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Micromachines Jun 2023Selective serotonin re-uptake inhibitors (SSRIs) are one of the most commonly prescribed classes of antidepressants used for the treatment of moderate to severe... (Review)
Review
Selective serotonin re-uptake inhibitors (SSRIs) are one of the most commonly prescribed classes of antidepressants used for the treatment of moderate to severe depressive disorder, personality disorders and various phobias. This class of antidepressants was created with improved margins of safety. However, genetic polymorphism may be responsible for the high variability in patients' responses to treatment, ranging from failure to delayed therapeutic responses to severe adverse effects of treatment. It is crucial that the appropriate amount of SSRI drugs is administered to ensure the optimum therapeutic efficacy and intervention to minimise severe and toxic effects in patients, which may be the result of accidental and deliberate cases of poisoning. Determining SSRI concentration in human fluids and the environment with high sensitivity, specificity and reproducibility, and at a low cost and real-time monitoring, is imperative. Electrochemical sensors with advanced functional materials have drawn the attention of researchers as a result of these advantages over conventional techniques. This review article aims to present functional materials such as polymers, carbon nanomaterials, metal nanomaterials as well as composites for surface modification of electrodes for sensitive detection and quantification of SSRIs, including fluoxetine, citalopram, paroxetine, fluvoxamine and sertraline. Sensor fabrication, sensor/analyte interactions, design rationale and properties of functional material and the electrocatalytic effect of the modified electrode on SSRI detection are discussed.
PubMed: 37512646
DOI: 10.3390/mi14071334 -
International Journal of Molecular... Dec 2023Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the...
Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression.
Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio ( < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I ( < 0.001), BNP ( < 0.01), ( < 0.001), hydroxyproline ( < 0.05), ( < 0.05), and ( < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression ( < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.
Topics: Rats; Animals; NF-kappa B; Paroxetine; NF-KappaB Inhibitor alpha; Isoproterenol; G-Protein-Coupled Receptor Kinase 2; Ventricular Remodeling; Myocytes, Cardiac; Cardiomegaly; Heart Failure; Rats, Wistar; Gene Expression
PubMed: 38139099
DOI: 10.3390/ijms242417270 -
Neuropsychopharmacologia Hungarica : a... Dec 2023Yawning is a normal, stereotyped physiological event in humans and animal kingdom. When excessive (>3 per 15 minutes), it is termed as pathological yawning (PY). PY...
INTRODUCTION
Yawning is a normal, stereotyped physiological event in humans and animal kingdom. When excessive (>3 per 15 minutes), it is termed as pathological yawning (PY). PY could be due to many causes but more commonly associated with side-effect of drugs, notably involving those used in psychopharmacology. Though there are isolated case reports and case-series, there are no large-scale reports of PY. This work attempted to address this lacuna.
MATERIAL AND METHODS
The current work attempted to identify characteristics of PY as collated from adverse drug effect databases of Australia (Database of Adverse Event Notifications), Canada (Canada Vigilance Adverse Reaction Online Database) and the United States of America (FDA Adverse Event Reporting System - FAERS). These databases collect and provide public access to reports of adverse events related to drugs and therapeutic goods. They act as a prime pharmacovigilance tool as well as a first-line resource for healthcare professionals, researchers, and the public to monitor the safety of these products and make informed decisions. In the first week of June 2023, open access, unrestricted adverse effect of drug databases were explored, using the word "YAWNING" as the only search term for the side effect of any drug without any restrictions. The collected details of PY cases with their gender, age, reason for drug use, other concomitant complaints as well as the nature of adverse event(s) and its treatment requirements were assessed. Descriptive statistics were used.
RESULT
Of the 2655 instances in USA database, 398(15%) had more than 1 suspect drug and in total 578 medications involved. The most commonly involved drugs were apomorphine, sertraline, fluoxetine and paroxetine. In all 341(12.8%) cases reported of YAWN alone or with one another sleep disorder, the most common off ending drug were fluoxetine hydrochloride.
DISCUSSION AND CONCLUSION
The neural mechanism and physiology of yawning are explained. This study stresses that a health care professional, particularly mental health professionals and neurologists, should be aware of the importance of PY to deliver the best for the patients under their care. (Neuropsychopharmacol Hung 2023; 25(4): 194-205)
Topics: Humans; United States; Adverse Drug Reaction Reporting Systems; Yawning; Incidence; United States Food and Drug Administration; Psychotropic Drugs
PubMed: 38170730
DOI: No ID Found -
Cureus Jan 2024An average of 60-80% of all menopausal women experience bothersome vasomotor symptoms (VMSs), such as flushing and sweating, within the first seven years of onset.... (Review)
Review
An average of 60-80% of all menopausal women experience bothersome vasomotor symptoms (VMSs), such as flushing and sweating, within the first seven years of onset. However, despite increasing prevalence, these hot flashes remain hard to treat and have a negative effect on the quality of life. Though hormone replacement therapy is commonly utilized as a standard treatment for VMSs, this therapy is not recommended for all women. Specifically, the oral form of hormone replacement therapy is associated with several contraindications, including a history of thromboembolic disease, migraine headache with aura, liver failure, heart disease, and hormone-dependent cancers. For women with these medical conditions, current literature indicates that nonhormonal therapies such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are suitable alternatives to reduce the frequency and intensity of VMSs. Currently, the only SSRI that is FDA-approved for the treatment of VMSs is paroxetine, but studies show that fluoxetine, citalopram, escitalopram, and sertraline are also proven to provide similar benefits. Similarly, the SNRI venlafaxine has also been well tolerated and has been shown to reduce the frequency and severity of hot flashes. The present investigation reviews the physiology of VMSs and examines the evidence for the use of nonhormonal pharmacologic therapies as treatment for women experiencing hot flashes. These interventions should be considered whenever hormone replacement therapy is contraindicated, with therapy individualized based on the severity of symptoms.
PubMed: 38371081
DOI: 10.7759/cureus.52467 -
Journal of Affective Disorders Reports Dec 2023Childhood sexual abuse is the leading cause of posttraumatic stress disorder (PTSD) in women, and is a prominent cause of morbidity and loss of function for which...
OBJECTIVE
Childhood sexual abuse is the leading cause of posttraumatic stress disorder (PTSD) in women, and is a prominent cause of morbidity and loss of function for which limited treatments are available. Understanding the neurobiology of treatment response is important for developing new treatments. The purpose of this study was to assess neural correlates of personalized traumatic memories in women with childhood sexual abuse with and without PTSD, and to assess response to treatment.
METHODS
Women with childhood sexual abuse with ( = 28) and without ( = 17) PTSD underwent brain imaging with High-Resolution Positron Emission Tomography scanning with radiolabeled water for brain blood flow measurements during exposure to personalized traumatic scripts and memory encoding tasks. Women with PTSD were randomized to paroxetine or placebo followed by three months of double-blind treatment and repeat imaging with the same protocol.
RESULTS
Women with PTSD showed decreases in areas involved in the Default Mode Network (DMN), a network of brain areas usually active when the brain is at rest, hippocampus and visual processing areas with exposure to traumatic scripts at baseline while women without PTSD showed increased activation in superior frontal gyrus and other areas ( < 0.005). Treatment of women with PTSD with paroxetine resulted in increased anterior cingulate activation and brain areas involved in the DMN and visual processing with scripts compared to placebo ( < 0.005).
CONCLUSION
PTSD related to childhood sexual abuse in women is associated with alterations in brain areas involved in memory and the stress response and treatment with paroxetine results in modulation of these areas.
PubMed: 38088987
DOI: 10.1016/j.jadr.2023.100615 -
Brain Sciences Sep 2023Social behavior is a complex term which involves different interactions between various individuals of a community. It is controlled by different neurotransmitter...
Social behavior is a complex term which involves different interactions between various individuals of a community. It is controlled by different neurotransmitter systems in a sexually dimorphic way. Certain environmental factors, like stress, cause various neurological disorders with associated social abnormalities in a sexually dimorphic way. Multiple drugs are used in clinical settings to treat behavioral disorders. However, the sexually dimorphic effects of these drugs, particularly on social behavior, still need to be studied. The present study was designed to investigate the sex-dependent effects of Risperidone, Donepezil, and Paroxetine in 8-12 weeks old male and female rats under normal and stressed conditions. There were four male and four female groups, i.e., control group (no drug treatment), Risperidone (3 mg/kg/day) treated group, Donepezil (5 mg/kg/day) treated group, and Paroxetine (10 mg/kg/day) treated group. Each group received its respective drug during phase 1 for 21 days, followed by a 10-day break with no drug treatment. After the break, same groups received the same drugs along with tilt-cage stress for an additional 21 days during phase 2. A social preference and novelty test was performed at the end of both phases (1 and 2). During phase 1, Risperidone treatment caused impaired social behavior and reduced locomotion in the male group only, compared to its control group. Donepezil treatment caused a reduction in social interaction, while Paroxetine treatment caused increased social interaction and locomotion in a sex-dependent manner. During phase 2, social novelty was affected in both male and female stress groups. Treatment with drugs along with stress showed differential sex-dependent effects. The study showed a predominant effect of Risperidone on males while there were differential effects of Donepezil and Paroxetine on both sexes. This study has paved the way for the development of more targeted and effective neuromodulatory drugs for use against various psychiatric and social deficits.
PubMed: 37891747
DOI: 10.3390/brainsci13101378 -
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 -
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 -
EBioMedicine Jun 2024Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. (Meta-Analysis)
Meta-Analysis
Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis.
BACKGROUND
Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing.
METHODS
We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses.
FINDINGS
After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population.
INTERPRETATION
Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach.
FUNDING
National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.
Topics: Adult; Female; Humans; Male; Middle Aged; Anxiety Disorders; China; Cytochrome P-450 CYP2D6; Depressive Disorder; East Asian People; Genotype; Paroxetine; Polymorphism, Single Nucleotide; Prospective Studies; Treatment Outcome
PubMed: 38776596
DOI: 10.1016/j.ebiom.2024.105165 -
Scientific Reports Jul 2023Rhabdomyolysis is a syndrome potentially fatal and has been associated with selective serotonin reuptake inhibitors (SSRIs) treatment in a few case reports. Herein, we...
Rhabdomyolysis is a syndrome potentially fatal and has been associated with selective serotonin reuptake inhibitors (SSRIs) treatment in a few case reports. Herein, we purpose to establish the correlation between SSRIs use and rhabdomyolysis using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. We conducted an analysis on reports that were submitted to the FAERS database during the period between January 1, 2004, and December 31, 2022. Four algorithms, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM), were employed to quantify the signals of rhabdomyolysis associated with SSRIs. In total, 16,011,277 non-duplicated reports were obtained and analyzed. Among 33,574 reports related to rhabdomyolysis, SSRIs were classified as primary suspected drug in 889 cases. Disproportionality analysis identified a positive signal between rhabdomyolysis and SSRIs (ROR: 2.86, 95% CI 2.67-3.05; PRR: 2.84, χ: 1037.16; IC = 1.39; EBGM = 2.64). Among six SSRIs, fluvoxamine had the strongest signal (ROR: 11.64, 95% CI 8.00-16.93; PRR: 11.38, χ: 265.51; IC = 2.41; EBGM = 8.31), whereas no significant signal of rhabdomyolysis was detected for paroxetine (ROR: 1.83, 95% CI 1.55-2.15; PRR: 1.82, χ: 53.82; IC = 0.73; EBGM = 1.59). After excluding cases co-administered with statins, the signal of rhabdomyolysis associated with SSRIs remains significant. Our analysis reveals that there are differences in safety signals among six SSRIs in respect to the risk of rhabdomyolysis, with fluvoxamine displaying the highest risk signal, while paroxetine did not show a significant signal. Given the potentially lethal nature of rhabdomyolysis, healthcare professionals should inform patients of the potential risk of rhabdomyolysis associated with SSRIs prior to initiating treatment.
Topics: United States; Humans; Selective Serotonin Reuptake Inhibitors; Bayes Theorem; Pharmacovigilance; Fluvoxamine; Paroxetine; Adverse Drug Reaction Reporting Systems; Rhabdomyolysis; United States Food and Drug Administration
PubMed: 37507539
DOI: 10.1038/s41598-023-39482-y