Application noopept in patients with mild cognitive impairment post-traumatic genesis

Content

  • Pathogenesis
  • goal

  • Materials and methods
  • Result
  • Result


  • In developed countries, steady growth is observed.neurotraumatism. So in the countries of Europe annually recorded 150-300 cases of head injury per 100 thousand people. In the United States alone, over 2003, there were more than 1.5 million cases of head injury. In Russia, this figure reaches 4 cases per 1,000 people. The most important problem in the medical and social plan is that a significant number of victims subsequently develop the so-called consequences of a previous head injury, often interpreted as part of post-traumatic encephalopathy. Among the most common syndromes that determine the level of social adaptation and the quality of life of patients are intellectual and mnestic disorders. Post-traumatic cognitive impairment is observed in isolation in 29.4% of all patients with traumatic brain injury, and in combination with other syndromes, in 35.7%. In general, among the consequences of a head injury, cognitive impairment as a syndrome occurs in 65.1% of cases.


    Pathogenesis

    Pathogenesis of the development of post-traumatic cognitiveThe disorder is very complex and multifaceted. The main factors that can lead to the formation of cognitive deficit in the acute period are considered as direct mechanical damage to brain tissue, and the indirect effect of certain pathophysiological processes that occur during brain injury, such as swelling, swelling of the brain, impaired cerebrospinal fluid, hemodynamics and etc. At the same time, it is known that, in some cases, disorders of intellectual-mnestic functions persist for a long time or are persistent. In other patients, they appear in the long term period of trauma and have a distinct tendency to progression. The mechanism of the occurrence of such violations remains unstudied to the necessary extent. The data obtained indicate that pathological factors acting on a nerve cell in the acute period contribute to the appearance of a cascade of biochemical changes in neurons, leading to the development of dystrophic processes in them and a decrease in the efficiency of synaptic transmission.

    Eventually, process disruption occurs.dissemination of information in neural networks, which is considered as one of the main aspects of the formation of cognitive impairment. A number of researchers note a certain similarity of pathogenetic mechanisms of development of cognitive impairment in brain injury and vascular lesions of the brain. In addition, the possible role of brain injury as a trigger for neurodegenerative diseases, in particular Alzheimer's disease, is shown. Currently, several pathophysiological processes are considered that play a significant role in the formation of post-traumatic cognitive disorders.

    One such process is development"Glutamate excitotoxicity." Under physiological conditions, glutamate acts as one of the most important excitatory mediators of the central nervous system, participating in the implementation of neuronal plasticity and integrative functions of the brain. A significant amount of glutamatergic receptors is observed in the cerebral cortex and hippocampus. At the same time, in pathology, an excess release of glutamate is observed, which under these conditions has a toxic effect on neuronal structures, which contributes to the activation of the reactions of the glutamate-calcium cascade, leading to an uncontrolled increase in the concentration of intracellular calcium, which has a negative effect on the energy supply of the cell. It has been shown that under conditions of ischemia, a significant increase in the level of formation of free radicals occurs in tissues, which is also promoted by excessive intracellular calcium accumulation.

    The brain is very sensitive to actionfree radicals. Under the prevalence of oxidative systems over antioxidant, the formation of so-called oxidative stress occurs. In this condition, hydrolysis of phospholipases is activated and cell membranes, including mitochondrial ones, are degraded. The elimination of arising disorders is a prerequisite for the successful management of patients with post-traumatic cognitive impairment. From this perspective, it is advisable to prescribe a drug such as noopept, which has similar properties. Noopept - ethyl ester of N-phenyl-acetyl-L-prolylglycine - a new domestic original dipeptide, created at the Research Institute of Pharmacology named after V.V.Zakusova RAMS. According to the data obtained during experimental studies, the noopept has nootropic and neuroprotective properties. The drug in its structural conformational characteristics is similar to piracetam and vasopressin. The development of this drug was carried out in the framework of the existing idea that some regulatory peptides have a significant impact on the mechanisms of memory formation and learning.

    The explanation of the action of noopept isthe hypothesis that the basic drug of this group, piracetam, is an analogue of the peptide ligand to specific nootropic receptors, similar in their characteristics to vasopressin metabolites. Noopept compares favorably with vasopressin in that it is able to be active in systemic, including oral, administration. In the course of the studies, a high bioavailability of the drug for brain tissue was shown, as well as its low toxicity. A study in an experiment on laboratory animals made it possible to establish that the use of dosages of the drug, from 2 to 20 times higher than nootropic, does not cause damage to internal organs, does not have significant violations of hematological and biochemical parameters. When conducting a number of clinical studies, the high safety of the drug and its good tolerance are also shown. In the course of studies, it was found that noopept has a complex mechanism of action.

    Firstly, it has a nootropic effect,due to the fact that one of the active metabolites of noopept is cycloprolyl glycine, which in its structure is similar to an endogenous cyclic dipeptide with antiamnestic activity.

    Secondly, noopept is able to increase stabilitybrain tissue to damaging effects, such as trauma, hypoxic, electroconvulsive and toxic damage, which characterizes the neuroprotective effect of this drug. Thirdly, the ability of noopept to prevent the death of neurons in tissue culture of the cerebral cortex and cerebellum under conditions of toxic concentrations of glutamate and reactive oxygen species has been shown. In addition, the experiment revealed the ability of noopept to reduce the toxic effect of b-amyloid, enhance the production of anti-amyloid antibodies, modulate the work of cholinergic receptors, and also stimulate the expression of neurotrophic factors (BDNF and NGF) in the cerebral cortex and hippocampus.

    The relevance of post-traumatic problemscognitive impairment, the validity of the use of noopept taking into account the presence of application points at the neurochemical level with the consequences of head injury, as well as preliminary, including experimental and clinical efficacy of the drug, were the cause of this study.


    goal

    The aim of the study was to evaluate effectiveness, andalso the safety of the use of the drug noopept in patients with mild post-traumatic cognitive impairment. The study was conducted according to a specially developed protocol and met all the requirements of good clinical practice (GCP) adopted in the Russian Federation. The study included patients who met the inclusion criteria after the mandatory signing of informed consent.

    The study involved 30 patients inaged 19–66 years (average age 33 ± 10.3 years) who underwent a head injury (concussion or bruise of the brain of a mild degree) at least 6 months ago and having intellectual and mnemonic functions associated with this condition that meet the criteria for moderate cognitive impairment syndrome . All patients met the criteria for moderate cognitive impairment syndrome, and their cognitive impairment was initially rated at 25 or more on the Mini-Mental State Examination (MMSE) scale.

    Exclusion criteria from the study were: the presence of concomitant severe or unstable somatic diseases that threaten the patient’s life, the presence of clinically significant other (except for moderate cognitive impairment syndrome in the aftermath of TBI) neurological or mental disorders, the presence of a gross motor or sensory defect or other disorders that would make it difficult to conduct a neuropsychological study or other studies prescribed by the protocol, the presence of a history of stroke or stage III discirculatory encephalopathy, at the same time the conduction of therapy with other vasoactive, metabolic or psychotropic drugs with a proven cognitive stimulating effect, intolerance of the studied drug, the period of pregnancy and lactation.


    Materials and methods

    In carrying out work for the objectification of the data were used
    the following methods:

    1) assessment of neurologic status;
    2) Mini-Mental State Examination - MMSE;
    3) Hamilton depression rating scale;
    4) The battery of tests to the frontal dysfunction - Frontal Assessment Battery (FAB);
    5) drawing test hours;
    6) test is 10 words;
    7) sample Schulte;
    8) the rating scale for the overall clinical impression of change - Clinician’s Interview Based Impression of Change Plus (CIBIC Plus);
    9) neuroimaging methods: computed or magnetic resonance imaging.

    General Clinical Impression Scoreincluded an assessment of the patient's condition before therapy and an assessment of the severity of changes during treatment. Before treatment, the attending physician made an assessment of the patient’s condition on the basis of an analysis of the disorders on a 7-point scale, while assessing the clinical picture of the disease, monitoring the patient, the state of the patient’s mental sphere, behavior, and the state of social functions.

    Screening was conducted at the beginning of the study.visit on which the patient's compliance with inclusion criteria was determined. Then, if the patient complied with the protocol, an informed consent was signed. At this visit, the results of an electrocardiogram, laboratory and neuroimaging studies were also evaluated. After that, neurological status was assessed, basic neuropsychological testing was performed to determine the initial level of cognitive function status.

    Starting next to screening visitdays, patients received noopept 10 mg 2 times a day for 60 days. Further, the effectiveness of therapy was assessed on the 30th and 60th days of treatment. The plan of activities is presented in the table.

    In our study, the average term afterthe injury was 7 ± 3.8 years. All 30 patients included in the study initially had mild abnormalities on the scale of the overall clinical impression of change (CIBIC Plus). During the screening visit, all examined patients complained of memory loss, attention span, decreased effectiveness of daily activities, general weakness, and increased fatigue. In addition, some patients presented other complaints: headache (43.3%), difficulties in planning various events (40%), sleep disorder (26.7%), mood instability (23.3%). During a neurological examination, gross violations were not detected. In 53.3% of patients, diffuse symptoms in the form of isolated microsymptoms were observed, in 13.3% - mild coordinatory disorders. The same number of observed revealed bilateral pathological carpal reflexes (Rossolimo, Wartenberg). All patients showed signs of asthenic syndrome. 53.3% showed signs of autonomic vascular instability.


    Result

    A dynamic study of cognitivefunctions of patients showed that according to the MMSE scale, significant differences with the initial level were shown 30 days after the start of treatment. In particular, before taking the drug, the average score was 26.5 ± 0.94; after 1 month from the start of therapy - 27.6 ± 0.99 points (p <0.01). At the same time, after 60 days from the start of therapy, the average score on this scale was 27.7 ± 1.09, which characterized the absence of further significant improvement (p> 0.05) and reflected only a slight tendency to decrease cognitive impairment. The dynamics of neuropsychological indicators on the MMSE scale is presented in Fig. 1.

    Application noopept in patients with mild cognitive impairment post-traumatic genesis

    Picture 1

    An interesting fact was that in the structureMMSE scale, the most significant improvement was obtained by the “attention” subscale, which characterizes to a certain extent the state of neurodynamic processes suffering from head injury (p <0.01), as well as by the “memory” subscale (p <0.05). On the scale of the battery of tests to assess the frontal dysfunction of FAB, there were no significant differences in the dynamics over the observation period (at the initial visit - 15.9 ± 0.78 points, after 60 days - 16.8 ± 0.87, p = 0.27 ) Performing a clock drawing test with a 10-point assessment at the initial visit, as a rule, was estimated at 9-10 points and did not undergo significant changes against the background of the therapy. Of absolute interest are the data obtained on the basis of an evaluation of the results of the Schulte test performed on all 3 visits. A comprehensive evaluation test using 5 sequentially presented tables to the patient most fully allows to characterize such neurodynamic changes as impaired concentration, increased exhaustion of mental processes and instability of attention. These changes were to some extent characteristic of most patients at the screening visit. The average test execution time for each of the five presentations at the first visit was 45.5 ± 6.24 s. 2 months after the start of therapy, the time decreased to 40.2 ± 5.20 s, which characterized a significant improvement in concentration (p <0.05). The dynamics of the Schulte test time is shown in Fig. 2.


    Application noopept in patients with mild cognitive impairment post-traumatic genesis

    Figure 2

    As can be seen from the graph in Fig. 2, the most significant decrease in the time spent on performing the samples was shown by patients already 30 days after the start of therapy. A distinct positive dynamics also persisted during the 2nd month of taking the drug and was characterized by an even more pronounced decrease in the test execution time with less significant stabilization of improvement than on the MMSE scale.

    General Clinical Impression Scoreincluded an assessment of the patient's condition before therapy and an assessment of the severity of changes during treatment. Before treatment, the attending physician made an assessment of the patient’s condition on the basis of an analysis of the disorders on a 7-point scale, while assessing the clinical picture of the disease, monitoring the patient, the state of the patient’s mental sphere, behavior, and the state of social functions.

    Screening was conducted at the beginning of the study.visit on which the patient's compliance with inclusion criteria was determined. Then, if the patient complied with the protocol, an informed consent was signed. At this visit, the results of an electrocardiogram, laboratory and neuroimaging studies were also evaluated. After that, neurological status was assessed, basic neuropsychological testing was performed to determine the initial level of cognitive function status.

    Starting next to screening visitdays, patients received noopept 10 mg 2 times a day for 60 days. Further, the effectiveness of therapy was assessed on the 30th and 60th days of treatment. The plan of activities is presented in the table.

    research Methods I II III
    Background 30th day 60th day
    Mini-Mental State Examination (MMSE) V V V
    Assessment of frontal dysfunction (FAB) V V
    Clock drawing test 10 - point grade V V
    Scale Clinical Global Impression (CGI) V V
    Test 10 words V V
    sample Schulte V V V
    Hamilton Scale V
    Assessment of adverse events and side effects V V

    Figure 3

    In our study, the average term afterthe injury was 7 ± 3.8 years. All 30 patients included in the study initially had mild abnormalities on the scale of the overall clinical impression of change (CIBIC Plus). During the screening visit, all examined patients complained of memory loss, attention span, decreased effectiveness of daily activities, general weakness, and increased fatigue. In addition, some patients presented other complaints: headache (43.3%), difficulties in planning various events (40%), sleep disorder (26.7%), mood instability (23.3%). During a neurological examination, gross violations were not detected. In 53.3% of patients, diffuse symptoms in the form of isolated microsymptoms were observed, in 13.3% - mild coordinatory disorders. The same number of observed revealed bilateral pathological carpal reflexes (Rossolimo, Wartenberg). All patients showed signs of asthenic syndrome. 53.3% showed signs of autonomic vascular instability.


    Result

    A dynamic study of cognitivefunctions of patients showed that according to the MMSE scale, significant differences with the initial level were shown 30 days after the start of treatment. In particular, before taking the drug, the average score was 26.5 ± 0.94; after 1 month from the start of therapy - 27.6 ± 0.99 points (p <0.01). At the same time, after 60 days from the start of therapy, the average score on this scale was 27.7 ± 1.09, which characterized the absence of further significant improvement (p> 0.05) and reflected only a slight decrease in cognitive impairment. The dynamics of neuropsychological indicators on the MMSE scale is presented in Fig. 1. The fact that in the MMSE scale structure the most significant improvement of the indicators was obtained by the “attention” subscale characterizing to a certain extent the state of neurodynamic processes suffering from head injury (p <0.01), as well as the “memory” subscale, turned out to be interesting. (p <0.05). On the scale of the battery of tests to assess the frontal dysfunction of FAB, there were no significant differences in the dynamics over the observation period (at the initial visit - 15.9 ± 0.78 points, after 60 days - 16.8 ± 0.87, p = 0.27 ) Performing a clock drawing test with a 10-point assessment at the initial visit, as a rule, was estimated at 9-10 points and did not undergo significant changes against the background of the therapy.

    Of great interest are the dataobtained on the basis of an evaluation of the results of the Schulte test performed on all 3 visits. A comprehensive evaluation test using 5 sequentially presented tables to the patient most fully allows to characterize such neurodynamic changes as impaired concentration, increased exhaustion of mental processes and instability of attention. These changes were to some extent characteristic of most patients at the screening visit. The average test execution time for each of the five presentations at the first visit was 45.5 ± 6.24 s. 2 months after the start of therapy, the time decreased to 40.2 ± 5.20 s, which characterized a significant improvement in concentration (p <0.05). The dynamics of the Schulte test time is shown in Fig. 2. As can be seen from the graph in Fig. 2, the most significant decrease in the time spent on performing the samples was shown by patients already 30 days after the start of therapy. A distinct positive dynamics also persisted during the 2nd month of taking the drug and was characterized by an even more pronounced decrease in the test execution time with less significant stabilization of improvement than on the MMSE scale.

    Leave a reply