Fundamental & Clinical Pharmacology最新文献

Background

Anxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3-diphenyl-2-proper-1-ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABA_A receptors and serotonergic system.

Objectives

This study evaluated the anxiolytic potential of chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa).

Methods

Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 μL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 μL), being submitted to the tests of locomotor activity and 96-h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR₁, 5-HTR_2A/2C, and 5-HTR_3A/3B receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration.

Results

As a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5-HT_2A and 5-HTR_3A/3B receptors. The interaction of C2OHPDA with 5-HT_2AR and 5-HT_3A receptors was confirmed by molecular docking study, the affinity energy observed was −8.7 and −9.1 kcal/mol, respectively.

Conclusion

Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.

Background

Using statins in combination with other drugs was reported to increase the risk of myopathy. However, there was a sparse number of studies on the incidence of adverse events (AEs) associated with the concomitant use of statin and contraindicated drugs in the real world.

Objectives

This study aimed to identify the risk of concomitant use of statins with contraindicated drugs by exploring signals related to statin–drug interactions.

Methods

We performed a disproportionality analysis for drugs and AEs by applying the case/non-case study using the KIDS-KAERS database (KIDS-KD), 2016–2020. A case was defined as an individual case safety reports (ICSRs) including “rhabdomyolysis/myopathy.” A non-case was defined as an ICSR, including all other AEs. We applied Ω shrinkage measure model, chi-square statics model, additive model, multiplicative model, and combination risk ratio model to detect signals of myopathy due to statin with concomitant drugs including antiviral agents, immunosuppressants, and antifungals.

Results

Among 1 011 234 ICSRs, 2708 were cases, with 861 cases of statin monotherapy and 1248 of concomitant uses of statin. The adjusted reporting odds ratios were 3.27 (95% confidence interval [CI]: 3.11–3.43), 8.70 (95% CI: 8.04–9.40), and 1.83 (95% CI: 1.73–1.94), respectively. Several combinations of signals were detected through an additive model or multiplicative model.

Conclusion

Signals of an increased risk of myopathy associated with the use of statins with concomitant drugs, including contraindicated drugs, were confirmed in a real-world setting.

Background

Valproate inhibits clearance of lamotrigine and greatly increases its concentrations. We assessed whether this effect was moderated by a polymorphism (ABCG2 c.421C>A) of the breast cancer resistance protein.

Methods

In two consecutive independent studies in adults with epilepsy on lamotrigine monotherapy or cotreated with valproate: (i) Exposure to valproate was considered treatment, (ii) dose-adjusted lamotrigine troughs at steady state were the outcome, and (iii) ABCG2 c.421C>A genotype (wild-type [wt] homozygosity or variant carriage) was the tested moderator. We used entropy balancing (primary analysis) and exact/optimal full matching (secondary analysis) to control for confounding, including polymorphisms (and linked polymorphisms) suggested to affect exposure to lamotrigine (UGT1A4*3 c.142T>G, rs2011425; UGT2B7–161C>T, rs7668258; ABCB1 1236C>T, rs1128503) to generate frequentist and Bayesian estimates of valproate effects (geometric means ratios [GMR]).

Results

The two studies yielded consistent results (replicated); hence, we analyzed combined data (total N = 471, 140 treated, 331 controls, 378 ABCG2 c.421C>A wt subjects, 93 variant carriers). Primary analysis: in variant carriers, valproate effect (GMR) on lamotrigine (treated, n = 21 vs. controls, n = 72) was around 60% higher than in wt subjects (treated, n = 119 vs. controls, n = 259)—ratio of GMRs 1.61 (95%CI 1.23–2.11) (frequentist) and 1.63 (95%CrI 1.26–2.10) (Bayes). Similar differences in valproate effects between variant carriers and wt subjects were found in the secondary analysis (valproate troughs up to 364 μmol/L vs. no valproate; or valproate ≥364 μmol/L vs. no valproate). Susceptibility of the estimates to unmeasured confounding was low.

Conclusion

Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine.

Background

Despite several hundred clinical trials of drugs that initially showed promise, there has been limited clinical improvement in Alzheimer's disease (AD). This may be attributed to the existence of at least 25 abnormal cellular pathways that underlie the disease. It is improbable for a single drug to address all or most of these pathways, thus even drugs that show promise when administered alone are unlikely to produce significant results. According to previous studies, eight drugs, namely, dantrolene, erythropoietin, lithium, memantine, minocycline, piracetam, riluzole, and silymarin, have been found to target multiple pathways that are involved in the development of AD. Among these drugs, riluzole is currently indicated for the treatment of medical conditions in both adult patients and children and has gained increased attention from scientists due to its potential in the excitotoxic hypothesis of neurodegenerative diseases.

Objective

The aim of this study was to investigate the effects of drugs on AD based on cellular and molecular mechanisms.

Methods

The literature search for this study utilized the Scopus, ScienceDirect, PubMed, and Google Scholar databases to identify relevant articles.

Results

Riluzole exerts its effects in AD through diverse pathways including the inhibition of voltage-dependent sodium and calcium channels, blocking AMPA and NMDA receptors and inhibiting the release of glutamic acid release and stimulation of EAAT1-EAAT2.

Conclusion

In this review article, we aimed to review the neuroprotective properties of riluzole, a glutamate modulator, in AD, which could benefit patients with the disease.

Background

Kaurenol, a diterpene alcohol found in Copaifera langsdorffii Desf. (known as “copaiba”), is historically used in traditional medicine for inflammatory conditions.

Objectives

This study aims to comprehensively assess the potential anti-inflammatory and antinociceptive properties of kaurenol.

Methods

To this end, the following experiments were conducted to evaluated toxicity: locomotor performance and acute toxicity; nociception: acetic acid-induced writhing and formalin-induced antinociception; and anti-inflammatory activity: carrageenan and dextran-induced paw edema at 10, 20, and 40 mg/kg, and measurement of nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in macrophages at 1, 3, and 9 μg/ml.

Results

Kaurenol did not show significant locomotor changes, acute toxicity, and central analgesic activity in the first phase of formalin test at dosages tested. Kaurenol showed 53%, 64%, 64%, and 58% of inhibition in the acetic acid-induced writhing, second phase of formalin test, carrageenan and dextran-induced paw edema, respectively.

Conclusion

The anti-inflammatory activity was associated with the regulation of NO release and probably with the regulation of mediators, such as serotonin and prostaglandin in vascular permeability, as well as by being associated with the regulation of IL-6 and IL-10. Kaurenol display anti-inflammatory activity but has no analgesic activity.

Background

The serotonergic neurotransmitter system is involved in many ethanol-induced changes, including many behavioural alterations, as well as contributing to alcohol dependence and its withdrawal.

Aims

This review has evaluated microdialysis studies where alterations in the serotonin system, that is, serotonin, 5-HT, or its metabolite 5-hydroxyindoleacetic acid, 5-HIAA, have been reported during different ethanol intoxication states, as well as in animals showing alcohol preference or not. Changes in 5-HT receptors and the 5-HT transporter are briefly reviewed to comprehend the significance of changes in microdialysate 5-HT concentrations.

Materials and methods

Changes in 5-HT content following acute, chronic and during ethanol withdrawal states are evaluated. In addition, the serotoninergic system was assessed in animals that have been genetically selected for alcohol preference to ascertain whether changes in this monoamine microdialysate content may contribute to alcohol preference.

Results and discussion

Changes occurred in 5-HT signalling in the limbic brain regions, increasing after acute ethanol administration in specific brain regions, particularly at higher doses, while chronic alcohol exposure essentially decreased serotonergic transmission. Such changes may play a pivotal role in emotion-driven craving and relapse. Depending on the dosage, mode of administration and consumption rate, ethanol affects specific brain regions in different ways, enhancing or reducing 5-HT microdialysate content, thereby inducing behavioural and cognitive functions and enhancing ethanol consumption.

Conclusion

Microdialysis studies demonstrated that ethanol induces several alterations in 5-HT content as well as its metabolites, 5-HIAA and 5-HTOL, not only in its release from a specific brain region but also in the modifications of its different receptor subtypes and its transporter.

Background

Astragaloside IV has emerged as a pharmaceutical monomer with great medical applications and potential. Astragaloside IV has many effects such as improving myocardial ischemia, cerebral ischemia–reperfusion injury, anti-inflammatory, analgesic, antiviral, promoting lymphocyte proliferation, and antitumor effects. However, there are few bibliometric studies on astragaloside IV.

Objectives

We aim to visualize the hotspots and trends in astragaloside IV research through bibliometric analysis to further understand the future development of basic and clinical research.

Methods The articles and reviews on astragaloside IV were screened from the Web of Science Core Collection, and knowledge maps were generated using CiteSpace software. Bibliometric analysis was performed on 971 articles published from 1998 to 2022.

Results

The number of articles on astragaloside IV increased yearly. These publications came from 42 countries/regions, with China being the largest. The primary research institutions were Shanghai University of Traditional Chinese Medicine and Guangzhou University of Traditional Chinese Medicine. Journal of Ethnopharmacology was the most studied journal and co-cited journal. A total of 473 authors were included, among which Hongxin Wang had the highest number of publications and Zhang Wd had the highest total citation frequency. After analysis, the most common keywords are astragaloside IV, expression, and oxidative stress. Cardiovascular disease, cerebral ischemia, cancer, and kidney disease are current and developing research fields.

Conclusion

This study used bibliometrics and visualization methods to analyze the research hotspots and trends of astragaloside IV. Astragaloside IV on ischemia–reperfusion injury, cancer, and tumor may become the focus of future research.

Background

Traditional Chinese medicinal formula (TCMF) has specific advantages in treating diseases. However, the pharmacological effects and mechanism of TCMF composed of traditional Chinese medicines (TCM) with unclear active components or targets have not yet been fully elucidated.

Objectives

This research proposed a strategy for elucidating the pharmacological effects and mechanism to address this issue systematically.

Methods

With Guilin Xiguashuang (GLXGS) taken as a case, this study newly provided the multi-level assays, which decomposes TCMF into components, TCM, and TCMF levels. The main pharmacological effects were acquired through a comprehensive analysis based on the active components, pharmacological effects of TCM, and clinical efficacy of TCMF, respectively. The core targets and pathways were further identified and verified to elucidate the mechanism.

Results

The main pharmacological effects of GLXGS were anti-inflammatory, analgesic, antibacterial, immunoregulatory, and wound healing. Moreover, the mechanism analysis demonstrated that GLXGS was involved in the regulation of NF-κB and VEGF signaling pathways and core targets, such as IL-6 and TNF-α. Finally, unproven immunomodulatory and anti-inflammatory mechanism were verified using RAW264.7 and THP-1 cells. GLXGS was verified to down-regulate IL-6, IL-1β, TNF-α, and CD86 in lipopolysaccharides-stimulated RAW264.7 cells, while enhancing polarization in both RAW264.7 and THP-1 cells, which were consistent with analysis results.

Conclusion

The present research provides a systematic strategy for the pharmacological effect prediction and mechanism analysis of TCMF, which is of great significance for studying complex TCMF.

Background

The antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients.

Objectives

This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells.

Methods

Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out.

Results

Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan-induced steatosis might be linked to the high expression of glutathione S-transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan-induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis.

Conclusion

While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug-induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.

Background

Metabolic stress predisposes to ventricular arrhythmias and sudden cardiac death. Right ventricular outflow tract (RVOT) is the common origin of ventricular arrhythmias. Adenosine monophosphate-regulated protein kinase (AMPK) activation is an important compensatory mechanism for cardiac remodeling during metabolic stress.

Objectives

The purpose of this study was to access whether AMPK inhibition would modulate RVOT electrophysiology, calcium (Ca²⁺) regulation, and RVOT arrhythmogenesis or not.

Methods

Conventional microelectrodes were used to record electrical activity before and after compound C (10 µM, an AMPK inhibitor) in isoproterenol (1 µM)-treated rabbit RVOT tissue preparations under electrical pacing. Whole-cell patch-clamp and confocal microscopic examinations were performed in baseline and compound C-treated rabbit RVOT cardiomyocytes to investigate ionic currents and intracellular Ca²⁺ transients in isolated rabbit RVOT cardiomyocytes.

Results

Compound C decreased RVOT contractility, and reversed isoproterenol increased RVOT contractility. Compound C decreased the incidence, rate, and duration of isoproterenol-induced RVOT burst firing under rapid pacing. Compared to baseline, compound C-treated RVOT cardiomyocytes had a longer action potential duration, smaller intracellular Ca²⁺ transients, late sodium (Na⁺), peak L-type Ca²⁺ current density, Na⁺-Ca²⁺ exchanger, transient outward potassium (K⁺) current, and rapid and slow delayed rectifier K⁺ currents.

Conclusion

AMPK inhibition modulates RVOT electrophysiological characteristics and Ca²⁺ homeostasis, contributing to lower RVOT arrhythmogenic activity. Accordingly, AMPK inhibition might potentially reduce ventricular tachyarrhythmias.