The biological activity assessment of potential drugs acting on cardiovascular system using Lipinski and Veber Rules

Advanced computational methods (in silico) play major role in the early stages of developing new pharmaceuticals. Precise knowledge on molecular structure gives the possibility of forecasting the drug candidates basic properties. Despite many drugs registered in the arrhythmia treatment, this disease currently is still a big therapeutic problem. Therefore, intensive search for new drugs acting on the cardiovascular system are performed. In the presented work, 77 pyrrolidin-2-one derivatives were analyzed for antiarrhythmic activity. Values of the key parameters proposed by Lipinski and Veber were obtained using computational chemistry methods. It's worth pointing out that the studied group of derivatives shows similar physicochemical properties to the anti-arrhythmic drugs used

Studies on the Activity of Selected Highly Lipophilic Compounds toward hGAT1 Inhibition. Part II

In this paper, we describe the latest results involving molecular modeling and pharmacodynamic studies of the selected highly lipophilic compounds acting by human GABA transporter 1 (hGAT1) inhibition. The chemical interaction of 17 GABA analogues with a model of hGAT1 is described using the molecular docking method. The biological role of GAT1 is related to the regulation of GABA level in the central nervous system and GAT1 inhibition plays an important role in the control of seizure threshold. To confirm that GAT1 can be also a molecular target for drugs used to treat other neurological and psychiatric diseases (e.g., pain and anxiety), in the in vivo part of this study, potential antinociceptive and anxiolytic-like properties of tiagabine, a selective GAT1 inhibitor, are described

Spatial distribution of white matter degenerative lesions and cognitive dysfunction in relapsing-remitting multiple sclerosis patients

Aim. The aim of this study was to assess degenerative lesion localisation in the course of relapsing-remitting multiple sclerosis (RRMS) and to identify the association between localisation and the frequency of T1-hypointense lesions (black holes) with cognitive dysfunction. We also searched for neuroradiological predictors of cognitive dysfunction in patients. The clinical rationale for the study was previous research, and our own findings suggest that lesion localisation plays an important role in cognitive performance and neurological disability of MS patients. Material and methods. Forty-two patients were included in the study. All subjects underwent neuropsychological examination using Raven’s Coloured Progressive Matrices, a naming task from the Brief Repeatable Battery of Neuropsychological Tests, and attention to detail tests. Magnetic resonance imaging (MRI) was acquired on 1.5 Tesla scanner and black holes were manually segmented on T1-weighted volumetric images using the FMRIB Software Library. Linear regression was applied to establish a relationship between black hole volume per lobe and cognitive parameters. Bonferroni correction of voxelwise analysis was used to correct for multiple comparisons. Results. The following associations between black hole volume and cognition were identified: frontal lobes black hole volume was associated with phonemic verbal fluency (t = –4.013, p < 0.001), parietal black hole volume was associated with attention (t = –3.776, p < 0.001), and parietal and temporal black hole volumes were associated with nonverbal intelligence (p < 0.001). The volume of parietal black holes was the best predictor of cognitive dysfunction. Conclusions. Our approach, including measurement of focal axonal loss based on T1-volumetric MRI sequence and brief neuropsychological assessment, might improve personalised diagnostic and therapeutic decisions in clinical practice

Narcolepsy in the light of modern diagnostic, clinical and therapeutic concepts

Narcolepsy is a chronic neurological disease classified as hypersomnia of central origin. Core symptoms of the disease (hypersomnia and cataplexy) are particularly burdensome for patients. The etiology of the disease is not fully understood. There are several theories explaining the essence of the disease. One of the possible causes is the disruption of the autoimmune system leading to the disappearance of hypocretin-releasing neurons. Currently, multicenter studies on synthesizing hypocretin-like proteins that may be the basis of causal narcolepsy treatment are conducted. As yet pharmacotherapy contributes only to reduce the symptoms of the disease. Commonly used medications are amphetamine derivatives, modafinil, pitolisant and γ-hydroxybutyric acid sodium salt (GHB)

QSAR studies on a number of pyrrolidin-2-one antiarrhythmic arylpiperazinyls

The activity of a number of 1-[3-(4-arylpiperazin-1-yl)propyl]pyrrolidin-2-one antiarrhythmic (AA) agents was described using the quantitative structure–activity relationship model by applying it to 33 compounds. The molecular descriptors of the AA activity were obtained by quantum chemical calculations combined with molecular modeling calculations. The resulting model explains up to 91% of the variance and it was successfully validated by four tests (LOO, LMO, external test, and Y-scrambling test). Statistical analysis shows that the AA activity of the studied compounds depends mainly on the PCR and JGI4 descriptors

Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties

A series of novel pyrrolidin-2-one derivatives (17 compounds) with adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity. Some of them displayed antiarrhythmic activity in barium chloride-induced arrhythmia and in the rat coronary artery ligation-reperfusion model, and slightly decreased the heart rate, prolonged P–Q, Q–T intervals and QRS complex. Among them, compound EP-40 (1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one showed excellent antiarrhythmic activity. This compound had significantly antioxidant effect, too. The present results suggest that the antiarrhythmic effect of compound EP-40 is related to their adrenolytic and antioxidant properties. A biological activity prediction using the PASS software shows that compound EP-35 and EP-40 can be characterized by antiischemic activity; whereas, compound EP-68, EP-70, EP-71 could be good tachycardia agents

Adaptation of Zen Buddhism in Europe and United States of America

Praca "Adaptacja buddyzmu zen w Europie i Stanach Zjednoczonych" omawia problematykę recepcji buddyzmu zen na terenie Stanów Zjednoczonych oraz państw Zachodniej i Centralnej Europy. Dotyczy to zarówno funkcjonowania oficjalnych ośrodków praktyki buddyzmu zen, jak i jego wpływów na różne dziedziny życia. W pracy omówione są kolejno zagadnienia dotyczące historii powstania buddyzmu zen oraz jego specyfiki, pojawienia się i charakterystyki działalności ośrodków buddyzmu zen w Stanach Zjednoczonych i Europie, zenistycznych wpływów w różnych dziedzinach życia (np. biznes, towary i usługi) oraz wpływ zenu na kulturę i sztukę Zachodu.The thesis "Adaptation of Zen Buddhism in Europe and United States" presents the problem of appearance and adaptation of Zen Buddhism in United States and both Central and Eastern European countries. This includes as well as Zen Buddhist centers and Zen Buddhist influences on various aspects of life. Following issues are discussed in this thesis: the history and general information about Zen Buddhism, appearance and characteristics of Zen centers in United States and Europe, the influences of Zen Buddhism on different aspects of life (such as business, goods and services) and the impact of Zen on western art and culture

Carbon Monoxide and Nitric Oxide as Examples of the Youngest Class of Transmitters

The year 2021 is the 100th anniversary of the confirmation of the neurotransmission phenomenon by Otto Loewi. Over the course of the hundred years, about 100 neurotransmitters belonging to many chemical groups have been discovered. In order to celebrate the 100th anniversary of the confirmation of neurotransmitters, we present an overview of the first two endogenous gaseous transmitters i.e., nitric oxide, and carbon monoxide, which are often termed as gasotransmitters

Paroxetine—Overview of the Molecular Mechanisms of Action

In the 21st century and especially during a pandemic, the diagnosis and treatment of depression is an essential part of the daily practice of many family doctors. It mainly affects patients in the age category 15–44 years, regardless of gender. Anxiety disorders are often diagnosed in children and adolescents. Social phobias can account for up to 13% of these diagnoses. Social anxiety manifests itself in fear of negative social assessment and humiliation, which disrupts the quality of social functioning. Treatment of the above-mentioned disorders is based on psychotherapy and pharmacotherapy. Serious side effects or mortality from antidepressant drug overdose are currently rare. Recent studies indicate that paroxetine (ATC code: N06AB), belonging to the selective serotonin reuptake inhibitors, has promising therapeutic effects and is used off-label in children and adolescents. The purpose of this review is to describe the interaction of paroxetine with several molecular targets in various points of view including the basic chemical and pharmaceutical properties. The central point of the review is focused on the pharmacodynamic analysis based on the molecular mechanism of binding paroxetine to various therapeutic targets