Antidote for eyes

RU (11) 2049464 (13) C1

(12) Description of the invention for the Russian Federation patent
Status: as of September 27, 2007 - terminated

(14) Date of publication: 1995.12.10
(21) Registration number of the application: 4493206/14
(22) Application submission date: 1988.08.01
(45) Published on: 1995.12.10
(56) Analogues of invention: G.R. Ivanitsky and F.F. Beloyartsev - in the book. Medico-biological aspects of the use of perfluorocarbon emulsions, Pushchino, 1983, p. 34-37.
(71) Name of applicant: Dnepropetrovsk Medical Institute (UA)
(72) The name of the inventor: Usenko Lyudmila Vasilyevna [UA]; Beloyartsev Felix Fedorovich [UA]; Kligunenko Elena Nikolaevna [UA]; Doronin Alexander Georgievich [UA]; Mikulskaya Svetlana Konstantinovna [UA]; Petrenko Valentina Grigoryevna [UA]
(73) The name of the patent holder: Dnepropetrovsk Medical Institute (UA)

The invention relates to medicine, and in particular topreparations of decongestant action. The purpose of the invention is to expand the range of products having anti-edematous effect. As a decongestant, perfluorane is used. The antitherotic effect of perfluorane was found in the experiment in the simulation of severe craniocerebral trauma in dogs and confirmed in a clinical trial. Perftoran has the ability to reduce the swelling of glial cells in the cerebral cortex, reduce perivascular edema of the vessels in the brain, acting on the affected brain cells. It prevents the dislocation of the brain stem cells. At the same time, by improving the rheological properties of the blood, it prevents the development of ischemia in areas remote from the affected area. The invention can be used in the treatment of edema-swelling of the brain. 1 yl. 3 tab.

The invention relates to medicine, in particular to preparations having anti-edematous action, and can be used for the treatment of edema-swelling of the brain.

It is known that "there is no neurosurgicala disease of the brain, in which, at a certain phase of its development, or postoperative course, this or that degree of the brain reaction would not develop. "According to modern ideas, four pathogenetic forms of the cerebral edema-swelling are distinguished: vasogenic, cytotoxic, osmotic, hydrostatic.

The main dramatic consequences forsevere craniocerebral trauma (CCT) are the first two forms. The essence of morphological changes associated with them is associated with the accumulation of intercellular fluid (free water) with vasogenic edema and with the accumulation of intracellular fluid and associated intercellular fluid in cytotoxic edema. The most unfavorable, difficult to give modern methods of intensive care, is cytotoxic edema, accompanied by swelling of brain cells. There was a clear correlation between the severity of the clinical course of brain injury and the severity of cerebral swelling, which predominates in the first 2 days after trauma.

At the heart of the development of edema-swelling of the brainwith severe TBI is a violation of neurohumoral, metabolic physicochemical processes in the brain cell in conjunction with changes in the tone of the cerebral vessels and the violation of oxygen transport to the cell.

Methods for treating swelling-swelling are knownbrain improvement of rheological properties of blood (use of low molecular weight dextrans), increased oxygen delivery to the cell (inhalation of oxygen, hyperbaric oxygenation). Their disadvantages are low anti-edematous activity, expressed in the slow restoration of the main function of the brain of consciousness, high lethality.

Of the known decongestants, the mostclose to the proposed is mannitol (the base object). However, the disadvantages of the known anti-edema are the uneven dehydration of various parts of the brain. Moreover, normal tissue is dehydrated to a greater extent than edematous, which facilitates the dislocation and wedging of the brain.

Deteriorated microcirculation in the brain,associated with the violation of rheological properties of blood (increased viscosity, acceleration of aggregation of uniform elements), which occurs in connection with a decrease in the volume of intravascular fluid. This can lead to additional ischemia of the brain tissue. In addition, the permeability of the vascular wall increases and the flow of fluid into brain tissue in areas of the brain with an impaired blood-brain barrier is increased.

The purpose of the invention is to expand the range of products having anti-edematous effect.

This is achieved by the fact that as adecongestants use perfluorane, which is administered to the patient from the moment of admission to hospital and exclusion of intracranial hematoma, intravenously slowly at a dose of 3-5 ml / kg of body weight at a rate of not more than 3 mg / min. At the same time and for 12-24 hours from the start of treatment oxygen inhalation (8-10 l / min) is carried out. The repeated administration of perfluorane is possible no more than twice in the same dose with an interval between administration of at least 24 hours.

The use of perfluorane as a decongestant in the patent and scientific literature has not been revealed, which proves the novelty and essential difference of the proposed technical solution.

The figure illustrates the change in frequency(RR), respiration (4D), arterial pressure in dogs with experimental craniocerebral trauma when used in the treatment of perfluorane and without it, where 1-5 stages of examination, and the stroke corresponds to the time of inhalation with oxygen.

The anti-edematous effect of perfluorane was revealedin an experiment in the simulation of severe craniocerebral trauma in 60 non-narcotized male dogs with an average body weight of 18.07 kg. 11 animals formed the first intact group and were observed when fixing in the experimental position a time equal to the duration of the experiment. 22 animals entered the II-th group with untreated traumatic brain injury. In 10 animals of Group III, acute post-traumatic period was treated with inhalation of oxygen for 60 min after injury. 17 animals, which formed the IV group, the treatment was carried out by intravenous drip introduction of the fluorocarbon emulsion of perfluorane in the above modes.

During the experiment, a continuouscontrol of the vital functions of the animal with periodic graphic recording of them after 30 minutes. At the same time, the functional state of the adrenal glands, thyroid gland, sympathoadrenal, histamine-reactive, serotonergic systems, rheological properties of blood (its viscosity, erythrocyte and platelet aggregation rate, acid erythrograms) were studied. At the end of the experiment, the animals were removed from the experiment, brain tissue was subjected to histochemical and morphometric analysis.

For most animals with untreatedThe first moments after the trauma were characterized by apnea and sharp bradycardia, a change in the tone of the skeletal muscles, involuntary urination and defecation. Therefore, there was a need for complex measures of urgent resuscitation, including a closed cardiac massage, intubation of the animal and its transfer to artificial ventilation of the lungs. Neurologically, they had gross organic fallouts, a prolonged loss of protective reflexes, impaired pupillary reactions, anisocoria, spontaneous nystagmus, and phenomena of decerebration with clonic-tonic convulsions. In the course of the experiment, a progressive increase in the severity of the condition of untreated animals was noted, expressed not only in the decompensation of hemodynamics, the lack of independent breathing, but practically in all animals and in the deepening of the coma, indicating an increase in edema-swelling of the brain. This found confirmation on the EEG, when registering it (Table 1), the amplitude of the potential oscillations in the range decreased. waves in the injured hemisphere. Oppression of the wave process captured in the injured hemisphere to the 90th minute and a range of low-frequency oscillations. Along with this, by the 90th minute after the injury, the amplitude-and-potential oscillations in the unexcavated hemisphere decreased. By the third hour since the injury, bioelectrical activity was inhibited in all frequency ranges of both hemispheres, making up 15-67% on the injured side and 44-60% of the original on the unaffected side.

At the same time when used for treatmentAcute trauma of inhalation of pure oxygen within 60 minutes after a trauma of a brain it is established, that in reply to treatment depression of amplitude of potentials occurs only in the traumatized hemisphere and is shown in the field of high-frequency oscillations. The amplitude of low-frequency oscillations decreases only to the third hour after injury (Table 2). And indeed, animals against the background of inhalation with oxygen became more active motor, they partially restored pupillary and defensive reflexes, decreased convulsive activity. In 7 out of 10 animals, independent breathing was restored. The level of blood pressure initially decreased by 35% from the initial, later remained stable, not only against the background of inhalation with oxygen, but also within 1.0-1.5 h after cessation of it. Hypotension sharply increased to the 3rd hour after injury. In response to developing hypotension, there was a compensatory increase in the number of cardiac contractions (RR was 67.5% of the baseline), 34% increased tachypnea.

On the deterioration of rheological properties and the threatDVS-syndrome showed the growth of platelets in the peripheral blood at 27% of the initial, acceleration of the process of their aggregation (by 62.5% of the original) and complete absence of the process of their disaggregation in most animals, while slowing down the rate of aggregation of erythrocytes by 72.9%.

When treated with the drip introduction of perfluoroan inindicated mode with simultaneous inhalation of oxygen through a catheter inserted into the intubation tube, the following results were obtained. The level of blood pressure almost returned to normal within 15 minutes from the start of perfluorane administration and not only the entire period of drug administration was retained but also within 60 minutes after discontinuation of administration. The magnitude of the pulse also did not differ much from the initial value for 2 hours of the experiment. Some destabilization of hemodynamics was noted only by the 3 rd hour from the moment of trauma. Against the background of the administration of perfluorane, all animals recovered independent respiration at a frequency close to the initial one. Neurologically, most animals treated with perfluorane restored consciousness, pupillary, corneal reflexes. This corresponds to the fact that the cortex of both hemispheres of the brain was restored to the initial value of bioelectric activity (Table 2) during the period of perfluorane administration and inhalation of oxygen. The above indicated the anti-edema action of the drug and was confirmed by comparative morphometry data of cells of identical cortical areas (Table 3), conducted with the aid of an eyepiece micrometer. The diameter of the cells of the cortex, glia, and also the overall diameter of the cell were measured taking into account perivascular and recyclical edema. This difference characterizes the degree of edema in micrometers and proves the anti-edematous effect of the drug on glial cells of the brain with a simultaneous anti-edematous perivascular action.

Clinical course of early post-traumaticperiod corresponded to the changes studied by us neuro-hormonal-hormonal systems. Thus, there is an increase in urinary excretion of adrenaline and norepinephrine by 25.8% and 30%, respectively, and the ratio of A / HA remained at an unchanged level, equal to the original, which indicated the ability of the sympathetic adrenal system and recovery. The lower level of cortisol and aldosterone concentration in the blood plasma of animals was indicative of a decrease in the stress reaction of the organism to trauma. Thus, the growth of cortisol was 165% against the initial, which is 148% lower than in animals treated with oxygen alone. At the same time, aldosterone increased by 90.4% against the original, which is 50.6% less than the previous group. This indicated tissue hypoxia and was confirmed by the dynamics of changes in lactate and pyruvate of blood serum with a significant difference in the age composition of erythrocytes. Thus, the number of old, slightly resistant to acid red blood cells increased by 128% with a parallel decrease of 46.5% in the number of mature and lack of highly resistant forms. The rate of disaggregation of red blood cells with alcyan blue (and, consequently, the magnitude of their electrokinetic potential) increases against the background of perfluorane treatment by 13.5% from the baseline and by 40.4% against the group of animals treated with oxygen alone, improvement of rheological properties of blood is indicated not only by the number of red blood cells and platelets close to the initial number, but also by the marked dynamics of changes in the rates of aggregation and disaggregation of the latter. So, the process of platelet aggregation slowed down by 31% from the initial and by 93.5% in comparison with the previous group. At the same time, the speed of their disaggregation accelerated more than 4 times.

Thus, the anti-edematous effect of the drug was established by experimental data.

The established anti-edematous effect of the drug was confirmed during clinical trials of the drug.

For the clinical trial of the decongestant effect of perfluorane, a contingent of patients requiring perfluorane was selected according to known indications.

Perftoran was included in complex therapy 15patients with severe craniocerebral trauma (duration of coma at least 6 hours from the time of injury). Treatment with perfluorane in these patients was shown in connection with the known property of the drug to reduce the severity of tissue hypoxia of any genesis.

Patients received perftoran intravenously drip in a dose of 3-5 ml / kg of body weight at a rate of no more than 3 ml / min with simultaneous inhalation of oxygen (gas flow 8-10 l / min) for 12-24 hours.

Parallel investigation of cerebralhemodynamics (according to rheoencephalography), the functional state of the cells of the cerebral cortex (EEG) allowed to confirm the anti-edematous effect of perfluorane in its clinical application.

Achieving the antipyretic effect of perfluoranewas monitored by the recording of REG and EEG at the 1st, 3rd, 5th, 7th, 10th and 14th days from the moment of brain injury. In addition, the parameters of KHS, blood gases, rheological properties of blood, its oxygen transport function, the state of sympathoadrenal, kallikrein-kinin, histamine-reactive and serotonergic systems were determined (in terms of urinary biogenic amines, their precursors and metabolites).

Analyzing the results, one canIt should be emphasized that in no patient was the administration of perfluorane accompanied by complications or adverse reactions. Of the 15 patients with severe brain injury, 5 died due to brain damage incompatible with life. Mortality in this group of patients was 33.3%, which is 8.3% lower than the control group. This, along with a high degree of restoration and preservation of the main function of the brain of consciousness, is completely associated with the anti-edematous action of perfluorane. The positive dynamics of the clinical course of the neurotrauma was determined by the anti-edematous nature of changes occurring in the state of the central nervous system under the influence of perfluorane. So, already by 5 days after the injury according to the REG, most patients had a practical normalization of cerebral hemodynamics, absence of venous congestion in the hemispheres of the brain. At the same time, the number of model pathological waves sharply decreased in the shift of the frequency spectrum toward more rapid oscillations, the rhythm appeared, modulation stability, zonal differences improved.

Stabilization of the functional state of the brain andcerebral hemodynamics, is due to the nature of the exchange of biogenic amines. The expressed normalization of excretion of epinephrine and norepinephrine with preservation of their reserves in the form of dopamine and Dopa is established. She was accompanied by a significant activation of the serotonergic system, manifested by the growth of excretory serotonin, which indicated an increase in the body's resistance to trauma in general and the absence of progressive cerebral edema. Simultaneously, against the background of perfluorane, the blood gas composition significantly improved, blood lactate level decreased, which indicated a decrease in tissue hypoxia in comparison with traditional treatment. And also the rheological properties of blood improved, the viscosity of blood in small diameter vessels decreased on the background of normalization of the processes of aggregation and disaggregation of thrombocytes.

EXAMPLE 1 Patient M. 42 years old (case history N 13412) was delivered from the scene in 1 hour 10 minutes. Mechanism of injury falling from the height of the 3rd floor. The condition is heavy. Coma I-II. Ophthalmic reflexes are depressed, are not caused constantly. Periodically, motor excitement takes place. Positive meningeal symptom complex. There is no anisoreflection. Cerebrospinal fluid is colored with blood. When the lumbar puncture flows under the pressure of 200 mm of water column. Diagnosis: Combined trauma. Severe craniocerebral injury. Contusion of the brain. Subarachnoid hemorrhage. An open fracture cf / 3 of the left hip. 9 hours after the injury, intravenous infusion of perfluorane was started against the background of oxygen inhalation. After her termination in 1,5 hours the patient regained consciousness. Available for verbal contact. During the next two days correct behavioral reactions, criticism, adequate bilateral verbal contact were restored. By the fifth day is adequate, fairly active. There is no focal neurological symptomatology. Meningeal syndrome, thermoregulation disorders are absent. On the seventh day after the injury the patient was transferred to the trauma department at the place of residence.

Thus, the anti-edematous effect of perfluorane appeared only after 1.5 hours after its administration.

Given the young age of the victims with TBT it is clear,that the return to social life, work is one of the most important and humane tasks. The defeat of the brain due to its high significance in the whole human body leads to severe violations of mental processes, such as speech and understanding, memory and perception, counting and constructive activity. In the retention of these processes under the influence of the decongestant action of perfluorane, the great social value of the preparation.

Thus, a comparative analysis shows that perfluorane has a pronounced anti-edematous effect due to the fact that the drug

Dehydrates mainly glial cells of the brain and reduces the phenomenon of pericellular edema, preventing edema and dislocation of the stem and mid-cerebral parts of the brain;

improves rheological properties of blood at the expense ofdecrease in viscosity and decrease in perivascular edema, i.e. reduction of the fullness of the brain, which eliminates the phenomenon of cerebral ischemia in the areas remote from the injury and prevents the development of cerebral edema in unaffected areas.

The above allows us to recommend the use of the drug in neuroreanimation practice.

Use of perfluorane as a decongestant.