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Analytical Chemistry Oct 2022Barbiturates are highly susceptible to dissociation in mass spectrometry (MS) because of their long side chains combined with a nonaromatic ring consisting of several...
Barbiturates are highly susceptible to dissociation in mass spectrometry (MS) because of their long side chains combined with a nonaromatic ring consisting of several carbonyl and amine groups. As a result, they exhibit extensive α-cleavage and subsequent rearrangement, making the identification of these compounds difficult. Although a library of electron ionization MS (EIMS) is available, most barbiturates have very similar fragment patterns. Accordingly, it would be desirable to develop a technique for soft ionization, providing a molecular ion and large fragment ions as well. In this study, a molecular ion was clearly observed, in addition to large fragment ions, for a variety of barbiturates based on multiphoton ionization MS (MPIMS) using a tunable ultraviolet femtosecond laser as the ionization source (fs-LIMS). This favorable result was achieved when the optimal laser wavelength for minimizing the excess energy remaining in the ionic state was used. An examination of the photofragmentation pathways suggested that an H atom in the side chain was abstracted by an oxygen atom in the carbonyl group in the ring structure thus initiating fragmentation and subsequent rearrangement. Barbiturates that are substituted with alkyl groups (amobarbital and pentobarbital) had narrower spectral regions for optimal ionization than the other barbiturates with alkyl and alkenyl groups (butalbital and secobarbital) and more with alkyl and phenyl groups (phenobarbital). All of the barbiturates studied provided unique mass spectral patterns in fs-LIMS, which was useful for the reliable identification of these compounds in practical trace analysis.
Topics: Secobarbital; Amobarbital; Pentobarbital; Barbiturates; Phenobarbital; Mass Spectrometry; Ions; Oxygen; Amines
PubMed: 36229898
DOI: 10.1021/acs.analchem.2c03077 -
Journal of Ethnopharmacology Apr 2024Qizhuyanggan Decoction (QZD), a traditional Chinese medicine formula, is frequently utilized in clinical practice for managing hepatic fibrosis. However, the specific...
Integration of network pharmacology and serum medicinal chemistry to investigate the pharmacological mechanisms of QiZhuYangGan Decoction in the treatment of hepatic fibrosis.
ETHNOPHARMACOLOGICAL RELEVANCE
Qizhuyanggan Decoction (QZD), a traditional Chinese medicine formula, is frequently utilized in clinical practice for managing hepatic fibrosis. However, the specific target and mechanism of action of QZD for hepatic fibrosis treatment remain unknown.
AIM OF THE STUDY
By combining network pharmacology, serum medicinal chemistry, and experimental validation methods, our study aimed to investigate the therapeutic effects of QZD on hepatic fibrosis, the anti-hepatic fibrosis active ingredients, and the possible mechanism of anti-hepatic fibrosis action.
MATERIALS AND METHODS
The study aimed to investigate the therapeutic effect of QZD on hepatic fibrosis induced by CCl in SD rats, as well as its mechanism of action. The rats were anesthetized intraperitoneally using 3% pentobarbital and were executed after asphyxiation with high concentrations of carbon dioxide. Several techniques were employed to evaluate the efficacy of QZD, including ELISA, Western blot, HYP reagent assay, and various pathological examinations such as HE, Masson, Sirius Red staining, and immunohistochemistry (IHC). Additionally, serum biochemical assays were conducted to assess the effect of QZD on liver injury. Network pharmacology, UPLC, molecular docking, and molecular dynamics simulation were utilized to explore the mechanism of QZD in treating hepatic fibrosis. Finally, experimental validation was performed through ELISA, IHC, RT-qPCR, and Western blot analysis.
RESULT
Liver histopathology showed that QZD reduced inflammation and inhibited collagen production, and QZD significantly reduced HA and LN content to treat hepatic fibrosis. Serum biochemical analysis showed that QZD improved liver injury. Network pharmacology combined with UPLC screened six active ingredients and obtained 87 targets for the intersection of active ingredients and diseases. The enrichment analysis results indicated that the PI3K/AKT pathway might be the mechanism of action of QZD in the treatment of hepatic fibrosis, and counteracting the inflammatory response might be one of the pathways of action of QZD. Molecular docking and molecular dynamics simulations showed that the active ingredient had good binding properties with PI3K, AKT, and mTOR proteins. Western blot, ELISA, PCR, and IHC results indicated that QZD may treat hepatic fibrosis by inhibiting the PI3K/AKT/mTOR pathway and suppressing M1 macrophage polarization, while also promoting M2 macrophage polarization.
CONCLUSIONS
QZD may be effective in the treatment of hepatic fibrosis by inhibiting the PI3K/AKT/mTOR signaling pathway and M1 macrophage polarization, while promoting M2 macrophage polarization. This provides a strong basis for the clinical application of QZD.
Topics: Animals; Rats; Rats, Sprague-Dawley; Chemistry, Pharmaceutical; Molecular Docking Simulation; Network Pharmacology; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Liver Cirrhosis; TOR Serine-Threonine Kinases; Drugs, Chinese Herbal
PubMed: 38190954
DOI: 10.1016/j.jep.2024.117730 -
The Journal of Pharmacology and... Jul 2022Breast cancer remains the leading cause of cancer-related death among women worldwide. Sodium pentobarbital was found to play an inhibitory role in glioma growth in...
Breast cancer remains the leading cause of cancer-related death among women worldwide. Sodium pentobarbital was found to play an inhibitory role in glioma growth in rats. In this study, we aimed to evaluate the effects of sodium pentobarbital on breast cancer growth both in vitro and in vivo, and its impacts on the microcirculatory changes on both skin and tumor surface in mice bearing subcutaneous xenograft. Cell counting assay was used to assess the antiproliferative effect of sodium pentobarbital on MDA-MB-231 breast cancer cells. Subcutaneous xenograft model was established to study the role of sodium pentobarbital on in vivo tumor growth. Speed-resolved blood perfusion, hemoglobin oxygen saturation (SO, %), total hemoglobin tissue concentration (ctTHb, M), and red blood cell (RBC) tissue fraction (%) were examined simultaneously by using enhanced perfusion and oxygen saturation system to investigate the effects of sodium pentobarbital on microcirculatory hemodynamics and oxygenation. Sodium pentobarbital suppressed breast tumor growth both in vitro and in vivo. Cutaneous blood flux in nutritive capillaries with low-speed flow was significantly increased in tumor-bearing mice, and high-dose sodium pentobarbital treatment cause a reduction in this low-speed blood flux, whereas sodium pentobarbital therapy caused an elevated blood flux in larger microvessels with mid and high speed in a dose-dependent manner. Different doses of sodium pentobarbital exerted different actions on SO, ctTHb, and RBC tissue fraction. Collectively, the inhibitory effect of sodium pentobarbital on breast tumor growth was at least partly associated with its ability to normalize microcirculatory hemodynamics and oxygenation in tumors. SIGNIFICANCE STATEMENT: This study is the first to demonstrate the inhibiting effect of sodium pentobarbital on breast cancer growth both in vitro and in vivo, and such an inhibition was at least partly associated with its ability to normalize microcirculatory hemodynamics and oxygenation in tumors.
Topics: Animals; Breast Neoplasms; Female; Hemodynamics; Hemoglobins; Humans; Mice; Microcirculation; Oxygen; Pentobarbital; Rats; Sodium
PubMed: 35512800
DOI: 10.1124/jpet.121.001058 -
Journal of Clinical Anesthesia Jun 2020Procedural sedation for non-painful pediatric examinations outside the operating room remains a challenge, this study was designed to compare the safety and... (Meta-Analysis)
Meta-Analysis Review
STUDY OBJECTIVE
Procedural sedation for non-painful pediatric examinations outside the operating room remains a challenge, this study was designed to compare the safety and effectiveness of sedation provided by dexmedetomidine versus other sedatives including chloral hydrate, midazolam, and pentobarbital for pediatric patients to complete diagnostic examinations.
DESIGN
Systematic review and meta-analysis of RCTs.
SETTING
Pediatric procedural sedation.
INTERVENTIONS
Comparison of sedation by dexmedetomidine and chloral hydrate, or pentobarbital, or midazolam for pediatric non-painful sedation.
PATIENTS
The PubMed, Embase, and Cochrane Library databases and the Cochrane Controlled Trials Register for randomized clinical trials were searched and limited the studies to those published in English through July 30, 2018.
MEASUREMENTS
Prospective randomized clinical trials (RCTs) comparing dexmedetomidine to chloral hydrate, pentobarbital, and midazolam for pediatric procedural examinations outside the operating room were included in the meta-analysis. Search terms included dexmedetomidine, precede, adrenergic alpha-2 receptor agonists, adrenergic alpha 2 agonists, adrenergic alpha-agonists, adrenergic alpha 2 receptor agonists, chloral hydrate, pentobarbital, midazolam, AND sedation.
MAIN RESULTS
A total of 1486 studies were screened and nine RCTs were identified; 1076 patients were analyzed. Sedation with dexmedetomidine provided statistically higher incidences in completing examinations with fewer episodes of desaturation than the other sedatives did (OR 2.90, 95% CI: 1.39-6.07, P = 0.005, I = 77%; OR 0.29, 95% CI: 0.15-0.57, P = 0.0004, I = 0%, respectively).
CONCLUSIONS
The meta-analysis shows that sedation by dexmedetomidine has lower incidence of respiratory depression and provides higher success rates in completing examinations than other traditional sedatives without compromising safety, indicating a prospective clinical use for procedural sedation.
Topics: Child; Chloral Hydrate; Conscious Sedation; Dexmedetomidine; Humans; Hypnotics and Sedatives; Midazolam; Randomized Controlled Trials as Topic
PubMed: 32018129
DOI: 10.1016/j.jclinane.2020.109736 -
Laboratory Animals Jun 2023To achieve surgical anesthesia in animal experimentation, it is important to select the appropriate anesthetic dose. However, few studies have investigated the... (Review)
Review
To achieve surgical anesthesia in animal experimentation, it is important to select the appropriate anesthetic dose. However, few studies have investigated the reasonable anesthetic dose in tree shrew (). The aim of the study was to review the literature to determine the most commonly used anesthetic dose in tree shrew and to calculate the reasonable equivalent dose between tree shrew and rat based on the body surface area conversion. Two groups of 10 adult tree shrews each were anesthetized with 1% sodium pentobarbital through intraperitoneal injection separately at doses of 62 mg/kg (equivalent dose) and 40 mg/kg (reported dose). Anesthetic depth and times were assessed in addition to vital signs. The results showed that the dosage was quite different across studies, ranging from 15 mg/kg to 80 mg/kg, with 40 mg/kg being the most frequently reported dose. However, the group of tree shrews anesthetized with the commonly reported dose were unable to meet the requirements of surgery. In contrast, the equivalent dose (62 mg/kg, intraperitoneal injection with sodium pentobarbital) calculated by body surface area conversion could achieve an anesthetic time of 44.28 ± 3.95 min with no serious or fatal effects. During anesthetic monitoring, we found that sodium pentobarbital had an inhibitory effect on the blood pressure, pulse rate, respiratory rate and rectal temperature in tree shrews, especially on the respiratory rate. Thus, our study indicated that the use of the equivalent dose of sodium pentobarbital was effective in anesthetizing tree shrews.
Topics: Animals; Rats; Tupaia; Tupaiidae; Pentobarbital; Anesthesia; Sodium
PubMed: 36604949
DOI: 10.1177/00236772221146419 -
Frontiers in Pharmacology 2021The interest in AMPA receptors as a target for epilepsy treatment increased substantially after the approval of perampanel, a negative AMPA receptor allosteric...
The interest in AMPA receptors as a target for epilepsy treatment increased substantially after the approval of perampanel, a negative AMPA receptor allosteric antagonist, for the treatment of partial-onset seizures and generalized tonic-clonic seizures. Here we performed a screening for activity against native calcium-permeable AMPA receptors (CP-AMPARs) and calcium-impermeable AMPA receptors (CI-AMPARs) among different anticonvulsants using the whole-cell patch-clamp method on isolated Wistar rat brain neurons. Lamotrigine, topiramate, levetiracetam, felbamate, carbamazepine, tiagabin, vigabatrin, zonisamide, and gabapentin in 100-µM concentration were practically inactive against both major subtypes of AMPARs, while phenytoin reversibly inhibited them with IC50 of 30 ± 4 μM and 250 ± 60 µM for CI-AMPARs and CP-AMPARs, respectively. The action of phenytoin on CI-AMPARs was attenuated in experiments with high agonist concentrations, in the presence of cyclothiazide and at pH 9.0. Features of phenytoin action matched those of the CI-AMPARs pore blocker pentobarbital, being different from classical competitive inhibitors, negative allosteric inhibitors, and CP-AMPARs selective channel blockers. Close 3D similarity between phenytoin and pentobarbital also suggests a common binding site in the pore and mechanism of inhibition. The main target for phenytoin in the brain, which is believed to underlie its anticonvulsant properties, are voltage-gated sodium channels. Here we have shown for the first time that phenytoin inhibits CI-AMPARs with similar potency. Thus, AMPAR inhibition by phenytoin may contribute to its anticonvulsant properties as well as its side effects.
PubMed: 34950035
DOI: 10.3389/fphar.2021.775040 -
Scientific Reports Jan 2020Rodents are widely used for animal research in Egypt. Pentobarbital is the most common anesthetic agent; however overdoses may affect the experimental outcomes and limit...
Rodents are widely used for animal research in Egypt. Pentobarbital is the most common anesthetic agent; however overdoses may affect the experimental outcomes and limit the use of tissues. To investigate the effects of sodium pentobarbital overdoses during exsanguination, three groups (6 rats/group) of male and female rats were injected i.p. with 50, 100 and 150 mg/kg of sodium pentobarbital, then carotid exsanguination was performed immediately after loss of consciousness. Hypoxia-inducible factor 1-alpha (Hif1a) and tumor necrosis factor-alpha (Tnfa) mRNA expressions in liver and kidney organs were evaluated. As well as, serum aminotransferase activities (AST&ALT), glucose, urea, creatinine, malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) levels were determined. The histological alterations in liver, kidney and spleen were studied. It was found that Hif1a and Tnfa were significantly overexpressed in the studied organs and serum AST, glucose, creatinine and urea levels were significantly increased after sodium pentobarbital overdoses (100 and 150 mg/kg) compared to 50 mg/kg dose. Similarly, significant increase in MDA and GSH levels of liver, kidney and spleen were noticed. Results showed gender difference where Hif1a and Tnfa levels were significantly overexpressed at high dose of sodium pentobarbital of liver and kidney organs in female more than male rats. Since euthanasia protocol may influence the physiological variables and affect genes' expression, it is recommended to avoid sodium pentobarbital overdose during euthanasia as it may interfere with the biochemical, molecular and histological measurements.
Topics: Adjuvants, Anesthesia; Animals; Biomarkers; Exsanguination; Female; Glutathione; Kidney; Liver; Liver Function Tests; Male; Malondialdehyde; Oxidative Stress; Pentobarbital; Rats; Rats, Wistar
PubMed: 31942001
DOI: 10.1038/s41598-019-57252-7 -
Journal of Neurophysiology Aug 2022Laryngeal function is vital to airway protection. Although swallow is mediated by the brainstem, the mechanism underlying the increased risk of dysphagia after cervical...
Laryngeal function is vital to airway protection. Although swallow is mediated by the brainstem, the mechanism underlying the increased risk of dysphagia after cervical spinal cord injury (SCI) is unknown. We hypothesized that: ) loss of descending phrenic drive affects swallow and breathing differently, and ) loss of ascending spinal afferent information alters swallow regulation. We recorded electromyograms (EMGs) from upper airway and chest wall muscles in freely breathing pentobarbital-anesthetized cats and rats. Laryngeal abductor activity during inspiration increased about twofold following C2 lateral hemisection. Ipsilateral to the injury, the crural diaphragm EMG amplitude was reduced during breathing (62 ± 25% change postinjury), but no animal had complete termination of activity; 75% of animals had increased contralateral diaphragm recruitment, but this did not reach significance. During swallow, laryngeal adductor and pharyngeal constrictor muscles increased activity, and diaphragm activity was bilaterally suppressed. This was unexpected because of the ipsilateral-specific response during breathing. Swallow-breathing coordination was disrupted by injury, and more swallows occurred during early expiration. Finally, to determine if the chest wall is a major source of feedback for laryngeal regulation, we performed T1 total transections in rats. As in the C2 lateral hemisection, inspiratory laryngeal recruitment was the first feature noted after injury. In contrast to the C2 lateral hemisection, diaphragmatic drive increased after T1 transection. Overall, we found that SCI alters laryngeal drive during swallow and breathing, and alters swallow-related diaphragm activity. Our results show behavior-specific effects, suggesting that swallow is affected more than breathing is by SCI, and emphasizing the need for additional studies on the effect of ascending afferents from the spinal cord on laryngeal function. This is the first manuscript to determine the impact of cSCI on laryngeal and swallow function, and to describe a possible mechanism for dysphagia and altered airway protection after injury.
Topics: Animals; Cervical Cord; Deglutition Disorders; Diaphragm; Phrenic Nerve; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries
PubMed: 35830612
DOI: 10.1152/jn.00469.2021 -
Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT Receptor Activation via NO Pathway.International Journal of Molecular... Jan 2023Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in...
Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in normoglycaemic rats. Considering that diabetes induces cardiovascular complications, we aimed to determine whether diabetic state modifies noradrenergic input at renal level and its serotonergic modulation in rats. Alloxan diabetic rats were anaesthetized (pentobarbital; 60 mg/kg i.p.) and prepared for in situ autoperfusion of the left kidney to continuously measure systemic blood pressure (SBP), heart rate (HR), and renal perfusion pressure (RPP). Electrical stimulation of renal sympathetic outflow induces frequency-dependent increases (Δ) in RPP (23.9 ± 2.1, 59.5 ± 1.9, and 80.5 ± 3.5 mm Hg at 2, 4, and 6 Hz, respectively), which were higher than in normoglycaemic rats, without modifying HR or SBP. Intraarterial bolus of 5-HT and 5-CT (5-HT agonist) reduced electrically induced ΔRPP. Only L-694,247 (5-HT agonist) reproduced 5-CT inhibition on sympathetic-induced vasoconstrictions, whereas it did not modify exogenous noradrenaline-induced ΔRPP. 5-CT inhibition was exclusively abolished by i.v. bolus of LY310762 (5-HT antagonist). An inhibitor of guanylyl cyclase, ODQ (i.v.), completely reversed the L-694,247 inhibitory effect. In conclusion, diabetes induces an enhancement in sympathetic-induced vasopressor responses at the renal level. Prejunctional 5-HT receptors, via the nitric oxide pathway, inhibit noradrenergic-induced vasoconstrictions in diabetic rats.
Topics: Rats; Animals; Serotonin; Rats, Wistar; Receptor, Serotonin, 5-HT1D; Diabetes Mellitus, Experimental; Kidney; Norepinephrine; Sympathetic Nervous System; Electric Stimulation; Blood Pressure
PubMed: 36674892
DOI: 10.3390/ijms24021378 -
Neurocritical Care Aug 2021Multimodality neurologic monitoring (MMM) is an emerging technique for management of traumatic brain injury (TBI). An increasing array of MMM-derived biomarkers now...
BACKGROUND/OBJECTIVE
Multimodality neurologic monitoring (MMM) is an emerging technique for management of traumatic brain injury (TBI). An increasing array of MMM-derived biomarkers now exist that are associated with injury severity and functional outcomes after TBI. A standardized MMM reporting process has not been well described, and a paucity of evidence exists relating MMM reporting in TBI management with functional outcomes or adverse events.
METHODS
Prospective implementation of standardized MMM reporting at a single pediatric intensive care unit (PICU) is described that included monitoring of intracranial pressure (ICP), cerebral oxygenation and electroencephalography (EEG). The incidence of clinical decisions made using MMM reporting is described, including timing of neuroimaging, ICP monitoring discontinuation, use of paralytic, hyperosmolar and pentobarbital therapies, neurosurgical interventions, ventilator and CPP adjustments and neurologic prognostication discussions. Retrospective analysis was performed on the association of MMM reporting with initial Glasgow Coma Scale (GCS) and Pediatric Risk of Mortality III (PRISM III) scores, duration of total hospitalization and PICU hospitalization, duration of mechanical ventilation and invasive ICP monitoring, inpatient complications, time with ICP > 20 mmHg, time with cerebral perfusion pressure (CPP) < 40 mmHg and 12-month Glasgow Outcome Scale-Extended Pediatrics (GOSE-Peds) scores. Association of outcomes with MMM reporting was investigated using the Wilcoxon rank-sum test or Fisher's exact test, as appropriate.
RESULTS
Eighty-five children with TBI underwent MMM over 6 years, among which 18 underwent daily MMM reporting over a 21-month period. Clinical decision-making influenced by MMM reporting included timing of neuroimaging (100.0%), ICP monitoring discontinuation (100.0%), timing of extubation trials of surviving patients (100.0%), body repositioning (11.1%), paralytic therapy (16.7%), hyperosmolar therapy (22.2%), pentobarbital therapy (33.3%), provocative cerebral autoregulation testing (16.7%), adjustments in CPP thresholds (16.7%), adjustments in PaCO2 thresholds (11.1%), neurosurgical interventions (16.7%) and neurologic prognostication discussions (11.1%). The implementation of MMM reporting was associated with a reduction in ICP monitoring duration (p = 0.0017) and mechanical ventilator duration (p = 0.0018). No significant differences were observed in initial GCS or PRISM III scores, total hospitalization length, PICU hospitalization length, total complications, time with ICP > 20 mmHg, time with CPP < 40 mmHg, use of tier 2 therapy, or 12-month GOS-E Peds scores.
CONCLUSION
Implementation of MMM reporting in pediatric TBI management is feasible and can be impactful in tailoring clinical decisions. Prospective work is needed to understand the impact of MMM and MMM reporting systems on functional outcomes and clinical care efficacy.
Topics: Brain Injuries, Traumatic; Child; Humans; Intracranial Pressure; Monitoring, Physiologic; Pediatrics; Prospective Studies; Retrospective Studies
PubMed: 33791948
DOI: 10.1007/s12028-021-01190-8