Method for protecting brain against hypoxic ischemic injuries

FIELD: medicine.

SUBSTANCE: method involves administering Clonidine (Clophelinum). The drug is introduced intramuscularly, intravenously or as pills on the background of neurotropic therapy at a dose of 2.5-3.0 mcg/kg of body weight during the first hours of posttraumatic period within 7-10 days.

EFFECT: accelerated and simplified treatment course.

1 dwg, 1 tbl

 

The invention relates to medicine and can be used for the treatment of diseases associated with hypoxia and/or ischemia-reoxygenation damage neurocytol with traumatic and nontraumatic lesions of the brain, namely in severe craniocerebral trauma (CCT), both isolated and combined (craniofacial)and in the treatment of various CNS disorders involving hypoxic-ischemic damage neurocytol (acute violation of cerebral circulation of various origins).

In the mechanisms of neuronal damage in the pathology of the CNS, in particular severe craniocerebral trauma (CCT), the leading role belongs to oxidative stress. This is due to the activity of the oxidative metabolism of brain tissue, the high content of lipids in the Central nervous system (50-70% on the dry substance of the brain), and with participation in the damage of free radicals. A consequence of the peculiarities of the oxidative metabolism of neurocytol is their extremely high sensitivity to the condition of microcirculation, the violation of which, in particular, for brain injury, leads to rapid development of hypoxic-ischemic cascade and free-radical destruction of neurocytol. In connection with this extremely important issue is to prevent the development of oxidative stress when H Is T or in other words, prevention of hypoxic-ischemic damage neurocytol.

The currently adopted methods of intensive therapy brain injury (Zotov J.V., Gasimov RD Tactics comprehensive treatment of severe traumatic brain injury // II Congress of neurosurgeons of the Russian Federation: proceedings of the Congress. St. Petersburg, 1998. - P.31) is insufficient to prevent hypoxic lesions of the brain (primary hypoxia), and body in General (secondary hypoxia), because many drug and non-drug (intravenous laser irradiation of blood, hyperbaric oxygen therapy and other) activities antihypoxic protection or not effective enough, or can be included in the plan of intensive therapy, as a rule, not previously 2-5 days post-traumatic period.

In monographs Yevsegneyeva and Adetoro "Hypoxia and free radicals in the development of pathological States of the organism" (M.: OOO "Terra Callander and Promotion, 2000) and other works as used antihypoxants called drugs of different pharmacological groups (vitamins, calcium channel antagonists, etc.), however, the effectiveness of either is not proven (Cavinton, pharmacological, nimotop etc), or drugs available for clinical use (dislocation).

The well-known "Method of treating hypoxia of the brain" (the Author is a certificate of the USSR No. 1138163, published 07.02.85, Bulletin No. 5; IPC a 61 K 31/00), which proposes to implement hypoxic brain protection by intravenous sodium oxybutyrate at a dose of 20 mg/kg of body weight at intervals of 2 hours (maximum daily dose of 150-200 mg/kg) and with an interval of 3 hours intravenous barbiturates (thiopental sodium, geksenal) 5 mg/kg (total dose of 3.0-3.5 g / day) for 5 days post-traumatic period. This method is most similar to the claimed and taken as a prototype, but it has, in our opinion, significant shortcomings. The method has not found wide application because the drugs used to belong to the group of means for intravenous anesthesia, have a number of side effects, such as destabilization of hemodynamics, inhibition of cardiac activity and the activity of the respiratory centre. This requires both special equipment for artificial ventilation of the lungs, and specially trained staff, owns the methods of restoration of patency of the upper respiratory tract (including intubation) and methods of cardiopulmonary resuscitation, which is quite difficult in the absence of the specialized hospital reanimation service. Furthermore, the method is quite cumbersome and complicates the work of nurses. In addition to the CSO, in randomized trials is not received convincing evidence for a neuroprotective effect of barbiturates.

Known drugs used to prevent development of ischemic brain damage, for example, perftoran (RF patent No. 2049464 published 10.12.95, Bulletin No. 34; IPC And 61 To 31/02). Despite the undoubted merits of perftoran as anti-ischemic funds, there are several features that significantly limits their use. This refers to the characteristics of its storage, transportation, special conditions of defrosting, since the drug is an emulsion, rather unstable, which can only be stored frozen at sub-zero temperatures. Violation of the technology of its preparation for intravenous infusion (inability to force it to defrost, the need for 3x a biological sample before the introduction, the need to introduce desensitizing means, in particular glucocorticoid hormones), as well as lack of knowledge of health workers regarding this medication and features of work with him, doing the real risk of severe adverse reactions. The high cost of the drug, its deficit further complicate its use in the clinic, especially in the early stages of posttraumatischer.

The objective of the invention: an expansion of the means to protect the brain from hypoxic-ischemic damage due to circulatory disorders of various origins.

The problem is solved by the fact that as a means of anti-ischemic protection of damaged brain uses clonidine. The drug is administered in pill form orally (or by nasogastric tube if you cannot swallowing) in a daily dose of 2.5-3.0 mg/kg of body weight, every 8 hours in equal installments within 7-10 days, or (in the absence of a tablet form) intramuscularly or intravenously according to the same scheme.

Know the use of clonidine as antihypertensives (Ubbelohde, Wesmosis, Achievedin. Clinical pharmacology and pharmacotherapy. M: Univesal publishing, 2000; RF patent №2173989 for the invention "Method of anesthetic management operations in severe traumatic brain injury" (published 27.09.01., bull. No. 27, IPC a 61 K 31/00, 31/355, 38/55), Analytica (Osheaga, Leepin. The clinical use of clonidine (clonidine) in anaesthesiology//Bulletin of intensive therapy. - 2000. No. 4. - P.76-81). Not described in literature, the use of clonidine for the treatment of hypoxic-ischemic brain damage.

To clarify the mechanism of antioxidant action of clonidine laboratory survey, the Finance of patients with severe traumatic brain injuries (1st group - 15 injured in the composition of conventional drug therapy is not treated with clonidine, 2-I group - 15 victims who received clonidine from the first hours of hospitalization). In both groups suffered clinical and neurological data (the severity of the condition and the severity of traumatic brain damage) were comparable.

- Hypoxic and anti-ischemic effect of clonidine was assessed by clinical signs and the percentage of mortality in 1 - control group of victims (not treated with clonidine) and in the 2 treatment group victims (treated with clonidine from the first hours post-injury period). Laboratory evaluated the activity of processes of lipid peroxidation (LPO) and antioxidant system (AOS) in erythrocyte membranes, as well as structural and functional properties of erythrocyte membranes (as a readily available model cells). Using the definition of FLOOR activity in erythrocytes as a measure of activity of the given process in the body has been possible thanks to the discovery H.Heckers and D.Platt in 1988, the community structure of the erythrocyte membrane with the membranes of other cells, in particular neurons, and the correlation between changes in membrane properties of red blood cells and cell membranes of internal organs. The degree of destruction of erythrocytes judged also by the concentration of varitrac the container hemoglobin (VAG) in plasma.

The data (table) indicate that the affected group 1 already by the end of 1 day post-injury period was marked by a sharp activation as activity of prooxidants and antioxidants in membranes, which was reflected in the increase in the concentration of malondialdehyde (MDA), diene conjugates (DC), Schiff bases (SB) and antioxidant enzymes - superoxiddismutase (SOD) and catalase.

To 7 days post-traumatic period in the background of a sharp activation of peroxidation processes in the membranes occurred depletion of SOD and catalase, the content of which at this point was only 67,7% and 86.4% of normal (p<0,05). This was accompanied by structural rearrangements in the membrane of erythrocytes. The microviscosity of the lipid layer (F/FM (344) and zones Annularly lipids (or zones protein-lipid contacts) - F/FM (282) in all study periods was significantly below normal values, indicating that the deterioration of the fluidity of lipids and increasing the "rigidity" of the cells. The polarity of the environment of the probe pyrene in the lipid bilayer (F372/393(334) and in the area Annularly lipids (F372/393(282) also were significantly altered compared with normal values, indicating that the appearance of membrane lipids hydrophilic clusters and increasing the permeability of the membrane. The index ΔF, the character is based on the degree of integration of membrane proteins, was significantly reduced in all study periods, indicating the displacement of the protein from the matrix of the membrane, and because membrane proteins are including ion channels, and receptors and immunoglobulins, and so on, it also indicates their functional blockade.

Another integral indicator of the degree of destruction of erythrocytes is the concentration decreased hemoglobin (VAG) in plasma. During all periods of the study the content of VEG exceeded the normal 3.1-4.9-fold (p<0,001), testifying along with the indicators of structural-functional state of the membrane on the degree of degradation of the membrane.

Patients of group 2, treated in the scheme standard neuroprotective therapy clonidine marked less dramatic activation of peroxidation processes and antioxidant soon as 1 day post-injury period: concentration of LPO products was significantly lower than the same values in the control group. The activity of enzymes antiradical protection - catalase and SOD) was also lower than the same values in the controls (p<0,05). To 7 days post-injury period, the concentration of LPO products was lower than the same values in the control 4.8-2.3 to 3.9 times (for MDA, CD and SB, respectively; p<0,001), and the enzyme activity of ACO was higher by 87.3 per cent -97,2% for catalase and SOD (p<0,01). This resulted in lower structural rearrangements of member the n erythrocytes, to 7 days post-traumatic period in the background of the action clonidine indicators of structural and functional properties of membranes from normal values did not differ. Stabilization of erythrocyte membranes has led to the fact that the concentration of VEG in plasma during the entire period remained at the hospital level, its comparative dynamics with similar values in the control group are shown on the graph (see drawing).

By optimizing drug therapy by appointment of clonidine from the first hours of post-traumatic period, the mortality in group 2 patients (31.5 per cent) compared with the 1st group (48,9%) decreased by 17.4%. Bed-day in the intensive care unit 1 (control) group was 22.3±1.2 days, in group 2 - 17,9±1,1 (p<0,01). The duration of coma in group 1 patients was 11.8±1.4 days, and in patients 2 groups - 7,9±0.9 days (p<0,05). Assessment of severity of condition of patients on a scale com Glasgow-Pittsburgh) to 7 days post-injury period was 8.5±0,4 and 10.7±0.9 points (p<0,05), respectively, at practically the same source.

Thus, studies have shown that the inclusion of clonidine therapy helps to change the structural rearrangements in the membrane and membrane proteins by:

1) a sharp reduction in the intensity of freely-R is the radical processes in the membranes;

2) activation of intracellular SOD is a key enzyme of primary antioxidant protection that may be associated with reactivation of the active centre of the enzyme.

3) membrane and membranostabilizirutm of action due to the high lipotropes preparation and ability to accumulate in lipid bilayer membranes and inhibit the FLOOR directly in the lipid phase of membranes.

Example 1.

Patient S., aged 35, was admitted to the hospital within 60 minutes after the road accident. The state of admission regarded as extremely difficult, wakefulness - moderate coma (score on a scale of whom wakefulness - moderate coma (score on a scale of whom Glasgow-Pittsburgh 7 points). In neurological status: severe cerebral and primary stem symptoms, pravostoronnei pyramidal insufficiency (up to level plegia), anisocoria right to left, the eyeballs are fixed, there is a divergence of the eye vertically. Meningeal symptoms with dissociation along the axis of the body, convulsive readiness. Lumbar puncture was not performed in view of the threat of dislocation and brain herniation before surgery. According to a computer tomography (CT): brain injury, signs of cerebral edema, subdural hematoma in the left temporal-parietal region of the volume to 100 ml systolic Blood pressure of 200 mm Hg, di is Stolichnoe 110 mm Hg, the body temperature of 38.5°C. Patient was operated under conditions of multicomponent endotracheal anesthesia using neyroleptanalgezii and clonidine in a dose of 100 µg intramuscularly in the composition of sedation. Then within 7 days post-traumatic period, he in addition to conventional neuroprotective therapy received clonidine nasogastric zones (up to 5 days), and then the oral dose of 75 mcg×3 times daily in equal doses (225 mg/day). By the end of 1 day post-injury period of wakefulness - spoor (score on a scale of whom Glasgow-Pittsburgh 10 points), neurological status positive dynamics in the appearance of the reaction to the pain, floating movements of the eyeballs, lowering the threshold of convulsive activity, systolic Blood pressure 160 mm Hg, diastolic 95 mmHg, body temperature decreased to 37.8°C. For 3-5 days post-traumatic period of wakefulness level ranged from spoor to deep stun (score on a scale of whom Glasgow-Pittsburgh 10-12 points), appeared purposeful response to painful stimuli opening eyes to strong sound stimuli, the degree of pyramidal insufficiency reached paresis, there was no convulsive readiness, moderately expressed in stem and meningeal symptoms (without dissociation along the axis of the body), risaki motor aphasia. Blood pressure systolic 150-145 mm Hg, diastolic 95-90 mmHg, body temperature did not exceed 38,0°S. In CT there was a slight reduction in the size of lesion of brain injury (15-20%) and the degree of brain edema. To 7 days post-injury period, the consciousness of the patient was regarded as clear (score on a scale of whom Glasgow-Pittsburgh 15 points), neurological status remained moderately expressed stem and meningeal symptoms, motor aphasia (appeared successful attempts at pronouncing malodoznyh words), pyramidal insufficiency to the degree of paresis. Blood pressure systolic 145-140 mm Hg, diastolic 90-80 mmHg, body temperature not exceeding 37,5°C. According to the CT signs of cerebral oedema absent, decrease the zone of injury compared to the baseline by about 30-40%.

The patient was discharged under the supervision of a neurologist at 39 days after the injury.

Example 2.

Patient C., 57 years old, was admitted to the hospital after 3 hours from the moment of the disease with complaints of dizziness, headache, Oneonta upper right limb and the impossibility of movement in it. From history revealed that over the last 10 years was noted periodic rise in blood pressure to 200 mm Hg usually after emotional stress. However, systematically which were examined and were not treated. The General condition for admission of moderate severity. HELL 190/110 mm Hg wakefulness - surface stun. In neurological status: asymmetry tendon reflexes on the axis of the body, D<S (to the level of plegia), melcorazmashisty horizontal nystagmus in the extreme abstraction of the eyeballs, cerebral symptoms. When lumbar puncture: CSF xanthochromia, pressure 180 mm Vogt MRI identified area of cerebral ischemia (3-11 slices) in aminosilicones area without dislocation median structures. Diagnosed with Acute violation of cerebral circulation in ischemic type on a background of hypertensive crisis. Hypertension III degree". To standard baseline therapy (improvement of cerebral circulation, rheological properties of blood, oxygen therapy, dehydration, anti-convulsants, drugs that block the massive proteolysis) was added clonidine at a dose of 300 mg/day (3 times a day in equal doses intramuscularly for 10 days). To 5 days noted a positive trend of reducing the severity of neurological deficit - emergence of movements in the shoulder and elbow joints of the right upper limb, level and cerebral stem symtomatic. MRI revealed a reduction of ischemia head what about the brain (4-8 slices). The patient was discharged in satisfactory condition on the 23rd day with a slight right-sided paresis of the right upper limb to outpatient treatment.

Example 3.

Patient T., aged 30, was admitted to the hospital 2 hours from the disease. According to accompanying dependents after exercise (engaged in wrestling) suddenly felt a strong headache and almost immediately lost consciousness. The state of admission regarded as heavy, wakefulness - spoor (score on a scale of whom Glasgow-Pittsburgh 9 points). In neurological status: severe cerebral, primary stem and meningeal symptoms, right-sided hemiparesis, "floating" movement of the eyeballs, melcorazmashisty horizontal nystagmus. Convulsive readiness. Lumbar puncture: a significant admixture of blood in the cerebrospinal fluid (up to 100 thousand cells in 1 ml) According to a computer tomography (CT): hemispheric subarachnoid hemorrhage. Systolic blood pressure of 180 mm Hg, diastolic 100 mm Hg, body temperature 38,0°C. preliminary diagnosis: "Extensive subarachnoid hemorrhage". Later (on day 15) after performing the radiopaque computer myelography was the final diagnosis of Arterial aneurysm in pool environments is her cerebral artery, extensive subarachnoid hemorrhage". Along with conventional therapy within 7 days post-traumatic period, he received clonidine intramuscularly at a dose of 300 mg/day 3 times a day in equal doses. To 3 days of wakefulness - deep stun (score on a scale of whom Glasgow-Pittsburgh 12 points), neurological status noted positive dynamics in the emergence of purposeful response to pain, lowering the threshold of convulsive activity, Motor aphasia. Systolic blood pressure 130 mm Hg, diastolic 85 mm Hg, body temperature decreased to 37,3°C. For 5-7 days post-traumatic period of wakefulness level ranged from deep to superficial stun (score on a scale of whom Glasgow-Pittsburgh 12-14 points), opening eyes to the strong sound stimuli, the degree of pyramidal insufficiency decreased from attempting movements in small joints, convulsive readiness was not observed, a moderately severe meningeal symptoms and signs of motor aphasia. Blood pressure systolic 130-135 mm Hg, diastolic 85-80 mmHg, body temperature not exceeding 37,5°C. According to the CT observed decrease in the severity of subarachnoid hemorrhage. The patient was discharged under the supervision of a neurologist within 30 days after hospitalization.

Three at the Eden clinical observation suggests, the purpose of clonidine from the first hours of the patients ' stay in hospital reduced the severity of the patient's condition, quickly stabilize vital functions, to reduce the degree of neurological deficit, according to computed tomography to reduce the severity of brain edema and sizes of fire damage. Thus, achieved the objective - increased efficiency of protection of the brain from hypoxic-ischemic damage.

Dynamics of activity of peroxidation processes and antioxidant in membranes of erythrocytes
IndicatorsNormaTime studies
1 dayday 7
the control groupmedical groupthe control groupmedical group
MDA, nmol/mg lipid1,75±0,434,48±0,92 p<0,023,57±0,31 p<0,0110,49±1,24 p<0,0012,40±0,35 p>0,05
DK, nmol/mg lipid6,63±0,4912,57±1,13 p<0,019,52±0,74 p<0,0117,97±1,42 p<0,0017,92±0,67 p>0,05
2,28±0,265,93±0,44 p<0,0014,12±0,28 p<0,001of 13.05±0,63 p<0,0013,34±, and 0.40 p<0,05
Catalase, nmol/H2About2/ml/min/mg73,08±3,42127,35±1,15 p<0,001107,57±2,03 p<0,00163,13±1,38 p>0,0593,65±2,21 p<0,001
SOD, umol/mg lipid3,19±0,246,90±0,42 p<0,0014,78±0,36 p<0,0012,16±0,39 p>0,054.26 deaths±0,38 p<0,05
F/FM (344), usled0,78±0,090,51±0,08 p<0,050,58±0,04 p<0,050,38±0,04 p<0,010,73±0,07 p>0,05
F/FM (282) usled3,66±0,282,18±0,34 p<0,012,84±0,10 p<0,0011,64±0,06 p<0,0013,52±0,09 p>0,05
F372/393(334) usled1,02±0,011,24±0,04 p<0,0011,19±0,04 p<0,0011,42±0,04 p<0,0011,08±0,04 p>0,05
F372/393(282) usled1,15±0,051,46±0,06 p<0,0011,31±0.05 to p<0,051,68±0,07 p<0,0011,22±0,05 p>0,05
ΔF usled 1,65±0,050,85±0.05 to p<0,0011,11±0,07 p<0,0010,51±0,06 p<0,0011,53±0,06 p>0,05
VEG µmol/l1,46±0,454,49±0,41 p<0,013,14±0,42 p<0,017,16±0,80 p<0,001is 3.08±0,12 p<0,001

A means to protect the brain from hypoxic-ischemic injury in acute violation of cerebral circulation of various origins, representing clonidine.



 

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13 cl, 1 tbl, 195 ex

FIELD: cosmetic industry.

SUBSTANCE: the present innovation deals with preparations to fix, strengthen, restructure, restore or stabilize keratin fibers, especially damaged fibers. For this purpose one should apply creatine, creatinine and/or their salts to provide improves glare, volume or combing capacity of one's hair, as well. Earlier these preparations had been known as hair moisturizers.

EFFECT: higher efficiency of application.

12 cl, 9 ex

The invention relates to medicine, namely neurotraumatology and neurotraumatology

The invention relates to medicine, namely to neuroregenerative, neurosurgery and neurology
The invention relates to medicine, anesthesiology, surgery, traumatology and orthopedics, and can be used for anesthesia in surgical treatment of injuries and diseases of the lower extremities

The invention relates to derivatives of 2-(arylvinyl)aminoimidazole formula I, where R1denotes a group of formula (A), (B) or (C), a R2, R3, R4, R5, R6and X are such as defined in the claims
The invention relates to medicine, obstetrics, and can be used for pain relief during childbirth
The invention relates to medicine, namely to dentistry, and for sedation in dental surgeries
The invention relates to medicine, in particular to addiction, and can be used for the treatment of acute opiate withdrawal syndrome of varying severity

The invention relates to new derivatives of formula (I), where R1- R4- hydrogen atoms; X - alkylene with 1 to 6 carbon atoms; Y is lower alkyl; B is - NR5R11where R5is a hydrogen atom, R11selected from 5 - to 6-membered heterocyclic radical, in which one ring member is a carbon and 1 to 4 members of the heteroatoms nitrogen, or sulfur, or their pharmaceutically acceptable salts, are useful as inhibitors of the synthesis of nitric oxide

FIELD: cosmetic industry.

SUBSTANCE: the present innovation deals with preparations to fix, strengthen, restructure, restore or stabilize keratin fibers, especially damaged fibers. For this purpose one should apply creatine, creatinine and/or their salts to provide improves glare, volume or combing capacity of one's hair, as well. Earlier these preparations had been known as hair moisturizers.

EFFECT: higher efficiency of application.

12 cl, 9 ex

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