RU2124365C1 - Method for treating the cases of ischemic insult - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves applying 4-6% aqueous solution of heptapeptide Met-Glu-His-Phe-Gly-Pro by means of its intranasal application in the amount of 1-4 drops in each nasal canal 1-4 times per day during 6-12 days. Patients of medium severity or severe insults take the heptapeptide in daily doses like 9-13 mg and 15-24 mg, respectively. EFFECT: favorable influence on recovery processes. 2 cl, 2 dwg, 4 tbl

Description

 The invention relates to medicine and relates to a means and method of treating ischemic stroke.

 A known treatment for ischemic stroke is cerebrolysin, which is an aqueous solution of a brain-free hydrolyzate protein substance containing 18 amino acids (85%) and 15% low molecular weight peptides, which are the active fraction of the drug (edited by Yu.F. Krylov. Register of Russian Medicines M.: Infarmhim., 1993, p. 935).

 However, the heterogeneity of the peptides included in the preparation (in terms of molecular weight, formula and properties) does not allow definiteness to relate the positive effects of the drug to a specific constituent substance. The effect of cerebrolysin is manifested primarily by its predominant effect on the severity of a focal neurological defect. However, the isolated use of cerebrolysin, for example, for initially severe strokes accompanied by not only focal, but also cerebral symptoms, signs of cerebral edema, is often not effective enough and requires its combined use with other anti-ischemic drugs. In addition, a strong dependence of the effectiveness of cerebrolysin on the adequacy of the selected dose was revealed. Uncontrolled excessive increase in the dose of cerebrolysin often has a negative effect on the pace and severity of recovery processes.

 Known Met - Glu - His - Phe - Pro - Gly - Pro as a stimulant of memory of prolonged action (USSR Patent 939440, CL C 07 C 103/52, 1981 - prototype for the tool).

 However, the possibility of using this known heptapeptide as a treatment for ischemic stroke is not described.

 There is a method of treating ischemic stroke by applying a solution of peptides (Mashkovsky M.D. Medicines. - Vilnius, 1993, v.2, p.88 - prototype for the method). In this known method, cerebrolysin is used as an aqueous solution of peptides, the disadvantages of which are described above as a treatment for ischemic stroke.

 The technical result achieved by the implementation of the invention is the recommendation of a new highly effective means of treating ischemic stroke, its effective use in practice at the early stages of the development of the disease, reducing the duration of course treatment, ensuring positive dynamics of objective neurological parameters of patients.

 This is achieved by the fact that the heptapeptide Met - Glu - His - Phe - Pro - Gly - Pro is used as a treatment for ischemic stroke. The indicated technical result is also achieved by the fact that in the method of treating ischemic stroke by using a peptide solution, a distinctive feature is that a solution of the heptapeptide Met - Glu - His - Phe - Pro - Gly - Pro in water or saline is used by intranasal administration. In a specific case, heptapeptide is recommended to be used at a dose of 9-13 and 15-24 mg / day for 8-12 days, respectively, for moderate patients and in severe strokes. In this case, a 4-6% solution of heptapeptide is administered 1-4 drops in each nasal passage 1-4 times a day.

 In FIG. 1 graphically shows the comparative effectiveness of various doses of heptapeptide in the acute period of moderate ischemic stroke (in total clinical scores).

 In FIG. 2 graphically shows the comparative effectiveness of various doses of heptapeptide in the acute period of severe ischemic stroke (in total clinical scores). (in Figs. 1 and 2 - reliability: * <0.05; ** <0.01; *** <0.001.

 Example 1. Patient D., 72 years old. Received May 29, 1996. Case history 137115. Diagnosis: stroke (acute cerebrovascular accident) according to ischemic type in the system of the right internal carotid artery. Hospitalized after 5 hours from the onset of the disease. The patient did not make complaints upon admission due to impaired consciousness to the level of stupor. A history of grade III hypertension, coronary heart disease (CHD), a persistent form of atrial fibrillation. The development of a stroke was subacute. In the morning after sleep, the patient noted weakness of the left limbs, then over 5 hours the weakness increased, and impaired consciousness. Objectively: upon admission the patient was “loaded”, there was meningeal syndrome, lack of eyeballs to the left, central paresis of 7.12 pairs of cranial nerves on the left, left-sided uniform spastic hemiparesis up to 3 points in the arm and leg, left-side hemigipalgesia). Toposelective electroencephalogram mapping (TSC EEG low energy level). Δ- and θ- activity in the fronto-central leads of the right hemisphere, α-rhythm with a frequency of 8-10 Hz with a predominance in the occipital branches of the left hemisphere. Somato-sensory evoked potentials (SSVP): all components of evoked potentials of low amplitude, N 30, N 150 altered shape and increased latency peaks. Treatment: against the background of unified basic therapy, a 5% solution of heptapeptide at a dose of 6 mg was administered intranasally in 4 drops - 2 times a day. Result: against the background of the first injection of the drug in response to external stimuli, the patient's motor activity increased within the bed, began to moan. By the end of the first day (second injection), disorders of consciousness decreased to the level of stunning, the patient became available to elementary adequate contact, and cortical dysarthria was noted. On the second day from the onset of the disease, disorders of consciousness, meningeal symptoms and oculomotor disorders completely regressed, the patient recognized relatives and staff well, remembered how the disease started, objectively and critically assessed his condition. The dynamics of focal neurological symptoms was characterized by normalization of articulation of speech and complete restoration of muscle strength of the left hand and foot by 5 days, by 21 days from the onset of the disease - normalization of muscle tone, complete restoration of sensory disorders, as well as muscle strength in the proximal left limbs; there remained the smoothness of the left nasolabial fold and the pyramidal "signs" in the form of a pathological Rossolimo reflex on the left foot. Monitoring of drug administration revealed its effect on the functional state of the brain: 20 minutes after the first dose was administered, an increase in the total power of the EEG spectrum by 40%, an increase in the α-component of the spectrum by 20%, and a tendency to smoothing hemisphere asymmetry in the α-range were noted. At the same time, there was a tendency to a decrease in the representation of slow pathological activity (Δ-, θ-) by 43 and 52%, respectively. On the fifth day, TSC EEG- Δ- and θ-activity is not expressed, the α-rhythm frequency of 10 Hz in the occipital leads of both hemispheres; SSVP - a decrease in latencies and an increase in the amplitude of components N 30, P 45, N 60.

 Example 2. Patient M., 63 years old. Received June 10, 1996. Case history 157209. Diagnosis: acute cerebrovascular accident (stroke) according to ischemic type in the system of the left internal carotid artery. Received after 8 hours from the onset of the disease. Could not present complaints in connection with speech disorders. A history of rheumatic combined mitral-aortic heart disease, atrial fibrillation, hypertension of the III degree, psoriasis. The development of stroke was acute and was manifested by a sudden speech disorder and weakness of the right extremities amid a stressful situation. There was no loss of consciousness. Objectively: upon receipt of cerebral and meningeal symptoms there. Sensorimotor aphasia, restriction of the patient's orientation in ongoing events are noted. Central paresis of 7.12 pairs of cranial nerves on the right, right-sided spastic monoparesis of the hand up to 3 points, anisoreflexion d> s, hemihypesthesia on the right. TSK EEG: average energy level, depression of α-activity in the right hemisphere, θ-rhythm with a frequency of 6.5 Hz prevails in the frontal parts. SSVP: change in the shape and distribution of components N 60 - P 240 with the safety of early evoked potentials. Treatment: against the background of unified basic therapy, a 5% solution of heptapeptide at a dose of 6 mg was administered intranasally in 4 drops 2 times a day. Result: against the background of the first injection of the drug, the patient's disorientation decreased and by the end of the first day (2nd injection), auditory speech disorders significantly decreased. On the second day of treatment, motor speech disorders decreased - “poor” appeared, but phrasal speech, the patient is quite oriented in what is happening, paresis of the hand regressed to 4 points. The patient was discharged from the hospital on the tenth day in connection with the full restoration of speech functions, a complete regression of motor sensory disorders. At the time of discharge, only anisoreflexion d> s without pathological stop signs remained in neurological status. Monitor control: 20 minutes after the first dose was administered, an increase in the total power of the EEG spectrum by 60%, an increase in the α-component of the spectrum by 45%, a tendency to smooth interhemispheric asymmetry in the α range were noted. At the same time, there was a tendency to a decrease in the representation of slow pathological activity Δ-, θ- by 58 and 62%, respectively. On the fifth day, TSC EEG: a decrease in the spectrum of the energy level due to slow-wave activity, the α-rhythm with a frequency of 9 Hz is symmetrically represented in the occipital leads of both hemispheres; SSVP - increase in the amplitudes of components N 60 - N 150 with an improvement in the cortical representation of late components of evoked potentials.

 Example 3. Patient E., 59 years old. Received October 27, 1996. Case history 30961. Diagnosis: ONMK by ischemic type in the basin of the left middle cerebral artery. Hospitalized after 8 hours from the onset of the disease. No complaints were made in connection with speech disorders. He had a history of transient ischemic attacks in the same vascular pool against the background of systemic atherosclerosis and arterial hypertension. The disease began at the time of physical activity and was characterized by a gradual increase in weakness of the right limbs, loss of speech, depression of consciousness. Objectively: at admission, the patient has impaired consciousness, has moderate meningeal syndrome, total aphasia, central paresis of 7, 12 pairs of cranial nerves on the right, right hemiplegia, anisoreflexia d> s, hemianesthesia on the right. Data from computed tomography studies (CT studies) revealed an extensive focus of ischemic lesions in the left hemisphere of the brain with deformation of the ventricular system. TSK EEG: high energy level, θ-, α- lesion in the frontal leads of the left hemisphere of the brain with a frequency of 6-7 Hz, the main rhythm of α- with a predominance in the right hemisphere of 8 Hz. SSEP: absence of most components in the affected hemisphere. Change in shape and drop in amplitudes in the intact hemisphere. Treatment: against the background of unified basic therapy, heptapeptide was prescribed at a dose of 9 mg intranasally in 6 drops - 2 times a day. Result: against the background of the first injection of the drug, the patient noted an acceleration of the targeted reaction to external stimuli in healthy limbs, after the second injection, the “awakening” in response to sound and nociceptive stimuli accelerated. On the second day, the patient completely regressed consciousness disorders, signs of orientation in the place of action and self appeared, as well as the possibility of elementary contact - understanding of the patient simple questions and tasks, their own speech production at the level of “yes” and “no”, minimal movements became possible in the lower limb. By the fifth day of the disease, meningeal syndrome disappeared, the range of perceived speech expanded, paresis of the lower limb decreased to 2 points. By the end of the acute period of the stroke (21 days), the patient had a good understanding of inverted speech with a persistent defect in expressive speech, it became possible to bend the right leg in the knee, however, movements in the arm did not recover, and sensitive disorders decreased. It is important to note that, despite the extensive lesion of the brain and a gross motor defect, the patient quickly regressed cerebral and meningeal symptoms, the course of the disease was regredient in nature, and trophic disorders did not develop. Monitor control: 20 minutes after the introduction of the first dose, an increase in the α-component of the spectrum by 17% was noted. At the same time, a tendency towards a decrease in the representation of slow pathological activity (Δ-, θ-) by 20 and 14%, respectively, was recorded. On the fifth day: TSK EEG - a significant decrease in total power due to pathological rhythms. The θ focus of low power with a frequency of 5 Hz, MPA (interhemispheric asymmetry) along the α rhythm with a frequency of 8 Hz with a predominance in the right parietal-occipital leads is preserved; SSEP - normalization of the shape and inter-peak relationships in the intact hemisphere, the appearance of the components of the SSEP in the affected hemisphere.

 Example 4. Patient L., 79 years old. Received October 25, 1996. Case history 30876. Diagnosis: ONMK by ischemic type in the system of the right internal carotid artery. She was hospitalized 3 hours after the onset of the disease with complaints of weakness of the left limbs. History of hypertension II tbsp. The disease began acutely, the patient fell amid a stressful situation (without loss of consciousness) due to the sudden weakness of the left limbs. Objectively: the consciousness is clear, but it is spontaneous, it underestimates its own defect, it is not critical of the disease, moderate meningeal syndrome, paresis of the gaze to the left, central paresis 7, 12 pairs of cranial nerves on the left, cortical dysarthria, choking on swallowing due to inhibition of the pharyngeal reflex on the left, left deep spastic hemiparesis up to 2 points in the distal extremities and 3 points in the proximal sections. Anisoreflexion s> d. Violation of complex types of sensitivity on the left, urinary disorders of a central nature. TSK EEG: average energy level. α- and β-activity are better expressed in the right hemisphere with a frequency of 8 and 13 Hz, respectively. Diffuse Δ-, θ-activity of low power. SSEP: Expanding the representation of the components of SSEP with the maximum severity of motor components (N 30, N 150) in the occipital leads, acceleration of the peaks N 30, N 60. Treatment: against the background of unified basic therapy, a 5% heptapeptide solution in a dose of 9 mg was prescribed intranasally in 6 drops - 2 times a day. Result: on the first injection of the drug, the patient began to engage more actively in conversation, criticism for her condition appeared; by the end of the first - on the second day the patient has an objective assessment of the existing defect, sheath symptoms have decreased and the range of movements in the hand and foot has increased to 3 points. By the fifth day from the onset of the disease, meningeal syndrome completely regressed, the range of movements of the eyeballs was restored, and swallowing returned to normal. On day 15, hemiparesis decreased to 4 points, urination disorders disappeared. By 21 days, the patient regressed sensitive disorders, intelligible speech was noted, only minimal muscle weakness of the left extremities remained, muscle tone in the leg returned to normal, anisoreflexion s> d remained, pathological stop signs of the flexor and extensor types were present. There were no trophic disorders during the acute period of the stroke. Monitor control: 20 minutes after the first dose was administered, an increase in the total power of the EEG spectrum by 48%, an increase in the α-component of the spectrum by 22%, and smoothing of interhemispheric asymmetry in the α-range were noted. At the same time, a tendency towards a decrease in the representation of slow pathological activity (Δ-, θ-) by 28 and 19%, respectively, was recorded. On the fifth day: TSC EEG - total spectrum power unchanged, the α-rhythm in the occipital leads is symmetrical with a frequency of 8 Hz, the β-rhythm in the central leads of both hemispheres with a frequency of 15-16 Hz; SSVP - the extended form of the peaks is preserved, but with a normal distribution value and a decrease in latency N 60 - P 100 -N 150.

 Example 5. The dependence of the effectiveness of treatment of groups of patients of varying severity on the used dose of heptapeptide was studied. The results are shown in FIG. 1 and 2. The following clinical scales were used: Original (I), Orgogozo (II), Scandinavian (III). The numbers 6 and 21 horizontally mean: an increase in the total clinical score by 6 and 21 days of stroke, respectively. Letters a) and b) indicate groups of patients who received 12 and 18-24 mg of heptapeptide per day, respectively.

 Figure 1 reflects the anticipatory increase in the total clinical score in patients with moderate severity who received 12 mg of heptapeptide per day, compared with patients who received 18-24 mg per day.

 Figure 2 reflects the anticipated increase in the total clinical score in patients with severe ischemic stroke who received 18-24 mg of heptapeptide per day, compared with patients who received 12 mg per day.

 The data presented in figures 1 and 2 indicate a greater dose efficiency of 12 mg per day in patients with moderate ischemic stroke and 18-24 mg per day in patients with severe ischemic stroke.

 Thus, a comparison of the effectiveness of different doses of heptapeptide (see Fig. 1) revealed in the moderate group of patients a slight prevalence of the effectiveness of the daily dose of 12 mg (on average 150 μg / kg, i.e. 6 mg twice a day) compared with higher doses. At the same time, in the group of severe patients (see Fig. 2), the severity of clinical dynamics somewhat prevailed in the treatment of daily doses of 18 mg (an average of 260 μg / kg, i.e. 9 mg twice a day).

 Example 6. To determine the therapeutic efficacy of the heptapeptide in the optimal doses used (see Example 5) in the acute period of hemispheric ischemic stroke, 110 patients were examined who were admitted to the clinic within the first 12 hours from the development of hemispheric ischemic stroke (56 men, 54 women; mean age 69.6 ± 2.11). In 61 patients, an acute violation of cerebral circulation in the system of the left internal carotid artery was diagnosed, in 49 - the right. The main etiological factor in the development of stroke was the combination of atherosclerosis with arterial hypertension - 89 people (80.9%). In 11 patients of a young age (10%), a stroke developed against a background of arterial hypertension, at the height of a hypertensive crisis. The combination of diabetes mellitus, atherosclerosis and hypertension was observed in 13 patients (11.8%). 5 (86.4%) patients showed signs of coronary heart disease, 8 (7.2%) patients had myocardial infarction in the past. In one patient, acute cerebrovascular accident (stroke) developed against the background of acute myocardial infarction (cardiocerebral syndrome). 13 (11.8%) patients had a constant form of atrial fibrillation (in two cases of a rheumatic nature), in four patients a stroke developed against the background of paroxysm of atrial fibrillation. According to the variant of stroke development, patients with an acute onset of the disease and the maximum occurrence of focal neurological symptoms within the first hour prevailed - 74 (67%), subacute development of the disease was noted in 31 (28%), focal symptoms increased within several hours, and 6 (5 , 4%) - an increase in existing symptoms and the appearance of new ones was noted during the first two days of the disease.

 From the moment of admission to the clinic, all patients received the most unified basic therapy, including correction of respiratory disorders, disorders of central and cerebral hemodynamics, hemorheology, and, if necessary, correction of homeostasis disorders, and fight against brain edema. Against this background, 30 patients from the first hours of the disease were treated with a 4 - 6% aqueous solution of the heptapeptide Met - Glu - His - Phe - Pro - Gly - Pro in a daily dose of 12, 18 and 24 mg (on average 150, 260 and 300 mcg / kg) in two administrations. The heptapeptide was administered intranasally in 4 drops of saline (2 drops in each nasal passage) during the first five days of the disease. 80 patients received only complex basic therapy without the inclusion of metabolically active drugs (control group). The clinical and electrophysiological effects of the heptapeptide were also compared with previously obtained test results of two other known treatments for ischemic stroke: cerebrolysin and kronassial (comparison group).

 An analysis of etiological factors, features of the onset of the disease, terms of hospitalization, age and gender composition of patients of all analyzed groups testified to their comparability, i.e. the possibility of a comparative study of the dynamics of clinical and neurophysiological parameters during the acute period of stroke. The first administration of heptapeptide to patients in a moderate state did not have a direct effect in the form of a regression of focal symptoms; however, in 11 of 16 cases, it led to general (motor and emotional) activation of patients, better “inclusion” in contact with a doctor. In patients with right-hemisphere localization of a stroke after 2-3-fold administration of a heptapeptide, there was an increase in motivation for recovery, elimination of bias in assessing the severity of one's own condition, a decrease in the severity of right-left orientation disorders, and in 2 cases, autotopagnosis.

 Analysis of the statistical processing of clinical scales (see table 1) established an acceleration in the rate of positive clinical dynamics by 6 (at the end of the heptapeptide course) and 21 days of illness. A statistically significant advance in the growth of the total clinical score was determined against the background of heptapeptide (by 6 days of stroke) compared with the control according to the Scandinavian (p <0.05) and original (p <0.001) scales.

 A study of the dynamics of individual focal symptoms revealed a predominant acceleration of the regression of motor disorders (p <0.01-0.05 compared with the control on all three scales - see table 2). In 87.5% of patients receiving heptapeptide, the course of the acute period of stroke was regredient with a stable regression of neurological disorders. Such a frequency of the regredient course of the disease was comparable to that in the comparison groups - with the use of other known treatments for ischemic stroke and significantly exceeded the control group.

 The group of severe strokes included 3 patients with a predominantly deep hemisphere lesion, clinically manifested capsular syndrome, and 11 patients with extensive cortical-subcortical lesion of the cerebral hemisphere, among whom 6 had a total clinical score of less than 30 on the original scale and less than 12 on the Scandinavian scale, which objectified the extreme severity of the condition. In all severe patients, along with a gross focal defect, pronounced cerebral symptoms occurred. Consciousness disorders up to the level of stunning were noted in 7 patients, up to the stupor level - in 6. Only one patient with a left hemispheric deep focus of ischemia had no disturbances in consciousness. In 12 patients (85.7%), a homolateral focus of ischemia, ankylosing spondylitis symptom, and Kernig symptoms were detected. In 9 cases (64.3%), the onset of vegetative-trophic disorders was noted early (for 1-2 days). In 6 patients with a state of extreme severity, along with cerebral and shell symptoms, respiratory disorders were revealed as regular tachypnea, in two of them - secondary stem syndrome (mesencephalic stage). The first introduction of heptapeptide had little effect on the general condition of severe patients. In no case was the “awakening" action of the drug noted. However, all patients who arrived in a state of stunning, by the end of the second day came to a clear consciousness; 5 patients who were in stupor, by the second day, “reached” the stage of stunning. Only in one case did the stupor persist until the end of 3 days of illness. By 6 days, in all severe patients treated with heptapeptide, consciousness disorders and meningeal symptoms detected in the first days of a stroke completely regressed. A quantitative assessment of the dynamics of the average values of the total clinical score showed a statistically significant advance in the rate of restoration of impaired functions during the use of heptapeptide (see Table 1) for all three scales used. Moreover, the differences with the control were more pronounced than in the group of patients with moderate severity (p <0.001-0.05). As in the group of moderate strokes, the most pronounced and reliable was the acceleration of the regression of motor disorders (p <0.05, see table 3). Among severe patients treated with heptapeptide, in 11 (78.6%) the regredient course of the disease was determined (in the control - only 32.0% of patients). In the remaining 3 patients, the course of the acute period was remitting. In the group, there was not a single case of a progressive course of a stroke with a fatal outcome, including among initially extremely severe patients (see Table 4). By the end of the acute period, all severely ill patients had limited recovery of impaired functions: in 6 - moderate and in 8 - severe disability.

 It was noteworthy that in all patients receiving heptapeptide, the acceleration in the increase in the total clinical score decreased after the end of the drug and by the end of the acute period of the stroke became unreliable, which could indicate the insufficiency of a five-day course of treatment with heptapeptide. In this regard, a 10-day course of heptapeptide was carried out in 5 patients with moderate hemispheric ischemic stroke (in three cases of left hemisphere, in two cases of right hemisphere localization). In all these patients, a regredient course of the disease was observed with a good restoration of motor and speech functions by the 21st day of the disease. A scoring of clinical dynamics revealed the preservation of the outstripping rates of restoration of impaired neurological functions throughout the acute period of a stroke. These results indicate the preference of a 10-day course of heptapeptide with a possible 8-10-day course of treatment.

 Thus, a clinical and neurophysiological study showed that the inclusion of the heptapeptide Met - Glu - His - Phe - Pro - Gly - Pro in the intensive care complex of acute hemispheric ischemic stroke has a significant beneficial effect on the severity and rate of recovery processes, contributing to the acceleration of regression of cerebral and focal, especially motor, disorders.

 It is most advisable to conduct a 10-day course of treatment with heptapeptide in daily doses of 12 mg in patients with moderate severity and 18 mg in severe strokes.

 These doses are provided by introducing mainly 2-3 drops of a 5% solution of heptapeptide in water or in physiological solution into each nasal passage 2 times a day for 10 days.

Claims (2)

 1. A method of treating ischemic stroke, including the appointment of therapeutic agents, characterized in that the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro is prescribed as a therapeutic agent for patients with moderate severity and severe strokes and daily dose, respectively 9 - 13 and 15 to 24 mg for 8 to 12 days.  2. The method according to claim 1, characterized in that the heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro is used in the form of a 4-6% solution and 1-4 drops are administered into each nasal passage 1-4 once a day.

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