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New clinical reports have recently been published on tofisopam—an anxiolytic drug currently registered as a benzodiazepine—after a long break in this research area. Neurobiological studies concerning its properties, which differ from those of benzodiazepines, are underway. The analyses presented in this study aimed to compare the effects of tofisopam, diazepam, and a placebo in the treatment of anxiety symptoms. A total of 66 outpatients (43 women and 23 men) with generalized anxiety disorder aged 19 to 74 years (M = 41.4; SD = 13.2) were randomized in three groups receiving (1) tofisopam (50 mg three times a day), (2) diazepam (5 mg three times a day), or (3) a placebo for 2 weeks. Then, throughout a 2-week washout period, the patients were monitored for withdrawal symptoms. During the last 2 weeks, the effects of tofisopam (50 mg three times a day) and diazepam (5 mg three times a day) were compared (crossover design). The mean improvement on the Hamilton Anxiety Rating Scale was significantly higher in both the tofisopam and diazepam groups compared to the placebo group. There were no significant differences between the effects of diazepam and tofisopam, whereas adverse effects and withdrawal symptoms occurred less frequently in the tofisopam group. Tofisopam did not impair cognitive abilities, and related withdrawal symptoms resembled those of the placebo. If larger future studies corroborate these findings, tofisopam should be classified as a homophtalazine. [ABSTRACT FROM AUTHOR]

New clinical reports have recently been published on tofisopam—an anxiolytic drug currently registered as a benzodiazepine—after a long break in this research area. Neurobiological studies concerning its properties, which differ from those of benzodiazepines, are underway. The analyses presented in this study aimed to compare the effects of tofisopam, diazepam, and a placebo in the treatment of anxiety symptoms. A total of 66 outpatients (43 women and 23 men) with generalized anxiety disorder aged 19 to 74 years (M = 41.4; SD = 13.2) were randomized in three groups receiving (1) tofisopam (50 mg three times a day), (2) diazepam (5 mg three times a day), or (3) a placebo for 2 weeks. Then, throughout a 2-week washout period, the patients were monitored for withdrawal symptoms. During the last 2 weeks, the effects of tofisopam (50 mg three times a day) and diazepam (5 mg three times a day) were compared (crossover design). The mean improvement on the Hamilton Anxiety Rating Scale was significantly higher in both the tofisopam and diazepam groups compared to the placebo group. There were no significant differences between the effects of diazepam and tofisopam, whereas adverse effects and withdrawal symptoms occurred less frequently in the tofisopam group. Tofisopam did not impair cognitive abilities, and related withdrawal symptoms resembled those of the placebo. If larger future studies corroborate these findings, tofisopam should be classified as a homophtalazine.

Introduction. Asthenia, vegetative manifestations, sleep disturbances and psycho-emotional background are companions of the coronavirus infection, the issue of drug correction of which is especially relevant. These symptoms disrupt the habitual way of life of patients for a long time, and in special cases lead to disability.Aim. To study the mental, somatoform and cognitive aspects of anxiety disorders after coronavirus infection during treatment with tofisopam (Grandaxin®) 150 mg/day.Materials and methods. The study included patients who had experienced a new coronavirus infection, who, after the end of treatment for the underlying disease, had complaints suggesting the presence of an anxiety disorder. The Hamilton scale was used to assess the level of anxiety. Examination of patients was carried out before the start of treatment, after 2, 4 and 6 weeks of therapy.Results and discussion. Prior to the start of therapy, all patients had an overall high level of anxiety: the average HAM-A score was 31.4 ± 2.92 points. At the end of Grandaxin® therapy, all patients showed a decrease in the level of anxiety: the average HAM-A score was 12.08 ± 2.27 points (p < 0.001). The maximum decrease in the severity of vegetative disorders was noted by the end of the 6th week of therapy with Grandaxin®. Thus, the indicator of this subscale decreased by more than 2 times – from 2.46 ± 0.54 to 1.05 ± 0.28 points (p < 0.001). The severity of insomnia during six weeks of therapy with Grandaxin® decreased from 2.56 ± 0.54 to 0.96 ± 0.45 points (p < 0.001).Conclusion. Psycho-emotional disorders (more often in the form of increased personal anxiety), sleep disorders, vegetative disorders, asthenic syndrome significantly affect the quality of life of patients who have had a new coronavirus infection. Involvement of the structures of the autonomic nervous system and central structures that regulate GABAergic transmission leads to significant vegetative failures, which requires pathogenetically substantiated drug correction of these disorders.

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Introduction. In addition to acute manifestations, coronavirus infection is characterized by long-lasting symptoms: asthenia, somatic vegetative manifestations, sleep disorders and psychoemotional background, the question of therapeutic correction of which is especially relevant.The aim of the study was to study the mental, somatoform and cognitive aspects of anxiety disorders after coronavirus infection during treatment with tofizopam (Grandaxin®) at 150 mg / day.Materials and methods. The study involved patients who had a new coronavirus infection, who 4 weeks after the end of treatment for the underlying disease had complaints that suggest the presence of an anxiety disorder. The Hamilton scale was used to assess the level of anxiety. The patients were examined before the start of treatment, after 2, 4 and 6 weeks of therapy.Results. Prior to the start of therapy, all patients had an overall high level of anxiety: the average HAM-A score was 31.72 ± 2.24 points. At the end of Grandaxin® therapy, all patients showed a decrease in the level of anxiety: the average score for HAM-A was 12.68 ± 2.04 points (p distinct – the average score on the “cognitive disorders” subscale decreased three times – from 1.6 ± 0.12 to 0.5 ± 0.09 (p˂0.001).Conclusions. Disorders of the psychoemotional background (more often in the form of increased personal anxiety), sleep disorders, autonomic disorders, asthenic syndrome significantly affect the quality of life of patients who have suffered a new coronavirus infection. A comprehensive approach is needed in the clinical diagnosis of the long-term consequences of a new coronavirus infection and their subsequent correction with drug therapy.

Background: Depression is a disease that affects millions of people worldwide, and the discovery and development of effective and safe antidepressant drugs is one of the important topics of psychopharmacology. Objectives: In this study, it was aimed to investigate the antidepressant-like activity potential of tofisopam, an anxiolytic drug with 2,3-benzodiazepine structure, and to elucidate the pharmacological mechanisms mediating this effect. Methods: The antidepressant-like activity of tofisopam was investigated using tail suspension and modified forced swimming tests. Possible interactions of tofisopam with µ- and δ-opioid receptor subtypes were clarified by pharmacological antagonism, molecular docking and molecular dynamics simulation studies. Results: Tofisopam (50 and 100 mg/kg) significantly shortened the immobility time of mice in both the tail suspension and the modified forced swimming tests. The drug, at the same doses, prolonged the duration of swimming and climbing behaviours measured in modified forced swimming tests. A dosage of 25 mg/kg was ineffective. Mechanistic studies showed that the pretreatment with p-chlorophenylalanine methyl ester (serotonin synthesis inhibitor; 4 consecutive days, 100 mg/kg), α-methyl-para-tyrosine methyl ester (catecholamine synthesis inhibitor; 100 mg/kg), naloxonazine (selective µ-opioid receptor blocker, 7 mg/kg) and naltrindole (a selective δ-opioid receptor blocker, 0.99 mg/kg) abolished the anti-immobility effect induced by the 50 mg/kg dose of tofisopam in the tail suspension tests. Our in silico studies supported the behavioural findings that the antidepressant-like effect of tofisopam is mediated by μ- and δ-opioid receptors. Conclusion: This study is the first to show that tofisopam has antidepressant-like activity mediated by the serotonergic, catecholaminergic and opioidergic systems. [ABSTRACT FROM AUTHOR]

The article is devoted to the possibilities of correction of neuropsychiatric disorders in perimenopause, a condition associated with the cessation of menstruation in a woman and a decrease in the level of ovarian steroid hormones (estrogen and progesterone) due to the loss of the ovarian follicular mass. It is known that biological and endocrine changes during this period are often accompanied by autonomic symptoms. In perimenopause, women may experience symptoms such as hot flashes and night sweats, insomnia, vaginal dryness, mood disorders, etc. Although most symptoms are not life-threatening, they can have a negative impact on the quality of life, physical and mental health of perimenopausal women. During menopause, women are at higher risk of developing depression, stress, anxiety and emotional disorders. In addition, during perimenopause, women experience not only depressive symptoms but also cognitive impairment, which may be related to changes in hormonal background. Drugs that are used in the treatment of mood disorders affect different neurotransmitters, in particular serotonin, norepinephrine and gamma-aminobutyric acid (GABA). One of the benzodiazepine derivatives is Tofisopam, first developed in Hungary and marketed in a number of European countries under the name Grandaxin. It is indicated for the treatment of neurotic and somatic disorders associated with tension, anxiety, autonomic disorders, lack of energy and motivation, apathy, fatigue, depressed mood and alcohol withdrawal syndrome, including during perimenopause. Tofisopam has good anxiolytic activity with no observable sedative, anticonvulsant, amnestic or muscle relaxant effects.

Tofisopam is an anxiolytic drug, available for prescription by gynecologist. This paper discusses three typical case vignettes, where woman’s anxiety interfered with her somatic condition and responded on tofisopam. There is also a discussion of combination of tofisopam with hormonal therapy and it’s efficacy and safety.

Despite the proven effect of menopausal hormone therapy on menopausal syndrome, a number of factors prevent perimenopausal women from receiving the treatment. The article is a review of literature on the possibility of non-hormonal treatment with tofisopam for neuro-vegetative and psycho-emotional disorders associated with climacteric syndrome. The article tells about the efficacy and safety of the drug taking into account its pharmacodynamic properties.

Herein reported is a unique synthetic route of Tofisopam, an anxiolytic drug containing a 2,3‐benzodiazepine core structure. 3,4‐Dimethoxypropylbenzene and 3,4‐dimethoxybenzoic acid, which are both of plant origin, and CO2 constitute its carbon skeleton. These three renewable substances are united by two C−C bond forming reactions, i.e. a Friedel–Crafts acylation reaction and a photoinduced carboxylation reaction to construct the major carbon framework. Finally, a methyl group is introduced by a Kumada‐type cross‐coupling reaction to furnish Tofisopam. Various analogs of Tofisopam are readily synthesized by introducing other substituents than a methyl group at the last C−C bond forming step. [ABSTRACT FROM AUTHOR]

Developed optimal conditions of quantitative analysis of tablets "Grandaxinum" and tablets "Fenazepam", using the method high-performance liquid chromatography. We used microcolony liquid chromatograph "milichrom A-02", condition analysis: gradient elution in the system lithium perchlorate, perchloric acid, water and acetonitrile, gradient linear 3700 mkl from 5 to 70 % at a flow rate of 100 mkl/min and a temperature of 40º C. Аs a standard substances were used pharmaceutical substance tofizopama and phenazepam. Conducted a validation assessment of the proposed conditions. The method is characterized by good linearity with the correlation coefficient at 0.9984 for tofizopama and 0,9991 for phenazepam in the concentration range of 0.025 – 0.5 mg/ml. the relative error of determination by the developed technique does notexceed of 1.94 %.

Aim. To compare the influence of the simple and combined with anxiolytic drug tofisopam (AT) antihypertesion therapy (AHT) on the 24-hour blood pressure (BP) profile, anxiety level and life quality of patients with uncontrolled arterial hypertension and anxiety spectrum disorder.Material and methods. Sixty-nine patients (mean age 48,5±5,3 y. o., 35 women) were randomized to 2 groups. Each group consequently during 1 year study received two types of medicines for 6 months each with cross-replacement: isolated AHT and combination AHT with AT (AHT+A). Group 1 (35 persons) for the 1st half year took AHT, and then following half year AHT+A; group 2 (34 persons) — in back order. At the end of every period the following parameters were controlled: ambulatory blood pressure monitoring, prominence of trait and reactive anxiety, and life quality. Also, the same comparisons were done for every group separately at the end of the first and second stages of treatment.Results. The initiation of combination AHT+A led to faster decrease of BP, achievement of lower mean daily and mean nocturnal systolic and diastolic BP, lower BP variability parameters. Only combination AHT+A showed adequate reducement of reactive anxiety. Combination and simple AHT in 6 months led to significant improvement of life quality, however combination AHT showed more significant values.Conclusion. Efficacy of combination AHT+A in hypertensive persons with anxiety disorder is higher comparing to simple AHT.

Nowadays in chronic diseases structure mental derangement leading to disability and mortality of population comes to the front. As a result of illicit traffic of drugs extension, using psychoactive medicinal agents by drug abusers for intensification of intoxication and alleviation of abstinence syndrome has been fixed to increase. It results in occurrence of poisonings. The main goal of the work is a development of strategy of chemical-toxicological analysis of psychoactive medical agents useable for combined poisonings via thin-layer chromatography method. The research offers the results of studying the chromatographic behaviour of tofisopam and fluoxetine combined with psychoactive medicinal agents on chromatographic plates "Sorbfil UV-254" and "Armcorb UV-254" in general solvent systems. It is shown that separation of psychoactive substances does not occur accurate enough. Therefore, it is necessary to develop particular chromatographic systems. A system of composition of toluol - acetone - 25% solution of ammonia is revealed and can be recommended in screening while carrying out a nondirectional analysis of tofisopam and fluoxetine. In this system, all combinations under research are detected. A search of particular chromatographic systems was carried out by changing the quantity of toluol, acetone and ammonia. It is established that solvent systems of toluol - acetone - 25% solution of ammonia in a ratio 50:50:1 and 50:50:4 are optimal for identification of combinations with tofisopam and fluoxetine accordingly. The developed method allows detecting tofisopam and fluoxetine in urine on a preliminary step of research both individually and in combinations with psychoactive medicinal agents.

Forensic chemical examination is carried out in order to isolate, identify and quantify toxic, narcotic, psychotropic and potent substances in the organs and fluids of the human body. The present study we researched the process of extraction of 2,3-benzodiazepine - tofisopam. There have been cases of tofisopam poisoning. And there are no descriptions of tofisopam isolation from biological fluids in the literature. Liquid extraction, an effective and commonly used method of isolation in the chemical-toxicological analysis, is used when extracting substances from blood, lymph, saliva, urine and stomach washings. The process of isolation may be influenced by the nature of the organic solvent, pH, the presence of an electrolyte, time and frequency of extraction. We have studied the effect of each factor on tofisopam isolation from aqueous solutions. It has been found that the optimal organic solvent for the extraction of the solutions is dichloroethane, which extracts maximum amount of the analyte at pH = 5.0. Saturated sodium sulphate has a salting-in effect for tofisopam. The optimum conditions for tofisopam isolating are 7 minutes with double extraction. Based on the research method of tofisopam isolating the model mixture of urine was developed. We found that this model urine mixture isolates 66.51-67.9l % of tofisopam. We performed validation assessment of the developed method for evaluation of precision and accuracy. The assessment showed the suitability of techniques for the analysis.

The article deals with the experience of tofisopam application in therapy of anxiety disorders in neurologic profile patients of the rehabilitation inpatient therapy. 45 patients with chronic vertebra-basilar insufficiency, consequences of the ischemic stroke, intervertebral discs lesions and spinal column dorsopathies were examined. The structure of psychic disorders was determined by the presence of the generalized anxiety disorder, organic anxiety disorder, emotionally instable disorder by ICD-10. The physiologic problem characterizing these patients was related to pain and mobility disturbance, general somatic state as well as situations preconditioned by a fact of chronic disease and its psychosocial consequences. The effectiveness of tofisopam is shown with use of psychometric scales CGI, HADS and Spielberg-Khanin Anxiety Scale with respect to reactive anxiety preconditioned by external factors as well as its good tolerability, safety and lack of negative effect on the cognitive sphere. A conclusion about the expediency of tofisopam for rehabilitation of neurologic patients is made, especially patients with vertebra-basilar insufficiency.

Aim. To study efficiency and safety of hydroxizine (H) and tofisopam (T) therapy in DM patients with generalized organic anxiety disorders and subsyndromicanxiety the overall prevalence of which among diabetic patients amounts to 45-50%. Materials and methods. This open prospective randomized comparative study included 60 DM patients with anxiety disorders (AD) of whom 95%presented with arterial hypertension. The medicines were prescribed at mean therapeutic doses for 3 months followed by 1 month withdrawal period.The efficiency of anxiolytics was estimated from dynamic patterns of reactive anxiety (RA), personal anxiety (PA, Spielberger scale), somatic anxietysymptoms (Giessen questionnaire), HbA1c level, systolic and diastolic AP (SAP, DAP), heart rate. Results. Therapy with anxiolytics for 3 months resulted in the decrease of the HbA1c level from 7.9?1.4 to 7.4?1.4%, total somatic anxiety scorefrom 38.0?13.2 to 31.5?12.2, PA from 52.5?9.7 to 47.1?8.8, RA from 32.3?9.0 to 25.5?9.3, SAP from 141.4?12.4 to 129.8?13.5 mmHg,DAP from 82.3?7.4 to 77.8?8.6 mm Hg, HR from 76.3?9.5 to 72.7-5.6 (in all cases p

Purpose: To develop a simple, fast and sensitive spectrophotometric method for the determination of tofisopam in tablet dosage form. Methods: Tofisopam as n-electron donor was reacted with two p-acceptors, namely, chloranilic acid (ChA), and 7,7,8,8 tetracyanoquinodimethane (TCNQ) to form charge transfer complexes. The complexes were evaluated spectrophotometrically at 520 and 824 nm for ChA and TCNQ, respectively. The optimum conditions for the reaction were determined and optimized. The developed method was compared with Japanese Pharmacopeia method. Results: The calibration curve was linear in the ranges 25 - 125 and 30 - 150 µg/mL for ChA and TCNQ, respectively. The lower limit of detection was 8.0 and 10.0 µg/mL for ChA and TCNQ, respectively while the slope and intercept of the calibration curves were 0.0025 and 0.011 and 0.0115 and -0.237, for ChA and TCNQ, respectively. Conclusion: The developed methods for tofisopam have good accuracy and precision, and comparable to a standard pharmacopeial method. The methods can be applied for routine analysis and in quality control. [ABSTRACT FROM AUTHOR]

In the course of the elaboration of a new manufacturing process of anxiolytic drug tofisopam, a stereospecific lithium-catalyzed Oppenauer-type oxidation was observed. Bromine-lithium exchange on the ethylene ketal of 3-(2-bromo-4,5-dimethoxyphenyl)pentan-2-one followed by quenching with 1 equivalent of 3,4-dimethoxybenzaldahyde gave the corresponding alcohols as a mixture of two diastereomeric racemates. On the other hand, when 2.5 equivalents of the aldehyde were applied, only one of the two alcohol diastereomers could be isolated. The lithium alkoxide precursor of the other diastereomeric alcohol, due to the presence of the excess of benzaldehyde as the oxidant, underwent an Oppenauer-type oxidation to give the corresponding ketone. [ABSTRACT FROM AUTHOR]

Abstract: 1-(3,4-Dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine (tofisopam) contains one chiral center, so two enantiomeric forms exist. The ring system of tofisopam possesses two sterically stable boat structures, leading to two distinct conformers for each enantiomer. A method was developed for the separation of these enantiomers and conformers in the drug substances and drug products. Separation was achieved with a separation factor of at least 3.9 for any adjacent peaks. Validation of the method challenged linearity, limit of detection, limit of quantification, specificity, accuracy, repeatability, intermediate precision, robustness, and stability of standard and sample solutions, and all validation results met the acceptance criteria. A study of accuracy at 80%, 100%, and 120% levels gave recoveries of 100±1%. The RSD of six sample injections for repeatability was less than 0.5%. The detection limit of tofisopam enantiomer was as low as 0.12μg/mL. The kinetics and thermodynamics of the interconversion of tofisopam conformers were also investigated, and the kinetic and equilibrium constants of the interconversion process were determined at 15°C, 25°C, and 35°C. [Copyright &y& Elsevier]

Abstract: Tofisopam (1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine) has been shown to be an effective anxiolytic agent in the wide-ranging clinical practice. A high sensitive gas chromatography nitrogen phosphorous detection (GC-NPD) bioanalytical method was developed and validated for the purpose of pharmacokinetic study of tofisopam. A liquid–liquid extraction method was used for the sample preparation. The mean recovery for tofisopam was 69.8% and the inter- and intra-day precision values were well below the 15% limit established for bioanalytical methods. A similar compound, girizopam was used as internal standard. The assay was linear in the 5–500ng/ml range corresponding to therapeutically relevant plasma levels. The concentrations of the compound were measured in the plasma samples of 12 healthy male volunteers and the pharmacokinetic parameters were determined from the plasma concentration–time data. A rapid absorption and distribution, relatively short biological half-life and considerable inter-individual variation in the plasma concentration levels of parent compound were the main characteristics of the pharmacokinetics of tofisopam. According to these results, the new (GC-NPD) bioanalytical method proved to be capable of measuring concentration of tofisopam in human plasma and was successfully applied in a single dose pharmacokinetic study. [Copyright &y& Elsevier]

Objective: To study the association between nitrazepam, medazepam, tofisopam, alprazolum and clonazepam treatments during pregnancy and prevalence of different congenital abnormalities (CAs). Materials and methods: A matched case–control study using cases with CAs and population controls from the dataset of the nationwide Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980–1996. Results: Of 38,151 pregnant women who had babies without any defects (population control group), 75 (0.20%) were treated with these five benzodiazepines during pregnancy. Of 22,865 pregnant women who delivered offspring with CAs, 57 (0.25%) had benzodiazepine treatment. The occurrence of five benzodiazepine treatments during the second and third months of gestation, i.e. in the critical period for most major CAs did not show significant differences in matched case–control pairs. Conclusion: Treatment with five benzodiazepines studied during pregnancy did not present detectable teratogenic risk to the fetus in humans but the amount of information was limited for different CAs. [Copyright &y& Elsevier]

Twelve normal subjects were tested on a number of measures both before and 1,3 and 5 h after 10 mg diazepam, 100 and 200 mg tofisopam and a placebo. The measures included self-ratings of mood, bodily symptoms, hostility and sleep, the electroencephalogram (EEG), reaction time, tapping, digit symbol substitution, the symbol copying test, and plasma levels. Diazepam showed a clear profile of action, producing EEG changes, pronounced sedation and psychological impairment. The last two effects were maximal at 1 h and had worn off by 5 h. The EEG was recorded at 3 h only. Tofisopam in no way resembled diazepam. It produced no changes on the EEG or psychological tests and a very mild stimulant effect was apparent on the ratings. While diazepam was easily detectable in the blood, tofisopam did not bind to benzodiazepine receptors. [ABSTRACT FROM AUTHOR]

Twelve healthy male volunteers were treated (double-blind crossover design) with tofisopam (a new 3,4-benzodiazepine), diazepam, or placebo, on 2 consecutive days each. Psychomotor skills were impaired after a single dose of diazepam (10 mg) given on day 1. Measurements on day 2 showed that some tolerance had developed to the diazepam-induced impairment of reactive and coordinative skills, but not to its effects on flicker fusion or on the extraocular muscle balance. Tofisopam failed to impair performance both as a single dose (100 mg) and after repeated doses (100+50+50+100 mg). The subjects felt more fatigue, dizziness, calmness, and passiveness after diazepam than after tofisopam. When either drug was given together with 0.8 g/kg ethanol on day 2, the breath ethanol concentrations were 0.7-1.0 mg/ml and all psychomotor skills were impaired. Diazepam+ethanol particularly impaired memory and learning as well. After this combination the subjects were classified (time anticipation test) as 'disqualified drivers' more often than after placebo. It is concluded that diazepam,as well as either benzodiazepine with ethanol, may reduce the ability to drive vehicles or operate machinery. [ABSTRACT FROM AUTHOR]