Фармакологические экспериментальные исследования побочных эффектов ассоциации алпразолам+бромазепам

Disciplina Farmacologie şi Farmacie clinică, Facultatea Farmacie, UMF Carol Davila, Bucureşti, RomâniaIn lucrarea de faţă ne-am propus cercetarea preclinică a potenţialului farmacotoxicologic al asocierii dintre două benzodiazepine: alprazolam şi bromazepam. Cercetările noastre s-au efectuat la şoareci prin teste farmacologice specifice de evaluare a efectului miorelaxant (testul rotarod) şi a efectului asupra memoriei şi achiziţiei spaţiale (labirintul acvatic Morris). Dozele administrate au fost. alprazolam 0,5 mg/kg corp şi bromazepam 0,75 mg/kg corp. In urma cercetărilor efectuate, putem afirma că cele două benzodiazepine studiate, alprazolam şi bromazepam, la dozele administrate, singure sau in asociere, nu influenţează in sens negativ abilitatea şoarecilor de a se menţine pe axul in rotaţie sau capacitatea de a invăţa şi de a memora poziţia platformei in testul labirintului acvatic Morris.In the present paper we have researched, through experimental pharmacology studies, the pharmacotoxicological potential of the association between two benzodiazepine drugs: alprazolam and bromazepam. Our research has performed using specific pharmacological tests to evaluate the effect of miorelaxant (rotarod test) and effect on memory and spatial acquisition (Morris aquatic labyrinth). The doses administered were alprazolam 0.5 mg/kg body weight and bromazepam 0.75 mg/ kg body weight. Based on our research, we can state that the studied benzodiazepines, alprazolam and bromazepam, at the doses administered alone or in combination, do not adversely affect the ability of mice to maintain on the rotating spindle or the ability to learn and to remember platform position in the Morris aquatic labyrinth test.В этой статье мы поставили себе цель провести доклинические исследования фармакотоксикологического потенциала ассоциации между двумя бензодиазепинами: альпразоламином и бромазепамом. Наши исследования проводились на мышах с помощью специфических фармакологических тестов для оценки влияния миорелаксанта (тест ротарода) и влияния на память и пространственное поглощение (водный лабиринт Морриса). Доза альпразолама была 0,5 мг/кг массы тела и бромазепа – 0,75 мг/кг массы тела. Основываясь на наших исследованиях, мы можем констатировать, что два исследуемых бензодиазепина, альпразолам и бромазепам в указанных дозах, вводимых отдельно или в комбинации, не оказывают отрицательного влияния на способность мышей поддерживать ось вращения или способность учиться и помнить позицию платформы в тесте водного лабиринта Морриса

Regulation of Gene Expression through Food—Curcumin as a Sirtuin Activity Modulator

The sirtuin family comprises NAD+-dependent protein lysine deacylases, mammalian sirtuins being either nuclear (SIRT1, SIRT2, SIRT6, and SIRT7), mitochondrial (SIRT3, SIRT4, and SIRT5) or cytosolic enzymes (SIRT2 and SIRT5). They are able to catalyze direct metabolic reactions, thus regulating several physiological functions, such as energy metabolism, stress response, inflammation, cell survival, DNA repair, tissue regeneration, neuronal signaling, and even circadian rhythms. Based on these data, recent research was focused on finding molecules that could regulate sirtuins’ expression and/or activity, natural compounds being among the most promising in the field. Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) can induce, through SIRT, modulation of cancer cell senescence, improve endothelial cells protection against atherosclerotic factors, enhance muscle regeneration in atrophy models, and act as a pro-longevity factor counteracting the neurotoxicity of amyloid-beta. Although a plethora of protective effects was reported (antioxidant, anti-inflammatory, anticancer, etc.), its therapeutical use is limited due to its bioavailability issues. However, all the reported effects may be explained via the bioactivation theory, which postulates that curcumin’s observed actions are modulated via its metabolites and/or degradation products. The present article is focused on bringing together the literature data correlating the ability of curcumin and its metabolites to modulate SIRT activity and its consequent beneficial effects

Vitamin E beyond Its Antioxidant Label

Vitamin E, comprising tocopherols and tocotrienols, is mainly known as an antioxidant. The aim of this review is to summarize the molecular mechanisms and signaling pathways linked to inflammation and malignancy modulated by its vitamers. Preclinical reports highlighted a myriad of cellular effects like modulating the synthesis of pro-inflammatory molecules and oxidative stress response, inhibiting the NF-κB pathway, regulating cell cycle, and apoptosis. Furthermore, animal-based models have shown that these molecules affect the activity of various enzymes and signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, and NF-κB, acting as the underlying mechanisms of their reported anti-inflammatory, neuroprotective, and anti-cancer effects. In clinical settings, not all of these were proven, with reports varying considerably. Nonetheless, vitamin E was shown to improve redox and inflammatory status in healthy, diabetic, and metabolic syndrome subjects. The anti-cancer effects were inconsistent, with both pro- and anti-malignant being reported. Regarding its neuroprotective properties, several studies have shown protective effects suggesting vitamin E as a potential prevention and therapeutic (as adjuvant) tool. However, source and dosage greatly influence the observed effects, with bioavailability seemingly a key factor in obtaining the preferred outcome. We conclude that this group of molecules presents exciting potential for the prevention and treatment of diseases with an inflammatory, redox, or malignant component

Understanding the Molecular Mechanisms Underlying the Analgesic Effect of Ginger

Chronic pain has a high prevalence and a profound impact on patients and society, and its treatment is a real challenge in clinical practice. Ginger is emerging as a promising analgesic—effective against various types of pain and well-tolerated by patients. However, we are just beginning to understand its complex mechanism of action. A good understanding of its mechanism would allow us to fully utilize the therapeutical potential of this herbal medicine as well as to identify a better strategy for treating chronic pain. To provide this information, we searched PubMed, SCOPUS, and Web of Science for in vitro studies or animal experiments investigating the analgesic effect of ginger extract or its components. The analysis of data was carried out in the form of a narrative review. Our research indicates that ginger extract, through its various active ingredients, suppresses the transmission of nociceptive signals while activating the descendent inhibitory pathways of pain

Structural Model Based on Genetic Algorithm for Inhibiting Fatty Acid Amide Hydrolase

The fatty acid amide hydrolase (FAAH) is an enzyme responsible for the degradation of anandamide, an endocannabinoid. Pharmacologically blocking this target can lead to anxiolytic effects; therefore, new inhibitors can improve therapy in this field. In order to speed up the process of drug discovery, various in silico methods can be used, such as molecular docking, quantitative structure–activity relationship models (QSAR), and artificial intelligence (AI) classification algorithms. Besides architecture, one important factor for an AI model with high accuracy is the dataset quality. This issue can be solved by a genetic algorithm that can select optimal features for the prediction. The objective of the current study is to use this feature selection method in order to identify the most relevant molecular descriptors that can be used as independent variables, thus improving the efficacy of AI algorithms that can predict FAAH inhibitors. The model that used features chosen by the genetic algorithm had better accuracy than the model that used all molecular descriptors generated by the CDK descriptor calculator 1.4.6 software. Hence, carefully selecting the input data used by AI classification algorithms by using a GA is a promising strategy in drug development

Structural Model Based on Genetic Algorithm for Inhibiting Fatty Acid Amide Hydrolase

The fatty acid amide hydrolase (FAAH) is an enzyme responsible for the degradation of anandamide, an endocannabinoid. Pharmacologically blocking this target can lead to anxiolytic effects; therefore, new inhibitors can improve therapy in this field. In order to speed up the process of drug discovery, various in silico methods can be used, such as molecular docking, quantitative structure–activity relationship models (QSAR), and artificial intelligence (AI) classification algorithms. Besides architecture, one important factor for an AI model with high accuracy is the dataset quality. This issue can be solved by a genetic algorithm that can select optimal features for the prediction. The objective of the current study is to use this feature selection method in order to identify the most relevant molecular descriptors that can be used as independent variables, thus improving the efficacy of AI algorithms that can predict FAAH inhibitors. The model that used features chosen by the genetic algorithm had better accuracy than the model that used all molecular descriptors generated by the CDK descriptor calculator 1.4.6 software. Hence, carefully selecting the input data used by AI classification algorithms by using a GA is a promising strategy in drug development

Identifying FAAH Inhibitors as New Therapeutic Options for the Treatment of Chronic Pain through Drug Repurposing

Chronic pain determines a substantial burden on individuals, employers, healthcare systems, and society. Most of the affected patients report dissatisfaction with currently available treatments. There are only a few and poor therapeutic options—some therapeutic agents are an outgrowth of drugs targeting acute pain, while others have several serious side effects. One of the primary degradative enzymes for endocannabinoids, fatty acid amide hydrolase (FAAH) attracted attention as a significant molecular target for developing new therapies for neuropsychiatric and neurological diseases, including chronic pain. Using chemical graph mining, quantitative structure–activity relationship (QSAR) modeling, and molecular docking techniques we developed a multi-step screening protocol to identify repurposable drugs as FAAH inhibitors. After screening the DrugBank database using our protocol, 273 structures were selected, with five already approved drugs, montelukast, repaglinide, revefenacin, raloxifene, and buclizine emerging as the most promising repurposable agents for treating chronic pain. Molecular docking studies indicated that the selected compounds interact with the enzyme mostly non-covalently (except for revefenacin) through shape complementarity to the large substrate-binding pocket in the active site. A molecular dynamics simulation was employed for montelukast and revealed stable interactions with the enzyme. The biological activity of the selected compounds should be further confirmed by employing in vitro and in vivo studies

Natural Active Ingredients and TRPV1 Modulation: Focus on Key Chemical Moieties Involved in Ligand–Target Interaction

Diseases such as cancer, neurological pathologies and chronic pain represent currently unmet needs. The existing pharmacotherapeutic options available for treating these conditions are limited by lack of efficiency and/or side effects. Transient receptor potential vanilloid 1 ion channel emerged as an attractive therapeutic target for developing new analgesic, anti-cancer and antiepileptic agents. Furthermore, various natural ingredients were shown to have affinity for this receptor. The aim of this narrative review was to summarize the diverse natural scaffolds of TRPV1 modulators based on their agonistic/antagonistic properties and to analyze the structure–activity relationships between the ligands and molecular targets based on the results of the existing molecular docking, mutagenesis and in vitro studies. We present here an exhaustive collection of TRPV1 modulators grouped by relevant chemical features: vanilloids, guaiacols, phenols, alkylbenzenes, monoterpenes, sesquiterpenoids, alkaloids, etc. The information herein is useful for understanding the key structural elements mediating the interaction with TRPV1 and how their structural variation impacts the interaction between the ligand and receptor. We hope this data will contribute to the design of novel effective and safe TRPV1 modulators, to help overcome the lack of effective therapeutic agents against pathologies with high morbidity and mortality

Targeting Bacterial Sortases in Search of Anti-virulence Therapies with Low Risk of Resistance Development

Increasingly ineffective antibiotics and rapid spread of multi- and pan-resistant bacteria represent a global health threat; hence, the need of developing new antimicrobial medicines. A first step in this direction is identifying new molecular targets, such as virulence factors. Sortase A represents a virulence factor essential for the pathogenesis of Gram-positive pathogens, some of which have a high risk for human health. We present here an exhaustive collection of sortases inhibitors grouped by relevant chemical features: vinyl sulfones, 3-aryl acrylic acids and derivatives, flavonoids, naphtoquinones, anthraquinones, indoles, pyrrolomycins, isoquinoline derivatives, aryl β-aminoethyl ketones, pyrazolethiones, pyridazinones, benzisothiazolinones, 2-phenyl-benzoxazole and 2-phenyl-benzofuran derivatives, thiadiazoles, triazolothiadiazoles, 2-(2-phenylhydrazinylidene)alkanoic acids, and 1,2,4-thiadiazolidine-3,5-dione. This review focuses on highlighting their structure–activity relationships, using the half maximal inhibitory concentration (IC50), when available, as an indicator of each compound effect on a specific sortase. The information herein is useful for acquiring knowledge on diverse natural and synthetic sortases inhibitors scaffolds and for understanding the way their structural variations impact IC50. It will hopefully be the inspiration for designing novel effective and safe sortase inhibitors in order to create new anti-infective compounds and to help overcoming the current worldwide antibiotic shortage