Search Results (22)

Benzodiazepines (BZDs) are globally prevalent psychotropic substances valued for their anxiolytic, hypnotic, anticonvulsant, and myorelaxant properties. Pharmacologically, they act as positive allosteric modulators of the ionotropic GABA_A receptor, enhancing inhibitory synaptic transmission. However, prolonged use poses a significant public health concern, risking adverse effects such as cognitive impairment, motor incoordination, tolerance, and physical dependence. The development of tolerance is mediated by complex neurobiological changes, notably the downregulation of GABA_A receptor subunits and a compensatory sensitization of excitatory glutamatergic systems. Effective management of established dependence requires comprehensive psychological intervention coupled with pharmacological substitution (switching to a long-acting BZD) and gradual dose tapering. Preventive measures are complex, emphasizing short-term prescriptions, minimum effective dosing, and selecting non-pharmacological or alternative pharmacological agents, such as SSRIs/SNRIs, to mitigate the risk of developing tolerance and dependence. This expert review aims to compile the most relevant, representative, and recent literature summarizing the pharmacology, clinical indications, adverse effects, misuse, and abuse of BZDs that ultimately lead to BZD use disorder (BUD). It also details the involved neurobiological mechanisms and discusses critical preventive and therapeutic strategies, providing readers with the main aspects to consider for addressing this global public health problem. Full article

Background: Bruxism and temporomandibular disorders (TMD) are commonly associated with increased masticatory muscle activity and pain. Cannabidiol (CBD) exhibits analgesic, myorelaxant, and anti-inflammatory properties, while halloysite may enhance mucosal delivery and bioavailability. Methods: In a randomized, double-blind pilot trial, 20 adults with TMD applied either a CBD gel or a CBD plus halloysite gel nightly for 6 weeks. Masseter muscle activity was recorded using surface electromyography (sEMG) at baseline and post-treatment. Results: Both formulations significantly reduced masseter sEMG activity. The mean decrease was 37.95% with CBD alone (SD = 9.37) and 37.41% with CBD plus halloysite (SD = 5.44). Minimum reductions were 20.44% and 20.02%, and maximum reductions reached 55.16% and 82.52%, respectively. Reductions were bilateral and comparable between right and left sides. Differences between formulations were not statistically significant by t-test (t(8) = 1.613, p = 0.145) or Mann–Whitney U test (p > 0.5). However, variability was lower with the CBD plus halloysite formulation, suggesting a more consistent response. A sex effect reached significance within one formulation (t(8) = 2.315, p = 0.049), while no sex difference was observed in the other. Treatment duration did not correlate with effect size for either gel (Spearman’s rₛ = 0.213 and −0.071, both p > 0.5). No adverse events were reported. Conclusions: Nightly intraoral CBD and CBD plus halloysite gels reduced masseter sEMG in adults with TMD, with similar mean efficacy and lower response variability for CBD plus halloysite. These pilot data support further adequately powered, placebo-controlled trials to confirm efficacy, define optimal dosing, and clarify subgroup effects. The trial registration number registered prospectively is NCT05562635 (accessed on 31 August 2022). Full article

Decoctions of stem barks from Aucoumea klaineana, Canarium schweinfurthii, Pentadesma butyracea and Scorodophloeus zenkeri are used against affections of irritable bowel syndrome in Gabonese traditional medicine. In the present study, we aim to determine whether the bark polysaccharides may contribute to the activity of these plants against the symptoms of gastrointestinal disorders. To this end, we investigated the structure and the pharmacological activity of polysaccharides extracted from their stem barks. The pectic and hemicellulose polysaccharides were isolated, and their sugar compositions were determined by gas chromatography. In addition, analysis by MALDI-TOF mass spectrometry of oligosaccharides released after digestion with an endo-xylanase indicated that glucuronoarabinoxylans are the main hemicellulose of stem barks. We then evaluated the influence of the polysaccharide fractions on the spontaneous contractile activity of rat ileal smooth muscle and the cholinergic system. Spasmolytic activity of pectic fractions from all stem barks, as well as lemon polygalacturonic acid, were observed, indicating that these extracts exhibit a myorelaxant activity. In contrast, the bark hemicellulose fractions, as well as commercially available beechwood glucuronoxylan and wheat arabinoxylan, were demonstrated to be able to increase the basal contractile activity of smooth muscle. These data show that, beyond physicochemical effects affecting the bowel water content, plant polysaccharides have also an impact on the spontaneous smooth muscle contractility, the main mechanism involved in the pathophysiology of gastrointestinal disorders. Full article

Background/Objectives: Natural products are gaining increasing importance due to the large variety of biological activities exerted by their constituents. Among these, the products deriving from Acmella oleracea (L.) R.K. Jansen can be exploited for their local anaesthetic, myorelaxant, anti-inflammatory/analgesic, and antifungal properties. In this regard, there is a need to develop novel formulations for the topical delivery of A. oleracea-derived extracts to widen their use in the pharmaceutical and cosmetic fields. Methods: Nanoformulations, i.e., nanoemulsions (NEs) and microemulsions (MEs), were investigated as a strategy to encapsulate an extract from A. oleracea at the nanoscale level in water and then incorporated into xanthan gum-based hydrogels. Results: Only NEs provided a physically stable formulation, while the precipitation of solid hydrophobic components from the extract was observed during ME preparation under all tested conditions despite the use of ethyl oleate as an oily co-solvent. The optimized NE-based hydrogel remained physically stable over six months, as confirmed by rheological measurements and polarized optical microscope observation, without a phase separation phenomenon. Therefore, NEs resulted more suitable nanodispersed systems than MEs for the encapsulation of A. oleracea extract, which contains a large amount of hydrophobic constituents that are solid at room temperature. Furthermore, the sustained spilanthol release across an artificial membrane (Franz cell apparatus) and the cytotoxic profile on HaCaT cell line support its potential topical application. Conclusions: The outcomes of this study provided valuable insights into the formulation of A. oleracea extract, broadening its fields of applicability, including topical administration. Full article

Background/Objectives: Approximately 1% of people worldwide suffer from epilepsy. The development of safer and more effective antiepileptic medications (AEDs) is still urgently needed because all AEDs have some unwanted side effects and roughly 30% of epileptic patients cannot stop having seizures when taking current AEDs. It should be noted that the derivatives of pyrazolo[3,4-b]pyridine are important core structures in many drug substances. The aim of this study is to synthesize new derivatives of piperazino-substituted pyrazolo[3,4-c]-2,7-naphthyridines and 9,11-dimethylpyrimido[1′,2′:1,5]pyrazolo[3,4-c]-2,7-naphthyridines for the evaluation of their neurotropic activity. Methods: The synthesis of the target compounds was performed starting from 1-amino-3-chloro-2,7-naphthyridines and using well-known methods. The structures of all the synthesized compounds were confirmed by spectroscopic data. Compounds were studied for their potential neurotropic activities (anticonvulsant, sedative, anti-anxiety, and antidepressive), as well as side effects, in 450 white mice of both sexes and 50 male Wistar rats. The anticonvulsant effect of the newly synthesized compounds was investigated by using the following tests: pentylenetetrazole, thiosemicarbazide-induced convulsions, and maximal electroshock. The psychotropic properties of the selected compounds were evaluated by using the following tests: the Open Field test, the Elevated Plus Maze (EPM), the Forced Swimming test, and Rotating Rod Test to study muscle relaxation. For the docking studies, AutoDock 4 (version 4.2.6) was used, as well as the structures of the GABA_A receptor (PDB ID: 4COF), the SERT transporter (PDB ID: 3F3A), and the 5-HT_1A receptor (PDB ID: 3NYA) obtained from the Protein Data Bank. Results: A series of piperazino-substituted pyrazolo[3,4-c]-2,7-naphthyridines (3a–j) and 9,11-dimethylpyrimido[1′,2′:1,5]pyrazolo[3,4-c]-2,7-naphthyridines (4a–j), as well as new heterocyclic systems, i.e., isoxazolo[5,4-c]-2,7-naphthyridines 6a–d, were synthesized and evaluated for their neurotropic activity. The investigation showed that some of these compounds (3a,b,d,f–i and 4a,d,f,i) display high anticonvulsant activity, especially in the test of antagonism with pentylenetetrazol, surpassing the well-known antiepileptic drug ethosuximide. Thus, the most active compounds in the pentylenpotetrazole test are 3h, 3i, and 4i; the ED50 of compound 4i is 23.8, and the therapeutic index is more than 33.6, which is the highest among these three active compounds. On the other hand, they simultaneously exhibit psychotropic (anxiolytic, antidepressant, or sedative) or behavioral depressant) effects. The effective compounds do not cause myorelaxation at the tested doses and have high therapeutic indices. Docking on the most active compounds, i.e., 3h, 3i, and 4i, is in agreement with the experimental results. Conclusions: The studies reveled that some of these compounds (3i, 4a, and 4i) display high anticonvulsant and psychotropic activities. The most active compounds contained methyl and diphenylmethyl groups in the piperazine ring. The docking studies identified compounds 3i, 4i, and 4a as the most potent anticonvulsants, showing strong affinity for GABA_A, 5-HT_1A receptors, and the SERT transporter. Notably, compound 4i formed two hydrogen bonds with Thr176 and Arg180 on GABA_A and exhibited a binding energy (−8.81 kcal/mol) comparable to that of diazepam (−8.90 kcal/mol). It also showed the strongest binding to SERT (−7.28 kcal/mol), stabilized by interactions with Gly439, Ile441, and Arg11. Furthermore, 4i displayed the best docking score with 5-HT_1A (−9.10 kcal/mol) due to multiple hydrogen bonds and hydrophobic interactions, supporting its potential as a dual-acting agent targeting both SERT and 5-HT_1A. Full article

Background: Modern societies and policymakers increasingly emphasize the advancement of organic farming practices and the preservation of rural culture. Sheep farming faces several challenges, including environmental impacts, antibiotic usage, and public concerns regarding animal welfare. The purpose of this study was to investigate the effects of Melissa officinalis extract and its principal phenolic acids on the motility of the sheep jejunum and colon, with the goal of assessing their potential as health-promoting feed additives, particularly in animals with dysmotilities. Methods: The trials were performed on isolated jejunum and colon preparations collected from sheep undergoing routine slaughter. The effect of extracts from Melissa Officinalis and three major phenolic acids (rosmarinic, chlorogenic, and lithospermic) was evaluated to identify their ability to modify the spontaneous and pharmacologically-induced contractility of circular and longitudinal smooth muscle. Results: Regarding spontaneous contractions: Melissa officinalis extract, rosmarinic acid, and lithospermic acid caused a significant decrease in spontaneous contractility in the jejunum and colon, while chlorogenic acid exhibited myocontractile effects except for colon circular preparations where the effect was myorelaxant as in the other acids. In the case of ACh-induced contractions, all acids and the Melissa officinalis extract caused mostly a significant decrease in the magnitude of acetylcholine-induced contractions in both longitudinal and circular smooth muscle strips of the colon and jejunum. Conclusions: The findings suggest a predominantly myorelaxant effect of the Melissa officinalis extract and its major phenolic acids on the smooth muscle of the sheep jejunum and colon. These results underscore the potential application of the Melissa officinalis extract as a feed additive to modulate intestinal motility and address challenges in livestock production. Full article

Background: Ceftriaxone upregulates GLT1 glutamate transporter in the brain and may have anti-CFC and anti-OCD effects. Methods: Twenty WZ-5HT rats were used to investigate the effects of ceftriaxone on obsessive–compulsive (OCD)-like behaviour in the marble-burying (MB) test, freezing behaviour in contextual fear conditioning (CFC) and expression of GLT1 protein in the hippocampus or amygdala using immunoblots. Fifteen DBA/2J mice were used in the MB test. We also compared diazepam with ceftriaxone in open-field, beam-walking, and wire-hanging tests on 47 DBA/2J mice. Ceftriaxone (200 mg/kg) and saline were applied intraperitoneally, once daily for 7 (rats) or 5 (mice) consecutive days. A single dose of diazepam (1.5–3.0 mg/kg) or saline was injected 30 min before the behavioural tests. Results: Ceftriaxone significantly diminished OCD-like behaviour (↓ number of marbles buried) and freezing behaviour in CFC context session (↑ latencies, ↓ total duration, ↓ duration over four 2 min periods of the session) but increased GLT1 protein expression in the amygdala and hippocampus of rats. Diazepam induced sedation, ataxia and myorelaxation in mice. Ceftriaxone did not have these side effects. Conclusions: The results of this study confirm the anti-CFC and anti-OCD effects of ceftriaxone, which did not produce the unwanted effects typical of diazepam. Full article

Background: Temporomandibular disorders (TMDs) are the most prevalent non-dental pain issues in the maxillofacial region. Despite advancements, diagnosing and managing TMDs continues to pose challenges. This study aimed to assess the efficacy of cannabidiol (CBD) formulations, with different concentrations, in patients experiencing sleep bruxism and muscle-related TMDs, with a particular emphasis on their myorelaxant, pain-relieving, and bruxism-reducing properties. Methods: The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMDs) was utilized as the diagnostic framework. Sixty patients completed the study, which followed a parallel-group, three-arm, randomized, double-blind clinical trial design, with a 1:1:1 allocation ratio across three groups: 1a, 1b, and 2. Groups 1a and 1b received CBD formulations at concentrations of 10% and 5%, respectively, while Group 2 received a placebo formulation. The trial consisted of four main visits, namely screening, baseline, first follow-up after 14 days, and second follow-up after 30 days, during which surface electromyography (sEMG), the visual analogue scale (VAS) for pain assessment, and Bruxoff examinations were conducted. Results: The reduction in pain, as measured by the visual analogue scale (VAS), among patients using the 10% CBD formulation was 57.4% (p < 0.05), accompanied by a decrease in sEMG activity by 42.1% (p < 0.05). Conversely, individuals using the 5% CBD formulation experienced a 40.8% (p < 0.05) decrease in pain. Regarding the decrease in the sleep bruxism index, users of the 10% CBD formulation saw the highest reduction of 51% (p < 0.05). These findings underscore the efficacy of the proposed treatment in both experimental groups, with a notable advantage observed in Group 1a. Conversely, the outcomes of the selected variables for the control group did not exhibit significant differences throughout the study. Conclusions: The intraoral use of CBD formulations in patients with TMDs have proven to be a successful treatment for reducing pain, muscle tension, and bruxing activity in individuals with sleep bruxism and muscle-related TMDs. Specifically, a concentration of 10% CBD has demonstrated superior results compared to 5% CBD. Full article

Urolithiasis is a complex and multifactorial disease characterized by the formation of calculi at the urinary tract level. Conventional therapeutic prophylaxis relies on the use of Ca-blockers, alkalis, diuretics, and anti-edema agents, but their prolonged utilization is often limited by several side effects. In this scenario, the aim of the present work was the design of an innovative multi-component nutraceutical formulation (NF) for the management of urinary stones consisting of a synergistic combination of natural aqueous extracts of Oreganum vulgare L. (1% of saponin), Urtica dioica (0.8% of β-sitosterol), Phyllanthus niruri (15% of tannins w/w), and Ceterach officinarum in association with bromelain, K, and Mg citrate. To assess the potential of NF also in the treatment of uric acid (UA) stones, the effects on the expression of the cellular UA transporters OAT1 and URAT1 were investigated in a renal tubular cell line. In addition, the myorelaxant effect of NF was investigated in a human pulmonary artery smooth muscle cell (HPASMC) model resulting in a decreased muscle contractility of −49.4% (p < 0.01) compared to the control. The treatment with NF also showed a valuable inhibition of in vitro calcium-oxalate crystal formation, both in prevention (−52.3% vs. control, p < 0.01) and treatment (−70.8% vs. control, p < 0.01) experiments. Finally, an ischemic reperfusion rat model was used to evaluate the NF anti-edema effects, resulting in a reduction in the edema-related vascular permeability (Normalized Gray Levels, NGL = 0.40 ± 0.09, p < 0.01, −67.1% vs. untreated rats). In conclusion, the present NF has shown to be a promising natural alternative for managing urinary tract stones. Full article

Etifoxine is an anxiolytic drug with a dual mechanism of action. In contrast to conventional benzodiazepine anxiolytics, which induce cognitive dysfunction and myorelaxation, no memory impairment nor a decrease in motor activity is observed with etifoxine. This study aims to evaluate the effects of etifoxine on locomotor activity and passive learning in rats with diazepam-induced memory deficit. Male Wistar rats were treated intraperitoneally for 7 days with: (1) saline; (2) diazepam 2.5 mg/kg bw or (3) diazepam 2.5 mg/kg bw and etifoxine in a dose of 50 mg/kg bw. Activity cage test was used for evaluation of locomotor activity, and step-through and step-down tests were performed to study the passive learning. Etifoxine increased the number of horizontal movements on the 7th and 14th days of the experiment. The drug exhibits anti-amnesic effect in a model of diazepam-induced anterograde amnesia by enhancing long-term memory in passive learning tests. The data obtained suggest that etifoxine can reduce the benzodiazepine-induced cognitive deficit. Moreover, such a combination can alleviate the negative influence of benzodiazepines on locomotor activity. However, additional studies are necessary to translate these results into clinical practice. Full article

Hypertension is a risk factor for cardiovascular diseases, which are the main cause of morbidity and mortality in the world. In the search for new molecules capable of targeting K_Ca1.1 and Ca_V1.2 channels, the expression of which is altered in hypertension, the in vitro vascular effects of a series of flavonoids extracted from the heartwoods, roots, and leaves of Dalbergia tonkinensis Prain, widely used in traditional medicine, were assessed. Rat aorta rings, tail artery myocytes, and docking and molecular dynamics simulations were used to analyse their effect on these channels. Formononetin, orobol, pinocembrin, and biochanin A showed a marked myorelaxant activity, particularly in rings stimulated by moderate rather than high KCl concentrations. Ba²⁺ currents through Ca_V1.2 channels (I_Ba1.2) were blocked in a concentration-dependent manner by sativanone, 3′-O-methylviolanone, pinocembrin, and biochanin A, while it was stimulated by ambocin. Sativanone, dalsissooside, and eriodictyol inhibited, while tectorigenin 7-O-[β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside], ambocin, butin, and biochanin A increased I_KCa1.1. In silico analyses showed that biochanin A, sativanone, and pinocembrin bound with high affinity in target-sensing regions of both channels, providing insight into their potential mechanism of action. In conclusion, Dalbergia tonkinensis is a valuable source of mono- and bifunctional, vasoactive scaffolds for the development of novel antihypertensive drugs. Full article

Amburana cearensis (Allemão) ACSm. belongs to the Fabaceae family and occurs in the Brazilian semiarid, Argentina, Paraguay, Bolivia, and Peru. Numerous studies that portray its ethnobotany, use in popular medicine, chemical composition, and biological activities exist in the literature. This review aimed to provide an overview of the chemical composition, ethnopharmacology, and biological activities associated with A. cearensis and its isolated constituents. Information was collected from internet searches in the Scopus, Medline, PubMed, Google Scholar, and ScienceDirect databases were performed covering publications from 1997–2020. An ethnopharmacological literature analysis revealed that A. cearensis is used to treat a wide range of respiratory disorders in addition to intestinal, circulatory, and inflammatory problems. Coumarins, flavonoids, phenolic glycosides, phenolic acids, phenylpropanoid derivatives, and triterpenoids, among others, have been reported as active compounds, with High-Performance Liquid Chromatography (HPLC) being the main analytical technique used. The A. cearensis extracts and compounds presented several biological activities, including antimicrobial, antinociceptive, anti-inflammatory, antioxidant, neuroprotective, and myorelaxant activities, among others. This review provides a useful bibliography for future investigations and A. cearensis applications; however, future studies should focus on its toxic effects and the mechanisms of action of its extracts and isolated constituents to guide clinical applications. Full article

Dysphania ambrosioides (L.) Mosyakin and Clemants is an annual or ephemeral perennial herb used traditionally in the Mediterranean region in folk medicine to treat various illnesses, including those related to the digestive system. This study aims to assess the antispasmodic, myorelaxant, and antioxidant effects of D. ambrosioides flower hydroethanolic extract and its chloroform and ethyl acetate fractions in a comparative study to evaluate the result of the extraction type on the potential activity of the extract. Both rat and rabbit jejunum were used to evaluate the antispasmodic and myorelaxant effect, while the antioxidant effect was evaluated using DPPH, a ferric reducing power assay, and a beta-carotene bleaching test. LC/MS-MS analysis was carried out to reveal the composition of the different types of extract. Following the results, the hydroethanolic extract showed a significant myorelaxant effect (IC₅₀ = 0.39 ± 0.01 mg/mL). Moreover, it was shown that the hydroethanolic extract demonstrated the best antispasmodic activity (IC₅₀ = 0.51 ± 0.05 mg/mL), followed by the ethyl acetate (IC₅₀ = 4.05 ± 0.32 mg/mL) and chloroform (IC₅₀ = 4.34 ± 0.45 mg/mL) fractions. The antioxidant tests showed that the hydroethanolic extract demonstrated high antioxidant activity, followed by the ethyl acetate and chloroform fractions. The LC/MS-MS analysis indicates that the plant extract was rich in flavonoids, to which the extract activity has been attributed. This study supports the traditional use of this plant to treat digestive problems, especially those with spasms. Full article

Cannabidiol (CBD) is a promising therapeutic agent with analgesic, myorelaxant, and anti-epileptic actions. Recently, a purified form of CBD (Epidiolex^®) has been approved by the European Medicines Agency (EMA) for the treatment of two highly-refractory childhood-onset epilepsies (Dravet and Lennox-Gastaut syndrome). Given the interindividual response and the relationship between the dose administered and CBD blood levels, therapeutic drug monitoring (TDM) is a valuable support in the clinical management of patients. We herein report for the first time a newly developed and validated method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS) to evaluate CBD and its metabolites (i.e., cannabidiol-7-oic acid (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α–OH–CBD) and 6-β-hydroxycannabidiol (6-β–OH–CBD)) in serum samples. The method reached the sensitivity needed to detect minimal amounts of analytes under investigation with limits of quantification ranging from 0.5 to 20 ng/mL. The validation results indicated in this method were accurate (average inter/intra-day error, <15%), precise (inter/intra-day imprecision, <15%), and fast (8 min run time). The method resulted to be linear in the range of 1–10,000 ng/mL for CBD-COOH, 1–500 ng/mL for 7-OH-CBD and CBD and 1–25 ng/mL for 6-α–OH–CBD and 6-β–OH–CBD. Serum levels of CBD (88.20–396.31 and 13.19–170.63 ng/mL) as well as of 7-OH-CBD (27.11–313.63 and 14.01–77.52 ng/mL) and 7-COOH-CBD (380.32–10,112.23 and 300.57–2851.82 ng/mL) were significantly higher (p < 0.05) in patients treated with GW pharma CBD compared to those of patients treated with galenic preparations. 6-α–OH–CBD and 6-β–OH–CBD were detected in the first group and were undetectable in the second group. 7-COOH-CBD was confirmed as the most abundant metabolite in serum (5–10 fold higher than CBD) followed by 7-OH-CBD. A significant correlation (p < 0.05) between the dose administrated and a higher bioavailability was confirmed in patients treated with a GW pharma CBD preparation. Full article

Benzodiazepines (BZDs) are an important class of psychoactive drugs with hypnotic-sedative, myorelaxant, anxiolytic and anticonvulsant properties due to interaction with the GABAa receptor in the central nervous system of mammals. BZDs are interesting both in clinical and forensic toxicology for their pharmacological characteristics and potential of abuse. The presence of a non-planar diazepine ring generates chiral conformational stereoisomers, even in the absence of stereogenic centers. A conformational enrichment of BZD at the binding sites has been reported in the literature, thus making interesting a stereodynamic screening of a wide range of BZDs. Herein, we report the investigation of three stereolabile 1,4-benzodiazepine included in the class of “designer benzodiazepines” (e.g., diclazepam, a chloro-derivative of diazepam, and two triazolo-benzodiazepines, flubromazolam and clonazolam) and a commercially available BZD known as flurazepam, in order to study the kinetic of the “ring-flip” process that allows two conformational enantiomers to interconvert at high rate at room temperature. A combination of low temperature enantioselective dynamic chromatography on chiral stationary phase and computer simulations of the experimental chromatograms allowed us to measure activation energies of enantiomerization (ΔG^‡) lower than 18.5 kcal/mol. The differences between compounds have been correlated to the pattern of substitutions on the 1,4-benzodiazepinic core. Full article