A Systematic Critical Review of Clinical Pharmacokinetics of Torasemide.

PURPOSE: Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen. METHODS: Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178). RESULTS: A decrease in maximum plasma concentration (C max ) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration-time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC 0-∞ that is, 42.9 versus 8.091 mcg.h -1 .mL -1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC 0-∞ of torasemide, whereas losartan and empagliflozin did not. CONCLUSIONS: The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug-drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases.

Exploring the pharmacokinetics of second-generation cephalosporin, cefaclor: a systematic review in healthy and diseased populations.

Cefaclor is a bactericidal antibiotic recommended for treating diverse types of infections. This review aims to comprehensively assess the pharmacokinetic (PK) data on cefaclor in humans.Google Scholar, PubMed, Cochrane Library, and EBSCO databases were systematically performed to identify all the relevant studies containing at least one reported PK parameter of cefaclor.Cefaclor shows the linear PK profile as the area under the plasma concentration-time curve from 0 to t (AUC0-t) and maximum plasma concentration (Cmax) increase in a dose-dependent manner. The AUC0-t of cefaclor in the rice diet was found to be higher than that of bread food, i.e. 19.9 ± 2.6 ug/ml.hr vs 15.4 ± 4 ug/ml.hr. The AUC in paediatrics during the fed state was significantly higher compared to that in adults. Patients with renal impairments showed a Cmax 2.2 times higher than that of normal subjects. A significant increase in Cmax was depicted among individuals following a vegetarian diet in comparison with the non-vegetarian diet. Moreover, cefaclor exhibits time-dependent killing above the minimum inhibitory concentration (MIC < 2 ug), favouring its use in treating infections caused by specific pathogens.This systematic review summarises all the reported PK parameters of cefaclor in healthy and diseased subjects in the literature. This data can help practitioners in adjusting cefaclor doses among different diseases and populations to avoid drug interactions and adverse effects.

Perampanel increases seizure threshold in pentylenetetrazole-kindled mice and improves behavioral dysfunctions by modifying mRNA expression levels of BDNF/TrkB and inflammatory markers.

Perampanel (PER), a novel 3rd-generation antiseizure drug that modulates altered post-synaptic glutamatergic storming by selectively inhibiting AMPA receptors, is recently approved to treat intractable forms of seizures. However, to date, presumably consequences of long-term PER therapy on the comorbid deleterious psychiatric disturbances and its correlation with neuroinflammatory parameters are not fully investigated in chronic models of epilepsy. Therefore, we investigated the real-time effect of PER on brain electroencephalographic (EEG) activity, behavioral alterations, redox balance, and relative mRNA expression in pentylenetetrazole (PTZ) induced kindling. Male BALB/c mice were pretreated with PER (0.125, 0.25, and 0.5 mg/kg) for 3 weeks and challenged with 11 injections of PTZ at the sub-threshold dose of 40 mg/kg every other day. vEEG from implanted cortical electrodes was monitored to elucidate seizure propagation and behavioral manifestations. Recorded EEG signals exhibited that PER 0.5 mg/kg pretreatment exceptionally impeded the onset of sharp epileptic spike-wave discharges and associated motor symptoms. Additionally, qEEG analysis showed that PER prevented alterations in absolute mean spectral power and reduced RMS amplitude of epileptogenic spikes vs PTZ control. Furthermore, our outcomes illustrated that PER dose-dependently attenuated PTZ-evoked anxiety-like behavior, memory deficits, and depressive-like behavior that was validated by a series of behavioral experiments. Moreover PER, significantly reduced lipid peroxidation, AChE, and increased levels of SOD and total thiol in the mice brain via AMPAR antagonism. Post-PTZ kindling provoked overstimulation of BDNF/TrkB signaling and increased release of pro-inflammatory cytokines that were reversed by PER with suppression of iNOS in brain immune cells. In conclusion, our findings highlight that PER might play an auspicious preventive role in the proepileptic transformation of brain circuits via suppression of BDNF/TrkB signaling and reduced transcriptional levels of neuroinflammatory markers leading to improvised epilepsy-induced neurobehavioral and neurochemical effects.

Therapeutic benefits of quercetin in traumatic brain injury model exposed to cigarette smoke.

Scientific evidences reported the deleterious effect of cigarette smoking or passive smoking on brain health particularly cognitive functions, blood-brain barrier (BBB) permeability, up-regulation of inflammatory cascades, and depletion of the antioxidant system. These combined effects become more progressive in the events of stroke, traumatic brain injury (TBI), and many other neurodegenerative diseases. In the current study, we investigated the long-term administered therapeutic potential of quercetin in ameliorating the deleterious neurobiological consequences of chronic tobacco smoke exposure in TBI mice. After exposure to 21 days of cigarette smoke and treatment with 50 mg/kg of quercetin, C57BL/6 mice were challenged for the induction of TBI by the weight drop method. Subsequently, a battery of behavioral tests and immunohistochemical analyses revealed the beneficial effect of quercetin on the locomotive and cognitive function of TBI + smoked group mice (p < 0.05 vs control sham). Immunohistochemistry analysis (Nrf2, HO-1, NFkB, caspase 3) demonstrated a marked protection after 21 days of quercetin treatment in the chronic tobacco smoking group possibly by up-regulation of antioxidant pathways, and decreased apoptosis. In conclusion, our findings support the therapeutic effectiveness of quercetin in partly protecting the central neurological functions that become aberrantly impaired in combined habitual cigarette-smoking individuals impacted with TBI.

Clinical pharmacokinetics of nebivolol: a systematic review.

Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC0-∞) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (Cmax) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher Cmax, AUC0-∞ and half-life (t1/2) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.

Effects of Volatile Anesthetics versus Ketamine on Blood-Brain Barrier Permeability via Lipid-Mediated Alterations of Endothelial Cell Membranes.

The purpose of this study was to investigate the effects of the volatile anesthetic agents isoflurane and sevoflurane, at clinically relevant concentrations, on the fluidity of lipid membranes and permeability of the blood-brain barrier (BBB). We analyzed the in vitro effects of isoflurane or ketamine using erythrocyte ghosts (sodium fluorescein permeability), monolayers of brain microvascular endothelial cells ([13C]sucrose and fluorescein permeability), or liposomes (fluorescence anisotropy). Additionally, we determined the effects of 30-minute exposure of mice to isoflurane on the brain tight junction proteins. Finally, we investigated in vivo brain uptake of [13C]mannitol and [13C]sucrose after intravenous administration in mice under anesthesia with isoflurane, sevoflurane, or ketamine/xylazine in addition to the awake condition. Isoflurane at 1-mM and 5-mM concentrations increased fluorescein efflux from the erythrocyte ghosts in a concentration-dependent manner. Similarly, in endothelial cell monolayers exposed to 3% (v/v) isoflurane, permeability coefficients rose by about 25% for fluorescein and 40% for [13C]sucrose, whereas transendothelial resistance and cell viability remained unaffected. Although isoflurane caused a significant decrease in liposomes anisotropy values, ketamine/xylazine did not show any effects. Brain uptake clearance (apparent Kin) of the passive permeability markers in vivo in mice approximately doubled under isoflurane or sevoflurane anesthesia compared with either ketamine/xylazine anesthesia or the awake condition. In vivo exposure of mice to isoflurane did not change any of the brain tight junction proteins. Our data support membrane permeabilization rather than loosening of intercellular tight junctions as an underlying mechanism for increased permeability of the endothelial cell monolayers and the BBB in vivo. SIGNIFICANCE STATEMENT: The blood-brain barrier controls the entry of endogenous substances and xenobiotics from the circulation into the central nervous system. Volatile anesthetic agents like isoflurane alter the lipid structure of cell membranes, transiently facilitating the brain uptake of otherwise poorly permeable, hydrophilic small molecules. Clinical implications may arise when potentially neurotoxic drugs gain enhanced access to the central nervous system under inhalational anesthetics.

Clinical pharmacokinetics of cefixime: a systematic review.

Cefixime is an antibiotic from the cephalosporin class used to treat various bacterial infections. The purpose of performing this review is to thoroughly evaluate the pharmacokinetic (PK) data on cefiximeFive databases were systematically searched to identify studies on the PK of cefixime.A total of 38 articles meeting the eligibility criteria were included that provide data on concentration-time profiles or PK parameters such as peak plasma and serum concentration (Cmax), area under the curve (AUC), clearance (CL), and time to reach Cmax (tmax). A dose-dependent increase in AUC and Cmax of cefixime was depicted in healthy volunteers. The clearance of cefixime decreased according to the degree of renal insufficiency among haemodialysis patients. A significant difference in CL was found in comparing fasted and fed states. A biphasic decline in serum concentrations of cefixime was reported when it was taken without probenecid.This review compiles all the reports on the PK of cefixime in healthy and really impaired patients; the summarised information can be used to optimise cefixime dosing in different disease states. Moreover, cefixime has increased time above MIC value suggesting that it may be an effective treatment for infections caused by certain pathogens.

Antidiabetic Drugs Can Reduce the Harmful Impact of Chronic Smoking on Post-Traumatic Brain Injuries.

Traumatic Brain Injury (TBI) is a primary cause of cerebrovascular and neurological disorders worldwide. The current scientific researchers believe that premorbid conditions such as tobacco smoking (TS) can exacerbate post-TBI brain injury and negatively affect recovery. This is related to vascular endothelial dysfunction resulting from the exposure to TS-released reactive oxygen species (ROS), nicotine, and oxidative stress (OS) stimuli impacting the blood-brain barrier (BBB) endothelium. Interestingly, these pathogenic modulators of BBB impairment are similar to those associated with hyperglycemia. Antidiabetic drugs such as metformin (MF) and rosiglitazone (RSG) were shown to prevent/reduce BBB damage promoted by chronic TS exposure. Thus, using in vivo approaches, we evaluated the effectiveness of post-TBI treatment with MF or RSG to reduce the TS-enhancement of BBB damage and brain injury after TBI. For this purpose, we employed an in vivo weight-drop TBI model using male C57BL/6J mice chronically exposed to TS with and without post-traumatic treatment with MF or RSG. Our results revealed that these antidiabetic drugs counteracted TS-promoted downregulation of nuclear factor erythroid 2-related factor 2 (NRF2) expression and concomitantly dampened TS-enhanced OS, inflammation, and loss of BBB integrity following TBI. In conclusion, our findings suggest that MF and RSG could reduce the harmful impact of chronic smoking on post-traumatic brain injuries.

A physiologically based pharmacokinetic model of cefepime to predict its pharmacokinetics in healthy, pediatric and disease populations.

The physiologically based pharmacokinetic modeling (PBPK) approach can predict drug pharmacokinetics (PK) by combining changes in blood flow and pathophysiological alterations for developing drug-disease models. Cefepime hydrochloride is a parenteral cephalosporin that is used to treat pneumonia, sepsis, and febrile neutropenia, among other things. The current study sought to identify the factors that impact cefepime pharmacokinetics (PK) following dosing in healthy, diseased (CKD and obese), and pediatric populations. For model construction and simulation, the modeling tool PK-SIM was utilized. Estimating cefepime PK following intravenous (IV) application in healthy subjects served as the primary step in the model-building procedure. The prediction of cefepime PK in chronic kidney disease (CKD) and obese populations were performed after the integration of the relevant pathophysiological changes. Visual predictive checks and a comparison of the observed and predicted values of the PK parameters were used to verify the developed model. The results of the PK parameters were consistent with the reported clinical data in healthy subjects. The developed PBPK model successfully predicted cefepime PK as observed from the ratio of the observed and predicted PK parameters as they were within a two-fold error range.

Effects of long-term Ailanthus altissima extract supplementation on fear, cognition and brain antioxidant levels.

Introduction: Ailanthus altissima is an indigenous plant known for various remedial properties. The present study aimed to evaluate the neuroprotective potential of methanolic extract Ailanthus altissima (AA) bark as current scientific trend is searching plant for neurodegenerative diseases, worldwide. Methodology: In in-vitro experiments, the AA was analyzed for phenols, flavonoids, antioxidative and cholinesterase inhibitory properties with subsequent detailed characterization for secondary metabolites. The in-vivo neurological effects were evaluated in rats through behavioral assessment for anxiety and memory after chronic administration (28 days) of 50-200 mg/kg of AA. At the end of behavior studies, isolated brains were biochemically tested to determine antioxidant enzyme activity. Results: AA was found rich in phenols/flavonoids and active in radical scavenging with the presence of 13 secondary metabolites in UHPLC-MS analysis. The AA yielded anxiolytic effects dose-dependently in the open field, light/dark and elevated-plus maze tests as animals significantly (P < 0.05 vs control group) preferred open arena, illuminated zone and exposed arms of maze. Similarly, the animals treated with AA showed significant (P < 0.05 vs amnesic group) increase in spontaneous alternation, discrimination index in y-maze, novel object recognition tests. Further, AA.Cr treated rats showed noticeably shorter escape latencies in Morris water maze tests.In biochemical analysis, the dissected brains AA treated rats showed reduced levels of AChE and malondialdehyde with increased levels of first-line antioxidant enzymes i.e. glutathione peroxidase and superoxide dismutase. These observed biological effects might be attributed to phenols and flavonoids constituents owned by AA. -The in-silico studies showed thatconessine and lophirone J phytocompounds have good blood-brain barrier permeability and interaction with AChE. Conclusion: The outcomes of this study validate that bark of Ailanthus altissima might work as a source of bioactive phytochemicals of neuroprotective potential.

Lck signaling inhibition causes improvement in clinical features of psoriatic inflammation through reduction in inflammatory cytokines in CD4+ T cells in imiquimod mouse model.

Psoriasis is a chronic dermal inflammatory disease with a world-wide prevalence in which different immune/non-immune cells, e.g. T cells, macrophages, neutrophils, and keratinocytes play a decisive role. These immune cells interact among themselves by releasing multiple mediators which eventually cause characteristic psoriatic plaques in the skin. T cells are reported to be significant contributors to psoriatic inflammation through release of multiple cytokines which are controlled by several kinases, one of them being Lymphocyte-specific protein tyrosine kinase (Lck). Lck has been reported to be crucial for expression/production of several key inflammatory cytokines though modulation of several other kinases/transcription factors in T cells. Therefore, in this investigation, effect of Lck inhibitor, A-770041 was examined on PLCγ, p38MAPK, NFATc1, NFkB and STAT3, TNF-α, IFN-γ, Foxp3, IL-17A, in CD4+ T cells in imiquimod (IMQ)-induced psoriatic inflammation in mice. Results from the present study exhibit that p-Lck expression is enhanced in CD4+ T cells of IMQ-treated mice which is concomitant with enhanced clinical features of psoriatic inflammation (ear/back skin thickness, MPO activity, acanthosis/leukocytic infiltration) and molecular parameters (enhanced expression of p-Lck, p-PLCγ, p-p38-MAPK, NFATc1, p-NFkB, TNF-α, IFN-γ, p-STAT3, and IL-17A in CD4+ T cells). Inhibition of Lck signaling led to amelioration of clinical features of psoriasis through attenuation of Th1/Th17 immune responses and upregulation of Treg cells in IMQ-treated mice. In summary, current investigations reveal that Lck signaling is a crucial executor of inflammatory signaling in CD4+ T cells in the context of psoriatic inflammation. Therefore, Lck inhibition may be pursued as an effective strategy to counteract psoriatic inflammation.

A Semi-Physiological Three-Compartment Model Describes Brain Uptake Clearance and Efflux of Sucrose and Mannitol after IV Injection in Awake Mice.

PURPOSE: To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake. METHODS: Stable isotope-labeled [13C]sucrose and [13C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h. Plasma and brain concentrations were quantified by UPLC-MS/MS. Brain uptake clearance (Kin) was analyzed using either the single-time point analysis, the multiple time point graphical method, or by fitting the parameters of a three-compartmental model that allows for symmetrical exchange across the blood-brain barrier and an additional brain efflux clearance. RESULTS: The three-compartment model was able to describe the experimental data well, yielding estimates for Kin of sucrose and mannitol of 0.068 ± 0.005 and 0.146 ± 0.020 µl.min-1.g-1, respectively, which were significantly different (p < 0.01). The separate brain efflux clearance had values of 0.693 ± 0.106 (sucrose) and 0.881 ± 0.20 (mannitol) µl.min-1.g-1, which were not statistically different. Kin values obtained by single time point and multiple time point analyses were dependent on the terminal sampling time and showed declining values for later time points. CONCLUSIONS: Using the three-compartment model allows determination of Kin for small molecule hydrophilic markers with low blood-brain barrier permeability. It also provides, for the first time, an estimate of brain efflux after systemic administration of a marker, which likely represents bulk flow clearance from brain tissue.

Clinical pharmacokinetics of nadolol: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Nadolol is a non-selective beta-adrenergic antagonist that is used for the treatment of hypertension and angina. The primary route for its administration is oral. It is given once daily as it has a longer half-life (t½). The purpose of conducting this systematic review is to provide a comprehensive view of all the available pharmacokinetic (PK) data on nadolol in humans. This review aimed to systematically collate and analyze publish data on the clinical PK of nadolol in humans and this can be beneficial for the clinicians in dosage adjustments. METHODS: Two electronic databases PubMed and Google Scholar were used for conducting a systematic literature search. All the relevant articles containing PK data of nadolol in humans were retrieved. A total of 1275 articles were searched from both databases and after applying eligibility criteria finally, 22 articles were included for conducting the systematic review. RESULTS AND DISCUSSION: The area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax ) of nadolol increased in a dose-dependent manner. The t½ of nadolol was increased to double (18.2-68.6 h) in the patients with chronic kidney disease while the serum t½ became shorter (3.2-4.3 h) when administered to the children. The bioavailability of nadolol was greatly reduced by the coadministration of green tea. Nadolol can be effectively removed by hemodialysis. It undergoes enterohepatic circulation thus activated charcoal decreased its bioavailability. WHAT IS NEW AND CONCLUSION: Since, there is no previous report of a systematic review on the PK of nadolol, the current review encompasses all the relevant published articles on nadolol in humans. The analysis and understanding of PK parameters (AUC, Cmax , and t½) of nadolol may be helpful in the development and evaluation of PK models.

Impact of the loss of smell on the sleep quality and fatigue level in COVID­19 survivors.

PURPOSE: Patients with Coronavirus disease 2019 (COVID-19) are reported to have symptoms such as shortness of breath, dry cough, headache, fatigue, and diarrhea. Loss of smell is a symptom that some patients have suffered from due to inflammation of olfactory epithelium and neuroinvasion of COVID-19 resulting in damage to the olfactory nerves and olfactory bulb. Losing an important sense such as smell might have unfavorable consequences on the lives of COVID-19 survivors; however, these unfavorable consequences have not been sufficiently investigated. METHODS: This was a cross-sectional descriptive study, 81 COVID-19 survivors (51.85% male) answered the Pittsburgh Sleep Quality Index, Fatigue Severity Scale, and Patient Health Questionnaire. RESULTS: COVID-19 survivors who lost their smell were more likely to have poor sleep quality, high fatigue severity, and depression symptoms compared to others who did not lose their smell. Most COVID-19 survivors who lost their smell were women and had breathing difficulties. CONCLUSION: Our knowledge of this relationship will assist in establishing more efficient treatment regimens that consider both psychological and physiological factors. Future research is needed to investigate the causality relationship between poor sleep quality, increased fatigue, and depression symptoms in COVID-19 survivors who experienced loss of the sense of smell.

Venetoclax Induces Cardiotoxicity through Modulation of Oxidative-Stress-Mediated Cardiac Inflammation and Apoptosis via NF-κB and BCL-2 Pathway.

Cardiovascular damage induced by anticancer therapy has become the main health problem after tumor elimination. Venetoclax (VTX) is a promising novel agent that has been proven to have a high efficacy in multiple hematological diseases, especially acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Considering its mechanism of action, the possibility that VTX may cause cardiotoxicity cannot be ruled out. Therefore, this study was designed to investigate the toxic effect of VTX on the heart. Male Sprague-Dawley rats were randomly divided into three groups: control, low-dose VTX (50 mg/kg via oral gavage), and high-dose VTX (100 mg/kg via oral gavage). After 21 days, blood and tissue samples were collected for histopathological, biochemical, gene, and protein analyses. We demonstrated that VTX treatment resulted in cardiac damages as evidenced by major changes in histopathology and markedly elevated cardiac enzymes and hypertrophic genes markers. Moreover, we observed a drastic increase in oxidative stress, as well as inflammatory and apoptotic markers, with a remarkable decline in the levels of Bcl-2. To the best of our knowledge, this study is the first to report the cardiotoxic effect of VTX. Further experiments and future studies are strongly needed to comprehensively understand the cardiotoxic effect of VTX.

The relationship between hydroxychloroquine plasma concentration and COVID-19 outcomes in rheumatoid arthritis patients in Saudi Arabia.

Background: The drug hydroxychloroquine (HCQ) is widely used to treat rheumatoid arthritis (RA) and has been repurposed for the treatment of COVID-19. This study aims to determine whether HCQ concentration levels in individuals with RA alter the incidence of COVID-19 or its complications. Methods: We collected plasma samples from 13 individuals with confirmed rheumatoid arthritis (RA) to measure HCQ concentration levels. The study included individuals at least 18 years old who had been taking HCQ for at least six months at daily doses ranging from 200 to 400 mg. Results: The study enrolled a total of 13 RA patients. All patients were chronic HCQ users. Among the 13 patients, 7 patients were receiving HCQ at a dose of 200 mg per day, and 6 patients were receiving HCQ at a dose of 400 mg per day. COVID-19 confirmed cases accounted for approximately 46% of all patients. Half of the infected patients (n = 3) were taking a daily dose of 200 mg daily, while the other half were taking 400 mg daily. COVID-19 symptoms ranged from mild to moderate, and the intensity of the symptoms was not severe enough to necessitate hospitalization. COVID-19 symptoms in RA patients included headache, fever, fatigue, dry cough, and loss of taste or smell. Conclusions: Our findings indicated that there was no correlation between HCQ concentrations in rheumatoid arthritis patients and the occurrence of COVID-19 or its complications.

Chronically administered Agave americana var. marginata extract ameliorates diabetes mellitus, associated behavioral comorbidities and biochemical parameters in alloxan-induced diabetic rats.

Introduction: Diabetes mellitus causes hyperglycemia and associated complications to the brain. In current study, the traditionally reported remedial claims of Agave americana var. marginata has been scientifically investigated in diabetic rats. Methodology: The methanolic extract of leaves of Agave americana var. marginata (Aa.Cr) was characterized for total phenols, flavonoids, and antioxidant potential through in-vitro testing. The rats chronically pre-treated with Aa.Cr (400 and 600 mg/kg) for 45 days were challenged with alloxan-induced hyperglycemia. The dose-dependent effects of Aa.Cr on blood glucose levels and body weights were compared with diabetic rats using glibenclamide (0.6 mg/kg) as a standard. The animals were tested for diabetes-associated neurological comorbidities through behavioral and biochemical evaluation. Results: The phenols and flavonoids enriched Aa.Cr caused a significant dose-dependent hypoglycemic effect. Aa.Cr showed protection from comorbid anxiety, depression and cognitive impairment as compared to diabetic rats. The alanine aminotransferase, total cholesterol, triglycerides and low-density lipoprotein were prominently reduced, and high-density lipoprotein was increased in rats treated with Aa.Cr. Moreover, the oxidative stress in isolated brains was reduced by Aa.Cr. Conclusion: These findings suggest that Aa.Cr is enriched with antioxidant and anti-inflammatory phytoconstituents valuable for diabetes and related neurological complications.

Combination of levetiracetam with sodium selenite prevents pentylenetetrazole-induced kindling and behavioral comorbidities in rats.

Introduction: The pentylenetetrazol (PTZ)-induced kindling model acts through the antagonism of central GABAA receptors and is one of the most widely used experimental animal models to study the characteristics of seizure development, behavioral manifestations and evaluation of antiseizure effects of existing and new drug candidates. Methodology: In the current study, we investigated the impact of chronically administered levetiracetam (50 mg/kg) and sodium selenite (Sod.Se: 0.25 and 0.5 mg/kg) alone and in combination during the kindling process (21 days) in rats. Moreover, the behavioral changes (through the integration of a wide array of behavioral tests) and markers of oxidative stress in isolated brain homogenates were assessed in PTZ- kindled rats. Results: The outcomes from the fully kindled rats revealed the increased seizure score and severity over time with marked behavioral deficits. However, the animals treated with the selected dose of LEV alone showed partial protection from epileptogenesis and amelioration (P < 0.05) of anxiety-like behavior (open filed, light/dark, elevated plus maze tests), cognitive impairment (y-maze, novel object recognition and water maze tests) and depression (sucrose preference test). Moreover, combining the LEV with sodium selenite resulted in a significant neuroprotective effect in comparison to monotherapy by reducing the disease progression and ameliorating behavioral outcomes. The combination of Sod.Se in a dose-dependent manner with LEV produced additive effects as maximum animals remained seizure-free compared to kindled rats (P < 0.05). The attenuation of PTZ induced oxidative stress was evident from the reduced malondialdehyde and elevated superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) level with P < 0.05, as compared to control epileptic rats. These observed results of combination therapy might be due to the antioxidant and neuroprotective properties of Sod.Se, thus augmenting the seizure-modifying potentials of levetiracetam. Conclusion: Overall, the current findings support the prominence of combining the Sod.Se with LEV, over monotherapy to deal with prevailing challenges of drug resistance and neuropsychiatric sufferings common in epileptic patients.

Impact of chronic smoking on traumatic brain microvascular injury: An in vitro study.

Traumatic brain injury (TBI) is a major reason of cerebrovascular and neurological damage. Premorbid conditions such as tobacco smoking (TS) can worsen post-TBI injuries by promoting vascular endothelial impairments. Indeed, TS-induced oxidative stress (OS) and inflammation can hamper the blood-brain barrier (BBB) endothelium. This study evaluated the subsequence of chronic TS exposure on BBB endothelial cells in an established in vitro model of traumatic cell injury. Experiments were conducted on confluent TS-exposed mouse brain microvascular endothelial cells (mBMEC-P5) following scratch injury. The expression of BBB integrity-associated tight junction (TJ) proteins was assessed by immunofluorescence imaging (IF), Western blotting (WB) and quantitative RT-PCR. We evaluated reactive oxygen species (ROS) generation, the nuclear factor 2-related (Nrf2) with its downstream effectors and several inflammatory markers. Thrombomodulin expression was used to assess the endothelial haemostatic response to injury and TS exposure. Our results show that TS significantly decreased Nrf2, thrombomodulin and TJ expression in the BBB endothelium injury models while increased OS and inflammation compared to parallel TS-free cultures. These data suggest that chronic TS exposure exacerbates traumatic endothelial injury and abrogates the protective antioxidative cell responses. The downstream effect was a more significant decline of BBB endothelial viability, which could aggravate subsequent neurological impairments.

Dynamics of Choline-Containing Phospholipids in Traumatic Brain Injury and Associated Comorbidities.

The incidences of traumatic brain injuries (TBIs) are increasing globally because of expanding population and increased dependencies on motorized vehicles and machines. This has resulted in increased socio-economic burden on the healthcare system, as TBIs are often associated with mental and physical morbidities with lifelong dependencies, and have severely limited therapeutic options. There is an emerging need to identify the molecular mechanisms orchestrating these injuries to life-long neurodegenerative disease and a therapeutic strategy to counter them. This review highlights the dynamics and role of choline-containing phospholipids during TBIs and how they can be used to evaluate the severity of injuries and later targeted to mitigate neuro-degradation, based on clinical and preclinical studies. Choline-based phospholipids are involved in maintaining the structural integrity of the neuronal/glial cell membranes and are simultaneously the essential component of various biochemical pathways, such as cholinergic neuronal transmission in the brain. Choline or its metabolite levels increase during acute and chronic phases of TBI because of excitotoxicity, ischemia and oxidative stress; this can serve as useful biomarker to predict the severity and prognosis of TBIs. Moreover, the effect of choline-replenishing agents as a post-TBI management strategy has been reviewed in clinical and preclinical studies. Overall, this review determines the theranostic potential of choline phospholipids and provides new insights in the management of TBI.