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Annals of Surgery Dec 2023Injured tissue predisposes the subject to local and systemic infection. We studied injury-induced immune dysfunction seeking novel means to reverse such predisposition.
OBJECTIVE
Injured tissue predisposes the subject to local and systemic infection. We studied injury-induced immune dysfunction seeking novel means to reverse such predisposition.
BACKGROUND
Injury mobilizes primitive "DANGER signals" [danger-associated molecular patterns (DAMPs)] activating innate immunocyte (neutrophils, PMN) signaling and function. Mitochondrial formyl peptides activate G -protein coupled receptors (GPCR) like formyl peptide receptor-1. Mitochondrial DNA and heme activate toll-like receptors (TLR9 and TLR2/4). GPCR kinases (GRKs) can regulate GPCR activation.
METHODS
We studied human and mouse PMN signaling elicited by mitochondrial DAMPs (GPCR surface expression; protein phosphorylation, or acetylation; Ca 2+ flux) and antimicrobial functions [cytoskeletal reorganization, chemotaxis (CTX), phagocytosis, bacterial killing] in cellular systems and clinical injury samples. Predicted rescue therapies were assessed in cell systems and mouse injury-dependent pneumonia models.
RESULTS
Mitochondrial formyl peptides activate GRK2, internalizing GPCRs and suppressing CTX. Mitochondrial DNA suppresses CTX, phagocytosis, and killing through TLR9 through a novel noncanonical mechanism that lacks GPCR endocytosis. Heme also activates GRK2. GRK2 inhibitors like paroxetine restore functions. GRK2 activation through TLR9 prevented actin reorganization, implicating histone deacetylases (HDACs). Actin polymerization, CTX, bacterial phagocytosis, and killing were also rescued, therefore, by the HDAC inhibitor valproate. Trauma repository PMN showed GRK2 activation and cortactin deacetylation, which varied with severity and was most marked in patients developing infections. Either GRK2 or HDAC inhibition prevented loss of mouse lung bacterial clearance, but only the combination rescued clearance when given postinjury.
CONCLUSIONS
Tissue injury-derived DAMPs suppress antimicrobial immunity through canonical GRK2 activation and a novel TLR-activated GRK2-pathway impairing cytoskeletal organization. Simultaneous GRK2/HDAC inhibition rescues susceptibility to infection after tissue injury.
Topics: Humans; Mice; Animals; Neutrophils; Actins; Toll-Like Receptor 9; DNA, Mitochondrial; Peptides; Anti-Infective Agents; Heme
PubMed: 37154066
DOI: 10.1097/SLA.0000000000005898 -
Fabrication of solid lipid nanoparticles-based patches of paroxetine and their permeation behaviour.Artificial Cells, Nanomedicine, and... Dec 2023Paroxetine is not suitable for oral administration due to its extensive first-pass metabolism, thus resulting in less bioavailability. This study aimed to prepare novel...
Paroxetine is not suitable for oral administration due to its extensive first-pass metabolism, thus resulting in less bioavailability. This study aimed to prepare novel paroxetine-loaded solid lipid nanoparticles (SLNs) based sustained-release transdermal patches to overcome these problems by enhancing drug absorption and bioavailability. Nine formulations of paroxetine SLNs were prepared by the hot melt-homogenization method using different concentrations of glycerol monostearate (Kolliwax) and Tween 80. Then these prepared SLNs were incorporated in a matrix type transdermal patch having a matrix of ethyl cellulose and polyvinyl pyrrolidone in 3:2 with polyvinyl alcohol. The SLNs showed a particle size range of 113-230 nm and an entrapment efficiency of 85.14%. The SLNs showed sustained paroxetine release (77.86-95.63% release) up to 48 h. FTIR studies showed no interaction between drug and formulation components. Paroxetine is evenly distributed in an amorphous form in SLNs, as demonstrated by DSC as well as PXRD analysis. SLNs formulated patches showed higher drug permeation through the skin than drug-based transdermal patches., Draize patch test revealed no sign of erythema after applying paroxetine-loaded SLN patches (score 0) as observed with the marketed product. The developed SLNs based transdermal patches showed increased permeability and sustained release behaviour.
Topics: Paroxetine; Liposomes; Administration, Oral; Biological Availability
PubMed: 36855254
DOI: 10.1080/21691401.2023.2179631 -
Journal of Pharmaceutical and... Aug 2024Desvenlafaxine (O-desmethylvenlafaxine) and paroxetine are antidepressants that inhibit serotonin reuptake. Despite their relatively safe profiles, several serious side...
Desvenlafaxine (O-desmethylvenlafaxine) and paroxetine are antidepressants that inhibit serotonin reuptake. Despite their relatively safe profiles, several serious side effects, including serotonin syndrome, bleeding, mania, and high blood pressure, are observed. We report the confirmation of the death of a 41-year-old female, with an overdose of desvenlafaxine and paroxetine suspected as the main cause of death. To quantify the level of desvenlafaxine and paroxetine in whole blood and urine, solid phase extraction combined with liquid chromatography-tandem mass spectrometry was developed and validated. Calibration curves were linear with coefficients of determination (r) >0.999 for desvenlafaxine and paroxetine. The limits of detection and the limits of quantification for both desvenlafaxine and paroxetine were 0.001 µg/mL and 0.02 µg/mL, respectively. Desvenlafaxine and paroxetine were detected in the postmortem samples, along with various psychiatric drugs, and the blood alcohol content level was below 0.010%. The concentrations of desvenlafaxine and paroxetine in the heart blood were 11.0 µg/mL and 2.1 µg/mL, respectively, indicating lethal concentrations. In the urine, the concentrations of desvenlafaxine and paroxetine were 87.7 µg/mL and 3.5 µg/mL, respectively. This is the first report to determine the blood concentration of desvenlafaxine in a fatal intoxication caused by an overdose of desvenlafaxine single formulation.
Topics: Humans; Desvenlafaxine Succinate; Paroxetine; Female; Adult; Tandem Mass Spectrometry; Drug Overdose; Chromatography, Liquid; Solid Phase Extraction; Fatal Outcome; Antidepressive Agents; Limit of Detection; Selective Serotonin Reuptake Inhibitors
PubMed: 38652939
DOI: 10.1016/j.jpba.2024.116148 -
Psychopharmacology Nov 2023Social hierarchies are important for individual's well-being, professional and domestic growth, harmony of the society, as well as survival and morbidity. Studies have...
BACKGROUND
Social hierarchies are important for individual's well-being, professional and domestic growth, harmony of the society, as well as survival and morbidity. Studies have revealed sexual dimorphism in the social abilities; however, data is limited on the sex-specific effects of various drugs used to treat psychiatric disorders and social deficits.
OBJECTIVE
The present study aimed at evaluating the sex-dependent effects of Risperidone (antipsychotic that targets D2 dopaminergic, 5HTA serotonergic, and α-adrenergic receptors), Donepezil (a reversible acetylcholinesterase inhibitor), and Paroxetine (a selective serotonin reuptake inhibitor) on social hierarchy in rats under normal and stressed states.
METHODS
8-12 weeks old male and female Wistar rats were divided into sex-wise 4-4 groups, i.e., 1. control group, 2. Risperidone treated group (3 mg/kg/day), 3. Donepezil treated group (5 mg/kg/day), and Paroxetine treated group (10 mg/kg/day). Rats were treated with these drugs in phase I for 21 days in distilled drinking water, followed by a no (drugs) treatment break of 10 days. After the break phase II started with the administration of drugs (same as in phase I) along with tilt-cage stress for 21 days. Home cage activity assessment was performed once a week during both phases (I & II), while tube dominance and resident intruder tests were performed at the end of each phase.
RESULTS
In phase I in both sexes, Risperidone treatment decreased social interaction and motor activity while Paroxetine treatment increased these in both sexes compared to their respective control groups. Social dominance and aggression were reduced after treatment with both of these drugs. In contrast, Donepezil treatment caused an increase in motor activity in females whereas reduced motor activity in males. Furthermore, Donepezil treatment caused reduction in interaction but increased social dominance and aggression were observed in both sexes. In phase II, stress led to an overall decrease in motor activity and social interaction of animals. Treatment with Risperidone, Paroxetine, and Donepezil caused a sex-specific effect on, motor activity, social interaction, and social exploration.
CONCLUSION
These results showed that Risperidone has stronger effects on male social behavior whereas Paroxetine and Donepezil differentially affect social abilities in both sexes during normal and stressed situations.
PubMed: 37994914
DOI: 10.1007/s00213-023-06503-7 -
The Lancet. Psychiatry Jul 2024Antidepressant discontinuation symptoms are becoming an increasingly important part of clinical practice, but the incidence of antidepressant discontinuation symptoms... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antidepressant discontinuation symptoms are becoming an increasingly important part of clinical practice, but the incidence of antidepressant discontinuation symptoms has not been quantified. An estimate of antidepressant discontinuation symptoms incidence could inform patients and clinicians in the discontinuation of treatment, and provide useful information to researchers in antidepressant treatments. We aimed to assess the incidence of antidepressant discontinuation symptoms in patients discontinuing both antidepressants and placebo in the published literature.
METHODS
We systematically searched Medline, EMBASE, and CENTRAL from database inception until Oct 13, 2022 for randomised controlled trials (RCTs), other controlled trials, and observational studies assessing the incidence of antidepressant discontinuation symptoms. To be included, studies must have investigated cessation or tapering of an established antidepressant drug (excluding antipsychotics, lithium, or thyroxine) or placebo in participants with any mental, behavioural, or neurodevelopmental disorder. We excluded studies in neonates, and those using antidepressants for physical conditions such as pain syndromes due to organic disease. After study selection, summary data extraction, and risk of bias evaluation, data were pooled in random-effects meta-analyses. The main outcome was the incidence of antidepressant discontinuation symptoms after discontinuation of antidepressants or placebo. We also analysed the incidence of severe discontinuation symptoms. Sensitivity and meta-regression analyses tested a selection of methodological variables.
FINDINGS
From 6095 articles screened, 79 studies (44 RCTs and 35 observational studies) covering 21 002 patients were selected (72% female, 28% male, mean age 45 years [range 19·6-64·5]). Data on ethnicity were not consistently reported. 16 532 patients discontinued from an antidepressant, and 4470 patients discontinued from placebo. Incidence of at least one antidepressant discontinuation symptom was 0·31 (95% CI 0·27-0·35) in 62 study groups after discontinuation of antidepressants, and 0·17 (0·14-0·21) in 22 study groups after discontinuation of placebo. Between antidepressant and placebo groups of included RCTs, the summary difference in incidence was 0·08 [0·04-0·12]. The incidence of severe antidepressant discontinuation symptoms after discontinuation of an antidepressant was 0·028 (0·014-0·057) compared with 0·006 (0·002-0·013) after discontinuation of placebo. Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequencies of discontinuation symptoms, and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms. Heterogeneity of results was substantial.
INTERPRETATION
Considering non-specific effects, as evidenced in placebo groups, the incidence of antidepressant discontinuation symptoms is approximately 15%, affecting one in six to seven patients who discontinue their medication. Subgroup analyses and heterogeneity figures point to factors not accounted for by diagnosis, medication, or trial-related characteristics, and might indicate subjective factors on the part of investigators, patients, or both. Residual or re-emerging psychopathology needs to be considered when interpreting the results, but our findings can inform clinicians and patients about the probable extent of antidepressant discontinuation symptoms without causing undue alarm.
FUNDING
None.
Topics: Humans; Antidepressive Agents; Incidence; Substance Withdrawal Syndrome; Randomized Controlled Trials as Topic
PubMed: 38851198
DOI: 10.1016/S2215-0366(24)00133-0 -
Acta Pharmaceutica Sinica. B Mar 2024Hyperplasia and migration of fibroblast-like synoviocytes (FLSs) are the key drivers in the pathogenesis of rheumatoid arthritis (RA) and joint destruction. Abundant...
Hyperplasia and migration of fibroblast-like synoviocytes (FLSs) are the key drivers in the pathogenesis of rheumatoid arthritis (RA) and joint destruction. Abundant Yes-associated protein (YAP), which is a powerful transcription co-activator for proliferative genes, was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms. Using Gene Expression Omnibus database analysis, it was found that Salvador homolog-1 (SAV1), the pivotal negative regulator of the Hippo-YAP pathway, was slightly downregulated in RA synovium. However, SAV1 protein expression is extremely reduced. Subsequently, it was revealed that SAV1 is phosphorylated, ubiquitinated, and degraded by interacting with an important serine-threonine kinase, G protein-coupled receptor (GPCR) kinase 2 (GRK2), which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E (PGE) in RA. This process further contributes to the decreased phosphorylation, nuclear translocation, and transcriptional potency of YAP, and leads to aberrant FLSs proliferation. Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration. Similarly, paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations. Collectively, these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.
PubMed: 38486990
DOI: 10.1016/j.apsb.2023.12.007 -
The Primary Care Companion For CNS... Jun 2024To review the literature on the neurobiological mechanisms of obsessive-compulsive symptoms (OCS) in people with dementia. MEDLINE/PubMed, CENTRAL, and PsycNet... (Review)
Review
To review the literature on the neurobiological mechanisms of obsessive-compulsive symptoms (OCS) in people with dementia. MEDLINE/PubMed, CENTRAL, and PsycNet databases were searched from inception to March 2023. Original studies of any methodology with newly published data on the neurobiological underpinnings of OCS in patients with dementia, regardless of patient age or comorbidity and publication year, were included. The following search terms were used: (Obses* OR compul* OR OCD) AND (cognitive de* OR cognitive dysfunction OR cognitive disfunction OR dementia). Individual study data were extracted onto a piloted extractions sheet. Patients with dementia and OCS were reported to have atrophy and hypoperfusion of frontal, temporal, striatal, and limbic structures. Serotonergic agents may be efficacious in reducing OCS. One randomized controlled trial of paroxetine in behavioral symptoms of dementia did not show efficacy. Evidence of dopaminergic dysfunction is too sparse to draw conclusions. Microglia dysfunction mediates obsessive-compulsive-like symptoms. Mutations of microtubule-associated protein τ may increase the risk of OCS. Cognitive self-consciousness and obsessive-compulsive-related cognitions may mediate OCS in old age. Dysfunction of the processing of one class of stimuli may increase the salience of other classes of stimuli, leading to OCS. Frontal lobe hypometabolism and temporal lobe atrophy and hypometabolism are unexpected given previous research in obsessive compulsive disorder. Serotonergic agents have encouraging efficacy in case reports but require more specific research. .
Topics: Humans; Obsessive-Compulsive Disorder; Dementia
PubMed: 38905511
DOI: 10.4088/PCC.23r03689 -
Scandinavian Journal of Psychology Dec 2023Patients with Social Anxiety Disorder (SAD) typically report interpersonal problems, and these are important targets in treatment beyond social anxiety symptoms as they... (Randomized Controlled Trial)
Randomized Controlled Trial
Patients with Social Anxiety Disorder (SAD) typically report interpersonal problems, and these are important targets in treatment beyond social anxiety symptoms as they impair quality of life, maintain emotion symptoms and effect on social functioning. What factors contribute to interpersonal problems? In the current study we set out to explore the role of metacognitive beliefs as correlates of interpersonal problems in patients treated for SAD when controlling for the effect of social phobic cognitions and symptoms. The sample consisted of 52 patients with a primary diagnosis of SAD participating in a randomized controlled trial comparing cognitive therapy, paroxetine, pill placebo, or the combination of cognitive therapy and paroxetine in treating SAD. Two hierarchical multiple linear regression analyses were conducted to explore change in metacognitions as predictors of change in interpersonal problems when controlling for change in social phobic cognitions and social anxiety. Change in metacognitions accounted for unique variance in interpersonal problems improvement beyond change in cognitions. Furthermore, change in cognitions overlapped with change in social anxiety symptoms, and when controlling the overlap between these three predictors, only change in metacognitions was uniquely associated with improvement in interpersonal problems. This finding indicates that metacognitions are linked to interpersonal problems in patients with SAD with the implication that treatment should aim to modify metacognitive beliefs to alleviate interpersonal dysfunction.
Topics: Humans; Phobia, Social; Paroxetine; Quality of Life; Metacognition; Cognition; Anxiety
PubMed: 37365879
DOI: 10.1111/sjop.12943 -
Chemosphere Sep 2023Paroxetine (abbreviated as PXT) has been widely used as one of the standard antidepressants for the treatment of depression. PXT has been detected in the aqueous...
Photodegradation fate of different dissociation species of antidepressant paroxetine and the effects of metal ion Mg: Theoretical basis for direct and indirect photolysis.
Paroxetine (abbreviated as PXT) has been widely used as one of the standard antidepressants for the treatment of depression. PXT has been detected in the aqueous environment. However, the photodegradation mechanism of PXT remains unclear. The present study aimed to use density functional theory and time-dependent density functional theory to study the photodegradation process of two dissociated forms of PXT in water. The main mechanisms include direct and indirect photodegradation via reaction with ·OH and O and photodegradation mediated by the metal ion Mg. Based on the calculations, PXT and PXT-Mg complexes in water are photodegraded mainly indirectly and directly. It was found that PXT and PXT-Mg complexes were photodegraded by H-abstraction, OH-addition and F-substitution. The main reaction of PXT indirect photolysis is OH-addition reaction, while the main reaction of PXT-Mg complex is H-abstraction. All the reaction pathways of H-abstraction, OH-addition and F-substitution are exothermic. PXT reacts more readily with ·OH or O in water than PXT. However, the higher activation energy of PXT with O indicates that the O reaction plays a minor role in the photodegradation pathway. The direct photolysis process of PXT includes ether bond cleavage, defluorination, and dioxolane ring-opening reaction. In the PXT-Mg complex, the direct photolysis process occurs via a dioxolane ring opening. Additionally, Mg in water has a dual effect on the direct and indirect photolysis of PXT. In other words, Mg can inhibit or promote their photolytic reactions. Overall, PXT in natural water mainly undergo direct and indirect photolysis reactions with ·OH. The main products include direct photodegradation products, hydroxyl addition products and F-substitution products. These findings provide critical information for predicting the environmental behavior and transformation of antidepressants.
Topics: Paroxetine; Photolysis; Dioxolanes; Water; Antidepressive Agents; Metals; Water Pollutants, Chemical; Kinetics
PubMed: 37279823
DOI: 10.1016/j.chemosphere.2023.139070 -
Cell Communication and Signaling : CCS Nov 2023In essence, the β adrenergic receptor (βAR) plays an antiproliferative role by increasing the intracellular cyclic 3',5'-adenosine monophosphate (cAMP) concentration...
In essence, the β adrenergic receptor (βAR) plays an antiproliferative role by increasing the intracellular cyclic 3',5'-adenosine monophosphate (cAMP) concentration through G coupling, but interestingly, βAR antagonists are able to effectively inhibit fibroblast-like synoviocytes (FLSs) proliferation, thus ameliorating experimental RA, indicating that the βAR signalling pathway is impaired in RA FLSs via unknown mechanisms. The local epinephrine (Epi) level was found to be much higher in inflammatory joints than in normal joints, and high-level stimulation with Epi or isoproterenol (ISO) directly promoted FLSs proliferation and migration due to impaired βAR signalling and cAMP production. By applying inhibitor of receptor internalization, and small interfering RNA (siRNA) of G and G, and by using fluorescence resonance energy transfer and coimmunoprecipitation assays, a switch in G-G coupling to βAR was observed in inflammatory FLSs as well as in FLSs with chronic ISO stimulation. This G coupling was then revealed to be initiated by G protein coupled receptor kinase 2 (GRK2) but not β-arrestin2 or protein kinase A-mediated phosphorylation of βAR. Inhibiting the activity of GRK2 with the novel GRK2 inhibitor paeoniflorin-6'-O-benzene sulfonate (CP-25), a derivative of paeoniflorin, or the accepted GRK2 inhibitor paroxetine effectively reversed the switch in G-G coupling to βAR during inflammation and restored the intracellular cAMP level in ISO-stimulated FLSs. As expected, CP-25 significantly inhibited the hyperplasia of FLSs in a collagen-induced arthritis (CIA) model (CIA FLSs) and normal FLSs stimulated with ISO and finally ameliorated CIA in rats. Together, our findings revealed the pathological changes in βAR signalling in CIA FLSs, determined the underlying mechanisms and identified the pharmacological target of the GRK2 inhibitor CP-25 in treating CIA. Video Abstract.
Topics: Animals; Rats; Arthritis, Experimental; Cell Proliferation; Cells, Cultured; Epinephrine; Fibroblasts; Inflammation; Isoproterenol; Signal Transduction; Synoviocytes
PubMed: 38037039
DOI: 10.1186/s12964-023-01358-z