RU2563123C1 - Method of treating cerebral oedema - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: treating cerebral oedema is ensured by administering Raleukin, a preparation of receptor recombinant interleukin-1 antagonist intravenously in a dose of 25-100 mg/kg of body weight.

EFFECT: reducing an intensity of oedema both unassisted, and assisted by other medicinal products.

2 tbl, 1 ex

Description

The invention relates to medicine, namely to methods for the prevention and treatment of cerebral edema.

Cerebral edema (OM) is a pathological process, manifested by excessive accumulation of fluid in the brain cells and intercellular space, an increase in brain volume and intracranial hypertension and is a response of the body to any irritation (infection, intoxication, head injury). Usually, this reaction develops rapidly, and if the patient is not provided with the necessary medical care in time, it will lead to death. An increase in intracranial pressure leads, in turn, to impaired blood circulation in the brain and the death of its cells, [en.wikipedia.org/wiki/Cerebral Mortality]. OM is one of the most difficult to treat diseases, and the methods for its treatment are of great practical importance. According to academician N.N. Burdenko “the one who knows the art of treating and preventing cerebral edema owns the key to the life and death of the patient!”

According to the pathogenesis, cerebral edema is divided into vasogenic, cytotoxic, interstitial and filtration. The clinical manifestations of edema - brain swelling are the same regardless of its pathogenetic type. They consist of a combination of symptoms due to intracranial hypertension syndrome, focal and stem symptoms.

The syndrome of intracranial hypertension occurs due to an increase in the fluid in the closed cavity of the skull and is manifested by bursting headache, nausea, vomiting at the height of pain, and a decrease in the level of consciousness. With long-term intracranial hypertension on the roentgenograms of the skull, amplification of finger impressions, osteoporosis of the back of the Turkish saddle can be noted; when examining the fundus - swelling of the nipples of the optic nerves.

Focal symptoms are manifested as a result of localization of edema in certain areas of the brain, which leads to disruption of their work and, accordingly, loss of their functions. Also, edema of some parts of the brain leads to their displacement relative to others and to the appearance of dislocation syndromes, which are accompanied by compression of the structures of blood vessels and the brain stem. The attachment of stem symptoms in the clinic is manifested by impaired breathing, blood circulation, inhibition of the reaction of the pupils and is life-threatening.

One of the main tasks in the treatment of a patient with intracranial pathology in the acute period is to ensure that he has a normal level of cerebral perfusion pressure (CPP), since it determines the adequacy of blood supply and the supply of nutrients to the neuron. The standard treatment regimen for OM involves maintaining oxygenation; elimination of motor excitement and cramps; prevention and elimination of pain and nociceptive reactions; maintaining normal body temperature; moderate hyperventilation; prescribing diuretics [en.wikipedia.org/wiki/Brain_Lab]. In addition, it is recommended the introduction of drugs that help supply the brain with enough oxygen, reduce intracranial pressure and eliminate the infection (if the infection has caused the development of edema). The choice of drugs depends on the cause of the edema and the severity of its main symptoms. [Brain edema: causes, treatment, consequences, lechenie-simptomy.ru/otek-golovnogo-mozga]. In particular, it is proposed to use clonidine, dibazole or caffeine sodium benzoate to normalize the systemic blood pressure of calcium channel blockers; verapamil and its derivatives (finoptin, isoptin), nimodipine, lidoflazin, nifedipine (corinfar), fendilin (senzid), cinnarizine (stugeron) to improve cerebral circulation, reduce the accumulation of tissue hormones and thereby provide increased brain resistance to hypoxia . Enhanced microcirculation of the brain is achieved by prescribing drugs that normalize vascular tone and rheological properties of blood (Cavinton, Xanthinol Nicotinate (compliment, Theonicol, Xarin), Eufillin, Tren-Tal (Agapurin), Dipyridamole (Curantil), Halidor, Sermion (Rederginum) , heparin, indomethacin (voltaren, orthophene, aspirin). Immunostimulating therapy includes the use of thymosin, T-activin, B-activin, thymogen, levamisole, propermyl, B vitamins. [http://meduniver.com/Medi-cal/Neotlogka /223.html MedUniver].

One of the promising drugs for the treatment of OM is dexamethasone, which, in particular, corrects the vascular (barrier) factor, has anti-inflammatory, anti-shock, immunosuppressive effects. Treatment of cerebral edema with dexamethasone is the closest analogue to the claimed treatment [http://www.rlsnet.ru/mnn_index_id_915.htm#primenenie-veshhestva-deksametazon]. The introduction of the drug is carried out slowly in a stream or drip in acute and emergency conditions at a dose of 4-20 mg (up to 80 mg) 3-4 times a day, and then maintenance doses - 0.2-9 mg per day for 3-4 days. After which the drug is taken orally.

The disadvantage of the drug is relatively low efficiency, as well as a large number of negative side effects and contraindications (confusion, disorientation, euphoria, hallucinations, depression or paranoia, increased intracranial pressure with congestive optic nerve syndrome, headache, worsening visual acuity or double vision , arterial hypertension, the development of chronic heart failure (in predisposed patients), myocardial dystrophy, hypercoagulation, thrombosis, nausea, Vaught, depression of adrenocortical function, impaired glucose tolerance, diabetes or steroid manifestation of latent diabetes, steroid myopathy, reduced muscle mass, osteoporosis, and decreased immunity activation of infectious diseases, etc.

The technical problem solved by the authors was the creation of a more effective and safe way to treat cerebral edema.

The technical result was achieved by the introduction of the intravenous preparation of the receptor antagonist intelleukin-1 (IL-1Ra) "Raleikin" at a dose of 25-100 mg / kg body weight. Using the drug in a dose of less than 25 mg / kg body weight is ineffective. Optimal doses are 50-100 mg / kg body weight. The use of large doses is possible, but not economically feasible.

A significant decrease in edema leads to a significant decrease in animal death in experimental cerebral edema, which opens up wide possibilities for the use of "Raleikin" in various brain lesions, both independently and in combination with other drugs.

Currently, "Raleikin" has shown high efficiency in the treatment of allergic rhinitis, bronchial asthma, has shown antitoxic and radioprotective effects, is a stimulator of hematopoiesis [www.rlsnet.ru/tn_index_id_46826.htm; fmbaros.ru/common/upload/13.doc] The effects of this drug and its analogues on OM are not described in the literature.

The essence and advantages of the proposed method are illustrated by an example based on the effect of the drug on artificially induced edema in rats.

Example 1. In the experiment, a model of C6 intracranial glioma was used in Wistar rats. Under anesthesia, an injection into the right caudate nucleus (nucl. Caudatus dexter) of a suspension of rat C6 glioma cells (concentration 1 × 10 ⁶ cells / ml; 10 μl per injection) was performed. Fifteen days after the implantation of the cells, intravenous administration (tail vein) of a solution of recombinant IL-1Ra or control preparations was carried out. The following comparison groups were used (in each group of 20 rats): (1) control group (administration of a solution of phosphate-saline buffer (FSB)); (2) an intravenous bovine serum albumin (BSA) group; (3) intravenous administration of the glucocorticoid hormone dexamethasone; (4) - (6) groups with intravenous administration of recombinant IL-1Ra in dosages of 25, 50 and 100 mg / kg.

The receptor antagonist was administered once every other day once into the tail vein on the 15th, 17th, 19th, 21st and 23rd days from the moment of inoculation of C6 cells into the brain of animals. In the control group, BSA was used at a concentration of 100 mg / kg with a frequency of administration as in the experimental group. As a positive control, intravenous dexamethasone (concentration 4 mg / kg) was used every other day once in the tail vein on the 15th, 17th, 19th, 21st and 23rd days from the moment of tumor cell inoculation.

Evaluation of peritumoral edema was carried out by magnetic resonance imaging (MRI). The animals underwent MR imaging of the brain using a high-field tomograph (Bruker, Germany) with a magnetic field strength of 11 T. The following modes were used to obtain sequential images of the animal brain: gradient echo mode (GEFI ORTO) (TR 350 ms, TE 5.4 ms; FA 40 °; section thickness 1.0 mm; (field of view) FoV 2.5 × 2.5 cm; matrix 256 × 256), pulse mode multi-scan multi-echo (MSME); tomograms weighted by T1 and T2 were obtained in the RARE-T1 modes (TR 1.500 ms, TE 7.5 ms; FA 180 °; cut thickness 1.0 mm; FoV 2.5 × 2.5 cm; matrix 256 × 256) and Turbo-RARE -T2 (TR 4,200 ms, TE 36 ms; FA 180 °; section thickness 1.0 mm, FoV 2.5 × 2.5 cm; matrix 256 × 256), respectively. Additionally, diffusion-weighted MRI tomograms (DWI) were obtained (TR 10,000 ms, TE 34.0 ms, FA 90 °, slice thickness 1.0 mm; FoV 2.5 × 2.5 cm; matrix 256 × 256) with subsequent measurement of the coefficient of visible diffusion (ADC ) When constructing maps and measuring ADC values, diffusion-weighted images obtained at b = 1000 s / mm ^{2 were used} . For a comparative visual assessment of the signal intensity in the pathological process visualized with the use of DWI, we used data from T2-weighted images (with b = 0). The diffusion coefficient (ADC) was calculated by the formula: ADC = - (l / b) In (S / S ₀ ), where

b - diffusion factor, including the physical characteristics of diffusion gradients, S ₀ and S, respectively, the signal intensity in the absence and under the action of the diffusion gradient.

The results of exposure to drugs are given in table. 1 .. Data are presented as mean values (M) of visible diffusion coefficient (ADC) (standard deviation (SD) in parentheses).

Table 1 The effect of drugs on the parameters characterizing the magnitude of OM Group Day fifteen twenty 25 thirty The control 2.28 (0.11) 2.45 (0.10) 2.61 (0.14) 2.62 (0.08) BSA 2.07 (0.08) 2.32 (0.10) 2.47 (0.08) 2.77 (0.08) Dexamethasone 2.28 (0.12) 1.77 (0.08) 1.43 (0.07) 2.75 (0.23) IL-1Ra 25 mg / kg 2.07 (0.13) 1.72 (.05) 1.44 (0.09) 1.40 (0.05) IL-1Ra 50 mg / kg 2.11 (0.16) 1.07 (0.09) 0.73 (0.11) 0.68 (0.03) IL-1Ra 100 mg / kg 2.30 (0.15) 0.69 (0.10) 0.65 (0.05) 0.57 (0.04)

All brain tomograms were obtained in the axial plane. After 15 days from the moment of inoculation of C6 glioma cells, tumor formation was noted in the right hemisphere of the animal’s brain with the development of significant peritumoral edema, which also spread to the contralateral hemisphere of the brain. In all observations, heterogeneous changes in the signal in the stroma of tumors in diffusion-weighted images from high to iso-intense with the brain and hypo-intense signal were determined. The diffusion coefficient was calculated on the 15th, 20th, 25th and 30th day from the moment of implantation of C6 glioma cells into the brain of the animal. The diffusion coefficient values were increased in the control groups.

Intravenous administration of dexamethasone led to a significant decrease in perifocal edema compared with the BSA group (P <0.01), however, in the stroma of the tumor, the diffusion coefficient values did not significantly differ compared to the control (P> 0.05).

The use of recombinant IL-1Ra at a dose of 25 μg / kg significantly reduced perifocal edema, however, as in the case of dexamethasone, it did not affect the ADC values in the tumor stroma. A subsequent increase in the concentration of IL-1Ra to 50 and 100 mg / kg led to a decrease not only in peritumoral, but also in stromal edema compared with dexamethasone (P <0.001). An analysis of the data showed that the values of the diffusion coefficient were significantly lower than those in the stromal component in groups with intravenous administration of FSB, BSA, and dexamethasone (P <0.001).

Along with exposure to OM, the end result of exposure, the survival of animals with cerebral edema, was analyzed. The results are shown in table 2. The data are presented as mean values (M) ± standard deviation (SD)

table 2 The effect of the drug on the survival of animals The survival of animals in groups (days) The control BSA Dexamethasone IL-1Ra (25 mg / kg) IL-1Ra (50 mg / kg) IL-1Ra (100 mg / kg) (M) 23.85 23,2 36.85 36.7 41.45 51.25 (SD) 3.44 3.38 8.18 7.42 11.9 15.62

The average life expectancy in the control group (administration of FSB) and the BSA group was 23.85 ± 3.44 and 23.20 ± 3.38 days, respectively (data are presented as mean ± standard deviation, M ± SD) (see table 2). The introduction of dexamethasone significantly increased the survival of animals compared with the control groups - 36.85 ± 8.18 days (P <0.05). The use of recombinant IL-1Ra at a dosage of 25 mg / kg also led to an increase in animal survival, which was comparable to the use of dexamethasone - 36.7 ± 7.42. Further escalation of the concentration doses of IL-1Ra led to a twofold increase in the survival of animals - 41.45 ± 11.9 (50 mg / kg) and 51.25 ± 15.62 (100 mg / kg) days (P <0.001).

The results showed that the use of "Raleikin" significantly reduces the value of cerebral edema in comparison with known analogues. Given the non-toxicity of the drug, its use in medical practice will significantly reduce the likelihood of complications with this pathology.

Claims (1)

A method of treating cerebral edema by intravenous administration of a pharmaceutical preparation, characterized in that the preparation of the receptor recombinant interleukin-1 antagonist Raleikin is administered intravenously at a dose of 25-100 mg / kg body weight.