Nootropics in Comlex Therapy of Chronic Cerebral Ischemia
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Science and Innovation. 2014. V. 10. No. 4. P. 56—68 Chekman1, I.S., Belenichev 2, I.F., Demchenko 2, A.V., Bobrova 3, V.I., Kucherenko1, L.I., Gorchakova 2, N.A., and Bukhtiyarova 2, N.V. 1 O.O. Bogomolets National Medical University, Kyiv 2 Zaporizhia State Medical University, Zaporizhia 3 P.L. Shupyk National Medical Academy of Postgraduate Education, Kyiv NOOTROPICS IN COMLEX THERAPY OF CHRONIC CEREBRAL ISCHEMIA The clinical and pharmacological characteristics of nootropics as one of the most effective groups of neuropsychotropic drugs have been considered. The nootropics has been classified by the principal mechanism of action. The examples of clinical use of drugs on patients with chronic cerebral ischemia have been given. Key words: cerebrovascular diseases, cognitive disorders, neuroprotection, and nootropics. Today, cerebrovascular disease (CVD) is one Chronic cerebral blood circulation failure that of the most important problems of modern medi- in the Soviet literature and clinical practice is re- cine in the view of its widespread occurrence, ferred to «discirculatory encephalopathy» (DE) high mortality or disability caused by it, and sig- has a significant share in the structure of brain nificant financial costs for its treatment and pre- vascular diseases [7]. Discirculatory encephalop- vention [1, 2]. In advanced economies, mortality athy is a syndrome of multiple-lesion brain affec- from cardiovascular diseases continues to range tion as a result of chronic cerebral vascular failure from 12 to 15% of the overall mortality [3]. Ac- and/or repeated episodes of acute cerebrovascu- cording to the statistical forecast, in 2020, it will lar accidents (venous insufficiency, transient reach 25 million cases annually [4]. In Ukraine, ischemic attack, and stroke). The disease is char- CVDs are ranked the second or the third by inci- acterized by a slow progressive course and pro- dence and by mortality among this class of dis- gressive brain function disorder [8]. eases [2]. In 2000—2010, in Ukraine, the number The most common causes of brain circulatory of stroke cases increased 1.6 times, while the total disorders are hypertension, atherosclerosis, cere- number of all CVDs grew from 3.4 to 4.5% [5]. bral arteries, diabetes, and heart disease with a This implies the relevance of pharmacological high risk of thromboembolism into the brain. In correction of cerebral blood circulation failure, as more seldom cases the cerebral circulation disor- well as the importance of means of prevention or ders develop as a result of inflammatory changes in treatment of brain vascular pathology, soma- blood vessels (vasculitis), blood coagulation disor- tovegetative and psychopathologic failures, and ders, abnormalities of vascular development, etc. personal reactions to the disease [6]. In most cases, the cerebral vascular insufficiency develops in the elderly [7, 9]. Stroke and DE can be considered to be two cerebrovascular syn- © CHEKMAN, I.S., BELENICHEV, I.F., DEMCHENKO, A.V., BOBROVA, V.I., KUCHERENKO, L.I., GORCHAKOVA, N.A., dromes which can be a manifestation of the same and BUKHTIYAROVA, N.V., 2014 disease [10]. However, it should be noted that in 56 The World of Innovations most cases, stroke is a result of affection of large of immune changes, and initiation of neuroapop- cerebral arteries (especially, their atherosclerosis), tosis as a consequence of formation of persistent while DE is often caused affection of small cerebral cognitive deficit [21]. vessels (cerebral microangiopathy) [11, 12]. The DE morphological substrate is character- Along with focal neurological symptoms the ized by small focal and diffuse changes in the clinical course of chronic cerebrovascular insuf- white matter of brain, hippocampal sclerosis, as ficiency includes cognitive impairment to which well as by phenomena of secondary cerebral atro- attention has been paid in the last decade because phy [11, 14, 22, and 23]. of its widespread occurrence [13, 14, 15, and 16]. The modern medical science advances thanks In the case of CVS, cognitive impairment has a to the use of new highly effective pharmacologi- progressive character and at some point reaches cal agents having a pronounced therapeutic effect the severity of dementia [13, 17]. Vascular de- of CVD. The introduction of new classes of phar- mentia is one of the most serious complications of macological agents acting at different stages of unfavorable course of cerebral vascular insuffi- pathogenesis and optimizing cerebral metabolism ciency. According to statistics, vascular etiology makes it possible to suspend CVD progression [6, underlies, at least, 10—15% of dementia cases in 24, 25, and 26]. Therefore, the application of neu- the elderly [18]. However, in recent years, on both roprotective agents which combines antioxidant, domestic and foreign publications the emphasis anti-ischemic, and nootropic properties are very in clinical research increasingly shifts from iden- relevant [20, 27]. tifying and studying the existing dementia to- The concept of pharmacotherapeutic neuropro- wards the pre-dementia stages of neurogeriatric tection makes it possible to distinguish two main diseases when the therapeutic cure can be more trends. The primary neuroprotection is for inter- effective and able to prevent or significantly defer rupting fast mechanisms of cell necrotic death, i.e. the social maladjustment [19]. the reactions of calcium glutamate cascade (an- Impaired cognitive and associative functions tagonists of NMDA- and AMPA-receptors and under the conditions of cerebral pathologies oc- calcium channel blockers: Remacemide, Rilutek, cur against the background of severe structural Nimotop, etc.) [28]. The secondary neuroprotec- changes of brain cells as a result of inhibition of tion is aimed at reducing the severity of late is- bioenergetic processes, development of glutamate chemia effects: the blockade of pro-inflammatory excitotoxicity, overproduction of reactive oxygen cytokines, adhesion of cell molecules, inhibition of species (ROS), deactivation of antioxidant sys- oxidative stress, normalization of neurometabolic tems, and activation of apoptosis [20]. The energy process, inhibition of apoptosis, and reduction of deficit initiating a glutamate-calcium cascade, i.e. cognitive deficit (antioxidants, antihypoxants, me- the release of aminoacidergic excitatory neuro- tabolitotropic drugs, nootropics: Emoxipin, Thiot- transmitters, aspartate and glutamate, and the riazoline, Glycine, Piracetam, Thiocetam, Citi co- intracellular accumulation of Ca2+ is a trigger link line, Cerebrolysin, Cortexin, Cerebrocurin, etc.) of ischemic death of neuronal cell. The processes [29, 30]. Nootropics are the most important means beginning at the early hours of hemorrhage and of secondary neuroprotection. underlying the glutamate-calcium cascade (chan- Nootropics formed a separate group in the early ges in the metabolism of glutamate and calcium, 1980s, when after successful application of the first oxidative stress, and overproduction of NO•) in- drug in this class, piracetam (nootropil), ot her duce long-term effects of ischemia. This is a reac- pyrrolidone derivatives appeared. Previo usly, in tion of genome with the launch of genetically the late 1960s, gamma amino butyric acid GA BA programmed molecular mechanisms, dysfunction (Gammalon, Aminalon) was used as a means of of astrocytic and microglial pools, development improving mnemonic processes. According to Science and Innovation. V. 10, no. 4, 2014 57 The World of Innovations WHO, the group of nootropics includes medicines eral classifications of nootropics. Below, the classifi- that directly activate the cognitive processes, im- cation by the principal mechanism of action is given. prove the memory and mental activity, as well as raise the brain resistance to aggressive factors. CLASSIFICATION OF NOOTROPICS Three decades hence the introduction of neuro- In clinical practice, these drugs are classified tropic drugs into clinical practice for regulation of into two major groups: nootropics of direct ac- memory processes they have become the most tion (cognitive enhancers) and neuroprotective commonly used medical drugs. Moreover, noot- agents [31, 32]: ropics gained a wide popularity not only in neu- I. Cognitive enhancers or «true» nootropics: rology and psychiatry, but also in other areas of 1. Pyrrolidone nootropics (racetams) with pre- the hospital and ambulatory pharmacotherapy. dominant metabolite action: Piracetam, Fenotro- Nootropics regulate higher mental processes in pil combined racetams (Thiocetam, Olatropil, and humans, such as cognitive functions and cognitive Phezam). abilities (education) due to modulating the mem- 2. Cholinergic agents: enhancers of synthesis and ory rate and reliability of storage of information release of acetylcholine (Phosphatidylserine, leci- received (introduced). At the same time, they thin, Citicoline); cholinergic receptor agonists (Oxo- change the ability to improve the reproduction tremorine, Bethanechol); and acetylcholi nes terase of already existing, i.e. stored information, or, inhibitors (Physostigmine, Galantha mine, etc.) conversely, to worsen the extraction of data from 3. Neuropeptides and neurotrophic cerebroprotec- memory and to forget unnecessary information tors: Semax, Cerebrolysin, Cortexin, Cerebrocu rin. (e.g., memories of pain during the surgery, stress- 4. Modulators of glutamatergic system: a) low- ful experiences in disasters, etc.). The modulation affinity NMDA receptor polyamine