DISCIRCULATORY ENCEPHALOPATHY: THE CAPABILITIES OF MODERN DRUG TREATMENT

     Cerebrovascular pathology is now the third leading cause of death and a major cause of disability in most countries. WHO predicts in the near future further growth due to the aging population and the prevalence rates of hypertension, diabetes, hypercholesterolemia, obesity, etc. In 2005 in Ukraine are more than 3 million patients with cerebrovascular disease, i.e. 6.4% of the population [1, 2]. What are the ways of preventing and treating these changes and what may in this respect modern medication? And what are the dangers of the use of vasoactive drugs and pharmacological methods of "rejuvenation"?

     Discirculatory encephalopathy (DEP) is the most common diagnosis in clinical practice, chronic ischemic which implies microfocal progressive brain damage. The term was coined G.A. Maksudov and V.M. Kogan in 1958 (according to other sources - E. Schmidt and G. Maksudov in the 70-s of the last century), and is traditionally used in the CIS countries, despite the fact that is not represented in the ICD-10. In English literature, especially in the United States, this state corresponds as subcortical arteriosclerotic encephalopathy (SAE), Binswanger's encephalopathy, multi-infarct dementia (Binswanger's type), subcortical dementia, vascular dementia (Binswanger's type), subcortical ischemic vascular disease and others (chronic cerebrovascular insufficiency, chronic cerebrovascular insufficiency, ischemic disease of the brain, etc).The vast majority (96%) was chronic ischemic – DEP.  [1, 3].

     Etiopathogenesis. Immediate causes DEP - is cerebral atherosclerosis, diabetic angiopathy, cerebral and cardiac pathology, blood diseases, systemic vasculitis, etc. However, leading, according to experts, is a long-existing hypertension, leading eventually to the development of lacunar infarcts of the brain tissue, often occurring mono- or asymptomatic. You could say that DEP - is the result of a slowly progressive disease of blood supply due to stenosis or obliteration of small intracranial atherosclerotic arteries. This process leads to the development of primary (acute, recurrent) and secondary changes in the brain substance. On the main reasons are the following types dyscirculatory encephalopathy: 1) atherosclerotic (often suffer great vessels of the head), 2) hypertensive, 3) mixed and 4) venous. In general, it could be a specific disease or a combination thereof (vegetative dystonia, rheumatism, vascular lesions with vasculitis and trauma, systemic hemodynamic disorders, blood disorders, etc.). Damage taking place in the white matter of nerve fibers leads to dissociation of the functions of the cortex and underlying structures, which results in the clinical manifestations of DEP. Almost half of all cases of disease detected in people of working age, although its frequency increases with age [2, 4].

     Development of DEP, in addition to the above common causes also contribute to certain factors: smoking, alcohol, various stressful situations. It is noted that the pathology is more common in people intellectuals (teachers, scientists, artists). Clinical manifestations of the disease worsen diseases of the spine (low back pain, spondylosis, etc.) and iatrogenic effects (an inadequate manipulation and improving physical education). A role in this is, according to most experts, and inadequate designation and mode of application of some popular nootropic and vasoactive drugs [5, 6].

DEP is inherently heterogeneous and depends on the state of the summation of many of these causes. But if it has more often multifocal nature of neurological signs and the obligatory presence of cognitive impairment - memory loss, impaired concentration, which result in the initial stages of mental decline and physical productivity.

     The clinical picture of DEP depends on the stage, directly connects with the degree of brain tissue damage. The first is characterized mainly subjective dissatisfaction: fatigue, headaches, irritability, mild sleep disturbances, decreased performance and moderate disorders of memory. The second stage shows DEP exacerbate disorders of memory, attention and coordination. The clinical picture is often dominated by asthenic disorders, and neurological examination may reveal significant intellectual and emotional disturbances. The patient, on the background of small focal neurological symptoms are often formed one of the characteristic syndrome (vestibular-atactic, psychopathological, amyostatic, dismnestic etc.). In the third stage of the disease there is poor judgment to his condition, which leads to a decrease in complaints. The clinical picture of growing intellectual-mental, coordination, psycho-organic disorders. Often there is unsteady gait, fainting. The survey reveals the availability of the complete neurological syndromes. At this stage patients often need help. Many developing major depression and dementia is formed.

In different stages of DEP, to the damage of cognitive and psychomotor functions, marked certain personality changes - varying degrees of disinhibition, conflict, increased aggression, affective lability. Patients suffer from headaches, hearing loss, tinnitus, visual disturbances (the emergence of "spots" field of view, blurred vision), etc. Many patients lose of interest in life.

     The stage and objective assessment of an individual symptom with DEP is possible, of course, only a neurological examination. At the same time, experts say the trend of the uncontrolled use of drugs for the treatment of DEP other physicians (most therapists). This is largely due to the myth of the "safety" of the treatment, based on a fairly superficial acquaintance with the pharmacology of vasoactive and neuroprotective drugs. In fact, however inadequate therapy, as noted above, can worsen DEP, especially for applications in elderly patients with concomitant diseases [4, 7].

     Diagnostics. When DEP arise, as a rule, presented three major neurological syndromes: 1) amyostatic (akinetic-rigid), 2) dyscoordinant and 3) pyramidal. An important addition to neurological examination and testing of target organs (ECG, Doppler of cervical vessels, etc.) in the diagnosis of DEP is an MRT of the brain. It allows you to verify the postischemic lesions, their number and location, severity of periventricular white matter changes (leukoaraiosis), the expansion of the ventricular system of the brain, etc. Required experimental psychological examination of patients can objectify the information available, the nature and extent of cognitive impairment. That, in general, and allows you to assign adequate medical treatment.

     Treatment of patients with DEP is complex and usually involves vasoactive, nootropic and neurometabolic therapy. In general, therapy can be represented by the following trends:

1. Improved circulation of the brain;

2. Correction of lipid metabolism, diet;

3. Relief of hypertension;

4. Treatment of concomitant diseases that affect the brain blood flow;

5. Physical therapy, chiropractic and acupuncture, cryotherapy, etc.

     Important to begin treatment at the earliest stages, as in these cases, you can expect a marked therapeutic effect. The main directions of drug therapy determined by the nature of the vascular process, which caused the cerebrovascular disease and must take place against the background normalization lifestyle and avoid risk factors (smoking cessation, diet correction, optimal physical activity, treatment of opportunistic infections). Of particular importance is the strict control of blood pressure levels. Treatment of hypertension is conducted according to generally accepted principles (diuretics, ACE inhibitors, calcium channel blockers and β-blockers). Recommended additional use antiplatelet (dipyridamole, clopidogrel, ticlopidine, aspirin) [8, 9].

Undisputed leader of specific therapy of DEP acts Vinpocetine (Cavinton, Bravinton, Vitsebrol) as most efficient and - more importantly - the safest drug to date, combining a vaso- and nootropic effects. Its mechanism of action on the function of the central nervous system is associated with inhibition of phosphodiesterase, an increase of cyclic AMP in the cells of the central nervous system, decrease platelet aggregation, normalization of the venous outflow resistance against decrease in cerebral vessels mainly in the ischemic areas. The clinical effect of vinpocetine at DEP, according to the literature, consisted of short-term memory disorders regression, as well as manifestations cephalgic and asthenic syndrome, relieving dizziness, asthenia and dissomnia disorders, increase intellectual productivity [1, 8, 10].

     In general, is well tolerated, low incidence of side effects (up to 2.5% of the tablet and less than 5% - injection). Among these reactions were observed: transient hypotension, headache, dizziness, dyspeptic reaction, tachycardia, extrasystoles. It should also be aware of the impossibility of its parenteral heparin. However, as the analysis of publications, such frequency of adverse reactions only applies to the original drug (Cavinton) and it is much larger and more significant in its generic [5, 11, 12] (see table).

     Nicergoline (Sermion, Nicerium) also combines vasotropic and nootropic mechanisms of action. Has spasmolytic activity, particularly pronounced in respect of the brain and peripheral vessels, which to some extent due to the presence in the molecule of nicotinic acid residue. In addition to the elimination of the typical symptoms of cerebrovascular insufficiency (headache, tinnitus, dizziness, etc.), normalizes cognitive disorders, emotional lability, insomnia, eliminate depression and anxiety. The drug affects the efficient initial manifestations of cerebrovascular insufficiency and almost no effect on the focal symptoms.

     Like most dihydrogenated derivatives of ergot alkaloids (dihydroergotamine, etc.), nicergoline has a strong α-adrenoceptor blocking action. And it raises its characteristic side effects: flushing, transient erythema, tachycardia, orthostatic hypotension, etc. Less commonly dizziness, headache, insomnia and dyspepsia associated with increased gastric secretion. Nicergoline increase in myocardial oxygen demand with a corresponding history may exacerbate angina or arrhythmia. Requires caution when used in patients older than 65 years, as well as in combination with antihypertensives and anticoagulants [6, 12, 13]. During treatment with nicergoline prohibited the use of alcohol and narcotic.

     For treatment of DEP are widely used calcium channel blockers slow, selectively affecting the blood vessels of the brain. This, above all, Nimodipine (Nimotop, Nemotan, Vasocor), in much the same the effect on cerebral blood flow to the two previous preparations. By inhibiting the effects of serotonin, catecholamines, histamine and thromboxane, the drug increases cerebral blood flow and has a protective effect on ischemic regions of brain. Treatment in clinical trials, gives a noticeable decrease cerebral symptoms and disorders of the mind. However, the regression of scattered organic symptoms it usually does not happen.

     The drug can not be combined with certain antiepileptic drugs (phenobarbital, phenytoin, carbamazepine). Are rare side effects are as facial flushing, hot flashes, headaches. In addition, the possible development of hypotension, erythema, and fluctuations in heart rate, overstimulation of the central nervous system symptoms (physical activity, aggressiveness). Risk of such side effects - up to the development of symptoms of heart failure - increases dramatically when used with antihypertensives, nitrates, β-blockers [4, 6]. To a certain extent this is true of other blockers of A group - Amlodipine and Isradipine. At the same time, the first of them - amlodipine - by blocking the smooth muscle spasm of cerebral vessels has a more prolonged dose-dependent antihypertensive effect is more pronounced vasodilator effect and reduces the load on the myocardium, reducing its need for oxygen.

     From calcium channel blockers of B group in the treatment DEP widely used Cinnarizine (Stugeron) and Flunarizine (Sibelium) possessing antihistaminic, antiarrhythmic and anticonvulsant activity, anti-vasoconstrictive and antianginal effects. Because of the ability to reduce the excitability of the vestibular apparatus used for the treatment of vascular disorders with this type of violation. Flunarizine has some larger affinity direct effect on brain blood vessels and works lasts longer, and cinnarizine additionally has a moderate positive effect on the rheological parameters of blood. Drugs are well tolerated, but may cause side effects: dry mouth, drowsiness, gastrointestinal disturbances, dizziness. In a certain percentage of cases can provoke extrapyramidal disorders. Moreover, according to some research data, cinnarizine induced parkinsonism is not less than 43% of all cases of drug-dependent parkinsonism. Complications are associated with long-term blockade of dopamine receptors and the decreased activity of tyrosine hydroxylase. This phenomenon has a clear dependence on age and duration of drug administration, covering in some categories more than half of patients. In addition, cinnarizine can trigger depression, further aggravating the clinical manifestations of DEP, especially in elderly and senile patients [2, 14, 15]. Antihistamine properties of the drug makes it incompatible with the work that requires special attention, alcohol, sleeping pills and neurotropic means [12] (see table).

     In the treatment of DEP widely used nootropic drugs, due to their neuroprotective and antihypoxic properties. Their effect is to improve thinking, attention, memory, speech, ability to learn. It is often used in practice this type of drug include Piracetam, Aminalon, B​aclofen (Lioresal) Pantogram, Pyritinol (Encephabol) and Acefen.

     Piracetam (Nootropil, Lucet, Nootobril) activates the redox processes of the cerebral cortex, increasing its resistance to hypoxia, improves cerebral blood flow and increases the synthesis of RNA. Improving hemispheric relations and synaptic conduction in neocortical structures in patients with DEP gives regression of encephalasthenia’s symptoms, increases intellectual activity, improves mood, memory, and speeds up recovery of disturbed functions. Although the possible side effects in most cases are not common, at the same time in the literature indicates that the use of the recommended therapeutic doses (more than 2.4 g / day) in many groups of patients, particularly the elderly, are able to significantly increase. These side effects include: induced anxiety, irritability, anxiety and aggression, sleep disturbances, rarely - dizziness, tremor, dyspeptic symptoms (nausea, diarrhea, abdominal pain), allergic skin reactions. In some cases, the same elderly patients may increase the expression of coronary disease, which should be considered as a serious risk of drug therapy in geriatric patients [6, 7, 16].

     Aminalon (Noofen, Pantocalcin, Picamilon, Gammalon) improves cerebral blood circulation, reduces vestibular disorders, increases energy processes. Effective in the cerebral circulation violations, including the DEP. Relatively rare side effects are nausea, vomiting, hot flashes, sleep disturbances, but at the beginning of treatment may also occur pronounced lability of blood pressure. That can provoke unjustified appointment of antihypertensive drugs. Keep in mind that aminalon enhances the effects of benzodiazepine anxiolytics, hypnotics and anticonvulsants, which leads to excessive CNS depression [4, 12].

     Pyritinol (Encephabol, Encefabol, Cerbon 6, Enerbol, Piritinol, Piritioxine) activates the energy metabolism of the brain, enhances the activity of the limbic system and the synthesis of ATP and creatine phosphate, alters the permeability of cell membranes. Leads to increased levels of acetylcholine in the cerebral cortex, an increase in sensitivity of postsynaptic acetylcholinergic membranes prevents neuronal death. Neuroprotective effect is associated with the stabilization of the cell membranes of neurons, reducing the amount of free radicals. Especially effective in asthenic-depressive, asthenic-apathetic states accompanying DEP, shallow depressions and encephalasthenia. Low toxic, but long-term usage may cause insomnia, irritability, nausea, irritability, headache. Contraindicated at psychomotor agitation, convulsions, epilepsy. Potentiates the action of barbiturates, amphetamines, antiepileptic drugs [12, 16].

     With the object of unite vasoactive and nootropic effects, which is especially important in patients with DEP, the pharmaceutical market has offer a combination of drugs piracetam and cinnarizine (Piracizin, Cisam, Noozam, Cinatropil, Neuro Norm, Fezam). Other combinations with piracetam include Olatropil and Tiocetam.

     Modern ideas about the features of cerebral ischemia resulted in widespread use in the treatment of DEP neurotrophic peptide drug filling deficit activating neurotransmitter, activating repair mechanisms (Cerebrolysin, Gliatilin, Cerepro, Deltaran, Carnitine and others). Although many of them have virtually no side effects, these drugs make demands higher requirements for technically correct parenteral administration to avoid possible negative action. Thus, with the rapid intravenous introduction can occur expressed hyper-ergic reaction, sometimes with vertigo and arrhythmia [12, 15].

     Ginkgo biloba preparations (Ginkgo, Ginkgo Extract, Ginkgo Folium, Giloba, Memoplant, Tanakan, Ginkogink, Ginkofar) - is phyto-pharmaceutical drugs for effective treatment of various forms of cognitive impairment, including those with DEP. They normalize metabolism in cells of the CNS, and blood rheology and microcirculation. In addition to improving cerebral blood flow and delivery of oxygen and glucose to the brain, there is stimulation of the synthesis of endothelium dependent relaxation factor (nitric oxide), the tone of the veins, reduced vascular permeability (anti-edema effect - both at the level of the brain and peripheral). Have antithrombotic effect (due to stabilization of the membranes of platelets and red blood cells, the effects on the synthesis of prostaglandins, reducing action of biologically active substances and platelet-activating factor). Prevent the formation of free radicals and lipid peroxidation of cell membranes. Normalize the release, re-uptake and catabolism of neurotransmitters (norepinephrine, dopamine, acetylcholine) and their ability to connect with the receptors. Have the least side effects. However, a crucial role in the safety of these drugs is purification plant material. It is known that, along with rare cases of headache and dyspepsia, some preparations of ginkgo can be potentially dangerous hemorrhagic effect due to the presence of undesirable components of these impurities - ginkgo acids [6, 17].

     In conclusion, it should be noted that the tactics of drug treatment in patients with DEP requires an individual approach with the mechanisms of disease development and the nature of the main clinical manifestations. The goal of therapy should be to improve the quality of life of patients and the prevention of complications and side effects, including caused by drug therapy. In this regard, preparations with vasotropic properties, along with increased responsibility for their intended strictly on the evidence must be used with caution in case of:

• severe (acute or chronic) cardiac pathology;

• clinically significant psychiatric symptoms;

• abnormalities blood clotting;

• in polypharmacy.

REFERENCES

1. Гераскина Л. А., Суслина З. А., Фонякин А. В., Шарыпова Т. Н. Церебральная перфузия у больных артериальной гипертонией и с хроническими формами сосудистой патологии головного мозга // Терапевтический архив. – №12. – 2003. – С.32-35
2. Коркушко О.В., Лишневская В.Ю., Чижова В.П. Роль системы микроциркуляции в развитии тканевой гипоксии у людей пожилого возраста // Фізіол. журн. — 2002. — т.48, № 2. — С. 145-147
3. Мищенко Т.С., Шестопалова Л.Ф. Дисциркуляторная энцефалопатия: современные взгляды на патогенез и диагностику // Здоров'я України. – №№15-16, август 2006
4. Кузьменко В.М. Распространенность и некоторые особенности профилактики цереброваскулярных заболеваний у лиц разного возраста // Пробл. старения и долголетия. – 2001. — т.10, № 4. — С. 401-409
5. Бурчинский С.Г. Опасности и риски ноотропной фармакотерапии: миф или реальность? // Рациональная фармакотерапия. – 2007. – № 2. – С.1-5.
6. Штрыголь С.Ю., Кортунова Т.В., Штрыголь Д.В. Побочные эффекты ноотропных средств // Провизор. – 2003. – № 11.
7. Winblad B. Piracetam: a review of pharmacological properties and clinical use. CNS Drug Rev 2005; 11: 169-182
8. Мультифокальная моторная невропатия /Ю.В.Мозолевский, Л.Т.Ахмеджанова, Л.Ф.Касаткина, Самойлов М.И. //Неврологический журнал. -2007. -N3. -C.32-36
9. Крыжановский Г.Н., Карабань И.Н., Магаева С.В. и др. Болезнь Паркинсона. — М. : Медицина, 2002. — 335 с.
10. Wesnes K.A, Harrison J.E. The evaluation of cognitive function in the dementias: methodological and regulatory considerations // Dialogues Clin. Neurosci. — 2003. — v.5. — P. 77-88.
11. Камчатнов П.Р. Диагностика и лечение вертебрально-базилярной недостаточности //Российский медицинский журнал. -2007. -N2. -C.49-53  
12. Компендиум 2006. – Т. I II. – К.: Морион, 2006.
13. Елагин Р.И. Адренергические средства. Альфа адреноблокаторы // Consilium Provisorum. – 2003. – Т. 3. – № 7.
14. WHO information. Calcium channel blockers and Parkinson’s disease. DRUGINFORM 2002; 23 (4): 27 29
15. Пирожков С.И., Сафарова Г.Л. Тенденции старения населения России и Украины: демографические аспекты // Успехи геронтол. — 2000. — № 4. — С. 14-21.
16. Аведисова А.С., Ахапкин Р.В., Ахапкина В.И., Вериго Н.И. Анализ зарубежных исследований ноотропных препаратов (на примере пирацетама) // Рос. психиатр. журн. – 2001. – № 1. – С. 46-53
17. Астахова А.В. Побочные эффекты компонентов БАД. Предостережения в отношении их использования в пред  и послеоперационном периодах // Безопасность лекарств. Экспресс информация. – 2002. – С. 16-23