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Assessment of the safety and clinical efficacy of the Brainmax in therapy of non-demented patients with a mild cognitive impairment
Abstract
Objective:
The assessment of the clinical efficiency and safety of the drug Brainmax and its influence on the degree of functional recovery in the treatment of patients with non-dementia cognitive disorders with this drug.
Material and methods:
An open multicenter randomized study included 60 patients of 18-55 years with light and moderate CI, having complaints of the cognitive spectrum. They used a clinical and neurological study using generally accepted scales and tests (MoCA, MMSE, MFI-20 tests, Schulta, DSST tests and an assessment of the quality of life of SF-36). Patients were randomized in two groups comparable by age and gender. Group 1 was treated with Brainmax per os twice every day for 14 days. After 10-days rest they received same medication for another 14 days. Group 2 was treated with Brainmax per os twice every day for 14 days, without the continuation. The total duration of the study was 40 days, the assessment of their condition was carried out on the 1st day (visit 1), after 15 days (visit 2) and after 40 days (visit 3) using the indicators of the above scales and tests in comparison with the background data. Safety assessment was carried out by the presence and structure of undesirable phenomena.
Results:
The use of Brainmax led to a significant improvement in cognitive performance according to all generally accepted scales and tests (concentration and maintaining of attention, working memory, visual-constructive skills, volume and speed of attention speed, information processing and executive functions), as well as to the decrease severity of asthenia and improvement of the quality of life.
Conclusion:
Brainmax has shown a good safety profile, tolerability and clinical efficacy in the treatment of young and middle-aged patients with non-demented cognitive impairment. Significant improvement was observed both with single and double course administration of the drug, but a significantly better effect was noted after its repeated course, which reflects, among other things, the cumulative effect of the active substances of this drug and makes longer use of the drug Brainmax justified and appropriate in these categories of patients. The data obtained allow us to recommend the wider use of the drug Brainmax in clinical practice for the treatment of CI in patients of different ages, which will optimize therapy and improve the course and outcome of the disease.
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Aim. To study the efficacy and safety of a drug product based on the succinic acid complex with trimethylhydrazine used to treat patients with asthenic syndrome after a new coronavirus infection (COVID-19).
Materials and methods. A prospective, multicenter, comparative, randomized, double-blind, placebo-controlled study of the safety and efficacy of sequential therapy with Brainmax enrolled 160 patients 1216 weeks after coronavirus infection (no more than 12 months). The study was conducted at 6 healthcare centers in different regions of the Russian Federation. At the enrollment, clinical and neurological examination and the following tests were performed: complete blood count, urinalysis, blood chemistry, coagulation test, pulse oximetry, electrocardiography, glomerular filtration rate calculation (according to CockcroftGault formula) were performed. Also, the patients were assessed using the following tools: VAS headache rating scale, MFI-20 asthenia scale, PSQI index, FAS-10 fatigue assessment scale, Dizziness Handicap Inventory (DHI), MoCA-test for cognitive impairment assessment, Beck Anxiety Inventory, Krd Autonomic Index.
Results. The primary endpoint was the mean reduction in the MFI-20 asthenia scale score after the therapy (Visit 5, 41st day of therapy) compared to data from Visit 0 (beginning of therapy). A clinically significant advantage of the study drug versus the placebo was demonstrated, with a median absolute change in the MFI-20 score of -19.5 [-27; -11] points in the Brainmax drug group and -3 [-7; 1] score in the placebo group (p0.001). A significant sleep quality improvement according to the PSQI index was shown in the study group: by -2.5 [-4; -1] points versus no improvement in the placebo group (0 [-3; 0], p0,001). Significant differences were also noted for the following secondary endpoints: PSQI sleep quality scale, FAS-10 fatigue assessment scale, DHI, and Beck Anxiety and Depression Inventory. There was also a decrease in patients' complaints of cognitive deterioration according to the CGI scale.
Conclusion. Our study clearly demonstrated the efficacy and high safety profile of Brainmax in a representative sample of patients with the post-COVID syndrome.
The article presents the results of an in vitro study of the synergetic effect evaluation of the combined preparation based on coordination complex ethylmethylhydroxypyridine succinate and trimethylhydrazinium propionate on energy metabolism and cell respiration.
The aim of the study was to evaluate the mitochondria-directed action of the metabolic and antioxidant preparation based on succinic acid coordination complex with trimethylhydrazinium in relation to optimizing the energy metabolism in the cells under the oxidative stress conditions, as well as against the background of ischemic processes.
Materials and methods. The study of the hydroxysuccinate complex effect of the drug Brainmax® components was carried out on isolated mouse liver mitochondria. In the course of the study, the potential of mitochondria, the generation rate of hydrogen peroxide during the respiration, the respiration rate were evaluated in the following positions: a) unstimulated by malate and pyruvate, b) stimulated by malate and pyruvate (complex I substrates), by succinate (complex II substrates), c) against the background of the initial section of the electron transport chain blockade by rotenone, d) in phosphorylation blockade by oligomycin, e) against the background of the FCCP-induced uncoupling, and f) in cyanide-blocked complex IV (cytochrome C oxidase).
Results. It has been shown that the succinic acid coordination complex with trimethylhydrazinium, which is the active principle of the Brainmax® drug, significantly reduced the transmembrane potential of mitochondria (IC 50 =197±5 µM), compared with the widely used preparations of ethylmethylhydroxypyridine succinate and trimethylhydrazinium propionate, which facilitates the transfer of the produced ATP into the cell and preserves a vital activity of mitochondria even under stress. In the study of the mitochondrial respiration stimulated by the substrates of complex I (NADP-coenzyme Q-oxidoreductase), pyruvate and malate, the studied drug led to a more pronounced increase in the oxygen consumption with IC 50 =75±6 µМ. When evaluating the effect of the complex on the production of ATP by mitochondria, the most pronounced effect was observed with the addition of studied complex, which indicated to the uncoupling of respiration and oxidative phosphorylation at the given concentrations of the studied compounds. When assessing the effect of the complex on the production of hydrogen peroxide by isolated mitochondria, a significant decrease in the peroxide production was shown in the samples containing the complex of trimethylhydrazinium propionate and EMHPS.
Conclusion. Based on totality of the results obtained, it can be assumed that a favorable conformation of the pharmacophore groups of ethylmethylhydroxypyridine succinate and trimethylhydrozinium propionate coordination complex included in the composition of Brainmax® leads to a synergetic interaction and more pronounced pharmacological effects on target cells. This complex provides stabilization of a mitochondrial function, intensification of the adenosine triphosphate energy production and the optimization of energy processes in the cell, reduces the severity of the oxidative stress and eliminates undesirable effects of an ischemic-hypoxic tissue damage.
Aim. To evaluate the efficacy and safety of Brainmax in comparison with ethylmethylhydroxypyridine succinate and trimethylhydrazinium propionate in patients with ischemic stroke in the acute and early recovery period.
Materials and methods. An open multicenter randomized study included 180 patients aged 1880 years (mean age 60.917.66 years, men 47.8%) with ischemic stroke in the acute and early recovery period (NIHSS from 3 to 15 points). Patients were randomized to receive Brainmax, ethylmethylhydroxypyridine succinate and trimethylhydrazinium propionate in an equal ratio (n=60). The drugs were administered intravenously for 10 days, followed by a transition to intramuscular injection for 14 days. Efficacy was assessed using the following scales: Modified Rankin Scale, NIHSS, Rivermead Mobility Index, Montreal Cognitive Assessment Scale (MoCA). Safety assessment was carried out according to the presence and structure of adverse events.
Results. The mean Modified Rankin Scale score for Visits 3 (day 10) and 5 (day 25) for the group treated with Brainmax was 2.410.85 and 1.440.91 points, for the group EMHPS 2.870.68 and 2.180.85 points, and for the group receiving trimethylhydrazinium propionate 2.870.50 and 2.550.70 points respectively, which reflects the best functional outcome in the Brainmax group (p0.05). Comparison of cognitive function indicators also showed statistically significant differences between the groups of drugs Brainmax and ethylmethylhydroxypyridine succinate. Evaluation according to the MoCA test showed that the use of Brainmax is 20% more effective in restoring cognitive functions (compared to monodrugs).
Conclusion. The present study confirms the superiority of combination therapy with Brainmax over monotherapy with each of the components.
Background
: Exercise is a promising non-pharmacological therapy for cognitive dysfunction, but it is unclear which type of exercise is most effective. The objective was to compare and rank the effectiveness of different exercise interventions on cognitive function in patients with mild cognitive impairment (MCI) or dementia and to examine the effects of exercise on the symptoms relevant to cognitive impairment.
Methods
: We searched PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, SPORTDiscus, and PsycInfo up to September 2019 and included randomized controlled trials that examined the effectiveness of exercise interventions in patients with MCI or dementia. Primary outcomes included global cognition, executive cognition, and memory cognition. Secondary outcomes included activities of daily living, neuropsychiatric symptoms, and quality of life. Pairwise analyses and network meta-analyses were performed using a random effects model.
Results
: A total of 73 articles from 71 trials with 5606 participants were included. All types of exercise were effective in increasing or maintaining global cognition, and resistance exercise had the highest probability of being the most effective intervention in slowing the decrease in global cognition (standard mean difference (SMD) = 1.05, 95% confidence interval (95%CI): 0.56−1.54), executive function (SMD = 0.85, 95%CI: 0.21−1.49), and memory function (SMD = 0.32, 95%CI: 0.01−0.63) among patients with cognitive dysfunction. Subgroup analyses for patients with MCI revealed different effects, and multi-component exercise was most likely to be the optimal exercise therapy for preventing the decline of global cognition (SMD = 0.99, 95%CI: 0.44−1.54) and executive function (SMD = 0.72, 95%CI: 0.06−1.38). However, only resistance exercise showed significant effects on memory function for patients with MCI (SMD = 0.35, 95%CI: 0.01−0.69). Exercise interventions also showed various effects on the secondary outcomes.
Conclusion
: Resistance exercise had the highest probability of being the optimal exercise type for slowing cognitive decline in patients with cognitive dysfunction, especially in patients with dementia. Multi-component exercise tended to be most effective in protecting global cognition and executive function in patients with MCI.
Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called ‘long COVID’, are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app¹. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76–4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.
To our knowledge, this is the largest cohort study (n=2,649) with the longest follow-up
since hospital discharge (6-8 months) of previously hospitalised adult patients. We found
that 6-8 months after discharge from the hospital, around a half (47.1%) of patients
reported at least one long-standing symptom since discharge. Once categories of
symptoms were assessed, chronic fatigue and respiratory problems were the most frequent
clusters of long-standing symptoms in our patients. Of those patients having long-term
symptoms, a smaller proportion (11.3%) had multisystem involvement, with three or more
categories of long-standing symptoms present. Although most patients developed
symptoms since discharge, a smaller number of individuals experienced symptom
beginning symptom appearing weeks or months after the acute phase. Female sex was a
predictor for most of the symptom categories at the time of the follow-up interview, with
chronic pulmonary disease associated with chronic fatigue-related symptoms, and asthma
with a higher risk of neurological symptoms, mood and behaviour problems.
As cases of coronavirus disease 2019 (COVID-19) mount worldwide, attention is needed on potential long-term neurologic impacts for the majority of patients who experience mild to moderate illness managed as outpatients. To date, there has not been discussion of persistent neurocognitive deficits in patients with milder COVID-19. We present two cases of non-hospitalized patients recovering from COVID-19 with persistent neurocognitive symptoms. Commonly used cognitive screens were normal, while more detailed testing revealed working memory and executive functioning deficits. An observational cohort study of individuals recovering from COVID-19 (14 or more days following symptom onset) identified that among the first 100 individuals enrolled, 14 were non-hospitalized patients reporting persistent cognitive issues. These 14 participants had a median age of 39 years (interquartile range: 35–56), and cognitive symptoms were present for at least a median of 98 days (interquartile range: 71–120 following acute COVID-19 symptoms); no participants with follow-up evaluation reported symptom resolution. We discuss potential mechanisms to be explored in future studies, including direct viral effects, indirect consequences of immune activation, and immune dysregulation causing auto-antibody production.
At the present stage of development of medicine and society, there is no doubt that early detection and treatment of nervous system diseases accompanied by impaired cognitive functions is one of the main tasks of clinical neurology. The prevalence of cognitive impairment (CI) is so high that today we can say that it exceeds the particular "epidemic" threshold, when the problem causes not only medical, but also a serious socioeconomic burden. Currently, studies of the problem of CI have shifted focus to the non-dementia stages of diseases. In recent years, it has become possible to make early nosological diagnosis of CI even before the development of dementia, which is associated with the development and introduction of in vivo laboratory and neuroimaging markers of Alzheimer's, neurodegenerative, and vascular processes. The paper discusses the existing classification and diagnostic criteria for non-dementia stages of CI. It proposes a new category, such as the initial signs of cognitive impairment, and presents diagnostic criteria. The author considers the importance of an integrated approach to diagnosing CI with the aim of early identification of the nosological entity of the syndrome. He presents a critical review of existing approaches to preventing and treating the non-dementia stages of CI.
The spectrum of cognitive decline in the elderly ranges from what can be classified as normal cognitive decline with aging to subjective cognitive impairment to mild cognitive impairment (MCI) to dementia. This article reviewed the up-to-date evidence of MCI including the diagnostic criteria of MCI due to Alzheimer’s disease, vascular cognitive impairment and MCI due to Parkinson disease, management and preventive intervention of MCI. There are various etiologies of MCI, and a large number of studies have been conducted to ascertain the practical modalities of preserving cognition in predementia stages. Lifestyle modification, such as aerobic exercise, is an approved modality to preserve cognitive ability and decrease the rate of progression to dementia, as well as being recommended for frailty prevention.
Few data are available on the prevalence of cognitive impairment (CI) in Spain, and the existing information shows important variations depending on the geographical setting and the methodology employed. The aim of this study was to determine the prevalence of CI in individuals aged over 65 in an urban area, and to analyze its associated risk factors.
Design: A descriptive, cross-sectional, home questionnaire-based study; Setting: Populational, urban setting. Participants: The reference population comprised over-65s living in the city of Salamanca (Spain) in 2009. Randomized sampling stratified according to health district was carried out, and a total of 480 people were selected. In all, 327 patients were interviewed (68.10%), with a mean age of 76.35 years (SD: 7.33). Women accounted for 64.5% of the total. Measurements: A home health questionnaire was used to obtain the following data: age, sex, educational level, family structure, morbidity and functionality. All participants completed a neuropsychological test battery. The prevalence data were compared with those of the European population, with direct adjustment for age and sex. Diagnoses were divided into three general categories: normal cognitive function, cognitive impairment - no dementia (CIND), and dementia.
The prevalence of CI among these over-65s was 19% (14.7% CIND and 4.3% dementia). The age-and sex-adjusted global prevalence of CI was 14.9%. CI increased with age (p < 0.001) and decreased with increasing educational level (p < 0.001). Significant risk factors were found with the multivariate analyses: age (OR = 1.08, 95%CI: 1.03-1.12), anxiety-depression (OR = 3.47, 95%CI: 1.61-7.51) and diabetes (OR = 2.07, 95%CI: 1.02-4.18). In turn, years of education was found to be a protective factor (OR = 0.79, 95%CI: 0.70-0.90). Although CI was more frequent among women and in people living without a partner, these characteristics were not significantly associated with CI risk.
The observed raw prevalence of CI was 19% (14.9% after adjusting for age and sex). Older age and the presence of diabetes and anxiety-depression increased the risk of CI, while higher educational level reduced the risk.
Mild cognitive impairment remains a clinical diagnosis, aided by history, neurologic examination, screening mental status examination, and secondary testing. It can be difficult to distinguish from normal aging without understanding a patient's prior level of intellectual function and new complaint. Geriatricians encounter patients with mild cognitive impairment in all long-term care settings. Making the diagnosis allows patients and their families to understand limits and develop strategies to maximize function. Etiologies associated with mild cognitive impairment include degenerative and vascular processes, psychiatric causes, and comorbid medical conditions. Treatable medical conditions may also present as mild cognitive impairment and have reversible outcomes.