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Application of Instenon in neurological practice

Numerous experimental studies have proven that a complex set of biochemical changes plays a huge role in the formation of ischemic brain damage, the result of which is both immediate and delayed death of neurons and neuroglia with disruption of associative interneuronal interactions and the formation of neurological deficits. Obviously, not only the correction of cerebral blood flow and metabolism, but also neuroprotective therapy, stimulation of reparative processes during the rehabilitation period and in chronic disorders of cerebral circulation, and replenishment of neurotransmitter deficiency seem to be pathogenetically justified. Of undoubted interest are combination drugs that have a complex effect on cerebral hemodynamics and metabolism, while being convenient to use and balanced in composition. One of the sufficiently studied drugs of mixed action, combining vasoactive and metabolic effects, is Instenon (“Nycomed” Austria). The drug is a combination of the cerebral metabolite hexabendine, the central stimulant etamivan and the vasoactive theophylline derivative etophylline [11,19]. This combination provides an effect on both cerebral metabolism and cerebral blood flow [11,20,22]. It is believed that etophylline, having an inhibitory effect on nucleotide phosphodiesterase, promotes the accumulation of cAMP in tissues and normalizes the functioning of membrane ion channels. In addition, some clinical effects of the drug may be due to the ability of etophylline to block adenosine receptors, including those localized in neurons of the central nervous system. In this regard, it is necessary to take into account the presence of etophylline not only vasodilating properties, but also its ability to directly influence brain metabolism. Etophylline, having vasoactive properties in relation to cerebral vessels, does not affect the state of systemic hemodynamics and does not reduce blood pressure, and therefore the risk of side hemodynamic effects of the drug is minimized. This may be important when selecting therapy in patients with severe damage to the vascular system of the brain (hypertensive arteriopathy, stenotic lesions of the main arteries of the head and intracranial arteries), in whom the ability to autoregulate cerebral blood flow is significantly limited [5,19,25,30]. The undoubted advantage of etophylline is its ability to improve bronchial obstruction and increase exercise tolerance due to a positive inotropic effect on the myocardium, which can positively influence the adaptation of patients in neurogeriatric practice [5,11]. Etamivan stimulates the activity of the subcortical formations of the midbrain, excites the respiratory and vasomotor center, has a pronounced activating effect on the limbic system and the reticular formation of the brain stem, as well as the nuclei of the cranial nerves, and primarily the vagus nerve, thus providing a neuroprotective effect. Hexobendine enhances the utilization of glucose and oxygen by activating anaerobic glycolysis and pentose cycles (implemented only under conditions of ischemia and hypoxia, when the aerobic oxidative phosphorylation cycle is disrupted). Stimulation of anaerobic oxidation provides an energy substrate for the synthesis and exchange of mediators and restoration of synaptic transmission, the suppression of which, along with the destruction of neuronal membranes, is the leading pathogenetic mechanism of neurological disorders during hypoxia and cerebral ischemia. In addition, hexobendine stabilizes the physiological mechanisms of autoregulation of cerebral and cardiac blood flow, which is associated with the effect of anaerobic glycolysis products (lactate and pyruvate) on the receptor apparatus of intracranial arterioles and capillaries [1,5,18,26,30]. One of the first studies on the effect of a course of Instenon in elderly patients was conducted more than 35 years ago. An improvement in cognitive function was found after 6 weeks of taking the drug, as evidenced by the results of neuropsychological tests. The use of Instenon contributed to increased mental performance, improved ability to memorize and retain new information in memory. The obtained data on the positive effect of the drug on the state of cognitive functions were then confirmed by the results of a double-blind, placebo-controlled study conducted in a group of patients with chronic cerebrovascular disorders [22]. The restoration of mental performance was accompanied by normalization of spontaneous bioelectrical activity of the brain in the form of an increase in the representation of a- and b-rhythms against the background of a decrease in the power of slow range oscillations [22,26,27]. Subsequently, numerous studies have been devoted to the use of the drug in cerebrovascular diseases and other conditions requiring correction of cerebral blood flow and metabolism, both abroad and in Russia. It should be noted that most of the studies devoted to the study of the clinical effectiveness of Instenon differ in their design from each other, which makes it difficult to conduct a correct meta-analysis of the results obtained [22]. At the same time, the data obtained highly likely indicate that the drug has positive effects combined with good tolerability. As a result of an open non-comparative study of the effectiveness of Instenon in the treatment of patients with dyscirculatory encephalopathy, it was found that a course of use of the drug has a clinically significant effect in the form of improving the ability to remember and concentrate. Moreover, the effect of treatment on the state of cognitive functions was more pronounced than on the degree of clinical neurological disorders. Comparison of the dynamics of the results of neuropsychological tests showed that the drug has a beneficial effect on the memory and motor skills of patients with dyscirculatory encephalopathy. Improving the memorization and reproduction of new information, according to some data, was not associated with the modality of information, but according to other studies, it mainly contributed to the improvement of auditory-verbal memory [11,13,18,23,28,29]. After a 6-week course of treatment, a significant improvement in mnestic functions, thinking, and performance was noted. Instenon caused an improvement in psychomotor functions, a positive effect of the drug on the function of attention was revealed, and the reaction time became shorter [11]. These functions are closely related to the level of involuntary attention. In patients treated with Instenon, according to a neuropsychological examination, there was a significant improvement in orientation and counting on the Brief Mental Status Assessment Scale, conceptualization on the Frontal Dysfunction Rating Scale, and attention on the Mattis scale [11,12]. Later studies demonstrated the effectiveness of Instenon in patients with manifestations of vertebrobasilar insufficiency in the form of reducing the severity of ataxic syndrome and improving walking. During treatment, the intensity of dizziness and noise in the head also decreased. The most significant positive dynamics were noted primarily in relation to subjective symptoms, indicating disorders in the cognitive sphere (decreased memory, increased fatigue when performing mental activity), while no statistically significant effect of the course of treatment on the emotional state of patients was revealed. The drug was noted to be highly effective in patients without a pronounced cognitive defect, in particular, with memory disorders caused by insufficient information processing at the stages of memorization and reproduction due to attention deficit and dysregulation of mnestic activity. A significantly less noticeable positive effect from the use of Instenon was observed in patients with dementia. However, in the majority of patients with vascular dementia and stage III dyscirculatory encephalopathy, the drug also had a positive effect, although a weaker one [3,6]. The positive effect of Instenon therapy on memorization and reproduction did not depend on the modality and was noted in both visual and auditory-verbal memory. At the same time, the results of cognitively complex tests underwent positive dynamics, which indicates Instenon’s ability to influence the most mobile components of cognitive activity, such as the ability to simultaneously solve several problems, resistance to interference, and active search for a memory trace. Thus, in tests with interference, the volume of delayed (after interference) reproduction in a test for learning 10 words significantly increased, while the volume of immediate reproduction remained the same [11]. Similar results were obtained in other studies. According to a clinical and neuropsychological study conducted by L.S. Kruglov, the improvement was manifested mainly by a decrease in fatigue and an increase in mental performance with the simultaneous achievement of greater stability of attention [15]. Thus, Instenon probably acts on memory indirectly, improving attention and the efficiency of information processing during memorization and recall. This may be due to the fact that one of the active components of Instenon, etamivan, enhances the ascending activating influences of the reticular formation of the brain stem [5]. It is known that the activating influences of the reticular formation are one of the main functional mechanisms for ensuring involuntary attention. The beneficial effect of Instenon on concentration is also associated with the impact on the pathogenetic factors of cognitive impairment in DE - impaired cerebral blood flow and metabolism. In this case, the effect of the drug on cerebral metabolism seems to be more important than its vasodilatory effect, since the tone of cerebral vessels depends mainly on local factors, and under conditions of ischemia, the cerebral vessels are apparently already maximally dilated [11,25]. In addition, one should also take into account the effect on the speed of performing intellectual operations of xanthine derivatives, which include theophylline and its derivative etophylline, which is part of Instenon, although the results of studying the cellular mechanisms of action of xanthine derivatives are quite contradictory and require additional clarification [5]. Another cognitive area in which positive dynamics were recorded under the influence of therapy was psychomotor functions. After treatment, the performance of the reciprocal coordination test significantly improved and its speed increased. The beneficial effect of Instenon on the motor abilities of patients is probably based on the same mechanisms as in relation to mnestic disorders. The positive effect of Instenon on motor abilities emphasizes its promise for cognitive impairment associated with chronic cerebrovascular insufficiency, and, possibly, for other diseases that are accompanied by cognitive impairment of the “subcortical” type [3,6]. The effect of Instenon on clinical neurological disorders in the examined patients was significantly less [11,13]. However, for some indicators reflecting ataxic disorders, statistically significant positive dynamics were recorded [3,6,20]. N.Yu. Efimova et al. We assessed the state of cerebral blood flow and cognitive function in patients with coronary heart disease after coronary artery bypass grafting performed under artificial circulation or on a beating heart, as well as studied the possibilities of drug correction of cerebral perfusion disorders and cognitive deficits in this category of patients. The study included 40 patients with coronary heart disease, in 30 of whom surgical myocardial revascularization was performed using artificial circulation. 11 patients in this group were prescribed Instenon to prevent cerebral complications. When performing myocardial revascularization on a beating heart and during drug correction with Instenon, the negative effect of the operation on all types of memory was observed to a lesser extent than in the absence of neuroprotective therapy. In patients receiving Instenon and in those undergoing surgery without cardiac arrest, there was no significant negative effect of coronary artery bypass grafting on cerebral perfusion in the group as a whole [8]. It is of significant clinical and scientific interest to study the effectiveness of Instenon during a long course of treatment. The results of such a study suggest that in this case we can expect a more significant beneficial effect of the drug on neurological disorders, primarily on the symptoms of ataxia, as well as on cognitive disorders [18,20]. In patients suffering from hypertensive encephalopathy, after a course of treatment with Instenon and Actovegin, the clinical manifestations of dyscirculation in the vertebrobasilar region and the frequency of hypertensive crises decreased. Moreover, within 1–2 months after the end of the course of treatment, patients reduced the usual doses of antihypertensive drugs due to the stabilization of the course of hypertension [20]. Experience is accumulating in the use of the drug in urgent conditions. A.A. Skoromets and V.V. Kovalchuk presented data from a retrospective analysis of the treatment of 587 patients who had suffered a stroke in various hospitals in St. Petersburg. Not as often as expected, drugs with neuromodulatory, neurotrophic and neurotransmitter effects were used for ischemic stroke (17.8%). From this group of drugs, Cerebrolysin (24.9%), Actovegin (23.8%), glycine (15.3%), Instenon (13.5%), and gliatilin (11.5%) were prescribed. The degree of functional recovery of patients was assessed using a combination of points scored on the Scandinavian Stroke Scale, Barthel and Lindmark scales. The most effective drugs turned out to be gliatilin, Instenon and Actovegin. The use of these drugs allowed an approximately 2-fold increase in the frequency of minimal functional restoration in initially severe neurological deficits, and one and a half times more often was accompanied by complete or sufficient restoration of lost functions [21]. The main clinical effect of Instenon in ischemic stroke was expressed by an improvement in the emotional-volitional sphere: increased mood, general activation of patients, normalization of appetite. Regression of focal neurological symptoms was minimal and was manifested by a slight decrease in the severity of paresis of the limbs and a decrease in muscle tone (with its initial spasticity). The authors noted that the dynamics of neurological symptoms somewhat prevailed in patients with a focal defect of moderate severity compared to patients with minimal or, on the contrary, severe focal disorders [21]. In case of severe traumatic brain injury, against the background of the combined use of Instenon and Actovegin, a significant decrease in the incidence of acute multiple organ failure syndrome and a decrease in the severity of its manifestation was noted compared with patients in the control group [7]. According to L.Ya. Lifshitz, with mild traumatic brain injury, as a result of treatment with Instenon, the intensity of the headache quickly decreased in patients; By the time the course was completed, the pain had practically disappeared and then did not recur. At the same time, sleep and mood normalized, memory improved, performance increased, and blood pressure stabilized. ECG dynamics indicated a decrease in the degree of myocardial hypoxia and normalization of heart rhythm. A favorable trend was also observed in relation to blood clotting indicators. EEG indicators indicated a positive trend in the organization of electrical activity of the brain, a decrease in desynchronizing influences and the severity of local pathological changes [17]. A parenteral course with high doses of Actovegin and Instenon was administered to 54 patients who were observed in the intensive care unit for ischemic stroke (28 patients), massive blood loss (4 patients), posthypoxic encephalopathy after clinical death (5 patients), shock (5 patients), cranial brain injury (12 patients). The patients reached a higher level of consciousness after a single administration of the pharmacological complex Actovegin + Instenon or by the end of the first day of treatment, which was significantly different from the condition of patients receiving standard therapy. When patients exit from a critical state, a significant activation of the mental sphere was revealed - an increase in memory, concentration, increased performance, and a decrease in anxiety [19]. The long -term combined use of these drugs in the postpartum period in women who have undergone eclampsia allowed to avoid the development of somatic complications and level the consequences of hypoxic encephalopathy [4]. N.N. Yakhno et al. A study of the combination of actovegin and instenon on the parameters of central hemodynamics and the processes of recovery in the heart muscle in patients in the acute period of myocardial infarction was studied. In a group of patients who received a combination of instenon and Actovegin, in comparison with the control group, a more favorable clinical course of the acute period of myocardial infarction was noted: there were practically no manifestations of the early postinfarct angina pectoris, and cases of myocardial infarction relapse were not recorded. With the introduction of Actovegin and Instenon in the acute period, he noted a rapid decrease in subepicardial damage in the first hours after the administration of the drugs. In the group of Actovegin and Inhenon, there was a faster ECG of indicators: the normalization of the ST segment in the most informative abduction was observed on average 24 hours faster than in the control group, and this effect was noted among patients who did not receive thrombolytics. When studying the level of enzymes, it was possible to trace the faster dynamics of the KFK, the normalization of the values of which occurred in the first 4-6 hours from the start of treatment, while in the control group, hyperfermentemia remained for more than 24 hours. The authors of the study believe that a decrease in the level of enzyme for therapy with Actovegin and Instenon may be associated with the direct effect of instenon, "working" in the zone of regional myocardial ischemia and with a direct antioxidant effect of Actovegin [24]. The cardioprotective effect of instenon can be explained by the effect of the hecticated, which stabilizes the physiological mechanisms of auto -regulation of cerebral and cardiac blood flow and helps to activate anaerobic glycolysis in damaged tissue, and vasoactive properties of ethophillin. After the course of instennone of various states, an improvement in cerebral and systemic hemodynamics was noted [5,8,11,11,13,13,14,20,22,23] during the study of systemic hemodynamics, it was revealed that the greatest increase in the values of the indicators of cardiac output (minute volume of blood flow, systolic index) After the course of treatment, it was observed in patients with the initially hypokinetic type of hemodynamics, while the difference in the values of the studied indicators before and after treatment was 1.01 l/min. and 0.57 l/min. respectively. The study of cerebral blood flow in ischemic stroke indicated that the direct administration of Instenu led to a slight increase in blood flow along the internal sleepy and vertebral arteries in patients with ischemic stroke. And when analyzing the results of the terminal use of instenon, a reliable increase in blood flow was revealed by internal sleepy (from 241.6 ± 6.14 ml/min. Up to 263.67 ± 5.12 ml/min.) And vertebrates (from 101.11 ± 10, 12 ml/min. Up to 137.83 ± 7.12 ml/min.) Arteries. According to echocardiography, they studied the indicators of central hemodynamics of 40 patients with hypertension of stage II aged 39 to 62 years: of of the end -system and final -diastolic volume of the left ventricle, shock volume, minute volume, emission fraction, the speed of circular shortening of myocardial fibers. In an acute test with instennone, the stroke volume, minute volume and ejection fraction have not changed significantly, which indicates the absence of a significant effect of the drug on central hemodynamics [20]. The favorable effect of instenon with discirculatory encephalopathy is manifested by both clinical improvement and the normalization of electroencephalographic indicators [5,14,16,26]. Correction of changes in the bioelectric activity of the brain consists primarily in a decrease in the amount of slow -wave activity of T- and D - DAPASON and the normalization of the indicators of the A -rhythm. Improving the indicators of the A - was observed both in the background EEG and during the period of rhythmic photostimulation and hyperventilation [16]. After treatment, the range of assimilation of rhythms was expanded during rhythmic photostimulation [14]. In patients with focal disorders, a decrease in their severity was recorded. The deterioration of the bioelectric activity of the brain was not observed after treatment with instennone. When evaluating the data of biomicroscopy, conjunctiva in patients with mixed (diabetic and vascular) encephalopathy after treatment with instenon, positive dynamics were noted. Against the background of treatment, a decrease in the indicator of the average conjunctival index was observed: from 18.32 ± 0.64 to 17.37 ± 0.70 after treatment [14]. In patients with acinetic -trigidal syndrome, the use of instenon in all observed cases revealed a noticeable improvement in the form of reducing stiffness, expansion of the volume of movements, partial regression of extrapyramidal muscle rigidity, and an improvement in the state of emotional -volitional sphere and intellectual -modest functions. The appointment of instenon for 45 days in patients in the initial stages of parkinsonism made it possible to achieve a statistically significant decrease in the number of points on the UPDRS scale. The positive impact of the exchange rate of instenon should first be noted in relation to bradykinesia, increased performance, reduction of stiffness, noticeable improvement in the emotional -volitional sphere [25]. There is data on the use of instenon in psycho -organic syndrome in the framework of various diseases [2.9,10,12,15,28]. The drug was especially effective when stopping cephalgia in the structure of these conditions [9]. According to the study of 37 patients with the formed alcohol dependence, which were at the stage of attenuation of acute withdrawal phenomena, under the influence of instenon decreased the severity of affective, astheno -neurotic and cephalgic disorders by the end of the 3rd week of treatment [9]. The use of instenon has broad prospects in children's neuropsychiatry, and above all in the treatment of minimal brain dysfunction. The high efficiency of instenon in the treatment of minimum brain dysfunction and the consequences of closed cranium -brain injury in children is indicated [2.10]. Apparently, it is advisable to conduct individual studies aimed at assessing the effect of the drug on speech functions and readers of reading, writing and accounts in children with a delay in speech development using special testing methods [10]. Studies in this direction are also very relevant due to the fact that the traditional use of psychostimulants and antidepressants in children's neuropsychiatric practice often causes serious side effects. Against the background of the treatment of instenon in children, there was a noticeable improvement in neuropsychological indicators in the field of arbitrary regulation of activity, general performance, attention and memory [2]. If the child had modal -specific disorders, such as defects in auditory or visual perception, kinesthetic or kinetic praxis, perceptual spatial sphere, etc., then there was no distinct dynamics against the background of treatment. An improvement in emotional and behavioral characteristics was revealed: against the background of treatment in children, social activity increased, interest in learning appeared, the mood improved, which contributed to their general social adaptation. It should be noted that the greatest positive dynamics of EEG indicators was observed in children with attention deficit syndrome and hyperactivity. At the same time, it was in this group of children in some cases that an undesirable side effect was noted in the form of increased hyperactivity. At the same time, however, cognitive functions and the ability to concentrate attention have always been improved [2]. In all patients with depressive states of various genes, Inhenon was effectively combined with antidepressants (amitriptylin, Nordriciptillin, Trittico, Lerivon, etc.). O.A. Balunov et al. It is noted that in all patients taking the therapy with instenon and antidepressants, the weakening of the severity of the symptoms occurred after 5-7 days. Supporting treatment with antidepressants turned out to be sufficient for 2 weeks instead of a traditionally recognized 4-6 - weekly use of the drug [1]. There are no significant adverse reactions against the background of instenon therapy in most studies. Given the possible synchronizing effect of instenon on spontaneous bioelectric activity of the brain, the drug should be used with caution in patients with the initially high power of the EEG spectrum, with signs of bilateral -synchronous activity. Inhenon, unlike other drugs that improve brain activity, does not worsen sleep, although some of the patients were forced to take an evening dose of the drug no later than five o’clock in the evening. At the same time, instenon therapy did not have a statistically significant effect on the symptoms associated with the emotional state of patients, such as headache and sleep disturbance [11]. V.A. Yavorskaya et al. indicate the possibility of headaches and a sense of discomfort in patients with changes in external respiration according to the type of hyperventilation, which the authors associate with the exciting effect of the drug on the respiratory center. According to other sources, in almost half of the patients, the first 2-3 infusions were accompanied, although short (not more than 1-3 hours), but a clear cephalgic syndrome, which was explained by the rapid administration of the drug [20]. Thus, indications for the prescription of combined drugs that improve brain bloodstream and metabolism are very diverse - in addition to vascular diseases of the brain, it is acute stage and consequences of cranial -brain injury, coma of various genes, dementia in alzheimer's disease and alcoholism, encephalopathy of various genesis, and encephalopathy, and cranial conditions. Surgical heart interventions and, presumably, cerebral vessels. Inhenon has demonstrated its effectiveness in a number of studies on the treatment of these conditions, and can be considered as one of the drugs of choice. Literature 1. Balunov O.A., Yankovskaya E.M. et al. Inhenon in patients with the consequences of cerebral stroke and discirculatory encephalopathy. // ed.: Dep. rehabilitation neurol. patients with research institutes to them. V.M.Bereva, S.-Pb./www.medlibary.ru/library/?rubric_id=93 - 87k. 2. Bikshaeva Ya.B. 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