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MMW Fortschritte Der Medizin Jun 2024
Review
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Gabapentin; gamma-Aminobutyric Acid; Amines; Cyclohexanecarboxylic Acids; Pregabalin
PubMed: 38871898
DOI: 10.1007/s15006-024-4030-0 -
Biomedicine & Pharmacotherapy =... Jul 2024Sclareol (SCL), a labdane diterpene compound found in Salvia sclarea L., exhibited therapeutic effects. This study investigated the potential interaction between SCL and...
BACKGROUND
Sclareol (SCL), a labdane diterpene compound found in Salvia sclarea L., exhibited therapeutic effects. This study investigated the potential interaction between SCL and diazepam (DZP) in modulating sedation in the thiopental sodium-induced sleeping animal model, supported by in-silico molecular docking analysis.
METHODS
The control, sclareol (5, 10 and 20 mg/kg), and the reference drugs [diazepam: 3 mg/kg and Caffeine (CAF): 10 mg/kg] were used in male albino mice. Then, sodium thiopental (40 mg/kg, i.p.) was administrated to induce sleep. The latent period, percentage of sleep incidence and modulation of latency were measured. Further, homology modeling of human γ-aminobutyric acid (GABA) was conducted examine the binding mode of GABA interaction with SCL, DZP, and CAF compounds RESULTS: SCL (low dose) slightly increased the sleep latency, while the higher dose significantly prolonged sleep latency. DZP, a GABA receptor agonist, exhibited strong sleep-inducing properties, reducing sleep latency, and increasing sleeping time. Caffeine (CAF) administration prolonged sleep latency and reduced sleeping time, consistent with its stimulant effects. The combination treatments involving SCL, DZP, and CAF showed mixed effects on sleep parameters. The molecular docking revealed good binding affinities of SCL, DZP, and CAF for GABA receptor subunits A2 and A5.
CONCLUSIONS
Our findings highlighted the complex interplay between SCL, DZP, and CAF in regulating sleep behaviors and provided insights into potential combination therapies for sleep disorders.
Topics: Animals; Male; Hypnotics and Sedatives; Molecular Docking Simulation; Mice; Diazepam; Sleep; Thiopental; Diterpenes; Caffeine; Computer Simulation; Receptors, GABA-A; Humans; Dose-Response Relationship, Drug; Sleep Latency
PubMed: 38870629
DOI: 10.1016/j.biopha.2024.116939 -
Redox Biology Aug 2024Silicosis, characterized by interstitial lung inflammation and fibrosis, poses a significant health threat. ATII cells play a crucial role in alveolar epithelial repair...
BACKGROUND
Silicosis, characterized by interstitial lung inflammation and fibrosis, poses a significant health threat. ATII cells play a crucial role in alveolar epithelial repair and structural integrity maintenance. Inhibiting ATII cell senescence has shown promise in silicosis treatment. However, the mechanism behind silica-induced senescence remains elusive.
METHODS
The study employed male C57BL/6 N mice and A549 human alveolar epithelial cells to investigate silicosis and its potential treatment. Silicosis was induced in mice via intratracheal instillation of crystalline silica particles, with honokiol administered intraperitoneally for 14 days. Silica-induced senescence in A549 cells was confirmed, and SIRT3 knockout and overexpression cell lines were generated. Various analyses were conducted, including immunoblotting, qRT-PCR, histology, and transmission electron microscopy. Statistical significance was determined using one-way ANOVA with Tukey's post-hoc test.
RESULTS
This study elucidates how silica induces ATII cell senescence, emphasizing mtDNA damage. Notably, honokiol (HKL) emerges as a promising anti-senescence and anti-fibrosis agent, acting through sirt3. honokiol effectively attenuated senescence in ATII cells, dependent on sirt3 expression, while mitigating mtDNA damage. Sirt3, a class III histone deacetylase, regulates senescence and mitochondrial stress. HKL activates sirt3, protecting against pulmonary fibrosis and mitochondrial damage. Additionally, HKL downregulated cGAS expression in senescent ATII cells induced by silica, suggesting sirt3's role as an upstream regulator of the cGAS/STING signaling pathway. Moreover, honokiol treatment inhibited the activation of the NF-κB signaling pathway, associated with reduced oxidative stress and mtDNA damage. Notably, HKL enhanced the activity of SOD2, crucial for mitochondrial function, through sirt3-mediated deacetylation. Additionally, HKL promoted the deacetylation activity of sirt3, further safeguarding mtDNA integrity.
CONCLUSIONS
This study uncovers a natural compound, HKL, with significant anti-fibrotic properties through activating sirt3, shedding light on silicosis pathogenesis and treatment avenues.
Topics: Animals; Silicosis; Sirtuin 3; Cellular Senescence; Mice; Alveolar Epithelial Cells; Biphenyl Compounds; Humans; Lignans; Signal Transduction; Male; A549 Cells; Nucleotidyltransferases; Disease Models, Animal; Membrane Proteins; Mice, Inbred C57BL; DNA Damage; Allyl Compounds; Phenols
PubMed: 38865904
DOI: 10.1016/j.redox.2024.103224 -
Biochemical and Biophysical Research... Sep 2024Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the...
Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects.
Topics: Animals; Rats, Sprague-Dawley; Rats; Neuralgia; Flavones; Hyperalgesia; Male; Diabetes Mellitus, Experimental; Gabapentin; Nociception; Diabetic Neuropathies; Female; gamma-Aminobutyric Acid; Amines; Sciatic Nerve; Vulvodynia; Constriction; Neuroprotective Agents; Analgesics
PubMed: 38865809
DOI: 10.1016/j.bbrc.2024.150217 -
Upsala Journal of Medical Sciences 2024Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses...
BACKGROUND
Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated.
METHODS
A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS).
RESULTS
Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations.
CONCLUSION
Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.
Topics: Humans; Hypnotics and Sedatives; Analgesics; Male; Female; Middle Aged; Aged; Intensive Care Units; Prospective Studies; Adult; Midazolam; Critical Care; Dexmedetomidine; Fentanyl; Critical Illness; Propofol; Clonidine; Ketamine; Morphine; Aged, 80 and over; Dose-Response Relationship, Drug; Thiopental; Acetaminophen
PubMed: 38863729
DOI: 10.48101/ujms.v129.10560 -
F1000Research 2023The open field assay is used to study anxiety-related traits and anxiolytic drugs in rodents. This assay entails measuring locomotor activity and time spent in the...
BACKGROUND
The open field assay is used to study anxiety-related traits and anxiolytic drugs in rodents. This assay entails measuring locomotor activity and time spent in the center of a chamber that is maintained at ambient room temperature. However, the ambient temperature in most laboratories varies daily and seasonally and can differ between buildings. We sought to evaluate how varying ambient temperature and core body temperature (CBT) affected open field locomotor activity and center time of male wild-type (WT, C57BL/6) and Transient Receptor Potential Subfamily M Member 8 ( ) knock-out ( ) mice. TRPM8 is an ion channel that detects cool temperatures and is activated by icilin.
METHODS
Mice were placed in the open field at 4°C and 23°C for 30 minutes. Distance traveled and time spent in the center were measured. Mice were injected with icilin, M8-B, diazepam, or saline, and changes in activity level were recorded.
RESULTS
The cooling agent icilin increased CBT and profoundly reduced distance traveled and center time of WT mice relative to controls. Likewise, cooling the ambient temperature to 4°C reduced distance traveled and center time of WT mice relative to mice. Conversely, the TRPM8 antagonist (M8-B) reduced CBT and increased distance traveled and center time of WT mice when tested at 4°C. The TRPM8 antagonist (M8-B) had no effect on CBT or open field behavior of mice. The anxiolytic diazepam reduced CBT in WT and mice. When tested at 4°C, diazepam increased distance traveled and center time in WT mice but did not alter open field behavior of mice.
CONCLUSIONS
Environmental temperature and drugs that affect CBT can influence locomotor behavior and center time in the open field assay, highlighting temperature (ambient and core) as sources of environmental and physiologic variability in this commonly used behavioral assay.
Topics: Animals; Male; TRPM Cation Channels; Temperature; Mice; Body Temperature; Mice, Inbred C57BL; Mice, Knockout; Diazepam; Anti-Anxiety Agents; Pyrimidinones; Open Field Test; Locomotion
PubMed: 38863500
DOI: 10.12688/f1000research.130474.3 -
Scientific Reports Jun 2024There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce... (Meta-Analysis)
Meta-Analysis
A systematic review and meta-analysis, investigating dose and time of fluvoxamine treatment efficacy for COVID-19 clinical deterioration, death, and Long-COVID complications.
There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce the severity of the disease and prevent the need for hospitalization to avoid stress on healthcare systems worldwide. The repurposing of drugs to prevent clinical deterioration of COVID-19 patients was trialed in many studies using many different drugs. Fluvoxamine (an SSRI and sigma-1 receptor agonist) was initially identified to potentially provide beneficial effects in COVID-19-infected patients, preventing clinical deterioration and the need for hospitalization. Fourteen clinical studies have been carried out to date, with seven of those being randomized placebo-controlled studies. This systematic review and meta-analysis covers the literature from the outbreak of SARS-CoV-2 in late 2019 until January 2024. Search terms related to fluvoxamine, such as its trade names and chemical names, along with words related to COVID-19, such as SARS-CoV-2 and coronavirus, were used in literature databases including PubMed, Google Scholar, Scopus, and the ClinicalTrials.gov database from NIH, to identify the trials used in the subsequent analysis. Clinical deterioration and death data were extracted from these studies where available and used in the meta-analysis. A total of 7153 patients were studied across 14 studies (both open-label and double-blind placebo-controlled). 681 out of 3553 (19.17%) in the standard care group and 255 out of 3600 (7.08%) in the fluvoxamine-treated group experienced clinical deterioration. The estimated average log odds ratio was 1.087 (95% CI 0.200 to 1.973), which differed significantly from zero (z = 2.402, p = 0.016). The seven placebo-controlled studies resulted in a log odds ratio of 0.359 (95% CI 0.1111 to 0.5294), which differed significantly from zero (z = 3.103, p = 0.002). The results of this study identified fluvoxamine as effective in preventing clinical deterioration, and subgrouping analysis suggests that earlier treatment with a dose of 200 mg or above provides the best outcomes. We hope the outcomes of this study can help design future studies into respiratory viral infections and potentially improve clinical outcomes.
Topics: Fluvoxamine; Humans; COVID-19 Drug Treatment; COVID-19; SARS-CoV-2; Treatment Outcome; Clinical Deterioration; Selective Serotonin Reuptake Inhibitors
PubMed: 38862591
DOI: 10.1038/s41598-024-64260-9 -
Journal of Applied Research in... Jul 2024In people with intellectual disabilities and/or autism spectrum disorder, oral midazolam (OM) is very effective as premedication for facilitating medical treatment. In...
BACKGROUND
In people with intellectual disabilities and/or autism spectrum disorder, oral midazolam (OM) is very effective as premedication for facilitating medical treatment. In this retrospective study, we investigated the optimal dosage of OM for premedication.
METHODS
Patients with intellectual disability and/or autism spectrum disorder who were given OM as a premedication were selected from anaesthesia records. The primary outcome variable was the dose of OM (mg/kg) required to produce an adequate sedation.
RESULTS
The mean OM dose required was 0.32 ± 0.10 mg/kg. The required OM dose decreased significantly as age and weight increased, and age and weight were also shown to be significantly associated with the dose of OM in the multivariate linear regression analysis.
CONCLUSION
The dosage of OM to achieve adequate sedation should decrease as the patient ages. Furthermore, adequate sedation can be achieved with even lower doses of OM in obese people.
Topics: Humans; Autism Spectrum Disorder; Intellectual Disability; Midazolam; Male; Female; Adult; Young Adult; Retrospective Studies; Hypnotics and Sedatives; Adolescent; Child; Middle Aged; Administration, Oral; Dose-Response Relationship, Drug; Premedication
PubMed: 38859732
DOI: 10.1111/jar.13265 -
Analytical Chemistry Jun 2024It is well-known in biochemistry that structure confers function, meaning that chemical structural elucidation is critical to truly understanding the function of a given...
It is well-known in biochemistry that structure confers function, meaning that chemical structural elucidation is critical to truly understanding the function of a given metabolite. Indole-3-pyruvate (IPyA) exists in an equilibrium between the keto and enol tautomeric forms. IPyA is suggested to play a role in immune function; however, determining whether the tautomeric forms function differently can only be studied if an analytical method is capable of distinguishing between the two forms. Herein, we describe the use of UHPLC-HRMS to gain insight into the physical variables that govern IPyA tautomer equilibrium, reactivity, and detection limit. We use hydrogen-deuterium exchange (HDX) to identify enol and keto peaks, and we show that tautomers exhibit a valley of fronting followed by a tailing peak shape (though separation is still attainable) and identical MS/MS spectra. We observed drastically different ratios of keto and enol forms in different solvents, which is an important consideration for in vitro studies. IPyA was found to be highly unstable with accelerated reactivity in peroxides. Through in vitro reactivity studies, IPyA produced a myriad of known and unknown metabolites via nonenzymatic processes, many of which were mapped in vivo via the analysis of human plasma. Finally, we show that vitamin C (ascorbic acid) can slow this reactivity and enable sensitive detection in whole blood.
Topics: Indoles; Chromatography, High Pressure Liquid; Humans; Tandem Mass Spectrometry; Isomerism
PubMed: 38858849
DOI: 10.1021/acs.analchem.4c01584 -
Clinical Nutrition ESPEN Aug 2024Curcumin is a polyphenolic natural compound that has been used to treat various ailments such as symptoms of anxiety. However, the findings of studies regarding the... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIM
Curcumin is a polyphenolic natural compound that has been used to treat various ailments such as symptoms of anxiety. However, the findings of studies regarding the anti-anxiety properties of curcumin are controversial. This review aims to evaluate if there are clinical benefits of curcumin in patients with symptoms of anxiety.
METHODS
PubMed, Embase, Web of Science, and the Cochrane Library were retrieved to collect randomized controlled trials (RCTs) from the database inception to August 16, 2023. The random-effects model was used to estimate the standard mean difference (SMD).
RESULTS
A total of eight RCTs involving 567 participants were included in the analysis. A pooled analysis showed a significant effect of curcumin on anxiety symptoms (SMD: -1.56; 95% CI: -2.48, -0.64, p < 0.001; I = 95.6%, p-heterogeneity< 0.001).
CONCLUSION
Present meta-analysis demonstrated that curcumin intake might contribute to alleviation of anxiety disorder. Due to the limited number of studies included, it is necessary to conduct more high-quality studies to confirm the clinical efficacy of curcumin.
Topics: Curcumin; Humans; Randomized Controlled Trials as Topic; Anxiety; Dietary Supplements; Anti-Anxiety Agents; Anxiety Disorders
PubMed: 38857152
DOI: 10.1016/j.clnesp.2024.05.017