RU2266737C1 - Method and preparation for treating the cases of hemorrhagic stroke - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves administering preparation like 1% histochrome solution in the amount of 5 ml daily during five days. The first intravenous histochrome injection is carried out slowly. The following ones are intravenously introduced drop-by-drop.

EFFECT: enhanced effectiveness of treatment; no adverse side effects.

2 cl, 4 dwg, 5 tbl

Description

The present invention relates to medicine, in particular to neurology, and relates to preparations and methods for treating such a frequent and serious disease as hemorrhagic stroke.

It is known to use the drug Aprotinin (Gordox, Contrical, Trasilol) for the treatment of hemorrhagic stroke, which has an antioxidant effect and is a multivalent proteinase inhibitor [1]. This drug showed a good clinical effect in experimental and clinical conditions in patients with hemorrhagic stroke. However, this drug can lower blood pressure, increase heart rate, and contribute to the development of a procoagulant state, which increases the risk of ischemic complications. Also, in some cases, allergic reactions are possible, which makes it necessary to perform a skin test for individual sensitivity before starting the drug. In addition, the use of the above drug requires constant monitoring of the hemostatic system.

It is also known that the drug Mexidol (Emoxipin) is used to treat patients with hemorrhagic stroke, an antioxidant drug that reduces the vascular permeability of the microvasculature and normalizes blood viscosity and platelet aggregation, as well as increases the resistance of brain tissue to hypoxia [2]. The use of this drug gives good results in patients with hemorrhagic stroke. For the treatment of patients with hemorrhage in the brain, a 1% solution of emoxipin is used intravenously or intramuscularly. In the treatment of emoxipin, control of the blood coagulation system is mandatory.

The closest by the mechanism of action and the achieved effect of the known drugs to the claimed is the drug Dicinon (sodium ethamylate) [3]. Dicinon is an antioxidant drug that normalizes the permeability of the vascular wall and improves microcirculation. The hemostatic effect of the drug is associated with an activating effect on the formation of thromboplastin. An undesirable feature of the action of the drug may be a decrease in blood pressure. A method of treatment with dicinone includes intravenous drip of the drug in a dose of 250 mg 4 times a day.

The objective of the invention is the expansion of the range of drugs used in the treatment of hemorrhagic stroke and its consequences, the development of a method for the treatment of hemorrhagic stroke with histochrome, increasing the effectiveness of treatment and reducing the frequency of side effects.

This problem is solved by the use of histochrome as a drug for the treatment of hemorrhagic stroke and a method for treating this serious disease.

Histochrome® is a dosage form of an individual substance - a natural quinoid pigment of marine invertebrates echinochrome (2,3,5,6,8-pentahydroxy-7-ethyl-1,4-naphthoquinone, state registration number P No. 002362 / 01-2003) .

The use of histochrome for the treatment of diseases of the eyes and heart is known. Since 2000, a 0.02% histochrome solution has been used as a treatment for inflammatory diseases of the retina and cornea (state registration number P No. 002363 / 02-2003) [4], and a 1.0% solution is used in cardiology to reduce the size of a heart attack myocardium and for the prevention of reperfusion injury of the myocardium (state registration number P No. 002363 / 01-2003) [5]. The drug is included in the register of medicines approved for use in the Russian Federation [6]. Pharmacotherapeutic group: antioxidant.

"Histochrome® solution for intravenous administration of 1%" is prescribed for acute myocardial infarction in combination with thrombolytic drugs to eliminate the reperfusion complications caused by them. The use of histochrome is indicated for angina pectoris, coronary heart disease [7, 8].

Indications for use "Histochrome® injection 0.02%" are: degenerative diseases of the retina and cornea; diabetic retinopathy of the retina; vitreous hemorrhages, retina, anterior chamber; discirculatory disorders in the central artery and retinal vein [9, 10].

The effectiveness of a 1% histochromic solution for hemorrhagic stroke was first studied in the Clinic of Neurology and Neurosurgery of the Russian State Medical University in 27 patients with cerebral hemorrhages that developed as a result of arterial hypertension.

The drug was prescribed to patients daily for 5 days, 5.0 ml of a 1% solution intravenously. The first introduction was carried out in a jet slowly, the subsequent ones were drip, with a frequency of about 60 drops per minute.

The effectiveness of the drug was evaluated by comparing the group in which patients received histochrome with the control group, where dicinone was prescribed to patients. The nature of the stroke was established on the basis of magnetic resonance or computed tomography (19 and 14 patients, respectively) or lumbar puncture (cerebrospinal fluid mixed with blood of 24 and 18 patients). The main and control groups were comparable by sex, age, the nature of the stroke, localization of the focus, concomitant diseases (table 1) and the severity of neurological disorders upon admission (table 2).

Neurological status was studied in dynamics on the 7th, 14th, 21st and 28th days of the disease. When analyzing motor disorders, it was found that by day 28 in the main group there were significantly more patients with mild hemiparesis compared to the control (table 3), as well as more patients with mild and moderate hemiparesis (tendency to significant differences, χ ² = 3.06 , 95% CI = 0.7-13.83, p = 0.089).

An analysis of the outcome of the disease on the Bartel scale showed that in the main group there were significantly higher self-care indicators, which primarily concerned self-nutrition, the possibility of a personal toilet and independence in movement (table 4). There was also a tendency to significant differences in the remaining sections of the scale.

It is known that in patients with cerebral stroke, the outcome of the disease in many cases depends on the attachment of somatic complications. When studying the frequency of somatic complications, it was found that pneumonia was less common in the main group (16 cases in the main and 22 cases in the control, χ ² = 6.91, p = 0.0086, CO = 0.60, 95% CI = 0, 42-0.85) and complications from the genitourinary tract (7 cases and 14 cases in the control group, χ ² = 4.25, p = 0.039, SD = 0.25, 95% CI = 0.06-0.94 )

In addition to clinical analysis, studies have shown the dynamics of histochromic in the blood (table 5 or figure 1) and the penetration of the drug through the blood-brain barrier into the cerebrospinal fluid. In this case, the concentration of histochrom in the cerebrospinal fluid was 5.7-11.8% of the content in the blood.

The invention is also illustrated by the following specific examples:

Example 1. Patient Chumichkina IK, 70 years old, medical history No. 3359, was admitted to the clinic of neurology and neurosurgery of the Russian state medical university on February 7, 2003 with a diagnosis of acute hemorrhagic type of cerebral circulation in the right hemisphere of the brain. From the anamnesis it is known that she fell ill on February 7, 2003, when suddenly a headache and weakness in the left extremities appeared. She was hospitalized in the clinic of neurology and neurosurgery of the Russian State Medical University and in the evening of the same day in connection with increasing disorders of consciousness and focal symptoms from the neurological department was transferred to the intensive care unit (ICU). When examined on the day of the disease in neurological status, the absence of consciousness disorders, moderate stiff neck muscles, deep left-side hemiparesis (up to 1.5 points) were determined.

In ICU, the diagnosis was confirmed by a lumbar puncture (cerebrospinal fluid stained with blood was obtained) and magnetic resonance imaging of the brain (figure 2).

According to the results of an MRI study, the maximum hematoma size was 7.0 × 4.5 × 4.0 cm, and pronounced edema was observed on its periphery. Also according to magnetic resonance imaging revealed a dislocation of the middle structures from right to left by 7 mm with a pronounced compression of the right lateral ventricle (the posterior horn is not visualized).

From the second day of the disease, histochrome therapy was started in a daily dose of 5.0 ml of a 1.0% solution. On the first day, the drug was injected intravenously in 100.0 ml of physiological saline; On the 2-5th day of the disease, treatment was continued at the above dose, which was already injected into 200.0 ml of physiological saline intravenously with a frequency of about 60 drops per minute.

The HPLC method was used to study the concentration of histochrome in the blood and cerebrospinal fluid of the patient 24 hours after its first injection. The presence of histochrom in the blood at a concentration of 9.8 μg / ml 24 hours after its first injection and in cerebrospinal fluid at a concentration of 0.22 μg / ml was established.

On the 13th day of her stay in the intensive care unit and intensive care unit, she was transferred to the neurological department to continue rehabilitation treatment. Discharged March 7, 2003 with significant improvement.

Example 2. Patient Nairov Sh. P., 34 years old, medical history No. 30492, was in the clinic of neurology and neurosurgery of the Russian State Medical University from December 16, 2002 to January 17, 2003 with a diagnosis of acute hemorrhagic type of cerebral circulation in both cerebral hemispheres with a breakthrough of blood into the ventricular system. Upon admission, the severity of the condition was sent to the intensive care unit and intensive care unit (ICU). From the anamnesis it is known that he fell ill on December 14, when he ceased to understand the addressed speech and make contact. Neurological status at admission showed impairment of consciousness to the level of stunning - stupor, meningeal syndrome in the form of stiff neck muscles, bilateral zygomatic symptom of ankylosing spondylitis, right-sided hemiparesis with a decrease in muscle strength to 3 points in the arm and up to 2.5-2.0 points in the leg . The patient was consulted by a neurosurgeon: surgical treatment is not indicated due to the severity of the condition. The diagnosis was confirmed by a lumbar puncture (obtained cerebrospinal fluid stained with blood) and magnetic resonance imaging and computed tomography (figure 3). The maximum hemorrhage in the left hemisphere was 7.0 × 5.0 × 4.5 cm, in the right hemisphere - 3 × 4 × 4.5 cm. On the periphery of the hemorrhage - pronounced edema. The ventricular system is shifted to the right, the left ventricle is moderately constricted, and the third ventricle is filled with blood. There is no clear visualization of the middle cerebral artery on the left, most likely due to compression by hemorrhage.

From the first day in the clinic, histochrome therapy was started in a dose of 5.0 ml of a 1.0% solution. The drug was administered according to a scheme similar to that in Example No. 1.

On the 9th day of the disease, due to an improvement in his condition, he was transferred to the neurological department, where rehabilitation treatment continued. Discharged on January 17, 2003 with significant improvement: changes in consciousness, meningeal syndrome and speech disorders regressed, the volume of active movements and strength in the right extremities were almost completely restored.

Example 3. Patient Demyanenko RL, 62 years old, medical history No. 1196, was in the clinic of neurology and neurosurgery of the Russian State Medical University from January 15 to February 28, 2003 with a diagnosis of acute hemorrhagic cerebrovascular accident in the right hemisphere brain. Upon admission due to the severity of the condition, she was hospitalized in the intensive care unit and intensive care unit (ICU). From the anamnesis it is known that she fell ill on January 15, when against the background of an increase in blood pressure to 240/130 mm Hg. disturbed speech and weakened left limbs. Neurological status at admission showed lethargy and drowsiness, meningeal syndrome in the form of stiff neck muscles, ankylosing spondylitis symptom on the right and Kernig symptom on the left, central paresis of the facial and hyoid nerves on the left, left-side hemiparesis with a decrease in muscle strength to 3 points in the arm and to 4, 0 points in the leg. The diagnosis was confirmed by magnetic resonance imaging (figure 4): hemorrhage in the frontotemporal sections of the right hemisphere with dimensions of 3.4 × 3.7 × 2.8 cm with a zone of perifocal edema. The median structures of the brain are shifted to the left by 4-5 mm. The front and rear horns and the body of the right lateral ventricle are significantly compressed.

From the third day of stay in the clinic, histochrome therapy was started in a dose of 5.0 ml of a 1.0% solution. The drug was administered according to a scheme similar to that in Example No. 1. With repeated magnetic resonance imaging dated February 7, 2003, a decrease in perifocal edema and dislocation to 2-3 mm is noted.

On the 23rd day of the disease, due to an improvement in the condition, the patient was transferred to the neurological department, where rehabilitation treatment continued. Moves around the ward independently. Discharged on February 28, 2003 with significant improvement: meningeal syndrome and speech disorders regressed, the volume of active movements in the left extremities was almost completely restored, the strength in them increased to 4.5 points.

As can be seen from the above examples, the proposed method of treatment is characterized in that it is focused not only on the treatment of the acute stage of stroke, but also on reducing the severity of residual effects in the long term. This allows you to reduce the length of your stay in bed and achieve a more pronounced regression of neurological symptoms and the most complete professional and social rehabilitation. This fact was established by us for the first time when comparing the results of treatment of patients with the claimed drug and patients treated in the usual way (tables 3 and 4). Previously, the histochrome was used exclusively in ophthalmology and cardiology, and for its use in neurology it was necessary to conduct studies including magnetic resonance imaging or computed tomography of the brain, study of the hemostatic system, determine its concentration in the blood and penetration through the blood-brain barrier. Observation of a representative group of patients, its comparison with the group that received the traditional treatment, and additional studies performed revealed the advantages of the drug compared to previously used drugs. These advantages were expressed in a more complete and faster restoration of impaired functions, primarily motor disorders, and statistically significantly differed from the comparison group (tables 3 and 4).

Clinical trials of the drug at a dose of 1.0% - 5.0 ml injected intravenously, drip and drop, did not reveal any side effects. Contraindications to the use of the drug have not been established. The use of the drug is safe, and it is presented in the current register of medicines approved for use in the Russian Federation in the form of 0.02% and 1.0% solutions for intramuscular, intravenous and retroorbital administration. Since clinical trials have shown its high efficiency in comparison with the above drugs, the feasibility of using histochrome for hemorrhagic stroke in the first hours and days of the disease is obvious to reduce mortality, reduce the incidence of somatic complications and the severity of the consequences of a stroke.

Table 1 Comparative characteristics of the main and control groups Research indicators Main group Control group Significance of differences (p) Gender (m / f) 15/12 12/12 0.90 Age (years) 63.8 ± 9.3 65.3 ± 11.7 0.71 The degree of arterial hypertension (2/3) 12/8 7/3 0.89 Duration of hypertension (years) 11.9 ± 5.7 13.4 ± 8.9 0.58 Localization of a stroke right / left hemisphere 14/14 * 14/10 0.69 Concomitant cardiovascular diseases including 16 fifteen 0.95 myocardial infarction 7 6 0.81 rhythm disturbances 5 8 0.37 where hypertension is arterial hypertension table 2 Neurological disorders in the main and control groups upon admission Research indicators The main group (27 people) The control group (24 people) R Level of consciousness Not modified 6 6 0.92 Stun thirteen 12 0.88 Sopor 4 4 0.83 Coma 4 2 0.77 Meningeal syndrome 25 23 0.92 Movement disorders including: 27 24 hemiplegia 8 7 0.78 deep hemiparesis nine 10 0.75 moderate hemiparesis nine 8 0.76 mild hemiparesis 1 0.95

Table 3 Neurological disorders in the main and control groups on the 28th day of the disease Research indicators Main group Control group Significance of differences (p) Consciousness changes - - - Meningeal syndrome - - - Movement disorders including: 21 twenty 0.88 hemiplegia 1 4 0.61 deep hemiparesis 5 7 0.66 moderate hemiparesis nine 8 0.84 mild hemiparesis 6 1 0,047 Table 4 Neurological disorders on the Barthel scale in the main and in the control groups Research indicators Main group Control group Significance of differences (p) 1 2 3 4 Nutrition Whatever thirteen 4 0.016 Via 8 16 Bath Whatever 5 1 0.21 Via 16 19 Private toilet Whatever 12 3 0.013 Via nine 17 Dressing Whatever 5 1 0.21 Via 16 19 Toilet use Whatever 16 7 0.019 Via 5 thirteen Pelvic function monitoring Is always 19 14 0.21 Not always 2 6

Continuation of table 4 1 2 3 4 Transition from chair to bed Whatever thirteen 5 0,053 With minimal help 4 6 Via 4 nine Movement 45 meters Whatever 12 4 0.051 Via 6 eleven In a wheelchair 3 5 Climbing stairs Whatever eleven 5 0.11 Via nine fifteen Table 5 The dynamics of the concentration of histochrome in the blood The time after the introduction of 5 ml of 1.0% solution of histochrome Sample Volume, ml The amount of echinochrome and tetraketone in the sample The concentration of histochrome in μg / ml in physiological fluids 1 hour 0.8 0.116 0.725 2 hours 0.5 0.018 0.18 3 hours 1,5 0,021 0,070 4 hours 1,5 0,025 0,085 5:00 1,5 0.007 0,023 6 o'clock 1,5 0.011 0,037 9 hours 1,2 0,040 0,041 24 hours 1,0 0,022 0,035

Literature

1. Gorbacheva F.E., Natyazhkina G.M., Krutik Z.I. On the tactics of hemorrhagic stroke. Bulletin of Practical Neurology 1995 №1 p. - 65-69.

2. Yakimova T.V. The effect of antioxidants on blood supply and energy metabolism in the brain during intracerebral hemorrhage. Abstract dis. Ph.D. Tomsk 1990.

3. Gorbacheva F.E., Ponyaev M.N. Pathogenetic therapy of hemorrhagic stroke. Journal of Neurology and Psychiatry. S.S. Korsakova. 1990, Volume 90, No. 7, pp. 19-21,

4. RF patent 2134107 A 61 K 31/05, 1999.

5. RF patent 2137472, A 61 K 31/05, 1999.

6. The Big Russian Encyclopedia of Medicines, Moscow, 2001, "Remedium", Volume 2, p.171

7. Zakirova A.N., Lebedev A.V., Kukharchuk V.V., Mishchenko N.P., Fedoreev S.A. Histochrome antioxidant: effect on lipid peroxidation and blood rheological properties in patients with unstable angina pectoris. Therapeutic Archive. 1996. No8. S.12-14.

8. Zakirova AN, Ivanova MV, Golubyatnikov VB, Mishchenko NP, Koltsova EA, Fedoreev SA, Krasnovid NI, Lebedev AV Pharmacokinetics and clinical efficacy of histochrome in patients with acute myocardial infarction. Experimental and clinical pharmacology. 1997.V.60. No. 6. S.21-24.

9. Polunin G.S., Makarov I.A., Mishchenko N.P., Fedoreev S.A. The new antioxidant drug Histochrome in the treatment of hemophthalmia of various etiologies. Refractive surgery and ophthalmology. 2002.V.2 (2). S.53-56.

10. Guseva M.R., Dubovskaya L.A., Chinenov I.M., Kotyasheva G.I., Gorbunova E.D., Mishchenko N.P., Fedoreev S.A. Comprehensive treatment of intraocular hemorrhage with the use of the antioxidant drug Histochrome in children. Refractive surgery and ophthalmology. 2003.Vol. 3 (1) S.70-77.

Claims (2)

1. The use of histochrome as a drug for the treatment of hemorrhagic stroke. 2. A method of treating hemorrhagic stroke, including intravenous administration of a therapeutic drug to a patient, characterized in that, as a therapeutic drug, a 1% histochromic solution is administered daily in a dose of 5 ml daily for 5 days, while the first administration of histochrom is carried out slowly jet, and the subsequent - drip.

Images