Abstract
Objective: The objective of this study was to determine if Divaza, a drug with nootropic and antioxidant effects, was safe and effective for the correction of oxidative disturbances and to stabilize cognitive impairment in patients with cerebral atherosclerosis. Study Design: The study design consisted of a 12-week multicenter, randomized, double-blind, placebo-controlled, prospective trial in parallel groups. Setting: The setting in which the study was conducted comprised 10 clinical centers across the Russian Federation. Interventions: Patients were randomized into 2 groups and instructed to take either 2 tablets of the study drug or a placebo 3 times per day in conjunction with basic therapy. Outcomes: The primary outcome was a change in the average endogenous antioxidant potential after the completion of the study. The blood indicators of the oxidative stress (OS) were analyzed at the baseline and then after 12 weeks of therapy using iron-induced chemiluminescence analysis. The Montreal cognitive assessment test was used as a secondary outcome measure to evaluate cognitive impairment at the end of the study. Results: 124 outpatients with a mean age of 60.7 ± 7.6 years were enrolled and randomly assigned to receive Divaza (n = 65) or a placebo (n = 59). An improvement of cognitive function was observed in all patients of the Divaza group at the end of the treatment; this was significantly better than the placebo group (100 [100] vs. 89.5 [89.1]%, respectively, p = 0.0272 [p = 0.0128]). The administration of Divaza restored the activity of the endogenous antioxidant system. The change in the average level of lipoprotein resistance to oxidation after 12 weeks of therapy, compared to the baseline, was significantly higher in the Divaza group (14.8 ± 14.7 [14.8 ± 14.7] seconds latent period vs. 6.4 ± 16.9 [6.9 ± 16.7] seconds in the placebo group (p = 0.007 [p = 0.0107]). Conclusions: Divaza is a safe and effective therapeutic option for attenuating OS and recovery of cognitive impairment in patients with cerebral atherosclerosis.
References
1.
Parfyonov
VA
, Neverovsky
DV
. Management of patients with discirculatory encephalopathy in outpatient practice
. Neurol Neuropsychiatry Psychosom
. 2015
;1
:37
–42
. In Russian.2.
Izzo
C
, Carrizzo
A
, Alfano
A
, Virtuoso
N
, Capunzo
M
, Calabrese
M
, et al. The impact of aging on cardio and cerebrovascular diseases
. Int J Mol Sci
. 2018
;19
(2
):481
. .3.
World Health Organization (WHO)
. World population ageing: 1950–2050
. 2016
. http://www.un.org/esa/population/publications/worldageing19502050/.4.
Kunz
A
, Iadecola
C
. Cerebral vascular dysregulation in the ischemic brain
. Handb Clin Neurol
. 2009
;92
:283
–305
. .5.
Falkowska
A
, Gutowska
I
, Goschorska
M
, Nowacki
P
, Chlubek
D
, Baranowska-Bosiacka
I
. Energy metabolism of the brain, including the cooperation between astrocytes and neurons, especially in the context of glycogen metabolism
. Int J Mol Sci
. 2015
;16
(11
):25959
–81
. .6.
Camandola
, S
, Mattson
, MP
. Brain metabolism in health, aging, and neurodegeneration
. EMBO J
. 2017
;36
(11
):1474
−92
. 7.
Higashi
Y
, Noma
K
, Yoshizumi
M
, Kihara
Y
. Endothelial function and oxidative stress in cardiovascular diseases
. Circ J
. 2009
;73
(3
):411
–8
. .8.
Chen
H
, Yoshioka
H
, Kim
GS
, Jung
JE
, Okami
N
, Sakata
H
, et al. Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection
. Antioxid Redox Signal
. 2011
;14
(8
):1505
–17
. .9.
Bhayadia
, R
, Schmidt
, BM
, Melk
, A
, Hömme
, M
. Senescence-induced oxidative stress causes endothelial dysfunction
. J Gerontol A Biol Sci Med Sci
. 2016
;71
(2
):161
−9
. 10.
Chen
SD
, Yang
DI
, Lin
TK
, Shaw
FZ
, Liou
CW
, Chuang
YC
. Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia
. Int J Mol Sci
. 2011
;12
(10
):7199
–215
. .11.
Lobo
V
, Patil
A
, Phatak
A
, Chandra
N
. Free radicals, antioxidants and functional foods: Impact on human health
. Pharmacogn Rev
. 2010
;4
(8
):118
–26
. .12.
Kurutas
EB
. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state
. Nutr J
. 2016
;15
(1
):71
. .13.
Valavanidis
A
, Vlachogianni
T
, Fiotakis
K
. Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles
. Int J Environ Res Public Health
. 2009
;6
(2
):445
–62
. .14.
Uttara
B
, Singh
AV
, Zamboni
P
, Mahajan
RT
. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options
. Curr Neuropharmacol
. 2009
;7
(1
):65
–74
. .15.
Rajendran
P
, Rengarajan
T
, Thangavel
J
, Nishigaki
Y
, Sakthisekaran
D
, Sethi
G
, et al. The vascular endothelium and human diseases
. Int J Biol Sci
. 2013
;9
(10
):1057
–69
. .16.
Sandoo
A
, van Zanten
JJ
, Metsios
GS
, Carroll
D
, Kitas
GD
. The endothelium and its role in regulating vascular tone
. Open Cardiovasc Med J
. 2010
;4
:302
–12
. .17.
Cipolla MJ
. The cerebral circulation
. San Rafael, CA
: Morgan & Claypool Life Sciences
; 2009
. Chapter 5, Control of Cerebral Blood Flow.18.
Fantini
S
, Sassaroli
A
, Tgavalekos
KT
, Kornbluth
J
. Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods
. Neurophotonics
. 2016
;3
(3
):031411
. .19.
Lee
JM
, Grabb
MC
, Zipfel
GJ
, Choi
DW
. Brain tissue responses to ischemia
. J Clin Invest
. 2000
;106
(6
):723
–31
. .20.
Phaniendra
A
, Jestadi
DB
, Periyasamy
L
. Free radicals: properties, sources, targets, and their implication in various diseases
. Indian J Clin Biochem
. 2015
;30
(1
):11
–26
. .21.
The official website of the manufacturer (OOO NPF MATERIA MEDICA HOLDING). Information list on Divaza product [Internet]. Accessed 2020 Dec 22. Available from: https://materiamedica.ru/en/catalogue/innovativemedicines/divaza/.
22.
Parfenov
VA
, Ostroumova
OD
, Ostroumova
TM
, Kochetkov
AI
, Fateeva
VV
, Khacheva
KK
, et al. Vascular cognitive impairment: pathophysiological mechanisms, insights into structural basis, and perspectives in specific treatments
. Neuropsychiatr Dis Treat
. 2019
;15
:1381
–402
. .23.
Vorob’eva
OV
, Fateeva
VV
, Nikulina
KV
, Khacheva
KK
, Khakimova
GR
, Epstein
OI
. Association between peripheral blood inflammatory markers, endothelial dysfunction markers, and depression
. London
: IntechOpen
; 2019
.25.
Fedorova
, TN
, Maksimova
, MY
, Varakin
, YY
, Gornostaeva
, GV
, Logvinenko
, AA
, Gnedovskaya
, EV
, et al. Oxidation of blood lipoproteins in patients with cerebrovascular accident
. Ann Clin Exp Neurol
. 2014
;8
(1
):30
−3
. In Russian.26.
Vladimirov
, YA
, Packer
, L
, Traber
, MG
, Xin
, W
. Natural antioxidants: molecular mechanism and health effects
. Champaign, IL
: AOCS Press
; 1996
. p. 125
−44
.27.
Fedorova
, TN
, Us
, KS
, Ostrovskaya
, RU
. Evaluation of the antioxidant effect of the nootropic dipeptide noopept on the model of Fe2+-induced chemiluminescence of human serum lipoproteins in vitro
. Neurochemistry
. 2007
;24
(1
):69
−73
. In Russian.28.
Berezhnoy
, DS
, Stvolinsky
, SL
, Lopachev
, AV
, Devyatov
AA
, Lopacheva
OM
, Kulikova
OI
, et al. Carnosine as an effective neuroprotector in brain pathology and potential neuromodulator in normal conditions
. Amino Acids
. 2019
;51
(1
):139
−50
. 29.
Kulikova
, OI
, Berezhnoy
, DS
, Stvolinsky
, SL
, Lopachev
, AV
, Orlova
, VS
, Fedorova
, TN
. Neuroprotective effect of the carnosine: α-lipoic acid nanomicellar complex in a model of early-stage Parkinson’s disease
. Regul Toxicol Pharmacol
. 2018
;95
:254
−9
. 30.
Parfenov
, VA
, Kamchatnov
, PR
, Vorobyova
, OV
, Gustov
, AV
, Glushkov
, KS
, Doronina
, OB
. Results of multicenter study of efficacy and safety of divaza in the treatment of the asthenic and mild to moderate cognitive disorders in elderly and senile subjects
. Zh Nevrol Psikhiatr Im S S Korsakova
. 2017
;117
(9
):43
−50
. 31.
Vladimirov
, GK
, Sergunova
, EV
, Sergunova
, EV
, Izmaylov
DY
, Vladimirov
YA
. Chemiluminescent determination of total antioxidant capacity in medicinal plant material
. Bull RSMU
. 2016
;2
(2
):62
−8
. 32.
Plotnikov
E
, Korotkova
E
, Voronova
O
, Sazhina
N
, Petrova
E
, Artamonov
A
, et al. Comparative investigation of antioxidant activity of human serum blood by amperometric, voltammetric and chemiluminescent methods
. Arch Med Sci
. 2016
;12
(5
):1071
–6
. .33.
Fedorova
, TN
. The use of chemiluminescent analysis for the comparative evaluation of certain pharmacological substances
. Exp Clin Pharmacol
. 2003
;66
(5
):56
−8
. In Russian.34.
Bianchi
R
, Kastrisianaki
E
, Giambanco
I
, Donato
R
. S100B protein stimulates microglia migration via RAGE-dependent up-regulation of chemokine expression and release
. J Biol Chem
. 2011
;286
(9
):7214
–26
. .35.
Förstermann
U
, Sessa
WC
. Nitric oxide synthases: regulation and function
. Eur Heart J
. 2012
;33
(7
):829
–37
. .36.
Sharpe
MA
, Robb
SJ
, Clark
JB
. Nitric oxide and Fenton/Haber-Weiss chemistry: nitric oxide is a potent antioxidant at physiological concentrations
. J Neurochem
. 2003
;87
(2
):386
–94
. .37.
Zhavbert
ES
, Guryanova
NN
, Surkova
EI
, Dugina
YL
, Kachaeva
EV
, Epshtein
OI
. Divaza influence on the processes of lipid peroxidation
. XXI Russ Nat Congr Man Med
. 2014 Apr 7–11
:242
. In Russian.© 2021 S. Karger AG, Basel
2021
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