[Teraligen in the complex treatment of anxiety-phobic, behavioral and depressive syndromes in children and adolescents with schizotypal disorder]. / Teralidzhen v kompleksnoi terapii trevozhno-fobicheskikh, povedencheskikh i depressivnykh narushenii u detei i podrostkov s shizotipicheskim rasstroistvom.

OBJECTIVE: To determine the frequency of prescribing and the main therapeutic targets of Teraligen in the treatment of Schizotypal disorder (STD) in childhood and adolescence. MATERIAL AND METHODS: The sample consisted of 151 patients aged 7 to 16 years with a diagnosis of STD (F 21), of which 31.1% (n=47) of female patients and 68.9% (n=104) of male patients who received inpatient or outpatient treatment at the FSBI NCPZ from 2008 to 2020. The study was conducted by clinical-psychopathological, clinical-catamnestic, and statistical methods. RESULTS: Teraligen was prescribed by psychiatrists to patients with STD in 74.2% of cases, of which in 46.4% of cases patients received Teraligen even before the diagnosis of STD in connection with complaints of neurotic disorders (anxiety, fears and sleep disorders) (n=30), as well as in connection with autistic-like behavior (n=22). At the time of follow-up, 55% (n=83) of patients received Teraligen, of which 63.9% (n=53) of patients were prescribed it for the first time. The applied schemes of prescribing Teraligen for the treatment of anxiety-phobic, depressive and behavioral syndromes within the framework of the STD in a relatively age-related aspect are presented. CONCLUSION: The high frequency of prescribing Teraligen by psychiatrists and neurologists to children and adolescents with STD at different stages of observation is shown, which reflects the confidence of specialists in this drug. Teraligen has demonstrated a multidimensional pharmacological effect, including a mild antipsychotic effect, providing reduction of a wide range of psychopathological symptoms, with good tolerability and drug interaction. The study of the possibilities of Teraligen, both for monotherapy and for augmentation of the treatment of mental pathology in childhood, remains relevant.

Rilmazafone: A designer benzodiazepine pro-drug involved in fatal intoxications.

Rilmazafone is a pro-drug that can be prescribed in Japan to treat insomnia. Rilmazafone metabolizes into active compounds by a ring closure resulting in a triazolo benzodiazepine structure similar to alprazolam. In mid-2022, the National Board of Forensic Medicine in Sweden were requested to investigate two separate deaths with the suspected use of pagoclone. Packages labeled "Pagoclone" were found at each scene that was suspected to contain rilmazafone based on website information. During screening by high resolution mass spectrometry, rilmazafone metabolites were presumptively identified. Due to the lack of reference material for the active metabolites, the metabolites were synthesized in house and quantification of the compounds identified in the two autopsy cases was prompted. In Case 1, femoral blood concentrations of 7.9, 65 and 170 ng/g of the metabolites rilmazolam, N-desmethyl rilmazolam and di-desmethyl rilmazolam, respectively, were detected. Additional toxicological findings included the medications haloperidol, alimemazine, fluoxetine, olanzapine and acetaminophen. In Case 2, femoral blood concentrations of 1.7, 1.4 and 70 ng/g of rimazolam, N-desmethyl rilmazolam and di-desmethyl rilmazolam, respectively, were detected. Additional toxicological findings included loperamide, alimemazine and pregabalin. The intake of rilmazafone was determined as the cause of death in Case 1 and contributed in the Case 2.

[Efficacy and safety studies review of Teraligen usage in psychiatric practice and general medicine]. / Obzor issledovanii effektivnosti i bezopasnosti primeneniya preparata Teralidzhen v psikhiatricheskoi praktike i obshchei meditsine.

OBJECTIVE: Determination of the dose-dependent effect of the Teraligen for various nosological forms of disorders in psychiatric practice and general medicine. MATERIAL AND METHODS: Analysis of 98 publications included in the database of the RISC (2012-2021) with the identification of disorders (according to ICD-10) in which Teraligen is prescribed or can be used (in adults and children from the age of 7). RESULTS: Despite a rather long and successful history use, research work on the study drug Teraligen continues. Currently Teraligen is widely and actively used by doctors of various specialties in the psychiatry, neurology, pediatrics, gerontology, internal medicine, gastroenterology, gynecology, cardiology, endocrinology and other disciplines. The drug is presented in several release forms: Teraligen 5 mg tablets; Teraligen retard 20 mg; Teraligen solution for intravenous injections. Teraligen is characterized by the following psychotropic effects: anxiolytic (++ - a distinct, moderately pronounced effect); sedative (++); hypnotic (++); antidepressant (+ - the effect is distinct, but expressed slightly and does not determine the drug main prescriptions spectrum); antipsychotic (± - the effect is weakly expressed and clinically insignificant when using conventional (5-80 mg/day) drug dosages). CONCLUSION: According to the authors, the main effect of the «small¼ neuroleptic/antipsychotic Alimemazine (Teraligen ) is primarily aimed at pathological anxiety and affective instability. Its use is possible in various age groups, as it has a fairly high safety. In addition, like other «small¼ neuroleptics/antipsychotics with a predominantly sedative effect, the drug can be used to correct neuroleptics-prolongs side effects with dominant manifestations in the form of anxiety, irritability and insomnia.

[Alimemazine in treatment of agitation in schizophrenia]. / Primenenie Alimemazina pri kupirovanii vozbuzhdeniya u bol'nykh shizofreniei.

OBJECTIVE: An analysis of the efficacy and safety of additional therapy of excitement with the injectable form of alimemazine during exacerbations of schizophrenia with psychomotor agitation, impulsivity, including dangerous behavior, irritability, conflict, hostility, aggressiveness, anxiety, sleep disturbances (insomnia). MATERIAL AND METHODS: Thirty patients, aged 18 to 65 years, with a diagnosis of «paranoid schizophrenia¼, established in accordance with the ICD-10 criteria, were studied. The patients received treatment with a second-generation antipsychotic and alimemazine (intramuscular injection solution) in daily dose from 25 mg to 150 mg during no more than 9 days. The patients were assessed with psychometric scales (PANSS, ABS, HARS and VAS) four times during the observation period. RESULTS AND CONCLUSION: During therapy with a combination of second-generation antipsychotics and alimemazine solution for intramuscular injection, a reliable (p<0.001) reduction in the severity of psychotic symptoms assessed with PANSS was achieved by 8-9 days (the average total score decreased by 30% relative to the initial level) that indicated the improvement in all manifestations of schizophrenia exacerbation. A decrease of 34.8% (p=0.007) in the risk of aggression (PANSS points S1-S3) was established. The level of excitation on the agitation scale (ABS) decreased by 3.6% (p<0.001). In 50% of patients, manifestations of anxiety disappeared, and the average HARS score decreased by 2.2 times compared with the initial level (p<0.001). Almost half of the patients noted the normalization of sleep, and the average value of sleep disturbance on a visual analogue scale decreased threefold compared with the initial level (p<0.001). The observed adverse events were moderate or mild. Alimemazine shows the highest efficacy in the treatment of anxiety arousal in patients with schizophrenia with affective-delusional attacks.

Neddylation of sterol regulatory element-binding protein 1c is a potential therapeutic target for nonalcoholic fatty liver treatment.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for progression of steatohepatitis, liver cirrhosis, and liver cancer. Although pathological condition of NAFLD, which arises from an excessive accumulation of triglyceride in the liver, is accompanied by elevated sterol regulatory element-binding protein 1c (SREBP1c) level, it is largely unknown which factors are involved in the modification of SREBP1c. In this study, we discovered that neddylation of SREBP1c competes with its ubiquitination and stabilizes SREBP1c protein level, and eventually promotes hepatic steatosis. We also demonstrated that human homolog of mouse double minute 2 (HDM2) acts as an E3 neddylation ligase of SREBP1c. Further, treatment with the neddylation inhibitor, MLN4924, attenuates high-fat diet-induced hepatic steatosis by reducing the levels of SREBP1c protein and hepatic triglyceride. Our results indicate that the blockade of SREBP1c neddylation could be a novel approach in the defense against NAFLD.

[The efficacy of alimemazine (solution for intramuscular injection) in complex with antidepressants in the treatment of anxiety and depressive disorders]. / Otsenka éffektivnosti preparata Alimemazin (rastvor dlia vnutrimyshechnogo vvedeniia) v lechenii trevozhno-depressivnykh rasstroistv.

AIM: To evaluate the efficacy of alimemazine in the form of a solution for intramuscular injections in the treatment of anxiety and depressive disorders. MATERIAL AND METHODS: Twenty patients, who met ICD-10 criteria for anxiety and depressive disorders, participated in the clinical observation. Alimemazine was used in the form of a solution for intramuscular injection (5 mg/ml) along with SSRIs and SNRIs. RESULTS: The significant positive dynamics in the reduction of anxiety-depressive disorders, sleep disorders and vegetative symptoms was observed in patients treated with alimemazine (solution) and antidepressants from the group of SSRIs and SSRIs. CONCLUSION: The drug has demonstrated efficacy and a favorable tolerability profile.

[The development of the methods for the extraction, identification, and quantitative determination of alimemazine in the biological fluids from the laboratory animals under the acute poisoning conditions]. / Razrabotka metodik izolirovaniia, obnaruzheniia i kolichestvennogo opredeleniia alimemazina v biologicheskikh zhidkostiakh laboratornykh zhivotnykh pri ostrykh otravleniiakh.

There is the present-day tendency toward prescribing atypical neuroleptics for the management of neurologic and psychic disorders. Alimemazine appears to be very frequently used for this purpose due to the broad spectrum of its actions. At the same time, cases of alimemazine poisoning with the fatal outcome have been described. The objective of the present study was determine alimemazine in the biological fluids from the laboratory animals under the acute poisoning conditions. The experiments were carried with the use of the Wistar rats having 200 g body weight. Alimemazine was isolated from their biological fluids (blood plasma and urine) using the liquid-liquid extraction techniques developed specially for the purpose of this study. Alimemazine was extracted and quantitatively determined by HPLC and HPLC/MS. The method for the isolation of alimemazine from the urine and blood plasma is described. The results of the study give evidence that the maximum amount of the substance of interest can be extracted from the blood plasma within 1 hour after the administration of the toxic dose of alimemazine and within 2 hours after the administration of its therapeutic dose. The maximum amount of alimemazine in the urine is found within 3 hours after the administration of its therapeutic dose to the laboratory animals. It is concluded that the proposed methods for the extraction of alimemazine from the biological fluids can be included in the scheme of the chemical toxicological analysis of this substance.

Trimeprazine is enantioselectively degraded by an activated sludge in ready biodegradability test conditions.

A great number of available pharmaceuticals are chiral compounds. Although they are usually manufactured as racemic mixtures, they can be enantioselectively biodegraded as a result of microbial processes. In this paper, a biodegradability assay in similar conditions to those recommended in OECD tests of enantiomers of trimeprazine (a phenothiazine employed as a racemate) is carried out. Experiments were performed in batch mode using a minimal salts medium inoculated with an activated sludge (collected from a Valencian Waste Water Treatment Plant, WWTP) and supplemented with the racemate. The concentration of the enantiomers of trimeprazine were monitored by means of a chiral HPLC method using a cellulose-based chiral stationary phase and 0.5 M NaClO4/acetonitrile (60:40, v/v) mobile phases. Experiments were performed at three concentration levels of the racemate. In parallel, the optical density at 600 nm (OD600) was measured to control the biomass growth and to connect it with enantioselectivity. The calculated enantiomeric fractions (EF) offer the first evidence of enantioselective biodegradation of trimeprazine. A simplified Monod equation was used as a curve fitting approach for concentration (S), biodegradation (BD), and for the first time, EF experimental data in order to expand the usefulness of the results. Precision studies on S (repeatability conditions) and, for the first time, EF (intermediate precision conditions) were also performed.

[The safety and efficacy of alimemazine (teraligen) in relieving anxiety in patients with alcohol addiction]. / Éffektivnost' i bezopasnost' primeneniia preparata alimemazin (teralidzhen) dlia kupirovaniia trevogi u patsientov s sindromom zavisimosti ot alkogolia.

AIM: To assess the efficacy of monotherapy of anxiety in alcoholism with alimemazine (teraligen). MATERIAL AND METHODS: Thirty-six patients with alcohol addiction were treated with alimemazine in dose 15 mg during 9 month. In control group (11 patients) teraligen was no used. RESULTS AND CONCLUSION: A significant positive effect of treatment with teraligen was observed. There were the improvement in alcohol addiction course, decrease in scores on the Addiction Severity Index (ASI) from severe to mild level and decrease in trait and state anxiety measured with the Spielberger-Khanin scale from high to low levels. The reduction on symptoms of depression from moderate (at baseline) to subdepressive levels on the Beck Depression Inventory was noted in the end of treatment.

Properties of the tick-borne encephalitis virus population during persistent infection of ixodid ticks and tick cell lines.

Tick-borne encephalitis virus (TBEV) is the causative agent of tick-borne encephalitis (TBE), a vector-borne zoonotic neuroinfection. For successful circulation in natural foci the virus has to survive in the vector for a long period of time. Information about the effect of long-term infection of ticks on properties of the viral population is of great importance. In recent years, changes in the eco-epidemiology of TBEV due to changes in distribution of ixodid ticks have been observed. These changes in TBEV-endemic areas could result in a shift of the main tick vector species, which in turn may lead to changes in properties of the virus. In the present study we evaluated the selective pressure on the TBEV population during persistent infection of various species of ticks and tick cell lines. TBEV effectively replicated and formed persistent infection in ticks and tick cell lines of the vector species (Ixodes spp.), potential vectors (Dermacentor spp.) and non-vector ticks (Hyalomma spp.). During TBEV persistence in Ixodes and Dermacentor ticks, properties of the viral population remained virtually unchanged. In contrast, persistent TBEV infection of tick cell lines from both vector and non-vector ticks favoured selection of viral variants with low neuroinvasiveness for laboratory mice and substitutions in the E protein that increased local positive charge of the virion. Thus, selective pressure on viral population may differ in ticks and tick cell lines during persistent infection. Nevertheless, virus variants with properties of the original strain adapted to mouse CNS were not eliminated from the viral population during long-term persistence of TBEV in ticks and tick cell lines.

Are antihistamines effective in children? A review of the evidence.

BACKGROUND AND AIMS: During the last decades, much attention has been paid to off-label and unlicensed prescriptions in paediatrics. However, on-label prescribing can also cause health issues. In this paper, the case of first-generation H1-antihistamines is investigated, notably the range of indications for which products are licensed in different European countries and the evidence base (or lack thereof) for each indication, as well as reported adverse drug reactions. METHODS: Review of the Summary of Product Characteristics of first-generation H1-antihistamines with a focus on paediatric use. This is plotted against the evidence available in the literature. RESULTS: This investigation shows a large variability in labelled indications and licensing ages when compared in five different European countries. Moreover, most of the indications are not based on clinical trials evaluating efficacy and safety of these drugs in children. CONCLUSIONS: Many of the licensed indications of first-generation antihistamines do not appear to be evidence based.

Alimemazine poisoning as evidence of Munchausen syndrome by proxy: A pediatric case report.

Munchausen syndrome by proxy (MSBP), also known as fabricated or induced illness in a child by a caretaker, is a form of abuse where a caregiver deliberately produces or feigns illness in a person under his or her care, so that the proxy will receive medical care that gratifies the caregiver. The affected children are often hospitalized for long periods and endure repetitive, painful and expensive diagnostic attempts. We present an analytically confirmed case of MSBP by alimemazine. A 3-year-old boy was brought repetitively to a Pediatric Emergency Department by his mother because he presented limb tremors, dysarthria, obnubilation, and ataxia and generalized tonic-clonic seizures coinciding with intermittent fever. Neither the rest of the physical examination nor the complementary tests showed any significant alterations. MSBP was suspected and a routine systematic toxicological analysis in urine and blood was requested. Alimemazine was detected in all biological samples. The administration of this drug was never mentioned by the mother and the subsequent interview with her corroborated the suspicion of MSBP. Clinically, after separation from the mother, the child's neurological symptoms gradually improved until the complete disappearance of the cerebellar symptoms. Alimemazine was quantified in serum, urine, gastric content and cerebrospinal fluid samples by gas chromatography-mass spectrometry (maximum serum level was 0.42µg/ml). Hair quantification of alimemazine was performed by ultra-performance liquid chromatography-tandem mass spectrometry in different segments of hair. The results confirmed regular substance use during the at least eight last months (8.8, 14.7, 19.7 and 4.6ng/mg hair starting from most proximal segment). This patient represents the first case published with analytical data of alimemazine in blood, urine, gastric content, cerebrospinal fluid and hair, which allowed us to prove an acute and repetitive poisoning with alimemazine as evidence of MSBP.

[The multicenter non-interventional, prospective observational program on the study of practical use of teraligen in patients diagnosed with autonomic disorder (START2): a local Russian experience with the use of the Russian version of The Four-Dimensional Symptom Questionnaire (4DSQ). An intermediate analysis].

AIM: To develop a new instrument able to identify pathological states and assess their changes during medication treatment. We aimed to study the typical practice of using alimemazine (teraligen) in patients with the diagnosis of autonomic nervous system disorder and to test the Russian version of @The Four-Dimensional Symptom Questionnaire@ (4DSQ) for measuring distress, depression, anxiety and somatization. MATERIAL AND METHODS: We examined 3053 patients (mean age 42.09 ± 11.71 years) who received teraligen in doses gradually increasing from 5 to 15 mg per day. The observational program was carried out in over 600 outpatient clinics of the Russian Federation. The 4DSQ was administered before treatment and 4 weeks after treatment. The Clinical Global Impression (CGI) scale was used before, during (after 2 weeks) and after (4 weeks) treatment with teraligen. RESULTS AND CONCLUSION: There was a significant improvement of patient's state assessed both by physicians (CGI scale) and by patients (96 and 98%, respectively). The 4DSQ was sensitive to the parameters of response to treatment with teraligen: parameters obtained at baseline and 4 weeks after the beginning of treatment differed significantly demonstrating a significant decrease in distress, anxiety and somatization.

[The efficacy and safety of teraligen in patients with brain ischemia, stages I and II, and psychoautonomic syndrome].

OBJECTIVE: To assess the efficacy and safety of teraligen in patients with psychoautonomic syndrome comorbid to brain ischemia. MATERIAL AND METHODS: Forty-five patients, aged from 42 to 65 years (mean age 56 years), diagnosed with brain ischemia, stages I and II, with the signs of psychoautonomic syndrome were examined. Thirty-five patients received teraligen in the daily dose of 15 mg. The control group comprised 10 patients who were not treated with this drug. The duration of treatment was 60 days. Neurological status, autonomic changes, cognitive functions and mental state were assessed during the treatment. Neurophysiological examination (EEG and P300 event-related potential) were performed in the first and last visits. RESULTS AND CONCLUSION: The distinct positive dynamics of the decrease of psychoautonomic symptoms, cephalgic syndrome, sleep normalization as well as the improvement of cognitive function were noted. Good tolerability and no side-effects, in particular, those related to vascular disorders, were demonstrated. Clinical results were supported by the results of neurophysiological examinations. The drug can be recommended for treatment of psychoautonomic syndrome in elderly patients with brain ischemia, stages I and II.

Death of an alcohol-dependent patient following intentional drug intoxication: implication of baclofen?

Used in the treatment of spasticity at low doses, baclofen is also prescribed off-label at high doses for the treatment of alcohol dependence. Several cases of baclofen intoxication have been reported, but only 1 case deals with the treatment of alcohol dependence. Thus, we report the first death in the context of baclofen off-label use of an alcohol-dependent patient with a high blood baclofen concentration after intentional drug intoxication. The safety profile of baclofen in the treatment of alcohol dependence is reviewed and discussed, underlining the obligatory caution that may support any prescription of high doses of baclofen in this off-label indication and especially in patients with concomitant psychiatric disorders.

Case report of atopic dermatitis with refractory pruritus markedly improved with the novel use of clonidine and trimeprazine.

We report a 6-year-old boy with severe atopic dermatitis and refractory pruritus. The novel use of clonidine, an adrenergic agonist, along with trimeprazine, led to dramatic improvement. This represents the first case report of clonidine's effect in relieving pruritus in atopic dermatitis.

Association between prescribing hypnotics for parents and children in Norway.

OBJECTIVE: To describe the dispensing of the hypnotic alimemazine to children aged 0-3 years and investigate the association between dispensing of alimemazine to children and dispensed hypnotics to their parents. DESIGN: An observational cohort study linking information from the Medical Birth Registry of Norway and the Norwegian Prescription Database. Hypnotics dispensed to parents in a 1-year period before pregnancy was associated with dispensed alimemazine for children aged 0-3 years. PATIENTS AND SETTING: All children born in Norway in 2008 (N=59 325) and their mothers and fathers were included. MAIN OUTCOME MEASURES: Dispensed alimemazine to children during the first 3 years of life. RESULTS: Three percent of children received alimemazine. Dispensed hypnotics to mothers increased the risk of the child receiving a prescription for alimemazine, OR of 2.3 (1.7-3.0) for boys and 1.7 (1.2-2.4) for girls. When both parents had been dispensed prescriptions for hypnotics, the risk increased nearly threefold. A dispensed alimemazine prescription was also associated with dispensed prescriptions for antidepressants to both mother and father, mother's smoking, the child's gender and child's prescriptions for antibiotics, respiratory drugs and dermatological steroids. CONCLUSIONS: Dispensed alimemazine to children under 3 was associated with parents' previous use of hypnotics, indicating that factors other than the child's health influence the use of hypnotic drugs in infancy and toddler years. The frequent usage of alimemazine in children below 3 years and the association with parents' use of hypnotics should concern prescribing doctors.

Identification of small molecules that promote human embryonic stem cell self-renewal.

Human embryonic stem cells (hESCs) and induced pluripotent cells have the potential to provide an unlimited source of tissues for regenerative medicine. For this purpose, development of defined/xeno-free culture systems under feeder-free conditions is essential for the expansion of hESCs. Most defined/xeno-free media for the culture of hESCs contain basic fibroblast growth factor (bFGF). Therefore, bFGF is thought to have an almost essential role for the expansion of hESCs in an undifferentiated state. Here, we report identification of small molecules, some of which were neurotransmitter antagonists (trimipramine and ethopropazine), which promote long-term hESC self-renewal without bFGF in the medium. The hESCs maintained high expression levels of pluripotency markers, had a normal karyotype after 20 passages, and could differentiate into all three germ layers.