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ADITUM Journal of Clinical Psychology and Mental Health Care
!
Nadir A Aliyev1*, Zafar N Aliyev2
1Azerbaijan State Advanced Training Institute for Doctors named by A. Aliyev department of psychiatry and drug
addiction, Baku, Azerbaijan Republic
2Azerbaijan Medical State University, Department of Psychiatry Baku City, Azerbaijan Republic
"
Received: March 05, 2021
Accepted: March 19, 2021
Published: March 24, 2021
# $ Nadir A Aliyev,
Professor, Department of Psychiatry and Addiction
Azerbaijan State Advanced Training Institute for Doctors
named by A. Aliyev, department of psychiatry and
addiction, Baku, Azerbaijan; Baku City, U. Chagibekov
Street, 46/50, F. 1. Baku P.O. AZ0010 Azerbaijan Republic.
$ Nadir A Aliyev, Zafar N Aliyev. “Alternative
Treatment Of Anxiety Disorders During Covid-19
Pandemic Which Snepco”. Clinical Psychology and Mental
Health Care, 2(4); DOI: http;//doi.org/03.2021/1.10022.
$ © 2021 Nadir A Aliyev. This is an open
access article distributed under the Creative Commons
Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the
original work is properly Cited.
%
Objective. The pharmacological drugs used (Antidepressants SSRIs Tricyclic,
MAO Benzodiazepines) for anxiety disorders in the context of the COVID-19
pandemic were not effective for several reasons. Time calls for finding new drugs
to treat anxiety disorders in the COVID-19 pandemic.
Method. Hundred patients (all men) were washout from the all medications. Each
patient was randomized to receive either Selective neuronal potassium channel
opener (SNEPCO) - flupirtine (50 patients) for 6 weeks or matched placebo (50
patients) in a double-blind manner. Eligible participants, in addition to meeting
the DSM-5 criteria for anxiety disorders and having a minimum score of 25 and
more on the Hamilton Anxiety Scale, were required to be between 18 and 65
years Response was defined as a 50% reduction in the Hamilton anxiety scale
score. Response and side effects with flupirtine and placebo were compared by
using analysis of variance (ANOVA) and chi-square tests.
Results. Fifty i.e all patients of the flupirtine - treated responded by 6 weeks, versus
four of the placebo-treated participants (p < 0.001).
Conclusions. The authors believe this to be the first double-blind placebo-
controlled randomization study to test the efficacy of a flupirtine in the
management of anxiety disorders. They need to be replicated in a larger study
group.
&'$Anxiety disorders; COVID-19 Pandemic; Flupirtine; Treatment
"$
Anxiety statistics worldwide show that anxiety disorders are common across the
globe. According to the World Health Organization, 3.6 percent — or about 264
million individuals worldwide — have an anxiety disorder. Additionally, 4.6
percent of females and 2.6 percent of males globally are affected by anxiety. In
the United States adult population, the prevalence of anxiety disorders is 19.1
percent within the past year, meaning that during a 12-month period, 19.1 percent
of adults had an anxiety disorder. Lifetime rates are even higher at 31.1 percent,
according to the National Institute of Mental Health (NIMH). The NIMH reports
that the incidence of anxiety disorders varies by age. Anxiety disorders in
adults are seen in 22.3 percent of those aged 18–29 and 22.7 percent of people
ages 30–44. The prevalence of anxiety disorders drops to 20.6 percent for
individuals ages 45–59. Anxiety in older adults is less common, affecting only 9
percent of people 60 years or older. [1]
(https://www.therecoveryvillage.com/mental- health/anxiety/related/anxiety-
disorder-statistics/). The anxiety disorders make up one of the most common
groups of psychiatric disorders. The National Comorbidity Study reported that
one of four persons met the diagnostic criteria for at least one anxiety disorder
and that there is a 12-month prevalence rate o 17.7 percent. Women (30.5 percent
lifetime prevalence) are more likely to have an anxiety disorder than are men
(19.2 percent lifetime prevalence). The prevalence of anxiety disorders decreases
with higher socioeconomic status. The 12-month prevalence of separation anxiety
disorder among adults in the United States is 0.9%-1.9%. In children, 6- to 12-
Thoracic CT scan with a large collection of dorsal subcutaneous
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J Clinical Psychology and Mental
Health Care
Aditum Publishing –
www. aditum.org
Page 2 of
6
1.6 %. Separation anxiety disorder decreases in
prevalence from childhood through adolescence and
adulthood and is the most prevalent anxiety disorder in
children younger than 12 years. In clinical samples of
children, the disorder is equally common in males and
females. In the community, the disorder is more frequent in
females. In the United States, the 12-month community
prevalence estimate for specific phobia is approximately
7%-9%. Prevalence rates in European countries are largely
similar to those in the United States (e.g., about 6%), but
rates are generally lower in Asian, African, and Latin
American countries (2%-4%). Prevalence rates are
approximately 5% in children and are approximately 16% in
13- to 17-year-olds. Prevalence rates are lower in older
individuals (about 3%-5%), possibly reflecting diminishing
severity to subclinical levels. Females are more frequently
affected than males, at a rate of approximately 2:1, although
rates vary across different phobic stimuli. That is, animal,
natural environment, and situational spe- cific phobias are
predominantly experienced by females, whereas blood-
injection-injury phobia is experienced nearly equally by
both genders [2, 3].
Anxiety disorders, including panic disorder with or without
agoraphobia, generalized anxiety disorder, social anxiety
disorder, specific phobias and separation anxiety disorder, are
the most common mental disorders and are associated with high
health care costs and a high burden of disease. According to
large population surveys, up to 33.7% of the population suffer
from anxiety disorder during their lifetime. Significant
misunderstanding and inadequate treatment of these disorders
has been demonstrated. There is no evidence that prevalence
rates for anxiety disorders have changed in recent years. In
cross-cultural comparisons, prevalence rates vary widely. This
heterogeneity is more likely due to differences in methodology
than cultural influences. Anxiety disorders are chronic; however,
with age, there is a natural decline in prevalence rates. Anxiety
disorders are often accompanied by other anxiety disorders and
other mental disorders [4].
Thus, Anxiety disorder is widely prevalence throughout the
world. However, the pharmacological drugs used
(Antidepressants SSRIs Tricyclic, MAO Benzodiazepines) for
anxiety disorders in the context of the COVID-19 pandemic
were not effective for several reasons.
The aim of this study was to develop a new treatment for anxiety
disorders in the COVID-19 pandemic.
(
In a previously published study, we found that anxiety disorders
are the most common mental disorder. [5]. Currently, for the
treatment of anxiety disorders, they are mainly used
benzodiazepine, antidepressants SSRIs, tricyclic, tetracyclic and
MAO for anxiety disorders in the context of the COVID-19
pandemic were not effective for several reasons. As the world
shudders with COVID-19, the US Food and Drug
Administration have made harsh admissions regarding hazardous
benzodiazepine drugs. At first the FDA has recognized that
patients can become "physically dependent" on them after taking
them for just "a few
days." Taking benzodiazepines for more than 3
or 4 weeks can put
someone at risk of becoming addicted or
physically dependent
J Clinical Psychology and Mental
Health Care
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Page 3 of
6
without developing dependence. The FDA warns that while
benzodiazepines can be a beneficial treatment, stopping them
suddenly or reducing the dose too quickly can lead to
withdrawal symptoms that can be life-threatening. The agency
recommends that patients speak with their healthcare providers
to develop a plan to safely and slowly taper their
benzodiazepine dose. [6]. Secondly, antidepressants SSRIs
Secondly, they can cause serotonin syndrome. Thirdly, tricyclic,
tetracyclic antidepressants have numerous adverse effect effects
and toxic properties. Therefore, we have developed alternative
Treatment of Anxiety disorders during COVID-19 Pandemic
which SNEPCO (flupirtine)
This was a double-blind, placebo-controlled trial for patients
diagnosed with DSM-5 for rapid cycle bipolar disorder. The
patients gave their informed, written consent to participate.
In accordance with the Helsinki Declaration of the World
Medical Association “Recommendations for doctors engaged in
biomedical research involving people”, adopted by the 18th
World Medical Assembly (Finland, 1964, revised in Japan in
1975, Italy-1983, Hong Kong-1989, the South African
Republic- 1996, Edinburgh-2000); The Constitution of the
Republic of Azerbaijan, the Law “On Psychiatric Assistance”
(adopted on 12.06.2001, with amendments and additions
-11.11.2011, Decisions of the Cabinet of Ministers of the
Republic of Azerbaijan No. 83, dated April 30, 2010 “On
Approval of the Rules for Conducting Scientific, Preclinical and
Clinical studies of medicines” are established. The conditions of
the conducted researches corresponded to the generally
accepted norms of morality, the requirements of ethical and
legal norms, as well as the rights, interests and personal dignity
of the participants of the studies were observed.
a) Conducted research is adequate to the topic of research
work.
b) There is no risk for the subject of research.
c) Participants in the study were informed about the goals,
methods, expected benefits of the study and associated
with risk and inconvenience in the study.
d) The subject’s informed consent about participation in
the research was received.
The decision of the Ethical Committee at the Azerbaijan
Psychiatric Association on the article of NA. Aliev, Z.N. Aliev
“Alternative Treatment of Anxiety disorders during COVID-
19 Pandemic which SNEPCO ” submitted for publication in
psychiatric journals: in connection with compliance with its
legislative requirements and regulatory documents is to approve
the article by N.A. Aliyev, Z.N. Aliev “Alternative Treatment
of Anxiety disorders during COVID-19 Pandemic which
SNEPCO ”. Patients were observed at the Mental Health Center
of the Ministry of Health of the Republic of Azerbaijan. The study
was conducted from January 01, 2020 to 01 of the January 2021
years.
We excluded sexually active subjects with active or unstable
epilepsy, other genetic syndromes or congenital infections
associated with autistic-like syndromes, prematurity; subjects
who have been treated within the previous 30 days by any
medication known to have a clearly defined potential for toxicity
or with any psychotropic drugs; subjects with clinically
significant abnormalities in laboratory tests or physical
examination; subjects with a history of hypersensitivity or
serious side effects associated with the use any drugs A detailed
clinical
interview with parents by a clinical expert, accompanied by
physical examination and blood analysis, was used to ensure that
subjects did not meet any exclusion criteria. A structured clinical
interview, for DSM-5 Axis I Disorder, Patient Edition, was used
to diagnose anxiety disorders DSM-5 [2] and in addition having
a minimum score of 25 and more on the Hamilton Anxiety Scale
[7]. Hundred patients all men whom we studied were under
observation in Mental Health Center of the Ministry of Health of
the Republic of Azerbaijan. The length of the washout was 2
weeks. Patients were washout from the all medications. Eligible
participants were required to be between 18 and 65 years of age.
We excluded serious medical conditions including with other
psychiatric disorders (e.g. bipolar disorder II tipi, schizophrenia,
patients judged to be at serious suicidal or homicidal risk,
dependence of psychoactive drugs, somatic, neurological illness
etc).
Patients clinically significant of abnormal laboratory or EEG
findings were ineligible. Patients before the study had not used
antidepressants, antipsychotics, anxiolytics, benzodiazepines,
SSRI and. Washout of all medicines was two weeks.
Eligible participants were required to be between 18 and 65
years of age.
The patients were evaluated by Hamilton Anxiety Scale at 4 and
6 weeks. Classification of symptoms: 0 — absent; 1 — mild; 2
— moderate; 3 — severe; 4 — incapacitating. Criteria: (1) Mild
Anxiety: 18; (2) Moderate Anxiety: 25; and (3) Severe Anxiety:
30.
The primary efficacy variable, as defined by the protocol, was
the reduction from baseline of the Hamilton Anxiety Scale total
score after 6 weeks of therapy. Response defined, a priori, as at
least a 50% improvement from baseline to end point and
recovery as a score of no greater than 18 at the end point in the
Hamilton Anxiety Scale total score, respectively. The side-
effects were recorded by spontaneous reports.
Analysis of response refers to the last observation carried
forward for all subjects who had valuables efficacy at baseline
and with
treatment. The responder analysis was conducted by using
the chi-
square (x2) and analysis of variance (ANOVA) according
to Glantz [8].
In our studies we used flupirtinum (cadadolone forte) was
prescribed the 200 mg 3 times a day, in capsules for 6 weeks
(Produced by Pliva Krakow, Pharma- ceutical Plant AO). This
dose was maintained until the end of the trial at week 6. Starting
on week 0, patients received study medication. Capsules were
supplied in numbered bottles containing study medication as
determined by a random number sequence. The randomization list
was held by the senior investigator outside the treatment team.
No communication regarding the status of patients under study
was permitted the unblended investigator and the other
investigators, save that the unblended investigator was informed
if patients complained of any adverse effects from the study
medication. Medically staff with no clinical responsibilities and
knowledge of the patients oversaw the procedure and assigned
medication in sequential order, strictly following the randomized
list. The
treating psychiatrist did not have access to the list. Both
the patient
and the treating psychiatrist were not aware of the
antipsychotic being prescribed. Contraindications in our patients
were following: patients with history of hypersensitivity to
flupirtine, hepatic encephalopathy, cholestasis, myasthenia
gravis, chronic alcoholism, primary biliary cirrhosis, and liver
disease. Patients underwent physical examination,
electrocardiography (if > 40
years), and laboratory analyses, including hematological
measures, partial thromboplastin time, and urinalysis. All
patients were evaluated on weeks 0 and 6 weeks of the study by
different psychiatrists. The adverse effects were recorded by
spontaneous
reports. Patients attended 4 visits: initial screening
(randomization
(week 0), further visits at weeks 4 and 6. Data
for clinical assessments were collected at weeks 0 and 6. Data
for adverse events were spontaneous complaints at each visit.
Patients were also requested to report immediately at any onset
of possible rash or other skin reactions. Adverse effects reported
by patients who received katadolone and placebo not observed
Comparison between the groups at baseline was performed
using the Mann-Whitney test. Analysis of response refers to the
last observation carried forward for all patients who had
valuables efficacy at baseline and with treatment. The responder
analysis was conduct- ed by using the x2 and Analysis of
Variance (ANOVA) according to Glantz [8].
Characteristic Katadolone n =50 Placebo n =
Age (Mean SD) years 38.0 ± 10.2 37.4 ± 9.8
Education:
— primary school 10 11
— secondary school 20 21
— high school 20 18
Marital status:
— never married 10
9
— married 30 31
— divorced 10 10
or separated
Employment status
— unemployed 18 20
— employed 32 30
Table1. Characteristics of study patients
Note: differences between groups are not significant.
According to the instructions for the medical use of the katadolone
(flupirtine), it refers to the clinical and pharmacological group -
the non-opioid analgesic of the central action.
Mean scores on the
Hamilton Anxiety Scale
during treatment
Treatment
groups n=50
Placebo
n=50
P
Completers analysis
means Hamilton
Anxiety Score at Start
31.0 ±3.41 30.0 ±
3.32
p >0.10
Hamilton Anxiety Score
at Week 4 of the Study 24.0 ±3.0 29.0 ±
2.0
p
<0.001
Hamilton Anxiety Score
at end of the Study
(Week 6)
20.0 ± 4.2 27.0 ±
3.5
p <
0.001
Katadolone was superior to placebo in the ratings on Hamilton
Anxiety Scale (Table 2).
Katadolone separated statically from placebo at the 4-week time
point and beyond at the 6-week. By study end (6-week) the mean
change in the total score on the Hamilton Anxiety scale was also
superior for katadolone than for placebo. The difference between
groups was statistically significantly.
The responder was conducted by x2 also demonstrated superior for
katadolone than for placebo (Table 3). Katadolone was generally
well tolerated by the patients in the study.
Table3. The results of the Hamilton Anxiety Scale during
treatment (observed and expected number from the chi square
analysis).
Note: observed and expected numbers indication in the brackets.
chi- x2= 22.68, df = 1, p< 0.001.
We suggest that one of the reasons of reduction of the anxiety
symptoms in our patients may be consequence of sedative and
other effect of katadolone.
)*
The data obtained by us in connection with a small number of
patients and a short period of observation (2 wk) should be
considered preliminary. The next stage of the work will be
carried out on a large number of patients and longer duration of
observation, with a place- bo-controlled, doubleblind method.
The classification of clinical and pharmacological groups is
based on the therapeutic effect. Pharmacological action:
Selective Neuronal Potassium Channel Opener. By its
pharmacological effects, the drug is a non-opioid analgesic of
central action that does not cause addiction and habituation, in
addition, it has a miorelaxing and neuroprotective effect. The
action of flupirtine is based on the activation of potential-
independent potassium channels, which leads to the stabilization
of the membrane potential of the neuron. The effect on the
current of potassium ions is mediated by the effect of the drug on
the regulatory G protein system. In therapeutic concentrations,
flupirtine does not link to α1, α2-adrenoreceptors, serotonin
5HT1, 5HT2 receptors, dopamine, benzodiazepine, opioid,
central m-and n-cholinergic receptors.
Flupirtine was administered as an alternative analgesic for opioids
and NSAIDs. Subsequently, several other actions have been
identified, such as muscle relaxation and neuroprotective
activity. Flupirtine acts indirectly as an N-Methyl-D-Aspartate
(NMDA) receptor antagonist by activating K+ channels [9].
Flupirtine causes a dose-dependent decrease in NMDA-induced
glutamate induced by an increase in the intracellular Ca++
concentration [10]. It binds and activates the G-protein bound to
the K+ channels directed inwards. Activation of this channel
leads to hyperpolariza- tion of the neuronal membrane, and the
neuron becomes less excitable; thus, stabilization of the resting
neuron membrane is observed [10]. Drugs that activate this
channel are
called Selective Neuronal
Potassium Channel Openers (SNEPCO), and flupirtine is a
prototype [9].Experimental evidence suggests that flupirtine can
inhibit channel opening by acting as an oxidant in the redox site
of the NMDA receptor [11]. This action inhibits the transfer of
nociceptive impulses when neurons are excited. The central
effect of flupirtine is based on 4 main effects [12].
Analgesic action
Flupirtine was introduced as an alternative analgesic to opioids
and NSAIDs. Subsequently, multiple other actions such as
muscle relaxation and neuroprotective activity were identified.
Flupirtine acts indirectly as N-Methyl-D-Aspartate (NMDA)
receptor antagonist by activation of K+ channels [13]. Flupirtine
causes a dose-dependent reduction of NMDA receptor mediated
glutamate induced rise in in- tracellular Ca++ concentration [9]. It
binds to and activates G- protein coupled inwardly rectifying K+
channels. Activation of this channel leads to hyperpolarization of
neuronal membrane and the neuron be- comes less excitable;
thus, there is stabilization of resting neuronal membrane [14].
The drugs activating this channel are called as Selec- tive
Neuronal Potassium Channel Openers (SNEPCO) and flupirtine
is the prototype [9]. Experimental evidence suggests that
flupirtine might suppress channel opening by acting as an
oxidizing agent at the redox site of the NMDA receptor [11].
This action inhibits the transmission of nociceptive impulses
during neuronal excitation.
(
The muscle relaxation is due to inhibition of both mono- and
poly- synaptic reflexes. The spinal polysynaptic flexor reflex,
mediated by NMDA receptors, was depressed by flupirtine,
whereas the monosynaptic Hoffmann reflex (H-reflex), mediated
by non- NMDA receptors, was not influenced. Healthy human
subjects responded with a significant reduction of both the early
phase of the electrically elicited polysynaptic flexor reflex of
pretibial muscles and the medium latency response of the toe-up
paradigm after 2 h of 200 mg of flupirtine. Flupirtine possesses
analgesic as well as muscle-relaxing effect in same dose ranges;
thus, it can be used in the treatment of painful diseases of the
motor system presenting with spasticity and chronic musculo-
skeletal pain [15].
+
Apoptosis, a programmed cell death, is caused by increased
intracellular Ca++ levels, mitochondrial dysfunction, cell
membrane disruption, and finally nucleolysis. In vitro studies
with primary cortical neurons from rat embryos have shown that
lead acetate; prions like PrPsc, HIV coat protein gp120, and β
amyloid peptide will cause apoptotic cell death. But if
preincubated with flupirtine, it completely protects apoptotic cell
death caused by above agents in the neurons [16]. It has been
found that flupirtine also antagonizes both glutamate and NMDA
induced increase in intracellular levels of Ca++, as observed in
vitro cultures of cortical and hippocampal neurons [16,17]. The
expression of Bcl-2, an antiapoptotic agent, and gluta- thione, a
scavenger of reactive oxygen, are reduced during glutamate or
NMDA-induced apoptosis in cells. Flupirtine is found to
The results of
the square
analysis)
observed
number
expected
number
the
chi- x2
Treatment
Groups
Yes
improvement
Not
improvement
Total
Placebo 4 (15.43) 46 (21.57) 50
Katadolone 50 (15.56) ------- 50
Total 54 46 100
increase
the levels of Bcl-2 and glutathione in glutamate or NMDA-
induced apoptosis of human Ntera/D1 (hNT) neurons as well as
cultured retinal pigment cells [11]. Flupirtine reduced the
expression of on-cogenes and formation of reactive oxygen
radicals in experimental models which explains its action of
preventing ischemia induced apoptosis.
,
Flupirtine has an NMDA receptor antagonistic action and hence
it was studied for its Antiparkinsonian effect as an adjuvant to L-
3, 4-Dihydroxyphenylalanine (L-DOPA). Akinesia and muscular
rigidity were produced in rats by giving reserving and α methyl
p- tyro- sine. Flupirtine was given alone and in combination with
L- DOPA, it strongly reduced muscle rigidity and increased the
ability of L-DOPA to reverse Akinesia [18]. In haloperidol-
induced catalepsy, which is considered as a model of Parkinson’s
disease, flupirtine alone and in combination with L-DOPA
exerted a potent and cataleptic effect [14, 17]. However, human
studies are not available till date to support this evidence. If
studies are done to prove effectiveness in Parkinson’s disease, it
can be combined with L-DOPA.
!
Safety Flupirtina in pregnant women, lactating women and
children less than 6 years is not established. If indicated in
lactating women, breastfeeding should be discontinued.
Flupirtine dose should be reduced to 50% in elderly patients and
patients with renal and hepatic insufficiency [18].
Flupirtine avoids patients with hypersensitivity to flupirtine,
hepatic encephalopathy, cholestasis, myasthenia gravis, chronic
alcoholism, primary biliary cirrhosis and liver diseases.
-.
Musculoskeletal pain: Flupirtine was compared with placebo
and standard analgesics to determine the efficacy and tolerability
of analgesics. Post-marketing surveillance for flupirtine 200-300
mg/day for 1 week, as assessed by visual analog pain scale. It
was noted that the response rates were 94%, 89.4% and 85.9%
for patients with acute, sub acute and chronic pain, respectively
[18,19].
Headache: Patients who had an inadequate response to
conventional analgesics for chronic headache showed a better
response to flupirtine [19]. Flupirtine acts at the presynaptic
membrane to reduce the release of glutamate, and it has been
shown to reverse depersonalization-related phenomena induced
by the NMDA receptor antagonist ketamine in a healthy
individual. The mechanisms of Flupirtine may be connected with
the influence of neuronal activity and glutamate and GABA
transmission.
The role of GABA in anxiety disorders is most strongly
supported by the undisputed efficacy of benzodiazepines, which
increase the activity of GABA at the GABA A (GABA) receptor,
in the treatment of certain types of anxiety disorders. Although
low potency benzodiazepines are most effective for the
symptoms of
generalized anxiety disorder, high potency benzodiazepines such
as alprazolam (xanax) and clonazepam are effective in treating
panic disorder. Studies in primates have shown that autonomic
anxiety symptoms are induced by the administration of a
benzodiazepine inverse agonist, β-carboline-3-carboxylic acid. β-
carboline-3-carboxylic acid is also of concern in healthy control
volunteers. The benzodiazepine antagonist flumazenil
(romazicone) causes frequent severe panic attacks in patients with
panic disorder. These findings have led researchers to speculate
that some patients with anxiety disorders have abnormal
functioning of their GABA receptors, although this link has not
been directly shown [3].
Thus our date indicated that the potassium channel may be as
targets for therapeutic intervention and novel therapeutic
strategies for anxiety disorders.
In such a way the available up-to-date literature data indicate an
increase in the membrane conductivity for K+ ions (i.e.,
activation-opening of the potassium channels) cause neuronal
hyper- polarization and, in most cases, reduces the frequency of
neuronal excitation, exerting a strong inhibitory effect on the
excitability of neurons. Potassium channels control the
membrane potential of rest and, therefore, play an important role
in regulating the excitability of neurons. Four limitations should
be noted. First was our small study group and we recommending
that these results be replicated in a larger group so that effect
sizes can be more precisely estimated. Second, it is necessary to
conduct this study for the possible generalizability of these data
on a sample of women with anxiety disorders. Third, the absence
of systemic side effects indeed to future investigations. Fourth, it
is necessarily study, side effects of the CNS. The fifth, fur ther
research is needed to establish the optimal dosage. Not withstand
ing these limitations, this study suggests that Flupirtine is
efficacious and well tolerated in the treatment of anxiety
disorders. In any event, pending a further understanding of
Flupirtine’ s mechanisms of action, the present data suggest that
this drug is a useful new agent for the treatment of anxiety
disorders, in patients who have failed to respond to other
traditional drugs. It will be important to explore further effects of
Flupirtine in other disorders treated with Flupirtine.
The results of our study showed high efficiency flupirtine in the
treatment of anxiety disorders. The biochemical mechanism of
action of flupirtine is similar to that of ritagabiline
(chlorzoxazone). Despite the tremendous progress that has been
made recently in elucidating the neurobiological basis of anxiety
disorders, the expected subsequent therapeutic improvements
have not been realized. Channel blockers represent a new goal that
can be translated into research clinical studies in the near future,
especially with the use of drugs already approved for other
indications. The novelty of the work is the first application of the
neuronal potassium channel openers in the treatment of anxiety
disorders.
"
The authors declare that the article is submitted on behalf of all
authors. None of the material in the article has been published
previously in any form and none of the material is currently
under
consideration for publication elsewhere other than noted in the
cover letter to the editor. Authors declare no financial and
personal relationship with other people or organizations that could
inappropriately influence this work. All authors contributed to
and have approved the final article.
/
No sponsor provided funding for this study. Mental Health
Center of the Ministry of Health of the Republic of Azerbaijan
provided the outpatient unit, the material for clinical and
neuropsychological assessments, and electronic resources.
,'
The authors would like to thank staff of the Mental Health
Center of the Ministry of Health of the Republic of Azerbaijan.
1. Anxiety
Disorders Facts and
Statistics.
By The Recovery
Village.
Editor Megan
Hull
About
our Editorial
Team.
Medically
Reviewed
By Jenni
Jacobsen,
LCSW,
LMFT.
Updated
on 11/03/20.
2. American Psychiatric Association. Diagnostic and
Statistical Manual
of
Mental
Disorders,
Fifth
Edition
(DSM-
5), American Psychiatric Association, Arlington
2013.
3. Sedoks Kaplan 2015 Sadock BJ, Sadock VA, Ruiz P, eds.
Synopsis of psychiatry. Eleventh edition. Lippincott
Williams & Wilkins; 2015:1472 pages.
4. Bandelow
B.,
Michaelis
S.
Epidemiology
of
anxiety
disorders
in
the
21st
century.
Dialogues
in
Clinical
Neuroscience, 01
Sep
2015,
17(3):327-335;
PMID:
26487813
PMCID: PMC4610617.
5. Aliyev NA, Aliyev ZN (2020) A Mental Disorders Caused
by the COVID-19 Pandemic. Ann Psychiatry Ment Health
8(2): 1151.
6. U.S. Food & Drug Administration. FDA Requiring Labeling
Changes for Benzodiazepines. Fda.gov.
.
7. Hamilton M. The assessment of anxiety states by rating. Br
J Med Psychol 1959;32:50-5 [Medline]
8. Glantz AS (2011) Primer of Biostatistics (7thedn). McGraw
Hill Profes-
sional, New York, USA. Pg
no: 1-320.
9. Kornhuber J, Maler M, Wiltfang J, Bleich S, Degner D, et
al. (1999)
[Neuronal
potassium
channel
opening
with
flupirtine]. Fortschr Neurol
Psychiatr
67: 466-475.
10. Rupalla K, Cao W, Krieglstein J (1995) Flupirtine protects
neurons against excitotoxic or ischemic damage and inhibits
the
increase
in
cyto-
solic
Ca 2+
concentration.
Eur
J
Pharmacol 294: 469-473.
11. Osborne NN, Cazevieille C, Wood JP, Nash MS, Pergande
G,
et
al.
(1998)
Flupirtine,
a
nonopioid
centrally
acting
analgesic, acts as an NMDA antagonist. Gen Pharmacol 30:
255-263.
12. Harish S, Bhuvana K, Bengalorkar GM, Kumar TN (2012)
Flupirtine:
Clinical
pharmacology.
J
Anaesthesiol
Clin
Pharmacol 28: 172-177.
13. Schmidt WJ, Schuster
G, Wacker
E, Pergande G (1997)
Antiparkinso- nian and other motor effects of flupirtine
alone and
in
combination
with
dopaminergic
drugs.
Eur
J
Pharmacol 327: 1-9.
14. Schuster G, Schwarz M, Block F, Pergande G, Schmidt WJ
(1998)
Flupirtine:
A
review
of
its
neuroprotective
and
behavioral properties. CNS
Drug
Rev 4: 149-164.
15. Zimmer G, Balakirev M, Hofmann M, Woodcock BG,
Pergande G (1998) Evidence that the cytoprotective action
of the triaminopyridine flupirtine involves increases in Ca2+
uptake and ATP synthesis in mito- chondria. Br J Pharmacol
123: 1154-1158.
16. Schwarz M, Nolden-Koch M, Purr J, Pergande G, Block F
(1996) An- tiparkinsonian effect of flupirtine in monoamine-
depleted rats. J Neural
Transm
(Vienna) 103: 581-590.
17. Devulder
J
(2010)
Flupirtine
in
pain
management:
pharmacological properties and clinical use. CNS Drugs 24:
867-881.
18. Friedel HA, Fitton A (1993) Flupirtine: A review of its
pharmacological properties, and therapeutic efficacy in pain
states. Drugs 45: 548-569.
19. Mueller-Schwefe G (2003) [Flupirtine in acute and chronic
pain
associated
with
muscle
tenseness.
Results
of
a
postmarket surveillance study]. Fortschr Med Orig 121: 11-
18.
