Cerebroprotective
effect of Quercetin in the treatment of patients with ischemic stroke in an
acute period.
Dobrovolskyi Vasyl,
MD, PhD; Lebed Olena, MD, PhD; Perkova Ganna, MD, PhD; Varbanets Olena, MD, PhD., Kolesnyk Olena, MD.
Department of Neurology, Odessa National Medical
University, Odessa, Ukraine.
ЦЕРЕБРОПРОТЕКТИВНЫЙ
ЭФФЕКТ КВЕРЦЕТИНА В ЛЕЧЕНИИ ПАЦИЕНТОВ С ИШЕМИЧКЕСКИМ ИНСУЛЬТОМ В ОСТРЫЙ ПЕРИОД.
Добровольский Василий, к.мед.н., Лебедь Елена, к.мед.н.,
Перькова Анна, к.мед.н., Варбанец Елена, к.мед.н., Колесник Олена.
Кафедра
неврологии Одесского Национального Медицинского Университета, Одесса, Украина.
Abstract
Objective - to
study cerebroprotective effect of quercetin in ischemia/reperfusion injury in
acute ischemic stroke. The study included 98 patients with acute ischemic
stroke. All patients: main and control group, received standard treatment in
accordance with the clinical protocol order Ministry of Health of Ukraine from
03.08.2012, № 602. Patients of the main group (n=68) on the back of the base
further treatment was administered Quercetin (Corvitin lyophilisate
injection solution)
course of 10 days according to the scheme: 500 mg of the drug diluted in 100 ml
of 0.9% of the physiological solution intravenously twice a day for the first
five days and once a day for the next five days. Patients in the control
group (n=30) - quercetin is not appointed. Assessment by GCS, NIHSS, Barthel
served in the 1st, 3rd, 5th, 10th day of the disease. Simultaneous with
standard treatment, the intravenous administration of Quercetin has a positive
effect on the regression of focal neurological symptoms according to the NIHSS
score and the Barthel index in patients in the acute period of ischemic stroke
and allows an increase in the proportion of patients in the mind or mild
impairment on the Glasgow coma scale, earlier "awakening" in the
acute period of ischemic stroke. Cerebroprotective effect of Quercetin (Corvitin lyophilisate injection solution) can be explained by its
polytropic, antioxidant, anti-inflammatory, membrane-stabilizing effect in
ischemia/reperfusion.
Аннотация
Цель - изучение церебропротективного эффекта
кверцетина в условиях ишемии/реперфузии при остром ишемическом инсульте. Обследовано
98 пациентов в остром периоде ишемического инсульта. Все пациенты: основная и
контрольная группы, получали стандартное лечение в соответствии с клиническим
протоколом МОЗ Украины от 03.08.2012 г. № 602. Пациентам основной группы (n=68) дополнительно назначали кверцетин (корвитин,
лиофилизированный инъекционный раствор) в течение 10 дней по схеме: 500 мг
препарата, разведенного в 100 мл 0,9% физиологического раствора внутривенно два
раза в день в течение первых пяти дней и один раз в день в течение следующих
пяти дней. Пациенты в контрольной группе (n=30) - кверцетин не получали. Оценку по шкалам ком
Глазго, NIHSS, индексу Barthel проводили в 1,
3, 5, 10-й день заболевания. Одновременное со стандартным лечением внутривенное
введение кверцетина положительно влияет на регресс очаговой неврологической
симптоматики согласно оценке по шкале NIHSS и индексу
Barthel у пациентов в острый период ишемического инсульта, и
позволяет увеличить долю пациентов в
сознании или легкой степенью его нарушения по шкале ком Глазго, то есть вызвать
более раннее «пробуждение» в острый период ишемического инсульта. Церебропротективный
эффект кверцетина (корвитин, лиофилизированный инъекционный раствор) можно
объяснить его политропностью, антиоксидантным, противовоспалительным и мембраностабилизирующим
действием в условиях ишемии/реперфузии.
Keywords: stroke,
reperfusion injury, quercetin.
Ключевые слова: инсульт, реперфузионное повреждение, кверцетин.
Introduction.
One of the main goals of treatment of ischemic stroke - the restoration
of blood flow in the ischemic area of the brain to maintain its viability, it
was found that the production of reactive oxygen species increased. The
results of reperfusion can be detrimental, since oxidative stress is quickly
replaced by reoxygenation [1]. Reperfusion can be associated with an early
increase in the blood-brain barrier permeability and, consequently, with
secondary reperfusion injury, and an unfavorable outcome [2]. Reperfusion
injury of ischemic tissues was first described by cardiologists in cases of
successful thrombolytic therapy of acute myocardial infarction due to
recanalization of thrombosed coronary artery. It can manifest itself in
the form of reperfusion arrhythmias, which are often fatal (ventricular
fibrillation), myocardial stunning phenomena, microvasculature vascular injury
and the absence of coronary blood flow restoration at the tissue level
(no-reflow phenomenon), accelerated development of necrosis Cardiomyocytes
whose function was disrupted by previous ischemia [3, 4, 5]. With the
introduction into neurological practice of thrombolytic therapy of acute
ischemic stroke, the problem of protecting the brain (ischemic
"penumbra" zone) from reperfusion injury is becoming more
urgent. The development of such damage is based on interrelated and
complementary mechanisms: adverse effects of reoxygenation of ischemic tissue
with the formation of free oxygen radicals ("oxygen paradox"),
excessive intake of calcium ions from the extracellular space into the cell,
followed by a disturbance of mitochondrial function, a decrease in adenosine
triphosphate production, and a progressive increase in the zone necrosis
("calcium paradox"), mechanical damage to cells during the
restoration of blood flow [6, 7].
The data of experimental and clinical studies of recent years indicate
the possibility of preventing reperfusion injury in cardiology with the use of
drugs that have membrane-protective properties (trimetazidine, quercetin) prior
to thrombolysis, which leads to the limitation of the necrosis zone, increased
electrical stability of the myocardium and, consequently, occurrence of
fatal complications.
Quercetin is a modulator
of enzyme activity. At the heart of biochemical and
pharmacological effects of quercetin is a selective inhibitory effect on a
number of important enzymes of the cell, which makes it possible to place it in
a series of specific bioregulators of many enzyme processes [8]. Probably the
inhibitory effect of quercetin is due to its ability to bind to active
ATP-binding sites of enzymes such as protein kinases, mitochondrial ATPases,
myosin, Na + / K + and Ca2 + plasma ATPases, topoisomerase II. Another important property of
quercetin, and its metabolites, is participation in intercellular transport,
due to activity with respect to ATP-dependent transport P-glycoproteins [9, 10,
11].
Quercetin has antioxidant
properties due to the ability to inhibit lipoxygenase and cyclooxygenase,
inhibiting the excessive formation of leukotrienes [12].
There is every reason to
believe that inhibition of enzymes such as phospholipase A2 and lipoxygenase,
as well as slowing of prooxidant processes, are the most important links in the
pathogenetic therapy of ischemic stroke in the acute period and prevention of
reperfusion syndrome.
Excess of active forms of oxygen acts as a cause of destruction of membranes,
violation of permeability of barriers, death of brain cells, expansion of the
necrosis zone. In this regard, the use of drugs with antioxidant
properties for cerebroprotection is pathogenetically justified. The above data
indicate the need to search for new optimal approaches that significantly reduce
the risk of development of reperfusion injury in the acute period of ischemic
stroke.
Materials and methods.
The study included 98 patients in the acute period of ischemic stroke.
The
criteria for including patients in the study were:
- Age not older than 85 years;
- The sudden emergence of focal neurological symptoms, characteristic of the
lesions of both the carotid and vertebrobasilar blood supply reservoirs of the
brain, lasting more than 24 hours;
- Excluded hemorrhagic character of stroke on CT;
- First diagnosed ischemic stroke;
- Absence of diseases on account of which it was possible to attribute this
clinical exacerbation and the appearance of neurologic symptoms.
The
exclusion criteria were:
- The presence of a previous history of a stroke;
- The level of impaired consciousness on the Glasgow scale is less than 7
points;
- Duration of neurologic focal symptoms is less than 24 hours;
- Oncological diseases.
The diagnosis of ischemic stroke was established according to the
standard method based on the analysis of the clinical picture, the history and
additional examination methods (instrumental (computed tomography, magnetic
resonance imaging, duplex scanning of the main arteries of the head and neck),
laboratory). The neurological status was assessed by the Glasgow Coma Scale,
according to Teasdale G.M., Jennett W., 1974, the NIHSS scale (Stroke Scale of
the National Institutes of Health, Brott T. et al., 1989), the Barthel Daily
Activity Index F. Mahoey, D. Barthel, 1965, S. Granger et al., 1979, D.
Wade, 2000) 24 hours after the onset of the stroke, and then on days 3, 5 and
10.
All patients, the main and control groups, received standard treatment
(support of respiratory and cardiovascular activity, correction of hypertension
and hyperglycemia, infusion therapy), thrombolytic or anticoagulant therapy,
treatment of cerebral edema, symptomatic therapy (in accordance with the
clinical protocol of the Ministry of Health of Ukraine No. 602 of 03.08.2012).
In the main group, basal treatment was additionally assigned to
Quercetin (Corvitin lyophilisate injection solution) with a course of 10 days
according to the scheme: 500 mg of the drug diluted in 100 ml of 0.9%
physiological solution intravenously twice a day for the first five days and
once a day for the next five days. Quercetin was not assigned to the control
group. The statistical treatment was carried out using the t-test of the
Student (p˂0.05). Differences were considered reliable at a
significance level of p <0.05.
Results.
When assessing the results of treatment in the study and control groups,
there was a positive dynamics in the recovery of consciousness, regression of
focal neurological symptoms.
Table 1. Main demographic and clinical characteristics of
patient groups.
|
Index |
Main group |
Control group |
|
Age (years) |
70,3±5,2 |
69,5±7,2 |
|
Male |
47,06% (32) |
46,7% (14) |
|
Female |
52,94% (36) |
53,3% (16) |
|
Hypertonic disease |
77,9% (53) |
83,3% (25) |
|
Atrial fibrillation |
39,7% (27) |
33,3% (10) |
|
Diabetes |
14,7% (10) |
10% (3) |
|
Hypercholesterolemia |
79,4% (54) |
93,3% (28) |
|
The subtype of ischemic stroke * |
||
|
Cardioembolic |
38,2% (26) |
33,3% (10) |
|
Atherothrombotic |
52,9% (36) |
56,7% (17) |
|
Lacunar |
8,8% (6) |
10% (3) |
|
Stroke in the carotid zone |
77,9% (53) |
80% (24) |
|
Stroke in the vertebrobasilar zone |
22,1% (15) |
20% (6) |
|
Glasgow Coma Scale |
9,2±1,2 |
9,8±1,6 |
|
NIHSS |
11,3±1,4 |
10,2±2,1 |
|
Barthel's index |
28,4±1,5 |
32,1±2,2 |
* according to the TOAST criteria (Adams H.P. et
al, 1993).
The dynamics of patients' condition for 10 days is reflected in Table 2.
In patients of the main group, starting from the 5th day, a more
pronounced effect of normalizing the level of consciousness was noted. Significant differences were also
revealed in the dynamics of recovery of the neurological deficit.
Table 2. Dynamics of average total indicators on different
scales.
|
Time of
examination after a stroke onset |
Glasgow Coma Scale |
NIHSS |
Barthel's index |
|||
|
Main group |
Control group |
Main group |
Control group |
Main group |
Control group |
|
|
24 hours |
9,5±1,4 |
9,8±1,6 |
11,3±1,4 |
10,2±1,1 |
29,4±2,4 |
32,1±2,2 |
|
3rd day |
11,5±1,6 |
11,2±1,0 |
8,7±1,6 |
9,5±1,2 |
53,1±1,6 |
51,8±1,4* |
|
5th day |
13,2±0,8* |
11,8±0,6* |
6,5±0,9* |
7,9±1,0* |
63,7±1,6* |
59,4±1,2* |
|
10th day |
14,3±0,9* |
12,4±1,1* |
5,2±1,1* |
7,6±1,3* |
73,1±1,4* |
70,4±1,5* |
* p˂0,05.
The best recovery of neurological deficit with the use of quercetin was
observed in patients who underwent lacunar or atherothrombotic stroke, in
comparison with cardio-embolic (Table 3).
Table 3. Dynamics of mean
total values on the scale of NIHSS in patients with different subtypes of
ischemic stroke in the main group.
|
Time of examination after a stroke onset |
The subtype of ischemic stroke |
|||
|
cardio-embolic |
atherothrombotic |
lacunar |
The total (average) indicator |
|
|
5th day |
8,2±1,1 |
6,2±0,9 |
5,0±0,8 |
6,5±0,9* |
|
10th day |
6,1±1,1 |
4,9±1,1 |
4,5±1,1 |
5,2±1,1* |
* p˂0,05.
Discussion.
In our study, there were no undesirable events, side effects of the
treatment. The results of the study indicated a positive dynamics of regression
of the neurological deficit according to the NIHSS scores and the Barthel
index, the effect of an earlier "awakening", i.e. increase in
the main group of the proportion of patients in consciousness or with a mild
degree of its violation on the Glasgow coma scale, starting from the 5th day,
in comparison with the control group of patients. The cerebroprotective effect
of quercetin can be explained by its polytropic, antioxidant,
anti-inflammatory, membrane-stabilizing action under ischemia / reperfusion
conditions.
Conclusions.
Intravenous administration of Quercetin (Corvitin
lyophilisate injection solution) at the same
time as standard treatment with a course of 10 days according to the scheme: 500
mg of the drug diluted in 100 ml of 0.9% of the physiological solution
intravenously twice a day for the first five days and once a day for the
next five days, positively affects the regression of focal neurologic symptoms
on the NIHSS and Barthel index scales in patients in the acute period of
ischemic stroke. The use of quercetin allows increasing the proportion of
patients in consciousness or mild degree of its violation on the Glasgow scale,
i.e. cause an earlier "awakening" in the acute period of an
ischemic stroke.
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