke, is a drug 2-ethyl-6-methyl-3-hydroxypyridine succinate - Mexidol (Register of medicines of Russia. Encyclopedia of medicines. M.: "radar-2006", vol.14, pp. 489-490). He is membranoprotector possessing nootropic, antioxidant and anxiolytic effects. However, it has several drawbacks: not always effective, has side effects and is rapidly excreted from the body. Coenzyme Q10is an endogenous lipid-soluble coenzyme, which is part of the mitochondrial respiratory chain and shunt the transfer of electrons 1 and 2 of the complex of the respiratory chain at cytochrome C. It possesses powerful antioxidant properties and, as ubidecarenone (international nonproprietary name of coenzyme Q10), in the composition of medicines and biologically active additives is applied in therapy of cardiovascular diseases. The main drawback of dosage forms of ubidecarenone for intake is �x low bioavailability (less than 2%). As a result, even the high doses does not provide the concentration in the blood is sufficient to overcome the blood-brain barrier and the receipt of ubidecarenone in the brain. Injectable dosage forms ubidecarenone today does not exist.

Disclosure of the invention

The invention is directed to a new method for treating ischemic stroke with intravenous ubidecarenone to ensure its neuroprotective action.

The authors of the present invention was first suggested and demonstrated that injectino introduction of ubidecarenone effective in the treatment of ischemic stroke. The proposed method ensures the effectiveness of treatment by providing maximum bioavailability of ubidecarenone and allows you to create high concentrations in the blood plasma, which in turn ensures the overcoming of the blood-brain barrier and the flow of ubidecarenone in the brain. The technical result of the invention is to expand the indications for the use of ubidecarenone, to expand the Arsenal of drugs for the treatment of ischemic stroke.

Ubidecarenone is a 2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetragonality)-5,6-dimethoxy-3-methyl-2,5-cyclohexadien-1,4-dione and is characterized by the structural formula, privedennyynizhe:

In conducting the experiments was studied the pharmacokinetics of ubidecarenone (as part of the drug "Qudesan", JSC Akvion, Russia) when administered intravenously to rats male Wistar dose of 30 mg/kg of the Drug "Qudesan" (CJSC Akvion, Russia) is a liquid for oral administration, containing the active substance ubidecarenone (30 mg in 1 ml). Excipients used in the composition of the drug include: alpha-tocopherol acetate - 4.5 mg, ascorbyl palmitate 1 mg, macrogol glycerylmonostearate (Cremophor RH-40) - 105 mg, sodium benzoate 2 mg, (citric acid food grade) - 1.6 mg, purified water to 1 ml of the Drug "Qudesan" represented 3% and 6% solution (dose of active substance 30 mg/ml and 60 mg/ml, respectively).

After 15 min, 30 min, 1, 2, 6, 8, 12, 24, 48 hours and 8 hours after drug administration animals were then, brains were removed and were used to define tissue content of ubidecarenone (5 animals per group). To do this, the brain tissue homogenized, were twofold extraction with a mixture of ethanol 95%: hexane (2:5). Selected upper hexane layer was evaporated to dryness. The dry residue was dissolved in an aliquot of ethanol. The assay was performed by high performance liquid chromatography (HPLC) with coulometric detection.

Data processing was performed using packetarium STATISTICA 6.0 and Microsoft Excel. Data is represented by Ms. Val. ± STD. deviation. Differences were considered significant when p<0,05.

It has been shown that the level of coenzyme Q10in the brain tissue after injection was increased (p<0.05) relative to control animals by 54% after 15 minutes, 72% after 30 minutes, 71% in 60 minutes, 75% after 2 hours, 53% after 6 hours, 36% after 8 hours and 32% after 12 hours. After 24 hours, 48 hours and 8 days was not significant differences in the level of coenzyme Q10compared with intact animals (figure 1).

Thus, a single intravenous injection of ubidecarenone at a dose of 30 mg/kg provides the increase of its content in the brain by more than 50% within 15 minutes after the administration and preservation of the increased levels of coenzyme Q10for at least 12 hours.

Determination of doses and modes of administration of the drug can be selected individually in each clinical case and is obvious to the specialist. Selection of the optimal dosage of the drug for use in clinical practice was carried out by the authors of the present invention using a lookup table of dosages between humans and animals that are listed in the manual Yanlin Wang-Fisher "Manual of stroke models in rats", 2008, in Accordance with the table to recalculate the doses to the average weight of an adult (70 kg), multiply the proposed dose�alacartoona (30 mg/kg) on the average weight of the rats (0.2 kg) and by a factor of 56. Received dose, normalized to 70 kg to 5 mg/kg, which corresponds to 10 ml of a 3% solution "Qudesan" or 5 ml of 6% solution. In accordance with the received data, the inventors propose to use a sterile composition comprising ubidecarenone, intravenously in the form of a single injection at a dose of 5-10 mg/kg in the acute period of ischemic stroke or double intravenous injection in the acute phase and after 6 hours after the first injection. Also according to the standards of the treatment of acute ischemic stroke after a single injection of the drug in a dose of 5-10 mg/kg intravenously to maintain a constant concentration of ubidecarenone in the blood may intravenous drip solution of ubidecarenone in a dose of 5-10 mg/kg, dissolved in 200 ml of physiological solution, 2 hours after the first bolus injection. In addition, to ensure a prolonged effect of ubidecarenone may be recommended intravenous drip solution at a dose of 5-10 mg/kg daily for 10 days after the first bolus injection.

The proposed composition for treating ischemic stroke contains as a main active ingredient ubidecarenone, and may further contain auxiliary substances and additives, in particular soljubilizatory and/or emulsifiers, preservatives, for example, to�to macrogolglycerol (solubilizer), ascorbyl palmitate and/or sodium benzoate, and/or citric acid (preservatives), purified water.

Brief description of the drawings (Fig. 1-4)

Figure 1. The content of coenzyme Q10(CoQ10) in brain tissue of rats after different time intervals after intravenous injection of a solution of ubidecarenone at a dose of 30 mg/kg. * - p<0.05 compared with intact animals.

Figure 2. The content of coenzyme Q10(CoQ10) in the ipsilateral hemisphere of the brain of rats of different experimental groups: intact; intact + saline; linopirdine; rats underwent occlusion of the middle cerebral artery + saline (OSMA + Fiz R-R); rats underwent occlusion of the middle cerebral artery + solution ubidecarenone at a dose of 30 mg/kg (OCMA + CoQ10). * - p<0,05 - relative to other experimental groups.

Figure 3. The content of coenzyme Q10 (CoQ10) in the contralateral hemisphere of the brain of rats of different experimental groups: intact; intact + saline; linopirdine; rats underwent occlusion of the middle cerebral artery + saline (OSMA + Fiz R-R); rats underwent occlusion of the middle cerebral artery + solution ubidecarenone at a dose of 30 mg/kg (OCMA + CoQ10). * - p<0,05 - relative to other experimental groups.

Figure 4. The content of coenzyme Q10 (CoQ10) in the hemispheres of the brain� rats after occlusion of the middle cerebral artery: in the group, received an intravenous injection, USP solution (OSMA + Fiz R-R), and the group that received intravenous injection of ubidecarenone at a dose of 30 mg/kg (OSMA + CoQ10). # - p<0,05 - between ipsilateral and contralateral hemispheres.

The implementation of the invention

Study of the neuroprotective role of coenzyme Q10conducted on the model of ischemic stroke with reperfusion, which allows you to more fully mimic ischemic stroke in humans.

The study was performed on rats male Wistar weighing 270-370 g. the Animals were divided into 5 groups: intact animals (n=3), intact animals, which were injected with a solution of ubidecarenone at a dose of 30 mg/kg (n=4), linopirdine animals which were subjected to all actions except for the performances of the occluder (n=9), animals that underwent surgery occlusion of the middle cerebral artery and injected an equivalent amount of saline (OSMA + Fiz R-R, n=12) and group of animals subjected to surgery, which were injected with a solution of ubidecarenone at a dose of 30 mg/kg (OCMA + CoQ10, n=11). Under intraperitoneal anesthesia (chloral hydrate at a dose of 400 mg/kg) in sterile conditions was performed by occlusion of the middle cerebral artery as described Longa E. Z. (1989). Allocated common carotid, external carotid and internal carotid artery. Common carotid and internal carotid artery was closed using �crocodilia clips, the external carotid artery was ligated. Through a small incision in the external carotid artery into the lumen of the introduced filament-occluder, representing a 30 mm nylon thread with the tip, covered with silicone (production DOCCOL, USA). The filament carefully carried out through the external carotid artery into the lumen of the internal carotid artery and promoted until you feel resistance. This method was able to fully close the mouth of the middle cerebral artery and to ensure the development of brain ischemia in her pool. Occlusion was performed for one hour. 45 minutes after the beginning of ischemia, the test group of animals was injected with a solution of ubidecarenone at a dose of 30 mg/kg through the catheter in the femoral vein. Animals from control group were injected the same volume of NaCl solution. An hour after the onset of ischemia, the filament was withdrawn, allowing reperfusion. 24 hours after ischemia were used to verify the neuroprotective efficacy on the severity of neurological deficit (Example 1) and the volume of the lesion (Example 2). Then we were evaluating tissue content of CoQ10 in tissues ipsilateral and contralateral cerebral hemispheres of rats by HPLC method (Example 3).

Example 1

Definition of neurological deficits was performed blind on the modified scale Neuropathy Symptom Score (mNSS), which uses a score �about 6 parameters. Each parameter was assigned a value from 1 to 3: the higher the score, the better-preserved function.

1. Spontaneous activity of the animal in the cage for 5 minutes

Recorded the activity of the animal by the number of visited corners of the cage for 5 minutes. In animals that received the drug, noted the important of physical activity compared to control animals (p<0.01).

2. The symmetry of the movements of the limbs affected and unaffected sides of the body

In animals treated with the drug's development was less pronounced paralysis of the limbs on the side of the body opposite to the affected side of the brain. They also noted a less pronounced difference in the movements of the limbs affected and unaffected sides of the bodies compared to animals from control group (p<0.01).

3. The symmetry of limb movement when hanging the animal by the tail

Animals not receiving the drug, compared with animals that received the drug proved unable to catch up to the tail and showed a more pronounced difference between the right and left limbs (p<0.01).

4. The ability to climb up in the implantation of the vertical grid

Animals not receiving an injection of ubidecarenone, compared with animals treated with the drug had been unable to get on the grid, fell; so�e noted a more pronounced difference in the use of left and right limbs (p< 0.01).

5. Evaluation of the sensitivity when touching the affected side of the body

In animals that received an injection of ubidecarenone, compared to animals of control group were observed less pronounced loss of sensitivity to touch (p<0.01).

6. Evaluation of the sensitivity when touching the vibrissae

In animals that received an injection of ubidecarenone, compared to animals of control group were observed less pronounced loss of sensitivity to touch (p<0.01).

The total score on all six parameters in the group of control animals was 9.0±1.0 and in the group of animals that received ubidecarenone, was significantly higher was 14.8±0,8 (p<0.01).

Example 2

After identifying neurological deficit in animals were then. Preparing brain slices for 20 minutes, treated their metabolic dye 2,3,5-triphenyltetrazolium chloride, which were stained viable tissue in crimson color, and the area of necrosis remained unpainted yellow. The obtained sections were photographed and processed using the program ImagJ (USA) to determine the affected area and calculation of stroke volume. The area of necrosis was calculated by the formula, taking into account swelling of the brain (Zhang Y, Pardridge WM, 2001):

Sish=Skont-(Sipsa-Snecr), where

Sish- the area of stroke

Skont- PL�the area of the affected hemisphere

Sipsa- the area of the intact hemisphere

Snecr- the area of necrosis.

The amount of stroke was calculated by the formula:

V=ΣSish*d

where d is the thickness of the slice.

The volume of stroke in animals that received an injection of a solution of ubidecarenone, was 3.5 times less in comparison with animals of the control group (38,1±27.8 mm3and 133,0±64,6 mm3accordingly, p<0.01).

Example 3

The level of coenzyme Q10in intact animals, intact animals received a solution of ubidecarenone and lonaprisan animals was not significantly different and were $ 27.3±1,38 mg/g, and 27.7±1,16 mg/g and 26.6±2,77 mg/g, respectively. This confirms the data presented above that of intact animals after intravenous injection of a solution of ubidecarenone tissue contents of coenzyme Q10after 24 hours does not differ from the norm.

In operated animals treated with saline, the level of coenzyme Q10was significantly lower (p<0.05) and amounted to 23.7±2.8 µg/g and 21.1±2,25 mg/g in the contralateral (figure 3) and ipsilateral (figure 2) hemispheres, respectively. This confirms the assumption of the authors that, in ischemic brain tissue levels of endogenous coenzyme Q10reduced in both hemispheres of the brain, while in the ipsilateral hemisphere its level is significantly lower than in the opposite contralateral�nom. In the group undergoing surgery and receiving the injection, showed a significant increase (p<0.05) tissue levels of coenzyme Q10in relation to the group of control animals: 28,2±2,76 µg/g and 29.9±2,72 mg/g in the IPSI - and contralateral hemisphere, respectively (figure 4). The data obtained show that intravenous injection of a solution of ubidecarenone in the acute period of ischemic stroke provides increased tissue contents of coenzyme Q10at least to normal within 24 hours to ensure prolonged neuroprotective effect.

Thus, for providing a neuroprotective effect ubidecarenone should be administered by intravenous bolus with possible support the introduction in the acute phase of ischemic stroke or immediately before thrombolytic therapy.

1. A method for the treatment of ischemic stroke, comprising injecting to a patient a pharmacologically effective amount of ubidecarenone.

2. A method according to claim 1, distinguish fact that the injection is an intravenous injection.

3. A method according to claim 1, characterized in that the acute ischemic stroke patient is administered a composition according to claim 1 in the form of a single intravenous injection at a dose of 5-10 mg/kg.

4. A method according to claim 1, distinguish fact that the acute eremicus�the first stroke, the patient is administered the composition, containing ubidecarenone, in the form of two-time intravenous injection at a dose of 5-10 mg/kg in the acute phase and after 6 hours after the first injection.

5. A method according to claim 1, characterized in that the acute ischemic stroke patient is administered a composition containing ubidecarenone, in the form of a single bolus intravenous injection at a dose of 5-10 mg/kg followed by intravenous infusion at a dose of 5-10 mg/kg in 200 ml of physiological solution 2 hours after the first injection.

6. A method according to claim 1, characterized in that the acute ischemic stroke patient is administered a composition containing ubidecarenone, in the form of a single intravenous injection at a dose of 5-10 mg/kg followed daily by intravenous infusion at a dose of 5-10 mg/kg in 200 ml of saline for 10 days.

7. The use of ubidecarenone for the treatment of acute ischemic stroke.



 

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